High Risk Pregnancy Management Options
High Risk Pregnancy Management Options FOURTH EDITION
Senior Editor
David James, MA, MD, FRCOG, DCH
Emeritus Professor of Fetomaternal Medicine, Foundation Director of Medical Education Queen’s Medical Centre, Nottingham, United Kingdom
Editors Philip J. Steer, BSc, MD, FRCOG, FCOGSA (hon)
Caroline A. Crowther, MD, FRANZCOG, FRCOG, Cert MFM
Emeritus Professor Faculty of Medicine Imperial College London Chelsea and Westminster Hospital London, United Kingdom
Professor Discipline of Obstetrics and Gynaecology The University of Adelaide Women’s and Children’s Hospital North Adelaide, South Australia, Australia
Carl P. Weiner, MD, MBA, FACOG
Stephen C. Robson, MD, MRCOG, MBBS
K.E. Krantz Professor and Chair Department of Obstetrics and Gynecology University of Kansas School of Medicine Kansas City, Kansas
Bernard Gonik, MD, FACOG
Professor and Fann Srere Chair of Perinatal Medicine Department of Obstetrics and Gynecology Wayne State University School of Medicine Detroit, Michigan
Associate Editors
Professor of Fetal Medicine Institute of Cellular Medicine University of Newcastle upon Tyne Newcastle upon Tyne, United Kingdom
3251 Riverport Lane St. Louis, MO 63403
HIGH RISK PREGNANCY: MANAGEMENT OPTIONS
ISBN: 978-1-4160-5908-0
Copyright © 2011 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail:
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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Previous editions copyrighted 2006, 1999, 1994.
Library of Congress Cataloging-in-Publication Data High risk pregnancy : management options / senior editor, David K. James; associate editors, Philip J. Steer … [et al.]. – 4th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-5908-0 1. Pregnancy–Complications. I. James, D. K. (David K.) [DNLM: 1. Pregnancy, High-Risk. 2. Pregnancy Complications. WQ 240 H6377 2011] RG571.H46 2011 618.3—dc22 2010012490
Acquisitions Editor: Stefanie Jewell-Thomas Senior Developmental Editor: Dee Simpson Design Direction: Steven Stave Publishing Services Manager: Pat Joiner-Myers Project Manager: Marlene Weeks
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INTERNATIONAL ADVISORY BOARD
Ahmad M. Abdel Wahed
Keun-Young Lee, MD
Gustaaf Dekker, MD
Kunihiro Okamura, MD
Tao Duan, MD, PhD
Friday E. Okonofua, MD
Department of Obstetrics and Gynaecology Jabal al-zaiton Hospital Zarka, Jordan Professor, Obstetrics and Gynaecology The University of Adelaide Adelaide, South Australia, Australia Professor, Obstetrics and Gynecology Tongji University Professor and Chief of the Hospital Department of Obstetrics and Gynecology Shanghai 1st Maternity and Infant Hospital Shanghai, China J. Ravichandran R. Jeganathan, MD
Associate Professor, Obstetrics and Gynaecology Monash Malaysia School of Medicine, Monash University Johor Bahru, Malaysia Tze Kin Lau, MD
Professor, Obstetrics and Gynaecology Faculty of Medicine The Chinese University of Hong Kong Hong Kong, SAR
Professor, Obstetrics and Gynecology College of Medicine, Hallym University Seoul, Korea Professor Emeritus, Obstetrics and Gynecology Tohoku University Graduate School of Medicine Sendai, Japan Professor, Obstetrics and Gynecology College of Medical Sciences, University of Benin Benin City, Nigeria Robert C. Pattinson, MD
Professor, Obstetrics and Gynaecology University of Pretoria Pretoria, Gauteng, South Africa Shantala Vadeyar, MD
Consultant, Obstetrics and Feto-Maternal Medicine Kokilaben Dhirubhai Ambani Hospital Mumbai, India Jose Villar, MD
Professor, Nuffield Department of Obstetrics and Gynaecology University of Oxford Oxfordshire, United Kingdom
v
CONTRIBUTORS
Anthony Ambrose, MD
Associate Professor, Maternal-Fetal Medicine, Penn State University College of Medicine; Staff Physician, The Milton S. Hershey Medical Center, Hershey, Pennsylvania Puerperal Problems Janet I. Andrews, MD
Assistant Professor, University of Iowa, Iowa City, Iowa Hepatitis Virus Infections John Anthony, MB, ChB, FCOG, MPhil
Professor, Department of Obstetrics and Gynaecology, University of Cape Town; Groote Schuur Hospital, Cape Town, South Africa Major Obstetric Hemorrhage and Disseminated Intravascular Coagulation; Critical Care of the Obstetric Patient Domenico Arduini
Professor and Chairman, Department of Obstetrics and Gynecology, Università Roma Tor Vergata; Department of Obstetrics and Gynecology, Ospedale Fatebenefratelli Isola Tiberina, Rome, Italy Fetal Cardiac Anomalies Vincent T. Armenti, MD, PhD
Administrative Course Director, Human Form and Development, Professor of Pathology, Anatomy and Cell Biology, and Professor of Surgery, Jefferson Medical College, Philadelphia, Pennsylvania; Thomas Jefferson University, Philadelphia, Pennsylvania Pregnancy after Transplantation George Attilakos, MD, MRCOG
Consultant in Obstetrics and Fetal Medicine, St. Michael’s Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom Invasive Procedures for Antenatal Diagnosis Marie-Cécile Aubry, MD
Department of Obstetrics and Gynaecology, Port Royal Hospital, Paris; Department of Obstetrics and Gynaecology, Antoine Beclere Hospital, Clamart, France Fetal Genitourinary Abnormalities Loraine J. Bacchus, PhD, MA, BSc
Lecturer, Gender Violence and Health Centre, Department of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, United Kingdom Domestic Violence May Backos, MBChB, MRCOG
Consultant in Obstetrics and Gynaecology, West Middlesex University Hospital, Isleworth, Middlesex, United Kingdom Recurrent Miscarriage
Mert O. Bahtiyar, MD
Assistant Professor, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut Fetal Cardiac Arrhythmias: Diagnosis and Therapy David Allan Baker, MD
Professor, Department of Obstetrics, Gynecology and Reproductive Medicine, Health Sciences Center, Stony Brook University Medical Center, Stony Brook, New York; Director, Division of Infectious Diseases, Department of Obstetrics and Gynecology, Kantonsspital Schaffhausen, Schaffhausen, Switzerland Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus Imelda Balchin, BSc, MBChB, MSc, MFFP, MRCOG
Academic Clinical Fellow, University College London Institute for Women’s Health; Honorary Research Fellow, CEMACH, London, United Kingdom Prolonged Pregnancy Ahmet Alexander Baschat, MD, MB, BCh, BAO
Professor, University of Maryland School of Medicine, Baltimore, Maryland Fetal Growth Disorders Marie H. Beall, MD
Clinical Professor of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles; Vice Chair, Harbor-UCLA Medical Center, Torrance, California Abnormalities of Amniotic Fluid Volume Michael A. Belfort, MD, PhD
Professor (tenured), Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah; Director of Perinatal Research, Director, HCA Fetal Therapy Program, and Director, HCA Obstetric Telemedicine Program, Hospital Corporation of America, Mountain Star Division, Nashville, Tennessee Postpartum Hemorrhage and Other Problems of the Third Stage Ron Beloosesky, MD
Faculty of Medicine, Technion Israel Institute of Technology; Rambam Medical Center, Haifa, Israel Abnormalities of Amniotic Fluid Volume Susan Bewley, MD, FRCOG, MA
Honorary Senior Lecturer, Kings College London; Consultant Obstetrician, Kings Health Partners, London, United Kingdom Domestic Violence
vii
viii Contributors Joseph R. Biggio, Jr., MD
Director, Division of Maternal Fetal Medicine, Medical Director, Obstetric Services, and Associate Professor, Department of Obstetrics and Gynecology and Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama Fetal Tumors Ralph B. Blasier, MD, JD
Professor of Orthopaedic Surgery, Wayne State University; Residency Program Director, Detroit Medical Center, Detroit, Michigan Spine and Joint Disorders Renee A. Bobrowski, MD
Director of Maternal Fetal Medicine and Women and Children’s Services, Saint Alphonsus Regional Medical Center, Boise, Idaho Trauma D. Ware Branch, MD
H.A. and Edna Benning Research Chair, and Professor, Obstetrics and Gynecology, University of Utah Health Sciences Center; Medical Director, Women and Newborns Clinical Program, Intermountain Healthcare, Salt Lake City, Utah Autoimmune Diseases Anneke Brand, PhD, MD
Professor, Department of Immunohaematology and Blood Transfusion, and Specialist, Hematology – Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Fetal Thrombocytopenia Christopher S. Bryant, MD
Fellow, Division of Gynecologic Oncology, Wayne State University/Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan Malignant Disease Catalin S. Buhimschi, MD
Director, Perinatal Research, Yale University, New Haven, Connecticut Medication David J. Cahill, MD, MRCPI, FRCOG
Reader in Reproductive Medicine, and Head of the Academic Unit of Obstetrics and Gynaecology, University of Bristol, St. Michael’s Hospital, Bristol, United Kingdom Bleeding and Pain in Early Pregnancy J. Ricardo Carhuapoma, MD
Assistant Professor, Department of Neurology, Neurosurgery and Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine; Faculty, Department of Neurology, Neurosurgery and Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, Maryland Neurologic Complications Frank A. Chervenak, MD, MMM
Given Foundation Professor and Chairman, Weill Cornell Medical Center, New York, New York Fetal Craniospinal and Facial Abnormalities
Lyn S. Chitty, BSc, PhD, MROCG
Professor of Genetics and Fetal Medicine, UCL Institute of Child Health; Consultant in Genetics and Fetal Medicine, University College London Hospitals NHS Foundation Trust, London, United Kingdom Fetal Skeletal Abnormalities Joshua A. Copel, MD
Professor, Obstetrics, Gynecology and Reproductive Sciences and Pediatrics, Yale University School of Medicine, New Haven, Connecticut Fetal Cardiac Arrhythmias: Diagnosis and Therapy Caroline A. Crowther, MD, FRANZCOG, FRCOG, Cert MFM
Professor, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia Multiple Pregnancy Peter Danielian, MA, MD, FRCOG
Honorary Senior Lecturer, Department of Obstetrics and Gynaecology, Aberdeen University Medical School; Consultant Obstetrician, Aberdeen Maternity Hospital, NHS Grampian, Aberdeen, United Kingdom Fetal Distress in Labor John Maelor Davies, MA, MD, FRCP, FRCPath
Consultant Haematologist, Western General Hospital, Edinburgh, United Kingdom Malignancies of the Hematologic and Immunologic Systems John M. Davison, BSc, MD, MSc, FRCOG
Professor, Newcastle University, Newcastle upon Tyne, United Kingdom Pregnancy after Transplantation Gustaaf Dekker, MD, PhD, DCOG, FRANZCOG
Professor, Obstetrics and Gynaecology, The University of Adelaide; Director, Women’s and Children’s Division, Lyell McEwin Hospital, Adelaide, South Australia, Australia Hypertension Isaac Delke, MD
Professor, Department of Obstetrics and Gynecology, University of Florida College of Medicine; Chief, Division of Maternal-Fetal Medicine, and Medical Director, Obstetric Services, Shands Jacksonville Medical Center, Jacksonville, Florida Induction of Labor and Termination of the Previable Pregnancy Jeff M. Denney, MD
Clinical Instructor, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin; Physician/Research Consultant, Division of Adolescent Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Autoimmune Diseases Jan Deprest, MD, PhD
University Hospitals Leuven, Leuven, Belgium Fetal Problems in Multiple Pregnancy
Contributors ix Jan E. Dickinson, MD, FRANZCOG, DDU, CMFM
Professor, Maternal Fetal Medicine, School of Women’s and Infants’ Health, The University of Western Australia, Perth; Maternal Fetal Medicine Specialist, King Edward Memorial Hospital, Subiaco, Western Australia, Australia Cesarean Section Gary A. Dildy III, MD
Clinical Professor, Department of Obstetrics and Gynecology, Louisiana State University School of Medicine, New Orleans, Louisiana; Director of Maternal-Fetal Medicine, Hospital Corporation of America, Mountain Star Division, Nashville, Tennessee Postpartum Hemorrhage and Other Problems of the Third Stage Jodie M. Dodd, MBBS, FRANZCOG, Cert MFM
Professor, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia Multiple Pregnancy; Threatened and Actual Preterm Labor Including Mode of Delivery; Prelabor Rupture of the Membranes Marc Dommergues, MD
Professor, Groupe Hospitalier Pitié Salpêtrière; Université Pierre et Marie Curie, Paris, France Fetal Genitourinary Abnormalities Tim Draycott, MD, MRCOG
Senior Clinical Lecturer in Obstetrics, University of Bristol; Consultant Obstetrician, Southmead Hospital, Bristol, United Kingdom Training for Obstetric Emergencies Joseph M. Ernest, MD
Clinical Professor, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill; Chair, Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, North Carolina Parasitic Infections Peter A. Farndon, MSc, MB BS, MD, FRCP, DCH
Professor of Clinical Genetics, University of Birmingham; Consultant Clinical Geneticist, West Midlands Regional Genetics Service, Birmingham, United Kingdom Genetics, Risks of Recurrence, and Genetic Counseling Roy G. Farquharson, MD, FRCOG
Consultant Gynaecologist, Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, United Kingdom Recurrent Miscarriage; Thromboembolic Disease Tom Farrell, MBChB, MD, FRCOG
Consultant Obstetrician and Gynaecologist, Jessop Wing, Royal Hallamshire Hospital, Sheffield, United Kingdom Diabetes Albert Franco, MD
Assistant Clinical Professor, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill; Assistant Director, Division of Maternal Fetal Medicine, Carolinas Medical Center, Charlotte, North Carolina Parasitic Infections
Robert Fraser, MBChB, MD (Sheffield), FRCOG, DCH
Reader in Obstetrics and Gynaecology, University of Sheffield; Honorary Consultant in Obstetrics and Gynaecology, Jessop Wing, Royal Hallamshire Hospital, Sheffield, United Kingdom Diabetes Harry Gee, MD, FRCOG
Consultant Obstetrician, and Retired Head of West Midlands Postgraduate School of Obstetrics and Gynaecology, Birmingham Women’s Hospital, Birmingham, West Midlands, United Kingdom Dysfunctional Labor Robert B. Gherman, MD
Head, Division of Maternal/Fetal, Prince George’s Hospital Center, Cheverly, Maryland Shoulder Dystocia Paul S. Gibson, MD
Associate Professor, University of Calgary, Calgary, Alberta, Canada Respiratory Disease Joanna Girling, MA, MRCP, FRCOG
Consultant Obstretrician and Gynaecologist, West Middlesex University Hospital, Isleworth, Surrey, United Kingdom Hepatic and Gastrointestinal Disease Francesca Gotsch, MD
Research Fellow, Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, Maryland, and Detroit, Michigan Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome Michael Greaves, MBChB, MD, FRCP, FRCPath
Professor of Haematology, and Head of School of Medicine and Dentistry, University of Aberdeen, Aberdeen, United Kingdom Thromboembolic Disease David R. Griffin, MD, FRCOG
Consultant Obstetrician and Gynaecologist, West Herts Hospital HMS Trust, Waterford, Hertferdshire, United Kingdom Fetal Skeletal Abnormalities Rosalie M. Grivell, BSc, BMBS, FRANZCOG
Senior Lecturer, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia Multiple Pregnancy A. Metin Gülmezoglu, MD, PhD
Coordinating Editor of the World Health Organization Reproductive Health Library, Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland Global Maternal and Perinatal Health Issues Christina S. Han, MD
Clinical Instructor, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine; Clinical Instructor, Yale-New Haven Hospital, New Haven, Connecticut Clotting Disorders
x Contributors Roger F. Haskett, MD
Professor of Psychiatry, University of Pittsburgh School of Medicine; Psychiatrist, Western Psychiatric Institute and Clinic of UPMC Presbyterian, Pittsburgh, Pennsylvania Psychiatric Illness Robert Hayashi, MD
J. Robert Wilson Professor Emeritus, University of Michigan, Ann Arbor, Michigan Assisted Vaginal Delivery Darren Travis Herzog, MD
Orthopaedic Surgery Resident, Detroit Medical Center, St. John’s Providence Hospital, Detroit, Michigan Spine and Joint Disorders G. Justus Hofmeyr, MRCOG
Consultant, East London Hospital Complex, East London, Eastern Cape, South Africa Global Maternal and Perinatal Health Issues Elizabeth Helen Horn, MD, FRCP, FRCPath
Royal Infirmary of Edinburgh, Edinburgh, United Kingdom Thrombocytopenia and Bleeding Disorders
Mark D. Kilby, MD, FRCOG
Professor of Fetal Medicine, Head of Reproduction, Genes and Development/Deputy Head of School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham; Head of Fetal Medicine Centre, Birmingham Women’s Foundation Trust, Edgbaston, Birmingham, United Kingdom Genetics, Risks of Recurrence, and Genetic Counseling Justin C. Konje, MD, FWACS, FMCOG (NIG), FRCOG
Professor of Obstetrics and Gynaecology, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester and University Hospitals of Leicester, Leicester, United Kingdom Bleeding in Late Pregnancy George Kroumpouzos, MD, PhD, FAAD
Clinical Assistant Professor of Dermatology, Brown Medical School, Providence, Rhode Island Skin Disease Juan Pedro Kusanovic, MD
Clinical Professor, Faculty of Obstetrics and Gynaecology, Central Clinical School, University of Sydney; Clinical Professor, RPA Women and Babies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Screening for Spontaneous Preterm Labor and Delivery
Assistant Professor, Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan; Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, Maryland, and Detroit, Michigan Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome
Robin B. Kalish, MD
Mark B. Landon, MD
Jonathon Hyett, MBBS, MSc, MD, MRCOG, FRANZCOG
Associate Professor, Weill Cornell Medical College; Attending Physician, New York Presbyterian Hospital, New York, New York Fetal Craniospinal and Facial Abnormalities Humphrey H. H. Kanhai, MD, PhD
Leiden University Medical Center, Leiden, The Netherlands Fetal Thrombocytopenia Lucy H. Kean, BM, BCh, DM, FRCOG
Consultant in Fetal and Maternal Medicine, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Malignancies of the Hematologic and Immunologic Systems; Thrombocytopenia and Bleeding Disorders Rohna Kearney, MD, MRCOG, MRCPI
Consultant Gynaecologist, Subspecialist in Urogynaecology, Addenbrooke’s Hospital, Cambridge University Hospitals Trust, Cambridge, United Kingdom Perineal Repair and Pelvic Floor Injury Anna P. Kenyon, MBChB, MD, MRCOG
Clinical Training Fellow, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, United Kingdom Thyroid Disease
Professor and Interim Chair, College of Medicine, and Director, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio Pituitary and Adrenal Disease Tze Kin Lau, MD
Professor, Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR Prenatal Fetal Surveillance Steven R. Levine, MD
Professor and Vice Chair, Neurology, and Associate Dean for Clinical Research and Faculty Development, The State University of New York Health Science Center - Brooklyn; Chief of Neurology, University Hospital of Brooklyn, Brooklyn, New York Neurologic Complications Liesbeth Lewi, MD, PhD
Professor, School of Medicine, Catholic University; Consultant, University Hospitals Leuven, Department of Obstetrics and Gynecology, Leuven, Belgium Fetal Problems in Multiple Pregnancy
Contributors xi Stephen W. Lindow, MB, ChB, MMed (O&G), MD, FCOG (SA), FRCOG
Senior Lecturer in Perinatology, University of Hull, Hull, East Yorkshire, United Kingdom; Honorary Associate Professor of Obstetrics and Gynaecology, University of Cape Town, Cape Town, South Africa; Honorary Consultant in Obstetrics and Gynaecology, Women and Childrens’ Hospital, Hull Royal Infirmary, Hull, East Yorkshire, United Kingdom Assisted Vaginal Delivery; Major Obstetric Hemorrhage and Disseminated Intravascular Coagulation Charles J. Lockwood, MD
Anita O'Keefe Young Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine; Director of Obstetrics and Gynecology, Yale-New Haven Hospital, New Haven, Connecticut Clotting Disorders
Michael J. Moritz, MD
Professor of Surgery, Penn State College of Medicine, Hershey; Chief, Transplantation Services, Lehigh Valley Health Network, Allentown, Pennsylvania Pregnancy after Transplantation Adnan R. Munkarah, MD
Professor, Wayne State University School of Medicine; Chairman, Women’s Health, Henry Ford Health System, Detroit, Michigan Malignant Disease Kimta Nanhornguè, MD
University of Padova; Medical Resident in Gynecology, Department of Gynecological Sciences and the Human Reproduction, University of Padua School of Medicine, Padova, Italy First-Trimester Screening for Fetal Abnormalities Osric B. Navti, MBBS, MRCOG
Professor, Khon Kaen University, Khon Kaen, Thailand Global Maternal and Perinatal Health Issues
Consultant in Fetal and Maternal Medicine, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom Bleeding in Late Pregnancy
Ian Z. Mackenzie, MD, FRCOG, DSc
Catherine Nelson-Piercy, MA, FRCP, FRCOG
Pisake Lumbiganon, MD, MS
Reader in Obstetrics and Gynaecology, University of Oxford; Honorary Consultant Obstetrician and Gynaecologist, John Radcliffe Hospital, Oxford, United Kingdom Unstable Lie, Malpresentations, and Malpositions Kassam Mahomed, MD (Bristol), FRCOG (UK), FRANZCOG
Associate Professor, Department of Obstetrics and Gynaecology, University of Queensland; Senior Staff Specialist, Department of Obstetrics and Gynaecology, Ipswich Hospital, Ipswich, Queensland, Australia Abdominal Pain; Nonmalignant Gynecology Melissa S. Mancuso
Instructor/Fellow, Maternal-Fetal Medicine and Medical Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Fetal Tumors Neil Marlow, DM, FMedSci
Professor of Neonatal Medicine, UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London; Honorary Consultant Neonatologist, University College London Hospitals NHS Foundation Trust, London, United Kingdom Resuscitation and Immediate Care of the Newborn Anthony J. Marren, BMed (Hons), MMed (R. H. & H. G.)
Registrar, Department of Obstetrics and Gynaecology, Royal Prince Alfred Hospital for Women and Babies, Sydney, New South Wales, Australia Screening for Spontaneous Preterm Labor and Delivery Alec McEwan, BA, BM, BCh, MRCOG
Consultant in Obstetrics and Fetal Medicine, Department of Obstetrics and Gynaecology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Video Editor
Consultant Obstetric Physician, Guy’s and St. Thomas Foundation, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare Trust, London, United Kingdom Thyroid Disease Robert Ogle, FRANZCOG, FHGSA
Director, Royal Prince Alfred Hospital, Sydney, Australia Screening for Spontaneous Preterm Labor and Delivery Colm O’Herlihy, MD, FRCPI, FRCOG
Professor, University College Dublin; Consultant Obstetrician/Gynaecologist, National Maternity Hospital, Dublin, Ireland Perineal Repair and Pelvic Floor Injury Michael J. Paidas, MD
Associate Professor, Co-Director, Yale Women and Children’s Center for Blood Disorders, and Co-Director, National Hemophilia Foundation - Baxter Clinical Fellowship at Yale, Yale University School of Medicine; Attending Physician, Yale-New Haven Hospital, New Haven, Connecticut Clotting Disorders Robert C. Pattinson, MD, FRCOG, FCOG (SA), MMed (O&G)
Professor, Obstetrics and Gynaecology, University of Pretoria, Pretoria, Gauteng, South Africa Global Maternal and Perinatal Health Issues Zoë Penn, MD, FRCOG
Consultant Obstetrician, Chelsea and Westminster Hospital, London, United Kingdom Breech Presentation Troy Flint Porter, MD, MPH
Director, Maternal-Fetal Medicine, Intermountain Healthcare; Associate Professor, University of Utah Health Sciences, Salt Lake City, Utah Autoimmune Diseases
xii Contributors Raymond O. Powrie, MD
Senior Vice President, Quality and Clinical Effectiveness, Women & Infants Hospital of Rhode Island; Associate Professor of Medicine and Obstetrics and Gynecology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island Respiratory Disease Susan M. Ramin, MD
Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas Renal Disorders Margaret Ramsay, MB, BChir, MA, MD, MRCP, FRCOG
Consultant in Fetomaternal Medicine, Nottingham University Hospitals, Queen’s Medical Centre Campus, Nottingham, United Kingdom Appendix: Normal Values Lesley Regan, MD
Professor, Consultant Obstetrician and Gynaecologist, Imperial College London, St. Mary’s Hospital, London, United Kingdom Recurrent Miscarriage John T. Repke, MD
University Professor and Chairman, Department of Obstetrics and Gynecology, Penn State University College of Medicine; Obstetrician-Gynecologist-inChief, The Milton S. Hershey Medical Center, Hershey, Pennsylvania Puerperal Problems Laura E. Riley, MD
Assistant Professor, Obstetrics and Gynecology and Reproductive Biology, Harvard Medical School, Cambridge; Medical Director of Labor and Delivery, Massachusetts General Hospital, Boston, Massachusetts Rubella, Measles, Mumps, Varicella, and Parvovirus Giuseppe Rizzo, MD
Professor, Università Roma Tor Vergata; Department of Obstetrics and Gynecology, Ospedale Fatebenefratelli Isola Tiberina, Rome, Italy Fetal Cardiac Anomalies Jeffrey S. Robinson, BSc (Hons), MB ChB, BAO (Hons), FRCOG, FRANZCOG
Roberto Romero, MD
Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan; Chief, Perinatology Research Branch, and Program Director for Obstetrics and Perinatology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, and Detroit, Michigan Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome Thomas Roos, MD
Assistant Professor, University of Regensburg Medical School, Regensburg, Germany; Chief, Section of Obstetrics, Department of Obstetrics and Gynecology, Kantonsspital Schaffhausen, Schaffhausen, Switzerland Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus Michael G. Ross, MD, MPH
Professor of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles; Professor of Public Health; UCLA School of Public Health; Los Angeles,Perinatologist, Harbor-UCLA Medical Center, Torrance, California Abnormalities of Amniotic Fluid Volume Rodrigo Ruano, MD
Research Fellow, Université Paris V; Consultant, Hôpital Necker Enfants Molades, Paris, France Fetal Genitourinary Abnormalities Jane M. Rutherford, MBChB, DM, MRCOG
Consultant in Fetomaternal Medicine, Nottingham University Hospitals, Nottingham, United Kingdom Anemia and White Blood Cell Disorders Luis Sanchez-Ramos, MD
Professor, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, Florida Induction of Labor and Termination of the Previable Pregnancy Veronica L. Schimp, DO
Associate Professor, M.D. Anderson Cancer Center Orlando, University of Central Florida College of Medicine, Orlando, Florida Malignant Disease
Emeritus Professor, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia Threatened and Actual Preterm Labor Including Mode of Delivery; Prelabor Rupture of the Membranes
Dimitrios Siassakos, MBBS, MRCOG, MSc, DLSHTM
Stephen C. Robson, MD, MRCOG, MBBS
Professor and Head, Department of Obstetrics and Gynaecology, University of Cambridge; Honorary Consultant in Maternal Fetal Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom Delivery after Previous Cesarean Section
Professor of Fetal Medicine, Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom Fetal Thyroid and Adrenal Disease
Clinical Lecturer in Medical Education, University of Bristol; Research Fellow in Obstetrics, Southmead Hospital, Bristol, United Kingdom Training for Obstetric Emergencies Gordon C. S. Smith, MD, PhD
Contributors xiii John S. Smoleniec, MD, FRCOG, FMS, FRANZCOG, CMFM, DDU
Associate Professor, University of New South Wales, Sydney; Director, Maternal Fetal Medicine, Liverpool Hospital, Sydney South West Area Health Service, New South Wales, Australia Fetal Hydrops Peter W. Soothill, BSc, MD, MBBS, FRCOG
Emeritus Professor of Maternal and Fetal Medicine, Medical School, University of Bristol; Consultant in Fetal Medicine, Fetal Medicine Unit, St. Michael’s Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom Invasive Procedures for Antenatal Diagnosis Philip J. Steer, BSc, MD, FRCOG, FCOGSA (hon)
Emeritus Professor, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom Prolonged Pregnancy; Fetal Distress in Labor Peter Stone, BSc, MBChB, MD (Bristol), FRCOG, FRANZCOG, DDU, CMFM
Frank P. H. A. Vandenbussche, MD, PhD
Professor of Obstetrics and Fetal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Fetal Thrombocytopenia Alex C. Vidaeff, MD, MPH
Professor of Obstetrics and Gynecology, Department of Obstetrics, Gynecology and Reproductive Sciences, Maternal-Fetal Medicine Division, University of Texas Health Science Center at Houston, Houston, Texas Renal Disorders Yves Ville, MD
Professor, Descartes University, GHU Necker-EnfantsMalades, Paris, France First-Trimester Screening for Fetal Abnormalities Anthony M. Vintzileos, MD
Professor of Obstetrics, Gynecology and Reproductive Medicine, Stony Brook University School of Medicine, Stony Brook; Chairman, Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, New York Second-Trimester Screening for Fetal Abnormalities
Professor of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Auckland; Professor of Maternal Fetal Medicine, National Women’s Hospital, Auckland Hospital, Auckland, New Zealand Fetal Gastrointestinal Abnormalities
Ann M. Walker, MBChB
Jane Strong, MBChB, MRCP, FRCPath
James J. Walker, MBChB, MD, FRCP (Edin), FRCPS (Glas), FRCOG
Consultant Pathologist (Haematology), Leicester Royal Infirmary, Leicester, United Kingdom Anemia and White Blood Cell Disorders John M. Svigos, MB BS, DRCOG, FRCOG, FRANZCOG
Associate Professor, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide; Senior Visiting Medical Specialist, Maternal Fetal Medicine Unit, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia Threatened and Actual Preterm Labor Including Mode of Delivery; Prelabor Rupture of the Membranes Rebecca Swingler, MSc, MRCOG
Academic Clinical Lecturer, University of Bristol, St. Michael’s Hospital; Senior Registrar in Obstetrics and Gynaecology, St. Michael’s Hospital, Bristol, United Kingdom Bleeding and Pain in Early Pregnancy Mark W. Tomlinson, MD
Regional Director of Obstetrics, Providence Health System, Providence St. Vincent’s Hospital, Portland, Oregon Cardiac Disease; Neurologic Complications Lawrence C. Tsen, MD
Associate Professor in Anaesthesia, Harvard Medical School; Co-Editor in Chief, International Journal of Obstetric Anesthesia; Director of Anesthesia, Center for Reproductive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Neuraxial Analgesia and Anesthesia in Obstetrics
Prescribing Doctor for Pregnancy and Parenting Team, Leeds Partnership NHS Foundation Trust, Leeds, West Yorkshire, United Kingdom Substance Abuse
Professor of Obstetrics and Gynaecology, University of Leeds; Consultant, Obstetrics and Gynaecology, St. James University Hospital; Chairman of Perinatal Research Group, Leeds Institute of Molecular Medicine, Leeds, West Yorkshire, United Kingdom Substance Abuse Peter G. Wardle, MD, FRCS, FRCOG
Honorary Senior Lecturer, University of Bristol; Consultant Gynaecologist and Subspecialist in Reproductive Medicine, and Lead Consultant for Fertility Services, North Bristol NHS Trust, Southmead Hospital, Bristol, United Kingdom Bleeding and Pain in Early Pregnancy Stephen P. Wardle, MB, ChB, FRCPCH, MD
Consultant Neonatologist, Nottingham University Hospitals, Nottingham, United Kingdom Resuscitation and Immediate Care of the Newborn D. Heather Watts, MD
Medical Officer, Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Children, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland Human Immunodeficiency Virus Bevin Weeks, MD
Assistant Professor of Pediatrics, Yale University School of Medicine; Director for Pediatrics, Yale Fetal Cardiovascular Center, New Haven, Connecticut Fetal Cardiac Arrhythmias: Diagnosis and Therapy
xiv Contributors Carl P. Weiner, MD, MBA, FACOG
K.E. Krantz Professor and Chair, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, Kansas Fetal Hemolytic Disease; Fetal Death; Medication Hajo I. J. Wildschut, MD
Consultant in Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands Constitutional and Environmental Factors Leading to a High Risk Pregnancy Catherine Williamson, MD, FRCP
Professor, Imperial College London, London, United Kingdom Hepatic and Gastrointestinal Disease
Lami Yeo, MD
Associate Professor, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; Director of Fetal and Maternal Imaging, Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, Maryland, and Detroit, Michigan Second-Trimester Screening for Fetal Abnormalities Mark H. Yudin, MD, MSc, FRCSC
Assistant Professor, University of Toronto; Attending Physician, Department of Obstetrics and Gynecology, St. Michael’s Hospital, Toronto, Ontario, Canada Other Infectious Conditions
EVIDENCE BASED SUMMARY OF MANAGEMENT OPTIONS BOXES
One of the most popular features of the first thee editions of High Risk Pregnancy—Management Options were the ‘Summary of Management Options’ (SOMO) Boxes. The SOMO Box was placed at the end of each chapter or section within a chapter and presented the reader with an aide memoire of the main points regarding the management options for a
specific condition discussed in detail in the preceding chapter. For the third edition, we included an evidence based approach in the SOMO Boxes. We continued this approach for the fourth edition. The following is the evidence based scoring system for the SOMO Boxes that we asked contributors to use.
SCORING SYSTEM FOR SUMMARY OF MANAGEMENT OPTIONS BOXES Quality (level) of Evidence Ia
Evidence obtained from meta-analysis of randomized controlled trials
Ib
Evidence obtained from at least one randomized controlled trial
IIa
Evidence obtained from at least one well-designed controlled study without randomization
IIb
Evidence obtained from at least one other type of well-designed quasi-experimental study
III
Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies
IV
Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Strength (grade) of Recommendation A
At least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (Evidence Levels Ia or Ib)
B
Well-controlled clinical studies available but no randomized clinical trials on the topic of the recommendations (Evidence Levels IIa, IIb or III)
C
Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (Evidence Level IV)
GPP
Good Practice Point: recommended best practice based on the clinical experience of the chapter authors and editors
xv
PREFACE TO THE FOURTH EDITION
The fourth edition of High Risk Pregnancy: Management Options brings growth and change while remaining true to the original vision of an evidence-based user friendly text. Good clinical practice should be a universal goal, and we have sought to produce a truly International Postgraduate Textbook. There are over 150 contributors who reflect expertise from around the world with 20 countries represented. The third edition was sold in over 80 countries in four different versions—English, Chinese, Turkish and an English language adaptation for the Indian market. It is now a standard text used in the qualifying examinations of many countries. The book continues to grow in popularity with the third edition being the best-seller yet. As the complexity of medicine continues to increase, so has the burden on the editors to review and process the material so it remains relevant to the reader. To that end, we are delighted that Caroline Crowther, an international leader in clinical design, performance and analysis of clinical trials, and Stephen Robson, a world recognized perinatologist have joined the original editorial team. In addition, we are most grateful to our contributors for their enormous efforts (and often those of their secretaries). We are especially indebted to Dee Simpson from Elsevier who has kept the project on course. Each chapter in the fourth edition has been revised and where indicated, new ones added to reflect new developments. As reassuring as the traditional textbook is to hold, the fourth edition is published with a greatly expanded electronic version providing easy access to references and expanded figures. In addition, the website not only includes these electronic features, but also has video clips (edited by Alec McEwan), each making learning dynamic. Other changes to the fourth edition include: ● A major overhaul and revision of the book’s appearance to further enhance readability including the transfer of the full reference list for each chapter to the accompanying complementary electronic publication so that only 10 key references (’Suggested Reading’) are retained in the printed text.
A clearer presentation of the text while keeping to the original layout style of ● “Introduction” ● “Risks (Maternal and Fetal)” ● “Management Options (Prepregnancy, Prenatal, Labor and Delivery, Postnatal)” ● “Summary of Management Options” Box ● The Summary of Management Options Box includes a simplified evidence-based scoring system for each management strategy proposed. It illustrates how strong the evidence is for each option. ● All chapters were written or updated to reflect the current management options and to incorporate changes in practice since the last edition. Twelve chapters are either new or rewritten by new authors to bring a fresh view [1, 2, 6, 10, 12, 35, 44, 49, 65, 67, 75, 77]. ● One feature that deserves special mention in the Preface is Margaret Ramsay’s popular and valuable Appendix on ‘Normal Values’. This section has had its own separate publication (both written and electronic) in the past and these publications will be updated in the future. As in prior editions, we have appreciated the comments of readers and reviewers and sought to respond to them wherever possible in this edition. Previous editions of High Risk Pregnancy: Management Options were popular because readers have found them relevant to their daily clinical practice; in other words the book is a manual for the management of problem pregnancies. We hope that the fourth edition will uphold and enhance that reputation and will prove even more valuable to busy clinicians. David James Philip J. Steer Carl P. Weiner Bernard Gonik Caroline A. Crowther Stephen C. Robson ●
xvii
PREFACE TO THE FIRST EDITION
This new international textbook in obstetrics will, we believe, be of major value to all practicing clinicians, be they trainees or established in practice. It aims to assist with the questions: How do I manage this patient? or How do I perform this procedure? It presents a wide range of reputable management options. Unlike many traditional texts, based on a single individual’s experience and view, all the contributors to each section were asked to give their preferred management in all areas of their section. Each resulting chapter reflects that wide range of acceptable practice. This means you will have a choice about which option or combination of options suits you and your patient. This book is designated to be practical. It addresses those difficult questions which arise in practice, which often stem
not only from the medical facts, but from the constraints of time, facilities, finance, and patient acceptability. Moreover, we have standardized the presentation of each topic as far as possible (while still allowing the personality of the original authors to shine through!) to enable the reader to become familiar with the format. We have deliberately chosen a panel of contributors who are both leaders in their field and who can represent practice in the USA, Europe, and Australasia and this we feel gives the text a unique universality. Finally it is our intention that the book is comprehensive. We hope that we will have something to say on all the important problems you come across. If you find any exceptions, please let us know, with your comments, in time for the next edition.
xix
C H A P T E R 1
Global Maternal and Perinatal Health Issues* A. METIN GÜLMEZOGLU, ROBERT C. PATTINSON, G. JUSTUS HOFMEYR, and PISAKE LUMBIGANON
INTRODUCTION In 2000, 189 member states of the United Nations signed up to the Millennium Development Declaration committing themselves to ambitious health and development goals to be achieved by 2015. Agreement on these important goals within the Declaration was later translated into a structured framework of Millennium Development Goals (MDGs) with measurable targets and indicators. This MDG framework is the most significant global public health event since the 1990s. It has encouraged many donors to prioritize their funding on specific areas linked to the MDGs. Three of the eight MDGs (4, 5, and 6) relate directly to maternal and perinatal health (Table 1–1). The MDG process has had several positive effects so far. By highlighting the areas of largest disease burden, the MDGs have not only improved resource flows to low- and middle-income countries toward effective practices such as antiretroviral treatments in sub-Saharan Africa but also led to better ascertainment of the causes of morbidity and mortality and improved evaluation of interventions likely to have an impact on health outcomes. Since 2000, there has been an increase in the number of analytical studies of the global burden of sexual and reproductive ill health, including the monitoring and evaluation of care, and these have improved our understanding of the barriers to improvement. For example, in 2003, a group of scientists initiated the “Countdown to 2015 Initiative,” tracking coverage levels for health interventions that have been shown to reduce maternal, newborn, and child mortality (http://www.countdown2015mnch.org/). In 2008, this group reported the coverage, equity, financing, and policy progress on those interventions.1 These analyses represent important advances on our ability to measure and report key global maternal and perinatal health markers.
THE MEASUREMENT CHALLENGES In the past, data on maternal and perinatal mortality and morbidity have been lacking in many parts of the world.2 *Copyright World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.
However, since 2000, the number of studies on maternal and perinatal mortality and morbidity has increased significantly, in terms both of primary studies such as Demographic and Health Surveys (DHS) collecting representative data at the national level and the number of systematic reviews synthesizing such data to assess current status and monitor trends. Confidential inquiries into maternal deaths are accepted as the relevant gold standard audit tool. In the United Kingdom, implementation of the confidential inquiry methodology and the consequent uptake of the recommendations from it are thought to have been a driver of the reduction in maternal deaths in this country over the past 50 years.3 More recently, India, Jamaica, Sri Lanka, South Africa, and Tunisia have all successfully implemented either confidential inquiries into maternal deaths or specific surveillance systems to capture the number and causes of maternal deaths.4–8 The 2005 Maternal Mortality estimates developed by the World Health Organization (WHO), United Nations Children’s Fund (UNICEF), United Nations Population Fund (UNFPA), and the World Bank represent a methodologic advance in an area that has often been controversial. Maternal mortality estimates for countries are sometimes contentious because of adjustments for underreporting, and modeling estimates for countries that do not have data from methodologically sound studies. However, the results of such studies are a big improvement on having no data at all, and more recent estimates have used improved methodology, including an analysis of trends. A systematic review of the global causes of maternal death was published in 2006, presenting for the first time a synthesis of population-based representative data on studies reporting the major causes of maternal death,9 and our current picture is much more robust compared to the 1990s.
MATERNAL MORTALITY AND SEVERE MORBIDITY About 99% of all maternal deaths occur in developing countries, and current estimates suggest that 536,000 women die every year during pregnancy or within the 42 days following completion of the pregnancy. Deaths in sub-Saharan Africa and southern Asia accounted for 86% of global maternal deaths. The trend analysis indicates a global reduction of 1
2 C HAPTER O ne • Global Maternal and Perinatal Health Issues
less than 1% annually, which is way behind the 5.5% required to reach MDG 5.10 The majority of maternal deaths in Africa and Asia are due to obstetric hemorrhage (Fig. 1–1).9 In Latin America and the Caribbean, hypertensive disorders are responsible for the largest proportion of direct obstetric deaths (26%). Unsafe abortion is an important cause of maternal death and probably one of the most preventable. In developed countries, the most common causes of death are direct causes such as thromboembolism and indirect causes such as cardiac disease. Maternal deaths in these countries are now rare, and the events that lead to death are often multifactorial, but this does not mean that pregnancy is entirely safe. Waterstone and coworkers11 reported that in the 1990s in the South East Thames region of the United Kingdom, there was a severe obstetric morbidity rate of 12.0 per 1000 births, and a “severe morbidity to mortality” ratio of 118 : 1. Say and colleagues12 conducted a systematic review of reports of severe acute morbidity worldwide up to 2004, using organ system–based criteria and unselected groups of women, and concluded that its incidence varied between 0.3% and 1.08%. Recently, the concept of maternal morbidity as a continuum ranging between healthy pregnancy and death has attracted much interest (Fig. 1–2). “Maternal severe morbidity” and “near-miss” are terms often used to identify women who experience a severe event during pregnancy, labor, or the postpartum period. Although there are currently no internationally agreed criteria, maternal near-miss can usefully be defined as “a woman who nearly died from a complication but survived.” The WHO Working Group on Maternal Mortality and Morbidity Classifications has recently proposed clinical, laboratory, and management
T A B L E 1 – 1
United Nations Millennium Development Goals Goal Goal Goal Goal Goal Goal Goal Goal
1: Eradicate extreme poverty and hunger 2: Achieve universal primary education 3: Promote gender equality and empower women 4: Reduce child mortality 5: Improve maternal health 6: Combat HIV/AIDS, malaria and other diseases 7: Ensure environmental sustainability 8: Develop a Global Partnership for Development
Non life-threatening conditions
criteria based on earlier studies and audit data from Brazil, Canada, and South Africa (Table 1–2).13 Maternal near-miss estimates can be regarded as a valid proxy for maternal death and have practical value. In an individual facility, the number of maternal deaths will usually be too few to be useful for monitoring progress and highlighting areas that require action. Maternal near-misses occur more frequently than mortality and allow identification of inadequate care in a way similar to confidential inquiries into maternal death. The criteria proposed by the WHO Working Group have been developed taking into consideration the lack of resources in low- and middle-income countries. The criteria have been validated in Latin American countries but still require validation in other parts of the world.14 It is widely acknowledged that poor and socially disadvantaged sections of our communities share the highest burden of ill health. The equity analysis conducted by the Countdown 2008 Equity Analysis Group15 found that the poorer quintiles of the communities are less likely to receive effective, guideline-recommended interventions. As expected, the equity gap has large variations within and between countries. Maternal and newborn health interventions represented an area of greater than average inequity, with a mean difference of 27.5% between the wealthiest and the poorest quintiles.
PERINATAL MORTALITY The MDGs identified a reduction in the mortality of children younger than 5 years of age as a priority (MDG 4), and within that group, reducing early neonatal deaths (~40% of the total) is a priority. It is estimated that around 4 million newborn babies die every year.16 In addition, stillbirths occur in about 1% to 3% of all births, amounting to more than 3 million perinatal deaths annually at a global level.17,18 Measuring and classifying perinatal deaths is not easy. Several classification systems exist, suggesting that no classification system is optimal.19–22 Kramer and associates23 suggest that antepartum, intrapartum, and early neonatal deaths should be reported separately. Global modeling estimates based on data from 45 countries suggest that preterm birth (28%), severe infections (36%, including pneumonia [26%], tetanus [7%], and diarrhea [3%]), and complications of asphyxia (23%) account Potentially life-threatening conditions Life-threatening conditions Maternal near miss Maternal death
Non complicated pregnancies All pregnancies
Complicated pregnancies FIGURE 1–1 Pregnancy morbidities as a continuum.
C HAPTER 1 • Global Maternal and Perinatal Health Issues 3 AFRICA
ASIA 6.1%
5.4% 12.5%
16.7%
30.8%
33.9%
3.7%
12.8%
6.2% 4.9% 2.0% 0.5%‡ 4.1%
0.0%* 1.6% 0.4%† 0.1%‡ 9.4%
9.1% 9.7%
3.9%
LATIN AMERICA AND THE CARIBBEAN
9.1% 5.7%
11.6%
DEVELOPED COUNTRIES
20.8%
4.8%
13.4%
14.4%
11.7%
0.0%*
3.9% 0.1%§ 3.8% 0.6% 0.5%
16.1%
25.7% 2.1%
21.3%
8.2%
13.4% 12.0%
FIGURE 1–2 Regional distribution of causes of maternal death.
Unclassified deaths Other indirect causes of death Anemia HIV/AIDS
for most neonatal deaths.24 In sub-Saharan Africa, 1.16 million babies die in the neonatal period, and another million babies are stillborn every year. In South Africa, in-depth analyses of perinatal deaths have been conducted since 1999 through the “Perinatal Problem Identification Programme” (PPIP) (http://www.ppip.co.za/savbab.htm). Each year about 22,000 babies die in South Africa. The Sixth Perinatal Care Survey of South Africa is a comprehensive report on causes of perinatal deaths, avoidable factors, and recommendations.25 Unexplained stillbirths and preterm-related deaths constitute the largest groups (Table 1–3). The top three causes of perinatal deaths in all birth weight categories were unexplained stillbirth, spontaneous preterm labor, and intrapartum asphyxia and birth trauma. Perinatal death rates in industrialized countries are generally much lower than in developing countries, and preterm births and congenital abnormalities tend to play a more prominent role.26 In 2006, in England, Wales, and Northern Ireland, the stillbirth rate was 5.3 (95% confidence interval [CI] 5.1, 5.5] per 1000 total births, the neonatal mortality
4.9%
7.7% 14.9% Other direct causes of death Embolism Ectopic pregnancy Obstructed labor
Abortion Sepsis/infections Hypertensive disorders Hemorrhage
rate was 3.4 (CI 3.3, 3.6) per 1000 live births, and the perinatal mortality rate was 7.9 (CI 7.7, 8.1) per 1000 total births. However, in the United Kingdom, the perinatal mortality rate is rising in the growing numbers of births to immigrant mothers, and immigration is increasing rapidly in many developed countries because of the need to rebalance the age pyramid (the indigenous population is aging owing to low birth rates).
STRATEGIES TO IMPROVE MATERNAL AND PERINATAL HEALTH Public Health and Political Context A comprehensive evaluation of global, regional, and national strategies to reduce maternal and perinatal mortality and morbidity is beyond the scope of this book. Broad population-level strategies have been summarized by the World Bank (Table 1–4).27
4 C HAPTER O ne • Global Maternal and Perinatal Health Issues T A B L E 1 – 2
The WHO Near-Miss Criteria A woman presenting any of the following life-threatening conditions and surviving a complication during pregnancy, childbirth, or within 42 days of termination of pregnancy should be considered a near-miss case. DYSFUNCTIONAL SYSTEM
CLINICAL CRITERIA
LABORATORY MARKERS
MANAGEMENT-BASED PROXIES
Cardiovascular
Shock Cardiac arrestb
pH 5 mEq/mL
Use of continuous vasoactive drugsi Cardiopulmonary resuscitation
Respiratory
Oxygen saturation 12 hr Strokeh Uncontrollable fit/status epilepticus Total paralysis
a
Alternative severity proxy
Dialysis for acute renal failure
Hysterectomy following infection or hemorrhage
Shock is a persistent severe hypotension, defined as a systolic blood pressure < 90 mm Hg for ≥ 60 min with a pulse rate at least 120 despite aggressive fluid replacement (>2 L). Cardiac arrest refers to the loss of consciousness AND absence of pulse/heartbeat. c Gasping is a terminal respiratory pattern and the breath is convulsively and audibly caught. d Oliguria is defined as an urinary output 40 kg/m2; “morbidly obese”). For an online BMI calculator, see www.nhlbisupport.com/bmi. There are also BMI percentiles, which are age-, gender-, and populationspecific.101 The prevalence of obesity in industrialized countries is increasing rapidly.102
RISKS Hypertensive disorders, including preexisting hypertension and pregnancy-induced hypertension, are more common in
women with excess weight, although reported prevalence varies widely (7%–46%).102,103 Gestational diabetes is also more frequent, affecting 7% to 17% of obese women.103 Other problems associated with obesity include gallbladder disease, shortness of breath, fatigue, hiatus hernia, raised cholesterol levels, urinary tract infections, postnatal hemorrhage, and possibly thrombophlebitis.102,104,105 Controversy exists regarding the association between obesity and congenital malformations. Watkins and coworkers106 explored the association between several birth defects and obesity in a population-based case-control study. They concluded that obese women (BMI ≥ 30) were more likely than averageweight women (BMI 18.5–24.9) to have an infant with spina bifida (unadjusted odds ratio [OR] 3.5; 95% confidence interval [CI] 1.2–10.3), omphalocele (OR 3.3; 95% CI 1.0– 10.3), heart defects (OR 2.0; 95% CI 1.2–3.4), and multiple anomalies (OR 2.0; 95% CI 1.0–3.8). The biologic mechanism behind obesity and birth defects is unknown. There is conflicting evidence about the effect of obesity on perinatal mortality. Obese women are more likely to give birth to large-for-gestational-age infants. Increased maternal weight is independently associated with poor labor progression and increased risk of cesarean delivery.102,104,105 Overall, the increased need for abdominal delivery in obese women can be attributed mainly to the relatively high rates of prenatal complications and to factors such as advanced age and high parity. When surgical delivery is required, obese women are more prone to wound infection than nonobese women.103,107 The risks of anesthesia are increased in obese women including failed epidural, difficult intubation, inability to identify landmarks, difficulty in placing the regional block, and erratic spread of anesthetic solution.102 Management of the airway in morbidly obese patients can be extremely difficult. They have an increased risk of aspiration because of a larger volume of gastric fluid and increased intra-abdominal pressure with a higher incidence of gastroesophageal reflux.108 The anesthetic problems can be compounded by coexistent cardiovascular and respiratory problems. Finally, transportation of the grossly obese patient can be extremely difficult.
MANAGEMENT OPTIONS Prepregnancy Ideally, an obese woman should be encouraged to lose weight before or after pregnancy. However, data on the efficacy of numerous dietary programs are limited 109–111 Dietary manipulation should not be advocated during pregnancy because it is difficult to achieve, offers no benefit to the mother, and may have ill effects on fetal weight and health after birth.112,113 Behavior modification including daily exercise programs is probably the key to weight loss100,109,114 (see “Physical Activity,” later). However, if a woman insists on severe caloric restriction for weight reduction, the problem of maintaining reduced weight for prolonged periods should also be addressed. The recurrence rate of obesity after weight reduction is high.114 Bariatric surgery encompasses the various surgical procedures performed to treat obesity by modification of the gastrointestinal tract to reduce nutrient intake and/or absorption. It is considered with morbid obesity when all other
22 S ECTION O NE • Prepregnancy
treatments have failed.115 The majority of patients are women.116 The three most common surgical procedures currently performed worldwide are laparoscopic gastric bypass, laparoscopic adjustable gastric banding and open gastric bypass. Sixty-three percent of bariatric surgery is now performed laparoscopically.117 A recent Cochrane review concluded that bariatric surgery resulted in greater weight loss than conventional treatment and led to improvements in quality of life and obesity-related diseases such as hypertension and diabetes. However, the comparative safety and effectiveness of the surgical procedures remain unclear.118 A systematic review concluded that women who had bariatric surgery before pregnancy had lower rates of a number of adverse maternal and neonatal outcomes when compared with rates in pregnant women who did not have surgery for morbid obesity.119 Most pregnancies after bariatric surgery appear to have a benign course.
Prenatal Prepregnancy weight and maternal height should be documented routinely at the first visit. Weight is usually recorded at each prenatal visit, using calibrated scales, although the value of this is uncertain. Blood pressure should also be monitored with an appropriately sized cuff to minimize the artificially high recordings that might result when a standard cuff is used.120 In obese women, it can be difficult to assess fetal growth and presentation clinically. Ultrasonography is helpful in resolving problems of presentation. However, poor ultrasound visualization in obese women lessens the accuracy of measurements and assessment of fetal anatomy.121 Tissue harmonic imaging improves the quality of ultrasound images of the fetal heart.122 Anesthetic consultation is advisable. This has greater urgency if patient has medical problems
SUMMARY OF MANAGEMENT OPTIONS
Overweight Women Management Options
Evidence Quality and Recommendation
References
Prepregnancy Provide advice on interventions for weight reduction.
Ia/A
110
Explain the risks of hypertension, diabetes, urinary infections, large fetal size, and postpartum hemorrhage.
III/B
104–107, 123
In the selected group of women, pregnancy following bariatric surgery is associated with a better outcome than being pregnant and morbidly obese.
Ia/A
119
Avoid attempts to manipulate the diet during pregnancy.
Ib/A
109,111,114
Screen for hypertension, diabetes, and bacteriuria.
III/B
105
Monitor the blood pressure with an appropriately sized cuff.
III/B
120
Monitor fetal growth with ultrasound.
III/B
123,124
III/B
123
Use regional rather than general anesthesia.
IIa/B
133
Give prophylactic antibiotics.
Ia/A
125
Use thromboprophylaxis.
IV/C
102
There is no evidence for the best incision.
Ia/A
127
Subcutaneous fat closure decreases the incidence of wound dehiscence.
Ia/A
130,131
Subcutaneous drains do not prevent wound complications.
Ia/A
131
Following cesarean section give subcutaneous heparin until the patient is fully ambulatory.
IV/C
126
Recommend early mobilization.
IV/C
126
Continue with measures to lose weight.
IV/C
100
Breast-feeding has a small protective effect against childhood obesity.
I/A
134
Prenatal
Labor and Delivery Maintain vigilance for cephalopelvic disproportion and shoulder dystocia. Cesarean Section
Postnatal
C HAPTER 2 • Constitutional and Environmental Factors Leading to a High Risk Pregnancy 23
such as hypertension, diabetes mellitus, or pulmonary dysfunction. Obese women should be evaluated for gestational diabetes at the first prenatal visit and at the start of the third trimester (see Chapter 44). Ultrasound screening for fetal macrosomia is commonly undertaken in pregnancy.
Labor and Delivery Fetal macrosomia is strongly associated with problems in labor, including poor progress as a result of cephalopelvic disproportion, shoulder dystocia, and birth asphyxia.123 Attempts to derive a prediction score to identify large-forgestational-age infants have been unsuccessful because of unacceptably high false-positive rates.124 Cesarean section in obese women requires specific considerations. Regional anesthesia has advantages over general anesthesia.104,125 As with all cesarean sections, obese patients should receive prophylactic antibiotics and thromboprophylactic measures.125,126 Evidence about the most appropriate surgical technique is limited127 (see also Chapter 74). Gross128 reviewed the benefits and risks of the two common operative approaches (Pfannenstiel and midline vertical) in obese women. He concluded that the favorable aspects of the Pfannenstiel incision are (1) less postoperative pain and early ambulation; (2) a more secure closure; (3) less adipose tissue to incise; and (4) better cosmetic results. However, the potential adverse effects of the Pfannenstiel incision are (1) greater likelihood of wound infection; (2) potentially restricted access to the infant; and (3) more difficult exposure of the upper abdomen. Exteriorization of the uterus is of no proven benefit.129 Naumann and colleagues130 tested the hypothesis that closure of the subcutaneous fat decreases the incidence of wound disruption after cesarean section. There was no significant difference in the incidence of wound infections between the two study groups. However, there was a significantly lower incidence of wound disruption in the subcutaneous closure group (relative risk [RR] 0.5; 95% CI 0.3–0.9). A recent multicenter randomized trial concluded that the additional use of a subcutaneous drain does not prevent of wound complications in obese women being delivered by cesarean section.131 There is no conclusive evidence about how the skin should be closed after cesarean section.132
Postnatal Prophylactic administration of anticoagulants should be continued until the patient is fully mobilized. Early mobilization appears to improve maternal outcome. In newborn infants born to grossly obese women, especially those that are large for gestational age, the blood glucose levels should be monitored during the first hours of life. From a systematic review, it was concluded that breastfeeding seems to have a small but consistent protective effect against obesity in children.133
Weight Gain in Pregnancy The total weight gain of a healthy nulliparous woman eating normally is approximately 12.5 kg (27.5 lb).92 However, large variations in weight gain are seen with normal outcomes.92,135 In western societies, average total weight gain ranges from 10 to 16 kg (22–35 lb).136 In healthy,
well-nourished women with uncomplicated pregnancies, the proportional weight gain (i.e., total weight gain at term expressed as a proportion of prepregnancy weight) is 17% to 20%.88 The increase is mainly due to an increase in total body water (~7.5 kg [16.4 lb] when no edema is present) and body fat mass (~2.2–3.5 kg [5.0–7.7 lb]).92,136,137 The remainder (~0.9 kg [2 lb]) is caused by an increase in protein content, half of which is fetal. Mean weight gain in pregnancy, from conception to birth, does not show a linear trend. In the normal, lean nulliparous woman, weight gain during the first trimester is 0.65 to 1.1 kg (1.4–2.4 lb).90,137 In the second trimester, average weekly weight gain is 0.45 kg (1 lb), and 0.36 kg (0.8 lb) thereafter.92 Weight loss or failure to gain weight over a 2-week interval in the third trimester is not uncommon in both nulliparous and parous women. The maximum rate of weight gain occurs between 17 and 24 weeks.135 After delivery, the most rapid weight loss, mainly as fluid, occurs between 4 and 10 days. Subsequently, weight loss is more gradual, at 0.25 kg (0.55 lb) per week due to mobilization of fat stores.138 The average woman eventually loses most of the weight she gained during pregnancy.92,139 Breastfeeding for longer than 60 days has a favorable effect on the rate of postpartum weight loss.140
RISKS Inadequate weight gain during pregnancy is associated with low–birth weight and small-for-gestational-age infants. Excessive weight gain during pregnancy does not necessarily enhance fetal growth and has been consistently found to contribute to postpartum weight retention and later obesity.141 The magnitude of the association between inadequate maternal weight gain and low birth weight depends on prepregnancy weight. Thus, women of low prepregnancy weight with little weight gain during pregnancy are more likely to give birth to a low–birth-weight infant than overweight women with a similar overall weight gain. Net weight gain in underweight women is strongly related to birth weight. In overweight women, net weight gain is only marginally related to birth weight.141,142 The optimum weight gain in terms of minimum perinatal mortality is 7.3 kg (16 lb) for overweight women, 9.1 kg (20 lb) for women of normal weight, and 13.6 kg (30 lb) for underweight women.112 The possibility of an eating disorder should be considered in women who do not gain appropriate weight or who have intractable vomiting.89
MANAGEMENT OPTIONS Prenatal Despite the risks previously discussed, evidence that interventions based on poor weight gain improve outcome is lacking and many units no longer weigh pregnant women regularly through pregnancy. Those that do often check for abnormal fetal growth in such women, consider physical and organic causes, and if the abnormal weight gain is thought to be dietary, offer advice about improving diet and lifestyle.113,124,138,142–144 Advice on reducing weight is not helpful.
Labor and Delivery Important considerations were discussed in the previous sections.
24 S ECTION O NE • Prepregnancy SUMMARY OF MANAGEMENT OPTIONS
Abnormal Weight Gain Evidence Quality and Recommendation
Management Options
References
Prenatal Check for abnormal fetal growth.
Ib/A
113
Consider physical and organic causes.
IIb/B
143
Offer advice on improving diet and lifestyle.
Ia/A
124,138,144
—/—
—
Advice on reducing weight is not useful. Labor and Delivery See the recommendations for “Overweight Women.”
Physical Activity Definition Physical activity can be ● Daily activities (domestic, occupational, and commuting). ● Leisure activities (sports and exercise). It accounts for 15% to 40% of total energy expenditure. The magnitude of the physiologic response is determined by age, fitness, body weight, body position, concurrent physical adaptations to pregnancy, and psychological factors.145
low birth weight, and preterm birth146 (see “Occupational Factors”). Regular recreational exercise in pregnancy, including aerobics and competitive sports, improves the outcome for both mother and fetus, in terms of maternal cardiovascular reserve, placental growth, and functional capacity.145–150 Activities with a high risk of abdominal trauma should be avoided.147 Scuba diving should be discouraged throughout pregnancy, because the fetus is not protected from decompression problems and is at risk for malformation and gas embolism after decompression disease.147,149
Management Options
Risks GENERAL HEALTH Physical activity, diet, and health are linked, especially through obesity.100 However, physical inactivity is an independent risk factor for type 2 diabetes, hypertension, cardiovascular disease, and stroke.100
PREGNANCY Physically and emotionally demanding work during pregnancy is associated with an increased risk of hypertension,
A woman’s overall health, including obstetric and medical risks, should be evaluated before an exercise program is prescribed. The American College of Obstetricians and Gynecologists (ACOG) recommends that healthy pregnant women engage in 30 minutes or more of moderate exercise daily, provided there are neither medical nor obstetric complications.147 Healthy pregnant women are allowed to exercise vigorously or take part in competitive sports, provided there are no noticeable health hazards to themselves or their infants.147,149,150
SUMMARY OF MANAGEMENT OPTIONS
Exercise in Pregnancy Evidence Quality and Recommendation
References
Healthy pregnant women may engage in daily exercise if there are no medical or obstetric complications.
Ia/A
147,149
Women should avoid activities with a high risk of abdominal trauma.
IV/C
147
Discourage scuba diving in pregnancy.
IIb/B
151
Regular aerobic exercise during pregnancy appears to improve or maintain physical fitness
Ia/A
150
Regular exercise carries no demonstrable harm to the mother or fetus.
Ia/A
149
Management Options
C HAPTER 2 • Constitutional and Environmental Factors Leading to a High Risk Pregnancy 25
ENVIRONMENTAL RISK General Some environmental risk (such as infection, prescribed drugs, drugs of abuse) is covered in other chapters. It is difficult to ascertain the clinical importance of each of these environmental influences on reproductive health because of lack of evidence and the existence of confounding variables.
Chemicals Polychlorinated Biphenyls Polychlorinated biphenyls (PCBs) have been used in pesticides, surface coatings, inks, adhesives, flame retardants, paints, and old electrical equipment.152 Many countries have severely restricted or banned the production of PCBs. Highly chlorinated PCB congeners persist in the environment, the air, drinking water, and food, particularly meat, fish, and poultry. They are rapidly absorbed from the intestinal tract and distribute to and accumulate in the liver. They also cross the placenta and are excreted in breast milk. Formula milk is free of PCBs. Much concern exists that PCBs transferred to the fetus across the placenta may induce long-lasting neurologic damage.153 The beneficial effects of breast-feeding, however, outweigh the potentially adverse effects of PCB exposure from breast milk.
Dioxins Dioxins are a heterogeneous mixture of chlorinated dibenzop-dioxin and dibenzofuran congeners. Dioxins are emissions of industrial incineration processes. They accumulate in the food chain to result in human exposure.154 Few data are available on the effects of dioxins on female reproductive health. In animal models, dioxin has an antiestrogenic effect. Environmental chemicals have been implicated in the temporal decline in the age of onset of puberty, the development of polycystic ovarian syndrome, and shortened lactation. Reports of cryptorchism and hypospadias need more careful study, particularly because they are linked to testicular cancer. The effects of environmental chemicals on sperm quality are inconsistent. Because of methodologic
shortcomings in epidemiologic studies, it is unknown whether dioxins affect spontaneous abortion rates or fetal growth restriction.
Pesticides Pesticides (e.g., fungicides, herbicides, insecticides, and rodenticides), often found in commercially available food products, are a reproductive health concern in many countries. However, the almost universal exposure to low concentrations of these compounds makes it very difficult to determine the effect of pesticides on the incidence of fetal abnormalities. Occupational exposure to pesticides has been implicated in increased birth defect rates.155,156
Occupational Risk Risks With the rising number of women in paid employment in both developing and developed countries,157 exposures to unsafe and unhealthy conditions, such as toxic chemicals, radiation, and physically or mentally demanding work, have become more common. Because women’s occupations are multidimensional and risk exposure perhaps subtle, a simple guide for establishing specific health risks is not always possible.156,158 However, the adverse effects of poor working environment can be magnified by problems of isolation, stress, tiredness, and depression. Physical violence is a major contributor to women’s health risks, either in the home or in the formal workplace (see Chapter 3). Occupational exposure to risk can be specific such as anesthetic agents, laboratory chemicals, organic solvents, and pesticides (see earlier).159,160 A meta-analysis of studies of working conditions in pregnancy concluded that physically demanding work is significantly associated with preterm birth (OR 1.22; 95% CI 1.16–1.29), fetal growth restriction (OR 1.37; 95% CI 1.30–1.44), and hypertension or preeclampsia (OR 1.60; 95% CI 1.30–1.96). Other occupational exposures significantly associated with preterm birth include prolonged standing (OR 1.26; 95% CI 1.13–1.40) and shift and night work (OR 1.24; 95% CI 1.06–1.46).161 It appears that interventions to reduce physical exertion among pregnant women could improve birth outcomes.161–164 Exposure to magnetic fields emitted by video display
SUMMARY OF MANAGEMENT OPTIONS
Work and Pregnancy Management Options
Evidence Quality and Recommendation
References
Precautions to protect women against specific occupational risks (e.g., toxic chemicals or radiation).
IV/C
157
Avoid long hours of standing and walking.
Ia/B
157
Avoid excess lifting and exercise.
Ia/B
161
Patients can continue to work if they wish and are not unduly tired.
Ia/B
161,163
There is no evidence that video display units (VDUs) are associated with adverse pregnancy outcome.
III/B
165,166
26 S ECTION O NE • Prepregnancy SUMMARY OF MANAGEMENT OPTIONS
Air Travel in Pregnancy Evidence Quality and Recommendation
References
Long-distance air travel is safe in normal pregnancy.
IV/C
167,171
Long-distance flights are not recommended for women 5.6-mm diameter) is often an early sign of impending miscarriage.18 Other early indicators of an almost certain miscarriage are when the gestation sac diameter exceeds 20 mm without any visible yolk sac or exceeds 25 mm without a visible fetus. When an intrauterine pregnancy is clearly visible, a useful formula to calculate approximate gestational age (in days from the last menstrual period) is Gestational age (days) = mean sac diameter (mm) + 3019
This formula is valid up to 9 weeks. A second, more accurate but more complex, formula and that is valid to at least 12 weeks is Mean sac diameter (mm) = 20 0.986 (days after ovulation conception) − 17.1
The presence of an intrauterine pregnancy with a live fetus is a good prognostic finding. When a live embryo or
ys
FIGURE 5–1 Pregnancy with yolk sac (ys) at eight weeks’ gestation.
T A B L E 5 – 2
Ultrasound Findings and β-hCG Concentrations for a Singleton Intrauterine Pregnancy at Particular Gestational Age Points in Early Fetal Life* TRANSVAGINAL ULTRASOUND FINDINGS FETAL HEART (RATE) (AFTER MERCHIERS ET AL, 1991,23 AND ROBINSON AND SHAW-DUNN, 197333)
SERUM HCG (IU/L; 3RD IRP) (MEAN 95% CI VALUES FOR IMMULITE HCG ASSAY) (AFTER NEPOMNASCHY ET AL, 2008,168 AND BARNHART ET AL, 200426) 88 73–105 600 1000 500–1500 1500 900–2900 6000 3500–14000 15000
ENDOMETRIUM
GESTATIONAL SAC (AFTER HOLLANDER, 1972,32 AND MILLS, 199220)
YOLK SAC (AFTER MILLS, 199220)
CROWN-RUMP LENGTH (AFTER HOLLANDER, 1972,32 AND MILLS, 199220)
4 weeks (28 days)
10–15 mm
—
—
—
—
5 weeks (35 days) 51 2 weeks (38–39 days)
15–20 mm 20 mm
3 mm 7–8 mm
2 mm 3 mm
— 3–4 mm
— —
6 weeks (42 days)
20 mm
10–12 mm
4 mm
4 mm
85–100
7 mm
—
10 mm
125
WEEKS (DAYS) FROM THE LAST MENSTRUAL PERIOD (ASSUMING A 28–30-DAY CYCLE)
61 2 weeks (45–46 days)
—
14–15 mm
4.5 mm
7 weeks (48–49 days)
—
17–18 mm
5 mm
6500–>25000 * For optimal interpretation, data are presented for half weeks where possible and from more than one source, leading to a range of values in some cells and no data in other cells. β-hCG, β-human chorionic gonadotropin; CI, confidence interval; hCG, human chorionic gonadotropin.
60 S ECTION TWO • Early Prenatal
fetus is seen on ultrasound, the pregnancy is likely to continue in over 95% of cases.21,22 As well as ultrasound structures, fetal circulation becomes evident at 5 12 weeks and is visible in all viable pregnancies by 6 weeks.20 Initially, the fetal heart rate is slower than normal, but it increases over time, from 85 to 90 beats/min at 6 weeks to levels of up to 180 beats/min at 9 weeks.23 Rates persistently slower than 100 are more likely to be associated with a poor outcome.23
Measurement of Human Chorionic Gonadotropin Serum β-hCG concentrations complement the information available from TVUS in assessing early pregnancy problems. For this chapter, β-hCG values and ranges relate to the Third International Reference Preparation (3rd IRP). Absolute levels may be helpful in recognizing when a normal intrauterine pregnancy should be seen at TVUS. Levels of β-hCG greater than 1500 to 2000 IU/L (depending on local laboratory variations) should almost always be associated with the finding of a gestational sac in the uterus if the pregnancy is intrauterine.24 If it cannot be seen in the uterus, it should be assumed there is a pregnancy elsewhere (Fig. 5–2). However, caution should be exercised when women have had assisted conception treatment (by in vitro fertilization or ovulation induction). In these situations, more than one embryo might be present and, therefore, an intrauterine and extrauterine pregnancy might coexist (i.e., a heterotopic pregnancy) or two intrauterine pregnancies might exist, giving rise to higher β-hCG levels (≤20 times normal) without a pregnancy yet being visible on TVUS. Excessively high serum β-hCG levels are also found with gestational trophoblastic disease and levels up to twice normal can be found in pregnancies affected by Down syndrome. Generally, β-hCG levels will be lower at any given gestational age with ectopic pregnancies than with normal intrauterine pregnancies. However, the overlap in values between the
two clinical conditions is too great for this to be a diagnostic criterion. Changes in β-hCG levels are more useful clinically. Usually, β-hCG values are best tested at intervals of 48 hours or longer. A falling β-hCG concentration in the first few weeks identifies a pregnancy as abnormal. If the β-hCG falls by more than more than half within 48 hours, it suggests that residual trophoblastic activity has ceased and that the pregnancy is likely to resolve without intervention. With a viable intrauterine pregnancy, previous data supported the view that β-hCG values should increase by at least 66% in 48 hours.25 However, more recent and more accurate data for viable pregnancies support a view that the slowest rise at 1 day was 24% and 53% at 2 days; median increases in hCG at 1 day and 2 days were 50% and 124% (considerably
FIGURE 5–2 Uterus with an ectopic pregnancy (crown-rump length [CRL] = 19 mm) shows fetal heart activity at 7 weeks’ gestation.
SUMMARY OF MANAGEMENT OPTIONS
Initial/General Management Management Option Identify cause by combination of history, examination, β-hCG assay, progesterone measurement, and transvaginal ultrasound The presence of an extrauterine mass is the most accurate predictor of an ectopic pregnancy
Evidence Quality and Recommendation
References
Ia/A
28
III/B
9,11–14,20–23,25,27,29–33
III/B
16,17
Assess amount and rate of blood loss
III/B
14
Regular recordings of pulse and blood pressure
IV/C
—
Intravenous access if actual or risk of hemodynamic instability
IV/C
—
FBC for all; clotting screening if coagulopathy suspected or excess blood loss; cross-match blood if excessive blood loss
IV/C
—
β-hCG, β-human chorionic gonadotropin; FBC, full blood count.
C HAPTER 5 • Bleeding and Pain in Early Pregnancy 61
lower than previously thought).26 In addition, a β-hCG doubling time of more than 7 days is never found in a normal pregnancy.25
Measurement of Progesterone In both natural conceptions and in pregnancies arising from assisted conception, progesterone has been assessed in its role to determine the health of a pregnancy, particularly with reference to the site of that pregnancy. Levels of 30 to 45 nmol/L (10–15 ng/mL) suggest a healthy ongoing pregnancy. However, low levels are poor at differentiating miscarriages from ectopics (though combining with hCG measurements may help).27–29
SPONTANEOUS ABORTION OR MISCARRIAGE
T A B L E 5 – 3
Requirements for an Early Pregnancy Assessment Clinic Appropriate resources for rostering of ultrasonographic, medical, and nursing staff (exact calculation of time required is not evidencebased; experience suggests that for a hospital with a delivery rate of 5000 deliveries/yr, 3 hours of patient contact time for all disciplines and 1 hour of telephone contact time later in the day is reasonable). ● Dedicated clinic space with rooms for ultrasonography, clinical assessment and investigation, counseling, and a waiting area. ● Good quality ultrasound machines with transvaginal facility. ● Availability of same-day hCG estimation. ● Responsibility for development of guidelines and resolution of conflicts and problems should be the responsibility of a designated senior member of the clinical staff. ●
hCG, human chorionic gonadotropin.
Definition Now used synonymously, the terms spontaneous abortion and miscarriage imply the natural loss of a pregnancy before independent viability of the fetus. Until recently, the term “abortion” was generally used in professional communication and “miscarriage” was used in discussion with patients. However, because this was not an exclusive definition, and as the term “abortion” (which many patients find offensive) has pejorative connotations of “elective termination of pregnancy,” there has been an overall shift away from using “abortion” to describe the spontaneous loss of a pregnancy.34 Viability implies the ability of the fetus to survive extrauterine life. This is generally taken to be around 24 weeks, and rarely, fetuses born before that will survive for a short while or at least show some signs of life. The cutoff point for the use of the term “miscarriage” might lie at 22 weeks (154 days), therefore, as recommended by the World Health Organization (WHO).35 The WHO also includes in this a baby’s weight (the value being < 500 g). In the United Kingdom, the legal definition changed in 1992 to 24 weeks (168 days) whereas in North America, the gestational age limit for a miscarriage is 20 weeks.36 In addition to these changes in terminology, there has been a marked alteration in the way in which early pregnancy problems of bleeding and pain are managed. Much of this is attributable to the ● Availability of rapid access to serum β-hCG estimations. ● High-resolution TVUS. ● Introduction of fast-track referrals to early pregnancy assessment units/clinics (EPU/EPC). In EPCs, access to integrated evaluation by ultrasonography, serum sampling for β-hCG, and the presence of experienced timetabled medical and nursing staff has permitted women to be managed more as outpatients or in the office, providing a more streamlined service. A summary of requirements for an EPC service is provided in Table 5–3. EPCs have improved the quality of care and produced savings in financial and staff resources. However, as a tool in patient management, EPC services have not yet been fully evaluated.37 Management of women through an EPC service is not without its drawbacks. Inappropriate delays in diagnosis of true ectopic pregnancies and overmanagement by laparoscopy of suspected ectopic pregnancies both occur, despite rigid adherence to protocols.
PROPORTION OF UNRECOGNIZED PREGNANCIES LOST TO RECOGNIZED MISCARRIAGES AND LIVE BIRTHS (AFTER CHARD, 1991)
Recognized pregnancies
30% as live births
10% as miscarriage Unrecognized pregnancies
30% as pregnancy loss before the missed period 30% as pregnancy loss before implantation
FIGURE 5–3 Proportion of unrecognized pregnancies lost to recognized miscarriages and live births. (From Chard T: Frequency of implantation and early pregnancy loss in natural cycles. Baillieres Clin Obstet Gynecol 1991;5:179–189.)
A pregnancy loss may be clinically evident, following presentation with bleeding or pain, or be clinically silent, identified at routine ultrasound scan. The introduction of almost routine scanning to confirm gestational age has had a dramatic effect of the management of early pregnancy loss. Bleeding occurs in a fifth of recognized pregnancies before 20 weeks. It is likely, however, that a far greater unrecognized pregnancy loss is present in the background, with more pregnancies being lost before the pregnancy has been suspected, recognized, or confirmed (giving rise to the term “pregnancy loss iceberg” ’; Fig. 5–3).38,39 In one study, 12% of pregnancies in which bleeding occurred went on to miscarry.40 Other studies have reported higher rates (≤16%),40 but these studies do not include those women who did not know they were pregnant (≤22%)41 or those who did not seek medical advice about their bleeding, knowing they were pregnant (~12%).40
Risks The maternal risks are blood loss, infection, and the psychological effects of the loss of the pregnancy.
62 S ECTION TWO • Early Prenatal
Presentation and Diagnosis Most women will present to a hospital, family doctor, or EPC in a number of ways: ● Bleeding without pain, ● Bleeding with pain (with possible passage of pregnancy tissue vaginally). ● Bleeding with pain with symptoms and signs of blood loss. ● Absence of bleeding with pregnancy symptoms diminishing. The amount of bleeding can vary and has some prognostic value. Bleeding without pain is more likely to be associated with a threatened miscarriage. Presentations to an EPC service will frequently be for painless bleeding. Once the pregnancy is confirmed on ultrasound to be ongoing, this situation can be dealt with by reassurance. Most of these cases will be due to bleeding from local causes such as physiologic changes in the cervix. The additional presence of pain is often associated with cervical opening or distention as a result of tissue or blood clot passing through and is a painful process. Blood loss can give rise to symptoms in itself, and the passage of tissue through the cervical os can promote a vagal response causing shock, which is rapidly relieved if the products are removed from the os.
Management Options Threatened miscarriages are managed expectantly. If the bleeding is slight and not associated with pain, then the woman can be reassured that the pregnancy is likely to continue. For all pregnancies in which bleeding occurs, more than 50% will continue.3 If the bleeding occurs at 10 weeks more than 90% will continue; at 13 weeks, 99% will continue.42 If the menstrual/gestational age is 6 weeks or older, then ultrasound may show a healthy ongoing pregnancy. In such cases, the likelihood of pregnancy loss is less than 3%.22 Ultrasonography before 6 weeks is less likely to be helpful. If a patient needs the reassurance of an ongoing pregnancy by ultrasound scan, then this should be undertaken after 6 weeks. The management options for the loss of an early intrauterine pregnancy are ● Expectant. ● Medical. ● Surgical. Cases of complete spontaneous miscarriage can be managed expectantly. Most difficulty in the management of early pregnancy bleeding concerns cases of missed or incomplete miscarriage. In most western countries, historically, the surgical approach (“evacuation of retained products of conception” [ERPC]) has been the most common emergency gynecologic procedure. The procedure was traditionally carried out with ovum forceps and curettage and evolved to vacuum aspiration. Vacuum aspiration is associated with less blood loss and pain and a shorter procedure than surgical curettage.43 Expectant management avoids a surgical procedure and allows the woman to continue in her normal daily routine. It is more acceptable to women and has less impact on quality of life.44 It is an approach that has
been adopted readily in primary care without hospital admission.45 Many reported studies compare two of the three modalities of treatment (expectant, medical, and surgical). Some are included in the Summary of Management Options at the end of this section. However, current management of miscarriage should now be based on published metaanalysis and randomized, controlled trial (RCT) papers, together with both economic and quality of life data, which these studies have also produced. The advice from these is not entirely in harmony. This is partly because the meta-analysis attempted to synthesize data from disparate studies comparing two modalities of treatment, whereas the RCTs compared all three modalities in a randomized approach. The RCTs were published after the metaanalysis. In their meta-analysis, Sotiriadis and colleagues46 suggest that surgical management appears most likely to achieve success and expectant management least so. The largest RCT combining all three modalities (the miscarriage treatment [MIST] trial) recruited 1200 women in approximately equal proportions to the three modalities of treatment.47 In that study, there were no differences in rates of infection, hemoglobin or hematocrit levels, incidence in surgical complications, sick leave, or scores in hospital anxiety and depression questionnaires between the three modalities. Compared with expectant and medical management, those patients managed surgically had fewer unplanned admissions and unplanned surgical curettages, no blood transfusion (compared with 1%–2%), and less analgesia. A second much smaller RCT (40 patients) had broadly similar results but was stopped early because of failure to recruit to randomization.48 Data from the MIST study on women’s preferences for treatment suggested that women particularly value alternatives being offered to expectant management49—clearly an important consideration when planning service provision. The level of pain experienced appeared to be the most important determinant for preference for an alterative treatment, and to a lesser extent, time to return to normal activity, number of days of bleeding, and likelihood of complications. When costs are analyzed, expectant management was least expensive and medical treatment was 40% and surgical treatment 50% more expensive.50 One other large study analyzed medical and surgical modalities for quality of life and acceptability, finding no differences.51 For practical purposes, expectant management is well tolerated, cost-efficient, and safe and should be used for women in the first instance, providing that they are hemodynamically stable. It appears difficult to predict for which women expectant management will be effective.52 Patients need to understand that they will bleed for slightly longer53 and have a risk of needing surgical evacuation47 so they need to have ready access to hospital services if needed. Medical management is not much more effective than expectant, but it is more expensive and, therefore, its role is less clear as a management option. Expectant and surgical seem to be the practical options—no intervention if possible, and then surgical if required. Vacuum aspiration is preferable to surgical curettage, being safer, less painful, and quicker to undertake.43 Whether any women should electively have surgical treatment rather
C HAPTER 5 • Bleeding and Pain in Early Pregnancy 63 SUMMARY OF MANAGEMENT OPTIONS
Spontaneous Miscarriage Management Options
Evidence Quality and Recommendation
References
Expectant, medical, and surgical all compared
Ia/A
46–48
Expectant management
Ia/A
46–48,55,61,62
Medical evacuation
Ia/A
46–48
Ib
55,61,63–65
Surgical evacuation
Ia/A
46–48,61,63
Adequately resourced; Early Pregnancy Clinic is key to management of early pregnancy problems
III/B
37
Many cases do not need hospital admission
Ia/A
45
Expectant and surgical managements are equally effective
Ia/A
62
Expectant management does not affect future fertility
Ib/A
62,66
Medical management before recourse to surgical management
Ib/A
63,67
Vacuum aspiration should be used in preference to surgical evacuation
Ia/A
43
Couples require no more psychological support and women no more time off work following expectant, medical, or surgical management of miscarriage
Ia/A
47
Ib
68
Patient preference should play a dominant role
Ia/A
46–48
than any other is not clear, though in terminations, women of high parity (>para 3) are more likely to have a complete abortion following surgical management.54 Ideally, tissue should be sent from all miscarriages for histologic examination. However, there are obvious practical problems in achieving that goal if medical and expectant management are undertaken. It certainly should be requested on all those having surgical curettage. Ultrasound findings suspicious of trophoblastic disease are an indication for surgical rather than medical management. Some have suggested that the optimum management option can be determined on the basis of ultrasound and biochemical evaluation. The volume of tissue remaining in the uterine cavity on ultrasound may be a useful guide in management. No intervention is required in the absence of tissue or if products of conception are present with a mean diameter less than 15 mm. Medical or expectant management may be considered if the tissue mass is between 15 and 50 mm, and an ERPC is probably required if tissue diameter is greater than 50 mm.55 More complications (37% vs. 3%) occurred when women with significant intrauterine tissue (an intrauterine sac >10 mm in diameter) were managed expectantly compared with surgically.56 Tissue volume has not been used in the evaluation of the data in the threemodality RCTs47,48 or the meta-analysis,46 so further clarification is still awaited. Evidence regarding the value of serum β-hCG levels56,57 or progesterone58 to determine the need for surgical intervention is insufficient. When color Doppler imaging of
uterine blood flow and of the intervillous space was examined in missed miscarriages,59 uterine blood flow could not differentiate between those women whose miscarriage resolved spontaneously and those who required an ERPC. Intervillous space blood flow was associated with an 80% chance of spontaneous resolution compared with 23% in those for whom flow was absent.59 Although this technique shows promise, it requires validation. At present, these adjuvant techniques are of little value in determining which women should be managed expectantly or otherwise. Should women undergoing surgical evacuation of uterus have Chlamydia screening in line with other invasive interventions in the uterine cavity? One inadequately powered randomized trial showed no benefit, but because the intervention reduces infection in induced abortion, it is probably worth continuing until evidence suggests otherwise.60 Much of the management of early pregnancy bleeding may remain within the remit of general practitioners45 or midwives,1 but accurate diagnosis of ectopic pregnancies56 and molar pregnancies52 remain particular concerns. Rapid access to ultrasound and β-hCG assays should remain as a fundamental part of the management of early pregnancy bleeding.
ECTOPIC PREGNANCY The management of ectopic pregnancy has changed over the past 20 years because of several important developments:
64 S ECTION TWO • Early Prenatal
● ● ● ●
Recognition of high risk individuals (Table 5–4). Increased sensitivity of home pregnancy tests. Early referral to dedicated EPCs in hospital settings. Development and refinement of high-resolution TVUS. Accurate and rapid estimation of serum β-hCG. Laboratory techniques allowing 24-hour access to automated sample processing. However, there is no room for complacency with regard to ectopic pregnancy management. The most recent report on maternal deaths in the United Kingdom shows an increase in ectopic pregnancy rates over the previous 20 years, from 8.6/1000 pregnancies in 1985 to 1987, to 11.1/1000 pregnancies in 2003 to 2005.69 Deaths from ectopic pregnancies in that report are no better than 20 years previously: 4.7 compared with 4.8 deaths/1,000,000 maternities. Although the death rate expressed as a proportion of ectopic pregnancies in that time span (6.1 compared with 3.5 /1000 ectopic pregnancies) is an apparent fall, in real terms, there have been about 10 deaths in each triennium from 1985 to 2005. A major recommendation from the most recent report on maternal deaths suggests that every unit should have clear guidelines for the management of pain and bleeding in early pregnancy because “there are persisting failures to recognise these conditions [ectopic pregnancies] promptly.”69
● ● ●
●
●
●
●
Definition An ectopic pregnancy is one that occurs in a site outside the uterine cavity, but usually in an adjacent site. In over 98% of ectopic pregnancies, the primary site is in the fallopian tube and the remainder will be in the abdominal cavity, the ovary, or the cervix. In the fallopian tube, about 80% of the pregnancies will occur in the ampullary region. Given these relative frequencies, this chapter deals largely with sites in the extrauterine fallopian tubes.
Risks These are blood loss and its consequences, implications for future reproductive performance (see later), and psychological effects of the loss of the pregnancy.
Diagnosis Symptoms Diagnosis of an ectopic pregnancy can be difficult. Some, all, or none of the following symptoms may be elicited in a woman presenting with an ectopic pregnancy:
T A B L E 5 – 4
Particular Risk Factors Associated with Ectopic Pregnancy Peak age-specific incidence 25–34 years Infertility (fourfold increased risk) Sexually transmitted disease (especially chlamydia) Raised Chlamydia antibody titer Tubal sterilization and reconstruction Intrauterine contraceptive device Endometriosis
Amenorrhea. Abdominal pain. Vaginal bleeding. Fainting. Shoulder tip pain.
Signs At presentation to an EPC, many women with an ectopic pregnancy may have few or no signs. Unilateral iliac fossa pain is more in keeping with ectopic pregnancy, but bilateral pain is not uncommon. Guarding, rigidity, and signs of peritonism may be elicited on abdominal palpation. Guarding may be reduced if the knees are drawn up to relax the abdominal muscles. On vaginal examination, it may be possible to elicit tenderness on the affected adnexal side by manipulating the cervix laterally (“cervical excitation”) or by direct adnexal palpation. Because the uterus moves in the opposite direction owing to rotation around the fulcrum of the transverse cervical ligaments, there is increased tension on the side where the ectopic pregnancy is sited. The uterus may be softer and even enlarged slightly in the presence of an ectopic pregnancy owing to the softening effect of increased levels of progesterone on the endometrium and myometrium. It is now rare in U.K. practice for women with an ectopic pregnancy to present with hypovolemic shock or in severe pain. The practical implications of this change in practice means that greater clinical acumen is required in managing those women presenting with pain and bleeding in early pregnancy.
Investigations The diagnosis of ectopic pregnancy needs to be differentiated from other causes of lower abdominal pain in a woman of reproductive years (see Table 5–1). Critical to the diagnosis of ectopic pregnancy are TVUS, and serum β-hCG, and to a lesser extent, serum progesterone. Confirmation of the diagnosis by laparoscopy is not always necessary. Laparoscopy is indeed not even the absolute answer, having a false-negative rate of 3% to 4% (being done too early) and a false-positive rate of 5% (owing to retrograde uterine bleeding).70 The complementary roles of TVUS and β-hCG measurements were discussed earlier. Serum progesterone is also considered to have a role in the differentiation of an ectopic pregnancy. Its use is not as widespread as β-hCG and TVUS. Serum progesterone concentrations well into the normal range for early pregnancy (>80 nmol/L) are associated with a high probability of the pregnancy being normal and intrauterine in site.31 Conversely, values lower than 15 nmol/L are highly likely (98%) to be associated with a nonviable pregnancy.71 Most ectopic pregnancies have progesterone concentrations between these values, making the test of little value at present for routine clinical practice. Algorithms have been devised with and without the use of serum progesterone and can be referred to and integrated into local practice guidelines if considered appropriate.24,72 Figure 5–4 shows an example of such a practical algorithm. The patient presenting acutely with obvious intraabdominal bleeding will be diagnosed without difficulty. The less acute clinical scenario in which a women presents
C HAPTER 5 • Bleeding and Pain in Early Pregnancy 65 ALGORITHM FOR THE MANAGEMENT OF A POSSIBLE EXTRA-UTERINE PREGNANCY, IN THE ABSENCE OF SUFFICIENT SYMPTOMS TO WARRANT SURGERY TV USS
Visualization of sac
Intra-uterine
Unless high risk of heterotopic, assume all well
Clearly extra-uterine
Tubal ectopic
Not seen
Site uncertain
Rescan in 2 days
Measure serum βhCG
Measure serum βhCG
hCG falling
hCG rising >1000 but 95th centile at 11-14
Karyotype/CVS
Abnormal
Normal
US at 16 weeks
Nuchal edema > 5 mm
Normal
20 week scan
Abnormal
Early detailed scan Echocardiography Genetic counseling
Normal
6.5 mm or greater.108,109 Another study of 6650 pregnancies undergoing NT screening reported that in chromosomally normal fetuses, the incidence of miscarriage or fetal death was 1.3% in those with NT below the 95th percentile, 1.2% for NT between the 95th and the 99th percentiles, and 12.3% for NT above the 99th percentile (3.5 mm).124 The authors concluded that once aneuploidy is ruled out, the risk of fetal mortality does not statistically increase until the NT reached 3.5 mm or above. The majority of fetuses that die do so by 20 weeks, progressing from the increased NT to severe hydrops fetalis. Chromosomally and structurally normal fetuses with history of thickened NT found to be alive and well at 20 weeks with no evidence of nuchal fold thickening or nonimmune hydrops are no longer considered at an increased risk for perinatal or long-term morbidity and mortality. The prevalence of neurodevelopmental delay in the group with normal findings on follow-up scans is 0.4%, but rises to 1.2% in those with persistent nuchal edema. Other studies report a 3.2% to 5.6% prevalence of residual neurodevelopmental delay in fetuses with increased NT thickness.125,126 Methodologic issues make it difficult to compare the prevalence of mental retardation in infants with increased NT measurements with the general population, which ranges from 0.5% to 2%.127 Etiologies include chromosomal abnormalities in 25% of cases and genetic syndromes in 7% to 10% of cases. Mental retardation is unexplained in 30% to 50% of cases,127 or less than 1% of the population. Children with an isolated NT measurement in utero of greater than 3.5 mm should be followed jointly by pediatricians and geneticists to allow enhanced prenatal counseling (Table 7–6).107,109,128,129 Elucidation and integration of these data are essential if the counseling is to be balanced. Otherwise, counseling may resemble this confusing statement: “The good news is that the karyotype is normal, and the bad news is the karyotype is normal.”128,129 Such uncertainty is potentially lethal, particularly when announced in the first trimester in countries in which pregnancy termination is an option at 14 weeks, but is challenged or forbidden at a later GA. The association between increased NT thickness and a wide range of structural abnormalities and genetic syndromes indicates the need for long-term follow-up of these children, even when they appear normal at birth. Hiippala and associates122 followed 50 chromosomally normal children 2.4 to 7.1 years of age who had NT thickness greater than 3 mm at 13 to 15 weeks’ gestation. Their growth was within normal limits, but 1 in 12 had a previously unrecognized cardiac defect. One child had Noonan’s syndrome, 1 had cleidocranial dysplasia, and a third had developmental delays and an undefined syndrome. Webbing was seen in the neck region of 2 children who were otherwise free of associated pathology.
Follow-up
FIGURE 7–11 Follow-up of fetuses with increased nuchal translucency and normal karyotype. CVS, chorionic villus sampling. (From Senat MV, De Keersmaecker B, Audibert F, et al: Pregnancy outcome in fetuses with increased nuchal translucency and normal karyotype. Prenat Diagn 2002;22:345–349.)
Nuchal Translucency in Multiple Pregnancies First-trimester NT thickness measurement in combination with maternal age is an efficient technique for trisomy 21 screening in multiple gestation. Sebire and coworkers130,131 reported that it has a performance comparable with that in singletons, although with a slightly higher false-positive
110 S ECTION TWO • Early Prenatal T A B L E 7 – 6
Outcome of Fetuses with Nuchal Translucency Greater than the 95th Percentile, Normal Karyotype, and Normal Findings on Examination at Birth NO. OF FETUSES
MEAN NT AT 11–14 WK (MM)
19 50 31
4.6 3.6 NA
18 mo (4–32 mo) 33.5 mo (7–75 mo) 23 mo (12–38 mo)
980
4.5
NA
Hiippala et al, 2001122
59
4.0
56 mo (29–85 mo)
15
Senat et al, 2002107
58
4.6
39 mo (12–72 mo)
7
STUDY Cha’ban et al, 1996129 Van Vugt et al, 1998125 Adekunle et al, 1999126 Souka et al, 2001109
MEAN POSTNATAL FOLLOW-UP (RANGE)
LOST TO FOLLOW-UP (%) 0 32 26 0
ADVERSE OUTCOME (N) 0 Various minor health problems, 5 (5/50; 10%) Developmental delay, 2; Noonan’s syndrome, 1 (3/23; 13%) 22 adverse outcomes including 4 with developmental delay (22/980; 2%) Noonan’s syndrome, 1; cleidocranial dysplasia, 1; unknown syndrome, 1; delayed speech and visuomotor disturbances, 2 (5/50; 10%) Developmental delay, 2; delay in walking, 1; stuttering, 1; torticolis, 1 (6/54; 11%)
NA, not applicable; NT, nuchal translucency. Adapted from Senat MV, De Keersmaecker B, Audibert F, et al: Pregnancy outcome in fetuses with increased nuchal translucency and normal karyotype. Prenat Diagn 2002;22:345–349.
rate. Fetus-specific risk estimation helps select the best invasive technique for diagnostic testing. In dichorionic multiples, the risk of aneuploidy depends on the number of fetuses, because each additional fetus proportionally increases the risk of aneuploidy per pregnancy. In monochorionic multiples, which are always monozygotic, the maternal age–related risk for chromosomal abnormalities is the same as in singleton pregnancies, and in the vast majority of cases, both fetuses are affected. The findings of a retrospective study of 769 monochorionic twin pregnancies suggests that effective screening for trisomy 21 is best provided by using the average of NT measured in the two fetuses. If the fetus with the smaller NT is considered, the detection rate of trisomy 21, for any given false-positive rate or risk cutoff, is substantially lower than using the average NT measured in the two fetuses.132 Moreover the false-positive rate of NT screening (13% per pregnancy) is higher than in dichorionic twins, because increased NT in at least one of the fetuses is an early manifestation of twintwin transfusion syndrome (TTTS; see next section for additional details).132
Increased Nuchal Translucency Measurement and Twin-Twin Transfusion Syndrome A NT measurement above the 95th percentile for CRL between 11 to 14 weeks is associated with a fourfold increase in the risk of severe TTTS in a study of 132 monochorionic twin pregnancies133 (see also Chapters 23 and 59). Another study of 287 monochorionic twin pregnancies, including 43 that developed severe TTTS at 16 to 24 weeks, reported that the NT was above the 95th percentile in at least one of the fetuses in 28% of the TTTS group at 11 to 13 + 6 weeks compared with 10% in the non-TTTS group.134 Although the positive predictive value of this screening test is low, it is important to follow these pregnancies closely for the early diagnosis of TTTS. A recent evaluation of 512 monochoronic twin pregnancies revealed that a NT discordance of 20% or more was found in about 25% of cases and that in this group, the risk of developing TTTS was more than 30%.135
NB
NT FIGURE 7–12 Ultrasound picture of a 12-week chromosomal fetus with normal nuchal translucency thickness and a present nasal bone. (From Nicolaides KH: Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45–67.)
Other Fetal Measurements as Markers for Fetal Aneuploidy Nasal Bones In the combined data from nine studies, the NB was absent in 176 of 12,652 (1.4%) chromosomally normal fetuses and in 274 of 397 (69.0%) fetuses with trisomy 21, yielding a likelihood ratio for absent NB of 49.3.136–144 The prevalence of absent NB (Fig. 7–12) reflects ethnicity (it is highest in individuals of African origin), NT thickness (it increases as the NT measurement increases), and the CRL measurement (it decreases with GA). Therefore, likelihood ratios for trisomy 21 must also be adjusted to account for these factors.137,138 Methodologic problems surrounding that part of the first-trimester scan can generate a high false-positive rate, together with significant interoperator and intraoperator variability.139
C HAPTER 7 • First-Trimester Screening for Fetal Abnormalities 111
Ductal Blood Flow A high proportion of fetuses with trisomy 21 and other chromosomal abnormalities have increased impedance to flow in the DV at 11–13 weeks’ gestation (Fig. 7–13). In combined data from seven studies, ductal blood flow with an absent or reversed a-wave was observed in 5.2% of euploid fetuses, and 70.8%, 89.3%, 81.8%, and 76.9% of fetuses with trisomies 21, 18, and 13 and Turner’s syndrome, respectively.145 In combined data from six studies, abnormal ductal flow was observed in 273 of 5462 (5.0%) chromosomally normal fetuses and in 108 of 131 (82.4%) fetuses with trisomy 21, and therefore the likelihood ratio for abnormal ductal flow was 16.5.146–151 There may be an association between increased fetal NT and the presence of abnormal ductal flow, but it appears weak. These findings suggest that Doppler evaluation of the DV flow can be combined with NT screening.149–151 Ductal flow measurement requires skilled operators because the interference from adjacent vessels is commonly encountered.
Blood Flow across the Tricuspid Valve Regurgitant flow across the tricuspid valve (TR), determined by pulsed wave Doppler, is a common finding in trisomy 21 fetuses at 11 + 0 to 13 + 6 weeks’ gestation (Fig. 7–14).152,153
A study performed by experienced fetal cardiologists revealed that the prevalence of TR in fetuses with trisomy 21 at this GA approximates 74% whereas only 7% of chromosomally normal fetuses have this finding.153 The prevalence of TR decreases with CRL in both normal and trisomic fetuses. In studies performed by the Fetal Medicine Foundation Center, TR was present in 72 of 1394 (5.2%) chromosomally normal fetuses and in 109 of 162 (67.3%) fetuses with trisomy 21.118 An additional benefit of this measurement is a high association between TR and cardiac defects, suggesting that the high prevalence of TR in the chromosomally abnormal fetuses can be partly attributed to the coincidence of cardiac defects.152 Like the DV examination, the assessment of tricuspid flow necessitates specialist training. It is questionable whether NB, abnormal ductal blood flow, and TR can be routinely combined with the other first-trimester sonographic and biochemical markers of chromosomal abnormalities to improve the performance of first-trimester screening. The complexity of the assessment of these procedures and the rigor required to maintain the skills, together with the potential for a subjective assessment, are limitations for their imple mentation as a one-step risk procedure performed at the time of NT measurement. However, these markers have the characteristics to be a second-line screening that can be performed in early pregnancy, resulting in a major reduction in the need for invasive testing. It is likely their use will grow in fetal medicine laboratories with added experience.
Other Markers of Aneuploidy
FIGURE 7–13 Reversed a-wave in the ductus venosus in a fetus with trisomy 21 at 12 weeks of gestation. (From Maiz N, Valencia C, Kagan KO, et al: Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 2009;33:512–517.)
FIGURE 7–14 Holosystolic regurgitation on pulsed Doppler examination of the tricuspid valve in a fetus at 12 weeks’ gestation. (From Huggon IC, DeFigueiredo DB, Allan LD: Tricuspid regurgitation in the diagnosis of chromosomal anomalies in the fetus at 11–14 weeks of gestation. Heart 2003;89:1071–1073.)
Several other measurements in the first trimester are more common in chromosomally abnormal fetuses than in the chromosomally normal population. A novel method for evaluating the relative position of the fetal maxilla with respect to the forehead was introduced in the first trimester to investigate the location of the front of the maxilla in relation to the forehead in fetuses with trisomy 21.154 A three-dimensional volume of the fetal head was obtained before karyotyping in 100 fetuses with trisomy 21 and 300 euploid fetuses. The frontomaxillary facial (FMF) angle (Fig. 7–15), defined as the angle between the upper surface of the upper palate and the frontal bone in a midsagittal view of the fetal face, was measured. The FMF angle was significantly larger in the trisomy 21 (mean 88.7 degrees, range 75.4–104 degrees) than in the euploid fetuses (mean 78.1 degrees, range 66.6–89.5 degrees). The FMF angle was more than 85 degrees in 69% of the trisomy 21 fetuses and in 5% of the euploid fetuses. There was no significant association between the FMF angle and the NT measurement. The authors postulate that measurement of FMF angle will be a useful adjunct in screening for trisomy 21. Unfortunately, it is more cumbersome to measure than all other sonographic markers. Other fetal measurements potentially affected in chromosomally abnormal fetuses include the fetal heart rate,155 maxillary length,156 ear length,157 femur length,158 and humeral length,158 and in general, fetal growth (see later). Even though statistical differences between trisomy 21 and euploid fetuses exist, the differences are small, limiting their clinical utility.1
112 S ECTION TWO • Early Prenatal
FIGURE 7–15 A, Frontomaxillary facial (FMF) angle in a chromosomally normal fetus. B, FMF angle in a trisomy 21 fetus.
A
(A and B, From Sonek J: First trimester ultrasonography in screening and detection of fetal anomalies [review]. Am J Med Genet C Semin Med Genet 2007;145C:45–61.)
B
T A B L E 7 – 7
Central Nervous System Defects
Most Common Structural Defects Diagnosed Prenatally during Screening at 11 to 14 Weeks
The development of the fetal central nervous system is not completed at the end of the first trimester and the anomalies reported differ from those described later in pregnancy. In first-trimester studies, the vast majority of defects described are lethal or severe major structural anomalies. Empty or enlarged brain cavities or abnormal contours of the head and spine are important diagnostic markers for the detection of central nervous system anomalies in the very early pregnancy.48
Atrioventricular septal defects and hypoplastic left heart syndrome Acrania and alobar holoprosencephaly Omphalocele and gastroschisis Megacystis Lethal skeletal defects
ACRANIA, EXENCEPHALY, AND ANENCEPHALY
Ultrasound Diagnosis of Fetal Abnormalities The majority (80%) of common fetal malformations develop before 12 weeks’ gestation; therefore, a good visualization of the fetus at this stage should be able to detect these malformations. Most fetal structures can be seen at 12 to 13 weeks, and this GA offers the earliest opportunity for screening for fetal abnormalities. Though the available reports of detection rates in the first trimester for fetal structural defects other than those associated with increased NT thickness are confined mostly to high risk or selected populations (Table 7–7),159–162 there is increasing evidence that early detailed ultrasonography is technically feasible as a screening test for fetal structural defects in low risk pregnancies.162 The most frequently detected first-trimester anomalies involve the central nervous system, such as anencephaly, encephalocele, and holoprosencephaly.163 Lethal, incurable, or curable severe abnormalities with a high risk of residual handicap are defined as major structural abnormalities. The diagnosis of spina bifida is a challenge because the indirect sonographic signs that are characteristic later in gestation are usually missing prior to 14 weeks.89 Omphalocoele, gastroschisis, and megacystis are also commonly diagnosed in the first trimester. There are case reports of the first-trimester diagnosis of a wide range of severe skeletal defects (see Fig. 7–5). The remaining cases of less severe or benign abnormalities, of no cosmetic or functional significance, constitute the group of minor structural abnormalities. A review44 analyzed several studies reporting firsttrimester detection rates that are comparable with those achieved in the routine second-trimester anatomic survey at 18 to 22 weeks (Table 7–8).159,162,164–183
Anencephaly can be diagnosed reliably on routine 11- to 14-week ultrasound examination. Acrania is the main feature of anencephaly in the first trimester. Fetuses with acrania may have a normal brain or one that shows varying degrees of disruption.184,185 In one large, multicenter study, screening for fetal abnormalities was performed in 53,435 singleton and 901 twin pregnancies. Eight of the 47 fetuses with anencephaly were missed.185 The sonographers were then instructed to look specifically for the cranial vault and at brain organization. All subsequent cases of anencephaly were identified at the 11- to 14-week scan.
ENCEPHALOCELE Encephalocele appears as a bony defect in the skull, with brain tissue protruding. It is associated with Meckel-Gruber syndrome.186,187 In most cases, the lesion arises midline in the occipital area. The main alternative diagnosis is cystic hygroma. Once the diagnosis is suspected, the prognosis usually cannot be ascertained before the late second trimester.
HOLOPROSENCEPHALY Holoprosencephaly results from incomplete cleavage of the forebrain. The most severe forms, alobar and semilobar, are amenable to first-trimester ultrasound diagnosis. They are characterized by a monoventricular cavity and fusion of the thalami. One study suggests that failure to identify both choroid plexuses (the “butterfly” sign) is a first-trimester warning sign of holoprosencephaly.188 These forms are often associated with facial abnormalities.189,190 The most common related chromosome abnormality is trisomy 13.
C HAPTER 7 • First-Trimester Screening for Fetal Abnormalities 113 T A B L E 7 – 8
Detection Rates of First-Trimester and Second-Trimester Ultrasound Screening for Fetal Structural Malformations AUTHOR
YEAR 164
Achiron and Tadmor Yagel et al159 Hernandi and Töröcsik165 Economides and Braithwaite166 D’Ottavio et al167 Whitlow et al168 Guariglia and Rosati169 Drysdale et al170 Den Hollander et al171 Carvalho et al172 Taipale et al162 Chen et al173 Taipale et al174 Markov et al175 McAuliffe et al176 Becker and Wegner177 Souka et al178 Saltvedt et al179 Cedergan and Selbing180 Weiner et al181 Dane et al182 Chen et al183
BASELINE RISK OF STUDY POPULATION
ULTRASOUND MODALITY (TAS/TVS)
GESTATIONAL AGE (WK)
N
N (%) OF MAJOR MALFORMATIONS
FIRST-TRIMESTER SENSITIVITY (%)
SECONDTRIMESTER SENSITIVITY (%)
1991 1995 1997 1998
Low High Low Low
Both TVS Both Both
9–13 13–16 11 0/7–14 6/7 12 0/7–13 6/7
800 536 3991 1632
15 (1.9) 50 (9.3) 64 (1.6) 17 (1.0)
57 84 55 65
93 89 69 82
1997 1999 2000 2002 2002 2002 2003 2004 2004 2004 2005 2006 2006 2006 2006 2007 2007 2008
Low Low Low Low High Low Low High Low N/A Low Medium Low Low Low Low Low Low
TVS Both TVS NR Both Both Both Both TVS NR Both Both Both TAS TAS Both Both Both
14 11 0/7–14 6/7 10–16 12 0/7–13 6/7 11–14 11–14 13–14 12 0/7–14 6/7 13–14 11 0/7–14 6/7 11 0/7–13 6/7 11 0/7–13 6/7 11 0/7–14 6/7 11–14 11–14 10 2/7–13 4/7 11–14 10–14 6/7
4078 6634 3478 984 101 2853 20,465 1609 4855 1135 325 3094 1148 39,572 2708 1723 1290 4282
88 (2.2) 92 (1.4) 64 (1.8) 31 (3.1) 11 (11) 66 (2.3) 307 (1.5) 26 (1.6) 33 (0.7) 53 (4.6) 6 (1.8) 86 (2.8) 14 (1.2) 1,252 (3.5) 32 (1.2) 22 (1.3) 24 (1.9) 63 (1.5)
61 59 52 16 82 38 52 54 18 22 17 84 50 38 40 41 71 48
89 81 84 NR 100 79 NR 77 48 69 83 91 93 47 NR 100 95 66
N/A, not applicable; NR, data not available; TAS, transabdominal scan; TVS, transvaginal scan. From Timor-Tritsch IE, Fuchs KM, Monteagudo A, D’Alton ME: Performing a fetal anatomy scan at the time of first-trimester screening. Obstet Gynecol 2009;113:402–407.
Different authors have used the 3DUS “inversion rendering” mode to described abnormal brains.51 Inversion rendering of early fetal brain ventricles is feasible and should be attempted if additional information is needed.191
SPINA BIFIDA The sonographic diagnosis of spina bifida aperta is difficult prior to 14 weeks. The diagnosis of hydrocephaly is also difficult to establish in the first trimester because of the large relative proportions of the lateral ventricles to the calvarium. Therefore, in the absence of cranial signs in the first trimester, the sensitivity of detection of spina bifida is unlikely to be as high as in second-trimester scanning. At this early gestation, indirect signs, such as sacral irregularities, the lemon (frontal bone scalloping) and banana signs (abnormal curvature of the cerebellar hemispheres), are usually absent.163,192 Other signs, such as a flattened occiput, parallel peduncles, a straight metencephalon, and the acorn sign (frontal bone narrowing), are not consistently present.163,192 Blaas and colleagues193 studied high risk pregnancies prospectively and identified three first-trimester fetuses with lumbosacral myelomeningocele characterized by an irregularity in the caudal part of the spine before 10 weeks. 3DUS examination might be helpful but is not necessary to make the diagnosis.
Heart Defects See the detailed discussion of NT thickness of greater than 3.5 mm and heart defects, earlier. The prevalence of major cardiac defects increases with NT thickness, from 5.4 per 1000 with an NT measurement of 2.5 to 3.4 mm, to 233 per 1000 with an NT measurement of greater than 5.5 mm. The sensitivity of NT is 15% to 56% for the diagnosis of major cardiac defects.102,110–112 Early fetal echocardiography is recommended and can be performed reliably by trained operators from 14 weeks onward.58,59,194 Care should be taken not to extrapolate the results of these studies to low risk populations.
Omphalocoele Reduction of the physiologic midgut hernia ends by 11 weeks and 5 days.195 An abdominal defect, especially omphalocoele, should be suspected if the herniation continues after 12 weeks. This defect is sporadic, having a birth prevalence of approximately 1 in 4000. Omphalocele is commonly associated with other abnormalities such as aneuploidy, most commonly trisomy 18.196 Because trisomy 18 has such a high rate of mortality, its association with an omphalocele decreases significantly with GA: 61% at 11 to 13 + 6 weeks’ gestation, 30% in the second trimester,
114 S ECTION TWO • Early Prenatal
and 15% at term.197 There are many reports of first-trimester ultrasound diagnosis of omphalocele,196,198 gastroschisis as well as body stalk anomaly, pentalogy of Cantrell, and ectopia cordis.44
Megacystis Megacystis is defined as a bladder with a longitudinal diameter of 7 mm or more at 10 to 14 weeks’ gestation. It is found in approximately 1 in 1500 pregnancies.67 One study of 145 fetuses with megacystis observed a 25% aneuploidy rate, mainly trisomies 13 and 18.199 In 75% of fetuses with chromosomal abnormalities, the NT was also increased, possibly the result of thoracic compression. Ninety percent of chromosomally normal fetuses had spontaneous resolution, with no obvious adverse effects on the development of the urinary system. The risk of a chromosomal abnormality when the longitudinal diameter is more than 15 mm is actually lower, approximately 11%.200 Here, there is a strong association with progressive obstructive uropathy.199 Favre and associates200 reported a high prevalence of aneuploidy in fetuses with megacystis and a longitudinal diameter of 9 to 15 mm. Parents can usually be reassured when the megacystis is between 7 and 15 mm and the karyotype is normal that 90% of abnormalities will resolve and renal function will be normal. Vesicoamniotic shunting in midgestation has no benefit and there is no experience with first-trimester decompression.201 It is interesting to note that megacystis is associated with an increased NT regardless of the karyotype.199
Renal Anomalies Bilateral renal agenesis, hydronephrosis, and multicystic dysplastic kidney have been diagnosed by ultrasound in the first trimester.165,202,203
Skeletal Defects Skeletal dysplasias complicate approximately 1 in 4000 births. Twenty-five percent of affected fetuses are stillborn, and 30% die in the neonatal period. In some skeletal dysplasias, growth impairment is not apparent until later in gestation. However, first-trimester diagnosis of isolated cases has been reported, mainly because they were associated with an increased NT.204,205
Two-Vessel Cord The finding of a two-vessel cord in the first trimester is not associated with an increased prevalence of trisomy 21, but it increases the risk of trisomy 18 approximately sevenfold.206
Variation in First-Trimester Growth First-trimester growth in normal pregnancy is influenced by maternal and fetal factors. Early fetal growth restriction is demonstrable in many pregnancies that subsequently end as a first-trimester loss. However, slow growth occurs prior to miscarriage in both chromosomally normal and abnormal pregnancies. Serial growth assessment of ongoing viable pregnancies and those that subsequently fail suggests that whereas they have significantly different growth rates, those that miscarry also fall broadly into two groups: those that have antecedent growth restriction and those that do not.33 It is potentially easy to overlook early growth delay by misdating an abnormal pregnancy.207 The
assessment of growth restriction in the first trimester using the cross-sectional studies described relies on an accurate recall of menstrual age and a regular menstrual cycle so that expected fetal size can be calculated. Functional linear discriminant analysis (FLDA) using serial measurements of CRL or MSD was found to differentiate normal from abnormal early pregnancy growth, predicting a spontaneous loss with a sensitivity of 60.7% and a specificity of 93.1%.32 In contrast, a single CRL more than 2 SD below expected has a sensitivity of only 53.6% and a specificity of 72.2%.33 In pregnancies that continue, various studies have shown some chromosomal abnormalities such as trisomy 18 as well as triploidies,207 but not trisomy 21, trisomy 13, monosomy X (Turner’s syndrome), or sex chromosome triploidies208 are associated with poor growth. The spectrum of aneuploidy associated with growth restriction and first-trimester miscarriage includes a wider range of trisomies, commonly 7, 16, and 22.209 Several studies document that slow growth in the first trimester (absent chromosomal abnormality or miscarriage) is associated with adverse late pregnancy outcomes.23 Smith and coworkers210 reviewed 30,000 pregnancies and concluded that a CRL 2 to 6 days smaller than expected is associated with an increased risk (compared with a normal or slightly larger than expected CRL) of a birth weight less than 2500 g (relative risk [RR] 1.8), a birth weight less than 2500 g at term (RR 2.3), a birth weight below the 5th percentile for GA (RR 3.0), and delivery between 24 and 32 weeks’ gestation (RR 2.1). In a prospective study of 976 assisted reproduction pregnancies, increased size for gestation in the first trimester was associated with higher birth weight, with the risk of of a small-for-GA newborn diminishing with increasing first-trimester embryonic/fetal size.34 Thus, adverse outcomes in late pregnancy may at least in part be predicted by early pregnancy growth assessment using ultrasound.23
Variation in Growth in Twin Pregnancies Twins provide a particularly useful model for assessing firsttrimester growth. In cases in which there is a discrepancy in size between the two embryos or fetuses, the normally growing twin can be used as a control for the other. The incidence and significance of early intertwin growth discrepancy are controversial. In a study of 182 twin pregnancies (20 monochorionic and 162 dichorionic),207 the authors observed that up to 95% of twins show discordance in CRL of up to 9.8 mm at 11 to 14 weeks, but there was no indication for further investigation should the fetal anatomy appear normal. In such cases, it may be more appropriate to date the pregnancy based on the smaller twin. Moreover, the risk of significant weight difference or poor outcome is not increased and discrepancy may simply reflect different growth patterns of two normal fetuses. In contrast, a discrepancy in the CRL greatly exceeding the 95th percentile is likely to reflect major growth delay in one twin, which is often aneuploid, and thus has the same significance as that in singletons.207 In another large study of 200 monochorionic diamniotic twin gestations, the authors concluded that those who ultimately develop TTTS (see also Chapters 23 and 59) can exhibit intertwin differences in growth as early as 11 to 14 weeks.211 The earlier the discordance, the earlier the manifestation of TTTS.211
C HAPTER 7 • First-Trimester Screening for Fetal Abnormalities 115
Three-Dimensional Ultrasound 3DUS is increasingly being used in obstetric practice. The method offers several advantages during the first trimester because it allows visualization of planes that are otherwise difficult to obtain with two-dimensional scanning (2DUS). It could potentially minimize scan time and provides an excellent way to store scanned data for later study. However, no randomized controlled trials of 3DUS versus 2DUS have been published, and the benefits of 3DUS scanning remain speculative. If the 2DUS images are of poor quality, the resulting 3DUS images will be of little clinical use. As shown by Michailidis and colleagues,124 2DUS seems the best way to examine the first-trimester fetal anatomy. In some 94% of cases, a complete anatomic survey can be achieved with 2DUS. However, the examination was adequate in only 81% of cases with 3DUS (P < .001). Several feasibility studies of NT measurement with 3DUS have been conducted.212–215 Theoretically, an NT measurement could be performed regardless of the fetal position, significantly shortening examination time. Moreover, tomographic examination of the three-orthogonal sectional images should make it easy to distinguish fetal skin from the amnion. Paul and associates212 concluded that reslicing of stored 3D volumes can be used to replicate NT measurements, but only if the nuchal skin is clearly seen on the 2DUS. When the fetus is lying in a position that precludes clear visualization of the nuchal area, 3DUS is unlikely to help.212 Whereas Paul and associates212 could repeat the NT measurement in only 60% using a 3D random volume, a number of other studies using 2D and 3D sonography for the measurement of NT show a good correlation between these two techniques at any position. Moreover, several investigators have observed benefit combining 3D with 2D scanning in the form of decreased acquisition time and an improvement in image resolution.124,213–218 As a result, some authors have suggested 3DUS may be useful in scanning fetuses in a suboptimal position.218,219 Chung and coworkers215 and, more recently, Shaw and colleagues219 demonstrated in pilot studies that the acquisition of 3D volumes can be a most effective and reproducible method of measuring NT. 3DUS also minimized scanning time and provided views not easily obtained using the strict NT guidelines.219
MATERNAL SERUM MARKERS AT 11 TO 14 WEEKS Median serum concentrations of α-fetoprotein, estriol, and β-hCG (total and free) are independent of maternal age and can be combined in the second trimester to refine the risk of trisomy 21. This testing allows for the identification of approximately 60% of fetuses with trisomy 21 (compared with 30% based on maternal age alone) with a 5% invasive testing rate.99,220 Free β-hCG is even more discriminant in the first trimester (11–14 wk), and when combined with PAPP-A and maternal age, it provides an estimated detection rate of 60%, with a 5% invasive testing rate.221
Free β-Human Chorionic Gonadotropin The maternal serum concentration of free β-hCG is higher in fetuses with trisomy 21 than in chromosomally normal
fetuses. The MoM in pregnacies affected with trisomy 21 is approximately 2. First-trimester measurement of free β-hCG alone allows for the detection of 35% of fetuses with trisomy 21, with a 5% invasive testing rate. The detection rate is increased to 45% if the findings are integrated with maternal age.221 The maternal serum free β-hCG level is decreased if the fetus has trisomy 13 or 18.222,223 It is usually normal in women whose fetus has a sex chromosomal abnormality.224
Pregnancy-Associated Plasma Protein A The PAPP-A level increases with gestation and is lower in pregnancies in which the fetus is affected with trisomy 21. The median value in trisomy 21 is approximately 0.5 MoM. When used alone in the first trimester, PAPP-A allows for the detection of 40% of fetuses with trisomy 21, with a 5% invasive testing rate. The detection rate increases to 50% when the findings are integrated with maternal age.221 The maternal serum PAPP-A level is also decreased if the fetus has trisomy 13 or 18 or sex chromosomal abnormalities.222–224
Free β-Human Chorionic Gonadotropin and Pregnancy-Associated Plasma Protein A When maternal age is combined with first-trimester maternal serum PAPP-A and free β-hCG levels, the estimated detection rate for trisomy 21 approximates 60%, with a 5% invasive testing rate.221,225,226 These rates are similar to those obtained in the second trimester. Screening with a combination of fetal NT measurement and maternal levels of serum PAPP-A and free β-hCG allows the detection of approximately 90% of these chromosomal abnormalities, with a 5% invasive testing rate (Table 7–9).1,227–235
T A B L E 7 – 9
Detection and False-Positive Rates of Screening Tests for Trisomy 21 DETECTION RATE (%)
FALSE-POSITIVE RATE (%)
30 (or 50) 60
5 (or 15) 5
75 (or 70) 90 90 (or 80)
5 (or 2) 5 5 (or 2)
MA + fetal NT + NB + serum β-hCG + PAPP-A at 11–14 wk MA + serum biochemistry at 15–18 wk Ultrasound for fetal defects and markers at 16–23 wk
97 (or 95)
5 (or 2)
60–70 75
5 10–15
MA + serum β-hCG + PAPP-A at 11–14 wk ± DV, TR, NB (individual risk-oriented two-stage)
90
2–3
SCREENING TEST MA MA + serum β-hCG + PAPP-A at 11–14 wk MA + fetal NT at 11–14 wk MA + fetal NT + NB at 11–14 wk MA + fetal NT + serum β-hCG + PAPP-A at 11–14 wk
β-hCG, β-human chorionic gonadotropin; DV, ductus venosus; MA, maternal age; NB, nasal bone; NT, nuchal translucency; PAPP-A, pregnancy-associated plasma protein-A; TR, tricuspid regurgitation.
116 S ECTION TWO • Early Prenatal
Logistic and Organizational Issues There is no significant relationship between the NT measurement and the maternal serum free β-hCG or PAPP-A levels whether or not the pregnancy is affected by aneuploidy. Therefore, ultrasonographic and biochemical markers can be combined in the first trimester to provide more effective screening than either method individually. The same is true for NT measurement and second-trimester biochemical markers.236 Many European countries have adopted first-trimester screening for chromosomal abnormalities with a combination of ultrasound NT measurement and maternal serum testing.237,238 In 1997, the 32nd Study Group of the Royal College of Obstetricians and Gynaecologists concluded that the evidence in favor of first-trimester screening for trisomy 21 by NT measurement or biochemical testing was sufficiently well developed to justify moving out of the research phase and into routine practice. They also concluded that ultrasound in early pregnancy is superior to biochemical screening in the second trimester. Several large studies support these conclusions.98,237–241 Spencer and associates242 studied 12,339 women with singleton pregnancies who were screened by the measurement of NT and maternal serum markers at 11 to 14 weeks in a one-stop clinic for assessment of risk (OSCAR).242 These authors too concluded it was time to shift the screening for trisomy 21 from the second to the first trimester.242
Fetal Nuchal Translucency Measurement and Maternal Serum Free β-Human Chorionic Gonadotropin and Pregnancy-Associated Plasma Protein A (Combined Screening Test) Spencer and coworkers235 concluded that the most effective method of screening for trisomy 21 was achieved by a combination of maternal age, fetal NT, and maternal serum free β-hCG and PAPP-A concentrations at 11 + 0 to 13 + 6
weeks’ gestation. The detection rate for trisomy 21 was 92% (23 of 25) for a 5% screen-positive rate, a rate far superior to that achieved with maternal age alone (30%) or by maternal age and second-trimester serum biochemistry (65%). This combined method for first-trimester screening also identified 94% of all other major chromosomal defects, such as trisomies 13 and 18, triploidy, and Turner’s syndrome, and 60% of other chromosomal defects, such as deletions, partial trisomies, unbalanced translocations, and sex chromosomal aneuploidy other than Turner’s syndrome.98 Wapner and colleagues240 achieved similar results in a prospective study of 8514 patients (detection rate 78.7%, 5% screen-positive rate) (Table 7–10). In twin pregnancies, the combination of first-trimester NT and maternal serum biochemistry is less effective than in singleton pregnancies because placental products from the normal twin can mask the abnormal levels of the affected twin. Further, an abnormal result cannot distinguish which twin is affected.243 As consequence, the combination of first-trimester NT and maternal serum biochemistry is less effective than in singleton pregnancies and not at present recommended. NT screening alone, however, provides similar detection and false-positive rates in multiples as in singleton pregnancies. There may be new options in the future. The authors of one large study concluded that twin pregnancy screening requires an adjustment of the calculated MoM to account for the presence of two fetuses. In general, this should be by dividing the observed corrected MoM by 2.023 for free β-HCG. Two different correction factors are required for PAPP-A, 2.192 in dichorionic twins and 1.788 in monochorionic twins.244 Further, the distribuition of PAPP-A in monochorionic twins is lower than in dichorionic twins, as previously suggested.245 Such corrections require an accurate diagnosis of chorionicity. Alternative strategies have been proposed246 that use estimated distributions of markers in twins rather than making correction for twins and the calculation of a singleton equivalent or pseudorisk. The problem with this approach is the sparse data available to determine the distribution of markers in twins concordant or discordant for trisomy 21.
T A B L E 7 – 1 0
Major Prospective and Retrospective Studies that Used a Combination of Maternal Age, Fetal Nuchal Translucency, Maternal Serum Pregnancy-Associated Plasma Protein A, and Free β-Human Chorionic Gonadotropin to Detect Down Syndrome STUDY Orlandi et al, 1997227 De Biasio et al, 1999231 Spencer et al, 1999221 Krantz et al, 2000228 Hafner et al, 2001232 Niemimaa et al, 2001230 Bindra et al, 2002234 Von Kaisenberg et al, 2002229 Crossley et al, 2002233 Spencer et al, 2003235
N 744 1467 1156 5809 3316 1602 15,030 3864 12,560 12,339
PREVALENCE OF TRISOMY 21 (%) 0.9 0.9 18 0.8 0.3 0.3 0.5 0.5 0.2 0.2
GESTATION (WK) 9–13.4 10–13+6 10–14 9–13+6 10–13 11–14 11–14 10–14 10–14
FALSE-POSITIVE RATE (%)
DETECTION RATE FOR TRISOMY 21 (%)
5 3.3 5 5 4.1 5 5 6.6 5 5.2
87 85 89 91 90 80 90.2 84.2 82 92
C HAPTER 7 • First-Trimester Screening for Fetal Abnormalities 117
Individual Risk-Oriented Two-Stage First-Trimester Screening Studies from fetal medicine centers demonstrate that in addition to NT, other highly sensitive and specific firsttrimester sonographic markers of trisomy 21 can be used to enhance screening. They include the absence of the NB and increased impedance to flow in the DV and TR.136,143,152 The addition of these new ultrasound markers to the combined screen (NT and free β-hCG and PAPP-A) requires a sufficient degree of independence among the markers, and this has been shown for NB,137 TR,147 and DV.151 A prospective study of more than 75,000 pregnancies examined the potential impact of a new individual risk-oriented two-stage approach to screening.118 After undergoing combined fetal NT and maternal serum free β-hCG and PAPP-A screening, patients were assigned to either a high risk category with a risk estimate of 1 in 100 or more, a low-risk category with a risk estimate of less than 1 in 1000, or an intermediate-risk category with a risk estimate of between 1 in 101 and 1 in 1000. Those in the intermediate-risk category had further assessment of risk by first-trimester ultrasound to determine the presence/absence of the NB, normal/abnormal Doppler velocity waveform in the DV, or the presence/absence of TR. Chorionic villus sampling was offered if their adjusted risk became 1 in 100 or more.118 The results of this study demonstrate that individual risk-oriented two-stage screening for trisomy 21 can potentially identify in the first trimester of pregnancy more than 90% of affected fetuses with a screen-positive rate of 2% to 3%. However, the accurate examination for these markers is time-consuming and requires skilled operators. Although it is unlikely this assessment will be incorporated into the routine first-trimester scan, it is likely to be used in fetal medicine centers across the board or to evaluate the risk in patients with intermediate risk after screening by fetal NT and maternal serum biochemistry.
FETAL NUCHAL TRANSLUCENCY MEASUREMENT AND MATERNAL SERUM MARKERS AT 14 TO 17 WEEKS Sonographic and biochemical screening methods evolved independently. As a result, many women undergo sequential two-stage screening, even if the NT screen result is negative. Each method is designed to generate a 5% invasive testing rate, and the two-stage screening paradigm has a cumulative rate. Thus, the proportion of patients undergoing invasive prenatal diagnostic testing can be as high as 10%, or even higher in countries that offer invasive prenatal diagnosis to women older than 35 years, regardless of the screening result. This illogical approach increases the iatrogenic loss rate of normal pregnancies and all related costs. The rate of invasive testing for fetal karyotyping is indeed an important public health issue that must be controlled. When the combined first-trimester test is not available, one approach is to combine NT measurement and second-trimester maternal serum screening into a single risk assessment and not to consider the results independently (integrated screening) (Table 7–11).236 At least in that instance, the screen-positive rate remains around 5%.
T A B L E 7 – 1 1
Definitions TERM Combined screening Fully integrated screening
Serum integrated screening Sequential screening Individual risk-oriented two-stage first-trimester screening
DEFINITION Nuchal translucency measurement + first-trimester serum markers Nuchal translucency measurement + first-trimester serum markers + second-trimester serum markers Pregnancy-associated plasma protein-A + second-trimester serum markers Successive independent risk assessments, leading to cumulative false-positive rates Nuchal translucency measurement + first-trimester serum markers ± NB, DV, TR
DV, ductus venosus; NB, nasal bone; TR, tricuspid regurgitation.
In women undergoing second-trimester biochemical testing after first-trimester NT screening (with or without maternal serum testing), the background risk must be adjusted to take into account the first-trimester screening results. Otherwise, it should not be done. For example, a 41-year-old woman whose age-related background risk of having a fetus with trisomy 21 is 1 in 50 has reduced risk (e.g., 1 in 200) after a thin NT. If the risk then after secondtrimester screening with serum markers is 1 in 100, this woman has an integrated risk of 1 in 400 because the NT measurement allowed a fourfold reduction of the background risk and maternal serum testing has done so by twofold. Use of both tests, therefore, divided the background risk by 8. Because first-trimester combined screen can identify almost 90% of pregnancies affected by trisomy 21, second-trimester serum testing identifies, at best, an additional 6% of affected pregnancies (60% of the residual 10%), but doubles the overall invasive testing rate from 5% to 10%. It is theoretically possible to use various statistical techniques to combine NT measurement with different components of first- and second-trimester serum testing.133 One hypothetical model combines the first-trimester NT measurement and PAPP-A testing with second-trimester free β-hCG, estriol, and inhibin A testing (fully integrated test), claiming a potential sensitivity of 90%, for a 5% falsepositive rate.241 This offers no advantage over comprehensive first-trimester screening. In a multicenter interventional study,236 NT was measured at 12 to 14 weeks’ gestation in 9444 women. Maternal serum markers were measured between 14 weeks and 1 day and 17 weeks’ gestation. Karyotyping was delayed until after maternal blood was obtained. A combined risk for NT measurement and maternal serum markers was estimated retrospectively. The invasive testing rate generated by sequential two-stage screening was 8.6%, which means that 8.6% of patients underwent amniocentesis because of an increased risk generated by any of these tests. Twenty-one fetuses (0.22%) had trisomy 21. Adjusting for a 5% invasive testing rate, the detection rates would have been 55% and 80% for NT measurement alone and NT measurement combined with second-trimester serum marker testing, respectively. The results of the study suggest a 25% increase in the
118 S ECTION TWO • Early Prenatal
detection rate with a combination of NT measurement at 12 to 14 weeks and serum marker studies between 14 weeks and 1 day and 17 weeks, with a 5% invasive testing rate and a modest increase in cost. Four other studies reported screening with a combination of fetal NT measurement in the first trimester and maternal serum marker testing in the second trimester, with similar results.236–239 Sequential (but not integrated) screening programs also increase the invasive procedure–related pregnancy loss rate. This increased rate is an important issue in populations in which the prevalence of Down syndrome is less than 1 in 1000 births. In these populations, an invasive testing rate of 8.6% might be considered unacceptably high in women who are at relatively low risk,236 compared with the 5% rate
generated by a single-test screening program. A single risk assessment that integrates the results of NT measurement, free β-hCG levels, and α-fetoprotein levels with maternal age is possible. Here, it would be possible to keep the sensitivity as high as that obtained with combined screening while maintaining an invasive testing rate as low as 5%. However, the cost is also significant because the 25% increase in the detection rate would delay risk calculation and invasive testing by 2 to 4 weeks. Such information should be included in genetic counseling, especially when termination for fetal abnormality is an issue. Further, screening strategies in the first trimester are cost-effective compared with the use of second-trimester biochemical markers.236
SUMMARY OF MANAGEMENT OPTIONS
First-Trimester Screening for Fetal Abnormalities Management Options
Evidence Quality and Recommendation
References
General Approach Prerequisites:
See also Chapter 4
Details of the history, examination, and routine tests completed and known relevant risk factors identified
●
Prescan interview, discussions, and counseling
●
Screening is performed ideally between 11 and 14 wk.
III/B
235
Ultrasound is considered safe in both the short and the long terms.
Ib/A
243
Confirm viability.
III/B
7,10
Dating the pregnancy by crown-rump length before 14 wk is the most accurate method and decreases the risk of post-term pregnancy.
III
22,24–28, 207
NT measurement, combined with maternal age and maternal serum markers for trisomy 21, has a detection rate of 80%–90%, for a 5% false-positive rate.
IIa/B
235,236
Other chromosomal abnormalities are also more likely with increased NT thickness.
III/B
103–106
Some major structural anomalies are detectable as early as 12 wk. These include anencephaly, holoprosencephaly, abdominal wall defects, and major limb defects.
IIb/B
71,109,113
Detection rates are dependent on sonographer experience.
III/B
162
Chorionicity is optimally determined by either visualization or absence of the lambda sign.
III/B
40
●
Twin–twin transfusion syndrome is more likely in monochorionic pregnancies with increased NT thickness.
III/B
133
Examine the uterus and adnexal structures.
GPP
First-Trimester Screening—Benefits
Screening for fetal aneuploidy: ●
●
Detection of structural abnormalities: ●
●
Multiple pregnancy: ●
GPP, good practice point; NT, nuchal translucency.
C HAPTER 7 • First-Trimester Screening for Fetal Abnormalities 119
SUGGESTED READINGS Bottomley C, Bourne T: Dating and growth in the first trimester. Best Pract Res Clin Obstet Gynaecol 2009;23:439–452. Cicero S, Rembouskos G, Vandecruys H, et al: Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11–14-week scan. Ultrasound Obstet Gynecol 2004;23:218–223. Nicolaides KH: Screening for chromosomal defects. Ultrasound Obstet Gynecol 2003;21:313–321. Nicolaides KH, Spencer K, Avgidou K, et al: Multicenter study of first trimester screening for trisomy 21 in 75,821 pregnancies: Results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221–226. Senat MV, De Keersmaecker B, Audibert F, et al: Pregnancy outcome in fetuses with increased nuchal translucency and normal karyotype. Prenat Diagn 2002;22:345–349.
Snijders RJM, Noble P, Sebire N, et al: UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Lancet 1998;351:343–346. Spencer K, Spencer CE, Power M, et al: Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: A review of three years prospective experience. BJOG 2003;110:281–286. Timor-Tritsch IE, Fuchs KM, Monteagudo A, D’Alton ME: Performing a fetal anatomy scan at the time of first-trimester screening. Obstet Gynecol 2009;113:402–407.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 8
Second-Trimester Screening for Fetal Abnormalities LAMI YEO and ANTHONY M. VINTZILEOS Videos corresponding to this chapter are available online at www.expertconsult.com.
INTRODUCTION Every pregnant woman desires a healthy child who is free of anomalies. In the general population, the overall risk of having a child with a major malformation is 3% to 5%. As a greater proportion of women delay childbirth, the shortened reproductive window has increased the pressure on all for a successful outcome and rendered the increasing sophistication of ultrasonography and biochemical testing for fetal abnormalities of growing importance to obstetricians and their patients. We find that genetic sonography is a patientdriven service. This chapter focuses on noninvasive modalities of screening for fetal abnormalities in the second trimester. In the early 1970s, the only method available to screen for fetal Down syndrome was based on maternal age; amniocentesis was offered to all women above a certain age, typically 35 years or older. However, maternal age proved a very inefficient screening tool with less than one third of fetuses with trisomy 21 identified by this means. In the 1980s, a new screening method incorporated second-trimester maternal serum biochemical markers in addition to maternal age. In the 1990s, screening for Down syndrome by combining maternal age and fetal nuchal translucency (NT) thickness in the first trimester was introduced (see Chapter 7). Subsequently, maternal serum biochemical markers of value in the first trimester were identified. In the recent past, threedimensional sonography entered the arena of screening. Invasive tests, such as amniocentesis, chorionic villus sampling, and cordocentesis, are diagnostic tools and not screening tests. They allow for essentially 100% accuracy in the diagnosis of fetal aneuploidy but carry a real risk of pregnancy loss. Thus, many women choose biochemical and ultrasound screening modalities for aneuploidy detection because the test efficiency (percentage of abnormal fetuses identified) is so much higher than that based on maternal age alone, even though they have a relatively high invasive testing rate (the so-called false-positive rate), typically set at 5%. Based on the result of the screening test, a decision is made as to whether an invasive test for diagnosis is indicated and acceptable to the patient. The combination of screening and diagnostic tests allows the maximum number of women to gain accurate information about their individual risk status.
SECOND-TRIMESTER BIOCHEMICAL SERUM MARKER SCREENING Maternal serum testing in the second trimester for the screening of women at low risk for fetal aneuploidy, neural tube defects, and other fetal anomalies remains a standard of care in many countries. Screening for trisomy 21 in low risk patients (women < 35 yr) was initiated in the mid-1980s with the observation that the mean maternal serum concentration of α-fetoprotein was 0.7 multiple of the median (MoM) in affected pregnancies.1–3 Subsequently, it was recognized that human chorionic gonadotropin (hCG) levels were higher (2.04 MoM) and unconjugated estriol levels were lower (0.79 MoM) in pregnancies with trisomy 21.4–7 By using the relative risks derived from maternal serum levels, the maternal age–related risk can be modified and a “triple-screen” risk can be derived for each woman. Triple-marker screening has been the preferred screening modality in some locales for the detection of fetal trisomy 21 in women younger than 35 years.7–10 In this group, the triple-marker screen identifies approximately 60% of pregnancies affected by trisomy 21 as being at risk, with a 5% screen-positive rate (Table 8–1). In the population of women 35 years and older, the triple-marker screen identifies 75% or more of pregnancies affected by trisomy 21 and some other aneuploidies.11 Because the maternal age–related risk of trisomy 21 is the basis of the serum screening protocol, both the trisomy 21 detection rate and the screenpositive rate increase with maternal age.12 Different laboratories use different screen-positive cutoffs. For example, some use the midtrimester risk of trisomy 21 in a 35-year-old woman (1 in 270). Others apply a screenpositive cutoff that provides an acceptable balance between the detection rate and the screen-positive rate (usually 1 in 190 or 1 in 200). Maternal serum screening can be performed between 15 and 20 weeks but is most accurate between 16 and 18 weeks. Similarly to first-trimester screening, the pregnancy must be dated accurately because an error will affect the assigned risk, causing false-negative and false-positive results. It is important to recalculate the results if the dates are found to be in error or to have a new sample drawn if the original sample was obtained before 15 weeks. Other factors that are 121
122 S ECTION TWO • Early Prenatal T A B L E 8 – 1
Various Sensitivities for Fetal Down Syndrome (False-Positive Rate of 5%) with Various Screening Tests in Combination SCREENING TEST Age Age, first-trimester biochemistry results Age, NT Age, first-trimester biochemistry results, NT NT, nasal bone Age, first-trimester biochemistry results, NT, nasal bone Age, second-trimester triple-screen results Age, second-trimester quadruple-screen results
SENSITIVITY FOR FETAL DOWN SYNDROME (%) 30 63 75 85–90 90 97 60–70 67–75
NT, nuchal translucency.
incorporated into the risk calculation include the number of fetuses, maternal weight, race, and diabetes. Serum screening is used primarily to detect trisomy 21, and it does not efficiently detect other fetal aneuploidies, except for possibly trisomy 18. Thus, serum screening misses both lethal (e.g., trisomy 13) and sex chromosomal abnormalities that are not associated with severe physical or developmental limitations or profound mental retardation. During the first trimester, the free beta subunit of hCG (β-hCG) is superior as a marker to the intact hCG molecule, but this has not been proved in the second trimester. In 1992, the potential use of a fourth analyte (inhibin) in second-trimester screening for Down syndrome was first suggested by Van Lith and coworkers.13 The median value of the maternal inhibin A level is increased at 1.77 MoM in Down syndrome pregnancies. However, inhibin A is not used in the calculation of risk for trisomy 18.14 Dimeric inhibin A has emerged as the most promising analyte and is used by many commercial laboratories in combination with the three traditional analytes. This four-analyte combination (“quad screen”) detects 67% to 76% cases of fetal trisomy 21 in women younger than 35 years, with a screenpositive rate of 5% or less.15,16 In 2003, Benn and colleagues17 screened over 23,000 women for Down syndrome using the quadruple test. They found the sensitivity to be 85.8% for an initial false-positive rate of 9% (which was further reduced to 8.2% after correction for major gestational age errors). Diagnostic options are limited for screening multiple gestations in the second trimester. In dizygotic twins, the risk of trisomy 21 is calculated by considering the maternal age– related risk and the probability that one or both fetuses will be affected. Thus, the midtrimester risk of trisomy 21 in at least one fetus of a twin gestation in a 33-year-old woman approximates the risk in a singleton pregnancy of a 35-yearold woman.18
FETAL ANATOMIC SURVEY ON SECOND-TRIMESTER SONOGRAPHY The introduction of two-dimensional (2D) static scanning in the early 1970s allowed physicians to view the fetus for the first time. In the late 1970s and early 1980s, real-time B-mode imaging emerged as a widespread clinical tool. The major advantage of ultrasound is the lack of a demonstrable adverse fetal effect19 because the image is generated with sound waves and not ionizing radiation. It quickly became the preferred method during pregnancy. Despite its apparent safety, some believe fetal sonography should be used only when there is a clear indication. However, most complicated pregnancies are unexpected and occur in low risk women, and ultrasound examinations are routine throughout pregnancy in many countries. We agree that all pregnant women should have access to expert obstetric sonography given that 90% of infants with congenital anomalies are born to women with no risk factors.20 Ultrasound resolution has improved dramatically, and a detailed examination of the fetus for both structural anomalies and markers of aneuploidy is possible. The diagnosis and management of specific congenital fetal abnormalities are discussed in other chapters. We focus here on the elements of a complete sonographic fetal anatomic survey. The sonographic examination should be systematic and thorough. Normal findings provide reassurance to patients, and the examination should detect most fetal malformations, along with abnormalities in fetal growth, the placenta, amniotic fluid, and the cervix. We also examined the value, from a patient’s perspective, of a targeted ultrasound examination performed after an abnormal karyotype was discovered.21 All women valued the scan because it helped them to visualize the fetal anomalies and accept the diagnosis of aneuploidy, which, in turn, affected their plans for pregnancy management. All patients considered the effect of the ultrasound greater than that of the chromosomal diagnosis alone, and all believed that ultrasound should be used for patients in similar clinical situations. The American Institute of Ultrasound in Medicine (AIUM) first published standards for the performance of obstetric ultrasound in 1994.22 The most recent AIUM Practice Guideline for the Performance of Obstetric Ultrasound Examinations was published in 2007.23 Although it describes indications for second- and third-trimester ultrasound examinations, it notes that the list is by no means inclusive. Imaging parameters for a standard fetal examination in the second and third trimester include (1) fetal cardiac activity, number, presentation (multiple gestations require additional documentation); (2) qualitative or semiquantitative estimate of amniotic fluid volume; (3) placental location, appearance, and relationship to the internal cervical os; (4) imaging of the umbilical cord, and the number of vessels in the cord should be evaluated when possible; (5) gestational (menstrual) age (via biparietal diameter, head circumference, femoral diaphysis length, abdominal circumference, or average abdominal diameter); (6) fetal weight estimation; (7) maternal anatomy (uterus, adnexal structures, cervix); (8) and fetal anatomic survey.23 The fetal anatomic survey, as described by the AIUM, involves the following areas of assessment: head, face, and neck, chest (including four-chamber view of the fetal heart), abdomen, stomach,
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 123
kidneys, bladder, abdominal cord insertion site, spine, extremities, and sex.23 They note that the basic cardiac examination includes a four-chamber view of the fetal heart; however, if technically feasible, views of the outflow tracts should be attempted as part of the cardiac screening examination.23
T A B L E 8 – 2
Content of Fetal Anatomic Survey on SecondTrimester Sonography ORGAN STRUCTURES Head Cranial shape, mineralization Cerebral hemispheres, thalami, cerebral peduncles, lateral ventricles and choroid plexus, third and fourth ventricles, cerebellum and vermis, cisterna magna, cavum septum pellucidum Face and Neck Profile, orbits, lips and palate, nasal bone, nuchal fold, ear Thoracic Cavity Lungs Configuration of the bony thorax Heart Four-chamber views (apical and subcostal), outflow tracts, longitudinal parasternal arches, inferior and superior vena cava, valves, atria and ventricular septa Abdomen Situs Stomach Liver, gallbladder, spleen Bowel Wall and cord insertion site Genitourinary System Kidneys Bladder Genitalia Spine Extremities Upper, including both hands Lower, including both feet Cord Number of vessels Biometric Measurements Biparietal diameter Head circumference Atria of lateral ventricles, cisterna magna, nuchal fold (when applicable) Cerebellum Thoracic circumference (when applicable) Abdominal circumference Femur length, humerus length, radius and ulna lengths, tibia and fibula lengths Foot length Nasal bone length Orbital diameters Other Number of fetuses, position Placenta Amniotic fluid Cervix and lower uterine segment
This was a compromise document, and we suggest the current state of the art requires a more detailed examination than that described by the AIUM for optimal diagnostic accuracy of fetal abnormalities (Table 8–2). Moreover, sonographer training must be focused and audited to ensure these detailed examinations are done appropriately. The sonographer must be familiar with normal fetal anatomy, sonographic landmarks, and normal variants. An adequate examination requires proper equipment. The highest-frequency transducer should be used to maximize the resolution of the fetal anatomy. The entire uterus is scanned transversely and longitudinally to determine the fetal position, amniotic fluid volume, and placental location. Accurate determination of the right and left sides of the fetus is crucial. Factors that may limit visualization (Table 8–3) include equipment quality, fluid abnormalities, maternal body habitus (discussed later) or tissue density, and other scanning characteristics. Techniques to improve visualization include changing the maternal position (to effectively change the fetal position) and using different scanning probes (including transvaginal). The timing of the second-trimester ultrasound varies with the center and physician preference. Repeating the examination later may aid the resolution of anatomic detail of some structures (e.g., heart) but hinder visualization of others (e.g., extremities). This is not to infer that scanning, even late in pregnancy, cannot provide important information and be highly sensitive for fetal anomalies whose diagnosis will alter pregnancy management. We recommend that the fetal anatomy survey be performed at 18 to 22 weeks to optimize the assessment of anatomy while leaving an adequate window for invasive testing, if necessary. Scans performed during this window are less likely than earlier scans to end incompletely and trigger the need for a repeat examination. In addition to evaluating the fetal anatomy, the number and position of fetuses should be determined. The placental appearance, thickness, echogenicity, and location are important to document, along with amniotic fluid volume. Amniotic fluid abnormalities may indicate an T A B L E 8 – 3
Factors That May Limit Sonographic Examination of the Fetal Anatomy Equipment quality Sonographer expertise Length of time spent scanning Quality of sonographic examination performed Frequency of sonographic examinations Maternal habitus, tissue density, and scanning characteristics Incomplete filling or overfilling of the bladder Fetal positioning Type of congenital anomaly Fluid abnormalities (increased or decreased) Gestational age (early or late) Timing of the exam (scan done before the development of detectable abnormalities or lesions resolve over time) Ossification of fetal bony structures (later in gestation) Fetal death in utero Fetal movement
124 S ECTION TWO • Early Prenatal
anomalous fetus (e.g., anhydramnios is associated with renal agenesis and polyhydramnios with esophageal atresia). The fetal echocardiogram is best performed between 22 and 24 weeks, when the cardiac structures are larger.
Content of the Fetal Anatomic Survey The examination begins with the fetal head and proceeds caudally. Imaging the fetal intracranial anatomy is extremely important because central nervous system anomalies can have a devastating effect on perinatal morbidity and mortality. The calvarium can be identified from the late first trimester onward. It should be well mineralized (hypomineralization may indicate a skeletal dysplasia) and elliptical in shape by the second trimester. Brachycephaly (anteroposterior shortening) suggests fetal trisomy 21 or 18 (“strawberry” head). A “lemon”-shaped head suggests a neural tube defect. Tangential imaging shows cranial sutures (hypoechoic spaces between bones) that are best visualized early in gestation. Premature closure of the sutures occurs in many syndromes (e.g., craniosynostosis) and with several skeletal dysplasias. The transthalamic view is an axial view through the brain at the level of the thalami (Fig. 8–1). It is here that the biparietal diameter and head circumference measurements are obtained. Biparietal diameter is measured from the outer margin of the near calvarium to the inner margin of the far calvarium (with cranial bones perpendicular to the ultrasound beam). The head circumference is measured circumferentially at the outer margin of the calvarium (see Fig. 8–1). Other structures that are visualized in the transthalamic view include the cavum septum pellucidum (a fluidfilled midline structure anterior to the thalami), midline falx, third ventricle (between the thalami), and frontal horns of the lateral ventricles. A normal cavum suggests proper midline brain formation; its absence may signal abnormalities, such as holoprosencephaly, septo-optic dysplasia, or agenesis of the corpus callosum. The transventricular view is just superior to the transthalamic view and includes the lateral ventricles that contain sonolucent cerebrospinal fluid. Within this lies the echogenic choroid plexus that normally
CSP
fills the atrium and may contain cysts (a potential marker for trisomy 18) (Figs. 8–2 and 8–3). The cerebral ventricle is measured through the atrium in an axial plane and is normally less than 10 mm. The transcerebellar view contains the cerebellum and vermis, cisterna magna (between the dorsum of the cerebellar hemispheres and inner calvarium), and nuchal fold (Fig. 8–4). Visualization of this area is important to exclude spina bifida; obliteration of the cisterna magna and a banana-shaped cerebellum typically occur with this disorder. This view is also used to exclude DandyWalker malformation or variant, occipital encephalocele, and cerebellar agenesis or hypoplasia. The nuchal fold should be less than 6 mm, although with a breech presentation, an extended head onto the neck, or increased pressure by the transducer over the fetal head, this may create a falsepositive thickening. The transcerebellar diameter provides a useful estimate of gestational age because it is relatively spared by fetal growth disturbances, including intrauterine growth restriction.24 Sometimes, the fetal head is low in the pelvis, blocking access to the intracranial structures; in this case, transvaginal scanning is often useful.
Choroid
FIGURE 8–2 Transventricular view of the fetal head shows measurement of the atria of the lateral ventricle (0.48 cm) and the echogenic choroid plexus (arrows).
T 30 days in neonatal unit. † Defined as admission to neonatal unit. ‡ Attributable to early detection of malformations, leading to termination of anomalous fetuses.
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 131
patient should be a routine practice, as it is in all aspects of adult medicine. The last screening issue to address is the cost-benefit analysis of routine second-trimester sonography. We performed a cost-benefit analysis based on the RADIUS trial, comparing routine second-trimester sonography in low risk pregnant women with a policy of not offering screening. Routine second-trimester sonographic screening is associated with net benefits only if the sonogram is performed at a tertiary care center.47 Another study showed that a onestage second-trimester screening ultrasound was both costeffective and associated with fewer perinatal deaths.48 Finally, Van Dorsten and coworkers38 assessed the costeffectiveness of anomaly screening in their patient population and concluded that routine screening was cost-effective. There seems to be little doubt that the cost-effectiveness of routine sonographic screening for fetal anomalies rests not on the tool but on the caliber of the sonographer. The costs of poor sonography cannot continue to be tolerated in an already stressed health care system. The cure is not to deny women access to valuable screening techniques; the cure is to require proof of the sonographer’s skill.
Sonographic Aneuploidy Markers and Genetic Sonography The most common autosomal trisomy in liveborn infants is Down syndrome, or trisomy 21, which was first described by John Langdon Down in 1866. Autosomal trisomies are primarily the result of meiotic nondisjunction, the risk of which increases with maternal age. The first screening method for fetal trisomy 21 was introduced in the early 1970s and was based on maternal age. Amniocentesis was offered to women 35 years or older, based on the findings of an early study that stated that the risk of a procedurerelated loss approximated the likelihood that a midtrimester fetus of a 35-year-old woman would have trisomy 21 (1 in 270). There has been a fundamental shift in birth trends since the 1970s, with more births occurring to women older than 35 years.49 In 1974, women 35 to 49 years old accounted for just 4.7% of live births compared with 12.6% in 1997.49 As a result, the prevalence of fetal trisomy 21 during the second trimester has increased from 1 in 740 in 1974 to 1 in 504 in 1997. However, the fact remains that most infants with trisomy 21 are born to women younger than 35 years. Fetuses with aneuploidy account for 6% to 11% of stillbirths and neonatal deaths,50 whereas chromosomal defects that are compatible with life, but associated with significant morbidity, occur in 0.65% of newborns.51 In January 2007, the American College of Obstetricians and Gynecologists (ACOG) in their Practice Bulletin52 raised the issue of whether invasive diagnostic testing for aneuploidy should be available to all women. They stated that the decision to offer invasive testing should not be solely age-based, and that a maternal age of 35 years alone “should no longer be used as a cutoff to determine who is offered screening versus who is offered invasive testing.” Therefore, all women (regardless of age) should have the option of invasive testing.52 Nevertheless, among high risk women while some will choose to have invasive testing as a first option, others will instead first undergo either first-trimester screening or
second-trimester genetic sonography (± biochemistry) and use the information derived from ultrasound to obtain an adjusted risk for Down syndrome to guide their decision about genetic amniocentesis. Accordingly, the genetic sonogram evolved from a patient’s perspective, with the purpose of possibly avoiding invasive testing. A large body of literature attests to the specific use of second-trimester genetic ultrasonography for antenatal detection of trisomy 21 by seeking aneuploidy markers. We offer genetic sonography as an option to all (and only) high risk patients (i.e., advanced maternal age at the time of delivery, abnormal serum marker screen results, or both). The information derived from this sonogram is used to generate an adjusted risk of Down syndrome to guide a woman’s decision about genetic amniocentesis. When the findings on genetic sonogram are normal in high risk patients, the amniocentesis rate is only 3%.53 The amniocentesis rate increases in direct proportion to the number of abnormal sonographic markers identified, with almost 100% of women selecting invasive testing when four or more markers are seen. Since the initiation of our genetic sonography service in 1992, over a 10-year period, more than 5000 women have avoided amniocentesis based on normal findings on genetic sonogram. If the fetal loss rate related directly to amniocentesis is between 1 in 100 and 1 in 300, then more than 17 to 50 fetal lives were saved, attesting to the power of genetic sonography. Screening based on maternal age identifies at most 47% of fetuses with trisomy 21, with a false-positive rate of 13% to 14% (a rate that has increased in recent years).49 Based on advanced maternal age, 140 amniocentesis procedures are required to detect one fetus with trisomy 21,54 implying that one healthy fetus will be lost for every two to three affected fetuses identified. Although the combination of maternal age and second-trimester biochemical screening results increases the detection rate to 60% to 65%,12 60 to 70 amniocentesis procedures are required to detect one fetus with trisomy 21.54 Thus, one healthy fetus will be lost for every three to five fetuses in which trisomy 21 is detected. As a result, some have challenged the practice of offering invasive testing to all high risk pregnant women (based on age or second-trimester biochemical screening results).12 Reducing the screen-positive rate is beneficial, regardless of an individual’s personal opinion on testing. Genetic sonography reduces the invasive testing rate by refining the selection of candidates for invasive testing without significantly decreasing detection rates. Ideally, genetic sonography is performed between 18 and 20 weeks. The window may be shifted higher to 20 to 22 weeks if the option of pregnancy termination is not lost by the delay because visualization might improve. It is a targeted examination for fetal aneuploidy (predominantly trisomy 21) during which the sonographer searches for abnormal fetal biometry, fetal structural anomalies, and other markers of aneuploidy.53 Because only 25% of fetuses with trisomy 21 have a sonographically detectable major anomaly in the second trimester,54 the examination must include other markers to increase sensitivity (Table 8–5). Markers of aneuploidy that are detectable on ultrasound include shortened long bones, increased nuchal fold thickness (Fig. 8–17), pyelectasis (Fig. 8–18), choroid plexus cysts (see Fig. 8–3), short ear length, wide iliac wing angle,
132 S ECTION TWO • Early Prenatal T A B L E 8 – 5
Aneuploidy Markers of the Genetic Sonogram Structural anomalies, including cardiac (four-chamber and outflow tracts) Short femur (observed to expected < 10th percentile)
FIGURE 8–19 Sandal gap (wide space between the first and the second toes) in a fetus with Down syndrome.
Sandle gap
Short humerus (observed to expected < 10th percentile) Pyelectasis (anteroposterior diameter of renal pelvis ≥ 4 mm) Nuchal fold thickening (≥6 mm) Echogenic bowel (similar to echogenicity of iliac bones) Choroid plexus cysts (>10 mm) Hypoplastic middle phalanx of the fifth digit Wide space between the first and the second toes (sandal gap) Two-vessel umbilical cord Echogenic intracardiac focus, short tibia, short fibula, short ear (since October 1997) Absent nasal bone (since 2003)
FIGURE 8–17 Thickened nuchal fold (0.86 cm) in a second trimester fetus with Down syndrome.
Pyelectasis
FIGURE 8–18 Bilateral pyelectasis in a second-trimester fetus.
hyperechoic bowel, echogenic intracardiac focus (see Fig. 8–12), sandal gap toes (Fig. 8–19), hypoplastic midphalanx of the fifth digit, clinodactyly, and absent NB (see Fig. 8–7). The risk of fetal trisomy 21 increases with the number of markers present. Each marker alone (except thickened nuchal fold or absent NB) has low to moderate sensitivity for trisomy 21 and does not necessarily increase the risk of aneuploidy when found in isolation in low risk patients. However, the risk of fetal aneuploidy may increase when thickened nuchal fold, absent NB, or multiple sonographic abnormalities or markers are detected in low risk patients or when any isolated markers are seen in high risk patients. A thickened nuchal fold (sensitivity 40%; false-positive rate 0.1%)55 along with absent NB (41% sensitivity and 100% specificity for fetal trisomy 21) are among the most sensitive and specific markers for Down syndrome and involve straightforward training.56 Importantly, when we added absent NB to the other sonographic markers of aneuploidy, the sensitivity of genetic sonography increased from 83% (24 of 29) to 90% (26 of 29).56 Absence of the NB was noted in two fetuses with trisomy 21 with no other ultrasound markers for aneuploidy. There is a large overlap in bone measurements between affected and normal fetuses. A short femur length (measurement-to-expected length ≤ 0.91) is found in 24%,57 and a short humerus (measurement-to-expected length < 0.90) in 50% of affected fetuses, with a false-positive rate of 6.25%.58 The sensitivity of pyelectasis (anteroposterior diameter of the renal pelvis ≥ 4 mm in the second trimester) for trisomy 21 is 25%.58 Echogenic bowel has a reported sensitivity of 7% to 12.5%, whereas an echogenic intracardiac focus (see Fig. 8–12) has a reported sensitivity of 18%.58 We examined the sensitivity of a short sonographic ear length for trisomy 21.59 Forty-one percent (21 of 51) had an ear length at or below the 10th percentile. However, a short ear length was not as sensitive a marker for trisomy 21 as it was for trisomy 13 (100%) or trisomy 18 (96%). The association between trisomy 21 and choroid plexus cyst(s) is controversial. In 2008, Molina and colleagues60 examined the frontomaxillary facial (FMF) angle in normal (n = 150) and trisomy 21 fetuses (n = 23) at 16 to 24 weeks of gestation using three-dimensional ultrasound. In the normal group, there
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 133
was no significant association between the FMF angle and gestational age. The mean FMF angle was 83.9 degrees (range 76.9–90.2 degrees), and the 95th percentile was 88.5 degrees. In 65.2% (n = 15) of the Down syndrome fetuses, the FMF angle was greater than 88.5 degrees. Therefore, they concluded that in the majority of second-trimester fetuses with trisomy 21, the FMF angle is increased. Several studies have reported the accuracy of genetic sonography to detect trisomy 21 in high risk populations.53 When “abnormal” is defined as the finding of at least one marker on ultrasound, the overall sensitivity was 77% (range 50%–93%), and the false-positive rate was 13% (range 7%– 17%).53 Thus, whereas it is clear that the use of multiple sonographic markers improves the sensitivity of sonography for detecting trisomy 21, it also results in a higher falsepositive rate. In 1998, an 11-center collaborative study examined the sensitivity of sonography for the detection of trisomy 21.61 Eighty-five percent of fetuses with trisomy 21 (n = 241) had at least one abnormal finding on ultrasound. In 2003, an eight-center study evaluated the utility of second-trimester genetic sonography in high risk women, including 176 fetuses with trisomy 21.62 The sensitivity for the detection of trisomy 21 was 72% (center range 64%–80%). Approximately half (47%) of the fetuses with trisomy 21 had a thickened nuchal fold of 5 mm or more. In 1996, our group63 was the first to publish findings on the use of second-trimester genetic sonography to guide clinical management of pregnancies in women at high risk for trisomy 21. In 1999, we began to counsel women that the likelihood of trisomy 21, in the absence of abnormalities or markers, was reduced by at least 80% from the a priori risk (second-trimester biochemical screening results or, if unavailable, maternal age).53 Our experience was reassuring. Over almost a 10-year period (November 1992–August 2002), we evaluated 5299 fetuses with genetic sonography. The findings were normal in 85% (no markers seen); 12% had one marker, and 3% had two or more markers. When at least one marker was present, the sensitivity, specificity, and positive and negative predictive values for trisomy 21 were 87% (52 of 60), 91% (4395 of 4831), 11% (52 of 488), and 99.8% (4395 of 4403), respectively. Approximately two thirds of fetuses with trisomy 21 had two or more abnormal sonographic markers. Over the years, we have found that more and more high risk women prefer genetic sonography as their first option, rather than amniocentesis (Table 8–6). Since 1998, more than 70% of women chose to begin with genetic sonography. Accordingly, the number of amniocenteses performed has decreased. The total amniocentesis rate (the sum of amniocentesis procedures as the first option plus amniocentesis procedures performed after genetic sonography) decreased from 99.6% in 1993 to 32% in 2002. Several years ago, we examined the accuracy of genetic sonography for the detection of fetal trisomy 21 according to the indication for testing (advanced maternal age, abnormal second-trimester biochemical screening results, abnormal second-trimester biochemical screening results in women younger than 35 years, and abnormal second-trimester biochemical screening results in women 35 years and older). We also examined the risk of trisomy 21 after normal findings on genetic sonography.64 We found that the magnitude of the risk adjustment after normal findings on a genetic scan was independent of
T A B L E 8 – 6
Annual Utilization Rates of Genetic Sonography for Detection of Fetal Trisomy 21 at Robert Wood Johnson Medical School YEAR 1993‡ 1994 1995 1996 1997 1998 1999 2000 2001 2002
CANDIDATES FOR PRENATAL DIAGNOSIS* 477 495 523 594 793 856 1285 1537 1497 1526
GENETIC ULTRASOUND (N (%)) 2 (0.4) 82 (17) 251 (48) 328 (55) 510 (64) 662 (77) 956 (74) 1114 (73) 1062 (71) 1110 (73)
TOTAL AMNIOCENTESES† N (%) 475 (99.6) 423 (85) 292 (56) 279 (47) 315 (40) 215 (25) 405 (31) 468 (30) 488 (32) 493 (32)
* Includes advanced maternal age (≥35 yr) with or without abnormal serum biochemistry results, abnormal serum biochemistry results in women younger than 35 years, or family history of chromosome abnormality. † Includes women who underwent genetic amniocentesis only as their first option and women who underwent amniocentesis after genetic sonography. ‡ The genetic sonogram service was available for only 2 months in 1993 (November and December).
the testing indication and there were no significant indication-specific variations in the accuracy of genetic sonography. Although some advocate second-trimester genetic sonography for screening of the general population, we believe that it should be reserved only for the high risk population for several reasons. First, a high degree of expertise is required to exclude sonographic fetal malformations (especially subtle cardiac defects), and this expertise is not widely available in many countries including the United States. Second, the application of genetic sonography to low risk women may be inappropriate and perhaps dangerous, in light of the high screen false-positive rate (12%–15% in the high risk population), which is likely even higher in a low risk population. In low risk women, the a priori risk of trisomy 21 may be so low that the presence of one aneuploidy marker (e.g., pyelectasis) would not elevate the risk enough to justify amniocentesis. Therefore, with this approach, the positive predictive value and perhaps even the sensitivity of genetic ultrasound for fetal trisomy 21 are likely to be decreased in low risk patients. Third, the accuracy of second-trimester aneuploidy markers has been studied mainly in high risk populations. Extrapolation of such accuracy to low risk women may not be appropriate. Some have concluded that an isolated marker (other than increased nuchal fold thickness, absent NB, or structural anomalies) should not be used as an indication for amniocentesis testing in the low risk population.53 Others argue that if it is applied to the low risk population, any risk adjustment must reflect both the a priori risk of trisomy 21 and the sensitivity of the specific marker identified. Clinicians should not recommend amniocentesis to low risk patients who have an isolated marker identified because the sensitivity is low, with the possible exception of increased
134 S ECTION TWO • Early Prenatal
nuchal fold thickness65 and/or absent/hypoplastic NB. However, the incidental finding of an organ or structural anomaly (with few exceptions), nuchal fold thickening, absent/hypoplastic NB, or two or more aneuploidy markers in a low risk patient should trigger counseling and informed consent with the patient. The patient should be informed that if the accuracy of genetic ultrasound is extrapolated from high risk to low risk women, then the risk of trisomy 21 is likely high enough to justify offering genetic amniocentesis. In these patients, the risk of trisomy 21 is higher than the risk of amniocentesis-related fetal loss, regardless of maternal age or second-trimester biochemical screening results (unless the a priori risk < 1 in 10,000). Certain isolated sonographic fetal abnormalities (e.g., gastroschisis) are not usually associated with aneuploidy and do not require further invasive testing. The following description is the approach that we have used successfully with high risk patients. Genetic sonography is an adjunct to maternal age and serum screening (triple or quadruple, whichever is available) to adjust the risk of fetal trisomy 21 for each patient, based on our accuracy. The a priori risk is based on serum screening results. If serum screening results are not available or if testing was not performed, the risk is based on maternal age. We then multiply the a priori risk with various likelihood ratios (LRs), depending on the presence or absence of aneuploidy markers. For example, if the a priori risk of fetal trisomy 21 is 1 in 274 and the results of genetic sonography are normal, the adjusted risk of fetal trisomy 21 is (1 in 274 × 0.20 [1/5 residual risk]), or 1 in 1370, a reduction of at least 80%. The degree of risk reduction depends on several factors, such as the sensitivity of the ultrasound and the criteria and number of aneuploidy markers sought. Most recent studies utilize a negative LR that ranges somewhere between 0.2 and 0.4 after a normal genetic scan, corresponding to a 60% to 80% reduction in risk. The revised risk is then discussed with the patient. The patient should be told that the genetic scan can never reduce her risk to 0%. In our experience, the presence of only one of the following markers increases the risk of trisomy 21 minimally or not at all: short femur length, short humerus length, pyelectasis, echogenic bowel, hyperechoic focus in the left ventricle, short tibia length, short fibula length, short ear length, choroid plexus cyst greater than 10 mm, a hypoplastic middle phalanx of the fifth digit, a sandal gap toe, and a two-vessel cord. Therefore, the risk of fetal trisomy 21 remains the same (1 in 274). Once two or more markers are visualized, or a thickened nuchal fold, or absent NB, no matter what the a priori risk is, the adjusted risk for trisomy 21 is almost always higher than the risk of amniocentesis. An adjusted risk of trisomy 21, based on the genetic sonogram, is given, even for high risk patients. For example, based on age alone, a 44-year-old patient is at high risk for fetal trisomy 21. However, if second-trimester biochemical screening results are 1 in 798 (a priori risk) and the findings on genetic sonogram are normal, the adjusted risk for trisomy 21 is 1 in 3990. If the same patient has one soft marker, the adjusted risk for Down syndrome remains the same, or is slightly higher than 1 in 798 (LR 1.00). Although it would intuitively seem that certain markers (e.g., nuchal fold thickening, absent NB, or cardiac defects) in isolation are very “strong” and would increase the risk for trisomy 21, we have found these markers most frequently in
combination with other markers. Either a triple or a quadruple screen risk is acceptable as an a priori risk, because most of our findings are based on high risk patients who underwent serum testing. If the results of genetic sonography are normal, we still reduce the risk of fetal trisomy 21 by 80%, and the revised risk is then discussed with the patient. However, in the presence of aneuploidy marker(s), we no longer multiply the a priori risk with various LRs to give an actual adjusted risk. Instead, we counsel the patient that her risk for fetal Down syndrome is “increased,” and we offer and discuss genetic amniocentesis. In other words, if only one marker is present (with the exception of structural anomaly, thickened nuchal fold, or absent NB), we recommend invasive testing only if the patient is high risk based on the a priori risk. Conversely, once two or more markers are visualized, or isolated thickened nuchal fold or absent NB, we offer invasive testing, regardless of a priori risk status. Ideally, it would be optimal to establish an individual LR for each aneuploidy marker so that risk adjustments may be made when a marker(s) is sonographically present. LRs of isolated markers have been reported in several studies.66–69 By using LRs, the post priori risk is then estimated. However, if one examines the LRs reported for a specific marker (such as short humerus), these values can vary widely. Thus, for this reason, we believe that in general the presence of isolated sonographic markers should not be used to adjust the a priori risk for fetal Down syndrome. We also do not utilize LRs of isolated markers because, in our experience, the overwhelming majority of Down syndrome fetuses have multiple markers in combination, rather than in isolation. In fact, based on our own data, approximately two thirds of fetuses with Down syndrome will have two or more abnormal sonographic markers. Therefore, we have been unable to generate stable and reliable positive LRs of isolated markers. Accordingly, until individualized LRs can be reliably established, we do not provide actual adjusted risks for fetal Down syndrome in the presence of aneuploidy marker(s). A different method that has been utilized is to integrate the risk of sonographic markers with the a priori risk based on maternal age.70 This is called AAURA (age-adjusted ultrasound risk adjustment) for fetal Down syndrome and is used for women of all ages. With this method, sonographic markers are “weighted” by the strength of individual findings, expressed as LRs. The authors base the individual risk assessment of fetal Down syndrome on maternal age and the presence or absence of each of the sonographic markers, in terms of LRs. Investigators using AAURA report that both the sensitivity of fetal Down syndrome detection and the false-positive rate increase with maternal age. This is felt to be appropriate because older women desire a high sensitivity, and the clinical alternative is amniocentesis for all women age 35 years or older (100% false-positive rate).71 AAURA also minimizes the false-positive rate for younger women (4%) with a satisfactory sensitivity (61.5%).71 Recently, we have also altered our clinical management to reflect the emergence of first-trimester screening. First-trimester screening is discussed in detail in Chapter 7. Studies performed in the 1990s revealed a strong association between the size of the fluid collection at the back of the fetal neck in the first trimester (NT) and the risk of Down syndrome.72
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 135
An increased NT thickness is now widely recognized to be an early presenting feature of a wide range of fetal genetic, chromosomal, and structural anomalies. Subsequently, an important achievement in first-trimester screening for Down syndrome occurred when large studies in the United States and United Kingdom demonstrated that NT could be combined with two first-trimester maternal serum analytes (free β-hCG and pregnancy-associated plasma protein A [PAPPA]). The mean level of free β-hCG in first-trimester Down syndrome pregnancies is elevated to 1.98 MoM,73 and the mean level of PAPP-A is reduced to approximately 0.43 MoM.74 When serum analytes are combined with NT (or combined first-trimester screening), the result is higher detection rates for Down syndrome. In looking at prospective first-trimester screening studies, when fetal NT (along with maternal age) is combined with free β-hCG and PAPP-A, the detection rate for Down syndrome is 87%, for a false-positive rate of 5%.75 Another recent paper examining prospective studies of combined first-trimester screening found that for a total of more than 160,000 pregnancies screened (>600 Down syndrome fetuses), the overall sensitivity for Down syndrome was 87% (95% CI 84.0%–89.4%), for a 5% false-positive rate.76 Therefore, it is evident that for a 5% false-positive rate, the sensitivity for Down syndrome by utilizing combined first-trimester screening is far superior to that of maternal age (30%) and second-trimester triple screen (60%–70%). Because of the current availability of both first- and second-trimester screening tests, several approaches to Down syndrome screening have been evaluated. However, it is important to point out that not all strategies include NT measurement because this screening approach is not available in all regions and this measurement may not be successfully obtained in all patients. Nevertheless, when women have undergone first-trimester screening for aneuploidy, they should not undergo independent secondtrimester serum screening in the same pregnancy52 because the false-positive rates are additive, resulting in many more unnecessary invasive procedures (11%–17%).77,78 Instead, women who desire a higher detection rate for Down syndrome can have either an integrated or a sequential screening test, which combines both first- and second-trimester screening results, or seek an ultrasound laboratory that is certified to perform comprehensive first-trimester screening (PAPP-A, hCG, NT, NB, ductus venosus, tricuspid valve). At present, patients undergo combined first-trimester screening, with a subsequent maternal serum concentration of α-fetoprotein (MSAFP) only in the second trimester. We then utilize the combined first-trimester screen risk as the a priori risk for genetic sonography. If the patient does not have first-trimester screening performed (but, rather, quadruple screening), then these results are used as the a priori risk, as has been done traditionally in the past. Others have evaluated second-trimester genetic sonography after first-trimester Down syndrome screening. In 2005, members of the FASTER (First and Second Trimester Evaluation of Risk) trial in the United States79 examined the role of second-trimester genetic sonography in a population that already underwent first-trimester combined screening and second-trimester quadruple screening. There were 8533 patients who underwent genetic sonography, including 62 cases of Down syndrome. Although there were 3 Down
syndrome cases undetected by either first- or second-trimester or combined screening, genetic sonography detected all these cases, so that no Down syndrome fetus was missed by the overall screening program. The sensitivity of combined first-trimester screening was 84% (false-positive rate 6.6%); however, by using the genetic sonogram to modify the risk, this resulted in higher sensitivity (92%), with a reduction in the false-positive rate to 5.6%. Similarly, the sensitivity of quadruple screening was 88% (false-positive rate 11%); however, by again using the genetic sonogram to modify the risk, this resulted in higher sensitivity (93%) with a reduction in the false-positive rate to 7.4%.79 Thus, secondtrimester genetic sonography improved the performance of both first- and second-trimester screens by significantly reducing the false-positive rates, with simultaneous increases in sensitivity. Krantz and associates80 used previously published data in 2007 to mathematically model the effect of second-trimester sonography after combined screening. In this model, when genetic sonography was used as the second part of a stepwise sequential screen, Down syndrome detection increased to 94.6% from 88.5% by combined screening alone, with an accompanying increase in the screen-positive rate from 4.2% to 5.4%. When genetic sonography was used as the second part of a contingent sequential test for intermediaterisk combined screen results, Down syndrome detection and screen-positive rates were 93.3% and 4.9%, respectively. The authors concluded that second-trimester genetic sonography could serve as an effective screening test after firsttrimester combined screening.80 In 2009, a retrospective cohort study was performed to evaluate Down syndrome screening performance of the first-trimester combined test followed by second-trimester genetic sonography.81 Sonography was evaluated as the second part of (1) a stepwise sequential test applied to combined screen-negative pregnancies and (2) an integrated test applied to all combined screen patients, regardless of the latter results. The authors found that second-trimester genetic sonography after firsttrimester combined screening may improve Down syndrome detection, but at the expense of increasing screen-positive rates, which they deemed unacceptably high. Risk adjustment for trisomy 21 is institution-specific and the published experience from one center does not necessarily apply to another.82 Each center performing genetic sonography must monitor their sensitivity for the detection of trisomy 21 to provide patients accurate, detailed, and updated counseling about their degree of risk reduction when ultrasound findings are normal. Considering the range of expertise available in many countries, it is reasonable to suggest limiting genetic sonography to specialized centers.11 In 2007, ACOG stated in their Practice Bulletin52 that risk adjustment based on second-trimester ultrasonographic markers should be limited to centers with ultrasonographic expertise and centers engaged in clinical research, to develop a standardized approach to evaluating these markers. We analyzed the cost of universal amniocentesis and genetic sonography and concluded that genetic sonography was cost-effective when the sensitivity for the detection of trisomy 21 was greater than 74%.64 We observed that genetic sonography saved the health care system 9% and reduced the loss rate of normal fetuses as a result of amniocentesis by 87%.83 Genetic sonography is also cost-effective in
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women younger than 35 years who are at moderate risk for Down syndrome based on their second-trimester biochemical screening results as well as in patients with advanced maternal age who decline amniocentesis after second-trimester genetic counseling.84 Offering genetic sonography to these patients is associated with cost savings for most acceptable genetic ultrasound accuracies. Finally, another study indicated that the combination of second-trimester genetic sonography with traditional serum markers may further improve diagnostic accuracy.85 Various integrated algorithms combining serum analytes and sonographic markers have been reported (e.g., nuchal thickness, humerus length, serum α-fetoprotein, hCG) but have not been validated prospectively.
THREE-DIMENSIONAL SONOGRAPHY Three-dimensional ultrasound (3DUS) was first introduced in the late 1980s. 2D ultrasound (2DUS) acquires a single plane of image information with traditional transducers. 3DUS, however, acquires volume data utilizing one of several techniques. The resulting data can be viewed in single or multiple planes or in combination with a rendered image that conveys the information from the entire volume (the “classic” 3D appearance).86 The initial machines were somewhat slow, but display times have decreased dramatically with the evolution of computer processors. With the current generation, 3D reconstruction is fast with high resolution, providing not only a 3D image in real time but also a display generated using standardized protocols. The image quality is directly related to the image quality of the 2D scan used to acquire volumes. In some cases, multiplanar imaging in a standard orientation allows the sonographer to be more confident of a finding compared with conventional 2D imaging. This technology has the potential to provide both the physician and the patient with more accurate and additional information about the fetus (e.g., extent or size of anomalies) than is possible with traditional 2DUS. Other advantages of 3DUS include rapid acquisition of volume data, use of new orientations and planes (not obtainable with 2D scanning), earlier maternal-fetal bonding, and improved comprehension of the fetal anatomy by the patient and family.86 Another important role of 3DUS relates to the ability to store volume data that can be manipulated long after the patient has left the examination room.87 Sonographic volumes can also be transmitted electronically from a remote site for full interpretation and evaluation elsewhere, making teleradiology ultrasound image interpretation easier and less operatordependent.88 This capability has the potential to increase the use of sonography in remote locations, where a sonographic expert is not present. 3DUS may be more useful than conventional 2DUS for the evaluation of malformations. Merz and colleagues89 studied 204 anomalous fetuses and concluded that 3DUS ultrasound was advantageous compared with 2DUS in 62%, equivalent in 36%, and disadvantageous in 2%. In a similar study of 63 fetuses with 103 anomalies, 3DUS was advantageous in 51%, equivalent in 45%, and disadvantageous in 4%.90 Several anomalies, such as cleft lip and abnormal facies, were seen only with 3DUS. Most anomalies were better visualized with 3D than with 2D imaging.89,90 Not only was patient management altered in 1 out of 20 patients,
but the improved visualization helped physician and family understand the anomalies. In 2005, Gonçalves and coworkers reviewed the published literature on 3DUS and fourdimensional ultrasound (4DUS) in obstetrics, to determine whether 3DUS adds diagnostic information to that currently provided by 2DUS.91 They concluded that 3DUS provides additional diagnostic information for the diagnosis of facial anomalies, especially facial clefts. Moreover, they found evidence that 3DUS provides additional diagnostic information for neural tube defects and skeletal malformations. However, large studies comparing 2DUS and 3DUS for the diagnosis of congenital anomalies have not provided conclusive results.91
Second- and Third-Trimesters 3D imaging is useful in the second and third trimesters for anomalies of the skull, brain, face, heart, spine, limbs, urinary tract, umbilical cord, and placenta.86 Other applications under study include evaluations of the placenta, umbilical cord, cervix, fetal weight, and uterine anomalies (e.g., bicornuate, septate). 3DUS can improve the accuracy of length, area, and volume measurements as well.88 Various strategies have been utilized, ranging from manual outlining of structures to semiautomatic and fully automatic algorithms that segment organs and structures for analysis.88 One of the most valuable features of 3DUS is the ability to rotate the face so that it can be viewed directly in an upright position. Surface-rendered displays are successfully obtained in 70%.86 The fetal face can be rotated into a standard symmetrical orientation and reviewed millimeter by millimeter by scrolling through the volumes.92 Several studies have concluded that 3DUS was beneficial for the detection of facial anomalies, such as cleft lip or palate, midface hypoplasia, asymmetrical facies, micrognathia, facial masses, hypotelorism or hypertelorism, facial dysmorphia (sloping forehead, flat facies, flat nose), holoprosencephaly, and deformed ears.86 3DUS is particularly valuable when seeking a cleft lip or palate, especially the primary, or hard, palate. Some anomalies detectable on 3DUS were missed on 2DUS, including cleft lip or palate, micrognathia, flat facies, unilateral orbital hypoplasia, and cranial ossification defect.86 In one series, 2DUS identified only 45% of fetuses with cleft palate, whereas 3DUS enabled the detection of 86%.93 Artifacts produced from 3D volumes can imitate “clefting” of lips that are actually normal. These artifacts include shadowing by an adjacent umbilical cord, motion during image acquisition, NB shadowing, and misidentifying a nostril as a cleft.86 It is almost always possible to obtain a fetal profile, a crucial part of the examination. In addition, rotation of the volume allows consistent and accurate depiction of the midsagittal plane. 3D imaging of the face may be difficult early in gestation, if there is oligohydramnios, if limbs obscure the face, or when the face is close to the uterine wall or placenta.86 3D imaging is valuable in the examination for fetal skull defects, intracranial pathology and symmetry, and abnormal sutures or fontanelles. The “three-horn view” contains the anterior, inferior, and posterior horns of the lateral ventricles in a single slice.94 Fluid in the inferior horn is abnormal and is an early sign of ventriculomegaly. By placing the
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 137
“marker dot” in the volume, the sonographer can “navigate” through ventricles, parenchyma, and cystic structures and along vascular structures.86 These images may be useful for consulting pediatric neurologists and neurosurgeons. The fetal spine is often imaged more clearly with 3DUS. Image quality is improved with rendering techniques that optimize the appearance of bone for the diagnosis of scoliosis, hemivertebrae, and neural tube defects. Studies suggest that 3D evaluation allows for an accurate determination of the level of a neural tube defect because the transverse and coronal images are viewed simultaneously with the rendered image.95 In the past, cardiac 3DUS was compromised by the rapid motion. However, recent technological developments of motion-gated cardiac scanning allow almost real-time 3D/4D fetal heart scans. Spatiotemporal image correlation (STIC) acquisition is an indirect motion-gated offline scanning mode.96 Consecutive volumes can then be used to reconstruct a complete heart cycle that displays in an endless loop. Accordingly, this cine-like file of a beating fetal heart can then be manipulated to display any acquired scanning plane at any stage in the cardiac cycle.97 3D/4D sonography has been used to estimate fetal cardiac ventricular volume, calculate ejection fraction and stroke volume,98 and diagnose or facilitate the diagnosis of congenital cardiovascular malformations.99,100 Abnormalities of the fetal abdomen and pelvis (and, in some cases, their volume) can be imaged with 3DUS (e.g., gastroschisis, omphalocele, bowel obstruction, hydronephrosis, multicystic dysplastic kidney). However, it is not clear whether additional information is obtained compared with 2D. Abnormalities of the genitalia may also be assessed with 3DUS. The fetal extremities can usually be imaged with 3DUS because of the rapid acquisition. If the limb moves during an acquisition, the volume should be discarded and another one acquired. With conventional 2D, motion often obscures limb anatomy or makes assessment difficult. However, once a 3D volume is obtained, the structure can be studied carefully without motion, and the limb can be “rotated” to various orientations for full evaluation. Rendered images can be used to evaluate surface and bony features and the number and position of digits. In evaluating the lower extremities for clubfeet, it is often difficult to determine whether this is a “transient” (false-positive) or “fixed” (true-positive) event. 3DUS may help in some cases. 3DUS offers several advantages over conventional 2D imaging in fetuses with skeletal dysplasia. Abnormal bone shapes, shortened ribs, and abnormal facies are more accurately identified with volume acquisition.86 Garjan and associates101 reported that 3DUS allowed for the identification of abnormalities that were not seen on 2D in three out of seven fetuses with skeletal dysplasias. Specific bones may be imaged with 3DUS to narrow the normally wide differential diagnosis of skeletal dysplasias (see Chapter 20). A recent study concluded that 3D/4D technology was a useful sonographic tool for evaluating the fetal thorax, in that it enhanced diagnostic precision and provided superior spatial visualization of the anomalies.102 3DUS has been used to estimate fetal weight using volume data for the abdomen and extremities because it is impossible to obtain an entire fetal volume.86 Some studies suggest that 3DUS may be more accurate than 2DUS for weight
prediction.103 Others, however, have found that fetal weight in prolonged pregnancies can be estimated using 2D sonography with the same accuracy as with 3D.104 Birth weight prediction has also been investigated using 3DUS and fractional limb volume.105 A 2009 prospective study compared inter- and intraobserver variation of fetal biometric measurements using 2D- and 3D-derived images.106 The authors observed that the use of 3DUS significantly reduced intra observer variation for head circumference, abdominal circumference, and femur length and reduced the interobserver variation for femur length. Fetal liver and lung volumes have also been reported.107,108 Chang and associates107 concluded that measurements made with 2DUS underestimated the fetal liver volume compared with 3DUS. The cervix can be imaged with 3DUS, along with the entire cerclage, if present. Vascular structures and their distribution and extent (e.g., umbilical cord, vasa previa, placenta accreta, velamentous insertions, aneurysm of the vein of Galen) have all been evaluated with 3DUS.86 Image acquisition can be difficult and time-consuming at times because of motion, flash artifacts, and the longer time volume acquisition with color and power Doppler techniques. A great advantage of 3DUS is the potential for enhanced early maternal bonding with the fetus. Among patients who undergo 3DUS for reassurance, those women with a history of fetal or neonatal demise, those with a history of a fetus with congenital anomalies, those carrying fetuses with lethal anomalies, those treated for infertility, and couples who have a surrogate carrying their pregnancy seem to derive the most benefit.86 In summary, the world is three-dimensional and 3DUS provides anatomic images that are more easily understood by both physicians and patients. It offers women and their care team an improved understanding of the anomalies found on 2DUS, clarifies the extent of the anomaly, and provides visual confirmation of the reality of the abnormality. It also facilitates bonding with the fetus.
SCREENING FOR TRISOMY 18 AND OTHER ANEUPLOIDIES Trisomy 18 (Edwards’ syndrome) is the second most common autosomal trisomy and has a uniformly poor prognosis. Second-trimester serum triple-marker screening can identify 60% to 75% of fetuses with trisomy 18 when a separate analysis is performed seeking low levels of all three analytes, with or without consideration of maternal age.109,110 Sonography has high but variable sensitivity for detecting trisomy 18 (64%–100%), particularly when the search is part of a thorough anatomic survey.26 We found that all fetuses with trisomy 18 had four or more sonographic anomalies (one fetus had 19 separate detectable anomalies).26 Shortened ear length was present in 96%, bilateral clenched or closed hands or overlapping digits in 95%, and central nervous system abnormalities in 87%. In another study, we observed shortened ear length (≤10th percentile) in 100% of fetuses with trisomy 13, 96% of fetuses with trisomy 18, 75% of those with Turner’s syndrome, and 91% of those with other various aneuploidies.59 Many investigators have confirmed that abnormal hands are seen in most fetuses with trisomy 18.26 Other sonographic abnormalities that are
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common in trisomy 18 include growth restriction, abnormal feet, choroid plexus cysts, and structural cardiac defects. We observed intrauterine growth restriction in 63% of fetuses with trisomy 18.26 In a large retrospective review of 98 second-trimester fetuses with trisomy 18, the authors were able to identify abnormal fetal anatomy or abnormal biometry in 97% of these fetuses.111 In 2008, Zheng and coworkers112 observed in a population of 26 trisomy 18 fetuses, that 3D/4D sonography enabled the identification of additional diagnostic information in 84 and influenced the obstetric management in 4. Choroid plexus cysts are visualized in 1% (range 0.3%– 3.6%) of normal fetuses in the second trimester (see Fig. 8–3). These cysts may be associated with trisomy 18,113 and in the past, genetic amniocentesis was considered even if they were isolated. However, a cyst can be considered “isolated” only after a detailed fetal survey shows no other structural abnormalities or markers. In our study, half of the fetuses with trisomy 18 had a choroid plexus cyst, but these were always associated with multiple other sonographic abnormalities (i.e., never isolated).26 In another study, none of 98 fetuses with an isolated choroid plexus cyst had aneuploidy, whereas 100% of the 13 fetuses with a choroid plexus cyst and major anatomic abnormalities had trisomy 18.114 In our experience, the risk of aneuploidy is very low and does not justify amniocentesis if no other anomalies are found (especially if the hands are open and the ear length is normal). Many investigators concur that if the choroid plexus cyst is isolated and the patient is at low risk for fetal aneuploidy, the presence of these cysts should not affect management. In fact, the authors of a 2004 editorial recommended that when a choroid plexus cyst is the only detected abnormality (an isolated marker on a second- or third-trimester sonogram that meets the most recently adopted AIUM performance guidelines), the sonographic report emphasizes that as an isolated finding in a patient considered low risk for fetal aneuploidy, a choroid plexus cyst is not clinically significant and does not change her from low to high risk status.115 Similarly to genetic sonography for fetal trisomy 21 screening, normal findings on a complete anatomic survey in experienced hands should “decrease” a patient’s risk of trisomy 18 (regardless of the presence of choroid plexus cysts or abnormal second-trimester biochemical screening results) to a low level sufficient to avoid genetic amniocentesis after appropriate patient counseling.26 A 2009 study of 8763 pregnancies at increased risk of trisomy 18 based on serum screening including 56 whose fetuses had trisomy 18 noted sonographic anomalies in 89% of trisomy 18 fetuses compared with 14% of normal.116 They reported that if the genetic sonogram was normal (no structural anomaly or soft marker), the risk was reduced by approximately 90%.116 Therefore, the authors concluded that if the genetic sonogram is used as a sequential test following serum biochemistry, a normal ultrasound study reduces the likelihood of trisomy 18 substantially, even if a woman has abnormal serum biochemistry. Trisomy 13 (Patau’s syndrome) has an extremely poor prognosis. Its phenotype is so characteristic that a diagnosis can often be based on clinical features alone. Because fetuses with trisomy 13 usually have severe abnormalities, it follows that the sensitivity of prenatal sonography for the detection
is very high, with most studies reporting sensitivities above 90%.117–119 Watson and colleagues120 achieved a 95% detection rate (36 out of 38) after 17 weeks based on either the presence of an anomaly or abnormal fetal biometry. Earlyonset growth restriction is common in trisomy 13 and triploidy. In particular, triploidy is associated with a characteristically small body relative to the head.
CRITICAL REVIEW OF THE EVIDENCE ON SECOND-TRIMESTER SCREENING FOR FETAL ABNORMALITY There is no uniform population-based screening for trisomy 21 in the United States. In fact, there are even laboratorydependent variations in the specific second-trimester serum markers used. Moreover, the emergence and availability of first-trimester screening has complicated screening strategies and choices even further for frontline clinicians. Whereas some centers now use an approach that involves both firstand second-trimester screening, others use second-trimester serum marker screening only, and some couple serum screening with an ultrasound for sonographic markers by unsupervised practitioners; only a small minority attempt to derive individual risks for fetal trisomy 21 (Table 8–7). In short, the current system in the United States is inconsistent with overall high quality and high value and should not be sustained. The addition of more screening tests (especially when additive or sequential) increases false-positive rates, patient anxiety, invasive testing rates, and procedure-related pregnancy losses. However, it may be possible to decrease the invasive testing rates while maintaining high sensitivity if sequential tests are interpreted in light of the results of earlier tests.121 Another variable to consider is that if 80% to 95% of fetuses with trisomy 21 are detected by firsttrimester screening, the predictive values of second-trimester screening (ultrasonography and biochemical screening) will be dramatically reduced.121 In theory, second-trimester biochemistry will probably identify at best-only 6% (60% of the residual 10%) of affected pregnancies screened by NT alone plus first trimester biochemistry while doubling the overall invasive testing rate (from 5% to 10%). There is also no uniformity in screening for fetal malformations. Table 8–7 lists several approaches that are used clinically. Examples include A and C (then J or K), B (then J or K), F (then J), H only, J only, and so on. We prefer A and C (then J or K), but believe that regardless of the firstand/or second-trimester screening tests performed, and even if the patient undergoes invasive testing, a second-trimester sonogram to evaluate the fetal anatomy is the standard. It is clear the plethora of trisomy 21 screening options has proved a source of confusion for patients and physicians. The type of test to offer also depends on several circumstances, such as when the patient presents for prenatal care, number of fetuses, the availability of chorionic villus sampling (CVS), prior obstetric history, family history, desire for early test results, and the availability of registered providers in the region of practice. Not every provider who does ultrasound is qualified; not every laboratory will provide up-to-date options. For example, not all strategies will include NT measurement because this screening approach requires specialized training on an annual basis to have
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 139 T A B L E 8 – 7
Various Approaches Used Clinically in Screening for Fetal Malformations and/or Aneuploidy APPROACH
DESCRIPTION
NOTES
A
First-trimester risk adjustment (age, NT, biochemistry results), with or without other markers (e.g., nasal bone, tricuspid regurgitation).
Might not be available in all regions, and NT measurement might not be obtained successfully in all patients.
B
Second-trimester serum screening (triple or quadruple).
Quadruple screening has higher sensitivity and should be utilized.
C
MSAFP.
Performed in the second trimester for those who had only first-trimester screening for aneuploidy or who have normal results from CVS.
D
Integrated (first plus second trimester).
NT, PAPP-A, quadruple screening. Results reported only after both first- and second-trimester screening tests are completed.
E
Serum integrated (first plus second trimester).
PAPP-A, quadruple screening. For patients without access to NT measurement or when reliable measurement cannot be obtained.
F
Stepwise sequential (first plus second trimester).
G
Contingent sequential (first plus second trimester).
H
Invasive testing (CVS, amnio) offered automatically to patients with AMA or abnormal screening results. Invasive testing (CVS, amnio) offered to all women, regardless of age. Sonographic fetal anatomy survey in second trimester; offer amnio, depending on results. Genetic sonogram (only high-risk patients); offer amnio if risk adjustment using negative LR is still abnormal or if marker(s) present.
First-trimester test result: a. Positive: diagnostic test offered. b. Negative: second trimester test offered. c. Final: risk assessment incorporates first and second results. First-trimester test result: a. Positive: diagnostic test offered. b. Negative: no further testing. c. Intermediate: second-trimester test offered. d. Final: risk assessment incorporates first and second results. Discuss risks and benefits of invasive testing. Genetic sonogram not performed. Discussed in ACOG Practice Bulletin: Screening for Fetal Chromosomal Abnormalities (January 2007)* Not AMA or has normal screening results. No calculated adjusted risk for aneuploidy given. A priori risk: first-trimester combined screening (if not done, then second-trimester serum screening or maternal age) Based on absence or presence of aneuploidy markers, structural anomalies, and abnormal biometry on ultrasound. Patient declines testing.
I J K
L
No testing performed.
AMA, advanced maternal age; amnio, amniocentesis; CVS, chorionic villus sampling; LR, likelihood ratio; MASFP, maternal serum α-fetoprotein; NT, nuchal translucency; PAPP-A, pregnancy-associated plasma protein A. * American College of Obstetricians and Gynecologists (ACOG): Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No. 77. Obstet Gynecol 2007;109:217–227.
access to the calculation algorithms, and this measurement may not be successfully obtained in a given subject. It is not practical to have the patient choose from among the large array of screening strategies that might be used.52 It is important that providers review the evidence, identify which tests are available in the practice area, and determine which strategy or strategies will best meet the needs of these patients before deciding which strategy to offer.52 The goal is to offer screening tests with high detection rates and low false-positive rates that also provide patients with the diagnostic options they prefer.52 It is important but often overlooked that discussions about sensitivity and false-positive rates, disadvantages and advantages, limitations, and risks/benefits of screening tests and invasive procedures be conducted with patients. One reasonable approach is to offer those patients seen in early pregnancy aneuploidy screening that combines first- and second-trimester testing in some fashion (integrated,
sequential, or contingency).52 The integrated approach to screening uses both first- and second-trimester markers (NT, PAPP-A, quadruple screen) to adjust a woman’s age-related risk of having a child with Down syndrome.122 However, the results are reported only after both first- and second-trimester screening tests are completed. In the FASTER trial, the detection rate was 94% to 96% (5% screen-positive rate).77 Whereas some patients value early first-trimester screening, others are willing to wait several weeks if this will result in a higher detection rate and decreased chance of an invasive test.123 The disadvantages of integrated screening are many and include (1) patient anxiety generated by having to wait 3 to 4 weeks between start and completion of the screening; (2) the loss of opportunity to consider CVS if the first-trimester screening indicates a high risk for aneuploidy124; and (3) patients may fail to complete the second-trimester portion of the screening test (after performing the firsttrimester component) and, as a result, be left with no
140 S ECTION TWO • Early Prenatal
screening results. If comprehensive first-trimester screening (biochemistry, NT, NB, ductus venosus, tricuspid valve) is available, there is little benefit to integrated screening for all women. Whether a patient chooses first-trimester screening or waits for an integrated screen will vary depending on personal preferences, the types of invasive tests available, the risks they present, the patient’s plans for termination, and the patient’s previous experiences. If NT cannot be performed for various reasons, an alternative is to perform serum integrated screening (PAPP-A, quadruple screen, no incorporation of NT measurement). In the FASTER trial, the serum integrated screen resulted in an 85% to 88% detection rate.77 Under these circumstance, the delay is acceptable to most women.125 Sequential screening may be more advantageous because the patient is informed of the first-trimester screening result. Those patients who are at highest risk may decide to have a diagnostic test, whereas those at lower risk can still take advantage of the higher detection rate achieved with additional second-trimester screening. There are two proposed strategies: stepwise sequential screening, and contingent sequential screening. In the stepwise sequential strategy, women determined to be at high risk (Down syndrome risk above a predetermined cutoff) after the first-trimester screen are offered genetic counseling and the option of invasive testing, whereas women below the cutoff are offered secondtrimester screening. For a 5% false-positive rate, the detection rate using the stepwise sequential strategy is 95%.77 In the contingent sequential strategy, patients are classified as high, intermediate, or low on the basis of first-trimester screen results. Women at high risk are offered CVS, and those at low risk have no further screening or testing. Only those women at intermediate risk are offered secondtrimester screening. Contingent sequential screening has been proposed as a model (88%–94% predicted detection rate; 5% false-positive rate),126 but large clinical trials using this approach have not yet been published. Therefore, this approach maintains high detection rates with low falsepositive rates, while reducing the number of second-trimester tests performed. For both the stepwise and the contingent strategies, patients at highest risk identified by first-trimester screening are offered an early invasive procedure. Both first- and second-trimester results are used to calculate a final risk for aneuploidy in patients at lower risk. As previously discussed, the performance of first- and second-trimester screening tests independently yields a high sensitivity for Down syndrome (94%–98%), but the screenpositive rates are additive, leading to many more unnecessary invasive procedures (11%–17%).77,78 Therefore, it has been recommended that women who have had firsttrimester screening for aneuploidy not undergo independent second-trimester serum screening in the same pregnancy.52 Women who desire the highest sensitivity can have either an integrated or a sequential screening test, which combines both first- and second-trimester screening results. Many still recommend maternal serum α-fetoprotein for neural tube defect detection; others argue that an examination by a skilled sonographer has an even higher yield. Ultimately, the screening strategy chosen will depend on the availability of CVS and sonologists who are appropriately trained in obtaining first-trimester sonographic
markers. For instance, when CVS and comprehensive firsttrimester screening are not available, one can offer: (1) integrated screening to patients who present in the first trimester, in order to take advantage of the improved detection rate and low-false positive rate and (2) second-trimester screening to those patients presenting after the first trimester.52 It is suboptimal to offer patients first-trimester screening but to have no physician available who can perform CVS if that is what the patient desires. If NT measurement is unavailable or cannot be obtained in a patient, a reasonable approach is to offer: (1) serum integrated screening to patients who present early and (2) second-trimester screening to those who present later.52 If one practices in an area where every possible screening strategy is available, it is reasonable to choose two screening strategies for the practice. For example, one can offer: (1) either comprehensive first-trimester screening or sequential screening for patients presenting for prenatal care prior to 14 weeks and (2) second-trimester serum screening for patients presenting after 13.6 weeks of gestation.52 A relatively new Down syndrome screening protocol is one that combines quadruple screening with nuchal fold and long bone measurements in the second trimester.127 It has been shown to be a feasible method (90% sensitivity; 3.1% false-positive rate) to improve Down syndrome screening performance over either sonography or second-trimester serum markers by themselves. The authors suggest that efficacy may be comparable with that reported for combined first- and second-trimester (integrated) screening.127 Another approach is to provide all women the option of invasive testing, regardless of age. As discussed previously, in January 2007, ACOG52 raised the issue in their Practice Bulletin that all women (regardless of age) should have the option of invasive diagnostic testing for aneuploidy. However, it is important to discuss the differences between screening and diagnostic testing with all women. Certainly, it would be ideal if all women were offered aneuploidy screening before 20 weeks’ gestation, regardless of maternal age.52 The significance of sonographic markers identified by a second-trimester ultrasound examination in a patient who has had a negative first-trimester screening test result is unknown.52 We believe that if the patient is otherwise low risk, the presence of only one marker (with the exception of structural anomaly, thickened nuchal fold, or absent NB) after a thorough, targeted survey will not significantly increase the risk of Down syndrome. However, if the patient is otherwise high risk, we would consider her a candidate for genetic sonography and, in the presence of marker(s), would counsel the patient that her risk for fetal Down syndrome is increased and offer and discuss genetic amniocentesis. We anticipate that, with growing expertise, more genetic sonograms will be offered as a first choice to high risk patients and will become the standard of care in this group, with targeted fetal scans reserved for the low risk patient. Some patients may prefer first-trimester screening, second-trimester screening, or a combination of both, just as some may prefer CVS to second-trimester amniocentesis. High sensitivity is important for high risk women, whereas low false-positive rates are most desirable among low risk women.
C HAPTER 8 • Second-Trimester Screening for Fetal Abnormalities 141 SUMMARY OF MANAGEMENT OPTIONS
Second Trimester Screening for Fetal Abnormalities Evidence Quality and Recommendation
Management Options
References
General Discuss the screening options in the first and second trimesters and decide on an individual pregnancy management plan (e.g., serum testing, ultrasound, invasive testing)
—/GPP
—
Invasive diagnostic testing (CVS, amniocentesis) for aneuploidy offered to all women, regardless of maternal age
IV/C
52
Use quadruple screen testing for greater sensitivity
IIa/B
15,16
Combine with detailed sonography to screen for aneuploidy
III/B
53
IIa/B
64
Neural tube defect screening should be offered in the second trimester to women who elect only first-trimester screening for aneuploidy or who have had a normal result from CVS
IV/C
52
After first-trimester screening, subsequent second-trimester Down syndrome screening is not indicated, unless it is being performed as a component of the integrated test, stepwise sequential, or contingent sequential test
IV/C
52
Perform a detailed survey to increase sensitivity, and screen all patients with this test
—/GPP
—
Genetic sonography should be offered only to high risk patients and performed by experienced laboratories
III/B
53
Use three-dimensional sonography to add more information to two-dimensional sonography, if available
IV/C
86
III/B
89,90
For all patients, perform combined first-trimester screening (age, nuchal translucency, biochemistry)
IIa/B
75
For all patients, perform MSAFP only in the second trimester
IV/C
52
For all patients, perform fetal anatomy survey or genetic sonogram in second trimester (both detailed examinations), depending on circumstances
III/B
53
IIa/B
64
Invasive testing also discussed as an option, when applicable
—/GPP
—
Perform three-dimensional ultrasound, if necessary
IV/C
86
III/B
89,90
Second-Trimester Serum Screening
Second-Trimester Sonography
Authors’ Practice
CVS, chorionic villus sampling; GPP, good practice point; MSAFP, maternal serum α-fetoprotein.
SUGGESTED READINGS American College of Obstetricians and Gynecologists: Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No. 77. Obstet Gynecol 2007;109:217–227. American Institute of Ultrasound in Medicine (AIUM): Practice Guideline for the Performance of Obstetric Ultrasound Examinations. Laurel, Md, AIUM, 2007.
Benacerraf BR, Benson CB, Abuhamad AZ, et al: Three- and 4-dimensional ultrasound in obstetrics and gynecology. Proceedings of the American Institute of Ultrasound in Medicine Consensus Conference. J Ultrasound Med 2005;24:1587–1597. Ewigman BG, Crane JP, Frigoletto FD, et al: Effect of prenatal ultrasound screening on perinatal outcome: RADIUS Study Group. N Engl J Med 1993;329:821–827.
142 S ECTION TWO • Early Prenatal Filly RA, Benacerraf BR, Nyberg DA, et al: Choroid plexus cyst and echogenic intracardiac focus in women at low risk for chromosomal anomalies. J Ultrasound Med 2004;23:447–449. Malone F, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down’s syndrome. First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. N Engl J Med 2005;353:2001–2011. Vintzileos AM, Campbell WA, Rodis JF, et al: The use of second-trimester genetic sonogram in guiding clinical management of patients at
increased risk for fetal trisomy 21. Obstet Gynecol 1996;87: 948–952. Yeo L, Vintzileos AM: The use of genetic sonography to reduce the need for amniocentesis in women at high-risk for Down syndrome. Semin Perinatol 2003;27:152–159.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 9
Invasive Procedures for Antenatal Diagnosis GEORGE ATTILAKOS and PETER W. SOOTHILL Videos corresponding to this chapter are available online at www.expertconsult.com.
INTRODUCTION Obstetric ultrasound fostered the development of invasive techniques to assist in antenatal diagnosis. Methods such as chorionic villus sampling (CVS), amniocentesis, fetal blood sampling (FBS), and fetal tissue biopsy allow testing of fetal materials for chromosomal, genetic, and biochemical abnormalities. The type of procedure selected depends on many factors, including the indication, the gestational age, and how soon the result is needed. Possible applications are increasing rapidly with advances in human genetics and the evolution of molecular tools, but all invasive in utero diagnostic techniques carry a risk of fetal injury or death. These risks must be properly explained to the parents during the informed consent process. Noninvasive approaches, such as measuring free fetal DNA in the mother’s blood, show great promise but, are at present, used clinically only in specific areas, such as fetal blood group or sex prediction.1 Although the use of free fetal DNA and the introduction of effective screening strategies have led to fewer invasive procedures being performed,2,3 the latter are required for the definitive diagnosis of most fetal genetic problems. This chapter summarizes the indications, methods, and complications of the most common invasive diagnostic methods.
ISSUES COMMON TO ALL INVASIVE DIAGNOSTIC TECHNIQUES All of the techniques described in this chapter share certain features.
Guidelines for Training The Royal College of Obstetricians and Gynaecologists (RCOG) published guidelines for amniocentesis and CVS, including guidance on training in antenatal invasive diagnostic methods.4 They are praised for their efforts to seek standards. They suggest that practitioners who perform invasive procedures must have a high level of training in obstetric ultrasound and that training with clinical skills models be considered. Because training is now
competency-based, they do not specify a minimum number of supervised procedures before practitioners can act independently. However, they suggest that trainers perform at least 50 ultrasound-guided invasive procedures annually. After completing training, physicians should perform at least 10 invasive procedures per year in order to retain their skills, although it is emphasized that there is no evidence on the subject. It is also recommended that amniocentesis for multiple gestation be performed in a tertiary fetal medicine unit. Training in CVS and FBS is not part of general obstetric training and is usually limited to trainees who specialize in fetal and maternal medicine. Units that perform more complex fetal procedures should perform enough procedures each year to maintain skills. They should periodically audit the results and make these available to patients and colleagues. A reasonable minimum number of complex procedures is 12 per year.
Consent The procedure, its goals, and likely or significant complications must be explained in language that is understandable to the patient so that written informed consent can be obtained. The specific considerations for each procedure are discussed later.
Audit of Practice It is important that the rate of complications for individual operators is monitored through robust mechanisms. Because the incidence of complications is small, it is proposed that the 95% confidence interval (CI) be used as a monitoring tool.4 For example, the miscarriage rate for amniocentesis should not be more than 3 out of 50 or 4 out of 100 consecutive procedures. If these values are triggered, a change may be necessary. A method of prospective performance monitoring by statistical process control charts has been described.5 The complication studied was multiple needle insertion for amniocentesis, and the authors used the 90% CI as a “warning” line and the 95% CI as an “action” line. An individual with poor performance would have triggered the action line after 55 procedures. 143
144 S ECTION TWO • Early Prenatal
Sampling Site Ultrasound is used to determine the best site to obtain the sample, considering the target size, needle length, needle path, and potential injury to structures in the path. The skin site for needle insertion is planned, but the position chosen reflects the ultrasound-guided technique used.
Ultrasound-Guided Needling Technique Two approaches to ultrasound-guided needling are used: needle guide and freehand.
technique allows the operator to adjust to changes during the procedure (such as contractions or fetal movements) and is the preferred approach of the authors. Some operators prefer to have an assistant control the scanning transducer, but then the operator forfeits control of the intended needle path. Others prefer a single-operator technique in which one hand holds the needle and the other holds the ultrasound transducer. An assistant is required to withdraw the needle stylet, fix a syringe, aspirate at the right time, and place the sample in appropriate containers without spillage, contamination, or mislabeling.
Needle Guide
Preparation
The needle guide technique uses a sector or curvilinear ultrasound transducer with a guide that has an attached needle channel. Lines on the ultrasound screen indicate the path of the needle when inserted down the guide. The transducer is moved until these lines cross the intended target. This approach allows the use of thinner needles (i.e., 22–26 gauge) than those needed for a freehand pro cedure (i.e., 20–22 gauge). Despite the use of a thinner needle and the fact that the entire length of the needle is not usually seen, the tip is visible as a bright dot. Some have suggested that the complication rate may be lower than with the freehand technique, perhaps because the needle is thin and its movement confined to a single plane, though data on this are limited.6 The guide does not seem to increase the need to remove and reinsert the needle, nor is there a relationship between the number of insertions and the complication rate.
Regardless of technique, the atmosphere should be informal, and any additional staff required should be present for the procedure and introduced to the patient. Anything that gives the patient an image of an “operation” (e.g., surgical masks, hats, drapes) should be minimized or replaced by a scrupulous “no-touch” technique. The length of the needle required depends on abdominal wall thickness, amniotic fluid volume, and fetal and placental positions. An 8- to 12-cm needle is usually sufficient, but if in doubt, the distance should be measured on the screen before the procedure. Detailed ultrasound examination of the fetus is performed before the procedure because the discovery of structural defects, impaired growth, or other problems may alter the physician’s and patient’s choice. New ultrasound findings may make the procedure unnecessary, or help subsequently, when there is an unusual chromosomal finding such as mosaicism.
Freehand The freehand technique uses a curvilinear or linear ultrasound transducer. The ultrasound transducer is moved until the intended sampling site is identified and appears on one side of the ultrasound screen, with the skin insertion point on the other. The intended needle path is nearly perpendicular to the ultrasound beam, allowing the length of the needle to be adequately imaged (Fig. 9–1). The freehand
Needle Path Selection If using the freehand technique, the target is visualized on screen, and the transducer is rotated through 180 degrees until a path that avoids fetal parts and maternal vessels is identified. The transducer is adjusted until the sampling site and the skin insertion point are on opposite sides of the screen. With the freehand technique, the best skin insertion point is determined by observing sonographically the effect of digital pressure on the maternal abdomen. When a needle guide is used, simply line up the needle track with the target.
Antiseptic and Anesthetic P
N
F
FIGURE 9–1 Ultrasound view of an amniocentesis needle (N) entering a pool of amniotic fluid. F, fluid; P, placenta.
The skin insertion site is scrupulously cleaned with antiseptic solution (e.g., chlorhexidine). Procedures that require larger than a 22-gauge needle may be helped by local anesthetic, which is injected first into the skin and then into the abdominal and uterine peritoneum. When using the freehand technique, the anesthetic injection may help confirm the needle angle required to follow the intended path and may decrease the need to change the direction of the sampling needle during the procedure. When a needle guide is used, simply line up the needle track with the target and inject the local anesthetic with a shorter needle. Patients who have undergone amniocentesis with a 22-gauge needle with and without local anesthesia reported similar pain scores and certainly lower pain scores than outpatient gynecologic procedures.7–9
C HAPTER 9 • Invasive Procedures for Antenatal Diagnosis 145
Viral Infections Consideration should be given to the possibility of fetal infection by maternal-fetal transmission during the procedure. It appears the risk of fetal infection by hepatitis B is low and the hepatitis B e-antigen status can help guide counseling.10 Similarly the risk of hepatitis C transmission appears low, but such data are limited.10 Vertical transmission of HIV is rare, and the virus is not detectable in amniotic fluid even if it is detectable in the maternal blood.11 However, the risk of vertical transmission may be increased by amniocentesis, particularly if the mother is not on antiretroviral therapy12 and if a fetal “needle-stick” occurs. It is recommended that all screening options are considered in the case of mothers with HIV before invasive procedures are offered.10 The use of antiretroviral therapy is likely to reduce the risk of infection.12,13
Postprocedure Considerations The patient should be shown both the fetus and the motion of the fetal heart on the ultrasound monitor after the procedure. The sample is carefully labeled, and the details are confirmed by the woman before the sample is taken to the laboratory. The information submitted to the laboratory must be sufficient for testing to be done and diagnosis to be made. It should include information about consent, including permission to store DNA and maintain cells lines, if applicable.
Alloimmunization An invasive procedure associated with placental bleeding has a risk of Rhesus sensitization.14–16 After an invasive intrauterine procedure, 500 IU rather than 250 IU anti-D immunoglobulin can be given intramuscularly to an at-risk Rhesus-negative woman, and indeed, the Society of Obstetricians and Gynaecologists of Canada recommends a dose of 1500 IU (300 µg) following amniocentesis, CVS, or cordocentesis.17
Multiple Pregnancies Invasive procedures should be performed in women with multiple pregnancies only in a fetal medicine unit.4 In the first trimester, the chorionicity of each sac should be carefully determined and the placental implantation site mapped.18 In monochorionic pregnancies, a single amniotic fluid sample may be reasonable, unless ultrasound shows discordance for fetal abnormalities when both fetuses should be sampled. In dichorionic pregnancies, both sacs should be sampled separately, either with a single needle through the intertwin septum19–21 or with two separate maternal abdominal punctures.22 The operator should be able and willing to perform a selective feticide if an abnormal result is discordant or refer the patient to an appropriate center. The fetal loss rate after amniocentesis in twin pregnancies appears slightly higher than in singleton pregnancies.23 The excess risk of miscarriage in various studies has been calculated between 1.2% and 1.8%,22,24 Ultrasound guidance eliminates the need for any dye injection, and if used, potentially harmful dyes such as
methylene blue should not be used.25 Instead of using a dye, some operators inject 2 to 3 mL of amniotic fluid mixed with air back in the amniotic sac after the first amniocentesis. This creates intense echogenicity in the first amniotic sac for 30 to 60 seconds, which allows adequate time for the second amniocentesis to be performed. If an injection of dye seems prudent, indigo carmine is preferred. Fetal zygosity can be determined from DNA when clinically indicated or when the fetuses are at risk for inheritable syndromes.26
Complications The loss rate after an invasive diagnostic procedure is a combination of the procedure-related loss rate and the background loss rate. The background loss rate is much higher if the fetus has an anomaly (e.g., chromosomal abnormality, intrauterine growth restriction, fetal hydrops).27 The procedure-related loss rate is the product of many factors, including maternal age, operator experience, type of procedure, technique used, and the difficulties experienced during the procedure.6,28 The gestational age at the time of the procedure is also relevant. In one study, the rate of fetal loss in older women after transabdominal and transcervical CVS was 5.8% and 6.2%, respectively, if done before 12 weeks, but 2.4% thereafter.29 Some portion of the excess loss early in gestation reflects losses destined to occur whether the procedure was done or not. Early CVS and diagnosis of aneuploidy may result in termination, with all of the physical and psychological implications for the parents, whereas delayed CVS or amniocentesis may, by virtue of the later gestation, allow time for spontaneous loss to precede the planned procedure. Several multicenter studies failed to show consistent procedure-related differences with regard to the safety of CVS compared with other methods.30,31 The procedure-related loss rate for CVS, amniocentesis, and FBS is reported in many studies, including those listed in Table 9–1.6,14,30,32–60 No standard criteria are used to determine background loss rates. Postprocedural loss rates generally include all up to 28 weeks and up to term in some studies.14,48 Others suggest that most procedure-related losses occur within 2 weeks of the procedure (Table 9–2).27 Procedures should be confined to centers with volumes large enough to calculate their own loss rates rather than to quote the rates of other units.
SPECIFIC PROCEDURES Chorionic Villus Sampling Introduction CVS, or placental biopsy, is performed from 11 weeks onward for the diagnosis of many chromosomal and genetic conditions. Amniocentesis used to be the most common invasive diagnostic test, but over the last few years, CVS use has grown in some countries to more than 50% of the invasive diagnostic procedures,3 and the procedure is associated with more than 50% of diagnoses of chromosomal abnormality,61 probably because of first-trimester screening. CVS is usually performed by transabdominal needle aspiration, although some practitioners still use a transcervical
146 S ECTION TWO • Early Prenatal T A B L E 9 – 1
Reported Outcomes after Invasive Prenatal Diagnostic Procedures SERIES
PROCEDURE
STUDY TYPE
REPORTING OF OUTCOMES
MRC, 197814 Tabor et al, 198658
Amnio Amnio
Controlled RCT
Reported outcome until the end of the neonatal period
Canadian trial, 198957
Amnio, CVS
RCT
Smidt-Jensen et al, 199255
Amnio, CVS
RCT
Johnson et al, 199653 Nicolaides et al, 199654
Amnio Amnio, CVS
RCT Observational
Sundberg et al, 199752 Hanson et al, 198756
Amnio, CVS Amnio, CVS
Observational Observational
Reported outcome as induced abortion, loss ≤ 140 days, between 141–196 days postprocedure Reported outcome until the neonatal period; classified as spontaneous loss before the procedure, elective abortion postprocedure, and unintentional loss Reported outcome as postprocedure total fetal loss rate until term Outcomes classified as total loss (spontaneous and induced) and spontaneous loss (IUD/NND) Reported outcome as total fetal loss rate and neonatal morbidity
Eiben et al, 199742
Amnio
Observational
CEMAT, 199859 Borrell et al, 199960
Amnio Amnio, CVS
RT RT
Roper et al, 199945
Amnio
Observational
Reported fetal loss < 24 wk, SB < 36 wk, preterm labor < 36 wk
Papantoniou et al, 200143
Amnio
Observational
Blessed et al, 200144 Salvador et al, 200239 Corrado et al, 200238
Amnio Amnio Amnio
Observational Observational RCT
Reported fetal loss < 2 wk, < 28 wk, and > 28 wk Reported fetal loss within 30 days Reported outcomes as second-trimester abortions
Blackwell et al, 200240 Muller et al, 200237
Amnio Amnio
Observational Observational
Eddleman et al, 200641
Amnio
Observational
Reported fetal loss < 24 wk
Caughey et al, 200636
Amnio, CVS
Observational
Rhoads et al, 198930 MRC European Trial, 199150
CVS CVS
Observational RCT
Reported fetal loss < 24 wk Reported outcome until the end of the neonatal period
Wapner, 199748 Papp et al, 200235
CVS CVS
Observational Observational
Brambati et al, 200234
CVS
Observational
Reported fetal loss < 24 wk, IUD > 24 wk and NND
Brun et al, 200332
CVS
Observational
Reported fetal loss < 28 wk and > 28 wk
Lau et al, 200533
CVS
Observational
Maxwell et al, 199147
FBS
Observational
Anandakumar et al, 199349
FBS
Observational
Reported SA < 24 wk, SB > 24 wk, and NND Reported losses in pregnancies with normal fetal anatomy, fetal abnormalities, fetal physiologic assessment, nonimmune hydrops; 2-wk cutoff for procedure-related loss Reported loss when FBS was done for fetal abnormality on scan, normal fetuses, nonimmune hydrops, advanced maternal age; 2-wk cutoff for procedure-related loss
Ghidini et al, 199346
FBS
Observational
Wilson et al, 199451
FBS
Observational
Weiner and Okumura, 19966
FBS
Observational
Reported outcome as SA (16 wk), induced abortion, SB (36 wk)
Reported outcomes < 2 wk, > 2 wk, and 28 wk postprocedure Reported outcomes < 28 wk Reported loss as preprocedure abortion, postprocedure abortion (20 wk), SB, LB, and NND Reported loss as preprocedure, 28 wk Reported procedure-related loss in cases with normal fetal growth and anatomy, fetal abnormality, or IUGR; 1-wk cutoff for procedure-related loss Reported outcomes until term; 2-wk cutoff for procedure-related loss
Amnio, amniocentesis; CVS, chorionic villus sampling; FBS, fetal blood sample; IUD, intrauterine death; IUGR, intrauterine growth restriction; LB, liveborn; NND, neonatal death; RCT, randomized controlled trial; RT, randomized trial; SA, spontaneous abortion; SB, stillbirth.
T A B L E 9 – 2
Overview of Pregnancy Losses after Amniocentesis, Chorionic Villus Sampling, and Fetal Blood Sampling as Classified TEST
TOTAL (%)
Amniocentesis Chorionic villus sampling Fetal blood sampling
10 (1.8) 18 (4.1) 18 (10.7)
MINUS
KNOWN LETHAL CONDITION 3 14 16
MINUS
>2/52
= PROCEDURE-RELATED (%)
3 3 0
4 (0.7) 1 (0.23) 2 (1.19)
From Nanal RKP, Soothill PW: A classification of pregnancy loss after invasive prenatal diagnostic procedures: An approach to allow comparison of units with a different case mix. Prenat Diagn 2003;23:488–492.
C HAPTER 9 • Invasive Procedures for Antenatal Diagnosis 147
technique, with catheter aspiration or biopsy. Many consider transcervical CVS an obsolete technique because of the higher procedure pregnancy loss rates.55
Indications Fetal trophoblast cells, especially from the mesenchymal core of the villi, divide rapidly. The advantage of first-trimester CVS is rapid diagnosis at an early gestation. If an abnormality is detected, surgical termination, rather than medical induction, can be offered. Early detection of chromosomal disorders is the most common indication for CVS. The introduction and growing availability of first-trimester screening for Down syndrome (e.g., nuchal translucency, β-human chorionic gonadotropin [β-HCG] and pregnancyassociated plasma protein A [PAPP-A] measurement)62 have increased the importance of CVS. Noninvasive approaches, such as measuring maternal plasma free fetal DNA, have made invasive testing for sex-related disease unnecessary in 50% of the cases because it is required only when the fetus is the at-risk sex.2,63 Because of the increasing number of diagnosable monogenic disorders, couples with a family history of a genetic disorder should be offered genetic counseling, either before conception or early in pregnancy. Rapid direct preparation of the fetal karyotype or fluorescent in situ hybridization (FISH) have largely been replaced with quantitative fluorescent polymerase chain reaction (QF-PCR) of chromosomes 13, 18, 21, and Y, if requested. Fetal cells are also cultured for karyotype analysis, but it is very likely that this will be replaced by molecular whole genome approaches such as array comparative genome hybridization (CGH). CVS can be used at any time in gestation, and placental biopsy is a very successful way to obtain a karyotype after delivery when the fetus has died.
PROCEDURE
CHORIONIC VILLUS SAMPLING Consent The procedure should be described to the patient. Counseling must include the aims of the CVS (i.e., karyotype, DNA analysis), and the risk of a serious complication (often described as 1%), including miscarriage, either procedure-related or background, should be quoted. The possible risk of limb defects is mentioned by some, but the risk is minimal after 10 weeks. The limitations of a karyotype and the risks of unrelated abnormalities that are not detected by a karyotype should be explained. Patients should also be informed of the small chance that testing will show confined placental mosaicism or sex chromosome abnormality and the small possibility of a further invasive technique such as amniocentesis or fetal blood sampling to confirm a diagnosis. Alternative diagnostic techniques may be discussed. Only after the counseling process is complete is the patient asked to provide written consent.
Sampling Site The ideal target is a thick part of the placenta that can be sampled at an angle that allows a long needle path through the placenta and avoids a perpendicular path toward the chorionic plate. Very rarely, at approximately 11 weeks, transabdominal CVS is difficult if the uterus is retroverted, the placenta is posterior, and a lateral approach is not possible. Some operators switch to a transcervical approach, but we would ask the patient to return in a week, when sampling may be easier. Target Puncture Transabdominal CVS can be done either freehand or with a needle guide. With the “double-needle” technique (Fig. 9–2), after a local anesthetic has been administered, the first needle is advanced through the maternal skin, through the uterine wall, and into the placenta. The stylet is removed, and a second needle is passed into the placenta and attached to a syringe that contains normal saline. The placental villi are then aspirated.64,65 By drawing the finer needle into the outer needle during aspiration, the sharp bevel of the first needle seems to cut the villi, reducing the need for needle movement and presumably reducing placental trauma.66 A placental biopsy forceps may also be used through an outer guide needle. With the double-needle technique, if the tip is inserted correctly into the placenta, maternal contamination cannot occur. If a single needle is used, the aspirated tissue can be examined with a dissection microscope to exclude maternal contamination, but the risk of contamination should be considered. Whatever technique is selected, the sample is placed in a suitable CVS medium before it is transferred to the cytogenetics laboratory. Maternal contamination of chorionic cell cultures may lead to a false-negative diagnosis, particularly when polymerase chain reaction (PCR) amplification is used and in some biochemical examinations. Operator experience reduces the risk of maternal cell contamination. Transcervical CVS This approach is less common now because of an apparent increased risk of fetal loss and an increased
FIGURE 9–2 An 18- to 21-g double needle for chorionic villus sampling (CVS). The stylet of the 18-g (pink) needle is removed and the thinner 21-g (green) needle is passed into the placenta for the aspiration of the villi.
148 S ECTION TWO • Early Prenatal
likelihood of failure.67–69 Only 2%, and now probably less, of fetal medicine consultants in the United Kingdom perform transcervical CVS.70 Some practitioners consider this approach useful in high risk patients who require early diagnosis or when the uterus is retroverted and the placenta is posterior or when an anterior wall leiomyoma makes an abdominal approach difficult. A bendable polyethylene catheter with a metal obturator is introduced through the cervix and advanced into the placenta under ultrasound guidance. A syringe that is partially filled with saline is attached to the hub and a vacuum created to aspirate 10 to 50 mg of tissue, which is then rinsed into a Petri dish. Some units prefer curved biopsy forceps.71
Complications CVS should be performed only under continuous ultrasound guidance. Canadian57 and Danish55 trials found no significant difference in procedure-related loss rates between the first and the second trimesters. Only the Danish study55 allowed a randomized comparison of transabdominal CVS and second-trimester amniocentesis and the fetal loss rates were similar. A 1% excess fetal loss rate is usually quoted for amniocentesis and CVS. Some reports suggest that first-trimester CVS (including those performed as early as 6–7 wk) may be associated with severe limb defects.72–74 These defects were not observed in CVS performed after 11 weeks’ gestation. The World Health Organization (WHO) International Registry for Limb Defects found no difference in the prevalence of limb defects
after CVS compared with the background population.75,76 Therefore, during counseling, it is standard practice to indicate that there is no increased incidence of limb defects after 10 weeks.
Placental Mosaicism Confined placental mosaicism occurs in approximately 1% of samples,77–80 but this rate may be lower with experienced laboratories. Analyzing several cultures makes it easier to detect in vitro changes because they are usually present in a single culture (pseudomosaicism). However, the same finding in several or all of the cultures increases the likelihood of true mosaicism, either confined to the placenta or present in both placenta and fetus. In this case, another fetal tissue, such as blood or amniotic fluid, should be tested depending in part on the particular chromosome involved. The finding of structural abnormality on ultrasound is very important and makes it much less likely that the results are caused by confined placental mosaicism.
Late Placental Biopsy Several small series indicate that late placental biopsy is both safe and reliable for diagnosis. The loss rate is similar to that of first-trimester CVS.81,82
Conclusion CVS provides a rich source of fetal cells or DNA for analysis of karyotypic and genetic disorders. It is usually performed after 11 weeks, typically by a transabdominal route. One advantage of first-trimester CVS is that an abnormal result allows surgical termination, if desired. Mosaicism is a rare complication in about 1% of samples; the rate is lower with amniocentesis.
SUMMARY OF MANAGEMENT OPTIONS
Chorionic Villus Sampling and Placental Biopsy Management Options
Evidence Quality and Recommendation
References
Indications Genetic
III/C
61
Ia/A
67
Fetal loss rate has been reported to be similar to amniocentesis, though this remains controversial
Ib/A
67
Fear of limb-reduction defects (gestation-dependent)
IIb/B
75,76
QF-PCR/fluorescent in situ hybridization, karyotype, DNA Procedural Options Transabdominal is the route of choice Complications
Placental mosaicism
III/B
79,80
Alloimmunization
III/B
17
Maternal contamination
III/B
86
QF-PCR, quantitative fluorescent polymerase chain reaction.
C HAPTER 9 • Invasive Procedures for Antenatal Diagnosis 149
Amniocentesis Introduction Amniotic fluid contains amniocytes in addition to fetal cells from the skin, genitourinary system, and gut, along with biochemical products that may be removed for analysis. Amniocentesis should be performed only under continuous ultrasound guidance.4
Indications GENETIC Amniocentesis is usually performed to determine fetal karyotype. Indications for fetal karyotyping include an abnormal screening test result for trisomy 21, advanced maternal age, a sonographically detected structural abnormality, previous aneuploidy, and known chromosomal translocation in either partner. With the advance of genetics and molecular biology, more genetic diseases can be diagnosed by amniocentesis rather than other more “direct” methods: for example, harlequin ichthyosis can now be diagnosed with DNA-based testing on amniotic fluid rather than fetal skin biopsy.83,84 The amniotic fluid container is labeled and examined by the patient for accuracy, and the sample is sent promptly to the cytogenetics laboratory for analysis. The amniocytes are studied during the metaphase stage of cell division. Although standard culture techniques require 2 to 3 weeks, newer methods, with the cells grown on a cover slip, allow a complete analysis in 7 to 10 days,85 and it is likely karyotyping will be replaced by molecular approaches in the next few years. Approximately 0.5% of cultures are unsuccessful; less often, maternal contamination complicates the diagnosis.86 Less than 0.4% of cultures show evidence of pseudomosaicism or true mosaicism.87,88 FBS may be helpful, but a normal result does not guarantee that all is well. Direct DNA probing of interphase chromosomes by FISH can be used to detect known deletions, such as 22q in at-risk pregnancies, in addition to rapid diagnosis of trisomy 13, 18, and 21,89,90 but the latter has been replaced by QF-PCR. Although a positive test result is reliable, detecting 90% or more of chromosomal abnor malities, some problems detectable by karyotyping will not be found on rapid testing. Currently, rapid aneuploidy screening is usually performed with QF-PCR whose detection rate for the common aneuploidies (chromosomes 13, 18, 21, X, and Y) is 98.6%.91 QF-PCR has some advantages over FISH, which is why it is used more widely. It has been argued that QF-RCR could be used as a “stand-alone” test (no karyotype performed), but this could result in a small proportion of abnormalities not being diagnosed.92 PCR-based primers are now used with DNA from amniotic fluid samples to determine almost all potentially relevant fetal red blood cell and platelet genotypes.93,94 Methods using free fetal DNA in maternal blood are likely to further reduce the need for amniocentesis. In some countries, it is already used to detect fetal D status, when indicated, as part of routine prenatal care,63 and high throughput testing is being introduced to reduce the administration of the blood product anti-D in routine antenatal prophylaxis.95
BIOCHEMISTRY Molecular DNA analysis has largely replaced amniocentesis to diagnose inborn errors of metabolism and cystic fibrosis by measuring fetal enzymes activity and their products or substrates. Likewise, amniocentesis to measure α-fetoprotein and acetylcholinesterase to diagnose a neural tube defect are rarely necessary because of the reliability of ultrasonography.96
FETAL INFECTION Although cytomegalovirus is excreted in fetal urine and fetal infection is reliably detected by culture of amniotic fluid,97,98 PCR technology is the method of choice for the antenatal diagnosis of fetal viral infection because many viruses grow poorly in clinical laboratories (also see Chapters 27–31). PCR has replaced the traditional mouse inoculation test for toxoplasmosis because it can be used earlier in pregnancy and has greater sensitivity (also see Chapter 32).99 As with traditional methods, a false-negative result may occur if there has been insufficient time for transplacental passage to occur. Therefore, in cases of suspected toxoplasmosis, a negative amniocentesis result does not provide complete reassurance and ultrasound follow-up is recommended.100
CHORIOAMNIONITIS Successful amniocentesis is possible in 49% to 98% of women with preterm premature rupture of the membranes (PPROM).101 The likelihood of successful sampling is higher in more recent publications.102 The specimen can be assessed by direct microscopy, Gram stain, culture, and a series of new proteomic tools. It is unclear whether management based on the information gained in women with PPROM changes the clinical outcome. No randomized trial supports the use of routine amniocentesis to diagnose chorioamnionitis in women with either preterm labor or PPROM, although a small study showed an increased hospital stay for babies in the “no amniocentesis” group.103 A recent feasibility study concluded that a randomized study of amniocentesis versus no amniocentesis in women with PPROM would be feasible.104 Amniocentesis may be useful when the woman is asymptomatic and fetal infection is suspected. Between 17% and 34% of asymptomatic women with PPROM have positive culture findings,101 which may allow for earlier diagnosis and treatment.105 However, most women with positive culture findings deliver within 48 hours, and there is inadequate information to guide antibiotic selection to ensure therapeutic concentrations at the site of infection.
FETAL LUNG MATURITY Improved gestational dating, appropriate use of corticosteroids, and a growing understanding of the timing of iatrogenic premature delivery have nearly eliminated the need for amniotic fluid analysis to assess fetal lung maturity.106
Early Amniocentesis Some had hoped that early amniocentesis (4000 g), low birth weight, very low birth weight, or extremely low birth weight (8
>24
Moderate
>11
>32
68
50
≤6
19
190
Severe
>15
>44
≤45
13
540
≤65
AFI, amniotic fluid index; SDP, single deep pocket. From Harman CR: Amniotic fluid abnormalities. Semin Perinatol 2008;32:288–294.
polyhydramnios was 10%.159 Whether a karyotype should be obtained in the absence of anomalies or growth restriction is more controversial because the likelihood of aneuploidy is much lower in the setting of a normal sonogram. In this same series, the prevalence of aneuploidy was 1%,159 a range consistent with that reported in prior series.109,160–163 We recommend karyotype in cases of severe polyhydramnios because of the increased risk of aneuploidy in most series, the possibility that anomalies escaped detection during the sonographic examination, and the low risk of the procedure, especially if fluid is being withdrawn for therapeutic reasons (see later). In addition to the fetal examination, maternal testing for diabetes and isoimmunization may be useful if not previously performed. Maternal history may suggest testing for other etiologies such as infections or drug exposures.
Management Options Standard The most effective treatments for polyhydramnios address the specific diagnosis, such as diabetes control and fetal TTTS. These treatments are described elsewhere in this text. The goal of nonspecific treatment in polyhydramnios is to relieve intolerable maternal symptoms and to avert preterm delivery. Mild and moderate polyhydramnios are usually managed expectantly, and treatment is reserved for symptomatic patients and for those with severe polyhydramnios. Many authors will treat severe polyhydramnios regardless of maternal symptoms due to the increase in intra-amniotic pressure found in these pregnancies.157 One possible treatment paradigm is to reduce maternal to fetal water flow. Although maternal dehydration should reduce transplacental water flow, manipulations of the maternal plasma volume or osmolality, as with diuretics, are not used because they may reduce placental blood flow and impair fetal oxygenation.164 Fetal urine flow in polyhydramnios has been manipulated with maternally administered prostaglandin synthase inhibitors with good results. Several series and case reports document the use of indomethacin to treat polyhydramnios,165–171 although there are no randomized trials for this indication. Indomethacin may also act through an effect on the fetal membranes,106 but most likely, it increases the resorption of water in the renal tubule by inhibition of prostaglandins.42,106 The most commonly used dose of indomethacin is 25 mg every 6 hours,106 although some report doses up to 200 mg/day.150,168,171 In most reports, the dose is reduced or stopped if there is oligohydramnios or signs of fetal ductal constriction. Otherwise, the
indomethacin may be continued if effective in reducing the AF volume until 32 to 34 weeks when the risk of ductal constriction begins to rise. It may be possible to taper the dose and discontinue indomethacin treatment earlier if severe polyhydramnios does not recur. Indomethacin is not used in TTTS, because there are serious concerns of exacerbating the condition of the donor fetus. Indomethacin has a variety of undesirable fetal effects, including closure or constriction of the ductus arteriosus,170 the development of oligohydramnios,172 and fetal renal damage,173,174 although not all reports support these associations.175 We obtain serial fetal echocardiographic evaluation at weekly intervals if the treatment exceeds 48 hours. Sonographic signs of ductal constriction include tricuspid regurgitation and right ventricular dysfunction. We also monitor the AF volume and reduce or discontinue indomethacin if the AFI is less than 8 cm.
Experimental SULINDAC Sulindac is a nonsteroidal anti-inflammatory agent that also results in reduction of the AF volume, but may have less potential than indomethacin to constrict the fetal ductus arteriosus106,176–178 when used as a tocolytic. One study concluded that sulindac has less effect than indomethacin on fetal urine production, a negative for this indication.106
OTHER THERAPIES In the ovine pregnancy, intra-amniotic DDAVP is rapidly absorbed by the fetus and causes a marked decrease in fetal urine flow.179 Modulation of the amniotic membrane water channels (aquaporins)180 may also represent a potential future therapeutic intervention to normalize AF volume.
Procedures Removal of large amounts of AF by amniocentesis (therapeutic amniocentesis, or amnioreduction) is used to manage the maternal symptoms of polyhydramnios. The procedure has also been used to avert preterm delivery and claimed to improve fetal oxygenation by reducing intra-amniotic pressure,181 though there is no good evidence of efficacy for fetal indications182 other than in TTTS.183–187 The role of amnioreduction in TTTS has diminished after studies showing improved outcome with fetoscopic laser therapy prior to viability.188 Two protocols are used for amnioreduction: standard amnioreduction, in which fluid is removed at a rate of 45 to 90 mL/min, and aggressive amnioreduction, in which fluid
206 S ECTION THREE • Late Prenatal–Fetal
is removed more rapidly.189 Both techniques are associated with similar complications rates (4%–15%) including PPROM, infection, placental abruption, and fetal death.183,189,190 It is uncertain whether some or all of these complications occur as a part of the natural history of polyhydramnios because none of the studies included an untreated control arm. On average, two procedures are needed to reduce AF volume chronically, although some patients, particularly those with TTTS, require many more.189–191 One case report described 12 amnioreductions removing a total of 21,600 mL of fluid; the infant was diagnosed with West’s syndrome at follow-up 16 months after delivery.107
PROCEDURE
may be angled slightly to allow for a decrease in uterine size with amnioreduction. 3. Once the cavity is entered, a stopcock and tubing are attached to the needle hub, and a large syringe is used to remove fluid one syringe at a time. Wall suction,192 vacuum bottles,193,194 and wound suction systems190 are all described to allow for more rapid fluid removal. The goal is a normal AFI of 10 to 20 cm (some are even more aggressive, aiming for an AFI 10 U/L on immunoassay) or ultrasound evidence of fetal involvement, one of the two cases of fetal hyperthyroidism (with TSAb of 259%) had neither fetal goiter nor tachycardia.5 Further studies are needed to determine whether the ultrasound score recently reported by
B
Huel and colleagues16 can replace invasive assessment of fetal thyroid status.
Risks Perinatal risks of fetal hyperthyroidism include FGR, hydrops, and hydramnios with the associated risks of preterm delivery and malpresentation. Early studies reported a perinatal mortality from fetal hyperthyroidism of up to 50%,23 but more recent studies, incorporating maternal and fetal surveillance, indicate the risks are much lower than this.25 Overt neonatal thyrotoxicosis is associated with tachycardia, tachypnea, flushing, difficulty in feeding, hyperirritability, and poor weight gain. There may be associated jaundice, hepatosplenomegaly, and a bleeding tendancy due to thrombocytopenia and low prothrombin levels.25 In severely affected babies, mortality may be as high as 25% owing to cardiac arrhythmias or high output failure.25 Long-term sequelae include craniosynostosis and neurodevelopmental impairment.26 The half-life of antithyroid drugs in the neonate is shorter than the maternal TRAbs, and therefore, symptoms of neonatal thyrotoxicosis might not present until 5 to 10 days of age.26 Further, TRAbs are excreted in breast milk, and there is some evidence that neonatal thyroid disease may be worse and more prolonged in TRAb-positive women who breast-feed.27
FETAL RISKS OF MATERNAL HYPERTHYROIDISM In women who become pregnant while their thyrotoxicosis is under control and in those in whom the condition is diagnosed and treated early, the prognosis for mother and fetus is excellent. However, untreated or poorly controlled maternal hyperthyroidism is associated with early pregnancy loss, stillbirth, FGR, and preterm birth.28,29 These adverse fetal effects are due to direct toxic effects of high levels of thyroid hormone because they occur in fetuses of euthyroid mothers with resistance to thyroid hormone secondary to mutations in the TR-β gene.30 In one large retrospective
C HAPTER 21 • Fetal Thyroid and Adrenal Disease 371
review of 249 cases of GD published in 1992, the fetal death/ stillbirth rate was 5.6%.31 Millar and coworkers32 reported preterm delivery in 33% of hyperthyroid mothers (odds ratio [OR] 16.5, 95% confidence interval [CI] 2.1–130), and 12% gave birth to a small–for–gestational age (SGA) infant (OR 2.2, CI 0.4–11.5). Thyrotoxicosis for 30 weeks or more during pregnancy, GD for 10 years or longer, onset of GD before 20 years of age, and high TBII at delivery (>30%) are each associated with an increased risk of delivering an SGA infant.8 Pregnancy outcome is closely associated with maternal thyroid status, with poorer outcomes in uncontrolled women at delivery.29,32
Management Options THERAPY FOR MATERNAL HYPERTHYROIDISM (See Also Chapter 45) Effective treatment of maternal hyperthyroidism is associated with improved maternal and fetal outcome.8,29,32 Ideally, this should be undertaken prior to pregnancy. Mothers who remain euthyroid throughout pregnancy do not appear to be at increased risk of preeclampsia, preterm delivery, or delivery of an SGA infant.28
Antithyroid Drugs Thionamides inhibit the synthesis of thyroid hormone by preventing iodination of the tyrosine molecule. Early evidence suggested that propylthiouracil (PTU) crossed the placenta more slowly than methimazole and carbimazole (which is metabolized to methimazole),33 but this has not been confirmed in subsequent studies.34 Case reports have linked methimazole with fetal scalp defects (aplasia cutis) and choanal or esophageal atresia.35 However, the overall incidence of major malformations is comparable in women taking PTU and methimazole (2%–3%),34,36 and in a prospective cohort study comparing methimazole exposed infants with controls, there was no difference in the incidence of major malformations.37 Further, there is no evidence that the use of PTU is associated with a reduced incidence of neonatal thyroid dysfunction.34,38 PTU, however, remains the initial preferred drug for maternal hyperthyroidism according to an expert consensus recommendation of the Endocrine Society.35 In utero exposure to antithyroid drugs has not been associated with long-term differences in IQ scores or psychomotor development compared with unexposed siblings.39,40 Methimazole and, to a lesser extent, PTU are excreted in breast milk. However, studies have reported no alteration in thyroid function in infants breast-fed by mothers treated with daily doses of PTU (50–300 mg), methimazole (5– 20 mg), or carbimazole (5–15 mg) for up to 8 months.35 Mothers should be advised to take their antithyroid medication just after a feed and wait 3 to 4 hours before feeding again. In newly diagnosed cases of maternal hyperthyroidism, the initial dose of PTU is usually 150 mg every 8 hours. The equivalent dose of carbimazole is 20 mg twice daily. Clinical and biochemical improvement is usually evident after 2 to 4 weeks, although the fetal response may take longer. Once maternal symptoms have improved and thyroid function is within the normal range, the dose should be halved. Further reductions may be possible owing to the tendency for GD
to ameliorate during the last trimester, and it is usually possible to reach a maintenance dose of 150 mg/day or less of PTU (or ≤15 mg/day of carbimazole). Side effects include nausea, arthralgia, skin rash, metallic taste, and fever. Leucopenia, agranulocytosis, and hepatitis can also occur. The aim of therapy is to keep the mother euthyroid using the minimum amount of thionamide. Maternal thyroid function should be monitored every 4 to 6 weeks, aiming to keep the FT4 at the upper third of the normal nonpregnant range.6,35 With this management, serum FT4 levels are normal in more than 90% of neonates.37 In contrast, FT4 levels are low in 36% of neonates when the maternal FT4 is in the lower two thirds of the nonpregnant range.37 If the mother remains euthyroid with a small dose of PTU (50–100 mg) or methimazole (5–10 mg), therapy should be discontinued. This may be possible in up to 30% of patients after 32 weeks.28 Reliable differentiation of thionamide-induced hypothyroidism (see later) from TRAb-induced hyperthyroidism in GD requires measurement of fetal FT4 and TSH. Although fetal heart rate alone is unreliable in detecting thyroid dysfunction,5 serial measurement of fetal thyroid size may allow early noninvasive detection of thyroid dysfunction.14,22 Cohen and colleagues22 measured thyroid size in 20 consecutive women with GD on PTU (1050–1150 mg/wk); thyroid width and circumference were above the 95% percentiles in 5 fetuses; in 3, thyroid size decreased concurrently with a decrease in maternal PTU dosage and all were born euthyroid. In 2 fetuses, thyroid size was unaffected by a decrement in maternal PTU dose and both were hyperthyroid at birth. Luton and colleagues14 measured fetal thyroid size monthly from 22 weeks’ gestation in 72 mothers with past or present GD; fetal thyroid circumference was normal in all 31 fetuses whose mothers were TRAb-negative and took no antithyroid drugs during late pregnancy. Thirty of the 41 other fetuses (of which 16 were exposed to maternal PTU) had normal fetal thyroid circumference; 29 were euthyroid and one hypothyroid at birth. Eleven fetuses developed a goiter; based on associated ultrasound features (see Table 21–3) and/or FBS (performed in 6 cases), 7 fetuses were diagnosed as hypothyroid and 4 as hyperthyroid. Overall, the sensitivity and specificity of fetal thyroid circumference at 32 weeks’ gestation for clinically relevant thyroid dysfunction were 92% and 100%, respectively.14 Thus, accumulating evidence suggests that serial measurement of fetal thyroid size is extremely valuable in monitoring thionamide dosage, although it remains to be determined whether, with the addition of other ultrasound parameters (see Table 21–3), ultrasound can replace FBS in the initial assessment of fetal goiter.
Surgery Subtotal thyroidectomy can be performed successfully during pregnancy but is usually considered only for those women who develop a serious adverse reaction to thionamides or who require persistently high doses to control hyperthyroidism.35 Maternal thyrotoxicosis must be adequately controlled preoperatively. This is most rapidly achieved with β-blocking agents and iodide. Surgical thyroidectomy of women with GD does not lead to immediate remission of the autoimmune abnormality and there is a risk, with withdrawal of antithyroid therapy and T4
372 S ECTION THREE • Late Prenatal–Fetal
replacement of the mother, of fetal hyperthyroidism.41 Surgical complications include hemorrhage, recurrent laryngeal nerve palsy, hypoparathyroidism, and hypothyroidism. The optimal time for surgery is during the second trimester.
Radioactive Iodine Radioiodine is contraindicated in pregnancy, particularly after the 12th week of gestation when the fetal thyroid is able to concentrate iodine. Inadvertent administration of 131I during the first trimester is associated with hypothyroidism in 3% of cases.42
THERAPY FOR FETAL HYPERTHYROIDISM Treatment for confirmed fetal hyperthyroidism has included thionamide therapy in a euthyroid mother (typically
following ablative therapy for GD)42 and increasing thionamide dose in mothers on antithyroid therapy.35 Of the four fetuses with a hyperthyroid goiter reported by Luton and colleagues14 (two of which were confirmed by FBS), increasing the maternal thionamide dose resulted in a decrease in goiter size within 2 weeks with a return to normal thyroid circumference in one case. One fetus, referred late in pregnancy with heart failure and cardiomyopathy, died in utero at 35 weeks after FBS confirmed persistent severe hyperthyroidism. Of the remaining three cases, two were euthyroid at birth and one fetus had a low FT4 but a normal TSH at birth. Other case reports have documented persistent hyperthyroidism despite maternal thionamide therapy.43,44 Thus, monitoring the fetal response to alterations in maternal thionamide dose by FBS is recommended.
SUMMARY OF MANAGEMENT OPTIONS
Fetal Hyperthyroidism Management Options
Evidence Quality and Recommendation
References
Prepregnancy Check maternal TSH and FT4.
III/B
6,35
Optimize antithyroid medication (consider changing to propythiouracil in preference to methimizole/ carbimazole) (see Chapter 45).
III/B
33–36
Monitor maternal FT4 every 4–6 wk (aim to keep FT4 at upper end of normal range on minimal dose of antithyroid drug) (see Chapter 45).
III/B
6,35
Measure TRAbs in women with Graves’ disease who have previously received radioiodine therapy or thyroid surgery or who are taking antithyroid drugs.
III/B
15
Serial ultrasound surveillance every 4–6 wk from 22 wk’ gestation in women with high TRAbs (measure thyroid circumference and fetal heart rate).
III/B
14–16
Measure fetal TSH and FT4 in fetuses with goiter or sustained tachycardia.
III/B
5,16
If fetal hyperthyroidism confirmed, adjust maternal antithyroid dose and monitor fetal response with ultrasound and/or measurement fetal TSH and FT4.
—/GPP
—
Measure TSH and FT4 in cord blood and at 7 days of age and manage accordingly,
IIa/B
35
Consider propylthiouracil if breast-feeding. Ensure antithyroid medication is taken immediately after breast-feeding.
—/GPP
—
Prenatal
Assessment of thyroid vascularization (by color Doppler) and bone maturation may be of value in fetuses with goiter.
Postnatal
FT4, free thyroxine; GPP, good practice point; TRAbs, thyroid-stimulating hormone antibodies; TSH, thyroid-stimulating hormone.
C HAPTER 21 • Fetal Thyroid and Adrenal Disease 373
Fetal Hypothyroidism Congenital hypothyroidism occurs 1 in 3000 to 4000 live births in nonendemic areas.45,46 The condition can be permanent or transient. The most common cause of permanent hypothyroidism is thyroid dysgenesis, accounting for 80% of cases (see Table 21–1). This term includes thyroid aplasia (40%), thyroid hypoplasia (20%), and an ectopic thyroid (40%). Most cases are sporadic, nonfamilial embryologic defects, although familial instances have been reported.47 Autosomal recessive inborn errors of thyroid hormone synthesis and secretion (dyshormonogenesis) occur in 1 in 40,000 births and account for 10% to 15% of congenital hypothyroidism.47 The two most common defects result from mutations in the thyroperoxidase and thyroglobulin genes. Hypothalamic-pituitary disorders (including holoprosencephaly, septo-optic dysplasia, and Pit-1 deficiency) account for the remainder of cases. TSAbs are responsible for about 2% of congenital hypothyroidism.48 Reduced T4 levels are transient and typically occur in infants of women with high levels of TBAbs.49,50 Inadequate treatment of maternal GD has also been associated with central congenital hypothyroidism (estimated incidence 1;35,000).51 Neonates have low FT4 but variable TSH levels, and TRH tests indicate pituitary dysfunction. It is hypothesized that a hyperthyroid fetal environment impairs maturation of the fetal hypothalamic-pituitarythyroid system.51 The common thyroid autoantibodies (thyroperoxidase and antithyroglobulin), present in women with chronic autoimmune (Hashimoto’s) thyroiditis, have little or no effect on fetal thyroid function. Transient hypothyroidism may follow administration of antithyroid drugs. The effects of thionamides on fetal thyroid function are unpredictable and there is a poor correlation between fetal thyroid status and dose.25,37 Elevated cord TSH levels occur in up to 23% of infants born to PTUtreated mothers.37 In one series,5 4 of 18 cases (22%) of maternal GD treated with PTU developed fetal hypothyroidism. This can occur even with doses as low as 50 to 100 mg/day.5 Hypothyroidism has also been reported after maternal ingestion of amiodarone and lithium and after excessive maternal iodide intake. Inadvertent administration of radioiodine after 12 weeks’ gestation invariably results in permanent fetal hypothyroidism. All preterm infants have a fall in FT4 during the first 2 weeks of life with a return to normal values by the third or fourth week.52 Levels of FT4 are around 50% of those in utero, with approximately one third of preterm neonates having T4 levels greater than 3 standard deviations (SDs) below the mean of newborns.52 However, acutely ill infants may also have lower levels of FT4 and FT3 due to reduced peripheral conversion. Hypoxic FGR fetuses also have low FT4 and FT3 levels associated with a slight elevation in TSH.53 The contribution of early thyroid hormone deficiency to neurodevelopmental delay in these children is unclear. Worldwide iodine deficiency, defined as a urinary iodine excretion less than 100 µg/L,54 is the most common cause of combined maternal-fetal hypothyroidism. The distribution of neonatal TSH concentrations has been used as an index of iodine intake; populations in which the proportion of TSH values greater than 5.0 mIU/L exceeds 3% are regarded
as iodine deficient.55 Iodine deficiency leads to deficient thyroid hormone production, TSH hypersecretion, and raised T3 : T4 ratio. Compensatory mechanisms can result in euthyroidism with goiter or varying degrees of goitrous hypothyroidism. In Zaire, where iodine intake is below 25 µg/day (recommended intake 200 µg/day), the frequency of fetal hypothyroidism, as evidenced by an elevated TSH at birth, is as high as 25%.54 However, iodine deficiency is not present only in developing countries; the problem is still common in some areas of Europe, Scandinavia and the Middle East.54,56 In some areas of severe iodine deficiency, infants are born with endemic or neurologic cretinism characterized by severe mental retardation, deafness, squint, and pyramidal and extrapyramidal signs. These infants are euthyroid but frequently have a goiter. In other areas, notably Africa, the infants have hypothyroid cretinism with grossly impaired thyroid function, dwarfism, and delayed sexual maturation but rarely a goiter. Variations in dietary ingestion of selenium, zinc, iron, retinoic acid, and other goitrogens are thought to account for the different phenotypes.49 In some tissues, notably the brain and endocrine and reproductive organs, the selenium-dependent type 2 iodothyronine deiodinase plays a critical role in conversion of T4 into T3. Thus, in selenium deficiency, these organs are spared from the effects of iodine deficiency.57
Diagnosis Fetal hypothyroidism is usually unrecognized. The condition may be suspected because of a maternal history of thyroid disease or antithyroid medication. Features include FGR, goiter, and reduced fetal movements. An abnormal fetal heart rate may occur, with both bradycardia and tachycardia reported.4 In severe cases, there may be delayed skeletal development, congenital heart block, and cardiomegaly.16,58 Malformations are reported in 8% of infants with hypothyroidism; of these, 28% are cardiac abnormalities.59 The classic neonatal features of congenital hypothyroidism are constipation, lethargy, poor feeding, and respiratory problems. Physical signs include macroglossia, dry mottled skin, “cretinoid” facies, abnormal cry, prolonged jaundice, enlarged fontanelle, umbilical hernia, and mental retardation. Depending on the cause and severity of congenital hypothyroidism, clinical features may not become apparent for several weeks or months.
MATERNAL THYROID FUNCTION AND ANTIBODY TESTS Most women with known hypothyroidism have a history of thyroid disease and will be on T4 replacement. Women presenting with features of hypothyroidism in pregnancy (malaise, cold intolerance, dry skin, myalgia, excessive weight gain) will often have discontinued or reduced their T4. However, the symptoms may be subtle and a goiter not palpable. The diagnosis of maternal hypothyroidism is confirmed by an elevated TSH and a reduced FT4. Women with GD previously treated with radioiodine or surgery should have their TRAb measured early in pregnancy7 (see Table 21–2).
FETAL IMAGING Hypothyroidism may be suspected if there is goiter, increased fetal movements, and delayed bone maturation
374 S ECTION THREE • Late Prenatal–Fetal
(see Table 21–3).14,16 Hydramnios, fetal tachycardia, and FGR may also be present.5,16 In the presence of a goiter, a color flow Doppler signal confined to the periphery of the gland is considered suggestive of fetal hypothyroidism (see Fig. 21–4); of the 32 fetuses with a hypothyroid goiter reported by Huel and colleagues,16 22 (69%) had peripheral vascularization of the thyroid and none had central vascularization. Fifteen (47%) also showed delayed bone maturation, 14 (44%) had increased fetal movements, and 2 (6%) had tachycardia. Using their ultrasound score (see Table 21–3), all the fetuses with a hypothyroid goiter had a score lower than 2.16 The majority of cases of fetal hypothyroidism occur as a consequence of sporadic, embryologic malformations and are not detected on routine ultrasound screening at 18 to 20 weeks’ gestation. Occasionally, a goiter may be detected later in pregnancy at an ultrasound examination performed for other reasons.60 When there is family history of congenital hypothyroidism due to defects in thyroid hormone synthesis or metabolism, serial ultrasound screening may detect a large goiter.
FETAL THYROID FUNCTION TESTS The development of a goiter and/or polyhydramnios does not correlate closely with the degree of fetal hypothyroidism.5,61 Definitive antenatal diagnosis, therefore, requires FBS and confirmation of an elevated TSH and low FT4. Reported values of TSH in fetuses with goiter have ranged from 25 to 1640 mU/L.60–62 If the ultrasound score reported by Huel and colleagues16 is confirmed to reliably differentiate hypo- from hyperthyroidism goiter in prospective series, it may be possible to avoid FBS in the future. Although elevated amniotic fluid TSH levels have been reported in fetal hypothyroidism, the sensitivity of this method is unclear.63 In many countries, all newborns are screened for congenital hypothyroidism by the measurement of TSH on a blood spot.
Risks CONGENITAL HYPOTHYROIDISM In congenital hypothyroidism (in which maternal thyroid function is normal), the fetal thyroidal supply is deficient to varying degrees in utero and during early infancy. Transplacental passage of maternal thyroid hormones, along with compensatory deiodinase activity, ensures thyroid hormone sufficiency during the first half of pregnancy. However, the fetal contribution is reduced or totally lacking in the second half of gestation and hypothyroxinemia persists until the diagnosis is made and treatment takes effect. As a result, children with congenital hypothyroidism manifest motor and cognitive defects, with a mean IQ significantly lower than controls. Infants with severe congenital hypothyroidism, particularly those with absent thyroid glands or who show ultrasonographic and/or serum evidence of hypothyroidism in utero, have lower IQ scores than those with less severe hypothyroidism.64,65 Perinatal hypothyroidism appears to contribute particularly to visuospatial and fine motor deficits.1 Although neonatal screening programs enable early T4 supplementation, subtle deficits in cognitive and motor skills are reported even into adolescence.66,67
MATERNAL HYPOTHYROIDISM In iodine-sufficient areas, overt maternal hypothyroidism occurs in 0.3% to 0.5% of pregnancies, whereas subclinical hypothyroidism (normal FT4 but elevated TSH) has been reported in 2% to 3% of pregnancies.68,69 In areas of endemic iodine deficiency, the incidence is even higher. Autoimmune thyroiditis is present in 15% to 55% of women with subclinical hypothyroidism and in more than 80% of women with overt hypothyroidism.69,70 The rate of miscarriage is increased approximately twofold in women with overt hypothyroidism. This risk appears to be related more to the presence of circulating thyroid antibodies than thyroid function.71 Pregnancyinduced hypertension, preeclampsia, and placental abruption are purported to be more common, leading to an increased rate of preterm delivery and stillbirth.70,72,73 Severe maternal hypothyroidism in early pregnancy has also been associated with a 56% rate of intrapartum cesarean section for fetal distress.74 Complications are more common with overt than subclinical hypothyroidism. However, one recent study found no adverse outcomes in women with subclinical hypothyroidism (TSH levels > 97.5th percentile and FT4 between the 2.5th and the 97.5th percentiles).69 In contrast, women with first-trimester hypothyroxinemia (TSH levels between the 2.5th and the 97.5th percentiles and FT4 < 2.5th percentile) had an increased risk of preterm labor (adjusted OR 1.62, 95% CI 1.00–2.62) and macrosomia (adjusted OR 1.97, 95% CI 1.37–2.83). Adequate T4 treatment greatly reduces the risk75,76; in a recent randomized trial in thyroid antibody–positive women, the rate of miscarriage was reduced by 75% and preterm delivery by 69% in those given T4 (started at 5–10 wk) throughout gestation compared with antibody-positive women who did not receive T4 and in whom TSH levels gradually rose during gestation.77 Infants born to hypothyroid women are at increased risk of impairment in neuropsychological development, IQ scores, and school learning abilities. The degree of impairment is dependent on the severity, duration, and timing of the maternal thyroid insufficiency.35 Man and Serunian78 initially reported that mean IQ at 7 years of age was 13 points lower in children born to women who were hypothyroid during pregnancy than in those born to women who were euthyroid on T4 replacement. Klein and associates79 measured maternal TSH levels in 25,216 pregnant women at 15 to 18 weeks’ gestation (from frozen samples obtained for Down syndrome screening) and found 2.5% had elevated TSH levels (≥6 mU/L), of which 12% (6/49) also had low FT4 levels. Children of mothers with high TSH levels scored lower than controls on all 15 of the neuropsychological tests and attained an average IQ that was 4 points below controls.80 Of the 62 women with thyroid deficiency, 48 were not treated during pregnancy and the IQ of their children averaged 7 points lower than children born to euthyroid and T4-treated women.80 Further, there were three times as many children with IQs more than 2 SDs below the mean IQ of controls (i.e., 8 cm) in sac recipient
• Normal amniotic fluid (DVP < 8 cm) in appropriately grown fetus
• “Stuck twin” = donor
• “Stuck twin” = growth restricted fetus
absence of hydramnios (deepest vertical pocket ≥ 8 cm prior to 20 wk, ≥10 cm after 20 wk) in the AGA twin in cases with discordant growth (Fig. 23–6). Recently, several studies have addressed the pregnancy outcome of isolated discordant growth in monochorionic pairs. It complicates about 10% to 15% of all monochorionic twin pregnancies and carries an overall mortality rate of about 10%.54,55 In about half of these, the discordancy presents at or prior to 20 weeks (early-onset), whereas in the other half, it appears only later on (late-onset). Pairs with early-onset discordant growth usually have an unequally shared placenta with large intertwin anastomoses. Also, most have abnormal umbilical artery Doppler measurements from 16 weeks onward, and consequently, the mortality is highest in this group with early-onset discordant growth (17%). Conversely, pairs with late-onset discordant growth usually have equally shared placentas with smaller anastomoses. Also, umbilical artery Doppler measurements are usually normal throughout pregnancy and their mortality rate is much lower (4%) than those with early-onset discordant growth. In a third of the pairs with late-onset discordant growth, severe hemoglobin differences are present at the time of birth. This complication is referred to as TAPS (twin anemia polycythemia sequence). This late intertwin transfusion imbalance may account for the growth discordancy and measurement of the peak systolic velocity (PSV) of the middle cerebral artery (MCA) plays an important role in the follow-up of these cases.34 Classification of growth restriction or discordance can also be based on the Doppler characteristics of the umbilical artery in addition to the gestational age at first presentation.56 If a large arterioarterial (AA) anastomosis is present, such as is typically seen in cases with early-onset discordant growth, this may result in a cyclic variation in the diastolic flow component of the umbilical artery Doppler image and, thus, an intermittent absent or reversed end-diastolic flow pattern in the umbilical artery of the smaller twin that shows cyclic variations. Growth-discordant monochorionic pairs may thus have either a normal umbilical artery flow pattern (type I), a persistent absent or reversed end-diastolic flow (type II) or an intermittent absent or reversed end-diastolic flow (type III). Each of these types has distinct placental features and a different clinical outcome. Large AA anastomoses (>2 mm) are present in 70%, 18%, and 98% of type I, type II, and type III, respectively. Pregnancies with normal umbilical artery Doppler measurements (type I) have the most favorable outcome with a low risk of deterioration or unexpected demise, whereas a persistent absent enddiastolic flow (type II) carries the worst prognosis because 90% eventually show signs of deterioration and imminent demise. In fact, type II cases behave quite similar to severely growth-restricted singletons with an abnormal umbilical artery Doppler pattern. Finally, pregnancies with an
410 S ECTION THREE • Late Prenatal–Fetal
intermittent absent end-diastolic flow pattern (type III) have an intermediate prognosis, but are the most unpredictable. Because of the presence of large AA anastomoses, unexpected demise without any signs of deterioration occurs in about 15% of fetuses and half of these are double demises.57 As mentioned previously, abnormal umbilical artery Doppler patterns are largely restricted to the group with early-onset discordant growth and most have an intermittent absent end-diastolic flow pattern (type III).34 Better criteria are urgently needed to distinguish the discordant-growth pairs with favorable outcome from those with high risk of an adverse pregnancy and long-term neurodevelopmental outcome. A subclassification based on uterine artery Doppler may help refine the prognosis. However, a large prospective series of monochorionic pairs is first necessary to document the prognosis according to the different Doppler patterns and to refine the current classification system. In dichorionic twins with discordant growth, the pattern of deterioration of the growth-restricted twin follows that of a growth-restricted singleton. In a series of growthdiscordant dichorionic twins managed expectantly until 32 weeks, the mortality was 24% with the larger twins sur viving in all cases.58 Twins with growth restriction and discordant growth also face increased risks of neonatal morbidity and mortality.59,60 In discordant pairs, the lighter twin more frequently has a low 5-minute Apgar score and is at higher risk of neonatal demise, whereas the heavier twin has more respiratory difficulties when delivered between 33 and 36 weeks.50 The fear of an intrauterine demise may prompt obstetric intervention, adding complications of iatrogenic preterm birth to the inherent complications of multiple gestations.61 Clearly, any decision for iatrogenic preterm delivery to prevent intrauterine demise must be weighed against the risks of demise and handicap for each twin as determined by gestational age and EFW. Finally, growth restriction is associated with increased risks of neurodevelopmental delay62 and cerebral palsy.63 Likewise, twins with discordant growth are at increased risk of neurodevelopmental morbidity and cerebral palsy compared with nondiscordant twins, and monochorionic pairs probably have the highest risk. Nevertheless, the magnitude of this risk for monochorionic twins is unclear and the reports conflicting. In one series of preterm twin pregnancies born between 24 and 34 weeks, the rate of impairment and cerebral palsy in growth discordant monochorionic twins was 42% and 19%, respectively, compared with 13% and 1% in growth-discordant dichorionic twins.64 Other reports also suggest a high risk of parenchymal brain damage (12%– 20%), particularly in the larger twin of a monochorionic twin pair with intermittent absent end-diastolic flow in the umbilical artery (type III).57,65,66 Yet, all of these studies include referral cases, which likely creates a bias toward worse outcome. Other studies failed to find that either discordant growth or a birth weight less than the 10th percentile are significant risk factors for impairment.67,68 As such, only large prospective follow-up studies of pairs with followup from the first trimester until infancy will establish the true morbidity of discordant growth in monochorionic twin pregnancies and can identify risk factors for adverse outcome.
Management Options Similar to singletons, the goals of management are to prevent intrauterine demise and long-term neurologic damage due to
poor oxygenation and nutritional supply. Though this discussion is restricted to twins, because twins are far more common than triplets, growth problems are more frequent and occur earlier in higher-order multiplets, and the management issues are comparable. Because of the different pathophysiology and prognosis, the managements of monochorionic and dichorionic twin gestations are discussed separately.
Dichorionic Twins Dichorionic twins are conceptually singletons who happen to occupy the same womb at the same time. Thus, the diagnostic workup and follow-up are comparable with those of a growth-restricted singleton (see Chapter 11).
Prenatal Diagnosis In instances of severe early-onset growth restriction, it is important to look for signs of aneuploidy and rule out structural anomalies and congenital infection because these fetuses will not, for the most part, benefit from intense antenatal surveillance and iatrogenic early birth. Study of Doppler flow profiles in multiple vessels can help to differentiate the hypoxic, growth-restricted fetus from the constitutionally or abnormal SGA but normoxic fetus.
Fetal Surveillance Methods of fetal surveillance for growth restriction in dichorionic twins include a combination of fetal growth and amniotic fluid assessment, nonstress test, biophysical profile score, and Doppler velocimetry. Similar to singletons, uteroplacental dysfunction is associated with a sequence of Doppler and fetal biophysical profile changes, suggesting progressive deterioration and hypoxia.
Treatment The risk of intrauterine demise with expectant management must be balanced against the risks of iatrogenic preterm birth. When both twins are growth-restricted to a similar degree (which is rare), the risks are similar for both. However, the most common scenario is discordant growth with one growth-restricted twin. The Doppler changes that allow the reliable identification of fetal hypoxemia are discussed in Chapter 11. Early delivery to rescue the hypoxemic twin may expose the AGA twin to the risks of prematurity. Therefore, it may be preferable in dichorionic twins with severe early-onset discordant growth to delay delivery until the risk of demise and handicap due to prematurity are minimal for the AGA twin, irrespective of the condition of the SGA twin. In one series, such an expectant management until 32 weeks or when EFW of the AGA twin was more than 1500 g resulted in intrauterine demise of the SGA twin in 35% of pregnancies, but no death or handicap in the AGA cotwins.58 The initiation of intensive fetal surveillance must be planned accordingly. The timing of any intervention depends on the clarity of the diagnosis in the SGA twin and the chances of survival with and without handicap for each fetus. Though the efficacy of antenatal corticosteroid therapy to enhance maturation has not been sufficiently studied in twins, the available information suggests it is reasonable to use with discordant twins whenever an early delivery is contemplated. One can also test for fetal lung maturity if there is an option to delay delivery; it is generally recommended to sample both sacs, especially before 32 weeks.69
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 411
Monochorionic Twins Monochorionic twins have an identical genetic constitution (though they will differ epigenetically) and share a single placenta with their circulations connected through vascular communications in the placenta. As such, the management of growth restriction in monochorionic twin pregnancies poses some unique challenges.
Prenatal Diagnosis The need to search for signs of aneuploidy and exclude discordant structural anomalies and congenital infection also applies to monochorionic twins. Monochorionic twins can be discordant for most common human aneuploidies.35,70–72 Both amniotic sacs must be sampled in order to diagnose these rare heterokaryotypic monochorionic twins. In addition, structural anomalies are more common in monochorionic twins73 and usually affect only one fetus.55,74 Conversely, congenital infection typically affects both twins, although the severity may vary. It is equally important to distinguish discordant growth from TTTS by the absence of hydramnios in the sac of the AGA twin.
Fetal Surveillance It is unclear what the best method is to monitor fetal wellbeing in growth-restricted monochorionic twins. Doppler velocimetry of the umbilical artery may not have the same prognostic value that it has in singletons and dichorionic twin gestations. Umbilical artery waveforms reflect downstream vascular resistance, which in monochorionic twins is determined not only by the adequacy of spiral artery invasion but also by the direction and shunting across the vascular anastomoses. Large AA anastomoses can, therefore, influence umbilical artery waveforms, leading to intermittent absent end-diastolic or even reversed flow.75 This phenomenon occurs typically in the SGA twin of a monochorionic pair with severe early-onset growth discordance (Fig. 23–7).56,76,77 Intrauterine demise may occur unexpectedly in these fetuses, without additional signs of deterioration of either the Doppler flow profile or the biophysical profile score, because these large AA anastomoses may facilitate acute exsanguination or other hemodynamic aberrations. Conversely, the SGA twin in some cases of discordant growth may have absent end-diastolic flow from early on in pregnancy for up to 15 weeks, without any adverse effect on
FIGURE 23–7 Doppler pattern of intermittent absent end-diastolic flow as typically seen in the smaller twin of a monochorionic pair with discordant growth.
fetal survival.78 Prior to 28 weeks, we usually review growthdiscordant monochorionic pairs with abnormal umbilical artery Doppler patterns and/or discordant amniotic fluid on a weekly basis for Doppler studies and assessment of amniotic fluid volumes. From 28 weeks onward, we admit those with abnormal umbilical artery Doppler patterns for twicedaily cardiotocography (CTG) and twice-weekly Doppler and biophysical profile scores and administer corticosteroid agents. Those with normal umbilical artery Doppler patterns are further followed on a weekly basis. In cases in which the discordant growth presents for the first time in the latter half of pregnancy, measurement of the PSV of the MCA may play an important role to detect the occurrence of TAPS as a cause of the late-onset discordant growth.34
Treatment In monochorionic twins, the management is complicated by the almost obligatory presence of a shared circulation. In dichorionic twins, sIUFD is associated with demise or handicap of the surviving twin in 4% and 1% and is largely attributable to extreme preterm birth. In contrast, sIUFD in monochorionic twins leads to double intrauterine fetal demise (dIUFD) in about 12% and neurologic impairment in 18% of surviving co-twins.79 This extra morbidity and mortality is due to a combination of pressure instability as the first twin dies and acute exsanguination in the fetoplacental unit of the demised twin, all in addition to the effects of extreme preterm birth. Expectant management irrespective of the condition of the SGA until 32 weeks is, therefore, not appropriate in monochorionic twins. Possible management options for severe early-onset discordant growth in monochorionic twins are expectant management with timely birth, selective feticide by umbilical cord occlusion, or selective coagulation of the vascular communications. The problems with expectant management are that intrauterine demise may occur before viability, is difficult to predict, and might have major consequences. Demise is especially dramatic once a viable stage of gestation has been reached. As a result, some advocate elective preterm birth of all monochorionic twins with a growth discordance of more than 25% at 32 weeks after the administration of maternal corticosteroids or, at the latest, after confirmation of fetal lung maturity. Umbilical cord occlusion may be considered prior to viability when there are signs of imminent fetal demise. The rationale for cord occlusion is that it may better protect the surviving twin against the adverse effects of spontaneous demise. However, a major drawback is that the maximum survival rate is 50%. Further, it is not always clear which signs predict impending demise in monochorionic twins. We usually offer cord coagulation when the smaller twin develops anhydramnios, persistent absent or reversed flow in the ductus venosus, or an arrest of growth over a 3-week observation period prior to viability. Selective photocoagulation of the vascular anastomoses as it is currently performed in the treatment for TTTS also seeks to protect the AGA twin against the adverse effect of sIUFD of the SGA twin by “unlinking” the two fetal circulations. However, a small case series comparing treated and expectantly managed cases series did not show any significant difference in survival or short-term neurologic morbidity.80,81 Several explanations for this apparent lack of benefit are possible. First, selective coagulation is technically more
412 S ECTION THREE • Late Prenatal–Fetal
challenging for discordant growth than for TTTS owing to the absence of hydramnios. Second, unequal sharing is frequently the reason for discordant growth, and coagulation of the vascular anastomoses might further diminish the already critical placental reserve of the SGA twin. Third, the elaborate intertwin transfusion in these unequally shared placentas may benefit the SGA twin by increasing its oxygen and nutrient supply. And finally, the survival rate of earlyonset discordant growth is about 85%,34,57 in contrast to a nearly 100% mortality of untreated mid-trimester TTTS. Also, long-term neurologic outcome of discordant growth appears to be much better than that of TTTS.68 As such, a recent series on laser coagulation of the vascular anastomoses as a treatment for discordant growth with intermittent absent or reversed end-diastolic flow (type III) showed a survival of only 64% in contrast to the 85% survival rate in conservatively managed cases.57 An overactive management might risk the loss of pregnancies that would have reached viability without demise of the SGA fetus. The potential role of laser coagulation of the vascular anastomoses in the management of discordant growth is currently the subject of a randomized controlled trial.82
Twins of Unknown Chorionicity Determining chorionicity in same-sex twins with discordant growth in the second trimester can be challenging. Oligohydramnios with the intertwin membrane plastered around the
FIGURE 23–8 Characteristic bidirectional Doppler pattern in an arterioarterial anastomosis, which confirms monochorionicity.
SGA twin makes assessment of membrane thickness or the presence or absence of a lambda sign especially unreliable. It is estimated that just 3 out of 10 same-sex twins have monochorionic placentation. In these instances, the detection of an AA anastomosis with its characteristic bidirectional waveform (Fig. 23–8) confirms monochorionicity with 100% reliability.83 Also, DNA determination of zygosity by amniocentesis generally rules out monochorionicity if dizygosity is confirmed.84 In cases of persistent doubt, it is prudent to manage the pregnancy as a monochorionic twin gestation.
SUMMARY OF MANAGEMENT OPTIONS
Poor Fetal Growth in Twin Pregnancies Management Options
Evidence Quality and Recommendation
References
Dichorionic Twins Exclude aneuploidy, structural anomalies, and congenital infection.
—/GPP
Determine when to intervene upon signs of fetal distress of the SGA twin and plan fetal surveillance accordingly.
See Chapters 10, 11 and 12
—
In severe early discordant growth, it may be preferable not to intervene to maximize the chances of the AGA twin at the expense of spontaneous demise of the SGA twin.
III/B
Fetal surveillance is usually done by a combination of fetal growth assessment, biophysical profile scoring, and Doppler velocimetry.
See Chapter 10
Consider administration of corticosteroids and fetal lung maturity testing whenever early delivery is contemplated.
Ia/A
299
Exclude aneuploidy, structural anomalies, congenital infection, and TTTS.
IIa/B
70,71,73
Consider referral to a tertiary care center.
—/GPP
—
If spontaneous demise is presumed imminent and in the previable period, selective feticide by cord occlusion may protect the AGA twin better against the side effects of spontaneous demise.
IV/C
81
Consider elective preterm delivery at 32 wk for cases with a growth difference of ≥ 25% and abnormal umbilical artery Doppler pattern after administration of corticosteriods or at the latest when lung maturity has been established.
—/GPP
—
Fetal surveillance is usually done by a combination of fetal growth assessment, biophysical profile scoring, and Doppler velocimetry.
See Chapter 10
58
Monochorionic Twins
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 413 Evidence Quality and Recommendation
Management Options
References
Nonstress testing and biophysical profile score are currently the best methods to ascertain acute fetal well-being, although IUFD can occur unexpectedly, despite normal biophysical profile scoring.
III/B
75–77
Assess for TTTS.
—/GPP
—
Consider DNA fingerprinting to exclude monochorionicity.
III/B
84
Check for arterioarterial anastomoses to confirm monochorionicity.
III/B
83
If chorionicity remains unconfirmed, manage as monochorionic twins.
—/GPP
—
Twins of Unknown Chorionicity
AGA, appropriate for gestational age; GPP, good practice point; IUFD, intrauterine fetal demise; SGA, small for gestational age.
MONOAMNIOTIC TWINS General Cleavage of the inner cell mass day 9 to day 12 after fertilization is thought to result in monochorionic monoamniotic twins. These twins share not only their placenta but also their amniotic sac. Monoamniotic twins are rare, occurring in about 1 in 10,000 pregnancies and, as such, constitute 5% of monochorionic twins.85 The umbilical cords insert usually close to each other mid placenta with multiple deep and superficial large-caliber (8–12 mm) anastomoses connecting the placental stem vessels of the twins (Fig. 23–9).86,87 The diagnosis of monoamniotic twin gestation is reliably made in the early first trimester by the presence one amniotic cavity containing two fetal poles and a single placenta. In contrast to what was previously suggested,88 the presence of a single yolk does not necessarily prove monoamnionicity, as is the case in up to 15% of diamniotic twins.89 Cord entanglement is diagnostic of monoamniotic twins and often already demonstrable in the first trimester by imaging two heart rates on pulsed Doppler in an entangled mass of umbilical cord vessels (Fig. 23–10).90,91 Current ultrasound technology with sharper resolution usually permits the distinction between diamniotic and monoamniotic monochorionic twins. On occasion, transvaginal scanning at high frequencies will help confirm or refute any dividing membrane. The
“stuck twin phenomenon” is regularly mistaken for a monoamniotic twin pregnancy because of the difficulty of seeing the dividing membrane. However, the fixed position of the stuck twin rules it out because in a monoamniotic gestation both fetuses move freely about.
Fetal Risks Monoamniotic twins are at increased risk of congenital malformation and IUFD. Although rare, conjoined twins must be excluded. Conjoined twins are thought to arise when the embryonic disk incompletely divides beyond the 12th day of fertilization and has an estimated incidence of 1 in 50,000 pregnancies. The diagnosis is possible as early as the first trimester by the close and fixed apposition of the fetal bodies with fusion of the skin lines at some point (Fig. 23–11).92 Intrauterine demise occurs in 60% of conjoined twins, and of those that are liveborn; the majority die owing to severe anomalies or as a consequence of surgery.93 Except for conjoined twinning, congenital malformations occur in 38% to 50% of monoamniotic twins, usually affecting only one twin.66,94 Up to a third of the perinatal mortality in monoamniotic twins is caused by congenital malformations.95 Late embryonic cleavage and hemodynamic imbalances due to the large and multiple anastomoses may account for the extremely high prevalence. Cord 1 Arterio arterial Venovenous
Cord 2
Shared cotyledon
A
B
FIGURE 23–9 A, Macroscopic image of large diameter anastomoses and side-to-side insertion of the umbilical cords as typically seen in a monoamniotic twin pregnancy. B, Diagnostic angiography in which injection of the umbilical vessels of one twin was sufficient to visualize the placental vascularization of both twins owing to the presence of a large arterioarterial and venovenous anastomosis. Furthermore, about half of the placenta consisted of shared cotyledons.
414 S ECTION THREE • Late Prenatal–Fetal
FIGURE 23–10 Ultrasound image of cord entanglement at 14 weeks’ gestational age in monoamniotic twins. A, Doppler demonstrates cord entanglement. B, Pulsed Doppler of the entangled mass shows two different heart rates.
A
B
(A and B, Courtesy of D. Van Schoubroeck, UZ Leuven, Belgium.)
FIGURE 23–11 Ultrasound image of conjoined twins at 9 weeks’ gestational age. (Courtesy of I. Witters, UZ Leuven, Belgium.)
In structurally normal monoamniotic twins, IUFD is the most important cause of mortality. More recent series report mortality rates of 0%96,97 to 17%95,98 with careful fetal surveillance and elective preterm birth compared with previously quoted risks of 30% to 70%.99,100 However, most pregnancies included in these series were diagnosed in the second trimester, and the mortality would likely be higher should first-trimester diagnoses be included.85 Umbilical cord entanglement was long considered the only reason for the high mortality rate, but almost all monoamniotic twins have entangled cords at birth (Fig. 23–12) and usually from early in gestation. “Acute” TTTS may be an important contributing factor, perhaps triggered by cord compression. Acute hemodynamic imbalances across the large-caliber anastomoses may also explain the 70% rate of dIUFD in monoamniotic twins compared with 25% in diamniotic twins.86 Indeed, chronic TTTS is only rarely reported in monoamniotic twins,98 probably because volume shifts through the largecaliber anastomoses are not tolerated for long periods and are more likely to lead to sudden death typically of both twins within a short time of each other. However, cord entanglement may still cause in utero demise101 or asphyxia later in gestation if the co-twin survives.102
Management Options The cornerstone of management is a targeted anomaly scan at 18 to 22 weeks to rule out associated anomalies, followed by scans every 2 weeks for growth and amniotic fluid volume, intense antenatal surveillance from 26 to 28 weeks onward, and timely delivery. It is the author’s opinion that birth should be planned around 32 weeks, or at the latest when
FIGURE 23–12 Cord entanglement and knotting at birth in a monoamniotic twin pregnancy. (Courtesy of S. Dobbelaere, H. Hart Hospital, Lier, Belgium.)
lung maturity is established, because unexpected intrauterine demise may occur even after 32 weeks.95,98 However, others have suggested the loss rates are extremely low after 32 weeks, possibly because there is less room for fetal movement.103 Selective feticide for discordant anomalies in monoamniotic twins can be accomplished by fetoscopic/ ultrasound-guided coagulation and laser transsection of the umbilical cord (Fig. 23–13).104,105 The procedure is technically more challenging than in diamniotic twins owing to cord entanglement. An accessory port for fetoscopy may facilitate cord transsection and, to a lesser degree, help identify the correct cord, albeit with an unknown additional risk of preterm premature rupture of the membranes (PPROM) when compared with single-port procedures. Although intrauterine demise in monoamniotic twins may be sudden and unpredictable, as mentioned previously, the best way to manage these cases is simply not known. Careful antenatal surveillance and elective preterm birth appear to improve perinatal survival to about 90%. Generally, it is
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 415
FIGURE 23–13 Fetoscopic image during (A) and after (B) umbilical cord transsection by laser in a monoamniotic twin pregnancy with a severe discordant anomaly.
A
B
agreed that intense fetal surveillance should be started from 26 to 28 weeks onward, with regular nonstress testing to identify symptomatic cord compression and ultrasound scans for a biophysical profile score, Doppler, and growth checks. The recommended frequency is disputed, and in the literature, nonstress testing varies from twice weekly to several times a day. The high frequency of nonstress testing is justified by the suddenness of the events, but fetal demise in between remains possible. Some advocate weekly ultrasound examinations with a biophysical profile score, yet these fetuses are lost because of acute events and not because of chronic hypoxemia. Abnormal umbilical artery Doppler flow waveforms such as diastolic notch106 or absent/reversed end-diastolic flow may indicate cord compression. But similar to monochorionic twins in general, the predictive value of an abnormal umbilical artery Doppler waveform
may be different than in singletons and, like biophysical profile scoring, requires additional validation.107 The need for hospitalization is likewise controversial and should be individualized based on the results of the ultrasound scan and antenatal testing,108,109 although surveillance as an inpatient may improve survival rates.110 The administration of sulindac was suggested as a means of medical amniodrainage to reduce fetal mobility in monoamniotic twins and thereby cord entanglement.97,111 Yet, because acute transfusion seems to be an important cofactor, intrauterine demise can still occur after 32 weeks95,98 despite sulindac.85 For all of these reasons, we advocate birth at 32 weeks when feasible. Even though cases of successful vaginal birth are reported, cesarean delivery is preferred to avoid cord entanglement and inadvertent clamping of the cord of the second twin, which may be tightly around the neck of the first.112
SUMMARY OF MANAGEMENT OPTIONS
Monoamniotic Twins Management Options Exclude structural anomalies.
Evidence Quality and Recommendation —/GPP
References —
Consider referral to tertiary care center.
—/GPP
—
Determine when to intervene upon signs of fetal distress and plan fetal surveillance accordingly.
III/B
95,96
Fetal surveillance is usually done by a combination of fetal growth assessment, biophysical profile scoring, and Doppler velocimetry.
See Chapter 10
Acute fetal surveillance consists of daily to twice-weekly nonstress testing and biophysical profile scoring.
III/B
95,96
Value of hospitalization is uncertain.
III/B
108
Risk of fetal death does not decline after 32 wk; thus, some advocate delivery at 32 wk after maternal steroids are given.
IIa/B
108,111
Others advocate delivery at term, or sooner if evidence of fetal compromise, but consider steroid administration.
III/B
69
Most advocate cesarean section; vaginal delivery requires continuous fetal heart rate monitoring of both twins and facilities for immediate cesarean section.
IIa/B
103,112
GPP, good practice point.
416 S ECTION THREE • Late Prenatal–Fetal
IN UTERO DEMISE OF ONE FETUS General Fetuses of multifetal pregnancies are more likely to die in utero than singletons.113 Not unexpectedly, the risk grows with an increasing number of fetuses.114 The rate of sIUFD in twins or higher-order multiplets is difficult to ascertain during the first trimester, because the loss might occur before the diagnosis of either a multifetal pregnancy or an sIUFD. Also, the “vanishing embryo syndrome” might go unrecognized or be wrongly diagnosed as a retromembranous blood collection (Fig. 23–14). The diagnosis of sIUFD should be made when fetal remnants are clearly identified or when a later ultrasound scan demonstrates the demise or disappearance of a previously known fetus. The risk of sIUFD in twin pregnancies resulting from IVF, which are regularly followed throughout the first trimester, is maternal age–dependent and ranges from 10% to 20%, with most cases occurring prior to 12 weeks.115 These figures are currently the best estimates available for first-trimester sIUFD in dichorionic twins, because about 90% of IVF pregnancies are dichorionic.116 In one general population scanned between 10 and 14 weeks’ gestation, the prevalence of sIUFD was 4% in dichorionic and less than 1% in monochorionic twin pregnancies (compared with 2% in singletons), with dIUFD in 1.6% of dichorionic and 2% of monochorionic twin pregnancies.117 Thus, dIUFD appears more common than sIUFD in monochorionic twins. Gross unequal placental sharing or hemodynamic imbalances in monochorionic twins may cause sIUFD, with the connected fetal circulations leading to dIUFD. Also, chromosomal abnormalities or an adverse maternal factor (infection, teratogens) will affect both fetuses similarly. In contrast, sIUFD in dichorionic twins is twice as common as dIUFD and may be explained by either a discordant chromosomal or structural anomaly or suboptimal placentation. Because each fetus has a separate fetoplacental circulation, sIUFD will not cause co-twin demise per se, though whatever killed one may harm or ultimately kill the other. About 10% of dichorionic twins are monozygotic and, therefore, concordant for chromosomal anomalies. From 10 to 14 weeks onward, sIUFD occurs in about 2% of dichorionic but 4% of monochorionic twin pregnancies, and dIUFD occurs in 0.2% of dichorionic and in at least 6% of monochorionic twins. This extra fetal loss of
A
monochorionic twins occurs before 24 weeks and is largely attributable to complications of the connected fetoplacental circulations.19,55 Toward the end of gestation, the risk of in utero demise in twins increases from 1 in 3333 at 33 weeks to 1 in 313 at 36 weeks and 1 in 69 beyond 39 weeks. The intrauterine mortality of twins at 37 to 38 weeks is equal that of postterm singleton pregnancies, and elective birth at 37 to 38 completed weeks may be justified when uncomplicated twin pregnancies reach that milestone.118 Recently, several studies have addressed the risk of unexpected late intrauterine demise in monochorionic twin pregnancies. Barigye and associates reported that after 32 weeks unexpected stillbirth occurred in 4% of otherwise uncomplicated pairs, supporting a policy of elective preterm birth of all monochorionic twins at 32 weeks.119 This figure was contradicted by other retrospective analyses120–122 and one prospective series55 that all report lower rates (1.2% and 2.1%) in complicated and uncomplicated monochorionic pairs. After 37 weeks, up to 2% of monochorionic twin pregnancies may be complicated by unexpected intrauterine demise.123 Based on these figures, we now see all monochorionic twin pregnancies on a weekly basis for Doppler velocimetry, biophysical profile score, and nonstress testing from 32 weeks onward; for uncomplicated cases, we plan an elective birth around 37 weeks.
Fetal Risks The prognosis of sIUFD for the surviving fetus depends first and foremost on chorionicity. To a lesser degree, outcome is determined by the gestational age of sIUFD. There is little evidence regarding the implications of sIUFD in the first trimester. Nonetheless, it seems most likely that sIUFD in a monochorionic twin pregnancy leads to either dIUFD or miscarriage. Rarely, the surviving co-twin may prevent the “vanishing” of the dead twin by reversed perfusion along the vascular anastomoses—a TRAP sequence.124 Color Doppler should be used to exclude TRAP whenever sIUFD occurs in a monochorionic twin pregnancy, and if there is any doubt, follow-up scans should be arranged. It is also hypothesized that unrecognized early sIUFD in a monochorionic twin pregnancy may explain some cases of cerebral palsy and certain congenital anomalies such as renal agenesis and intestinal atresia in birth singletons, attributable to the
B
FIGURE 23–14 Ultrasound image of a retromembranous blood collection (arrow) in a singleton pregnancy (A), which must be differentiated from “vanishing twin syndrome” (B) in which felt remnants (arrow) can be clearly identified.
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 417
agonal hemodynamic events.125 The outcome of sIUFD in the first trimester in dichorionic twins is usually favorable, although the rate of preterm birth and subsequent miscarriage may be increased especially if the sIUFD occurs toward the end of the first trimester. In the case series of sIUFD diagnosed between 10 to 14 weeks, 18% (3/16) of dichorionic twins subsequently miscarried.91 This contrasts with the low rate of loss following selective embryo reduction. A recent meta-analysis showed that sIUFD in dichorionic twins during the second and third trimester leads to co-twin demise or neurologic abnormality in 4% and 1%, respectively,79 presumably in great part secondary to the conditions that lead to extreme preterm birth. Conversely, the same meta-analysis showed that in monochorionic twins, sIUFD results in dIUFD in 12%, and cerebral damage in 18% owing in part to acute intertwin transfusion plus the risks of extreme preterm birth.79 Yet, this meta-analysis most likely underestimates co-twin mortality rate, because it covers survival only after sIUFD whereas a significant proportion of monochorionic twins present as dIUFD at first diagnosis. Also, immediate delivery after the diagnosis of sIUFD will reduce the rate of co-twin intrauterine demise, while increasing the neonatal death rate.126 In a prospective series from Sebire and associates19 that was not included in the metaanalysis, 10 monochorionic twin pregnancies were complicated by intrauterine demise, 6 were dIUFD from the start and only 4 presented as a sIUFD. In dichorionic twins, survival seems inversely related to the gestational age at which the sIUFD occurred, with infant survival rates improving from 71% when the sIUFD occurs between 20 and 24 weeks to 98% for sIUFD occurring beyond 37 weeks.114 In monochorionic twins, the influence of gestational age of sIUFD on outcome is less clear. It seems that early sIUFD is more often associated with death of the co-twin. However, if the co-twin survives, severe morbidity is less common. In contrast, a late sIUFD more frequently results in the birth of a liveborn infant who is neurologically damaged.127,128 The reported rate of cerebral palsy after sIUFD in dichorionic twins is 30 per 1000 infant survivors, with preterm birth the greatest association with this excess risk, compared with 1 per 1000 in singletons.129,130 Specific cerebral palsy rates are not available for sIUFD in monochorionic twins. However, the cerebral palsy rate in same-sex twins (30% monochorionic and 70% dichorionic) after sIUFD is 106 per 1000 survivors, which is about three times higher than that of different-sex twins (100% dichorionic).129 In addition, most of the twins in the same-sex group with cerebral palsy had monochorionic placentation.130 Cerebral damage is often detectable sonographically but does not usually become apparent until weeks after the insult. Prenatal magnetic resonance imaging (MRI) may detect brain lesions earlier and with better definition.131,132 Sonographic evidence of brain injury includes porencephaly, multicystic periventricular leukoencephalomalacia, ventriculomegaly, cerebral atrophy, and cerebellar or cerebral infarcts. Less frequently reported complications include renal cortical necrosis, small bowel atresia, aplasia cutis, and limb infarction. Originally, thromboembolic phenomena with passage of thromboplastin from the dead to the living twin were thought to be responsible for these lesions.133 There is no evidence to support this line of reasoning, though
circulatory instability and acute exsanguination are well documented.134 Reversed perfusion of the dead twin has been demonstrated by Doppler interrogation of the chorionic plate vessels,135 and fetal blood sampling within 24 hours of sIUFD has consistently revealed a decreased hematocrit in the survivors with normal coagulation profiles.136 Further, fetoscopy within 3 hours of the donor twin dying has documented reversal of transfusion with a plethoric donor and anemic recipient.137 The outcome of the survivor may depend not only on the gestational age at sIUFD but also on the type and direction of vascular anastomoses and the fetoplacental mass of the dead twin. The presence of superficial AA anastomoses is associated with higher rates of death and neurologic damage.126 However, significant anemia and co-twin demise may occur, even in the absence of AA anastomoses.127 The outcome of sIUFD associated with TTTS treated by amniodrainage does not differ from sIUFD in untreated cases, and the risk of sIUFD is similar for donors and recipients. It has been suggested that the risk of co-twin death and neurologic damage is lower with sIUFD of the donor compared with sIUFD of the recipient, because transfusion is more likely to be directed toward the recipient.126 However, small series show similar prevalences of anemia and adverse outcome in surviving recipients and donors.127,138 Even though treatment by laser coagulation of the vascular anastomoses more frequently results in sIUFD than amniodrainage, it consistently leads less often to a dIUFD.139,140 Significantly, anemia in the survivor is rare in the event of sIUFD after laser,141 and the neurologic morbidity is lower than after amniodrainage.142,143 These findings provide further support for the concept that the vascular anastomoses are responsible for most of the adverse outcomes associated with sIUFD in monochorionic twins.
Management Options Knowledge of chorionicity is fundamental to the management of sIUFD in multiple pregnancies because the pathophysiology and prognosis varies, though not to complicate matters unnecessarily, our discussion is restricted to twins. Although sIUFD is more common in higher-order multiplets and management issues are more complex, they are based largely on the same principles as in twins. A small paragraph is dedicated to issues that are relevant to both groups of twins.
Dichorionic Twins The main risks of sIUFD in dichorionic twins are miscarriage and severe preterm birth. Conservative management is advocated with regular ultrasound scans to check the growth and well-being of the survivor. Admittedly, parental anxiety may be an important factor in persuading the obstetrician to intervene, and these complex emotional responses should be adequately addressed by education rather than a precocious response.144
Monochorionic Twins The main risks of sIUFD in monochorionic twins are co-twin demise and ischemic brain lesions secondary to acute exsanguination. Depending upon gestational age, there are additional risks of either miscarriage or severe preterm birth. It is presumed that death and especially ischemic brain damage
418 S ECTION THREE • Late Prenatal–Fetal FIGURE 23–15 Doppler examination of the middle cerebral artery of the surviving twin of a monochorionic pair at 20 weeks’ gestation, within 4 days after single intrauterine fetal demise (sIUFD) of the growth-retarded co-twin.
intrauterine transfusion improves outcome, though it may prevent co-twin demise probably too late to prevent brain injury.127,138,146 Intrauterine transfusion may thus increase survival of severely handicapped infants. Additional multicenter studies are necessary to determine the benefit of rescue transfusion. In the meantime, it is best performed only in settings in which a late termination is an option if cerebral lesions are detected later in pregnancy.146 After birth, a thorough neonatal evaluation should be performed to detect any neurologic, renal, circulatory, and cutaneous defects. All survivors should undergo an early neonatal brain scan and ideally be enrolled for long-term neurodevelopmental follow-up.
Issues Applicable to Dichorionic and Monochorionic Twins
in the survivor occurs during or soon after the death of the co-twin. Therefore, a preemptive preterm birth is inappropriate once an sIUFD has been diagnosed, because this would only worsen the outcome of the surviving twin by adding the complications of preterm birth. Moreover, a long demise-to-birth interval is associated with a better outcome than a short demise-to-birth interval, supporting the premise of conservative management.128 Monochorionic twin pregnancies with an sIUFD should be managed in a tertiary referral center with sufficient neonatal support. Also, regular detailed (transvaginal if vertex) ultrasound examinations of the fetal brain are indicated to detect brain injury. Unlike hemorrhage, ischemic brain injury is difficult to visualize in the early phase, and MRI scan may aid early detection.131,132 MRI is also more sensitive than ultrasound scan to detect more subtle brain lesions.145 It is recommended that an MRI be performed at least 2 weeks after sIUFD to optimize the detection of any injury. Fetal blood sampling shortly after sIUFD may have prognostic value because all nonanemic fetuses in one study had a good outcome and did not develop any brain injury.127 MCA Doppler velocimetry effectively predicts fetal anemia after sIUFD in cases associated with TTTS and obviates the need of cordocentesis (Fig. 23–15). There is currently insufficient evidence that a rescue
It seems justified to administer rhesus (Rh) prophylaxis whenever an sIUFD is diagnosed in a Rh-negative woman. Maternal disseminated intravascular coagulation does occur in singletons after intrauterine demise and retention of the fetus for more than 5 weeks. However, in twins, its incidence with conservative management appears extremely low, and it can be treated with heparin should it occur.147,148 Vaginal birth is not contraindicated after sIUFD, but labor may be obstructed, especially if the sIUFD occurs late and the dead twin is presenting. A postmortem examination of the dead twin is advisable, especially if the cause is unknown, and the placenta should be sent for histologic examination to confirm chorionicity. The family will require psychological support and counseling prior to, during, and after birth. The grief experienced after an sIUFD equals that for a singleton loss, and yet the parents rarely receive equal sympathy.149 The death is invisible for the parents and their immediate associates, which hampers the grieving process. Many parents worry the dead twin will have an adverse effect on the remaining fetus and need reassurance that no additional harm is expected except for the possibility of an earlier birth. The delay between diagnosis and birth permits some grieving, but sorrow resurfaces at birth.150 It is important not to ignore the deceased twin; the parents may wish to see it during ultrasound examination and after birth. Death after 12 to 15 weeks should end with an identifiable fetus at birth, though compressed and mummified, and parents should be prepared and told what to expect.151
SUMMARY OF MANAGEMENT OPTIONS
Single Fetal Death in Twins Management Options
Evidence Quality and Recommendation
References
Issues Applicable to All Twins Offer counseling and psychological support to patient and family.
III/B
149,150
Administer rhesus prophylaxis if Rh-negative.
—/GPP
—
Give steroids if preterm delivery is contemplated.
Ia/A
299
Check for signs of threatening miscarriage and severe preterm delivery.
III/B
144
If dichorionic pregnancy, continue fetal surveillance in survivor.
III/B
144
Dichorionic Twins
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 419 Evidence Quality and Recommendation
Management Options
References
Monochorionic Twins Check for signs of threatening miscarriage and severe preterm delivery.
III/B
144
Continue fetal surveillance in surviving twin with a combination of fetal growth assessment, biophysical profile scoring, and Doppler velocimetry (see Chapter 10).
III/B
144
Consider Doppler of the middle cerebral artery to detect anemia, which may predict the risk of brain damage.
III/B
127,138
Check for brain injury by (transvaginal) ultrasound scan or MRI.
III/B
131,132
Preemptive preterm delivery is no longer advocated.
III/B
128
Perform pediatric assessment and neurodevelopmental follow-up.
III/B
144
GPP, good practice point; MRI, magnetic resonance imaging.
TWIN REVERSED ARTERIAL PERFUSION General The TRAP sequence, also known as “acardiac twinning,” is an anomaly unique to monochorionic multiple pregnancies that affects approximately 1 of 35,000 pregnancies and 1% of monochorionic twins.152 In TRAP, blood flows from an umbilical artery of the pump twin in a reverse direction into the umbilical artery of the perfused twin via an AA anastomosis. The perfused (or acardiac) twin is a true parasite. Its blood is poorly oxygenated, and the hypoxemia contributes to variable degrees of deficient development of the head, heart, and upper limb structures. The lower half of the body is usually better developed, which may be explained by the mechanism of perfusion. Blood enters the acardiac twin via the umbilical artery and flows through the common iliac artery and aorta. What little oxygen is present is extracted in the lower part of the body, allowing at least partial development of the lower limbs and abdomen. By the time the blood reaches the upper body, most of the oxygen will already have been extracted, leading to poor development of upper body structures (Fig. 23–16).148
FIGURE 23–16 Macroscopic image of an acardiac twin with absent head and partial development of lower limbs and abdomen. This acardiac mass weighed about 4 kg and was not diagnosed until the third trimester. The patient delivered at 37 weeks, and the pump twin survived.
Two criteria must be fulfilled for the development of a TRAP sequence. The first is an AA anastomosis and the second discordant development153 or in utero demise101 of one of monochorionic twins, allowing for the blood flow reversal. Not infrequently, chromosomal abnormalities are identified in the acardiac twin, whereas the pump twin has a normal karyotype.154,155 Embryos/fetuses with chromosomal abnormalities have a high risk for spontaneous intrauterine demise, which in dichorionic twins would lead to a “vanishing” twin. However, in monochorionic twins, the “vanishing” can be prevented by the occurrence of persistent, yet reversed, flow to the chromosomally abnormal twin via the vascular anastomoses. Therefore, whenever sIUFD is suspected in monochorionic twins on a first-trimester scan, the differential diagnosis or development of TRAP should be kept in mind and follow-up scans arranged.124 The diagnosis can be reliably made on ultrasound scan in the first trimester.156 TRAP sequence is characterized by a grossly abnormal fetus that grows, may even show movements, but has no functional cardiac activity of its own. Rarely, a rudimentary heart may show pulsatility (Fig. 23– 17). Marked hydrops and cystic hygroma are frequently
FIGURE 23–17 Doppler examination demonstrates cardiac activity in the rudimentary heart (70 beats/min) of the acardiac twin, with flow in the opposite direction in the aorta (140 beats/min).
420 S ECTION THREE • Late Prenatal–Fetal FIGURE 23–18 A, Ultrasound image of an acardiac twin at the level of the rudimentary head with typical, severe subcutaneous edema. B, Doppler examination at 15 weeks’ gestation demonstrates the typical retrograde flow from the pump twin toward the acardiac twin over an arterioarterial anastomosis (arrow).
A
present, especially toward the end of pregnancy. Doppler studies reveal pathognomonic features of reversed arterial perfusion through an AA anastomosis (Fig. 23–18). TRAP can easily be distinguished from sIUFD by the presence of fetal movements and the typical retrograde perfusion.
Fetal Risks The pump twin is at risk for high-output cardiac failure secondary to the strain of perfusing the acardiac twin and extreme preterm birth associated with hydramnios.154,157 The pump twin may be chronically hypoxemic if the deoxygenated blood from the acardiac returns by a vein-to-vein anastomosis. The natural history of TRAP is poorly documented owing to the rarity of the disorder. Reported perinatal mortality rates for the pump twin vary between 35% to 50%154,157 of cases diagnosed at birth, whereas some series of antenatally diagnosed cases report better,158 similar,159,160 and worse161 outcomes. One explanation for a better outcome in antenatally diagnosed cases may be spontaneous resolution of the TRAP sequence following complete cessation of flow to the acardiac twin.158,160,162 Conversely, outcome may be worse due to spontaneous demise of the pump twin leading to an early second-trimester loss not otherwise identified as a TRAP.158 Long-term outcome data are not available for pump twins, although it is reasonable to speculate the risk of long-term cardiac and neurodevelopmental sequelae is high163,164 owing to vascular imbalances in utero. The prediction of outcome for antenatally diagnosed TRAP is challenging. An acardiac–to–pump weight ratio above 70% at birth was associated with increased rates of high-output cardiac failure, hydramnios, and preterm birth, suggesting that a relatively small acardiac mass is a good sign. Certainly, a larger acardiac mass will put a greater hemodynamic strain on the pump twin. However, antenatal weight estimation of the acardiac mass is hampered by the absence of normal biometric structures, and the errors are likely large. Others suggest a rapid increase in the acardiac mass to be indicative of poor prognosis.159 Doppler velocimetry is probably the best tool to predict outcome. Large differences in the umbilical artery Doppler values suggest
B
relatively little flow to the acardiac twin, thereby predicting a more favorable outcome.159–161,165 In contrast, small differences in the umbilical artery Doppler values would signify similar flows, the presence of large anastomoses placing a greater hemodynamic strain on the pump twin. Additional factors thought predictive of poor outcome are high-output cardiac failure with hydrops, hydramnios,154 and certain morphologic characteristics of the acardiac twin such as the presence of a head and upper limbs.157 It is unknown to what degree these parameters apply in the early second trimester, and spontaneous resolution as well as sudden demise of the pump twin remains largely unpredictable.
Management Options As the natural history of antenatally diagnosed TRAP remains poorly documented, its treatment is equally controversial, ranging from conservative to palliative to causative. Conservative management consists of close antenatal surveillance and timed birth for signs of cardiac failure, whereas palliative treatment involves prolongation of pregnancy by serial amniodrainage and maternal administration of indomethacin for preterm labor and digoxin for cardiac failure. Reported perinatal mortality rates from conservative and palliative treatment vary widely between 10%158 and 50%.154 This is not surprising considering how poor the placental transport of digoxin is normally, much less when the fetus is hydropic. Also, little or no data are available on the longterm outcome of surviving pump twins, but as stated previously, there is concern about long-term neurologic and cardiac sequelae. Causative treatment seeks to arrest the flow of blood to the acardiac twin. Several methods are proposed, ranging from hysterotomy and birth of the acardiac twin166 to embolization of the acardiac twin’s circulation167 to fetoscopic cord ligation168 to ultrasound-guided or fetoscopic coagulation of the umbilical cord169,170 or intrafetal vessels.171 Clearly, hysterotomy with selective birth of the acardiac twin is unacceptable because of the high maternal morbidity. Also, embolization by the injection of thrombogenic substances into the acardiac twin’s circulation (e.g., absolute alcohol, coils, and enbucrilate gel) is also unacceptable as a first-line treatment, because dIUFD due to incomplete vascular
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 421 FIGURE 23–19 A, This 1.0-mm fetoscope is used for fetoscopic interventions early in the second trimester (Karl Storz). B, Doppler examination confirms arrest of flow after laser cord coagulation at 16 weeks’ gestation.
B
A
B
A
B
FIGURE 23–20 A, Disposable 3-mm bipolar forceps (Everest Medical). B, Reusable 2.4-mm bipolar forceps (Karl Storz).
occlusion or embolization of the product to pump twin is not uncommon.172,173 A number of minimally invasive techniques are now available to produce complete circulatory confinement of the acardiac twin. Fetoscopic cord ligation causes immediate and complete interruption of both arterial and venous flow, irrespective of umbilical cord size, but is cumbersome and has a high risk of PPROM. At present, ultrasound- or fetoscopic-guided cord coagulation together with needle-based intrafetal coagulation appear to yield the most consistent results. The method of cord coagulation by laser is derived from that used for the coagulation of vascular anastomoses in TTTS.170 It can be performed as early as 16 weeks using a double needle loaded with a 1.0-mm fetoscope and a 400µm laser fiber (Fig. 23–19).174 Fetoscopic laser coagulation is performed percutaneously under local or regional anesthesia using a single 1.3-mm operating sheath or 10-Fr (3.3mm) trocar depending on the gestation. Fetoscopically guided laser offers good visual control of the coagulation site, but may fail if the umbilical cord diameter is large or, more rarely, if the amniotic fluid is stained. In these instances, bipolar cord coagulation with purpose-designed 2.4- to
3-mm bipolar forceps under ultrasound guidance is a secondary technique (Fig. 23–20). A recent series reported on the outcome of 60 pregnancies complicated by TRAP and treated with laser coagulation of the anastomoses or the umbilical cord.175 The survival rate was 80%, and 67% gave birth after 36 weeks. In 15%, additional bipolar coagulation was necessary to achieve arrest of flow. Needle-based coagulation techniques using laser,176 monopolar technique,171 or radiofrequency177 each involve the insertion of a 14- to 18-gauge needle into the fetal abdomen under ultrasound aiming for the intra-abdominal rather than the umbilical vessels. This technique is attractive for its simplicity, the smaller membrane defect produced, and the seemingly lower risks of PPROM. It may be the preferred technique when the acardiac twin has a short umbilical cord and/or oligohydramnios. Two small recent series reporting on 13178 and 29 cases179 with TRAP treated with intrafetal radiofrequency ablation report survival rates for the pump twin of more than 90%. However, in monoamniotic pregnancies, the umbilical cord cannot be transected and thus late dIUFD remains a risk owing to cord entanglement. Currently, it is not possible to conclude what the best management is for TRAP. Most cases of TRAP are diagnosed early in the second trimester when it is impossible to predict outcome. The outcome may be good without treatment if spontaneous arrest of flow occurs. Conversely, the pump twin may die unexpectedly or sustain sequelae from very preterm birth, cardiac failure, and chronic hypoxia. Early intervention may preclude the difficulties of arresting blood flow in larger, often hydropic acardiac masses, and it seems preferable not to await signs of decompensation. We believe it is justifiable to offer prophylactic, minimally invasive intervention if no spontaneous arrest of flow has occurred by 16 weeks, recognizing the pump twin may survive without any intervention in at least half of cases. The choice of technique will reflect gestational age and access to and the size of the acardiac twin. These procedures should be performed in specialized units by fetal medicine specialists familiar with different techniques in order to tailor therapy to the needs of each individual case.
422 S ECTION THREE • Late Prenatal–Fetal SUMMARY OF MANAGEMENT OPTIONS
Twin Reversed Arterial Perfusion Sequence Evidence Quality and Recommendation
Management Options
References
Conservative with no hydramnios or hydrops—maintain surveillance in “pump twin” for the development of hydramnios and/or hydrops and timely delivery.
III/B
154
Palliative with hydramnios or cardiac failure (variable prognosis)— serial amniodrainage and tocolysis for hydramnios and digoxin for the cardiac failure. This is a backup option if intervention is not possible.
III/B
154,158
Coagulation of cord to acardiac twin.
III/B
169,170
Ligation of cord to acardiac twin.
III/B
168
Intrafetal (in acardiac twin) coagulation of fetal vessels.
III/B
171
For invasive treatment before 21 wk, intrafetal coagulation and cord coagulation (laser and bipolar) are effective methods to arrest flow.
III/B
169,170,172
Beyond 21 wk and in cases with hydropic cord, bipolar cord coagulation may be more effective.
III/B
169
It is justifiable to offer invasive treatment if no spontaneous arrest has occurred by 16 wk.
—/GPP
—
Mode of delivery depends on factors such as presentation and fetal health,
III/B
154
Intervention with hydramnios or cardiac failure (hydrops)—arrest of flow toward the cardiac twin by a number of possible methods:
●
●
●
GPP, good practice point.
TWIN-TO-TWIN TRANSFUSION SYNDROME General TTTS is another complication unique to monochorionic multiple pregnancies. In most monochorionic twin gestations, interfetal transfusion across the anastomoses is a constant, but balanced, phenomenon. However, in 10% of monochorionic twins, a chronic imbalance in net flow develops, resulting in TTTS.54,55 Hypovolemia, oliguria, and oligohydramnios develop in the donor twin, producing the stuck twin phenomenon. Hypervolemia, polyuria, and hydramnios evolve in the recipient twin, who can develop circulatory overload and hydrops (Fig. 23–21). TTTS usually occurs between 15 and 26 weeks and is a sonographic diagnosis based on the following criteria: hydramnios in the sac of the recipient twin (defined as deepest vertical pocket of
A
≥ 8 cm prior to 20 wk and ≥ 10 cm after 20 wk) secondary to polyuria, combined with oligohydramnios in the donor’s sac (deepest vertical pocket ≤2 cm) secondary to oliguria. Quintero and coworkers180 suggested a cancer-like staging system, which despite its several limitations, is still widely used. Stage I cases include those with hydramnios in the recipient sac but the bladder of the donor twin still visible. In stage II, the bladder of the donor twin remains empty (stuck twin). Stage III is characterized by severely abnormal Doppler studies: absent or reversed end-diastolic flow in the umbilical artery of the donor or abnormal venous Doppler pattern in the recipient, such as reverse flow in the ductus venosus or pulsatile umbilical venous flow. Fetal hydrops means stage IV, and the end-stage V corresponds to fetal demise of one or both twins. The purpose of any classification system in medicine is to assess disease severity, to
B
FIGURE 23–21 Ultrasound image of twin-twin transfusion syndrome. A, The donor is stuck to the uterine wall without bladder filling. B, There is hydramnios in the sac of the recipient, who has a distended bladder.
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 423
stratify therapy, and to predict the response to a given therapy. The Quintero staging system only weakly correlates with outcome181 and the treatment is the same for stage I to stage IV. Further, the Quintero staging system does not reflect a timescale of progressive deterioration. As such, TTTS can present as stage III from the start. Also, stage I disease can progress to stage V directly, without passing through stages II, III, and IV. At best, the Quintero staging system reflects the different possible clinical manifestations that may result from a variable contribution of intertwin transfusion imbalance, hormonal factors, and the degree of placental sharing. As discussed previously, the differential diagnosis includes discordant growth in which the growth-restricted twin can appear “stuck” owing to oligohydramnios, but in which hydramnios is absent in the larger twin. Likewise, the isolated presence of hydramnios in one sac with normal amniotic fluid in the other precludes the diagnosis of TTTS, and in that case, other causes for hydramnios must be sought. Many questions remain concerning the exact pathophysiology of TTTS. Nevertheless, TTTS remains best explained by the angioarchitecture. Placental anastomoses can be AA, arteriovenous (AV or VA), and venovenous (VV).182 AA and VV anastomoses are typically superficial, bidirectional anastomoses on the surface of the chorionic plate, forming direct communications between the arteries and the veins of the two fetal circulations. The direction of flow depends on the relative interfetal vascular pressure gradients. AV anastomoses are usually referred to as “deep” anastomoses. They occur at the capillary level deep within the depth of the placenta, receiving arterial supply from one twin and providing venous (well-oxygenated) drainage to the other. The supplying artery and draining vein of the AV anastomosis can be visualized on the placental surface as an unpaired artery and vein that pierce the chorionic plate at close proximity to each other (Fig. 23–22). The AV anastomoses allow flow in one direction only and, hence, may create an imbalance in the interfetal transfusion leading to TTTS, unless balanced by an oppositely directed transfusion through other superficial or deep anastomoses.
Artery
Vein
A C
Ma
FIGURE 23–22 Schematic three-dimensional drawing of the human “shared” cotyledon. Artery and vein enter the chorionic plate very close to each other. A, amnion; C, chorion; Ma, maternal circulation; depicted as solid shading. (Drawing by Luc Brullemans.)
Both postnatal injection studies15 and in vivo fetoscopic observations183,184 indicate the presence of at least one unidirectional AV anastomosis as an anatomic prerequisite for the development of TTTS. Although a TTTS case was reported with only superficial anastomoses (one AA and one VV),184 this seems the exception confirming the rule. The presence of bidirectional AA anastomoses is believed to protect against the development of TTTS because most non-TTTS monochorionic placentas have AA anastomoses (84%) in contrast to TTTS placentas (20%–30%).15,184 Although vascular anastomoses are an anatomic prerequisite for the development of TTTS, other pathophysiologic mechanisms are likely involved. Because 75% of sonographically defined TTTS has an intertwin hemoglobin difference of less than 15%,185 this syndrome cannot be explained by the simple transfer of blood from one twin to the other. Further, there is no increased erythropoietin production in the donor186 and no evidence of iron depletion/overload in the donor/recipient.187 It is suggested that discordant placental function may offset TTTS, because placental dysfunction is associated with an increased fetoplacental resistance, which may promote transfusion from the growth-restricted donor twin to the recipient twin. Reduced insulin growth factor-II188 and decreased leptin levels189 in donors compared with recipients may indicate discordant placental development rather than transfusion as a cause of the growth restriction. Other hormonal changes occur in donors and recipients. Raised endothelin-1 levels were observed in recipients, potentially causing increased peripheral vasoconstriction and hypertension. Recipients have increased levels of atrial natriuretic peptide,190 and those with severe cardiac dysfunction have higher levels of brain natriuretic peptide, suggestive of cardiac remodeling. Increased renin gene and protein expression are found in donor kidneys, but the expression is virtually absent in the recipient kidneys,191,192 implicating a role of the renin-angiotensin system in TTTS. Thus, the pathophysiology of sonographically defined TTTS is most likely multifactorial with vascular anastomoses providing the anatomic basis, whereas hemodynamic and hormonal factors contribute in varying degrees to its clinical development. Early identification of the monochorionic twin pregnancies at increased risk of TTTS would assist patient counseling and planning of follow-up. As such, pregnancies at increased risk may be followed in a fetal medicine center, which is especially relevant in geographic settings in which access is problematic. Further, for dichorionic triplets, an increased risk in the first trimester might be an argument in favor of reduction of the monochorionic pair. Finally, timely treatment of TTTS might improve outcome by preventing PPROM and/or cervical shortening, which is an important risk factor for preterm birth.193,194 An increased nuchal translucency (NT) (>95th percentile) in at least one fetus during the 11 to 14 weeks’ examination occurs in 13% of monochorionic twins and is a marker for chromosomal anomalies, cardiac defects, and a wide range of genetic syndromes. In monochorionic twins, an increased NT may reflect early cardiac dysfunction due to hypervolemic congestion in the recipient and, thus, herald the subsequent development of TTTS. Indeed, fetuses of monochorionic twin pregnancies with increased NT have a higher likelihood for the subsequent development of TTTS (likelihood ratio 3.5; 95% confidence interval [CI]
424 S ECTION THREE • Late Prenatal–Fetal FIGURE 23–23 Ultrasound image of membrane folding in a monochorionic twin pregnancy, which reflects discordant amniotic fluid in a monochorionic twin pregnancy.
1.9–6.2).195 However, the sensitivity of the NT measurement for TTTS is only 28%, with a positive predictive value of 33%. These figures were somewhat improved in a more recent study by the same group, in which an NT discordance of 20% or more detected 52% of cases with TTTS with a positive predictive value of 24%.196 In the same series, the difference in crown-rump length (CRL) had a similar predictive value as NT discordance. However, two other studies did not confirm NT discordance to be a significant risk factor for the subsequent development of TTTS,197,198 although both demonstrated the difference in CRL to be predictive. As such, difference in CRL of 6 mm or more detected 52% of cases TTTS with a positive predictive value of 19%. It seems unlikely that all TTTS cases will be predictable in the first trimester. The intertwin transfusion equilibrium is probably fragile and might become unbalanced at any stage in pregnancy without any warning. Further, TTTS may result from a random and asymmetrical reduction in vascular anastomoses with placental expansion later on in pregnancy.199 Folding of the intertwin membrane (Fig. 23–23) at 15 to 17 weeks may be a more promising sign for the prediction of TTTS. It is present in 32% of monochorionic twin pregnancies and believed to reflect oliguria and a reduced amniotic fluid in the sac of the donor. It is associated with an increased likelihood for the development of TTTS (likelihood ratio 4.2; 95% CI 3.0–6.0). Early mid-trimester membrane folding identifies 91% of TTTS with a positive predictive value of 43%.195 Another proposed marker for the prediction of TTTS is the absence of AA anastomoses. These anastomoses can be detected by color-flow mapping and pulsed Doppler83 as early as 12 weeks, though the majority become detectable after 18 weeks.200 The difficulty with using the absence of AA anastomoses as a prognostic sign is that it is impossible in early pregnancy to ascertain whether they are truly absent or just undetected. However, when an AA anastomosis is identified, 15% of monochorionic twin pregnancies develop TTTS compared with 61% when no AA anastomosis can be detected. Finally, a velamentous cord insertion was suggested to increase the risk for TTTS, and cord insertions can be reliably determined at 16 weeks. Fries and colleagues201
demonstrated a higher prevalence of velamentous cord insertion in TTTS placentas than in non-TTTS placentas, 32% and 9%, respectively. In another series, the combination of an eccentric cord insertion in one twin and a marginal or velamentous cord insertion in the other was more frequently seen in TTTS,18 though several other studies failed to identify an association.202,203 Discordant cord insertions reflect unequal placental sharing and, therefore, seem to increase the risk of discordant growth, but not the risk of TTTS. Within the Eurofoetus consortium,204 we developed a two-step sonographic scoring system in the first trimester and at 16 weeks to predict a complicated outcome, defined as the occurrence of TTTS, discordant growth, or intrauterine demise.197 If the CRL difference is 12 mm or more or if there is discordant amniotic fluid in the first trimester, then the probability of a complicated fetal outcome is about 80% and the survival rate only 50%, as compared with an 80% uncomplicated outcome and a survival rate of 93% in the screen-negative group. At 16 weeks, significant predictors for a complicated fetal outcome were difference in abdominal circumference, discordant amniotic fluid, and discordant cord insertions. This two-step risk assessment in the first trimester and at 16 weeks identified a high risk group with a more than 70% risk of complicated outcome, in contrast to an 86% uncomplicated outcome in the group predicted to be at low risk. This information is useful for patient counseling and to identify patients who may benefit from followup in a dedicated fetal medicine center, especially in areas where access is limited.
Fetal Risks Untreated, TTTS has been quoted to have a mortality of nearly 100%, although advances in neonatal care mortality rates may have decreased that rate to 63%.205 Spontaneous abortion and extreme preterm birth are associated with hydramnios, and fetal demise may result from cardiac failure in the recipient or poor perfusion in the donor. Substantial cerebral and cardiac sequelae may occur in survivors owing to the chronic hemodynamic imbalances. Both the donor and the recipient are at risk of antenatally acquired cerebral lesions with, depending on the therapy used, reported incidences of 10%206 to 50%.207 In donor twins, hypovolemia, hypotension, and anemia may induce cerebral hypoxia and brain damage, whereas in the recipient, hyperviscosity and cardiac failure may impair cerebral perfusion. Again depending on the therapy used, the reported incidences of cerebral palsy and major neurologic deficiencies range from 6%208 to 26%.143 The risks of neurologic damage are dramatically increased after an sIUFD when the vascular anastomoses remain patent, presumably due to acute exsanguination of the survivor into the fetoplacental unit of the deceased co-twin. MCA PSV measurement seems a reliable noninvasive method to detect anemia after sIUFD in TTTS.138 Though it is tempting to intervene based on this finding, it remains to be demonstrated whether a rescue transfusion decreases risks of neurologic sequelae.146 Monochorionic twins with TTTS have a reported 8% prevalence of pulmonary valve stenosis in recipients, regardless of whether these pregnancies were treated primarily by
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 425
amniodrainage or laser.209,210 Further, up to 48% of survivors have signs of transient oliguric renal failure affecting the donor as well as the recipient, although long-term renal impairment does not appear to be a problem.211 Also, limb,212 gastrointestinal,213 and cerebral infarctions214 that preferentially affect the recipient are described and may originate from hyperviscosity or hypoperfusion.
FIGURE 23–24 Macroscopic image of a placenta at birth demonstrates “bichorionization” and laser impact (arrows) on the monochorionic placenta after laser coagulation for twin-twin transfusion syndrome.
Management Options Laser Coagulation versus Amniodrainage In view of the poor survival rates with conservative management, there is no disagreement that therapy should be offered. The two most commonly used therapies for midtrimester TTTS are amniodrainage and fetoscopic laser coagulation of the vascular anastomoses. However, since the Eurofetus randomized, controlled trial comparing laser treatment with amniodrainage, there is general consensus that the best treatment option for all stages of TTTS is currently laser coagulation of the vascular anastomoses.140,215 Women with suspected TTS should be informed that amniodrainage should be reserved only for regions in which laser coagulation is not available and otherwise referred to a fetal medicine center that performs laser coagulation. Before the advent of fetoscopic surgery, amniodrainage was the most commonly used treatment for TTTS. It controls the amniotic fluid volume, is relatively simple to perform, and is widely available. It was suggested the fetal condition might be improved by reducing the amniotic fluid pressure and perhaps enhancing uteroplacental perfusion.216,217 The evidence for such benefit is scant. Decompression does appear to prolong pregnancy. However, amniodrainage does not address the vascular basis of TTTS and usually needs to be repeated several times to control the amniotic fluid volume. In addition, because it does not cure the disease, amniodrainage often leads to the preterm birth of two sick neonates, which increases their risk of neonatal mortality and morbidity.218 Also, in the event of an sIUFD, the surviving twin is at high risk for anemia and neurologic sequelae.138,214 Available data suggest that amniodrainage is “effective” only in mild cases of TTTS (stages I–II) and outright fails in a third. Such a high failure rate may indicate that its purported efficacy is a reflection of the disease’s natural history. The overall perinatal survival rate with amniodrainage in uncontrolled series with cases diagnosed prior to 26 weeks was 57%.205 This rate was confirmed in a literature review by Skupsi and associates219 (double survival 50%; single survival rate 20%; total survival rate 61%). Worse yet, amniodrainage is associated with a 16% to 26% risk of severe sequelae in survivors.143,205 Whereas amniodrainage is a palliative and repetitive measure, fetoscopic laser coagulation of the vascular anastomoses seeks to address the underlying cause of the disease through a single intervention. Complete coagulation of all visible anastomotic occlusion results in the resolution of TTTS.220 Most fetoscopic laser centers agree that coagulation of nonanastomosing vessels should be avoided whenever possible, because this increases the area of nonfunctional placental territory and, therefore, the risk of intrauterine demise.221,222 Most centers have abandoned the nonselective technique of simply coagulating all vessels crossing the intertwin septum.223 The vascular equator does usually not
coincide with the membranous equator, and coagulation along the intertwin septum will, therefore, lead to unnecessary placental loss. In some monochorionic pregnancies with unequal placental sharing or a large shared part of the placenta, coagulation of all anastomoses may leave too little unshared placenta for one or both fetuses, leading to sIUFD or even dIUFD. As a result, most centers now are selective, coagulating all visibly communicating vessels between the two fetuses as well as the ones from which it could not be excluded that they are anastomosing (Fig. 23–24). A “hyperselective” approach, as discussed by Feldstein and coworkers,224 coagulating only the causative AV anastomosis is interesting from a theoretical point of view because it is simply not possible to identify this anastomosis in the presence of others. Also, leaving certain anastomoses open places the remaining fetus at risk for hypovolemic events in case of sIUFD and might lead even to a reversal of transfusion. Two adaptations of the currently practiced technique have been suggested to improve survival rates. One is to draw a complete line of coagulation between the two vascular territories to avoid small and potentially invisible anastomoses (unpublished). Another is a sequential technique in which all AV anastomoses from the donor to the recipient are coagulated first in an attempt to minimize blood loss from the already hypovolemic donor and increase its survival rate.225 Laser coagulation is performed percutaneously (Fig. 23– 25) under local or locoregional anesthesia. A cannula or fetoscopic sheath is inserted into the hydramniotic sac and the placenta inspected. For coagulation, the laser tip is directed toward the target vessels at as close to a 90-degree angle as possible, and with a nontouch technique, a 1- to 2-cm section of the selected vessel is photocoagulated (Fig. 23–26). At the conclusion, amniodrainage is performed until the amniotic fluid pockets on ultrasound are normal. With an anterior placenta, the amniotic sac as well as the vessels on the placenta might be more difficult to access. Some instruments have been purposely developed, but it is yet unclear whether they improve performance.226 Placental localization does not appear to influence outcome.227
426 S ECTION THREE • Late Prenatal–Fetal
Few laser procedures have been reported before 16 weeks and after 26 weeks. Similar to amniocentesis, the minimum requirement for intervention should be chorioamniotic membrane fusion. Therefore, the lower limit for safe laser coagulation seems to be 15 weeks, when the use of a 1.2-mm scope is recommended to reduce membrane trauma. After 26 weeks, the procedure is more challenging because the amniotic fluid is often turbid and the anastomotic vessel much larger. Nevertheless, laser separation seems preferable to serial amniodrainage or elective preterm birth. Curing the disease prior to birth may indeed reduce the incidence of cerebral lesions.228 In uncontrolled series, the overall fetal survival has consistently been between 62% and 77%,140,221 with a risk for long-term neurologic morbidity in survivors of 13% to 18%.208,229 The Eurofetus research consortium granted by the European Commission was the first to conduct a
FIGURE 23–25 Image of the operative setup and percutaneous access used for fetoscopic interventions.
A
B
randomized trial comparing serial amniodrainage withlaser coagulation as a primary therapy for TTTS prior to 26 weeks. The primary outcome measure was survival of at least one twin at 6 months of age, and the secondary outcome measure was intact neurologic survival (Table 23–1).140 Compared with the amniodrainage group, the laser group had a higher likelihood of survival of at least one twin to 28 days of age (76.4% vs. 51.4%). Infants in the laser group also had a lower incidence of cystic periventricular leukomalacia (laser 6% vs. drainage 14%) and were more likely to be free of neurologic complications at 6 months of age (52% vs. 31%). A recent long-term follow-up study conducted in three European centers showed an incidence of neurodevelopmental impairment of 18% at the age of 2 years.229 Cerebral palsy was diagnosed in 6%. Donors were similarly affected as recipients. Only a low gestational age at birth was independently associated with the risk of neurodevelopmental impairment. Another randomized controlled trial comparing laser with amniodrainage sponsored by the National Institutes of Health was stopped at 40 patients because of poor recruitment and was inconclusive.230 Surprisingly, they reported a 70% intrauterine demise rate for the recipient and an overall survival rate of only 45% after laser treatment. A major difference with the European trial was that all patients underwent a test amniodrainage, and only patients who failed to respond were randomized. It is well established that an amniodrainage may hamper later laser treatment because of septostomy, intra-amniotic bleeding, or membrane detachment. The high mortality of the recipient might be due to the detrimental effect of the failed amniodrainage on recipient cardiac function. A recent metaanalysis that covered the Eurofetus trial as well as nine other observational cohorts concluded that laser as compared with amniodrainage was associated with an odds ratio of 2.0 for perinatal survival and 0.24 for short-term neurologic morbidity.231 Recipients appear more likely to survive than donors. At present, laser coagulation is therefore the best available treatment and amniodrainage should be performed as an obstetric emergency in places in which there is no access to fetoscopic laser surgery or when
C
FIGURE 23–26 A, Fetoscopic image of laser coagulation of an arteriovenous anastomosis for twin-twin transfusion syndrome. B, Fetoscopic image of the hands of the donor twin, who is stuck behind the intertwin septum. C, Fetoscopic image of the face of the recipient, who moves freely in the hydramniotic sac.
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 427 T A B L E 2 3 – 1
Randomized Controlled Trial of Fetoscopic Laser Surgery versus Serial Amniodrainage* AMNIOREDUCTION LASER (N = 72)
(N = 70)
P VALUE
Gestational age at randomization (wk)
20.6 (±2.4)
20.9 (±2.5)
ns
Quintero stage at randomization Stage 1 Stage 2 Stage 3 Stage 4 Number of procedures
6 (8%) 31 (43%) 34 (47%) 1 (1%) 1†
5 (7%) 31 (44%) 33 (47%) 1 (1%)
ns ns ns ns
2.6 (±1.9)
—
Volume of amniotic fluid drained per procedure—mL‡ Median Range Total volume of amniotic fluid drained—mL‡
1725 500–5500
2000 243–4000
Median Range
1725 500–5500
3800 600–18,000
Pregnancy loss at or within 7 days of the initial procedure Premature rupture of membranes at or within 7 days of the first procedure Premature rupture of membranes at or within 28 days of the first procedure Intrauterine death within 7 days of the first procedure§ At least one survivor at 6 mo of life No survivors One survivor Two survivors At least one survivor at 6 mo stratified by stage Quintero stages I and II Quintero stages III and IV Gestational age at delivery—median (interquartile range) Neonatal and infant death Intraventricular hemorrhage (grades III–IV)| Donor Recipient Cystic periventricular leukomalacia¶ Donor Recipient
8 (12%) 4 (6%) 6 (9%) 16/138 (12%) 55 (76%) 17 (24%) 29 (40%) 26 (36%)
2 (3%) 1 (1%) 6 (9%) 9/136 (7%) 36 (51%) 34 (49%) 18 (26%) 18 (26%)
.10 .37 .98 .23 .002
32/37 (86%) 23/35 (66%) 33.3 (26.1–35.6) 12 (8%) 2 (1%) 2 (3%) 0 (0%) 8 (6%) 2/72 (3%) 6/72 (8%)
21/36 (58%) 15/34 (44%) 29.0 (25.6–33.3) 41 (29%) 8 (6%) 2 (3%) 6 (9%) 20 (14%) 5/70 (7%) 15/70 (21%)
.007 .07 .004
—
15 wk after the procedure).169 Nicolini and colleagues287 reported their experience with 17 cases. The survival rate was 81% (13/16 survivors; 1 patient had a termination of pregnancy because of an abnormality diagnosed later in gestation). There was 1 fetal hemorrhage caused by cord perforation, which is a complication of too much energy. We reported the outcome of 80 consecutive cord coagulations in complicated monochorionic multiplets (including 7 triplets) by laser and/or bipolar coagulation performed between 16 and 28 weeks (mean 21 wk).288 Indications were TRAP (27.5%), discordant anomaly (35%), severe TTTS (30%), and selective growth restriction (7.5%). In 70%, the laser was used as the primary technique; additional bipolar was necessary in about half of cases. Overall survival was 83% with normal neurodevelopmental outcome in 92% of infants. Persistent PPROM occurred in 38%, and if prior to 25 weeks, this was associated with a mortality of 80%. There were no serious maternal complications, except for one mild transient mirror or Ballantyne’s syndrome. Five cases involved heterokaryotypic monochorionic twins (46, XY/47,XY,+21; 46, XX/47,XX,+13; 46,XY/45,X; 2 46,XX/45,X), and umbilical cord occlusion resulted in a successful outcome in all 5 cases. All 5 surviving children were phenotypically normal at birth (range 34–40 wk) and are developing normally.72 Robyr and associates289 reported their experience with umbilical cord coagulation in 46 consecutive cases. They reported a 72% survival rate. In their series, there was a higher incidence of intrauterine demise in procedures performed prior to 18 weeks. Putting all the previously mentioned series together, the overall survival of umbilical cord coagulation is about 80%. About half of the losses are attributable to intrauterine demise of the healthy co-twin and about half to postnatal losses due to very preterm birth, mostly related to PPROM. Again, about half of the intrauterine deaths occur within 24 hours of surgery, and may reflect either intraoperative vessel perforation, incomplete cord coagulation by laser coagulation, or exsanguination of the surviving twin into the placenta of the dead twin, which may be especially relevant prior to 18 weeks when the placental mass is still relatively large compared with the fetal mass. Late intrauterine death has been diagnosed up to 10 weeks after the procedure and was commonly related to cord entanglement after septostomy. This finding supports the use of cord transection after septostomy or in monoamniotic gestations. Postoperative anemia diagnosed by MCA PSV measurements within 24 hours and requiring an intrauterine transfusion occurred in
2% to 3% of cases and resulted in a normal outcome in all instances. Similar to the treatment for TTTS, PPROM is an important complication of umbilical cord coagulation, account ing for miscarriage, severe preterm birth, neonatal death, and developmental delay. We demonstrated a significant decrease from 42% to 6% in PPROM prior to 31 weeks with increasing experience, which again underscores the need to restrict this procedure to a limited number of hands.290 To avoid the risks of early PPROM for the healthy co-twin, it may be preferable to defer selective feticide until after 24 weeks in highly selected cases of discordant anomaly in which the risk of spontaneous intrauterine demise is small (such as in severe discordant central nervous system, genitourinary, skeletal anomaly). Bipolar coagulation can then be performed using the 3.0-mm forceps by overstretching the blades, whereupon the forceps opens more widely to accommodate for the larger cord diameter. We reported on a consecutive series of five cases in which selective feticide was performed between 26 to 30 weeks’ gestation. All deliveries occurred beyond 31 weeks (range 31–37 wk). All infants survived, except for one unrelated neonatal demise of a child born at 36 weeks due to a complication of failed therapy for pulmonary stenosis.290 It remains to be demonstrated whether needle-based intrafetal coagulation techniques291,292 are as effective to achieve selective feticide for discordant monochorionic twins as for TRAP. As such, radiofrequency ablation for non-TRAP indications resulted in an overall survival rate of only 60% (9/15 fetuses intended to continue).293–295 Similar survival rates were reported after intrafetal laser coagulation.296 Although these techniques perform well in the lowflow conditions of acardiac twins in TRAP, they may fail in the normal flow conditions of a monochorionic twin with a discordant anomaly. Accordingly, larger series with longterm neurodevelopmental follow-up are necessary to establish the efficacy of intrafetal coagulation for non-TRAP monochorionic pathologies. Currently, it is not possible to state the single best method for selective feticide in monochorionic pregnancies. The surgeon should be familiar with several techniques in order to tailor therapy to the individual requirements of each case. Generally, we recommend laser fetoscopic cord coagulation as a primary technique before 21 weeks, whereas beyond 21 weeks, laser or bipolar coagulation can be used depending on cord diameter.297 Cord ligation should be available as back up should all other methods fail. These procedures should be performed in experienced tertiary referral centers to ensure a large enough caseload. Also, the surviving twin should be followed carefully throughout pregnancy and after birth with the minimum of an early neonatal brain scan and developmental assessment at 1 year of age.
Issues Applicable to Monochorionic and Dichorionic Twins As for singletons, Rh prophylaxis should be given in all instances of invasive antenatal procedures in Rh-negative women in which the fetal genotype is unknown. As with the intrauterine death of one twin, the incidence of maternal disseminated intravascular coagulation appears rare and routine checks of coagulation parameters may therefore be
C HAPTER 23 • Fetal Problems in Multiple Pregnancy 435
unnecessary. From 20 weeks onward, the use of fetal analgesia or anesthesia by administration of fentanyl or other opioid alternative should be considered prior to feticide to reduce fetal awareness and pain sensation.298 To many people, any deliberate termination of a fetus is controversial and the decision to proceed to selective feticide may be difficult. Therefore, psychological support and counseling for the family is strongly recommended before and after the selective feticide.
Acknowledgment Dr. L. Lewi is beneficent from a grant of the European Commission in its 5th Framework Programme (#QLG1-CT2002-01632 EuroTwin2Twin). The other members of the EuroTwin2Twin Consortium are thanked for setting up the group: Y. Ville (Poissy), K. Hecher (Hamburg), E. Gratacos (Barcelona), R. Vlietinck (Leuven), M. van Gemert (Amsterdam), G. Barki (Tuttlingen), K. Nicolaides (London), R. Denk (Munchen), and C. Jackson (London).
SUMMARY OF MANAGEMENT OPTIONS
Congenital Abnomalies in Twins Evidence Quality and Recommendation
Management Options
References
Issues Applicable to All Twins Options
—/GPP
—
Offer counseling and psychological support.
—/GPP
—
Accurate chorionicity determination is essential.
IIb/B
20,21
Anti-D prophylaxis for procedures.
—/GPP
—
Conservative management is usually preferred if the condition is lethal to avoid intervention loss rates.
III/B
279
Selective feticide is performed by intracardiac or intrafunicular injection of KCl.
III/B
279
Loss of the healthy fetus occurs in about 7.5% with delivery before 33 wk in 22%.
III/B
277,279
Conditions with a high risk of IUFD may indicate selective feticide.
—/GPP
—
Selective feticide is performed by cord occlusion (to avoid the loss of normal co-twin if KCI used).
III/B
281,290
After cord occlusion, the healthy fetus survives in about 80%, with 80% delivering after 32 wk.
III/B
290
Careful follow-up of surviving normal twin.
—/GPP
—
Conservative management. Selective feticide of the abnormal fetus. Termination of the pregnancy.
Dichorionic Twins
Monochorionic Twins
GPP, good practice point; IUFD, intrauterine fetal demise.
SUGGESTED READINGS Allen VM, Windrim R, Barrett J, Ohlsson A: Management of monoamniotic twin pregnancies: A case series and systemic review of the literature. BJOG 2001;108:931–936. Denbow ML, Cox P, Taylor M, et al: Placental angioarchitecture in monochorionic twin pregnancies: Relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000;182:417–426. Eddleman KA, Stone JL, Lynch L, Berkowitz RL: Selective termination of anomalous fetuses in multifetal pregnancies: Two hundred cases at a single center. Am J Obstet Gynecol 2002;187:1168–1172.
Gratacós E, Lewi L, Muñoz B, et al: A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30:28–34. Lenclen R, Paupe A, Ciarlo G, et al: Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: Comparison with dichorionic twins. Am J Obstet Gynecol 2007;196:450. e1–450.e7. Lewi L, Blickstein I, Van Schoubroeck D, et al: Diagnosis and manage ment of heterokaryotypic monochorionic twins. Am J Med Genet A 2006;140:272–275.
436 S ECTION THREE • Late Prenatal–Fetal Lewi L, Gucciardo L, Huber A, et al: Clinical outcome and placental characteristics of monochorionic diamniotic twin pairs with early- and late-onset discordant growth. Am J Obstet Gynecol 2008;199:511. e1–511.e7. Lopriore E, Ortibus E, Acosta-Rojas R, et al: Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery. Obstet Gynecol 2009;113:361–366. Senat MV, Deprest J, Boulvain M, et al: Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–144.
Tan TY, Sepulveda W: Acardiac twin: A systematic review of minimally invasive treatment modalities. Ultrasound Obstet Gynecol 2003;22: 409–419.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 2 4
Fetal Hydrops JOHN S. SMOLENIEC Videos corresponding to this chapter are available online at www.expertconsult.com.
INTRODUCTION Fetal hydrops is associated with high perinatal morbidity and mortality rates at all gestational ages. However, outcome statistics are greatly influenced by such factors as the etiology (immune vs. nonimmune), gestation at diagnosis, timely referral, prenatal compared with neonatal study groups, and the available health resources in the particular population and their use in the implementation of preconception and antenatal screening programs1–3 (see Chapters 4 and 7–9). These factors are reflected in the range of reported incidences from 1 : 4242 to approximately 1 : 17004 to 1 : 20003 neonatal admissions for hydropic fetuses born alive in developed countries. Traditionally, fetal hydrops is categorized into immune (IH) and nonimmune (NIH) disease. Although rhesus (RhD) hemolytic disease was the most common cause of hydrops in the past (see Chapter 13), the widespread implementation of anti-D immunoglobulin prophylaxis and the improved antenatal management of at-risk fetuses have led to a significant decrease in its incidence and associated morbidity and mortality (e.g., perinatal mortality decreased from 50% to 2% in Canada5; see Chapter 13). In contrast, the survival rates for NIH remain less than 10%4 and as low as 1.5% (2/138).1 At present, NIH is more prevalent than IH (4 : 1)3 in most countries with adequate anti-D immunoglobulin prophylaxis supplies and fetomaternal expertise. Human fetal hydrops is the endpoint of a multitude of pathophysiologic pathways, a number of which have not been elucidated. Advances in ultrasound make fetal hydrops easy to diagnose. The “causes” or rather associations with NIH are many1–4,6 (Table 24–1). Research using animal models7–9 provides some understanding of the complexity of fluid dynamics within the uterus (fetal, fetoplacental, fetoamniotic fluid, and between the uterine decidua and the placenta and membranes).
INCIDENCE The incidence is regionally dependent1,3,4 (e.g., alphathalassemia) and subject to seasonal variation (e.g., parvovirus B19 epidemics.10,11 Alpha-thalassemia is the most common cause of fetal hydrops in Southeast Asia,2,12 where the carrier frequency ranges from 4.14%2 for alpha-thalassemia caused
by the Southeast Asian deletion in southern China to 14% in northern Thailand,13 accounting for between 28%13 and 55%2 of cases in these regions. Considering the population density in this region, alpha-thalassemia is probably the leading cause of NIH in the world. Population screening can reduce the incidence of thalassemia,1,12,13 as it has in Cyprus, providing the resources are available. Similarly, the incidence of NIH associated with aneuploidy and congenital heart disease14,15 is likely to decrease with the implementation of first-trimester screening (see Chapter 7).
DEFINITION Hydrops is defined as the excessive extravascular accumulation of fluid in the interstitial compartment secondary to the disruption of the normal intravascular interstitial fluid homeostatic mechanisms. The excessive accumulation of interstitial fluid, particularly in serous cavities (peritoneal, pleural, pericardial), placenta, and amniotic fluid, facilitates the sonographic diagnosis of fetal hydrops (Figs. 24–1 to 24–3). Classically, the sonographic diagnosis of hydrops requires the presence of generalized edema plus the accumulation of fluid within two or more serous cavities. However, many of the pathophysiologic pathways leading to such a diagnosis go through progressive phases in which initially fluid may be recognized sonographically in only one site.
PATHOPHYSIOLOGY Hydrops occurs when the microvascular fluid exchange regulatory system is disturbed. Microvascular fluid exchange mechanisms in the human fetus are complex, gestational age–dependent, and poorly understood. The number of fluid exchange pathways in the fetus is greater than in either the infant or the adult. They include transplacental, transmembrane, and transcutaneous pathways. Transplacental fluid exchange has a large influence on blood volume, because the placental blood volume accounts for approximately 40% of the total fetal circulation.16 Fetal development is associated with a continual change in the different fluid exchange pathways and forces. These routes of fetal fluid exchange may be important compensatory mechanisms when fluid homeostasis is disturbed, as shown by the common clinical 437
438 S ECTION THREE • Late Prenatal–Fetal T A B L E 2 4 – 1
Abnormalities Associated with Hydrops* Immune (see Chapter 13) Anti-D and other Rh antibodies Antibodies to K in Kell system Antibodies to Fya in Duffy system Nonimmune Idiopathic/unknown Anemia (other than alloimmunization) Alpha-thalassemia major 1 (see Chapter 38) Parvovirus B19 congenital infection (see Chapter 29) Fetomaternal transfusion TTTS and variants (see Chapter 23) Erythroleukemia Congenital erythropoietic porphyria35 (Gunther’s disease) Cardiovascular (see Chapters 15 and 16) Severe congenital heart disease43 (atrial septal defect, ventriculoseptal defect, hypoplastic left heart, pulmonary valve insufficiency, Ebstein’s anomaly, subaortic stenosis, atrioventricular canal defect, tetralogy of Fallot, heterotaxy; premature closure of foramen ovale) High-output cardiac failure: associated with large arteriovenous malformation within the fetal vasculature or tumors Premature closure of ductus (? indomethacin therapy) Myocarditis (coxsackievirus, cytomegalovirus, parvovirus B19, adenovirus infections) Tachyarrhythmias (supraventricular tachycardia, atrial flutter)88 Bradyarrhythmias (heart block) Wolff-Parkinson-White syndrome Intracardiac tumors (teratoma, rhabdomyoma84) (see Chapter 22) Cardiomyopathy (e.g., fibroelastosis) Myocardial infarction Arterial calcification (e.g., idiopathic infantile arterial calcification85) Chromosomal (see Chapter 4) Trisomies Turner’s syndrome (45 XO) Triploidy Pulmonary Congenital hydro-/chylothorax Pulmonary lymphangiectasia Congenital pulmonary tumors/anomalies46,47,48 CCAM (see Chapter 23) Pulmonary sequestration Bronchogenic cysts and other tumors (see Chapter 23) Diaphragmatic hernia (see Chapter 19) Chondrodysplasia Pulmonary hypoplasia Renal (see Chapter 18) Congenital nephrosis (Finnish type) Renal vein thrombosis Urethral obstruction (atresia, posterior valves) Spontaneous bladder perforation Cloacal malformation Prune-belly syndrome Infection (intrauterine) (see Chapters 29–32) Parvovirus B1936,69 (either by anemia, myocarditis, or hepatitis) Syphilis1 Cytomegalovirus (primary & secodary34; adenovirus; coxsackievirus) Toxoplasmosis Herpes simplex Leptospirosis Chagas’ disease
Liver Hepatic calcifications Hepatic fibrosis Congenital hepatitis (see Chapter 47) Cholestasis Polycystic disease Biliary atresia Familial cirrhosis Inborn errors of metabolism74,75 Congenital disorder of glycosylation74 Lysosmal storage diseases (>20) include75: Gaucher’s disease GM1 gangliosidosis MPS types VIa and VII Iron-storage disease Anomalies (many associated with fetal immobility) (see Chapter 20) Achondroplasia Achondrogenesis type 2 Thanatophoric dwarfism Arthrogryphosis Multiple pterygium syndrome Neu-Laxova syndrome76 Pena-Shokeir type 1 syndrome COFS syndrome Noonan’s syndrome83 Myotonic dystrophy Neuronal degeneration Tumors63 Sacrococcygeal teratoma (see Chapter 22) Tuberous sclerosis (see Chapter 22) Miscellaneous Nonaneuploid cystic hygroma (see Chapter 22) Meconium peritonitis Fetal neuroblastosis Small bowel volvulus (see Chapter 19) Amniotic band syndrome Torsion of ovarian cyst Polysplenia syndrome Lymphatic: intestinal lymphatic hypoplasia26 Placental Monochorionic twins—TTTS (see Chapter 23) Chorioangioma67 (see Chapter 22) Umbilical cord anomalies86 Umbilical vein thrombosis True cord knots Umbilical cord cysts Hemagioma Maternal Diabetes mellitus (see Chapter 44) Thyroid disease (see Chapter 45) Preeclampsia (see Chapter 35)27,28 Severe anemia (see Chapter 38) Hypoalbuminemia
* Chapter numbers in text refer the reader to detailed discussion of management options for specific conditions within a given group. CCAM, congenital cystic adenomatoid malformation; COFS, cerebro-oculofacial-skeletal; Rh, rhesus; MPS, mucopolysaccharidosis; TTTS, twin-twin transfusion syndrome.
C HAPTER 24 • Fetal Hydrops 439 FIGURE 24–1 Ascites and cardiomegaly associated with alpha-thalassemia major (Bart’s hemoglobin) at 29 weeks’ gestation.
Placental edema Pericardial effusion
association of hydramnios and placental edema with fetal hydrops regardless of the underlying cause. The fetal extracellular fluid volume (ECF) exceeds the intracellular fluid volume (ICF), though the ECF : ICF ratio declines progressively with gestation, becoming less than 1 after birth.17 The interstitial–to–plasma volume ratio is therefore greatest in the fetus and then declines into adulthood. Control of this relatively large interstitial fluid compartment is fundamental to the understanding of fetal hydrops. Unfortunately, interstitial fluid control mechanisms are poorly understood because of the difficulty of measuring plasma and interstitial volumes.18 The many influences on fetal fluid homeostasis make it unlikely there is a single or simple pathophysiologic explanation for all cases of fetal hydrops. The “Starling equation” does not provide pathophysiologic explanations in the fetus.19 The fluid-dominated milieu of the fetus and the specific physiologic characteristics of the fetal heart and the lymphatic system make it particularly susceptible to hydrops. Animal research7,8,20,21 coupled with clinical studies19,22,23 suggest that raised central venous pressure (CVP) is a critical step in the pathophysiology of hydrops, at least with a cause associated with poor heart function (e.g., myocardopathy, obstructed cardiac return or outflow, profound anemia). The clinical use of umbilical venous pressure (UVP) in the investigation and management of some cases of fetal hydrops is a vindication of the physiologic research findings on the importance of the CVP and the lymphatic system.22,23 At the same time, some of the traditional pathophysiologic forces such as colloid oncotic pressure are being relegated to a lower tier of importance.
RISKS FIGURE 24–2 Pericardial effusion, cardiomegaly and placental edema associated with parvovirus B19 infection at 19 weeks’ gestation.
FIGURE 24–3 Polyhydramnios and massive ascites associated with Niemann-Pick type C inborn errors of metabolism.
Fetal Risks The fetal risks from hydrops are mainly fetal death with infant morbidity, an important risk in the few survivors. The commonly reported conditions associated with fetal hydrops are ● Alpha-thalassemia; aneuploidy; congenital malformations, infection, and the idiopathic (unknown) group. ● Fetal death is mostly influenced by the associated condition, gestation at diagnosis, gestation at delivery, and mana gement. The reported mortality rate ranges between 45%2 and greater than 90%.1,3 Management options include elective abortion, various invasive diagnostic and fewer therapeutic procedures, which are in themselves associated with a risk of pregnancy loss, preterm delivery, intrauterine fetal death, and fetal trauma (see Chapters 9 and 25). ● Infant mortality is influenced by the etiology, severity, and duration of the hydrops, prenatal procedures performed, gestational age at delivery, and neonatal management. Congenital anomalies are consistently reported with a 57% mortality.2 In contrast, mortality associated with primary chylothorax, an uncommon association with NIH, may be as low as 6%2 after admission to a neonatal unit in a developed country. ● Infant morbidity. The short- and long-term prognosis depends on many of the factors associated with mortality. The range of more severe morbidity includes terminal cardiac failure and heart transplantation,24 fetal cerebellar
440 S ECTION THREE • Late Prenatal–Fetal
hemorrhage associated with parvovirus B19 infection,25 cardiac anomaly needing surgical correction, chromosomal abnormality, persistent generalized edema as a result of protein-losing enteropathy associated with congenital intestinal lymphatic hypoplasia,26 and cerebral palsy.
Maternal Risks Antenatal consequences of fetal hydrops may be classified as direct or indirect: ● Direct consequences include associated hyperplacentosis and hydramnios. Hyperplacentosis is a large placental mass with associated dysfunction such as villus edema, impaired oxygen exchange–hypoxia–increased angiogenic factors (i.e., soluble fms-like tyrosine kinase 1 [sFlt-1]).27,28 This pathophysiologic process is associated with maternal dilutional anemia, edema, proteinuria, and gestational hypertension (i.e., preeclampsia or “mirror syndrome”).27,28 Hydramnios is associated with malpresentation, preterm labor, and preterm rupture of membranes (PROM) with the associated risk of placental abruption and chorioamnionitis. ● Indirect consequences include the complications of intrauterine investigations and therapy, namely, PROM, chorioamnionitis, abruption (associated with amniodrainage), anemia, and maternal red blood cell alloimmunization. In the event of fetal surgery, the maternal risks include anesthetic risks, fluid overload and electrolyte imbalance, uterine hemorrhage (during entry for fetal shunting and intrauterine laser procedures29,30), psychological stress and associated mental illness, and even maternal death.30 In patients undergoing open fetal surgery, the risks include adverse reproductive outcomes in 35% of future pregnancies, including uterine rupture or dehiscence, antepartum hemorrhage, and cesarean hysterectomy.31 ● During labor and delivery: Hydrops may be associated with preterm labor, the side effects of tocolysis, dystocia (e.g., large tumors), cesarean delivery (e.g., associated with malpresentation, cord prolapse), abruption associated with membrane rupture in cases with hydramnios, postpartum hemorrhage (primary and secondary), and retained placenta.
●
MANAGEMENT OPTIONS Prepregnancy Prevention initiatives are based on the prevalence of conditions associated with fetal hydrops ideally identified by an audit in the region. Prevention initiatives may include ● Prenatal screening for preventable conditions such as ● Alpha-thalassaemia.1,12,13 ● Inborn errors of metabolism. ● Assessing immunity: ● Of at-risk women of exposure to parvovirus B19 infection in densely populated areas10 during an outbreak. ● Possibly cytomegalovirus (CMV). ● Syphilis.1
Prenatally Once fetal hydrops is identified, the mother should be counseled regarding the following: ● Diagnosis: based on maternal and fetal investigations (Tables 24–2 and 24–3) and associated fetal risks from invasive procedures. ● Prognosis: fetal risks, both short and long term, which are influenced by the diagnosis and may remain unknown. ● Treatment: if available and feasible in the circumstances.
DIAGNOSIS Presentation Fetal hydrops clinically presents in one of several ways (Table 24–4). The fetal sites of fluid collection and the amount of fluid (severity) may be helpful in the management of the hydrops once the cause is ascertained. In general, oligohydramnios is a poor prognostic sign.
Investigations A comprehensive search in the mother and fetus for the “cause” usually involves antenatal invasive procedures (see T A B L E 2 4 – 2
Maternal Investigations for Fetal Hydrops Maternal History Parvovirus B19 epidemic and close proximity to children, immunity10 Previous fetal hydrops or diagnosis associated with hydrops74,75 Previous baby with jaundice Ethnic origin1,12,13 Hemoglobinopathy trait (e.g., alpha-thalassemia1,12,13,38) Consanguinity75 Congenital heart disease Family history of hydrops (inborn errors of metabolism)74,75 Endocrine disorder Symptoms of “mirror syndrome”27,28 (i.e., preeclampsia; see Chapter 35) Maternal Blood Complete blood count (e.g., microcytosis—alpha-thalassemia trait) Electrophoresis (depending upon blood count result and ethnic background) Blood group and antibody screen (titer if antibodies present)37 Glucose-6-phosphate dehydrogenase and pyruvate kinase carrier status α-Fetoprotein Serologic tests (of limited value; see Chapters 29–32) Syphilis1 Parvovirus B1936,69 Toxoplasmosis Cytomegalovirus (primary and also secondary)34 Herpes simplex virus Adenovirus Coxsackievirus Uric acid, urea, and electrolytes Liver function including albumin Kleihauer (-Betke) test42 Test of glucose tolerance SLE, especially anti-Ro/SSA or anti-La/SSB antigens, if bradycardia/ heart block Thyroid function tests including antibodies: TSH and TSH-binding inhibitor IgG (see Chapter 21) IgG, immunoglobulin G; SLE, systemic lupus erythematosus; TSH, thyroidstimulating hormone.
C HAPTER 24 • Fetal Hydrops 441 T A B L E 2 4 – 3
Fetal Prenatal Investigations for Fetal Hydrops
FIGURE 24–4 Twin-twin transfusion syndrome. Recipient hydropic at 20 weeks’ gestational age.
Ultrasound Sites and severity of hydrops (see Figs. 24–1 to 24–5) Detailed real-time ultrasound for congenital abnormality14 and abnormality of placenta (chorioangioma63,67) and cord (cysts86) Fetal echocardiography,44 pulsed43 and color Doppler studies and M-mode Amniotic fluid volume Biophysical assessment (nonstress testing or biophysical profile score). Invasive (Mainly Fetal Blood) Hematologic tests: full blood count, hemoglobin electrophoresis (depending on ethnic background); group and Coombs’ Infection: polymerase chain reaction, serologic tests for acute phase-specific IgM antibodies for infection; culture Blood gas analysis and pH estimation to provide an indication of the immediate well-being of the fetus Karyotype (blood, placenta, amniotic fluid, ascitic or pleural fluids are suitable sources) Intrathoracic pressure58/UVP23 Liver function tests (albumin) Cultured amniotic fluid cells enzyme testing for lysosomal storage diseases (e.g., Gaucher’s mucopolysaccharidoses75) IgM, immunoglobulin M; UVP, umbilical venous pressure.
CRL
T A B L E 2 4 – 4
Presentation of Fetal Hydrops By chance: Ultrasound examination Fetal heart rate recording Ultrasound surveillance of pregnancies at risk of fetal hydrops (i.e., TTTS in monochorionic twin pregnancy; alpha-thalassemia trait parents1; large fetomaternal hemorrhage following trauma; fetal arrhythmia; fetal anomaly [e.g., congenital heart defect44]; fetal tumor,63 cystic hygroma, large nuchal translucency) Large-for-dates/hydramnios Reduced fetal movements Placental abruption (e.g., associated with “mirror syndrome”28 or chorioangioma67) Maternal diabetes Maternal SLE/anti-Ro antibodies Maternal preeclampsia/mirror syndrome27,28 Maternal parvovirus B19 primary infection or contact/at risk for infection10,28,31,69 SLE, systemic lupus erythematosus; TTTS, twin-twin transfusion syndrome.
Tables 24–2 and 24–3). The hydrops severity, gestational age, ultrasound identified anomalies, ultrasound Doppler assessment, and the parents’ consent will influence the decision to perform these procedures. The ultrasound scan (Figs. 24–4 and 24–5; see also Fig. 24–1) may in the majority of cases assist in the diagnosis. The diagnosis may escape antenatal detection in 10%1 to 33%.32 Real-time gray scale and pulsed Doppler ultrasound assessment of the hydropic fetus are assuming an ever-increasing important role in the noninvasive assessment of associated causes such as structural cardiac anomalies or cardiac dysfunction secondary to hyperdynamic flow (i.e., anemia or associated with tumors or twin-twin transfusion syndrome [TTTS]). On completion of both the noninvasive fetal assessment and, ideally, the
FIGURE 24–5 First-trimester large nuchal translucency and hydrops associated with aneuploidy.
maternal investigations, the most common invasive procedures will be fetal blood sampling (FBS) and/or amniocentesis. FBS is preferred (Table 24–5), but the associated mortality rates higher than for nonhydropic indications,33 especially if the fetus is thrombocytopenic (e.g., parvovirus B19 infection) and when it is technically more difficult (e.g., maternal obesity, 9588 6249 to 6755
B19 hydrops secondary to anemia is associated with an elevated UVP. Anemic fetuses with reticulocytes present are likely on their way to recovery and may or may not benefit from a “top-off” transfusion. Serial ultrasound examinations have been used to assess severity, but are of little practical use in isolation.11,36,70 The risk of FBS and therapy may be increased specifically in parvovirus infection because of the associated risk of thrombocytopenia.71 However, a successful outcome may be expected in the majority of cases (77%71) but is influenced by fetal vascular access (i.e., method of puncture), maternal obesity, and fetal gestational age younger than 20 weeks (Table 24–6). Myocarditis secondary to parvovirus is characterized by hydrops, a normal or near-normal hemoglobin, but an elevated UVP. Hydrops secondary to B19 myocarditis has been treated with fetal digitalization. Lastly, hydrops secondary to hepatitis/peritonitis is characterized by ascites, little truncal edema, normal UVP and hemogrobin by grossly elevated hepatic transaminases. Infant follow-up is mandatory in view of the rare complications (e.g., risk of congenital red blood cell aplasia)72 or even the need for perinatal heart transplantation.24
Other Causes Generalized lymphatic dysfunction (e.g., primary hydrothorax is believed to be a variant) can be associated with abnormal vascular development. The prognosis is guarded and may include significant infant morbidity25 and recurrence with autosomal recessive inheritance.73 Forms of recurrent NIH associated with inborn errors of metabolism (see Fig. 24–3) and autosomal recessive inheritance are being increasingly recognized (1%–2% of NIH cases74,75). Once recognized, there is the potential for prenatal diagnosis in subsequent pregnancies. Fetal akinesia (arthrogryphosis) is another collection of conditions with numerous causes (cerebro-oculofacial-skeletal syndrome, Pena-Shokeir, multiple pterygium syndrome, Neu-Laxova syndrome) associated with fetal hydrops each of which carries a poor prognosis. The risk of recurrence is generally low, but certainly influenced by the cause (e.g., Neu-Laxova syndrome has autosomal recessive inheritance76). Renal associations with hydrops are discussed in detail in Chapter 18.
Fetal Albumin “Therapy” Pathophysiologic research suggests that fetal hypoproteinemia or hypoalbuminemia may occur as a secondary effect9,19
C HAPTER 24 • Fetal Hydrops 447
in approximately a third of nonimmune hydrops fetuses, but is distributed with equal frequency in groups with a high and low UVP (the exception being TTTS, which is discussed in Chapter 23). Clearly, the practice of giving the fetus albumin77 in the absence of a clear understanding of the pathophysiology cannot be recommended (e.g., albumin would aggravate hydrops associated with increased capillary permeability). A more productive approach would be to conduct a comprehensive investigation to reduce this “idiopathic” group.
Outcomes Long-term follow-up data are sadly lacking, being sporadic and by nature condition-specific.45,78–81 The challenge aside, such follow-up is particularly important with the emergence and rapid increase in research into the developmental origins of health and disease.82 One may speculate that fetal hydrops puts survivors at increased risk for a wide range of adult diseases via environmental and/or epigenetic mechanisms.82 Such knowledge would be indispensable for families attempting to make an informed decision.
SUMMARY OF MANAGEMENT OPTIONS
Fetal Hydrops (See also Chapter 13) Management Options
Evidence Quality and Recommendation
References
Prevention Preconceptual and prenatal screening for Alpha-thalassemia.
III/B
38
Fetal aneuploidy.
IIb/B
15
Fetal anomalies, especially severe cardiac disease.
III/B
14
Monochorionicity screening for TTTS.
III/B
89
Maternal (see Table 24–2).
III/B
1,3,4,6
Fetal (see Table 24–3).
III/B
Diagnosis will be made in 75%–90% of cases.
III/B
1,3,4,6,32
Risks of fetal invasive procedures are increased in presence of hydrops.
III/B
33
Counseling is given before and after investigations.
—/GPP
—
Prognosis is determined by the underlying etiology.
III/B
1,3,4,6,32
The earlier it is detected, the worse the prognosis.
III/B
15,69
Earlier detection is more likely to be associated with chromosomal abnormality.
III/B
1,3,4,6,15
Presence of a congenital anomaly worsens the prognosis.
III/B
43,44
Prognosis for isolated hydrothorax with hydrops is fairly good.
III/B
49,55
Generally, prognosis is good for psychomotor development in survivors.
III/B
79–81
Intrauterine transfusions for fetal anemia (hemolytic disease [see Chapter 13], fetomaternal bleed, parvovirus)
III/B
36,70,77,79
Antiarrhythmic medication
III/B
88
Laser for TTTS stages 2–4 (see Chapter 23)
Ib/A
29,30
Pleuroamniotic shunts for primary hydrothorax, cystic adenomatous malformation.
III/B
49,55
Open surgery for chest lesions should be regarded as exceptional.
IV/C
48
●
●
●
●
Diagnosis—Investigations
Counseling and Prognosis
Management—Treatment In utero, therapy can be effective in selected cases: ●
●
●
●
●
448 S ECTION THREE • Late Prenatal–Fetal SUMMARY OF MANAGEMENT OPTIONS
Fetal Hydrops (See also Chapter 13)—cont’d Evidence Quality and Recommendation
Management Options
References
Management—General Interdisciplinary approach is used for ongoing pregnancies.
III/B
2,36,43–45,48
Consider termination in those with severe hydrops at a previable gestation with a condition for which there is no effective treatment.
III/B
1,38
Perform postmortem examination in cases of fetal/neonatal death.
III/B
90–92
Pediatric follow-up and counseling are needed in survivors.
III/B
78–82
Postnatal
GPP, good practice point; TTTS, twin-twin transfusion syndnrome.
SUGGESTED READINGS Fairley CK, Smoleniec JS, Caul OE, Miller E: Observational study of effect of intrauterine transfusions on outcome of fetal hydrops after parvovirus B19 infection. Lancet 1995;346:1335–1337. Haverkamp F, Noeker M, Gerresheim G, Fahnenstich H: Good prognosis for psychomotor development in survivors with non-immune hydrops fetalis. BJOG 2000;107:282–284. Isaacs H Jr: Fetal hydrops associated with tumors. Am J Perinatol 2008;25:43–68. Kooper A, Janssens P, de Groot A, et al: Lysosomal storage diseases in non-immune hydrops fetalis pregnancies. Clin Chim Acta 2006;371: 176–182. Leung WC, Leung KY, Lau ET, et al: Alpha-thalassemia (review). Semin Fetal Neonat Med 2008;13:215–222. Liao C, Wei J, Qiuming L, et al: Nonimmune hydrops fetalis diagnosed during the second half of pregnancy in southern China. Fetal Diagn Ther 2007;22:302–305.
Roberts D, Neilson J, Kilby M, Gates S: Interventions for the treatment of twin-twin transfusion syndrome. Cochrane Database Syst Rev 2008;1:CD002073. Rustico MA, Lanna M, Coviello D, et al: Fetal pleural effusion (review). Prenat Diagn 2007;27:793–799. Smoleniec JS, Pillai M: Fetal hydrops associated with parvovirus B19 infection: Management. Br J Obstet Gynaecol 1994;101:1079– 1081. Wald NJ, Morris JK, Walker K, Simpson JM: Prenatal screening for serious congenital heart defects using nuchal translucency: a meta-analysis (review). Prenat Diagn 2008;28:1094–1104.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 2 5
Fetal Death CARL P. WEINER
INTRODUCTION Though 80% of pregnancies are unplanned, a fetal death is virtually always viewed as a tragedy. The known threat of an embryonic loss has passed, and both patient and caregiver are optimistic about the future. Whether the death occurs in a single or multiple gestations, it spurs the search for an explanation and changes both pregnancy management and the patient’s psychosocial needs. The resulting grief may begin prior to fetal death when associated with the antenatal diagnosis of a lethal abnormality. The successful identification of the etiology may be crucial for the management of any subsequent pregnancy and have a profound impact on the woman’s long-term health.
MANAGEMENT OPTIONS Giving Bad News Providing a patient bad news is one of the most difficult tasks a physician faces on a regular basis. The problem now is not whether it is necessary to tell the patient, but how to deliver it. There is no room for physician paternalism. Unfortunately, the act of teaching techniques for the breaking of bad news may seem as awkward as the teaching of contraception must have been in the Victorian era. Yet, these techniques can be learned and used in a busy clinical practice. There are a number of plausible explanations as to why is it difficult to give bad news including the fear of causing emotional pain, sympathetic pain, fear of being blamed for the poor outcome, fear of a therapeutic failure and all that it entails, fear of the medical-legal consequences, fear of eliciting a loud or threatening reaction, fear of saying “I don’t know,” and fear of expressing emotion to a patient. Why are patients unhappy with the way they are told bad news? The most common complaints are that the physician is not listening, is using jargon, or is “talking down” to them. The process of informing a patient about bad news should follow the basic steps of the traditional medical interview: ● Prepare for listening. ● Question. ● Listen actively. ● Show verbally that you have heard. ● Respond. The necessary modifications and additions to the basic interview as they relate to fetal medicine include first finding out how much the patient knows or understands of the
events and identifying the misinformation that must be corrected and how much the patient wants to know before beginning to share the information in an unambiguous, plain-spoken fashion that minimizes the chance of denial; responding to the patient’s feelings; and then presenting an appropriate action plan. Perhaps the most difficult component of the interview arises when the patient starts reacting to the news. People perceive bad news in a myriad of ways, some of which may not be clear to the health care provider. A mentally competent and informed patient has the right to accept or reject any treatment offered and to react to the news or express their feelings in any (legal) way they choose. Unexpected reactions often reflect a misunderstanding of the information presented. It is important to reinforce those parts of what the patient has said that are correct and then continue on from there. Avoid jargon, use diagrams and written messages, and then look for evidence of understanding. Listen for and try to address the patient’s concerns; do not dismiss them as irrelevant. Common reactions run the gamut and include disbelief, anger, blame, shock, guilt, denial, hope, despair, depression, displacement, fear and anxiety, crying, bargaining, awkward questions, relief, threats, and humor. There is no question that giving parents bad news tests the entire range of one’s professional skills and abilities. But if it is done poorly, the family will never forgive and their anger will grow. But if the interview is done well, they will never forget their physician’s kindness.
Evaluation The investigation of a fetal death involves both fetus and mother. It is essential that the cause of death be determined whenever possible. Only then can the likelihood of a recurrence and the possibility of prevention be ascertained. An understanding of the actual cause aids the grieving process by eliminating the natural tendency for self-recrimination. A thorough maternal past and current medical history should again be obtained and the physical examination repeated in search of an unsuspected preexisting or acquired systemic illness. If the fetus is still in utero, a targeted ultrasound examination of the uterus and contents is performed in search of fetal or placental malformations and evidence of fetal growth restriction. The more common, known causes of fetal death are listed in Table 25–1. The fetal death rate has declined since the late 1960s and the “causes” changed.1 For example, fetal death due to intrapartum asphyxia and Rh disease has 449
450 S ECTION THREE • Late Prenatal–Fetal T A B L E 2 5 – 1
Causes of Fetal Death Maternal Systemic Illness Diabetes mellitus Hypertension—includes prepregnancy and pregnancy-associated connective tissue disorders Any disorder causing septicemia with associated hypoperfusion—fetal malformations, structural and chromosomal Fetal Infection—bacterial, viral Fetal immune hemolytic disease Cord accident—includes prolapse, thrombosis, strangulation Bands or knots and torsion (likely to be greatly overdiagnosed) Metabolic disorders Placental dysfunction includes those associated with fetal growth restriction, postmaturity, and abruption causing hypoxemia, placenta previa, or infarction, twin-twin transfusion, fetal-maternal hemorrhage Inherited disorders: thombophilias
T A B L E 2 5 – 2
Routine Laboratory Evaluation and Follow-up of Fetal Death Maternal (On Detection) Fasting blood glucose Platelet count, fibrinogen Indirect Coombs’ test Stain of a peripheral smear for fetal red blood cells (Kleihauer-Betke test) Anticardiolipins, antinuclear antibodies, lupus anticoagulant Fetal karyotype Thrombophilia workup Polymerase chain reaction studies of fetal products for evidence of viral infection Amniotic fluid culture for cytomegalovirus, anaerobic and aerobic bacteria Subsequent maternal weekly fibrinogen measurements and platelet counts if fetal death is of 4 wk’ duration or more Fetal (At Delivery) Repeat infection workup (see Chapter 26) Karyotype (if not done antenatally) Postmortem examination Fetogram (total body radiograph) if dysmorphic stigmata at postmortem examination
declined dramatically in the industrialized world, as has the death rate from unexplained growth restriction also declined. Adolescents too are at increased risk of having a fetal demise.2 Unless the history and physical examination pinpoint the cause, a basic group of laboratory tests (Table 25–2) should be performed. A chromosome abnormality underlies about 15% of second-trimester stillbirths. An amniocentesis to both search for fetal infection (see Chapter 9) and obtain a karyotype is recommended in all cases of fetal death,3 even in the apparent absence of extrinsic structural malformations, because the usual dysmorphic features of aneuploidy may be obscured by postmortem changes. Amniocytes can be cultured successfully weeks after the death in contrast to fetal fascia, muscle, or subcutaneous tissue, which commonly fail to provide viable cells for
culture. Another advantage of amniotic fluid is that it can be used to conduct viral polymerase chain reaction (PCR) studies. Placental tissue is also a viable source for karyotyping. After delivery, photographs of the child are made for both the medical record and the parents. If the parents decline the photographs (a common grief/fear response), the pictures are stored with the medical record in case the parents change their minds subsequently. A checklist describing the gross presentation is a useful document, a fetogram made (xerography is an excellent modality), and permission for an autopsy sought. The performance of an autopsy significantly increases the likelihood of discovering a presumed cause.4 Ideally, an individual with both an interest and experience in perinatal pathology should perform the autopsy. The placenta is an important component of that examination. The fetal organ cavities are cultured for both bacteria and viruses, even if an infection workup was initiated antenatally. If amniotic fluid was obtained prior to delivery, an aliquot is sent for viral PCR. There is a growing body of evidence that viral infection can have a role in poor fetal outcome. Maternal serology is, however, rarely useful.5 Many stillborn fetuses are small for gestational age. Customized fetal growth charts may required to demonstrate this because the use of preterm neonatal birth weight charts, derived from preterm newborns who are commonly growthrestricted, might obscure this finding.6,7 In the absence of another explanation, growth restriction increases the likelihood that severe placental dysfunction of some etiology is the explanation.3
Pregnancy Management The approach to the pregnancy after a fetal loss depends on whether it is a single or a multiple gestation, the gestational age at death, and the parents’ wishes.
Singleton Gestation At least 90% of women with an intrauterine demise labor spontaneously within 3 weeks of its detection.8,9 About a quarter of women who retain their dead fetus for 4 or more weeks after 20 weeks’ gestation develop a chronic, consumptive coagulopathy. It is a true disseminated intravascular coagulopathy (DIC) characterized by degrees of decreased fibrinogen, plasminogen, antithrombin III, and platelets and increased fibrin degradation products.10–14 The etiology of the coagulopathy has never been conclusively determined. Using sensitive coagulation tests, pathologic activation of the clotting cascade is demonstrable within 48 hours of the demise. The incidence of the coagulopathy increases with the duration of the delay, but fewer than 2% of these women experience a hemorrhagic complication. Traditionally, labor was induced after treatment of the coagulopathy even if the cervix was unfavorable and the coagulopathy resolved within 48 hours of the delivery. Fortunately, this coagulopathy can be reversed by the administration of low-dose heparin.15–17 However, delay decreases any hope of an informative autopsy. A dilation and evacuation can be performed prior to 15 weeks’ gestation. It remains an option until 24 weeks if the practitioner is so skilled, but the risk of maternal hemorrhage may be increased after fetal death.18 Caution is advised. The
C HAPTER 25 • Fetal Death 451
second and more common alternative after 15 weeks’ gestation is an induction of labor. This has the advantage of leaving the fetus intact for autopsy. The method of termination has no significant impact on the rate of grief resolution.19 Oxytocin is not the agent of choice because it is frequently ineffective early in gestation. And although instillation of intra-amniotic hypertonic saline or glucose may shorten the time interval, it has been associated with several maternal deaths. The development of the stable prostaglandin E and F analogues for the induction of labor has simplified induction because the efficacy of these agents exceeds 90%.20–23 Delivery shortly after detection of the demise has several advantages. First, it brings an end to an emotionally painful event and allows the psychological healing process to begin. Second, any postmortem examination is more likely to yield useful information if done before the development of severe autolysis. The various prostaglandin preparations may be administered via oral, vaginal, intracervical, extraovular, or intramuscular routes, depending on regional availability. Misoprostol (either per vaginam or by mouth) has a favorable cost profile and is at least as effective as other forms of prostaglandin. When used specifically for pregnancy termination in the second trimester, misoprostol administered orally is less effective (i.e., more failures) than the vaginal route (relative risk [RR] 3.00, 95% confidence interval [CI] 1.44–6.24) and side effects are more common.24 Misoprostol regimens used for the induction of labor with fetal death during the second and third trimester range from 50 to 400 µg every 3 to 12 hours; all are clinically effective.25 The current scientific evidence supports vaginal misoprostol dosages that are adjusted to gestational age: between 13 and 17 weeks, 200 µg q6h; between 18 and 26 weeks, 100 µg q6h; and after 27 weeks, 25 to 50 µg q4h. Caution is advised in women with a previous cesarean and lower doses should be used. In all instances, the patient should be monitored after delivery because of the risk of postpartum atony and/or placenta retention. Common complications of misoprostol include nausea and vomiting, fever, and tachycardia. Their prevalence is generally dependent on route of administration and dose and is greatly reduced by premedication.17 Their use is discussed further in Chapter 66.
The second item to consider is whether the dead twin’s continued presence poses a risk to the surviving twin. In monochorionic twin gestations, approximately half of the co-twins in an affected pregnancy will either die or experience serious morbidity28 (see Chapters 23 and 59). Sequelae in survivors of monochorionic gestations with a single demise include bilateral renal cortical necrosis, multicystic encephalomalacia, gastrointestinal structural malformations, and even a DIC.29–34 It was previously thought the sequelae result from the fetus-to-fetus transfer of necrotic, throm boplastic emboli through placental anastomoses. If this were true, delivery of the surviving twin as soon as possible would be prudent. However, this long-stated explanation has never been supported by a shred of evidence and can now be definitively categorized as a myth. The explanation is one or more hypotensive events occurring either during the co-twin’s death associated with extensive vascular anastomosis or after the death as the surviving twin acutely hemorrhages into the dead twin’s placenta.35 As a result, preterm delivery is too late to prevent the sequelae and can only add complications of prematurity. Thus, it is prudent to observe the surviving co-twin very closely, if not con tinuously for the first 7 days, should the gestation appear monochorionic. It is unclear whether “prophylactic” laser photocoagulation of anastomotic placental vessels will prevent damage once the death has occurred. Survivors should be watched serially for evidence of multicystic leukoencephalomalacia. If the pregnancy is dizygotic, the risk of death for the surviving co-twin is less than 5%.26 There is no reason for an iatrogenic delivery prior to 36 weeks solely for the indication of a dead co-twin. The third and final concern after the death of a co-twin is that the mother will develop coagulopathy should the pregnancy continue. This is an uncommon but treatable event. Laboratory testing for hypofibrinogenemia and thrombocytopenia should be done biweekly after the first 4 weeks. Low-dose heparin, between 10,000 and 30,000 units given subcutaneously in divided doses, is usually adequate to reverse the hypofibrinogenemia.36,37 There is no need to prolong the partial thromboplastin time. The amount of heparin necessary may seem quite high, and is likely explained by the DIC-mediated decrease in antithrombin. Heparin can usually be discontinued 6 to 8 weeks later without recurrence of the hypofibrinogenemia.
Multiple Gestation (See also Chapters 23 and 59)
Parental Psychosocial Care
The optimal management of the multiple gestation with a singleton demise reflects chorionicity. The incidence of this complication is low (11 pg/mL
0.8
inflammatory response that can progress toward multiple organ dysfunction, septic shock, and death in the absence of timely delivery.
Hematopoietic System Neutrophilia is present in two thirds of fetuses with FIRS, whereas neutropenia is observed in 7%.172 FIRS has also been associated with changes in the immunophenotype of mono cyte and granulocytes consistent with activation.173 Numbers of circulating nucleated red blood cells are also increased. IL-6 has been proposed to have a role in elevating the fetal nucleated red blood cell count.174
Lung
0.6 0.4 0.2 0 0
4
8
12
16
20
24
28
33
Cordocentesis-to-delivery interval (days)
THE FETAL INFLAMMATORY RESPONSE SYNDROME The term fetal inflammatory response syndrome (FIRS) was coined to define a subclinical condition originally described in fetuses of women presenting with PTL as well as those pre senting with PPROM.11,12 The definition was an elevation of fetal plasma IL-6 above 11 pg/mL.11 The original work was based on fetal blood samples, but the association with ele vated pro-inflammatory cytokines and sepsis has since been confirmed in umbilical cord blood at the time of birth.14 Pathologic examination of the umbilical cord is an easy approach to determine whether fetal inflammation was present before birth. Funisitis and chorionic vasculitis are the histopathologic hallmark of FIRS.51 Neonates with funisitis are at increased risk for neonatal sepsis171 as well as longterm handicap such as bronchopulmonary dysplasia (BPD)14 and CP.13 Among women with PPROM, FIRS is associated with the impending onset of PTL, regardless of the inflam matory state of the AF (Fig. 26–2).12 This suggests that the human fetus plays a role in initiating the onset of labor. However, maternal cooperation must be present for parturi tion to occur.
Fetal Target Organs during Fetal Inflammatory Response Syndrome Fetuses with FIRS are frequently born to mothers with sub clinical MIAC.12 Affected fetuses have evidence of multior gan involvement with a higher rate of severe neonatal morbidity after adjustment for gestational age12 and cases of PPROM had a shorter cordocentesis-to-delivery inter val.11 Fetal microbial invasion results in a systemic fetal
FIRS is associated with BPD.175 Amniotic fluid and its con tents can be inhaled by the fetus and reach the distal parts of the airways and the alveoli. Ghezzi and colleagues176 reported that fetuses who subsequently developed BPD had a higher AF IL-8 concentration than those who did not. These observations were confirmed in another study that reported higher AF concentrations of IL-6, TNF-α, and IL-8 in fetuses who eventually developed BPD,177 suggesting that antenatal exposure to pro-inflammatory cytokines is also a risk factor for the development of BPD. As for whether fetal systemic inflammation is a risk factor for chronic lung disease, neonates who develop BPD have a higher IL-6 con centration in umbilical cord plasma at birth than those who do not (68.3 pg/mL vs. 6.9 pg/mL; P < .001).14 The same group175 has also found FIRS in 76% on infants with atypical chronic lung disease (defined as chronic lung disease in the absence of respiratory distress syndrome).
Kidneys Yoon and associates36 reported an association between oli gohydramnios and fetal infection/inflammation in patients with PPROM. In view of the antimicrobial properties of the AF, oligohydramnios may reduce the protective effect of this component of innate immunity. Alternatively, oligohydram nios may be the result of a redistribution of blood flow away from the kidneys occurring during the host response to microbial products.36
Heart In the presence of IAI, fetuses show changes in cardiac func tion consistent with a high left ventricular compliance.178 In cases of overwhelming fetal sepsis, myocardial depression may lead to fetal death. In the context of FIRS, bacterial products and cytokines may contribute to the myocardial depression. Fetuses that are unable to modify their cardiac compliance or maintain ventricular cardiac output may suffer an inadequate brain perfusion, predisposing to hypotension and brain ischemia in utero.179 This could create conditions for the development of periventricular leukomalacia (PVL) and brain injury.
Adrenal Glands FIRS is associated with endocrine evidence of “stress,” which is expressed by an elevated cortisol–to–dehydroepiandros terone sulfate (DHEA-S) ratio.180 These endocrine changes may contribute to the onset of spontaneous PTL. Indeed, Yoon and coworkers180 reported that in patients with PPROM, there is an association between the fetal plasma
C HAPTER 26 • Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome 465
cortisol-to-DHEA-S ratio and a shorter interval from cordo centesis to delivery (hazards ratio 2.9; 95% CI 1–8.4). Patients with PPROM who went into spontaneous labor and delivered within 7 days of cordocentesis had a higher fetal plasma cortisol than those delivered after 7 days (P < .0001). Fetal plasma cortisol, but not maternal cortisol, was an inde pendent predictor of the duration of pregnancy. These endocrine changes may have short- and long-term implica tions given the recent observations about the effect of glu cocorticoids in fetal programming of several metabolic functions.181,182
Skin Fetal dermatitis is a new entity described in FIRS. Skin samples from fetuses delivered between 21 and 24 weeks’ gestation had histologic evidence of dermatitis.183 TLR-2 expression in the skin was dramatically increased in fetuses born from mothers with histologic chorioamnionitis. More over, TLR-2 and TLR-4 were also expressed in the mono nuclear inflammatory infiltrate of the dermal-epidermal junction, suggesting that microorganisms are recognized by the fetal skin through PRRs and, thus, participate in the fetal inflammatory response to microbial products.183
Thymus Subclinical chorioamnionitis has been associated with a small thymus,184 and thymus involution has been demon strated antenatally with ultrasound in fetuses exposed to IAI in patients with PTL185 and in those with PPROM.186 In another study, infants born at less than 28 weeks’ gestation and with ultrasonographic signs of cerebral white matter damage (WMD) were more likely to have undergone thymic involution.187
CONTRIBUTION OF FETAL INFECTION/ INFLAMMATION TO LONG-TERM HANDICAP Cerebral Palsy CP is a symptom complex characterized by aberrant control of movement or posture that appears in early life and can lead to costly lifelong disability. The estimated annual prev alence of CP ranges from 1.5 to 2.5 per 1000 live births, depending on the cohort studied.188,189 Prematurity has a strong association with CP190; one third of all neonates who later have signs of CP weigh less than 2500 g.191 Newborns with birth weights less than 1500 g have a rate of CP 25 to 31 times higher than those with a normal birth weight.191 The most common form of CP affecting preterm babies is spastic diplegia.191 In turn, preterm babies that subsequently develop spastic diplegia have a high rate of PVL.190,192,193 Strong evidence links brain injury and infant exposure to perinatal infection and inflammation.194–196 In 1955, Eastman and Deleon197 observed that intrapartum maternal fever was associated with a sevenfold increase in the risk of CP. In 1978, Nelson and Ellenberg198 showed, using data from the Collaborative Perinatal Project, that among low–birth weight infants, chorioamnionitis increased the risk of CP from 12 in 1000 to 39 in 1000 live births. The general view is that an initiator event (either systemic or intrauterine infection) leads to maternal and fetal inflammatory responses that, in turn, contribute to adverse outcomes such as preterm
delivery, IVH, WMD, and neurodevelopmental disability (mainly CP). PVL describes foci of coagulation necrosis of the white matter near the lateral ventricles. This condition is fre quently associated with the subsequent development of CP,199,200 is more common in infants born between 28 and 31 weeks, and is nine times more common among those with documented bacteremia.190 Among preterm neonates, the frequency of IVH and PVL is higher for those born after spontaneous PTL or PPROM than for infants delivered for fetal or maternal indications.201,202
Experimental Evidence Linking Infection with White Matter Damage WMD is more common among children of pregnancies complicated by chorioamnionitis202 and purulent AF192 as well as among neonates with bacteremia.190 Experimental evidence indicates that intrauterine infection results in WMD and neuronal lesions.203–205 Yoon and coworkers203 experimentally induced ascending intrauterine infection with E. coli rabbits. Histologic evidence of WMD was iden tified in 12 fetuses born to 10 E. coli–inoculated rabbits compared with none in the control group (P < .05). All cases with WMD had evidence of intrauterine inflam mation. Similar findings were reported by Debillon and colleagues.204
Fetal Cytokinemia Is Associated with Intraventricular Hemorrhage, White Matter Damage, and Long-Term Disability Leviton206 proposed that inflammatory cytokines (TNF-α) released during the course of intrauterine infection could play a central role in the pathophysiology of WMD. TNF could participate in the pathogenesis of PVL by four differ ent mechanisms: (1) induction of fetal hypotension and brain ischemia207; (2) stimulation of tissue factor production and release, which activates the hemostatic system and con tributes to coagulation necrosis of white matter208; (3) release of platelet-activating factor, which could act as a membrane detergent causing direct brain damage209; and (4) a direct cytotoxic effect on oligodendrocytes and myelin.210 The hypothesis that fetal inflammation is linked to brain injury is supported by studies documenting higher concen trations of IL-6 in the umbilical cord plasma201 and AF195 of fetuses who subsequently develop WMD. Moreover, increased expression of TNF-α and IL-6 is observed in hypertrophic astrocytes and microglia cells obtained from subjects with PVL.211 Yoon and associates195 advanced one mechanism to explain how inflammatory cytokines might lead to WMD and CP. According to their theory, MIAC (which occurs in 25% of preterm births) results in congenital fetal infection/inflammation that stimulates fetal mononu clear cells to produce IL-1β and TNF-α. These cytokines increase the permeability of the blood-brain barrier, facili tating the passage of microbial products and cytokines into the brain.212 Microbial products then stimulate the human fetal microglia to produce IL-1 and TNF-α with subsequent activation of astrocyte proliferation and production of TNFα. Oligodendrocytes, the cells responsible for the deposi tion of myelin, are damaged by TNF-α.
466 S ECTION F OUR • Infection
Fetal Vasculitis, Intraventricular Hemorrhage, White Matter Damage, and Cerebral Palsy Yoon and coworkers13 observed in a study of 123 preterm infants followed to age 3 years that the odds of developing CP were higher in the presence of funisitis (OR 5.5; 95% CI 1.2–24.5), increased AF IL-6 concentrations (OR 6.4; 95% CI 1.3–33.0), and increased AF IL-8 concentrations (OR 5.9; 95% CI 1.1–30.7). All 14 children who developed CP had evidence of WMD and 11 had evidence of intra uterine inflammation. Fifty percent of the children had posi tive AF cultures. Histologic chorioamnionitis was not associated with subsequent development of CP after adjust ing for gestational age at birth, suggesting that it is the fetal, rather than the maternal, inflammatory response that predis poses to CP. Nonetheless, neither infection nor inflamma tion was considered a sufficient causal factor for WMD or CP, because the latter did not develop in 82% of fetuses with documented MIAC and in 76% of those with evidence of intrauterine inflammation. Factors implicated in the genesis of brain injury include (1) gestational age, (2) virulence of the microorganisms, (3) fetal attack rate, (4) the nature of the fetal immunoresponse, and (5) vulnerability of the central nervous system.
APPROACHES TO FETAL IINFLAMMATORY RESPONSE SYNDROME Three approaches can be used to interrupt the course of FIRS: (1) delivery, (2) antimicrobial treatment of women in whom the FIRS is due to microbial invasion of susceptible bacteria, and (3) administration of agents that down-regulate the inflammatory response. Preterm delivery places the unborn child at risk for complications of prematurity. There fore, the risks of prematurity and intrauterine infection must be balanced.
The administration of antimicrobial agents may eradicate MIAC in cases of PPROM. The results of the ORACLE I trial suggest that antibiotic administration may not only delay the onset of labor but also improve neonatal outcome.76 These findings are supported by experimental evidence in pregnant rabbits inoculated with E. coli. Antibiotic adminis tration within 12 hours of microbial inoculation (but not after 18 hours) effectively prevented maternal fever, reduced the rate of preterm delivery, and improved neonatal sur vival.213 It is tempting to postulate that this was accom plished by improving or preventing a fetal inflammatory response. It is important to note that the 7-year follow-up of infants in ORACLE trial I did not demonstrate any reduc tion in the rate of CP in infants given antibiotics.214 Agents that down-regulate the inflammatory response, such as anti-inflammatory cytokines, antibodies to macro phage migration inhibitory factor, and antioxidants, may also play a role in preventing preterm delivery, neonatal injury, and long-term perinatal morbidity. A combination of antibiotics and immunomodulators (dexamethasone and indomethacin) given to nonhuman pregnant primates was effective in eradicating infection, suppressing the inflamma tory response, and prolonging gestation in experimental premature labor induced by intra-amniotic inoculation with group B streptococci.215 The administration of magnesium sulfate as a neuroprotective agent has also been found to be beneficial for fetuses of less than 34 weeks’ gestation.216–221
Acknowledgment This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. The authors wish to acknowl edge the contribution of authors of chapters published in previous editions of this book. The current authors also gratefully acknowledge the intellectual contributions of Luís F. Gonçalves and Tinnakorn Chaiworapongsa.
SUMMARY OF MANAGEMENT OPTIONS
Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome Management Options
Evidence Quality and Recommendation
References
Diagnosis of Intra-amniotic Infection/Inflammation (IAI) Perform amniocentesis to retrieve AF Rapid tests: Gram stain, WBC count, glucose, and IL-6 concentration.
●
●
●
Culture: Aerobic, anaerobic bacteria, and genital mycoplasmas. PCR with specific primers for the detection of organisms in patients with IAI and negative culture.
III/B
222
C HAPTER 26 • Intrauterine Infection, Preterm Parturition, and the Fetal Inflammatory Response Syndrome 467 Evidence Quality and Recommendation
References
The diagnosis of FIRS suggests antenatal exposure to an agent that promoted inflammation.
—/GPP
—
It may have medicolegal value because there is no current evidence that treatment can modify the natural history and the risk for adverse outcome conferred by fetal systemic inflammation.
—/GPP
—
Management Options Diagnosis of a Fetal Inflammatory Response Syndrome (FIRS) General:
●
●
Collect umbilical cord blood at delivery:
●
●
51,171,201,223–226
CBC and differential, platelet count. C-Reactive protein; elevated levels associated with
●
●
●
III/B
Histologic chorioamnionitis. Funisitis. Neonatal sepsis.
IL-6 concentration; elevated levels associated with
51,224,225,227
●
●
●
Positive AF cultures (MIAC).
●
●
●
●
●
●
●
Histologic chorioamnionitis. Funisitis. Neonatal sepsis. Congenital pneumonia. Necrotizing enterocolitis. Intracranial hemorrhage. White matter damage. Impaired neurologic outcome (lower Bayley psychomotor developmental index scores).
Examine the placenta:
●
●
III/B
51,52,171,228
III/B
13,192,229,230
Histologic chorioamnionitis. Funisitis is a marker for fetal inflammation.
For Premature Neonates Perform pathologic examination of the placenta.
Histologic chorioamnionitis associated with
●
Intracranial hemorrhage.
●
Funisitis associated with
●
●
Neonatal sepsis.
●
●
White matter damage. Cerebral palsy.
AF, amniotic fluid; CBC, complete blood count; IL-6, interleukin-6; MIAC, microbial invasion of the amniotic cavity; PCR, polymerase chain reaction; WBC, white blood cell.
SUGGESTED READINGS Conde-Agudelo A, Romero R: Antenatal magnesium sulfate for the preven tion of cerebral palsy in preterm infants less than 34 weeks’ gestation: A systematic review and meta-analysis. Am J Obstet Gynecol 2009;200:595–609. DiGiulio DB, Romero R, Amogan HP, et al: Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: A molecular and culture-based investigation. PLoS ONE 2008;3:e3056.
Gomez R, Romero R, Ghezzi F, et al: The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202. Gomez R, Romero R, Nien JK, et al: Antibiotic administration to patients with preterm premature rupture of membranes does not eradi cate intra-amniotic infection. J Matern Fetal Neonatal Med 2007;20: 167–173. Gonçalves LF, Chaiworapongsa T, Romero R: Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8:3–13. Kenyon SL, Taylor DJ, Tarnow-Mordi W: Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: The ORACLE I ran
468 S ECTION F OUR • Infection domised trial. ORACLE Collaborative Group. Lancet 2001;357: 979–988. Kenyon S, Pike K, Jones DR, et al: Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the mem branes: 7-year follow-up of the ORACLE I trial. Lancet 2008;372: 1310–1318. Leviton A, Paneth N: White matter damage in preterm newborns—An epidemiologic perspective. Early Hum Dev 1990;24:1–22. Nien JK, Yoon BH, Espinoza J, et al: A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk
for imminent preterm delivery. Am J Obstet Gynecol 2006;195: 1025–1030. Romero R, Brody DT, Oyarzun E, et al: Infection and labor. III. Interleu kin-1: A signal for the onset of parturition. Am J Obstet Gynecol 1989;160:1117–1123.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
CHAPTER 27
Hepatitis Virus Infections JANET I. ANDREWS
INTRODUCTION Viral hepatitis is one of the more commonly diagnosed viral infections in pregnancy. Six subtypes of the hepatitis virus have been identified (A, B, C, D, E, and G). These viral subtypes differ according to structure, routes of transmission, and implications for management during pregnancy and the neonatal period (Table 27–1). In general, diagnosis of viral hepatitis is based on specific clinical symptoms (malaise, fever, abdominal pain, and/or jaundice) and virusspecific laboratory criteria including serology. The purpose of this chapter is to describe each of the viral hepatitis subtypes and their maternal and perinatal implications as they relate to prevention and treatment.
HEPATITIS A General
Although person-to-person contact resulting in “infectious jaundice” was described in a review of hepatitis epidemics published by Blumer in 1923,1 the hepatitis A virus (HAV) was not identified until 1973, when Feinstone and colleagues,2 using immunofluorescent electron microscopy, described virus-like particles in filtered stool samples that stained positively when mixed with HAV convalescent serum. Subsequent work by this group then demonstrated a temporal link between detectable shedding of the HAV antigen in feces and symptomatic illness in experimentally infected subjects.3 As a member of the Picornaviridae family, HAV is nonenveloped and resistant to organic solvent dissolution owing to its lipid-poor coating. Compared with other picornaviruses such as poliovirus, HAV is relatively stable in the environment. The virus is resistant to heat and inactivation by drying for up to 1 month.4 Autoclaving, heating food to above 185°F for 1 minute, or disinfecting surfaces with dilute chlorine bleach will inactivate the virus.5 This latter effect helps explain the propagation of HAV in areas of poor sanitation. The distribution of HAV is global, though outbreaks are typically seen in areas with crowded conditions, inadequate water supplies, or poor hygiene and sanitation. The virus is highly contagious and can be isolated from the feces of all infected persons, which facilitates the fecal-oral route of
person-to-person transmission. Outbreaks and sporadic cases also can occur from exposure to contaminated food and water. Contaminated food needs to be cooked to the appropriate temperature to kill the virus. Parenteral transmission is rare, because the virus is present only transiently in serum. Prior to the introduction of the HAV vaccine in 1995, HAV accounted for approximately one third of cases of hepatitis in the United States. Since 1995, HAV rates in the United States have declined by 89%. In 2006, 3579 acute symptomatic cases of HAV were reported, the lowest rate recorded. After adjusting for underreporting bias and asymptomatic cases, the estimated number of cases in 2006 was 32,000.6 The rate of HAV infection during pregnancy is unknown, but retrospective reviews estimate that HAV is a rare cause of acute hepatitis in pregnancy. In large retrospective case series from Ireland and Isreal, the incidence of HAV infection during pregnancy was extremely low with reported rates of 1/13,181 and 13/79,458 pregnant women, respectively.7,8 Major risk factors for HAV infection in pregnant women in developed countries include (1) travel to developing countries (especially Southeast Asia, Africa, central America, Mexico, and the Middle East), (2) household or sexual contact with infected individuals, and (3) contact with contaminated food or water. In the United States, personto-person transmission is the primary means of HAV transmission via a close personal contact with a household member or sex partner. Because most HAV-infected children are asymptomatic, they serve a key role in the transmission of the virus.9,10 Bivalve mollusks such as clams and oysters can act also as reservoirs for HAV within contaminated waters; crustaceans such as shrimp do not seem to carry the same infectious risk. Infected food handlers have also been implicated in HAV outbreaks, especially when they are from global areas with endemic HAV infection rates.11 Although HAV infection tends to be clinically less severe than infection with other viral hepatitides, and serious complications are uncommon, distinction between infection with HAV and other viruses can only be made serologically. Conversely, not all HAV infections are symptomatic. Before immune globulin was available for preventive passive immunization, 80% to 95% of infected adults in HAV epidemics were symptomatic, two thirds of whom were icteric.12 469
470 S ECTION F OUR • Infection T A B L E 2 7 – 1
Comparison of Hepatitis Virus Subtypes HEPATITIS A
HEPATITIS B
HEPATITIS C
HEPATITIS D
HEPATITIS E
Virus family Diagnosis
Picornaviridae Anti-HAV
Similar to Calciviridae Anti-HEV
Fecal-oral
Flaviviridae Anti-HCV by ELISA (see text for confirmatory testing) Blood/body fluids
Deltavirus genus Anti-HDV and D antigen
Primary route of transmission
Hepadnaviridae HBsAg, anti-HBs, anti-HBc, HBeAg Blood/body fluids
Fecal-oral
Average incubation period in days (range) Incidence rate* (United States) Rate of vertical transmission risk Vaccine available? Breast-feeding contraindicated?
28 (15–50)
90 (60–150)
28–84 (14–168)
Blood/body fluids (requires HBV for replication) 21–49
1.2/100,000
1.6/100,000
0.3/100,000
N/A
N/A
Rare
10%–20% if no immunoprophylaxis Yes No (risk unknown if HBeAg-positive mom)
2%–7% (unless high HCV-RNA and/or HIV-positive) No No (unless nipples cracked or bleeding)
Rare
Rare
No No
No No
Yes No
40 (21–56)
* Centers for Disease Control and Prevention: Surveillance for Acute Viral Hepatitis—United States, 2006. MMWR Surveill Summ March 21, 2008. MMWR 2008;57/No. SS-2. ELISA, enzyme-linked immunosorbent assay; HAV, hepatitis A virus; HBeAg, hepatitis Be antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; N/A, not applicable.
Severity of illness with HAV infection appears to be directly related to the patient’s age (older patients are more severely ill) as well as to the size of the viral inoculum. Virus transmissibility is of greatest concern during the incubation period, which has a mean of 28 days and range of 15 to 50 days.
Diagnosis The initial clinical symptoms of acute HAV infection are nonspecific, consisting of fatigue, malaise, fever, nausea, and anorexia. Significant weight loss may be a presenting complaint in pregnant women. The classic picture of icteric illness becomes apparent within 10 days of the generalized symptoms and is usually preceded by palpable hepatosplenomegaly. Liver function abnormalities, typically characterized by elevations in serum alanine aminotransferase (ALT) higher than aspartate aminotransferase (AST), peak prior to the appearance of jaundice. They may remain elevated for over a month in adults. Prolonged illness, with elevations in liver functions tests (LFTs) lasting over 12 months, has been reported in 8% to 10% of older patients, and jaundice and pruritus may persist despite an overall improving trend in symptoms and LFTs. Fulminant hepatitis, resulting in death, occurs in fewer than 1% of cases.13 HAV-specific immunoglobulin M (IgM) is the serologic marker for acute infection and can be reliably identified with an automated enzyme-linked immunosorbent assay (ELISA).14,15 By the time a patient is symptomatic, she will almost uniformly be seropositive for IgM anti-HAV. IgM levels drop below the detectable range within 4 to 6 months in most patients and parallel a concomitant normalization of LFTs in 80% to 85% of cases.16 HAV-specific IgG, however, will remain positive for years after acute infection.
Maternal and Fetal Risks As an almost entirely self-limited illness, acute HAV infection usually does not confer an increased risk of adverse outcome to a pregnant woman. Supportive care for the woman is essential, and in areas where the virus may be endemic as the result of sanitation or housing issues, the availability of such care might not exist. Nutritional needs should be addressed, and infected pregnant women may require hospitalization with strict contact isolation precautions. A chronic carrier state for HAV does not exist. Perinatal transmission of HAV is rare.17–19 Administration of immune globulin is recommended for neonates born within 2 weeks of acute maternal illness with HAV conferring protection for up to 3 months at 80% to 90% efficacy level.20
Management Options No specific antiviral treatment of HAV is currently available. However, both preventive vaccination and postexposure prophylaxis with immunoglobulin are available. The current HAV vaccine is available either as a single-agent vaccine (Havrix and Vaqta) or as one combined with hepatitis B virus (HBV) vaccine (Twinrix). Single-agent HAV vaccine is given as two doses, 6 to 12 months apart. Currently, the Advisory Committee on Immunization Practices (ACIP) recommends a single-antigen vaccine series for all children at age 12 to 23 months, catch-up vaccination of older children in selected areas, and vaccination of persons at increased risk for HAV (e.g., travelers to endemic areas, users of illicit drugs, or men who have sex with men).21 As an inactivatedvirus vaccine, there is no contraindication to the use of HAV vaccine during pregnancy. Individuals who have close personal or sexual contact with an HAV-infected person should receive postexposure
C HAPTER 27 • Hepatitis Virus Infections 471
prophylaxis unless they have been immunized. Until recently, immune globulin was the recommended choice for postexposure prophylaxis. The 2007 ACIP guidelines were revised to recommend the HAV vaccine be given following exposure, based on the data indicating that immune globulin and vaccine have similar postexposure efficacy among healthy persons younger than 40 years of age.22 The current recommendations state that for healthy persons aged 1 to 40 years, single-antigen HAV vaccine at the age-appropriate dose is preferred to immune globulin for postexposure prophylaxis because of vaccine advantages that include longterm protection and ease of administration. For persons older than 40 years, immune globulin is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of HAV in this age group. A single intramuscular dose of 0.02 mL/kg should be given as soon as possible after contact with the infected individual, within 2 weeks of exposure. The efficacy of immune globulin after 2 weeks from exposure is unknown.21 Administration of immune globulin is still recommended for neonates born to mothers with recent HAV infection.23
HEPATITIS B General According to the World Health Organization (WHO), approximately 2 billion people have been infected with worldwide and 350 million are chronically infected.24 HBV infection is a major global health problem with 600,000 annual deaths attributable to the consequences of HBV infection.24 In areas of Asia, 8% to 10% of the adult population is chronically infected with HBV, and liver cancer attributable to HBV is a major cause of cancer in women. High rates of chronic infections are also found in the Middle East and the Indian subcontinent, with an estimated 2% to 5% of the adult population infected.24 In many of these endemic areas, perinatal and childhood infections exist as a primary route for perpetuating the reservoir of carriers. The likelihood that a person infected with HBV will develop a chronic infection depends upon the age at which the person is infected. The earlier in life that a person is infected, the higher the risk of being a chronic carrier. This finding is especially significant because the risk of chronic HBV infection for a child infected in the newborn period, in the absence of prophylactic therapy, is 70% to 90%.25,26 In areas of low endemicity for HBV carriage, such as the United States, screening programs for the general population have been targeted to decrease household, transfusion, sexual, and perinatal transmission risks among contacts of hepatitis B surface antigen (HBsAg)–positive individuals. Population subsets have been identified that are at increased risk for HBV acquisition, and HBV vaccination is recommended for individuals within those groups who are serologically negative for HBsAg and hepatitis B surface antibody (HBsAb). The efficacy of a serum-derived HBV vaccine was demonstrated initially on a large scale in a cohort of more than 1000 homosexual men in the United States; this trial showed an antibody (HBsAb) response in 96% of those vaccinated, with an overall protective efficacy of 88% against all HBsAg-positive events for vaccine compared with placebo.27
More recently, two single-antigen and three combination vaccines were developed and licensed in the United States. These vaccines are prepared from yeast culture and utilize a recombinant HBsAg protein dose. In 2006, an estimated 46,000 persons in the United States were newly infected with HBV after taking into account asymptomatic infections and underreporting. This estimate represents a decline by approximately 81% since 1991.6 Among pregnant women, Asian American women from urban areas have the highest HBsAg prevalence rate of 6%, followed by blacks (1%), whites (0.6%), and Latinos (0.14%).28 Blood and blood products are the most thoroughly established sources of HBV infection, although HBsAg has been demonstrated in a variety of body fluids. Of those, however, only serum, saliva, and semen have been associated consistently with transmission in experimental models.29 Percutaneous transfer of the virus is the most obvious route of transmission in the medical setting, through either blood products or needle-stick accidents. Contact of infectious material with broken skin or mucous membranes also can result in effective transmission. Compared with other transmissible viruses, such as HIV, HBV is a fairly stable virus and remains infectious on household surfaces up to 7 days. Although transmission in households is more common through sexual contact than through fomite contact,30 nonsexual household transmission has been established as a route for HBV infection.31 Therefore, any surfaces potentially contaminated with infectious blood should be cleaned with 1 : 10 dilution of bleach solution. In areas of the world with higher HBV carrier rates than the United States, nonparenteral transmission would be expected to constitute the major route of person-to-person HBV infection. Vertical transmission is a major source; investigators in Taiwan estimated that 40% to 50% of HBsAg carriers became infected in the perinatal period.25,32 Children born to carrier mothers who escape the neonatal period without evidence of infection are still at risk for childhood acquisition of HBV. One of the early vaccine trials conducted in Senegal showed that among children seronegative at the beginning of a randomized HBV vaccination trial, almost 10% acquired HBV infection in the absence of vaccination by the end of a 12-month follow-up period.33
Diagnosis HBV is distinguished from the other viral hepatitides by its long incubation period (1–6 mo), by the presence of extrahepatic symptoms in up to 20% of patients (arthralgia, rash, and myalgia thought to be a result of antigen-antibody complex deposition),34 and by the detection of HBV-specific serum markers (Table 27–2). HBV consists of three structural antigens: surface, core, and e antigen. The appearance of surface antigen (HBsAg) in the serum usually predates any clinical symptoms by 4 weeks on average and remains detectable for 1 to 6 weeks in most patients.35 In the 90% to 95% of patients in whom chronic infection does not develop, HBsAg titers decrease as symptoms diminish. The appearance of HBsAb defines the absence of the carrier state; titers increase slowly during the clinical recovery period and may continue to increase up to 10 to 12 months after HBsAg is no longer detectable. In most patients with self-limited, acute HBV, HBsAb is
472 S ECTION F OUR • Infection T A B L E 2 7 – 2
Interpretation of Hepatitis B Panel TESTS
RESULTS
INTERPRETATION
HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc IgM anti-HBc Anti-HBs HBsAg Anti-HBc IgM anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs
Negative Negative Negative Negative Positive Positive Negative Negative Positive Positive Positive Positive Negative Positive Positive Negative Negative Negative Positive Negative
Susceptible
Immune due to natural infection
Immune due to hepatitis B vaccination
Acutely infected
Chronically infected
Interpretation unclear; four possibilities: 1. Resolved infection (most common) 2. False-positive anti-HBc, thus susceptible 3. “Low level”: chronic infection 4. Resolving acute infection
HBc, hepatitis B core antigen; HBs, hepatitis Bs; HBsAg; hepatitis B surface antigen; IgM, immunoglobulin M. Adapted from A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: Immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-16):1–31.
detectable only after HBsAg titers in serum disappear.36 A “window” of time has been described in which a patient still with clinical hepatitis is negative for both HBsAg and HBsAb. During this time, HBV infection still can be diagnosed by the detection of hepatitis B core antibody (HBcAb), which begins to appear 3 to 5 weeks after HBsAg does. HBcAb titers may drop off in the first 1 to 2 years after infection, although the antibody is still detectable years after acute disease in most patients.36 The appearance of hepatitis Be antigen (HBeAg) parallels that of HBsAg; in self-limited infections, HBeAb is detectable shortly after the time that HBeAg disappears. The chronic HBV carrier state usually can be predicted by HBsAg seropositivity for 20 weeks or longer. HBcAb is detectable in the serum of carriers at levels higher than those seen in either acute or recovering selflimited infections, and e antigen markers are variable. The presence of HBsAb in the absence of HBsAg and HBcAb differentiates vaccine-mediated immunity from naturalinfection–mediated immunity.
Maternal and Fetal Risks Risks during Pregnancy Acute HBV infection during pregnancy is usually a mild illness with only up to 30% of patients reporting icterus, nausea, vomiting, and right upper quadrant discomfort.37 Treatment during pregnancy is mainly supportive, as in the nonpregnant state. Symptoms generally resolve within several weeks; however, 0.5% to 1.5% of infective individuals will develop fulminant liver failure.38 Hospitalization
should be considered for pregnant women with acute HBV infection if they have encephalopathy, coagulopathy, or severe fluid and nutritional imbalances. The diagnosis of acute HBV during the later stages of pregnancy can be differentiated from preeclampsia or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome using normal blood pressure criteria and presence of jaundice. Encouragement is necessary to maintain adequate nutrition during the early symptomatic phase, and liver-metabolized drugs, if not avoidable, need to be monitored carefully through blood levels. In addition, household and sexual contacts of patients should be offered appropriate immunoprophylaxis. No teratogenic association has been established for maternal HBV infections,39,40 despite evidence of viral infection within the placenta.41,42 The rate of vertical transmission during acute maternal HBV infection depends on the gestational age of the fetus. When maternal infection occurs during the first trimester, up to 10% of neonates will be infected. In contrast, 80% to 90% of neonates are HBsAg-positive when maternal infection occurs during the third trimester.20,43 Although evidence is limited, there is an association between prematurity and acute HBV infection (32% vs. 11% in controls).39 Chronic HBV is endemic in certain areas of Asia where the estimated prevalence among women of reproductive age is 10% to 20%. Studies from these areas indicate that the presence of HBsAg does not appear to increase the risk of adverse pregnancy outcomes.44 In addition, pregnancy does not exacerbate chronic HBV infection or alter HBV viral levels.45
Hepatitis B Screening in Pregnancy The opportunity to provide almost complete protection against perinatally acquired HBV infection makes antenatal identification of HBV carriers critical so that combined neonatal prophylaxis can be administered in a timely fashion. Previously, in nonendemic areas such as the United States, risk factor–based prenatal screening protocols were implemented, but these protocols detected only up to 60% of HBV carriers. Therefore, the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention (CDC) recommended routine prenatal screening with HBsAg for all pregnant women regardless of risk factors.20,43 Furthermore, the CDC recommends that pregnant women who are HBsAg-negative and at high risk for HBV infection (including >1 sex partner in past 6 mo, evaluation or treatment for sexually transmitted infection, recent or current injection drug use, or HBsAg-positive sex partner) should be retested upon admission to labor and delivery.
Management Options Prevention of Hepatitis B Virus Infection Immunoprophylaxis regimens to prevent HBV transmission in the perinatal period were a direct extension of the success of these therapies in high risk adult populations. Postexposure immunization was first demonstrated through the use of immunoglobulin preparations with high titers of HBsAb, when given within 4 hours of experimental infection with HBV.46 Before the development of an effective HBV-specific vaccine, transient preexposure prophylaxis was demonstrated using hepatitis B immunoglobulin (HBIG),47 although such use of HBIG is now of purely historical interest in terms
C HAPTER 27 • Hepatitis Virus Infections 473
of understanding the evolution of therapeutic standards. Currently, postexposure treatment consists of a single dose of HBIG administered as temporally as possible to the exposure. Immediate therapy is optimal for maximal protection, although 75% efficacy has been shown when HBIG is given within 7 days of exposure.48 Although it does not increase the efficacy of HBIG therapy, a series of HBV vaccinations also should be initiated if the exposure was within a setting of ongoing risk, such as a health care or institutional setting. This regimen consists of injections at 0, 1, and 6 months and results in high antibody titers in more than 90% of those younger than 60 years of age. Administration of HBV vaccine simultaneously with HBIG does not diminish the immunologic response to the vaccine.49 Still, the currently available HBV vaccine’s efficacy is conferred by stimulating production of HBsAb by exposure to HBsAg; vaccine-related immunity can be distinguished from natural immunity in most cases by the absence of HBcAb in the serum of successfully vaccinated patients.
Prevention of Hepatitis B Virus in Utero Infection In utero HBV infection is determined by multiple potential factors including HBV DNA level, gestational age, placenta integrity, and possibly genetic susceptibility of fetus.50 Several prophylactic therapies (including hyperimmunoglobulin, HBV vaccine, and lamivudine) have been proposed to possibly reduce the risk of in utero transmission. Lamivudine is approved for treatment and can achieve suppression of HBV replication and remission.20,51–53 Although wellcontrolled, large studies are needed, several reports have shown potential benefit from maternal lamivudine therapy to reduce the risk of in utero infection.52,53 However, there is currently no effective, well-studied prophylactic treatment aimed at prevention in utero transmission.54–57
Preventing Perinatal Hepatitis B Virus Transmission Although there may be a theoretical risk of HBV transmission, a lack of data exists regarding risk of transmission with fetal scalp monitoring and operative vaginal delivery. The route of delivery has not demonstrated to influence of the risk of perinatal HBV transmission.20 According to the CDC, an HBsAg-positive mother can breast-feed even prior to the infant receiving the HBV vaccine and HBIG. The potential for vertical transmission of HBV at birth is significant. Most infants born to carrier mothers are HBsAg-negative at birth but seroconvert in the first 3 months after delivery, suggesting acquisition of the virus at birth.58 Early attempts at interrupting the perinatal transmission cycle employed HBIG alone, administered in the neonatal period. Globulin alone had a protective efficacy against the carrier state of 70% to 75%, although the protection was not permanent, and many children eventually became infected after the passively acquired antibody was cleared, undoubtedly through household contact.59,60 With the advent of the HBV vaccine, trials were established to test its efficacy when administered in the newborn period, both alone and in conjunction with HBIG. A combination of HBIG and vaccine in the newborn period conferred significantly greater protection against perinatally transmitted HBV than even the vaccine alone, increasing
efficacy from a range of 75% to 85% up to 90% to 95%.59 The small but identifiable percentage of infants who become infected, despite even combined HBV therapy at birth, is believed to represent in utero infection.61,62 Combination HBV-specific immunotherapy provides the best opportunity to prevent the chronic carrier state in the offspring of HBsAg-positive mothers. CDC guidelines have been changed recently to reflect timing of the vaccine based on infant birth weight. Infants born to HBsAg-positive women should receive HBIG (0.5 mL) intramuscularly (IM) and HBV vaccine concurrently at a different site (0.5 mL, IM) within 12 hours of birth. For infants weighing less than 2000 g, the vaccine dose does not count as the first dose in the vaccine series and the full vaccine series should be initiated at 1 to 2 months. Infants (>2000 g) born to women of HBsAg-negative status receive the HBV vaccine prior to discharge. Infants (3 mo) occurs in 75% to 85% of acutely infected individuals. Chronic HCV infection is the leading cause of liver transplantation in the United States.69
Diagnosis Laboratory tests for diagnostic confirmation of acute HCV include at least a sevenfold increase in serum ALT levels, IgM anti-HAV–negative, IgM anti-HBc– or HBsAg–negative, and either a positive anti-HCV screening test with a cut-off predictive of a true positive OR anti-HCV–positive screening test verified with a more specific assay.6 In a patient at high risk for HCV infection with a positive
anti-HCV test result, the chance of a false-positive ELISA is exceedingly low. However, recognizing that most clnical laboratories report positive anti-HCV results using screening assays alone despite previous recommendations, the CDC expanded its HCV testing algorithm to include an option for supplemental testing based on “signal-to-cut-off (s/co)” ratios of positive commercial assay results.76 The s/co of anti-HCV screening test positive results can be used minimize the number of specimens that require supplemental testing while providing results that have high probability of reflecting the person’s true antibody status. Because pregnant women without risk factors do not constitute a high risk group requiring HCV screening by CDC guidelines, it is critical for clinicians to understand the limitations and interpretations of the currently available HCV screening assays. At least six HCV genotypes and 50 subtypes have been identified. Viral genotyping is valuable to help guide therapy.77 Genotype 1 is the most common HCV genotype found in the United States and is less responsive to treatment than genotypes 2 and 3. Genotypes 2 and 3 are almost threefold more likely than genotype 1 to respond to therapy with interferon-α (IFN-α) or IFN-α and ribavirin.77 This variation may limit the reproducibility of results in clinical trials, and therefore, genotyping information should be included for subjects enrolled in these trials. HCV genotype has not been determined to be an independent risk factor for perinatal HCV transmission, although data are very limited.78,79
Maternal and Fetal Risks The prevalence of HCV infection among pregnant women ranges from approximately 0.3% to 2% in the United States and Europe, with higher rates in urban settings.64,80,81 Routine prenatal screening for HCV is not recommended because of the lack of proven cost-effectiveness and available safe treatment.82 However, screening is recommended for the subset of women with known risk factors for HCV infection as listed in Table 27–3.20 Identifying HCV-seropositive pregnant women is important to guide postnatal follow-up and potential therapy for both women and neonates. Overall, pregnancy does not significantly affect the clinical course of acute or chronic HCV infection. Studies have demonstrated decreases in transaminase levels as pregnancy progresses in HCV-infected women, although there are conflicting results regarding whether pregnancy alters viral load.83–85 It is postulated that immunomodulatory factors play a role in these findings. Conversely, HCV infection may lead to adverse maternal or neonatal outcomes. Several studies have suggested that maternal HCV reactivity is associated with an increase risk of cholestasis of pregnancy and increased neonatal methadone withdrawal in those infants born to women taking methadone.86,87 Therefore, clinicians should be aware of the increased risk of cholestasis and its associated morbidity. Vertical HCV transmission rates range between 2% and 7%.77,78,80,88,89 Although reported rates of transmission have been variable, overall it is encouraging that most series show the risk to be generally less than 5%. Maternal viremia (HCV RNA detected in maternal blood) near the time of delivery is a key determinant for vertical HCV transmission, regardless of maternal HIV status.90–92 If an HCV-infected pregnant woman has no detectable HCV RNA, the risk of
C HAPTER 27 • Hepatitis Virus Infections 475 T A B L E 2 7 – 3
Risk Factors Warranting Hepatitis C Screening: Centers for Disease Control and Prevention Guidelines Individuals Who Should Be Screened Routinely? ● Persons who ever injected illegal drugs (even once) ● Persons notified that they received blood/blood products from a donor who later tested positive for HCV ● Recipients of transfusions or organ transplants, particularly if received before July 1992 ● Persons ever on long-term hemodialysis ● Persons with persistently elevated alanine aminotransferase (ALT) levels or other evidence of liver disease ● Persons seeking evaluation or care for a sexually transmitted infection, including HIV Individuals for Whom Routine Testing Is of Uncertain Need ● Recipients of tissue transplants (e.g., corneal, skin, sperm, ova) ● Users of intranasal cocaine or other illegal noninjected drugs ● Persons with a history of tattooing or body piercing ● Persons with a history of sexually transmitted diseases or multiple sexual partners ● Long-term steady sex partner of an HCV-infected individual HCV, hepatitis C virus. From Centers for Disease Control and Prevention (CDC): Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(RR-19):1–33; and CDC: Sexually transmitted diseases treatment guidelines, 2006. MMWR 2006;55(RR-11):1–94.
transmission is approximately 0% to 3%.80,93 In a recent study of over 500 HCV-infected women, the vertical transmission rate was 7.1% (95% confidence interval [CI] 6.3%– 7.9%) in those women with detectable HCV RNA and 0% in those women who were HCV RNA–negative.80 In contrast to HIV, the critical titer predictive of perinatal transmission remains unknown. Women coinfected with HCV and HIV have consistently higher rates of perinatal transmission than women infected with HCV alone. Recent series have demonstrated that the risk may be lower that previously reported, ranging from 5.4% to 13.6% 80,88,94 The interaction between maternal and fetal humoral and immunologic factors is thought to be a critical contributor to both the occurrence and the persistence of perinatally acquired neonatal HCV infection. The fact that maternal or neonatal co-infection with HIV increases the risk of vertical HCV infection suggests that HIV-infected infants, who are known to have early deficits in cell-mediated and humoral immunity, may be less able to clear small amounts of perinatally presented HCV than HIV-uninfected infants.95,96 Although no large-scale longitudinal follow-up studies exist into the natural history of perinatal HCV infection through childhood, at least one published case report has documented clearance of neonatally documented HCV RNA by 24 months of age in a child born to an HIV-negative, HCV RNA–positive mother.72 Therefore, an intact neonatal immune system may allow for HCV clearance in early infancy, as can occur in HIVuninfected adults.
Management Options Similar to HBV, invasive monitoring during labor should be avoided if possible in HCV-infected women. Internal fetal
heart rate monitoring is associated with a 6.7-fold (95% CI 1.1–35.9) increased risk of transmission.79 Optimal route of delivery, in the context of maternal HCV infection, has been an area of controversy. This debate, to some degree, parallels the one that evolved regarding maternal HIV infection. However, unlike with HCV infection, maternal HIV viral load was a clearly established independent predictor of vertical transmission97 and had a direct bearing on the current guidelines regarding route of delivery and maternal HIV infection, specifically when maternal HIV viral load is durably suppressed to greater than 1000 RNA copies/mL.98 Several studies indicate that route of delivery is much less clearly associated with an increased risk of HCV transmission.68,80,89 Current consensus opinions, therefore, recommend cesarean delivery in HCV-infected women only for usual obstetric indications.20,80 The experience with antiretroviral treatment in decreasing both maternal viral load and the risk of neonatal HIV infections raises the question of potential comparable treatment options in the context of maternal HCV infection. Currently, there is no safe treatment for chronic HCV infection during pregnancy. The standard combination therapy for nonpregnant adults consists of weekly injections with pegylated IFN-α and daily ribavirin.99 Ribavirin is contraindicated during pregnancy and in male partners of pregnant women due to potential teratogenic effects.73,100,101 Finally, questions surrounding the safety of breast-feeding frequently arise from HCV-infected women. Many of these women have other risk factors, such as ongoing substance addiction or coexisting HIV infection, which preclude breast-feeding in general and override concerns about transmission of HCV through breast milk. For those women who have no other obstetric or medical issues that prevent nursing, data have failed to demonstrate breast milk as an effective route for HCV transmission. Although most of these studies were not designed to specifically address this topic, the authors’ evaluation of mother-infant pairs enrolled in some of the published vertical HCV transmission studies failed to document any neonatal HCV infection in breastfed infants, even when the mother was HCV RNA–positive. One study from China that did look at breast milk specifically found a correlation between maternal HCV serum titer and detection of HCV by means of polymerase chain reaction (PCR) in breast milk; however, no infants in this small series (n = 15) became infected with HCV.102 Additional studies from Australia,103 United Arab Emirates,104 and Switzerland105 examined 100 pregnancies in HCV-infected women who breast-fed (up to two thirds of whom were HCV RNA–positive in sera), with no detectable impact of breast-feeding on the risk of neonatal infection. As a result of the available supporting data, consensus opinions do not view maternal HCV infection as a contraindication to breast-feeding except, perhaps, in cases in which a mother experiences cracked or bleeding nipples.20,77,106 A survey study, in fact, did demonstrate that that the majority of community-based obstetricians are questioning patients about issues that could relate to HCV infection risk. However, the authors showed that HCV screening practices and counseling provided were discrepant with CDC recommendations up to 53% of the time, particularly in the area of counseling against breast-feeding in the face of maternal HCV infection.107
476 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Hepatitis Virus Infections Evidence Quality and Recommendation
Management Options
References
Hepatitis A Prenatal
●
Women traveling to endemic areas during pregnancy should be vaccinated.
III/C
23
●
Vaccine is recommended for postexposure prophylaxis for women aged up to 40 yr.
Ia/B
23
●
●
Hepatitis A vaccine not contraindicated during pregnancy.
IV/C
20
Supportive care for acute infection.
GPP
—
GPP
—
Newborn immune globulin if acute maternal infection occurs proximate to delivery.
IV/C
23
Hepatitis A vaccine recommended for all children aged 12–23 mo.
Ib/A
21
Supportive care.
GPP
—
Universal HBsAg screening of all pregnant women.
Ib/A
20,43
No contraindications to HBV vaccine during pregnancy.
IV/C
49
III/B
20
Newborns of chronic carrier mothers should all receive HBIG within 12 hr of birth and HBV vaccine within 12 hr of birth.
Ib/A
20,60
Encourage breast-feeding.
IIa/B
20,43
Screen pregnant women in high risk groups.
IV/C
20,77
Most cases asymptomatic; supportive care for clinical illness.
GPP
—
Counsel regarding increased risk of cholestasis.
III/B
87,88
Route of delivery does not influence risk of vertical transmission.
III/B
79,80,83,89
Avoid invasive monitoring during labor if possible.
III/B
79
Encourage breast-feeding.
II/B
102,104,105
Referral to specialist for potential combination therapy (interferon and ribavirin).
IV/C
73,86
Labor and Delivery
Supportive care for acute infection.
●
Postnatal
●
●
Hepatitis B Prenatal
●
●
●
Labor and Delivery
Route of delivery does not influence vertical transmission.
●
Postnatal
●
●
Hepatitis C Prenatal
●
●
●
Labor and Delivery
●
●
Postnatal
●
●
GPP, good practice point; HBIG, hepatitis B virus immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
C HAPTER 27 • Hepatitis Virus Infections 477
SUGGESTED READINGS Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP: Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55:1–23. American College of Obstetricians and Gynecologists (ACOG): Viral hepatitis in pregnancy (ACOG Practice Bulletin No. 86). Obstet Gynecol 2007;110:941–956. Berkley EM, Leslie KK, Arora S, et al: Chronic hepatitis C in pregnancy. Obstet Gynecol 2008;112:304–310. Gambarin-Gelwan M: Hepatitis B in pregnancy. Clin Liver Dis 2007;11:945–963,x. Gonik B: The role of obstetrician/gynecologists in the management of hepatitis C virus infection. Infect Dis Obstet Gynecol 2008;2008:374517. Mast EE, Weinbaum CM, Fiore AE, et al: A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the
United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: Immunization of adults. MMWR Recomm Rep 2006;55:1–33; quiz CE1–4. McMenamin MB, Jackson AD, Lambert J, et al: Obstetric management of hepatitis C–positive mothers: Analysis of vertical transmission in 559 mother-infant pairs. Am J Obstet Gynecol 2008;199:315.e1– 315.e5. Victor JC, Monto AS, Surdina TY, et al: Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007; 357:1685–1694. Wasley A, Grytdal S, Gallagher K, Centers for Disease Control and Prevention (CDC): Surveillance for acute viral hepatitis—United States, 2006. MMWR Surveill Summ 2008;57:1–24.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 2 8
Human Immunodeficiency Virus* D. HEATHER WATTS
INTRODUCTION The management of HIV infection continues to evolve rapidly. Amazing advances have been made in therapy of primary infection, prevention of opportunistic infections, and prevention of perinatal transmission since the first cases of AIDS were described in 1981. Perinatal transmission rates have decreased from 20% to 30% early in the epidemic to 1% to 2% in developed countries with the use of antiretroviral therapy and scheduled cesarean delivery. While reducing transmission, these interventions have increased the complexity of prenatal care for HIV-infected women. As standards of care evolve rapidly, providers are urged to access resources available on the Internet such as www. aidsinfo.nih.gov or www.WHO.int/hiv/topics/arv/ for the most recent update. Women represent the fastest growing group of persons with new HIV infections. In the United States, over 130,000 women are estimated to be infected, and worldwide, the number is over 15 million.1,2 Approximately 6000 HIVinfected women deliver annually in the United States, with approximately 144 to 236 infants acquiring HIV infection compared with 2 million deliveries to HIV-infected women worldwide resulting in over 600,000 HIV-infected infants.2,3 Improvements in availability of prenatal care, HIV counseling and testing, antiretroviral therapy, and strategies to reduce HIV transmission through breast-feeding are vitally needed in areas of the world most affected by HIV to improve maternal health and survival and reduce perinatal transmission.4 This chapter focuses on interventions currently available to maximize maternal health and minimize perinatal transmission in resource-rich countries.
DIAGNOSIS All pregnant women should be tested for HIV infection to allow optimal care for maternal health and prevention of perinatal transmission. A policy of universal HIV testing, with patient notification and right of refusal, is recommended.5 All pregnant women should be encouraged to be tested regardless of perceived risk factors or local seroprevalence, because many HIV-infected women were infected heterosexually and are unaware of their risk. If women *This chapter is in the public domain.
decline testing, the reasons for declining should be explored and further education provided regarding the benefits and risks of testing. Federal policy recommends universal HIV testing along with other prenatal laboratory studies unless the woman refuses testing, but state laws may require detailed pretest counseling and written informed consent. Providers should be aware of their own local and state requirements while striving for universal testing for pregnant women. HIV testing should be repeated in the third trimester for all women in high-prevalence areas (HIV incidence >17/100,0005) and for those with ongoing risk factors in pregnancy including injection drug use, an HIV-infected partner, or new or multiple partners during pregnancy.5 In addition, pregnant women with symptoms suggestive of acute HIV infection, such as fever, rash, sore throat, and myalgias, should undergo both antibody testing and HIV RNA testing to diagnose infection as early as possible. The recommended algorithm for HIV testing consists of initial screening with a U.S. Food and Drug Administration (FDA)–licensed enzyme immunoassay (EIA) or rapid test followed by confirmatory testing with an FDA-licensed supplemental test, usually a Western blot (WB), if the initial test is repeatedly reactive.6 If the EIA is repeatedly reactive and the WB is positive, HIV infection is confirmed, because false-positive WB results are rare.7 However, given the implications of a positive HIV test result, repeat testing on a separate blood sample is recommended to rule out any possibility of mislabeling or other clerical error. A more common, though still infrequent, event is an indeterminate WB. Indeterminate WB results can be caused by incomplete antibody response seen with recent HIV infection or latestage disease or by nonspecific reactions in uninfected persons, possibly related to recent immunizations or current or previous pregnancy. Although indeterminate results are more common among pregnant or parous women, they are estimated to occur during pregnancy at a rate of fewer than 1 per 4000 samples based on a study of over 1 million specimens.8,9 Pregnant women with indeterminate WB results should be queried regarding potential recent exposures to HIV through occupational, sexual, or needle-sharing activity; have repeat testing to evaluate for evolving infection versus resolution of nonspecific reactivity; and consider testing of sexual partners to clarify risk. For women with repeatedly indeterminate testing, alternate testing for HIV itself using an approved HIV RNA test may be helpful, 479
480 S ECTION F OUR • Infection
although these tests are not approved for diagnosis of HIV infection. If no recent high-risk exposures are identified, women with repeatedly indeterminate WB results should be reassured that HIV infection is unlikely. Women delivering with no prenatal care represent a group at high risk for perinatal HIV transmission. During the period 1993 to 1996, approximately 15% of HIVinfected pregnant women in the United States received no prenatal care, compared with 2% in the general population.10 Given the reduction in transmission achieved with several different intrapartum/neonatal prophylaxis regimens11–14 and the increased risk of HIV infection among women presenting without prenatal care, rapid HIV testing should be offered to all pregnant women presenting in labor without prenatal care or documentation of previous testing during pregnancy.5 Testing should be done only after pretest counseling, including discussion of the need for confirmatory testing if rapid assays are positive, and informed consent. Rapid testing may be done using approved rapid tests or EIA testing.15 Because of the relatively low prevalence of HIV even in this setting, the negative predictive value of a single negative rapid test is high, so no further testing is required to confirm a negative rapid test.15 All positive rapid tests should be confirmed by supplemental testing with either a WB or an immunofluorescence assay but decisions regarding use of antiretrovirals for prevention of perinatal transmission may need to be made pending confirmatory test results because initiation of therapy during labor or shortly after birth is required to reduce risk of transmission.15
MATERNAL AND FETAL RISKS Disease Progression Studies in the United States and Europe have been consistent in not demonstrating an effect of pregnancy on HIV disease progression.16–18 More recently, a report from the Women and Infants Transmission Study (WITS) did not show a difference in CD4+ lymphocyte count or HIV RNA trajectory or clinical AIDS rate between women with one or multiple pregnancies after HIV diagnosis.19 Studies in developing countries suggest that pregnancy may enhance disease progression, but they included small numbers and might have had selection bias in HIV testing.20,21
Increased Toxicity of Antiretroviral Therapy The hormonal effects of pregnancy may increase the risk of toxicity of antiretroviral therapy, especially the nucleoside reverse transcriptase inhibitors. Several cases of lactic acidosis and hepatic failure, some resulting in maternal deaths, have been reported among women on long-term nucleoside therapy during pregnancy, most frequently stavudine and didanosine in combination.22,23 Clinical findings were similar to those seen in acute fatty liver of pregnancy, which occurs more frequently among women with heterozygous defects of mitochondrial fatty acid metabolism carrying fetuses homozygous for the defect.24 Similar enhancement of mitochondrial toxicity due to reduced fatty acid oxidation has been shown in pregnant mice and in mice treated with high doses of estrogen and progesterone to simulate pregnancy.25,26 The potential for lactic acidosis and hepatic
failure is present with the use of any nucleoside agent, with the binding affinity for mitochondrial polymerase gamma, the key enzyme, highest for zalcitabine, then decreasing for didanosine, stavudine, lamivudine, zidovudine, and abacavir.27 Thus, all pregnant women on nucleoside antiretroviral therapy should be educated regarding the signs and symptoms of lactic acidosis and hepatic dysfunction including nausea, vomiting, fatigue, tachycardia, dyspnea or hyperventilation, and abdominal pain, and clinicians should be vigilant for these signs and symptoms that might be difficult to distinguish from normal pregnancy symptoms.
Impact on Future Therapy Current indications for initiation of antiretroviral therapy in nonpregnant adults are a CD4+ lymphocyte count below 500 cells/µL or opportunistic infections.28 Many pregnant women do not meet these criteria for therapy but will take antiretrovirals to reduce the risk of perinatal transmission and stop therapy after delivery. As discussed in more detail later, these women should receive highly active therapy with a combination of three or more drugs to minimize HIV RNA levels and risk of transmission.29 Although aggressive combination therapy with suppression of HIV RNA to undetectable levels during pregnancy should minimize the risk of resistance, the impact of short-term highly active antiretroviral therapy on future response to therapy and maternal health has not been well studied. Although studies following women postpartum after zidovudine monotherapy and dual nucleoside therapy in pregnancy have not suggested an increased risk of disease progression with stopping therapy,30,31 studies of structured treatment interruption have raised concern about stopping highly active antiretroviral therapy (HAART) once initiated.32 However, most subjects in treatment interruption studies had lower nadir CD4+ cell counts, longer duration of antiretroviral therapy, and older age than the pregnant women using HAART during pregnancy for interruption of transmission, making extrapolation of results difficult. More research is needed on the risks of stopping or continuing HAART after use in pregnancy among women with higher CD4+ lymphocyte counts.
Pregnancy Complications The effect of HIV infection and antiretroviral therapy on pregnancy outcome is another issue for consideration. The majority of studies in developed countries done before the availability of antiretroviral therapy did not demonstrate an increased rate of adverse pregnancy outcomes such as preterm birth and stillbirth among HIV-infected women compared with uninfected women with similar risk profiles.33–35 Conversely, most studies in developing countries have suggested an increased risk of preterm birth, low birth weight, intrauterine growth restriction, stillbirth, and infant death among infants born to HIV-infected women, with increasing risk with more advanced HIV infection.33,36 Factors associated with an increased risk of preterm birth and low birth weight among HIV-infected women included previous adverse pregnancy outcome, hypertension, multiple gestation, smoking, bleeding, alcohol use, low maternal weight, Trichomonas vaginalis infection, and other sexually transmitted infections, similar to risk factors in
C HAPTER 28 • Human Immunodeficiency Virus 481
HIV-uninfected women.35,37,38 Low CD4+ percentage was an additional risk factor for adverse outcome among women not receiving antiretroviral therapy,37 but neither CD4+ lymphocyte count nor HIV RNA levels were associated with adverse outcomes among women receiving zidovudine therapy.38 Zidovudine monotherapy has not been associated with an increased risk of preterm birth or low birth weight in any study to date, but the potential impact of combination antiretroviral therapy on pregnancy outcome is less clear.39,40 In the early HAART era, a small study from Europe41 and an analysis of the European Collaborative Study42 found an increased risk of preterm birth with increasing numbers of drugs, with the highest rate occurring among women receiving protease inhibitor (PI) therapy. A combined analysis of several cohorts in the United States did not find an increased risk of preterm delivery among women on dual therapy or regimens including PIs, although there was a slight increase in risk of very low–birth weight infants born to women receiving PI therapy compared with those on no therapy or zidovudine.43 A meta-analysis published in 2007 incorporating 14 studies found no increase in risk of preterm birth with antiretroviral therapy compared with no therapy.44 HAART regimens including PIs did not increase the risk of preterm birth compared with the no therapy group, but were associated with an increased risk compared with combination regimens without PIs (odds ratio [OR] 1.35; 95% confidence interval [CI] 1.08–1.70).44 Among the subset starting any HAART before pregnancy or in the first trimester, the risk of preterm birth was increased compared with those starting HAART later in pregnancy (OR 1.71; 95% CI 1.09–2.67).44 Subsequent studies have found an increased risk of preterm birth with HAART, in some cases specifically with PI therapy. A large, population-based study from the United Kingdom and Ireland found an adjusted odds ration (AOR) of 1.51 (95% CI 1.19–1.93) for preterm birth with HAART compared with mono- or dual therapy, regardless of whether a PI was included in the HAART.45 A Brazilian study found in increased rate of preterm birth (AOR 5.0; 95% CI 1.5– 17.0) with HAART started preconception compared with therapy started later in pregnancy.46 Recent studies from the United States, Germany/Austria, and Italy have found increased risks of preterm delivery with PI-based HAART in pregnancy, with AORs ranging from 1.21 to 3.40.47–49 Clinicians should be aware of a possible increased risk of preterm birth with PI use, but given the clear benefits for maternal health and reduction in perinatal transmission, these agents should not be withheld because of these concerns.
Perinatal Transmission A major concern with HIV infection in pregnancy is the risk of perinatal transmission of HIV to the infant. Among untreated women who do not breast-feed, transmission will occur in 20% to 30%.50 Estimates are that about two thirds of transmissions from untreated women occur at delivery and one third occur in utero, many late in pregnancy.51 An additional transmission risk of 15% to 20% occurs during breast-feeding.52 Maternal HIV RNA levels appear to be the factor most predictive of transmission.53,54 Antiretroviral therapy during pregnancy and in the neonatal period clearly reduces the risk of perinatal transmission of HIV. The first
study demonstrating this benefit was the Pediatric AIDS Clinical Trials Group (PACTG) 076 study39 with a transmission rate of 8.3% among those receiving oral antepartum, intravenous intrapartum, and oral neonatal zidovudine for 6 weeks compared with 25.5% among those receiving placebo. The PACTG 185 trial55 found no benefit from addition of HIV immunoglobulin to the PACTG 076 regimen but demonstrated benefit of zidovudine among women with CD4+ lymphocyte counts under 500 cells/µL at enrollment, with a transmission rate of 4.6%. Subsequent trials have demonstrated benefit from shorter courses of antepartum/ intrapartum or antepartum/intrapartum/neonatal zidovudine or zidovudine/lamivudine compared with placebo, but no benefit was seen from intrapartum zidovudine/lamivudine alone.14,56–61 In addition, the HIVNET 012 trial11 demonstrated the benefit of a two-dose nevirapine regimen (one dose intrapartum to the mother and one dose to the infant at 48 hr of age) compared with oral intrapartum and 1 week of neonatal zidovudine. A subsequent trial demonstrated that intrapartum and 1 week of neonatal zidovudine/lamivudine therapy was similar in efficacy to the HIVNET 012 nevirapine regimen.14 These trials provide data for implementation of shorter, less complex regimens for reduction of transmission of HIV in resource-limited settings or for women diagnosed in the peripartum period as being HIV-infected. A trial in the United States, Europe, and Latin America (PACTG 316) evaluating addition of the HIVNET 012 nevirapine regimen to established antiretroviral therapy demonstrated no benefit of adding nevirapine to ongoing therapy.62 However, this trial provides updated data regarding transmission of HIV with the use of combination antiretroviral therapy. The transmission rate overall was 1.5%, with rates of 2.1% for women on zidovudine alone, 1.1% with combination nucleoside therapy, and 1.6% with combination with PI.62 Similarly, an analysis from WITS, including women enrolled from 1990 through 2000, observed transmission rates of 20.0% for women not receiving antiretroviral agents, 10.4% for women receiving zidovudine monotherapy (not necessarily the complete 076 regimen), 3.8% for those receiving dual nucleoside therapy, and 1.2% for those receiving highly active antiretroviral regimens.50 These low rates of transmission with highly active regimens occurred despite potential confounding by indication in which women with the highest HIV RNA levels and lowest CD4+ lymphocyte counts were most likely to be treated with highly active regimens, especially early in the period of availability. More recent data from a study of HIV transmission among women delivering in the United Kingdom and Ireland from 2000 to 2006, transmission occurred in 0.7% of 2845 women on HAART, regardless of mode of delivery.63 Thus, current data demonstrate significant fetal benefit from combination antiretroviral regimens, which would require significant evidence of harm to negate.
Antiretroviral Therapy Teratogenesis Another concern with the use of antiretroviral drugs in pregnancy is the potential for birth defects, especially with firsttrimester exposure. Limited data from animal studies are available for most of the drugs (Table 28–1). Of concern,
482 S ECTION F OUR • Infection T A B L E 2 8 – 1
Preclinical and Clinical Data Relevant to the Use of Antiretrovirals in Pregnancy DRUG
FDA PREG CAT
NEWBORN:MATERNAL DRUG RATIO
ANIMAL STUDIES
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Zidovudine (Retrovir, AZT, ZVD)
C
~0.8 human
No effect on rodent fertility, but cytotoxic to mouse embryos. Positive teratogenicity in rodents only at near-lethal doses. Negative teratogenicity studies in mice and rabbits.
Emtricitabine (Emtriva, FTC)
B
0.4–0.5 mice, rabbits
Didanosine (Videx, ddI)
B
0.5 human
No effect on rodent fertility or mouse embryos. No teratogenicity in mice, rats, rabbits.
Stavudine (Zerit, d4T)
C
0.76 rhesus monkey
No effect on rodent fertility, but cytotoxic to mouse embryos. No evidence of teratogenicity. Ossification delay at high doses in rats.
Lamivudine (Epivir, 3TC)
C
~1.0 human
No effect on rodent fertility or mouse embryos. No teratogenicity.
Abacavir (Ziagen, ABC)
C
Passage in rats
No effect on fertility in rodents. Anasarca, skeletal abnormalities at 35 times human dose in rodents, not seen in rabbits.
Tenofovir (Viread)
B
0.6–1.0 human
No effect on fertility. No birth defects, but growth restriction, reversible bone changes with chronic use in monkeys.
Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine (Viramune)
C
~0.9 human
Impaired fertility in female rats. Not teratogenic in rats, rabbits.
Delavirdine (Rescriptor)
C
Unknown
Efavirenz (Sustiva)
D
0.13 human
Etrvirine (Intelence)
B
Unknown
No effect on fertility in rodents. Embryotoxic in rabbits. VSD in rats, maternal toxicity, developmental delay, decreased pup survival. Increased fetal resorptions in rats. Defects (anencephaly, anophthalmia, cleft palate) in 3/20 monkeys treated with human doses. Negative in rats, rabbits.
Protease Inhibitors
Indinavir (Crixivan)
C
Minimal
No effect on fertility in rodents. No teratogenicity in rats, rabbits or dogs. Extra ribs in rats.
MAJOR TOXICITIES
HUMAN STUDIES; CONCERNS SPECIFIC TO PREGNANCY
Class effect: Rare, but potentially fatal, lactic acidosis with hepatic steatosis. Bone marrow suppression, ARV agent most used in pregnancy, myopathy safe in short term. See discussion of rodent tumors, mitochondrial toxicity in text. Hyperpigmentation of palms/ Pk study shows slightly lower levels soles. Possible hepatitis B flare in third trimester compared with when stopping. postpartum but no clear need to increase dose. Alternate NRTI for use in pregnancy. Pancreatitis, peripheral Pk study (n = 14) shows no need for neuropathy, nausea, diarrhea dose modification, well-tolerated. Alternate NRTI for use in pregnancy. Do not use with d4T in pregnancy because of enhanced toxicity. Peripheral neuropathy Phase I/II study indicated no change in pk in pregnancy; well-tolerated. Do not use with ddI in pregnancy because of enhanced toxicity. Antagonizes ZDV, do not use together. Pancreatitis increased in Pk study (n = 20) shows no need for children. Possible hepatitis B dose modification, well-tolerated. flare when stopping. Preferred NRTI in pregnancy based on experience with use. Potentially fatal hypersensitivity No change in pk in pregnancy. reactions, symptoms: fever, Alternate NRTI for use in pregnancy. rash, fatigue, nausea, vomiting, Screen for HLA-B*5701 before use diarrhea, abdominal pain in to reduce risk of hypersensitivity 2%–9%. reaction. Asthenia, nausea, vomiting, Limited data in human pregnancy diarrhea, headache, flatulence. thus far. Use only after careful Possible hepatitis B flare when consideration of alternatives. stopping. Class effects: rash with rare cases of Stevens-Johnson syndrome; increased transaminase levels. Rash, drug interactions, No change in pk in pregnancy. Not potential for fulminant hepatitis recommended for women initiating and hepatic failure, especially therapy with CD4 count >250 cells/ among women with CD4 mL due to increased risk of counts >250 cells/mL at potentially fatal liver toxicity. Single initiation. dose at delivery not associated with increased risk. See text for use of NRTI “tail” after single dose in labor. Rash, drug interactions. No studies. Not recommended for use in pregnancy.
Rash, drug interactions, CNS symptoms such as dizziness, insomnia, confusion.
Avoid use in first trimester. May be considered for use later in pregnancy. Ensure adequate contraception postpartum.
Rash, rare hypersensitivity reactions; drug interactions
No data on use in human pregnancy so not currently recommended.
Class effects: Hyperglycemia, possible fat redistribution and lipid abnormalities, increased bleeding episodes in hemophiliacs. Kidney stones, Use with low-dose ritonavir boosting hyperbilirubinemia, drug to assure adequate dosing in interactions, nausea. pregnancy. Alternate PI for use in pregnancy.
C HAPTER 28 • Human Immunodeficiency Virus 483 T A B L E 2 8 – 1
Preclinical and Clinical Data Relevant to the Use of Antiretrovirals in Pregnancy—cont’d FDA PREG CAT
NEWBORN:MATERNAL DRUG RATIO
Ritonavir (Norvir)
B
Minimal
Saquinavir hard gel capsules (Invirase) Nelfinavir (Viracept)
B
Minimal
B
Fosamprenavir (Lexiava)
DRUG
HUMAN STUDIES; CONCERNS SPECIFIC TO PREGNANCY
ANIMAL STUDIES
MAJOR TOXICITIES
No effect on fertility in rodents at half the human dose. Hepatotoxicity at higher doses. Developmental toxicity at toxic doses but no teratogenicity in rats, rabbits. No effect on fertility in rodents. Negative teratogenicity.
Nausea, vomiting, diarrhea; increased triglycerides, transaminases; drug interactions, paresthesias.
Use only at low doses to boost levels of other PIs in pregnancy.
Nausea, diarrhea, elevated transaminases.
Minimal
No effect on fertility in rodents. Studies negative in rats, rabbits.
Diarrhea, drug interactions
C
Unknown
No effect on fertility in rodents. Negative teratogenicity studies.
Lopinavir/ ritonavir (Kaletra)
C
0.20 human
No effects on fertility. No teratogenicity in rats, rabbits.
Nausea, vomiting, diarrhea, rash, oral paresthesias, increased liver function tests. Drug interactions. Nausea, vomiting, diarrhea, asthenia, elevated transaminase levels.
Use with low-dose ritonavir boosting to ensure adequate dosing in pregnancy. Alternate PI for use in pregnancy. Extensive experience in pregnancy but not recommended for treatment in nonpregnant adults. May be used as part of triple-agent regimen for pregnant women receiving HAART for prophylaxis rather than therapy. No studies in human pregnancy, not recommended.
Atazanavir (Reyataz®-)
B
Minimal (1000 copies/mL after 34 wk. Schedule at or after 38 wk’ gestation if dating criteria adequate. Perform vaginal delivery only if on antiretroviral therapy with undetectable HIV RNA.
Ia/A
29,86
490 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Human Immunodeficiency Virus—cont’d Management Options Routine prenatal care. If indicated, discuss unknown risk of transmission with amniocentesis or chorionic villus sampling.
Evidence Quality and Recommendation
References
III/B
29
Ia/A
29,39
If vaginal delivery, minimize duration of ruptured membranes as much as possible.
II/B
29,98,99
Avoid scalp electrodes, scalp sampling, instrumented delivery.
II/B
93,94
Discuss option of stopping or continuing antiretroviral therapy if initiated solely for transmission prophylaxis. Reinforce adherence if continuing therapy.
Ia/A
29
Counsel against breast-feeding.
Ia/A
29
Provide contraception and ensure continued HIV and reproductive health care. If partner is HIV-negative, advise male condom to avoid unprotected intercourse.
Ia/A
29
Provide psychosocial support as infant infection status assessed.
Ia/A
29
Ensure routine and HIV-specific care for infant including zidovudine 2 mg/kg every 6 hr or equivalent until 6 wk of age, HIV DNA PCR testing, initiation of prophylaxis against Pneumocystis carinii pneumonia beginning at 4–6 wk of age unless infant presumptively HIV-infected based on serial testing.
Ia/A
106
Labor and Delivery Start intravenous zidovudine infusion: a. For those choosing vaginal delivery 2 mg/kg over 1 hr followed by 1 mg/kg/hr until delivery with onset of labor. b. Same regimen at least 3 hr before scheduled cesarean delivery. Continue other medications orally except stavudine, which may antagonize zidovudine.
Wash infant before blood draws, injections. Postnatal
CMV, cytomegalovirus; GPP, good practice point; PCR, polymerase chain reaction.
SUGGESTED READINGS The Antiretroviral Pregnancy Registry: Interim Report. 1/1/89–7/31/08; issued December 2008. Available at www.APRegistry.com Centers for Disease Control and Prevention: Achievements in public health: Reduction in perinatal transmission of HIV infection, United States, 1985–2005. MMWR Morb Mortal Wkly Rep 2006;55:592–597. Centers for Disease Control and Prevention: Rapid HIV antibody testing during labor and delivery for women of unknown HIV status: A practical guide and model protocol. January 30, 2004. Available at
http://www.cdc.gov/hiv/topics/testing/resources/guidelines/pdf/ Labor&DeliveryRapidTesting.pdf Centers for Disease Control and Prevention: Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health care settings. MMWR Morb Mortal Wkly Rep 2006;55(RR-14):1–17. Kourtis AP, Schmid CH, Jamieson DJ, Lau J: Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: A meta-analysis. AIDS 2007;21:607–615. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral agents in HIV-1–infected Adults and
C HAPTER 28 • Human Immunodeficiency Virus 491 Adolescents. Washington, DC, Department of Health and Human Services. November 3, 2008, pp 1–139. Available at http://www. aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed February 19, 2009). Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1–infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1–Transmission in the United States. July 8, 2008. Available at http://aidsinfo.nih.gov/ guidelines/ (accessed February 19, 2008). Townsend CL, Cortina-Borja M, Peckham CS, et al: Low rates of motherto-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000–2006. AIDS 2008;22:973–981.
USPHS/IDSA Guidelines for the Prevention and Treatment of Opportunistic Infection in HIV-infected Adults and Adolescents. June 18, 2008. Available at http://aidsinfo.nih.gov/guidelines/ Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children: Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. February 23, 2009, pp 1–139. Available at http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines. pdf
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 2 9
Rubella, Measles, Mumps, Varicella, and Parvovirus LAURA E. RILEY Videos corresponding to this chapter are available online at www.expertconsult.com.
RUBELLA Maternal and Fetal Risks Rubella (German measles or third disease) is an exanthematous disease caused by a single-stranded RNA virus of the togavirus family.1 Like rubeola, rubella is acquired via respiratory droplet exposure. After a 2- to 3-week incubation period, symptomatic patients develop a rash that spreads from the face to the trunk and extremities, lasting about 3 days. Fever, arthralgias, and postauricular, posterior cervical, and suboccipital lymphadenopathy are characteristic. Severe complications such as encephalitis, bleeding diathesis, and arthritis are rare. Overt clinical symptoms occur in only 50% to 75% of rubella-infected patients, and thus, clinical history is not a useful marker of prior illness.2 Rubella infection is usually a mild illness in both adults and children. However, fetal infection may be devastating. Congenital rubella syndrome (CRS) may produce transient abnormalities, including purpura, splenomegaly, jaundice, meningoencephalitis, and thrombocytopenia, or permanent anomalies such as cataracts, glaucoma, heart disease, deafness, microcephaly, and mental retardation. Long-term sequelae might include diabetes, thyroid abnormalities, precocious puberty, and progressive rubella panencephalitis.2,3 Defects involving virtually every organ have been reported (Table 29–1).4 A 50-year follow-up of 40 survivors of CRS born between 1939 and 1943 revealed that all had hearing impairment; 23 had eye defects related to the rubella.5 The results of one large survey of maternal rubella infection in pregnancy are summarized in Table 29–2.6 The rate of fetal infection is highest at 11 weeks and greater than 36 weeks. However, the overall rate of congenital defects is greatest in the first trimester (90%) and declines steadily in the second and third trimesters. Rubella vaccine became available in the United States in 1969. Vaccination given as a trivalent preparation of measles, mumps, and rubella (MMR) vaccine produces long-term immunity in 95% of vaccinees. The rates of rubella dropped precipitously after introduction of the vaccine. Ten years later, the annual incidence of rubella infections, including CRS, had decreased by 99.6%.7 However, in the 1990s, there were several outbreaks in groups of adults with unknown vaccination status living in close quarters.8 The largest outbreak in the United States occurred in Nebraska
in 1999 and involved 125 cases; 87% of these patients were born in Latin America.9 In this outbreak, 7 pregnant women were infected and 1 child was born with CRS. Almost half of these women had prior births in the United States and had missed prior vaccination opportunities. Since then, the number of CRS cases has steadily declined in part due to rubella immunization campaigns in Latin America and Mexico.10,11
Diagnosis The clinical diagnosis of rubella infection is difficult. Most infections are subclinical, and the rash is nonspecific. Serologic testing is the primary mode of diagnosis using enzymelinked immunoassay (ELISA). In a woman with exposure or suspected illness, seroconversion demonstrated by paired acute and convalescent specimens is indicative of acute infection. Acute infection may also be diagnosed by isolation of virus from the blood, nasopharynx, urine, or cerebrospinal fluid. Serologic testing for immunity is based on the assumption that rubella-specific antibodies of the immunoglobulin G (IgG) class are present for life after natural infection or vaccination.
Management Options Prepregnancy Vaccination of all children and susceptible adults will help prevent outbreaks of rubella. All children should receive a single dose of live attenuated rubella vaccine at 12 to 15 months of age in a trivalent preparation of MMR strains. The second dose of MMR may be administered at least 1 month after the first dose but before 6 years of age. Susceptible young women should be vaccinated and refrain from pregnancy for 1 month following vaccination.12 Evidence of immunity is required of health care workers and women of childbearing age.13 Studies on a MMR-vaccinated cohort followed for 20 years shows that rubella antibodies remain elevated for at least that long in many individuals.14 However, individuals with low levels of antibody after vaccination may be susceptible to viremia and clinical infection.15 CRS after previous maternal rubella vaccination has been rarely reported.16 The rubella vaccine is a live virus preparation, which may cross the placenta; thus, it should not be administered to 493
494 S ECTION F OUR • Infection
pregnant women. However, the Centers for Disease Control and Prevention (CDC) have monitored inadvertent rubella vaccination during pregnancy, collecting over 500 cases. No case of CRS due to vaccination was documented, although virus was isolated from the conceptus in several cases.17 Thus, patients inadvertently vaccinated during pregnancy, or becoming pregnant shortly after vaccination, should be reassured and counseled that the risk of fetal infection is negligible.18,19 Furthermore, follow-up studies on fetuses inadvertently exposed to rubella vaccine RA27/3 in pregnancy in Costa Rica did not have increased rates of miscarriage or stillbirth.20
T A B L E 2 9 – 1
Abnormalities in Congenital Rubella: Triad of Gregg ABNORMALITY Eye Cataract Retinopathy
Microphthalmia Glaucoma Heart Patent ductus arteriosus Pulmonary valvular stenosis
Pulmonary artery stenosis Coarctation of the aorta Ventricular septal defects Atrial septal defects Ear Commonly damaged
Bilateral and progressive
DESCRIPTION
Usually bilateral and present at birth. “Salt and pepper” appearance, may have a delayed onset, frequently bilateral, visual acuity is not affected. Often associated with cataract. Rare but leads to blindness if not recognized.
Prenatal A pregnant woman infected with rubella is at little risk. However, depending on the gestational age at infection, the fetus may be at great risk for congenital anomalies. Methods for in utero diagnosis include fetal blood sampling measurement of rubella-specific IgM,21 rubella-specific reverse transcriptase polymerase chain reaction (RT-PCR), and virus isolation from amniotic fluid or products of conception.22,23 RT-PCR can detect the presence of viral RNA even when the fetal rubella virus–specific IgM obtained by fetal blood sampling is negative.24 Although these tests may indicate fetal infection, the counseling is largely based on the gestational age–related risk of congenital abnormalities due to CRS. No treatment other than pregnancy termination is available. Treatment for acute maternal rubella is generally symptomatic. Rarely, patients who develop thrombocytopenia or encephalitis may benefit from glucocorticoids or platelet transfusion. Immunoglobulin for pregnant women with acute infection is controversial. Furthermore, no data suggest that immunoglobulin will prevent fetal anomalies.
Common, often associated with persistence of the foramen ovale. Common, due to intimal proliferation and arterial elastic hypertrophy. Infrequent. Rare. Rare. Injury of cells of the middle ear leading to sensorineural deafness may also have a central origin. May be present at birth or develop later in childhood. Severe enough for the child to need education at a special school; rare when maternal rubella occurs after the fourth mo of pregnancy.
Adapted from Freij BJ, South MA, Sever JL, et al: Maternal rubella and the congenital rubella syndrome. Clin Perinatol 1988;15:247–257.
Labor, Delivery, and Postnatal Acute infection during these time periods is unlikely. If suspected, appropriate infection control measures should be instituted. The neonate should be evaluated for infection following birth.
T A B L E 2 9 – 2
Fetal Consequences of Symptomatic Maternal Rubella during Pregnancy INFECTION STAGE OF PREGNANCY (WK) 36 Total
NO. TESTED
DEFECTS
NO. POSITIVE
NO. FOLLOWED
RATE (%)
OVERALL RISK OF DEFECT (RATE OF INFECTION × RATE OF DEFECTS) (%)
10
9 (90%)
9
100
90
6 18 36 33 59 32 31 25 8
4 (67%) 12 (67%) 17 (47%) 13 (39%) 20 (34%) 8 (25%) 11 (35%) 15 (60%) 8 (100%)
4 12 14 10
50 17 50 0
33 11 24 0
53
0
0
102
20
9
258
117 (45%)
From Miller E, Cradock-Watson JE, Pollock TM: Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;2:781–784.
C HAPTER 29 • Rubella, Measles, Mumps, Varicella, and Parvovirus 495 SUMMARY OF MANAGEMENT OPTIONS
Rubella Management Options
Evidence Quality and Recommendation
References
Prepregnancy Prevent by childhood vaccination.
III/B
13
Vaccination programs for girls in their early teens contribute to prevention.
III/B
13
Serologic evaluation and, if negative, vaccination of woman inquiring about status.
III/B
13
Routine check of rubella immunity status at first visit for all women is standard practice in many centers.
III/B
13,19
Accidental vaccination in early pregnancy is not an indication for termination.
IIa/B
13,16–20
If suspected exposure in woman with immunity:
—/GPP
—
Establish validity of diagnosis serologically in index case if possible.
III/B
13
Check for appearance of IgM (acute-phase) antibodies.
III/B
13
If there is no serologic evidence of infection, reassure patient.
—/GPP
—
In early pregnancy, termination should be discussed; it may be performed immediately or only after confirmation by invasive procedure.
IIb/B
5,6
In late pregnancy, confirmation of fetal infection by invasive procedure can be considered; fetal growth and health should be monitored if infection is suspected or confirmed.
—/GPP
—
If fetal infection is suspected, cord blood should be sent for serologic confirmation.
III/C
13
If fetal infection is confirmed, careful pediatric assessment and follow-up are needed.
—/GPP
—
Prenatal
Confirm presence of rubella-specific IgG (if immediately after exposure).
●
Confirm failure of appearance of IgM (acute phase) antibodies with two serum samples 2–3 wk apart.
●
Reassure patient.
●
If suspected exposure in susceptible woman:
●
●
●
If maternal infection is confirmed serologically, options will depend on gestation at time of infection:
●
●
Labor, Delivery, and Postnatal
GPP, good practice point; Ig, immunoglobulin.
RUBEOLA Maternal and Fetal Risks Rubeola (red measles or first disease), caused by a paramyxovirus, is highly infectious and commonly attacks children. The illness is spread by respiratory droplet and may include high fever, rash, cough and rhinorrhea, conjunctivitis, and
the pathognomonic Koplik spots on the oral buccal epithelium. The incubation period is generally 10 to 14 days. The infection is usually self-limited in children.25 Rarely, the disease might be severe and might be complicated by bronchopneumonia, hepatitis, otitis media, diarrhea, or death.13,26 Encephalitis occurs in 1 of every 1000 reported cases and may lead to permanent brain damage and mental
496 S ECTION F OUR • Infection
retardation. Death, usually due to pneumonia or encephalitis, is reported to occur in 1 to 2 per 1000 cases in the United States. The fatality rate is greater in infants, young children, and adults. In addition, subacute sclerosing panencephalitis, an extremely rare degenerative disease of the central nervous system, is caused by this virus presenting years after the initial measles infection. The number of cases of measles in the United States and other industrialized countries has decreased markedly since the introduction of an effective vaccine in 1963.13,27 Still, in 1990, there were 55,000 cases and 120 measles-related deaths. This resurgence was largely due to an increase in unvaccinated preschool children, particularly in urban areas.27,28 Although data from the National Health and Nutrition Examination Survey show that the overall seroprevalence of measles IgG antibody was 95.9% between 1999 and 2004, outbreaks continue to occur.29,30 Some report that measles during pregnancy is not associated with increased maternal or fetal death rates.31 Others find higher rates of measles-related hospitalization, pneumonia, and death for infected pregnant women.32 Placental damage from the infection has been implicated in stillbirths.33 Furthermore, measles infection of mothers in developing countries is associated with an increase in the perinatal mortality rate.34 As with any febrile illness, measles infection may precipitate premature uterine activity and lead to premature delivery.35 No specific syndrome is attributed to intrauterine measles infection. However, the newborn delivered to a woman with active disease is at high risk for severe neonatal measles. Pneumonia is the primary cause of death and is more common in the premature newborn. Some reports suggest an association between in utero measles infection and postnatal development of Crohn’s disease.36 This potential relationship has yet to be confirmed and does not warrant prenatal diagnosis in the fetus.
Diagnosis The clinical diagnosis of rubeola is based on the presence of a maculopapular rash occurring 1 to 2 days after a specific exanthematous rash (Koplik’s spots), photophobia, and upper respiratory symptoms. Serologic tests can provide a definitive diagnosis. In addition, a diagnosis can also be confirmed by isolating the virus or using RT-PCR from serum or throat swabs.37
Management Options Prepregnancy Prevention is the best available mechanism to protect against measles. All children should receive one dose of the live measles virus vaccine as part of MMR between 12 and 15 months of age, followed by a second dose at age 6. Vaccination results in long-lasting immunity in over 95% of recipients. Likewise, immunity to natural infection is lifelong, and the high infectivity of the virus during childhood leaves few susceptible adults. Women contemplating pregnancy with a negative or questionable history of measles illness or vaccination or laboratory evidence of susceptibility should receive the live attenuated virus vaccine followed by a second dose not less than 1 month later. Women vaccinated before 1967 (and likely to have received a heat-killed viral vaccine), or who were vaccinated before 1 year of age, or those with equivocal serology should also receive two doses of vaccine.13 Pregnancy should be delayed 1 month after receiving MMR vaccine.
Prenatal The upper respiratory symptoms of acute measles can be ameliorated with cough suppressants. Fever, especially if high, should be treated aggressively with antipyretics. Measles pneumonia may require respiratory support, and if superimposed bacterial pneumonia develops, antibiotic therapy is required. Even when there is no life-threatening disease, pregnant women should be closely monitored during the acute illness for evidence of uterine activity. Although pregnant women are not candidates for vaccination with any live virus vaccine, accidental vaccination with rubeola vaccine is not a cause for alarm or an indication for pregnancy termination. Immune serum globulin (ISG) may be given to susceptible pregnant women exposed to rubeola in an attempt to prevent or modify the clinical expression of the disease. The intramuscular preparation (0.25 mL/kg, maximum 15 mL) should be given within 6 days of exposure.13
Labor, Delivery, and Postnatal There are no specific management recommendations for these intervals because acute disease is unlikely. Clinicians, however, should be aware of appropriate isolation precautions instituted for rubeola in the hospital. Observation of the neonate for infection is mandatory.
SUMMARY OF MANAGEMENT OPTIONS
Measles (Rubeola) Management Options
Evidence Quality and Recommendation
References
Prepregnancy Prevent by childhood vaccination.
III/B
13
Serologic evaluation and, if negative, vaccination of woman inquiring about status.
III/B
13
C HAPTER 29 • Rubella, Measles, Mumps, Varicella, and Parvovirus 497 Evidence Quality and Recommendation
References
Treat acute infection symptomatically.
—/GPP
—
Antibiotics are given if secondary bacterial infection is suspected.
—/GPP
—
Immunoglobulin should be considered for the susceptible woman exposed to the infection.
III/B
13
Inadvertent vaccination is not an indication for termination.
III/B
13
—/GPP
—
Management Options Prenatal
Labor, Delivery, and Postnatal Appropriate isolation precautions must be taken when in hospital. GPP, good practice point.
MUMPS Maternal and Fetal Risks Mumps is a contagious acute viral illness caused by a paramyxovirus, primarily infecting children and young adults. Human beings are the only recognized natural host for this pathogen. The classic presenting symptom for mumps is either unilateral or bilateral parotitis, which usually develops 14 to 18 days after exposure. Respiratory droplets typically transmit the virus. Prodromal symptoms include fever, chills, malaise, and myalgias. The disease can also remain asymptomatic in 20% of cases. Persons are considered infectious from 2 days before the onset of symptoms to approximately 9 days after the parotitis is noted. Although generally a self-limited disease with symptoms resolving within 5 to 7 days, mumps can result in significant complications, particularly in the adult population. Orchitis occurs in up to 38% of cases in postpuberal males and may lead to infertility.13 Conversely, mastitis and oophoritis have been reported in women, but infertility is rare.38 Other complications include aseptic meningitis, pancreatitis, and thyroiditis. Mumps meningoencephalitis can cause permanent sequelae such as sensorineural hearing loss, seizures, nerve palsies, and hydrocephalus.13 There are limited data on mumps in pregnancy. In a cohort study of measles, mumps, and rubella, Siegel39 reported an increased incidence of first-trimester pregnancy loss with acute mumps infection. No data suggest mumps specifically increases the incidence of stillbirths or preterm deliveries. Early studies suggested an association between endocardial fibroelastosis and mumps virus antigen; however, a clear relationship of mumps to this or other congenital malformations has not been confirmed.40 The number of reported cases of mumps in the United States has decreased dramatically since the broad institution of effective vaccination. In 1968, over 180,000 cases of mumps were reported in the United States compared with 266 cases reported in 2001.41 Most cases occurred in persons younger than 20 years. Although the presumption was that these outbreaks were due to failure to vaccinate, surveillance data suggested that there may be a waning of vaccineinduced immunity over time, allowing for susceptibility to wild virus infection.42 Hence, current recommendations,
which were enacted in 1989, include a second dose of MMR vaccine given at age 6 years. This practice has resulted in a further decline in mumps infection.43 A remaining concern is that only 38% of countries worldwide use routine mumps vaccination. Still, outbreaks occur intermittently such as the outbreak in Iowa among 605 18- to 25-year-olds in which the source is unknown but the G genotype of mumps was isolated. The latter is the same strain found in a large outbreak (>70,000 cases over 3 yr) in the United Kingdom.44 The importation of mumps into previously protected communities has become increasingly recognized.
Diagnosis The diagnosis of mumps is usually suspected based on presenting features of the disease in the appropriate clinical setting. Although the virus can be isolated in culture or by RT-PCR detection from a clinical specimen (saliva, cerebrospinal fluid, urine, or other infected organ system), the diagnosis is more typically established by serologic techniques. Enzyme immunoassay (EIA) is the most widely used methodology and is more sensitive than complement fixation or hemagglutination inhibition. Both IgM and IgG antibody testing is available. A positive mumps-specific IgM result from a reliable laboratory or a significant rise between acute and convalescent titers of IgG antibody helps establish the diagnosis of acute infection. After acute infection, it is presumed that one has lifelong immunity and persistent IgG titers.
Management Options Prepregnancy Two doses of mumps vaccine in combination with measles and rubella (MMR) are routinely recommended for children in the United States. Therefore, adequate protection against infection should be established prior to a woman reaching her reproductive years. There are no current routine recommendations to test for mumps immunity prior to conception. However, if there is reasonable concern that prior vaccination is not adequate, IgG testing can be obtained. If susceptible, a dose of MMR vaccine should be administered at least 1 month prior to attempting pregnancy.45
498 S ECTION F OUR • Infection
Prenatal Because the mumps component in MMR is a live attenuated virus, the vaccine is contraindicated in pregnancy. Because no data indicate that mumps vaccination is associated with congenital malformations or other specific adverse outcomes, the inadvertent administration of the vaccine during pregnancy is not an indication for pregnancy termination. During pregnancy, if exposure to an infected individual is reported, immediate testing for IgG antibody will in most cases confirm immunity and can be used to reassure the patient. In those individuals who lack proven immunity, postexposure immunoglobulin has not been shown to be beneficial as a prophylactic agent. Careful surveillance and symptomatic care should be instituted. Appropriate
infection control procedures should be undertaken. These procedures can be rapidly procured from hospital infection control authorities and via the CDC website.
Labor, Delivery, and Postpartum There are no specific recommendations for these periods of time because an acute outbreak is unlikely to occur. However, in suspected cases in the laboring gravida, the previously mentioned infection control measures should be started as the diagnostic workup is begun. The neonate should be carefully observed for early signs of infection manifested by parotitis or aseptic meningitis. Pediatric infectious disease consultation should be sought.
SUMMARY OF MANAGEMENT OPTIONS
Mumps Management Options
Evidence Quality and Recommendation
References
Prepregnancy Prevent by childhood vaccination.
III/B
13
Accidental vaccination is not an indication for termination.
III/B
13
If suspected exposure in woman with “immunity,” confirm presence of mumps-specific IgG.
III/B
13
—/GPP
—
Prenatal
Labor, Delivery, and Postnatal Observe neonate for parotitis or aseptic meningitis. GPP, good practice point; IgG, immunoglobulin G.
VARICELLA Maternal and Fetal Risks Varicella-zoster virus (VZV) is a member of the herpesvirus family and is the causative agent of varicella (chickenpox) and herpes zoster (shingles). Varicella is generally a mild, self-limited illness in healthy children. It is transmitted by infected secretions from the nasopharynx, by direct contact with vesicular fluids, or by airborne spread of the virus. This is followed by viral replication in regional lymph nodes and the tonsils. Viral replication continues for approximately 4 to 6 days. Primary viremia develops and virus spreads to internal organs. When the virus replicates again and is released into the bloodstream, it invades the skin, resulting in the classic viral exanthem by 14 days. Therefore, patients are infectious 1 to 2 days prior to developing this rash. The incubation period of chickenpox is 10 to 12 days. Many patients have a prodrome of fever, malaise, or myalgia a few days prior to the rash, which is vesicular and erupts in crops over the trunk, face, oropharynx, and scalp. Several crops erupt every 2 to 3 days and last 6 to 10 days. Complications are rare but may include bacterial superinfection of vesicles, pneumonia, arthritis, glomerulonephritis, myocarditis, ocular disease, adrenal insufficiency, and central nervous system abnormalities.46
Retrospective studies suggest that varicella pneumonia in pregnant women is more severe than in nonpregnant adults.47 In a case-control study, smoking and the occurrence of 100 or more skin lesions were risk factors for developing pneumonia.48 A pregnant woman with varicella and cough, dyspnea, fever, or tachypnea warrants immediate attention. Pneumonia generally develops within a week of the rash and may rapidly progress to hypoxia and respiratory failure. The mortality rate in untreated varicella pneumonia in pregnancy exceeds 40%.49 If treated aggressively with intravenous acyclovir and supportive measures, reported mortality rates are less than 15%, but patients may still require intubation and ventilatory support.50 Congenital varicella syndrome (CVS) is characterized by dermatomal scarring; ocular abnormalities such as cataracts, chorioretinitis, and microphthalmia; low birth weight; cortical atrophy; and mental retardation (Table 29–3). Most cases occur in infants whose mothers were infected between 8 and 20 weeks’ gestation. However, the number of cases is low. Data compiled from multiple retrospective cohort studies have determined the rate of embryopathy is approximately 2%.51–54 In fact, in a prospective study of 347 varicella-infected mothers, the incidence of CVS was 3 per 231 births (1.3%; 95% confidence interval [CI] 0.3–0.7) where follow-up was complete.55 In a study of babies who were
C HAPTER 29 • Rubella, Measles, Mumps, Varicella, and Parvovirus 499 T A B L E 2 9 – 3
Fetal Abnormalities Associated with Congenital (Intrauterine) Varicella Infection Cutaneous scarring Limb hypoplasia Missing/hypoplastic digits Limb paralysis/muscle atrophy Psychomotor retardation Convulsions Microcephaly Cerebral cortical atrophy Chorioretinitis Cataracts Chorioretinal scarring Optic disk hypoplasia Horner syndrome Early childhood zoster
However, despite detection of virus, the presence of embryopathy cannot be predicted.
Management Options Prepregnancy Varivax, a live attenuated varicella vaccine, is recommended for susceptible children under age 13 and susceptible adults.60 The vaccine is given in two doses 4 to 8 weeks apart, and approximately 82% of adults will seroconvert. Women should avoid pregnancy for at least 1 month after vaccination. Results from a voluntary registry of Varivax administered in early pregnancy gathered between 1995 and 2005 revealed no cases of CVS among 131 live births.61 Thus, inadvertent Varivax exposure should not prompt medical recommendations for pregnancy termination.
Pregnancy exposed in utero to primary varicella and did not develop CVS, there appeared to be no differences in neurobehavioral outcomes when compared with uninfected controls.56 Neonatal varicella generally occurs in neonates born to mothers who are infected with varicella within 2 weeks of delivery.57 It is a serious illness characterized by fever and vesicular rash, which resolves, but in some cases, disseminated disease or visceral involvement may ensue. In the latter, the mortality rate may be as high as 25%. Herpes zoster or shingles, which arises from reactivated VZV, which had been dormant in the dorsal root ganglia, does not lead to CVS.
Diagnosis Varicella is usually diagnosed clinically based on the characteristic exanthem. Culture of the vesicular fluid is a lengthy process. Serologic tests are useful to document immunity (when IgG is present) in a patient immediately following exposure. IgM antibody specific to VZV may be identified as soon as 3 days after the onset of symptoms in an acutely infected gravida. IgG seroconversion can be seen by 7 days after VZV symptom onset. Paired sample analysis for IgG may be useful to establish the diagnosis of primary infection. Prenatal diagnosis of varicella is possible. Ultrasonography may detect limb abnormalities, and fetal blood or amniotic fluid may be tested for VZV antibody or DNA.58,59
Varicella zoster immunoglobulin should be administered to pregnant women who are susceptible to VZV and are exposed to varicella or herpes zoster. The only product currently available is VariZIG, an investigational varicella immune globulin product that may be obtained under expanded access following patient consent.62 VariZIG should be administered with 48 hours of exposure but may be effective up to 96 hours. Although it diminishes the severity of maternal disease, there is no evidence that VariZIG prevents congenital varicella. If a pregnant woman becomes infected with chickenpox, she may be offered oral acyclovir to decrease the number of febrile days and shorten the duration of active lesions.63 As previously noted, parenteral antiviral therapy is indicated in cases of varicella complicated by pneumonia or central nervous system involvement.
Labor, Delivery, and Postnatal There are no specific management recommendations for labor. Infected pregnant women should be placed in a negative-pressure room for labor, delivery, and the postpartum period in accordance with infection control protocols. Neonates should be given VariZIG after birth and monitored closely because the neonate at greatest risk for chickenpox is born within 4 days prior to or 2 days after maternal chickenpox.62 A small study of 24 prenatally infected newborns suggests that VariZIG in conjunction with intravenous acyclovir is a more effective prevention strategy than VariZIG alone.64
SUMMARY OF MANAGEMENT OPTIONS
Varicella-Zoster Virus Infection Management Options
Evidence Quality and Recommendation
References
Prepregnancy Prevent by childhood vaccination.
III/B
60
Vaccinate susceptible adults.
IV/C
60
—/GPP
—
Prenatal If mother exposed to VZV, check immunity status.
500 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Varicella-Zoster Virus Infection—cont’d Evidence Quality and Recommendation
Management Options If mother is IgG-negative (susceptible), give VariZIG within 96 hr of exposure.
References
IV/C
60,62
Counsel about minimal fetal risks.
IIa/B
51–57
Offer acyclovir to decrease lesions.
IIa/B
63
Monitor for signs of pneumonia or disseminated infection.
III/C
47–50
Take appropriate infection control measures.
—/GPP
—
Evaluate newborn clinically and serologically.
—/GPP
—
Administer active or passive immunization to neonate if not infected.
IV/C
60,62
If mother develops chickenpox:
●
●
●
Labor, Delivery, and Postnatal
GPP, good practice point; IgG, immunoglobulin G; VZV, varicella-zoster virus.
PARVOVIRUS B19 Maternal and Fetal Risks Human parvovirus B19 (erythema infectiosum, fifth disease) is an infectious exanthematous childhood illness transmitted by droplet. Parvovirus B19 viremia occurs 6 to 8 days after exposure and may persist for up to a week. An infected individual is contagious before the onset of symptoms, and the virus can be detected in the blood or secretions as early as 5 to 10 days after exposure. Parvovirus B19 infection is characterized by fever, rash, and arthropathy. The rash has a “slapped cheek” appearance on the face and a “lacelike” appearance on the trunk and extremities. The arthropathy may affect the joints of the hands, wrist, knees, and ankles. In addition, the virus may cause aplastic crisis in patients with sickle cell disease65 and other hemolytic states,66 chronic bone marrow failure in patients with immunodeficiency,67 a chronic arthropathy,68 and the childhood illness fifth disease (erythema infectiosum).69 Parvovirus B19 infection preferentially infects rapidly dividing cells and is cytotoxic for erythroid progenitor cells.70,71 As a result, B19 virus also may stimulate a cellular process involving programmed cell death.72 Parvovirus B19 infections during pregnancy might rarely be associated with fetal loss or hydrops fetalis. The risk of fetal loss appears highest in the first 20 weeks of pregnancy. In a prospective study of 186 pregnancies with confirmed parvovirus B19 infection, there were 27 first-trimester spontaneous abortions versus 7 abortions or fetal deaths in the second trimester and only 1 death in the third trimester.73 Several additional series of parvovirus infection in pregnancy have been reported. When these series are summarized, the risk of fetal loss among pregnancies infected prior to 20 weeks’ gestation is approximately 10%.74–76 The risk of loss after 20 weeks’ gestation is less than 1% and the risk of hydrops is 0.3%.77 A prospective study of 618 exposed pregnancies showed no hydrops or fetal death attributable to B19 in 52 babies born to infected mothers.78 The hydrops may develop rapidly
within 7 to 14 days and can either lead to fetal death or resolve spontaneously.79 In the largest prospective study of 1018 women with acute parvovirus infection, 6.3% of pregnancies ended with fetal death, and all were infected prior to 20 weeks’ gestation.80 The rate of death in the first trimester was 13% (34/256 < 12 weeks’ gestation); 9% (30/222 13–20 weeks’ gestation); and 0/439 after 20 weeks’ gestation. There were a total of 6 stillbirths, 4 prior to 24 weeks’ gestation and 2 at term. These term deaths were not attributed to B19. Although B19 infection appears to be teratogenic in fetal animals (cerebellar hypoplasia and ataxia in cats and anencephaly, microcephaly, facial defects, and ectopic hearts in hamsters have been described), epidemiologic studies do not suggest that B19 infection is teratogenic in human fetuses.81 Furthermore, long-term follow-up of offspring of women with B19 infections suggests the children are normal.82,83 Parvovirus B19 infection is distributed worldwide. Antibody to B19 virus occurs in 30% to 60% of adults.84,85 Secondary attack rates for household contacts may be as high as 50% but as low as 20% to 30% for classroom contacts.86 Serologic surveys of pregnant women revealed that 35% to 65% are B19-seropositive.75,78 In one large study during an epidemic, the risk of seroconversion for pregnant women was highest in those with the greatest exposure to young children.87
Diagnosis B19 virus is difficult to culture, and clinical manifestations are often lacking. Serology is the easiest method to detect infection using either IgM antibody capture radioimmunoassay or ELISA. These tests will detect between 80% and 90% of B19 seropositive individuals.88 IgM, indicating acute infection, can be detected approximately 10 days after exposure and can last for 3 months or longer.89,90 IgG antibodies may be detected several days after IgM and can persist for years as markers of past infection. Polymerase chain reaction
C HAPTER 29 • Rubella, Measles, Mumps, Varicella, and Parvovirus 501
(PCR) to detect small amounts of B19 virus is useful to diagnose in utero infection from amniotic fluid.91–93 In cases of unexplained hydrops, the presence of B19 DNA in maternal blood is useful for diagnosis, although avidity testing and EIA for specific parvovirus IgG epitope might be more useful for timing of infection.94 Additional methods such as electron microscopy, detection of viral DNA, and hybridization assays for nucleic acids may be useful for pathologic specimens in the evaluation of stillbirths.
Management Options Prepregnancy Immunocompetent adults rarely need treatment; however, patients at risk for hemolysis may need multiple transfusions.
Prenatal Pregnant women following exposure to B19 virus should have immediate serologic testing. Presence of IgG and absence of IgM suggests prior exposure to B19 virus and that the fetus is protected from infection. If the IgG is negative or positive and the IgM is positive, this finding is consistent with acute infection. Women should be counseled about the low risk of fetal loss in the first trimester and low risks of hydrops or stillbirth in the second and third trimesters. Prior to 20 weeks’ gestation, no further action is required. However, after 20 weeks’ gestation, periodic ultrasound examinations may be useful to identify hydrops. In addition,
Doppler studies of the fetal middle cerebral artery peak velocity may yield an accurate reflection of fetal anemia.95 In some reported cases, hydrops did not appear until 8 weeks following maternal infection; hence, the recommendation to continue monitoring for 8 to 12 weeks after infection.96 If hydrops is noted, percutaneous umbilical blood sampling may be warranted to determine fetal hematocrit and provide transfusion.97,98 Although some small series show improvement following transfusion, other reports note spontaneous resolution in the absence of intervention.99,100 Further discussion of fetal hydrops can be found in Chapter 24. The pregnant woman who is IgG-negative and IgM-negative is susceptible to infection. She should be counseled that repeat testing may be required if her serologic results were obtained within 2 weeks of her exposure. Preventive measures include minimizing contact with known parvovirus infection and good contact precautions. According to the CDC, there is no proven benefit to removing seronegative women from high risk employment for the duration of the pregnancy.
Labor, Delivery, and Postpartum Onset of signs and symptoms suggesting acute infection during these time periods requires appropriate infection control measures. The neonate should be carefully observed for vertical transmission of the infection. Neonatal IgG levels immediately after birth reflect transplacentally passed maternal immunoglobulin.
SUMMARY OF MANAGEMENT OPTIONS
Parvovirus B19 Infection Management Options
Evidence Quality and Recommendation
References
Prepregnancy If the diagnosis is confirmed before pregnancy, avoid contraception until clinical cure and antibody response.
—/GPP
—
If mother is exposed to B19 parvovirus or symptoms are noted, check immunity status.
—/GPP
—
If mother is IgG-negative/IgM-negative (susceptible), repeat testing in 3–4 wk.
—/GPP
—
Counsel that risks are small.
IIb/B
73–78,80
If greater than 20 wk, screen with serial ultrasound for hydrops.
III/B
73–77
If hydrops is detected, consider intrauterine fetal transfusion.
III/B
97,98
Prenatal
If mother is IgG-negative/IgM-positive:
●
●
●
Labor, Delivery, and Postnatal Take appropriate infection control measures.
—/GPP
Evaluate newborn clinically and serologically.
—/GPP
GPP, good practice point; Ig, immunoglobulin.
— —
502 S ECTION F OUR • Infection
SUGGESTED READINGS American College of Obstetricians and Gynecologists: Immunization during pregnancy (ACOG Committee Opinion No. 282). Obstet Gynecol 2003;101:207–212. Centers for Disease Control and Prevention: A new product (VariZIG(tm)) for postexposure prophylaxis of Varicella available under an investigational new drug application expanded access protocol. MMWR Morb Mortal Wkly Rep 2006;55:209–210. Centers for Disease Control and Prevention: Rubella and congenital rubella syndrome—United States, 1994–1997. MMWR Morb Mortal Wkly Rep 1997;46:350–353. Davidkin I: Persistence of measles, mumps, and rubella antibodies in an MMR-vaccinated cohort: A 20 year follow-up. J Infect Dis 2008;197:950–956. Enders G, Miller E, Cradock-Watson J, et al: Consequences of varicella and herpes zoster in pregnancy: Prospective study of 1739 cases. Lancet 1994;343:1547–1550.
Enders M, Weidner A, Rosental T, et al: Improved diagnosis of gestational parvovirus B19 infection at the time of nonimmune fetal hydrops. J Infect Dis 2008;197:58–62. Enders M, Weidner A, Zoellner I, et al: Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn 2004;24:513. McQuillan GM, Kruszon-Moran D, Hyde TB, et al: Seroprevalence of measles antibody in the US population, 1999–2004. J Infect Dis 2007;196:1459–1464. Siegel M: Congenital malformations following chickenpox, measles, mumps, and hepatitis: Results of a cohort study. JAMA 1993;226:1521–1524. Wilson E, Goss MA, Marin M, et al: Varicella vaccine exposure during pregnancy: data from 10 years of the Pregnancy Registry. J Infect Dis 2008;197(Suppl 2):S178–S184.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 3 0
Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus THOMAS ROOS and DAVID ALLAN BAKER
INTRODUCTION Viral infections can pose a serious threat to the fetus and the newborn. In the healthy adult, infections might be asymptomatic or cause only mild unspecific symptoms. Some viruses may reside dormant for prolonged periods, and asymptomatic virus shedding may occur unnoticed. Viruses can be transmitted by trivial interpersonal contacts such as occurs when handling a baby (cytomegalovirus [CMV], herpes simplex virus [HSV], adenovirus, coxsackievirus) or in a swimming pool (adenovirus). Sexual activities with multiple partners confer a high risk for infection with some viruses associated with severe disease in the adult and in the infant. Pregnancy is associated with decreased maternal cellmediated immunity to viral infections; thus, the pregnant woman and her fetus are theoretically at increased risk for serious illness. Depending on gestational age, transplacental viral infection may range from asymptomatic to severe, causing fetal or neonatal death or long-term sequelae in the survivors. Intrauterine growth restriction (IUGR), nonimmune hydrops, isolated ascites, intracranial calcifications, microcephaly, and hydrocephaly are common ultrasound findings associated with some in utero viral infections. The possible severe impact of viral infections and the lack of specific antiviral treatment options in the fetus and newborn available to date imply that prevention is the most important approach to disease containment. The development of antiviral drugs and vaccines in progress holds the promise of a reduced incidence of fetal viral infections and of their sequelae in the future.
CYTOMEGALOVIRUS General CMV, a DNA virus, is a member of the herpes family of viruses, which causes a number of infectious syndromes in humans. However, because CMV is highly efficient in
remaining dormant or silent in the host, the most common manifestation of CMV infection in humans is the lack of demonstrable disease. Three disease states are particularly important: intrauterine and neonatal infection, heterophilnegative mononucleosis, and infection in the immunocompromised patient.
Diagnosis Human CMV is readily grown in cell lines of human fibroblasts. In patients with symptoms suggestive of acute CMV infection, viral culture from urine, nasopharynx, or blood may document the presence of the organism. Direct immunofluorescence tests in combination with a limited culture can detect the virus more rapidly. More recently, nucleic acid amplification systems using polymerase chain reaction (PCR) techniques have been used to identify the virus in amniotic and other fluid samples and in dried newborn blood.1–4 High numbers of virus copies in the amniotic fluid can possibly signal a fetus at risk for severe CMV disease; however, this relationship remains controversial.5–7 Viral load detected in newborn dried blood spot test might indicate children at increased risk of sensoneurinal hearing loss.8 Tissue specimens (biopsy, necropsy) may also be evaluated for virus by immunofluorescence, in situ hybridization, or PCR techniques,9 thus, providing a better understanding of fetal CMV infection mechanisms.10,11 Because many previously infected patients excrete CMV intermittently throughout their lives depending on certain circumstances (e.g., pregnancy, immunosuppression), the presence of CMV in a specimen does not automatically confirm that the illness in question is caused by this particular virus. The physician must be extremely careful with the interpretation of these results. Approximately 50% of reproductive age women have antibody to CMV. Thus, paired specimens are necessary if seroconversion from negative to positive has not been documented. A significant rise in titer is usually consistent with 503
504 S ECTION F OUR • Infection
a primary infection. Immunoglobulin M (IgM)–specific antibody is usually present 4 to 8 weeks after a primary infection but can increase periodically or persist at a low titer for years. IgM and, less frequently, IgA are of use in distinguishing transplacental transfer of maternal antibodies in the diagnosis of congenital infection.12 Serologic testing consists of the older complement fixation test or the more current indirect fluorescent antibody (FA) and anticomplement immunofluorescent tests. In a primary infection, these tests become positive sooner than the complement fixation test.13 Enzyme immunoassay (EIA) methods also have been used to detect CMV-specific IgG, IgM, IgA, and IgE antibodies.14 This is important because reactivation of latent CMV during pregnancy may be accompanied by either an increase or a reappearance of IgM antibodies (depending on the methodology used), which theoretically would help differentiate it from new infection.15 More recently, more labor-intensive EIA assays have been used to detect low-avidity IgG antibodies that are produced early in infection.16–18 In one study, CMV immediate-early messenger RNA in maternal blood was detected only in cases of primary CMV infection and not in immune subjects; thus, this later EIA test has been suggested to be helpful in differentiating primary from recurrent infection.19 Isolation of the virus or DNA from amniotic fluid and demonstration of viral DNA, immunologic response, or nonspecific markers in fetal blood collected by cordocentesis have all been used to supplement antenatal diagnosis.20–23 A prospective evaluation of 1771 pregnant Belgian women by serial serology and culture of urine, saliva, and cervical secretions at each prenatal visit revealed a seronegative rate of 49%.24 Of this group, seroconversion occurred in 20 susceptible women (2.3%). Five of the 7 who agreed to cordocentesis and amniocentesis had positive amniotic fluid cultures for CMV; 3 had a positive fetal IgM for CMV. The presence of CMV in fetal tissue was confirmed after termination, supporting the authors’ contention that amniotic fluid culture is superior to fetal IgM in diagnosing fetal infection.24 Others have reported either a lack of fetal CMV seropositivity for IgM in culture-positive fetuses or the failure of the fetus to sustain the IgM response. Thus, amniotic fluid culture or PCR analysis of amniotic fluid is superior to fetal CMVspecific IgM.25,26 There have been a few reports of falsenegative amniotic fluid cultures, as ascertained by neonatal shedding, but the relationship of these apparently negative results to the timing of infection and to long-term sequelae is unclear. Culture failure may be related to performance of amniocentesis too close to the time of initial maternal infection or too early in gestation, that is, before the fetal kidneys produce sufficient amounts of urine containing shedded virus.27,28 The best results for detecting congenital CMV infection by testing amniotic fluid samples occur when amniocentesis is performed after 21 weeks’ gestation and after an interval of at least 6 weeks from the first diagnosis of maternal infection.29,30 Sensitivity to CMV can be enhanced using PCR or nested PCR assays.16,31 Nested PCR technique has effectively been applied in a dried blood spot test of newborn Guthrie card in a trial evaluating newborn CMV screening.4 Because all of these techniques can produce false-negative results, a negative diagnostic workup does not guarantee absence of infection.
Detection of specific IgM in fetal blood has been found to be associated with severe CMV disease.29 Some, but not all, infected fetuses have sonographic abnormalities (e.g., intracranial calcifications, growth restriction), anemia, thrombocytopenia, and elevated liver function test results.20,32 The natural history of the disease was followed antenatally by serial ultrasound and cordocentesis in at least one reported case.33 Hyperechoic bowel may precede development of ventriculomegaly, IUGR, nonimmune hydrops, and fetal death in infected fetuses.34 In a group of 50 pregnant women (51 fetuses) with primary CMV infection and confirmed in utero transmission, abnormal fetal ultrasound findings could be demonstrated in 22% (11 of 51 fetuses). In the same study, 3 out of 16 newborns (19%) with normal ultrasound findings had neurologic abnormalities.35 Thus, normal midtrimester ultrasound findings in infected fetuses can exclude neither an abnormal ultrasound later in pregnancy or the birth of a severely affected child. Recently, in addition to ultrasonography, magnetic resonance imaging (MRI) in proven CMV-infected fetuses has demonstrated to be helpful in providing additional information on gyration, cerebellar hypoplasia, and changes in the white matter of the fetal brain. However, MRI may not detect brain anomalies in cases of normal ultrasound findings; thus, MRI is not recommended as a first-line diagnostic procedure in evaluating CMV-infected fetuses.36,37
Maternal and Fetal Risks Approximately 10% of healthy adults infected with CMV for the first time may develop a syndrome of fever, atypical lymphocytosis, malaise, and mild lymphadenopathy, which generally follows a benign course. This illness is clinically indistinguishable from Epstein-Barr virus (EBV) mono nucleosis, save that the heterophil-antibody test is negative in patients with CMV infection. Patients with CMV mononucleosis tend to be slightly older than patients with EBV infection. This syndrome is generally self-limiting, although the fever may last for over a month. Serious complications of the acute infection rarely occur, including interstitial pneumonitis, hepatitis, Guillain-Barré syndrome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia.38 The virus may be excreted in tears, saliva, breast milk, cervical secretions, and urine for weeks, months, or years after a primary infection. A latency period eventually occurs, but reinfection and reactivation are common.39 CMV infection in the immunosuppressed patient can be serious, depending on the type and degree of immunosuppression.40 Patients on immunosuppressive drugs because of organ transplantation or patients with AIDS most commonly exhibit the mononucleosis syndrome. The next most frequent manifestation is interstitial pneumonia, which may progress rapidly from asymptomatic to fatal disease (often in association with Pneumocystis infection in AIDS patients). A large percentage of persons suffering primary CMV infection exhibit hepatitis; severely immunosuppressed patients may develop clinical symptoms, including malaise, nausea, and vomiting. Gastrointestinal disease, including ulceration leading to hemorrhage and perforation, is another effect of CMV in the immunocompromised patient. The AIDS patient may suffer coexistent CMV infection with other infections such as cryptosporidiosis and Mycobacterium
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 505
avium-intracellulare. In fact, endoscopic examination of the AIDS patient with colitis due to CMV may demonstrate lesions that resemble Kaposi’s sarcoma. Finally, in the AIDS patient specifically, CMV infection of the eye may produce retinitis, typically noted in neonates with the disease, and miscellaneous effects on endocrine organs, including adrenals, pancreas, parathyroids, pituitary, and ovaries. Venereal spread of CMV is conceptually attributed to the presence of virus in the semen and to cervical shedding. CMV has been isolated from semen of both homosexual and heterosexual men.41 Heterosexual transmission has been demonstrated by outbreaks of CMV mononucleosis among populations of sexual partners.42 Aside from the fact that differences in rates of cervical shedding are noted in different patient groups throughout the world, it is fairly clear that sexual activity, in particular higher numbers of sexual partners and earlier age at onset of sexual activity, is positively correlated with CMV isolation from the cervix.43 Whereas CMV is transmitted by such routes as transfused blood44 and bone marrow,45 a common route of acquisition is through perinatal transmission. The fetus may be infected either transplacentally or by exposure to the virus from the cervix and birth canal. The neonate may also be infected by virus excreted in breast milk46; however, the risk appears to be low.47,48 Another source of childhood infection is exposure to other babies in nurseries and daycare centers,49–51 because infected children tend to shed virus from the urine and respiratory tract for a prolonged time (unlike infected but otherwise healthy adults). The rate of seropositivity varies by age and multiple demographic factors. The rate increases steadily after the first year or two of life. The prevalence is higher in underdeveloped countries52 and in lower socioeconomic patient populations.53 One study of over 21,000 women attending a prenatal clinic in London revealed marked variation by race (white, 46%; Asian, 88%; black, 77%), parity (increasing seropositivity with increasing parity), and socioeconomic status.54,55 Among most middle-income women in Alabama, 54% were seropositive, with whites having a lower rate than blacks.53 The incidence of seroconversion in women of childbearing age approximates 2% in high socioeconomic groups and up to 6% in lower socioeconomic groups. The higher infection rate in young adults (hence mothers) does not necessarily lead to higher congenital infection rates.56 Primary infection occurs in 1% to 3% during pregnancy, with approximately 40% to 50% of women of childbearing age being serologically determined to be susceptible to such primary infection.53,57 Estimates are that each year in the United States, approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection.58 Serologic or culture evidence of in utero CMV infection is present in 0.2% to 2.2% of all liveborns. Thus, congenital CMV infection is a major health problem; CMV is still thought to be the most common congenital infection in the United States based on serologic study.39,59,60 Unlike other viral infections, CMV, on the basis of its latency and intermittent shedding from the female genital tract, may infect a fetus or neonate despite the presence of maternal antibody. Virus is shed from the cervix more
readily as gestation progresses and occurs in approximately 0% to 2% of women in the first, 6% to 10% in the second, and 11% to 28% in the third trimester.13 The infection rates at birth are higher in newborns whose mothers excrete virus. The most severe neonatal disease usually occurs in children born to women who experience primary infection during pregnancy. Vertical transmission of CMV occurs in 21% to 50% of fetuses following primary maternal infection.29,30,61 A study of preconceptional and periconceptional primary CMV infection in 25 women identified a 9% risk for congenital fetal infection in the preconceptional group (1 of 12 newborns) and a 31% risk in the periconceptional group (4 of 13 newborns).62 Naturally acquired immunity results in a 69% reduction in the risk of congenital CMV infection in future pregnancies.63 In addition, severe transplacental infection is not usually seen in children of women with preexisting antibody.64 However, maternal preconceptional immunity to CMV does not provide complete fetal protection, and secondary CMV infection might cause severe sequelae in the fetus.65–67 Thus, sonographic findings suggestive of CMV infection should prompt further investigation even if maternal serology does not support recent maternal infection. CMV infection occurs in approximately 1 of 150 newborn infants. In the United States, this results in an estimated 33,000 infected newborns annually68–70; in the United Kingdom, CMV causes much more neonatal disease than rubella.59 Approximately 5% to 10% of infected newborns are clinically symptomatic at birth. This is one of the classic TORCH (toxoplasmosis, other infections, rubella, CMV infection, and HSV) syndromes, consisting of hepatosplenomegaly, hyperbilirubinemia, petechiae, thrombocytopenia, intracranial calcifications, microcephaly, and often growth restriction. In primary infection, mortality may be as high as 20% to 30%, with 90% of survivors suffering late complications (Fig. 30–1) using “averaged” published data.71 Of the asymptomatic infected neonates, 5% to 15% develop some abnormality attributable to CMV before their second birthday, primarily sensorineural hearing loss.60,72 Vertical transmission may also occur in recurrent CMV infection73; however, the percentage of symptomatic children at birth or of those developing sequelae is much lower (Table 30–1).74 CMV is the most common cause of congenital sensorineural hearing loss, developing in 30% of neonates symptomatic at birth.75 Hepatosplenomegaly is the most common clinical finding. Microcephaly, frequently associated with paraventricular cerebral calcifications, is also common.76 Chorioretinitis, optic atrophy, mental and psychomotor delay, learning disabilities, and dental abnormalities are reported. Overall, congenital CMV infection leads to severe sequelae in 1 of 750 newborn infants, affecting close to 8000 children annually. Thus, congenital CMV infection is the most common cause of birth defects and childhood disabilities. Better-known childhood disabilities such as Down syndrome affect approximately 4000 children per year, fetal alcohol syndrome approximately 5000 infants per year, and spina bifida approximately 3500 newborns annually. Public and physicians awareness of these conditions are high compared with congenital CMV disease.68–70 In a recent survey, 44% of obstetrician-gynecologists counseled their patients on preventing CMV infection, emphasizing the need for
506 S ECTION F OUR • Infection Pregnant women of higher income group
55% immune
Pregnant women of lower income group
45% susceptible
0.15% congenital infection (recurrent maternal infection)
15% susceptible
40% transmit infection to fetus
10–15% infected infants may have clinically apparent disease (mild to severe)
10% develop normally
0.5–1% congenital infection (recurrent maternal infection)
1–4% primary infection
0–1% infected infants may have clinically apparent disease or sequelae
90% develop sequelae
5–15% develop sequelae
Sequelae in Children with Congenital Cytomegalovirus Infection According to Type of Maternal Infection
IQ < 70 Death
0–1% infected infants may have clinically apparent disease or sequelae
85–90% infected infants are asymptomatic
T A B L E 3 0 – 1
Symptomatic disease at birth Any sequelae More than one sequela Sensorineural hearing loss Bilateral hearing loss Microcephaly Seizures
85% immune
PRIMARY
RECURRENT
24/132 (18%) 31/125 (25%) 7/125 (6%) 18/120 (15%) 10/120 (8%) 6/125 (5%) 6/125 (5%) 9/68 (13%)
0/65 (0%) 5/64 (8%) 0/64 (0%) 3/56 (5%) 0/56 (0%) 1/64 (2%) 0/64 (0%) 0/32 (0%)
3/125 (2%)
0/64 (0%)
From Fowler KB, Stagno S, Pass RF, et al: The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 1992;326:663–667.
additional training.68 In a different study, only 14% of women had heard of CMV, indicating the potential of preventional behavior education.77
Management Options Treatment of acute, symptomatic CMV infection in the immunocompetent normal individual is palliative. The vast majority of infections are asymptomatic; the remainder are mild. Currently, eradication of the virus is beyond the capacity of modern medicine. In the patient with compromised immunity, such as the transplant patient or the patient with AIDS, the antiviral drug ganciclovir provides temporary relief
FIGURE 30–1 Infant outcome following cytomegalovirus (CMV) maternal infection in pregnancy. 85–95% develop normally
(Adapted from Stagno S: Cytomegalovirus. In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, 4th ed. Philadelphia, Saunders, 1995, p 322.)
from such severe effects as retinitis.13 To date, there is no accepted therapy for acute maternal or neonatal infection.78 There is progress in the development of a specific CMV vaccine,79 although a number of real and theoretical obstacles remain.80 Even though complete eradication of the virus may appear unlikely, antibody presence similar to that after primary human infection could reduce the rate of congenital fetal infection and its sequelae. Thus, an effective CMV vaccine will be a significant step forward. Passive immunization with specific anti-CMV immunoglobulins appears to be useful as prophylaxis in cases of renal and marrow transplantation.81 Thus, prevention of maternal infection is clearly the strategy to avert intrauterine infection. Three different areas offer potential to reduce the likelihood of maternal CMV infection in pregnancy: patient education, physician education, and vaccine development. CMV is typically spread by interpersonal contact with transmission of infected secretions from person to person, so, in particular, pregnant women working in high risk situations (e.g., daycare centers) should be counseled to wash their hands carefully after changing diapers and after any contact with children’s secretions (e.g., saliva).78,82 Mouth-to-mouth kissing with children should be discouraged. Physicians need to be aware of the risk of transfusion-related CMV transmission.83 Thus, when transfusing women of childbearing age who could potentially be or soon become pregnant, CMV-negative blood products should be used whenever possible. Any fetal transfusion in utero must use CMV-negative washed packed cells to avoid fetal CMV contamination. It is not appropriate, however, to screen all pregnant women for either anti-CMV IgG or viral excretion with the aim of isolating them for the duration of the pregnancy. The most reasonable course is to serologically screen all women in high risk areas (e.g., daycare workers) and recommend to susceptible individuals
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 507
that they pay attention to hygiene measures. For prevention of CMV as well as other sexually transmitted diseases (STDs), all women with nonmonogamous relationships should be strongly encouraged to use condoms during sexual contact.78 No effective fetal therapy is yet available. Ganciclovir has been administered into the umbilical vein of a fetus at about 27 weeks. The dosage was 10 mg/day for 5 days, 15 mg/day for 3 days, and 20 mg/day for 4 days. Several episodes of bradycardia were noted after administration. Although the viral load in amniotic fluid decreased dramatically over the time of treatment and liver function tests improved, a fetal demise was noted at 32 weeks.84 Antiviral treatments in pregnant women have been performed only on a small scale and with moderate effect.85,86 Toxicity and costeffectiveness are the main concerns. CMV hyperimmuno-
globulin therapy in women with primary CMV infection during pregnancy appears to be promising in reducing CMV disease in the infants; however, the effectiveness and safety of this treatment await results of an international trial under way.87–89 Therapy of severely infected newborns with antiviral drugs had only a moderate effect.90 In the absence of safe and effective treatment of fetal CMV infection, prevention through education of patients and physicians remains the most effective means to reduce the incidence of congenital CMV disease to date. Assessment of effective newborn screening is the next step in order to early identify infants at risk for CMV disease and to reduce sequelae. Advances in the development of vaccines are promising; however, a licensed CMV vaccine appears to be years away.
SUMMARY OF MANAGEMENT OPTIONS
Cytomegalovirus Evidence Quality and Recommendation
Management Options
References
Prepregnancy Advise women working in high risk environment (e.g., child care) about risks.
III/B
50,78,82
Counsel pregnancy planning in women with history of proven CMV infection
—/GPP
—
—/GPP
—
Encourage use of condoms in nonmonogamous relationships.
IV/C
78
Use CMV-negative blood products in transfusions.
IV/C
83
Advise women working in high risk environment (e.g., child care) about risks.
III/B
50,78,82
Use CMV-negative blood products in transfusions.
IV/C
83
If patient is diagnosed to have CMV infection in pregnancy:
—/GPP
—
IV/C
13,84,85, 88,89
—/GPP
—
Establishing their “shedding status” may help.
●
Prenatal
Offer careful counseling about fetal risks.
●
●
●
●
●
Consider invasive procedure to establish fetal risk. Check fetal growth and health. Consider pregnancy termination (if early gestational age). No effective treatment, although acyclovir, ganciclovir, valaciclovir, CMV-specific hyperimmunoglobulin have been used.
Labor, Delivery, and Postnatal If patient is diagnosed to have CMV infection in pregnancy: Put infection control measures in place.
●
Conduct clinical and serologic evaluation of the newborn with pediatric follow-up if infection confirmed.
●
CMV, cytomegalovirus; GPP, good practice point.
HERPES SIMPLEX VIRUS General HSV is a DNA virus of the herpes family. HSV-1 has classically been considered the cause of orolabial herpes, referred to commonly as fever blisters; HSV-2 has been considered the cause of genital herpes infection, a well-known STD. Although these two types of HSV are generally thought to
be segregated in this way, there is a great deal of overlap, that is, of HSV-2 causing oral disease and HSV-1 causing genital infection. In fact, up to a third of genital infections may be due to HSV-1. However, HSV-1 is somewhat less prone to produce recurrent infection than HSV-2. Generally, the two viruses may be considered identical in the clinical circumstance of a patient with characteristic ulcerative lesions.91
508 S ECTION F OUR • Infection
Diagnosis HSV is relatively easy to culture; viral culture is the preferred test of genital HSV infection in patients who present with genital ulcers. The sensitivity of culture declines rapidly as lesions begin to heal, usually within a few days of onset. When more rapid diagnosis is desirable, FA staining performed on short-incubation tissue culture slides allows identification within 48 hours, especially when the original specimen contains large numbers of virus. In high-inocula situations, direct FA staining of the original specimen may give the diagnosis, though it is neither as sensitive nor as specific as tissue culture.92,93 PCR assays for HSV DNA are highly sensitive and can be used to rapidly detect HSV DNA in pregnant women.94 Type-specific antibodies to HSV develop during the first 6 to 8 weeks after infection and persist indefinitely. Accurate type-specific assays must be based on the HSV-1–specific glycoprotein G1 for diagnosis of infection with HSV-1 and on the HSV-2–specific glycoprotein G2 for diagnosis of infection with HSV-2.95,96 Sensitivity of serology tests vary between 80% and 90%, and false-negative results may occur, especially at early stages of infection. Specificity is greater than 96%, and false-positive results can occur. Thus, repeat testing may be indicated in some settings. Type-specific serology in combination with HSV culture and DNA testing by PCR might prove helpful in confirming a clinical diagnosis of genital herpes, especially in patients with healing sores or recurrent episodes of genital herpes when HSV culture provides false-negative results.97 Clinical examination is likely to miss many cases of genital herpes,98 and antepartum cultures do not predict viral shedding at the time of delivery.99 The Centers for Disease Control and Prevention (CDC)95 provides guidelines on the use of type-specific serologic tests. The CDC recognize the significance of using serologic testing: (1) to confirm clinical diagnoses, (2) to diagnose people with unrecognized infection, and (3) to manage sex partners of persons with genital herpes. Because cultures are frequently false-negative, serologic tests can be useful in confirming a clinical diagnosis. The guidelines note that some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to help them with counseling regarding the risk of acquiring genital herpes during pregnancy. There is no place for using IgM antibody testing to determine primary versus recurrent HSV infection. There are three stages of HSV infection based on clinical presentation and serology.
Primary Infection Primary HSV infection is confirmed when no HSV-1 or HSV-2 IgG antibodies are present. Primary genital infection, due to HSV-2 or HSV 1, when symptomatic, presents with mild to severe symptoms and numerous genital lesions. Genital lesions occur on the vulva, vagina, and cervix, between 2 and 14 days, and are multiple and more numerous than those observed in recurrent disease. Vaginal discharge, dysuria, and vaginal burning can be presenting symptoms. Regional lymphadenopathy is caused by virus replication in the sites of lymphatic drainage. Systemic symptoms (malaise, myalgia, and fever) are found during primary herpetic
infection. It is important to appreciate that primary infection may be asymptomatic.
Nonprimary First-episode Disease In nonprimary first-episode disease, HSV-1 antibodies are present in the woman who acquires genital HSV-2 infection for the first time. If the infected person possesses preexisting anti-HSV 1 antibody, there are fewer constitutional symptoms, lesions, and complications, and the duration of the lesions and the time of viral shedding are reduced.91
Recurrent Infections In recurrent infections, homologous antibodies are present.100 Routine screening in the general population appears not to be cost-effective101 and is not recommended.95 However, identification of seronegative women provides the opportunity to properly address the risk of primary transmission during pregnancy and counsel serologically discordant couples, in particular.102 In recurrent genital herpes, lesions tend to be limited in size and number. They recur usually on one area of the external vulva, and no more than three lesions are found with clinical examination. A diffuse cervicitis or a single large ulcer may demonstrate cervical involvement. Local irritation or pain is the presenting complaint, and there may be an increase in vaginal discharge or dysuria. The external genital tract is the site of intermittent virus replication. Virus shedding without a lesion (asymptomatic shedding) can occur from the vulva and cervix intermittently in subsequent years after primary infection. Asymptomatic shedding of virus lasts an average of 1.5 days.
Epidemiology and Transmission of Herpes Simplex Virus-1 and Herpes Simplex Virus-2 A susceptible partner can acquire this virus during times of asymptomatic shedding.103 Shedding of virus without any symptoms or signs of clinical lesions (asymptomatic shedding) makes this viral STD difficult to control and prevent. Patients will experience recurrent disease after clinical or asymptomatic primary HSV genital infection. Recurrences of genital HSV infection can be symptomatic or asymptomatic, and there is significant variation from patient to patient in the frequency, severity, and duration of symptoms and viral shedding. Young adult women typically acquire the first episode of genital herpes between the ages of 20 and 24 years. Primary orolabial herpes is mainly a disease of childhood, children acquiring the infection from family members through close contact. Although 90% to 95% of primary oral infections are asymptomatic, a few may consist of a rather florid vesiculoulcerative outbreak in the oropharynx and lips about a week after exposure. Adenopathy and viremia, along with fever and malaise, may persist for a week or two, with viral shedding for up to 6 weeks. Thereafter, antibody production limits the virus such that it remains dormant, occasionally flaring up as localized blisters on the lips in times of stress, sunburn, or febrile systemic illness (hence the term fever blisters). During recurrent disease, viral shedding lasts up to a week.104 Genital herpes may occur after sexual contact, either genital-genital or orogenital, with an infected person. The
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 509
incubation period is 2 to 14 days. Persons transmitting the virus may be asymptomatic themselves,105 confusing identification of the origin of the infection. In one study, 10% of pregnant women were at risk for contracting primary HSV-2 infection from their HSV-2–seropositive husbands.102 Asymptomatic cervical and vulvar shedding following a primary HSV infection occurs in 2.3% of women with HSV-2 infection and 0.65% with HSV-1 infection.106 In the absence of circulating antibody, primary HSV genital infection can be severe, with symptoms of fever, malaise, myalgias, and aseptic meningitis. HSV encephalitis107 and hepatitis108 have proved fatal. Lower motor neuron and autonomic dysfunction may lead to bladder atony and urine retention. Increased viral shedding occurs for nearly 3 weeks in severe cases if untreated. Local disease may recur weeks or months later if the offending virus is HSV-2, in particular, which recurs much more frequently than does HSV-1, especially in the genital area.109 Genital herpes infection is common in the United States, with 45 million people ages 12 and older, or one out of five of the total adolescent and adult population, infected with HSV-2.110 Since the late 1970s, the number of people in the United States with genital herpes infection has increased by 30%. HSV-2 infection is more common in women (∼1 of 4) than in men (∼1 of 5), and more in blacks (45.9%) than in whites (17.6%). The largest increase is now occurring in young white teens. HSV-2 infection is now five times more common in 12- to 19-year-old whites, and it is twice as common in young adults ages 20 to 29 than it was in the late 1980s.110 Among sexual partners discordant for HSV infection, the annual risk of acquisition of genital HSV infection was 31.9% among women who were both HSV-1– and HSV-2–negative versus 9.1% among women who were HSV-1–positive.111 Approximately 1.6 million new HSV-2 infections are acquired yearly, and approximately 2% of women seroconvert to HSV-2 during pregnancy.112,113
Maternal and Fetal Risks Because of the relative immunosuppression during pregnancy,114 dissemination of HSV may lead to death from hepatitis, encephalitis, and general viral dissemination.115 Primary infection early in pregnancy, perhaps due to a viral endometritis ascending from cervical infection, may end in spontaneous abortion. However, there are no consistent reports of a congenital syndrome due to intrauterine infection with HSV. The spectrum of fetal/neonatal infection includes abortion, prematurity, and intrapartum infection with resultant disseminated HSV infection.116 Primary HSV infection in the second or third trimester increases the risk for preterm delivery as well as the risk of virus transmission to the newborn.117 The fetus acquiring HSV, especially if the mother suffers an acute, primary infection, may sustain severe neonatal morbidity, including chorioretinitis, meningitis, encephalitis, mental retardation, seizures, and death.118 Since the late 1980s or 1990s, industrialized countries have reported a decrease in seropositivity rates of HSV-1, due perhaps to increasing sanitation measures, and increasing rates of HSV-2, due to increasingly permissive sexual behavior.119 The rates of clinical genital HSV infection have
risen dramatically since the 1960s in the United States,120 United Kingdom, and other parts of Europe.119 The incidence of a positive culture in laboring women is 0.5% in the general population.121 Rates of 0.96%99 to 2.4%122 have been reported in asymptomatic women with known histories of genital HSV infection. The rate of neonatal disease is in the range of 0.01% to 0.05%. The variability is due to differences in maternal antibody (and thus passively acquired fetal antibody) levels and the size of the viral inoculum (i.e., primary, severe infection versus mild, recurrent infection in the mother). The majority of infants developing neonatal HSV infection are born to mothers without symptoms or even a history of genital herpes infection and who test seronegative for specific HSV antibodies.99,121,123 In Seattle, a prospective study was conducted in a cohort of 58,362 pregnant women, of whom 40,023 had genital HSV cultures at the time of labor and 31,663 had HSV specific serology; 202 women (0.5%) had a positive HSV culture, of whom 10 (5%) had neonates with HSV infection.121 Women without a history of genital herpes were more likely to shed HSV asymptomatically than women with such a history. However, women with a history of genital herpes were more likely to have cesarean deliveries. The rate of vertical HSV transmission was 31.3% (5/16) in HSV-1–culture-positive mothers, and 2.7% (5/186) in HSV2–positive mothers. Neonatal HSV infection rates per 100,000 live births were 54 among HSV-seronegative women, 26 among women who were HSV-1–seropositive only, and 22 among all HSV-2–seropositive women. Thus, the highest rate of neonatal HSV infection occurred in women who were seronegative and had no specific HSV antibodies. Heterologous antibody in this study did not seem to protect against transmission for primary versus nonprimary first-episode as, in contrast, did homologous antibody. The results emphasize the need for counseling seronegative women, in particular, to reduce the risk of neonatal HSV infection. Most neonatal HSV infection is the consequence of delivery of a neonate through an infected birth canal. Most infants have localized skin, eye, and mouth disease, which usually is a mild illness. However, localized disease may progress to encephalitis or disseminated disease. Disseminated disease is associated with a 57% mortality rate; central nervous system (CNS) disease has 15% mortality; and localized disease shows no mortality.124 In a group of 202 women from whom HSV was isolated, HSV transmission occurred in 9 of 117 (7.7%) infants after vaginal delivery, and in 1 of 85 (1.2%) newborns delivered by cesarean section.121 Thus, cesarean section could reduce the rate of HSV transmission from mother to infant, but cannot completely prevent HSV infection in the newborn.
Management Options Prepregnancy The consistent, correct use of latex condoms can help protect against infection, particularly in women.125 However, condoms do not provide complete protection because the condom may not cover the herpes sore(s) and viral shedding may nevertheless occur, which makes this STD difficult to prevent. In case of symptomatic genital herpes, it is best to abstain from sex and to use latex condoms between
510 S ECTION F OUR • Infection
outbreaks. More recently, daily valacyclovir (500 mg) suppressed overt acquisition of HSV-2 in susceptible sexual partners. Overall acquisition, symptomatic and asymptomatic, was reduced by 48% in the valacyclovir group compared with the placebo group. Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences.95,103
T A B L E 3 0 – 2
Treatment Recommendations for Genital Herpes in the Nonpregnant Patient CLINICAL SETTING
RECOMMENDED REGIMEN
First clinical episode of genital herpes
Acyclovir 400 mg orally three times a day for 7–10 days* OR Acyclovir 200 mg orally five times a day for 7–10 days OR Famciclovir 250 mg orally three times a day for 7–10 days OR Valacyclovir 1 g orally twice a day for 7–10 days Acyclovir 400 mg orally twice a day OR Famciclovir 250 mg orally twice a day OR Valacyclovir 500 mg orally once a day OR Valacyclovir 1.0 g orally once a day Acyclovir 400 mg orally three times a day for 5 days OR Acyclovir 800 mg orally twice a day for 5 days OR Acyclovir 800 mg orally three times a day for 2 days OR Famciclovir 125 mg orally twice daily for 5 days OR Famciclovir 1000 mg orally twice daily for 1 day OR Valacyclovir 500 mg orally twice a day for 3 days OR Valacyclovir 1.0 g orally once a day for 5 days
Prenatal It is important that women avoid contracting herpes during pregnancy because a primary infection during pregnancy causes a greater risk of transmission to the newborn. All pregnant women should be asked whether they have a history of genital herpes. However, history is an unreliable method for identifying women at risk of acquiring genital herpes or those who are already infected.110 Women without known genital herpes should be counseled to avoid intercourse during the third trimester, in particular, with partners known or suspected of having genital herpes. In addition, women with no history of orolabial herpes should be advised to avoid cunnilingus during the third trimester with partners known or suspected to have orolabial herpes.95 When a woman’s sex partner has a history of HSV infection, serologic testing for HSV-1 and HSV-2 antibodies might prove to be helpful to identify and consequently counsel seronegative women at risk for primary HSV infection during pregnancy. Pregnant women with a significant primary HSV infection may need to be hospitalized and monitored closely for evidence of sequelae. Premature labor should be appropriately treated when identified. Evidence of severe, disseminated disease such as hepatitis (elevated hepatic transaminase levels) and encephalitis (abnormal neurologic testing) should trigger the administration of intravenous acyclovir to prevent serious morbidity.115 Treatment of primary genital herpes with oral antiherpetic agents is indicated to reduce viral shedding, reduce pain, and heal lesions faster.126 Different studies have demonstrated that the use of acyclovir and valacyclovir is safe during pregnancy and does not impose an increased risk to the developing fetus even during the first trimester.126–128 Dosing schedules are presented in Table 30–2. No induction of acyclovir-resistant HSV strains was noted in immunocompetent patients.129 However, the extent to which suppressive therapy prevents HSV transmission to the infant is unknown.95 In severe HSV disease, intravenous acyclovir is given at 5 to 10 mg/kg body weight every 8 hours for 2 to 7 days or until clinical improvement is observed. Oral antiviral therapy should follow to complete at least 10 days total therapy.95 Oral acyclovir or valacyclovir and intravenously administered acyclovir reached therapeutic concentrations in the breast milk, the amniotic fluid, and the fetus.130 Topical treatment with acyclovir offers no clinical benefit and should not be used to treat genital herpes.95 Newer antiherpetic drugs, valacyclovir and famciclovir, demonstrate increased bioavailability over acyclovir and thus require less frequent dosing. Antiviral prophylaxis of the mother to prevent maternal symptomatic and asymptomatic viral shedding during the
Suppressive therapy for recurrent genital herpes
Episodic therapy for recurrent genital herpes
* Treatment might be extended if healing is incomplete after 10 days of therapy. From Centers for Disease Control and Prevention, Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55(RR-11):1–91.
intrapartum period is now recommended by the American College of Obstetricians and Gynecologists.131–134 Acyclovir, valacyclovir, and famciclovir are class B medications as categorized by the U.S. Food and Drug Administration. Starting in 1984, an acyclovir pregnancy registry has been compiled. The CDC published data in 1993 showing there was no increase in fetal problems in women who received acyclovir in the first trimester of their pregnancy.135 Ongoing studies examining newer recommendations to reduce the number of newborns infected with HSV are focused on identifying pregnant women susceptible to HSV infection.135 The strategy is to test all pregnant women for antibodies to HSV-1 and HSV-2 (using a type-specific glycoprotein G-based testing) and to initiate the antiviral prophylaxis starting at 36 weeks’ gestation in selected cases. Intervention is aimed at preventing primary infection in those at risk.
Labor and Delivery On admission to the delivery suite, all women should be questioned carefully about symptoms of genital herpes, and all women should be examined carefully for herpetic
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 511
lesions.95 In the absence of visible lesions in the genital area at the onset of labor, vaginal delivery is permitted. If active genital lesions or prodromal symptoms of vulvar pain or burning (which may indicate an impending outbreak) are present, cesarean delivery is indicated. The incidence of infection in newborns whose mothers have recurrent infection is low, but cesarean delivery is warranted because of the serious nature of the disease. The extent to which maternal antibodies will protect a neonate from an infection during a recurrence has not been determined with certainty. Cesarean delivery is not recommended in women with a history of HSV infection but no active disease during labor.95,136 In women with premature rupture of membranes (PROM) near term and active HSV infection, cesarean delivery should be performed as soon as possible. It should not, however, be assumed the fetus is infected just because of prolonged rupture of membranes. Women with preterm PROM and active lesions are considered individually, taking into account gestational age and other relevant factors.
Remote from term, expectant management and use of glucocorticoids are increasingly supported, and antiviral therapy is indicated because premature neonates are at greatest risk of infection.136 Fetal HSV infection has been attributed to the use of fetal scalp electrodes even in the absence of active lesions.121,137 Thus, fetal scalp monitoring should be used cautiously even in women with a history of recurrent HSV and no active lesions.
Postnatal Postpartum, endometritis due to HSV infection has been reported138 and is responsive to acyclovir. Postnatally acquired HSV infections in the newborn can be severe, and mothers with skin or oropharyngeal lesions should use caution when handling their babies. HSV-1 is more likely to cause nosocomial infections in the infant than is HSV-2. Breast-feeding is unlikely to cause infection in the infant; only in the case of an obvious lesion on the breast is breastfeeding contraindicated.130
SUMMARY OF MANAGEMENT OPTIONS
Herpes Simplex Virus Management Options
Evidence Quality and Recommendation
References
Prepregnancy and Prenatal Inform about nature of the disease and that sexual transmission can occur during asymptomatic periods; counsel about condom protection during asymptomatic intervals and sexual abstinence during active disease.
IV/C
95,125
Perform HSV type-specific serology testing; allows more specific advice by identifying seronegative women at risk for HSV acquisition.
IV/C
95
—/GPP
—
Oral (7–14 days) for primary local infection.
Ib/A
126
IV (for 2–7 days then oral) for primary systemic disease.
IV/C
115
Oral (5 days) for recurrent disease.
Advise HSV-2–negative women to abstain from intercourse during third trimester with men who have genital herpes.
●
Advise HSV-1–negative women to avoid intercourse with a partner who has genital HSV-1 infection; no cunnilingus with a partner who has orolabial herpes.
●
Provide symptomatic treatment of infections (primary and recurrent); hospitalize for severe cases. Give acyclovir for active disease:
●
●
●
III/B
136
Provide prophylactic acyclovir (400 mg bid) for last trimester in patients with previous HSV to reduce recurrence risk (no known effect on fetal/neonatal transmission).
Ib/A
131,132
No information about newer anti-HSV drugs; not recommended for pregnancy.
—/GPP
—
Remain vigilant for dissemination.
—/GPP
—
Remain vigilant for preterm uterine activity.
—/GPP
—
Serial viral cultures are no longer recommended in the last trimester for patients who are asymptomatic; culture only to document a new case.
IV/C
95
Consider delivery with septicemic cases.
—/GPP
—
512 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Herpes Simplex Virus—cont’d Evidence Quality and Recommendation
Management Options
References
Labor and Delivery Inquire and inspect perineum, vagina, and cervix for HSV in all women at onset of labor (especially those with history of HSV).
IV/C
95
Allow vaginal delivery if no active lesions and no prodromal symptoms at time of labor.
—/GPP
—
Active lesions at time of labor is considered an indication for cesarean section by most obstetricians, though the risk of fetal infection is less with recurrent disease.
—/GPP
—
Counseling about the benefits of cesarean section in preventing fetal infection with membrane rupture is controversial, although most would still advise cesarean section. Expectant approach with suspected preterm labor and PROM is reasonable.
—/GPP
—
Avoid fetal electrodes and fetal scalp sampling.
Ib/A
121,137
Maintain infection control measures if mother has active lesions.
—/GPP
—
Treat maternal infection; reduces dissemination and morbidity.
III/B
136
Perform clinical, microbiologic, and serologic evaluation of the newborn if active maternal lesions are present.
—/GPP
—
Give IV acyclovir to HSV-infected newborns.
III/B
136
Postnatal
GPP, good practice point; HSV, herpes simplex virus; PROM, premature rupture of the membranes.
ADENOVIRUS General Adenoviruses are medium-sized (90- to 100-nm) doublestranded DNA viruses. There are 6 subgenera (A through F) with 49 immunologically distinct types that can cause infection in the human. Most commonly, in the healthy adult, adenovirus infection causes gastrointestinal and respiratory tract illness with a wide range of symptoms. There has been considerable interest in developing adenoviruses as defective vectors to deliver and express foreign genes for therapeutic purposes.139–141 Furthermore, adenovirus vectors have been used to better understand mechanisms of intrauterine inflammation and fetal programming.142,143 Adenovirus is relatively easy to manipulate in vitro, and the coupled genes are effectively expressed in large amounts. Direct administration of adenovirus gene vectors to the fetus can be achieved by fetoscopy or ultrasonographic guidance.144,145 However, repeated prenatal exposure to an adenovirus vector was associated with pulmonary inflammation as reported in newborn sheep.146 Alternatively, selective placental and maternal intravenous adenovirus vector application has demonstrated only low numbers of adenovirus replication in the fetus, thus reducing the risk of fetal exposure to the virus.147 In addition, intraplacental adenovirus-mediated gene delivery showed only low numbers of virus in the mother, thus possibly providing a suitable strategy for basic studies of placental function or even a method of correcting placental dysfunction in the future.148 Amniotic fluid–derived stem cells have been effectively transduced by adenovirus vectors,
thus possibly providing pluripotent stem cells for use in gene therapy treatment.149
Diagnosis Conventional virus culture, electronmicroscopy and serology tests,150,151 and modern laboratory techniques such as antigen detection by immunofluorescence tests152 and PCR assay23 are all suitable means to identify adenovirus disease. Adenovirus typing requires the use of type-specific antisera in hemagglutination-inhibition and/or neutralization tests.150,151 Adenovirus infection in tissues or cell smears can be identified using in situ hybridization technique.153 The presence of adenovirus does not necessarily mean disease because viruses can be shed for a prolonged time. Adenovirus genome could be identified in amniotic fluid of 30 of 91 (33%) fetuses with ultrasound evidence of nonimmune hydrops. However, concomitant infection with parvovirus, CMV, enterovirus, HSV, and respiratory syncytial virus was found in the majority of cases by PCR technique.23
Maternal and Fetal Risks In healthy adults, adenoviruses commonly cause respiratory illness with symptoms that range from the common cold to pneumonia, croup, and bronchitis. However, depending on the serotype or route of infection (inhalation or ingestion), adenoviruses might cause febrile disease and keratoconjunctivitis, rash illness, gastroenteritis, or cystitis. Immunocompromised patients are susceptible to severe complications of adenovirus infections.
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 513
Transmission is by direct contact and the fecal-oral route. Adenoviruses are unusually stable in adverse conditions. Occasionally, waterborne transmission occurs, often centering around swimming pools and small lakes. Infection is usually acquired during childhood and at a higher incidence in late winter, spring, and early summer. Depending on the serotype, adenovirus infection can persist in either the tonsils, the adenoids, or the intestines of infected patients. Virus shedding can continue for years. Adenovirus types 40 and 41 are known to cause gastroenteritis, primarily in children. Inhalation of adenovirus type 7 is known to cause severe lower respiratory tract infection, and acute respiratory disease is most often associated with types 4 and 7.150,151 Adenovirus infection of the infant might occur transplacentally or at delivery via birth canal or contact with feces. Amniotic fluid obtained from 303 pregnancies with abnormal ultrasound findings tested positive for adenovirus infection in 124 cases (41%). PCR technique could demonstrate adenovirus to be the only viral genome present in the amniotic fluid of oligohydramnios in 18% (2/11; 2 additional patients positive for CMV), hydrothorax/pleural effusion in 22% (4/18; 2 additional patients positive for enterovirus and CMV), ventriculomegaly in 23% (6/26; 1 additional patient positive for CMV), microcephaly in 20% (1/5), and echogenic bowel in 5% (1/22; 5 additional patients positive for CMV and HSV). In the control group of 154 structurally normal fetuses, viral infection of the amniotic fluid was detected in 4 cases (3%), and adenovirus was the only microorganism in 2% (3/154; 1 additional patient positive for CMV). Intrauterine adenovirus infection might cause fetal myocarditis with tachyarrhythmia, dilated cardiac chambers, poor ventricular function, and subsequent hydrops fetalis.154,155 Severe neonatal adenovirus illness is rare, but is most often manifested as necrotizing pneumonitis.152,153,156,157 Within 10 days of birth, infected infants demonstrate rapidly progressing pneumonia, thrombocytopenia, disseminated intravascular coagulopathy, hepatomegaly, and hepatitis. Respiratory
failure might require extracorporeal membrane oxygenation in the newborn.158 Case fatality might be as high as 84% and death often occurs around day 16.156,159,160 Neonatal infection may also be seen in epidemic proportions in neonatal nurseries.161 Severity of the disease in newborns seems to be less pronounced in the presence of maternal antibodies.
Management Options Prepregnancy and Prenatal To date, no specific therapy is available for adenovirus infections in pregnancy or for the infected newborn, although new antiviral drugs (cidofovir, ribavirin) show promising results in pediatric patients.162,163 Thus, the best treatment of adenovirus infection is prevention. Women should be counseled on proper hygiene measures to avoid fecal-oral transmission. Also, inadequately chlorinated swimming pools should be avoided. Most infections are mild and require no therapy. Severe adenovirus infection can be managed only by treatment of symptoms and complications. Fetal tachyarrythmia and associated fetal hydrops may be treated by maternal oral digoxin and other agents (see Chapter 15). Maternal therapy with oral digoxin at 0.5 mg loading, and 0.125 to 0.25 mg/day maintenance dose has shown to convert fetal tachyarrhythmia to normal sinus rhythm and to produce spontaneous resolution of hydrops. Transplacental transfer of digoxin is at an estimated rate of 60% to 100%. Maternal digoxin levels or persistent fetal tachyarrhythmia might require adjustment of the daily administered digoxin dosage. Vaccines for adenovirus types 4 and 7 were developed for military use only. Risk to the general population is so low that vaccination is not a viable proposition.
Labor, Delivery, and Postnatal Strict attention to good infection control practices is effective in stopping nosocomial outbreaks of adenovirus disease such as epidemic keratoconjunctivitis.
SUMMARY OF MANAGEMENT OPTIONS
Adenovirus Evidence Quality and Recommendation
References
—/GPP
—
—/GPP
—
—/—
—
Strictly implement infection control policies.
—/GPP
—
No neonatal therapy other than symptomatic and supportive.
—/GPP
—
Severe pneumonitis in the newborn might require extracorporeal oxygenation.
—/GPP
—
Management Options Prepregnancy and Prenatal Route of transmission is fecal-oral and waterborne; thus, transmission can be prevented by Personal hygiene.
●
Public hygiene (chlorinated swimming pools).
●
Treat adenovirus infections symptomatically because there is no proven therapy for maternal infection. If hydrops develops due to fetal tachyarrhythmia, see Chapters 15 and 24. Labor, Delivery, and Postnatal
GPP, good practice point.
514 S ECTION F OUR • Infection
COXSACKIEVIRUS General Coxsackievirus is a single-strand RNA virus, a member of the picornaviridae, which includes human enteroviruses and rhinoviruses. The enterovirus serotypes are determined by type-specific antisera and are traditionally grouped into four classes: poliovirus, group A coxsackievirus, group B coxsackievirus, and echovirus. Newly discovered serotypes are assigned enteroviral numbers (e.g., hepatitis A virus: enterovirus 72). In northern latitudes, enterovirus infections are more firmly associated with a seasonal periodicity (pronounced in summer and fall) than can be observed in more tropical climates. However, infections may occur at any time of the year. Group B coxsackievirus serotypes 2 to 5 are isolated more frequently, whereas other serotypes are rarely reported. Group A coxsackievirus infections have been identified less frequently, possibly owing to poor growth in routine cell culture. Enteroviruses are transmitted by direct contact with nose and throat discharge or feces of infected humans. Because many infections are clinically not apparent, spread of coxsackievirus infection may occur accidentally; the incubation period is 3 to 5 days (range 2–15 days).164 In healthy, nonpregnant adults, enterovirus infections either are asymptomatic or cause simple febrile illness with or without signs of upper respiratory tract infection or rash. However, some clinical syndromes are characteristically associated with enterovirus infection, including aseptic meningitis, pleurodynia, and the hand-foot-and-mouth disease. The rate of infection is higher in young children than among older children and adults.
Diagnosis Coxsackievirus infection can be identified by virus culture from the oropharynx, stool, blood, urine, cerebrospinal fluid, and amniotic fluid. After virus isolation by culture, virus typing is performed by conventional neutralization tests. More rapid specific virus identification techniques using immunofluorescence assay (IFA) or enzyme-linked immunosorbent assay (ELISA) have not proved to be useful because of the large number of different serotypes.165 However, development of monoclonal group-specific antibodies that can be used for rapid identification of enterovirus groups by IFA and ELISA is in progress.166–168 Modern laboratory methods provide accurate and fast diagnosis of coxsackievirus infection by PCR technique.23,169 In addition, PCR seems to be more suitable for detection of group A coxsackievirus that grows poorly in culture, which has led to a possible clinical underrecognition of this virus as a cause of disease. Serology using hemagglutination-inhibition, complement fixation, and ELISA tests can readily identify IgG, IgM, IgA, and IgE classes of specific antibodies; however, the large number of different enterovirus type-specific antigens requires the performance of large numbers of serologic tests. Gene-sequencing technology has identified a common epitope in a number of enteroviruses, which might prove to be helpful for serology tests in the future.168 When case serology is performed, paired specimens should be obtained to ensure proper diagnosis.
Tissue samples can be examined for specific enteroviral antigens by immunofluorescence or PCR technique.170
Maternal and Fetal Risks The prevalence of enterovirus infection is inversely related to socioeconomic status and age, whereas individual factors, including age, sex, immune status, and pregnancy, are important determinants of the severity of infection.171 In pregnancy, most maternal coxsackievirus infections either are not apparent or cause only minimal symptoms similar to a viral upper respiratory tract infection or viral gastroenteritis172; however, hepatic failure has been reported.173 The exact incidence of coxsackievirus infections in pregnancy is not known. There is no direct virologic evidence available that suggests that coxsackievirus infections in pregnancy may result in miscarriage.165 However, an increased frequency of coxsackievirus IgM in women with spontaneous abortion has been reported.174 In a collaborative study, serologic evidence of coxsackievirus B (types 1–6) infection during pregnancy was demonstrated in 9% of 198 women175; during peak enterovirus season, a seroconversion rate of 25% was noted during the last 2 to 6 weeks of pregnancy among 55 women.176 Most women either were asymptomatic or had only mild symptoms, and no newborn had signs of severe enterovirus infection. The incidence of neonatal coxsackievirus B infection, based on laboratory records, was estimated at a minimum of 50 per 100,000 liveborn children.177 Thus, enterovirus infection during late pregnancy might be a rather common event; however, most infections did not produce a significant maternal or neonatal morbidity. Alternatively, in women delivering newborns with evidence of group B coxsackievirus infection, 59% to 65% had symptomatic illness during the perinatal period with febrile disease and upper respiratory symptoms, pleurodynia, myocarditis, and aseptic meningitis.171,177 In animal studies, pregnant mice experimentally infected with different strains of enterovirus have a shorter incubation period, develop higher titers in blood and various organs, and remain viremic longer. Susceptibility increases with advancing gestation and rapidly reverts to that of nonpregnant animals within days of delivery. In nonpregnant female mice, administration of corticosterone or estrogen reduced the resistance to encephalomyocarditis virus infection, but this resistance was not altered by exogenous progesterone. Group B coxsackievirus infection of the pregnant mouse may also result in infection of the fetus before delivery or in infection of the mouse intrapartum.171 In humans, in vitro experiments demonstrated that vertical infection from mother to fetus rarely happens through transplacental passage.178 However, 22% to 25% of neonatal group B coxsackievirus infections have been attributed to antepartal transmission.172,177 The mechanisms of intrauterine coxsackievirus infection are poorly understood. Evidence of congenital disease is inconsistently related to recovery of virus from the placenta and the respective fetus,165,176,179 and it is assumed that besides hematogeneous transmission involving the placenta, a number of fetuses might be infected by ingesting coxsackievirus contained in the amniotic fluid.180 Transplacental infection of the fetus occurs in the
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 515
absence of maternal immunity and is unrelated to the clinical severity of the disease in the mother. Viral shedding from the cervix has been reported; however, ascending viral infection seems to be a rare event.181 At the time of delivery, infection of the infant might occur by cervical or fecal contamination. Fecal carriage rates of coxsackievirus was reported to range from 0% to more than 6% in different population groups.165,166 In a study of 630 infants with 778 anomalies of different organ systems, intrauterine infection with coxsackievirus B2 and B4 was associated with urogenital anomalies and coxsackievirus B3 and B4 with cardiovascular anomalies. The likelihood of congenital heart disease was increased by maternal infection with two or more coxsackievirus B serotypes rather than one. Also, first-trimester infection with coxsackievirus B4 occurred more frequently in mothers of infants with any anomaly than in the control group.182 In 28 newborns with severe congenital defects of the CNS, neutralizing antibody to coxsackievirus B6 was demonstrated in 4 cases (14%); 2 had hydranencephaly, 1 had occipital meningocele, and 1 had aqueductal stenosis.183 In a stillborn infant with calcific pancarditis and hydrops fetalis, coxsackievirus B3 antigen could be demonstrated.179 Newborns who acquire coxsackievirus infection in the immediate peripartum period are more likely to experience severe disease in the absence of protecting maternal antibodies. Neonatal infection might range from asymptomatic viral shedding to severe and rapidly fatal illness. Infection that occurs more than 5 days before delivery is likely to induce production of maternal IgG that can cross the placenta and protect the newborn from severe disease, but not necessarily from infection. In the newborn, coxsackievirus infection may cause benign neonatal arrhythmias184; fever177; oral vesicular lesions185; vesiculopapular rash186; severe respiratory failure187; pneumonitis172; fatal pulmonary hemorrhage177,188; hepatitis, hepatomegaly, jaundice, bleeding diatheses, hepatic failure, and necrosis165,177; aseptic meningitis177; meningoencephalitis, fatal encephalomyocarditis, and encephalohepatomyocarditis172,189; acute aseptic and interstitial myocarditis190; and result in heart disease.191 A study of 16 neonates with enterovirus hepatitis and coagulopathy demonstrated hemorrhagic complications in 10 of 16 cases (63%); 5 infants had intracranial bleeding.192 The overall fatality rate was 31% (5/16). In the group of 5 neonates with intracranial bleeding, 4 (80%) died. Overall, mortality rates are highest in children with myocarditis, encephalitis, or sepsis-like illness with liver involvement. In addition, prognosis seems to be related to the infecting viral strain. In general, infection with coxsackievirus B1 to B4 seems to carry the most ominous prognoses. Long-term sequelae are mostly reported with regard to heart and CNSrelated impairment. Animal studies of coxsackievirus myocarditis demonstrated a T-cell–mediated immunopathic process and a virus-induced autoimmunity. In a study of 7 newborn infants with neurodevelopmental delays, coxsackievirus was retrieved from the respective placenta in 6 of the 7 cases (86%).187 A 28-year follow-up study of 145 patients, particularly those with coxsackievirus B5 CNS infection during childhood, demonstrated an increased risk for adult onset of schizophrenia or other psychoses.193 In a group of 15 children who had meningoencephalitis due to coxsackievirus B5, 2 were reported to have developed spasticity, and
their intelligence was low.194 Epidemiologic and serologic studies suggest a role for intrauterine coxsackievirus infection for the onset of insulin-dependent diabetes mellitus (IDDM) in childhood.195–197 However, conflicting serologic data exist that do not indicate an association of coxsackievirus infections during pregnancy with the development of islet autoantibodies; these results do not support a major role of fetal coxsackievirus infection in the development of IDDM.198,199 Infection with coxsackievirus A in neonates has been reported less frequently than with coxsackievirus B. Coxsackievirus A infection has been associated with small–for– gestational-age newborns,172 sudden infant death,200–202 anorexia, fever, bronchopneumonia, pericarditis, and meningitis.165 A number of reports have confirmed that coxsackieviruses may be responsible for outbreaks of apparent infections with fatalities among neonates in obstetric wards and maternity homes.203–205 Most commonly, mild nonspecific febrile illness is observed in full-term infants. A careful history frequently reveals a trivial illness in a family member. Feeding difficulties are frequently observed, and short periods of vomiting and diarrhea may occur. The most consistent source of original nursery infection is coxsackievirus transmission from mother to her child, but introduction of the virus into the nursery by personnel also occurs. After infection of the pharynx and lower alimentary tract, minor viremia with spread to regional lymph nodes and secondary infection sites (CNS, heart, liver, pancreas, respiratory tract, skin) occurs on the third day. Major viremia ceases with the appearance of antibodies on day 7. Infection can continue in the lower intestinal tract for prolonged periods, and isolation measures are warranted.165
Management Options Prenatal, Labor, and Delivery Coxsackievirus infections during late pregnancy seem to be a common event, in particular during late summer and early autumn in temperate climates. Epidemics in the region may be signaled by the occurrence of aseptic meningitis, pleurodynia, or Bornholm’s disease (myalgia epidemica). Unseasonal respiratory tract infection or symptoms of fever, muscle pain, neck stiffness, skin rashes, and vesicular lesions (mouth, hand, foot) are suggestive of an enteroviral infection. Ultrasound examination in some cases may reveal an enlarged fetal heart with dilated chambers and unusually thick myocardium. Fetal arrythmias and congestive heart failure in combination with nonimmune hydrops may be treated by maternal digoxin or other agents (see Chapter 15) (oral digoxin at 0.5 mg loading, and 0.125–0.25 mg/day maintenance dose). Conversion of fetal arrhythmia to normal sinus rhythm and, consequently, spontaneous resolution of hydrops may be observed. If a woman is suspected of having an acute coxsackievirus infection, she is a potential risk for transmitting coxsackievirus in the obstetric wards. Isolation measures for delivery, newborn care, and postpartum care are warranted.165 Coxsackievirus infection in the adult usually takes a benign course. If delivery occurs within 4 days of maternal infection, the newborn is at risk for severe disease.
516 S ECTION F OUR • Infection
Postnatal No specific therapy is available to treat coxsackievirus infection in the newborn. Commercially available immune serum globulin contains titers of antibodies to coxsackievirus; however, no beneficial clinical effect has been observed when administered to an infected infant.206,207 However, viremia and viruria ceased earlier in treated infants than in the control group. Some studies with new antiviral drugs (e.g., pleconaril) seem promising.208 In most cases, transmission of coxsackievirus occurs by direct contact from mother or staff members to the newborn or by mouth and gavage feeding. Coxsackievirus B and echoviruses have been recovered from specimens obtained from nurses and physicians caring for infected patients.205
Rigorous attention to hygienic measures and handwashing after handling each baby are imperative to avoid the transmission of enteroviruses. Infected newborns should be isolated, and closure on the neonatal unit to new admissions has been advocated.165 In sudden and virulent nursery outbreaks passive immunization by intramuscular or intravenous immunoglobulin can be useful in preventing disease.206,209 A vaccine to prevent coxsackievirus infection is not available. However, an experimental attenuated vaccine has been developed.210 Because of the considerable morbidity and mortality associated with coxsackievirus B infection in neonates (and in older persons as well), these agents should be candidates for vaccine development.
SUMMARY OF MANAGEMENT OPTIONS
Coxsackievirus Evidence Quality and Recommendation
Management Options
References
Prenatal, Labor, and Delivery Suspect coxsackievirus infection if unseasonal respiratory tract infection and/or clinical signs of meningitis.
—/GPP
—
Treat infections symptomatically (hospitalize severe cases).
—/GPP
—
Evaluate hydropic fetuses for tachyarrhythmia, congestive heart failure; see Chapters 15, 16, and 24 for management options.
—/GPP
—
Deliver women suspected for acute coxsackievirus infection in an isolated unit.
IV/C
165
Isolate women known to have coxsackievirus infection during postpartum care.
IV/C
165
Maintain strict attention to infection control measures.
IV/C
165
Isolate newborns of mothers suspected of having coxsackievirus infection.
IV/C
165
Consider passive immunization of newborns in case of sudden virulent coxsackievirus infection outbreak.
III/B
206,209
Postnatal
Provide clinical, microbiologic, and serologic evaluation of the newborn if acute maternal infection is present within the peripartum period.
GPP, good practice point.
HUMAN PAPILLOMAVIRUS General Human papillomavirus (HPV) is a double-stranded DNA virus that can persist as a latent provirus in epithelial cells after infection. Nucleotide sequencing of the DNA has identified more than 100 genotypes of HPV associated with epithelial neoplasias of the skin and mucosa. More than 30 different HPV types can infect the genital tract, and 8 HPV types are predominantly identified in the most common HPV-associated genital diseases. HPV types 6 and 11 are detected in more than 90% of condylomata acuminata (genital warts), and also in laryngeal
papillomatosis, and conjunctival, oral, and nasal warts. HPV types 16, 18, 31, 33, 51, and 54 have been designated high risk HPV types because they have been strongly associated with cervical intraepithelial neoplasia (CIN) and cervical cancer.211 Genital warts are contagious and are spread during oral, genital, or anal sex. About two thirds of people who have sex with a partner with genital warts will develop warts, usually within 3 months after contact.
Diagnosis The diagnosis of condylomata acuminata can be made visually by the appearance of white or pink verrucous friable
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 517
growths. However, most cases of HPV infection are subclinical. Cytologic evaluation of the Pap smear may reveal evidence of infection in 31% to 71% of cases, depending on age.212 If koilocytosis is noted on the Pap smear, liberal use of colposcopy is warranted, given the association of HPV infection and CIN. Colposcopy may identify up to 70% of infected cases; however, colposcopy during pregnancy is challenging. Directed biopsies can support diagnostic evaluation in certain cases (e.g., unresponsiveness to therapy, uncertain clinical diagnosis). During pregnancy, limiting biopsy to lesions suspicious for CIN 2 or 3 or cancer is preferred, but biopsy of any lesion is acceptable. Biopsy during pregnancy has not been linked to fetal loss or preterm delivery, whereas failure to perform biopsy during pregnancy has been linked to missed invasive cancer.95,212 The goal of cytology and colposcopy during pregnancy is to identify invasive cancer that requires treatment before or at the time of delivery. However, unless cancer is identified or suspected, treatment of CIN is contraindicated during pregnancy.212 HPV isolation in culture is difficult to accomplish. Highly specific and sensitive DNA methods utilizing typespecific HPV gene probes can identify HPV infection in vaginal washings, Pap smears, and amniotic fluid. In situ hybridization technique is useful to demonstrate typespecific HPV infection in tissues and cervical cell scrapings. PCR methods can identify even the lowest levels of HPV infection in blood and other kinds of fluids or in tissue samples. Identification of high risk HPV types might prove helpful for follow-up strategies of women in whom cervical cytology has demonstrated atypical squamous cells of undetermined significance (ASCUS).212 The usefulness of DNA technology in the clinical diagnosis of genital warts is not supported by any data.95 Routine screening for subclinical HPV infection by DNA tests should be reserved for women aged 30 years and older.95,212
Maternal and Fetal Risks Epidemiologic data suggest that HPV infection is the most prevalent STD. Although the occurrence of grossly visible genital warts is infrequent, sensitive detection tests utilizing dot blot DNA analysis or PCR for detection of HPV DNA indicate that as many as 30% of sexually active adults in the United States may be infected,213 with a similar rate seen in pregnancy.214 The highest rates of genital HPV infection (71%) are detected in adults aged 18 to 28. Many adolescents experience multiple sequential HPV infections; thus, repetitively positive HPV DNA tests in this group may represent consecutive incident infections rather than a single persistent infection. Consequently, routine subclinical HPV screening should not be used in this age group, and if inadvertently performed, a positive result should not influence management.212 Major risk factors to acquiring genital HPV infection include multiple sex partners, younger age at first intercourse and first pregnancy, oral contraceptive use, pregnancy, and impairment of cell-mediated immunity.213,215,216 Estimates indicate that approximately 1% of the sexually active population have clinically apparent genital warts.213 Controversial data exist on a possible increase in the prevalence of HPV infections during pregnancy. A threefold increase in HPV DNA–positive women during the third trimester compared with nonpregnant controls has been
reported.217,218 Possible underlying reasons to facilitate HPV infection during late pregnancy could involve hormonal changes inducing virus transcription and the transient immunosuppression experienced by pregnant women. Genital HPV infections in pregnant women have long been suspected to cause genital warts or laryngeal papillomatosis in the respective infants.219 Juvenile laryngeal papillomatosis represents the most common neoplasm of the larynx in infants and young children and usually occurs by age 5.220 The symptoms range from hoarseness to complete upper airway obstruction. A history of genital warts can be obtained from over 50% of women whose infants subsequently develop laryngeal papillomatosis.221 However, the absolute risk of laryngeal papillomatosis following exposure to maternal infection is extremely low. Conservative estimates suggest the risk of papillomatosis developing in an offspring of a mother with HPV genital infection is approximately 1 in 400.220 Surgical excision is the mainstream therapy, and most afflicted patients experience spontaneous remission. However, some endure several hundred surgical procedures. Further development of new antiviral drugs (e.g., cidofovir) and preventive and therapeutic vaccines hold promise for reducing the incidence of recurrent respiratory papillomatosis and, at best, eliminating the virus.222,223 Genital warts in children show spontaneous resolution in up to 75% of cases. In a cohort of 41 children, overall resolution of condylomata was noted in 31 infants (76%), with spontaneous resolution in 22 of 41 (54%); girls were affected three times more often than boys.224 HPV vaccination should reduce the incidence of vertical HPV transmission.225 Vertical transmission and persistence of high risk cancerassociated HPV in the infant is of great concern.226 Amniotic fluid samples of 37 women with cervical lesions tested positive for HPV in 24 cases (65%) using PCR technique.227 HPV type 16 amniotic fluid infection was present in 54% (13/24), and HPV type 18 was detected in 21% (5/24). A correlation was noted between viral DNA amplification and grade of the cervical lesions. In a group of 11 women carrying HPV type 16, 7 infants of 11 (64%) tested positive for HPV type 16.228 Viruses were detected in buccal or genital swabs collected 24 hours after delivery, demonstrating infection rather than contamination. Persistence of HPV type 16 infection after a 6-month interval was noted in 83% of infants. In 270 healthy children between the ages of 3 and 11, 131 (49%) buccal swabs tested positive for HPV type 16. Serologic study performed on 229 children demonstrated IgM seropositivity rates indicative of acute infection that peaked between ages 2 and 5, and again between ages 13 and 16.228 Thus, given the lack of demonstrable disease in children, consequences of perinatal high risk HPV transmission need to be clarified in long-term studies to establish whether perinatal acquisition of high risk HPV types predisposes for an increased risk of cervical neoplasia later in life. The frequency of perinatal HPV transmission is a controversial subject. Transmission rates may be as low as 2.8%– 12.2%,228–230 whereas other studies demonstrate vertical transmission in up to 73% of newborns.231 Discrepancies in infection rates of the newborn may be due to different PCR techniques, with up to a 100-fold difference in sensitivity, differences in study population (e.g., concomitant STDs), sampling technique (nasopharyngeal, buccal, genital), and
518 S ECTION F OUR • Infection
timing (immediately after birth, contamination versus infection). HPV is thought to cause infection in the infant by direct contact during the passage through the birth canal. However, several studies have shown infants being infected with different strains of HPV despite being delivered by cesarean section.232,233 In a study of 68 HPV-positive women, 35 delivered vaginally and 33 by cesarean section,234 at 3 to 4 days of age, buccal and genital swabs were collected. In the group of vaginally born infants, 18 of 35 (51%) had a positive HPV test, whereas in 9 of 33 (27%) infants delivered by cesarean section, HPV was detected. Although the study did show a lower incidence of HPV infection in infants delivered by cesarean section, the study also demonstrated that cesarean section did not consistently protect from vertical HPV transmission. In addition, the presence of HPV has been demonstrated in amniotic fluid, placenta, and cord blood; thus, the fetus is at risk for exposure to the virus prior to delivery.227,230,231,233,235
Management Options Prepregnancy Parents and women should be advised on HPV vaccination. Two vaccines, a bivalent (HPV 16, 18) and a quadrivalent (HPV 6, 11, 16, 18) are available. Vaccine efficacy for the prevention of the primary composite endpoint (CIN grades 2–3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18) was greater than 90%. The quadrivalent vaccine also demonstrated high efficacy against HPV-6 and HPV-11 related external genital lesions. Maximum efficacy is suggested in girls receiving the vaccine prior to sexual activity. However, women who were already infected with one or more of the respective HPV types targeted by the vaccine were protected from clinical disease caused by the remaining HPV types in the vaccine.236 The recommended age for vaccination of girls is 11 to 12 years, with catch-up vaccination for females aged 13 to 26 years who have not been previously vaccinated. Vaccination during pregnancy is not advocated; however, it appears to be safe.237 Finishing trials on HPV vaccination of women aged 30 to 45 years are under way. Vaccination of males has been approved in 40 countries worldwide, including a recent permissive approval for the quadrivalent vaccine in the United States. Widely applied HPV vaccination holds the promise of greatly reducing the incidence of genital warts, precancerous lesions, vulvovaginal and cervical cancer, as well as penile and anal cancer. In addition, reduction of severe respiratory problems due to a laryngopapillomtosis in children infected by vertical transmission from their mothers during pregnancy is expected to occur. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.225 Patients should be counseled on the nature of genital warts and advised on using protection (e.g., latex condoms) when having sex with an infected partner.216 Some genital warts may resolve spontaneously; however, treatment should be considered for expanding genital warts. Treatment for genital warts reduces but does not eradicate infectivity. In nonpregnant women, podophyllum resin 10% to 25% antimitotic solution, podofilox 0.5% solution, and 5fluorouracil are commonly used for topical treatment.
However, they should not be applied during pregnancy because of the potential for fetal toxicity. All treatments show a 10% to 40% probability of recurrence. Intralesional injections of different types of interferon have demonstrated efficacy comparable with other modalities for the treatment of genital warts; however, use of interferons has been frequently associated with systemic adverse effects.238 Interferons should not be used during pregnancy.239 Although some HPV types are associated with CIN and cervical cancer, HPV infection does not necessarily progress to cancer. It is important for women with a history of abnormal Pap smears to receive appropriate cytologic testing on a regular basis so that early treatment, if necessary, can be instituted.
Prenatal There is no single definitive treatment for HPV infection in pregnancy. Treatment is dependent on the size, location, and number of identified lesions and entails the removal or ablation of all visible warts. Owing to the subclinical and multifocal nature of HPV infection, recurrences are common. Certain treatment modalities that are effective in the nonpregnant patient are contraindicated during pregnancy. In pregnant women, topical application of 80% to 90% trichloroacetic acid (TCA) can be used for small lesions and is the least expensive treatment.240 TCA is not absorbed systemically and can be used in pregnancy. However, it has a cure rate of only 20% to 30% after a single application; therefore, weekly applications may be required until the lesions are resolved. TCA solutions have a low viscosity and can spread rapidly, thus damaging adjacent tissues. If an excess amount is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid.95 Cryotherapy with liquid nitrogen has also been successfully used in pregnancy and is a reasonable first-line treatment option. Cryotherapy is not recommended for use in the vagina because of the risk of vaginal perforation and fistula formation.95,238 Surgical removal by tangential scissor excision, tangential shave excision, curettage, or electrosurgery has the advantage of eliminating warts at a single visit in most cases.238 Carbon dioxide laser vaporization has been used successfully in pregnancy, although recurrence rates of 10% to 14% have been reported. In particular, laser therapy is recommended for those patients with large or multiple lesions or with lesions refractory to TCA application or cryotherapy.240 Recurrences usually occur during the first 3 months after treatment, and a followup evaluation should be offered. Imiquimod 5% cream, an immune-response modulator that induces host T helper-1 (Th-1) cytokines, including interferon-γ, has been demonstrated to be effective in eradicating genital warts when applied topically three times weekly in nonpregnant patients. Although not yet recommended in pregnancy, imiquimod may represent an effective alternative to other topical or destructive therapies during pregnancy. New antiviral drugs (e.g., cidofovir) have not been evaluated for safety and efficacy during pregnancy.241
Labor and Delivery Elective debulking of genital warts should not be done at the time of delivery for two reasons: first, these lesions may
C HAPTER 30 • Cytomegalovirus, Herpes Simplex Virus, Adenovirus, Coxsackievirus, and Human Papillomavirus 519
be very vascular and obstetric hemorrhage may ensue; second, most lesions regress to some extent after delivery. Because of the lack of substantial evidence for the preventive value of cesarean delivery, cesarean section should not be performed solely to prevent transmission of HPV infection to the newborn.95 However, cesarean section may be indicated in women with genital warts obstructing the pelvic outlet or when vaginal delivery would result in excessive bleeding.
Postnatal Large lesions should be observed for secondary infection, if they involve an episiotomy site. Sitz baths may be particularly useful in comforting and cleansing the perineal area with multiple HPV lesions. Parents should be counseled on HPV vaccination in order to reduce HPV infection and related disease in the future.225,236
SUMMARY OF MANAGEMENT OPTIONS
Human Papillomavirus Management Options
Evidence Quality and Recommendation
References
Prepregnancy Counsel about HPV vaccination
IIa/B
225
Identify and treat lesions:
—/GPP
—
Counsel about risks (infectious condition) and use of condoms if partner infected.
IIa/B
216,226
Advise that treatment does not eradicate infectivity.
—/GPP
—
Implications from cervical smear screening programs:
—/GPP
—
Ib/A
212
Perform colposcopy, consider biopsy.
Ib/A
212
Perform pelvic examination, Pap smear on a regular basis.
Ib/A
212
IV/C
212
Topical 80% TCA.
III/B
240
Cryotherapy.
IV/C
238
Topical therapy (podophyllum, podofilox, 5-fluorouracil).
●
Ablation (e.g., cryocautery).
●
Removal.
●
If Pap smear reports ASCUS but no other types of abnormalities:
Consider HPV testing.
●
If Pap smear reports ASCUS, and high risk HPV types are detected:
●
●
Screening for subclinical HPV infection is not recommended in women aged 29 and younger. Prenatal
Electrodiathermy.
IV/C
238
Laser vaporization (carbon dioxide).
III/B
240
Excision (tangential scissors, excision, curettage).
IV/C
238
Podophyllum.
IV/C
238
Podofilox.
—/GPP
—
5-Fluorouracil.
—/GPP
—
Interferon
IV/C
237
—/GPP
—
Contraindicated preparations:
●
●
●
●
Counsel about low newborn risk, and about nature of HPV infection in the infant.
520 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Human Papillomavirus—cont’d Management Options
Evidence Quality and Recommendation
References
Labor and Delivery Avoid treatment at delivery, especially debulking, because of risk of hemorrhage.
—/GPP
—
Cesarean section may be indicated in women with genital warts obstructing labor or vaginal delivery that would result in excessive bleeding; not recommended solely to prevent HPV transmission to the infant.
III/B
95
Maintain vigilance for secondary infection, especially in episiotomy site.
—/GPP
—
Offer sitz baths.
—/GPP
—
Postnatal
ASCUS, atypical squamous cells of undetermined significance; GPP, good practice point; HPV, human papilloma virus; TCA, trichloroacetic acid.
SUGGESTED READINGS Boppana SB, Rivera LB, Fowler KB, et al: Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001;344:1366–1371. Brown ZA, Wald A, Morrow A, et al: Effect of serologic status and caesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003;289:203–209. Cheeran MC, Lokensgard JR, Schleiss MR: Neuropathogenesis of congenital cytomegalovirus infection: Disease mechanisms and prospects for intervention. Clin Microbiol Rev 2009;22:99–126. Corey L, Wald A, Patel R, et al: Once daily valacyclovir reduces transmission of genital herpes. N Engl J Med 2004;343:11–20.
FUTURE II Study Group: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927. Ross DS, Dollard SC, Victor M, et al: The epidemiology and prevention of congenital cytomegalovirus infection and disease: Activities of the Centers for Disease Control and Prevention Workgroup. J Womens Health 2006;15:224–229. Sheffield JS, Wendel GD, Laibl V, et al: Valacyclovir prophylaxis to prevent recurrent herpes at delivery: A randomized controlled trial. Obstet Gynecol 2006;108:1550–1552.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 3 1
Other Infectious Conditions MARK H. YUDIN
Infections are an important contributor to maternal and perinatal morbidity and mortality rates. The relative immunosuppression that occurs during pregnancy may alter the natural course of many infectious diseases. Higher attack rates for a variety of bacterial and viral infections are seen in pregnancy. Furthermore, many of these infections may be associated with adverse outcomes, including preterm labor and delivery, low birth weight, and stillbirth. This chapter addresses a large group of infectious diseases and conditions not discussed in other chapters, including streptococcal infections, listeriosis, common sexually transmitted infections (STIs), and vaginitis.
to T-cell receptors and the class II major histocompatibility complex (MHC) without first undergoing antigen processing and presentation. The cross-linking of a T-cell receptor with a class II MHC molecule by a superantigen stimulates the proliferation and activation of T cells and macrophages, causing them to release large amounts of cytokines, which can cause shock or inflammation and tissue damage.2,6 A large number of SPE superantigens have been identified, but SPE A, SPE B, SPE C, SPE F, and streptococcal superantigen (SSA) are among the best characterized. By stimulating cytokine production, these streptococcal exotoxins likely play an important role in the pathogenicity of invasive GAS infections by exacerbating the onset of clinical signs and symptoms of infection.
GROUP A STREPTOCOCCUS
Maternal and Fetal Risks
Group A streptococcus (GAS; Streptococcus pyogenes) has been associated with obstetric and neonatal infections since the 16th century. It is probable that GAS was responsible for much of puerperal sepsis, or “childbed fever,” described by Semmelweis in 19th-century Vienna.1 However, with the advent of the antibiotic era, GAS infections became increasingly infrequent until the 1980s, when GAS infections dramatically increased again for poorly understood reasons.2 GAS causes a broad spectrum of invasive and noninvasive diseases, including bacterial pharyngitis, impetigo, scarlet fever, necrotizing fasciitis, and the more recently recognized streptococcal toxic shock syndrome (STSS), as outlined in Table 31–1.2,3 S. pyogenes, the etiologic agent for GAS infections, was first described by Louis Pasteur in 1879. The Streptococcus genus is classified into groups, based upon polysaccharide capsular antigens and the cell wall M protein, as first described by Lancefield.4 S. pyogenes is divided into serotypes according to the M protein, and to date, more than 80 M protein serotypes have been identified. Different serotypes are associated with different forms of infection, and M1 and M3 have been the most common serotypes identified in serious infection in more recent years.5 M protein is also important as a virulence factor because of its antiphagocytic properties. Other significant virulence factors are the streptococcal pyrogenic exotoxins (SPE), which act as superantigens. Superantigens are able to bind
GAS may be recovered from the skin or mucous membranes of asymptomatic colonized patients. GAS may gain entry to the body via the skin, mucosa, pharynx, and vagina and cause infections with both suppurative and nonsuppurative complications.2,7 The most notable GAS infections encountered during pregnancy are presented in Table 31–2 and include bacteremia without a focus of infection and endometritis, but invasive infections including STSS and necrotizing fasciitis also occur. The reasons for the increased susceptibility seen during the puerperium include the breach of integrity in the integumentary system associated with either vaginal delivery or cesarean section. Invasive infections are characterized by hypotension and shock, multiple organ failure, systemic toxicity, severe local pain, rapid necrosis of subcutaneous tissues and skin, renal dysfunction, and fever.2,7 GAS invasive disease is characterized by a rapid, often fatal course and by difficulties in the early diagnosis, when intervention may be more successful. Postpartum invasive GAS infection occurs in approximately 1 in 11,000 to 1 in 17,000 births, with an average of 220 cases occurring in the United States every year.8,9 The rate of invasive GAS infection is 1.6- to 2.0-fold greater among black patients than white patients.8 Maternal case fatality rate ranges from 3.5% to 30% in postpartum invasive GAS. Maternal GAS disease has also been associated with stillbirth.
INTRODUCTION
521
522 S ECTION F OUR • Infection T A B L E 3 1 – 1
T A B L E 3 1 – 3
Classification of Group A Streptococcal Infections
Diagnostic Criteria for Streptococcal Toxic Shock Syndrome
1. Streptococcal toxic shock syndrome (streptococcal TSS) 2. Other invasive infections (isolation of Streptococcus pyogenes from a normally sterile site in patients not fulfilling criteria from streptococcal TSS) a. Bacteremia with no identifiable focus b. Focal infection with or without bacteremia (meningitis, pneumonia, peritonitis, puerperal sepsis, osteomyelitis, septic arthritis, necrotizing fasciitis, surgical wound infections, erysipelas, cellulitis) 3. Scarlet fever 4. Noninvasive infections (recovery of S. pyogenes from a nonsterile site) a. Mucous membranes (pharyngitis, tonsillitis, otitis media, sinusitis, vaginitis) b. Cutaneous (impetigo) 5. Nonsuppurative sequelae (specific clinical findings with evidence of a recent group A streptococcal infection) a. Acute rheumatic fever b. Acute glomerulonephritis
I. Isolation of Streptococcus pyogenes A. From a normally sterile site B. From a nonsterile site (throat, sputum, vagina, superficial skin lesion) II. Clinical evidence of severity A. Hypotension (systolic blood pressure ≤ 90 mm Hg in adults or ≤ 5th percentile for age in children) and B. Two or more of the following: 1. Renal impairment (serum creatinine ≥ 2.0 mg/dL or a twofold elevation over baseline level in patients with preexisting renal impairment) 2. Coagulopathy (platelets ≤ 100 × 106/L or disseminated intravascular coagulation) 3. Liver involvement (AST, ALT, or total bilirubin ≥ two times upper limits of normal) 4. Adult respiratory distress syndrome 5. Generalized erythematous macular rash 6. Soft tissue necrosis (necrotizing fasciitis, myositis, or gangrene)
Adapted from The Working Group on Severe Streptococcal Infections: Defining the group A streptococcal toxic shock syndrome. JAMA 1993;269:390– 391.
ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adapted from The Working Group on Severe Streptococcal Infections: Defining the group A streptococcal toxic shock syndrome. JAMA 1993;269: 390–391.
T A B L E 3 1 – 2
Diagnosis
Diseases Seen among Patients with Postpartum Group A Streptococcus Infection
GASs can be readily recovered from most patients with evidence of GAS disease. GASs are catalase-negative grampositive cocci that are β-hemolytic on blood agar. The colonies may appear as highly mucoid to nonmucoid, and the organisms are usually 1 to 2 mm in diameter. Although cultures may be helpful in confirming the diagnosis of GAS disease, they are seldom available when considering the initial diagnosis. GAS disease may progress rapidly, and therapy must be initiated before cultures are generally available. Therefore, the diagnosis of GAS disease depends upon a high index of suspicion. Fever is the most common presenting sign, and 20% of patients have a flulike syndrome with fever, chills, myalgia, nausea, vomiting, and diarrhea.13 Confusion or altered mental status is present in over one half of patients. Renal dysfunction occurs in 80% of patients and may precede hypotension or shock. The presence of hemaglobinuria or an elevated serum creatinine is evidence of renal involvement. Hemoconcentration, as a result of a fluid shift to the extravascular compartment, and leukocytosis (often > 20,000/mm3), with a predominance of immature neutrophils, are common. Respiratory failure and adult respiratory distress syndrome occur in approximately 50% of patients but usually develop after the onset of clinically recognized shock. Criteria for the diagnosis of STSS are outlined in Table 31–3. Eighty percent of patients have evidence of soft tissue infection characterized by induration and erythema, which progress to necrotizing fasciitis in 70% of cases.13 The hallmark of these soft tissue infections is the abrupt onset of severe pain, which usually precedes physical findings or is out of proportion to physical findings. Any patient suspected of having GAS-associated necrotizing fasciitis must have the
INFECTION Bacteremia without focus Endometritis Peritonitis Septic abortion Cellulitis Septic arthritis Necrotizing fasciitis Streptococcal toxic shock syndrome Chorioamnionitis Pneumonia Other
NUMBER OF PATIENTS (N = 87) 40 24 7 6 3 3 3 3 3 1 3
(46%) (28%) (8%) (7%) (3%) (3%) (3%) (3%) (3%) (1%) (3%)
Adapted from Chuang I, Van Beneden C, Beall B, Schuchat A: Population-based surveillance for postpartum invasive group A streptococcus infections, 1995–2000. Clin Infect Dis 2002;35:665–670.
Neonatal invasive GAS has also been reported and has a case fatality rate of up to 30%.9–11 Although the neonate may be colonized following horizontal transmission within the nursery, vertical transmission from a colonized mother has also been demonstrated.10,12 Furthermore, 50% of neonatal cases of invasive GAS disease occur within the first week of life, suggesting that vertical transmission from a colonized parturient may be the most important route of infection. The most frequent manifestation of neonatal GAS disease is omphalitis, but cellulitis, meningitis, sepsis, and fasciitis may also occur. Fortunately, neonatal GAS disease is rare, with an estimated incidence of 1 in 18,000 births.
C HAPTER 31 • Other Infectious Conditions 523
diagnosis confirmed by immediate wound exploration and débridement. A purulent discharge is usually not present, and a limited wound inspection may fail to confirm the diagnosis. When the wound is opened, a thin, watery, nonmalodorous discharge is frequently present. The diagnosis of necrotizing fasciitis can be easily confirmed by the bloodless blunt dissection of the superficial fascia and by pathologic frozen section. In summary, the diagnosis of GAS disease should be considered in any patient with the sudden onset of hypotension and shock, the abrupt onset of severe pain in a wound, or systemic signs and symptoms such as confusion, renal impairment, or respiratory distress in a patient with a wound or episiotomy infection. Aggressive intravenous fluid resuscitation, antibiotic therapy, and wound débridement are necessary in these patients.
Management Options Prepregnancy No current evidence suggests that the identification of GAS carriers prior to pregnancy is predictive of subsequent pregnancy outcome or effective in reducing puerperal infectious morbidity. Therefore, prepregnancy screening is not recommended.
Prenatal Women may be identified as being GAS carriers as a result of routine screening for group B streptococcus (GBS) near the end of pregnancy. In one study, 0.03% of women screened at 35 to 37 weeks’ gestation were found to have vaginal colonization with GAS.14 At present, there are not sufficient data to make a recommendation regarding management of asymptomatic carriers. However, there are published case reports of women identified as carriers during pregnancy who then developed GAS sepsis after delivery.15 A case of puerperal sepsis in a woman with a strain of GAS identical to that identified in her husband’s throat swab has also been reported.16 A high index of suspicion is necessary for the early diagnosis of GAS infection. Unfortunately, diagnosis may be difficult in the early stages of GAS infection, and delays in therapy may be associated with increased morbidity and mortality rates. Many patients die within 24 to 48 hours of infection.17 In general, treatment must be directed at hemodynamic stabilization with intravenous fluids and vasopressors, antibiotic therapy, and in the case of soft tissue infections, surgical exploration and aggressive débridement of involved tissues. Massive amounts of intravenous crystalloids, in the range of 10 to 20 L/day, are often necessary to maintain blood pressure and tissue perfusion. Vasopressors such as dopamine are also frequently required. In soft tissue GAS infections such as necrotizing fasciitis, antibiotic therapy alone, without surgical débridement, usually results in maternal death. Intraoperative Gram stain and histologic frozen section may be necessary to fully delineate the extent of involved tissues. Hyperbaric oxygen therapy has no role in the treatment of necrotizing fasciitis but might be a useful adjunct in delineating necrotic tissue that must be surgically débrided.
Broad-spectrum parenteral antibiotics should be administered promptly. Penicillin G (200,000–400,000 U/kg/ day) is the drug of choice for GAS invasive infections. However, studies in mice have demonstrated that even a short delay of 2 hours after initiation of infection dramatically reduces the efficacy of penicillin G.17 Some studies indicate that clindamycin may be more efficacious than penicillin when therapy is delayed. In an experimental model with mice, survival was 70% even when initiated 16 hours after GAS infection.17 Several potential advantages to clindamycin therapy (900 mg IV q8h) have been identified.7 First, in contrast to penicillins, clindamycin is not affected by bacterial inoculum size or rate of growth. Second, clindamycin suppresses the synthesis of bacterial toxins. Third, clindamycin facilitates phagocytosis of S. pyogenes by inhibition of M protein synthesis. Fourth, clindamycin has a longer postantibiotic effect than penicillin. Last, clindamycin suppresses lipopolysaccharideinduced monocyte synthesis of tumor necrosis factor-alpha (TNF-α), a cytokine that contributes to hypotension and shock. However, a small proportion of GAS infections are resistant to clindamycin, and clindamycin should not be used alone until the organism is demonstrated to be susceptible by susceptibility testing. Therefore, initial therapy usually includes a combination of both penicillin G and clindamycin. Some data also indicate that intravenous immunoglobulin (IVIG) (1–2 g/kg given once) may be a useful adjunct to antibiotic therapy in the treatment of STSS. Commercial preparations of IVIG have been shown to contain neutralizing antibodies to several streptococcal virulence factors.18 Recently, investigators reported a significant reduction in mortality rate among patients with GAS disease treated with IVIG when compared with a historical cohort. Thus, the optimal treatment for invasive GAS disease includes a high index of suspicion, aggressive fluid resuscitation and hemodynamic support, surgical exploration and aggressive débridement, parenteral antibiotics including penicillin G and clindamycin, and possibly IVIG.
Labor and Delivery GAS may be associated with intra-amniotic infection and with stillbirth. However, most patients with invasive GAS disease usually present in the postpartum period, frequently within the first 24 to 48 hours. Treatment should follow the general guidelines provided earlier.
Postnatal There are no current recommendations for screening for or treating asymptomatic parturients colonized with GAS. However, careful attention should be given to any parturient with the sudden onset of systemic signs such as hypotension or shock or to parturients with severe pain out of proportion of physical findings or rapidly progressive soft tissue infections, as noted earlier. Although these findings, which are consistent with necrotizing fasciitis, usually suggest a polymicrobial infection, GAS should be considered in the diagnosis, and broad-spectrum antibiotics including penicillin and clindamycin should be utilized in the initial management.
524 S ECTION F OUR • Infection SUMMARY OF MANAGEMENT OPTIONS
Group A Streptococcal Infection Evidence Quality and Recommendation
Management Options
References
Prepregnancy No benefit to screening.
—/GPP
—
—/GPP
—
Prenatal, Labor, and Delivery No benefit to screening. May cause intra-amniotic infection.
—/GPP
—
Diagnosis requires a high index of suspicion:
III/B
13
Ib/A
17,18
Infection may cause toxic shock syndrome or soft tissue infection.
—/GPP
—
Diagnosis requires a high index of suspicion:
III/B
13
Ib/A
17,18
Severe pain.
●
Hypotension or shock.
●
Altered mental status.
●
Renal or respiratory impairment.
●
Treatment requires prompt intervention: IV antibiotics (penicillin G, clindamycin).
●
IV fluids and circulatory support including vasopressors.
●
IVIG in nonresponsive cases.
●
Surgical débridement if appropriate
●
Postnatal
Severe pain.
●
Hypotension or shock.
●
Altered mental status.
●
Renal or respiratory impairment.
●
Therapy: Broad-spectrum antibiotics (penicillin and clindamycin).
●
Surgical wound exploration and débridement.
●
GPP, good practice point; IVIG, intravenous immunoglobulin.
GROUP B STREPTOCOCCUS GBS (Streptococcus agalactiae) has become recognized since the 1980s as one of the most important causes of neonatal infection and is currently considered one of the leading infectious causes of neonatal morbidity and death. Although early reports in the 1930s and 1940s linked GBS with postpartum infections and neonatal meningitis, it was not until the early 1960s that the scope of perinatal and neonatal GBS infections became evident.19 Initial case series reported case fatality rates as high as 50%. In the 1980s, trials of empirical intrapartum antibiotics to women at risk of transmitting infection to their newborns demonstrated a protective benefit against neonatal infection in the first week of life (early-onset disease). In the 1990s, these efforts led to the implementation of guidelines for intrapartum antibiotic prophylaxis of at-risk mothers, endorsed and issued by the American College of Obstetricians and Gynecologists (ACOG),20 the Centers for Disease Control and Prevention (CDC),21 and the American Academy of Pediatrics (AAP).22
This practice has resulted in a significant reduction in earlyonset disease, as well as a smaller impact on maternal morbidity. Based upon these results, updated guidelines were issued by the CDC in 200223 to recommend optimization of screening and treatment of pregnant women in an attempt to improve upon the success already demonstrated. GBSs are one of many serologically distinct species within the genus Streptococcus. Streptococci are facultatively anaerobic gram-positive cocci, usually arranged in chains on Gram stain. The most important pathogenic streptococcal species for humans include group A (S. pyogenes), group B (S. agalactiae), group D (enterococci), Streptococcus pneumoniae, and Streptococcus viridans. Definitive identification is based on the presence of a polysaccharide group-specific antigen common to all group B streptococcal strains as determined by serologic testing. GBSs can be further subdivided into eight distinct serotypes (Ia, Ib, Ia/c, II, III, IV, V, and VI) on the basis of distinctive type-specific polysaccharide antigens. About 99% of strains can be typed into one of these six antigen types. GBSs can be recovered from the vagina or
C HAPTER 31 • Other Infectious Conditions 525
cervix in 10% to 30% of pregnant women at some point during gestation.24 The colonization may be transient, chronic, or intermittent, and the rate of colonization does not vary with gestational age. Women with GBS colonization in one pregnancy are at increased risk, relative to women who are negative in the initial pregnancy, for colonization in a subsequent pregnancy.25 There is evidence that the gastrointestinal tract is the major primary reservoir and that vaginal or cervical contamination and colonization occur from a gastrointestinal source. The frequency of GBS isolation increases as one proceeds from the cervix to the introitus, and GBS can be recovered twice as frequently from rectal cultures as from vaginal cultures. GBSs can also be recovered from the urethra of 45% to 63% of the male consorts of female carriers, implying that sexual transmission may also occur. Neonatal GBS colonization may occur either by vertical transmission from a colonized mother as the neonate passes through the birth canal or by horizontal transmission, including both nosocomial spread in the nursery from colonized personnel or other colonized neonates and acquisition from community sources. Overall, 3% to 12% of all neonates are colonized with GBS in the first week of life. Forty percent to 70% of neonates born to colonized mothers become colonized, usually with the same serotype that is present in the mother. In contrast, only 1% to 12% of neonates born to noncolonized mothers will become culturepositive. Several additional factors may modify or enhance the risk of GBS vertical transmission. Higher neonatal transmission rates occur when women are persistently culturepositive carriers or when women are heavily colonized with GBS as demonstrated by semiquantitative vaginal cultures.26 The site of maternal carriage is also important; vertical transmission is more likely to occur with cervical GBS carriage than with rectal carriage. The most important determinant of susceptibility to invasive infection after colonization may be maternal antibodies directed against the capsular polysaccharide antigens of GBS. Immunity to GBS is mediated by antibody-dependent phagocytosis. Mothers of infants with type III GBS invasive disease have lower serum levels of type-specific antibodies than women giving birth to asymptomatically colonized infants. This antibody, which has some broad reactivity to all GBS types, is an immunoglobulin G (IgG) that readily crosses the placenta. When measured in mother-infant pairs, an excellent correlation exists between maternal and cord antibody levels. Baker and associates27 demonstrated that 73% of 45 GBS-colonized mothers with healthy neonates had high serum levels of type III antibody in contrast to only 19% of 32 GBS-colonized mothers whose neonates developed early-onset septicemia or meningitis (P < .001). Strain virulence is also an important determinant of disease. Although type III strains of GBS represent approximately one third of isolates from symptomatically colonized infants, they account for over 85% of the isolates from early-onset meningitis or late-onset disease. Overall, type III strains account for more than 60% of isolates from infants with all varieties of invasive GBS infections.
Maternal and Fetal Risks Although most research has focused on GBS neonatal infection, GBS is also an important pathogen for maternal
intrapartum, postpartum, and occasionally prenatal infections. Data from an early report suggest puerperal septicemia due to GBS occurs with an incidence of approximately 1 to 2 per 1000 deliveries and accounts for up to 15% of positive blood cultures from postpartum patients.28 Postpartum endometritis is reported to be more frequently observed among GBS-colonized parturients than among noncolonized parturients. GBS is also associated with clinical intraamniotic infection and is a frequent isolate from amniotic fluid of patients with intra-amniotic infection. Finally, GBS has been isolated from the urine of pregnant women, with or without symptoms of urinary tract infection. Untreated antepartum GBS bacteriuria has been associated with intrapartum chorioamnionitis.29 GBS has also been associated with premature rupture of membranes (PROM) and with preterm delivery prior to the 32nd gestational week in some, but not all, studies.30 Previous studies have indicated that this association may be strongest for patients with GBS bacteriuria.31 Thomsen and coworkers32 have demonstrated significant reductions in PROM and preterm labor among patients with asymptomatic GBS bacteriuria who were treated with penicillin. However, antepartum antibiotic treatment to eradicate GBS from patients with asymptomatic vaginal colonization without bacteriuria has not been demonstrated to alter pregnancy outcome. Thus, a causal relationship between GBS colonization and prematurity remains to be established. Since the 1970s, GBS has become a leading cause of septicemia and meningitis during the first 3 months of life in neonates. Early surveillance data in the 1990s suggested an incidence of 1.8 cases per 1000 live births. Two distinct clinical syndromes occur among neonates with GBS infections. These differ in the age at onset, pathogenesis, and outcome. The first clinical syndrome, early-onset infection, occurs within the first 7 days of life and represents nearly three fourths of all cases in infants younger than 3 months. The mean age at onset is 20 hours of life, and 72% will present within the first 24 hours of life.33 A significant portion of these infections are apparent at birth or become symptomatic within the first 90 minutes of life, indicating that in utero GBS exposure and infection often occur. Early infection attack rates were estimated at 1.5 per 1000 for all live births prior to widespread use of intrapartum antibiotics. Among offspring of maternal GBS carriers, however, the attack rate is much higher, ranging from 10 to 60 per 1000 live births. Early neonatal infection is presumed to result from vertical transmission of GBS from a colonized mother. There is a direct relationship between neonatal attack rates and the size of the inoculum and number of colonized neonatal sites. In one epidemiologic review, early-onset infection presented as bacteremia (80%), pneumonia (7%), or meningitis (6%).33 Eighty-three percent of cases were in term infants (≥37 wk’ gestation). The overall case fatality rate was approximately 4% but was significantly higher in preterm infants, approaching 30% in infants of 33 weeks’ gestation or less. The second type of disease (late-onset infection) occurs in infants after the first week of life until 3 months of age, with a typical range of 3 to 4 weeks. The overall attack rate is estimated to be 0.5 cases per 1000 live births, and these cases represent 28% of infections in infants younger than 3 months.33 In contrast to early-onset infection, nosocomial transmission may be as important as vertical transmission,
526 S ECTION F OUR • Infection
although it is believed that some infants are colonized at birth, with subsequent development of invasive disease. The serotype distribution of strains recovered from late-onset infection does not reflect the serotypes present in the maternal genital tract; over 90% of late-onset infection is caused by type III GBS. Late-onset disease also presents most commonly as bacteremia (63%), but may appear as meningitis (24%, relative risk [RR] 4.3 vs. early-onset disease; P < .001) and may demonstrate other sites of infection, such as septic arthritis or osteomyelitis. The overall case fatality rate for late-onset disease is 2.8%.33 Approximately 50% of meningitis survivors will have neurologic sequelae, including cortical blindness, diabetes insipidus, deafness or other cranial nerve deficits, and spasticity.
Diagnosis The recommended technique for collecting specimens for culture of GBS in pregnant women involves obtaining a combined vaginal-rectal swab. Although some studies have shown that the GBS detection rate is not significantly different when comparing vaginal-rectal specimens with vaginal-perianal specimens,34,35 the current standard of care is still to obtain a combined vaginal-rectal swab. A speculum is not necessary, and there is no difference in detection rates or accuracy if the culture is collected by the patient or the health care provider.36 GBS can be easily grown on selective or nonselective media. Most GBS colonies appear on blood plates as small, 1- to 2-mm, gray-white colonies surrounded by a zone of β-hemolysis, although 2% of strains are nonhemolytic. Preliminary identification and distinction of GBS from other streptococci is based on biochemical reactions including resistance to bacitracin, hydrolysis of sodium hippurate, and the production of a soluble hemolysin that acts synergistically with B-lysin of Staphylococcus aureus to produce hemolysis (CAMP [Christie-Atkins-Munch-Petersen] test). Although GBS can be recovered after overnight growth on nonselective media, such as blood agar, the use of a selective broth medium such as Todd-Hewitt broth or Lim broth greatly enhances the isolation rate of GBS from any culture site. A major limitation of cultures is the length of time necessary for growth and identification. Therefore, research has been focused on developing a more rapid screening test that could be used at the time of labor and delivery to identify colonized women. A number of rapid screening tests have been developed to directly detect GBS in either body fluids or cervical-vaginal secretions. These culture-independent tests include Gram stain, latex particle agglutination (LPA), optical immunoassay, enzyme immunoassay, DNA hybridization, and polymerase chain reaction (PCR). A large number of studies have evaluated the ability of these indirect tests to rapidly detect GBS colonization of the maternal lower genital tract. Such identification is important to interrupt maternal-neonatal vertical transmission that leads to early-onset neonatal disease. Initial results were encouraging,37,38 although subsequent studies have demonstrated that these tests do not always perform well.39,40 PCR tests appear to have the most promise and the best test performance characteristics relative to culture.41–43 Recent studies from the United States and Canada have used PCR
assays that demonstrate excellent sensitivity and specificity compared with traditional culture methods, but these assays await further testing to determine the feasibility of widespread application.43–45 A cost-benefit analysis showed that the use of a rapid PCR test resulted in fewer courses of maternal antibiotics, fewer perinatal GBS infections, and fewer infant deaths compared with culture.46 However, only culture techniques currently allow for antibiotic sensitivity profiling of positive cultures, which is particularly important in cases of maternal penicillin hypersensitivity.
Management Options Prepregnancy No current evidence suggests that the identification of GBS carrier status prior to pregnancy is predictive of subsequent pregnancy outcome. Similarly, treatment of asymptomatic women found to be colonized with GBS prior to pregnancy does not impart any recognized benefit, with the possible exception of women with asymptomatic bacteriuria.
Prenatal, Labor, and Delivery GBS rarely causes maternal symptoms in the prenatal period, but may cause symptoms of urinary tract infection. However, GBS bacteriuria (whether symptomatic or not) provides a significant risk factor for neonatal disease, as previously mentioned. When detected, GBS bacteriuria should be treated according to current standard of care for urinary tract infections during pregnancy. Pregnant women with documented GBS bacteriuria at any time during their prenatal course do not require routine screening cultures and should receive intrapartum antibiotics, which are discussed in further detail later. Although the attack rate for neonatal GBS infection is low, a variety of prevention strategies have been advocated because of the high mortality and morbidity rates seen in neonatal GBS disease. These strategies have involved chemoprophylaxis, aimed at eradicating the organism from the mother or the neonate, or immunoprophylaxis, aimed at inducing humoral immunity. Antibiotic chemoprophylaxis has been advocated for the pregnant patient in either the antepartum or the intrapartum period or for the neonate in the immediate neonatal period. Attempts to eradicate GBS colonization with antepartum treatment have been unsuccessful, and early neonatal prophylaxis is also frequently unsuccessful because many neonates are already septic at birth as a result of in utero infection.47 Initial chemoprophylactic prevention strategies released in the 1990s focused upon selective intrapartum treatment based on either the presence of risk factors associated with neonatal infection, the maternal genital tract colonization, or both. Major risk factors for neonatal early-onset GBS disease include low birth weight ( 50% predicted) initiate oral corticosteroids (i,e., prednisone ~ 1 mg/kg) 4. If exacerbation is severe (i.e., FEV1 or PEF < 50% predicted) administer either oral or systemic steroids (e.g., methylprednisolone 125 mg IV acutely and then 40–60 mg IV q6h or hydrocortisone 60–80 mg IV q6h. When the patient improves, she can be switched to a tapering oral regimen of prednisone). 5. Consider use of ipratropium MDI (2 puffs of 18 µg/spray q6h) or nebulizer (one 62.5-mL vial by nebulizer q6h) in first 24 hr after presentation. 6. Initiate assessment of fetal well-being if pregnancy has reached fetal viability. 7. Make individualized assessment of need for hospitalization (see text). FEV1, forced expiratory volume in 1 sec; MDI, metered-dose inhaler; PEF, peak expiratory flow. Adapted from Powrie RO: Drugs in pregnancy. Respiratory disease. Best Pract Res Clin Obstet Gynaecol 2001;15:913–936.
Prostaglandin E2 compounds and oxytocin can be safely used in asthmatics. 15-Methyl prostaglandin F2α should not be used in asthmatic patients because it can cause bronchoconstriction.41,42 Ergonovine and other ergot derivatives should also not be used in asthmatics because they too have caused severe bronchospasm in asthmatic patients, particularly in association with general anesthesia. Although morphine and meperidine may theoretically cause bronchoconstriction through histamine release, this is not generally a problem in clinical practice. Nonetheless, some experts prefer to use butorphanol or fentanyl as alternatives in
pregnant asthmatics because these agents are less likely to cause histamine release. Regional anesthesia is preferable to general anesthesia because of the lower risks of pulmonary infection and atelectasis. For those women who do require a general anesthetic, bronchodilatory agents such as ketamine and halogenated anesthetics are preferred. It is known that supraphysiologic daily doses of systemic steroids, given for as little as several weeks, may suppress the hypothalamic-pituitary-adrenal (HPA) axis for up to 1 year. This could blunt the normal physiologic outpouring of adrenal corticosteroids that occurs with stressors such as illness, surgery, and labor, though the prevalence of clinical complications seems to be low. The significance of this theoretical risk in pregnancy remains unstudied. To avoid the risk of precipitating an adrenal insufficiency crisis, however, many experts advise giving an empirical “stress dose” of systemic steroids (e.g., hydrocortisone 50–100 mg IV q8h on the day of delivery followed by 25–50 mg IV q8h on day 1 after delivery and then back to the baseline dose) to any woman in labor who has received systemic steroids in doses greater than 5 mg.day for longer than 2 to 4 weeks in the preceding year. If stress-dose steroids are not given, it is advisable to watch the patient for signs of adrenal insufficiency (anorexia, nausea, vomiting, weakness, hypotension, hyponatremia, and hyperkalemia) in the peripartum interval and postpartum.
Postnatal Physicians should ensure that asthmatic women have their asthma medications reordered and continued postpartum. These women should also have their PEFR monitored in the days following delivery. Breast-feeding is recommended in women regardless of their asthma treatment. In fact, breastfeeding for between 1 and 6 months reduces the prevalence of atopy by about 30% to 50% in 17-year-olds who were breast-fed.43
C HAPTER 37 • Respiratory Disease 663 SUMMARY OF MANAGEMENT OPTIONS
Asthma Evidence Quality and Recommendation
Management Options
References
Prepregnancy Adjust maintenance medication to optimize respiratory function.
IV/C
15,33,37
Educate patient about use of spacers and peak expiratory flow meters.
III/B
15,33,37
Educate patient to continue maintenance medications in pregnancy.
III/B
15,33,37
Provide patient with a stepwise asthma action plan.
III/B
15,33,37
Advise early referral for prenatal care.
III/B
15
Use same drugs as outside pregnancy—especially steroids and β-agonists.
III/B
15,33,36
If theophylline is used, monitor blood levels, because blood volume expansion in pregnancy may mandate higher doses of the drug.
III/B
15,33,36
Monitor peak flow and adjust asthma medication as needed to control symptomatology and minimize need for “rescue” therapy.
III/B
15,33,36,37
Utilize inhalation rather than oral route.
III/B
34,35
Ensure adequate fetal oxygenation with acute exacerbation by keeping maternal oxygen saturation > 95%.
III/B
15,36
In the woman with active asthma, increase fetal growth monitoring and assessment of immediate fetal health by fetal heart rate monitoring.
III/B
15,36
Seek anesthesiology consultation in preparation for delivery if general anesthesia is anticipated.
III/B
15
Regional is preferable to general anesthesia.
III/B
15
Ensure adequate fetal oxygenation with acute exacerbation by keeping oxygen saturation > 95%.
III/B
15,36
Avoid prostaglandin F2α and ergometrine
III/B
41,42
Consider parenteral “stress-dose” steroids for patients on chronic oral therapy or in those who have received more than 3 wk of systemic steroids in the past year.
III/B
15
Continue maintenance drug therapy.
III/B
15,36
Encourage breast-feeding.
III/B
15,43
Physiotherapy to maintain adequate pulmonary toilet.
III/B
15,36
Prenatal
Labor and Delivery
Postnatal
SARCOIDOSIS General Sarcoidosis is a chronic condition most commonly seen in women of reproductive age, and thus, may complicate pregnancy. The prevalence of sarcoidosis in the general population is estimated to be 10 to 20 per 100,000 population, with a lifetime risk of 0.85% among whites and three to four times more common in the black population.44 The lung is the organ most likely to be affected in sarcoidosis, and the majority of cases are found incidentally on
routine chest x-rays. The differential diagnosis of pulmonary sarcoidosis includes malignancy, TB, HIV infection, collagen vascular disease, and occupational lung disease. Tissue biopsy is required for an accurate diagnosis in all but the most classic presentations. Pulmonary involvement in sarcoidosis is classified by the radiographic stage of disease. Stage I is defined by the presence of bilateral hilar adenopathy, often accompanied by right paratracheal lymph node enlargement. Stage II involves bilateral hilar adenopathy along with interstitial infiltrates. Stage III disease consists of interstitial lung disease with
664 S ECTION F IVE • Late Prenatal
shrinking hilar nodes, and stage IV disease is defined by advanced pulmonary fibrosis. Most individuals (~75%) with stage I disease will have spontaneous regression in 1 to 3 years, and about two thirds of patients at stage II will undergo spontaneous resolution. Those with stages III and IV disease are likely to progress to serious lung impairment without treatment. Sarcoidosis may also involve other organ systems including the skin (maculopapular eruptions, skin nodules, and erythema nodosum), the lymphatic system (lymphadenopathy), the eyes (iridocyclitis, chorioretinitis, and keratoconjunctivitis), and the liver. Rarely, sarcoidosis can occur in the spleen (splenomegaly); the neurologic system; the salivary glands; the bone marrow; the ear, nose, and throat; the heart; the kidneys; bones, joints, or muscle.45,46 Sarcoidosis can also have effects on calcium homeostasis (hypercalciuria and hypercalcemia). The cornerstone of treatment for sarcoidosis is systemic corticosteroids. In general, steroid treatment is reserved for those with significant symptoms due to pulmonary compromise or major extrapulmonary involvement. Corticosteroid therapy may also be of some benefit in milder cases of pulmonary sarcoid in which there is chest x-ray evidence of parenchymal disease (i.e., stage II or above). Whether the risks of long-term corticosteroids are worth the modest (~10%) benefit seen in asymptomatic patients remains unclear.47,48 Chloroquine, hydroxychloroquine, methotrexate, azathioprine, pentoxifylline, thalidomide, cyclophosphamide, cyclosporine, and infliximab have all also been tried in the treatment of chronic or steroid-unresponsive sarcoidosis with variable success.49
well studied in pregnancy. Untreated severe hypercalcemia in the mother could precipitate neonatal hypocalcemia and tetany, but the hypercalcemia associated with sarcoidosis is usually mild and unlikely to lead to such neonatal problems. Sarcoid granulomas have occasionally been noted in the placenta55 but not in the fetus.
Management Options Prepregnancy Preconception counseling should be undertaken in women with sarcoidosis, incorporating the previous information.53 Measurement of baseline parameters should include SaO2 (both resting and with exercise), PFT (including a diffusing capacity for carbon monoxide [DLCO], as a measure of gas exchange that is sensitive to the presence of interstitial lung disease), a chest x-ray, CBC, liver function tests, blood urea nitrogen, creatinine, and serum calcium. In the setting of moderate to severe pulmonary disease, echocardiography should be considered to evaluate for pulmonary hypertension. On the basis of these data, patients with stage I or II disease (and minor extrapulmonary manifestations) may be advised to expect a good pregnancy outcome. Women with more severe and active disease should be counseled that their pregnancy may be complicated by their disease and/or its treatment and that there is the potential for severe maternal illness to have a secondary effect on the well being of the fetus. Severe pulmonary arterial hypertension of any cause poses a very serious maternal mortality risk, and therefore, such women should be discouraged from proceeding with pregnancy (see Chapter 36).
Maternal Risks
Prenatal
Whereas sarcoidosis rarely infiltrates the female reproductive organs, involvement of the endometrium, ovary, and leiomyoma have all been reported.50,51 In the absence of significant cardiopulmonary compromise, sarcoidosis does not appear to adversely affect fertility and does not increase the incidence of fetal or obstetric complications.52 Although some series have described a pregnancy-associated improvement in sarcoidosis,53 followed by a postpartum exacerbation, the general consensus is that pregnancy does not predictably influence the natural history of sarcoidosis.54 It has been postulated that improvement during pregnancy might be due to physiologic increases in maternal free cortisol and/or the immune modulation intrinsic to pregnancy. Among the unfortunate patients in whom sarcoidosis has progressed to the stage of extensive pulmonary fibrosis and hypoxemia, along with cor pulmonale and pulmonary hypertension, the maternal and fetal prognosis is poor.
Breathlessness is common in normal pregnancy but can also be seen in stages II to IV sarcoidosis. Women with sarcoidosis who develop complaints of increased dyspnea require reevaluation with SaO2 (both resting and with exercise), chest x-ray, and PFT. Comparison with the baseline investigations (listed previously) will facilitate the interpretation of this additional testing. In some circumstances, a highresolution CT scan may be needed to define the extent of disease. This evaluation may be undertaken with an acceptable degree of risk owing to fetal radiation exposure. Serial monitoring of maternal calcium (ionized or total calcium corrected for decreasing albumin in normal pregnancy), liver enzymes, creatinine, and CBC approximately once per trimester is also advisable. This may be helpful in identifying hypercalcemia prior to delivery as well as establishing a baseline that may help prevent the inappropriate attribution of abnormalities in creatinine or liver tests to preeclampsia later in pregnancy. Painful joints and erythema nodosum are manifestations of sarcoidosis that may also be seen in normal pregnancies but need to be evaluated carefully, because they may be a manifestation of disease progression. Symptomatic disease attributable to sarcoidosis should generally be treated with systemic steroids, under the supervision of a pulmonologist/internist experienced in treating this disease. As previously stated, the safety of steroids in pregnancy is well established and is discussed in the preceding section on “Asthma.” Symptomatic disease unresponsive
Fetal Risks Beyond severe maternal disease from pulmonary or other organ involvement, leading to fetal compromise, there are no specific risks to the fetus from maternal sarcoidosis. The use of systemic steroids in pregnancy for maternal sarcoidosis poses little risk to the developing fetus. Severe maternal sarcoidosis that is unresponsive to steroids, however, might lead physicians to consider other treatments that are less
C HAPTER 37 • Respiratory Disease 665
to steroids may require treatment with other agents that are less well studied in pregnancy and will require careful consideration of both risk and potential benefits of treatment. Patients with sarcoidosis have a risk of developing hypercalcemia, particularly in the setting of vitamin D supplementation.56 Even in women with a normal serum calcium level, sarcoidosis-associated hypercalciuria can lead to nephrocalcinosis. Pregnant patients with sarcoidosis should, therefore, avoid both vitamin D and calcium supplementation, and the ingredients of their prenatal vitamins should be reviewed to prevent unintended supplementation. The level of angiotensin-converting enzyme (ACE) has been advocated by some experts as an index of disease activity in sarcoidosis, but this may be invalid in pregnancy because ACE levels seem to change independently of sarcoid activity in pregnancy.57
Labor and Delivery Among women with parenchymal lung disease due to sarcoidosis, regional techniques are strongly preferred to general anesthesia for cesarean delivery. Women with severe pulmonary involvement will benefit from an early epidural in labor (to reduce oxygen consumption in response to pain), and an assisted second stage of labor (forceps or vacuum suction) to reduce maternal exhaustion should be considered. Women who have been on supraphysiologic systemic steroids for more than 3 weeks in the preceding year should be considered for stress-dose steroids around the time of labor and delivery.
Postnatal There are no specific recommendations regarding the postpartum management of the parturient with sarcoidosis.
SUMMARY OF MANAGEMENT OPTIONS
Sarcoidosis Management Options
Evidence Quality and Recommendation
References
Prepregnancy Reassure patient of benign nature of sarcoidosis during pregnancy (unless there is preexisting evidence of pulmonary fibrosis, hypoxemia, or pulmonary hypertension).
III/C
53,54
Obtain baseline laboratory and pulmonary function studies.
IV/C
53,54
If lung disease is significant, obtain echocardiogram for assessment of pulmonary hypertension. Discourage pregnancy in presence of severe pulmonary hypertension.
III/B
53,54
Avoid multivitamins containing vitamin D.
III/B
53,54
Monitor serum calcium once per trimester (because of potential neonatal toxicities with maternal hypercalcemia).
III/B
53,54
Monitor for signs and symptoms of progressive pulmonary disease; institute steroid therapy if evidence of significant disease advancement.
III/B
53,54
With substantial parenchymal disease, avoid inhalation anesthesia.
IV/C
53,54
Obtain early anesthesiology consultation in patients with severe disease.
IV/C
53,54
Use parenteral “stress-dose” steroids for patients on chronic oral therapy or in those who have received more than 2–4 wk of systemic steroids in the past year.
III/B
53,54
Watch for neonatal tetany if mother has hypercalcemia.
III/B
53,54
Prenatal
Labor and Delivery
Postnatal No specific recommendations.
666 S ECTION F IVE • Late Prenatal
TUBERCULOSIS General Although TB made a significant resurgence in the western world in the early 1990s, the incidence of TB is once again declining in the United States. In 2004, the Centers for Disease Control and Prevention (CDC) reported a rate of new TB infections of 4.9 per 100,000 individuals.58 There remain, however, a large number of latent (unidentified) and active cases of TB in the western world.59,60 Most of these cases are occurring among the homeless and inner-city residents, among recent immigrants from countries with a high prevalence of TB, and among drug abusers and individuals with HIV infection. Worldwide, TB infection remains a much more daunting problem. It is estimated that one third of the world’s population has been infected with TB and that there are 8 million new cases of TB and 2 million deaths worldwide caused by TB each year.59 Medical contact during pregnancy is an opportunity for the identification and treatment of TB among young women. Such therapy will benefit the mother, her child, and the general public.
Maternal and Fetal Risks Although the incidence and transmission factors for TB are not altered by pregnancy, management requires additional consideration by the clinician. The main concerns are potential fetal infection and drug safety.
Maternal Risks Pregnancy does not alter the clinical course of TB for the mother, and with modern antituberculous therapy, immunocompetent women should expect to make a complete recovery even if the TB is first diagnosed in pregnancy. It has been reported in some series that hepatotoxicity due to isoniazid (INH)—one of the key agents in antituberculous therapy— may occur with increased frequency in pregnancy.61–63
Fetal Risks Risks to the fetus in the setting of maternal TB relate to (1) risk of fetal infection, (2) risk of fetal harm from antituberculous medications, and (3) fetal risks from severe maternal illness. Overall, TBs that is confined to the thorax or limited to lymphadenitis poses little risk to the fetus. Adverse fetal outcomes may be more frequent with disseminated disease.64,65 Mycobacterium tuberculosis rarely crosses the placenta,65 although granulomata may be found in the placenta in the setting of primary or disseminated or miliary disease. True congenital infection is therefore extremely uncommon. This may relate to the observation that disseminated TB almost invariably involves the genital tract, which is a cause of infertility. Criteria for congenital TB include (1) confirmed diagnosis of TB in the newborn; (2) primary granulomatous complexes identifiable in the neonatal liver; and (3) in the absence of neonatal liver lesions, the diagnosis of TB in the newborn is made within a few days of birth (in order to differentiate congenital TB from neonatal/postpartum infection).58,66 The neonate is at risk of postnatally acquired infection only if the mother is still infectious with active TB at the time of delivery. In that unusual setting, the risk of transmission to the neonate is high.67
Low birth weight, preterm delivery, and increased perinatal mortality rates have been reported in the setting of incomplete treatment and advanced or disseminated TB. One small study that compared pregnancy outcomes in pregnant women with extrapulmonary TB versus healthy controls found a significantly higher frequency of low–birth weight infants and infants with low Apgar scores among mothers with extrapulmonary TB.58,67 Given the very low risk of congenital TB infection and the generally good maternal prognosis, the main risk to the developing fetus is the issue of potential teratogenicity/ toxicity of the antituberculous medications.
Management Options Prepregnancy Preconception counseling should address the possible effects of the antituberculous drugs on the developing fetus. Women undergoing treatment for active TB should be advised to delay pregnancy until their course of treatment course is complete. They should be counseled that in the event of an unplanned pregnancy, they should seek prompt medical attention rather than abruptly stopping their treatment. Women who have previously completed an adequate course of antituberculous therapy have no contraindication to pregnancy. Women with latent TB should be offered appropriate treatment prior to pregnancy, with a review of effective contraception if necessary in order to delay pregnancy until after the completion of the treatment.
Prenatal Screening for TB with a tuberculin skin test (TST) is not justified for the whole general obstetric population.68 Pregnant women from high risk populations for TB, however, should undergo a TST unless documentation of recent TST status is available. High risk populations include HIVinfected women; close contacts of persons known or suspected to have TB; immigrants or visitors from areas with a high prevalence of TB; residents and employees of high risk settings (prison, institutions) including health care workers; injection drug users; and medically underserviced, lowincome populations (e.g., inner-city minority populations). TST is both safe and reasonably sensitive throughout pregnancy.69,70 Women who have a positive skin reaction according to standard criteria71 and women with symptoms suggestive of active pulmonary TB (regardless of their TST results) should have a chest x-ray performed to look for evidence of active or latent pulmonary TB. If the chest x-ray is suggestive of active TB, sputum specimens must be obtained to evaluate for Mycobacteria. Susceptibility testing for INH, rifampin, and ethambutol should be performed on a positive initial culture. Prior to commencing antituberculous treatment, baseline measurements of liver enzymes, bilirubin, alkaline phosphatase, serum creatinine, and platelet count should be obtained. HIV testing, if not already completed as part of prenatal care, is recommended for all pregnant patients with evidence of active or prior TB. Testing of visual acuity and red-green color discrimination should be obtained when ethambutol is to be used.
C HAPTER 37 • Respiratory Disease 667
If sputum testing is positive (on acid-fast bacillus [AFB] smear, polymerase chain reaction [PCR] testing, or culture), treatment should be promptly initiated. The maternal and fetal benefits of treatment dramatically outweigh any concerns about potential drug toxicity to the fetus. Tuberculous infections in pregnancy should be managed jointly by an obstetrician and a physician experienced in the treatment of TB. Directly observed therapy is recommended because it ensures compliance. Pregnancy data about the commonly used antimycobacterial agents are reviewed in Table 37–5.72–76 Streptomycin is the only commonly used antituberculous drug that is clearly contraindicated in pregnancy, because it has the potential to cause eighth cranial nerve damage,77 leading to neonatal deafness. The recommendations by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) for uncomplicated TB in a pregnant individual
include an initial 2-month course of INH, rifampin, ethambutol, and pyrazinamide. This is followed by a further 4 months of treatment with just INH and rifampin (for a total of 6 mo of treatment).71 The current guidelines for Americans by the American Thoracic Society, in contrast, suggest that the initial treatment regimen in pregnancy should consist of INH, rifampin, and ethambutol without pyrazinamide. They comment that pyrazinamide is excluded “because of insufficient data to determine safety.” If pyrazinamide is not included in the treatment regimen, the minimum recommended duration of treatment is 9 months.72 All women taking INH should also receive pyridoxine 25 to 50 mg daily to minimize the risk of neuropathy.78 The amount of pyridoxine in multivitamins is variable but generally less than the needed amount. Vitamin K should probably also be given to the mother from 36 weeks’ gestation onward in a dose of 10 mg daily to decrease the risk of
T A B L E 3 7 – 5
Pregnancy Data Regarding Commonly Used Antimycobacterial Agents72–76,209 AGENT AND USUAL DOSE Isoniazid (INH) ● 5 mg/kg, up to a maximum of 300 mg daily ● Dispensed in the United States as 50-, 100-, and 300-mg tablets and 50 mg/5 mL syrup
Rifampin ● 10 mg/kg, up to a maximum of 600 mg daily ● Dispensed as 150- and 300-mg scored tablets in the United States
Ethambutol ● 15–25 mg/kg, up to a maximum of 2500 mg daily ● Dispensed as 100- and 400-mg tablets in the United States Pyrazinamide ● 15–30 mg/kg PO daily, up to a maximum of 3000 mg daily Streptomycin ● Dose varies
ADVERSE EFFECTS IN GENERAL
PREGNANCY DATA
ADDITIONAL NOTES
FDA pregnancy classification C. High lipid solubility; easily passes into fetal circulation. ● Fair data to suggest this agent is safe in human pregnancy and any risk is outweighed by potential benefit. However, concerns about potential increase in INH hepatotoxicity in pregnancy make its routine use for prophylaxis in pregnancy in low risk cases not advisable.
●
FDA pregnancy classification C. Limited data suggest no adverse fetal effects.
●
FDA pregnancy classification B. Limited data suggest no adverse fetal effects.
●
FDA pregnancy classification C. Human data extremely limited.
●
FDA pregnancy classification D. Reports of fetal ototoxicity preclude use.
●
●
Hepatitis Peripheral neuropathy ● Drug interaction with many agents, especially anticonvulsants ● Cutaneous hypersensitivity
●
●
●
●
● ● ●
Fever Nausea Hepatitis Purpura Flulike symptoms at high doses ● Orange secretions ● Increased metabolism of many agents
●
●
●
Retrobulbar neuritis in 1% of patients ● Peripheral neuropathy
●
● ●
●
●
● ●
Thrombocytopenia Hepatotoxicity Interstitial nephritis Nephrotoxicity
Ototoxicity
●
●
●
●
Always administer with 25–50 mg/day of pyridoxine (vitamin B6) to decrease the risk of neurotoxicity in the mother. ● Give vitamin K to mother near birth (10 mg PO daily from 36 wk on) and infant at birth to decrease risk of postpartum hemorrhage and hemorrhagic disease of the newborn. ● Check transaminases monthly while on the medication.
Give vitamin K to mother near birth (10 mg PO daily from 36 wk on) and infant at birth to decrease risk of postpartum hemorrhage and hemorrhagic disease of the newborn. ● Limited data suggest no adverse fetal effects.
At each monthly visit, patients taking this agent should be questioned regarding possible visual disturbances, including blurred vision or scotomata; monthly testing of visual acuity and color discrimination is recommended for patients receiving the drug for longer than 2 mo. Use in pregnancy supported by international recommendations but current ATS guidelines caution against use. Essential for multidrugresistant TB and HIV-positive patients. Avoid use in pregnancy.
●
ATS, American Thoracic Society; FDA, U.S. Food and Drug Administration; TB, tuberculosis. Adapted from Powrie RO: Drugs in pregnancy. Respiratory disease. Best Pract Res Clin Obstet Gynaecol 2001;15:913–936.
668 S ECTION F IVE • Late Prenatal
hemorrhagic disease of the newborn.79 The most common serious adverse effect of INH is a toxic hepatitis. Symptoms of hepatotoxicity (e.g., nausea, abdominal pain, hepatic tenderness) in association with hepatic transaminase elevations greater than three times the normal range or asymptomatic elevations in transaminases greater than five times the normal range should prompt discontinuation of therapy (and consideration of an alternative regimen). Pregnant women are at a higher risk of developing INH-related hepatotoxicity; therefore, testing of hepatic transaminases at initiation of treatment and at monthly intervals thereafter is advisable.61–63 Management of HIV-related TB is complex and requires expertise in the management of both HIV disease and TB. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculous medications, it is strongly encouraged that experts in the treatment of HIV-related TB be consulted. Whether a positive TST, in the absence of active pulmonary TB, merits treatment with antituberculous medications during pregnancy depends on several factors: the size of the woman’s TST response, her HIV status, and whether or not the woman has had recent contact with someone with an active case of TB. Indications to treat a positive TST in pregnancy, because of a high short-term risk of progression to active disease, include HIV-infected women exposed to an active case of TB; HIV-infected women with a TST result greater than 5 mm; any woman with recent active TB contact and a TST result greater than 5 mm; and women with a recent conversion from a negative to a positive TST. It remains controversial whether other pregnant women with normal immune status and a positive TST (not previously treated) should receive prophylaxis during pregnancy. A decision analysis found that antepartum treatment of a positive TST would result in fewer active TB cases, would be less expensive, and would improve life expectancy of the pregnant women affected.80 Nonetheless, among asymptomatic
immunocompetent pregnant women who are reliable to follow-up, treatment of a positive TST can generally be delayed until the postpartum period.81,82 The standard regimen for treatment of a positive TST is INH 5 mg/kg (up to a maximum of 300 mg) daily for 9 months. Twice-weekly doses of 15 mg/kg (up to a maximum of 900 mg) for 9 months may also be used as an alternative as part of directly observed therapy. Pyridoxine 25 to 50 mg daily should also be given, as in treatment of active TB.
Labor and Delivery There are no specific recommendations regarding the pregnant woman with TB at the time of labor and delivery, except for appropriate infection control issues in the infectious patient. Because transmission of TB infection from mother to infant (neonatal TB) may occur postpartum, medical contact at the time of delivery may be an opportunity to evaluate the symptomatic woman for active and infectious pulmonary TB.83
Postnatal In the rare circumstance of identifying a woman with active and infectious (sputum-positive) TB in late gestation or at the time of delivery, the neonate must unfortunately be separated from the mother until she is no longer infectious. In this circumstance, the neonate should also be given INH to prevent it acquiring neonatal infection. It is also reasonable to consider treating the neonate with INH-resistant bacilli Calmette-Guérin (BCG) vaccine to boost its immunity.84 Breast-feeding should not be discouraged for women being treated with INH, pyrazinamide, ethambutol, and/or rifampin. These agents are found in only small concentrations in breast milk and are not known to produce toxicity in the nursing newborn. These concentrations are also not significant enough to provide any protection to the nursing infant from infection with TB.85
SUMMARY OF MANAGEMENT OPTIONS
Tuberculosis Evidence Quality and Recommendation
References
Screen at-risk populations for TB with a TST prior to pregnancy.
III/B
68–70
If positive TST, treat as appropriate and delay pregnancy until after completion of antituberculous therapy.
III/B
71,72
Counsel regarding the potential teratogenesis of streptomycin, if being used.
III/B
77
Perform TST on all women from high risk populations (see text).
III/B
68–72
Arrange HIV testing for all women with a positive TST.
IV/C
71,72
Administer INH prophylaxis during pregnancy to TST-positive women (without active TB) if they are HIV-positive, have a known recent TB exposure, or are new TST-converters.
IV/C
71,72
Management Options Prepregnancy
Prenatal
C HAPTER 37 • Respiratory Disease 669 Evidence Quality and Recommendation
References
Send sputum cultures (with antibiotic sensitivity testing) from women with active TB and start a recommended drug regimen: INH, rifampin, ethambutol ± pyrazinamide.
IV/C
71,72
Give pyridoxine 25–50 mg/day when using INH.
III/B
78
Measure hepatic transaminases monthly in pregnant women on INH.
IV/C
71,72
IV/C
71,72
Only separate baby from mother at birth if mother has infectious TB, and only until no longer infectious (~10 days into therapy).
IV/C
71,72
Administer INH and BCG vaccine to neonate if mother infectious at birth.
III/B
84
Encourage breast-feeding.
IV/C
85
Management Options
Labor and Delivery No specific recommendations except infection precautions needed with active disease. Postnatal
BCG, bacillus Calmette-Guérin; INH, isoniazid; TB, tuberculosis; TST, tuberculin skin test.
KYPHOSCOLIOSIS General Kyphoscoliosis is usually an idiopathic disorder (>80%) involving kyphosis (anteroposterior spinal angulation) and/ or scoliosis (lateral spinal curvature) that begins in childhood—and hence, often affects women of reproductive age. Affected individuals may develop functional lung impairment, the degree of which correlates well with the severity of spinal deformity. The pattern of abnormality on PFTs is restrictive, with decreased total lung capacity (TLC) and vital capacity (VC) and preserved RV. Chest wall compliance also typically decreases with age, increasing the work of breathing. Kyphoscoliosis that is mild has a good prognosis. Conversely, in severe cases, pulmonary hypertension may develop as a result of persistent hypoxemia and result in cor pulmonale. Such individuals have a life expectancy of less than 1 year. Although various surgical and nonsurgical treatments are often undertaken in childhood, surgery has little role in adults with kyphoscoliosis. Medical therapy can include pulmonary rehabilitation, the use of supplemental oxygen, and occasionally, the use of negative- or positivepressure ventilators.86 Mild degrees of kyphoscoliosis are common among pregnant women. More severe deformity resulting in respiratory impairment occurs in less than 0.1% of pregnancies. In some severe cases, it is remarkable that patients can complete a successful pregnancy despite their degree of deformity; the abdominal cavity may appear so contracted that there seems to be insufficient room for a fetus to develop normally. Nonetheless, positive outcomes are usually seen.87
Maternal and Fetal Risks Among women with significant kyphoscoliosis, the maternal risks are mainly cardiac failure and cor pulmonale in the rare
patient with significant pulmonary hypertension. To develop pulmonary hypertension, the condition has to be severe enough to produce hypoxemia at rest. The patient is at risk of respiratory failure if the VC is less than 1.5 L, particularly if it is less than 1 L.88,89 The main risks to the fetus are IUGR and preterm delivery related to maternal hypoxemia.90 Fetal hypoxic brain damage has been described in a patient with kyphoscoliosis and severe hypoxia (maternal PaO2 < 59 mm Hg).91
Management Options Prepregnancy Preconception counseling should be undertaken, incorporating the previous information. PFTs should be obtained. If the VC is greater than 2 L, patients may be advised that they will generally tolerate pregnancy and delivery. If the VC is less than 2 L, the woman should be advised that she will be at increased risk for pulmonary complications with pregnancy. A blood gas analysis should be obtained in all women with a VC less than 2 L and if the resting PaO2 is decreased, the fetus should be considered at risk of growth restriction. If the resting PaCO2 is increased prepregnancy, the risk of maternal pulmonary complications in pregnancy is high. In the setting of significant abnormalities on ABGs and PFTs—particularly resting hypoxia or hypercapnia—the woman should be evaluated for pulmonary hypertension. An ECG may be uninformative at evaluating for right ventricular hypertrophy in kyphoscoliosis, owing to the deformity of the chest. The pulmonary artery pressure and right heart function should therefore be assessed by echocardiography. Moderate to severe pulmonary hypertension is a relative contraindication to pregnancy (see Chapter 36). Before such a drastic recommendation is made, however, the physician may want to consider performing a direct measurement of
670 S ECTION F IVE • Late Prenatal
pulmonary vascular indices via a formal right cardiac catheterization.
Prenatal Women with significant kyphoscoliosis require comprehensive medical care and follow-up regarding diagnosis and treatment of respiratory infections, bronchospasm, and evidence of cardiac failure. Women with hypoxia should be provided with supplementary oxygen therapy to reduce the risk of adverse fetal effects such as growth restriction. Patients identified to have significantly elevated pulmonary artery pressures and vascular resistance should be offered a termination of pregnancy, in view of the markedly increased risk of maternal mortality or severe morbidity. These women may require hospitalization in later gestation, owing to impending respiratory compromise or for fetal concerns. Respiratory support with nasal positivepressure ventilation has been used in some patients who have deteriorated in the third trimester.92,93 Obstetric
prenatal care relates mainly to monitoring for IUGR and preterm labor. Elective preterm delivery may be indicated for either maternal (increasing hypoxemia or frank respiratory failure) or fetal (signs of fetal hypoxia ± IUGR) indications.
Labor and Delivery Women with severe kyphoscoliosis are often delivered by cesarean section because of concerns about concomitant pelvic deformity.94 Regional anesthesia is much preferred to general anesthesia, and despite the severity of back deformity, a spinal or epidural puncture and catheterization is often possible in these patients—because the defect in kyphoscoliosis is typically in the upper part of the spine.
Postnatal After delivery, optimal medical care includes early mobilization, physiotherapy, and ongoing monitoring for cardiac complications and respiratory infections.
SUMMARY OF MANAGEMENT OPTIONS
Kyphoscoliosis Management Options
Evidence Quality and Recommendation
References
Prepregnancy Obtain PFTs for assessment of vital capacity; obtain ABGs to assess O2 and CO2 levels.
III/B
88–90
If PFTs/ABGs are abnormal, assess for evidence of pulmonary hypertension; if present, advise against pregnancy.
IV/C
88–90
Counsel regarding risk for increase in pulmonary compromise as pregnancy progresses; discuss risk for fetal growth restriction and possible need for preterm delivery.
IV/C
88–90
Monitor respiratory function: clinically and with periodic oxygen saturation measurement.
IV/C
88–90
Discuss pregnancy termination if pulmonary hypertension is present.
III/B
88–90
If severe cardiorespiratory compromise develops, initiate surveillance for fetal growth restriction and well-being.
III/B
88–91
Administer oxygen if maternal Sao2 < 95%. Consider use of nasal intermittent positive-pressure ventilation if respiratory status deteriorating.
IV/C
92,93
Consider elective preterm delivery for frank respiratory failure or severe fetal compromise.
III/B
88–90
Supplementary oxygen if low Sao2 values.
III/B
88–90
Consider cesarean section if associated pelvic deformities, though vaginal delivery possible in most cases; regional anesthesia for cesarean section is possible in most cases.
IV/C
88–90
—/GPP
—
Prenatal
Labor and Delivery
Postnatal Chest physiotherapy, especially following general anesthesia.
ABGs, arterial blood gases; GPP, good practice point; PFTs, pulmonary function tests; Sao2, arterial oxygen saturation.
C HAPTER 37 • Respiratory Disease 671
CYSTIC FIBROSIS General CF is an autosomal recessive multisystem disorder characterized by recurrent pulmonary infections due to unusually thick bronchial secretions. The incidence of CF is about 1 in 2000 live births. Five percent of whites are carriers of the CF gene. Although CF remains a potentially fatal disease associated with a decreased life expectancy, the therapy of CF has undergone rapid evolution in the past few decades with a resulting significant improvement in patient survival. Many more women with CF are now surviving to reproductive age, and so we can expect to see more cases of CF in pregnancy.95 The symptoms and signs of CF include recurrent and persistent pulmonary infections, pancreatic exocrine insufficiency, and elevated sweat chloride levels. A functional defect in the complex chloride channel found in all exocrine tissues results in thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract.96 The resulting chronic pulmonary disease is the leading cause of morbidity and mortality in patients with CF. Pulmonary involvement is characterized by recurrent pneumonias, chronic bronchitis (with or without bronchiectasis), and an obstructive pattern on PFTs. The tenacious respiratory secretions facilitate colonization of the airway and sinuses with pathogenic bacteria. Staphylococcus aureus and Haemophilus influenzae are common pathogens during early childhood, but over 70% of adults with CF are chronically ultimately infected with Pseudomonas aeruginosa, a highly pathogenic and resistant bacteria. Persistent infection with the species Burkholderia cepacia, notorious for inducing airway injury and exhibiting high-level antibiotic resistance,97 is associated with an accelerated decline in pulmonary function and shortened survival among CF patients. Acute or subacute exacerbations in CF patients are characterized by increased cough, sputum production, fever, and/or shortness of breath. Spirometry usually demonstrates a decline in airflow relative to baseline during these episodes, although chest radiographs may not show significant changes over baseline. Antibiotics are routinely prescribed when patients with CF develop an exacerbation. Most physicians also prescribe aerosolized β-adrenergic agents to CF patients, particularly those who have clinical or spirometric evidence of reactive airways. Ipratropium bromide is also occasionally prescribed. The nebulized endonuclease DNase I is often used in CF patients with persistent productive cough, because it can decrease the viscosity of expectorated sputum by cleaving long strands of DNA into smaller segments. Patients who chronically produce purulent sputum, particularly those with concomitant bronchiectasis, benefit from chest physiotherapy and postural drainage to assist the clearance of secretions. Inhaled corticosteroids and/or daily azithromycin therapy are also sometimes used in the long-term management of this disease. Pancreatic insufficiency is another common sequela of CF which may lead to malabsorption of fat and protein, an issue that can often be reversed with oral supplementation of pancreatic enzyme extracts. Nonetheless, many CF patients remain significantly underweight. Endocrine pancreatic
insufficiency resulting in diabetes mellitus can also be seen, particularly in individuals surviving into adulthood. Optimal medical therapy of CF lung disease can delay but does not stop disease progression, and premature death from respiratory failure still occurs in the majority of patients. As in other progressive lung diseases, lung transplantation provides an additional, albeit imperfect, management option for end-stage CF. Thirty-three percent of all double-lung transplants in adults are performed in CF patients.98
Maternal and Fetal Risks Maternal Risks Women with CF often suffer from reduced fertility, owing to both malnutrition-related amenorrhea and the production of an abnormally tenacious cervical mucus.99 Data from the United States100 and the United Kingdom101 report a pregnancy rate for women with CF of 40 per 1000 per year, compared with 80 per 1000 for unaffected women. Of those who successfully conceive, 70% to 80% of pregnancies in patients with CF will result in a live birth. Among women with CF who do not have frank diabetes, glucose tolerance may be more subtly impaired, and as such, the risk of gestational diabetes appears to be increased.102 In contrast to early case reports of poor maternal outcome in CF patients, more recent studies have demonstrated the relative safety of pregnancy among women with CF who have good preexisting lung function.103–108 It is reported that maternal and fetal outcomes are generally favorable if the prepregnancy FEV1 exceeds 50% to 60% of the predicted value. If the mother has any evidence of pulmonary hypertension, however, her prognosis is much more guarded. Pulmonary hypertension from any cause confers a significant risk of right ventricular decompensation and maternal mortality in pregnancy. Available data indicate that pregnancy does not appear to affect the rate of decline in FEV1 or survival compared with those in nonpregnant reproductive-age women.108,109 Following pregnancy, deaths among new mothers usually occur in those with the most severe lung disease. The absence of B. cepacia colonization, pancreatic insufficiency, or a prepregnancy FEV1 below 50% of predicted were all associated with better maternal survival rates. Women with CF who become pregnant face an additional nutritional demand as well. Those who achieve pregnancy despite being significantly underweight may become emaciated if they are unable to keep up with the significant nutritional demands of the fetoplacental unit.110
Fetal Risks Well-nourished mothers with reasonably preserved lung function can expect a good pregnancy outcome. Following successful conception, 70% to 80% of pregnancies in women with CF will result in a live birth. In women with greater disability, however, IUGR and premature labor can result from chronic hypoxia and malnutrition, and maternal diabetes is associated with an increased risk of adverse pregnancy outcome in women with CF. Over half of women with severe CF lung disease deliver prematurely,108 with acute episodes of pneumonia in pregnancy particularly associated with an increased risk of preterm delivery and
672 S ECTION F IVE • Late Prenatal
pregnancy loss. Malnutrition can also lead to fetal growth restriction. Although most medications used for treatment of CF are safe for use in pregnancy, infection with some multidrugresistant organisms may require use of antibiotic agents with less extensive fetal safety data. All offspring of a mother with CF will be at least heterozygous for the condition and, in view of the high prevalence of the CF gene in the community, will have a considerable risk of being phenotypically affected.
Management Options Prepregnancy Preconception counseling should be undertaken in women with CF, including detailed genetic counseling. Genetic counseling is useful to explain to the parents the risk of having a child affected with CF, as determined by the partner’s carrier status. Identification of the specific gene mutation in the mother will facilitate screening her partner and fetus, because most CF mutations can be identified by screening for the 20 to 30 most prevalent mutations.109 If a mutation is identified in both mother and father, prenatal diagnosis with chorionic villus sampling or amniocentesis can be undertaken.111 Prenatal diagnosis should be undertaken with the understanding that if the fetus is found to be affected, it may help the couple emotionally prepare for an affected child or may lead them to consider pregnancy termination.112 General medical care and pharmacologic treatment of CF should also be reviewed and optimized prior to conception. Given the complex nature of the disease, this is best accomplished by a multidisciplinary team led by a physician experienced in the care of CF and involving chest therapists, nutritionists, and social workers. The nutritional status of the woman should be assessed and optimized prior to pregnancy, with a body mass index (BMI) less than 18 kg/m2 considered a relative contraindication to pregnancy. The presence of pulmonary vascular disease should be sought, with a clear description of the substantial maternal risks communicated if significant pulmonary hypertension is found.113,114 Pulmonary function tests, ABGs, and echocardiography (with estimation of pulmonary artery pressures) should be obtained or reviewed. Pregnancy should be strongly discouraged if the FEV1 is less than 50% of predicted.115 In the setting of severe disease, the issue that offspring may be left without a mother at a relatively young age needs to be tactfully discussed with the woman, because the 10-year mortality rate among pregnant women with CF is approximately 20%. Although heart and lung transplantation may be a future option for some patients with CF, it will not be available for the majority given the shortage of organ donors.
Prenatal The primary goals of management for women with CF in pregnancy include optimization of her pulmonary and nutritional status. Women with severe lung impairment and/or pulmonary hypertension presenting in early pregnancy should be informed of the substantial personal risk of a
pregnancy to their own health and should be offered a termination of pregnancy. CF patients require ongoing optimal medical care throughout pregnancy. These women are usually utilizing chest physiotherapy and/or postural drainage on a daily basis, and this treatment should be continued. Exacerbations of lung involvement should be managed as they would be outside of pregnancy, recognizing that severe pulmonary exacerbations can lead to hypoxia and increase the risk of preterm delivery and fetal death. These should be a very low threshold for hospital admission in the setting of respiratory infections. The dosing of antibiotic agents may require adjustment owing to the altered pharmacokinetics of pregnancy. The use of penicillins, cephalosporins, trimethoprim/ sulfamethoxazole, and/or aminoglycosides is safe in pregnancy.116,117 Quinolone antibiotics have limited data regarding fetal safety in humans, but should be used when clinically indicated in pregnancy for the management of CF.118,119 Bronchodilator drugs can be used safely in pregnancy. The use of supplemental oxygen is essential for maternal and fetal well-being in the setting of hypoxia. Maternal malnutrition may lead to IUGR. Women who enter pregnancy significantly underweight may become emaciated in pregnancy owing to the additional nutritional demands of the fetoplacental unit. Whereas normal pregnancy is associated with an average weight gain of 10 to 12 kg, this can be difficult for the pregnant woman with CF. These women may need to eat 120% to 150% of their recommended daily caloric intake to maintain their body weight even when not pregnant, and to achieve adequate weight gain in pregnancy, they typically need to consume a further 300 kcal/day.120 Even among CF women with normal prepregnancy weight, pregnancy-related dyspepsia, reflux, nausea and vomiting, and constipation may lead to a decrease in caloric intake. The additional calories needed for a healthy pregnancy may, therefore, be difficult to meet without resorting to enteral feeding. Involvement of a clinical dietician is thus advisable for monitoring and enhancement of the woman’s nutritional status. Because many women with CF will have underlying impaired glucose tolerance, screening for gestational diabetes should occur early in gestation (i.e., initially at ~18 wk’ gestation, repeated at 24 to 28 weeks if initially normal). Most CF patients who are identified to have gestational diabetes will require insulin therapy. CF patients with diabetes should achieve the usual tight control of blood glucose to optimize pregnancy outcome. If women with CF develop IUGR, decreasing maternal weight, or deteriorating respiratory function despite optimal medical treatment, facilitation of preterm delivery might be considered in individual cases—considering both maternal and fetal risks and benefits.
Labor and Delivery A vaginal delivery is preferable for women with CF to reduce the risk of postoperative pneumonia and other maternal complications associated with an operative delivery. Use of regional anesthesia is ideal, because it will decrease maternal oxygen requirements associated with pain and avoid the need for general anesthesia should an urgent cesarean delivery be needed. In women with moderate to severe lung disease, an assisted second stage of delivery (with forceps or
C HAPTER 37 • Respiratory Disease 673
vacuum suction) should be considered to avoid maternal exhaustion.
Postnatal The vast majority of women with CF should be strongly encouraged to breast-feed their babies, because the common medications for the treatment of CF are safe to take during breast-feeding. Breast-feeding might not advisable, however,
in severely ill or malnourished women. If the mother’s general health is very poor, bottle feeding may permit alternate caregivers to assist in feeding and thus allow the mother to rest. The breast milk of mothers with CF has a slightly lower fat content than usual (mainly essential fatty acids) but normal electrolyte content and is adequate to nourish the child.121–123 Infants of mothers with CF are typically screened for CF by their pediatrician.
SUMMARY OF MANAGEMENT OPTIONS
Cystic Fibrosis (Maternal) Management Options
Evidence Quality and Recommendation
References
Prepregnancy Document baseline respiratory function with PFTs, ABGs, echo.
III/B
103–108,110
Counsel regarding maternal risks of respiratory failure, congestive cardiac failure, IUGR, and preterm delivery if FEV1 < 50% and/or pulmonary hypertension exists
III/B
103–108,110
Counsel regarding fetal risks of developing CF and certainty of being a carrier.
III/B
109,110
Assess patient weight and encourage patient to optimize nutritional status.
III/B
110
Optimize medical management of CF
III/B
110
Care for patient via multidisciplinary team led by individual with expertise in CF management.
—/GPP
—
Counsel regarding fetal risks of developing CF and certainty of being a carrier—if not done prepregnancy (as above).
III/B
109,110
Optimize medical management:
III/B
110
Increase calorific intake in pregnancy.
III/B
110,120
Monitor for IUGR and preterm delivery.
III/B
108
III/B
110
Assisted vaginal delivery may be necessary.
III/B
110
Avoid general anesthesia for cesarean section.
III/B
110
Monitor respiratory function.
III/B
110
Continue regular medications; breast-feeding is not contraindicated.
III/B
121–123
Gene test father for CF carrier status—will determine fetal CF risk and inform the potential for informative prenatal diagnosis (genes for CF identifiable in about 99% of cases).
Prenatal
Chest physiotherapy.
●
Bronchodilators.
●
Treat pulmonary exacerbations as when nonpregnant.
●
Labor and Delivery Monitor respiratory function (oxygen saturation). Supplemental oxygen if hypoxic. Hemodynamic monitoring of women with pulmonary hypertension.
Postnatal
ABGs, arterial blood gases; CF, cystic fibrosis; FEV1, forced expiratory volume in 1 sec; GPP, good practice point; IUGR, intrauterine growth restriction; PFTs, pulmonary function tests.
674 S ECTION F IVE • Late Prenatal
PNEUMONIA General Pneumonia and influenza are the seventh leading cause of death in the United States, and the leading cause of infectious death.124 The incidence of pneumonia in pregnancy is between 0.8 and 2.7 cases per 1000 deliveries,125,126 a rate similar to that in the nonpregnant population. The onset of pneumonia does not seem to occur at any particular point in gestation, with one study noting an average gestational age at diagnosis of 32 weeks.127 Respiratory failure develops in up to 10% of pregnant women with pneumonia128 and accounts for 12% of obstetric patients requiring intubation.129 Overall, pneumonia accounts for 4.2% of antepartum admissions for nonobstetric causes.130 Risk factors for the development of pneumonia in pregnancy are maternal disease, including HIV infection, asthma, and CF; smoking; anemia; cocaine use; alcohol abuse; maternal corticosteroid administration for fetal lung maturity; and tocolytic therapy use. Overall, about 24% of women with pneumonia in pregnancy have a predisposing condition.131 Perhaps the most important role for physicians in the assessment and management of suspected pneumonia in pregnancy is to carefully review the differential diagnosis. Community-acquired pneumonia in the pregnant patient generally presents with typical features (abrupt onset of fever and rigors, productive cough, tachycardia, tachypnea, fever, and localized inspiratory “crackles”). Pulmonary embolism is the leading cause of maternal mortality in the United States and the United Kingdom, and it can present very similarly with dyspnea, cough, chest pain, fever, and pulmonary infiltrates. Aspiration pneumonitis and pulmonary edema related to sepsis, tocolysis, or preeclampsia can also present with a similar clinical picture. The maternal physiologic changes to the respiratory system do not significantly alter the susceptibility to pneumonia. An exception to this principle is the pregnancyassociated reduction in cell-mediated immunity, which leaves pregnant women with an increased susceptibility to viral and fungal pneumonias. As such, pregnant women are at an increased risk of severe pneumonia and disseminated disease from atypical pathogens such as herpesvirus, influenza,132,133 varicella,134 and coccidioidomycosis.135
to 1 day’s background radiation), there should be no hesitation about performing chest radiology in pregnant patients suspected of having pulmonary disease. Other fetal risks in the setting of maternal pneumonia include an increased risk of miscarriage, preterm labor, prematurity, and low birth weight. Most cases of pneumonia in pregnancy are caused by organisms that do not directly affect the fetus, but occasionally, the organism causing pneumonia may present a specific risk to the fetus (e.g., varicella pneumonia and congenital varicella syndrome).138
Management Options Prepregnancy Preconception counseling is usually not relevant to bacterial pneumonia in otherwise healthy women. In HIV-infected women with low CD4 cell counts, however, continuation of Pneumocystis prophylaxis during pregnancy should be advised because this infection is the leading cause of AIDS-related death of pregnant women in the United States.139 Given the increased attack rate and morbidity of influenza infection among pregnant women, the CDC and the American College of Obstetricians and Gynecologists (ACOG) have recommended that women currently pregnant or anticipating pregnancy should routinely receive influenza vaccination during the influenza season regardless of gestational age.140 Pneumococcal vaccine is advised for women with high risk conditions—such as diabetes mellitus, asthma, chronic cardiac or pulmonary disease, or any other disease or treatment affecting immune function—either before or during pregnancy. Pneumococcal vaccine is also mandatory in women with prior splenectomy and in women with functional hyposplenism (e.g., sickle cell disease) and is recommended for women living in long-term care facilities or prisons.141 Women without demonstrable immunity to the varicella virus should also be offered immunization with the varicella vaccine prior to pregnancy, though this live attenuated virus should not be administered during gestation.
Prenatal and Postnatal Recommendations regarding empirical therapy for community-acquired pneumonia, per the American Thoracic Society (ATS),142 are reviewed in Table 37–6. Per these
Maternal and Fetal Risks Pneumonia in pregnant women may not be more common than in the general population, but it may result in greater morbidity and mortality owing to the physiologic changes of pregnancy and the needs of the fetus. Maternal prognosis from pneumonia is generally good in the antibiotic era, although severe maternal morbidity and significant mortality from primary varicella (maternal mortality ~14%)136 and influenza pneumonia remain a major concern. Women with immunodeficiency due to HIV are at the additional risk of opportunistic infections (e.g., Pneumocystis carinii pneumonia, TB) and require very careful attention. Because radiographic evidence of a pulmonary infiltrate is considered the gold standard for diagnosing pneumonia, a chest x-ray should be obtained in almost all patients.137 Given the negligible fetal radiation exposure of a single chest x-ray with abdominal shielding (approximately equal
T A B L E 3 7 – 6
Empirical Antibiotic Regimens for the Treatment of Community-acquired Pneumonia in Pregnancy222,228,229 For uncomplicated pneumonia in patients who do not require hospitalization: Standard: azithromycin 500 mg PO on day 1 followed by 250 mg daily for 4 days Alternate: erythromycin 250 mg qid PO for 10–14 days ● For uncomplicated pneumonia in patients requiring hospitalization: ceftriaxone 2 g IV once daily with azithromycin 500 mg IV daily (or erythromycin 500 mg IV q6h). Once patient is afebrile and stable, switch to azithromycin 500 mg PO daily × 7–10 days (or erythromycin 250–500 mg PO qid × 10–14 days) with cefuroxime axetil 500 mg PO bid for 10–14 days. ●
C HAPTER 37 • Respiratory Disease 675
guidelines, treatment varies according to the severity of illness (as reflected by whether the patient qualifies for inpatient versus outpatient care) and also reflects the increasing prevalence of drug-resistant organisms. In pregnancy, the threshold for hospitalization of borderline patients should be low, given the potential maternal and fetal risks of hypoxia from a worsening condition. Routine collection of sputum and blood cultures before initiation of antibiotic therapy is advisable, at least among hospitalized patients, even though an etiologic organism is found in only about half of cases investigated.142,143 In the hospital, patients initially treated with intravenous antibiotics can be switched to oral agents once the patient is afebrile and improving. With appropriate antibiotic therapy, some improvement in the clinical course is expected within 72 hours. A full adequate course of therapy is 10 to 14 days, except for azithromycin, which can be given for only a shorter course because of its extended tissue half-life. Although the ATS guidelines apply quite well to pregnant women, the treating physician should bear a few additional points in mind. If parenteral erythromycin is selected, the use of the estolate ester should be avoided owing to a relatively high incidence of subclinical, reversible hepatotoxicity when used during pregnancy.144 Although clarithromycin and levofloxacin are often recommended for the treatment of possible drug-resistant pneumococci in the nonpregnant population, these drugs should be avoided in pregnancy. Clarithromycin appears to be teratogenic in the animal model and, therefore, should be used in only situations in which it is the drug of choice. The use of fluoroquinolones
such as levofloxacin has also been discouraged owing to a described ability (ciprofloxacin and ofloxacin) to cause an irreversible arthropathy in immature experimental animals. Although subsequent human data have been generally reassuring, these agents should still be considered relatively contraindicated in pregnancy.118,119 Tetracyclines cause staining of fetal bones and teeth and should not be used in pregnancy. Doses of antibiotics selected should be in the upper recommended range in pregnancy145 because of increased renal clearance. Patients may use acetaminophen as an antipyretic. Critically ill women with sepsis or refractory hypoxia may require intubation and assisted ventilation. Fairly standard ventilatory settings can be utilized, with adjustment to maintain the acid-base changes typical of pregnancy (i.e., PaCO2 28–32, normal pH). Varicella infection in pregnancy confers a risk of transplacental infection and embryopathy, particularly in the first half of pregnancy, with an incidence of 1% to 2%. Varicella of the newborn is a life-threatening illness that may occur when a newborn is delivered within 5 days of the onset of maternal illness or after postdelivery exposure to varicella. Therefore, if exposure to varicella virus occurs in pregnancy in a woman without protective immunity, varicella zoster immune globulin (VZIG) should be administered within 96 hours in an attempt to prevent maternal infection. Because of the high prevalence and morbidity of pneumonia associated with primary varicella infection in pregnancy, parenteral acyclovir should be given to all women who develop varicella infection in pregnancy.146–150
SUMMARY OF MANAGEMENT OPTIONS
Pneumonia Management Options
Evidence Quality and Recommendation
References
Prepregnancy Vaccinate for influenza during flu season.
IV/C
140
Pneumococcal vaccination for women with splenectomy or immunodeficiency.
IV/C
141
In patients with HIV and low CD4, counsel to continue PCP prophylaxis in pregnancy.
IV/C
139
Vaccinate for influenza during flu season (regardless of gestational age) if not done preconception.
IV/C
132,140
Differentiate pneumonia from other conditions, especially pulmonary embolus and ARDS.
IV/C
58
Perform chest radiographs as needed to confirm diagnosis.
III/B
137
Use standard approach with sputum and blood cultures for seriously ill women.
IV/C
58,142
Begin appropriate antimicrobial therapy based on underlying conditions and presentation:
IV/C
58
Prenatal
Avoid tetracyclines in pregnancy.
●
Avoid fluoroquinolones unless specifically indicated.
●
Continue treatment for 10–14 days
●
676 S ECTION F IVE • Late Prenatal SUMMARY OF MANAGEMENT OPTIONS
Pneumonia—cont’d Management Options
Evidence Quality and Recommendation
References
Oxygen therapy to maintain saturation levels > 94%.
IV/C
58
Treat varicella infection in a pregnant woman with acyclovir.
—/GPP
—
Labor and Delivery None specific. Postnatal None specific. ARDS, acute respiratory distress syndrome; GPP, good practice point; PCP, Pneumocystis carinii pneumonia
PULMONARY EDEMA, ACUTE LUNG INJURY, AND ACUTE RESPIRATORY DISTRESS SYNDROME General The physiologic changes of pregnancy predispose pregnant women to the development of pulmonary edema (Table 35–7), and as such, this dangerous condition is not rare in pregnancy and occurs more frequently than in the nonpregnant population. The overall incidence of pulmonary edema in pregnancy is approximately 80 in 100,000 pregnancies.151 Pulmonary edema may be classified as cardiogenic or noncardiogenic. Cardiogenic pulmonary edema is the result of elevated pulmonary venous pressure leading to a hydrostatic pressure gradient that causes the movement of fluid into the alveoli,152 a phenomenon referred to as congestive heart failure. Causes specific to pregnancy include peripartum cardiomyopathy and preeclampsia-associated myocardial dysfunction. The causes and treatment of cardiogenic pulmonary edema are discussed in Chapter 36. Noncardiogenic pulmonary edema, in contrast, is the result of fluid leaking into the alveoli across a leaky pulmonary capillary bed despite normal intravascular pressures. This may be caused by a variety of disorders in pregnancy, some pregnancy-specific and others incidental to or exacerbated by pregnancy (Table 37–8). For a diagnosis of noncardiogenic pulmonary edema to be made, the pulmonary capillary wedge pressure (PCWP) should be
T A B L E 3 7 – 7
Normal Physiologic Changes of Pregnancy That Predispose to and May Exacerbate Pulmonary Edema230 20% decrease in colloid osmotic pressure 50% increase in blood volume and cardiac output Decreased FRC in pregnancy means end-expiratory volumes closer to critical closing volumes FRC, functional residual capacity.
less than 18 mm Hg and there should be no evidence of a cardiac cause.153 Noncardiogenic pulmonary edema may be subclassified as acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). These two entities represent a spectrum of disease: the syndrome is defined by a scoring system based on the level of positive end-expiratory pressure (PEEP) required, the PaO2-FIO2 (fractional concentration of oxygen in inspired gas) ratio, the degree of static lung compliance, the degree of pulmonary infiltrates, and the clinical cause (as defined in Table 37–9).154 Patients with less severe lung injury are defined as ALI and those more severely affected have ARDS. ARDS has an incidence in the general population of 13.5 in 100,000 per year.155 It is considered a relatively rare but often lethal condition in pregnancy, contributing significantly to maternal mortality. Precipitants
T A B L E 3 7 – 8
Select Causes of Noncardiogenic Pulmonary Edema in Pregnancy Incidental to Pregnancy Sepsis: appendicitis, bacterial pneumonia Chemical pneumonitis Inhalational lung injury Venous air embolism Cocaine and high-dose opiates in susceptible patients Exacerbated or Facilitated by Pregnancy Aspiration (Mendelson’s syndrome) Sepsis: pyelonephritis, viral pneumonia, listeriosis Severe hemorrhage, especially related to systemic inflammatory response, low PCOP, and rarely leukoagglutination in the lung Pancreatitis Unique to Pregnancy Tocolytic therapy Preeclampsia/eclampsia/HELLP syndrome Amniotic fluid embolism Neurogenic pulmonary edema after eclamptic seizure Sepsis: chorioamnionitis, endometritis, septic abortion HELLP, hemolysis, elevated liver enzymes, and low platelets; PCOP, plasma colloid osmotic pressure.
C HAPTER 37 • Respiratory Disease 677 T A B L E 3 7 – 9
Diagnostic Criteria for Acute Lung Injury and Acute Respiratory Distress Syndrome153,154,160,230,231 1. Acute onset. 2. Bilateral chest radiographic infiltrates. 3. A pulmonary artery occlusion pressure 10 cm H2O) should be avoided, however, because it may reduce cardiac preload and cardiac output, thereby compromising uteroplacental blood flow. Similarly, respiratory alkalosis from overventilation should be avoided, because alkalemia can also adversely effect uterine blood flow.
Role of Pulmonary Artery Catheters in Pregnant Women with Pulmonary Edema In most cases of pulmonary edema in pregnancy, central hemodynamic monitoring will not be necessary for diagnostic purposes. In the absence of clinical evidence of cardiac disease or preeclampsia, it can generally be assumed that the PCWP is unlikely to be greater than 18 mm Hg in a
pregnant woman. Preeclampsia is an exception, because severe preeclampsia may be associated with systolic and/or diastolic cardiac dysfunction. In cases in which cardiac dysfunction is suspected, an ECG may be useful in deciding if central hemodynamic monitoring may be helpful. Such monitoring may also be useful in the setting of presumed cardiogenic pulmonary edema that does not improve quickly in response to supplemental oxygen and diuresis. The goal of invasive monitoring in the setting of pulmonary edema in pregnancy is to safely reduce the PCWP and improve left ventricular performance. It must be remembered, however, that a PCWP that is normal outside of pregnancy may represent a level that will still lead to pulmonary congestion given the predisposing physiology of pregnancy/preeclampsia. It is most helpful, therefore, to follow trends in the PCWP during treatment than to look at absolute numbers. Although central hemodynamic monitoring in a critical care setting may be quite helpful in difficult cases of pulmonary edema in pregnancy, it is widely accepted that beyond complex cardiac disease or sepsis, it is not generally necessary.187–201
Use of Vasoactive and Inotropic Medications Use of vasoactive and/or inotropic drugs to maintain blood pressure and cardiac output may be helpful in some cases of pulmonary edema in pregnancy, particularly when sepsis or cardiac dysfunction is present. It is critical not to withhold any potentially beneficial treatment from a critically ill pregnant woman because of concerns about possible fetal effects. The paucity of human data on the effects of most of these medications on placental blood flow, however, should caution against their use to “fine-tune” maternal hemodynamic parameters.201
682 S ECTION F IVE • Late Prenatal SUMMARY OF MANAGEMENT OPTIONS
Pulmonary Edema, Acute Lung Injury, and Acute Respiratory Distress Syndrome Evidence Quality and Recommendation
Management Options
References
High or intensive care setting; nurse patient at 45-degree angle if possible.
—/GPP
—
Provide supplemental oxygen to maintain PaO2 > 65 mm Hg and oxygen saturation > 95%.
III/B
179–181
If patient is maintaining blood pressure and placental perfusion is not in question, consider administration of IV furosemide (at a dose of 10 mg if patient has not received furosemide in past).
IV/C
182–184
Consider possibility of cardiogenic cause of pulmonary edema. Obtain echocardiogram in most cases to rule out cardiogenic causes.
III/B
170
Monitor fluid balance and avoid fluid overload; minimize IV fluids
III/B
182–184
Remove or treat underlying causes of pulmonary edema in pregnancy:
—/GPP
—
If oxygenation cannot be maintained, consider use of intermittent positive-pressure nasal ventilation or semielective intubation.
IV/C
185,186
Consider placement of central hemodynamic monitoring line if:
IV/C
187–192
IV/C
201
Discontinue tocolytics.
●
Evaluate for presence of preeclampsia and begin active efforts toward delivery of fetus if patient has preeclampsia.
●
Evaluate for presence of infection (especially pyelonephritis) and treat if present.
●
Protect airway if aspiration is suspected.
●
Check INR, aPTT, and CBC if AFE suspected.
●
Cardiac cause suspected and patient unresponsive to diuretics.
●
Poor urine output despite diuretic administration.
●
If hypotension present.
●
Consider use of inotropic and vasoactive agents to maximize cardiac output in the minority of cases. Therapy should be guided in this setting by central hemodynamic monitoring.
AFE, amniotic fluid embolism; aPTT, activate partial thromboplastin time; CBC, complete blood count; GPP, good practice point; INR, International Normalized Ratio; Pao2, arterial oxygen pressure.
SUGGESTED READINGS American Thoracic Society/Centers for Disease Control and Prevention/ Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662. Bandi VD, Mannur U, Matthay MA: Acute lung injury and acute respiratory distress syndrome in pregnancy. Crit Care Clin 2004;20:577–607. Bartlett JG, Breiman RF, Mandell LA, File TM Jr: Community-acquired pneumonia in adults: Guidelines for management. Guidelines from the Infectious Disease Society of America. Clin Infect Dis 1998;26:811. Graves CR: Acute pulmonary complications during pregnancy. Clin Obstet Gynecol 2002;45:369–376. Laibl V, Sheffield J: The Management of respiratory infections during pregnancy. Immunol Allergy Clin North Am 2006;26:155–172. National Asthma Education Program: Report of the Working Group on Asthma and Pregnancy. Management of Asthma During Pregnancy.
Update 2004 (NIH Publication No. 05-5236). Bethesda, Md, National Institutes of Health, March 2005. Powrie RO: Drugs in pregnancy. Respiratory disease. Best Pract Res Clin Obstet Gynaecol 2001;15:913–936. Sciscione AC, Ivester T, Largoza M, et al: Acute pulmonary edema in pregnancy. Obstet Gynecol 2003;101:511–515. Subramanian P, Chinthalapalli H, Krishnan M, et al: Pregnancy and sarcoidosis. Chest 2004;126:995–998. Tonelli MR, Aitken ML: Pregnancy in cystic fibrosis. Curr Opin Pulm Med 2007;13:537–540.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 3 8
Anemia and White Blood Cell Disorders JANE STRONG and JANE M. RUTHERFORD
ANEMIA: OVERVIEW Anemia is defined as a hemoglobin value that is lower than the threshold of 2 standard deviations below the median value for a healthy matched population. The World Health Organization (WHO) defines anemia in pregnancy as a hemoglobin concentration of less than 11 g/dL.1 The cutoff point suggested by the U.S. Centers for Disease Control and Prevention (CDC) is 10.5 g/dL in the second trimester.2 Marked physiologic changes in the composition of the blood occur in healthy pregnancy. Increased total blood volume3 and hemostatic changes4 help to combat the hazard of hemorrhage at delivery. Plasma volume increases by 50%, and red cell mass by 18% to 25%, depending on iron status. These changes cause a physiologic dilution in hemoglobin concentration that is greatest at 32 weeks’ gestation. In ironreplete women, hemoglobin returns to normal by 1 week postpartum. Worldwide, pathologic anemia is the most common medical disorder of pregnancy. Deficiency of essential hematinics usually arises from increased requirements and inadequate intake. Iron deficiency is the most common hematinic deficiency in pregnancy, followed by folate deficiency. Vitamin B12 deficiency rarely causes anemia in pregnancy. In nonindustrialized countries, anemia is associated with up to 13% of maternal deaths.5 The global prevalence of anemia is 42%, but this ranges from 5% in the United States to more than 60% in parts of Central Africa.1
ANEMIA: IRON DEFICIENCY Maternal Risks To maintain iron balance, women of reproductive age require 2 mg of iron daily. Pregnancy further stresses iron balance. The total iron requirements in normal pregnancy are approximately 1240 mg.6 The main demands for iron arise from expansion of the red cell mass (~500–600 mg), and the fetus and placenta require approximately 300 mg. The daily iron requirement in pregnancy is approximately 4.4 mg (0.8 mg/day in the first trimester, increasing to 7.5 mg/day in the third trimester).6,7 These requirements can be achieved only by maximizing dietary iron absorption and
mobilizing iron stores.8,9 If a woman enters pregnancy with depleted iron stores, the effects of iron deficiency develop. Vegetarians are at an additional disadvantage because heme iron (derived from meat) is more readily absorbed than nonheme iron, and heme iron also facilitates the absorption of nonheme iron in a mixed diet. Absorption of iron is less than 10%, so an average of 40 mg of dietary iron is required daily. As iron deficiency develops, the ferritin level decreases first and then the serum iron level. A decrease in hemoglobin concentration is a late development. Iron-dependent enzymes in every cell are affected, and there is a profound effect on body functions.10 Tissue enzyme malfunction occurs, even in the early stages of iron deficiency. This might explain the reported association between anemia during pregnancy and preterm birth and the anecdotal evidence that blood loss at delivery is greater in women with anemia.11,12 In normal pregnancy, hypervolemia modifies the response to blood loss.4 Blood volume decreases after the acute loss at delivery but remains relatively stable as long as the loss does not exceed 25% of predelivery volume. No compensatory increase in blood volume occurs, and plasma volume decreases gradually, primarily because of diuresis. Thus, hematocrit gradually increases and blood volume returns to nonpregnant values.
Fetal Risks The fetus obtains iron from maternal transferrin, regardless of maternal iron stores. The placenta traps maternal transferrin, removes the iron, and actively transports it to the fetus, mainly in the last 4 weeks of pregnancy.6 If maternal iron stores are depleted, the fetus obtains iron from erythrocyte breakdown or maternal intestinal absorption. Most fetal iron is found in fetal hemoglobin, but one third is stored in the fetal liver as ferritin. When maternal iron stores are depleted, there is a decrease in fetal iron stores,13 and this might have an important bearing on the development of anemia during the first year of life, when oral iron intake is very poor.14–16 Studies suggest that behavioral abnormalities occur in children with iron deficiency.17 Iron deficiency in the absence of anemia is associated with poor performance on the Bayley 683
684 S ECTION F IVE • Late Prenatal
Mental Development Index.18 Development delays in irondeficient infants can be reversed by treatment with iron.17 Cognitive function can also be improved with iron supplementation, as was shown in a randomized study in nonanemic, iron-deficient adolescent girls.19 Studies suggest that prophylaxis of iron deficiency during pregnancy might have an important role in the prevention of adult hypertension.20,21 High blood pressure in adults appears to originate in fetal life and is associated with lower birth weight and high ratios of placenta to birth weight. Placental size at term was shown to be inversely proportional to serum ferritin concentrations at initial evaluation.21
Diagnosis Hemoglobin Concentration Although reduction in hemoglobin concentration is a relatively late development in iron deficiency, measuring hemoglobin concentration is the simplest noninvasive practical test available. Hemoglobin values of less than 10.5 g/dL in the second and third trimesters are probably abnormal and require further investigation.
Red Cell Indices The increased drive to erythropoiesis, resulting in a higher proportion of young large red cells, appears to mask the effect of iron deficiency on mean corpuscular volume (MCV) in pregnancy, even when anemia is established. Healthy, iron-replete pregnancy is associated with a small physiologic increase in red cell size, on average 4 femtoliters (fL; 10–15 L), but in some women, the increase may be as high as 20 fL.22 MCV is a poor indicator of iron deficiency that develops during pregnancy.23 Some women enter pregnancy with established iron-deficiency anemia or with grossly depleted iron stores. These do not present diagnostic problems. Those who enter pregnancy with a precarious iron balance and a normal hemoglobin value present the most difficult diagnostic problems.
Serum Iron and Total Iron-Binding Capacity Serum iron level and total iron-binding capacity (TIBC) provide an estimate of transferrin saturation. Reduced transferrin saturation indicates a deficient iron supply to the tissues and the development of iron deficiency. At this early stage, erythropoiesis is impaired and iron-dependent tissue enzymes are adversely affected. In health, the serum iron of adult nonpregnant women shows considerable diurnal variation and can fluctuate from hour to hour. TIBC rises in association with iron deficiency and decreases in chronic inflammatory states. It is increased in pregnancy because of the increase in plasma volume. In nonanemic patients, TIBC is approximately one-third saturated with iron. In pregnancy, most reports describe a decrease in both serum iron and percentage saturation of TIBC, which can be largely prevented by iron supplements. Serum iron, even in combination with TIBC, is not a reliable indicator of iron stores, because it fluctuates widely and is affected by recent ingestion of iron and other factors that are not directly involved in iron metabolism, such as infection.
Zinc Protoporphyrin Zinc protoporphyrin increases when there is a defective iron supply to the developing red cell. Although zinc protoporphyrin may increase in patients with chronic inflammatory disease, malignancy, or infection, the increase usually is not as marked as the increase in ferritin.
Ferritin Ferritin is a high-molecular-weight glycoprotein that is stable and is not affected by recent ingestion of iron. It appears to reflect iron stores accurately and quantitatively in the absence of inflammation, particularly in the lower range associated with iron deficiency, which is so important in pregnancy. In the development of iron deficiency, a low serum ferritin level is the first abnormal laboratory test result.
Transferrin Receptor Serum transferrin receptor (TfR) is a relatively new method for assessing cellular iron status.24 It is present in all cells as a transmembrane protein that binds transferrin-bound iron and transports it to the cell interior. A reduction in the iron supply increases TfR synthesis. Sensitive immunologic techniques show that TfR, like ferritin, circulates in small amounts in the plasma of all individuals, and the concentration is proportional to the total body mass of TfR. In irondeficiency anemia, the plasma receptor is elevated threefold and the density of surface TfR in iron-deficient cells increases. Little or no change in the serum TfR concentration occurs during the early stages of storage iron depletion, but as soon as tissue iron deficiency is established, the serum TfR concentration increases in direct proportion to the degree of iron deficiency. This change, which precedes the reduction in MCV and the increase in zinc protoporphyrin, is a valuable measurement of early tissue iron deficiency. This measurement is particularly helpful in identifying iron deficiency in pregnancy.25 It differentiates truly iron-deficient women from those who have a low serum ferritin level as a result of storage iron mobilization or those who have a low hemoglobin concentration as a result of hemodilution. It also helps to distinguish those with a normal or high serum ferritin level as a result of chronic inflammatory disease from those who have low stores that lead to genuine cellular iron deficiency. TfR accurately reflects tissue iron deficiency, both in pregnancy and in anemia of chronic disease, in which serum ferritin may be inappropriately elevated because of release from cells. In combination with serum ferritin, TfR gives a complete picture of iron status. Serum ferritin reflects iron stores (in the absence of chronic inflammatory disease), and TfR reflects tissue iron status.24
Marrow Iron The most rapid and reliable method of assessing iron stores in pregnancy is to examine an appropriately stained preparation of a bone marrow sample. Without iron supplementation, there is no detectable, stainable iron in more than 80% of women at term.26 No stainable iron (hemosiderin) may be visible once serum ferritin has decreased to less than 40 mg/L,27,28 but other signs of iron deficiency in developing erythroblasts, particularly late normoblasts, confirm that anemia is caused by iron deficiency in the absence of stainable iron. The effects of folate deficiency, which often accompanies iron deficiency, are also apparent (discussed
C HAPTER 38 • Anemia and White Blood Cell Disorders 685
later). Iron incorporation into hemoglobin is blocked if there is acute or chronic inflammation, particularly if it is caused by urinary tract infection, even if iron stores are replete. This problem is shown by examination of the marrow aspirate stained for iron and can be predicted by simultaneous assessment of serum ferritin and TfR and an indicator of chronic inflammatory disease, such as C-reactive protein. With the development of noninvasive tests of iron status (described earlier), bone marrow examination is reserved for the differential diagnosis of severe anemia during pregnancy when the cause cannot be determined by any other means and for the investigation of other hematologic abnormalities that arise de novo during the index pregnancy.
Management Options Prepregnancy Iron and folate supplementation should be considered in all women of childbearing age in areas of high prevalence of iron-deficiency anemia.29,30
Prenatal PROPHYLACTIC IRON SUPPLEMENTATION Iron supplementation is used to prophylactically treat women with low iron stores or those at risk for low iron levels in pregnancy. Women with iron-deficiency anemia are a different group requiring treatment doses of iron (discussed later). Iron supplementation in pregnancy is controversial. Despite increased iron absorption from the gastrointestinal tract,31 physiologic iron requirements in pregnancy often are not met by diet alone. In addition, many women enter pregnancy with depleted iron stores. The goal of prophylactic iron administration is to maintain maternal iron stores during the time of increased physiologic iron demand; it may also prevent anemia in infancy.13 According to the Cochrane Database, routine supplementation with iron or iron and folate does prevent low maternal hemoglobin at delivery, but there is very little information regarding pregnancy outcomes for mother or baby.32,33 Unfortunately, few goodquality studies of iron and folate supplementation have been carried out in areas where iron and folate deficiency are common and anemia is a significant health problem. Some studies have suggested that iron supplementation improves maternal iron status and increases neonatal iron reserves, preventing iron deficiency in the first year of life.34 In pregnant women who did not receive supplementation, iron deficiency persisted many months after delivery.35,36 Iron supplementation may prevent reduced or absent iron stores after pregnancy and reduce the risk of iron deficiency in subsequent pregnancies.37 Iron supplementation has few adverse effects. The dosage is generally low enough to avoid the gastrointestinal side effects seen with treatment doses. Iron supplements may interfere with the absorption of other trace elements, such as zinc.38 Zinc depletion may be associated with fetal growth restriction.39 A study of the effects of oral iron supplementation on zinc and magnesium levels during pregnancy concluded that decreases in the concentration of these elements were physiologic and unaffected by iron supplementation.40
High maternal hemoglobin concentrations are associated with poor pregnancy outcome.41,42 This has led to concerns about iron prophylaxis. However, iron supplementation in iron-replete women does not increase the hemoglobin level.43 In iron-replete pregnancies, the hemoglobin concentration is largely dependent on the increase in plasma volume. Ineffective plasma volume expansion increases the rate of poor pregnancy outcome. The other concern about iron prophylaxis is that excess iron can result in the production of free radicals and oxidative damage and may be implicated in cardiovascular disease and cancer.44,45 Concerns about iron overloading in women with hemochromatosis have been raised. Approximately 12% of western white women are heterozygous for the common mutation of the hemochromatosis gene, and 0.5% are homozygous. A study of hemochromatosis and iron stores in pregnancy suggested that heterozygosity for the hemochromatosis mutation did not affect iron storage levels in reproductive-age women. One woman in the study who had markedly reduced iron stores was homozygous for the gene.46 Iron supplementation can be given on a selective or routine basis. Selective administration is appropriate for women with low or depleted iron stores, usually based on ferritin levels in early pregnancy. Ferritin cutoff levels for action vary between publications. A serum ferritin level less than 50 µg/L in early pregnancy is an indication for iron supplements. Some groups further stratify the starting time of these supplements, depending on ferritin levels.47 This approach avoids unnecessary supplementation in women with adequate iron stores. It identifies those who are at risk for iron depletion and anemia and targets these women with prophylactic or treatment doses of iron. The need for routine iron supplementation is debatable in western countries, but supplementation is recommended in nonindustrialized countries.48,49 Various official bodies made recommendations for routine iron supplementation. WHO recommends universal oral iron supplementation with 60 mg of elemental iron daily for 6 months in pregnancy in areas where the prevalence of iron deficiency is less than 40%. In areas where the prevalence is greater than 40%, the recommendation is to continue supplementation for 3 months postpartum.29 The CDC recommends supplementation with 30 mg of elemental iron daily, as does the American College of Obstetricians and Gynecologists.50,51 Some consider universal supplementation to be a practical and cost-effective approach.52 The debate is ongoing, and the decision to choose universal or selective prophylaxis depends on the prevalence of iron deficiency in the obstetric population served, along with nutritional, economic, and social factors. Prevention of iron deficiency also requires education about diet. Dietary iron has two forms, heme and nonheme iron. Heme iron is the most bioavailable form of iron in the diet and comes from food containing heme molecules, essentially animal meat, viscera, and blood. Nonheme iron is obtained from cereals, vegetables, milk, and eggs. Absorption of nonheme iron is enhanced by ascorbic acid, proteins, and heme and inhibited by phytates, tea, coffee, and calcium. Many countries now fortify food products with iron compounds.53 In nonindustrialized countries, other actions to prevent iron deficiency include iron prophylaxis in nonpregnant women29 and treatment of hookworm infestation.54
686 S ECTION F IVE • Late Prenatal
Prophylaxis of iron deficiency is generally provided with oral iron. Various iron salts are available in tablet or syrup form (ferrous fumarate, gluconate, sulfate, and succinate). The elemental iron content of the different salts varies slightly. Compound preparations with folic acid are available, as are modified-release preparations, which release iron into the gastrointestinal tract slowly. However, these preparations may carry iron past the first part of the duodenum, where absorption is optimal, to areas of the gut where iron absorption is poor. The frequency of oral dosing with iron supplementation has been questioned. Intermittent weekly or twice-weekly dosing schedules are as effective as daily dosing schedules.55–57 In nonindustrialized countries, intermittent intramuscular iron dextran injections are used to ensure compliance and maintenance of adequate iron stores.58 Compliance is a major problem with iron supplementation and may be as low as 36%.59 In oral intermittent iron supplementation, compliance may be an even larger issue than with daily dosing schedules.60 Iron-rich natural mineral water may be an acceptable alternative to oral iron prophylaxis. For example, Spatone Iron-Plus contains ferrous sulfate 0.20 mg/ mL, which is highly bioavailable and maintains ferritin levels more effectively than placebo.61
MANAGEMENT OF IRON DEFICIENCY Iron-deficiency anemia is usually treated with oral iron preparations. The oral dose of elemental iron required to treat iron deficiency is 100 to 200 mg daily. Ferrous sulfate 200 mg three times daily is equivalent to 195 mg of elemental iron daily. Many iron preparations are available, and no scientific evidence suggests that one brand is superior. Treatment doses of iron should continue until hemoglobin normalizes and should be followed with prophylactic or maintenance doses until 3 months postpartum to ensure that iron stores are replenished. Side effects with oral iron are common. Iron salts cause gastrointestinal irritation, with dose-related nausea and epigastric discomfort. Altered bowel habits (constipation or diarrhea) and abdominal cramping are common and have a less clear dose relationship. If side effects occur, reducing the dose or taking the tablets before meals (absorption can be reduced up to 50% if the dose is taken with meals) may help. Alternative iron salts can be tried, but tolerance is often related to reducing the dose of elemental iron. The addition of laxatives should overcome problems with constipation. The response to treatment doses of elemental iron is rapid. Reticulocyte counts increase within 5 to 10 days of initiation, and hemoglobin should rise 0.8 g/dL/wk (1.0 g/dL/wk in nonpregnant women). If no clinical or hematologic response is seen after 3 to 4 weeks of oral iron therapy, diagnostic reevaluation is required. Patients who do not respond to oral iron should be evaluated for ongoing blood loss, concomitant infection, additional hematinic deficiency, noncompliance, and other causes of anemia. Parenteral iron therapy can be administered intravenously as an infusion or injection and also intramuscularly. It has no advantage over oral therapy if oral iron is well tolerated and absorbed. The response rate to parenteral iron is similar to that with oral preparations.62 The advantage of parenteral therapy over oral therapy is the certainty of its administration.63 Parenteral iron is given when oral iron therapy is
unsuccessful because of patient intolerance, noncompliance, or malabsorption. Parenteral forms of iron include iron dextran, iron sucrose, and ferric carboxymaltose. Iron dextran is a complex of ferric hydroxide that contains 50 mg/ mL of iron and can be given intravenously. Dosage is calculated according to body weight and iron deficit. A small test dose is given, and the patient is observed for 1 hour for evidence of anaphylaxis. If the test dose is tolerated, the total dose can be administered in a 0.9% sodium chloride infusion over several hours. The product is licensed in the United Kingdom in the second and third trimesters but contraindicated in patients with a history of allergy. Anaphylactic reactions have been reported, and facilities for cardiopulmonary resuscitation must be available when these drugs are administered. Patients require close monitoring during and after administration, and treatment should be given in a hospital setting. Iron dextran is available by deep intramuscular injections. Total dosage is calculated according to body weight and iron deficit. It is administered as a series of undiluted injections of up to 100 mg of iron each. As with the intravenous preparation, anaphylactic emergency treatment should be available. Preparations of iron sucrose complex contain 20 mg/mL of iron and are used in pregnancy as 5- to 10-mL aliquots up to three times per week in the second and third trimesters.64 Ferric carboxymaltose is a new compound that is now available, although there are little human data on pregnancy effects. It does not require a test dose to be administered and can be given by bolus intravenous injection or a fast intravenous infusion.65 Blood transfusions are rarely indicated in pregnant women with iron-deficiency anemia. With vigilant antenatal care and appropriate iron prophylaxis and treatment, severe anemia should not be detected late in pregnancy. If a woman has severe anemia beyond 36 weeks’ gestation and there is not time to achieve a reasonable hemoglobin concentration before delivery, blood transfusion should be considered. Recombinant human erythropoietin has also been used in difficult cases. Most experience has been with Jehovah’s Witnesses. It does not cross the placenta but carries a risk of hypertension and thrombosis. Its role in pregnancy is not well established. Trials have shown that in combination with intravenous iron, hemoglobin rose more quickly than with parenteral iron alone; however, parenteral iron alone should be the first-line treatment in resistant iron-deficiency anemia.66 Treatment of iron-deficiency anemia in pregnancy was the subject of a Cochrane review.67 Only 17 trials met the inclusion criteria. The reviewers concluded that there was a paucity of good trials assessing the maternal and neonatal effects of iron administration in women with anemia and that large-scale, good-quality trials assessing clinical outcomes and adverse effects are required.
Labor and Delivery There are no specific recommendations for the management of iron-deficient patients during labor. Cross-matching should be carried out for women who are anemic on admission for labor. Blood transfusion may be necessary if
C HAPTER 38 • Anemia and White Blood Cell Disorders 687
significant blood loss occurs, because these women have little reserve to tolerate bleeding.
Postnatal As the physiologic effects of pregnancy diminish, hemoglobin levels rise during the puerperium. There is no consensus on the management of severe postpartum anemia. Treatment is usually with either oral supplementation or blood transfusion. The Cochrane review of treatments for women with postpartum anemia concludes that there is some limited evidence of favorable outcomes for the treatment of postpartum anemia with erythropoietin.68 However, most of the data focus on laboratory hematologic indices rather than clinical outcomes, and further trials are required to assess the treatment of postpartum anemia with blood transfusions and both oral and parenteral iron supplementation.68 Any women who have clear evidence of iron-deficiency anemia should continue oral supplementation for at least 3 months.
ANEMIA: FOLATE DEFICIENCY Folic acid, together with iron, has assumed a central role in the nutrition of pregnancy. At a cellular level, folic acid is reduced first to dihydrofolate and then to tetrahydrofolate, which is fundamental to cell growth and division.
Maternal Risks Megaloblastic anemia in pregnancy is nearly always secondary to folate deficiency. Plasma folate levels decrease as pregnancy advances, reaching approximately half of nonpregnant values at term.22 Explanations for the reduction in folate levels include reduced dietary folate intake because of loss of appetite,69 increased plasma clearance of folate by the kidneys (believed to play a minor role),70,71 transfer of folate from the mother to the fetus (~800 µg at term), and uterine hypertrophy and expanded red cell mass. As pregnancy proceeds, increased folate catabolites are excreted in maternal urine.72 Worldwide, folic acid deficiency may complicate one third of pregnancies. The incidence is higher in multiple pregnancies and closely spaced successive gestations.73 Folate is readily available in most diets. Good sources include broccoli, Brussel sprouts, and spinach. Folate is often lost in the cooking process. It is heat-labile and rapidly destroyed by boiling or steaming. Body stores of folate are found predominantly in the liver and total approximately 10 mg. Folate stores last approximately 4 to 5 months before symptomatic anemia develops. A survey of reports from the United Kingdom suggests that the incidence of folate deficiency is 0.2% to 5.0%, but more women have megaloblastic changes in their bone marrow that are not suspected based on examination of peripheral blood alone.74 The incidence of megaloblastic anemia in other parts of the world is considerably greater and is believed to reflect the nutritional standards of the population. Current WHO recommendations advise folic acid intake of 400 µg daily with 60 mg of iron for 6 months during pregnancy and continuing for 3 months postpartum in areas of the world with poor nutrition.29
The maternal risk of folate deficiency appears to be megaloblastic anemia. This condition usually has an insidious onset, with gradually progressive symptoms and signs of anemia. It can be abolished with routine use of folic acid supplements during pregnancy.75
Fetal Risks The risk of megaloblastic anemia is increased in the neonate of a folate-deficient mother, especially if delivery is preterm. Data also suggest an association between periconceptional folic acid deficiency and cleft lip and palate and, most important, neural tube defects.76–82 Folate supplementation has been shown to reduce the incidence of neural tube defects.78 It is not known how folate supplements reduce the incidence of neural tube defects.
Diagnosis Outside of pregnancy, the hallmark of megaloblastic hemopoiesis is macrocytosis. This can be more difficult to interpret in pregnancy when there is a physiologic increase in red cell size and the possibility of masking iron-deficiency anemia. Examination of the blood film with oval macrocytes and hypersegmented neutrophil nuclei can provide useful diagnostic clues. The reticulocyte count is also low in relation to the hemoglobin. To diagnose folate deficiency, red cell folate assay is performed. Plasma folate levels fluctuate substantially from day to day, and postprandial increases are noted, limiting the use of serum folate as a diagnostic test. Red cell folate is believed to give a better indication of overall body tissue levels. However, the turnover of red blood cells is slow, and there is a delay before significant reductions in the folate concentration of red cells is evident. Patients who have a low red cell folate concentration at the beginning of pregnancy have megaloblastic anemia in the third trimester.22 Folate deficiency in pregnancy is not always accompanied by significant hematologic changes. In the absence of changes, megaloblastic hemopoiesis is suspected when the expected response to adequate iron therapy is not achieved. Ultimately, the diagnosis of folate deficiency may depend on bone marrow examination and the finding of large erythroblasts and giant, abnormally shaped metamyelocytes. This test is usually reserved for patients with pancytopenia rather than isolated anemia.
Management Options Prepregnancy As with other anemias, a careful diagnostic evaluation should be undertaken, followed by prompt therapy before conception. The risks (described in earlier and later sections) should be discussed before pregnancy, and dietary advice about folate-rich foods should be given. Women who are contemplating pregnancy should be advised to take folate supplements of 400 µg daily.29,83–85 In the United States, the Food and Drug Administration has made folic acid food fortification mandatory since 1998. All enriched flour, pasta, rice, and grain products contain 140 µg of folic acid per 100 g. Targeted fortification of food is under consideration in the United Kingdom.
688 S ECTION F IVE • Late Prenatal
Prenatal PROPHYLAXIS The case for giving prophylactic folate supplementation throughout pregnancy is relatively strong,86,87 particularly in countries where nutritional and megaloblastic anemia is common. A systematic review of folic acid supplementation showed that hemoglobin levels were improved with supplementation, but there was insufficient evidence to evaluate other clinical outcomes for the mother or baby.88 Folate should be given in combination with iron supplements. The folic acid content must be approximately 200 to 300 µg daily. The concern about routine folate supplementation is the risk to a woman with undiagnosed vitamin B12 deficiency. Folate treatment can worsen neuropathy in patients with vitamin B12 deficiency. The risk is low in pregnancy, and patients with severe vitamin B12 deficiency are usually infertile. Pernicious anemia is generally a disease of older people. Not one case of subacute combined degeneration of the spinal cord was reported among the thousands of women receiving folate supplements during pregnancy.22 Folate deficiency is also an independent risk factor for thrombosis.
MANAGEMENT OF ESTABLISHED FOLATE DEFICIENCY Severe megaloblastic anemia is uncommon in the United Kingdom and the United States, largely as a result of prophylaxis and prompt treatment. Once megaloblastic hematopoiesis is established, treatment of folic acid deficiency is more difficult, presumably as a result of megaloblastic changes in the gastrointestinal tract that impair absorption. If the diagnosis is made prenatally, initial treatment is with folic acid, 5 mg once daily, continued for several weeks postpartum.
ANTICONVULSANTS AND FOLIC ACID Outside of pregnancy, folate deficiency can develop in patients who take anticonvulsants. Folate status is further
compromised in pregnancy.86 Interference with epilepsy control by folate supplementation may be overestimated.89 Anticonvulsant therapy is associated with an increased incidence of congenital abnormalities,90 prematurity, and low birth weight.91 Hence, folate supplements should be given to all pregnant epileptic women who take anticonvulsants.
DISORDERS THAT MAY AFFECT FOLATE REQUIREMENTS Women with hemolytic anemia, particularly hereditary hemolytic conditions, such as hemoglobinopathy and red cell membrane and enzyme disorders, require extra folate supplements from early pregnancy. The recommended supplementation is 5 to 10 mg orally daily. Anemia as a result of thalassemia trait is caused by ineffective erythropoiesis. However, the increased abortive marrow turnover results in folate depletion, and these women probably benefit from routine administration of folic acid, 5.0 mg orally daily, from early pregnancy.
Labor and Delivery There are no specific management recommendations for folate-associated anemia during labor and delivery, as long as the patient is hemodynamically stable and blood replacement therapy is available, if needed.
Postnatal In the 6 weeks after delivery, indices of folate metabolism return to nonpregnant values. However, if folate deficiency develops and remains untreated in pregnancy, it may be seen clinically for the first time in the puerperium. Lactation provides an added folate stress. A folate content of 5 µg/100 mL in human milk and a yield of 500 mL daily implies a loss of 25 µg of folate daily in breast milk.92 Red cell folate levels in lactating women are significantly lower than those in infants during the first year of life.
SUMMARY OF MANAGEMENT OPTIONS
Iron and Folate Deficiency Anemia Management Options
Evidence Quality and Recommendation
References
At Any Time Studies if hemoglobin < 10.5 g/dL (opinions vary; range 10.0–11.0 g/dL): Complete blood count.
●
Blood film.
●
Red cell indices.
●
Reticulocyte count.
●
Iron status (e.g., ferritin).
●
Red cell folate.
●
Serum vitamin B12.
●
Other studies as indicated by clinical findings and laboratory results.
●
—/GPP
—
C HAPTER 38 • Anemia and White Blood Cell Disorders 689 Evidence Quality and Recommendation
Management Options
References
Prepregnancy Provide dietary advice and iron therapy to ensure satisfactory hemoglobin status before pregnancy.
—/GPP
—
Institute public health measures to prevent periconceptual folate deficiency.
Ia/A
82
Use of folic acid periconceptually reduces the risk of neural tube defects.
Ia/A
78
Prophylactic use of iron or folate is controversial in industrialized countries, but important for pregnant women in developing countries to maintain or increase predelivery hemoglobin levels.
Ia/A
32,33
When iron or folate is prescribed, selective use is better than routine use if women can have their hemoglobin status assessed and followed up reliably.
Ia/A
32,33
Oral iron preparations are preferred; different compounds are used to minimize side effects.
—/GPP
—
Side effects related to dose and weekly oral iron administration may be an alternative to improve compliance without losing efficacy.
Ib/A
56,57
Give parenteral iron therapy if oral iron treatment is unsuccessful because of noncompliance, poor follow-up, or poor absorption.
IIa/B
63
Consider blood transfusion in patients with severe symptomatic anemia close to delivery.
—/GPP
—
Provide folate prophylaxis with anticonvulsants.
—/GPP
—
Continue routine oral folate therapy in cases of autoimmune hemolytic anemia.
—/GPP
—
Give parenteral folate therapy if deficiency is severe.
—/GPP
—
—/GPP
—
—/GPP
—
Prenatal
Labor and Delivery Cross-match blood if anemia is severe. Postnatal Continue iron therapy for patients with iron deficiency. GPP, good practice point.
ANEMIA: VITAMIN B12 DEFICIENCY Muscle, red cell, and serum vitamin B12 concentrations decrease during pregnancy.93,94 Women who smoke tend to have lower serum vitamin B12 levels, which may account for the positive correlation between birth weight and serum levels in women without deficiency.
Maternal and Fetal Risks Vitamin B12 absorption is unaltered in pregnancy,95 but tissue uptake is increased under the influence of estrogens. Oral contraceptives also cause a decrease in serum vitamin B12 levels. This decrease in pregnancy is related to preferential transfer of absorbed vitamin B12 to the fetus at the expense of maintaining maternal serum concentration. The vitamin B12-binding capacity of plasma increases in pregnancy because of the increased levels of transcobalamin II, which is derived from the liver and affects vitamin B12 transport.
Cord blood serum vitamin B12 levels are higher than maternal vitamin B12 levels. Pregnancy does not greatly affect maternal vitamin B12 stores. Adult stores are 3000 µg or more, and stores in newborns are approximately 50 µg. Minimal amounts of vitamin B12 are required for fetal development, which may account for the few fetal problems seen in pregnancies complicated by vitamin B12 deficiency. A deficiency syndrome is described in breast-fed neonates of mothers with significant vitamin B12 deficiency. It is usually apparent by 6 months of age and is characterized by failure to thrive, developmental regression, and anemia.96 Addisonian pernicious anemia is unusual during the reproductive years and is usually associated with infertility. Pregnancy is likely only if the deficiency is corrected. Dietary deficiency of vitamin B12 is possible in strict vegans who consume no animal products. Other disorders associated with vitamin B12 deficiency include tropical and nontropical sprue, Crohn’s disease, and surgical resection of the distal ileum.
690 S ECTION F IVE • Late Prenatal
Management Options Prepregnancy Women with vitamin B12 deficiency should have their therapy optimized and their anemia corrected before they become pregnant. This approach may be needed to restore fertility.
Prenatal The recommended intake of vitamin B12 is 2.6 µg daily during pregnancy.97 This intake is met by almost any diet that contains animal products. Strict vegans, who do not eat any animal-derived substances, may have a deficient intake of vitamin B12, and this type of diet should be supplemented in pregnancy. Difficulties can arise when interpreting vitamin B12 levels measured in pregnancy because many women have lower values than those quoted as the normal range outside of pregnancy.98 This decline in vitamin B12 levels is not believed to represent a true deficiency.99 Levels return to normal in the puerperium. Care must be taken in the interpretation of vitamin B12 levels in pregnancy. If deficiency is suspected,
the etiology should be considered. Intrinsic factor antibodies may be useful if the results are positive. Therapy is instituted empirically if there is clinical concern, especially if neurologic findings are consistent with vitamin B12 deficiency. The earliest symptoms are numbness and paresthesia of the fingers and toes, followed by weakness, ataxia, and poor concentration. Patients may have changes in mental status. Treatment of vitamin B12 deficiency is generally parenteral because patients usually have absorptive problems. Cyanocobalamin or hydroxycobalamin 1 mg is given three times a week for 2 weeks, and then every 3 months. In patients who have neurologic involvement, the dosage is higher. These patients are given 1 mg on alternate days until no further improvement is noted, and then 1 mg every 2 months. Oral vitamin B12 can be used in patients with dietary deficiency.
Labor and Delivery and Postnatal There are no specific measures for patients with genuine vitamin B12 deficiency, apart from continuing maintenance therapy.
SUMMARY OF MANAGEMENT OPTIONS
Vitamin B12 Deficiency Evidence Quality and Recommendation
References
—/GPP
—
Continue treatment if it was instituted before conception.
—/GPP
—
Consider oral supplementation and other components for strict vegans and women with diets deficient in animal protein.
—/GPP
—
Consider checking intrinsic factor antibodies if the diet is adequate.
—/GPP
—
—/GPP
—
—/GPP
—
Management Options Prepregnancy Deficiency is rare. Prenatal
Labor and Delivery Continue treatment if already instituted. Postnatal Continue treatment if already instituted; if the patient is not receiving treatment, check vitamin B12 levels postpartum. GPP, good practice point.
HEMOGLOBINOPATHIES Hemoglobinopathies are inherited disorders of hemoglobin. Hemoglobin is composed of heme (a combination of iron and porphyrin) and four globin chains. The type of globin chain determines many of the characteristics of the hemoglobin. Several types of globin chains are present at different times in embryonic development, in fetal life, and through to adulthood (Fig. 38–1 and Table 38–1). Abnormalities of the quantity or quality of the globin chains produced result in conditions known as hemoglobinopathies.
Hemoglobinopathies can be divided into two subgroups: ● Sickling disorders, which are qualitative abnormalities— an amino acid substitution in an α globin or β globin chain results in the synthesis of an abnormal hemoglobin. Many types of hemoglobin can sickle. ● Thalassemia syndromes are usually quantitative problems of globin chain synthesis. They result in impaired production and imbalance of globin chains. α-Thalassemia is caused by reduced α-chain production, and β-thalassemia is caused by reduced or abnormal β chain production.
C HAPTER 38 • Anemia and White Blood Cell Disorders 691 FIGURE 38–1 Production of different globin chains. (From Hoffbrand AV, Pettit J (eds): Genetic defects of haemoglobin. In: Essential Haematology, 3rd ed. Oxford, Blackwell, 1993, p 95.)
% of total globin synthesis
Yolk sac
50
Liver
α
Spleen
Bone marrow
β
γ
30 ε
10
ζ
0 0
δ 6
18
30
Birth 6
Prenatal age (wk)
hemoglobinopathies is universal in high-prevalence areas but selective in low-prevalence areas, depending on ethnicity and red cell indices. The chance of being a carrier is dependent on ancestry. Tables are available that show the prevalence of traits in different countries and ethnic groups.101 Neonatal screening uses blood from the heelprick Guthrie card samples. All births in England are screened. Regional laboratories use high performance liquid chromatography as first-line screening for hemoglobin disorders and isoelectric focusing for confirmation of abnormalities. The Guthrie card hemoglobinopathy results are available to Child Health professionals, allowing appropriate early referrals of children requiring follow-up.
Sickle Cell Syndromes 18
30
42
Postnatal age (wk)
T A B L E 3 8 – 1
Composition of Adult Hemoglobin FEATURE
HEMOGLOBIN A
HEMOGLOBIN F
HEMOGLOBIN A2
Structure
α2β2
Normal (%)
97–99
α2γ2 0.5–0.8
α2δ2 1.5–3.7
Women with major sickling and thalassemic conditions require specialized multidisciplinary team management preconception and throughout pregnancy. Neonates with major sickling and thalassemic conditions require early identification and appropriate referral for specialized management, and this necessitates genetic screening to identify at-risk couples.
Screening for Hemoglobin Disorders100 Timely antenatal screening programs identify women and their partners who are carriers of these conditions and couples who are at risk for having an infant affected with a major hemoglobinopathy. This allows informed decisions regarding reproduction and prenatal diagnosis. Detection of major hemoglobinopathies leads to early identification of affected infants with improvements in care and survival. In sickle cell disease, the first 5 years of life carries a high morbidity and mortality. Protective levels of hemoglobin F have declined by 6 months, and pneumococcal septicemia and acute splenic sequestration pose significant risks. Identification of these infants and targeted antibiotic prophylaxis, pneumococcal vaccination, and education programs have significantly improved survival. Identifying infants at risk of β-thalassemia major ensures timely further investigation and appropriate care for transfusion-dependent anemia. In the United Kingdom, the National Health Service Sickle and Thalassemia Screening Program is a linked antenatal and neonatal program. Antenatal screening for
More than 300 abnormal (variant) hemoglobins are recognized. Sickle cell disease caused by homozygosity of hemoglobin S (i.e., HbSS) is the most common sickling disorder. It is caused by a point mutation in the β globin gene on chromosome 11 that produces an amino acid change at position 6, changing valine to glutamic acid. This enhances the polymerization of hemoglobin S in the deoxygenated state and causes increased red cell rigidity and sickling. Chronic intravascular and extravascular hemolysis is a hallmark of sickle cell disease with significantly reduced red cell survival from 120 days to approximately 20 days. This results in intravascular nitric oxide depletion, endothelial activation, and vasoconstriction. Increased blood viscosity and tissue hypoxia occur as sickled cells occlude the microcirculation. Clinical consequences of sickling include ● Vaso-occlusive crises (micro- and macroinfarcts, leading to a painful crisis and organ damage). ● Anemic crises as a result of severe hemolysis, red cell aplasia, or splenic sequestration. ● Chest and girdle syndrome. ● Neurologic events.
Maternal and Fetal Risks Sickling occurs in the homozygous condition (HbSS) or in compound heterozygous states (e.g., HbSC or HbS β-thalassemia, HbSD-Punjab, HbSE, HbSLepore, HbSOArab). Hemoglobin C, D-Punjab, E, and O-Arab are variant hemoglobins with mutations in the B globin gene. Hemoglobin Lepore is a variant hemoglobin that behaves like β-thalassemia. The heterozygous state, or sickle cell trait (HbAS), is essentially a benign condition believed to have no particular antenatal sequelae. However, women with sickle cell trait are slightly more prone to renal papillary necrosis and urinary tract infection.102 Their hemoglobin levels are similar to those of other pregnant women and should be managed similarly. Their sickle cell trait should be noted on their records, and the anesthesiologist should be informed of this condition if a general anesthetic is required. A study showed an increased incidence of preeclampsia in women with sickle cell trait.103 Women with sickle cell trait should be identified by antenatal hemoglobinopathy screening. If the partner of a woman with sickle cell trait also carries the trait, there is a one in four chance that the offspring will be
692 S ECTION F IVE • Late Prenatal
affected by homozygous sickle cell disease. These couples require counseling and the opportunity for antenatal diagnosis. Pediatricians must be alerted to the possibility of sickle cell disease in neonates because antipneumococcal vaccines can now be given from 2 months of age and infants with sickle cell disease require long-term prophylactic penicillin treatment and regular evaluation. People with major sickling disorders start life relatively protected from crises for 3 to 6 months because of the ongoing production of fetal hemoglobin. When hemoglobin A production becomes predominant, chronic hemolytic anemia develops. The severity and complications of the disease vary widely between patients. Many have debilitating chronic disease and frequent crises that require hospital admission. Others appear to be free of complications but have progressive organ damage. The life expectancy of these patients is still 25 to 30 years less than that of the general population, even in the developed world, with access to medical care.104 There are increased risks in pregnancy for the mother with sickle cell disease and her fetus.105 The risks are not so great as to prohibit pregnancy. Maternal mortality is increased but has significantly improved since the early 1980s. Mortality rates of 30% to 40% are reported before the 1970s but have reduced to 1% to 2% in the United States and Europe.105 Recognition of this at-risk group along with improvements in medical management, transfusion, and neonatal care has significantly reduced morbidity and mortality.105 Maternal risks include exacerbated sickle cell disease phenomena,106 such as anemia, vaso-occlusion, ischemic injury, and organ damage as a result of the physiologic stress of pregnancy. These patients have greater susceptibility to infection (chest and urinary tract), hypertensive disorders of pregnancy, and thromboembolic complications. Risks to the fetus include increased frequency of miscarriage, intrauterine growth restriction, preterm labor, and preterm birth.107,108 Perinatal morbidity and mortality rates vary widely in different regions of the world109–111 but are higher than in the general population. Perinatal mortality rates of 50% to 80% are reported before the 1970s, but more recent studies report rates of 1% to 8% in the United States and Europe.105
Diagnosis and Management Options PREPREGNANCY Before an affected woman becomes pregnant, a number of issues should be addressed.
Sickle Cell Disease The frequency and management of crises outside of pregnancy is a useful starting point and may indicate the likelihood of crises throughout pregnancy. The patient’s transfusion history and red cell antibody values should be documented. Hydroxyurea should be discontinued 3 months prior to conception in both men and women who are planning to conceive because it is teratogenic in animal models. Although there is little information about its effect on the human fetus, there are case reports in which hydroxyurea
was taken throughout pregnancy with no reported adverse fetal effects.112,113 Hydroxyurea is a disease-modifying drug that increases hemoglobin F, improves red cell hydration, and decreases the rate of polymerization of hemoglobin S. Its use decreases the frequency of crises.114
Contraception Pregnancy planning is useful in women who have a chronic debilitating disease. No contraceptive choices are absolutely contraindicated on the grounds of sickle cell disease. Based on the theoretical risks of thromboembolism, sickle cell disease is listed as a relative contraindication for some combined oral contraceptives. The risks of pregnancy outweigh those of contraception.
Maternal and Fetal Complications Past obstetric history is important, including a discussion of maternal and fetal risks associated with sickle cell disease. Patients should be told that active prenatal management significantly affects pregnancy outcome, and the importance of attending visits should be emphasized.
Multidisciplinary Team Approach The community sickle cell service and midwifery team, along with hospital obstetric, hematology, anesthetic, and pediatric teams, plays an important role in the care of the pregnant woman and fetus.
Partner’s Hemoglobinopathy Status It is important to establish the partner’s hemoglobinopathy status, ideally, before pregnancy. This information facilitates appropriate, timely, and nondirective counseling about antenatal diagnosis.
PRENATAL These women should be seen early in pregnancy. Ideally, they should be seen by an obstetrician and hematologist with experience in this area. Partner screening should be carried out if it has not been done. A discussion about prenatal diagnosis should take place, if appropriate, and time should be taken to review the patient’s obstetric history and history of sickle cell disease, including a drug history and the typical management of crises. Laboratory evaluation should include a complete blood count, hemoglobin electrophoresis (if not previously done or available), reticulocyte count, ferritin level, folate level, urea and electrolyte levels, liver function tests, blood typing, and red cell antibody screen. The red cell antibody screen serves two purposes: (1) to identify women whose fetuses and newborns may be at risk of hemolysis because of red cell antibodies and (2) to ensure screening for the most common minor red cell antigens so that phenotypically matched blood will be available for transfusion. This is especially important because the donor population differs in ethnic origin, carries different minor cell antigens, and may sensitize this group of patients. As a result, it may be difficult to obtain suitable blood for transfusion. Blood tests should be performed to determine hepatitis A, B, and C, HIV, and rubella antibody status. Urine dipstick and culture allow identification and treatment of women with asymptomatic bacteruria. This group is more susceptible to urinary tract infections.
C HAPTER 38 • Anemia and White Blood Cell Disorders 693
People with homozygous sickle cell disease may have a hemoglobin concentration of 5 to 12 g/dL, but concentrations are typically 6 to 10 g/dL. Hemoglobin S has a lower affinity for oxygen. Symptoms of anemia are decreased by the increased delivery of oxygen to the tissues. The reticulocyte count is elevated, reflecting increased red cell turnover. The bilirubin level also indicates the rate of hemolysis. Other abnormal liver function test results may indicate chololithiasis or acute cholecystitis as a result of chronic hemolysis or chronic hepatitis. Pregnancy outcome appears to be similar in women who undergo prophylactic transfusion compared with those who undergo selective transfusion for clinical reasons.115 No improvement in obstetric outcome was seen in a retrospective multicenter study in the United Kingdom.116 There is debate about the use of blood transfusions throughout pregnancy. Prophylactic versus selective blood transfusions was the subject of a Cochrane review.117 This review found that there was not enough evidence to reach conclusions about the use of prophylactic blood transfusions. The development of atypical red cell antibodies is a real concern.118 Transfusion is generally given before anesthesia or as an exchange procedure in severe crises, but no data suggest that transfusions should be given prophylactically. Red cell indices in patients with sickle cell disease alone should be normal, but low MCV and mean corpuscular hemoglobin (MCH) may indicate iron deficiency or an associated thalassemia trait. The blood film shows variable numbers of sickle cells and features of hyposplenism (Howell-Jolly bodies, target cells, and increased platelet and white cell counts). Hemoglobin electrophoresis and high-performance liquid chromatography can separate out the various hemoglobins and allow detection and characterization of variant hemoglobins. In homozygous sickle cell disease, hemoglobins S, F, and A2 are seen. Hemoglobin S is usually the predominant hemoglobin, making up 90% to 95% of total hemoglobin. Hemoglobin A is absent. In compound heterozygous states, other hemoglobins are found, except in hemoglobin S β-thalassemia, in which the hemoglobin S level is lower than that in homozygotes. A sickle solubility test is a quick screening test for sickling hemoglobin, but it does not elucidate the type or quantity of sickling hemoglobin. It does not distinguish between homozygous sickle cell disease and a person with sickle cell trait. The antenatal care plan should be outlined, with a discussion of the risks for both mother and fetus and strategies to reduce these risks. The patient should be advised to avoid precipitating factors that may cause sickle crises, including education about the signs and symptoms of infection and appropriate analgesics. Return visits should be scheduled every 2 to 3 weeks to allow early detection of maternal or fetal complications. These visits monitor the course of the pregnancy, with regular monitoring of blood pressure, and assessment of fetal growth and development at appropriate intervals. Patients with sickle cell disease also should be asked about pain and crises and should undergo laboratory assessment, including complete blood counts, reticulocyte counts, and bilirubin measurements.
COMPLICATIONS OF SICKLE CELL DISEASE Vaso-occlusive or Painful Crisis119,120 Crises occur when rigid sickle cells obstruct blood vessels in the microvasculature. This obstruction leads to tissue hypoxia, infarction, and pain. It is the most common type of crisis and the reason for most hospital admissions. Factors that may precipitate or exacerbate a crisis include cold, infection, dehydration, exercise, and stress. The pain is usually bony, although it may occur in the chest or abdomen. Systemic markers include low-grade fever, tachycardia, and mild leukocytosis. As a result of sickling in the splenic circulation, most patients become hyposplenic at a young age, increasing their susceptibility to encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae. This is the rationale for pneumococcal, H. influenzae B, and meningococcal vaccination and prophylactic penicillin administration. Treatment and evaluation are as for nonpregnant women. Most pain occurs in the third trimester and the postpartum period. Underlying precipitants of pain, such as infection and toxemia, should be sought. The management hinges on good rehydration, with careful fluid balance and adequate analgesia. The pain normally requires opioid analgesia as an infusion or patient-controlled analgesia. Nonsteroidal antiinflammatory drugs are a useful adjunct but should be avoided in the second half of pregnancy because of the risk of patent ductus arteriosus. Oxygen supplementation and intravenous antibiotics covering encapsulated organisms may be required. If intravenous antibiotics are not required, penicillin prophylaxis should be ongoing. Folic acid supplementation (5 mg daily) also should be ongoing. The patient should be kept warm. All of the relevant teams should be involved, including obstetricians, hematologists, and obstetric anesthesiologists. In women who have frequent sickling crises and heavy narcotic use, fetal growth must be monitored carefully because of the risk of intrauterine growth retardation. Pediatricians must be made aware of the risk of opiate dependence in the newborn and the need for opiate tapering. On admission, the patient should have a complete blood count, reticulocyte count, biochemistry testing, blood typing, blood cultures, arterial gases, and/or pulse oximetry. Potential sites of infection require culturing (e.g., throat swab, midstream urine, sputum, blood). Hemoglobin requires regular monitoring. Transfusion is generally given if hemoglobin is less than 5 g/dL. Review is required at regular intervals to assess the response to pain relief and look for evidence of infection, girdle or chest syndrome, splenic or hepatic sequestration, and complications of pregnancy, such as preeclampsia.
Acute Anemia When a precipitate decrease in hemoglobin occurs, the differential diagnosis includes blood loss, bone marrow suppression secondary to infection, hyperhemolysis, and sequestration. Careful examination and basic blood tests are useful in determining the cause. A reticulocyte count will determine whether the bone marrow is responding appropriately to the anemia. If the count is low or absent, parvovirus B19 infection should be considered. This infection causes red cell aplasia, and transfusion is required. It can also cause miscarriage or hydrops, so careful fetal monitoring is required.
694 S ECTION F IVE • Late Prenatal
Prompt transfusion in splenic sequestration can be lifesaving when the decrease in hemoglobin is precipitous and hazardous for the mother and fetus. Patients have acute abdominal pain, with rapid enlargement of the spleen. This situation is rare because most patients with homozygous sickle cell disease are hyposplenic. Approximately 5% have splenomegaly, but it is more common in compound heterozygote sickling states, such as HbSC and HbS β - thalassemia.
Acute Chest Syndrome121 Acute chest syndrome is a form of acute lung injury that is distinct from pneumonia. It is believed to be caused by fat emboli from the bone marrow along with red cell sequestration. It does not resolve with antibiotics but may become secondarily infected. It usually causes clinical or radiologic evidence of consolidation, with elevated temperature, cough, and pleuritic chest pain. Hypoxemia, which may be severe, and leukocytosis are also features. Treatment is the same as for a crisis, as discussed earlier, with early recourse to top-up or exchange transfusion, depending on the baseline hemoglobin. Oxygen saturation and blood gas values must be monitored carefully, and antibiotics and bronchodilators are useful. An intensive care setting is often the best place to monitor these patients.
Neurologic Events Neurologic events are common in patients with sickle cell disease. Thrombotic cerebrovascular accidents and seizures are the main concern. The differential diagnosis (including metabolic disturbances, toxemia, subarachnoid or intracerebral hemorrhage, ischemic stroke, cerebral venous thrombosis, meningitis, cerebral abscess, epilepsy, or tumor) must be considered, and studies may include neuroimaging, examination of the cerebrospinal fluid if fever is present, and assessment for toxemia. Sickle-related central nervous system events should be treated with exchange transfusion to reduce the sickle hemoglobin percentage to less than 30%. This value should be maintained by transfusions to keep hemoglobin levels between 10 and 11 g/dL.
LABOR AND DELIVERY Close supervision is required during labor. The risk of sickle cell crisis in labor increases if the woman is dehydrated or has hypoxia, acidosis, or infection. Care should be taken to prevent these complications. Labor is also a time of increased cardiac output, exacerbated by the pain of uterine contractions. Cardiac function may be reduced by chronic hypoxemia and long-standing anemia. Pain relief is important in reducing cardiac work, and epidural is particularly effective.122 Prolonged labor should be avoided. The woman should be kept warm, wellhydrated, and oxygenated. Continuous intrapartum monitoring should take place. The timing and mode of delivery must be determined by obstetric factors. Transfusion is considered if the hemoglobin is less than 8 g/dL.123 Thromboprophylaxis is given to women who are immobilized or experiencing a sickle crisis at the time of delivery. Routine thromboprophylaxis for women with sickle cell disease is controversial. There are no randomized, controlled trials, and efficacy has not been conclusively shown. Patients who have cesarean delivery should have chest physiotherapy, and early mobilization is encouraged. Cord blood can be sent to the laboratory for hemoglobinopathy screening. Those who interpret the results must be aware of the possibility of maternal contamination. Universal neonatal screening for sickle cell disorders has been introduced in England as part of the newborn blood spot test.
POSTPARTUM The heightened risks of sickle crisis persist after delivery. Adequate oxygenation and hydration need to be ensured. Patients must be monitored for infection and crises, and thromboprophylaxis may be considered, depending on the degree of mobility and individual risk assessment. Contraception can be discussed at this time (discussed earlier). The results of neonatal screening and follow-up arrangements with the pediatrician should be confirmed before discharge.
SUMMARY OF MANAGEMENT OPTIONS
Sickle Cell Syndromes Management Options
Evidence Quality and Recommendation
References
Prepregnancy Counsel against conception until disease status is optimized; assess renal and liver function.
—/GPP
—
Counsel about the risks of pregnancy.
—/GPP
—
Screen partner; if the result is positive, counsel about prenatal diagnosis.
Ia/A
100
Review medication—ensure on folic acid supplements, stop hydroxycarbamide 3 mo prior to conception.
—/GPP
—
C HAPTER 38 • Anemia and White Blood Cell Disorders 695
Management Options
Evidence Quality and Recommendation
References
Prenatal Early booking appointment with planned schedule of care between obstetrician and hematologist with expertise and experience in the field of hemoglobinopathies.
—/GPP
—
Hemoglobin electrophoresis screening of the entire population or high risk groups.
Ia/A
100
Screen partner; if the result is positive, consider counseling and prenatal diagnosis.
Ia/A
100
Administer folic acid 5 mg daily.
—/GPP
—
Prompt treatment of crises (adequate hydration, oxygen, screening for infection) may include exchange transfusion.
—/GPP
—
Prenatal fetal surveillance and tests for fetal well-being.
—/GPP
—
Screen for:
—/GPP
—
Ensure adequate hydration, strict fluid balance.
—/GPP
—
Avoid hypoxia, continuous pulse oximetry.
—/GPP
—
Continuous cardiotocography.
—/GPP
—
Keep warm.
—/GPP
—
Provide thromboprophylaxis.
—/GPP
—
Alert pediatricians.
—/GPP
—
Use of prophylactic antibiotics is controversial; low threshold for use on clinical grounds especially after an operative delivery.
—/GPP
—
Maintain good hydration and oxygenation, especially for the first 24 hr.
—/GPP
—
Provide contraceptive counseling.
—/GPP
—
Test the neonate for hemoglobinopathies.
—/GPP
—
Urinary infection.
●
Hypertension or preeclampsia.
●
Renal and liver function.
●
Pathologic fetal growth and umbilical artery blood flow.
●
Labor and Delivery
Postnatal
GPP, good practice point.
Thalassemia Syndromes Thalassemia syndromes are usually quantitative disorders of globin chain production that affect either the α or the β globin chain.
α-Thalassemia There are normally two pairs (i.e., four) of functional α globin genes on chromosome 16. If one or two of these genes are missing, the result is an α-thalassemia trait. The type of thalassemia trait is an important factor to consider when offering antenatal counseling and diagnosis. These traits are not detected on hemoglobin electrophoresis
because no abnormal hemoglobin is made. In addition, there is neither excess nor lack of any normal hemoglobins. Deletion of three α globin genes results in hemoglobin H (HbH) disease, a chronic hemolytic anemia, with moderate anemia, hypochromia, and marked microcytosis and normal life expectancy. Nondeletional HbH disease also exists when there is deletion of two α globin genes plus a nondeletional mutation affecting a third α globin gene. The condition can be detected by hemoglobin electrophoresis by an HbH peak on the high-performance liquid chromatography trace and the presence of HbH inclusion bodies in the red cell that appear like “golf ball” cells on supravital staining.
696 S ECTION F IVE • Late Prenatal
In α-thalassemia major, there is no α chain production and no synthesis of hemoglobin F, A, or A2. Tetramers of fetal gamma chains (γ4) form because no α chains are present. This condition is known as hemoglobin Barts. Patients have severe anemia, failure of oxygen delivery to tissues, cardiac failure, and abnormal organogenesis. The condition is incompatible with life and causes intrauterine hydrops. Serious obstetric complications often occur, including preeclampsia and delivery difficulties because of the large fetus and placenta. The nonviability of the fetus and the maternal complications make early termination advisable. Experimental fetal treatment may be available if the condition is detected early in pregnancy. There are ethical issues with this practice, and antenatal screening for α-thalassemia is directed at preventing hemoglobin Barts hydrops. To prevent this condition, women and their partners who have a cis-(2) α gene deletion (i.e., genotype – –/αα or –α0thalassemia trait) must be identified. These couples have a one in four chance of having a fetus with hydrops. In practice, these couples are identified on the basis of otherwise unexplained hypochromic, microcytic red cell indices (iron deficiency and β-thalassemia should be excluded). An MCH of less than 25 pg suggests the genotype – –/αα or –α/–α. Hemoglobin electrophoresis does not detect α-thalassemia traits, and definitive diagnosis requires DNA analysis to detect thalassemia-causing mutations. This diagnostic procedure is undertaken only if both the woman and her partner have indices and test results that suggest α0-thalassemia trait or HbH disease or a combination of both within the partnership. Persons particularly at risk for α0-thalassemia trait are those of Chinese, Southeast Asian, or Mediterranean descent.
DIAGNOSIS AND MANAGEMENT OPTIONS Prepregnancy Women who have α0-thalassemia trait should be identified before pregnancy so that they can be alerted to the one in four chance of having a hydropic fetus if their partner carries the same trait. Early screening of partners is strongly encouraged. If the woman and her partner are at risk, the possibility and techniques of antenatal diagnosis can be discussed. Women with HbH disease should be encouraged to take regular folate supplementation outside of pregnancy to meet the demands of increased bone marrow turnover.
Prenatal Prenatally, the main issues are antenatal diagnosis (if required) and maintenance of adequate hemoglobin. In women with indices that suggest α0-thalassemia trait or HbH disease, partner carrier status should be sought early in pregnancy to determine risk, especially in affected racial groups. At-risk couples should be counseled about the risks and offered antenatal diagnosis with chorionic villus sampling or amniocentesis. Oral iron supplements should not be prescribed on the basis of red cell indices alone (i.e., hypochromia and microcytosis). They are indicated when ferritin levels are reduced. In HbH disease, folate supplementation (5 mg daily) is recommended, and transfusion may be needed for women with severe symptomatic anemia or early signs of fetal compromise.
Labor and Delivery and Postpartum There are no specific management recommendations.
β-Thalassemia MATERNAL AND FETAL RISKS β-Thalassemia has three phenotypic presentations: the trait, intermedia, and major. β-Thalassemia trait, or heterozygote state, is important to detect for antenatal screening purposes. It does not affect the mother’s health, but causes hypochromic, microcytic red cell indices. Iron therapy must be based on hematinic measurements rather than the complete blood count. Partner screening should be performed to determine the risk of having a child affected with a major hemoglobinopathy. If the partner carries a sickle cell trait, a β-thalassemia trait, or hemoglobin E, and the mother carries a β-thalassemia trait, there is a one in four risk of having a child with a major hemoglobinopathy. Sickle cell/β-thalassemia is a major sickling disorder, whereas hemoglobin E/β-thalassemia and homozygous β-thalassemia are transfusion-dependent states, with the associated problems of iron overload and iron chelation therapy. Couples at risk for having a child with a major hemoglobinopathy need timely, nondirective counseling, with education about the possibility and techniques available for antenatal diagnosis. Partners of women with β-thalassemia or hemoglobin E/β-thalassemia need antenatal screening to determine the risk of major hemoglobinopathy. If the partner has a relevant heterozygous condition, the risk of having an affected fetus increases to one in two. Although fertility is reduced in women with transfusion-dependent thalassemia, pregnancy has been reported.124–126 The physiologic stress of pregnancy may exacerbate symptoms of thalassemia. The transfusion regimen needs careful monitoring because blood requirements tend to increase in pregnancy. Iron chelation therapy also needs to be reviewed. Outside of pregnancy, iron chelation is usually performed with desferrioxamine mesylate (Desferal), which is given as a subcutaneous infusion over 12 hours 5 to 7 days per week. Continuing this treatment periconceptually and during pregnancy may put the fetus at risk for skeletal anomalies. This finding was noted in animal studies at doses equivalent to human dosages. The small number of reported cases in pregnant women is not sufficient to establish the safety of desferrioxamine mesylate in this setting. There are case reports of desferrioxamine mesylate use in early pregnancy,127 but ideally, iron status is optimized prepregnancy and chelation is discontinued periconceptually, at least for the first trimester, but ideally, throughout pregnancy. A riskbenefit assessment of continuing iron chelation in pregnancy is required, and the results will depend on the degree of iron overload at the start of pregnancy. At conception, various organs may already be affected by iron overload, particularly the heart, liver, and endocrine system. These patients require careful evaluation prepregnancy and monitoring throughout gestation. Patients with β-thalassemia major are often small in stature, and affected women have small pelvic bones. This finding might be the reason for the increased rate of cesarean delivery reported in these women.126
C HAPTER 38 • Anemia and White Blood Cell Disorders 697
The fetus is primarily at risk if the transfusion regimen is inadequate and the mother is anemic. Fetal hypoxia may occur and has been associated with intrauterine growth restriction, pregnancy loss, and preterm labor. These complications do not occur when maternal anemia is managed well. Women with iron overload are at increased risk for maternal diabetes, which can lead to an increased risk of birth defects and prenatal and maternal complications.
DIAGNOSIS AND MANAGEMENT OPTIONS Prepregnancy and Prenatal β-Thalassemia trait is indicated by hypochromic, microcytic red cell indices and usually is seen with a finding of increased hemoglobin A2 on hemoglobin electrophoresis. Complications in diagnosis can arise in patients with iron-deficiency anemia because it can falsely decrease hemoglobin A2. Racial groups at greatest risk include those of Mediterranean origin and some Asian populations, but it can occur in any racial group. The overall carrier rate in the United Kingdom is approximately 1 in 10,000 compared with 1 in 7 in Cyprus. Women who are carriers of β-thalassemia trait need early education about the advisability of partner testing and the availability of antenatal diagnosis.128,129 In most cases, women with β-thalassemia intermedia or major are identified well before pregnancy and are receiving regular follow-up. Fertility is often reduced in women with transfusion-dependent thalassemia major owing to iron overload and central hypogonadism, but pregnancy is possible for some. Many require regular transfusion programs and iron chelation therapy. Unnecessary iron loading should be avoided. Oral and intravenous iron supplements are contraindicated. If possible, iron chelation therapy should be optimized prior to pregnancy and then discontinued during pregnancy. Iron chelation can be restarted after delivery. Desferrioxamine is safe to use if breast-feeding. Assessment of the function of organs affected by iron overload (heart,
liver, and endocrine system) should be carried out regularly throughout medical follow-up. Assessment includes evaluation of cardiac status, liver function tests, thyroid and parathyroid function tests, and glucose testing. Baseline cardiac status is important because the demands of a 30% to 50% increase in cardiac output that occurs in pregnancy can lead to cardiac decompensation with serious arrhythmias and heart failure in those with cardiac siderosis. Echocardiography assessment should be carried out, and the magnetic relaxation parameter T2* measured by magnetic reasonance imaging is useful in the quantification of cardiac iron, where available, although its predictive value for heart failure is unknown.130 If pregnancy was achieved spontaneously (i.e., without fertility treatment), the pituitary axis is likely to be functioning. Thyroid function and a glucose tolerance test should be carried out. Thyroid dysfunction is present in up to 75% of patients with thalassemia major, and the occurrence of treated hypothyroidism is approximately 9%. There is a high incidence of gestational diabetes among this group of women. If known to be diabetic (incidence of approximately 7% in thalassemia major), the control should be optimized prior to pregnancy. Bone problems with osteopenia and osteoporosis often occur in transfusion-dependent thalassemics, and these can worsen during pregnancy. Vitamin D and calcium supplements are advisable if bone density is reduced, but bisphosphonates should be discontinued. Transfusion requirements tend to increase in pregnancy, and the transfusion regimen needs monitoring. The fetomaternal medicine team should monitor the health of the mother and the growth and wellbeing of the fetus. Partner screening should be performed.
Labor and Delivery and Postpartum There are no specific management recommendations. As discussed earlier, issues relating to pelvis size, diabetes, and cardiac function may require assessment on an individual basis.
SUMMARY OF MANAGEMENT OPTIONS
Thalassemia Syndromes Evidence Quality and Recommendation
Management Options
References
β-Thalassemia Major Prepregnancy and Prenatal Pregnancy is rare.
—/GPP
—
Review medication: stop iron chelators, give calcium and vitamin D supplements if bone density is reduced prepregnancy.
—/GPP
—
Avoid iron.
—/GPP
—
Give folate.
—/GPP
—
Give regular transfusions for anemia.
—/GPP
—
Screen partner; if the result is positive, consider counseling and prenatal diagnosis.
Ia/A
100
698 S ECTION F IVE • Late Prenatal SUMMARY OF MANAGEMENT OPTIONS
Thalassemia Syndromes—cont’d Evidence Quality and Recommendation
Management Options
References
Labor and Delivery Mode of delivery is dependent on cardiac status and presence of cephalopelvic disproportion.
—/GPP
—
Cord sample.
—/GPP
—
—/GPP
—
Give folate.
—/GPP
—
Give oral (not parenteral) iron if ferritin level is low.
—/GPP
—
Screen partner; if the result is positive, consider counseling and prenatal diagnosis.
Ia/A
100
—/GPP
—
—/GPP
—
Give folate.
—/GPP
—
Transfusion for severe anemia.
—/GPP
—
Screen partner; if the result is positive, consider counseling and prenatal diagnosis.
Ia/A
100
—/GPP
—
—/GPP
—
Postnatal Neonatal follow-up. β-Thalassemia Minor Prepregnancy and Prenatal
Labor and Delivery Obtain a cord sample if the patient has an at-risk pregnancy. Postnatal Provide neonatal follow-up if the patient has an at-risk pregnancy. α-Thalassemia (Hemglobin-H) Prepregnancy and Prenatal
Labor and Delivery Cross-match blood if the anemia is severe. Postnatal Provide hematologic follow-up.
α-Thalassemia (Hemoglobin Bart’s Hydrops) Prenatal No treatment for fetal hydrops (incompatible with life).
—/GPP
—
—/GPP
—
—/GPP
—
Provide iron and folate supplementation.
—/GPP
—
Screen partner; if the result is positive, consider counseling and prenatal diagnosis.
—/GPP
—
Labor and Delivery Problems related to large fetus. Postnatal Counsel about events and approaches to future pregnancy. α-Thalassemia Minor/Trait Prepregnancy and Prenatal
GPP, good practice point.
C HAPTER 38 • Anemia and White Blood Cell Disorders 699
HEMOLYTIC ANEMIAS Hemolytic anemias are characterized by accelerated red cell destruction, which typically results in an increased unconjugated bilirubin level, increased urobilinogen excretion, and an increased lactate dehydrogenase level. The reticulocyte count increases as the bone marrow responds. If intravascular hemolysis is present, free plasma hemoglobin and absent serum haptoglobins are characteristic findings. Clinically, patients may have anemia, jaundice, splenomegaly, and pigment gallstones. Hemolytic anemias are caused by something intrinsic or extrinsic to the red blood cell. Intrinsic causes of hemolysis include abnormalities in hemoglobin structure or function (i.e., hemoglobinopathies), the red cell membrane (e.g., hereditary spherocytosis), or red cell metabolism (e.g., pyruvate kinase, glucose-6-phosphate dehydrogenase [G-6-PD] deficiency). Extrinsic causes may be the result of a red cell– directed antibody (i.e., autoimmune hemolytic anemia), altered intravascular circulation (e.g., disseminated intravascular coagulation, thrombotic thrombocytopenic purpura; see Chapters 78 and 79), or infection.
Red Cell Membrane Disorders Hereditary spherocytosis occurs in approximately 1 in 2000 individuals of Northern European descent.131 The inheritance pattern is autosomal dominant. The red cells are spherocytic and osmotically fragile. The condition is caused by a wide range of molecular lesions resulting in defects in red cell membrane proteins. This leads to loss of red cell membrane surface, reduced red cell deformability, and accelerated red cell destruction. It is clinically and genetically heterogeneous. Diagnosis is made by a combination of nonimmune hemolysis and typical blood film findings, with spherocytes and osmotic fragility testing, or flow cytometry using an eosin-5-maleimide probe. This probe is a flow cytometric test that measures the fluorescence intensity of intact red cell membrane labeled with the dye eosin-5-maleimide. This fluorescent label binds to a component of the red cell membrane known as band 3. Binding is significantly reduced in hereditary spherocytosis.132 Hemoglobin concentrations are usually between 9 and12 g/dL but may be lower (6–8 g/dL) in up to 10% of patients. A pregnant woman with this condition should be monitored for anemia and should receive folic acid supplementation (≤5 mg daily). Aplastic and hyperhemolytic crises may occur. Aplastic crises are usually caused by parvovirus B19, which switches off erythropoiesis and causes a dramatic decrease in hemoglobin.133 The virus may also affect fetal erythropoiesis and development. Hyperhemolysis is characterized by increased jaundice and splenic enlargement. In severe anemia, treatment with blood transfusion may be necessary. Splenectomy ameliorates hemolytic anemia and reduces gallstone formation, but does not alter the underlying red cell defect. After splenectomy, women should ensure that their presplenectomy vaccinations (pneumococcal, H. influenzae B, and meningococcal) are current preconception and should take prophylactic penicillin V. Some small case series suggest that maternal morbidity and fetal outcome may be more favorable after splenectomy.134 Pediatricians should be
made aware of infants who are born to these women because there is a 50% chance that these children will be affected with hereditary spherocytosis, which may cause neonatal jaundice. Affected infants require long-term follow-up.
Red Cell Metabolism Disorders The mature red cell has two principal pathways of glucose metabolism, the glycolytic pathway and the hexose monophosphate shunt. The glycolytic pathway provides the red cell with adenosine triphosphate as an energy source. Other products include the reduced form of nicotinamide adenine dinucleotide to reduce methemoglobin and 2,3-diphosphoglyceric acid to regulate the oxygen affinity of hemoglobin. Pyruvate kinase deficiency is the most common defect of the glycolytic pathway. It is inherited in an autosomal recessive fashion and is clinically and genetically heterogeneous.135,136 Varying degrees of nonspherocytic hemolytic anemia are seen. Hemolysis can worsen during pregnancy.136 The need for transfusion of red cells must be assessed throughout pregnancy. Folic acid supplements are important for these patients, especially during pregnancy. Patients who have had splenectomy should be current with their vaccinations and receiving prophylactic penicillin. Metabolism of glucose through the hexose monophosphate shunt produces the reduced form of nicotinamide adenine dinucleotide phosphate to maintain the antioxidative activity of the red cell. G-6-PD deficiency is a defect in the hexose monophosphate shunt and is the most common abnormality of red cell metabolism.137 Worldwide, it affects more than 200 million people and offers a survival advantage in the face of Plasmodium falciparum malaria.138 G-6-PD deficiency is X-linked. More than 300 genetic variants occur, and they are categorized according to the variant enzyme activity. The severity of this nonspherocytic hemolytic anemia in heterozygous women depends on the degree of lyonization, the type of defect, the level of enzyme activity, and the oxidative challenge (typically, drugs and fava beans). Heinz bodies can be seen on supravital staining of peripheral blood at times of hemolysis, and they indicate the presence of denatured hemoglobin within the red cell. The G-6-PD A variant is an unstable enzyme, with a halflife of 13 days (normal half-life 62 days) and the enzyme activity decreases as the red cells age. This variant is found in approximately 10% to 15% of African American men. Women with this condition usually are only mildly anemic. Enzyme levels are between 10% and 60% of normal and hemolysis is intermittent and usually secondary to drugs or infection. The G-6-PD B variant (also known as G-6-PD Mediterranean) is found in up to 5% of people with Mediterranean or Asian ancestry and is clinically more severe. The unstable enzyme has a half-life measured in hours. Men and heterozygous women may have severe enzyme deficiency, but the hemolysis is usually only intermittent. The responsible agent must be removed because even the reticulocytes have low enzyme levels and are prone to hemolysis. Some variants cause congenital hemolytic anemia with persistent splenomegaly. G-6-PD deficiency screening tests are available in most hematology laboratories. Direct quantification of G-6-PD is
700 S ECTION F IVE • Late Prenatal
available at more specialist red cell laboratories and is applicable when screening tests are positive. In more severe variants, women must be monitored for anemia throughout pregnancy, should avoid oxidant stresses, should take folic acid, and might need transfusion. Women heterozygous for G-6-PD deficiency should avoid oxidant drugs in pregnancy and when breast-feeding because hemolysis may occur in the fetus or neonate if the drugs cross into the fetal circulation or breast milk. The pediatrician must be alerted to the risk of hemolysis and neonatal jaundice because affected patients need careful monitoring and early therapy with phototherapy or exchange transfusion with G-6-PD–screened blood if indicated by the bilirubin levels.
Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia may be primary or secondary to drugs, infection, autoimmune disease (typically systemic lupus erythematosus), neoplasia, or other hematologic disorders. Usually, the antibodies are of the immunoglobulin G class, and antibody-coated red cells are cleared by the spleen. Symptoms of autoimmune hemolytic anemia are
indistinguishable from those of other causes of hemolysis. The positive direct antiglobulin test (Coombs’ test) is the mainstay of diagnosis. Treatment is usually with glucocorticoids, but some patients have undergone splenectomy or are taking other immunosuppressive agents, such as cyclophosphamide, azathioprine, and cyclosporine. Transfusion may be required in patients who do not respond to treatment, but the autoantibodies may cause difficulties with cross-matching and close liaison with the blood bank is advisable. Women who have autoimmune hemolytic anemia should have prepregnancy counseling, and treatment should be optimized. Careful antenatal supervision to assess maternal hemoglobin and markers of hemolysis, with adjustment of steroid therapy, is required.139 Transplacental antibody transfer may occur, and hemoglobin levels in the newborn should be evaluated. Some infants require exchange transfusion,140 but usually no treatment is necessary.141 Autoimmune hemolytic anemia has been reported specifically associated with pregnancy, with remission occurring after delivery. This condition tends to recur in subsequent pregnancies. The anemia responds to steroids, and most infants are not affected.142
SUMMARY OF MANAGEMENT OPTIONS
Hemolytic Anemias Evidence Quality and Recommendation
Management Options
References
Red Cell Membrane Disorders (Hereditary Sperocytosis) Prepregnancy and Prenatal Consider splenectomy prepregnancy (with appropriate up-to-date vaccination and penicillin V cover for pregnancy).
III/B
134
Monitor hemoglobin, folate supplementation during pregnancy.
III/B
133
Blood transfusion if anemia is severe.
GPP
Consult with pediatricians to arrange screening of infant.
GPP
Red Cell Metabolism Disorders Prepregnancy and Prenatal Consider splenectomy prepregnancy (with appropriate up-to-date vaccination and penicillin V cover for pregnancy).
III/B
136
Monitor hemoglobin, folate supplementation during pregnancy.
III/B
136
Blood transfusion if anemia is severe.
GPP
G-6-PD patients should avoid antioxidants during pregnancy.
GPP
Autoimmune Prepregnancy and Prenatal Prepregnancy counseling and optimization of drug treatment and continue with “pregnancy-safe” drugs during pregnancy.
III/B
Blood transfusion if medical treatment not successful.
GPP
G-6-PD, glucose-6-phosphate dehydrogenase; GPP, good practice point.
139
C HAPTER 38 • Anemia and White Blood Cell Disorders 701
ANEMIA: BONE MARROW APLASIA Aplastic Anemia Aplastic anemia is a syndrome of bone marrow failure defined by pancytopenia and bone marrow hypocellularity. Normal hematopoietic tissue in the marrow is replaced by fat. Causative agents include infection, medications, and toxins, but most cases are idiopathic. Patients have pallor and fatigue as a result of anemia and bruising and bleeding as a result of thrombocytopenia. Infection is a risk because of neutropenia. Musculoskeletal abnormalities may indicate an inherited syndrome of bone marrow failure. The patient should be examined carefully for organomegaly and lymphadenopathy. These findings suggest viral infection or another underlying disease. In patients with pancytopenia, testing should be directed by a hematologist and will include bone marrow aspirate and trephine with cytogenetic analysis and chromosome fragility tests. Treatment of aplastic anemia is initially supportive, with blood products and growth factors. For younger patients with matched sibling donors, bone marrow transplantation is the treatment of choice. Immunosuppressive therapy with antilymphocyte globulin in combination with cyclosporin is also effective.
There are sporadic case reports of aplastic anemia in pregnancy143–146 and reports of pregnancy occurring in women with underlying aplastic anemia.147–152 However, overall, aplastic anemia in pregnancy is rare. The relationship between aplastic anemia and pregnancy is uncertain, but the literature suggests that there is not a strong association in most cases.153 In a few women, however, pregnancy may play an etiologic role. There are case reports of aplastic anemia that are diagnosed for the first time in pregnancy, with spontaneous remission occurring after cessation of pregnancy.154 Pregnancy may exacerbate bone marrow depression and cause clinical deterioration.155 If severe aplastic anemia occurs in the first trimester, early termination should be considered. If spontaneous recovery does not occur after termination, bone marrow transplantation is performed as soon as possible in women who have a histocompatible sibling donor. In women with severe aplastic anemia later in pregnancy and those who refuse termination, intensive hematologic support with red cells and platelet transfusions is required until delivery. After delivery, bone marrow transplantation should be considered if spontaneous recovery does not occur. There are case reports of the use of antilymphocyte globulin in pregnancy,154 but each case requires individual assessment and close liaison between obstetricians and hematologists.
SUMMARY OF MANAGEMENT OPTIONS
Aplastic Anemia Management Options
Evidence Quality and Recommendation
References
Prepregnancy and Prenatal Optimize medical treatment prepregnancy.
GPP
Consider termination of pregnancy if in first trimester.
GPP
Provide supportive treatment.
GPP
Provide multidisciplinary approach.
GPP
GPP, good practice point.
WHITE BLOOD CELL DISORDERS Neutrophilia The neutrophil count increases throughout pregnancy. The increase is more marked during labor and immediately postpartum. Occasional band forms and myelocytes in the peripheral blood may be a normal finding during pregnancy. Neutrophilia may be associated with ● Bacterial infection. ● Acute or chronic inflammatory disorders. ● Tissue damage or infarction. ● Preeclampsia. ● Hemorrhage. ● Malignant disease, either hematologic (e.g., chronic myeloid leukemia) or nonhematologic.
Neutropenia The finding of neutropenia on an automated complete blood count should be verified by examination of the peripheral blood film. Aged samples may show spurious neutropenia or neutrophil clumping. A repeat count should be obtained to ensure that the findings are reproducible. Ethnic origin affects the neutrophil count; persons of African and Caribbean descent tend to have a lower peripheral blood neutrophil count because of an increase in the marginating pool. Neutropenia may be acute or chronic and isolated or part of generalized pancytopenia. It may be caused by peripheral destruction or underlying bone marrow disease. A summary of the causes of nonmalignant neutropenia is shown in Table 38–2. The investigation of neutropenia in the pregnant woman is identical to that outside pregnancy. Drugs that
702 S ECTION F IVE • Late Prenatal T A B L E 3 8 – 2
Nonmalignant Neutropenia TYPE
CAUSES
Acute
Drug-induced bone marrow suppression Agranulocytosis Viral infection Vitamin B12 or folate deficiency Race Immune neutropenia Primary Associated with connective tissue disorder or autoimmune disease Felty’s syndrome Congenital neutropenia Kostmann’s neutropenia Associated with other congenital disorders Chronic idiopathic neutropenia
Chronic
Cyclic neutropenia Aplastic anemia
may be implicated should be discontinued immediately, especially if neutropenia is severe. There are case reports of ritodrine-induced neutropenia.156 If clinical assessment and examination of the blood film do not show the cause of neutropenia, bone marrow examination is indicated.
Maternal and Fetal Risks In severe neutropenia, the principal maternal risk is sepsis. A patient with moderate or severe neutropenia (neutrophil count < 1.0 × 109/L) and fever should have prompt cultures of blood, urine, and sputum, if available, followed immediately by empirical treatment with broad-spectrum intravenous antibiotics, according to local policy. Antifungal therapy is considered if the fever does not resolve after 48 to 72 hours, especially when neutropenia is prolonged.
There are many case reports of pregnancy in patients with cyclic neutropenia.157,158 This disorder is characterized by cyclic fluctuations of the neutrophil count, with a periodicity of approximately 21 days. At its nadir, neutropenia is usually severe and is often associated with clinical infection. The onset is usually in childhood, but adult-onset cyclic neutropenia is also described. Pregnancy in cyclic neutropenia is associated with preterm labor and stillbirth, possibly because of chorioamnionitis associated with the neutropenia. There are also reports of improvements in symptoms and neutrophil counts during pregnancy in patients with cyclic neutropenia, possibly because of the production of neutrophil growth factors, such as granulocyte-macrophage colony-stimulating factor, by the placenta.159 In approximately one third of cases, cyclic neutropenia appears to be inherited in an autosomal dominant fashion; therefore, the fetus may be affected.
Management Options Recombinant granulocyte colony-stimulating factor is successfully used to treat patients with severe chronic neutropenia of differing etiologies, including cyclic and congenital types.160 A few pregnancies have occurred in patients treated with granulocyte colony-stimulating factor for severe chronic or cyclic neutropenia.161 Pregnancy outcome was normal in some, but fetal abnormality, including bilateral hydronephrosis, occurred in others. Data on the safety of the use of granulocyte colony-stimulating factor during pregnancy are inconclusive. Risks and benefits should be evaluated individually. For a patient with severe neutropenia, prophylactic antibiotics should be considered to cover invasive procedures for labor and delivery. Some viral infections that cause neutropenia have implications for fetal development and congenital infection (e.g., rubella, parvovirus, cytomegalovirus) or hepatitis. Maternal autoimmune neutropenia may lead to transfer of antineutrophil antibodies across the placenta, resulting in fetal neutropenia.162,163
SUMMARY OF MANAGEMENT OPTIONS
White Cell Disorders Evidence Quality and Recommendation
Management Options
References
Neutrophilia Prenatal Increase in values for pregnancy.
—/GPP
—
Search for pathology and treat if the count is above normal.
—/GPP
—
Give antibiotics for fever (and antifungals if fever persists).
—/GPP
—
For severe cases, consider recombinant granulocyte colonystimulating factor; experience in pregnancy is limited to case reports.
Ib/A
160
IV/C
157
Neutropenia Prepregnancy and Prenatal
Labor and Delivery Consider prophylactic antibiotics. GPP, good practice point.
C HAPTER 38 • Anemia and White Blood Cell Disorders 703
SUGGESTED READINGS Dodd J, Dare MR, Middleton P: Treatment for women with postpartum iron deficiency anaemia. Cochrane Database Syst Rev 2004;3:CD004222. Howard RJ, Tuck SM, Pearson TC: Pregnancy in sickle cell disease in the UK: Results of a multicentre survey on the effect of prophylactic blood transfusion on maternal and fetal outcome. Br J Obstet Gynaecol 1995;102:947–951. Jenson CE, Tuck SM, Wonke B: Fertility in β thalassaemia major: A report of 16 pregnancies, preconceptual evaluation and review of the literature. Br J Obstet Gynaecol 1995;102:625–629. Mahomed K: Iron and folate supplementation in pregnancy. Cochrane Database Syst Rev 2006;3;CD001135. Mahomed K: Iron supplementation in pregnancy. Cochrane Database Syst Rev 2006;3:CD000117. Milman N: Prepartum anaemia: prevention and treatment. Ann Hematol 2008;87:949–959.
Model B, Harris R, Lane B, et al: Informed choice in genetic screening for thalassaemia during pregnancy: Audit from a national confidential inquiry. BMJ 2000;320:337–341. Singh K, Fon YF, Kuperan P: A comparison between intravenous iron polymaltose complex (Ferram Hausmann) and oral ferrous fumarate in the treatment of iron deficiency anemia in pregnancy. Eur J Hematol 1998;60:119–124. Smith JA, Espeland M, Bellevue R, et al: Pregnancy in sickle cell disease: Experience of the co-operative study of sickle cell disease. Obstet Gynecol 1996;87:199–203. Zanella A, Fermo E, Bianchi P, Valentini G: Red cell pyruvate kinase deficiency: Molecular and clinical aspects. Br J Haematol 2005;130:11.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 3 9
Malignancies of the Hematologic and Immunologic Systems JOHN MAELOR DAVIES and LUCY H. KEAN
INTRODUCTION
Maternal Risks
Malignancy complicating pregnancy is uncommon; however, hematologic disorders account for most malignancies in women of reproductive age. Acute leukemia complicates approximately 1 in 75,000 pregnancies, and lymphoma complicates 1 in 5000 pregnancies.1,2 Hematologic malignancies are an important consideration in pregnancy because, although they may threaten life, many are potentially curable. It is also important that the clinician has an understanding of the impact on reproduction of previously treated disease, because many women who have undergone successful treatment will later become pregnant. The classification of tumors of the hemopoietic and lymphoid tissues is complex and subject to change. The World Health Organization classification3 provides the major framework for categorizing these disorders. Much of the literature on these conditions in pregnancy predates the introduction of effective modern management. In some areas, data are necessarily limited, but as far as possible, the management principles discussed are evidence-based.
Pregnancy does not appear to affect either the development or the course of acute leukemia. Patients who have symptoms or signs with abnormalities in the complete blood count suggesting bone marrow failure or infiltration should undergo appropriate investigation. The diagnostic workup in pregnant patients with suspected acute leukemia should not differ from that in nonpregnant patients. This includes bone marrow aspiration, trephine biopsy, and examination of the cerebrospinal fluid, as appropriate. Cytogenetic and molecular diagnostic techniques are now routine and provide rapid additional prognostic information.3 Blood chemistry including renal and hepatic function and urate should be monitored. Infection and bleeding are major risks in uncontrolled acute leukemia, particularly in some subtypes, such as acute promyelocytic leukemia. Laboratory assessment of the degree of thrombocytopenia is essential, and evidence of coagulation factor depletion and disseminated intravascular coagulation should be sought. Supportive care, with blood and platelet transfusions and antibiotic administration, should be instituted early. However, chemotherapy offers the only prospect for longterm maternal survival. If delivery is contemplated before complete remission is achieved, then infection and bleeding pose a major risk to maternal survival. Patients may require intensive supportive care including antibiotic administration and appropriate blood, coagulation factor, and platelet replacement. The outcome in both AML and ALL depends on a number of pretreatment prognostic factors. The prognosis is also determined by the response to treatment and the type of treatment offered. Recent population-based data from the United States show that for AML, approximately 50% of patients in the 15- to 35-year-old age group will be alive at 10 years. Similar Scandinavian data for ALL give a 60% event-free survival in patients aged 17 to 25 years. The acute leukemias are, however, a very heterogeneous group of disorders with widely varying outcomes. For example, patients with acute promyelocytic leukemia treated with modern protocols have an approximately 70% long-term survival,3 whereas patients with Philadelphia chromosome–positive
ACUTE LEUKEMIA Acute leukemia results from malignant change in hemopoietic precursor cells at various stages of differentiation. Acute leukemia is traditionally subdivided into acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL), depending on the major cell lineage involved. Further subdivision of AML and ALL provides additional prognostic and therapeutic information. Both AML and ALL are usually rapidly progressive and lead to bone marrow failure, with symptoms and signs of anemia, neutropenia, and thrombocytopenia. More unusually acute leukemias may present with extramedullary involvement. The myelodysplastic syndromes (MDSs) represent a heterogenous group of clonal disorders characterized by peripheral blood cytopenias and abnormal marrow morphology often with cytogenetic abnormalities. MDS may behave indolently, in which case outcome for pregnancy is excellent, whereas more aggressive forms of MDS resemble and overlap with AML in their prognosis and management.4
705
706 S ECTION F IVE • Late Prenatal
ALL continue to present significant management problems. Despite the introduction of tyrosine kinase inhibitors, this disease remains essentially incurable with current chemotherapy regimens alone.5 Discussion of prognosis should be highly individualized and undertaken only when all necessary information is available. Fertility is likely to be maintained in many patients with AML and ALL treated with conventional chemotherapy, and future pregnancy outcome in survivors of AML and ALL is also likely to be favorable. Counseling and contraceptive advice should include these considerations. Increasing numbers of patients have been treated with high-dose therapy including both autologous and allogeneic hemopoietic stem cell transplantation for acute leukemia. Although successful pregnancy has been reported, in most patients, these procedures significantly impair subsequent fertility.6,7
extensively to treat acute promyelocytic leukemia, is related to other retinoids that are potent human teratogens. These agents are contraindicated in women of childbearing age. There are, however, increasing case reports of the successful use of all-trans-retinoic acid in pregnancy, and these data emphasize that maternal versus fetal risk must be balanced at all stages in patient management.15 Finally, exposure to many chemotherapeutic agents is associated with the development of markers of chromosomal damage. The significance of this observation is not clear, and data on long-term effects in surviving infants exposed to chemotherapeutic agents in utero are encouraging.16–18 However, this observation may reflect a lack of good information rather than a true lack of adverse events, with late chemotherapy-induced malignancies representing the major potential concern.19
Fetal Risks
Management Options
The main risks to the fetus are growth restriction, which occurs in both treated and untreated pregnancies, and chemotherapy-induced effects, both reversible and irreversible. Historically, fetal growth restriction and spontaneous preterm delivery occurred in approximately 40% to 50% of cases, and causation appeared to be multifactorial.8 With modern chemotherapy and the attainment of remission in the majority of patients within 4 to 6 weeks, the fetal survival rate improves significantly.9 Congenital leukemia is rare and essentially can be discounted. The fetal risks associated with chemotherapy depend, in part, on the timing of the treatment in terms of gestational age and also on the agents used. Although data are limited, general conclusions can be drawn about the fetal risks of chemotherapy. First, adverse fetal events may occur at any point in gestation, although congenital malformation is more likely to occur with first-trimester exposure to chemotherapy. The literature suggests that the risk of major fetal abnormality with first-trimester exposure is 10% to 30%, depending on the degree of exposure and the agents used.10 When a patient has known first-trimester exposure to cytotoxic agents, a careful fetal ultrasound should be performed at 18 to 22 weeks. However, not all teratogenic effects are detectable by ultrasound examination, and parents should be carefully counseled. Serial scans may improve the detection of some abnormalities, especially central nervous system (CNS), cardiac, and growth abnormalities. Second, some chemotherapeutic agents are more likely than others to produce adverse fetal effects. For example, first-trimester use of high-dose methotrexate produces an approximately 25% risk of significant adverse fetal effects, with CNS, skeletal, and facial abnormalities being most common. Data on other agents used to treat acute leukemia are limited, and the degree of fetal risk is not known. However, successful fetal outcomes have been described following fetal exposure to many commonly used classes of cytotoxics particularly in the second and third trimesters. This includes vinca alkaloids, corticosteroids, anthracyclines, and cytarabine.11–14 The situation is further complicated by an apparent “weakening” of predicted class effects with some agents, in that agents structurally closely linked to known human teratogens may produce less fetal abnormality than expected. All-trans-retinoic acid, which is used
Prepregnancy Women who undergo chemotherapy for acute leukemia should be counseled and advised against conception until remission is achieved and chemotherapy is discontinued. Oral contraceptives are not contraindicated. Methotrexate has a long “wash-out” period and can remain in tissues for periods of at least 3 months. It is, therefore, recommended that women wait at least 6 months before conceiving after receiving the drug. The risk of teratogenesis does not seem to be increased, but spontaneous miscarriage rates are higher. For women in sustained complete remission, which is now a more common scenario, prepregnancy counseling should include a discussion of the prognosis in terms of the disease and the effect of the disease and its treatment on pregnancy. As a result of the 1994 European Registration of Congenital Anomalies (EUROCAT) study of policies for karyotyping in pregnancy, patients began to seek invasive prenatal testing because of maternal anxiety about exposure to chemotherapy or radiation therapy.20 As discussed, although chemotherapy may cause chromosome breaks, there does not appear to be a documented increase in the risk of chromosomal or genetic problems in offspring of successfully treated patients. Importantly, previous chemotherapy exposure does not appear to increase the risk of miscarriage, growth restriction, or stillbirth.21,22 It has not been possible to perform large studies to determine whether the incidence of childhood cancer is increased in the offspring of patients who have undergone chemotherapy. However, smaller studies suggest that there is no increased risk. Given the lack of evidence suggesting an increase in the risk of chromosomal abnormalities in the fetus, invasive prenatal diagnosis should be based on normal criteria in relation to age and screening test results. Women who have undergone pelvic radiation therapy, however, have a significantly increased risk of growth restriction in the fetus and should be counseled that increased surveillance is needed in pregnancy.
Prenatal A pregnant woman with acute leukemia should be treated aggressively, with full supportive care and combination chemotherapy. A broad-based multidisciplinary team approach is required to manage the hematologic and obstetric aspects of care. Untreated acute leukemia is fatal to both mother
C HAPTER 39 • Malignancies of the Hematologic and Immunologic Systems 707
and fetus. Standard treatment should be given, when possible, with appropriate counseling about fetal risk. No robust data are available on the need for dosage modifications of chemotherapeutic drugs in pregnancy. In some cases, agents that are less likely to cause fetal abnormalities can be used (e.g., intrathecal cytarabine rather than intrathecal methotrexate for central nervous system prophylaxis in ALL). However, nonstandard regimens of unproven efficacy should not be substituted on the basis of fetal risk without full and informed discussion of maternal risks. Counseling about the teratogenic risks of treatment should be provided, and fetal and maternal well-being should be monitored throughout pregnancy by a hematooncologist and an obstetrician. Regular monitoring of fetal growth is indicated for patients who have received pelvic radiotherapy in the past. Whether more intensive surveillance in all patients previously treated for hematologic malignancy is necessary is unclear. However, it would seem sensible to provide an enhanced level of fetal monitoring when this provides additional reassurance to the mother and the attending physician that the pregnancy is progressing normally.
Labor and Delivery Delivery should be expedited for normal obstetric indications. The goal of management is to deliver a viable infant while the mother is in hematologic remission. This approach offers the best prospect for uncomplicated delivery and infant survival. There is no contraindication to the use of steroids before delivery to enhance fetal surfactant production. Early assessment of the infant should be undertaken to
detect complications from in utero exposure to chemotherapy. This evaluation includes assessment of potential congenital abnormalities and hematologic testing to exclude short-term effects (e.g., neutropenia as a result of recent in utero exposure to cytotoxic agents administered to the mother). When indicated, a cord blood sample should be sent for a complete blood count.
Postnatal If delivery is inevitable in a patient who is not in remission, vigorous supportive care should be continued peri- and postnatally. If the disease is in remission at the time of delivery, counseling and appropriate contraceptive advice should be given after delivery. Data on the excretion of cytotoxic drugs in breast milk are variable. Methotrexate is excreted into breast milk in small amounts with a measured milk-to-plasma ratio of 0.08. However, there is a risk for tissue accumulation in the neonate, which may lead to potential problems including myelosuppression. Results of excretion studies for cisplatin are mixed. The maximum reported excretion showed that milk-to-plasma ratios may reach 1, with consequent neonatal concerns regarding breast-feeding. A small number of reports of mothers breast-feeding while taking cyclophosphamide have shown significant neonatal myelosuppression. The data on anthracycline excretion are so limited that no assessment of safety is possible. This is also the case for newer classes of drugs. The absence of good data for most cytotoxics and evidence of potential harm for some lead to the general recommendation of avoidance of breast-feeding while taking cytotoxic drugs.
SUMMARY OF MANAGEMENT OPTIONS
Hematologic Malignancies: Acute Leukemia Management Options
Evidence Quality and Recommendation
References
Prepregnancy Counsel about the prognosis.
—/GPP
—
Advise against conception until the patient is in remission and not on chemotherapy.
IV/C
10,11
Provide an interdisciplinary approach.
—/GPP
—
Start chemotherapy as for a nonpregnant patient if the disease is diagnosed in pregnancy.
III/B
9,12–14
Prenatal
Provide supportive therapy (e.g., blood, platelets, antibiotics).
—/GPP
—
Counsel carefully, especially if treatment is commenced in the first trimester.
IV/C
10,11
Monitor fetal growth and health.
IV/C
12,13
Expedite for normal obstetric indications (ideally when the patient is in remission and the fetus is mature).
—/GPP
—
Give steroids if preterm delivery is contemplated.
—/GPP
—
Labor and Delivery
708 S ECTION F IVE • Late Prenatal SUMMARY OF MANAGEMENT OPTIONS
Hematologic Malignancies: Acute Leukemia—cont’d Evidence Quality and Recommendation
Management Options
References
Postnatal Provide contraceptive advice.
—/GPP
—
Counsel about the long-term prognosis.
—/GPP
—
Avoid breast-feeding if the patient is receiving cytotoxic treatment.
III/B
48
Examine and follow-up of the newborn.
—/GPP
—
GPP, good practice point.
CHRONIC LEUKEMIA Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is traditionally considered a triphasic disease (chronic phase, accelerated phase, and blast crisis) that is usually diagnosed in the chronic (early) phase. It accounts for 15% to 20% of cases of leukemia, and the median age at diagnosis is in the fifth and sixth decades. CML arises from a cytogenetic abnormality that results in production of the Philadelphia chromosome. As a result, the BCR/ABL fusion gene is produced that encodes for a protein with tyrosine kinase activity. CML causes systemic symptoms, such as weight loss, fatigue, and often significant splenomegaly. Laboratory findings include marked leukocytosis, and as discussed earlier, a specific marker chromosome that is detectable in blood and bone marrow. Hyperleukocytosis with ocular and other CNS effects may occur.
Management Options outside Pregnancy The management of CML has been revolutionized by the introduction of specific tyrosine kinase inhibitors, the first of which was imatinib mesylate.23 A recent update of one of the major comparative studies with imatinib has demonstrated an estimated event-free survival at 6-year follow-up of 83% with an overall survival of 95% when only deaths from CML are included in analysis. Tyrosine kinase inhibitors have accordingly replaced the now-historic treatment options of hydroxyurea and interferon-alfa as first-line therapy. Related or unrelated allogeneic hemopoietic stem cell transplantation, which traditionally has been used to treat this condition, is now reserved for those failing or intolerant of tyrosine kinase inhibitors.24 The practical management of patients with CML in the imatinib era including the role of molecular monitoring and approach to imatinib resistance or intolerance has recently been reviewed.25
Maternal and Fetal Risks There is no evidence that the behavior of CML is altered in pregnancy. Control of the maternal white count may be achieved in a number of ways. The risk to the fetus is probably secondary to exposure to maternal therapy, and control of the maternal white count with physical means, such as leukapheresis, should be considered. Patients on treatment
with imatinib or other tyrosine kinase inhibitors should currently be counseled against becoming pregnant because good data on their use in pregnancy are insufficient.
Management Options PREPREGNANCY The implications and risks of pregnancy should be fully explained, and appropriate contraceptive advice should be given.
PRENATAL Regular hematologic review is required to determine the need for active treatment. Leukapheresis may be an effective method to control the white cell count, particularly in the first trimester. This approach may be continued throughout pregnancy. Successful pregnancies are described in patients treated with hydroxyurea and interferon-alfa,26,27 though cumulative data are insufficient to allow an estimate of the real risk of fetal abnormality. Measurement of interferon-alfa in fetuses following administration of high doses has shown that it does not appear to readily cross the placenta. This also appears to be the case for excretion into breast milk, with levels no higher than controls found following highdose administration. Patients who become pregnant while taking imatinib should be counseled about the uncertainty regarding the risk of fetal abnormality. The degree of risk and the type of potential fetal abnormality are unknown, but this advice is based on lack of extensive evidence that imatinib is safe rather than positive evidence of high risk of harm. However, the safe option for patients in the chronic phase who become pregnant while taking imatinib is to discontinue use of the agent and to institute other methods to control the white cell count. There are, however, several case reports of successful pregnancy outcome in patients treated with imatinib at all stages of gestation.28,29 Imatinib does not appear to cross the placenta in the third trimester, but data regarding transplacental passage at earlier gestations are not available. Therefore, careful ultrasonographic examination of the fetus should be performed in women who wish to continue the pregnancy after first-trimester exposure. Imatinib is excreted into breast milk with a milk-toplasma ratio of 0.5 for imatinib and 0.9 for its main metabolite. This could potentially lead to levels in a term
C HAPTER 39 • Malignancies of the Hematologic and Immunologic Systems 709
infant of 10% of the therapeutic level. The effects of even low-dose exposure to the baby are unknown, and full discussion with the pediatric team should be considered in women who want to breast-feed. Hematologic abnormalities that suggest disease progression, such as signs of the accelerated phase or blast crisis, should lead to management review. In the accelerated phase, expediting delivery should be considered. Maternal options include reintroduction of imatinib, use of an alternative tyrosine kinase inhibitor, and referral for hemopoietic stem cell transplantation, which is the only likely curative option. Blast crisis in pregnancy may be treated with tyrosine kinase inhibitors, if the patient is not already receiving these agents, or with combination chemotherapy, as for other forms of acute leukemia. However, the maternal outlook long-term is poor, and urgent consideration should be given to early delivery and referral of the mother, if appropriate, for hemopoietic stem cell transplantation, particularly if a second chronic phase can be obtained.30
Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a disease of older populations3 and rarely occurs in pregnancy. A “wait-andwatch” approach is often appropriate, and the patient may need treatment only if symptoms occur. When treatment is required, standard first-line therapies include corticosteroids, alkylating agents, fludarabine, and rituximab.31 Given
the usual indolent course of CLL, most pregnancies will be managed without fetal exposure to potentially teratogenic agents and with no detriment to maternal outcome.
Myeloma Myeloma is also a disease of older age groups and is rare in pregnancy. It presents a unique set of management problems and may cause significant skeletal damage, bone marrow failure, extended risk of infection, and renal failure. Radiologic assessment of potential skeletal damage should be undertaken in a manner that limits fetal exposure to radiation. Magnetic resonance imaging (MRI) may be useful in this regard.32 A number of chemotherapeutic agents are active in the treatment of myeloma. If treatment is required in pregnancy, then high-dose corticosteroids either alone or in combination with older agents such alkylators and anthracyclines may be preferred to newer agents such as bortezomib in which data on fetal outcome are very limited.33 Thalidomide and its structural analogue lenalidomide, now commonly incorporated into front-line and salvage regimes, are absolutely contraindicated in pregnancy.34 Radiotherapy has a significant role in the management of myeloma, particularly in the context of cord compression. The management of maternal spinal cord compression in pregnancy is challenging, and treatment needs to be highly individualized following full interdisciplinary discussion, which includes neurosurgical opinion.
SUMMARY OF MANAGEMENT OPTIONS
Hematologic Malignancies: Chronic Myeloid Leukemia Management Options
Evidence Quality and Recommendation
References
Prepregnancy Counsel about the prognosis for pregnancy and in the long term.
IV/C
26
Give contraceptive advice.
—/GPP
—
Provide an interdisciplinary approach.
—/GPP
—
Provide regular hematologic monitoring.
—/GPP
—
Consider leukapheresis
—/GPP
—
Control with hydroxyurea or interferon-alfa (avoid cytotoxics in the first trimester); data on imatinib are limited–current recommendation is not to use in pregnancy.
IV/C
27–29
Manage accelerated phase and blast crisis as for nonpregnant patients, and expedite delivery if possible (to allow for the possibility of bone marrow transplantation).
IV/C
30
Provide contraceptive advice.
—/GPP
—
Counsel about the long-term prognosis.
—/GPP
—
Avoid breast-feeding if the patient is receiving cytotoxic treatment.
III/B
48
Examine and follow-up of the newborn.
—/GPP
—
Prenatal
Postnatal
GPP, good practice point.
710 S ECTION F IVE • Late Prenatal
LYMPHOMA The lymphomas are a heterogeneous group of malignant disorders that arise in lymphoid tissue. The major histologic subdivision of lymphoma is into the following categories: ● Hodgkin’s disease. ● Non-Hodgkin lymphoma.
Hodgkin’s Disease Hodgkin’s disease is an uncommon lymphoid malignancy.35 However, because of the age distribution of patients with Hodgkin’s disease, it is the most common type of lymphoma seen in pregnancy. Hodgkin’s disease causes nodal enlargement, classically in the neck, and diagnosis requires biopsy of the affected tissue. Further management depends on the stage of disease. Early-stage or localized Hodgkin’s disease may be cured with either radiation therapy alone or a combination of chemotherapy and radiation therapy in modified dosage. More extensive stage disease requires combination chemotherapy for cure. The Ann Arbor system is still the most commonly used staging system, but staging may be refined anatomically with the Cotswolds revision.36 In addition, information available from laboratory tests (e.g., lymphocyte count, erythrocyte sedimentation rate, serum albumin level) may be used to produce a prognostic index that may affect management. However, none of the commonly used prognostic scoring systems have been validated in pregnancy.
Maternal Risks Hodgkin’s disease in pregnancy does not appear to differ from that in nonpregnant patients, although Hodgkin’s disease is less common in multiparous women. Diagnosis is made by biopsy. Further studies in the pregnant patient are associated with specific problems, particularly with regard to computed tomography (CT); however, MRI, which is considered safe in pregnancy, may be used.37 Staging laparotomy has essentially been abandoned.38 The outlook for cure in patients with early-stage disease treated with radiation therapy, with or without a short course of chemotherapy, is excellent.39 The greater than 5-year disease-free survival rate in patients with advanced disease treated with combination chemotherapy is 70% to 80%.39 After relapse, high-dose therapy may produce additional long-term survivors.40 Most patients who are successfully treated for Hodgkin’s disease return to a normal or very near normal quality of life on cessation of treatment. Many women who receive combination chemotherapy for Hodgkin’s disease remain fertile, although there is a risk of premature menopause.41 No apparent increase in the complications of pregnancy or fetal abnormality in subsequent pregnancy is seen after combination chemotherapy for Hodgkin’s disease.42
Fetal Risks The risks to the fetus stem chiefly from the effects of either radiation therapy or chemotherapy. The risks to the fetus of diagnostic radiation have been reviewed.43,44 Both CT and positron-emission tomography (PET) scanning are now routinely used in the evaluation of lymphoma including Hodgkin’s disease. Exposure of pregnant women to the radiation
doses used in standard abdominal and pelvic CT appears to have no substantial effect on the risk of fetal death or malformation. The risk of childhood cancer is more than doubled after fetal irradiation. Where possible, irradiation of the fetus in utero should be avoided, but staging should be sufficient to determine the correct modality of treatment. MRI is an adequate tool for staging evaluation in most circumstances and avoids exposure to ionizing radiation.37 The risk to the fetus of therapeutic irradiation depends on whether early-stage Hodgkin’s disease involves the abdomen or pelvis. Supradiaphragmatic irradiation with heavy lead shielding of the uterus resulted in no congenital abnormalities in one series.45 When high-dose irradiation cannot be avoided by field manipulation, infradiaphragmatic radiation therapy even with appropriate shielding carries a substantial risk of spontaneous miscarriage and fetal abnormality throughout pregnancy. Under these circumstances, chemotherapy alone rather than radiation therapy should be considered, with delivery before therapeutic irradiation. The fetal effects of combination chemotherapy used to treat Hodgkin’s disease are unlikely to be substantially different from those seen in acute leukemia. The teratogenic risk is potentially greatest with first-trimester exposure. However, one series found no apparent adverse fetal effects even with first-trimester exposure to the current gold standard treatment of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD).46
Management Options PREPREGNANCY Women with active Hodgkin’s disease should be counseled about the risks of pregnancy and should take appropriate contraceptive measures. Pregnancy outcome is good in patients who have been successfully treated for Hodgkin’s disease, and routine amniocentesis is not recommended.
PRENATAL The outlook for patients treated for Hodgkin’s disease is good to excellent. Diagnosis and investigation are discussed previously. Patients diagnosed in the first trimester should be counseled about the risks of continuing with the pregnancy. In highly selected cases, early-stage supradiaphragmatic disease can be successfully treated with radiation therapy alone, with little fetal risk. Historically, early-stage intraabdominal disease presented a management problem. The options were therapeutic abortion or early delivery, followed by local radiation therapy. Conventional management of early-stage Hodgkin’s disease now uses combined modality treatment; thus, both supradiaphragmatic and infradiaphragmatic disease may be treated with a short course of combination chemotherapy until delivery, with radiation therapy given after delivery. Management decisions are, however, complex and discussion should include the patient, hemato-oncologist, obstetrician, and radiation oncologist. Patients with more extensive disease should be counseled about the risks of proceeding with pregnancy. Some women may wish to continue with the pregnancy and opt for combination chemotherapy on evidence of disease progression. The optimum management in this context is not
C HAPTER 39 • Malignancies of the Hematologic and Immunologic Systems 711
clear, but early in pregnancy, patients with symptomatic or progressive disease could reasonably receive standard chemotherapy, currently ABVD or an equivalent. Beyond the first trimester, treatment options include ABVD, corticosteroids, alone or single-agent vinblastine, which is not associated with a teratogenic risk at this point in gestation.47 After delivery, patients may be treated with more aggressive combination chemotherapy, such as ABVD, as appropriate. There appears to be no detriment to outcome
if ABVD is used after corticosteroids or vinblastine in this situation.
POSTNATAL Careful counseling about the prognosis for both long-term disease-free survival and preservation of fertility should be given. Patients who are undergoing active treatment for Hodgkin’s disease with combination chemotherapy should be advised not to breast-feed.48
SUMMARY OF MANAGEMENT OPTIONS
Hematologic Malignancies: Hodgkin’s Disease Evidence Quality and Recommendation
Management Options
References
Prepregnancy Counsel about risks and prognosis.
IIa/B
42
Give contraceptive advice.
III/B
47
Provide an interdisciplinary approach.
—/GPP
—
Diagnose by lymph node biopsy.
—/GPP
—
Stage by clinical assessment and magnetic resonance imaging; counsel about the prognosis and risks to the fetus.
IV/C
37,43
Ib/A
63
Delivery and radiation therapy with or without abbreviated chemotherapy.
Ib/A
63
Continue pregnancy with chemotherapy only.
III/B
47
IIa/B
47
III/C
2
Prenatal
Treatment Stage IIa/IIa nonbulky (localized disease): Extra-abdominal: Radiation therapy with shielding with or without abbreviated chemotherapy.
●
Intra-abdominal (depends on gestation and the patient’s wishes): ●
●
Other stages (extensive-stage disease): Chemotherapy with supportive care.
●
Postnatal Provide contraceptive advice Counsel about the long-term prognosis. Avoid breast-feeding if the patient is receiving cytotoxic treatment. Examine and follow-up of the newborn. GPP, good practice point.
Non-Hodgkin Lymphomas Non-Hodgkin lymphomas comprise a heterogeneous group of malignancies. Unlike in Hodgkin disease, extranodal presentation of non-Hodgkin lymphoma is not uncommon. The increase in the incidence of non-Hodgkin lymphomas is partly attributable to an aging population and risk factors such as HIV infection, but an unexplained real increase in
incidence has been noted. Non-Hodgkin lymphomas are uncommon in the reproductive years. The subclassification of non-Hodgkin lymphomas is complex and changing. However, in general, three types of biologic behavior are seen.3 Low-grade, or indolent, lymphomas that are slowgrowing do not immediately threaten life and may be treated either on a wait-and-watch basis, with single-agent or
712 S ECTION F IVE • Late Prenatal
combination chemoimmunotherapy or local radiation therapy.49 More aggressive lymphomas, such as diffuse large B cell lymphoma, have a much shorter clinical history and may cause early life-threatening complications. These are treated with combination chemoimmunotherapy.50,51 Some lymphomas, such as lymphoblastic lymphoma or Burkitt’s lymphoma behave biologically like subtypes of ALL. These are treated with aggressive combination chemotherapy, the nature of which depends on the histologic subtype.
lymphomas are unknown. Insufficient data are available on the effects of rituximab on pregnancy to allow formal risk stratification, and the conventional wisdom is that rituximab is contraindicated in pregnancy.53 The introduction of an agent such as rituximab, which clearly improves outcome but has limited data in pregnancy, illustrates the dilemma that many physicians face.
Maternal Risks
Management Options PREPREGNANCY
Diagnosis is made on biopsy, and testing and staging are as for Hodgkin’s disease, although advanced disease is more common in non-Hodgkin lymphomas. Treatment must be highly individualized and may, as discussed earlier, vary from a wait-and-watch policy to administration of intermediate- or high-dose combination chemotherapy.
Women who have active non-Hodgkin lymphoma should be counseled about the outlook for the particular subtype of disease and receive appropriate contraceptive advice. Patients who are receiving active treatment for nonHodgkin lymphoma should be advised against becoming pregnant.
Fetal Risks
PRENATAL
Non-Hodgkin lymphoma does not appear to affect the outcome of pregnancy. The risks to the fetus are those of treatment. In terms of exposure to cytotoxic agents, fetal risk should not be substantially different from that seen in acute leukemia and Hodgkin’s disease. The potential long-term effects on the fetus due to the recent introduction of chemoimmunotherapy into the management of many B cell
Management depends on the histologic subtype and extent of disease (discussed previously).
POSTNATAL Although data are limited, patients undergoing active treatment for non-Hodgkin lymphoma should be advised against breast-feeding.
SUMMARY OF MANAGEMENT OPTIONS
Hematologic Malignancies: Non-Hodgkin Lymphoma Management Options
Evidence Quality and Recommendation
References
Prepregnancy As for Hodgkin’s disease.
—/GPP
—
Provide an interdisciplinary approach.
—/GPP
—
See comments about staging and diagnosis as for Hodgkin’s disease.
—/GPP
—
Treat as for a nonpregnant patient; options vary from “wait and watch” to aggressive combination chemotherapy with supportive care; termination and preterm delivery before chemotherapy are options.
Ib/A
51,52
III/C
49
Counsel about the prognosis and risk to the fetus.
III/C
64
III/C
2
Prenatal
Postnatal Provide contraceptive advice. Counsel about the long-term prognosis. Avoid breast-feeding if the patient is receiving cytotoxic treatment. Examine and follow-up of the newborn. GPP, good practice point.
C HAPTER 39 • Malignancies of the Hematologic and Immunologic Systems 713
MYELOPROLIFERATIVE DISORDERS Essential Thrombocythemia Diagnosis, Assessment, and Risks Essential thrombocythemia is a myeloproliferative disorder that usually occurs in older age groups. Occasional cases complicating pregnancy are reported in the literature. Causes of reactive thrombocytosis are much more common and should be carefully excluded. Common causes of reactive thrombocytosis include iron deficiency, hemorrhage, infection, and inflammatory conditions. In essential thrombocythemia, the platelet count is consistently elevated in the absence of an apparent underlying cause. Approximately 50% of patients will have evidence of the JAK 2 mutation, and this may provide the diagnosis.54 Bone marrow biopsy may have a characteristic appearance and cytogenetic studies should be performed to exclude CML. Essential thrombocythemia may be complicated by abnormal bleeding as a result of defective platelet function or by both arterial and venous thrombosis. The incidence of these complications in younger patients is unknown, and thrombosis in particular may be less common than in older age groups. The literature on pregnancy includes small series and case reports. Spontaneous abortion, intrauterine death, and intrauterine growth restriction are possible risks, due primarily to placental infarction.38,39 However, other small series have reported good pregnancy outcomes in asymptomatic women.40,41
Management Options If the patient is asymptomatic and the platelet count is only moderately increased, in the range of 400 to 600 × 109/L, an expectant approach is reasonable.38 If thrombosis or hemorrhage occurs, however, treatment is necessary. Because of a reluctance to use cytotoxic agents in pregnancy, plateletpheresis has been used.38 However, each pheresis is a shortterm measure, and it may be practically difficult to achieve good long-term platelet control. If plateletpheresis is used, response may be assessed over a number of days initially and the intervals between phereses extended if possible. Subsequent management decisions should balance the pheresis interval against the degree of platelet control, and alternative treatment should be introduced if necessary. Aspirin may be used to treat thrombotic complications,39 but may aggravate an underlying platelet function defect. Aspirin may have a role in patients with essential thrombocythemia and a history of previous pregnancy failure or growth restriction, but few data are available.40 There are anecdotal reports of the use of hydroxyurea in essential thrombocythemia in pregnancy.39 Most experience with this agent in pregnancy is with CML, when hydroxyurea has been used for prolonged periods. However, because teratogenicity is reported in animals, first-trimester use of hydroxyurea should ideally be avoided. The safety profile is good in the second and third trimesters. Interferon-alfa has been used successfully throughout pregnancy in patients with essential thrombocythemia, without adverse effects.42,43 More data are needed on the safety of interferon-alfa in pregnancy, but reported experience is encouraging.42,43 It may emerge as the agent of choice if treatment of essential thrombocythemia is necessary in a pregnant woman.
Similarly, data on the safety of anagrelide, a new agent used to treat essential thrombocythemia, are limited. This agent should currently be avoided in pregnancy, and alternative methods should be used to control the platelet count, when necessary. Because data are inconsistent, increased fetal surveillance during pregnancy is appropriate, particularly if assessment of growth and umbilical artery Doppler recordings show intrauterine growth restriction and placental dysfunction. Platelet dysfunction may lead to an increased risk of primary and secondary postpartum hemorrhage. Secondary hemorrhage is exacerbated by the risk of retained placental fragments from an infarcted placenta. Thrombosis prophylaxis in the puerperium should include compression stockings and early mobilization. Patients with uncontrolled platelet count or a previous history of thrombosis should be treated with low-molecular-weight heparin or equivalent according to unit protocol.
Polycythemia Polycythemia occurs when hemoglobin, hematocrit, and the red cell mass are increased above the upper limit of normal for the patient’s age and sex. Polycythemia may be relative or true. Relative, or stress, polycythemia occurs when plasma volume is reduced with no increase in the red cell mass. In true polycythemia, the red cell mass is greater than 32 mL/ kg for women and 36 mL/kg for men. True polycythemia may be primary or secondary. Secondary polycythemia occurs in conditions associated with either chronic hypoxia or inappropriate erythropoietin production (e.g., renal cysts or tumors). Primary proliferative polycythemia, or polycythemia vera (PV), is characterized by proliferation of erythroid precursors in the bone marrow arising as a result of a clonal stem cell defect. Understanding of the pathogenesis of PV has been revolutionized by the demonstration of the JAK 2 mutation in approximately 95% of cases. PV is usually seen in older patients, but rare cases are described in women of childbearing age.44 The diagnosis of polycythemia is difficult during pregnancy because physiologic changes in plasma volume may decrease hemoglobin and hematocrit.62 Further, isotopic techniques used to determine the red cell mass are contraindicated in pregnancy. However JAK 2 testing by molecular methods may now be used to diagnose PV with features such as splenomegaly, increased white cell, and platelet counts supporting the diagnosis. However, definitive testing and diagnosis may need to be postponed until after delivery. In women who have a high hematocrit in pregnancy, secondary causes should be excluded, particularly pulmonary disease leading to chronic hypoxia. Other causes such as renal tumor are much less likely to present in this way. If erythropoietin levels are available, a low level suggests primary rather than secondary polycythemia. However, erythropoietin levels increase physiologically during pregnancy,45 and a normal or high level is difficult to interpret. Preeclampsia and intrauterine growth restriction can be the result of failure of normal plasma volume expansion. In these conditions, the hematocrit may be relatively increased compared with levels in normal pregnancy, but an increase above the normal range in nonpregnant women usually does not occur.
714 S ECTION F IVE • Late Prenatal
Maternal and Fetal Risks
Management Options
In a series of 13 pregnancies in 8 women with PV maternal outcome was good, but fetal outcome was adversely affected. Miscarriage, intra-uterine growth restriction, preterm delivery, and stillbirth were more common than expected.44 The risk of pre-eclampsia may also be increased. A relationship between pregnancy outcome and maternal red cell count was suggested, but the numbers in this study were too small to allow firm conclusions to be drawn. In some patients, hematocrit values decreased significantly during pregnancy.
Venesection may be performed to maintain the hematocrit below 0.45. Myelosuppressive therapy should be avoided but may be necessary in patients with associated marked thrombocytosis. Management principles are similar to those outlined for essential thrombocythemia. Thrombosis prophylaxis in the puerperium should include compression stockings and early mobilization. Peripartum treatment with subcutaneous low-molecular-weight heparin should be considered even in the absence of a previous history of thrombosis, although there are no data specific to this patient group.
SUMMARY OF MANAGEMENT OPTIONS
Myeloproliferative Disorders Evidence Quality and Recommendation
Management Options
References
Essential Thrombocythemia Prenatal Provide expectant approach in asymptomatic patients with moderate elevation of platelets.
III/B
56–58
If the patient is symptomatic (thrombosis or bleeding), consider plateletpheresis.
III/B
55
Give low-dose aspirin if the patient has thrombosis; no evidence supports use in all cases.
III/B
56,57
Hydroxyurea has been used, but most experience is with chronic myeloid leukemia.
III/B
56
Limited experience with interferon-alfa.
III/B
59,60
Limited experience with anagrelide thus avoid.
—/GPP
—
Obtain serial fetal growth and umbilical artery Doppler recordings.
—/GPP
—
—/GPP
—
Maintain vigilance for hypertensive disease.
III/B
61
Obtain serial fetal growth and umbilical artery Doppler recordings.
III/B
61
Some advocate regular venesection to keep hematocrit < 0.45.
IV/C
61
—/GPP
—
Labor and Delivery and Postnatal Maintain vigilance for PPH. Consider prophylactic low-molecular-weight heparin. Polycythemia Prenatal
Labor and Delivery and Postnatal Maintain vigilance for PPH. Consider prophylactic low-molecular-weight heparin. GPP, good practice point; PPH, primary postpartum hemorrhage.
C HAPTER 39 • Malignancies of the Hematologic and Immunologic Systems 715
SUGGESTED READINGS Ali R, Ozkalemkas F, Kimya Y, et al: Imatinib use during pregnancy and breast feeding: A case report and review of the literature. Arch Gynecol Obstet 2009;280:169–175. Aviles A, Diaz-Maqueo JC, Talavera A, et al: Growth and development of children of mothers treated with chemotherapy during pregnancy: Current status of 43 children. Am J Hematol 1991;6:234–248. Aviles A, Neri N: Haematological malignancies and pregnancy: A final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2001;2:173–177. Beressi AH, Tefferi A, Silverstein MN, et al: Outcome analysis of 34 pregnancies in women with essential thrombocythemia. Arch Intern Med 1995;155:1217–1222. Byrne J, Rasmussen SA, Steinhorn SC, et al: Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 1998;62:45–52.
Chelqhoum Y, Vey N, Raffoux E, et al: Acute leukemia in pregnancy. A report of 37 patients and review of the literature. Cancer 2005;104:110–117. Friedrichs B, Tiemann M, Salwender H, et al: The effects of rituximab treatment during pregnancy on a neonate. Haematologica 2006;91:1426– 1427. Green DM, Whitton JA, Stovall M, et al: Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002;187:1070–1080. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 2000;27:623–632.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 4 0
Thrombocytopenia and Bleeding Disorders ELIZABETH HELEN HORN and LUCY H. KEAN
THROMBOCYTOPENIA Introduction The normal range for peripheral blood platelet count in nonpregnant individuals is generally reported as 150 to 400 × 109/L. If a low platelet count is seen on an automated complete blood count, spurious thrombocytopenia should be excluded. This phenomenon may occur because of a small clot in the blood sample or because of platelet clumping caused by the addition of the anticoagulant ethylenediaminetetraacetic acid (EDTA) to the sample. A repeat count for confirmation and examination of the peripheral blood film can ascertain whether the thrombocytopenia is genuine. If the blood film shows platelet clumps, a repeat complete blood count in a sample anticoagulated with citrate may resolve the problem. Studies of platelet counts during normal pregnancy differed in their conclusions, with some suggesting no overall effect of pregnancy on platelet count1–3 and others showing a modest reduction in late pregnancy.4–6 One study of platelet counts in 6715 consecutive patients delivering in a single Canadian center showed that thrombocytopenia (platelet count < 150 × 109/L) occurred in 7.6% of women, and most (65.1%) had no associated pathology.7 From a practical point of view, any pregnant woman with a platelet count of less than 100 × 109/L in pregnancy should undergo further clinical and laboratory assessment. All pregnant women with a platelet count less than 150 × 109/L after 20 weeks’ gestation should have blood pressure and urinalysis checked. In the absence of hypertension or proteinuria, no pathology is found in most women with mild thrombocytopenia at this stage of pregnancy.8
Causes of Thrombocytopenia in Pregnancy Causes of thrombocytopenia in pregnancy are summarized in Table 40–1. They can be broadly divided into the following categories: ● Platelet destruction or consumption. ● Splenic sequestration of platelets. ● Failure of platelet production in the bone marrow. Platelet destruction or consumption is much more common than bone marrow failure in obstetric practice.
Causes with management implications in pregnancy are discussed in detail.
Investigation of Thrombocytopenia in Pregnancy As discussed earlier, spurious thrombocytopenia should first be excluded. In assessing pregnant women with genuine thrombocytopenia, close liaison is required between the obstetrician and the hematologist. Clinical assessment and examination of the blood film are the starting points in making a diagnosis. Documentation of previous platelet counts and the timing of development of thrombocytopenia are helpful. For patients developing thrombocytopenia after 20 weeks’ gestation, particular attention should be paid to blood pressure and urinalysis for protein. Renal and liver function should be assessed and the presence of any major obstetric complications such as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome or acute fatty liver of pregnancy should be rapidly excluded. The peripheral blood film should be examined for red cell fragmentation, the presence of which suggests HELLP syndrome or another thrombotic microangiopathy. For the remainder of those patients who have developed mild thrombocytopenia after 20 weeks’ gestation and who are clinically well and without abnormalities in the peripheral blood film, gestational thrombocytopenia is the likely diagnosis.9 More detailed clinical and laboratory assessment are required if the platelet count is less than 70 × 109/L, if the blood film is abnormal, if thrombocytopenia occurs before 20 weeks’ gestation, or if there is a previous history of thrombocytopenia or bleeding. In such patients who have a normal blood film, autoimmune thrombocytopenia (AITP) is the most likely diagnosis and is a diagnosis of exclusion9 In the history, the presence of current or previous bleeding problems should be noted. The clinical severity of any hemorrhagic problems should be assessed. Other medical or obstetric problems, a drug and alcohol history, and a recent transfusion history should be noted. For example, a history of recurrent miscarriage may suggest antiphospholipid syndrome. Risk factors for HIV and hepatitis B or C virus 717
718 S ECTION F IVE • Late Prenatal T A B L E 4 0 – 1
Causes of Thrombocytopenia in Pregnancy Platelet Consumption or Destruction Gestational thrombocytopenia Autoimmune thrombocytopenia Primary Secondary Antiphospholipid syndrome Systemic lupus erythematosus and connective tissue disorders Drug-induced HIV-associated Other viral infection (e.g., Epstein-Barr virus) Lymphoproliferative disorder Nonimmune Disseminated intravascular coagulation Preeclampsia or HELLP syndrome Thrombotic thrombocytopenia purpura or hemolytic uremic syndrome Acute fatty liver of pregnancy Large vascular malformations Heparin-induced thrombocytopenia (rare in pregnancy) Splenic Sequestration Splenomegaly Portal hypertension Liver disease Portal or hepatic vein thrombosis Myeloproliferative disorders Lymphoproliferative disorders Storage disease (e.g., Gaucher’s disease) Infection (e.g., tropical splenomegaly or malaria) Failure of Platelet Production Bone marrow suppression Drug-induced Aplastic anemia Paroxysmal nocturnal hemoglobinuria Infection (e.g., parvovirus B19) Bone marrow infiltration Hematologic malignancy Nonhematologic malignancy Severe vitamin B12 or folate deficiency HELLP, hemolysis, elevated liver enzymes, and low platelets.
(HCV) should be assessed. Enquiry should be made regarding a family history of hemorrhagic problems. On examination, important features include petechiae and signs of mucosal bleeding. The clinician should look for clinical features that suggest underlying autoimmune disease or chronic liver disease and should exclude splenomegaly. Careful examination of the blood film is mandatory because it may give important clues to the diagnosis. For example, red cell fragmentation narrows the differential diagnosis to thrombotic microangiopathies (discussed later) (Table 40–2). Hypersegmented neutrophils and oval macrocytes suggest folate deficiency, and other red and white cell abnormalities may suggest underlying bone marrow disease. In gestational thrombocytopenia and AITP, the blood film
is normal except for the apparent reduction in platelet count. Renal and liver function should be routinely checked. After initial assessment, further tests may be indicated, including antinuclear factor, specific tests for lupus anticoagulant and anticardiolipin antibodies, or tests for the diagnosis and typing of von Willebrand’s disease (vWD). The lactate dehydrogenase level is usually elevated in microangiopathic hemolysis. The results of coagulation screening tests and D-dimer may be abnormal in thrombocytopenia associated with consumptive coagulopathy. The serum urate level may be increased in preeclampsia, HELLP syndrome, or acute fatty liver of pregnancy. Bone marrow examination is necessary only when features suggest underlying bone marrow disease. However, bone marrow examination should be carried out in AITP if the patient fails to respond to firstline therapy.8 Platelet antibody testing is of little value both diagnostically and prognostically in suspected cases of AITP.8,10–12 In cases of suspected thrombotic thrombocytopenic purpura (TTP), some specialized laboratories carry out assays of ADAMTS 13 activity. ADAMTS 13 (discussed later) is a plasma von Willebrand’s factor (vWf)–cleaving protease whose activity is reduced in most cases of primary idiopathic TTP.13
Gestational Thrombocytopenia Gestational thrombocytopenia, or incidental thrombocytopenia of pregnancy, accounts for approximately 70% of cases of maternal thrombocytopenia at delivery.7,14 The cause is unknown. There is evidence of a degree of physiologic platelet activation in vivo during pregnancy; platelet life span is reduced, and the site of platelet activation is believed to be the placental circulation.15,16 These mechanisms and hemodilution may contribute to gestational thrombocytopenia.9 Gestational thrombocytopenia usually develops in the third trimester and is usually mild to moderate. Results of other studies are normal. The platelet count is usually greater than 80 × 109/L, but counts of 40 to 50 × 109/L can occasionally occur due to gestational thrombocytopenia.7,17,18 The platelet count rapidly returns to normal after delivery, usually within 7 days.7,17 Gestational thrombocytopenia is a diagnosis of exclusion. Antenatally, it can be difficult to distinguish from mild AITP. The diagnosis is suggested by a late decrease in platelet count in a patient with no history of previous thrombocytopenia outside of pregnancy. One group of investigators attempted to define predictors of AITP versus gestational thrombocytopenia in pregnancy. They reported that the detection of thrombocytopenia before 28 weeks’ gestation and a platelet count less than 50 × 109/L were independently predictive of AITP.19 Certainty often rests on observations of platelet counts in the puerperium.
Maternal and Fetal Risks Gestational thrombocytopenia has no pathologic significance for the mother or fetus.7,8,14,17,18,20 If AITP cannot be excluded, a potential concern is the transfer of antiplatelet antibodies across the placenta, leading to fetal and neonatal thrombocytopenia. However, neonatal thrombocytopenia is uncommon in women in whom thrombocytopenia is
C HAPTER 40 • Thrombocytopenia and Bleeding Disorders 719 T A B L E 4 0 – 2
Variation in the Features and Management of Thrombotic Microangiopathic Hemolytic Anemia DIAGNOSIS
TTP
POSTPARTUM HEMOLYTIC UREMIC SYNDROME
HELLP SYNDROME
PREECLAMPSIA OR ECLAMPSIA
Time of onset
Usually < 24 wk
Postpartum
After 20 wk, most > 34 wk
After 20 wk, most > 34 wk
Hemolysis
+++
++
++
+
Thrombocytopenia
++ –
++
++
Coagulopathy
+++ –
±
±
CNS symptoms
+++
±
±
±
Liver disease
±
±
+++
±
Renal disease
± Rare
+++
+
+
± None, if maternal disease is controlled None
± Placental ischemia/increased neonatal mortality Recovery
+++ IUGR; occasional mortality
Supportive (±PEX)
Supportive/steroids (±PEX)
Hypertension Effect on fetus Effect of delivery Management
Placental infarct can lead to IUGR and mortality None PEX
Recovery Supportive
CNS, central nervous system; HELLP, hemolysis, elevated liver enzymes, and low platelets; IUGR, intrauterine growth restriction; PEX, plasma exchange; TTP, thrombotic thrombocytopenic purpura.
incidentally detected in pregnancy and in whom there is no history of AITP. The incidence of neonatal thrombocytopenia in these patients is approximately 4%,18,21 which is not statistically different from the incidence of thrombocytopenia in infants of nonthrombocytopenic mothers. Further, no infants in these studies had cord platelet counts less than 50 × 109/L, and none had clinical hemostatic impairment.18,21
platelet counts should also be followed postnatally. A rapid return to normal confirms the diagnosis of gestational thrombocytopenia, whereas continued thrombocytopenia after pregnancy should prompt reassessment of the patient.
Management Options PREPREGNANCY AND PRENATAL
AITP is relatively common in women of childbearing age. AITP occurs in approximately 0.14% of pregnant women at delivery and accounts for 3% of cases of thrombocytopenia at that time.17 AITP is the most common cause of thrombocytopenia in the first trimester of pregnancy.9 AITP is caused by autoantibodies, which are usually directed against platelet surface glycoproteins, particularly glycoprotein IIb/IIIa and glycoprotein Ib/IX.22,23 These antibodies adhere to the platelet membrane, causing platelet destruction through Fc receptors in the reticuloendothelial system. The major site of platelet destruction is usually the spleen. AITP may cause purpura and self-limiting mucosal bleeding. This pattern of acute AITP, often after a viral infection, is most commonly seen in children. Conversely, AITP in adults is usually chronic. The symptoms are variable and often insidious. Although fluctuations in the platelet count may occur, the condition is not self-limiting, and continuing thrombocytopenia is the usual course. Chronic AITP may be asymptomatic and may be found by routine testing, such as the testing that is performed during pregnancy. AITP may be primary or idiopathic or may be secondary to another disorder (see Table 40–1). In primary AITP, if the thrombocytopenia is severe, the clinical examination may show purpura, bruising, or signs of mucosal bleeding, but findings are otherwise normal. Other than a reduced platelet count, findings on the blood film are normal, and the bone marrow is normal, with normal or increased numbers of megakaryocytes. As noted previously, bone marrow examination is no longer routinely recommended in AITP. In primary or idiopathic AITP, all other test results
If a woman with previous gestational thrombocytopenia seeks prepregnancy counseling, the most important issue is the exclusion of alternative diagnoses. This is also the case when thrombocytopenia is detected incidentally in the antenatal period. The maternal platelet count should be monitored at a frequency determined by the platelet count, rate of decline, and expected date of delivery.8 No treatment is necessary for gestational thrombocytopenia. Invasive approaches to fetal monitoring, such as fetal blood sampling to determine the fetal platelet count, are not indicated because the risks are not justifiable (discussed later).8,20
LABOR AND DELIVERY Because the fetus is not at risk for hemorrhage, the mode of delivery is determined by obstetric considerations, and invasive fetal blood sampling to determine the fetal platelet count is not indicated. Although there is no evidence that gestational thrombocytopenia is associated with a risk of maternal bleeding, most anesthetists would not contemplate the use of regional analgesia if the platelet count was below 80 × 109/L.8 If AITP has not been excluded, management options for labor and delivery are the same as those for AITP.8
POSTNATAL If it is difficult to distinguish between gestational thrombocytopenia and AITP, management of the infant should be the same as in maternal AITP (discussed later). Maternal
Autoimmune Thrombocytopenia
720 S ECTION F IVE • Late Prenatal
are normal. Secondary causes of AITP may be associated with antinuclear antibodies or increased levels of antiphospholipid antibodies. HIV and HCV testing should be offered in all cases. Neither assays of platelet-associated immunoglobulin G (IgG) nor assays of glycoprotein-specific antibodies are reliable as diagnostic tools in suspected AITP.23 Further, no assay of platelet antibodies has predictive value for maternal or fetal outcome.8,10–12
Maternal Risks The risk of maternal bleeding has generally been thought to relate to the severity of thrombocytopenia. In AITP, clinical bleeding is often less severe for a given platelet count than in conditions in which thrombocytopenia is caused by an underlying bone marrow disorder. Women with severe thrombocytopenia (platelet count < 20 × 109/L) are at risk for spontaneous bleeding antenatally as well as at delivery, and they generally require treatment. Women with platelet counts less than 50 × 109/L may be at risk for increased bleeding at delivery8,24,25; therefore, treatment may be required in late pregnancy to ensure a safe platelet count for delivery in asymptomatic women. Both British8 and American24 guidelines suggest that a platelet count greater than 50 × 109/L is safe for a vaginal delivery. British guidelines suggest aiming for a platelet count above 80 × 109/L for cesarean section,8 whereas American guidelines considered a platelet count greater than 50 × 109/L was suitable for all modes of delivery.24 A platelet count of greater than 80 × 109/L is recommended for epidural anesthesia by the British Committee for Standards in Haematology (BCSH).8 These figures are generally accepted by clinicians but are somewhat arbitrary. A retrospective series of 119 pregnancies in 92 women with AITP reported a 21% incidence of bleeding in pregnancy. Bleeding was uncommon at delivery and was not correlated with the platelet count, even although 15% of women had a platelet count less than 50 × 109/L.26 Another observational series showed that bleeding at delivery was increased in women with platelet counts less than 50 × 109/L who underwent cesarean section but not vaginal delivery.25,27 There is no evidence that bleeding time is helpful in predicting hemorrhagic problems in AITP.
Fetal Risks In mothers with AITP, IgG antiplatelet antibodies may cross the placenta and cause fetal thrombocytopenia, resulting in fetal or neonatal bleeding. Maternal findings, such as platelet count and platelet-associated IgG level, are of no value in predicting fetal thrombocytopenia.11,28,29 It has been suggested that the only clear predictor of neonatal thrombocytopenia in pregnant women with thrombocytopenia is a history of AITP, and even then, the incidence of neonatal bleeding is low (11 × 109/L; often 20–30 × 109/L). ● Coagulopathy (PT > 14 sec, activated partial thromboplastin time [aPTT] > 34 sec). ● Ascites or bright liver on ultrasound scan. ● Microvesicular steatosis on liver biopsy. One of the keys to the diagnosis of AFLP is the rapidity with which LFT can deteriorate in the aggressive phase of the disease. This typically is combined with features of hepatic synthetic failure, including hypoglycemia, deranged clotting, and confusion secondary to hepatic encephalopathy. Other pregnancy-specific liver conditions do not impair liver function in this way. Other causes of fulminating liver failure must be excluded: Paracetamol (acetaminophen) overdose and acute viral hepatitis are the most common causes; rarer causes include Wilson’s disease, poisoning with carbon tetrachloride, and drug reactions (e.g., to halothane or isoniazid). Imaging of the liver has not been successful in accurately detecting fatty infiltration nor, if it is present, in determining
its cause. Techniques that have been used include ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Apart from ultrasound, it is unlikely that imaging will be either portable or easily accessible to the delivery suite. Abdominal CT is better avoided when possible prior to delivery because of radiation exposure to the fetus, and many pregnant women will be too large to fit inside a standard MRI machine even if they are well enough to be moved there. False-positive and false-negative diagnoses are equally common with all modalities.54 In the recent UKOSS study,53 80% of women had an ultrasound scan, of which only one quarter showed the classic features of bright liver or ascites. If the diagnosis remains in doubt and, in particular, if there is not a rapid improvement after delivery, the place for imaging the liver should be reconsidered. Liver biopsy is another possibly helpful diagnostic tool. Bearing in mind the histopathologic caveats outlined earlier and the potential complexities of performing a biopsy in the presence of deranged clotting, the need for a tissue diagnosis should be carefully assessed on an individual basis.
Maternal and Fetal Risks Women experiencing AFLP have increased maternal and fetal mortality and morbidity. However, it is likely that the outcome for mother and baby has improved in recent years. In the 1960s, 16 cases of AFLP associated with the use of tetracycline were reported, with a 70% maternal mortality.55 Among 33 pregnancies with biopsy-proven AFLP reported in the 1980s, maternal mortality was 21% and fetal mortality was 27%.56 Castro and associates in the 1990s51 reported 28 clinically diagnosed cases with no maternal mortality and a 7% neonatal mortality. The UKOSS report,53 which is the most robust and recent series of cases, gives maternal mortality of 2% (1 death in 57 cases) and 10% fetal mortality. There is an ongoing need for all obstetricians, anesthetists, and midwives to be aware of AFLP, not just those working in large tertiary referral centers.
Etiology The cause of AFLP is uncertain, but is likely to be multifactorial, with a genetic component in a number of cases. In some women, AFLP may occur because of an autosomal recessive abnormality in fetal long-chain fatty acid beta oxidation. This is an interesting concept, because it demonstrates that the fetus may determine maternal complications of pregnancy. In addition, for these families, the risk of recurrence is significant and in the order of 15% to 20%. Long-chain hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency is a recently described disorder of mitochondrial fatty acid oxidation that is usually asymptomatic in heterozygous carriers. Affected (homozygous) individuals often die in early childhood or sooner from complications of hypoglycemia, cardiomyopathy, or fatty liver failure. Those who live longer develop chorioretinopathy, rhabdomyolysis, and peripheral neuropathy, although these can be ameliorated by a high-carbohydrate and low-fat diet, in which the fat component is medium-chain triglycerides. Several mutations of the α-subunit of the mitochondrial trifunctional protein cause deficiency of LCHAD. In Finland, a guanine cytosine transposition, G1528C, and in America, a
848 S ECTION F IVE • Late Prenatal
glutamic acid to glutamine change, E474Q, have been identified.57,58 The latter group estimates that 1 in 175 of their population is heterozygous for E474Q and, therefore, that 1 in 62,000 pregnancies results in LCHAD deficiency. Affected fetuses do not metabolize long-chain fatty acids completely, resulting in accumulation of abnormal and highly toxic intermediates in the heterozygous mother’s liver, and the acute clinical picture we recognize as AFLP. It is also hypothesized that fat accumulation may occur in the placenta and that this may induce the clinical picture of preeclampsia. Preeclampsia has been described in pregnancies with fetuses affected by homozygous LCHAD deficiency more commonly than would be expected, and more than in pregnancies in the same women with unaffected fetuses.59 It is not certain what proportion of cases of AFLP may be due to LCHAD deficiency. It is likely that this will vary between countries, depending in part on the prevalence of the known (and unknown) genetic mutations in the local populations. Mansouri and colleagues60 reported no carriers of the G1528C mutation in 14 histologically proven cases of AFLP, but Treem and coworkers61 found that 75% of 12 women with AFLP had LCHAD levels compatible with carrier status. A larger study identified LCHAD mutations in 5 of 27 women with AFLP, all of whom had a fetus with LCHAD deficiency.62 All 5 affected fetuses had at least one copy of the E474Q mutation, and the authors therefore recommended screening for this mutation in the children of women who have had pregnancies complicated by AFLP. In contrast, the same study demonstrated that only 1 of 81 women with HELLP had an LCHAD mutation, and this was not inherited by the fetus, indicating that it is not justified to screen the offspring from all pregnancies affected by HELLP. Conversely, not all pregnancies in which the baby has LCHAD deficiency will result in AFLP or other serious maternal liver disease. Ibdah and colleagues63 found that in 15 of 24 pregnancies in which the baby had LCHAD deficiency, either AFLP (n = 12) or HELLP (n = 3) syndrome developed; in the other 9 pregnancies, there were no complications. These women had 11 other pregnancies with unaffected babies in which maternal liver disease did not occur. Similarly, Tyni and associates59 found some form of liver disease of pregnancy and/or preeclampsia in 15 of 29 pregnancies in which the fetus was homozygous for LCHAD deficiency and described 7 of the remaining 14 pregnancies as completely normal; none of the other 34 pregnancies from these women (when the fetus did not have homozygous LCHAD deficiency) was complicated by significant liver disease.
Management Options The ultimate management option is to deliver the baby, because this seems to be the optimal way to improve the maternal condition and to protect the fetus. The decision to deliver brings with it a not uncommon conundrum for obstetricians: A vaginal delivery minimizes the risk of maternal hemorrhage in the face of a coagulopathy but may take several hours or longer to achieve, and this could be significantly detrimental to the mother or fetus; a cesarean section allows delivery to be achieved more quickly but may be complicated by bleeding. An individual decision regarding
the severity of the maternal and fetal conditions needs to be made. Often, induction of labor can be started while the maternal condition is stabilized and blood products made available, and then the ongoing management can be reviewed according to the current balance of concerns. A further challenge is the best choice of analgesia and anesthesia, because regional blockade may be contraindicated if coagulopathy ensues, but general anesthesia can worsen hepatic encephalopathy. From the maternal perspective, she should have one-toone nursing on the delivery suite, preferably in a highdependency area. All vital signs should be measured and recorded clearly on a 24-hour spread sheet; it is usually advisable to insert a central line early in the course of the disease before coagulopathy ensues. Glucose assessments should be made at least every 2 hours, and hypoglycemia treated with large doses of high-concentration intravenous glucose via a long line. PT should also be measured every 6 hours along with LFTs, renal function tests and electrolytes, and full blood count. Formal assessment of level of consciousness must be made hourly, because hepatic coma is a potential complication of AFLP. One of the keys to successful management is a multidisciplinary approach. Senior obstetric, anesthesiology, hematology, and hepatology colleagues should be involved at an early stage. If no hepatologists are in-house, the obstetrician should liaise directly with the nearest liver transplant unit. This serves several purposes: (1) it provides expert advice on both the investigations and the management and (2) it alerts the transplant team who are usually able to accept transfer after delivery if recovery does not commence. Most women will be transferred from the delivery suite to the intensive care unit after delivery.
Follow-up and Recurrence Once they have recovered, all women affected by AFLP should have the opportunity with their partners to be debriefed about the complications of their pregnancy. In women who survive and do not need a transplant, complete recovery of the liver is expected without long-term sequelae. Pediatricians should consider screening all babies of women with AFLP for LCHAD deficiency, either by measuring LCHAD activity in cultured skin fibroblasts or liver or by doing DNA studies looking for the common mutations. Affected babies should be placed on the appropriate dietary restrictions. Not only does this screening minimize the complications for the index baby, but also it allows the couple to make an informed choice about the risks to the mother and fetus in a future pregnancy. The risk of recurrence of AFLP depends largely on whether the baby has LCHAD deficiency. If he or she does, the rate is between 15% and 25% for future pregnancies from the same partnership; if the baby does not, then the recurrence risk is very much lower, although it is difficult to give a precise figure because so many women decide against a further pregnancy. When a woman has had an affected baby previously, prenatal diagnosis of LCHAD is possible in subsequent pregnancies by enzyme assay in amniocytes64 or DNA analysis from chorionic villus sampling (CVS).63
C HAPTER 47 • Hepatic and Gastrointestinal Disease 849 SUMMARY OF MANAGEMENT OPTIONS
Acute Fatty Liver of Pregnancy Evidence Quality and Recommendation
Management Options
References
Prepregnancy None, unless previous pregnancy is affected, in which case, confirm previous diagnosis, check LFTs, advise risk of recurrence.
IV/C
56
Consider screening for LCHAD deficiency.
III/B
59,63
If previous AFLP, check baseline LFT; advise to report any new symptoms; start home testing for urinary protein from 24 wk; monitor BP every 2 wk.
—/GPP
—
Establish diagnosis, resuscitate.
—/GPP
—
Intensive care/high dependency setting
—/GPP
—
Provide supportive therapy (see “Labor and Delivery”).
—/GPP
—
Plan delivery or end pregnancy.
—/GPP
—
—/GPP
—
Use multidisciplinary approach ideally in liaison with liver unit to manage liver failure.
—/GPP
—
Use intensive fetal monitoring.
—/GPP
—
Perform urgent delivery when maternal condition is stabilized, vaginal delivery preferable for mother.
—/GPP
—
Maintain meticulous hemostasis.
—/GPP
—
Continue intensive care management
—/GPP
—
Watch for postpartum wound hematoma formation and sepsis, postpartum hemorrhage.
—/GPP
—
Recurrence risk is difficult to estimate, perhaps as high as 10%–20%.
—/GPP
—
Support contraceptive measures.
—/GPP
—
Full hepatic recovery expected without further sequelae; occasionally emergency liver transplant needed.
—/GPP
—
Pediatricians to consider screening baby for LCHAD deficiency.
—/GPP
—
Prenatal diagnosis of LCHAD possible by amniocentesis/CVS if previous baby affected.
III/B
63,64
Prenatal
Labor and Delivery Maternal resuscitation by correction of Hypoglycemia.
●
Fluid balance.
●
Coagulopathy.
●
Postnatal
AFLP, acute fatty liver of pregnancy; BP, blood pressure; CVS, chorionic villus sampling; GPP, good practice point; LCHAD, long-chain hydroxyacyl coenzyme A dehydrogenase; LFT, liver function test.
LIVER HEMATOMA AND NONTRAUMATIC LIVER RUPTURE General Liver hematoma is an uncommon and potentially dangerous problem in pregnancy, its most hazardous complication being hepatic rupture. Rupture of the liver capsule occurs in between 1 in 45,000 and 1 in 225,000 deliveries.65,66
The vast majority of cases are reported in association with preeclampsia, and a very high proportion are in multiparous women older than 30 years. Only a few cases have been described in the puerperium following a normal pregnancy.67 In over 85% of cases, the right lobe of the liver is affected. Rinehart and coworkers68 reviewed the literature and presented figures for the common symptoms and signs of hepatic rupture. Not surprisingly, they found that almost 70% of
850 S ECTION F IVE • Late Prenatal FIGURE 47–3 Liver hematoma.
patients had epigastric pain, 65% had hypertension, and over 50% were shocked. However, there was a wide range of other presentations, including some women with mild symptoms prior to massive circulatory collapse. HELLP syndrome seems to be particularly associated with intrahepatic hemorrhage, subcapsular hematoma, and capsular rupture. The pathogenesis is debated. One attractive theory suggests that preeclampsia causes hepatic ischemia via intravascular volume depletion, which results in local necrosis and hemorrhage. Subsequently, neovascularization occurs, and these vessels are especially susceptible to rupture and further hemorrhage, particularly during hypertensive episodes. Subcapsular hematoma may then expand sufficiently to result in hepatic rupture.68
Maternal and Fetal Risks Hepatic rupture is dangerous for mother and baby. Maternal mortality is between 16% and 60%, and perinatal mortality is between 40% and 60%.69,70 Current management options have contributed greatly to lowering the mortality rates.
Management Options The management will obviously be determined by the seriousness of the situation. There should be a low threshold for imaging the liver in older, multiparous women with preeclampsia and epigastric pain. Ultrasound will usually be readily available and is helpful in diagnosing subcapsular hematomas. CT (Fig. 47–3) and MRI hepatic digital subtraction angiography may have greater sensitivity for identifying small amounts of intraperitoneal blood and small hematomas but have the disadvantage of being less readily available and less portable if the patient is unwell. Treatment of hepatic rupture is based on resuscitating the patient and stopping the hemorrhage. If the diagnosis is suspected, a midline laparotomy with the involvement of an experienced surgeon should be considered: This allows the diagnosis to be confirmed, the baby to be delivered (which will improve the maternal circulation and remove the baby to a place of safety), and treatment to be instituted. If unexplained hemoperitoneum is found at a Pfannenstiel laparotomy for presumed abruption or uterine rupture, careful exploration of the upper abdomen, preferably by an
experienced general or hepatic surgeon and possibly with an upper midline incision to improve access, must be strongly considered. A wide variety of therapeutic maneuvers for liver rupture have been described. Currently, the most successful seem to involve digital compression of the hepatic artery and portal vein to temporarily arrest the hemorrhage (Pringle’s maneuver),69 evacuation of the residual hematoma, and temporary packing with large dry gauze swabs.71 Packs are removed at a further laparotomy 24 to 36 hours later, once correction of hypovolemia, coagulopathy, acidosis, and hypothermia is complete. Liver resection and transplantation have also been described, but not surprisingly, the mortality rate is very high. Unruptured small hematomas have been managed conservatively, following delivery of the baby, with serial imaging of their size to exclude expansion.69 Delayed rupture 6 weeks after initial diagnosis has been reported,72 so care must be taken if this option is adopted. Tense, large, or expanding hematomas should probably be evacuated surgically to obviate the impending rupture. Hepatic embolization has been described in these circumstances (and in others) but seems to carry a high risk of ischemic necrosis of the liver, liver failure, and sepsis73 and may not be accessible to many units; others have described this technique as a “gold standard.”67
SUMMARY OF MANAGEMENT OPTIONS
Liver Hematoma and Rupture Management Options
Evidence Quality and Recommendation
References
Prepregnancy None.
—/GPP
—
—/GPP
—
—/GPP
—
Prenatal Treat upper abdominal discomfort seriously, especially in parous women with PET or HELLP; consider imaging the liver. Labor and Delivery Consider liver rupture in a woman with unexplained shock or if unexpected hemoperitoneum is found at cesarean section.
C HAPTER 47 • Hepatic and Gastrointestinal Disease 851 Evidence Quality and Recommendation
Management Options
References
Management: Resuscitation.
—/GPP
—
Laparotomy and stop hemorrhage (by liver surgeon preferably) with temporary occlusion of portal vein and packing.
IV/C
69,71
Embolization has varied success.
III/B
67,73
Manage unruptured hematomas conservatively (though danger of delayed rupture).
IV/C
69
Patients who survive do not have permanent liver damage.
—/GPP
—
Recurrence has been recorded but very rarely.
—/GPP
—
● ●
● ●
Postnatal
HELLP, hemolysis, elevated liver enzymes, low platelets; GPP, good practice point; PET, preeclampsia.
HYPEREMESIS GRAVIDARUM General Nausea and vomiting affect up to 50% of pregnant women. Most women are able to maintain fluid and nutrient intake by dietary modification, and the symptoms will resolve by the end of the first trimester. Hyperemesis gravidarum affects 0.5% to 1% of pregnancies and causes severe and protracted vomiting that results in ketosis, dehydration, and weight loss. The cause of hyperemesis gravidarum remains unidentified, but it is thought to result from a combination of endocrine, biochemical, and psychological factors. Seropositivity for Helicobacter pylori is more common in women with hyperemesis than in controls.74,75
Diagnosis The onset of hyperemesis gravidarum is always in the first trimester. In addition to nausea, vomiting, and weight loss, women often report ptyalism (excessive salivation), and there may be signs of dehydration, including postural hypotension and tachycardia. Hyperemesis gravidarum is a diagnosis of exclusion (Table 47–5), and it is important to make a thorough clinical assessment and to ensure that investigations are performed for common and serious causes of vomiting. An ultrasound of the uterus should be performed to confirm pregnancy, to establish the number of fetuses, and to exclude hydatidiform mole. Laboratory investigations commonly reveal hyponatremia, hypokalemia, and raised hematocrit. A biochemical hyperthyroidism and abnormal LFTs may also be present. These are both markers of the severity of the disease and resolve with successful treatment. Women with biochemical hyperthyroidism should be examined for signs of hyperthyroidism, but these are rarely present.
encephalopathy can develop as a result of thiamine (vitamin B1) deficiency. This is associated with diplopia, sixth nerve palsy, nystagmus, ataxia, and confusion. If untreated, Wernicke’s encephalopathy may lead to Korsakoff’s psychosis (amnesia, impaired ability to learn) or death. Other vitamin deficiencies may occur, for example, peripheral neuropathy and anemia may result from deficiency of vitamins B12 and B6.
T A B L E 4 7 – 5
Differential Diagnosis of Hyperemesis Gravidarum SYSTEM
DIAGNOSIS
Genitourinary
Urinary tract infection Uremia Molar pregnancy Gastritis/peptic ulceration Pancreatitis
Gastrointestinal
Bowel obstruction Endocrine
Hyperthyroidism
Diabetic ketoacidosis
CNS
Intracranial tumor
Drug-induced
Vestibular disease —
Maternal and Fetal Risks Maternal Risks Serious maternal morbidity and mortality may result if hyper emesis gravidarum is not managed correctly. Wernicke’s
Addison’s disease
INVESTIGATION/INITIAL ASSESSMENT Mid-stream urine specimen Urea and electrolytes Ultrasound of the uterus Helicobacter pylori antibodies Amylase, blood glucose, calcium Plain supine abdominal radiograph Urea and electrolytes, early-morning cortisol, short synacthen test with ACTH Surveillance for symptoms and signs of hyperthyroidism, TFTs, thyroid autoantibodies Blood glucose, urinary dipstick for ketones, glucose tolerance test CNS examination, brain imaging CNS examination Discontinue agent
ACTH, adrenocorticotrophic hormone; CNS, central nervous system; TFT, thyroid function test.
852 S ECTION F IVE • Late Prenatal
Hyponatremia (plasma sodium < 120 mmol/L) can cause confusion, seizures, and respiratory arrest. If hyponatremia is severe, or if it is treated too rapidly, women may develop central pontine myelinolysis. This is caused by symmetrical destruction of myelin at the center of the basal pons and can result in pyramidal tract signs, spastic quadraparesis, pseudobulbar palsy, and impaired consciousness. Other risks include deep venous thrombosis that may result from dehydration and reduced mobility, MalloryWeiss tear due to prolonged vomiting, and muscle wasting with weakness.
Corticosteroids
Management Options
Corticosteroids have been reported to be an effective treatment for hyperemesis gravidarum in several case reports.83–85 In an American double-blind study of 40 women with hyperemesis who were randomized to receive either oral methylprednisolone 16 mg or oral promethazine 25 mg (three times daily for both), the response to both drugs was similar after 2 days, but no women who received methylprednisolone were readmitted within 1 week of discharge. In contrast, 5 (25%) women who received promethazine were readmitted with hyperemesis.86 A British double-blind study of 25 women who were randomized to receive either 40 mg prednisolone or placebo daily demonstrated a trend toward improved nausea and vomiting and reduced dependence on intravenous fluids, but this did not reach statistical significance.87 However, steroid therapy did result in an improved sense of well-being, improved appetite, and weight gain compared with placebo.87 Overall, the studies of corticosteroid treatment for hyperemesis suggest that the treatment is effective for some patients. We recommend starting intravenous hydrocortisone 100 mg three times a day in women with severe and resistant symptoms who are unable to tolerate fluids, followed by prednisolone 40 mg once daily. This should be reduced by approximately 5 mg every 5 days, provided symptoms are controlled.
Rehydration and Vitamin Supplementation
5-Hydroxytryptamine Receptor Antagonists
Fluid replacement therapy should be with either normal saline (NaCl 0.9%; 150 mmol/L Na+) or Hartmann’s solution (NaCl 0.6%; 131 mmol/L Na+). Dextrose-containing fluids should not be used because they do not contain sufficient sodium to correct hyponatremia, and Wernicke’s encephalopathy can be precipitated by intravenous dextrose and carbohydrate-rich foods. Double-strength saline should not be used to correct hyponatremia in hyperemesis gravidarum, because central pontine myelinolysis can occur if the serum sodium level is corrected too rapidly. Potassium supplements should be added to the intravenous fluid replacement therapy as required. Thiamine supplements should be given, as a daily dose of either 50 to 150 mg orally or 100 mg diluted in 100 mL normal saline as an intravenous infusion. Urine output should be monitored and dipsticks used to assess ketonuria. Women should be weighed on admission and regularly thereafter if their symptoms do not resolve. Serial assessments of electrolytes should be carried out.
Ondansetron is a 5-HT3 receptor antagonist and a potent antiemetic drug for the treatment of chemotherapyassociated and postoperative nausea. It has been used to treat hyperemesis successfully in several case reports, in which it was given for between 2 and 19 weeks.88–90 In all cases, there were no known adverse fetal events. One double-blind, controlled trial in which 30 patients were randomized to receive either 10 mg intravenous ondansetron or 50 mg intravenous promethazine failed to demonstrate any significant difference in the degree of nausea, weight gain, or days of hospitalization between the two groups.91 However, the entry criteria for this study were less stringent than for the randomized, double-blind studies of corticosteroid treatment for hyperemesis gravidarum.86,87 Therefore, it remains likely that ondansetron may be an effective treatment for women with more severe disease.
Fetal Risks The infants of women with hyperemesis gravidarum with low pregnancy weight gain ( 5.65 mg/dL) BUN, blood urea nitrogen; SCr, serum creatinine.
TABLE 49–5
Hyperkalemia and Associated Electrocardiographic Changes SERUM POTASSIUM LEVEL
ECG CHANGES
>5.5 mEq/L 7.0–7.5 mEq/L 8.0–9.0 mEq/L
Peaked T waves, atrioventricular block
>9.0 mEq/L
Widening QRS complex Atrial standstill Ventricular fibrillation, asystole
ECG, electrocardiographic.
only 30 mmol/L NaCl, compared with 150 mmol/L NaCl in 0.9% NaCl solution). Colloid solutions (albumin) given to women with severe preeclampsia have the risk of markedly increasing PCWP, even in cases with low serum albumin level, and should be avoided. Persistent oliguria and a rising serum creatinine despite adequate intravascular volume and blood pressure correction would indicate the presence of ATN. Fluid intake should then be restricted to avoid fluid overload. Indications for dialysis are volume overload with congestive heart failure not responding to standard therapy, intractable electrolyte abnormalities, severe metabolic acidosis, or BUN greater than 39.2 mg/dL and serum creatinine greater than 5.65 mg/ dL (Tables 49–4 and 49–5). The risk of fetal demise is significantly increased if BUN exceeds 60 to 80 mg/dL. Maternal acidosis will result in progressive fetal acidemia. The goal is to maintain the maternal blood pH greater than 7.2. In a series of 60 postpartum preeclamptic women with oliguric renal failure treated with both furosemide infusion and lowdose dopamine, 13 required at least temporary dialysis.40 Dialysis in pregnancy should be started before the patient becomes symptomatic secondary to acidosis or electrolyte abnormalities.
Acute Renal Failure Due to Renal Obstruction in Pregnancy Obstruction of the renal tracts during pregnancy may be due to renal calculi (see later discussion), an overdistended uterus, congenital renal tract abnormalities, or the gestational overdistention syndrome. Women with urinary tract surgery in childhood for congenital obstructive uropathy are at increased risk for urine outflow obstruction in the second half of pregnancy, besides a higher incidence of UTI.41 Obstruction can cause high back-pressures with damaging
C HAPTER 49 • Renal Disorders 901
effect on the renal medulla, leading to loss of renal concentrating ability and production of dilute urine. Patients may also develop hypertension. With incomplete obstructions, in spite of the renal impairment, the patient may still have an apparently good urine output and the urine sediment is usually negative. The serum and urinary indices are not helpful in differentiating renal from postrenal causes of ARF, and imaging studies must be used to confirm the diagnosis. Urinary outflow obstruction requires ureteric stents that can remain in place for up to 3 months during pregnancy and will be removed 4 to 6 weeks after delivery. A temporary nephrostomy may be necessary if the ureteric stents are ineffective.42 During pregnancy, the renal tracts can rarely become grossly overdistended. If untreated, this overdistention can rarely lead to rupture of the kidney or urinary tract.43 Women with overdistention of the urinary tract present with mild to severe back pain, most commonly on the right side and radiating to the lower abdomen. The pain is characteristically relieved by lying on the opposite side and tucking the knees up to the chest. A palpable, tender flank mass and gross or microscopic hematuria suggest renal tract rupture.43 Rupture of the kidney usually occurs with preexistent renal conditions, such as hamartomas or chronic infections.43 Occasionally, a urinoma will be evident around the kidney on ultrasound examination. Rupture of the kidney necessitates immediate surgery and almost invariably an emergency nephrectomy.43
Other Causes of Acute Renal Failure during Pregnancy
headaches, and jaundice. The laboratory studies usually reveal hemoconcentration, elevated white blood cell count, hypofibrinogenemia, prolonged prothrombin time, low antithrombin, metabolic acidosis, elevated liver enzymes and bilirubin, increased ammonia, and elevated serum creatinine and uric acid. In a series of 28 women with AFLP, mean serum creatinine at the time of delivery was 2.32 mg/dL and mean uric acid 11 mg/dL.45 Intensive care by a multidisciplinary team is necessary because, in addition to hepatic impairment and coagulopathy, other complications frequently arise. Pulmonary edema and ARDS develop in about 25% of cases, pancreatitis in about 15%, sepsis in 10%, and renal failure in 44% to 50% of cases.46 The ultimate treatment is maternal stabilization and delivery, with close monitoring before and after delivery of vital signs, intake-output balance, and any hemorrhagic diathesis. It is important to treat maternal hypotension aggressively to avoid further injury to liver, kidneys, and other organs. It may be necessary to use invasive hemodynamic monitoring to adequately correct and maintain the intravascular volume, cardiac output, and renal perfusion. In general, patients with AFLP will start to improve 3 days after delivery and will recover normal renal and liver function. Occasionally, temporary dialysis may be necessary.
THROMBOTIC THROMBOCYTOPENIC PURPURA–HEMOLYTIC UREMIC SYNDROME (See also Chapters 41 and 78)
Nephrotoxic Drugs
Maternal and Fetal Risks and Management Options
Nonsteroidal anti-inflammatory drugs (NSAIDs), when given to the mother peripartum, reduce renal blood flow and can cause acute renal impairment to both mother and fetus.44 Women with reduced intravascular volume, especially if they have preexisting renal impairment, are particularly vulnerable and should be prescribed NSAIDs with caution. Indomethacin may also precipitate hyperkalemia.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are very similar, sometimes even undistinguishable, syndromes characterized by microangiopathic hemolytic anemia and thrombocytopenia (thrombotic microangiopathy). They are extremely rare during pregnancy and postpartum, occurring in less than 1 case in 100,000 pregnancies.46
Postoperative Oliguria Postoperatively, oliguria is usually secondary to hypovolemia from hemorrhage and third-space losses, although renal function may also be depressed by general anesthetics. A decrease in RPF may be seen with regional anesthesia causing sympathetic blockade and cardiac preload reduction. Volume depletion with oliguria may sometimes occur several days after surgery owing to continuous nasogastric suction or third-space sequestration (ileus, ascites, pleural effusion). In the assessment of oliguria after pelvic surgery, exclusion of obstructive uropathy or nephrotoxic agents (drugs or radiologic contrast) should always be considered before proceeding with adequate volume and electrolyte replacement.
Acute Fatty Liver of Pregnancy (See also Chapter 47) Acute fatty liver of pregnancy (AFLP) is a rare but potentially fatal complication of the third trimester or postpartum period. The typical presentation is with nausea, vomiting, anorexia, malaise, epigastric or right upper quadrant pain,
Thrombotic Thrombocytopenic Purpura The classic pentad of TTP, first described in 1925 by Moschcowitz,47 consists of thrombocytopenia, hemolytic anemia, neurologic abnormalities, fever, and renal impairment. The complete pentad is present in only 40% of cases, but the first three components are manifested by 50% to 75% of patients.46 Thrombocytopenia is frequently severe ( 2.4 mg/dL), there is a markedly attenuated increase in blood volume and no increase in GFR.66 Large multicenter series appear to suggest a linear relationship between the preconception serum creatinine level and the likelihood of further renal damage during pregnancy, although a more reliable interpretation of data should have been based on creatinine clearance rather than conventional serum creatinine levels. Women with mild renal disease who become pregnant have only a slightly increased risk of long-term damage to their kidneys from pregnancy compared with women with mild renal disease who had never become pregnant.66 Even with moderate renal disease, irreversible deterioration of maternal renal function is uncommon. In an analysis of 82 pregnancies complicated by primary renal disease, Jones and Hayslett64 reported that pregnancy-related deterioration in renal function occurs in 40% of women with initial serum creatinine level of 1.4 to 2.0 mg/dL. In half of these cases, the deterioration will persist postpartum, but only 2% will rapidly decline to endstage renal disease (ESRD). When the serum creatinine level is above 2.0 mg/dL at the beginning of pregnancy, 66% of women will have gestational deterioration in renal function, deterioration that nearly always persists in postpartum and progresses to ESRD within 6 months after delivery in 23% of cases.64 The risk of accelerated progression to ESRD within a few years after pregnancy is 45% when the serum creatinine level is greater than 2.6 mg/dL. Although termination of pregnancy per se will not result in an improvement in renal function,67 a rapid and significant decline reflected by changes in serum creatinine or creatinine clearance of at least 25% may justify delivery or termination of pregnancy. However, if the gestational age is between 24 and 31 weeks, with a normally grown fetus and controllable hypertension, expectant management with dialysis as indicated may be considered.
With regard to obstetric outcomes, available data indicate that fetal survival of pregnant women with mild or moderate renal disease is only slightly diminished. In contrast, fetal outcome is particularly reserved with severe disease, when the perinatal mortality rate is approximately four times higher compared with mild or moderate disease (36% vs, 8%).68 In a Japanese retrospective study of 240 pregnancies in women with underlying renal disease, the rate in perinatal mortality was correlated with the decline in GFR.69 The rate of perinatal morbidity as a consequence of low birth weight or prematurity doubles from mild to moderate renal insufficiency and again from moderate to severe disease. Reported rates of fetal growth restriction are 24% for pregnancies complicated by mild renal disease, 35% for moderate disease, and approximately 50% for severe disease.68 Preterm delivery occurs with a frequency of 20%, 48%, and 80%, respectively, for mild, moderate, and severe degrees of renal failure.68 Furthermore, early pregnancy losses, which are often ignored in analyses of pregnancy outcome, are more common in women with severe renal impairment.64
The Influence of Associated Hypertension The degree of renal function impairment is not the only outcome modifier. Hypertensive renal disease is associated with increased maternal-fetal risk compared with normotensive renal disease, and the presence of hypertension increases the risk of further decline in renal function during pregnancy. Hypertension present at conception or early in pregnancy increases the perinatal mortality rate 6- to 10-fold.69,70 In a retrospective study of 51 pregnancies from India, all women delivered prematurely when the diastolic blood pressure was greater than 100 mm Hg at initiation of prenatal care.9 Pregnancy outcome is improved when blood pressure is optimized prior to conception and the control is maintained throughout gestation.71 Pregnant women with renal disease have a 50% increased risk of preeclampsia.72,73 The risk increases to 80% with preexisting hypertension.66 Such risk levels might have been overestimated as a result of the inherent pitfalls in differentiating an exacerbation of the renal disease with new-onset hypertension from superimposed preeclampsia.
The Influence of Associated Proteinuria Limited postpartum follow-up of women with proteinuria identified in early pregnancy has shown an increased risk of progressive renal impairment.74 Approximately 20% of women with nephrotic syndrome (proteinuria > 3 g/day, hypoalbuminemia, and hyperlipidemia) will progress to ESRD within 4 years. It is, therefore, important that women with proteinuria recognized in early pregnancy be investigated for previously occult renal disease and monitored serially throughout pregnancy for changes in renal function, hypertension, and urinary infection. Frequently, in the absence of pregestational information, the diagnosis of preexistent renal disease will be possible only retrospectively, when the manifestations are still present at 6 months postpartum. The only certain way of first making the diagnosis during pregnancy is by renal biopsy, with the theoretical advantage that some primary glomerular diseases that are adversely influenced by pregnancy may be
906 S ECTION F IVE • Late Prenatal
steroid-responsive. However, renal biopsy is considered potentially beneficial only in highly selected women before 28 weeks’ gestation who are found to have sudden unexplained deterioration of renal function or new-onset heavy proteinuria (>5 g/24 hr) with no history of renal disease, in the absence of preeclampsia.68,75 After 28 weeks’ gestation, if progressive renal deterioration is noted, early delivery can be considered, with biopsy postpartum if necessary. There is a poor correlation between the degree of proteinuria and obstetric outcomes. Significant proteinuria may result, however, in a poorer nutritional status and inappropriate maternal weight gain, a known risk factor for both fetal growth restriction and preterm delivery. These women also have an increased risk of preeclampsia (~30%).74 Severe proteinuria may contribute to hypoalbuminemia and a diminished capacity to excrete sodium. Retention of salt and water may lead to extensive edema, a situation particularly seen in diabetic nephropathy. In order to reduce the edema, it may be necessary to prescribe a low-sodium diet (1.5 g Na) close to term, bedrest in the lateral decubitus position to increase GFR, and an intermittent, small dose of a loop diuretic.71 The use of diuretics in these patients should
be undertaken very cautiously because they may increase the risk of uteroplacental hypoperfusion and may precipitate circulatory collapse or thromboembolic episodes. Nephrotic syndrome increases the risk of arterial and venous thrombosis, including renal vein thrombosis, but the efficacy of prophylactic anticoagulation has never been proved in pregnancy or outside of pregnancy. Based on available data, it is difficult to separate the independent contribution to poor fetal outcome of maternal renal impairment, hypertension, and sometimes proteinuria. The evidence suggests that especially the first two parameters are individually and cumulatively detrimental to fetal outcome. For both maternal and fetal monitoring, more frequent prenatal visits are recommended, initially every 2 weeks, and weekly after 32 weeks’ gestation. It may be necessary to initiate weekly or twice-weekly biophysical profiles at 28 weeks’ gestation depending on the degree of renal insufficiency, hypertension, proteinuria, fetal growth velocity, and past obstetric outcome. In the absence of maternal or fetal deterioration, consideration should be given to delivery at or near term, with cesarean delivery reserved for the usual obstetric indications.
SUMMARY OF MANAGEMENT OPTIONS
Chronic Renal Failure Management Options
Evidence Quality and Recommendation
References
Any gravida with preexisting renal disease or at risk for renal deterioration during pregnancy needs a baseline determination of proteinuria and creatinine clearance early in pregnancy, then monitoring with monthly serum creatinine levels. Repeat 24-hr urine collections when indicated.
III/B
9
Women with proteinuria recognized in early pregnancy should be investigated for previously occult renal disease. Renal biopsy is potentially beneficial only in highly selected women < 28 wk gestation with sudden unexplained deterioration of renal function or new-onset heavy proteinuria (>5 g/24 hr), with no history of renal disease, in the absence of preeclampsia.
IV/C
68,75
Pregnancy outcome is improved when blood pressure is optimized prior to conception and the control is maintained throughout gestation.
III/B
71
Changes in serum creatinine or creatinine clearance of at least 25% may justify delivery or termination of pregnancy. If the gestational age is between 24 and 31 wk, with a normally grown fetus and controllable hypertension, manage expectantly, with dialysis as indicated.
IV/C
64,67,68
For extensive edema in nephrotic syndrome, prescribe a low-sodium diet (1.5 g Na), bedrest in lateral decubitus to increase GFR, and cautiously, an intermittent, small dose of a loop diuretic.
IV/C
71
Prenatal visits initially every 2 wk, then weekly after 32 wk gestation. Serial measurement of fetal growth and umbilical artery Doppler recordings.
—/GPP
—
Weekly or twice weekly biophysical profiles starting at 28 wk gestation depending on the degree of renal insufficiency, hypertension, proteinuria, fetal growth velocity and umbilical artery Doppler values.
—/GPP
—
In the absence of maternal or fetal deterioration, delivery at or near term, with cesarean delivery reserved for the usual obstetrical indications.
—/GPP
—
GFR, glomerular filtration rate; GPP, good practice point.
C HAPTER 49 • Renal Disorders 907
SPECIFIC RENAL DISEASES IN PREGNANCY Maternal and Fetal Risks and Management Options Primary Glomerulonephritis Immunoglobulin A (IgA) glomerulonephritis is the most common type of primary nephropathy in young people and the most frequently occurring variety in pregnancy. Information derived from small case series appears to suggest that the histologic type of glomerulonephritis influences the fetal and maternal outcomes, although this conclusion has been challenged in the literature.76 There is consensus, however, that clinical parameters, such as the presence of impaired renal function, hypertension, and nephrotic range proteinuria in the first trimester, correlate with less favorable fetal and maternal outcomes, regardless of histopathologic diagnosis.71 No increase in adverse outcomes occurs when nephrotic syndrome develops late in pregnancy.76 The presence of severe vascular lesions on renal biopsy has also been associated with increased perinatal mortality, but this has no significant effect on maternal complications during pregnancy.71 Based on more recent data, the overall fetal loss rate in primary glomerular disease is 21%, with the highest fetal loss rate (23%–45%) and low birth weight (32%) being associated with focal glomerulosclerosis.77 About 20% of women with chronic primary glomerulonephritis will experience worsening of preexisting hypertension or new-onset hypertension during pregnancy.78 Changes in the preconceptional immunosuppressive regimen are not advisable during pregnancy.79 However, chlorambucil is preferably avoided in pregnancy, and cyclophosphamide should not be used in the first trimester. Based on a large cohort study with patient follow-up over an average of 15 years, pregnancy is not an independent contributor to renal function deterioration in patients with chronic primary glomerulonephritis provided that they have normal or nearnormal renal function (serum creatinine < 1.4 mg/dL) at conception.80 Women who had Henoch-Schönlein purpura (HSP) with primary glomerulonephritis in childhood are at an increased risk of preeclampsia during their pregnancies (70%) according to a small Finnish retrospective study.81 There are also case reports of pregnancy triggering recurrent HSP.82 In one such case, early pregnancy was associated with progressive renal failure, purpura, and arthralgia, unresponsive to corticosteroids, requiring treatment with cyclophosphamide.83
Autosomal Dominant Polycystic Kidney Disease Pregnant women with autosomal dominant polycystic kidney disease (ADPKD) frequently manifest hypertension, which may predate the pregnancy or develop during the pregnancy, including superimposed preeclampsia. Increases in serum creatinine and proteinuria may also develop with advancing gestation, but in general, unless renal insufficiency was present before conception, the chance of a successful pregnancy outcome is unaffected.84 Extrarenal manifestations are seen in 50% of patients, including cerebral aneurysms (in up to 10%), liver and choledochal cysts, cardiac valvular defects, and aortic aneurysms.85 The risk of rupture of asymptomatic intracranial aneurysms in pregnant ADPKD women has never been
defined, but the event may be devastating, with over 50% mortality or permanent disability.86 Although the detection of an aneurysm may not lead to immediate treatment, the presence of the aneurysm would influence the mode of delivery. The general consensus is that cesarean delivery is indicated for uncorrected arterial lesions such as arteriovenous malformations and berry aneurysms, because blood pressure elevations with pushing during the second stage can elicit hemorrhage.87 For these reasons, we feel that screening with magnetic resonance angiography in pregnancy, or ideally in the immediate preconceptional period, is advisable.88 Genetic counseling should also be considered in pregnancy or preconceptionally because, as with any autosomal dominant condition, the chance for the offspring to be affected is 50%. Genetic linkage analysis is available for in utero molecular diagnosis, but although the results are essentially unequivocal, it is impossible to predict the severity of disease or clinical outcome.
Reflux Nephropathy Reflux nephropathy is common in women of childbearing age and is characterized by renal scarring and reduced GFR. Women with surgically corrected VUR in childhood remain at increased risk of reflux nephropathy in pregnancy. Pregnancy increases the risk of irreversible renal function deterioration as result of tubulointerstitial disease (in up to 13% of cases) and gestational overdistention (in ~4%).89 Close monitoring is necessary to detect significant hydroureteronephrosis, particularly if the woman develops flank pain, decreased urinary output, persistent infections, or hypertension. Ultrasonography of the renal pelvis at the end of the first trimester will provide a useful baseline measurement to be compared with subsequent imaging. Worsening proteinuria is rare and more indicative of preeclampsia. Detection of renal deterioration on serial serum creatinine measurements may require temporary urinary drainage. The changes may be reversible, and unnecessary surgical procedures soon after delivery should be avoided. VUR at the time of conception increases the risk of pyelonephritis. Monitoring for asymptomatic bacteriuria every 4 to 6 weeks throughout pregnancy is essential, and for women with persistent bacteriuria, low-dose prophylactic antibiotics chosen according to the sensitivity of the most recent UTI would prevent symptomatic infection. Women with surgically corrected VUR in childhood also have a high incidence of UTIs in pregnancy (18%–57%), a much higher rate than in women who had correction at adult age or in whom the reflux subsided spontaneously.89 The risk of superimposed preeclampsia (≤75%), and the rate of fetal morbidity and mortality are influenced by maternal hypertension and serum creatinine at conception.89,90 When serum creatinine levels are increased over 1.24 mg/ dL, the rate of preterm delivery is as high as 20%, and the fetal loss rate, excluding elective abortions, may reach 37%.89 There is increasing evidence that VUR may be a familial disorder affecting 20% of infants who have a parent with a family history of VUR, compared with a 1% to 2% frequency of VUR in the general population.91 If kidney damage is to be prevented, early diagnosis and treatment of VUR are necessary, before the neonate develops a UTI.92 It has
908 S ECTION F IVE • Late Prenatal
been suggested that infants of mothers with reflux nephropathy be prescribed prophylactic antibiotics immediately after birth and undergo renal ultrasound and voiding cystourethrogram.91 Evidence for renal scarring can be sought in
those positive for VUR using a 2,3-dimercaptosuccinic acid (DMSA) radioisotope scan at 3 months of age.91 It seems prudent to also offer screening to infants whose father has VUR.
SUMMARY OF MANAGEMENT OPTIONS
Primary Glomerulonephritis, Autosomal Dominant Polycystic Kidney Disease, and Reflux Nephropathy Evidence Quality and Recommendation
Management Options
References
Primary Glomerulonephritis Changes in the preconceptional immunosuppressive regimen are not advisable.
III/B
79
Screen for cerebral aneurysms with magnetic resonance angiography in the immediate preconceptional period or in pregnancy.
IV/C
88
Cesarean delivery for uncorrected cerebral aneurysms.
IV/C
87,88
Hereditary autosomal dominant condition requires preconceptional or prenatal genetic counseling.
—/GPP
—
Baseline renal ultrasound at 12 wk gestation.
III/B
89,90
Repeat renal ultrasound if flank pain, decreased urinary output, hypertension, persistent infections, or increase in serum creatinine.
—/GPP
—
Monitor for asymptomatic bacteriuria with urine cultures every 4–6 wk.
III/B
89
Autosomal Dominant Polycystic Kidney Disease
Reflux Nephropathy
Low-dose prophylactic antibiotics if persistent bacteriuria.
III/B
89
Renal function deterioration may require temporary urinary drainage.
III/B
89
Screen fetus and neonate for VUR and consider neonatal prophylactic antibiotics.
III/B
91
GPP, good practice point; VUR, vesicoureteric reflux.
Urolithiasis The incidence of urolitiasis during pregnancy is similar to that in the nongravid state.93 Although gestational hypercalciuria, urinary stasis, and urinary tract dilation may appear as an ideal environment for stone formation, de novo formation of stones during pregnancy is prevented by a concomitant increase in the urinary excretion of crystallization inhibitors, such as magnesium, citrate, and nephrocalcin.94 Uric acid and cystine stones rarely form in pregnancy owing to the physiologic alkalinization of the urine. The physiologic ureteropelvic dilation in pregnancy favors migration of preexisting stones. Pregnant women in the process of passing a renal calculus usually develop severe colicky lumbar pain associated with fever and hematuria. In the absence of a typical acute renal colic, urolithiasis may be suggested by flank pain or tenderness, hematuria, or persistent bacteriuria. Symptomatic calculi are more common in white than in African American women and in multigravidas than in
primigravidas.93 Renal colic is also more common in the second and third trimesters.93 Based on large published series of pregnancies complicated by renal stones, the affected women have an increased frequency of UTI, preterm labor, and preterm rupture of membranes.95 The diagnosis may be confirmed by a renal tract ultrasound in about half of the cases.96 When inconclusive, more definitive information may be obtained with a plain abdominal radiograph or an one-shot intravenous pyelograph.33 The radiation exposure of the fetus from one or two radiographs is minimal, only 0.4 to 1.0 rads.96 Alternatively, in an effort to avoid even a small dose of radiation to the fetus, magnetic resonance urography can be used.34 Initial conservative management of renal colic during pregnancy is successful in close to 70% of cases.96 Hydration, bedrest, analgesia with meperidine, and antibiotics will allow the spontaneous passage of the stones in many cases. The passage of the stone may be facilitated by epidural anesthesia, which will relieve the ureteral spasm. Continued
C HAPTER 49 • Renal Disorders 909
symptoms may necessitate cystoscopy for stone removal by ureteroscopy or passage of a double-J stent catheter that will relieve the obstruction and then be maintained in place under antibiotic prophylaxis until delivery. A percutaneous or open nephrostomy is another option, especially for an obstructed single kidney. Nephrostomy is also likely to have to remain in place for the rest of the pregnancy. Invasive procedures do place the gravida at increased risk of preterm delivery and other complications. They are indicated only in cases of intractable pain, severe infection, or deterioration of renal function. Lithotripsy is generally contraindicated in pregnancy because of fetal safety concerns. An alternative with a 91% success rate for ureteral calculi, as reported in a series of eight pregnant women, is the flexible ureteroscopy with holmium laser lithotripsy.97 This technique appears to have a good margin of safety because the direct stone-crushing energy is confined to within
0.5 mm of the laser fiber tip. It can be used in all stages of pregnancy.97 Women who are recurrent stone formers with persistent gross hypercalciuria, despite increased fluid intake, can use thiazide diuretics in pregnancy to increase distal tubular resorbtion of calcium. For problematic cases of cystinuria or recurrent uric acid calculi, high diuresis should be maintained and the urine should be further alkalinized to a pH greatrer than 6, preferably with potassium citrate.98 During pregnancy, xanthine oxidase inhibitors for prevention of uric acid stones should be avoided, especially during the first trimester. Although the outcome of most pregnancies is normal under D-penicillamine for the prevention of cystine stones,99 a teratogenic effect of the drug is suggested by animal studies, and a few cases of children with cutis laxa whose mothers received D-penicillamine during pregnancy are reported in the literature, dictating extreme caution.100
SUMMARY OF MANAGEMENT OPTIONS
Urolithiasis Evidence Quality and Recommendation
Management Options Identify renal calculus with renal tract ultrasound and when inconclusive, KUB, one-shot IV pyelography, or MRU.
References
III/B
33,34,96
IV hydration, bedrest, analgesia (meperidine), and antibiotics. Initial conservative management is successful in 70% of cases.
III/B
96
Epidural anesthesia may facilitate the passage of the stone.
—/GPP
—
Continued symptoms, or obstruction, especially in a single kidney, require cystoscopy for stone removal by ureteroscopy or passage of a ureteric stent, or nephrostomy.
III/B
96
Definitive removal of obstructing calculus by ureteroscopic holmium laser lithotripsy.
III/B
97
III/B
98,99
If Renal Colic:
For Recurrent Stone Formers: In case of persistent gross hypercalciuria, increase fluid intake and give thiazide diuretics. In case of cystinuria or recurrent uric acid calculi, maintain high diuresis and alkalinize the urine with potassium citrate. GPP, good practice point; KUB, kidneys, ureter, bladder (plain abdominal radiography); MRU, magnetic resonance urography.
Diabetic Nephropathy (See also Chapter 44) Although only 5% to 10% of pregnant women with pregestational DM have diabetic nephropathy, this is the most common chronic renal disorder in pregnancy. It also represents the highest risk subgroup among pregnant women with DM. When the renal function is only minimally diminished, pregnancy does not have any negative impact on kidney function.101 Conversely, women with diabetic nephropathy and moderate to severe renal impairment (serum creatinine > 1.4 mg/dL) have a 45% chance of an accelerated decline in renal function, significantly higher than in nonpregnant controls.102 The prognosis is especially worse if hypertension coexists. The data on the impact of pregnancy on renal
function in cases of moderate to severe renal impairment are based almost exclusively on studies conducted on type 1 DM cases, with only limited data from type 2 DM. Pregnancies in women with diabetic nephropathy are complicated by an overall rate of hypertension of more than 60% and superimposed preeclampsia in 41% of cases.103 In class F diabetics, the rate of preeclampsia is 50%, and even 60% in association with chronic hypertension. Besides chronic hypertension, other risk factors independently associated with the development of preeclampsia are an elevated glycosylated hemoglobin in the first trimester and the prepregnancy duration of DM.104 Effective antihypertensive treatment is essential because, even in women with advanced diabetic disease, blood pressure control can considerably
910 S ECTION F IVE • Late Prenatal
slow the deterioration of maternal renal function.105 The target diastolic blood pressure is 90 mm Hg or less, lower than that usually recommended for nondiabetic pregnant women with chronic hypertension.106 In all cases of diabetic nephropathy, proteinuria will increase in pregnancy, peaking in the third trimester, and decreasing postpartum.103 The increase during pregnancy is dramatic in 58% of cases.107 However, increased protein excretion, in the absence of preeclampsia, does not influence pregnancy outcome or the rate of change in creatinine clearance.107 Although pregnancy in women with diabetic nephropathy and moderate renal function impairment appears to accelerate the progression of their disease, fetal prognosis remains generally favorable in the absence of uncontrolled
hypertension.108 With severely impaired renal function, early delivery between 32 and 36 weeks frequently becomes necessary for fetal concerns or superimposed preeclampsia or to prevent further deterioration of maternal renal function. The mainstay of management before conception and during pregnancy is adequate glycemic and blood pressure control. However, even with normoglycemia throughout pregnancy, the risk of preterm delivery remains high (22%–30%). Other pregnancy complications are fetal growth restriction in 16% of cases and more frequent bacteriuria.103 The willingness to expectantly manage women with increasing proteinuria without other signs of preeclampsia may at least in part explain the current fetal survival rate of 95%.103
SUMMARY OF MANAGEMENT OPTIONS
Diabetic Nephropathy (See also Chapter 44) Management Options
Evidence Quality and Recommendation
References
Adequate glycemic control.
III/B
103
Control hypertension to ≤150/90 mm Hg.
III/B
103,105,106
In cases with severe renal failure, consider early delivery (32–36 wk gestation).
—/GPP
—
GPP, good practice point.
Lupus Nephritis (See also Chapter 43) Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that predominantly affects young women, without impact on their fertility.109 Renal involvement (lupus nephritis) occurs in 50% of SLE cases and, in pregnancy, is one of the most serious complications of lupus. Possible manifestations include hematuria, proteinuria, elevated serum creatinine, hyperuricemia, thrombocytopenia, and hypertension. Women with active lupus nephritis at conception, especially in association with proteinuria, hypertension, and antiphospholipid antibodies, have an increased risk of fetal loss (≤50%), fetal growth restriction, preterm delivery, preeclampsia, and perinatal and maternal mortality.110 Severe lupus nephritis with manifestations early in pregnancy may justify termination of pregnancy because this clinical context is not only associated with poor fetal outcome but also life-threatening for the mother. In contrast, women with absent antiphospholipid antibodies, normal or near-normal renal function, proteinuria lower than 500 mg/24 hr, controlled hypertension, and SLE in remission for at least 6 months before conception can expect better fetal and maternal outcomes.110,111 The risk of preeclampsia in pregnancies complicated by lupus nephritis is 15%.111 Differentiating an exacerbation of lupus nephropathy from preeclampsia during the second half of pregnancy is often a diagnostic challenge. Hypocomplementemia (C3 and C4 fractions) and an increase in baseline anti-DNA antibodies favor the diagnosis of lupus flare,112
although some degree of complement activation may also be present in preeclampsia.113 Clinical features that may also be discriminatory are the presence of hematuria and red cell casts in the urine sediment in active lupus nephritis, as well as extrarenal manifestations affecting the skin and joints. Treatment with corticosteroids usually improves the complement level and decreases proteinuria, but the very high doses needed to control the disease activity have been associated with a sharp increase in fetal loss rate. Antepartum fetal surveillance should be utilized. When the response to corticosteroids is suboptimal, it may be necessary to add hydroxychloroquine or even cytotoxic drugs, such as cyclophosphamide, azathioprine, or cyclosporine.114 Cyclophosphamide should be avoided in the first trimester because of possible teratogenicity.115 Additional treatment includes antihypertensive medication and, in the presence of antiphospholipid antibodies, prophylaxis with low-dose aspirin and heparin. In a series of 70 pregnancies with lupus, the presence of antiphospholipid antibodies increased the rate of adverse fetal outcome to 76%, compared with13% in antibody-negative pregnancies (OR 17.8).111 Results of one randomized trial indicated that administration of low-dose aspirin plus heparin in patients with antiphospholipid antibodies improves the rate of live birth in comparison with treatment with low-dose aspirin alone.116 Lupus nephritis may flare postpartum, especially when the histologic type is active diffuse proliferative glomerulonephritis,117 but the consensus is not to use prophylactic steroids peripartum unless there are signs of disease activity.111
C HAPTER 49 • Renal Disorders 911 SUMMARY OF MANAGEMENT OPTIONS
Lupus Nephropathy (See also Chapter 43) Evidence Quality and Recommendation
Management Options
References
Severe lupus nephritis (SCr > 1.4 mg/dL, proteinuria > 500 mg/24 hr, hypertension) with manifestations early in pregnancy may justify termination of pregnancy.
III/B
110,111
Advise increased risk of adverse pregnancy outcome, if active lupus at conception, SCr > 1.36 mg/dL, BP > 140/90 mm Hg, antiphospholipid antibodies.
III/B
110,111
Corticosteroids, hydroxychloroquine, azathioprine, cyclophosphamide (avoid in first trimester), cyclosporine to be used to treat lupus nephritis flare as necessary.
III/B
111,114
Antihypertensive medication as needed.
III/B
110,111
Prophylaxis with heparin and low-dose aspirin if antiphospholipid antibodies are present.
Ib/A
111,116
Advise increased risk of postpartum lupus flare, but no need for prophylactic increase in immunosuppression
III/B
111,117
BP, blood pressure; SCr, serum creatinine.
CHRONIC DIALYSIS AND PREGNANCY Maternal and Fetal Risks and Management Options Women with ESRD have reduced fertility, but improvements in renal replacement therapy have increased the likelihood of spontaneous conception, especially with hemodyalisis.118,119 The available data do not permit comparative statistical interpretations on outcomes between peritoneal dialysis and hemodialysis; however, there does not appear to be any obvious superiority of one modality over the other, and there is no compelling argument for changing dialysis modality in pregnancy.120 When starting dialysis during pregnancy, the usual criteria for choosing the dialysis modality can be used, with the recommendation of catheter placement higher in the abdomen if the peritoneal modality is elected. Chan and coworkers121 reported less preeclampsia and higher infant birth weight in pregnancies managed with peritoneal dialysis compared with hemodialysis, but the rate of preterm delivery was higher. The outcome of pregnancies occurring in women on dialysis has improved in recent years but the prognosis remains limited. The various maternal and fetal complications should temper any optimism and raise questions about the advisability of pregnancy in dialysis patients. Only 60% of pregnancies result in a live infant,119 with a 85% rate of preterm delivery.122 The management of pregnancy for women with ESRD requires knowledge of the pregnancy-related physiologic changes and a willingness to balance maternal benefit and fetal well-being. Gestational reduction in serum sodium concentration necessitates a concomitant reduction in dialysate sodium concentration to around 135 mmol/L, and the gestational reduction in serum bicarbonate concentration should be matched with a low bicarbonate concentration in
dialysate.123 The requirement for calcium and vitamin D supplements is also likely to change as pregnancy progresses, and plasma levels of calcium and phosphate need to be monitored and adjusted accordingly. Aggressive dialysis can lead to maternal hypovolemia/ hypotension and result in fetal hypoxia. Slow rate ultrafiltration, increased frequency of hemodialysis to almost daily sessions, and limitation in the ultrafiltration volume per session limit the risk of hypotension, extracellular volume contraction, and compromised uteroplacental blood flow.121 Pregnancy outcomes are improved when the sessions are prolonged to 4 hours, occur six times a week, the fluid removal is limited to 400 mL per session, and the predialysis serum creatinine level is maintained at 4.5 mg/dL.122,124 In those women who had been on dialysis less than 6 years and in those who still produce more than 50 mL of urine daily, fluid balance is easier to manage, and the likelihood of a successful pregnancy increases.125 The exchange volumes also have to be decreased in peritoneal dialysis (from 2 L to 1.5 L), and the exchange frequency increased. Because more frequent exchanges increase the risk of peritonitis, it may be necessary to use a combination of daytime with nighttime continuous cycling peritoneal dialysis. The disadvantages of almost daily hemodialysis may include hypercalcemia, alkalosis, and hypokalemia. If worsening alkalosis is noted, an individually formulated dialysate solution with less bicarbonate may be required, and for hypokalemia, a higher concentration of potassium in the dialysate or potassium supplements. Conversely, an increased dialysis frequency will allow for a more liberal diet and greater protein intake, improving the nutritional status. The protein supply is calculated based on pregravid weight and is recommended to be about 1.8 g/kg/day.119 Water-soluble vitamins are dialyzed off, and it is important to ensure their
912 S ECTION F IVE • Late Prenatal
supplementation. Vitamin C supplementation is necessary at 170 mg/day and folic acid at 2 mg/day, amounts that may not be present in prenatal vitamin formulations. Electronic fetal monitoring for viable pregnancies immediately after the dialysis session is important because of the acute fluid shifts that may occur. Increased fetal heart rate after hemodialysis may be an indication of excessive fluid removal with fetal hypovolemia.126 Uterine contractions frequently occur during and after dialysis but usually resolve and do not require any treatment. Significant changes in amniotic fluid volume have also been reported during hemodialysis.127 In ESRD, anemia occurs with almost 100% incidence128 and the hematocrit will decrease even further when the patient with renal insufficiency conceives.120 Serum iron, ferritin, and hemoglobin levels need to be monitored monthly, and when the hemoglobin level decreases below 8 g/dL (hematocrit < 25%), erythropoietin (EPO) treatment is indicated to maintain the hemoglobin above 10 g/dL and transferrin saturation above 30%. The dose of EPO needs to be 50% to 100% higher in pregnancy because of relative resistance to EPO. EPO is administered intravenously or subcutaneously and can also be administered at the time of hemodialysis. It does not cross the placenta and there are no reports of teratogenicity or polycythemia in the infant.122 Rarely, maternal thrombogenic activity may be increased, causing clotting of the dialyzer. Other rare adverse effects may be hyperkalemia, hyperphosphatemia, seizures, and severe hypertension. EPO is contraindicated in women with
uncontrolled hypertension. The development of hypertension is more likely when the hematocrit increases rapidly. A rise in hemoglobin of greater than 1 g/dL in 2 weeks requires EPO dose reduction. Adjustments in antihypertensive medication and reduction in EPO dose allowing the hematocrit to decrease slightly will correct the situation.129 The treatment with EPO frequently has to be supported by 200 mg iron intravenously weekly. With intravenous iron, the rise in hemoglobin concentration is significantly faster than after orally administered iron.130 For women on dialysis, pregnancy should not be continued beyond 38 weeks’ gestation, and even early delivery at 34 to 36 weeks’ gestation with documentation of fetal lung maturity may be advisable.125 Surveillance of fetal growth and umbilical artery Doppler recordings during pregnancy is common practice. The reported rate of cesarean delivery is about 50%. After cesarean delivery, peritoneal dialysis may be resumed with small 1-L exchange volumes 24 hours after surgery, gradually building back up to 2 L by day 3 after delivery.131 If there is leakage, hemodialysis may be used instead for 2 weeks. Infants of women on dialysis are born with BUN and creatinine levels equal to the mother’s and will experience osmotic diuresis after birth. Without careful monitoring and replacement, they may develop volume contraction and electrolyte abnormalities.132 Fetuses exposed to hypercalcemia are at risk for hypocalcemia at birth and tetany. Fetal osmotic diuresis caused by high BUN levels is also responsible for the more than 50% rate of polyhydramnios in patients with ESRD.133
SUMMARY OF MANAGEMENT OPTIONS
Chronic Dialysis Management Options
Evidence Quality and Recommendation
References
Advise on increased risk of adverse pregnancy outcome and limited prognosis, raising questions about the advisability of pregnancy.
III/B
119,122
When starting dialysis during pregnancy, the usual criteria for choosing the dialysis modality (peritoneal vs hemodialysis) can be used.
III/B
120
Dialysis regime to mimic physiologic renal changes of pregnancy (lower sodium and bicarbonate concentration in dialysate). Adjust potassium, calcium and phosphate binders according to serum chemistry.
III/B
119,120, 122,123
After first trimester, increase the dialysis regime to almost daily (20–24 hr/wk) to keep predialysis BUN < 50 mg/dL or SCr < 4.5 mg/dL, and limit fluid removal to 400 mL/session.
III/B
119,120, 122,124
Monitor serum iron, ferritin, and Hb monthly, and when Hb decreases below 8 g/dL (hematocrit < 25%), give EPO and iron (may need IV iron) to keep Hb > 10 g/dL. A rise in Hb > 1 g/dL in 2 wk requires EPO dose reduction.
III/B
120,122, 128,129
Fetal surveillance
—/GPP
—
Fetal monitoring after each dialysis session.
●
Serial recording of fetal growth and umbilical artery Doppler.
●
Vigilance for polyhydramnios
●
C HAPTER 49 • Renal Disorders 913
Management Options
Evidence Quality and Recommendation
References
Consider delivery at 34–36 wk gestation with documentation of fetal lung maturity; pregnancy should not be continued beyond 38 wk gestation.
III/B
125
Infants are born with BUN and creatinine levels equal to the mother’s and will experience osmotic diuresis after birth. Careful monitoring and replacement is necessary to avoid volume contraction and electrolyte abnormalities. Fetuses exposed to hypercalcemia are at risk for hypocalcemia at birth and tetany.
III/B
132
BUN, blood urea nitrogen; EPO, erythtropoietin; GPP, good practice point; Hb, hemoglobin; SCr, serum creatinine.
RENAL TRANSPLANT PATIENTS AND PREGNANCY (See Also Chapter 53) Maternal and Fetal Risks and Management Options Current consensus opinion is that pregnancy can be relatively safely undertaken by 1 year after transplant if the woman has had no rejections, the immunosuppressive medication dosing is stable, allograft function is adequate (serum creatinine < 1.5 mg/dL and urinary protein excretion < 500 mg/day), and there are no infections that could affect the fetus.134 About 1 in 20 women of childbearing age who have a functioning kidney transplant will become pregnant, and for those that go beyond the first trimester, fetal survival is 95%.135 Pregnancies in renal transplant patients are more likely to be complicated by preterm delivery (55%) and fetal growth restriction (20%).135 As for all renal disease, obstetric and maternal outcome is worse in the presence of hypertension, recurrent UTIs, proteinuria greater than 500 mg/day, and renal impairment (serum creatinine > 1.5 mg/dL). According to data from the European Dialysis and Transplant Association Registry,136 if serum creatinine is greater than 1.5 mg/ dL, fetal survival is only 75%. The rate of maternal complications in renal transplant recipients is up to 70%, including worsening of renal function, worsening hypertension, and infectious morbidity.135 Although the deterioration in renal function cannot be categorically attributed to pregnancy,137 graft loss can be expected in up to 11% of pregnancies within 2 years of delivery, according to the North American National Transplantation Pregnancy Registry.138 Long-term maternal renal function correlates with serum creatinine level measured within 3 months before conception. The majority of controlled studies have shown that pregnancy has no influence on renal function if serum creatinine is less than 1.5 mg/ dL,137 but a serum creatinine level in excess of 2.3 mg/dL should be regarded as a contraindication to pregnancy because in the United Kingdom Transplant Pregnancy Registry experience,139 all transplant recipients with such prepregnancy creatinine levels had progression of renal impairment and required renal replacement therapy within 2 years of delivery.
About one third of pregnancies in renal allograft recipients will develop worsening hypertension, often representing superimposed preeclampsia.135 The differential diagnosis of preeclampsia from allograft dysfunction or postrenal obstruction may be very challenging because worsening proteinuria, increased uric acid level, and hypertension can occur with many causes of renal deterioration. Biopsy may be necessary to distinguish severe preeclampsia that may require delivery from acute rejection that can be treated with high-dose methylprednisolone as the first-line treatment. The most frequent intercurrent infections in pregnant renal transplant patients are UTIs (40% risk).136 Other infections that may be encountered include Pneumocystis carinii pneumonia, toxoplasmosis, cytomegalovirus, and herpesvirus infections.68 Monthly urine cultures are recommended and even asymptomatic bacteriuria should be treated for 2 weeks followed by suppressive therapy.140 Urethral instrumentation should be minimized during pregnancy and peripartum. Prophylactic antibiotics are indicated before any type of surgery and for vaginal delivery. Live vaccines are contraindicated in immunosuppressed patients, and if necessary, vaccination should ideally be given prior to transplantation. During pregnancy, the allograft should be followed with monthly ultrasound examinations and a technetium renal scan each trimester, in addition to serum BUN, creatinine, and electrolytes every other week. The pelvic transplant kidney may have some baseline pyelectasis, not necessarily indicative of obstruction. But pelvicaliceal distention is concerning and, if detected preconceptionally, contraindicates pregnancy. Even a small rise in serum creatinine level or oliguria may indicate allograft rejection, the same as renal enlargement, tenderness, and fever. The rate of 2% to 11% allograft rejection episodes in pregnancy138 would suggest a need for monitoring immunosuppressive levels. In practice, though, prednisone, azathioprine, or tacrolimus dosage alterations are only rarely necessary during pregnancy,141 and in spite of conflicting opinions, most experts suggest that it is unnecessary to increase the dose of cyclosporine to prevent rejection in pregnancy.142 Antepartum exposure to immunosuppressive drugs is frequently associated with low birth weight. The rate of low birth weight may be higher in women requiring cyclosporine
914 S ECTION F IVE • Late Prenatal
(46%) than in women receiving prednisone and azathioprine (39%), although the two groups are not comparable as clinical condition.138 Cyclosporine is otherwise well tolerated in pregnancy, and a meta-analysis of 15 studies suggested no increased risk of teratogenesis.143 Several reports have raised the possibility of autoimmune disorders developing later in life in exposed children, underscoring concerns for still undefined long-term consequences.144 Prolonged administration of corticosteroids has been associated with preterm birth, and in utero first-trimester exposure may also increase the risk of facial midline fusion defects by approximately threefold. No definite pattern of teratogenesis has been detected with the use of azathioprine in a prospective, controlled, international study including 189 women who took azathioprine during pregnancy.145 Although azathioprine crosses the placenta, the immature fetal liver lacks the enzyme inosinate pyrophosphorylase needed for conversion of azathioprine to its active metabolite 6-mercaptopurine, and consequently, the fetus is relatively protected from the effects of the drug. Significant problems attributable to the drug have been reported only rarely, as long as the used dose is low enough to maintain maternal white count greater than 7500/mm3.146 Dose reductions in azathioprine may also be necessary to correct maternal liver toxicity when occuring.147 Cyclosporine has also been associated with maternal liver toxicity, diabetes, tremor, convulsions, and HUS. A series of 100 pregnancies in which the mother was treated with tacrolimus revealed a side effect profile similar to that of cyclosporine.148 The incidence of hypertension, including pregnancy-induced hypertension, was lower with tacrolimus- than with cyclosporine-receiving patients (27% vs. 67%), but the incidence of DM was higher (27% vs. 6%).148 Because cyclosporine and tacrolimus may be associated with serious adverse effects, particularly nephrotoxicity, new, highly effective immunosuppressive drugs have been introduced, such as mycophenolate mofetil. Mycophenolate mofetil has fewer nephrotoxic effects, but its administration in pregnancy is unadvisable because of documented teratogenicity in animals and humans (18%–26% rate of
congenital anomalies based on registry data: www.fda. gov/medwatch/safety/2007/safety07.htm#CellCept2). The reported malformations after first-trimester exposure demonstrate clustering of similar defects and include microtia, micrognathia, cleft lip and palate, hypoplastic nails and shortened fingers, diaphragmatic hernia, and heart defects. If a kidney transplant patient taking mycophenolate mofetil plans a pregnancy, she should consider switching to cyclosporine for a period of time.149 The use of sirolimus in pregnancy may be contraindicated because only limited data are available and the animal studies have suggested teratogenicity.150 There is also very limited experience in human pregnancy with monoclonal antibodies against lymphocytes (OKT3) or antithymocyte globulin (ATG) to recommend their use in pregnancy. Other chemotherapeutics with immunosuppressive activity such as cyclophosphamide, methotrexate, chlorambucil, and leflunomide are better avoided in pregnancy. Although the available information is often controversial, the Consensus Conference Report published in 2005144 did not view breast-feeding as absolutely contraindicated in immunosuppressed transplant recipients. Immunosuppressants are excreted in breast milk at drug concentrations similar to maternal blood concentrations, but the dose absorbed by the infant is very small,79 and the additional exposure for a few weeks postpartum is unlikely to be harmful compared with the in utero exposure over the previous 9 months. In the absence of complications, pregnancies after transplantation can be delivered at term, with cesarean delivery reserved for usual obstetric indications.151 The renal allograft is placed extraperitoneally and is not expected to obstruct the birth canal during labor.136 Cesarean delivery is eventually necessary in 50% of women with renal transplants because of the higher rate of obstetric complications.137 At cesarean delivery, care should be taken to identify the graft; the ureter may be superior to the uterine artery and may enter the bladder over the lower uterine segment. Cesarean delivery is preferred in combined pancreas-kidney recipients, because the effect of vaginal delivery on a pancreas graft placed in the pelvis is still unknown.
SUMMARY OF MANAGEMENT OPTIONS
Renal Transplant (See also Chapter 53) Management Options
Evidence Quality and Recommendation
References
Prepregnancy Advise that pregnancy can be undertaken 1 yr post-transplantation if the woman had no rejections, the immunosuppressive medication dosing is stable, allograft function is adequate (serum creatinine < 1.5 mg/dL and urinary protein excretion < 500 mg/ day), and there are no infections that could affect the fetus.
III/B
134,137
Pelvicaliceal distension detected preconceptionally contraindicates pregnancy.
—/GPP
—
SCr > 2.3 mg/dL contraindicates pregnancy because of universal progression of renal impairment and requirement for renal replacement therapy within 2 yr of delivery.
III/B
139
C HAPTER 49 • Renal Disorders 915 Evidence Quality and Recommendation
Management Options
References
Prenatal Keep maintenance immunosuppression the same as before pregnancy, despite dilutional fall in cyclosporine level
III/B
141,142,148
The use of sirolimus, mycophenolate mofetil, OKT3, ATG, cyclophosphamide, methotrexate, chlorambucil, and leflunomide is better avoided in pregnancy.
III/B
149,150
Monitor BUN, SCr, electrolytes every other wk. Monitor allograft with monthly US and technetium renal scan each trimester.
—/GPP
—
Monthly urine cultures. Treat asymptomatic bacteriuria for 2 wk followed by suppressive therapy.
III/B
140
Screen for and differentiate preeclampsia, allograft dysfunction, or postrenal obstruction. Biopsy may be necessary to distinguish severe preeclampsia from acute rejection
III/B
135
Vigilance for preterm labor.
III/B
135
Detailed anomaly scan at ~20 wk.
III/B
149
Serial monitoring of growth and umbilical artery Doppler.
III/B
135
Prophylactic antibiotics for any type of surgery and vaginal delivery.
—/GPP
—
In the absence of complications, deliver at term, with cesarean delivery reserved for usual obstetric indications.
III/B
151
Temporary stress dose corticosteroids to cover delivery.
—/GPP
—
Cesarean delivery is preferred in combined pancreas-kidney recipients.
—/GPP
—
III/B
79,144
Fetal assessment
●
●
Labor and Delivery
Postnatal No good evidence that limited (≤4 wk) breast-feeding while taking immunosuppressants is harmful.
ATG, antithymocyte globulin; BUN, blood urea nitrogen; GPP, good practice point; SCr, serum creatinine; US, ultrasound.
SUGGESTED READINGS George JN: The association of pregnancy with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome. Curr Opin Hematol 2003;10:339–344. Gilbert WM, Towner DR, Field NT, Anthony J: The safety and utility of pulmonary artery catheterization in severe preeclampsia and eclampsia. Am J Obstet Gynecol 2000;182:1397–1403. Gilstrap LC III, Ramin SM: Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am 2001;28:581–591. Hou SH: Modifications of dialysis regimens for pregnancy. Int J Artif Organs 2002;25:823–826. Jeyabalan A, Conrad KP: Renal function during normal pregnancy and preeclampsia. Front Biosci 2007;12:2425–2437. Josephson MA, McKay DB: Considerations in the medical management of pregnancy in transplant recipients. Adv Chronic Kidney Dis 2007;14:156–167.
Moroni G, Quaglini S, Banfi G, et al: Pregnancy in lupus nephritis. Am J Kidney Dis 2002;40:713–720. Ramin SM, Vidaeff AC, Yeomans ER, et al: Chronic renal disease in pregnancy. Obstet Gynecol 2006;108:1531–1539. Vidaeff AC, Yeomans ER, Ramin SM: Pregnancy in women with renal disease. Part I: General principles. Am J Perinatol 2008;25:385–397. Vidaeff AC, Yeomans ER, Ramin SM: Pregnancy in women with renal disease. Part II: Specific underlying renal conditions. Am J Perinatol 2008;25:399–405.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 5 0
Spine and Joint Disorders DARREN TRAVIS HERZOG and RALPH B. BLASIER
INTRODUCTION During pregnancy, maternal anatomic changes present mechanical challenges to the musculoskeletal system. Hormonal changes occur that modify the connective tissues and their response to mechanical stress. Complaints of musculoskeletal discomfort during pregnancy are common1,2 and may be temporarily disabling.3 These problems usually do resolve spontaneously with completion of pregnancy, but occasionally, they may remain as chronic disorders. Some musculoskeletal conditions that exist prior to pregnancy may affect the course of the pregnancy.
LOW BACK AND PELVIC PAIN General Considerations In 2003, Wu and coworkers3 published a meta-analysis of English-language papers concerning “pregnancy-related pelvic girdle pain (PPP)” and “pregnancy-related low back pain (PLBP),” considered together to be “lumbopelvic pain.” They found 761 papers, of which 106 contained sufficient material for analysis. They concluded that about 45% of women have lumbopelvic pain during pregnancy and 25% of women have lumbopelvic pain after pregnancy. They also concluded that about 25% of women have severe lumbopelvic pain during pregnancy, with severe disability in 8%. The many terms used in the literature such as “sacroiliac joint dysfunction,” “pelvic girdle relaxation,” “pelvic insufficiency,” and even “sacroiliac joint pain” allude to an unjustified knowledge of pain mechanisms and describe a mixed group of patients. Albert and colleagues4 proposed a more clear delineation between the subtle differences in the types of pregnancy-related pelvic joint pain. In their prospective epidemiologic cohort study of 1460 women, they found a total incidence of 20.1%. This total was subdivided into four groups based on objective findings and symptoms: pelvic girdle syndrome 6%, symphysiolysis 2.3%, one-sided sacroiliac syndrome 5.5%, and double-sided sacroiliac syndrome 6.3%.
Hormonal Considerations Relaxin is a polypeptide hormone. In the human female, production sites for relaxin are the corpus luteum, the
deciduas, and the chorion. The known target organs for relaxin are the uterine cervix, the myometrium, the endometrium, and the decidua. Unproven probable target organs are the pubic symphysis and the sacroiliac joints.5 It has been taught that relaxin relaxes connective tissue, and a side effect of this instability may be pelvic pain.6 Mens and associates in a 2009 meta-analysis7 concluded that in the last months of pregnancy and in the first month after delivery, motion in the pelvic joints (sacroiliac and symphseal areas) is larger in women with pelvic girdle pain and/or low back pain than pelvic joint motion in pain-free controls. Other studies have called into question whether circulating relaxin levels do actually correlate with onset or severity of PPP or PLBP.5 Björklund and coworkers8 evaluated symphyseal distention, circulating relaxin levels, and pelvic pain in 68 patients. The patients’ pain ranged from little–to–no pain to severe pain. They concluded that severe pelvic pain during pregnancy was strongly associated with an increased symphyseal distention, but relaxin levels were not associated with the degree of symphyseal distention or pelvic pain. The best conclusion is that the relationship between hormone levels and joint pain in pregnancy is unclear.
Mechanical Explanations for Back and Pelvic Pain in Pregnancy Load on the spine is increased by general weight gain and the weight of the uterus, fetus, and breasts. Theories of increasing lumbar lordosis occurring in response to the more anterior center of mass and increased shear stress across the motion segments of the lumbar spine have long been entertained. The contribution of abdominal musculature to support of the spine may be diminished, and postural adjustments in response to increased loads are required. Radicular symptoms are commonly noted in pregnancy.9 This may be caused by direct pressure of the uterus on nerve roots and lumbar and sacral plexi. Bushnell10 is credited with describing the “parietal neuralgia of pregnancy” as mechanical pressure on nerve roots by ligamentous structures of an increasingly lordotic spine. With descent of the fetus into the pelvis in late pregnancy, radicular symptoms attributed to pressure on the lumbosacral plexus may be experienced. Ostgaard and colleagues11 provided a biomechanical analysis, which demonstrates that the flexion moment caused by 917
918 S ECTION F IVE • Late Prenatal
the more anterior center of increasing mass of the fetus and uterus can be accommodated by large increases in extensor muscle forces and consequential lumbar spine compression forces. Extension of the upper trunk, head, and neck can partially offset the increase in flexion moment by moving the new center of gravity closer to the spine. Ostgaard and colleagues11 analyzed biomechanical factors and low back pain in 855 pregnant women and found that lumbar lordosis did not increase during gestation. However, a correlation has been identified between back pain and prepartum lumbar lordosis, suggesting that women with increased lumbar lordosis for any reason prior to pregnancy may be at higher risk for back pain while pregnant. However, in two separate prospective studies, no correlation was found between spinal configuration and complaints of back pain.11,12 If lordosis does not increase during pregnancy, then hip joint extension, rather than lumbar spine extension, may be a major mechanism used by pregnant women to cope with the increased flexion moment produced by pregnancy. If so, back pain in pregnancy ought to occur more often in women with intrinsic limitation of hip extension, and women with hip flexion contracture ought to have a greater tendency toward back pain with pregnancy. However, these hypotheses are unproved. Peripheral joint laxity, followed throughout pregnancy in the prospective back pain study by Ostgaard and colleagues11 of biomechanical factors, was measured by the presence of striae distensae, by serial measurement of ulnar deviation angle of the fourth finger to a defined force, and by the Bishop score (a 1–10 scale of cervix “ripeness”). Peripheral laxity was seen to significantly increase from weeks 12 through 20 in primiparous women. Laxity in multiparous women was the same at 12 weeks as that in primigravidas at 36 weeks and did not change during pregnancy. The correlation between increased peripheral laxity and increased abdominal sagittal diameter was strong. These data suggest that an increase in laxity after an initial pregnancy does not return to normal.11 All persons lose stature (total height) with physical exertion. Control individuals and pregnant women without back pain regain stature after exertion faster than pregnant women with symptoms of back pain.13 A presumed common inheritable disorder called benign joint hypermobility syndrome has been recognized in the medical literature since 1967. At times linked to entities such as fibromyalgia, osteogenesis imperfecta, and Ehlers-Danlos and Marfan’s syndromes, several investigations suggest that the underlying pathophysiology for this ill-defined condition may relate to altered collagen synthesis. Grahame and associates14 have attempted to establish specific clinical diagnostic criteria for this constellation of joint-related symptoms. Their “revised Brighton criteria” for diagnosis include major and minor articular and extra-articular symptoms or physical examination findings. Relative to spine and joint symptoms in pregnancy, an underlying hypermobility syndrome may add risk to affected individuals.
Lumbar Disk Disease The association of lumbar disk disease and pregnancy has been suggested by several authors. Relaxin may weaken the annulus of the intervertebral disks.15 No prospective, controlled studies have related lumbar disk disease to
pregnancy, yet the prevalence of symptomatic lumbar disk herniation may be on the rise owing to the increasing age of patients who are becoming pregnant.16 Thus, the potential for disk herniation and lumbar nerve root compression, with radicular pain and definite neurologic loss, should be considered in the evaluation of the pregnant patient with back pain. Magnetic resonance imaging (MRI), as well as electromyographic studies, may be helpful in diagnosis and management. Initial treatment of the pregnant patient with a documented herniated disk may involve conservative approaches such as bedrest, heat therapy, and lumbrosacral bracing. Progressive paralysis or loss of bowel and bladder control secures the diagnosis of cauda equina syndrome, and this requires urgent imaging studies, usually with MRI, and urgent surgical decompression. Unless decompression of the affected nerve roots is accomplished fairly quickly, the loss of bowel and bladder control becomes permanent. Pregnancy at any stage is not a contraindication to undergoing an MRI, regional or general anesthesia, and surgical diskectomy, if necessary.17–20
Vascular Congestion and Night Backache Back pain in pregnancy is common in the evening. It has been proposed that this pain is due to increased venous flow through lumbar veins, the vertebral venous plexus, paraspinal veins, and azygous veins that occurs at night in response to redistribution of an already large extracellular and venous fluid volume. This may be worsened owinge to mechanical vena caval compression by the gravid uterus in a supine patient. Edema and increased pressure occur, which causes pain.
Sacroiliac Pain and Osteitis Condensans Illii Inflammatory changes in the sacroiliac joints have been suggested as a cause for sacroiliac pain. “Osteitis condensans illii,” as described by Wells,21 is a “fairly uniform area of increased density in the lower iliac bone, adjacent to the sacroiliac joint, unilateral or bilateral.” This finding is most common in women, particularly those who have been pregnant. Of the 67 patients reported by Wells, all were females, 80% had been pregnant, and 30 patients had had low back pain. Shipp and Haggart in 195022 suggested that the motion and/or strain associated with pregnancy on the sacroiliac ligaments may explain that osteitis condensans illii is found most often in postpartum women. However, Wells21 concluded, probably incorrectly, that there is little relationship between back pain and oteitis condensans illii and that the association with pregnancy is due to some unknown mechanism.
Risk Factors Borg-Stein and coworkers in a 2005 review article23 summarized risk factors for PLBP. Risk factors for back pain during pregnancy include increasing parity, older maternal age (except one study that said younger maternal age), and back pain during a previous pregnancy.23 Risk factors for postpartum low back pain include early onset of severe pain during the pregnancy and inability to reduce maternal body
C HAPTER 50 • Spine and Joint Disorders 919
weight to prepregnancy levels. Risk factors did not include maternal height, weight, weight gain, or weight of the baby. Other investigators found that risk factors for pelvic girdle syndrome included history of previous low back pain, history of trauma to the back or pelvis, multiparity, higher maternal body weight, and self-reported on-the-job stress. Risk factors for symphysiolysis included multiparity, higher maternal body weight, and smoking. Risk factors for onesided sacroiliac syndrome included maternal professional education or vocational training, self-reported stress, history of previous low back pain, history of trauma to the back or pelvis, and history of salpingitis. Risk factors for doublesided sacroiliac syndrome included history of previous low back pain, history of trauma to the back or pelvis, multiparity, poor relationship with the spouse, and low job satisfaction.24
General Low Back and Pelvic Pain—Management Options Evaluation History and physical examination can give some insight into pain mechanisms and direct the management of back and pelvic pain. Extraskeletal causes for backache must be considered. Obstetric complications and urologic disorders may present with symptoms ranging from vaginal discharge, flank pain, nausea, vomiting, and dysuria. Atypical presentations of refractory pain may indicate more significant and rare pathology such as disk herniation, infection, or tumor. Although complaints of back pain are common, vigilance must be maintained if serious diagnoses are not to be missed. A history of pain at night, a radicular pain distribution, paresthesias, and bowel or bladder dysfunction may herald radiculopathy from nerve root irritation by lumbar disk disease. Differentiation from similar symptoms related to direct fetal pressure on nerve roots, such as paresthesias, in the distribution of the ilioinguinal and iliofemoral nerves and even of quadriceps weakness and giving-way episodes, is necessary. A number of physical examination signs may help locate the anatomic site of the pain generator. Straight-leg raise testing (Lasègue’s sign) is performed with the patient supine, noting the presence and distribution of pain and the angle of lower limb elevation at which pain occurs as the examiner raises the straight leg from the examining table by flexion at the hip only. In the normal patient, the angle between the leg and the examining table should reach 70 degrees or more without pain, and the maneuver should not cause any pain beyond hamstring discomfort with stretching. A positive test reproduces the patient’s radicular pain and suggests nerve root compression. Posterior superior iliac spine pressure in the standing patient may reproduce sacroiliac pain. Sacrospinous and sacrotuberous ligament tenderness by direct pressure during vaginal examination suggests a pelvic contribution to the patient’s pain. Symphyseal pain is reproduced by direct pressure over the pubic symphysis. The femoral compression test, or “posterior shea,” or “thigh thrust” test, is performed with the patient supine and the hip in 90 degrees of flexion. Axial pressure is applied to the femur. The test is positive if pain is produced in the
sacral area or ipsilateral buttock. If positive, the test suggests a sacroiliac source of pain on the positive side(s). The iliac or ventral gapping test involves lateral opening pressure against the medial aspect of the anterosuperior iliac spine, that is, the pelvis of the supine patient is pressed apart. The iliac compression or dorsal gapping test involves compressive or closing pressure against the lateral iliac wings of the patient in a lateral decubitus or supine position. Pain provoked in either right or left sacral area and/or buttock area denotes a positive test. If positive, the test suggests a sacroiliac source of pain on the positive side(s). The Patrick test is performed on the supine patient by flexing, abducting, externally rotating, then extending the hip, placing the ankle of the side being tested across the thigh of the opposite leg. This is also named the FABERE (flexion, abduction, external rotation, and extension) test. The examiner places one hand on the contralateral pelvis to stabilize it. The test is positive if pain is provoked in the sacroiliac area with the pelvis stabilized. If positive, the test suggests a sacroiliac source of pain on the ipsilateral side(s). Pain provoked in the groin with rotation of the lower limb suggests the hip joint itself is a source of the pain, whereas posterior pelvic or symphyseal pain indicates sacral or symphyseal causes. Limitation of extension (flexion contracture) may be associated with increased lumbar lordosis, likely of long duration (before pregnancy), and predisposing to low back pain with pregnancy. Radiographic evaluation, undesirable during pregnancy, may be warranted if pain cannot be explained by the common hormonal, mechanical, and vascular mechanisms, especially if neoplasm or infection is being considered. No harm to the fetus has been demonstrated with fetal exposure of less than 5 rads, a dose greater than that incurred in a routine spine radiography series. MRI may be helpful in diagnosis of tumor and infection or herniated vertebral disk.20 It is generally agreed now that MRI does not have any deleterious effects on mother or fetus.17 Mass lesions impinging on nerve roots, such as disk herniations, can be safely evaluated with electromyographic and nerve conduction studies, although these are not highly sensitive and depend strongly upon operator skill and technique.
Treatment The majority of complaints regarding back and pelvic pain during pregnancy require only symptomatic care. Lumbar disk disease, urologic disorders, venous thrombosis, or other vascular or visceral causes for back pain must be considered in refractory or atypical cases. The institution of either an individualized physiotherapy or a stretching and/or stabilizing exercise program may be a cost-effective and useful option to alleviate the intensity of pelvic pain in both the pre- and the postpartum periods.24–26 In a randomized, controlled trial of 81 postpartum women with pelvic girdle pain, Stuge and colleagues24 sought to establish whether a program of specific stabilizing exercises would reduce pain, increase functional status, and improve quality of life. The women were assigned randomly to one of two groups for 20 weeks, one received physical therapy with the addition of specific stabilizing exercises and the other received a traditional physical therapy regimen. The study group received specific training, which included
920 S ECTION F IVE • Late Prenatal
stretching and strengthening of the abdominal musculature, the lumbar multifidus, gluteus maximus, latissimus dorsi, erector spinae, quadratus lumborum, hip adductors, and hip abductors. The participants were required to exercise for 30 to 60 minutes a day, three times a week for 18 to 20 weeks. At 1-year follow up, the study group had significant improvements in pain, functional status, and health-related quality of life in comparison with the control group. This study alludes to the probable importance of the musculature surrounding and stabilizing the pelvic girdle, specifically the abdominal musculature, which has been shown in previous studies to play a pivotal role in the stability of the sacroiliac joints.27,28 A subsequent study looking at the role of three different regimens of physical therapy instituted during gestation showed no significant difference regarding pain and activity between the groups during pregnancy or at postpartum follow-up.25 However, in all groups, there was a reduction in pain and an increase in activity ability between gestational week 38 and at 12 months postpartum. The results of this study are obscured by the fact that the home exercise group was not required to record the exercise sessions, which were performed and merely relied on patient compliance. The authors concluded that most pelvic pain will improve with
time and recommended patient education and a sacroiliac belt. Exercise may also play a role in altering the relationship between flexibility of the spine and low back pain during pregnancy. The reason for this may be that as weight gain during pregnancy increases, some instability of the sacroiliac joint must result.29 Waller and associates in a 2009 meta-analysis30 concluded that there is evidence that therapeutic aqua exercise is beneficial to patients with PLBP, but the clinical trials available for inclusion into the meta-analysis were not of good quality. The utility of “water gymnastics” for reduction in PLBP was confirmed in another meta-analysis.2 Stuber and Smith,31 in a 2008 meta-analysis of papers evaluating chiropractic care for PLBP, found that every paper reported positive results. However, they also found that none of the included papers had randomization and a control group and all seemed subject to bias. Intradermal injection of sterile water has been found to provide analgesia for low back pain in pregnancy.32–34 However, the pain relief lasts only approximately 2 hours, so this modality is reserved for pain during labor. Acupuncture has been found to decrease pregnancy-related pelvic and low back pain.2
SUMMARY OF MANAGEMENT OPTIONS
Back and Pelvic Pain—General Management Options
Evidence Quality and Recommendation
References
Evaluation Consider extraskeletal causes for backache (obstetric complications and urologic disorders).
Ib/A
3
Atypical presentation or pain refractory to the usual care may indicate more significant, rare pathology (disk herniation, infection, tumor).
Ib/A
3
Differentiation from similar symptoms from direct fetal pressure on nerve roots (paresthesias in the distribution of the ilioinguinal and iliofemoral nerves and even of quadriceps weakness) is necessary.
IV/C
9,10
Radiographic evaluation, although undesirable during pregnancy, may be warranted if insidious causes for pain are suspected.
III/B IV/C
17–20
MRI may be particularly helpful in the diagnosis of tumor, infection, or disk herniation.
III/B IV/C
17–20
Mass lesions compressing nerve roots, such as disk herniations, can be initially evaluated with electromyographic and nerve conduction studies without radiation.
GPP
Treatment Physiotherapy for strengthening and/or stretching, aqua therapy, acupuncture, chiropractic manipulation, and subdermal injection of sterile water have all been found to be beneficial in the symptomatic treatment of back and pelvic pain.
Ia/A II/B III/B IV/C
2,24–26, 29–34
For mild to moderate pain, general comfort measures including rest, activity modification, and physical therapy, including massage and pelvic and low back exercises, as well as general back care are helpful.
II/B IV/C
24,26,29
For night pain, the use of a “maternity cushion” may give relief.
Ia/A
2
C HAPTER 50 • Spine and Joint Disorders 921 Evidence Quality and Recommendation
Management Options
References
Elastic compression stockings worn throughout the day may, by limiting lower extremity edema, diminish the fluid shifts and venous engorgement that occur at night.
GPP
Analgesic options are limited, and NSAIDs should be avoided for potential adverse fetal effects.
GPP
Persistent pain, including diskogenic pain, not responsive to rest may benefit from lumbar epidural steroids.
GPP
TENS may be helpful.
GPP
Acute loss of bowel and bladder function or acute paralysis indicates a need for decompressive surgery during pregnancy.
III/B, IV/C
17–20
Treatment with a trochanteric belt or girdle provides relief, particularly for women with posterior pelvic pain.
Ia/A
2
Sacroiliac injection with corticosteroids and local anesthetic may be indicated in severe cases.
GPP
GPP, good practice point; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; TENS, transcutaneous electrical nerve stimulation.
SPONDYLOLYSIS AND SPONDYLOLISTHESIS Spondylolysis is a bony insufficiency at the pars interarticularis of the spine. The condition can cause instability and pain. Spondylolisthesis is the slipping forward of one vertebra on another. This can result from a spondylolytic defect or from degenerative change in the facet joints.15 Depending on the cause and the nature of the defect, the disorder is classified into five different types. Dysplastic and isthmic spondylolisthesis represent congenital and developmental disorders, which have a high familial incidence. These slips are more common in males than females (2:1), although females have a higher chance of progression. These slips most commonly occur at the L5–S1 level. The condition probably develops or presents in the first 2 decades of life, with the diagnosis most often being made in adolescence.
immobilization. The choice of analgesics is limited in pregnancy and should not include aspirin or nonsteroidal antiinflammatory agents. In the event that significant neurologic impairment is detected, consultation should be obtained emergently.
SCOLIOSIS Scoliosis is a three-dimensional deformity of the spine, most prominently manifested by curvature in the coronal plane. The disorder is usually idiopathic, commonly familial, and presents and progresses most dramatically during the adolescent growth spurt. Spinal curvature may also be due to congenital defects in the vertebral bodies, spinal cord disorders, intracranial pathology, or muscle spasm and back pain. Scoliosis is more common in females than in males.
Risks
Risks
Degenerative spondylolisthesis usually occurs at the L4–5 level and presents later in life and more commonly in women than in men (4:1). Sanderson and Fraser15 found, in a review of radiographs of 949 women, that those who had borne children had a significantly higher incidence of degenerative spondylolisthesis than those who had not. Proposed explanations for their findings include the generalized increase in laxity of pregnancy and residual relative joint relaxation and the effects of relaxin on the collagen of the facet joint capsules and of the annulus of the intervertebral disk. Women have generally greater joint laxity than men. Possibly, compromised abdominal musculature in parous women may allow perpetually increased sheer and rotatory stresses at the L4–5 joints.15
The influence of pregnancy on preexisting scoliosis, particularly with regard to curve progression, has been controversial. An increase in curve progression during pregnancy has been demonstrated in scoliosis patients in small series. In particular, those treated with bracing who have multiple pregnancies before age 23, those with curves greater than 25 degrees, and patients who already had ongoing curve progression at the time of the pregnancy have been found to have increases in their curves during pregnancy.35 Subsequent reviews have not found the same associations.35,36 Betz and coworkers36 retrospectively reviewed 355 women with idiopathic scoliosis who had reached skeletal maturity. Two groups, 175 who had had at least one pregnancy and 180 who had never been pregnant, were compared. No effects on curve progression during pregnancy were demonstrated with regard to age of the patient at the time of pregnancy, ongoing progression of the curve at the time of pregnancy, or the number of pregnancies. Those having severe back pain during pregnancy (12%) may be slightly higher in unfused patients with scoliosis than in nonscoliotic
Management Options The management of spondylolysis and spondylolisthesis during pregnancy differs little from that in the nonpregnant patient. Symptomatic relief can be obtained by rest and
922 S ECTION F IVE • Late Prenatal
patients. In patients who had undergone posterior spinal fusion, no progression of the unfused portion of the curve was demonstrated. In these patients, no problems during the pregnancy were attributed to the scoliosis. In 159 deliveries of women who had scoliosis without a spinal fusion, spinal anesthesia could not be administered in 2 patients because of the scoliosis and cesarean section was necessary in 12 (7.4%) for reasons unrelated to the scoliosis.36 In patients who had undergone posterior fusion, 2 patients had minor problems during delivery related to the fusion. In 1, spinal anesthesia could not be administered, and in the other, proper positioning was difficult. The incidence of complications or deformity in the newborn was not increased. Postpartum back pain in scoliotic women or women with scoliosis who had not been pregnant was no greater than in the general population. As in other series, potential for progression of curves greater than 30 degrees during adulthood at a general rate of 1 degree per year was seen. However, increased progression, especially of the 6 to 8 degrees per pregnancy previously reported, was not found. They recommend that for women of childbearing age with curves greater than 30 degrees, radiographs should be done soon after each delivery to minimize the potential for fetal exposure.36 A more recent, long-term, case-control study looked at various outcomes after treatment for adolescent idiopathic scoliosis.37 In a period between 1968 and 1977, 136 women who were surgically treated with distraction and/or fusion using Harrington rods and 111 who were treated by bracing were followed for 22 years. These women were compared with age-matched controls and displayed no significant difference in regard to the number of children born, rates of low back pain, or necessity to undergo cesarean section during first pregnancy. There was no correlation between progression of spinal curvature and number of pregnancies or between this progression and age at first pregnancy. They did find that the rate of vacuum extractions was greater in the surgically treated group (16%) than in the control group (5%) and the brace-treated group (8%). In addition, there was a significant difference in sexual function between the surgically treated group and the control group, with the surgically treated group reporting more limitation of sexual function owing to back-related issues, 33% versus 15%, respectively. There was no significant difference in sexual function between the surgically treated group and the bracetreated group. The patients reported that pain was not a predominant factor in limiting their sexual activity but was more related to physical difficulty and self-consciousness about appearance.
Management Options Prepregnancy and Prenatal The affected patient should be counseled that no significant increase in the rate or incidence of curve progression during pregnancy has been demonstrated in large series of pregnant scoliosis patients compared with nonpregnant ones.35,36 In patients who had undergone posterior spinal fusion, no progression of the unfused portion of the curve is seen in the majority.
Labor and Delivery In patients who have undergone posterior fusion, 1.5% have minor problems during delivery related to the fusion.36 In one report, spinal anesthesia could not be administered, and in another, proper positioning for delivery was difficult.36 More recent reports have presented successful ultrasoundguided spinal anesthesia after spinal fusion.38 Overall, fewer than 3% of deliveries in women who had undergone posterior spinal fusion for scoliosis had problems requiring cesarean section. The indications for operative delivery were unrelated to the fusion or the scoliosis. The incidence of complications or deformity in the newborn was not increased in patients who had undergone posterior fusion for scoliosis. The risk of cardiorespiratory complications during pregnancy should be considered in patients with severe kyphoscoliotic deformity. Involvement of the respiratory team, with possible use of nasal intermittent positive-pressure ventilation, may be of benefit for a successful outcome for both mother and child.
Postpartum Scoliotic women show no increase in postpartum back pain compared with women with scoliosis who had not been pregnant. Therefore, no specific postpartum recommendations are offered. In general, for women with curves greater than 30 degrees, radiographs should be done every 2 years up to age 25 and every 5 years thereafter. Appropriate radiographic and clinical evaluation by a surgeon who manages scoliosis should be considered in the months following delivery, taking the opportunity to have a radiograph when pregnancy is unlikely.
PELVIC ARTHROPATHY AND RUPTURE OF THE PUBIC SYMPHYSIS Pelvic arthropathy usually occurs in two recognizable syndromes, though there may be overlap between them: ● Abnormal mobility of the pelvic joints may lead to pain and a waddling gait. ● After a difficult delivery, there may be a rupture of the symphysis.
Pelvic Arthropathy The weight and position of the developing fetus increases the stress on the lumbosacral junction and the sacroiliac joints. In patients with a more sagittal than oblique orientation of these joints, there is less inherent stability and there may be a predisposition to pelvic laxity. The ligaments of the pubic symphysis and the sacroiliac joints relax during the first half of pregnancy. Excessive relaxation of the ligaments of the pelvis may cause symptoms at about the sixth or seventh month, consisting of pain with walking, turning in bed, or other exertion. There may be a unilateral limp or even a bilateral waddling gait. The pain may rarely be so severe that standing or walking is precluded. Asymmetrical sacroiliac laxity (right different from left) is much more strongly associated with pelvic pain than is the absolute amount of laxity.28,39,40 In some cases, symptoms appear only during labor, due to excessive loosening of the symphysis and sacroiliac joints.
C HAPTER 50 • Spine and Joint Disorders 923
Separation of the pubic symphysis during pregnancy is common, varying between 0 and 35 mm (average 7–8 mm). Separation over 8 to 9 mm is considered pathologic. Rupture of the ligaments of the pubic symphysis may occur spontaneously during labor or as a result of forceps delivery. Patients often complain of prelabor pain in the pubis and sacroiliac joints. During and after labor, the patient may complain of pain over the symphysis and sacroiliac joints, radiating down the thighs and often exacerbated by leg movement. Commonly, there is tenderness over the greater trochanters, and severe pain can be elicited in the pubic symphysis when the greater trochanters are compressed toward the midline. The lower limbs may be externally rotated, and the patient may be unable to walk normally for weeks or months. The diagnosis is made with a history of pregnancy, pain at the pubic symphysis or the sacroiliac joints, tenderness at the pubic symphysis or the sacroiliac joints, and excessive laxity of the ligaments. A gap may be felt at the symphysis externally or by vaginal examination. Relaxation of the symphysis can be ascertained by placing the examiner’s fingers on the superior edges of the pubic bones and noting vertical translation during walking. A prevaginal examination of the symphysis can be made while an assistant pulls down on one of the patient’s ankles while pushing up on the other. Ultrasonography has been used to confirm the diagnosis, with symptomatic patients having a symphyseal gap of 20 mm (range 10–35 mm) and asymptomatic controls 4.8 mm (range 4.3–5.1 mm).41,42 MRI has been used to diagnose postpartum pubic and pelvic pain, but its clinical benefit has not been established.43,44
Management Options Treatment is generally by rest, with or without a pelvic band or girdle. Some investigators report treatment with early injection of steroid or local anesthetic or use of oral antiinflammatories.39–41 A limited number of reports mention pelvic arthropathy with onset 1 to 2 days after delivery, characterized by pain and tenderness at the symphysis, but without swelling or bruising and without widening or abnormal mobility of the symphysis.40 Symptoms abate within a week or 2 with rest and analgesics. It has been speculated that this is caused by swelling and pressure within the fibrous confines of a relatively normal pubic symphysis.
Rupture of the Pubic Symphysis Separation of the pubic symphysis in association with labor and delivery is rare and is sometimes unrecognized when it does occur. Some widening of the pubic symphysis has been noted as being necessary for normal delivery and some widening normally does occur. Rarely, the separation is greater than 10 mm, and this is usually asymptomatic. The pubic symphysis consists of a thick fibrocartilagenous disk between two thin layers of hyaline cartilage covering the articular surfaces of the bone. It is held together by four ligaments: the anterior pubic (strong), the superior and inferior arcuate, and the posterior pubic (weak). Occasionally, actual rupture of the pubic symphysis may occur. The onset of pain may be abrupt and may even be accompanied by an audible “crack.”45 Associated factors may include hard labor, precipitous labor, difficult forceps
delivery, cephalopelvic disproportion, abnormal presentation, multiparity, forceful abduction of the thighs, or previous pelvic trauma.46–49 Estimates of incidence range between 1 in 500 and 1 in 30,000.50,51 The incidence appears to be decreasing over time, because many difficult vaginal deliveries are being replaced by cesarean section.50 Separations of as much as 120 mm have been reported, and the sacroiliac joints become affected with more than 40 mm of separation.50
Management Options Treatment may begin with tight pelvic binding and/or rest in the lateral decubitus position. Symptoms may last as little as 2 days, typically 8 weeks, or up to 8 months.50 For inadequate reduction, recurrent diastasis, or persistent symptoms, external skeletal fixation, and open reduction and internal fixation are the treatment options available to maintain stability while the ligaments heal.45 Pin tract infections in association with external fixation pins are common and are usually readily manageable. Internal fixation by plate and screws or cerclage wire has been reported with good results.45 In addition, concurrent open reduction and internal fixation at the time of cesarean delivery has been described.52 Advantages of this option include a definitive treatment that would ensure stability, facilitating pain relief and earlier mobilization. This approach may help avoid rare but potential complications associated with conservative management. Using a pelvic binder or sling may require several weeks of bedrest, thus placing the patient at increased risk of decubitus ulcers, pulmonary and urogenital infections, venous thromboembolism, muscle atrophy, and joint stiffness. There is some concern that if the symphysis has been fixed by a plate and screws, the plate and screws should be removed before the next pregnancy. However, there is a report of two normal vaginal deliveries with symphyseal plate and screws remaining in situ.53 Complications of separation of the pubic symphysis include nonunion (failure to heal with reduction), pubic degenerative joint disease, osteitis pubis, and hemorrhage. The separation may occur in association with a connecting vaginal laceration, and there have been reports of these being complicated by suppurative arthritis, abscess of the vulva, and abscess of the space of Retzius.50 Some investigators report irrigation and immediate closure of such a connecting vaginal laceration, under the belief that lack of a cortical fracture, unexposed bone ends, and coverage of the bone by articular cartilage may decrease the chance of a resulting wound infection.54 A previous symphyseal rupture has been found to increase the risk of a recurrence, especially with subsequent vaginal delivery.49,55 Thus, it may be reasonable to offer cesarean delivery to patients who sustained a severe symphyseal disruption during a prior vaginal delivery.
POSTPARTUM OSTEITIS PUBIS Osteitis pubis is a self-limited, apparently noninfective, osteonecrosis that begins at the pubic symphysis and extends into the pubic bones. It is rarely associated with pregnancy, either antepartum or postpartum. It is similar to pelvic arthropathy in its presentation, with accompanying pubic tenderness and pain that may prevent ambulation. It
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is differentiated from pelvic arthropathy and symphyseal disruption by radiographic rarefaction of the pubic bones, without symphyseal widening. It is differentiated from septic symphysitis by its lack of fever, leukocytosis, and radiographic bony sequestrum. Steroids and nonsteroidal antiinflammatories have been recommended for treatment.56 Treatment of symptomatic osteitis pubis with intravenous pamidronate has been reported.57
SEPTIC PUBIC SYMPHYSITIS AND SACROILITIS Osteomyelitis in or adjacent to the pubic symphysis has rarely been reported in association with pregnancy. Fever is not universal, though leukocyte count, erythrocyte sedimentation rate, and C-reactive protein levels are usually elevated. Surgical drainage and antibiotics should be curative.58,59
STRESS FRACTURES OF THE PUBIC BONE Stress fracture of the body of the pubic bone has rarely been reported during pregnancy, unrelated to athletics or physical training. In the few cases reported, no underlying pathologic process has been found. The cause is thought to be due to ligament laxity, muscle imbalance, and increased load. Pain is usually insidious in onset. There is tenderness at the fracture. Radiography is diagnostic but not usually until some healing has occurred. MRI has been suggested to diagnose pelvic stress fractures immediately.60,61 Management is usually directed toward symptomatic relief.
PELVIC TRAUMA AND PREGNANCY In a study of 34 women who had had a displaced pelvic ring fracture, all of whom had at least one full-term pregnancy after healing, only 2 required elective cesarean section, and the need for the cesarean section was determined at the first presentation by pelvimetry.62 Of these 34 women, 17 had healed with displacement of the fracture involving the birth canal. Of 8 who had had previous traumatic pubic symphyseal disruption, 2 had recurrence of pain during pregnancy. Recently, orthopedic surgical exposure and fixation techniques have improved to the point at which restoration of the preinjury pelvic size and shape is closely approached, but sometimes that goal is not met. In cases in which the pelvic inlet, the mid pelvis, and/or the outlet measurements are less than 9.5 cm, consideration should be given to cesarean delivery.
TRANSIENT OSTEOPOROSIS OF THE HIP Transient osteoporosis of the hip is a rare condition. It has been defined by multiple case reports over the last half century.63 It is characterized by a gradually developing pain in the hip with weight-bearing.64 Symptoms begin in the third (or late second) trimester. The pain is predominantly in the anterior thigh and groin. The patient often presents with an antalgic gait and functional disability on the affected side. For unknown reasons, the left hip is affected more often than the right, though both may be affected.63 The pain is relieved by rest. There is no associated history of trauma or illness. Musculoskeletal examination is normal, except for
discomfort at the extremes of hip motion and a slight decrease in total range of hip motion.64 Joints other than the hip may become involved, and the process may regress at one joint and progress at another. Other areas affected may include knee, ankle, foot, ribs, shoulders, and spine. Radiographic osteopenia can occur, beginning 2 to 4 weeks after onset of symptoms. Radiographically, the joint space is preserved.63,64 The indistinctness of the subchondral cortical bone on radiographs may be striking. MRI of the involved joint reveals a joint effusion and diffuse signal abnormalities in the marrow, suggestive of marrow edema (decreased signal on T1-weighted images and increased signal on T2-weighted images). This is in contrast to the findings of avascular necrosis, which on MRI, may typically show a focal lesion often in the anterosuperior region of the femoral head and decreased signal intensity on both T1- and T2-weighted images. The differential diagnosis includes joint infection, rheumatoid arthritis, pigmented villinodular synovitis, and osteonecrosis. Radionucleide bone scanning shows an increased uptake in the affected femoral head and often the acetabulum. One report of a case followed by serial dual-energy x-ray absorptiometry (DEXA) over a period of 4 years showed a loss of 20% of bone mineral density (compared with age-matched controls) that resolved rapidly in the first year and returned to the normal range after cessation of lactation.63 The cause of transient osteoporosis of the hip is unknown. Some hypothesize that the cause may be neurovascular and perhaps related to reflex sympathetic dystrophy.64 However, lack of trauma; lack of the characteristic burning, pulsing pain; lack of changes in skin color, temperature, and moisture; and failure to respond to sympathetic blockade all militate against this explanation.65,66 Some authors have speculated about other causes, including abnormalities in local blood flow, viral infection, rheumatic and other inflammatory conditions, and metabolic abnormalities, but none of these explanations has been convincingly upheld.67 Other investigators have speculated that mechanical compression of the obturator nerve in pregnancy may be a causative factor, but animal experimentation has failed to produce hip osteoporosis by this mechanism.68 It appears that by an unknown stimulus, intense bone resorption is initiated in the femoral head.63,69 Later, during resolution, osteoid is laid down and mineralized. Between resorption and remineralization, the bone is weak and susceptible to microtrauma, thus explaining the pain with weight-bearing. If the microtrauma accumulates faster than it can be repaired, a pathologic fracture may ensue. For this reason, weight-bearing should be limited until resolution of osteopenia.
Management Options The condition is self-limiting, usually resolving spontaneously in 6 to 8 months. Treatment is conservative, including protection from weight-bearing, maintenance of joint motion, and analgesic medications.65 Bone and synovial biopsies are not necessary. In cases in which joint aspiration has been performed, the effusion is sterile and the joint fluid is normal. Some cases report associated pathologic fracture of the pubic rami or the femoral neck. In a series by Guerra and Steinberg,66 the authors report two patients with transient osteoporosis in their third trimester of pregnancy.
C HAPTER 50 • Spine and Joint Disorders 925
They both sustained a subcapital femoral neck fracture after a fall, which was treated with simultaneous pinning and birth by cesarean section. One of these patients went on to have two successful pregnancies with no recurrence of the transient osteoporosis. The authors advised restricted weight-bearing until confirmatory radiographs show the reestablishment of bone mass. Various treatments have been used, including limitation of weight-bearing by wheelchairs, crutches, or canes. Corticosteroids, phenylbutazone, and calcitonin have been tried without beneficial effect.65 After delivery, symptoms completely resolve over 3 to 9 months.
AVASCULAR NECROSIS OF THE HIP Avascular necrosis is not an uncommon disorder. Incidence in the United States has been estimated to be approximately 15,000 new cases annually. However, avascular necrosis during pregnancy has only rarely been reported, and thus, it is difficult to demonstrate a causal relationship between the two.66,69 Traditionally, the risk factors most commonly associated with nontraumatic avascular necrosis of the hip have included systemic administration of steroids, excessive alcohol consumption, collagen vascular diseases, renal transplantation, and pregnancy, among others. Despite this diverse spectrum of conditions, the most widely accepted precipitating event is a mechanical interruption of the circulation to the femoral head. It is not entirely clear that there is any difference between pregnancy-related transient osteoporosis of the hip and pregnancy-related avascular necrosis of the hip. Some authors have defined aseptic necrosis of the femoral head during pregnancy as an entity separate from transient osteoporosis of the hip in pregnancy,66 but the clinical presentation is very similar to transient osteoporosis. Symptoms begin in the third trimester; the hip is painful with weightbearing; the pain is relieved by rest; there is no associated history of trauma or illness; and the musculoskeletal examination is normal, except for discomfort at the extremes of hip motion and a slight decrease in total range of hip motion. Radiographs show osteoporotic changes, and radionucleide bone scanning shows an increased uptake in the affected femoral head.66 Unlike nonpregnancy-related aseptic necrosis of the hip, which often mandates operative treatment and often leads to predictable degenerative joint disease, it has been observed that aseptic necrosis of the hip in pregnancy gives good results with conservative treatment, consisting of reduction in weight-bearing. However, the optimum treatment of avascular necrosis in the pregnant patient remains controversial. Accepted surgical treatment options include osteotomy, use of a nonvascularized structural graft, electrical stimulation, core decompression, and use of a vascularized structural graft.69 One radiographic finding that may differentiate aseptic necrosis of the femoral head during pregnancy from transient osteoporosis of the hip has been a “crescent sign,” with subchondral lucency or subchondral collapse of the weightbearing dome of the femoral head. Actual bone necrosis, dead osteocytes, or empty osteocyte lacunae have not been well documented. The crescent sign of the femoral head radiographically resembles other proven cases of aseptic necrosis that occur without pregnancy, and this has been the
basis for calling the osteoporotic hip with a crescent sign in pregnancy, “aseptic necrosis during pregnancy.” However, the crescent sign might as well be a pathologic fracture in osteoporotic bone, making the distinction between these two entities questionable. With MRI, avascular necrosis typically shows focal lesions in the anterolateral femoral head with decreased signal intensity on both T1- and T2-weighted images. There may frequently be a double-density signal surrounding the lesion. In a series by Montella and colleagues,69 the authors followed 13 women who developed hip pain during pregnancy and were later diagnosed with avascular necrosis. Eleven of these women were treated with a free vascularized fibular graft. They differentiated necrosis from transient osteoporosis based on the presentation, radiographic characteristics, and natural history. Specifically, the diagnosis was made based on MRI findings of the double-density signal as well as radiographic features, including the crescent sign, progression, and collapse of the femoral head. All 13 of their patients had severe, debilitating symptoms that worsened over 12 months. They also found that there were significant demographic differences in women who have osteonecrosis associated with pregnancy compared with nonpregnant women of childbearing age who have an idiopathic avascular necrosis. The pregnancy-associated form was more likely to be found in older primigravid women with a smaller body frame who gain a relatively larger amount of weight during their pregnancy. The diagnosis of avascular necrosis is frequently delayed, and thus, the practitioner should have a high clinical suspicion. The use of MRI may be efficacious in earlier diagnosis and a better prognosis. The incidence of this disease in pregnancy may be increasing as more women delay childbearing.
HIP ARTHROPLASTY Historically, hip joint replacement has not been an option in women of childbearing age, because this operation was typically reserved for patients with limited physical activities and a relatively short expected life span. However, there are a few rare indications for hip joint replacement in the young, such as avascular necrosis of the hip, severe rheumatoid disease, post-traumatic arthritis, or certain aggressive tumorous conditions. With the advent of more durable bearing materials with superior wear characteristics, as well as hip resurfacing designs, younger patients are being more readily considered for hip joint replacement. There have been reports of completely normal impregnation, labor, and delivery in girls who had had a prior total hip replacement.70 Sierra and associates conducted a survey of 343 women, all of child bearing age with a total of 420 total hip arthroplasties.70 Of these women, 13.7% had a successful pregnancy after their procedure. The authors concluded that childbirth is not affected by the presence of hip arthroplasty implants, nor is a pregnancy after hip arthroplasty associated with decreased survival of the prosthesis. Previous smaller studies corroborate these findings in the use of both total hip prostheses and bipolar designs.71,72 Women who have had a previous total hip replacement may have increased pain during their pregnancy in the respective hip with an increased risk of continued pain
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postpartum. Persistence of pain in the groin and joint should be investigated to determine whether it is related to implant loosening, wear, or osteolysis, which may necessitate revision. Although the need for revision may increase in these situations, it is not likely attributed to the evolution and completion of pregnancy, but more likely directly related to the age at which the primary arthroplasty was done. A prosthetic hip does not have as much inherent joint stability as a biologic hip. Dislocation during positioning is a theoretical concern. However, hip flexion as long as it is
accompanied by abduction ought to be relatively safe. The dangerous positions are hip flexion with internal rotation and/or adduction and, to a lesser extent, hip extension with external rotation and/or adduction. Neither of these positions would be likely to occur during delivery, with or without stirrups, or squatting with a birthing chair. Other preexisting hip conditions, such as severe slipped capital femoral epiphysis, especially bilateral or hip fusion, may make positioning for delivery challenging. They do not otherwise preclude vaginal delivery.
SUMMARY OF MANAGEMENT OPTIONS
Back and Pelvic Pain—Specific Conditions Evidence Quality and Recommendation
Management Options
References
Scoliosis Prepregnancy and Prenatal Curvature does not usually worsen.
III/B
35,36
Compromise of respiratory function may occur in some (see Chapter 37). Labor and Delivery Regional analgesia may not be possible.
IV/C
36
Positioning for delivery may have to be individualized.
IV/C
36
For respiratory compromise, see Chapter 37. Pelvic Arthropathy Rest, with or without a pelvic band or girdle.
GPP
Analgesia and anti-inflammatory drugs.
III/B
48
If this fails, consider injection of steroids and local anesthetic.
III/B
48
Rupture of the Pubic Symphysis Treatment is generally nonsurgical, and complete recovery is to be expected.
GPP
Steroids and anti-inflammatory drugs.
IV/C
56
Treatment may begin with tight pelvic binding and rest in the lateral decubitus position.
IV/C
50
Symptoms may last as little as 2 days, typically 8 wk, or reportedly up to 8 mo.
IV/C
50
For inadequate reduction, recurrent diastasis, or persistent symptoms, external skeletal fixation is the treatment of choice to maintain stability while the ligaments heal.
IV/C
45,52
Internal fixation by plate and screws or metallic cerclage wire is considered in extreme cases.
IV/C
52,53
Pelvic Problems Postpartum Osteitis Pubis Needs to be differentiated From pelvic arthropathy and symphyseal disruption by w-ray.
●
From septic symphysitis by lack of fever, leukocytosis, and radiographic bony sequestrum.
●
GPP
C HAPTER 50 • Spine and Joint Disorders 927 Evidence Quality and Recommendation
Management Options
References
Steroids and NSAIDs recommended for treatment.
IV/C
56
Treatment with intravenous pamidronate has been reported.
III/B
57
III/B
58,59
III/B
60,61
III/B
62
If this has been performed before skeletal maturity, there is greater risk of smaller pelvis and greater need for cesarean delivery.
III/B
73
Acetabular rotational osteotomy after skeletal maturation appears to have no effect on pelvic dimensions and need for cesarean delivery.
III/B
74
Limit weight-bearing.
IV/C
65,66
Encourage movement.
IV/C
65
Analgesia.
IV/C
65
Septic Pubic Symphysitis and Sacroilitis A rare condition in pregnancy; surgical drainage and antibiotics should be curative. Stress Fractures of the Pubic Bone Radiography is diagnostic, but often after some healing; MRI may give earlier diagnosis. Management is symptomatic relief. Pelvic Trauma and Pregnancy Manage as for nonpregnancy. Critical issue is the degree to which pelvic anatomy is distorted and cesarean delivery indicated. Maternal Pelvic Osteotomy
Hip Problems Transient Osteoporosis—Conservative Approach
Avascular Necrosis Manage as for transient osteoporosis.
GPP
Hip Arthroplasty Usually no significant problem encountered nor special management required.
IV/C
Normal birthing position can be used.
GPP
Avoid flexion to more than 90 degrees and internal rotation or adduction of the hips, which can provoke dislocation.
GPP
70
GPP, good practice point; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs.
MATERNAL PELVIC OSTEOTOMY Historically, pelvic osteotomy was reserved for young patients, predominantly female, for the treatment of developmental dysplasia of the hip. When the osteotomies were done at a young age, the pelvis would remodel during growth to a normal size and shape. When the osteotomies were done at an older age, the pelvis might not remodel to a normal size and shape. Loder73 compiled a series of 40 pelvic osteotomies in 37 patients done for developmental dysplasia of the hips. He was able to follow 30 patients to skeletal maturity. At skeletal maturity, the mid-pelvis and/or outlet measurements were less than 9.5 cm in 6 of the 30 cases, and these tended to be those in whom the osteotomy had been done at an older age.
Recently, the use of pelvic osteotomies has been expanded to patients after skeletal maturity, typically in the childbearing years. Such osteotomies are for the purpose of delaying or avoiding the need for a hip replacement later in life. These osteotomies are typically rotational osteotomies at the acetabulum for the purpose of correcting slight residual hip dysplasia or redirecting a slightly arthritic joint. Masui and colleagues74 studied 21 patients who had had successful pregnancy and childbirth after rotational acetabular osteotomy. They concuded that rotational acetabular osteotomy caused no substantial difference in the bony birth canal before or after surgery. Fortunately, in case of osteotomy, the treating orthopedic surgeon would most likely have large numbers of the patient’s radiographs, so new radiation exposure for pelvimetry might not be needed.
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SUGGESTED READINGS Betz RR, Bunnell WP, Lombrecht-Mulier E, et al: Scoliosis and pregnancy. J Bone Joint Surg Am 1987;69:90–96. Borg-Stein J, Dugan SA, Gruber J: Musculoskeletal aspects of pregnancy: Am J Phys Med Rehabil 2005;84:180–192. Danielsson AJ, Nachemson AL: Childbearing, curve progression, and sexual function in women 22 years after treatment for adolescent idiopathic scoliosis: A case-control study. Spine 2001;26:1449–1456. Goldsmith LT, Weiss G, Steinetz BG: Relaxin and its role in pregnancy. Endocrinol Metab Clin North Am 1995;24:171–186. Grahame R, Bird HA, Child A: The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rhematol 2000;27:1777–1779. Mens JM, Pool-Goudzwaard A, Stam HJ: Mobility of the pelvic joints in pregnancy-related lumbopelvic pain: A systematic review. Obstet Gynecol Surv 2009;64:200–208.
Sierra RJ, Trousdale RT, Cabanela ME: Pregnancy and childbirth after otal hip arthroplasty. J Bone Joint Surg Br 2005;87:21–24. Smith MW, Marcus PS, Wurtz LD: Orthopedic issues in pregnancy. Obstet Gynecol Surv 2008;63:103–111. Wu WH, Meijer OG, Uegaki K, et al: Pregnancy-related pelvic girdle pain (PPP), I: Terminology, clinical presentation, and prevalence. Eur Spine J 2004;13:575–589. Wurdinger S, Humbsch K, Reichenbach JR, et al: MRI of the pelvic ring joints postpartum: Normal and pathologic findings. J Magn Reson Imaging 2002;15:324–329.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 5 1
Skin Disease GEORGE KROUMPOUZOS
INTRODUCTION Skin problems in pregnancy can be categorized as follows1: ● Physiologic skin changes of pregnancy. ● Preexisting skin diseases and tumors affected by pregnancy. ● Pruritus in pregnancy. ● Specific dermatoses of pregnancy. Prompt recognition and correct classification of the skin problem are essential for treatment, when necessary. The pregnant woman should be counseled about the nature of her skin condition, possible maternal or fetal risks associated with it, and management options.
PHYSIOLOGIC SKIN CHANGES OF PREGNANCY The skin undergoes changes during pregnancy that are caused by the profound endocrine and metabolic alterations during the gestational period. The physiologic skin changes of pregnancy include pigmentary changes such as hyperpigmentation and melasma, vascular changes such as spider angiomas (Fig. 51–1), palmar erythema, nonpitting edema, and varicosities, stretch marks (striae gravidarum) (Fig. 51–2), as well as mucosal, hair (Fig. 51–3), nail, and glandular changes.1–3 These changes are not associated with any risks for the mother or fetus and are expected to resolve postpartum. The types of pigmentation seen in pregnancy are summarized in Table 51–1. The most common pigmentary changes of pregnancy are hyperpigmentation and melasma (Fig. 51–4). Uncommon pigmentary patterns, such as pseudoacanthosis nigricans (Fig. 51–5) and dermal melanocytosis (Fig. 51–6), can also be seen.4–8 Furthermore, postinflammatory hyperpigmentation secondary to specific dermatoses of pregnancy (Fig. 51–7) is particularly common
in skin of color. A mild form of localized or generalized hyperpigmentation occurs to some extent in up to 90% of pregnant women1,3 and shows accentuation of the areolae, nipples, genital skin, axillae, and inner thighs. The most familiar examples are darkening of the linea alba (linea nigra) (see Fig. 51–2) and periareolar skin (secondary areolae). Melasma (chloasma or mask of pregnancy) is a type of facial melanosis reported in up to 70% of pregnant women2 and one third of nonpregnant women taking an oral contraceptive.9 Although the malar pattern is common, the entire central face is affected in most patients (centrofacial pattern) (see Fig. 51–4) and, less often, the ramus of the mandible (mandibular pattern).10 Melasma results from melanin deposition in the epidermis (70%, accentuated by Wood’s lamp examination), dermal macrophages (10%–15%), or both (20%). This type of melanosis is thought to be associated with the hormonal changes of gestation and worsens with exposure to ultraviolet and visible light.10,11 Melasma usually resolves postpartum but may recur in subsequent pregnancies or with the use of oral contraceptives. The dermal type of melasma is less responsive to treatment than the epidermal. Mild gestational melasma can be treated with azelaic acid, which is safe during pregnancy. Persistent melasma can be treated postpartum with topical hydroquinone 2% to 4% and a broad-spectrum sunscreen, with12 or without a topical retinoid and mild topical steroid. Melasma, whether caused by pregnancy or oral contraceptives,3 is resistant to treatment in 30% of patients. Combination therapies, including laser treatment13,14 and chemical peels,15 may be effective to some extent in resistant cases. The physiologic vascular, connective tissue, mucosal, glandular, hair, and nail changes of pregnancy are summarized in the Summary of Management Options box. The oral pyogenic granuloma of pregnancy (granuloma gravidarum or pregnancy epulis) is discussed under “Skin Tumors.” 929
930 S ECTION F IVE • Late Prenatal FIGURE 51–1 Spider angioma (telangiectasia) on the arm.
FIGURE 51–3 Telogen effluvium, which developed in the immediate postpartum period, with typical temporal recession and thinning.
FIGURE 51–2 Stretchmarks (striae gravidarum) on the lateral aspects of the abdomen and hyperpigmentation of the linea alba, causing development of the linea nigra.
FIGURE 51–4 Melasma of the entire central face.
T A B L E 5 1 – 1
Patterns of Pigmentation in Pregnancy Common Hypermelanoses Hyperpigmentation Melasma Uncommon Hypermelanoses Pseudoacanthosis nigricans Dermal melanocytosis Vulvar melanosis Verrucous areolar pigmentation Localized reticulate pigmentation Darkening of Preexisting Pigmentation Acanthosis nigricans Pigmentary demarcation lines
FIGURE 51–5 Pseudoacanthosis nigricans may develop in skin of color during pregnancy and manifests itself as hyperpigmented velvety plaques on the axillae (as shown) and neck.
Darkening of Benign Skin Lesions Scars Melanocytic nevi Skin tags, seborrheic keratoses Postinflammatory Hyperpigmentation Secondary to specific dermatoses of pregnancy (see specific section in text) Jaundice (see specific section in text)
C HAPTER 51 • Skin Disease 931 FIGURE 51–6 Grayish-brown ill-defined patches of dermal melanocytosis may develop in pregnancy and persist in the postpartum period.
FIGURE 51–7 Extensive postinflammatory hyperpigmentation secondary to pruritic urticarial papules and plaques of pregnancy in an Asian female.
SUMMARY OF MANAGEMENT OPTIONS
Physiologic Skin Changes of Pregnancy Evidence Quality and Recommendation
Management Options
References
Pigmentation Follow-up for spontaneous resolution in postpartum period.
—/GPP
—
Sun protection is mandatory in all cases.
—/GPP
—
Hydroquinone 2%–4% cream with or without tretinoin and mild topical steroids.
IV/C
12
Combination therapies including laser treatment (Er:YAG, Q-switched ruby, or Q-switched Nd:YAG).
IIa/B
13,14
Combination therapies, including chemical peels (glycolic acid and Jessner’s solution).
IIb/B
15
—/GPP
—
—/GPP
—
—/GPP
—
—/GPP
—
For persistent cases postpartum, consider: ●
●
●
Spider Nervus (see Fig. 51–1) Reassure (occurs in 67% of white women, in the second to fifth mo; resolves within 3 mo postpartum); persistent lesions can be treated with fine-needle electrocautery, cryotherapy, or laser. Palmar Erythema Reassure (occurs in 70% of white and 30% of African American women). Varicosities Explain (occurs in 40% of women; thrombosis in < 10%); recommend leg elevation, compression stockings. To treat symptomatic hemorrhoids, recommend stool softeners, hot sitz baths, topical anesthetics, suppositories, laxatives. Nonpitting Edema Reassure; exclude preeclampsia. Recommend leg elevation; compression stockings, diuretics if severe.
932 S ECTION F IVE • Late Prenatal SUMMARY OF MANAGEMENT OPTIONS
Physiologic Skin Changes of Pregnancy—cont’d Evidence Quality and Recommendation
Management Options
References
Striae Gravidarum (see Fig. 51–2) Reassure (occurs in 90% of white women; less common in other groups; less apparent postpartum but may never disappear); prescribe antipruritics, topical steroids if itchy; laser can improve the color changes.
—/GPP
—
—/GPP
—
—/GPP
—
—/GPP
—
—/GPP
—
—/GPP
—
Pyogenic Granuloma (Granuloma Gravidarum) Reassure (occurs in 2% of pregnant women at second to fifth mo; typically on the gingivae; postpartum shrinkage). Recommend good dental hygiene; excision if excessive discomfort or bleeding Gum Hyperemia/Gingivitis Seen in most pregnant women in the third trimester; resolves postpartum. Reassure; recommend good dental hygiene. Hair Changes (see Fig. 51–3) Mild hursutism regresses within 6 mo postpartum. Postpartum hair shedding (telogen effluvium) lasts 1–5 mo. Frontoparietal hair recession and diffuse thinning also reported. Exclude pathologic androgen production if hirsutism. Follow-up postpartum hair changes. Glandular Changes Reassure (enlargement of sebaceous glands of the areolae); axillary sweating can be controlled with aluminum chloride solution (20%). Nail Changes Reassure (start in the first trimester; onycholysis, subungual hyperkeratosis, transverse grooving, brittleness). Er:YAG, erbium:yttrium-aluminum-garnet; GPP, good practice point; Nd:YAG, neodymium:yttrium-aluminum-garnet.
PREEXISTING SKIN DISEASES AND TUMORS AFFECTED BY PREGNANCY The pregnant woman is susceptible to aggravation or, less often, to improvement of skin diseases and tumors.16 The conditions that may improve during pregnancy are listed in Table 51–2.
Inflammatory Skin Diseases ATOPIC DERMATITIS (ECZEMA) Eczema is the most common pregnancy dermatosis, accounting for 36% of total cases.17 Atopic dermatitis is more likely to worsen than remit in pregnancy, although remission has
T A B L E 5 1 – 2
Preexisting Disorders That May Improve in Pregnancy Acne Atopic dermatitis Autoimmune progesterone dermatitis Chronic plaque psoriasis Fox-Fordyce disease Hidradenitis suppurativa Linear IgA disease Rheumatoid arthritis Sarcoidosis IgA, immunoglobulin A.
C HAPTER 51 • Skin Disease 933
been reported in up to 24% of cases.17 There is a personal history of atopy in 27% of pregnant females with atopic dermatitis, a family history of atopy in 50% of cases, and infantile eczema in 19% of the offspring.17 Some studies indicate that atopic dermatitis may start before the third trimester in up to 75% cases.17 There have been no adverse effects on the fetal outcome. Maternal smoking may be implicated in the development of atopic eczema during pregnancy and lactation.18 The effect of breast-feeding on atopic eczema has been debated. Gestational atopic eczema is treated with moisturizers and low- to mid-potency topical steroids. A short course of oral steroid may be required for severe eczema. Systemic antibiotics, such as erythromycin base or penicillin, are necessary in superinfected eczema. Systemic antihistamines, such as diphenhydramine, are often required for severe pruritus. Ultraviolet B (UVB) light is a safe adjunct in treating chronic eczema. Irritant hand dermatitis and nipple eczema are often seen postpartum.1 Nipple eczema can show painful fissures and be complicated with bacterial infection, most commonly from Staphylococcus aureus.
ACNE VULGARIS The effect of pregnancy on acne vulgaris is unpredictable. Some patients may develop acne for the first time during pregnancy, and acne conglobata may worsen during pregnancy. In one study, pregnancy affected acne in approximately 70% of women, with 41% reporting improvement and 29% worsening in pregnancy.19 Comedonal acne can be treated with topical keratolytic agents, such as benzoyl peroxide, whereas inflammatory acne can be treated with azelaic acid, topical erythromycin, topical clindamycin phosphate, or oral erythromycin base. All these medications are safe to use during gestation.19 Urticaria may worsen in pregnancy, whereas hidradenitis suppurativa and Fox-Fordyce disease may remit during gestation as a result of reduced apocrine gland activity (see Table 51–2).1
CHRONIC PLAQUE PSORIASIS Chronic plaque psoriasis is the most common type of psoriasis to develop or exacerbate during pregnancy.20 It is more likely to improve (40%–63%) than worsen (14%) during gestation; it commonly flares, however, within 4 months of
A
delivery. Psoriatic arthritis may develop or worsen during pregnancy and often starts postpartum or perimenopausally (30%–45%).21 Topical steroids and topical calcipotriene as well as topical anthralin and topical tacrolimus appear to be safe treatment options for localized psoriasis in pregnancy.22 UVB is the safest treatment for severe psoriasis that has not responded to topical medications. A short course of cyclosporine can be administered for psoriasis that has not responded to UVB.
GENERALIZED PUSTULAR PSORIASIS/ IMPETIGO HERPETIFORMIS A very rare variant of generalized pustular psoriasis develops in pregnancy, often associated with hypocalcemia23 or low serum levels of vitamin D.24 When compared with nonpregnant women with various forms of psoriasis, pregnant women with impetigo herpetiformis rarely have a personal or family history of psoriasis, develop the eruption strictly during pregnancy, and improve postpartum. The eruption usually starts in the third trimester. It often persists until delivery and occasionally runs a protracted course postpartum. It can exacerbate with the use of oral contraceptives.25 Impetigo herpetiformis is manifested as grouped discrete sterile pustules at the periphery of erythematous patches (Fig. 51–8A). The lesions start in the major flexures and extend centrifugally onto the trunk and around the umbilicus, usually sparing the face, hands, and feet. The lesions may become crusted (see Fig. 51–8B) or vegetative, and the mucous membranes may show erosive or circinate lesions. Postinflammatory hyperpigmentation commonly develops; nail changes secondary to subungual pustules are exceptionally seen. Skin histopathology shows features of pustular psoriasis, and direct immunofluorescence is negative. The laboratory workup reveals leukocytosis, elevated erythrocyte sedimentation rate, and occasionally, hypocalcemia or decreased serum vitamin D levels. Impetigo herpetiformis is thought to be an outbreak of psoriasis probably triggered by a metabolic milieu, such as pregnancy or hypocalcemia.1 The latter is known to exacerbate generalized pustular psoriasis and can develop secondary to hypoalbuminemia in pregnancy. A report that showed reduced levels of an inhibitor of skin elastase in a patient with impetigo herpetiformis warrants further investigation.26 Furthermore, one report raised speculation that infections during pregnancy may trigger a flare
B
FIGURE 51–8 A, Early impetigo herpetiformis: discrete group sterile papules at the periphery of erythematous patch. B, Generalized advanced lesions of impetigo herpetiformis show crusting or vegetations. (A and B, Photographs courtesy of Aleksandr Itkin, MD.)
934 S ECTION F IVE • Late Prenatal
of pustular psoriasis in an individual with psoriatic tendency.27 Impetigo herpetiformis can be treated with systemic steroids at daily doses up to 60 mg/day of prednisone. Calcium and vitamin D replacement therapy should be undertaken if necessary and can lead to remission of the eruption.23 A severe case was treated with cyclosporine.28 Impetigo herpetiformis has been treated postpartum with oral retinoids29 or PUVA30 (psoralens with ultraviolet A light). Systemic antibiotics should be administered in superinfected cases. The eruption commonly resolves postpartum but recurs in each successive pregnancy with earlier onset and increased morbidity.25,31 There are serious risks for the mother and fetus. Maternal risks include tetany, seizures, delirium, and exceptionally, death from cardiac or renal failure. Fetal risks25 such as stillbirth, neonatal birth, and fetal abnormalities may result from placental insufficiency, which often complicates impetigo herpetiformis, and have been reported even when the skin disease was well controlled.31 Maternal and fetal monitoring is of utmost importance. In severe cases, termination of pregnancy is warranted, the timing of which depends on the maternal and fetal status. The eruption resolves promptly afterward.
Infections Pregnancy can affect the vast majority of common infections, causing an increase in the prevalence or exacerbation of candida vaginitis, Trichomonas, Pityrosporum folliculitis, and papillomavirus infections.1,16 Other infections, such as recurrent genital herpes simplex virus infection, are not exacerbated in pregnancy but are of critical interest because they significantly increase fetal morbidity and mortality32 (see Chapter 30). Disseminated infections are more likely to occur during gestation and may have devastating effects for the fetus. Viral exanthems can have significant maternal and/ or fetal risks for complications; their management options are summarized in Chapters 29 and 32. The prevalence of candida vaginitis increases during pregnancy. The infection has been reported in 17% to 50% of pregnant women33; of those, 10% to 40% are asymptomatic.34 Candida albicans has been associated with intraamniotic infection.35 The organism can be cultured from up to 50% of neonates born to infected mothers.16 Neonatal candidiasis can result from passage of the infant through an infected birth canal and congenital candidiasis from an ascending infection in utero. The latter is characterized by generalized skin lesions that appear within 12 hours of delivery.16 Trichomonas infection is seen in 12% to 27% of pregnant women.36 An association with preterm delivery and low birth weight37 has been debated.38 Pityrosporum folliculitis and tinea versicolor (Fig. 51–9), both caused by yeasts of the Malassezia species, occur with greater frequency in pregnant women.39 Papillomavirus infections may worsen during gestation, and condylomata acuminata can show accelerated growth, blocking the birth canal.16 Early studies showed exacerbation of leprosy during pregnancy or within the first 6 months of lactation,40 a finding that was debated by one study.41 Leprosy reactions are triggered by pregnancy: type 1 (reversal) reaction occurs maximally postpartum,42 when the cell-mediated immunity
FIGURE 51–9 Hyperpigmented minimally scaly patches on the chest in a pregnant female with tinea versicolor.
returns to prepregnancy levels, and type 2 reaction (erythema nodosum leprosum) throughout pregnancy and lactation.43 The increased incidence of erythema nodosum leprosum in pregnant women has been associated with early loss of nerve function secondary to “silent neuritis.”44 Multidrug therapy of rifampin, dapsone, and clofazimine is the treatment of choice during pregnancy. Leprosy reactions should be treated with oral steroids and not thalidomide, which is contraindicated in pregnancy. Patients with leprosy should be counseled about the effects of pregnancy on the disease before they become pregnant, and pregnancies should be planned when the disease is well controlled. Leprosy has been associated with increased fetal mortality and low birth weight.40 Approximately 20% of children born to mothers with leprosy will develop the disease by puberty.
Autoimmune Disorders SYSTEMIC LUPUS ERYTHEMATOSUS (See also Chapter 43) Chronic discoid lupus is not affected by pregnancy. The data as to whether flares of systemic lupus erythematosus (SLE) are more common during pregnancy are conflicting.45–47 The discrepancy among previous studies is due to methodologic differences,48 including the definition of lupus flare, and the fact that several typical manifestations of active SLE, such as facial erythema (Fig. 51–10), alopecia, fatigue, edema, anemia, musculoskeletal pain, mild proteinuria, and elevated erythrocyte sedimentation rate, are common findings in pregnancy. In most studies, the frequency of flare during pregnancy was higher than 57%.48 Pregnancy is well tolerated by mothers in remission for at least 3 months before conception, but if conception occurs during the active stage of disease, 50% of gravidas will worsen during pregnancy and might experience life-threatening progression of the renal disease.45 When SLE first appears during pregnancy, it may show severe manifestations but usually remits postpartum. Cutaneous flares and arthralgias are the
C HAPTER 51 • Skin Disease 935 FIGURE 51–10 Malar erythema in a butterfly distribution in a pregnant woman with systemic lupus erythematosus. (Photograph courtesy of Cameron Thomas, Campbell Kennedy, and Phillipa Kyle.)
(HLA) DR2 and DR3 positivity in the mother has been reported.50 The female-to-male ratio is 3 : 1.50 Neonatal lupus is characterized by a transient skin eruption and systemic manifestations, including congenital heart block (15%– 30%), cytopenias, hepatosplenomegaly, and pericarditis/ myocarditis. The eruption becomes manifest several weeks into postnatal life and resolves by 6 to 8 months of age, coincident with the clearance of maternal autoantibody from the infant’s circulation. The skin lesions frequently affect the face and scalp, with a predilection for the eyelids. Other sun-exposed areas may be also affected; occasionally, the eruption becomes generalized. The lesions are papulosquamous or annular/polycyclic, indistinguishable from subacute cutaneous lupus of the adult. Skin histopathology shows interface dermatitis and superficial dermal mononuclear cell infiltrate. Immunofluorescence shows a particulate pattern of immunoglobulin G (IgG) in the epidermis. Congenital heart block carries a substantial neonatal morbidity and mortality and can be detected in utero at 18 to 20 weeks’ gestation.50 Twenty-two percent of affected infants die in the perinatal period, and 62% of the infants require a pacemaker.50 The risk of bearing a second child with heart block is 25%, rising to 50% after two or more affected infants. The maternal and fetal anti-Ro, anti-La, and antiU1-RNP status should be determined, and the newborn should be screened for heart block. Survivors of neonatal lupus may be at increased risk of developing connective tissue disease in adulthood.
DERMATOMYOSITIS/POLYMYOSITIS
most common manifestations of SLE in pregnancy. Flares are not more severe during than outside of pregnancy and can be treated with oral steroids. Yet, steroids do not prevent flares and should not be prescribed prophylactically. The effects of lupus on fetal outcome correlate with the severity of maternal lupus, active disease at the time of conception or first presentation of SLE during pregnancy, and presence of anticardiolipin antibody or lupus anticoagulant. Preterm delivery occurs in 16% to 37% of pregnancies, and spontaneous abortion rates are two to four times normal. Other risks include fetal death, intrauterine growth restriction (IUGR), and preeclampsia.48 These obstetric complications have been associated with uteroplacental hypoperfusion, defective placentation, and chronic inflammation. The antiphospholipid syndrome49 may complicate SLE, but many patients have primary antiphospholipid syndrome without lupus. It presents with manifestations that can worsen or lead to its initial diagnosis during gestation, such as recurrent miscarriage, thrombosis, livedo reticularis, migraine, stroke, and thrombocytopenia. Treatment with low-molecularweight heparin or aspirin and close antenatal surveillance for maternal and fetal complications is warranted.
NEONATAL LUPUS (See also Chapter 43) Neonatal lupus50 can develop owing to transplacental passage of maternal anti-Ro (SS-A) and, less commonly, anti-La (SS-B) or anti-U1-RNP antibody. The risk is 5% if anti-Ro–positive, and the incidence is 1.6% of all lupus pregnancies. An association with human leukocyte antigen
Dermatomyositis/polymyositis may show a flare of the heliotrope rash, worsening of proximal muscle weakness, or subcutaneous calcification in approximately half of the affected individuals.51 When the disease is in remission during pregnancy, there are no maternal or fetal risks involved. Nevertheless, when the disease starts or relapses during gestation, it can be detrimental to the mother and/or fetus. High doses of oral steroids may be required to control the disease. Fetal demise owing to abortion, stillbirth, or neonatal death has been reported in over half of the cases of active disease, and prenatal surveillance is crucial. An assisted vaginal delivery may be required in case of active myositis during labor. If the disease is diagnosed in the first trimester, the option of therapeutic abortion should be offered to the mother because of the high risk of maternal and/or fetal complications.
SYSTEMIC SCLEROSIS (See also Chapter 43) The course of scleroderma is not significantly altered by pregnancy. Gravidas with limited scleroderma without systemic disease do better than those with diffuse scleroderma.52 Women with early (50 rads).
III/B
13
After embryogenesis, the main risks are growth restriction and impaired neurobehavioral development (if >50 rads).
III/B
13–16
Physiologic changes of pregnancy may alter the pharmacokinetics of chemotherapeutic agents.
III/B
25
In first trimester, the main risks are miscarriage and fetal abnormality (17%), especially with the folate antagonists.
III/B
24–32
In second and third trimester, the main risks are growth restriction, preterm delivery, and impaired neurobehavioral development.
III/B
29
Chemotherapy
T A B L E 5 2 – 2
Estimated Average Fetal Dose ROENTGENOGRAM OF MOTHER Barium enema Upper gastrointestinal series Intravenous pyelogram Hip Abdomen Lumbar spine Cholecystography Pelvis Chest Skull Cervical spine Shoulder Extremity (upper or lower) Computed tomography scan of abdomen and pelvis
DOSE TO FETUS (RAD) 0.800 0.560 0.400 0.300 0.290 0.275 0.200 0.040 0.008 0.004 0.002 0.001 0.001 3.00
From Deppe G, Munkarah A, Malone JM Jr: Neoplasia. In Gleicher N, Buttino L (eds): Principles and Practice of Medical Therapy in Pregnancy, 2nd ed. Norwalk, CT, Appleton & Lange, 1988, pp 1231–1234.
CERVICAL CANCER Cervical cancer is diagnosed in pregnancy with a frequency of 10 to 1000 cases per 100,000 pregnancies.37 The wide variability in the incidence reported in the literature seems to be caused by the inclusion of patients with postpartum cancer, carcinoma in situ, and preinvasive disease. A recent cancer registry study5 reported cervical cancer as the most common gynecologic malignancy to occur during pregnancy and represented 15% of all cancers during pregnancy. It is estimated that between 1% and 3% of patients
with cervical cancer are pregnant at the time of diagnosis.38 The mean age of pregnant patients at the time of diagnosis of cervical cancer is 31.6 years (range 31–36.5 yr).39 As in nonpregnant patients, the most common histologic type is squamous cell carcinoma, which accounts for more than 80% of all cervical cancers.40 More than 70% of patients have early-stage disease, which includes FIGO (International Federation of Gynecology and Obstetrics) stages I to IIA lesions.40–43 Diagnosis may be made at an earlier stage in pregnancy because pregnant women are seen frequently by health care providers and undergo routine examinations and Pap smears. One third of pregnant patients who are diagnosed with cervical cancer are asymptomatic, with diagnosis made at the time of an abnormal Pap smear result. The interpretation of Pap smears obtained during pregnancy can be problematic, because several common physiologic changes associated with the gravid state can lead to falsepositive results.44–46 For example, eversion of the transformation zone and exposure of columnar cells to the acid pH of the vagina cause squamous metaplasia that may be falsely interpreted as dysplasia. The changes seen with Arias-Stella reaction can resemble those of endocervical adenocarcinoma.47,48 In one study of gravid hysterectomy specimens, Arias-Stella reaction was reported in 9% of specimens examined.49 Another cause of false-positive Pap smear is related to the presence of trophoblastic cells that may be misinterpreted as dysplastic cells in the cytologic specimen. It is essential to inform the cytopathologist interpreting the Pap smear that the patient is pregnant. Historically, it was believed that pregnancy had an adverse effect on the natural history of cervical cancer. Multiple studies have shown that there is no difference in survival between pregnant and nonpregnant cervical cancer patients when matched by age, stage, and year of diagnosis.5,38–40,43,48,50–52 In addition, the decision for a vaginal delivery versus a cesarean delivery depends on the stage of disease
954 S ECTION F IVE • Late Prenatal
at the time of diagnosis.44 Microinvasive or early invasion is not a contraindication to vaginal delivery.44,53 However, gross tumor present at the time of delivery may have a higher likelihood of peripartum complications and potentially higher risk of locoregional recurrence and death.54,55
Management Options Colposcopy is a safe and reliable method for evaluation pregnant patients with abnormal cervical cytologic findings.56–60 The interpretation of colposcopy during pregnancy is more difficult owing to increased cervical volume, stromal edema, glandular hyperplasia, and increased vascularization.4 Colposcopy-direct biopsy may be performed during any trimester, although most colposcopists suggest delaying biopsy until the second trimester. The main complication associated with cervical biopsy during pregnancy is bleeding; however, this usually can be controlled with the application of Monsel’s solution and pressure. Endocervical biopsy must be avoided during pregnancy because of the risk of premature rupture of the membranes, preterm labor, and uncontrollable bleeding.55 Many investigators estimate that without colposcopic findings suggestive of cancer, the likelihood of invasive cancer or progression to invasive cancer is low and that carcinoma in situ lesions may be treated conservatively until the postpartum period with periodic control colposcopy antenatally.61 During pregnancy, diagnostic cervical conization is reserved for selected indications including (1) the diagnosis of minimal stromal invasion on a colposcopically directed biopsy and (2) persistent cytologic abnormalities suspicious of invasive cancer on Pap smear.44 Fortunately, eversion of the squamocolumnar junction during pregnancy improves access to the endocervix and decreases the necessary volume of tissue to be removed if conization is performed. The risks of immediate and delayed bleeding after conization are 8.9% and 3.7%, respectively.51 An estimated blood loss of 500 mL has been reported to occur during conization procedures performed during pregnancy.44 Other infrequent complications include premature labor, chorioamnionitis, and fetal loss.62 Pregnant women who are diagnosed with invasive cervical cancer should be counseled extensively about treatment options as well as the effect of the treatment on the mother and fetus. Many factors should be considered in treatment planning, including gestational age, tumor size and stage, and the patient’s desire to preserve the pregnancy. Few studies have evaluated the effect of delaying definitive therapy until fetal maturity is reached.63–70 In these reports, treatment delays ranging from 21 to 212 days to allow for
fetal maturity did not result in decreased maternal survival. At last follow-up, 96% of the patients were alive without disease. However, the numbers of patients in these series are small and definitive conclusions should be drawn cautiously. Two intervention options have been described in case reports for patients diagnosed with cervical cancer greater than FIGO stage IA and who desire pregnancy preservation. One is a surgical excision option, which involves an abdominal radical trachelectomy during pregnancy; it is hazardous and associated with significant risk of surgical complication and pregnancy loss.71 Alternatively, neoadjuvant chemotherapy during pregnancy has been used with the intent to stabilize or reduce the cervical tumor.67 Cesarean delivery followed by definitive treatment would be performed after fetal maturity. For patients with more advanced disease and at less than 20 weeks’ gestation, termination of pregnancy is an option so that definitive management is not delayed.38,44,72 The choice of treatment modality for pregnant patients with invasive cervical cancer is based on the same principles that are used in the nonpregnant state. Patients with early-stage disease can be treated surgically with radical hysterectomy and bilateral pelvic lymphadenectomy.63,64,73,74 Depending on the time of diagnosis, surgery can be done early in gestation with termination of the pregnancy or at cesarean delivery. Except for increased blood loss, there is no significant increase in other perioperative complications compared with nonpregnant patients, and the cure rates are comparable.64 Radiation therapy with chemosensitization is used to treat advanced disease that is not amenable to surgical management. When radiation is administered in the first trimester, spontaneous abortion usually occurs at a cumulative dose of 30 to 50 Gy. Treatment in the second trimester results in abortion at a higher cumulative radiation dose and less reliably. If spontaneous abortion did not occur by the end of the external radiation therapy, surgical evacuation should be performed before brachytherapy.75 For patients who are treated after delivery, most radiotherapists wait a few weeks for uterine involution before starting treatment. Tumor stage is an important predictor of survival in cervical cancer. The outcome of patients with early-stage disease is excellent, with 5-year survival rates exceeding 90%.40 In one report, the survival rate was worse and risk of recurrence was higher in women who were diagnosed postpartum than in those diagnosed during pregnancy.65 One uncommon site of tumor recurrence when cervical cancer occurs in pregnancy is the episiotomy incision line.76–78 It is believed that tumor cells can implant at the site of the episiotomy incision after vaginal delivery.
SUMMARY OF MANAGEMENT OPTIONS
Cervical Cancer Management Options
Evidence Quality and Recommendation
References
Diagnosis Physical examination and cervical smear at first prenatal visit in high risk and those without smear in previous 3 yr.
III/B
56–61
Colposcopy and directed biopsies for suspicious lesions, though measures are needed to deal with increased bleeding risk.
III/B
51,55–61
C HAPTER 52 • Malignant Disease 955 Evidence Quality and Recommendation
Management Options Cone biopsy when microinvasion suspected on directed biopsies; loop excision may be associated with increased preterm births.
References
III/B
55,62
III/B
59,61
III/B
51–53, 63–70,74
Before 20 wk: consider termination and immediate therapy.
III/B
38,44,63, 64,71–74
After 20 wk: consider awaiting fetal maturity (enhance with steroids), then deliver and implement therapy postnatally.
III/B
63,64,73, 74,78
Elective cesarean hysterectomy can be considered with early-stage disease.
III/B
53
Careful patient counseling required with either presentation.
III/B
63,64,73, 74,78
Impact of cervical cancer during pregnancy does not appear to influence outcomes. However, some studies suggest a worse prognosis when diagnosed after pregnancy.
III/B
65,68
Reports of recurrences in episiotomy sites after vaginal birth.
III/B
63,78
Treatment Cervical Intraepithelial Neoplasia Follow-up with colposcopy during pregnancy. Microinvasive Cancer After careful maternal counseling, consider delaying definitive therapy until fetal maturity is reached (enhance with steroids) and delivery is completed. Invasive Cancer Use same therapy guidelines as for nonpregnant patient: ●
●
Prognosis
OVARIAN CANCER Ovarian cancer occurs in between 10 and 40 per 100,000 pregnancies and is the fifth most common malignancy diagnosed during pregnancy.37,79 Most ovarian masses are diagnosed incidentally at the time of obstetric ultrasound. They are frequently nonmalignant and are found on histologic examination to be functional ovarian cysts (41%), endometriomas (24%), dermoid (18%), serous cystadenoma (6%), mucinous cystadenoma (3%), paraovarian cyst (3%), and borderline serous tumor (5%).80 The risk of malignant or borderline ovarian neoplasm discovered during pregnancy ranges from 2% to 5% compared with 20% outside of pregnancy.81–83 The histologic distribution of ovarian cancers diagnosed in pregnancy is different from that seen in the general population, partly because pregnant women are relatively young and have a higher incidence of germ cell tumors. Germ cell tumors account for 6% to 40% of malignant neoplasm complicating pregnancy; conversely, epithelial malignancies account for 49% to 75% and gonadal stromal tumors for 9% to 16%.84–89 The distribution of subtypes of germ cell tumors diagnosed during pregnancy has varied among published series. Whereas some indicate that dysgerminomas are the most common subtype,82,86,87 others indicate that malignant teratomas84,85 and endodermal sinus tumors90 are more common. Most ovarian malignancies
diagnosed in pregnancy are stage I, as would be expected with germ cell tumors.
Management Options Management of an adnexal mass during pregnancy depends on the ultrasonographic characteristics of the mass and the gestational age. Some authors recommend to proceed with surgical exploration early in the second trimester for lesions that are larger than 6 cm, have a significant solid component, are bilateral, or persist after 14 weeks’ gestation.91,92 However, others encourage conservative management secondary to the low risk of malignancy and acute complications.93 The serum cancer antigen 125 (CA-125) level can be elevated in normal pregnancies, especially in the first trimester, and low-level elevations are typically not associated with pregnancy.93,94 Ovarian neoplasms, even when benign, are associated with increased risk of complications during pregnancy. Adnexal torsion is reported in up to 25% of patients.95–97 Other complications include rupture and hemorrhage.93,98 The risk of pregnancy loss or preterm labor is increased if surgery is performed for one of these acute complications. Unilateral salpingo-oophorectomy with staging biopsy is the recommended surgery for stage I germ cell tumors.
956 S ECTION F IVE • Late Prenatal
Patients with stage IA dysgerminomas and stage IA grade 1 immature teratomas do not require further adjuvant therapy. The remaining germ cell tumors behave more aggressively and usually require adjuvant chemotherapy even in early stages. Treatment of advanced germ cell tumors of any histologic subtype includes surgery and chemotherapy. In anecdotal reports of pregnant patients with malignant ovarian germ cell tumors treated with combination chemotherapy (bleomycin, etoposide, cisplatin and vinblastine), good maternal and fetal outcomes were achieved.99–101 Patients with early-stage epithelial ovarian carcinomas can be treated successfully with conservative surgery, including
salpingo-oophorectomy and staging biopsy. Advancedstage disease presents a management problem. Tumor debulking surgery is often extensive and may result in adverse pregnancy outcome. This surgery may be performed after vaginal delivery or at the same time as the cesarean section. Platinum-based chemotherapy is usually used postoperatively. Few case reports describe successful treatment of advanced ovarian cancer in pregnancy with surgery and chemotherapy.16,21,26,34–36,92 Gonadal stromal tumors are uncommon in pregnancy. They are often confined to the ovary and have an indolent course. Treatment involves unilateral salpingo-oophorectomy.
SUMMARY OF MANAGEMENT OPTIONS
Ovarian Cancer Management Options
Evidence Quality and Recommendation
References
Diagnosis Often diagnosed as a chance finding during an obstetric ultrasound examination.
III/B
80,91,92
CA-125 levels are unhelpful because they can be raised in normal pregnancy.
III/B
93,94
MRI helpful.
IV/C
89
Surgical exploration ideally performed in second trimester.
III/B
84–86
Pregnancy preservation and conservative surgery with unilateral salpingo-oophorectomy and staging biopsies are possible in most early-stage ovarian cancers (uncommon).
III/B
84–86
Chemotherapy, if needed, has risks (see earlier and Chapter 39).
III/B
16,21,24–32
Salvage of the pregnancy may not be possible with advanced disease.
III/B
16,21,26,34–36, 84–86,92
Treatment
MRI, magnetic resonance imaging.
OTHER GYNECOLOGIC MALIGNANCIES Vulvar carcinoma in pregnancy is extremely rare. The most common histologic varieties are invasive squamous cell carcinoma and melanoma.102 Radical excision of the primary lesion with inguinofemoral node dissection is the treatment of choice for stage I and II tumors.103 The timing of treatment and mode of delivery are usually dependent on the time of diagnosis during pregnancy. The current recommendation is to proceed with definitive surgical treatment before 36 weeks’ gestation.102,104,105 If wounds have healed, then cesarean is indicated only for obstetric indications.
Human papillomavirus–related intraepithelial neoplasia might be treated with laser vaporization, surgical excision, or observation. Although the use of imiquimod has been described during pregnancy,106 the application of podophylline or imiquimod is contraindicated. Few cases of endometrial carcinoma have been reported during pregnancy.107–109 Surprisingly, some were associated with a viable fetus.84,85 The remaining cases were diagnosed at the time of dilation and curettage performed for miscarriage or postpartum bleeding. This highlights the importance of evaluation of abnormal postpartum bleeding despite the protective effects of pregnancy.110
C HAPTER 52 • Malignant Disease 957 SUMMARY OF MANAGEMENT OPTIONS
Other Gynecologic Malignant Disease in Pregnancy Evidence Quality and Recommendation
References
Histologic varieties most commonly encountered are invasive squamous cell carcinomas and melanomas.
III/B
102–105
Radical excision of the primary lesion and inguinal femoral node dissection is the treatment of choice for stages I and II squamous cell cancer.
III/B
102–105
Timing of treatment and mode of delivery are usually dependent on the time of diagnosis during pregnancy. It has been recommended to proceed with definitive surgical treatment at any time during pregnancy up to 36 wk’ gestation. Patients can be allowed to deliver vaginally, provided the wounds have healed.
III/B
102–105
III/B
107–110
Management Options Vulval Carcinoma
Endometrial Carcinoma Endometrial cancers rarely occur during pregnancy. Surprisingly, 30% were associated with a viable fetus. The remaining cases were diagnosed at the time of dilation and curettage performed for irregular bleeding.
BREAST CANCER Pregnancy-associated breast cancer is usually defined as carcinoma that is diagnosed during pregnancy or within 1 year postpartum.111,112 It is second only to cervical cancer as one of the most common types of pregnancy-associated cancers.37 Approximately 15% of breast cancers occur in women of childbearing age and 3% of breast cancers occur in pregnancy. The incidence is approximately 10 to 40 per 100,000 pregnancies.37,113 Pregnancy-associated breast cancer usually presents as advanced disease; the largest proportion of stages II to IV breast cancers are reported among women diagnosed during pregnancy or less than 2 years postpartum.114 Between 53% and 74% of pregnant women who are diagnosed with breast cancer have evidence of lymph node metastases. A delay in diagnosis has been reported as a potential cause for the advance stage at diagnosis. The estimated delay in the diagnosis of breast during pregnancy is between 1 and 6 months or more.111 Physiologic changes that affect the breast during gestation make clinical examination difficult and inaccurate. In addition, physicians may be reluctant to perform breast biopsy during pregnancy and lactation because of the increased risk of bleeding, infection, and milk fistulas. Traditionally, it was believed that pregnancy adversely affected the outcome of patients with breast cancer. Earlier reports had shown poor survival in women with pregnancy-associated breast cancer.115–118 In at least one series, pregnancy was found to be an independent adverse prognostic factor in multivariate analysis; however, it is unclear whether delay in treatment may have contributed to the poorer survival.115 In contrast, there are data that show identical survival rates in pregnant women and nonpregnant cohorts when matched for disease stage.5,72,119–121 The 5-year survival rate for pregnant women with stage I disease have been reported to be 90%.122 In an analysis of selected studies,
an expert panel concluded that the worse prognosis in pregnant women with breast cancer is probably caused by the advanced stages of the cancer at diagnosis or a less standardized therapy.123
Management Options Pregnant women should have a baseline breast examination at the first prenatal visit. Diagnostic mammography can be performed safely during pregnancy when clinically indicated; however, it should not be done routinely because of concern about fetal irradiation. A bilateral mammogram performed with modern equipment yields less than 500 µGy to the human embryo, which is well below the 100-mGy toxic level.7 The mammogram may have limited diagnostic utility because of the hyperemia and edema that affect the mammary tissues and contribute to the generalized radiographic density of the breasts. Mammography is one of the most intensely studied imaging procedures during pregnancy and the only imaging procedure to rule out microcalcifications and should be used if it is necessary.123 Ultrasound is accurate in differentiating between cystic and solid masses. The detection of a mass necessitates prompt evaluation with fineneedle aspiration or surgical biopsy. An experienced cytologist should evaluate the cells obtained from aspirates because hyperproliferative physiologic changes in the mammary tissue may be mistaken for malignancy. Because atypical cytomorphologic findings are encountered during gestation and lactation, some authors describe a core biopsy as a more sensitive and specific method for evaluating a suspicious, palpable mass.124 The increased risk of complications associated with breast biopsy during pregnancy should not deter the surgeon from performing these procedures when clinically indicated.111
958 S ECTION F IVE • Late Prenatal
As in the nonpregnant patient, staging of breast cancer during pregnancy involves a complete physical examination, blood testing, and chest x-ray with abdominal shielding. Evaluation of the liver can be safely performed using ultrasound.125 A radionuclide bone scan can cause significant fetal exposure to radiation. Because of lower yield in early-stage disease, bone scans should be limited to patients with more advanced disease. Magnetic resonance imaging (MRI) during pregnancy is generally considered safe for the mother and fetus; it is being used with increasing frequency to diagnose bone, liver, and brain metastases. MRI has been used to evaluate many obstetric and fetal conditions without any evidence of harmful effects.126 One advantage of this imaging modality is its avoidance of exposure of the fetus to ionizing radiation. However, gadolinium is known to cross the placenta and was associated with fetal abnormalities in animal models, especially during the first trimester.127 Mastectomy with axillary lymph node dissection has been the most common breast surgery for stages I, II and some stage III breast cancers when the patient wants to continue the pregnancy.128,129 A major advantage of mastectomy is the elimination of the need for breast radiation therapy. The indications for axillary lymph node dissection are similar in the pregnant and the nonpregnant patients with breast cancer. Lumpectomy with axillary lymph node dissection is feasible and safe in pregnant woman with breast cancer130,131 and is reported to have no adverse impact on locoregional recurrence rates.132 Owing to the reduction in short- as well as long-term morbidity, there has an increasing interest in sentinel node biopsy. The use of radiocolloid injections during sentinel node localization procedures does not appear to significantly increase the risk of prenatal death, fetal malformation, or mental impairment.133 A recent review of a prospectively collected database revealed that sentinel lymph node biopsy could be performed safely during pregnancy.113 Sixty percent of the population had combined sentinel node localization procedures (technetium-99m and blue dye) with 90% achieving successful pregnancy and delivery. The most common reported reason for unsuccessful pregnancy was first-trimester voluntary termination of pregnancy.113 Alternatively, blue-staining alone can be used and appears to be of little risk to the fetus. More data are needed regarding the use of sentinel node biopsy as a standard in pregnant women with localized disease.134 The standard breast radiation therapy course of approximately 5000 cGy exposes the fetus to a radiation dose that varies according to gestational age and the associated anatomic changes. Early in pregnancy, when the uterus is still in the pelvis, fetal exposure may be as low as 10 cGy. However, in late pregnancy, when the fetus moves up into the mother’s abdomen, fetal exposure can reach 200 cGy. Conversely, for some women diagnosed with early breast cancer in the third trimester, delaying treatment until after parturition is an acceptable option with minimal maternal risks and obvious fetal benefit.135,136 Adjuvant chemotherapy is indicated in patients with specific high risk factors including those with lymph node metastases. During organogenesis in the first trimester, the risks of teratogenicity and fetal malformation should be weighed carefully against the potential benefits. Chemotherapy administration during the second and third trimesters appears to be feasible. Many agents with known activity
in breast cancer have been safely administered during pregnancy for the treatment of other cancers.137–140 However, some agents may offer a potentially excessive risk of fetal toxicity.141,142 Antimicrotubule agents paclitaxel, docetaxel, and vinorelbine display a high activity against breast cancer and have a favorable toxicity profile when administered during pregnancy.36 The transplacental transfer of chemotherapy agents varies greatly, and it is commonly recommended that chemotherapy administration be discontinued 3 weeks preceding delivery.36 Chemotherapy during pregnancy may also result in maternal complications, including sepsis and hemorrhage, with unplanned labor and delivery. Breast cancer in young patients (≤35 yr) overexpress HER-2 in up to 35% of cases.143 The HER-2 targeting agent trastuzumab has been used for the treatment of advanced breast cancer in pregnant patients. Although assigned a category B pregnancy risk on the basis of trials in monkeys, fetal effects vary based on gestational age and length of exposure. Its use has been associated with uteroplacental complications.144 Lapatinib, a tyrosine kinase inhibitor, has been reported in only one patient who unexpectedly became pregnant during a phase I trial. There were no reported adverse events during the pregnancy or delivery.145 Hormonal therapy with tamoxifen is contraindicated during pregnancy because of its teratogenic effect and the risk of severe fetal malformations.146 There are no published reports of the use of aromatase inhibitors for the treatment of breast cancer during pregnancy. Animal studies have reported that aromatase is needed during embryo and fetal development. The inhibition of aromatase during the prenatal period may interfere with the development of fetal gonadocytes and sexual differentiation of the brain and significantly impair the pregnancy outcome.147,148 Advanced-stage disease requires both chemotherapy and radiation therapy. The prognosis is poor, and maternal survival is limited. Management of these patients during pregnancy presents ethical and medical dilemmas and should be planned on an individual basis. Published literature does not support the routine recommendation of therapeutic abortion in pregnant patients with breast cancer.111,149 Many authors showed that survival is not improved by pregnancy termination for maternal indications.150–152 In some cases, therapeutic abortion may be strongly recommended because of potential fetal damage from the proposed chemotherapy or radiation treatments. In early pregnancy, treatment is greatly simplified with therapeutic abortion.111 Subsequent pregnancy in women who have been treated for breast cancer does not seem to confer a worse prognosis than that in patients who did not become pregnant. Interestingly, few population-based studies have shown that a subsequent pregnancy results in an improvement in survival, with favorable relative risks of 0.2 (range 0.1–0.5)112 to 0.8 (range 0.3–2.3).135,136 However, it is difficult to draw definite conclusions from available studies because of the small number of patients reported and the associated selection bias. Because recurrence is most likely to occur in the first 2 years, most investigators recommend delaying conception for 2 to 3 years after treatment. A recent publication has even suggested that premenopausal women with localized disease and good prognosis are unlikely to have a reduced survival if conception is delayed only 6 months after treatment.153
C HAPTER 52 • Malignant Disease 959 SUMMARY OF MANAGEMENT OPTIONS
Breast Cancer and Pregnancy Evidence Quality and Recommendation
Management Options
References
Diagnosis Physiologic changes of pregnancy reduce the sensitivity of physical examination and mammography.
IV/C
111,123
Fine-needle aspiration of any suspicious lesion.
IV/C
111,124
Open biopsy if the results of needle biopsy are equivocal.
IV/C
111,124
Mastectomy with lymph node dissection is the preferred treatment for early cancers. Indications for lymph node dissection are similar in the pregnant and the nonpregnant patients.
III/B
129
Sentinal node localization procedures appear safe during pregnancy.
III/B
113,133,134
Adjuvant chemotherapy may be indicated for some patients with high risk cancers. Both maternal benefits and potential risks to the fetus should be weighed carefully.
III,IV/B,C
111,129
If diagnosis is made late in pregnancy and chemotherapy or radiation treatment is indicated, consider delaying therapy until after delivery.
IIb/B
128,135,136
Routine therapeutic abortions are not indicated.
III/B
111,122,149
Termination of pregnancy may be considered in patients with advanced disease if chemotherapy and/or radiation treatment is indicated in early pregnancy.
IIa/B
136
Recommend delaying conception for 2–3 yr after treatment.
IIa/B
111,136,153
Treatment
PLACENTAL METASTASES Metastasis of maternal malignancy into the placenta is rare and poorly understood. Malignant melanoma is the most common maternal malignancy associated with placental metastasis; it accounts for nearly one third of reported cases.151,154 Next in frequency are hematopoietic malignancies and breast carcinoma.151,155,156 Fetal metastasis is extremely rare, even when the maternal surface of the placenta contains evidence of metastatic tumor. The low incidence of fetal metastasis has been attributed to two factors: inherent resistance of the trophoblast to tumor invasion and possible immune rejection by the fetal immune system.155 Interestingly, after delivery, some infants with metastatic melanoma have complete tumor regression and long-term survival. Comprehensive understanding of maternal cancers with metastasis to the placenta or fetus would benefit from a registry of malignancies associated with pregnancy.156,157
Cradonick E, Iacobuxxi A: Use of chemotherapy during human pregnancy. Lancet Oncol 2004;5:283–291. Kal HB, Struikmans H: Radiotherapy during pregnancy: Fact and fiction. Lancet Oncol 2005;6:328–333. Lee JM, Lee KB, Kim YT, et al: Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG-1006). Am J Obstet Gynecol 2008;1981:92.e1–92.e6. Loibl S, von Minckwitz G, Gwyn K, et al: Breast carcinoma during pregnancy. International recommendations from an expert meeting. Cancer 2006:106:237–246. McIntyre-Seltman K, Lesnock JL: Cervical cancer screening in pregnancy. Obstet Gynecol Clin North Am 2008;35:645–658. Mir O, Berveiller P, Ropert S, et al: Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Ann Oncol 2008;19:607– 613. Patel SJ, Reede DL, Katz DS, et al: Imaging the pregnant patient for nonobstetric conditions: Algorithms and radiation dose considerations. Radiographics 2007;27:1705–1722. Stensheim H, Moller B, van Dijk T, Fossa SD: Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: A registry-based cohort study. J Clin Oncol 2009;27:45–51.
SUGGESTED READINGS Amant F, Van Calstseren K, Vergote I, Ottevanger N: Gynecologic oncology in pregnancy. Crit Rev Oncol Hematol 2007;67:187–195. Behtash N, Zarchi MK, Gilani MM, et al: Ovarian carcinoma associated with pregnancy: A clinicopathologic analysis of 23 cases and review of the literature. BMC Pregnancy Childbirth 2008;8:3.
REFERENCES For a complete list of references, log onto www.expertconsult.com.
C H A P T E R 5 3
Pregnancy after Transplantation V I N C E NT T. ARMENTI, MICHAEL J. MORITZ, and JOHN M. DAVIS O N
INTRODUCTION Transplantation is now an accepted therapeutic option for patients with end-stage organ failure. The first successful human kidney transplant took place in 1954.1 However, it was not until the 1960s that immunosuppression became available and not until the 1980s, with the introduction of cyclosporine, that consistently acceptable graft and patient survival was achieved. With the restoration of organ function, patients experience an overall improvement in their health, increased libido, and return of fertility. The first post-transplant pregnancy occurred in March 1958 and was reported in 1963.2 It occurred in a patient who had received a kidney from her identical twin.2 This pregnancy resulted in cesarean delivery of a healthy boy. As transplantation has progressed, with improvements in surgical techniques and medical therapy and advances in immunosuppression, pregnancies have been reported in recipients of each organ type. Most outcomes reported are in kidney transplant recipients. Issues that must be considered include maternal graft function and maternal health, the effect of pregnancy on graft function, and the effect of the medications and graft function on the developing fetus. There is also concern about the long-term effects of pregnancy on graft function. Finally, there is the question of whether more subtle and long-term effects, although not apparent at birth, might affect the growth and development of the offspring of these recipients or future generations.
ORGAN TRANSPLANTATION Patients with end-stage renal disease who are receiving or will soon need dialysis are candidates for renal transplantation. Common indications for renal transplantation are glomerulonephritis, diabetes, polycystic kidney disease, and hypertension. In 2008, in the United States, 16,514 kidney transplants were performed.3 The 1-year graft survival rate was 90% for deceased donor kidneys and 98% for living donor kidneys.4 Recent technical advances that allow laparoscopic removal of living donor kidneys have helped to make living donation more acceptable, removing disincentives.5 Standard requirements for donor-recipient pairs for kidney transplantation are ABO compatibility and a negative
pretransplant cross-match (i.e., absence of preformed antidonor antibodies). Efforts to increase the number of kidney transplants include the use of methods to use ABOincompatible donor treatment protocols to alter antidonor antibodies and exchange programs. Patients with type 1 diabetes and concomitant end-stage renal disease are candidates for simultaneous kidneypancreas transplantation. These patients may opt for a kidney transplant first, especially if they have a living donor, and later undergo a pancreas transplant. In 2008, there were 836 pancreas-kidney transplants performed in the United States,3 with a 1-year graft survival rate of 95% for simul taneous pancreas-kidney allografts.4 Patients with end-stage liver disease are candidates for liver transplantation. The first successful human liver transplant was performed in 1967.1 Of candidates for liver transplantation, 95% have chronic liver disease (i.e., cirrhosis) and 5% have fulminant hepatic failure, a disorder that progresses rapidly. Chronic diseases that require transplantation include cirrhosis as a result of hepatitis C, hepatitis B, alcohol use, biliary cirrhosis, and primary sclerosing cholangitis. In children, the most common cause of liver failure is biliary atresia. Complications of end-stage liver disease that suggest the need for transplantation include ascites, encephalopathy, and bleeding as a result of esophageal varices. In 2008, in the United States,3 6318 liver transplants were performed, with a 1-year graft survival rate of 88% for deceased donor liver transplantation.4 Living donation, in which part of an adult liver is donated, is now an option for both adult and pediatric recipients; 249 living related liver transplants were performed in the United States in 2008.3 Cardiomyopathy and coronary artery disease are the most common indications for heart transplantation. Peripartum cardiomyopathy is a rare indication for heart transplantation. On average, these adults are older than patients in other organ groups, which is likely part of the reason why fewer pregnancies have been reported. In the United States, 2163 heart transplants were performed in 2008,3 with a 1-year graft survival rate of 85%.4 Fewer heart-lung and liver-kidney transplants are performed, and few pregnancies have been reported in these recipients. Patients with end-stage lung disease and an anticipated survival of less than 2 years without transplantation 961
962 S ECTION F IVE • Late Prenatal
are candidates for lung transplantation. Three common indications are emphysema or chronic obstructive pulmonary disease, including α1-antitrypsin deficiency, primary pulmonary hypertension, and cystic fibrosis. The 1-year graft survival rate is lower than the groups discussed, at 76%,4 with 1478 transplants performed in the United States in 2008.3 Living donation has been an option, although none were performed in the United States in 2008 and the number has declined over the last several years. The majority of patients who receive an intestinal transplant (70%) have had the diagnosis of short gut syndrome. This type of transplant may be performed in conjunction with a liver in up to 71% of the cases.4 In 2008, 185 transplants were performed with a 1-year graft survival rate of 73%.3,4
RISKS OF TRANSPLANTATION Immunosuppressive Agents and Teratology Corticosteroids In animal studies, corticosteroids have caused cleft palate, although this has not been seen in humans.8 Clinically, these agents are associated with an increased risk of premature rupture of the membranes and adrenal insufficiency in newborns.9 Prednisone has been used for more than 45 years for maintenance therapy, and intravenous methylprednisolone is used for induction and treatment of rejection. At current doses, it is considered an adjunctive drug. More recently, given the many side effects, steroid withdrawal and steroid avoidance regimens have become common.
Azathioprine
SUCCESS OF TRANSPLANTATION Medication regimens to maintain graft survival and prevent rejection have been evolving since the 1960s. In general, these can be divided into the following three categories: ● Induction regimens are used in the first week after transplantation. These include agents such as antilymphocyte sera and interleukin-2–receptor blockade antibodies. ● Antirejection regimens are used to treat episodes of rejection. They typically include high-dose, short-term treatments with either corticosteroids or antilymphocyte sera. ● Maintenance regimens are initiated soon after transplantation to prevent acute rejection episodes and provide long-term immunosuppression. The goal of this treatment is to minimize acute rejection episodes and toxicity. Combination therapies are used to balance benefits against side effects and toxicities. A major goal of therapy is to avoid acute rejection episodes, which affect graft survival. Different organs show different effects of acute rejection, but the result can be chronic rejection, which has no effective treatment and ultimately leads to graft loss. Maintenance regimens in the early 1960s included azathioprine and prednisone. In the 1980s, the mainstay of immunosuppression was cyclosporine, either in combination with azathioprine and prednisone or with prednisone alone. Tacrolimus (Prograf), introduced in the 1990s, has a mechanism very similar to that of cyclosporine, but is more potent and with different side effects. Mycophenolate mofetil (CellCept, MMF) was introduced in the mid-1990s. A few years later, mycophenolic acid (Myfortic, MPA), an entericcoated capsule with less gastrointestinal side effects than MMF, was introduced. These agents have essentially replaced azathioprine and, in most cases, are used as an adjunct. Sirolimus was introduced in 2000 and has a different mechanism of action and the added advantage of not being nephrotoxic. In standard combination regimens, two drugs of the same class are not used together (e.g., cyclosporine and tacrolimus). Table 53–1 summarizes the current agents and their mechanisms of action and side effects, including agents used for induction and rejection.6 The U.S. Food and Drug Administration (FDA) categories for these drugs are shown in Table 53–2, including information on published reproductive or clinical outcome data.7
Azathioprine (1.5–3 mg/kg/day), a primary drug used for immunosuppression before the introduction of cyclosporine, is now an adjunctive agent at doses of 0.5 to 1.5 mg/kg/day. Clinical data do not support early concerns about teratogenicity in animal studies, nor has a predominant structural malformation pattern been identified. It is listed as a category D agent, and reviews show occasional attributable newborn problems, including thymic atrophy, leukopenia, anemia, thrombocytopenia, chromosomal aberrations, sepsis, and reduced immunoglobulin levels.10,11
Cyclosporine As the first calcineurin inhibitor, cyclosporine became the mainstay of immunosuppression and remains a commonly used agent. Cyclosporine was originally available as Sandimmune, which was later reformulated as Neoral. The two formulations are not bioequivalent and should not be interchanged. Generic versions are available. It is usually used with one or two adjunctive agents. Maternal problems include hypertension and nephrotoxicity. Although fetal toxicity and abnormality were reported in animal studies, these occurred at dosages higher than those used clinically.12,13 Some early clinical reports suggested a greater risk of fetal growth restriction, not borne out by later studies.14 The magnitude of teratogenic risk appears minimal, and no predominant pattern of newborn malformations is evident.
Tacrolimus (Prograf) Tacrolimus, approved for use in the United States in 1995, is more potent than cyclosporine. In animal studies, fetal resorption occurred at doses higher than those used clinically.15 Transient neonatal hyperkalemia has been reported,16 as has a higher incidence of maternal diabetes. Tacrolimus is usually used with an adjunctive agent.
Mycophenolate Mofetil/Mycophenolic Acid The mycophenolate drugs, first approved for use in 1995, are typically used in combination with a calcineurin inhibitor. In contrast to the calcineurin inhibitors, there is greater concern about the potential risk of teratogenicity with MMF/MPA, based on reproductive toxicity studies in animals. Developmental toxicity in rats and rabbits included malformations and intrauterine growth restriction. Death occurred at dosages that appeared to be within the recommended clinical dosages based on body surface area.17,18
C HAPTER 53 • Pregnancy after Transplantation 963 T A B L E 5 3 – 1
Immunosuppressive Drugs DRUG
USES
EFFECTS
SIDE EFFECTS
COMMENTS
Cyclosporine (Sandimmune, others), cyclosporine modified, USP (Neoral, Gengraf) Tacrolimus (Prograf)
Maintenance
Inhibitor of helper T-cell function
Nephrotoxicity, hypertension, tremor, hirsutism
Relatively selective for alloimmune responses; synergistic nephrotoxicity with tacrolimus
Maintenance
Corticosteroids (oral prednisone, IV methylprednisolone) Azathioprine
Maintenance, antirejection, induction Maintenance
Nephrotoxicity, neurotoxicity, diabetes Cushingoid facies, diabetes, excessive weight gain, aseptic necrosis of joints Leukopenia
Antithymocyte globulin, antilymphocyte globulin
Antirejection, induction
Inhibitor of helper T-cell function Inhibits all leukocytes; high doses cause lymphocytolysis Inhibits clonal proliferation of T cells Depletes T cells
Mycophenolate mofetil (CellCept) Mycophenolic acid (Myfortic)
Maintenance
Diarrhea, leukopenia
Sirolimus (Rapamune)
Maintenance
Inhibits lymphocyte proliferation Inhibits lymphocyte proliferation Inhibits helper T cells
Basiliximab (Simulect)
Induction
Daclizumab (Zenapax)
Induction
Muromonab-CD3 (OKT3)
Antirejection, induction
Maintenance
Many troublesome side effects; nonspecific immunosuppressant Nonspecific
Fevers, chills
Polyclonal serum made in rabbits, horses; Maximum duration of therapy 2 wk More lymphocyte-selective than azathioprine More lymphocyte-selective than azathioprine Site of action distinct from other drugs Immunosuppressive chimeric monoclonal antibody
Leukopenia
Inhibits interleukin2–mediated activation of lymphocytes Inhibits interleukin2–mediated activation of lymphocytes Disables or depletes all T cells
Anemia, thrombocytopenia, hyperlipidemia Possible anaphylactoid reaction
Chimeric humanized monoclonal antibody First dose can cause fever, chills, or bronchospasm as a result of cytokine release
Murine monoclonal, maximum duration of therapy 2 wk
USP, U.S. Pharmacopeia. Adapted from Moritz MJ, Armenti VT: Organ transplantation. In Jarrell BE, Carabasi RA (eds): National Medical Series for Independent Study: Surgery. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 461–477.
T A B L E 5 3 – 2
Immunosuppressive Drugs Commonly Used in Transplantation DRUG Corticosteroids (prednisone, prednisolone, methylprednisolone) Azathioprine Cyclosporine Cyclosporine modified, USP Tacrolimus Mycophenolate mofetil Mycophenolic acid Antithymocyte globulin (Atgam, ATG) Antithymocyte globulin (Thymoglobulin) Sirolimus Basiliximab Daclizumab Muromonab-CD3 (OKT3)
USUAL ORAL DOSAGE 5–20 mg/day
500–1000 mg/day IV (antirejection) 0.5–1.5 mg/kg/day 3–10 mg/kg/day 3–10 mg/kg/day 0.05–0.2 mg/kg/day 2–3 g/day 1440 mg/day 15–30 mg/kg/day IV 1.0–1.5 mg/kg/day IV 2–5 mg/day 20 mg/day IV 1 mg/kg/day IV 0.5–10 mg/day IV
ANIMAL REPRODUCTIVE DATA
PUBLISHED PREGNANCY CLINICAL OUTCOMES?
FDA PREGNANCY CATEGORY
Yes
Yes*
B
Yes Yes Yes Yes Yes Yes No No
Yes* Yes* Yes* Yes* Yes* Yes*† No Yes*†
B D C C C D D C
No
No*
C
Yes Yes No No
Yes* No No Yes*†
C B C C
* Registry data. † Case reports only. B, no evidence of risk in humans; C, risk cannot be excluded; D, positive evidence of risk; FDA, U.S. Food and Drug Administration; USP, U.S. Pharmacopeia. Adapted from Armenti VT, Moritz MJ, Davison JM: Drug safety issues in pregnancy following transplantation and immunosuppression. Drug Saf 1998;19:219–232.
964 S ECTION F IVE • Late Prenatal
Maternal Risks
T A B L E 5 3 – 3
Structural Birth Defects in Transplant Recipient Offspring with Exposure to Mycophenolate Mofetil during Pregnancy Reported to the National Transplantation Pregnancy Registry
Recipients (N) Pregnancies (N) Live births (N) Liveborn with birth defects (N) Incidence of birth defects (%)
KIDNEY
LIVER
PANCREASKIDNEY
HEART
34 44 27 5*
7 10 5 1*
3 6 1 0
7 11 5 2
19
20
0
40
* Includes one neonatal death. From Coscia LA, Constantinescu S, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. In Cecka JM, Terasaki PI (eds): Clinical Transplants 2008. Los Angeles, UCLA Terasaki Foundation Laboratory, 2009, pp 89–105.
Clinical data have demonstrated a particular pattern of malformation noted in the National Transplantation Pregnancy Registry (NTPR) database, with additional reports of problems in newborns with exposure to MMF.19–31 In 2007, the package inserts of MMF and MPA included a change from pregnancy category C to category D.17,18 These package inserts state that females of childbearing potential must use contraception while taking MMF or MPA, because use during pregnancy is associated with increased rates of pregnancy loss and congenital malformations. This is also the recommendation of the European Best Practice Guidelines.32 In addition to the NTPR data, in postmarketing data collected by Roche Laboratories, Inc., between 1995 and 2007, among the 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of these 14 had ear abnormalities. Table 53–3 lists the structural birth defects in transplant recipient offspring with exposure to MMF during pregnancy.33 Women using MMF or MPA at any time during pregnancy are encouraged to enroll in the NTPR.
Sirolimus Sirolimus, approved for use in the United States in 1999, is an antiproliferative agent of its own class. It is used in combination with cyclosporine or tacrolimus or with prednisone alone (European and U.S. labeling). There are concerns about its use in pregnancy. Teratogenicity has not been noted in animal studies, although decreased fetal weight and delayed ossification have been reported.34 When it was used with cyclosporine in pregnant animals, resorption and fetal mortality rates were increased, suggesting increased toxicity; however, there are insufficient data on clinical outcome.19,35–37 Data remain limited with regard to sirolimus exposure during pregnancy. Other agents used for short-term induction or rejection have a minor role in pregnancy. In a small series of patients, muromonab-CD3 (OKT3)7 and corticosteroids were used for rejection in pregnancy (discussed later).
Transplant recipients have varying degrees of post-transplant recovery. One difficulty in assessing pregnancy risk in this population overall is that many of the conclusions have been derived only from experience in kidney transplant recipients. In 1976, a management plan was suggested in a detailed case report of a renal transplant recipient during pregnancy.38 Based on this information and a survey of literature at the time, the following criteria were derived for counseling renal recipients who are contemplating pregnancy: ● Good general health for at least 2 years after the transplant. ● Stature compatible with good obstetric outcome. ● No proteinuria. ● No significant hypertension. ● No evidence of renal rejection. ● No evidence of renal obstruction on excretory urogram or ultrasound. ● Stable renal function. ● Stable immunosuppressive therapy. Most of these guidelines still apply, although recipients can safely become pregnant sooner than 2 years post-transplant.39 Drug-treated hypertension is now much more prevalent.40 It has been more difficult to identify criteria for recipients of other organs, but good, stable graft function would seem to be essential for pregnancy to be well tolerated. The appropriate interval after transplant and the features of good, stable graft function for each group of organ recipients are harder to define. For renal recipients, graft function can be assessed by measuring the serum creatinine level or creatinine clearance. Studies in both clinical and animal models in the nontransplant population have assessed the effect of pregnancy on renal function. Renal function is unaffected if the kidney is stable.41 In the transplant population, this finding is supported by well-designed case-control studies showing that pregnancy does not cause deterioration of graft function when prepregnancy graft function is stable.42–46 Factors that must be considered in nonrenal recipients are the nephrotoxic effect of calcineurin inhibitors on native kidney function and the increased likelihood of hypertension. Thus, nonrenal recipients who receive calcineurin inhibitor therapy often have baseline renal impairment. These guidelines have been revised and published as Consensus Guidelines through the American Society of Transplantation (AST).39 The European Best Practice Guidelines32 are also available for clinicians. Literature surveys from the azathioprine era of the 1970s and 1980s attest to thousands of successful post-transplant pregnancies in renal transplant recipients. The spontaneous abortion rate was approximately 14%, and the therapeutic abortion rate was approximately 20%. Of pregnancies that continued beyond the first trimester, more than 90% were successful. Renal impairment occurred in approximately 15% of women, and hypertension complicated approximately 30% of pregnancies. Preterm delivery was common, affecting 45% to 60% of pregnancies, with fetal growth restriction occurring in approximately 20%.47,48 Initial reports of cyclosporine exposure during pregnancy raised concern because a higher rate of fetal growth restriction, which may have been related to higher doses, was
C HAPTER 53 • Pregnancy after Transplantation 965 T A B L E 5 3 – 4
Prepregnancy Renal Function in Renal Transplant Recipients with Estimates for Pregnancy Outcome (>24 weeks) and Impact on Maternal Renal Function LOSS OF >25% RENAL FUNCTION SCR mMOL/L (MG/DL) 1.85)
FETAL GROWTH RESTRICTION (%)
PRETERM DELIVERY (%)
PREECLAMPSIA (%)
PERINATAL DEATHS (%)
PREGNANCY (%)
PERSISTS POSTPARTUM (%)
ESRF IN 1 YR (%)
30
35
24
3
15
4
—
50 60
70 90
45 60
7 12
20 45
7 35
10 70
ESRF, end-stage renal failure; SCr, serum creatinine. Estimates based on literature from 1991 to 2007, with all pregnancies attaining at least 24 wk’ gestation (unpublished data from Dr. John Davison).
noted.14 Also apparent was a higher incidence of hypertension than was previously noted in the azathioprine era.40 With the advent of cyclosporine, it was suggested that this drug might not be optimal for use in pregnancy and that patients should be switched back to azathioprine-based regimens because of the longer experience with these drugs. Given the need to provide more consistent and effective surveillance for the transplant community, the NTPR was established in 1991 with the goal of maintaining an ongoing database to assess the safety of pregnancy in female transplant recipients as well as pregnancies fathered by male transplant recipients.33,49 A pregnancy registry was established in the United Kingdom in 199750 but discontinued in 2002, although there has been an updated publication reporting the pregnancy outcomes in the United Kingdom.51 This report depicts outcomes similar to those of the NTPR. After the introduction of cyclosporine, case and indi vidual transplant center reports and registry data reported successful pregnancies in female transplant recipients while highlighting potential risks to mothers and newborns. Most conclusions came from data on renal recipients, but information is accruing from other organ recipients, with differences evident among the groups. Overall, compared with the general population, female transplant recipients are at greater risk for preeclampsia and hypertension during pregnancy. A higher percentage of cesarean deliveries are reported as well. The balance between graft function and management of immunosuppression during pregnancy is crucial. Fortunately, in organ recipients, the incidence of rejection during pregnancy does not appear to be higher than that in the nonpregnant population, and similarly, graft loss within 2 years of delivery does not appear to be affected by pregnancy. When irreversible and unpredictable graft events occur, they more often happen in patients with impaired prepregnancy graft function. Many recipients have had successful successive pregnancies, and some have had successful outcomes with multiple gestations and in vitro fertilization.52–55 An overview of the literature in renal transplant recipients is summarized in Table 53–4. Current data for each organ recipient group reported to the NTPR are summarized in Tables 53–5 to 53–9.33 High incidences of preterm delivery and low birth weight are reported and are more apparent among pancreas-kidney recipients and less apparent in liver and heart recipients. Pancreas-kidney recipients usually tolerate pregnancy without gestational diabetes. Most infectious complications
T A B L E 5 3 – 5
Pregnancies in Female Transplant Recipients Reported to the National Transplantation Pregnancy Registry as of January 2009 ORGAN Kidney Liver Liver-kidney Pancreas-kidney Pancreas alone Heart Heart-lung Lung Totals
RECIPIENTS
PREGNANCIES
OUTCOMES*
834 143 4 43 1 48 4 17 1094
1301 247 6 76 4 82 4 23 1743
1339 251 7 78 5 83 4 25 1792
* Includes twins and triplets.
involve the urinary tract. Rejection during pregnancy is associated with poorer outcomes for the newborn and for graft survival (Tables 53–10 and 53–11). Rejection should be biopsy-proven, if possible; treatment is with steroids, antilymphocyte sera, or adjustment of baseline immunosuppression.
Fetal Risks Two large reports on the two primary calcineurin inhibitors, cyclosporine and tacrolimus, examined the overall prevalence of malformations in newborns. In the offspring of cyclosporine-treated recipients, the malformation rate was 4.1% (14 of 339 births), based on a meta-analysis.56 NTPR data on the offspring of cyclosporine-treated liver or kidney recipients showed malformations in 3% to 5% of a total of 425 liveborn infants.57 The types of malformations varied among different systems, with no predominant type noted. In a report of patients treated with tacrolimus during pregnancy (84 women, 100 pregnancies), 4 of 71 liveborn infants analyzed (5.6%) had evidence of structural malformations, but no specific pattern was evident.58 Transplant recipients, on average, delivered 1 month early, with birth weights of 2160 to 2600 g reported. Differences were seen among organ recipient groups. Genetic considerations must be taken into account. They may contribute to organ failure in
966 S ECTION F IVE • Late Prenatal T A B L E 5 3 – 6
T A B L E 5 3 – 7
National Transplantation Pregnancy Registry: Pregnancy Outcomes in Female Kidney Transplant Recipients with Cyclosporine, Neoral, and Prograf Exposure during Pregnancy
National Transplantation Pregnancy Registry: Pregnancy Outcomes in 138 Liver Transplant Recipients with 241 Pregnancies and 245 Outcomes
CSA
NEORAL
PROGRAF
(512)
(190)
(152)
3.5 ± 2.8
5.8 ± 3.9
4.0 ± 2.6
62
66
54
12
2
10
23
20
24
1
2
2
Maternal Factors (N = pregnancies) Transplant to conception interval (yr; mean) Hypertension during pregnancy (%) Diabetes during pregnancy (%) Infection during pregnancy (%) Rejection episode during pregnancy (%)* Preeclampsia (%) Mean serum creatinine (mg/dL) Before pregnancy
29
28
31
1.4 ± 0.5
1.3 ± 0.4
1.2 ± 0.4
During pregnancy
1.4 ± 0.7
1.4 ± 0.5
1.3 ± 1.0
After pregnancy
1.6 ± 0.97
1.4 ± 0.6
1.4 ± 0.9
Graft loss within 2 yr of delivery (%)
11
7
9
Outcomes (N)† Therapeutic abortions (%) Spontaneous abortions (%) Ectopic (%) Stillborn (%) Live births (%)
(524) 8
(199) 1
(155) 0.7
12
18
21
0.6 3 76
0.5 1.5 79
0.7 2 75
Live Births (N) Mean gestational age (wk) Premature (