Textbook of Periconceptional Medicine (Reproductive Medicine and Assisted Reproductive Techniques)

Periconceptional Medicine CONTENTS: PRECONCEPTION: Genetics and Conception • Lifestyle and Conception • Preconceptional...

Author: Macklon N. (ed.) | Greer I. (ed.) | Steegers E. (ed.)

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Periconceptional Medicine

CONTENTS: PRECONCEPTION: Genetics and Conception • Lifestyle and Conception • Preconceptional Counselling

ACHIEVING PREGNANCY: How to Conceive: Evidence Based Fertility Investigation • The Anovulatory Patient • The Patient with Endometriosis • The Patient with Poor Sperm Quality • The Patient with Tubal Disease • The Couple with Unexplained Infertility * The Patient from the Developing World • The Older Woman Wishing to Conceive • Psychological Aspects of Fertility Therapy • The Luteal Phase • Implantation Failure MANAGEMENT OF EARLY PREGNANCY: Early Placental Development • The Immunology of Early Pregnancy • Mechanisms and Nomenclature of Early Pregnancy Loss • Antiphospholipid Syndrome, Heritable Thrombophilia and Early Pregnancy Loss • Ultrasound in Early Pregnancy • Evidence Based Investigation and Management of Miscarriage • Ectopic Pregnancy after Fertility Treatment • Molar Pregnancy • Multiple Pregnancy • Cervical Cerclage and Pregnancy Loss • Are Pregnancies Conceived by IVF ‘High Risk’?

Nick S Macklon, MD, FRCOG, is Professor of Infertility and Periconceptional Medicine and Head of Reproductive Medicine and Gynaecology at the University Medical Center, Utrecht, The Netherlands: his previous publications include IVF in the Medically Complicated Patient (Informa 2005). Ian A Greer, MD, FRCP(Glas), FRCPE, FRCP, FRCPI, FRCOG, FFFP, FMedSci, is Professor of Obstetric

Medicine and Dean, Hull York Medical School, UK: his most recent publications include Maternal Medicine (Mosby 2008), Fertility and Conception (Collins 2007), Women’s Vascular Health (Arnold 2007), Practical Obstetric Hematology (Informa 2006), and Prevention of Preterm Labor (Cambridge University Press 2005).

Eric AP Steegers, MD, is Professor, Obstetrics and Prenatal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands: his previous publications include Preventive Care in Obstetrics (Baillière Tindall 1995).

Cover design and image by Oxmed

www.informahealthcare.com


PREPARING THE HIGH-RISK PATIENT: The Patient with Renal Disease • The Patient with an Organ Transplant • The Patient with Hypertension • The Patient with Cardiac Disease • The Patient with Thyroid Disease • The Patient with Diabetes • The Patient with Epilepsy • The Patient at risk from Thrombosis and Bleeding Disorders • The Patient with Polycystic Ovary Syndrome • The Patient with HIV • The Patient with Cystic Fibrosis • The Patient with Inflammatory Bowel Disease • The Patient with Prolactinoma • The Patient at Risk with Severe Mental Illness • The Patient with Myotonic Dystrophy

Textbook of

It is inceasingly recognized that the outcome of pregnancy is largely determined during the periconceptional period. Both Perinatologists and Reproductive Endocrinologists treating couples with infertility have an important role in ensuring optimal management of this crucial, and sometimes complex, phase. At the interface between reproductive medicine, perinatology, internal medicine and genetics, the new field of Periconceptional Medicine is now emerging. This major new textbook from respected international experts provides the first major and definitive collection of work in this area, and will be of value to all those working with or advising patients planning a pregnancy.

Macklon • Greer • Steegers

Textbook of

Textbook of


Edited by

Nick S Macklon Ian A Greer • Eric AP Steegers

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Textbook of Periconceptional Medicine

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Reproductive Medicine and Assisted Reproductive Techniques Series Series editors David Gardner, University of Melbourne, Australia Jan Gerris, University Hospital Ghent, Belgium Zeev Shoham, Kaplan Hospital, Rehovot, Israel Titles 1 Jan Gerris, Annick Delvigne, François Olivennes Ovarian Hyperstimulation Syndrome, ISBN: 9781842143285 2 Alastair G Sutcliffe Health and Welfare of ART Children, ISBN 9780415379304 3 Seang Lin Tan, Ri-Chen Chian, William Buckett In-vitro Maturation of Human Oocytes, ISBN: 9781842143322 4 Christoph Keck, Clemens Tempfer, Jen-Noel Hugues Conservative Infertility Management, ISBN: 9780415384513 5 Carlos Simon, Antonio Pellicer Stem Cells in Human Reproduction, ISBN: 9780415397773 6 Kay Elder, Jacques Cohen Human Preimplantation Embryo Selection, ISBN: 9780415399739 7 Michael Tucker, Juergen Liebermann Vitrification in Assisted Reproduction, ISBN: 9780415408820 8 John D Aplin, Asgerally T Fazleabas, Stanley R Glasser, Linda C Giudice The Endometrium, Second Edition, ISBN: 9780415385831 9 Adam H Balen Infertility in Practice, Third Edition, ISBN: 9780415450676 10 Nick Macklon, Ian Greer, Eric Steegers Textbook of Periconceptional Medicine, ISBN: 9780415458924 Forthcoming 11 Carlos Simon, Antonio Pellicer Stem Cells in Human Reproduction, Second Edition, ISBN: 9780415471718 12 Andrea Borini, Giovanni Coticchio Preservation of Human Oocytes, ISBN 9780415476799

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Textbook of Periconceptional Medicine Edited by Nick S Macklon Department of Reproductive Medicine and Gynaecology University Medical Center Utrecht, The Netherlands Ian A Greer Department of Obstetrics and Gynaecology Hull York Medical School UK and Eric AP Steegers Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands

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© 2009 Informa UK Ltd First published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN-13: 978–0–415–45892–4 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Book orders in the rest of the world Paul Abrahams Tel: +44 (0)20 7017 4036 Email: [email protected] Composition by C&M Digitals (P) Ltd., Chennai, India Printed and bound in the United States of America

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Contents

List of contributors Preface

vii xi

SECTION A: PRECONCEPTION 1 2 3

The genetics of conception JPM Geraedts Lifestyle and conception S Temel, JS Laven, and RPM Steegers-Theunissen Preconception care K Boer, RPM Steegers-Theunissen, and EAP Steegers

1 13 23

SECTION B: PREPARING THE HIGH RISK PATIENT 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

The patient with renal disease RJA Sims and M Ramsay The patient with organ transplantation S Winfield and JM Davison The patient with hypertension C Nelson-Piercy The patient with cardiac disease Y Karamermer and JW Roos-Hesselink The patient with thyroid disease W Visser The patient with diabetes mellitus JJN Oats The patient with epilepsy J Craig The patient at risk from thrombosis and bleeding disorders SM Nelson and IA Greer The patient with polycystic ovary syndrome RJ Norman and S Lim The patient with HIV K Boer and MH Godfried The patient with cystic fibrosis GCML Page-Christiaens and F Teding van Berkhout The patient with inflammatory bowel disease S Kane and R Kowalczyk The patient with prolactinoma ME Molitch Periconceptional issues in neuromuscular disorders W Verpoest and M De Vos The patient with, or at risk of, severe mental illness R Cantwell

41 57 69 77 89 99 107 121 137 143 159 173 179 191 199

SECTION C: ACHIEVING PREGNANCY 19

How to conceive: evidence-based fertility investigation BW Mol, JW van der Steeg, HR Verhoeve, and F van der Veen

205

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Contents

Achieving pregnancy in the anovulatory woman RS Legro and A Dokras The patient with endometriosis: achieving pregnancy A Vodolazkaia and TM D’Hooghe The patient with poor sperm quality BJ Cohlen and H Tournaye The patient with tubal disease A Strandell The couple with unexplained infertility GI Serour and M Aboulghar The patient from the developing world W Ombelet and G Nargund The older woman wishing to conceive CB Lambalk and FJ Broekmans Psychological issues in periconceptional care L Bunting and J Boivin The luteal phase HM Fatemi, B Fauser, P Devroey, and NS Macklon Implantation failure JA Garcia-Velasco and E Sánchez

215 223 233 241 251 261 273 287 297 309

SECTION D: MANAGEMENT OF EARLY PREGNANCY 30 31 32 33 34 35 36 37 38 39 40

Early placental development and pregnancy outcome GJ Burton and E Jauniaux The immunology of early pregnancy S Scherjon Nomenclature and mechanisms of early pregnancy loss R Farquharson and N Exalto Antiphospholipid syndrome, heritable thrombophilia and early pregnancy loss B Brenner, A Aharon, and G Sarig Ultrasound in early pregnancy S Suri, J Johns, and E Jauniaux Evidence-based investigations and treatments of recurrent miscarriage OB Christiansen Ectopic pregnancy after fertility treatment B Refaat, M Al-Azemi, and W Ledger Molar pregnancy: pathology and management RS Berkowitz and DP Goldstein Multiple pregnancy DLH Moore, NM Fisk, and J Hyett Cervical cerclage and pregnancy loss M Chandiramani and AH Shennan Are pregnancies conceived by IVF ‘high risk’? CE Fox and MD Kilby

Index

317 329 341 349 357 367 379 393 405 419 433

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List of contributors

M Aboulghar Egyptian IVF-ET Center Cairo, Egypt A Aharon Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel M Al-Azemi Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK RS Berkowitz Dept of Obstetrics, Gynecology, and Reproductive Medicine Division of Gynecologic Oncology Brigham & Women’s Hospital Harvard Medical School Boston, MA, USA K Boer Department of Obstetrics and Gynecology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands J Boivin School of Psychiatry Cardiff University Cardiff, UK B Brenner Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel FJ Broekmans Department of Reproductive Medicine & Gynecology Division of Perinatology & Gynecology University Medical Center Utrecht, The Netherlands L Bunting School of Psychiatry Cardiff University Cardiff, UK

GJ Burton Centre for Trophoblast Research University of Cambridge Cambridge, UK R Cantwell Perinatal Mental Health Service Glasgow, UK M Chandiramani Maternal and Fetal Research Unit King’s College London Division of Reproduction and Endocrinology London, UK OB Christiansen Fertility Clinic Rigshospitalet Copenhagen, Denmark BJ Cohlen Division of Reproductive Medicine Department of Obsterics and Gynaecology Isala Clinics Zwolle Zwolle, The Netherlands J Craig Department of Neurology Royal Group of Hospitals Belfast, UK JM Davison Department of Obstetrics and Gynaecology Royal Victoria Hospital Queen Victoria Road Newcastle-upon-Tyne, UK M De Vos Centre for Reproductive Medicine Universitair Ziekenhuis Brussel Vrije Universiteit Brussel Brussels, Belgium P Devroey Centrum voor Reproductieve Geneeskunde Universitaire Ziekenhuis Brussel Brussel, Belgium TM D’Hooghe Leuven University Fertility Center Department of Obstetrics and Gynecology UZ Gasthuisberg Leuven, Belgium

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A Dokras Department of Obstetrics and Gynecology University of Pennsylvania Philadelphia, PA, USA N Exalto Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands R Farquharson Liverpool Women’s Hospital Liverpool, UK HM Fatemi Centrum voor Reproductieve Geneeskunde Universitaire Ziekenhuis Brussel Brussel, Belgium BC Fauser Department of Reproductive Medicine & Gynecology Division of Perinatology & Gynecology University Medical Center Utrecht, The Netherlands N Fisk University of Queensland Centre for Clinical Research Brisbane, Queensland, Australia CE Fox Department of Obstetrics and Gynaecology Birmingham Women’s Hospital University of Birmingham Birmingham, UK JA Garcia-Velasco IVI-Madrid Rey Juan Carlos University Madrid, Spain JPM Geraedts Genetics and Cell Biology Academic Hospital Maastricht Universiteit Maastricht Maastricht, The Netherlands MH Godfried Department of Internal Medicine Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

DP Goldstein Dept of Obstetrics, Gynecology, and Reproductive Medicine Division of Gynecologic Oncology Brigham & Women’s Hospital Harvard Medical School Boston, MA, USA IA Greer Department of Obstetrics and Gynaecology Hull York Medical School UK J Hyett Department of Obstetrics and Gynaecology Royal Prince Alfred Hospital University of Sydney Sydney, New South Wales, Australia E Jauniaux Academic Department of Obstetrics and Gynaecology Royal Free Hospital and University College Hospital London, UK J Johns Academic Department of Obstetrics and Gynaecology University College London London, UK S Kane Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Y Karamermer Department of Cardiology Thoraxcenter Erasmus Medical Center University Medical Center Rotterdam, The Netherlands M Kilby Maternal and Fetal Medicine College of Medicine and Dentistry University of Birmingham Birmingham Women’s Hospital Birmingham, UK R Kowalczyk Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

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CB Lambalk Department of Reproductive Medcine Vrije Universiteit Medical Center Amsterdam, The Netherlands W Ledger Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK RS Legro Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, PA, USA S Lim Research Centre for Reproductive Health School of Paediatrics and Reproductive Health Discipline of Obstetrics and Gynaecology, University of Adelaide and CSIRO Human Nutrition, Adelaide, Australia NS Macklon Department of Reproductive Medicine and Gynaecology University Medical Center Utrecht, The Netherlands BW Mol Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands ME Molitch Division of Endocrinology, Metabolism & Molecular Medicine Chicago, IL, USA DLH Moore Department of Obstetrics and Gynaecology Royal Brisbane & Women’s Hospital Herston, Queensland, Australia G Nargund Department of Obstetrics & Gynecology St George’s Hospital Medical School London, UK SM Nelson Reproductive and Maternal Medicine University of Glasgow Glasgow Royal Infirmary Glasgow, UK

ix

C Nelson-Piercy Guy’s & St Thomas’ NHS Foundation Trust and Queen Charlotte’s Hospital, Imperial College Healthcare NHS Trust London, UK RJ Norman Research Centre for Reproductive Health School of Paediatrics and Reproductive Health Discipline of Obstetrics and Gynaecology, University of Adelaide and CSIRO Human Nutrition, Adelaide, Australia JJN Oats Clinical Director Women's Services The Royal Women's Hospital Carlton, Victoria, Australia W Ombelet Genk Institute for Fertility Technology Department of Obstetrics & Gynecology Ziekenhuis Oost-Limburg Genk, Belgium GCML Page-Christiaens Maternal-Fetal Department University Medical Center Utrecht, The Netherlands M Ramsay Queen’s Medical Centre Campus Nottingham University Hospitals Nottingham, UK B Refaat Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK J Roos-Hesselink Department of Cardiology Thoraxcenter Erasmus Medical Center University Medical Center Rotterdam, The Netherlands E Sánchez IVI-Madrid, Rey Juan Carlos University Madrid, Spain

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G Sarig Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel S Scherjon Department of Obstetrics and Gynecology Leiden University Medical Center Leiden, The Netherlands GI Serour Al-Azhar University Cairo, Egypt AH Shennan Maternal and Fetal Research Unit King’s College London Division of Reproduction and Endocrinology London, UK RJA Sims Queen’s Medical Centre Campus Nottingham University Hospitals Nottingham, UK JW van der Steeg Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands EAP Steegers Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands RPM Steegers-Theunissen Depts of Obstetrics & Gynaecology, Epidemiology & Biostatistics, Paediatrics / Division of Paediatric Cardiology and Clinical Genetics, Erasmus Medical Center University Medical Center Rotterdam, The Netherlands A Strandell Reproductive Medicine Department of Obstetrics and Gynecology Sahlgrenska University Hospital Göteborg, Sweden

S Suri Academic Department of Obstetrics and Gynaecology University College London London, UK F Teding van Berkhout Department of Heart and Lungs University Medical Center Utrecht, The Netherlands H Tournaye Center for Reproductive Medicine AZ-Vrije Universiteit Brussels Brussels, Belgium F van der Veen Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands HR Verhoeve Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands W Verpoest Centre for Reproductive Medicine Academisck Ziekenhuis Vrije Universiteit Brussel Brussels, Belgium W Visser Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands A Vodolazkaia Leuven University Fertility Center Department of Obstetrics and Gynecology UZ Gasthuisberg Leuven, Belgium S Winfield Department of Obstetrics and Gynaecology James Cook University Hospital Middlesbrough, UK

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Preface

The introduction of in vitro fertilization into fertility practice revolutionized the field of Reproductive Medicine, invigorating its emergence as a new subspecialty distinct from, but associated with, Obstetrics or Gynaecology. Over the past 20 years we have observed increasing divergence of these subspecialties. However, increasing recognition that periconceptional events determine not only fertility, but also pregnancy outcome and the long term health of mother and offspring, is causing a reverse in this trend. As perinatologists acknowledge that the outcome of pregnancy is largely determined during the periconceptional period, their focus is increasingly turning to optimizing early pregnancy and preconceptional health. At the same time, the improved prognosis associated with illnesses such as cystic fibrosis mean that many chronically ill women are now achieving reproductive age and wishing to have children. In addition, the increasing age of women presenting for fertility treatment is placing new demands on reproductive endocrinologists to ensure safe and effective treatment of the subfertile couple and the establishment of a healthy pregnancy. Reproductive endocrinologists are

now taking responsibility for optimizing preconceptional conditions in their patients and are working closely with perinatologists and other disciplines to ensure that optimal pregnancy outcomes are achieved. At this interface between Reproductive Medicine, Perinatology, Internal Medicine and Genetics, the new field of Periconceptional Medicine is emerging. As three clinicians approaching this area from the different perspectives of Reproductive Medicine and Perinatology, we recognized the need for a single integrated and authoritative textbook to provide a theoretical and clinical basis to this new field of medicine. In drawing together the different strands of knowledge into a single text, we have been fortunate to engage the services of diverse leading authorities from around the world. We hope that the result of their efforts will provide a sound theoretical basis for those practising in this new and exciting field of Periconceptional Medicine. Nick Macklon Ian Greer Eric Steegers

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1 The genetics of conception Joep Geraedts

Introduction

Meiosis

Genetic variability and epigenetic factors affect reproduction and fertility from one generation to the next. This starts with sex determination and the onset of gametogenesis and finishes at the end of the reproductive period. From each generation to the next, the haploid complement of the human genome is transmitted. The diploid complement contains 23 pairs of chromosomes, each containing hundreds or thousands of genes. The estimated 25 000 genes each make on average several proteins. The nuclear genome involves three billion base pairs which are subject to countless variations that may affect health and disease. Furthermore, there is a small mitochondrial genome. Sexual reproduction and genetics are firmly connected. Sex determination, which takes place during embryogenesis, is determined by the chromosomal sex. Sexual reproduction is characterised by the formation of haploid gametes which combine at fertilisation to give rise to a new diploid individual. The gametes are all genetically unique. During meiosis new combinations of the genetic characteristics are formed, which are present on the homologous chromosomes.

Meiosis consists of two sequential divisions: meiosis I and II. The first is a real reduction division: the diploid number is halved. The second division resembles mitosis since the two chromatids of each chromosome are separated. The first meiotic division is divided into several phases. During the prophase the homologous chromosomes start to pair and to become thicker and shorter. At the pachytene phase there is an exchange of homologous material between the chromatids. This process is directly visible down the microscope as chiasmata formation and genetically as crossing-over between linked genes or genetic markers. It eventually results in recombination. Furthermore, new combinations arise from segregation of maternal and paternal chromosomes.

Gametogenesis Before the onset of meiosis a number of successive mitotic divisions leads to the production of sufficient cells to enter meiosis. This process is completely different in both sexes. Before the onset of spermatogenesis in the male, at least 30 cell divisions have taken place between the embryonic age and puberty. The spermatogonia that are formed are stem cells that will continuously divide during the entire life of the adult male. Approximately 23 divisions take place each year. This means that at the age of 28 years already 335 cell divisions and at the age of 35 almost 500 have occurred before these cells enter meiosis. In the female all mitotic divisions take place in the foetal ovary. Already at the end of the first trimester some 8 million primary oocytes are present, which enter meiosis simultaneously.

Inheritance patterns The behaviour of the chromosomes and the genes during meiosis is most easily studied in pedigrees of inherited diseases. These may be caused at the level of the gene and the chromosome. In principle single gene mutations can lead to genetic diseases which can be distinguished on the basis of five simple modes of inheritance: autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant and Ylinked. In practice, only the first three are clinically relevant. At the chromosome level a distinction can be made between numerical and structural chromosomal abnormalities. The first usually result from meiotic non-disjunction and are sporadic in the vast majority of cases. Chromosomal rearrangements are carried by a parent and can lead to the production of genetically unbalanced gametes. Besides these modes of nuclear inheritance, there is also mitochondrial inheritance which shows completely maternal inheritance. In recent literature, the term “complex” disorders is preferred for all genetic conditions that are not strictly Mendelian or chromosomal in nature. Complex disorders might result from two or more genes (polygenic inheritance) as well as from more than one gene in combination with environmental factors. Disorders such as diabetes and schizophrenia are caused by the

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interaction of many different genes together with environmental influences. The latter situation is sometimes called multifactorial inheritance.

(a)

Gene mutations and polymorphisms Mutation simply means change. Change in gene function can be brought about by loss of the whole or part of the coding sequence of the gene (deletion) or by alteration in the bases that make up the DNA molecule (substitution). More rarely, gene duplication can cause disease. Surrounding each gene are modifying sequences that affect gene expression; these too can mutate. Mutations also affect non-coding DNA sequences, usually regions of repetitive DNA that are associated with each gene. Mutations in these regions are unlikely to be disease causing. Several forms of these variants may exist in the population and if they are common enough to be found in at least 1% of people they are known as polymorphisms. Polymorphisms are very useful as genetic markers since a particular variant will tend to be inherited along with the gene mutation in each family.1

(b)

(c)

Mendelian inheritance of monogenic disorders The relevant genes may be carried either on the X chromosome or on the non-sex chromosomes (the autosomes). Autosomal conditions are either dominant or recessive. At the outset it is important to remember that chromosomes exist in pairs, one from each parent, which in turn means that a gene for a particular character is also present twice in each cell. The exception is the pair of sex chromosomes. In females one of both X chromosomes is inherited from each parent. The X chromosome in males, which comes from the mother, has no counterpart. The Y chromosome, which is inherited from the father, is much smaller and carries few expressed genes, which are different from those on the X chromosome. It carries genes which are important for sex determination and fertility. The loss of part of this chromosome or of the function of one or more of these genes is therefore harmful. During the formation of the gametes recombination takes place between paired chromosomes after which both parental chromosomes segregate. This means that half of the genome becomes incorporated in the oocyte or sperm. At fertilisation new combinations of maternal and paternal chromosomes will always be formed. Examples of pedigrees with these typical patterns of inheritance are shown in Figure 1.1. An autosomal recessive mode of inheritance is suggested when there are affected children in a family with no known history of the disease. This happens when a gene carrier “marries” into the family. In dominant conditions affected children can be seen in every generation since the parent has a one in two chance of passing on the condition

Key Male

Female

Carrier

Affected

Fig 1.1 Modes of inheritance. (a) Autosomal recessive. (b) Autosomal dominant. (c) X-linked recessive.

irrespective of the genetic status of his/her partner. In families with an X-linked recessive condition only males are affected and they may appear in every generation because some of the mothers will be carriers of the gene but there is no male to male transmission.

Autosomal recessive inheritance In recessive single gene disorders a person who is a gene carrier has one abnormal copy of a particular gene in each of the cells along with one normal copy on the other chromosome. This carrier will not manifest the disease. This person is a heterozygote. If the

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The genetics of conception

partner is not a carrier the couple can safely produce children who will be unaffected. If by chance the partner is also a carrier for the same abnormal gene then the couple has a one in four chance of having a child with two copies of the abnormal gene. This child will then be affected by the disease in question. On average, half of the children of the couple with both parents being carriers of the same abnormal gene will be gene carriers like themselves and a quarter will have two normal genes (Fig 1.1). The commonest autosomal recessive disorder in Caucasian populations is cystic fibrosis (CF).2 Therefore, in Europe this is by far the most frequent reason for referral to a centre offering preimplantation genetic diagnosis (PGD). More than 1000 different mutations are known. In the majority of cases the mutation in this gene is a three base pair deletion known as p.F508del. In most cases both parents of an affected child are likely to be carrying this mutation (Fig 1.2a). This situation makes single cell diagnosis relatively straightforward. However, there are a number of rare CF mutations that are not so easily detected. If the parents carry different mutations the child who inherits these two different abnormal genes will be affected. Such a child is called a “compound heterozygote” (Fig 1.2b). Worldwide, the commonest autosomal recessive disease is β-thalassaemia.3 In contrast to CF, there are numerous different common mutations in this gene. Certain types predominate in different populations, but it is still the case that most parents of affected children will be carriers of different mutations. Many inborn errors of metabolism are autosomal recessive.4 Since one gene is responsible for the production of one enzyme, these diseases cause enzyme deficiency. If one gene coding for an enzyme is affected, 50% of the enzyme will still be produced from the wild type gene. In general this level of enzyme activity is sufficient for normal life. Therefore, both copies of the gene need to be affected in order to result in a severe clinical phenotype.

Autosomal dominant inheritance Autosomal dominant disorders require only one copy of the abnormal gene to be present in each cell for the disease to be expressed. The presence of a normal copy on the other chromosome is not sufficient to ensure normality. Generally, at birth dominant disorders are not so severe or life threatening as recessive disorders. In dominant disease, usually the gene carriers are able to have children either despite being affected, as in the case of achondroplasia (dwarfism) or because the disease itself is of late onset (e.g. Huntington’s disease). On average, half the children of an affected mutant gene carrier will also be affected. From this it might be concluded that diseases which, when studying the pedigree, seem to follow a more complex pattern cannot result from simple point

3

(a)

Normal

Carrier

Normal

Normal

Carrier

Normal

Carrier

Carrier

Normal

Carrier

Carrier

Cystic fibrosis (CF)

(b)

Normal

Carrier

Normal

Normal

Carrier

Carrier

Carrier

CF (compound heterozygote)

Key Male

Female

p.F508del mutation

? Mutation

Chromosome 7

Fig 1.2 Cystic fibrosis (CF) family pedigree illustrating the typical inheritance of an autosomal recessive gene defect. (a) In this family the common CF mutation p.F508del is passed through healthy carriers in the grandparents’ and parents’ generations to the grandchildren, one of whom is affected by the disease. (b) In this case the father carries the p.F508del mutation whilst the mother carries a different, much rarer mutation of the CF gene. The child affected by cystic fibrosis who has inherited both defective copies is essentially a carrier of each mutation and is termed a compound heterozygote.

mutations in individual genes. However, complexity might result from incomplete penetrance and variable expression. Incomplete penetrance means that a number of genotypically affected carriers do not demonstrate any symptoms of the condition. Variable expression means that not all disease carriers show the

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Queen Victoria of England

2 Emperor Frederick III of Germany

King Edward VII of England

Leopold of Albany

Frederik of Hesse

Tsar Nicholas of Russia

Leopold of Battenberg

4 Waldemer of Prussia

Henry of Prussia

2

Tsarewitsch Alexis of Russia

Carrier

Fig 1.3

Maurice of Battenberg

Rupert

Alfonso of Spain

Gonzalo of Spain

Patient with haemophilia

Pedigree of a Royal Family with X-linked disease Haemophilia.

same severity of the condition and suggests that environmental factors or other genes are also involved. Furthermore pleiotropy occurs, in which one mutation can cause more than one effect on development. It should always be kept in mind that new mutations arising during gamete formation may be responsible for sporadic cases in a family. It is also possible that the legal father is not the biological father. Sometimes an individual is mosaic for the mutation. In that case it must have arisen as a somatic event after fertilisation. Sometimes the mutation is confined to the germline. The breast cancer mutations BRCA1 and 2 can either have no effect at all (non-penetrance) or result in breast cancer on the one hand or ovarian cancer on the other with variable risks5 as follows:

an expansion in the number of copies of a CTG repeat in the 3′ untranslated part of the DM1 kinase gene on chromosome 19. The repeat copy number varies from 5 to 37 in normal individuals and from 50 to several thousands in people affected with the disease. Intermediate repeat numbers result in an unstable, permutation state. The expansion of the triplet repeat may lead to the phenomenon of anticipation, which means that the disorder starts at a younger age and becomes more severe with each generation. Mildly affected mothers can give birth to severely affected offspring with the congenital form of the disease.6

X-linked inheritance

A special category of dominant disorders is caused by a variable increase in the number of copies of a particular trinucleotide repeat sequence (i.e. three base pairs, for example cytosine, guanine, guanine (CGG) and their paired bases on the opposite DNA strand) within the vicinity of a gene. Myotonic dystrophy and Huntington’s disease belong to this category.

X-linked disorders (caused by mutation in genes that are carried on the X chromosome) can be either recessively or dominantly inherited. The vast majority are recessives and are carried by females who are themselves unaffected or only mildly so, because of the normal copy of the gene on their second X chromosome (Fig 1.3). Distorted X chromosome inactivation can result in symptoms in females, although much milder than those that occur in males. Half the sons (who get their single X chromosome from their mother) will be normal, however, the others will be affected with the disease as their Y chromosome will not have the normal gene. Common X-linked recessives include Duchenne muscular dystrophy and haemophilia. There are well over 1000 known X-linked disorders and for most of them the molecular basis is not yet known.7

Myotonic dystrophy

Fragile X syndrome

Myotonic dystrophy, DM1, also known as Steinert’s disease, is a progressive muscular dystrophy caused by

Fragile X syndrome is a form of X-linked mental retardation caused by unstable expansion of a CGG repeat in

(1) Risk of female carriers of a mutation in BRCA1/2 to develop breast cancer before the age of 70: 60–80%; (2) Risk of female carriers of a mutation in BRCA1 to develop ovarian cancer before the age of 70: 30– 60%; (3) Risk of female carriers of a mutation in BRCA2 to develop ovarian cancer before the age of 70: 5–20%.

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the 5′ untranslated region of the FMR1 gene. In the normal population the number of repeats is polymorphic with different individuals possessing between 6 and 54 copies and is usually inherited unchanged from parent to child. In families with fragile X syndrome the number of copies of the repeat has a tendency to expand with each generation, which is an unstable, premutation, situation. Once the number of repeats exceeds 200 excessive methylation occurs leading to transcriptional inactivation and absence of gene product. Males with repeat copy numbers in excess of 200 will show symptoms and females, who also have a transcriptionally active copy of the gene, show variable disease manifestation. Fragile X syndrome shows a 10-fold increase in premature ovarian failure.8

1

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Chromosome abnormalities Chromosome abnormalities are normally divided in numerical abnormalities, structural abnormalities and mosaicism. Numerical chromosome abnormalities are abnormalities which deviate in number from the normal karyotype, which has 2n=46 chromosomes, that is, two haploid sets (Fig 1.4). They are the result of simultaneous chromosome breakage either within the same chromosome or in different chromosomes and subsequent rejoining in an abnormal fashion. Mosaicism means that there is more than one cell line present.

Numerical chromosome abnormalities Numerical chromosome abnormalities can be divided into aneuploidy, an extra (trisomy) or missing (monosomy) chromosome of a pair, and ploidy abnormalities, in which the number of haploid sets of chromosomes is abnormal. An embryo may be haploid (1n=23), triploid (3n=69) or tetraploid (4n=96). Aneuploidy is not normally inherited. Typically the imbalance arises at meiosis I in the mother when two homologous chromosomes pass to the same pole of the spindle at anaphase. The mature oocyte formed after meiosis II will have either an extra or missing copy of the chromosome which will result in trisomy or monosomy in the embryo after fertilisation. The most common numerical chromosome abnormalities are trisomies and monosomies, arising de novo as a result of meiotic non-disjunction during gametogenesis in parents with a normal karyotype. For all chromosomes, except the largest, the non-disjunction rate increases with maternal age. The cause of nondisjunction in oocytes of older women is largely unknown. An increase in maternal age results in an increased embryonic aneuploidy rate as well as an increased frequency of spontaneous abortion. This is not only reflected in a higher miscarriage rate but also in a lower success rate for in vitro fertilisation (IVF). The most frequent abnormality in spontaneous abortions is trisomy 16, representing about 30% of all such trisomies; however, in cleavage stage embryos

Fig 1.4

21

22

X

Y

Human karyotype.

trisomies for chromosomes 13, 21 and 22 are the most common. Trisomies for all chromosomes have been observed in spontaneous abortion, except trisomy 1. Autosomal monosomies are practically unknown in human miscarriages, since they stop development before or soon after implantation.9 On the other hand, monosomy X is a frequent finding in abortions. Nondisjunction may occur at either meiotic division. Trisomy 16, for example, always shows a maternal meiosis I error. Trisomy 18, on the other hand, results predominantly from errors during the second division. Premature centromere division at meiosis I leading to separated chromatids, is an alternative mechanism for trisomy formation, occurring as frequently as whole chromosome non-disjunction.10 The abnormality most frequently resulting from abnormal fertilisation is triploidy. There seems to be no effect of maternal age on triploidy and tetraploidy, the latter of which originates during preimplantation development. Only three autosomal trisomies are regularly observed at birth: trisomies 13, 18 and 21. They have an estimated prenatal survival of 3, 5 and 20%, respectively. The other autosomal trisomies have an estimated survival to term of less than one in 1000. Sex chromosome aneuploidies survive normally with the exception of 45,X which is lethal in about 98% of conceptions.9

Aneuploidy and gonadal mosaicism Occasionally couples present with a history of repeated conceptions involving trisomy for the same chromosome. The reason for this may be mosaicism in a parent with a second, trisomic, cell line present in addition to the normal population of cells. When the trisomic cells are present in the gonads this results

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Textbook of Periconceptional Medicine (a)

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in a high frequency of gametes which are unbalanced for the involved chromosome. Aneuploidy for the sex chromosomes, leading to Klinefelter syndrome (47,XXY), triple X or Turner syndrome (45,X), has a less severe effect on the phenotype of surviving individuals (in addition to the almost total lethality of 45,X conceptions, 50% of 47,XXY foetuses abort). Full Klinefelter syndrome leads to azoospermia but epididymal sperm may sometimes be recovered and used for fertilisation. Any embryos generated using this method should be checked for sex chromosome aneuploidy by PGD. Also, some infertile males are mosaic for a 47,XXY cell line; if this is discovered their embryos should undergo PGD as there is an increased risk of the production of XY sperm.

Structural chromosomal rearrangements Structural chromosomal rearrangements are common in the human population. They usually occur before or during gamete formation so that every cell of the embryo that results from fertilisation with that gamete carries the same rearrangement. Providing that the breakage in the chromosomes has not affected gene transcription the individual carrying the rearrangement will develop normally. The problems occur in oogenesis or spermatogenesis when the rearranged chromosomes have to pair with their normal homologues and abnormal products of segregation result.11

Chromosomal translocations The most common type of chromosome rearrangement is a translocation which is the movement of a segment of chromosome from its normal position to a new site. Reciprocal translocations involve breaks along the arms of two chromosomes and exchange of material with reunion creating two abnormal derivatives (Fig 1.5a). Robertsonian translocations involve breakage and reunion around the centromere of the “acrocentric” chromosomes; the minute short arms of these chromosomes are normally lost in the process so that the chromosome number per cell is reduced to 45,

Fig 1.5 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). (a) Reciprocal translocation – reciprocal exchange of material between two nonhomologous chromosomes. (b) Cross-shaped arrangement (quadrivalent) adopted by reciprocal translocations during early meiosis allows pairing of homologous chromosomes.

again with no phenotypic effect (Fig 1.6a). Robertsonian translocations are unusual in that identical types occur repeatedly in humans, whereas reciprocal translocations are normally unique to the family. In the case of reciprocal translocations a group of four chromosomes is formed at meiosis in the parental carrier and this group can separate into two groups of two in four ways, only one of which will be balanced genetically (Fig 1.5b). It is also possible for three of the four chromosomes to go to one daughter cell and only one to the other (3:1 segregation). It is clear that there is a high risk of producing chromosomally unbalanced gametes but the exact risk depends on several factors including the chromosomes involved, the position of the breakpoints and the sex of the parent with the translocation.12 In Robertsonian translocation carriers a group of three chromosomes is formed when pairing occurs in meiosis but in the same way as for reciprocals this group can segregate in three ways, only one of which is balanced (Fig 1.6b). An example of a typical family with an inherited Robertsonian translocation is shown in (Fig 1.7).

Insertions Much rarer types of translocation occur which are known as insertions. These involve three simultaneous breaks, either within one chromosome or involving two different chromosomes. The segment freed by two of the breaks within one chromosome is then inserted into a new position within the same chromosome or into a second one (Fig 1.8). In the case of intrachromosomal insertions unbalanced gametes can be formed merely by recombination between the paired homologous chromosomes in the prophase of meiosis I, whereas for interchromosomal insertions the involved chromosomes come together as a group of four in a similar way to reciprocal translocations and the type of gametes formed is again dependent on the segregation pattern.

Inversions When two breaks occur within one chromosome the free segment may rotate through 180 degrees before rejoining (Fig 1.9). This produces an inversion of genetic material

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(a)

7

(b)

A

der(A;B)

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der(A;B)

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Normal

Fig 1.6 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). (a) Robertsonian translocation – fusion of two acrocentric chromosomes with varying loss of centromeric and short-arm material. (b) Pairing arrangement (trivalent) adopted by Robertsonian translocations during early meiosis allowing pairing of most homologous regions.

Carrier

Normal

Carrier

Down syndrome

Normal

Carrier

Down syndrome

Normal

Key Male Miscarriage

Female Chromosome 21

Robertsonian translocation der(13;21)(q10;q10)

Chromosome 13

Fig 1.7 Pedigree of a family with a Robertsonian translocation between chromosomes 13 and 21. This balanced chromosome rearrangement was only detected in the healthy mother after the birth of two children with Down syndrome.

between the breakpoints which usually has no phenotypic effect in heterozygous form when only one of a pair of chromosomes is involved. The problems for carrier parents occur in gamete formation.12 The genetic effects are different depending upon whether the centromere is included within the inverted segment. Classically, when the inverted chromosome pairs with its normal homologue there is loop formation. If crossing over takes place within this loop the chromatids involved will be genetically unbalanced due to deletion of some genetic loci and duplication of others. Cross-over chromatids from inversions that include the centromere (pericentric) may lead to viable but congenitally abnormal embryos, whereas those from paracentric inversions (without the centromere) will either have two centromeres or none, a condition that is incompatible with further development of the gamete as the chromosomes will be lost or broken.

For this reason paracentric inversions usually pass undetected from one generation to another as no affected offspring are born. However, couples with repeated births of chromosomally abnormal children as a result of a pericentric inversion in one parent have come forward to request PGD.

Ring chromosomes Ring chromosomes are formed when genetic material is lost from both ends of a chromosome, creating an unstable situation which is resolved by the fusion of the broken ends (Fig 1.10). It is unusual to find ring chromosomes in a normal adult but they do occasionally occur as ring X chromosomes or affecting an autosome if only the telomeres themselves are lost. Ring chromosomes are unstable during cell division as interlocking chromatids

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(a)

(b)

A

derA

(c)

A

derA

A

derA

derB

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Fig 1.8 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). Insertions – translocation of a chromosome segment to another chromosome (interchromosomal) or to another position on the same chromosome (intrachromosomal), either in the same orientation with respect to the centromere (direct) or reversed (inverted). Inserted segment is shown cross-hatched. (a) Within-arm intrachromosomal insertion. (b) Between-arm intrachromosomal insertion. (c) Interchromosomal insertion.

(b)

(a)

A

derA

A

derA

Fig 1.9 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). Inversions – inversion of a chromosome segment with (pericentric) or without (paracentric) involvement of the centromere. Inverted segment is shown cross-hatched. (a) Pericentric inversion. (b) Paracentric inversion.

may be formed leading to breakage and loss. Adult carriers are usually mosaics with a monosomic cell line in the case of the X chromosome or a normal line if an autosome is involved. PGD has been requested in at least one case involving an autosome.

Mitochondrial disorders Mitochondrial disorders are a group of diseases and syndromes commonly defined by lack of energy due to defects in oxidative phosphorylation (OXPHOS). They affect at least one in 8000 of the general population, making them the most common inherited metabolic diseases. Clinical manifestations of OXPHOS diseases are extremely variable and range from a single affected tissue, like the loss of vision in Leber’s hereditary optic neuropathy (LHON), to multisystemic syndromes like Leigh syndrome (subacute necrotising encephalomyelopathy, LS), mitochondrial encephalopathy lactic acidosis and stroke-like

A

derA

Fig 1.10 Ring chromosome – loss of telomeric material with fusion of the resulting free ends.

episodes (MELAS), neuropathy, ataxia and retinitis pigmentosa (NARP) and myoclonic epilepsy with ragged red fibres (MERRF).13 The mitochondrial DNA is double stranded, circular and consists of 16 569 base pairs. The mtDNA encodes 37 genes, of which 13 genes encode proteins. Furthermore, there are 22 tRNA and two rRNA genes, required for mitochondrial translation.14 Several unique characteristics discriminate mitochondrial from nuclear DNA: (1) The mtDNA is a multicopy genome. A cell contains hundreds of mitochondria and each mitochondrion contains five to ten copies of mtDNA. Dependent on the tissue and energy demand each cell contains between 500 and 10 000 mtDNA molecules, except for mature oocytes which contain between 100 000 and 600 000 mtDNA molecules. (2) In a cell all mtDNA molecules can be identical (homoplasmy), or two types of mtDNA molecules, that differ in sequence, in the same cell, tissue or even in the same organelle can coexist. (3) The mtDNA is transmitted entirely through the maternal line.

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Segregation of mtDNA diseases in families The segregation of mtDNA disease in families is not straightforward and is highly dependent on the nature and amount of the mtDNA mutation. A woman carrying an mtDNA mutation will transmit a variable amount of this mutation to her offspring. The percentage heteroplasmy of point mutations in the offspring is related to the mutation percentage in the mother, although extreme shifts in mutation percentages occur. The ‘mtDNA bottleneck’ is a restriction in the number of mtDNA molecules to be transmitted followed by an amplification of these founder molecules. The exclusive maternal transmission of mtDNA, the high mutation rate and the lack of a good repair mechanism and recombination would lead to decay of the mtDNA. The stringent bottleneck has an evolutionary advantage as a sort of reset and acts to maintain a healthy mtDNA by filtering out mutations and minimising heteroplasmy. Because this filtering happens very early during the development the chance to preserve age-related mutations in the early oocyte is small, although the low amount of mtDNA copies per mitochondria in the early developmental stages of the oocytes renders these oocytes vulnerable for mutational events. Besides the variation which is present in the DNA sequence, epigenetic changes play an important role in the regulation of gene expression. Several epigenetic mechanisms are operative, including, among others, histone modifications and DNA methylation, RNA associated gene silencing and chromosome inactivation, and genomic imprinting.15

9

defined as regions of more than 500 base pairs in size and with a GC content greater than 55%. They are located within the promoter regions of about 40% of mammalian genes. These CpG islands are normally kept free of methylation and are targets for proteins that bind to unmethylated CpGs and initiate gene transcription. However, methylated CpGs are associated with silent DNA and cause stable heritable transcriptional silencing. The establishment and maintenance of DNA methylation patterns is maintained by DNA methyl transferases (DNMTs).16 The folate-methylation cycle demethylates homocysteine to produce methionine and then S-adenylmethionine (SAM), which is a prime source of methyl groups for DNA methylation and for the synthesis of nucleic acids, proteins and lipids. Deficiencies in the enzyme methylenetetrahydrofolate reductase (MTHFR), which is central to the methylation pathway, cause DNA hypomethylation and could be related to imprinting disorders.17

X-chromosome inactivation

Histone modifications influence the organisation of the chromatin. DNA is wrapped around clusters of histone proteins to form nucleosomes. These structures contain eight histone molecules. Per nucleosome there are two of each of H2A, H2B, H3 and H4. These basic histone proteins allow interaction with acidic DNA. The nucleosomes of DNA and histones are the building blocks of chromatin and influence gene expression. Transcriptionally inactive DNA is characterised by chromatin, which is condensed and is associated with regions of the genome that undergo late replication during S phase of the cell cycle. Transcriptionally active chromatin is more open and replicated early in S phase. These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modifications, such as (combinations of) acetylation, methylation, and other post-translational modifications such as phosphorylation.16

In mammals, one of the two X chromosomes in females (XX) will undergo a process of inactivation early in embryo development in order to ensure an equal gene dosage as in males (XY). In the mouse, a dynamic multistep process of X-chromosome inactivation has been proposed.18,19 After fertilisation, during the early cleavage stages, the paternal X chromosome, after being initially active, undergoes imprinted inactivation. Initiation of this imprinted X-chromosome inactivation was shown to occur at the 4-cell stage.19 At the 32-cell stage, the paternal X chromosome is inactivated in all cells of the embryo and this inactive state was found to be maintained up to the early blastocyst stage, including in the cells of the inner cell mass (ICM).19 At the late blastocyst stage, this inactive state of the paternal X chromosome is reversed in all cells and the process of inactivating one of the X chromosomes in females is repeated. In epiblast cells derived from the ICM and giving rise to the embryo proper, the imprint is erased and selection of the X chromosome to be inactivated is random. In the extraembryonic tissues such as trophectoderm and yolk sac endoderm, the imprint is retained and the paternal X chromosome is preferentially silenced. The X-chromosome inactivation process starts with the expression of a non-coding RNA (XIST) that, from there, will coat one of the X chromosomes and will lead to its inactivation. Immediately after coating with XIST, lysines 9 (K9) and 27 (K27) of histone H3 are methylated. These changes in the nucleosomal core histones play an important role in the changes of the chromatine structure: locally, binding sites for several repressive protein complexes are formed by methylation.

DNA methylation

Genomic imprinting

Another epigenetic mechanism is methylation of the C5 position of cytosine/guanine pairs (CpG). CpG islands are

For the majority of the autosomal genes there is no discrimination between the capacity of the two

Histone modifications

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parental alleles to be expressed, other than that caused by genetic mutational difference between them. However, several genes are known in which the expression of one parental allele, either the paternal or the maternal allele but not both, is normally repressed in some cells (allelic exclusion), although the sequences of both parental alleles are normal. In some cases, the choice of which of the two inherited copies is expressed is not random, and the allele the expression of which is repressed is always the paternally inherited allele; in others, it is always the maternally inherited allele. This process, known as imprinting, involves the reversible modification of gene activity depending on the sex of the parent that transmits it.15 Well-known examples of imprinting diseases, are Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Several studies have suggested a possible association between assisted reproductive technologies (ART) and genomic imprinting defects. In several studies an increase in the risk of imprinting disorders such as for children conceived by ART has been reported.20,21 It has been suggested that, besides in vitro culture, the intracytoplasmic sperm injection (ICSI) technique could be a possible causal factor.22

Complex genetic inheritance Many of the differences between individuals reflect features that show continuous quantitative variability. The inheritance of such features does not follow the rules of simple, monogenic heredity. Complex genetic inheritance of disease is characterised by familial clustering and a recurrence risk which is higher than the population risk. The incidence is always less than that with Mendelian disorders and can be estimated only by observations among families and population samples. In genetic terms the complexity results from the interaction of endogenous (genetic) and exogenous (environmental) factors. Such a pedigree pattern might also result, however, from the interaction of more than one genetic factor. Family and population data help to explain diseases with complex genetic inheritance, but heritability estimates obtained from twin studies are of special importance.

Conclusions Even for professional human geneticists it is impossible to keep up to date with the rapid progress that is being made in working out the molecular basis of inherited disease. Because of the widespread interest and importance of the subject textbooks (such as the one listed below) are regularly revised and provide a good introduction to the field. The professionals rely on McKusick’s Mendelian Inheritance in Man,7 now available online (OMIM), a comprehensive catalogue of known single gene disorders. Each described condition

is given a number (the OMIM number) enabling geneticists to be sure which disease has been diagnosed, rather than relying on the name of the syndrome.

References 1. Wang L, Luhm R, Lei M. SNP and mutation analysis. Adv Exp Med Biol 2007; 593: 105–16. 2. Sermon KD, Michiels A, Harton G et al. ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004. Hum Reprod 2007; 22: 323–36. 3. Kornblit B, Hagve TA, Taaning P, Birgens H. Phenotypic presentation and underlying mutations in carriers of beta-thalassaemia and alpha-thalassaemia in the Danish immigrant population. Scand J Clin Lab Invest 2007; 67: 97–104. 4. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Basis of Inherited Disease, 8th edn. New York: McGraw-Hill, 2001. 5. Sinilnikova OM, Mazoyer S, Bonnardel C et al. BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families. Fam Cancer 2006; 5: 15–20. 6. Harper P. Myotonic dystrophy, 3rd edn. USA: Oxford University Press, 2002. 7. McKusick VA. Mendelian Inheritance in Man, 12th edn. Baltimore: Johns Hopkins Univerity Press, 1998. Also available Online: OMIM http://www.ncbi.nlm. nih.gov/Omim/ 8. Hundscheid RD, Smits AP, Thomas CM, Kiemeney LA, Braat DD. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. Am J Med Genet A 2003; 117: 6–9. 9. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 2002; 8: 333–43. 10. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001; 2: 280–91. 11. Passarge E. Color Atlas of Genetics. Stuttgart-New York: Thieme, 2001. 12. Kayser-Rogers K, Rao K. Structural chromosome rearrangements. In: Gersen SL, Keagle MB, eds. The Principles of Clinical Cytogenetics. Totowa, NJ: Humana Press, 2005. 13. Jacobs LJ, de Wert G, Geraedts JP, de Coo IF, Smeets HJ. The transmission of OXPHOS disease and methods to prevent this. Hum Reprod Update 2006; 12: 119–36. 14. Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1999; 1410: 103–23. 15. Waggoner D. Mechanisms of disease: epigenesis. Semin Pediatr Neurol 2007; 14: 7–14. 16. Egger G, Liang G, Aparicio A et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457–63. 17. Dobson AT, Davis RM, Rosen MP et al. Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF. Hum Reprod 2007; 22: 450–6.

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The genetics of conception 18. Huynh KD, Lee JT. Imprinted X inactivation in eutherians: a model of gametic execution and zygotic relaxation. Curr Opin Cell Biol 2001; 13: 690–7. 19. Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 2004; 303: 644–9. 20. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann

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syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003; 72: 156–60. 21. Allen C, Reardon W. Assisted reproduction technology and defects of genomic imprinting. Br J Obstet Gynaecol 2005; 112: 1589–94. 22. Devroey P, Van Steirteghem A. A review of ten years experience of ICSI. Hum Reprod Update 2004; 10: 19–28.

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2 Lifestyle and conception Sevilay Temel, Joop S Laven, Régine PM Steegers-Theunissen

Introduction It is clear from epidemiological and experimental studies that adverse periconceptional lifestyles significantly contribute to reproductive health and performance.1 During the periconceptional period, defined as the time span before and surrounding the conception, gametes further develop and are being programmed by epigenetic mechanisms in order to achieve successful conception and subsequent embryogenesis.2 Adverse lifestyles, such as alcohol use and malnutrition, may induce alterations in the DNA sequence and in the epigenetic (re)programming of the genome.3,4 Thus, adverse periconceptional lifestyles may irreversibly affect the gametes of parents-to-be and the subsequent embryonic genome with consequences for its future health and late-onset diseases.5,6 Failure of conception due to compromised quality of the gametes or early embryo presents in the pre-conceptional period as subfertility and is defined as a failure of conception after 1 year of regular, unprotected intercourse with the same partner. Nowadays, approximately 15% of all couples experience primary or secondary subfertility at some time during reproductive life. In around 58% the cause of subfertility predominantly originates from the woman, in 22% from the man, in 5% from both partners and in the remaining 15% no clear cause can be identified.7 In the past decade it has become apparent that subfertility is an increasing problem particularly in rich countries.8 Besides the rising age of primiparae, the adverse lifestyles of the couples exerted by the increasing demands and stresses from jobs and social obligations may significantly contribute to this problem. Recent figures show that 25% and 35% of women and men in reproductive age are smoking, and 80% and 85% use alcohol, respectively.9 Furthermore, unhealthy diets, characterised by low intakes of fruits and vegetables, and high intakes of saturated fats, are also increasingly used in this age group.10 It is well known that the aforementioned lifestyles significantly contribute to the epidemic of complex diseases such as cardiovascular disease, cancer and obesity by epigenetic mechanisms.11 However, the emerging concept that the same adverse lifestyles in the periconceptional period significantly affect conception and reproductive performance with

short- and long-term effects for the newborn, can no longer be neglected. Therefore, this chapter gives an overview of several adverse lifestyles and phenotypes of lifestyles that impact conception and some preconceptional advice.

Lifestyle factors Table 2.1 depicts the associations between the lifestyle factors cigarette smoking, (social) alcohol use, recreational drug use, malnutrition with a focus on low folate and zinc intake, and exercise in women and men, and the conception parameters fertility, fecundity and semen.

The effects of smoking The strongest lifestyle factor that compromises conception is cigarette smoking. Because one-third of the world’s population over 15 years of age smokes, its impact on reproduction is substantial. Cigarette smoke contains more than 3000 different chemical compounds, such as nicotine, nitrosamine, polycyclic hydrocarbons, cadmium and carbon monoxide. Some of these toxins enter the blood circulation of the gonads and can have direct cytotoxic and genotoxic effects on the gametes. There is some evidence that cigarette compounds have an effect only after biotransformation into reactive products or via alterations of hormone levels.47 Several of these compounds may also interact with the hypothalamic–pituitary– ovarian axis possibly by epigenetic mechanisms, such as the demethylation of CpG islands, thereby influencing gametogenesis and conception.48,49 In the woman, the tobacco compounds cadmium and cotinine, as biomarker of nicotine, accumulate in a doserelated manner in follicular fluid.48 These toxins either damage the oocytes resulting in an average 30% reduced fecundity or a 1.5–1.7- fold increased risk of reduced fecundity, defined as the probability of pregnancy in each cycle, or completely destroy the otherwise healthy oocytes with a subsequent up to 4 years shorter reproductive life span.12–15 One of the possible explanations for these findings is that cigarette smoke disrupts the meiotic spindle function of

1.6 (1.3–1.9)12

1.7 (1.3–2.1)13 1.5 (1.2–2.0)14 0.9 (0.8–1.0)15

3% morphology18

18% count17,18

15% Sperm concentration17 17% motility17

12%15,16

0.7 (1.3–1.9)12

Man

0.3 (0.2–0.5)19 0.4 (0.3–0.8)20

sperm morphology23–25

sperm quality23–25 sperm motility23–25

0.6 (0.4–0.9)19 No effect15,19,21,22

Woman

Alcohol

20–30% acrosome reaction28

ovulation27

LH26

Woman

20–30% motility28

Man

Marijuana

oocyte quality29,30 oocyte maturity29,30

follicle diameter29,30

Woman

70% sperm count31,32 seminal plasma folate:30 aneuploidy

Man

Folic acid

Subfertility33,34

sexual maturation33

Woman

morphology count, motility

Oligozoo s-permia35–38 Zinc treatment:32,39–42

Man

Zinc

Excessive: 5–7% subfertility43

Moderate: no association43

Woman

morphology concentration motility

No effects44 Short-term exhaustive Endurance:45,46

Man

Exercise

--

LH, luteinising hormone.

Semen parameters

Fertility

Fecundity

Man

Woman

Smoking

Periconceptional lifestyles in association with fecundity, fertility and semen parameters.

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Table 2.1

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Lifestyle and conception

the oocyte.50 A meta-analysis demonstrates that smoking increases the risk for subfertility 1.6-fold.12 Cohort and case–control studies strongly support this association by showing risk estimates of around 1.6.13,51,52 Although in some studies the effects of cigarette smoking on fertility were only observed in women who smoked more than 20 cigarettes per day, a significant dose-response relationship was identified. Besides the direct effects on the oocytes, cigarette smoke also influences tubal and cervical function, thereby detrimentally affecting the migrating spermatozoa as well. It is important to realise that the effects of cigarette smoke are reversible.51 In men, the cigarette smoke compounds cadmium and cotinine are measured in seminal plasma, indicating that these metabolites pass the blood–testes barrier and hence might induce DNA damage.48 The adverse effects of cigarette smoke might also be due to the suppression of the antioxidant concentrations in blood and semen and as such increase the oxidative DNA damage in sperm.53 In men cigarette smoking resulted in a 12% decrease of fecundity and time to pregnancy of more than 6 months.15,16 However, not all studies substantiate these associations.13,14,17,54 Two meta-analyses reveal also a reduction of 13% in the sperm concentration, 10% in sperm motility and a 3% increase in the abnormal sperm morphology in cigarette smokers.17,18 Although, semen parameters are reduced after smoking, the values often remain within the normal ranges. This has led to the use of new markers for DNA damage in the assessment of semen quality, such as the DNA defragmentation index (DFI).55 So far, the associations between cigarette smoking and DFI are contradictory and need further investigation. Experimental studies largely substantiate the findings of the human studies. Studies in rats exposed to cigarette smoke showed that its constituents and reactive metabolic intermediates directly interact with the DNA of spermatozoa leading to defective spermatogenesis and sperm maturation.56 In addition, shortterm exposure of rats to cigarette smoke resulted in a secretory deficiency of Leydig and Sertoli cells, leading to impaired epididymal sperm maturation and a diminished capacity of spermatozoa to penetrate the oocyte.57 This is very interesting because it may imply that during conception, DNA damage of the spermatozoa might also be directly transmitted to the oocyte. Subsequently this may compromise the epigenetic (re)programming of the early embryo resulting in failed implantation, early pregnancy loss, birth defects and childhood cancers in the offspring.2,58,59 In conclusion, there is enough evidence that pre-conceptional cigarette smoking has a significant impact on oocyte and semen quality. However, whether it also affects the success of conception is not clear. Most interesting, but also worrying, are first indications that early paternal cigarette smoking may exert transgenerational effects.60

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The effects of alcohol Periconceptional excessive alcohol use is detrimental for conception.61 However, less is known about the effects of social alcohol use. This is relevant because around 80% of the reproductive population uses social alcohol. Alcohol consumption causes direct cellular injury. Moreover, recent developments also indicate that ethanol induces epigenetic alterations, particularly the acetylation and the methylation of histones and hypo- and hypermethylation of DNA.3 The epigenetic effects are mainly attributable to ethanol metabolic stress generated by the oxidative and nonoxidative metabolism of ethanol, and dysregulation of methionine metabolism. In women, the frequent use of alcoholic drinks results in more menstrual disorders, such as amenorrhoea, dysmenorrhoea and irregular menstrual periods.62 Hence, the probability of conception in these women might be diminished. A 40% and 70% reduced fecundity has been reported in women with any alcohol intake and intakes above ten drinks per week, respectively.19 Social alcohol use revealed an approximately 60% reduced fecundity.20 This association was not found in subfertile women.15,21,63 Thus, there is some evidence that social alcohol use in the periconceptional period is not absolutely safe. In men, excessive alcohol consumption leads to significant morphological changes in ejaculated spermatozoa thereby reducing sperm quality, motility and sperm count.23–25 In an in vitro study the percentages of progressive motility and morphology were significantly decreased in a dose-dependent manner after exposure to high amounts of alcohol.64 However, several studies did not show a significant effect of alcohol intake on fecundity.15,19,21,22 The hamster ovum test has shown that the fertilisation rate was only 16.7% in men using alcohol compared with 50% in nonusers. In vitro and in vivo studies also showed that alcohol exposure resulted in a reduced ability of sperm to fertilise oocytes.65,66 Thus, there is some evidence that pre-conceptional excessive and social alcohol use affect the quality of the gametes and the success of conception. The potential epigenetic effects of alcohol use are intriguing and certainly warrant further investigations.

The effects of recreational drug use Recreational drug use is particularly high in teenage pregnancies. The effects of these drugs on conception, however, have been scarcely investigated. Marijuana, i.e. cannabis, is the most commonly used recreational drug worldwide. It contains at least 20 active cannabinoids including delta-9-tetrahydocannabinol (THC).67 It is known that the endocannabinoid system regulates many functions in the human body, including the reproductive tract. Two cannabinoid receptors CB1 and CB2 have been identified, that can be bound by THC. The binding of these receptors by THC antagonises the

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endocannabinoid system and as such exerts reproductive dysfunction in both women and men. In women, it has been shown that depending on the menstrual phase of the cycle the administration of the marijuana metabolite THC immediately suppresses the secretion of luteinising hormone (LH) in a dosedependent manner.26 In experimental studies in mice the cannabinoid receptors CB1 and CB2 are expressed in the uterus. Of interest is that the uterine embryo receptivity for embryo implantation can be influenced by interference with these cannabinoid receptors.68 Due to interactions between marijuana and the receptors, the oestrous preovulatory LH surge can also be blocked and hence ovulation possibly by interactions with the oestrogen receptors.27 In men, a cannabinoid receptor which is expressed in the human testes has been identified and cloned.69 Cannabinoid receptors have also been found in rat testes, the mouse vas deferens and sperm from sea urchins.28,70 It was shown that pretreatment of sperm with the marijuana metabolite THC reduces sperm motility and inhibits the acrosome reaction in a dosedependent manner thereby reducing fertilisation capacity by 20–30%.28 Of interest is that the adverse effects of THC on sperm-fertilising capacity are reversible. Despite the reported reduction of testosterone levels by marijuana use, the detrimental effects on semen parameters are still contradictory.71,72

The effects of nutrition In recent decades, in women and men of reproductive age the intake of vegetables and fruits has dramatically decreased and the intake of saturated fats, proteins and carbohydrates has increased.73 This has resulted in marginal to severe deficiencies of several micronutrients of which the most important investigated in regard to conception are folate and zinc. The B vitamin folate is important for the synthesis of DNA, transfer RNA and the amino acids cysteine and methionine as well as the methylation of DNA and histones, lipids and proteins. DNA synthesis and DNA and histone methylation (epigenetic modification) play an important role in gametogenesis, conception and (re)programming of the early embryo. Furthermore, folate serves as a substrate in the homocysteine pathway. A folate deficiency leads to hyperhomocysteinaemia of which several detrimental effects have been reported in association with reproductive outcomes.74 Zinc is a trace element that serves as cofactor for more than 80 metalloenzymes involved in DNA transcription and protein synthesis. The zinc finger proteins are implicated in the genetic expression of steroid hormone receptors.75 Zinc also has anti-apoptotic and antioxidant properties important in gametogenesis and conception.74,76,77 Evidence for the role of periconceptional nutrition on the intrauterine programming by epigenetic mechanisms, such as DNA methylation, is increasing.59,78–80

In women, beside the preventive effect of periconceptional folic acid supplementation on several congenital malformations, other effects on fertility, twinning rate and spontaneous miscarriages have been suggested.81 Folate is present in ovarian follicular fluid and as such influences the homocysteine pathway in the microenvironment of the follicle.29,82,83 Women receiving folic acid supplementation demonstrated a larger follicular diameter, a better oocyte quality and a higher degree of oocyte maturation.29,30 Moreover, it has been demonstrated that embryo quality was significantly lower in women undergoing in vitro fertilisation (IVF) treatment with a high homocysteine concentration in ovarian follicular fluid.84 Mouse preimplantation embryo studies substantiate these findings by showing that folate is essential for fertilisation and early embryo development.85 In men, folic acid supplementation increased sperm count by up to 70%.31,32 The effects are observed in dosages 20– 60 times higher than can be reached by a regular diet and are dependent on the duration of treatment and the combination with other minerals, such as zinc. This is supported by the finding that the sperm concentrations in men carrying the 677CC MTHFR wild type, leading to a normal folate state, significantly improved after folic acid and zinc sulphate intervention and that 677T MTHFR homozygotes with a lower folate state are at risk for subfertility.86,87 Of interest is also the finding that a low folate concentration in seminal plasma resulted in more sperm aneuploidy in fertile males.30 In women, a delay in sexual maturation and longstanding subfertility has been described in association with zinc deficiency.33,34 In contrast, normal menstrual cycles have been reported in subfertile and fertile women with low plasma zinc levels. So far, no significant correlation has been found between ovarian follicular fluid zinc concentrations and follicular volume, the presence of an oocyte in the follicle, or subsequent fertilisation.88 In female animals, however, a zinc deficiency resulted in disinterest in their male counterparts, failure of abnormal oestrous cycles with subsequent anovulation and lower pregnancy rates.89,90 Zinc is very important in male fertility because it directly affects testicular steroidogenesis, the oxygen consumption of spermatozoa in seminal plasma, nuclear chromatin condensation, acrosome reaction, acrosin activity and sperm chromatin stabilisation.75,91–94 Zinc deficiency leads to oligozoospermia, impotence, reduced sexual drive and hypogonadism in males and rats possibly due to a decreased testosterone synthesis by the Leydig cells.35–38 Zinc treatment, however, significantly increases testosterone and dihydrotestosterone in subfertile males.38 Correlations between low seminal zinc levels and low sperm count or subfertility are contradictory.95,96 Zinc treatment may improve sperm count, sperm motility and morphology, testosterone concentration and sexual potency in subfertile males.32,39–42 However, the

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associations between zinc concentrations in seminal plasma and conception are not very clear.32,41,42,74,96 Zinc finger proteins are transcription factors and as such may be involved in periconceptional epigenetic mechanisms.

The effects of exercise Evidence of the influence of periconceptional exercise on conception is limited. It is known that physical exercise affects general health and well-being and probably provides some protection from obesity, chronic diseases and psychological stress that may influence conception. Most research in relation to physical exercise and reproduction is primarily focused on athletes rather than on women and men who have a moderate level of exercise. In women, intensive physical exercise leads to anovulation and concomitant disorders of the menstrual cycle and subfertility. It is not clear whether moderate exercise also affects reproductive functions.97 The Nurses’ Health Study II conducted in normo-ovulatory women shows that each hour of vigorous exercise was associated with a 5–7% reduction of anovulatory subfertility independent of body mass index (BMI).43 No association was found with moderate activity. In a case–control study of subfertile women and pregnant controls, women with less than 60 minutes of vigorous exercise per day in the preconception period showed a significant reduction of anovulatory subfertility.98 This is in line with the findings in patients with polycystic ovary syndrome in whom weight loss improved physiological wellbeing, ovulation and pregnancy rates.99 One theory that needs further investigation is that exercise increases insulin sensitivity, which improves ovarian function and thereby fertilisation.100 In men, no significant effects of exercise on semen parameters or conception have been reported.44 Several studies evaluated the effects of endurance exercise on total testosterone levels with contradictory results.101,102 It has been reported that LH levels were inadequate in trained males.44,103 Furthermore, short-term exhaustive endurance training detrimentally affected spermatogenesis by reducing ejaculate volume, sperm concentration and total number of sperm.45 These findings are in line with those of others showing a reduction of sperm concentrations, total numbers of motile sperms and percentage of normal forms.46 Thus, more research is needed with regard to the effects of periconceptional moderate and low-level exercise on fertility parameters.

Some phenotypes of lifestyles Age and BMI are individual characteristics that can affect lifestyle but can also be used as a proxy of certain lifestyles. Although there are many other factors

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that affect lifestyle, such as ethnicity and religion, this section is focused on age and BMI, being the bestinvestigated characteristics in association with conception (Table 2.2). In the woman, the number and quality of oocytes sharply decrease around the age of 35 years. As a result fecundity declines from the late 20s onwards with women aged 35–39 years being half as fecund as women of 19–26 years.8,104 It was shown that in a period of 3 months 71% of conceptions occurred in women aged 32 kg/m2.43 Because it takes a woman with central obesity longer to become pregnant, fat distribution may play a role in the chance of conception.119 This is in line with the findings that a waist-to-hip ratio equal to or above 0.8 was associated with a 66% reduced fecundity in women undergoing IVF treatment.113 A modest weight loss of approximately 10% in obese women can improve conception by restoring the

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Table 2.2

Phenotypes of lifestyles in association with fecundity, fertility and semen parameters. Age Woman

Fecundity

Weight Man

Woman

35–39 years50%8,104

Man

BMI

Textbook of Periconceptional Medicine (Reproductive Medicine and Assisted Reproductive Techniques)

Textbook of Periconceptional Medicine (Reproductive Medicine and Assisted Reproductive Techniques Series Vol 10)

Preservation of Human Oocytes (Reproductive Medicine and Assisted Reproductive Techniques)

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The Endometrium: Molecular, Cellular and Clinical Perspectives, 2nd edition (Reproductive Medicine & Assisted Reproductive Techniques)

Vitrification in Assisted Reproduction: A User's Manual and Trouble-Shooting Guide (Reproductive Medicine and Assisted Reproductive Techniques)

Ultrasonography in Reproductive Medicine and Infertility

Textbook of Assisted Reproductive Technologies: Laboratory and Clinical Perspectives

The Art and Science of Assisted Reproductive Techniques

An Introduction to Male Reproductive Medicine

Surgery, Assisted Reproductive Technology and Infertility: Diagnosis and Management of Problems in Gynecologic Reproductive Medicine, Second Edition

Textbook of Natural Medicine

Textbook of Rabbit Medicine

Textbook of Natural Medicine

Textbook of Family Medicine

Textbook of Cardiovascular Medicine

Textbook of Musculoskeletal Medicine

Oxford Textbook of Medicine

Textbook of Personalized Medicine

Textbook of Rabbit Medicine

Cecil Textbook of Medicine

Textbook of Stroke Medicine (Cambridge Medicine)

Reproductive Biology and Phylogeny of Annelida (Reproductive Biology and Phylogeny)

Reproductive Endocrinology And Fertility

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Reproductive Endocrinology

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Textbook of Periconceptional Medicine (Reproductive Medicine and Assisted Reproductive Techniques)