Office-Based Infertility Practice: Practice and Procedures

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Office-Based Infertility Practice

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David B. Seifer, M.D.

Robert L. Collins, M.D.

Director, Division of Reproductive Endocrinology and Infertility and Professor and Vice-Chair of Academic Affairs Department of Obstetrics, Gynecology and Reproductive Sciences UMDNJ-Robert Wood Johnson Medical School New Brunswick, New Jersey

Medical Director, The Reproductive Center Youngstown, Ohio and Associate Professor Department of Obstetrics and Gynecology Northeast Ohio University College of Medicine Rootstown, Ohio

Editors

Office-Based Infertility Practice With 58 Figures

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David B. Seifer, M.D. Director, Division of Reproductive Endocrinology and Infertility and Professor and Vice-Chair of Academic Affairs Department of Obstetrics, Gynecology and Reproductive Sciences UMDNJ-Robert Wood Johnson Medical School 303 George Street New Brunswick, NJ 08901, USA

Robert L. Collins, M.D. Medical Director Reproductive Endocrinologist The Reproductive Center Youngstown, OH 44514, USA and Associate Professor Department of Obstetrics and Gynecology Northeast Ohio University College of Medicine Rootstown, OH 44272, USA

Cover illustration: Bottom illustration represents the profile of a 20 week-old fetus. © Department of Prenatal Diagnosis and Therapy, Chairman: G. Bernaschek, University of Vienna, Austria.

Library of Congress Cataloging-in-Publication Data Office-based infertility practice / editors, David B. Seifer, Robert L. Collins p. cm. Includes bibliographical references and index. ISBN 0-387-98390-2 (hbk : alk. paper) 1. Infertility. 2. Office practice. 3. Human reproductive technology. I. Seifer, David B., 1955– II. Collins, Robert L. RC889 .O35 2001 616.6.9206—dc21 00-053200 Printed on acid-free paper. © 2002 Springer-Verlag New York, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York, NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use of general descriptive names, trade names, trademarks, etc., in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Production managed by Jenny Wolkowicki; manufacturing supervised by Joseph Quatela. Typeset by Matrix Publishing Services, Inc., York, PA. Printed and bound by Edwards Brothers, Inc., Ann Arbor, MI. Printed in the United States of America. 9 8 7 6 5 4 3 2 1 ISBN 0-387-98390-2

SPIN 10660187

Springer-Verlag New York Berlin Heidelberg A member of BertelsmannSpringer Science+Business Media GmbH

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This book is dedicated to our children Ben Joseph Seifer, Charlie Max Seifer, Denise Collins, and Robbie Collins, for the joy, love and promise they represent.

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Preface The practice of clinical reproductive medicine has gradually moved from its initial 1980–90 hospital base to its present (circa 2001) office site of operation. With this transition have been improvements in efficiency of practice often in response to increased pressure to provide the most patient satisfaction. An added challenge of office-based practice has been taking on many of the responsibilities of what had been traditionally the hospital’s domain. Some of these new responsibilities have included the ordering of operative supplies and equipment, the establishment of quality control programs, construction and maintenance of special laboratory spaces, redesigning efficient methods of

practice in the era of managed care and coordinating ancillary offsite medical personnel. The objective of this text is to assist in this ongoing endeavor by presenting in a clear, concise manner many of the topics relevant to contemporary office-based infertility practice. The initial half of this text addresses topics which focus upon general concepts of infertility evaluation and practice. The latter half is a practical approach to the execution of specific office-based infertility procedures. We hope this book will assist all medical personnel who dedicate their clinical effort in achieving what is most coveted by our patients, the birth of a healthy newborn. DAVID B. SEIFER, M.D. UMDNJ-Robert Wood Johnson Medical School ROBERT L. COLLINS, M.D. The Reproductive Center, Youngstown, Ohio October 2001

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Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1 Evaluation of the Female for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bryan D. Cowan

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2 Evaluation of the Male for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kevin A. Spear

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3 Detection and Therapeutic Approaches to Age-Related Infertility . . . . . . . . . . . . . . . . . . . . Fady I. Sharara, Richard T. Scott, Jr., and David B. Seifer

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4 Role of Ultrasonography in Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theresa Widrich

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5 Coping with Infertility: Practical Psychosocial Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dorothy Greenfeld

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6 Impact of Managed Care on Office-Based Infertility Practice . . . . . . . . . . . . . . . . . . . . . . Richard E. Blackwell

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7 Basics of Laboratory Set-Up in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dean E. Morbeck

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8 Office Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angeline N. Beltsos

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9 Ovulation Induction and Controlled Ovarian Hyperstimulation with Intrauterine Insemination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Robert L. Collins 10 Diagnostic and Therapeutic Hysteroscopy in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 David A. Grainger, Bruce l. Tjaden, and Arjav Shah 11 Endoscopic Evaluation of the Fallopian Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Eric S. Surrey 12 Transcervical Tubal Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Jacek W. Graczykowski and David B. Seifer 13 Microlaparoscopy for Infertility in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Steven F. Palter 14 Treatment of Cervical Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Gary N. Frishman 15 Treatment of Male Reproductive Dysfunction in the Office . . . . . . . . . . . . . . . . . . . . . . . . 150 Hossein Sadeghi-Nejad and Robert Oates

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Contents

16 In Vitro Fertilization in the Office Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Glen K. Adaniya and Bradford L. Bopp 17 Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation . . . . . . . . . . . . . . . . . . 174 Phillip E. Patton and Don P. Wolf 18 Intratubal Gamete Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Kristin Sinnock Friel and Alan S. Penzias 19 Complications of Ovulation Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Janee A. Fonslick and David B. Seifer Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

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Contributors

Glen K. Adaniya, P.h.D., Midwest Reproductive Medicine, 8081 Township Live Road, Indianapolis, IN 46260, USA Angeline N. Beltsos, M.D., Suite 195, 135 North Arlington Heights Road, Buffalo Grove, IL 60089, USA Richard E. Blackwell, M.D., University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 1918 University Boulevard, Birmingham, AL 35294-0005, USA Bradford L. Bopp, M.D., Midwest Reproductive Medicine, 8081 Township Live Road, Indianapolis, IN 46260, USA Robert L. Collins, M.D., Medical Director, The Reproductive Center, Youngstown, OH 44514 and Associate Professor of Obstetrics and Gynecology, Northeast Ohio College of Medicine, Rootstown, OH 44272, USA Bryan D. Cowan, M.D., Professor, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA Janee A. Fonslick, M.D., Abington Obstetrical and Gynecological Associates, Building 2, 300 Welsh Road, Horsham, PA 19044, USA Kristin Sinnock Friel, Lehigh Valley Hospital Allentown, PA 18103, USA Gary N. Frishman, Women’s and Infant’s Hospital, Brown Medical School, 101 Dudley Street, Providence, RI 02 905-0000, USA Jacek W. Graczykowski, Reproductive Health and Fertility Center, 973 Featherstone Road, Suite 100, Rockford IL 61107, USA David A. Grainger, M.D., Director, Division of Reproductive Endocrinology, 9220 E., 29th N Suite 102, Wichita, KS 67226, USA Dorothy Greenfeld, M.S.W., Yale University School of Medicine, Department of Obstetrics and Gynecology WP-402, PO Box 208063, New Haven, CT 06520-8063, USA Dean E. Morbeck, Ph.D., Midwest Center for Reproductive Health, Oakdale Medical Building, 3366 Oakdale Ave North #550, Minneapolis, MN 55422, USA Robert D. Oates, M.D., Department of Urology, Boston University Medical Center, 720 Harrison Avenue, Suite 606, Boston, MA 02118-2334, USA Steven F. Palter, Yale University School of Medicine, Department of Obstetrics and Gynecology, WP402 PO Box 208063, New Haven, CT 06520-8063, USA Phillip E. Patton, M.D. and Professor, University Fertility Consultants Department of Obstetrics and Gynecology, Oregon Health Services University, 1750 SW Harbor Way, Suite 100, Portland, OR 97201, USA

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Contributors

Alan S. Penzias, M.D., Boston IVF, 40 Second Avenue Suite 300, Waltham MA 02451, USA Hossein Sadeghi-Nejad, Director, Center for Male Reproductive Medicine, UMD-New Jersey Medical School and Hackensack University Medical Center, 20 Prospect Ave, Suite 711, Hackensack NJ 07601, USA Richard T. Scott, Jr., M.D., Reproductive Medicine Associates, 111 Madison Avenue Suite 100, Morristown, NJ 07962, USA David B. Seifer, M.D., Director, Division of Reproductive Endocrinology and Infertility, and Professor and Vice-Chair of Academic Affairs, Department of Obstetrics, Gynecology and Reproductive Sciences, UMDNJ–Robert Wood Johnson Medical School, 303 George Street, Suite 250, New Brunswick NJ 08901, USA Arjav Shah, M.D., Orange Park Medical Center, 1605 Kinsley Avenue, Orange Park, FL 32073, USA Fady I. Sharara, M.D., The Fertility and Reproductive Health Center, 4316 Evergreen Lane, Annandale, VA 22003, USA Kevin A. Spear, M.D., Advanced Urology Associates, Professional Center North, 75 Arch Street, Suite 101, Akron, OH 44304, USA Eric S. Surrey, Colorado Center for Reproductive Medicine, 799 East Hampden Ave. Suite 300, Englewood, CO 80110, USA Bruce L. Tjaden, M.D., Center for Reproductive Medicine, 2903 E. Central, Wichita, KS 67214, USA Theresa Widrich, M.D., Department of Obstetrics and Gynecology, Landeskrankenhaus Mödling, Sr. M. Restitutag 12, A-2340, Mödling, Austria Don P. Wolf, Ph.D., Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006-3448, USA

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1 Evaluation of the Female for Infertility Bryan D. Cowan

Evaluation of women with infertility is an increasingly important part of the primary care practitioner’s role. Reproductive dysfunction affects more than 2 million married couples during their reproductive lives, and approximately 10–15% of women between the ages of 25 and 45 seek office consultation concerning reproductive dysfunction. As a perspective, the fertility rate in the United States has remained nearly constant for more than a decade at 2.1 live births per reproductive-age female. This is coincident with the ideal fertility rate that maintains a population profile consistent with “zero population growth.” Because our society has this population growth philosophy, there is great pressure on couples to have their families at a time that is convenient for them personally and professionally. Thus many couples seek fertility services to overcome acquired diseases, enhance natural decreasing fertility associated with age, and accommodate life style agendas.

Confirmation of Infertility Infertility is established when a couple attempts a pregnancy for 12 months or longer and conception fails. It is important to remember that the natural fertility rate is expressed in two ways. The overall cumulative pregnancy rate is the expected probability of conception within a population when all the pregnancies have occurred. The second important factor to consider is the occurrence of pregnancy with each opportunity (ovulation) for conception. In young, unencumbered couples, this fecundity rate is approximately 20% per month. Three important factors are associated with infertility. They are represented by major disturbances in male gamete production, female gamete pro-

duction, and female tuboperitoneal diseases. Although the distribution of these defects varies with infertility populations, it is convenient to consider that about 40% of couples have male factor dysfunction, ovulatory dysfunction occurs in 20%, and anatomic abnormalities are present in 30% (Table 1–1). Ten percent of couples have no identifiable cause of their reproductive dysfunction after a thorough infertility evaluation.

Strategy for Infertility Testing Once the diagnosis of infertility is confirmed, a thorough evaluation correctly classifies the cause of infertility in 85–90% of patients. Most of the evaluation is conducted in an office environment and usually requires no more than 60–90 days to complete. The timing of the tests is generally coordinated with the female ovarian menstrual cycle. Figure 1–1 illustrates the hormone levels during the menstrual cycle. It is usually convenient to schedule tests throughout the course of two cycles to avoid disruption of the ovarian menstrual cycle and potential errors in interpretation if tests conflict.

Male Factor Evaluation The history from the male partner should include important information concerning a history of previously fathered pregnancies, testicular trauma or infection, environmental exposure to toxins or heat, and coital and sexual performance. If a physical examination can be performed, the genitalia are inspected and the developmental stage classified. The scrotum is evaluated for masses, varicocele, or inguinal hernia.

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B.D. Cowan TABLE 1–1. Causes of Infertility

TABLE 1–2. Semen Analysis Parameters

Cause

%

Male factor Ovulation defect Pelvic diseases Unexplained

40 20 30 10

Volume pH Concentration Count Motility Morphology Vitality

Semen analysis is the single most important laboratory test for male factor evaluation. Although many parameters can be measured, the volume, total number of ejaculated sperm, percent motility of the sperm, and percent normal forms (Table 1–2) represent the major and most important parameters. It is important to remember that the time required to complete a cycle of sperm production is 70–80 days. Thus if antecedent illness, stress, or injury has occurred, it is advisable to repeat the semen analysis after an appropriate interval of time has elapsed that would ensure measurement of an unaffected sperm cycle. Adjuncts to the traditional semen analysis have been sought to assess the fertilizing capability of the semen or the fertility of the man. These adjuncts include a postcoital test, zona-free hamster pene-

2 ml 7.2–8.0 20  106 spermatozoa/ml 40  106 spermatozoa/ejaculate 50% forward progression or 25% rapid progression 30% normal forms 75% live

Source: WHO, 1992.

tration, zona binding assays, cervical mucus penetration assays, and seminal antibody detection. Detecting antibody on sperm has been associated with the prediction of infertility, particularly if the antibody is recognized to be a head-to-head agglutinating antibody of the immunoglobulin G class. Unfortunately, except for antibody testing, other adjunctive tests are less helpful, difficult to perform, and expensive. In particular, most authorities recommend that routine use of the postcoital test be abandoned. This test is difficult to interpret and dependent on female cervical mucus production during the ovarian menstrual cycle; moreover, uniform norms have not been established. Additionally, critical evaluation of reported case series reveal an inability of the test to predict fertility. Thus we believe that semen analysis represents the single and most important test for evaluating the man. When necessary, this test should be repeated at 2- to 3-week intervals to encompass a complete 70- to 80-day sperm cycle. Other than seminal antisperm antibodies, other routine adjunctive tests of sperm function are not justifiable and should be used only for special indications.

Assessment of Ovulation

FIGURE 1–1. Hormone levels during the menstrual cycle. During the proliferative phase (days 1–14) estrogen levels progressively rise. Ovulation (day 14) is preceded by an increase in the gonadotropins and is signaled by a sharp rise in luteinizing hormone (LH). During the secretory phase (days 15–28) the corpus luteum produces increasing levels of progesterone. In the absence of fertilization, menstruation (days 1–5) occurs as the endometrium is shed.

The history of the female partner should include the time of menarche, the interval between menstrual cycles, the presence or absence of molimina, the duration of menstrual flow, and the presence or absence of dysmenorrhea. Women with regular, predictable cycles (26–34 days) can be predicted to be ovulatory with a high degree of certainty (99.8%). In perspective, only two to three of every 1000 women who offer a history of regular, predictable cycles are discovered to be anovulatory. It is important to remember that the menstrual history reflects subjective information, and confirmation of ovulatory status should be determined by appropriate laboratory tests. Three office-based procedures are used to confirm that ovulation has

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1. Evaluation of the Female for Infertility TABLE 1–3. Assessment of Ovulatory Status Test BBT Serum progesterone Endometrial biopsy Sonography LH testing

Timing Complete cycle Mid-luteal Late luteal Late follicular Late follicular

BBT, basal body temperature; LH, luteinizing hormone.

occurred, and two additional office-based procedures are used to determine that ovulation will occur in the immediate future. To determine that ovulation has occurred, most clinicians use basal body temperature (BBT) chart monitoring, luteal phase serum progesterone measurements, or secretory phase endometrial biopsy. BBT chart monitoring typically reveals a temperature below 98°F during the follicular phase (Table 1–3). After ovulation the temperature rises 0.2°– 0.6°F and is sustained for 9–13 days during the luteal phase. Immediately before or coincident with the onset of menses, the temperature falls below 98°F. This typical “biphasic” profile is demonstrated repeatedly in ovulatory women. Use of BBT chart monitoring to determine dysfunctional ovulation (in contrast to the absence of ovulation) is generally not helpful. Unfortunately, parameters such as the number of temperature-elevated days and the magnitude of the temperature rise have correlated with other measures of luteal function (progesterone, endometrial biopsy) and have not been used reliably to initiate therapy. Thus BBT chart monitoring can establish ovulation but is unable to determine the presence or absence of ovulatory disturbances. Serum progesterone concentrations are higher than 5 ng/ml during the luteal phase. Most clinicians use the luteal phase progesterone level to establish both ovulation and the quality of ovulation. If the serum progesterone is higher than 5 ng/ml, ovulation is confirmed. This measurement can apply to any day of the luteal phase. When more rigorous criteria are set for the time of progesterone measurement (6–8 days prior to the onset of menses—typically day 20–22 of the cycle), several investigators have reported that the “quality” of ovulation can be determined. The precise threshold value of progesterone is controversial, but most agree that a mid-luteal progesterone level of less than 10 ng/ml is consistent with luteal dysfunction. Additionally, most authors agree that a serum progesterone level higher than 20 ng/ml is consistent with adequate luteal function. There is no consensus on what a serum progesterone level of 10–20

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ng/ml indicates about luteal function, but it clearly means that ovulation has occurred. Endometrial biopsy is typically performed during the late luteal phase to classify the morphologic transformation of the secretory endometrium. The “luteal phase defect” has been defined as endometrium that is more than 48 hours “out of phase” with the cycle. The proper interpretation of this test requires three pieces of information: (1) the date the test was performed; (2) the date natural menstruation occurred; and (3) the morphologic dating of the endometrial specimen. For example, a specimen obtained on day 26 of a 28-day cycle that was interpreted as consistent with day 23 endometrium would be considered out of phase, but a specimen obtained 6 days before the onset of menstruation consistent with day 23 secretory endometrium would be considered in phase. Finally, interest has emerged concerning adjunctive measurement of endometrial peptides. In particular, some integrins are known to be expressed at unique times during the secretory phase. Measurement of these factors may increase the accuracy of properly classifying endometrial specimens. Endometrial biopsy is inconvenient to the patient, is associated with mild discomfort, and is approximately four to six times more expensive than serum progesterone measurements. Unfortunately, there is a mixed degree of agreement regarding serum progesterone measurements and endometrial maturity. Hence these two tests currently stand at the “discretion of the practitioner” as independent but not correlated tests. Follicular measurements (sonography) have been used to predict ovulation. In general, a naturally growing follicle expands at approximately 2–3 mm per day and ruptures after the follicular diameter approaches 20–22 mm. In contrast, a clomiphene citrate-stimulated follicle ruptures when the diameter approaches 24–26 mm. After rupture the follicle generally collapses, and fluid collects in the cul-de-sac. Commonly, a luteal structure can be observed in the ovary. Finally, urinary measurements of mid-cycle luteinizing hormone (LH) can detect the preovulatory LH surge. Because urinary LH measurements are done infrequently (usually once or twice daily), it is reasonable to estimate that ovulation will occur 24–36 hours after detection of the surge.

Anatomic Defects Figure 1–2 reviews the anatomy of the female pelvic organs. Two principal anatomic defects deserve evaluation for couples with infertility. Uter-

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B.D. Cowan TABLE 1–4. Assessment of Tuboperitoneal/ Anatomic Status Test Hysterosalpingography Laparoscopy Hysteroscopy Sonohysterography Sonography

FIGURE 1–2. Female pelvic organs. (A). The relations between uterus, bladder, colon, and great vessels are noted in the transverse plane. (B) These relations are emphasized in the sagittal plane.

ine abnormalities (malformations, uterine fibroids, endometrial polyps) and tuboperitoneal factors (pelvic scarring from infection or prior surgery, endometriosis, congenital tubal abnormalities) can be evaluated by several techniques (Table 1–4). A time-honored test for evaluating uterine and tubal factors is hysterosalpingography. It is a contrast study performed under fluoroscopy, where radiopaque solutions are injected into the uterus to define the outline of the uterus and fallopian tubes.

Comment High false-negative rate Confirms peritoneal disease Confirms intrauterine disease Visualizes mural and intrauterine lesions Identifies uterine and endometrial contour

Currently, both aqueous and oil-based contrast solutions are available for use. Studies have provided evidence concerning the value of hysterosalpingography. If the hysterosalpingogram is normal (normal uterine contour with bilateral tubal fill and spill), it has a negative predictive value of only about 60%. This is principally because the infertility population has a high incidence of endometriosis, which typically represents peritoneal disease but not tubal disease. Therefore the tubes appear open on the hysterosalpingogram, but the disease remains unrecognized by this limited study. Similarly, proximal tubal occlusion has a 50% positive predictive value. At the time of further diagnostic studies (below) proximal tubal occlusion cannot be demonstrated, probably related to the presence of tubal spasm or another technical problem associated with the procedure. However, the hysterosalpingogram has a high positive predictive value if distal tubal occlusion is detected. When distal tubal occlusion is detected, untreated patients are at increased risk for pelvic infection. Therefore these patients should be treated with an outpatient course of antibiotics. We recommend doxycycline 100 mg bid for 5 days. The efficacy of antibiotic treatment for patients without hydrosalpinx has not been demonstrated convincingly. The presence of acute cervical or pelvic infections represents a contraindication. Most clinicians use water-based contrast material for hysterosalpingography. The use of oil-based contrast material has been associated with an intravasation syndrome. The oil-based droplets are absorbed into the circulation and then wedge in the microcapillary spaces throughout the body. This syndrome presents as respiratory difficulty (pulmonary involvement) and changes in mental status (cerebral involvement). The syndrome typically appears a few hours after the procedure. Deaths have been reported. The diagnosis is relatively easy, usually based on a chest radiograph demonstrating contrast dispersed throughout the lung. Treatment is supportive.

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1. Evaluation of the Female for Infertility

Sonography is a valuable tool for detecting uterine structural lesions such as uterine fibroids and adnexal pathology. Although the role of sonography has been limited by its inability to evaluate tubal status and subtle abnormalities of the endometrium (polyps, small fibroids), it is emerging as a relatively simple office-based procedure that can provide the clinician with extra details concerning the pelvic anatomy. The inclusion of sonohysterography has expanded our view of the endometrium to detect intrauterine abnormalities that may go undetected. However, even with sonohysterography, demonstration of tubal patency is difficult. Some authors have reported using special solutions, adding microspheres, and color-flow Doppler to demonstrate flow into the fallopian tubes. Despite the problems, sonography and sonohysterography currently are best applied to the evaluation of the uterus and endometrium. Endoscopy is currently considered the most thorough, comprehensive tool for evaluating pelvic anatomy. Laparoscopy allows visualization of the peritoneum to detect endometriosis and to assess tubal status. Hysteroscopy can be used to evaluate the endometrium and the tubal ostia. Additionally, when disease is detected, therapy can be provided. These therapies include adhesiolysis, neosalpingostomy, and adnexal surgery.

Evaluation Strategy The strategy for female infertility evaluation has evolved into an efficient, cost-effective investigation that can usually be performed during two cycles. Figure 1–3 shows the usual timing of the

major tests to evaluate male factor, tuboperitoneal status, and ovulation status. Invasive procedures such as hysterosalpingogram and laparoscopy are scheduled during the proliferative phase of the cycle to avoid the risk of a procedure during a concomitant pregnancy. Serum progesterone measurements are timed for 6–8 days before the onset of menses, and endometrial biopsy is performed 2–3 days prior to the onset of menses. Semen analysis can be performed at any time during the cycle. In general, we recommend hysterosalpingography, serum progesterone, and semen analysis during the first month. An office visit can be scheduled at the conclusion of these studies to review the data and to advance to laparoscopy based on any detected abnormalities (below). If no explanation is discovered after these initial studies, endoscopy (hysteroscopy and laparoscopy) is performed to exclude endometriosis and nonobstructive tubal adhesions (found in approximately 50% of cases with negative basal studies) and occult intrauterine lesions (fewer than 1% of patients).

Treatment Treatment strategy is based on the level of clinical care available for the couple. Three levels of care have evolved, classified as basic, complex level I, and complex level II. The basic level of care is based on treating anovulation. Patients with more complex disorders are referred to higher levels. As seen in Table 1–5, women more than 35 years of age should be considered to have a complex problem and so be referred to a higher level of evaluation. Only women less than 35 years of age with ovulation dysfunction are candidates for basic levels of treatment. If ovulation defects exist, clomiphene citrate is initiated for up to four cycles. Thyroid and prolactin screening should exclude correctable endocrine dysfunction.

TABLE 1–5. Levels of Complexity of Reproductive Care

FIGURE 1–3. Usual timing of fertility testing during the female ovarian menstrual cycle. HSG, hysterosalpingogram; P, progesterone; Bx, endometrial biopsy; PCT, postcoital test; surgery, laparoscopy, and/or hysteroscopy.

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Basic level 35 years old Anovulation No male or tubal factors Complex level I 35 years old Tubal disease Male factor No conception at basic level Complex level II Gamete technologies

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B.D. Cowan

TABLE 1–6. Outcome of ART Procedures (1997*) Procedure IVF IVF  ICSI GIFT ZIFT Donor Cryopreserved cycle

# of Cycles

Deliveries (%)

Ectopic (%)

33,032 18,312 1,943 1,104 4,616 10,181

28.4 27.1 30.0 28.0 35.7 16.9

0.9 0.6 1.0 1.2 0.5 0.7

*Fertil Steril 2000;74:641–654.

Complex level I is a level of care designed to treat diagnosis-related conditions of male gamete production, tuboperitoneal disease, and complex anovulation. Complex level I treatment facilities have the ability to treat couples with insemination, advanced follicular stimulation, and advanced endoscopic management. It makes little sense to perform expensive, time-consuming diagnostic procedures (e.g., laparoscopy) if the operating surgeon does not have the skill to treat the conditions detected properly. Complex level II facilities provide gamete technologies to correct infertility. An array of assisted reproductive technology (ART) (Table 1–6) can be used under the umbrella “gamete technologies.” Commonly, patients who receive these treatments have failed conservative therapies at the basic and complex level I or are of advanced maternal age when seeking fertility treatment. Therapeutic options are classified as diagnosisrelated or empiric. Diagnosis-related treatments are provided for couples affected by disordered male factors, tubal factors, or ovulation defects. Empiric therapy is provided to couples with unexplained infertility.

Male Factor Treatment Male factor treatment is principally insemination. Two types of insemination are provided: homologous and donor. In general, homologous intrauterine insemination has a per-cycle fecundity (see

below) that ranges from 3% to 9% and a cumulative probability of conception that approaches 30% over 8–12 inseminations. Donor insemination has an expected fecundity of 12–18% and a cumulative success rate that approaches 70% after 8–10 treatment cycles. In special cases, retrograde ejaculation, electrostimulatory ejaculation, and testicular aspiration/biopsy have allowed acquisition of sperm for use in insemination or ART.

Tubal Disease Pelvic adhesions and endometriosis represent diseases of the pelvis that impair fertility. Laparoscopic adhesiolysis produces a pregnancy success rate of nearly 50%. On the other hand, women who require neosalpingostomy for hydrosalpinx have an overall expected maximum probability of pregnancy of less than 20%. Endometriosis is classified into stages based on the extent of disease. In women with early disease (stage I–II) the cumulative probability of pregnancy is 60%. In contrast, women with stage III or IV disease benefit from surgery, but the cumulative probability of pregnancy is only 35% for these women.

Ovulation Defects Women with estrogenized/androgenized chronic anovulation are typically treated successfully with

TABLE 1–7. Fecundity and Cumulative Probability of Conception for Various Infertility Treatment Options Treatment option Unexplained and untreated Anovulatory with clomiphene Surgery for adhesiolysis Surgery for neosalpingostomy Surgery for stage I–II endometriosis Surgery for stage III–IV endometriosis hMG for hypothalamic amenorrhea Normal hMG, human menopausal gonadotropin.

Fecundity

Cumulative conceptions (%)

0.08 0.12 0.04 0.02 0.06 0.06 0.30 0.20

50 65 40 12 65 35 90 90

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1. Evaluation of the Female for Infertility

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these parameters. Two models are commonly used today to estimate fecundity and cumulative probability. Life-table analysis and logistic regression allow analysis of time-dependent data. Table 1–7 demonstrates fecundity and cumulative probability of conception for various treatment options, and Figure 1–4 illustrates the logistic analysis using these parameters.

Impact of Age on Reproduction

FIGURE 1–4. Logistic regression demonstrating the cumulative probability of conception for common infertility conditions.

clomiphene citrate: 85% of patients on this therapy ovulate. Of those who ovulate, 65% achieve a pregnancy within 4–6 months. Human menopausal gonadotropin (hMG) (Metrodin, Pergonal, Humegon, Fertinex) has been used to treat women with hypogonadotrophic hypogonadism and estrogenized/androgenized chronic anovulatory patients who fail to respond to clomiphene citrate. Curiously, those with hypogonadotrophic hypogonadism have an excellent response to hMG therapy. Approximately 90% of these patients achieve a pregnancy within 6 months of therapy. This remarkable response represents the highest fertility treatment option available to clinicians. In contrast, chronically anovulatory patients refractory to clomiphene citrate fare much worse: Their expected maximum probability of pregnancy is only 30% despite the high ovulatory rates established with hMG.

Measures of Fertility Treatment Success Fertility treatment measurements require an analysis of time-dependent events. As such, two expressions are used to discuss fertility success. Fecundity is the measure of pregnancy occurrence per single ovulatory cycle. The cumulative probability of pregnancy represents the expectations of conception in a population over time. That expectation is time-dependent and may occur within 6 months or 6 years, depending on the duration of the measurement. Analytic tools have been developed to assess

No discussion of female fertility would be complete without considering ovarian maturity. Two detrimental reproductive events affect oocyte development over time. Increased occurrence of nondisjunction leads to genetic abnormalities associated with trisomy. Table 1–8 demonstrates the agedependent association of Down syndrome (trisomy 21). Reproductive efficiency is also dramatically influenced by age. Two important examples must be considered. A 40-year-old population undergoing donor insemination demonstrated a 50% preg-

TABLE 1–8. Age-Dependent Association of Down Syndrome Maternal age (years)

Risk of Down syndrome

Risk for all chromosome abnormalities

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

1/1923 1/1695 1/1538 1/1408 1/1299 1/1205 1/1124 1/1053 1/990 1/935 1/885 1/826 1/725 1/592 1/465 1/365 1/287 1/225 1/177 1/139 1/109 1/85 1/67 1/53 1/41 1/32 1/25 1/20 1/16 1/12

1/526 1/526 1/500 1/500 1/476 1/476 1/476 1/455 1/435 1/417 1/384 1/384 1/322 1/285 1/243 1/178 1/149 1/123 1/105 1/80 1/63 1/48 1/39 1/31 1/24 1/18 1/15 1/11 1/8 1/7

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FIGURE 1–5. Historic population analysis of female fertility rate by age from Morman genealogic data. Modified from Mineau G and Trussell J, Demography, 1982.

nancy occurrence and a 50% miscarriage rate, for a take-home pregnancy success rate of 25%. This population was compared to a 30-year-old group who demonstrated an 80% chance of pregnancy and a 20% chance of miscarriage, resulting in a 65% take-home pregnancy rate. Lastly, historic populations have demonstrated profound aberrations of the fertility rate after age 35 (Fig. 1–5). Historic populations are of interest because contraception was unknown, and in some (e.g., Mormans) large families were desired. Thus women after age 35 are at increased risk for nondisjunction events leading to trisomy and decreased reproductive efficiency. Fertility evaluation and treatments become urgent in this population.

Suggested Reading Diagnosis Baker HWG, Burger HG, de Krester DM, et al. Testicular vein ligation and fertility in men with varicoceles. BMJ 1985;291:1678–1680. Barnea ER, Holford TR, McInnes DRA. Long-term prognosis of infertile couples with normal basic investigations: a life-table analysis. Obstet Gynecol 1985;66: 24–26. Barratt CLR. On the accuracy and clinical value of semen laboratory tests. Hum Reprod 1995;10:250–252. Chalmers TC, Celano P, Sacks H, Smith H Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983;309:1358–1361. Dunphy BC, Scudamore I, Cooke ID. Falloposcopy, a

technological gimmick or a clinical tool? J Soc Obstet Gynecol Can 1993;15:25–32. Eggert-Kruse W, Leinhos G, Gerhard I, et al. Prognostic value of in vitro sperm penetration into hormonally standardized human cervical mucus. Fertil Steril 1989; 51:317–323. ESHRE Capri Workshop Group. Male sterility and subfertility: guidelines for managements. Hum Reprod 1994;9:1260–1264. Forti G, Krausz C. Clinical review 100: evaluation and treatment of the infertile couple. J Clin Endocrinol Metab 1998;83:4177–4188. Griffith CS, Grimes DA. The validity of the postcoital test. Am J Obstet Gynecol 1990;162:616–620. Gwatkin RBL, Collins JA, Jarrell JF, et al. The value of semen analysis and sperm function assays in predicting pregnancy among infertile couples. Fertil Steril 1990;53:693–699. Hanson MA, Dumesic DA. Initial evaluation and treatment of infertility in a primary-care setting. Mayo Clin Proc 1998;73:681–685. Hughes EG, Fedorkow DM, Collins JA. A qualitative overview of controlled trials in endometriosis-associated infertility. Fertil Steril 1993;59:963–970. Kremer J, Jager S. The significance of antisperm antibodies for sperm-cervical mucus interaction. Hum Reprod 1992;7:781–784. Opsahl MS, Miller B, Klein TA. The predictive value of hysterosalpingography for tubal and peritoneal infertility factors. Fertil Steril 1993;60:444. Shalev J, Meizner I, Bar-Hava I, et al. Predictive value of transvaginal sonography performed before routine diagnostic hysteroscopy for evaluation of infertility. Fertil Steril 2000;73:412–417. Taylor PJ, Lewinthal D, Leader A, et al. A comparison of dextran 70 with carbon dioxide as the distention medium for hysteroscopy in patients with infertility or requesting reversal of a prior tubal sterilization. Fertil Steril 1987;47:861–863. Wentz AC, Kossoy LR, Parker RA. The impact of luteal phase inadequacy in an infertile population. Am J Obstet Gynecol 1990;162:937–945. Yoder IC, Hall DA. Hysterosalpingography in the 1990s. AJR 1991;157:675–683.

Treatment Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994; 171:1488–1505. American Fertility Society. The American Fertility Society classification of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–955. Chung CC, Fleming R, Jamieson ME, et al. Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility. Hum Reprod 1995;10:3139–3141. Collins JA, Burrows EA, Willan AR. The prognosis for

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1. Evaluation of the Female for Infertility live birth among untreated infertile couples. Fertil Steril 1995;64:22–28. Crosignani PG, Walters DE, Soliani A. The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report. Hum Reprod 1991;6:953– 958. Dlugi AM, Reddy S, Saleh WA, et al. Pregnancy rates after operative endoscopic treatment of total (neosalpingostomy) or near total (salpingostomy) distal tubal occlusion. Fertil Steril 1994;62:913–920. Edvinsson A, Forssman L, Milsom I, et al. Factors in the infertile couple influencing the success of artificial insemination with donor semen. 1990;53:81–87. Friedman AJ, Juneau-Norcross M, Sedensky B, et al. Life table analysis of intrauterine insemination pregnancy rates for couples with cervical factor, male factor, and idiopathic infertility. Fertil Steril 1991;55:1005–1007. Gysler M, March CM, Mishell DR Jr, et al. A decade’s experience with an individualization of clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982;37:161–167. Haan G. Effects and costs of in-vitro fertilization. Int J Technol Assess Health Care 1991;7:585–593. Hammond MG, Hlame JK, Talbert LM. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation. Obstet Gynecol 1983;62:196–202. International Federation of Fertility Societies, Montpellier, pp 1–43. International Working Group for Registers on Assisted Reproduction. World Collaborative Report 1993. Lindheim SR, Kavic S, Shulman SV, Sauer MV. Operative hysteroscopy in the office setting. J Am Assoc Gynecol Laparosc 2000;7:65–9. Mineau G, Trussell J. A specification of marital fertility by parents’ age, age at marriage, and marital duration. Demography 1982;19:335–350. Office of Technology, US Congress. Infertility: Medical and Social Choices. US Government Printing Office, Washington, DC, pp 3–402.

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Pal L, Lapensee L, Toth TL, Isaacson KB. Comparison of office hysteroscopy, transvaginal ultrasonography, and endometrial biopsy in evaluation of abnormal uterine bleeding. J Soc Laparoendosc Surg 1997;1:125–30. Reiss H. Management of tubal infertility in the 1990s. Br J Obstet Gynaecol 1991;98:619–623. Saidi MH, Sadler RK, Theis VD, Akright BD, Farhart SA, Villanueva GR. Comparison of sonography, sonohysterography, and hysteroscopy for evaluation of abnormal uterine bleeding. J Ultrasound Med 1997; 16:587–91. Saravelos, et al. Microsurgery versus laparoscopic adhesiolysis for fertility. Hum Reprod 1995;10:2887–2928. Schlesinger MH, Wilets IF, Nagler HM. Treatment outcome after varicocelectomy: a critical analysis. Urol Clin North Am 1994;21:517–529. Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted reproductive technology in the United States: 1997 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2000;74: 641–654. Speroff L. The effect of aging on fertility. Curr Opin Obstet Gynecol 1994;6:115–120. Toner JP, Glood JR. Fertility after the age of 40. Obstet Gynecol Clin North Am 1993;20:261–272. Valli E, Zupi E, Marconi D, Solima E, Nagar G, Romanini C. Outpatient diagnostic hysteroscopy. J Am Assoc Gynecol Laparosc 1998;5:397–402. Van Steirteghem A, Liu J, Joris H, et al. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination: report of a second series of 300 consecutive treatment cycles. Hum Reprod 1993;8: 1055–1060. Zullo F, Pellicano M, Stigliano CM, DiCarlo C, Fabrizio A, Nappi C. Topical anesthesia for office hysteroscopy. A prospective randomized study comparing two modalities. J Reprod med 1999;6:331–6.

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2 Evaluation of the Male for Infertility Kevin A. Spear

The purpose of this chapter is to give a concise but practical overview of the in-office evaluation of the infertile man. Women have traditionally sought consultation and treatment for infertility, so the focus of therapy for many years has been on female factors. Because approximately 40% of infertility cases involve male factors, it is imperative that the couple be considered as a unit and the infertility evaluation proceed in a parallel manner. Also, significant medical pathology can be uncovered by a comprehensive infertility evaluation of the man. Additionally, with advances in the diagnosis and treatment of male factor infertility, and the refinement of assisted reproductive techniques, many men whose problems were once untreatable are now excellent candidates for therapy. As economic issues are becoming increasingly important, it is evident that treatment of male factor infertility is cost-effective. The man must not be ignored, and the following is a guide to his evaluation.

Evaluation The initial workup begins whenever the patient presents. This is predicated by the fact that the longer a couple remains infertile the less chance there is for cure. A rapid, noninvasive, cost-effective evaluation is essential.

History The cornerstone of the evaluation of the infertile man is the history and physical examination. Table 2–1 outlines the complete pertinent history. The sexual history is paramount. Some of the problems most commonly encountered in this patient population are related to the timing of intercourse, with it being too frequent or too infrequent. Often nei10

ther husband nor wife understands the menstrual cycle and does not know the optimal time for intercourse. Because sperm survive in the female reproductive tract for approximately 2 days, the most effective frequency of intercourse is every 48 hours around the ovulatory peak, which ensures that viable spermatozoa are present during the 12- to 24-hour period when the egg is in the fallopian tube and capable of being fertilized. Lubricant use should be investigated. Commonly used substances such as K-Y Jelly, Lubifax, Surgilube, Keri Lotion, and saliva have been shown to decrease sperm motility in vitro. If lubricant use is necessary, couples should be instructed to use a minimal amount of one that does not impair motility. Substances that do not impair in vitro motility include petroleum jelly, vegetable oil, and peanut oil. The history of an undescended testicle is significant. In a patient with a history of unilateral cryptorchidism, regardless of the time of orchidopexy, overall semen quality is considerably less than that found in normal men. Despite this fact, most men with one undescended testis are able to initiate a pregnancy without difficulty. Bilateral cryptorchidism is extremely important. Progressive damage occurs to the germinal epithelium if the testicle is not in its proper position in the scrotum. It has been shown that orchidopexy should be performed prior to 2 years of age to maintain a significant level of spermatogenic function. Any previous surgery of the retroperitoneum, bladder neck (prostate), pelvis, inguinal region, or scrotum should be assessed. Retroperitoneal lymph node dissection with interruption of the sympathetic chain causes anejaculation with resultant azoospermia. Today nerve-sparing techniques allow more than 90% of patients to retain ejaculatory function after retroperitoneal lymph node dissection. Any

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2. Evaluation of the Male for Infertility TABLE 2–1. Infertility History Sexual history Duration of infertility Prior pregnancies, with present and any previous partners Previous treatments Evaluation and treatment of female partner Potency Use of lubricants Timing and frequency of intercourse Frequency of masturbation Past medical history, including childhood Undescended testicles Testicular torsion Testicular trauma Delayed puberty Pelvic injury Diabetes, multiple sclerosis Previous or current therapy Viral and febrile illness history Postpubertal mumps orchitis Sexually transmitted diseases Urinary tract infections Cystic fibrosis, or family history of it Past surgical history Orchiectomy Orchidopexy Retroperitoneal surgery Pelvic, inguinal, or scrotal surgery Herniorrhaphy Medications and gonadotoxins Chemotherapeutic agents Therapeutic drugs: cimetidine, sulfasalazine, nitrofurantoin Chemicals (pesticides) Recreational drugs: smoking, marijuana, cocaine Androgenic steroids Thermal exposure (hot tubs) Radiation

surgery on the bladder neck may cause retrograde ejaculation. Inguinal surgery such as herniorrhaphy, undertaken when an infant or an adult, may have caused vasal occlusion or vascular insufficiency to the testicle. Fever can cause impaired testicular function. The ejaculate may not be affected for more than 3 months after the event, as spermatogenesis takes about 74 days. Therefore events that have occurred during the previous 3–6 months are important. Postpubertal mumps may cause mumps orchitis, which results in an atrophic testis. Fifty percent of patients with testicular cancer have subnormal sperm densities prior to therapy. A history of diabetes or multiple sclerosis should raise questions about potency and ejaculatory function. Exposure to drugs and toxins should be detailed. Withdrawal of the medications listed under gonadotoxins in Table 2–1 may allow the return of normal spermatogenesis. The routine use of hot tubs or saunas should be discontinued, as elevated temperatures impair spermatogenesis.

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A family history of cystic fibrosis is important owing to associated vasal agenesis and epididymal abnormalities. Finally, a history of anosmia (lack of smell) indicates the possibility of hypogonadotropic hypogonadism. Galactorrhea, headaches, and impaired visual fields suggest the presence of a central nervous system tumor. It is useful to use a preprinted history form filled out by the patient. It ensures that all pertinent historical data are obtained prior to the physical examination.

Physical Examination The physical examination must be thorough, with special attention to the genitalia. Figure 2–1 depicts the pertinent male reproductive anatomy. The penile curvature and location of the urethral meatus should be assessed, as abnormalities may result in improper delivery of the ejaculate. Testicular size and consistency must be recorded, with the length

FIGURE 2–1. Pertinent male reproductive tract anatomy in coronal view. Arrows depict flow of sperm and ejaculate. (By permission of the American Society of Reproductive Medicine)

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FIGURE 2–2. Measuring the length of a testicle with a Seager orchidometer. (From Goldstein, 1995, by permission of W.B. Saunders)

testicle in the scrotum—must be identified (Fig. 2–3). A varicocele can cause abnormalities in gonadal function. The scrotal contents should be palpated with the patient in both the supine and standing positions. Many varicoceles are not visible and may be discernible only when the patient stands or performs a Valsalva maneuver. Varicoceles often result in a smaller testis on that side. Ninety percent are left-sided, and any discrepancy in size between the two testes should arouse suspicion of a varicocele. A rectal examination is essential to assess prostate size, evidence of infection, and the presence of midline cysts. Look carefully for signs of hypogonadism, such as decreased body hair, gynecomastia, infantile genitalia, and decreased muscular development.

Laboratory Evaluation measured with calipers (Fig. 2–2) and the volume estimated with an orchidometer. Size is an important indicator of spermatogenic capability, as 85% of the testis is involved in sperm production. When there is damage to the testicular tubules, loss of mass occurs. The normal length of the testis is more than 4 cm and the volume more than 20 ml. Epididymal induration and irregularities should be noted. The presence of a vas must be documented, as 2% of infertile men have congenital absence of the vas. Varicoceles—dilated spermatic veins that present as a “bag of worms” above the

FIGURE 2–3. (A) Left visible (grade 3) varicocele. (B) dilated veins underneath the scrotal skin.

The laboratory is an integral part of a full-service infertility center. If an on-site laboratory is not available, specimens must be analyzed by a dedicated infertility laboratory. Data from a reputable laboratory are critical. Unfortunately, the semen analysis must be done locally because the specimen must be evaluated shortly after production. Most other studies can be sent out to any reputable laboratory.

Semen Analysis The primary laboratory test is the semen analysis. It must be emphasized that semen analysis is not a test for fertility. It does not separate patients into sterile and fertile groups; it does give diagnostic information and allows a directed evaluation and treatment. At least two semen analyses must be obtained to establish a baseline. The specimen should be collected with a consistent abstinence of 2–3 days. The specimen container must be clean, not necessarily sterile, and wide-mouthed to minimize collection error. The preferred technique of collection is by masturbation, although coitus interruptus or use of a special condom devoid of spermatocidal agents may be used. The specimen must be evaluated within 2 hours of collection. The standard semen analysis allows evaluation of semen volume, pH, density (sperm per milliliter), motility, measurement of forward progression of sperm, and sperm morphology. The semen is examined also for evidence of sperm agglutination, hyperviscosity, and the presence of white

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2. Evaluation of the Male for Infertility TABLE 2–2. WHO Criteria for Normal Semen Analysis Semen parameter Volume Density Motility Forward progression Morphology Leukocytes Agglutination Hyperviscosity

Value 2.0–5.0 ml 20 million/ml 50% 2 (scale 1–4) 30% normal forms 1 million/ml None None

Source: World Health Organization, 1992.

blood cells. The World Health Organization (WHO) range of values for normal semen analysis is given in Table 2–2. Some laboratories use computer-assisted semen analyses, which are of some value for measuring sperm motility; however, they should be used only as a source of supplemental information. Attention has been turned to a more accurate manual analysis of sperm morphology. Using strict criteria (Kruger criteria) for defining “normal” morphology, in patients undergoing in vitro fertilization (IVF), a significantly higher fertilization rate may be achieved from semen specimens with more than 4% normal forms.

Adjunctive Semen Studies White Blood Cell Staining Leukocytes in semen have significant effects on sperm function. They modulate an autoimmune response, adversely affect motility and fertilizing capacity, and deter sperm transport in the female reproductive tract. The semen of most men contains some immature sperm forms (round cells), which ordinarily cannot be distinguished from white blood cells (WBCs). This often leads to an erroneous diagnosis of pyospermia or infection. Special immunohistochemical stains identify WBCs. These stains should be employed if more than 1 million round cells/ml or more than 1 million WBCs/ml are reported on routine semen analysis. The peroxidase stain can be employed: It stains polymorphonuclear leukocytes brown. Monoclonal antibodies directed against the leukocyte CD45 or HLE-1 antigen are the current “gold standard.” Although more accurate, they are expensive and labor-intensive. In most clinical cases, a cytochemical stain is sufficient. Semen cultures are not indicated in asymptomatic patients, as they are essentially always negative. Routine cultures for atypical organisms are unwarranted because they

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are not always accurate, are labor- and cost-prohibitive, and have not been shown to have a clinical impact. For the few patients with symptoms of urinary or genital tract infections cultures should be prepared. The specific cultures obtained depend on the individuals’ symptoms and examination but should include cultures of urine, expressed prostatic secretions, and a postprostatic massage urine sample. It has been demonstrated that exotoxins of Escherichia coli can significantly affect sperm motility and may also decrease sperm production. Common sexually transmitted organisms such as Chlamydia, Mycoplasma, and Ureaplasma have been implicated in reproductive failure. Patients with active prostatitis or other urinary tract infections frequently have decreased sperm count and motility.

Fructose With low-volume oligospermia or low-volume azoospermia, one should be concerned about retrograde ejaculation and ejaculatory duct obstruction. The assessment for ejaculatory duct obstruction may incorporate a test for seminal fructose, a sugar produced in the seminal vesicles. Its absence may indicate the possible absence of the seminal vesicles or obstruction of the ejaculatory ducts. Problematically, the fructose test is not entirely accurate and hence is unreliable. The state of the art now is transrectal ultrasonography (TRUS) to detect ejaculatory duct obstruction or seminal vesicle aplasia.

Anti-sperm Antibodies Great attention has been focused recently on immunologic infertility, resulting in a better understanding of the etiology and biology of anti-sperm antibodies. The incidence of anti-sperm antibodies in the infertile man range from 8% to 21%. In contrast, only 0.9–4.0% of fertile men and women have detectable antibodies. Aggregate evidence documents that anti-sperm antibodies comprise significant infertility factor. In men only antibodies present on the sperm surface are clinically important. Anti-sperm antibodies have implications at various stages in the fertilization process. Clarke et al. showed that sperm agglutination is significantly higher in men with positive immunobead tests. Thus sperm agglutination is a definite sign of antisperm antibodies. Others have found that antibodies decrease motility. Poor sperm penetration into cervical mucus has been noted in many of these patients. Additionally, the acrosome reaction may be impaired in patients with antibodies attached to

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the sperm head. Of great importance is evidence that anti-sperm antibodies may cause impairment of zona binding and fertilization. In Zonari et al.’s study, IVF cycles with no fertilization showed a lack of zona binding and antibodies on the sperm head. Witkin et al. studied unsuccessful IVF cycles and found a high correlation between sperm-bound antibodies and low fertilization rates. Risk factors for the development of sperm-bound antibodies include previous testicular surgery, trauma, or infection, as does a history of torsion, cryptorchidism, and genitourinary infections. Additionally, obstructive azoospermia (possibly due to obstruction from a previous hernia repair, congenital absence of the vas deferens, or vasectomy) can induce sperm autoimmunity. No prevasectomy reversal evaluation is required, as only serum antibodies can be assessed. Serum antibodies are nonspecific and cannot accurately predict postoperative results. Selective testing for anti-sperm antibodies is important. Patients who should be evaluated include those with the previously mentioned risk factors as well as those with sperm agglutination noted on semen analysis, low sperm motility, abnormal cervical mucus penetration test, or multiple failed intrauterine insemination (IUI) or IVF cycles, and couples with unexplained infertility. There is no good correlation between serum antisperm antibodies and the presence of sperm-bound antibodies. Additionally, it is the sperm-bound antibodies that cause abnormalities in reproductive function, which is where testing should be focused. Direct assays measure sperm-bound antibodies. Indirect tests are serum studies. The preferred test is the direct immunobead test (IBT), but it requires motile sperm. Results show the percent of sperm bound, the antibody isotype, and the binding location. The clinically significant range is 20–50% of sperm demonstrating immunobead binding. Immunoglobulin G (IgG) and IgA antibodies are assessed. It is unlikely that IgM immunoglobulin will be found in the male genital tract, so testing for this subclass is unwarranted. In instances where this level of sophisticated testing is not available or a screening test is desired, Sperm Mar (Ortho Diagnostic Systems, Beerse, Belgium) is a commercially available assay that does not require sperm processing.

Sperm Function Tests Sperm–Cervical Mucus Interaction The postcoital test assesses the sperm in the partner’s cervical mucus and the interaction between the two. The test is performed just prior to ovula-

tion. A specimen of cervical mucus, obtained within a few hours of intercourse, is examined under a microscope. More than 10 sperm per high power field, most of which demonstrate progressive motility, constitutes a normal study. Indications for postcoital testing include hyperviscous semen, unexplained infertility, and lowvolume semen with good sperm density. This test is contraindicated for patients with poor quality semen specimens. Inherent poor reproducibility and the fact that there are specimens from both parties make the study difficult to interpret. If an abnormal result is obtained, an in vitro cervical mucus penetration test may be performed. These tests have been developed to standardize and isolate semen factors. Several commercially available tests allow measurement of sperm migration and penetration through standard (usually bovine) cervical mucus. An example of this type of test is the Penetrak (Serono Diagnostics, Braintree, MA). These test results usually correlate with the quality of the semen specimen, but there are patients who have abnormal results and normal semen parameters. In these individuals, look for the presence of antisperm antibodies. Currently, the definitive role of cervical mucus penetration tests in the evaluation of the infertile male is not clear.

Sperm Penetration Assay The sperm penetration assay is a sophisticated test that measures the physiologic ability of the human sperm to enter a zona-free hamster egg and begin the fertilization reaction. The zona pellucida is the barrier to cross-species fertilization. When hamster eggs are rendered zona-free and penetrated by human spermatozoa in vitro, they serve as a substitute for human ova in a preliminary assessment of fertilizing capacity. For successful penetration, sperm must be able to undergo capacitation, the acrosome reaction, fusion with the oolema, and incorporation into the ooplasm. Scoring is based on the percentage of ova penetrated, or number of penetrations per ovum. The lower limit of normal is 10–30% of ova penetrated. Results are expressed as the mean number of penetrations per ovum, which Lipshultz’s laboratory has termed the sperm capacitation index (SCI). An SCI of less than 5 is abnormal. Although interpretation of this study is controversial, the results generally correlate with IVF success rates. The test may be useful is if one is contemplating IUI versus IVF/ICSI (intracytoplasmic sperm injection) or IVF versus ICSI. If the sperm penetration assay is normal, IUI would be logical in the IUI versus IVF/ICSI case, and IVF

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would be indicated in the IVF versus ICSI case. Familiarity with the laboratory performing the assay is critical to allow proper interpretation.

Hormonal Screening A brief review of male reproductive endocrine physiology is essential. The testes are dual organs. There is an endocrine (hormonal) component consisting of Leydig cells, Sertoli cells, and germ (sperm) cells. This component is necessary for male sexual differentiation and maturation, normal potency and ejaculatory capability, and spermatogenic maturation. Endocrine and spermatogenic compartments are anatomically and functionally integrated. Proper hormone balance is initiated by a pulsatile hypothalamic release of gonadotropinreleasing hormone (GnRH). This causes pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which have a direct action on the testis. FSH acts on Sertoli cells to provide a favorable milieu for spermatogenesis. LH stimulates the Leydig cell to secrete testosterone, providing the locally high concentration required for spermatogenesis. Serum testosterone reflects Leydig cell function and provides an indication of intratesticular testosterone. There is a diurnal rhythm, with the peak during early morning. Consequently, it is optimal to perform serum testosterone evaluations in the morning. Additionally, when monitoring an individual patient it is optimal if the tests are done at a relatively consistent time of day. Serum testosterone includes both bound and unbound (free) fractions. The free fraction is the biologically active component and comprises 2% of the total testosterone. Alterations in the sex hormone-binding globulin (SHBG) may give spurious estimates of the biologically active unbound testosterone, as changes in SHBG are reflected in the total testosterone. SHBG is increased by estrogens, thyroid hormone administration, and cirrhosis; it is decreased by androgens, growth hormone, and obesity. For example, in obese men the total testosterone may be lowered secondary to a decrease in SHBG, whereas the free testosterone may be within normal limits. Furthermore, testosterone is aromatized in peripheral tissue to estrogen. There is increased aromatization in the presence of alcoholism, chronic liver disease, testis tumors, and obesity. Most importantly, if the serum testosterone does not correlate with the clinical situation or is equivocal, the free testosterone should be assayed. The endocrine workup should be tailored to the

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individual to allow a cost-conscious, efficient evaluation. Fewer than 3% of infertility cases are due to a primary endocrinopathy. Sigman studied 1034 men to determine what hormonal workup should be done and which patients should be studied. He found that by limiting screening to men with sperm densities less than 10 million/ml only one case of endocrinopathy would have been missed. A higher degree of confidence and detection results when patients with higher sperm counts are screened, although the likelihood of discovering a significant abnormality is low. What studies are appropriate? It is uncommon to find clinically important abnormalities in LH or testosterone if the FSH is normal. In Sigman’s study, no significant endocrine aberrance would have been missed by screening FSH and testosterone alone. Evaluation of FSH and testosterone seems to be the most efficient, cost-effective, and revealing hormonal survey. If the FSH is abnormal, or the testosterone is low, the serum LH should be assayed. Also, consider a free testosterone assay in equivocal cases or in clinical situations such as obesity. If the LH and testosterone levels are low, prolactin should be evaluated. Hyperprolactinemia causes LH suppression, which in turn lowers serum testosterone. Low serum testosterone decreases libido and may cause infertility. Certain patient historic factors raise suspicions of given entities. With hypogonadotropic hypogonadism, or Kallmann syndrome (congenital form), there is failure of GnRH secretion; clinical signs include anosmia (lack of smell) and delayed puberty. Hyperprolactinemia may manifest with impaired visual fields and severe headaches secondary to a prolactin-secreting pituitary tumor. The patient may also complain of impotence. Be aware that gonadotropin production is inhibited by negative feedback from estrogens and androgens at the hypothalamus and pituitary. A hypogonadal state is induced by androgen excess, either exogenous or endogenous. Exogenous sources include testosterone supplementation and anabolic steroids, each of which has a contraceptive effect. Congenital adrenal hyperplasia is the most common cause of endogenous androgen excess. These patients have a history of precocious puberty, short stature, and underdeveloped testes. Urinary 17-ketosteroids should be measured in these individuals. Of note is the fact that patients with hypothyroidism do not present primarily with infertility, and routine thyroid-stimulating hormone (TSH) screening is not indicated. Table 2–3 depicts the various hormonal patterns and their corresponding clinical entities.

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TABLE 2–3. Hormonal Patterns and Corresponding Clinical Status Clinical status Normal Testicular failure Germinal aplasia Hypogonadotropic hypogonadism

FSH

LH

T

Normal Elevated Elevated Low

Normal Elevated Normal Low

Normal Normal or low Normal Low

FSH, follicle-stimulating hormone; LH, luteinizing hormone; T, testosterone.

Genetic Testing Genetic testing should be considered in the man with severe oligospermia or azoospermia. This becomes important especially when ICSI is being contemplated. It has been demonstrated by Page and others, that men with Y chromosome deletions, such as AZFc, will likely transmit the deletion and infertility to their sons who were conceived by ICSI. Several laboratories proficient in this testing include Boston University School of Medicine Center for Human Genetics (617-638-7083) and the Genetics and IVF Institute Molecular Genetics Laboratory in Fairfax, VA (800-654-4363) Genetic screening is mandated in patients with bilateral congenital absence of the vas deferens. Cystic fibrosis gene screening is required as discussed in this chapter.

Diagnostic Studies Scrotal Ultrasonography The use of ultrasonography to image organs and vessels and to measure blood flow is beneficial during evaluation of the infertile man. Its principal application regarding male factor infertility is for the diagnosis of varicoceles. Varicocele is usually diagnosed by physical examination, although the physical examination is sometimes complicated by body habitus and is sometimes equivocal. Some investigators believe that small varicoceles are as important as large ones. Whether nonpalpable or subclinical varicoceles are clinically significant remains a subject of controversy. Several adjuncts in the diagnosis of varicocele are available. Portable, pencil-probe directional Doppler units can be utilized in the office to assist in varicocele detection. This modality detects changes in blood flow (reflux) during a Valsalva maneuver, but the accuracy and reproducibility of this technique are limited. Standard scrotal ultrasonography is readily available, familiar to urologists and infertility clinicians, noninvasive, and relatively inexpensive. The diag-

nosis is based on a venous diameter of 3.5 mm or more with the patient at rest so he can be scanned in the supine position. Subclinical varicoceles are approximately 3 mm in diameter. Color flow Doppler allows determination of the direction and magnitude of blood flow. To detect the change in flow, or reflux, the patient must perform the Valsalva maneuver and may require examination in the standing position. This positioning allows adequate assessment of reflux in the testicular veins, although the accuracy and clinical significance are not absolute. Scrotal ultrasonography and color duplex Doppler are excellent adjuncts in patients with equivocal examinations.

Transrectal Ultrasonography In the past, evaluation of patients with low-volume ejaculates, especially those with azoospermia, included postejaculate urinalysis and subsequent vasography. Historically, surgical vasotomy with vasography were required to image the seminal vesicles and ejaculatory ducts to diagnose ejaculatory duct obstruction. Vasography is an invasive surgical procedure, and there is a risk of vasal scarring and obstruction. Transrectal ultrasonography (TRUS) is now being used to detect varying degrees of ejaculatory duct obstruction. It is essentially a noninvasive, inexpensive office procedure that is readily available. Patients do not require pre-TRUS preparation, antibiotics, or enemas. Urologists are comfortable with this technique, as it is used routinely for the evaluation and diagnosis of prostate carcinoma. Transrectal images of the prostate and seminal vesicles are vastly superior to those obtained with transabdominal imaging. High-resolution images using a 7.5 MHz rectal probe are produced in transverse and sagittal planes. Ejaculatory duct obstruction is easily diagnosed, and the results are highly accurate when using TRUS in azoospermic patients with low ejaculate volume. Obstruction is documented by the presence of dilated seminal vesicles more than 1.5 cm in diameter seen on transverse imaging. Additional findings indicating obstruction

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technique. Patients are prepared with an oral fluoroquinolone, one dose the night prior and a second dose the morning of the procedure. A Fleets enema is self-administered the morning of the aspiration. Interpretation of TRUS in the oligospermic patient is more difficult, and the entity of partial ejaculatory duct obstruction is not definitive. The seminal vesicle aspiration technique mentioned above may prove useful in this scenario. The role of TRUS in infertile men is evolving and currently provides a specific, accurate diagnosis in a select group of patients.

Postejaculate Urinalysis FIGURE 2–4. Transverse view of the prostate (within cursors) with a large midline cyst (hypoechoic lesion within prostate), as seen by transrectal ultrasonography (TRUS). (From Goldstein, 1995, by permission of W.B. Saunders)

include midline intraprostatic cystic structures and intraprostatic calcifications along the projected course of the ejaculatory ducts (Figs. 2–4, 2–5). The absence of seminal vesicles and ampulla of the vas is diagnostic of congenital abnormalities. Jarow has demonstrated that sperm are not normally noted in the seminal vesicles in an unobstructed state immediately after ejaculation. Fluid can be aspirated from the seminal vesicles via transrectal ultrasonic guidance to confirm ejaculatory duct obstruction. A 15-cm, 18- or 20-gauge disposable Echotip Turner biopsy needle (Cook) is well suited for this

FIGURE 2–5. Transverse view of the prostate with a calcification (arrow) in the region of the ejaculatory ducts, as seen by TRUS. (From Goldstein, 1995, by permission of W.B. Saunders)

A postejaculate urinalysis to detect retrograde ejaculation should be obtained in patients with an ejaculation (no antegrade ejaculate), those with low-volume azoospermia, and all others with lowvolume semen samples, including those with oligospermia and normal concentration. The patient voids to completion, produces anejaculate, and then immediately voids into a specimen container. The unspun voided specimen is then evaluated. A diagnosis of retrograde ejaculation is confirmed when more than 10 sperm are noted per high power field. The sample is then centrifuged and evaluated, by semen analysis, to obtain concentration and motility values.

Testis Biopsy Historically, testis biopsy has been used to diagnose a variety of impaired male fertility disorders. With the advent of hormonal screening and noninvasive imaging modalities, testis biopsy and operative vasography have assumed a limited role. Testis biopsy is reserved for patients who have azoospermia, essentially normal-size testes, palpable vas deferens and epididymis, and a normal volume of semen. In these cases, testis biopsy allows the differentiation between patients with microtubular obstructive disease who are candidates for microsurgical repair and patients with disorders of sperm development. In the age of intracytoplasmic sperm injection (ICSI), testicular biopsy has taken on an increased role. Patients who were previously untreatable are now candidates for extraction of testicular sperm. In the past it was stated that if an individual has an FSH level more than three times normal, testicular failure is present, and no treatment is available. However, in 50% of patients with an elevated FSH level up to three times the normal value, sperm or spermatids are noted on testicular biopsy. The

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sperm is extracted from the testicular tissue in the laboratory and used in conjunction with ICSI. Testicular biopsy can be performed in the office under local anesthesia. Plain 1% lidocaine is used to infiltrate the anterior scrotal skin and dartos layers. With the testicle firmly held in position and with the epididymis in a posterior position and the anterior surface up against the scrotal wall, a 1 cm incision is made down to the tunica vaginalis. Holding stitches are placed in the tunica vaginalis, and it is opened sharply the length of the incision. An eyelid retractor is placed and additional 1% lidocaine is dripped on the tunica albuginia. A holding stitch is placed in the tunica albuginia, which is then incised approximately 0.5–1.0 cm in length. Testicular tubules extrude from the opening and are excised with tenotomy scissors. The tissue is placed in support medium, such as human tubular fluid or Hamm’s F-10, for transport to the laboratory. The biopsy is best done where intravenous sedation can be administered. Testicular biopsy remains the gold standard in regard to diagnosis when one is searching for a small number of sperm. When extraction of testicular sperm is to be utilized with ICSI, testicular biopsy affords a better chance of obtaining sperm than testicular aspiration. Furthermore, testicular tissue can be frozen to be utilized in the future. ICSI pregnancies and good fertilization rates have been reported using cryopreserved testicular sperm. Testicular aspiration can be performed in the office setting. Start with 1% lidocaine local infiltration at the puncture site. A spermatic cord block may aid with anesthesia. The lidocaine is injected perivasally. A 23-gauge needle and the Fratzen apparatus for fine-needle aspiration is used. An alternative is a syringe with a three-pronged handle. The needle is inserted into the testicle, and negative pressure is exerted on the syringe (plunger is pulled back) while moving the needle up and down within the testicle to obtain a sample. This technique is limited because the chance of obtaining sperm is low, the yield is low, and currently it must be coordinated with egg retrieval. There are no reports of cryopreserved aspirates resulting in ICSI pregnancies. Therefore, aspiration must be performed in a coordinated fashion with egg retrieval, and donor sperm are required for backup.

Results of Evaluation Evaluation of the infertile male categorizes patients. Not only can diagnoses be made (Table 2–4), treatment plans can be discussed and initiated. Both part-

TABLE 2–4. Diagnoses After Evaluation Diagnosis Varicocele Idiopathic Obstruction Anti-sperm antibodies Testicular failure Pyospermia/infection Ejaculatory dysfunction Endocrinopathies

Patients (%) 37–42 20–25 6–14 3–9 1–9 1–5 1–3 1

ners should be present during the initial visit and any subsequent visit during which treatment decisions are made. Each case must be individualized with male partner issues, female partner issues, success rates for treatment options, costs, morbidities, and the couple’s expectations being addressed. In the office, various treatment options can be initiated. In cases where surgery is indicated, explanation of the procedure and its potential outcome is required. The following is a review of the treatment for infertile males in the office environment.

Treatment Medical Therapy Hormonal Causes In patients with hypogonadotropic hypogonadism, treatment is highly effective. The congenital form, Kallman syndrome, is a result of failure of GnRH secretion. Thus FSH, LH, and testosterone are all low. Treatment consists of hCG 2000 IU given intramuscularly three times a week. This dosage adequately virilizes the man, although spermatogenesis proceeds to completion in only 20% of patients. In most patients, after 6 months one-half of a 75 IU ampule of pergonal is administered three times a week to supply FSH. Sperm counts below 10 million/ml, with good sperm motility, are usually noted. Many of these patients are able to conceive despite the decreased sperm density. Individuals with hyperprolactinemia require computed tomography (CT) or magnetic resonance imaging (MRI) of the head, with attention to the sella turcica, to rule out a pituitary tumor. Patients with mild elevations of prolactin need repeat testing for prolactin to confirm a significant elevation, as prolactin production is stress-related and levels vary. Repeat studies are important in cases where the prolactin level is less than 30 ng/ml. Serum prolactin levels over 300 ng/ml are diagnostic of a pituitary adenoma; a level of over 100 ng/ml is usually

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caused by an adenoma. If a pituitary tumor is found, neurosurgery, irradiation, or bromocriptine is required. If a tumor cannot be delineated on imaging studies or a microadenoma (10 mm) is found, bromocriptine is the therapy of choice. Begin with a 1.25 mg dose by mouth at bedtime to minimize the side effects of nausea, vomiting, fatigue, nasal stuffiness, and postural hypotension. The dosage is increased to an average of 2.5 mg twice a day. Prolactin levels return to normal in virtually all patients within days of achieving the full therapeutic dose, which usually is 5.0–7.5 mg. Consequently, prolactin levels should be monitored 4–7 days after dosage changes to determine the therapeutic response. The effects of bromocriptine are usually not permanent, but one-sixth of patients maintain normal prolactin levels after cessation of the drug. This is evident in patients with idiopathic hyperprolactinemia, when no tumor is noted. Bromocriptine can be withdrawn yearly to determine if the abnormality persists. Testosterone levels rise in about 3 months; and as with most therapy, semen analyses are delayed until 3 months after initiation to allow completion of spermatogenesis. Congenital adrenal hyperplasia, the most common cause of endogenous androgen excess, is usually detected prior to any infertility problems. It is treated with glucocorticoids. In an oligospermic patient with low testosterone and nonelevated LH, clomiphene citrate (Clomid) is beneficial. It is of note that if an individual has a low LH level, a prolactin assay should be performed. Clomiphene citrate is an antiestrogen– estrogen receptor blocker that prevents negative feedback of estrogens to the pituitary and hypothalamus. Estrogen is present in men, and it plays an important role in the pituitary–hypothalamic– gonadal axis. Ablation of feedback inhibition causes augmentation of GnRH and of LH and FSH secretion. Increased LH stimulates the Leydig cell production of testosterone. Possibly, the increase in FSH enhances sperm production. A clomiphene citrate dose of 25 mg daily is initiated. Serum testosterone should be tested 2–4 weeks after initiation of treatment and every 3 months thereafter to avoid excessive serum testosterone levels. Some authors recommend monitoring estradiol levels, as testosterone is converted peripherally, and elevated estrogens may be detrimental to sperm production. Because the spermatogenic cycle takes 74 days, semen analysis is undertaken 3 months into therapy. Clomiphene citrate is well tolerated in men, and side effects such as gastrointestinal (GI) upset, changes in libido, weight gain, and visual disturbances are rare.

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Empiric Therapy Despite extensive evaluation, as many as 25% of infertile men have no obvious demonstrable cause for their infertility. Such patients are categorized as having “idiopathic” infertility. A variety of empiric therapies have been utilized for these patients. There is no convincing evidence that any empiric therapy is beneficial. Data from placebo-controlled studies of clomiphene citrate show little or no benefit. Other agents have been assessed, including other antiestrogens such as tamoxifen, aromatase inhibitors such as testolactone, gonadotropins, kallikrein, indomethacin, pentoxifylline, zinc, and antioxidants including vitamins C and E. There is a paucity of data to document the benefit of any of these agents in the idiopathic setting. Evaluation of treatment regimens for idiopathic infertility is complicated when many etiologies are classified together. Various drugs and dosages are utilized, placebo-controlled studies are lacking, and various outcomes are assessed including semen parameters and pregnancy rates. Additionally, treatment-independent pregnancy rates must be considered. At this point there is no individual treatment that can predictably improve sperm function or fertility in men with idiopathic infertility. Therefore empiric therapy for these patients is not recommended. If one chooses to attempt a trial of empiric therapy, consideration of side effects, costs, and potential detriment to fertility must be considered.

Anti-sperm Antibodies Options for therapy are limited for those with antisperm antibodies. The washing and dilution techniques currently available are inadequate owing to the high affinity of antibodies. Corticosteroid therapy is controversial, and few controlled studies are available. One controlled study showed benefit of immunosuppression, but a definitive answer is lacking. One problem is the risk profile of corticosteroids, which includes mood changes, glucose intolerance, ulcers, GI bleeding, and (most severe) aspetic necrosis of the hip. Because of the controversial nature of this treatment and the inherent risks, it is not the treatment of choice. If one chooses to use this therapy, an appropriate regimen consists of prednisolone 20 mg twice a day on days 1–10 of the partner’s cycle, followed by a 5 mg dose twice a day on days 11 and 12. This treatment cycle should be continued for at least 6 months. Hendry found statistically significant improvement in pregnancy rates between the treatment and control arms after 6 months of treatment.

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The other well controlled study, by Haas, had a treatment period of 3 months, and no significant difference was noted. The longer, 6-month treatment may be advantageous and required. The best results are obtained when the regimen is used in conjunction with stimulated IUI cycles. In vitro fertilization is not a good therapeutic option, as fertilization rates are markedly decreased when sperm-bound antibodies are present. The treatment of choice is ICSI. Studies have shown excellent, standard fertilization rates and pregnancy and birth rates. ICSI has an associated cost burden that must be factored into the assessment and plan. An additional modality is donor insemination. Couples should be counseled regarding their options, along with risk/benefit and cost profiles.

Pyospermia If a significant number of white blood cells (1 million/ml) are noted in a semen sample, treatment is indicated. Treatment consists of: (1) frequent ejaculation, once every other day; (2) doxycycline, 100 mg twice a day; and (3) an over-the-counter nonsteroidal antiinflammatory drug (NSAID). Begin treatment at the start of the partner’s menstrual cycle and discontinue it several days after ovulation. This regimen may be administered in a cyclic fashion. Treatment is monitored by semen analysis, with the sample given a few days after ovulation or several days prior to a scheduled IUI. Studies indicate a marked decrease in leukocytospermia with this regimen. In the few patients who have symptoms and positive cultures, appropriate antibiotics are employed. Nitrofurantoin (Macrodantin) should be avoided because of adverse affects on spermatogenesis.

Retrograde Ejaculation With retrograde ejaculation, incomplete closure of the bladder neck during ejaculation leads to retrograde flow of semen into the bladder. Patients present with low-volume semen, oligospermia (decreased sperm count), or azoospermia. This condition commonly occurs in men with diabetes mellitus or those who have undergone retroperitoneal or pelvic surgery that disrupts the sympathetic nerves required for normal ejaculation. The condition is confirmed by finding large numbers of sperm in the postejaculate urine. These patients can be treated effectively with sympathomimetic such as pseudoephedrine hydrochloride (Sudafed) 60 mg four times a day. Alternative agents are ephedrine 25–50 mg four times a day or phenylpropanolamine (Ornade) 75 mg twice

a day. The drugs are taken for 10–14 days before assessing their effectiveness. If one of the three compounds is ineffective, try imipramine (Tofranil) 25 mg twice a day. If this is not efficacious, try a combination of one of the first three drugs and imipramine. This treatment is most effective in patients with diabetes. If medical therapy fails, one can retrieve semen from a postejaculatory urine specimen to be used in conjunction with an assisted reproductive technique (ART). To optimize the quality of the specimen, two methods are available: alkalization of the urine and catheterization with instillation of buffered solution. To alkalize the urine, administer sodium bicarbonate tablets 650 mg four times a day or one or two tablespoons of baking soda mixed in a glass of water every 6 hours. This regimen should begin at least 24 hours prior to sperm retrieval. Also, optimize the urine osmolality in the range of 300–380 mosm/L, as it is in semen. This is accomplished by increasing or restricting fluids. In general, the patient voids 1 hour prior to the planned ejaculation and then drinks 300–500 ml of fluid. The patient then ejaculates and voids into a container with buffered medium. An additional method is to catheterize the individual prior to ejaculation. Drain the bladder and then instill 50–100 ml of a physiologic solution such as human tubule fluid or Hamm’s F-10. The patient then masturbates and urinates into a specimen container. These specimens are processed and used in the appropriate ART (i.e., IUI, IVF).

Anejaculation Some patients who have undergone retroperitoneal or pelvic surgery or who had a spinal cord injury suffer from anejaculation, rather than retrograde ejaculation, which is a total absence of ejaculatory function. Although these patients occasionally respond to sympathomimetics such as pseudoephedrine, with the regimen as described, most require vibratory stimulation, electroejaculation, or surgical extraction of sperm from the vas or epididymis to obtain sperm for the ART procedure. Vibratory stimulation of ejaculation is easily performed in the office and is most successful in patients with upper spinal cord lesions. This technique uses a vibrator, the commercial Acuvibe model 6001 or a small hand-held unit with a cone tip that is sold in drugstores as a foot/body massager. The unit is applied to the frenulum of the penis and then may be moved to the dorsum of the glans. Patients who respond to this therapy do so

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within 5–10 minutes. Usually pelvic floor contractions, and possibly lower extremity contractions, are demonstrated prior to ejaculation. Most patients who respond exhibit antegrade ejaculation, but catheterization may be performed to retrieve the retrograde component. No anesthesia is required, but patients with lesions above T6 and those with a history of autonomic dysreflexia are pretreated with 10 mg sublingual nifedipine. Additional pretreatment includes one of the two methods described, alkalization or catheterization, to optimize the quality of the specimen obtained from the bladder. Also, if the patient self-catheterizes, has a Foley catheter, or has a history of voiding dysfunction, a urine culture should be obtained prior to therapy and antibiotics instituted. Patients who respond consistently with an antegrade specimen can learn to perform this technique with the aid of their partner. Pregnancies have been reported by utilizing this technique with intravaginal insemination. Electroejaculation utilizes a rectal probe that electrically stimulates contraction of the seminal vesicles and vasal ampullae, resulting in discharge of semen into the urethra. The model 12 electroejaculator, developed and refined by Seager, is distributed by the National Rehabilitation Hospital, Washington, DC. Electroejaculation can be performed in an office or procedure room in select patients with spinal cord injuries. No anesthesia is required. Keep autonomic dysreflexia in mind for patients with lesions above T6. The sample is processed to be used in conjunction with IUI or IVF.

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ligation, all of which are outpatient procedures. Open surgical ligation, performed under local anesthesia with or without intravenous sedation, is the preferred method. A subinguinal incision is an excellent approach. Its small size translates into superb patient comfort postoperatively. This technique is cost-effective and low risk. A microsurgical approach may be advocated so the vasal and testicular arteries and the lymphatics are spared. The literature confirms that varicocelectomy improves fertility rates. A compilation of controlled studies demonstrates significantly improved pregnancy rates, and an international WHO study supports the influence of varicoceles on fertility. A prospective, randomized, crossover study by Madgar et al. clearly demonstrated significant improvement in fertility in patients undergoing varicocelectomy versus patients who were simply observed.

Ejaculatory Duct Obstruction Ejaculatory duct obstruction can be treated with transurethral resection of the ejaculatory ducts. Prior to treatment it is optimal if the obstruction is verified by transrectal aspiration of the seminal vesicles or by vasography. These studies also confirm the presence of sperm, ruling out proximal obstruction. Figure 2–6 illustrates potential sites of obstruction in the reproductive tract, including the ejaculatory duct. Published results of treatment show that one-half of patients have sperm in the ejaculate postoperatively, and 25% of all those undergoing treatment contribute to a pregnancy. Complications include (1) impairment of semen parameters due to urine pooling in the prostatic

Surgical Therapy Although a concise description of surgical techniques is beyond the scope of this chapter, an understanding of the breadth of corrective procedures available is imperative. The major techniques utilized are briefly addressed, with an emphasis on outcomes and expectations.

Varicocele A varicocele is an abnormal dilation of the testicular veins in the scrotum. It is the most common cause of male infertility, with a 15% incidence in the general population and a 40% incidence in infertile men. Among men with secondary infertility, there is an 80% incidence. Treatment results in semen improvement in 70% of men and pregnancies in 40% of couples. Repair is done by open surgical ligation of the vessels, transvenous embolization of the internal spermatic vein, or laparoscopic

FIGURE 2–6. Sites of potential obstruction in the male reproductive tract. Sagittal view. (By permission of Bayer Corp.)

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TABLE 2–5. Time Since Vasectomy Related to Results After Reversal Time since vasectomy (years)

Sperm noted after reversal (%)

Partners pregnant (%)

3 3–8 9–14 15

97 88 79 71

76 53 44 30

Source: Belker et al., 1991.

fossa and mixing with semen and (2) urinary reflux into the ejaculatory ducts. Many of these men have a yellow, watery ejaculate. They should dilute the urine by increasing fluid intake and alkalinizing the urine by taking sodium bicarbonate tablets (650 mg four times a day) or Poly-citra (5 ml every 8 hours starting a day prior to planned ejaculation).

Microtubular Obstructive Disease Between 5% and 10% of patients with normalvolume azoospermia have microtubular obstruction. Prior vasectomy and de novo epididymal obstruction are the most common causes. Both of these entities can be corrected with sophisticated microsurgical techniques. The vasovasostomy study group demonstrated that the length of time since vasectomy is the most important predictor of success of a reversal (Table 2–5). Vasoepididymostomy results in an approximately 70% patency rate with pregnancy rates reported in the 30–50% range. The average length of time before a pregnancy occurs after vasectomy reversal is 1 year. Regarding vasoepididymostomy, most patients have sperm in their ejaculate 3–6 months after surgery, but the surgery should not be considered a technical failure until 18 months postoperatively, as it may take that long for sperm to appear.

Congenital Absence of the Vas Deferens Among azoospermic patients, 1.4% are found on physical examination to have bilateral congenital absence of the vas deferens. Sperm can be obtained from these patients by microsurgical epididymal sperm aspiration (MESA). This procedure has the best chance of success and highest yield. Percutaneous epididymal or testicular aspiration has several drawbacks, including inconsistent success, low yield, and inability to cryopreserve the sperm. The sperm can be utilized with ICSI. Cystic fibrosis (CF) and congenital absence of the vas deferens are different ends of a phenotypic spectrum resulting from deletions in the CF gene. Prior to MESA, both

partners should undergo CF mutation analysis from a serum sample to estimate their risk of transmitting CF or congenital absence of the vas to offspring. If the couple is at risk and proceeds with an ART procedure, amniocentesis, chorionic villous sampling, or preimplantation genetics should be considered.

Assisted Reproductive Techniques A variety of ART techniques have been used to treat male factor infertility. It must be pointed out that an ART should not be considered primary therapy for male factor infertility. The most cost-effective treatment with the highest success rate, combined with low patient morbidity, is the goal. An ART technique should be combined with treatment of the infertile man to gain the highest possible pregnancy rates. Schelegel has reported extensive cost analysis studies comparing varicocelectomy and vasectomy reversal with primary ART. He convincingly showed the cost-effectiveness of treating infertile men.

Conclusions Infertility is a major health concern for a large proportion of reproductive-age patients. Recognizing this entity as a “couple” problem is essential to successful treatment. Advances in the understanding, diagnosis, and treatment of male factor infertility is advancing at a rapid pace. Health professionals treating the infertile man are an integral part of the team addressing couple fertility.

Suggested Reading Acacio BD, Gottfried T, Israel R, et al. Evaluation of a large cohort of men presenting for a screening semen analysis. Fertil Steril 2000;73:595–597. Amer M, Haggar SE, Moustafa T, et al. Testicular sperm extraction: impact of testicular histology on outcome, number of biopsies to be performed and optimal time for repetition. Hum Reprod 1999;14:3030–3034. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol 1991;145:505. Chuang AT, Howards SS. Male infertility: evaluation and nonsurgical therapy. Urol Clin North Am. 1998;25: 703–713. Clarke GN, Elliott PJ, Smaila C. Detection of sperm antibodies in semen using the immunobead test: a survey of 813 consecutive patients. Am J Reprod Immunol Microbiol 1985;7;118–123. Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu B, Audrins P, Saunders D, Quinn F, deKretser D, McLachlan R: Y chromosome analysis of infertile men

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2. Evaluation of the Male for Infertility and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions, Fertil Steril 74:909, 2000. Goldenberg RL, White R. The effect of vaginal lubricants on sperm motility in vitro. Fertil Steril 1975; 26:872. Goldstein M. Surgery of Male Infertility. Philadelphia: Saunders, 1995. Haas GC Jr, Manganiello P: A double-blind, placebo controlled study of the use of methylprednisolone in infertile men with sperm-associated immunoglobulins, Fertil Steril 47:295, 1987. Hellstrom WJ, Overstreet JW, Samuels SJ, et al. The relationship of circulating antisperm antibodies to sperm surface antibodies in infertile men. J Urol 1980;140: 1039. Hendry WF: The significance of antisperm antibodies: measurement and management, Clin Endocrinol 36: 219, 1992. Honig SC, Oates RD. Infertility. In: Krane RJ, Siroky MB, Fitzpatrick IM (eds) Clinical Urology. Philadelphia: Lippincott, 1994;1102–1142. Honig SC, Lipshultz LI, and Jarow J. Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertil Steril 62:1028, 1994. Jarow IP. Seminal vesicle aspiration of fertile men. J Urol 1996;156:1005–1007. Kamischke A, Nieschlag E. Analysis of medical treatment of male infertility. Hum Reprod 1999;14(suppl 1):1–23. Kleiman SE, Yogev L, Hauser R, Botcham A, Lessing JB, Paz G, et al. Genetic evaluation of infertile men. Hum Reprod 14:33, 1999. Kruger TF, Acosta AA, Simmons KE, et al. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988;49:112. Lamb EJ. Prognosis for the infertile couple. Fertil Steril 1972;23:320. Lipschultz LI. Cryptoorchidism in the subfertile male. Fertil Steril 1976;27:609. Lipschultz LI, Howards SS. Infertility in the Male, 3rd ed. St. Louis: Mosby-Year Book, 1996. Lubs HA Jr. Testicular size in Klinefelter’s syndrome in men over fifty. N Engl J Med 1962;267:326. Madgar I, et al. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril 1995;63:120.

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McClure RD. Male infertility. In: Tanagho EA, McAninch JW (eds) General Urology. Norwalk, CT: Lange, 1992:669–695. Muller CH. Rationale, interpretation, validation, and uses of sperm function tests. J Androl 2000;21:10–30. Ohl DA, Naz RK. Infertility due to antisperm antibodies. Urology 1995;46:591–602. Schlesinger MS, Nagler HM. Treatment outcome after varicocelectomy. Urol Clin North Am 1994;21:517. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 14:1722, 1999. Schlegel PN: Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A costeffectiveness analysis. Urology, 49:83, 1997. Sigman M, Howards SS. Male infertility. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED (eds) Campbell’s Urology. Philadelphia: Saunders, 1992:661–705. Sigman M, Lipshultz LI. Male infertility. In: Stein BS, Caldamone AA, Smith JA (eds) Clinical Urological Practice. New York: Norton, 1995:1219–1270. Silber SJ, Alagappan R, Brown LG, Page DC. Y chromosome deletions in azoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum Reprod 13:3332, 1998. Witkin SS, David SS. Effect of sperm antibodies on pregnancy outcome in a subfertile population. Am J Obstet Gynecol 1988;158:59–62. Witkin SS, Viti D, David SS, et al. Relation between antisperm antibodies and the rate of fertilization of human oocytes in vitro. J Assist Reprod Genet 1992;9:207– 210. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and SpermCervical Mucus Interaction, 3rd ed. New York: Cambridge University Press, 1992. Yanagimachi R, Yanagimachi H, Rogers BJ. The use of zona-free animal ova as a test system for the assessment of the fertilizing capacity of human spermatozoa. Biol Reprod 1976;15:471. Zonari R, deAlmeida M, Rodrigues D, et al. Localization of antibodies on spermatozoa and sperm movement characteristics are good predictors of in vitro fertilization success in cases of male autoimmune infertility. Fertil Steril 1993;59:606–612.

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3 Detection and Therapeutic Approaches to Age-Related Infertility Fady I. Sharara, Richard T. Scott Jr., and David B. Seifer

Two social factors, delayed childbearing and an increase in the prevalence of divorce followed by remarriage, are contributing to a growing number of women in their mid to late thirties who desire fertility at a time when fecundity is declining. One of the most difficult challenges is the evaluation and treatment of these women, who desire fertility but have diminished ovarian reserve. The latter is due to the fact that they frequently do not produce enough quality oocytes to take full advantage of the various options offered by assisted reproductive technologies. In addition, pregnancy rates during natural and assisted cycles are dramatically reduced, and the rate of spontaneous miscarriages is markedly increased. The challenge of increasing miscarriages with diminished ovarian reserve was highlighted in a retrospective study examining the influence of maternal age on pregnancy loss rates after early documentation of fetal cardiac activity by transvaginal ultrasonography in women undergoing ovulation induction for infertility. A spontaneous abortion rate of 2% was observed for maternal ages 35 years but increased to 16% for those 36 years old following documentation of fetal cardiac activity.1 The development of diminished ovarian reserve generally reflects the age-related decline in reproductive performance.2 As such, diminished ovarian reserve represents a natural physiologic occurrence noted in most women during their mid to late thirties. This presents a particular challenge to the practicing clinician, who must attempt to identify those women with markedly reduced ovarian reserve prior to embarking on expensive, invasive treatments. If women have diminished ovarian reserve, they should be counseled to consider oocyte donation or adoption. Although these options frequently are 24

disappointing, they do represent realistic options for many couples. For couples unwilling to consider these options, the next step may be to optimize their treatment as much as possible. These patients require more aggressive stimulation and treatment protocols and continue to have relatively decreased pregnancy rates compared to women with undiminished ovarian reserve. This chapter reviews various methods for ovarian reserve screening and considers treatment approaches for optimizing chances for women with diminished ovarian reserve to become a biologic parent.

Follicle-Stimulating Hormone Basal FSH Levels The traditional techniques used to estimate a patients’ ovarian reserve are of limited clinical value because of poor predictive values, invasiveness, or expense. A parameter that is easily measurable, minimally invasive, and inexpensive and that has good predictive value is needed. The basal follicle-stimulating hormone (FSH) level on cycle day 3 has been described by some as meeting these criteria.3–6

Age-Related Changes in FSH Levels A series of studies during the 1970s and 1980s characterized the endocrinologic aspects of the transition through the climacteric.7–10 Sherman and colleagues documented that women with normal ovulatory cycles commonly begin to have subtle elevations in their FSH levels in their midthirties.9,10 Further studies confirmed these findings and consistently demonstrated that the first eleva-

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tions occur during the early follicular phase.7,8 Although these studies did not evaluate the relation between the FSH level and ovarian reserve, they documented that FSH levels increase at the same general time the incidence of diminished ovarian reserve increases. The physiologic basis for the increase in basal FSH with aging has received renewed vigor. Batista et al. evaluated luteinizing hormone (LH), FSH, 17-estradiol inhibin, progesterone, PP-14, and endometrial biopsies (EMBs) in young (age 20–30) and older (age 40–50) volunteers.11 FSH levels were increased, and inhibin levels (Monash assay) were decreased in the older group. None of the other parameters were different; in particular, the incidence of out-of-phase EMBs was similar among the two groups. More recently, Klein and coworkers could not find any decrease in estradiol, progesterone, LH, or total immunoreactive inhibin (Monash assay) levels with reproductive aging.12 These investigators were able to show that the older group (age 40–45) had accelerated follicular development leading to a shortened follicular phase compared to the younger group (age 20–25). The same investigators also measured the 24-hour mean FSH and LH levels during the early follicular and midluteal phases of the cycle in both the younger and older groups. The 24-hour mean FSH levels were significantly higher in the older group during both phases of the cycle than in the younger group, whereas no differences were noted for LH. These investigators suggested that elevated FSH levels seen with reproductive aging may represent a primary neuroendocrine change rather than an ovarian one. More recently the same investigators evaluated the correlation between follicular FSH, estradiol, and inhibin A and B using a newly developed dimeric (bioactive) inhibin assay and found an inverse correlation between follicular FSH and inhibin B levels in the two groups of women described above (young versus older).13 This observation suggests that reproductive aging is primarily of ovarian origin. Furthermore, there are data to support the hypothesis that both diminished follicular quantity and quality occur in women with diminished ovarian reserve, as is discussed in the next section. These follicles have diminished capacity for steroidogenesis and inhibin production; they have fewer cells, and these cells have a good chance of undergoing apoptosis.14

Basal FSH Levels and Pregnancy Rates The earliest description of pregnancy rates and basal FSH levels was in a study by Muasher et al.,

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who was evaluating the relation between gonadotropin-releasing hormone (GnRH) stimulation test results and the ovarian response to gonadotropins.15 Evaluation of the pregnancy rates following in vitro fertilization (IVF) cycles revealed high pregnancy rates in groups in whom FSH levels were relatively low, whereas no pregnancies occurred in groups in whom the basal FSH values were higher. Although the small number of patients in the study precluded a meaningful evaluation of basal FSH levels and pregnancy rates, it indicated the need for a larger, more detailed study. Scott et al. found in a large retrospective study of 758 IVF cycles that pregnancy rates decreased markedly as FSH levels rose.5 Ongoing pregnancy rates were highest in women whose FSH levels were 15 IU/L and fell to less than 5% in those whose basal FSH levels were over 25 IU/L. This reduction in pregnancy rate was attributed to diminished ovarian reserve, as these patients developed fewer follicles, produced fewer oocytes, and had fewer embryos transferred. Significantly, age would not have predicted the differences in clinical response because the ages of the women in the various groups were equivalent (mean age approximately 35 years). Thus assessment of basal FSH levels provided a means of predicting ovarian responsiveness and eventual pregnancy rates prior to assuming the risks and expense of treatment. Another study from the same center evaluated the relative predictive values of basal FSH levels and age in 1478 consecutive IVF cycles. Although there was a definable decline in pregnancy rate as age increased, basal day 3 FSH levels provided much better predictive values for both pregnancy and cancellation rates.6 This finding was confirmed in other studies. The precise physiologic basis for basal FSH screening is the subject of intense investigation. Originally several researchers postulated that because these elevations occur when circulating estradiol levels are at their nadir, differences in FSH levels could reflect differences in inhibin activity. Studies comparing inhibin levels in women of different ages provide little support for that specific mechanism. Hughes et al. found that although there was an age-related decline in peak inhibin levels during complex ovulation induction, those levels were not different earlier in the cycle (basal).16 Other authors found differences between inhibin levels in high and low responders during complex ovulation induction cycles, but again basal levels were not different.17 It is important to note that the above studies used the Monash assay to measure total immunoreactive inhibin, which is based on a

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heterologous double-antibody radioimmunoassay based on purified 31-kDa bovine follicular fluid inhibin, which also binds to the free -subunit and its precursors. Using a newly developed dimeric inhibin assay, which measures specific forms of bioactive inhibins (A and B) by enzyme-linked immunosorbent assay, the rise in early follicular FSH with reproductive aging correlates with a fall in inhibin B levels.13 Hopefully, introduction of this assay will allow investigators to examine the relative contributions of estradiol and inhibins A and B to controlling FSH secretion. It has been reported that luteinized granulosa cells from women with elevated day 3 FSH levels produce less steroids, are less viable in culture, have a reduced mitotic index, and produce decreased quantities of insulin-like growth factor (IGF-I and IGF-II). Moreover, it has been demonstrated that preovulatory follicles from women with diminished ovarian reserve contained fewer number of luteinized granulosa cells and have a higher percentage of cells undergoing apoptosis compared with women with uncompromised ovarian reserve undergoing superovulation for in vitro fertilization–embryo transfer (IVF-ET).14 More importantly, these investigators reported that the secretion of total and dimeric inhibin A (using a specific assay) was lower in granulosa cell cultures obtained at IVF from patients with high basal FSH, but no significant differences in either estradiol or progesterone concentrations were seen. This hopefully provides one explanation for the long-sought physiologic reason for the increase in basal FSH in women with diminished ovarian reserve.18

Inhibin Seifer et al.19 examined assisted reproductive technology (ART) outcomes in women characterized as having low or high day 3 serum inhibin B concentrations (45 pg/ml vs. 45 pg/ml). Women with low day 3 serum inhibin B demonstrated 70% of the estradiol response, 66% of the number of occytes retrieved, 28% of the clinical pregnancy rate per initiated cycle and three times the cancellation rate per initiated cycle than women with a day 3 inhibin B level 45 pg/ml. After controlling for age, day 3 serum FSH, day 3 serum estradiol, patient cycle number, and ART method, day 3 serum inhibin B 45 pg/ml was noted to be prognostic of the number of oocytes retrieved and the clinical pregnancy rate. These data suggest that women with low day 3 serum concentrations of inhibin B have less ovarian reserve, as demonstrated by a poor response to ovulation induction

and a reduced probability of conceiving a clinical pregnancy through ART than women with high day 3 inhibin B. Danforth and coworkers evaluated luteal phase inhibin A and follicular phase inhibin B levels and noted an inverse relation with advancing age. Also noted was a decline in inhibin A and inhibin B before the monotropic FSH rise. Additional data support the observation that day 3 serum inhibin B levels decline before the monotropic FSH rise. Seifer and coworkers studied women undergoing ART who demonstrated a poor response to stimulation as measured by increased ampules of gonadotropins for stimulation yielding a higher cancellation rate, a lower estradiol response, fewer oocytes retrieved, and lower clinical pregnancy rate. They found that this group of women also had lower inhibin B levels than women undergoing ART with normal ovarian responsiveness, despite both groups having similar nonelevated day 3 FSH levels. In addition to confirming the inverse relation between declining inhibin levels and rising FSH levels, Santoro and colleagues demonstrated an increase in activin A, which may also contribute to the FSH elevation. The results of these studies call for follow-up investigations with larger patient populations. If future investigations confirm the above findings, dimeric inhibin measurements along with day 3 FSH may provide a better screening test than either test alone.

Intercycle and Intracycle Variability in Basal FSH Levels If basal FSH levels are to be used to counsel patients regarding their chances for conception, a number of questions regarding the reproducibility of the test must be addressed. One is defining the magnitude of the intercycle variation in basal FSH levels. Scott et al. evaluated the intercycle variability in basal FSH levels in 81 women undergoing multiple IVF cycles.20 The mean deviation was 4.2  0.4 IU/L, with a range that extended from 1 IU/L to 42 IU/L. However, the patients with normal basal FSH levels (15 IU/L) had low intercycle variations (mean 2.6  0.2 IU/L). In contrast, patients with elevated basal FSH levels had a much higher degree of variation (mean 7.4  0.9 IU/L). Scott et al. noted that the intercycle variability in basal FSH levels generally did not affect the patients’ prognostic category and therefore should have a minimal impact on clinical decision-making. In the same study, 28 patients had an intercycle variability in basal FSH values that resulted in the patient having a basal FSH value in the normal or

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intermediate range during one cycle and elevated in another. If basal FSH levels reflect the overall metabolic activity of the developing cohort of follicles, it seemed possible that reproductive performance would be enhanced during cycles when the basal FSH levels were lower. Perhaps patients needed to be monitored from cycle to cycle and then stimulated during the cycle when their FSH levels were normal. A paired analysis of the high and low FSH cycles in these patients revealed no differences in stimulation quality, number of oocytes retrieved, or fertilization rates. Interestingly, the patients all behaved as low responders in both cycles. These data indicate that by the time patients develop more variability in their basal FSH concentrations they have already had a significant diminution in ovarian reserve. Furthermore, it strongly suggests that serial screening of FSH levels to select the optimal cycle for stimulation would be of limited clinical value. This study was limited, however, because information regarding pregnancy outcome was not available. Selection criteria for entry into the study required patients to have had repeated ART cycles without successful pregnancy. Martin et al.21 examined the pregnancy outcomes of four cohorts of couples regarding intercycle variability of the day 3 serum FSH level. More than 1850 cycles of women who underwent IVF were categorized as follows: only 20 mIU/ml; always 20 mIU/ml; current 20 mIU/ml but one previous 20 mIU/ml; and current 20 mIU/ml but two or more previous 20 mIU/ml. No pregnancies occurred in 53 cycles with day 3 FSH only 20 mIU/ml. In 1750 women whose day 3 FSH levels were always 20 mIU/ml, the pregnancy rate per cycle was 16.5%. For 54 cycles in which day 3 FSH was 20 mIU/ml one time only but 20 mIU/ml during the treatment cycle, the pregnancy rate as 5.6%. For 11 cycles where two or more previous FSH determinations were 20 mIU/ml but with a current day 3 FSH 20 mIU/ml, no pregnancy occurred. Based on these results the investigators came to the conclusion that patients with day 3 serum FSH 20 mIU/ml should be strongly discouraged from proceeding with IVF. The 5.6% pregnancy per cycle rate with one previously elevated FSH supports the concept that once a patient has an elevated FSH level she is unlikely to be successful during further IVF cycles regardless of what future day 3 FSH values may be. Another study examined intracycle variability in a healthy population of women with regular menstrual cycles. It noted serum FSH on days 2–5 to be similar.22 This result appears to have been confirmed by other investigators.12

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Basal FSH Screening in Women with One Ovary Because basal FSH level screening is believed to reflect the activity of the developing cohort of follicles as a whole, there was considerable concern as to whether the predictive value of the test would be maintained in women with one ovary. There is a decrease in the size of the initial cohort of follicles in these patients, but there is not necessarily a corresponding decrease in their quality. Khalifa et al. compared the basal FSH levels in women with one or two ovaries and evaluated the predictive values of the test in each group.23 The 162 women with one ovary had higher mean basal FSH levels and correspondingly had a poorer response to gonadotropin stimulation than the 1066 patients with two ovaries. After controlling for the basal FSH level, however, there were no differences in gonadotropin responsiveness or pregnancy and delivery rates. These data indicate that basal FSH screening retains its predictive value in women with one ovary, even when using the same thresholds for defining an abnormal test.

Estradiol Levels and Basal Day 3 FSH Levels The validity of FSH screening depend on the time during the cycle the sample is collected. Timing is considered optimal when circulating estradiol (E2) levels are at their nadir, which is typically around cycle day 3. Some patients have inappropriately high E2 levels on day 3, which suggests that they may be farther into their follicular phase than is clinically apparent. In these circumstances, it is possible that the higher circulating E2 level is suppressing FSH levels back into the normal range even if the patient has diminished ovarian reserve. The original studies evaluating the relation between basal E2 and FSH levels in an effort to determine if there was a threshold value above the predictive value of a normal FSH level was lost.5 No such threshold value could be identified. More recently, two investigators revisited this question. Licciardi et al. determined that progressive increases in basal day 3 E2 levels were associated with declining ovarian responsiveness and pregnancy rates.24 After controlling for FSH levels, however, there was no difference in pregnancy rates in women with normal or “elevated” basal E2 levels. Thus the authors were unable to demonstrate that the E2 levels added information beyond that seen with FSH levels alone. In contrast, Smotrich et al. demonstrated a sig-

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nificant decline in pregnancy rates with elevated E2 levels, even after controlling for the FSH levels.25 These authors chose a higher threshold E2 value for defining a significant elevation (80 pg/ml compared to 45 pg/ml in Licciardi et al.’s paper), although no data regarding the comparability of the assays are available. In aggregate, these data suggest that patients with elevated E2 levels may have reduced reproductive potential. Further studies are needed to define more clearly the appropriate threshold values and to determine exactly how they should alter interpretation of circulating FSH concentrations.

Basal FSH/LH Ratios Although extensive data are available regarding the high level of specificity of basal FSH levels, the fact remains that the test may have limited sensitivity. Stated otherwise, patients with abnormal levels are typically low responders with poor pregnancy rates (highly specific), but a substantial group of patients have normal levels and still respond poorly to stimulation with associated poor pregnancy rates. This led some investigators to seek more sensitive tests (i.e., FSH/LH ratios, dimeric inhibin, E2 as previously mentioned) to determine if a given patient has diminished ovarian reserve. Mukherjee et al. reported that patients with elevated FSH/LH ratios (indicating disproportionally more FSH secretion) were low responders with lower peak E2 levels and fewer oocytes recovered.26 The authors evaluated 74 patients with normal basal FSH and E2 who underwent IVF, 14 of whom had an FSH/LH ratio 3.6. The cancellation rate in that group was 12 of 14, compared to a significantly lower cancellation rate of 6 of 60 if the FSH/LH ratio was 3.6. It is of note that pregnancy rate in patients with an FSH/LH ratio 3.6 was 25% (neither of the two patients with an FSH/LH ratio 3.6 conceived). Obviously a larger sample size is needed before this ratio can be used clinically as a marker of diminished ovarian reserve. In a review of the basal FSH/LH ratios and pregnancy outcome data from the Saint Barnabas Medical Center program in Livingston, NJ, there were no definable differences in pregnancy or implantation rates among 336 patients with normal basal FSH levels and varying FSH/LH ratios. More data are needed to determine if evaluation of this relation can provide clinically meaningful information.

Current Status of Basal FSH Screening Elevated basal day 3 FSH concentrations are highly predictive of diminished ovarian reserve as defined

by poor gonadotropin responsiveness and pregnancy rates in patients undergoing complex ovulation induction or one of the assisted reproductive technologies.5,6,15–18,20,23–25 The test is simple, inexpensive, and routinely available. The studies performed to date are limited to clinical circumstances requiring complex ovulation induction. No data are currently available to assess the predictive value of basal FSH screening during spontaneous ovulatory cycles or in women from a general infertility population.

Clomiphene Citrate Challenge Test The clomiphene citrate (CC) challenge test (CCCT) was described in 1987 by Navot et al. as a means of assessing ovarian reserve in women 35 years of age and older.27 This simple test consists of measuring serum FSH concentrations on cycle day 3 (basal) and then again on cycle day 10 following administration of 100 mg of CC on cycle days 5 through 9. In the original study, reported prior to any of the studies addressing the value of basal FSH levels, an abnormal test was defined by an elevated level in the day 10 sample. Obviously, an abnormal value on cycle day 3 also results in the test being considered abnormal. Similar to the information regarding basal FSH levels, the precise physiology of the CCCT has not been clearly defined. The premise of the test is that in women with normal ovarian reserve the overall metabolic activity of the developing follicles should be able to overcome the impact of CC on the hypothalamic-pituitary axis and suppress FSH levels back into the normal range by cycle day 10. Addition of CC creates a “provocative” test that unmasks patients who might not be detected by basal FSH screening alone. Investigators have demonstrated different serum inhibin B concentrations in normal versus abnormal CCCTs, supporting the concept that diminished granulosa cell inhibin B production may be responsible for an abnormal CCCT.

CCCT and Pregnancy Rates In its original description, the CCCT was used to evaluate 51 infertile women over age 35.27 All 51 of these women had normal basal FSH concentrations, but 18 had elevated values following CC administration and were categorized as having diminished ovarian reserve. Demographically, the patients with diminished reserve were similar to those with adequate reserve at equivalent ages, durations of infertility, and requirements for augmentation of ovulation. However, only 1 of the 18

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(6%) patients with diminished reserve conceived, whereas 14 of 33 (42%) of the adequate reserve group became pregnant. Following this initial report, several groups evaluated the predictive value of the CCCT for screening patients participating in ART programs.28 Tanbo et al. studied 91 women over age 35 and found abnormal CCCTs in 37.29 Of these 37 patients, 20 also had an elevated basal FSH concentration on cycle day 3. Only one patient had an abnormal value on day 3 and a normal value on day 10. The predictive value of an abnormal test was 85% for cycle cancellation due to poor ovarian responsiveness and 100% for failing to conceive. In contrast, cancellation rates were much lower (31.5%) and the pregnancy rates much higher (11%) in patients with normal tests. Most significantly, approximately twice as many patients were identified using the CCCT compared to basal FSH screening alone. Loumaye et al. also evaluated the CCCT but defined an abnormal test by adding the day 3 and day 10 FSH values together.28 In their series of 114 patients a threshold effect was evident, with pregnancy rates remaining equivalent until the summed FSH concentrations exceeded 26 IU/L, when they became zero. Here again the predictive value of an abnormal test for failing to become pregnant was 100%.

CCCT for Screening the General Infertility Population The data generated during the initial evaluation of the CCCT were similar to those obtained when evaluating basal FSH levels alone. The CCCT evaluates the predictive value of the test in ART programs or for patients undergoing complex ovulation induction. Although the test is clearly useful for identifying patients with a poor prognosis in that setting, the results may not be readily extrapolated to the general infertility population. There were legitimate concerns that because the CCCT reflected the inability of the developing cohort of follicles to suppress FSH levels into the normal range, the test would be predictive only of the quality of the cohort as a whole. If a single follicle in a cohort has good reproductive potential (even if the others did not), the natural processes of recruitment and selection could lead to ovulation of the highest-quality follicle, and the predictive value of the CCCT would be diminished. Scott et al. completed a long-term prospective evaluation of CCCT screening in women from the general infertility population.30 Approximately 10% of the 236 patients who were evaluated and

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followed for a minimum of 1 year had an abnormal CCCT. The incidence of abnormal tests rose with age and was 3% when the woman was 30 years, 7% at 30–34 years, 10% at 35–39 years, and 26% for women 40 years. Most importantly, the pregnancy rates in the patients with diminished ovarian reserve were markedly lower (9%) than those with adequate reserve (43%). The pregnancy rates were still significantly decreased after controlling for age. It is of note that only 7 of the 23 patients with abnormal tests had an elevated day 3 FSH level, again suggesting that the CCCT may be substantially more sensitive than screening with day 3 samples alone. An examination of the E2 response between days 3 and 10 failed to reveal any correlation differentiating those women with normal or abnormal FSH responses. Evaluation of the relation between the eventual clinical diagnoses and CCCT results in these 236 couples revealed a high incidence of abnormal tests in the patients with unexplained infertility. In fact, the incidence of abnormal CCCTs was highest among patients with unexplained infertility (38%) and was unaffected by age.30 This finding suggests that diminished ovarian reserve should be considered an etiology of infertility, and that couples with abnormal tests should no longer be considered to have unexplained infertility.

Predictive Value of Age and the CCCT The data from the studies described above clearly define that the CCCT has been predictive values for pregnancy rates than does age alone. In clinical practice both age and CCCT results are now available. Scott et al. performed a life-table analysis of the pregnancy rates of 589 couples from the general infertility population who were followed for up to 45 months.31 Analysis of the patients with abnormal CCCTs revealed that the pregnancy rates were uniformly poor independent of the patient’s age. This finding provides further support to the contention that diminished ovarian reserve is a specific etiology of infertility. In contrast, evaluation of the patients with adequate ovarian reserve (normal tests) revealed a significant diminution in pregnancy rates with increasing age. This underscores the importance of considering the patients’ age when counseling them regarding their long-term chances for conception, even when their CCCT results are normal. Pearlstone et al. noted similar findings when evaluating the combined predictive value of age and basal FSH concentrations in women over age 40 who were undergoing complex ovulation induction.4 The poor predictive value of a normal test result

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in women over age 40 emphasizes that there are changes in the reproductive system that are not detected by a CCCT that may significantly limit the reproductive potential of individual patients.2 As noted previously, there are definable changes in the nonovarian components of the reproductive system that could theoretically account for some of the agerelated decline in reproductive potential. The fact that tubal transfer of donor eggs produces equivalent pregnancy rates in all age groups suggests that the most significant component of the age-related decline in reproductive potential relates to gamete quality. Taken in aggregate, it appears that the development of an abnormal CCCT is in fact a late finding, and that a significant oocyte-related diminution in reproductive potential occurs prior to the development of an abnormal test. A test predicting oocyte quality would obviously be of significant clinical importance.

Smoking and the CCCT Women who smoke cigarettes go through menopause 1–4 years earlier than nonsmokers, and a direct relation between the number of cigarettes smoked and early menopause has been noted.32,33 It suggests that smokers deplete their pool of follicles at an accelerated rate, suggesting that these women may have an onset of diminished ovarian reserve at an earlier age. Sharara et al. examined the relation between cigarette smoking and the prevalence of diminished ovarian reserve.34 They evaluated women over age 35 because it is unlikely that women at younger ages, even if they were depleting their pool of follicles at an accelerated rate, would have depleted enough of their follicles to manifest diminished reserve. This was confirmed in two studies where the mean age of smoking women was 35.35,36 In our study, women who smoked cigarettes had a significantly higher prevalence of abnormal CCCTs, implicating smoking in the loss of reproductive potential at an earlier age. It may be appropriate to add loss of reproductive potential to the already long list of health hazards induced by smoking in reproductive-age women. This information is of critical importance when counseling smoking women. Other environmental and endogenous factors (e.g., galactosemia) that may affect ovarian reserve are being investigated.

Current Status of CCCT Screening An abnormal CCCT has excellent predictive value for diminished ovarian reserve and poor long-term pregnancy rates during natural cycles, during ovu-

lation induction, and with IVF.27–30,34 Although the test is specific, it has limited sensitivity, with a significant age-related diminution in reproductive potential occurring even among women with normal test results.2 The CCCT may be superior to basal FSH screening because it is two to three times more sensitive than basal FSH screening alone. Although abnormal day 3 FSH values appear to be accompanied by abnormal day 10 values in most cases, the current literature does not contain enough data to recommend omission of the day 3 sample, and the authors continue to screen patients with both day 3 and day 10 FSH levels. Specific screening guidelines are described below.

Ovarian Reserve Screening Threshold Values When applying the tests to a given patient population, the practicing clinician is critically dependent on the validity of the assay results and the threshold values used for counseling. The importance of validating any given assay system is described below. The broader issue of selecting a threshold value for normal and abnormal is also important. In some of the early reports, authors used the distribution of results among healthy and apparently normal women to determine the 95% confidence interval of anticipated results. Values above this range were considered abnormal. Although this approach is intuitively logical, it is not appropriate for validation of this type of test result. For example, if the women screened were all in their early twenties, it would be illogical and probably incorrect to assume that 5% of them had a degree of diminished ovarian reserve adequate to compromise their fertility. Similarly, if a group of women in their early forties were evaluated, the number with diminished ovarian reserve would greatly exceed the 5%, which would be defined as abnormal. Clearly, defining threshold values by creating a general population confidence interval is inappropriate. The threshold values for normal and abnormal tests should be based on clinically defined endpoints. Because the specific changes that account for the loss of reproductive potential remain undefined, all the studies reported to date are observational in nature. The only way to determine a threshold value is to perform the screening test in a large group of women and then follow them clinically to determine who is able to conceive. An eval-

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uation of the distribution of these data may then be used to define normal and abnormal test results. For centers that do not have a large clinical volume or that want to apply these screening tests without waiting the required time to accumulate all the follow-up data, comparison of their assay system with those from one of the centers where the original research was done is indicated.

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Seifer et al.38 reported a technique for quantitatively translating the results obtained at different institutions. They derived an equation that allowed them to predict the values obtained in one system based on the results obtained in the other (r  0.99). These data suggest that institutions may compare their assay to those used at centers that have validated their threshold levels based on clinical performance.

Assay Variability Immunoassays of LH and FSH are intrinsically difficult and imprecise, reflecting the fact that LH and FSH are glycoprotein hormones composed of a protein dimer backbone with variable degrees of glycosylation. Because these hormones have a common  chain, the specificity of their actions is determined by the unique  chain. The amino acid sequences of the  and  chains are believed to remain constant, although the degree of glycosylation varies substantially throughout the menstrual cycle. The different degrees of glycosylation affect the bioactivity and circulating half-lives of both LH and FSH and may also substantially influence the immunoassayability of these hormones. This is one of the main factors that explains the varying discrepancy between bioassay and immunoassay hormone levels in samples collected throughout the menstrual cycle. Differences in the antibodies used to measure gonadotropin levels also contribute to the imprecision of these assays. Most of the commercially available assay systems use polyclonal antibody systems that bind differently to different haptens on the glycoprotein hormone. It is important to recognize that immunoassays do not measure the total quantity of the glycoprotein present but, rather, the overall number of binding sites recognized by the antibodies used in the system. Consequently, as the distribution of the various isoforms changes throughout the menstrual cycle, the ability of any single assay to recognize the gonadotropins present may differ substantially. Obviously, this problem would be amplified when using another system with different antibodies that may recognize a different set of haptens. For all of these reasons, comparison of results among different assay systems may be difficult.37 The problems go beyond simple calculation of proportionality because an assay that reports a relatively higher value with one set of isoforms could present a lower value when measuring another. Additionally, different assays may be calibrated against different reference preparations, adding further variability to the results reported.

Morphologic Tests Investigators have attempted to quantify potential ovarian responsiveness using ultrasonographic measurements of various morphologic ovarian characteristics. An example is correlating antral follicle counts with ART outcomes. It has been observed that the number of antral follicles detected by transvaginal ultrasonography decreases with advancing age. Antral follicle counts have been found to correlate well with ovarian responsiveness to stimulation and pregnancy outcomes. Transvaginal ultrasonographic ovarian volume measurement represents another morphologic test of ovarian reserve. Syrop and coworkers39 examined ovarian volumes and noted that total ovarian volume and the volume of the smallest ovary were predictive of a woman’s response to gonadotropin stimulation and ART success. Specifically, large ovarian volumes were predictive of good ART outcome, whereas small ovarian volumes were associated with poor ART outcomes.

Recommendations for Ovarian Reserve Screening Based on the data currently available in the literature, it is possible to recommend guidelines about who should be screened for evidence of diminished ovarian reserve. All infertile women over age 30 should be screened because the rise in the incidence of diminished ovarian reserve begins at approximately that time. We believe that women should be screened early in their overall infertility evaluation, as the test is simple and inexpensive, and it provides valuable prognostic information. Additionally, younger women with unexplained infertility should be screened because the incidence of abnormal tests approaches 50% among these patients independent of their age. Perhaps the most important aspect of using the various tools available for assessing ovarian reserve is the way in which the information is applied to patient counseling. These tests do not have absolute

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sensitivity or specificity. Patients with abnormal values should be counseled that their chances for conception are poor and that they may want to consider other options, such as oocyte donation or adoption. These patients have excellent pregnancy rates in oocyte donation programs, indicating that the remainder of their reproductive system usually functions normally. The results of these tests, however, should not be used to exclude patients from care. This information is similar in nature to that provided by a semen analysis. Just as men with severe oligoasthenospermia occasionally father a child, women with evidence of diminished ovarian reserve occasionally conceive. The information is best used to counsel patients regarding their individual chances for conception. Decisions about how to apply that information is a personal decision made by the infertile couple and their clinician. Finally, the absolute dependence of these tests on clinically determined threshold values makes it imperative that clinicians have confidence in the significance of the results from their own laboratory. This may be achieved by evaluating clinically defined endpoints in their own population or by parallel comparison with the results obtained in an established laboratory.

Treatment of Women with Diminished Ovarian Reserve Prior to the advent of intracytoplasmic sperm injection (ICSI), it was believed that the major obstacle to treatment of the infertile couple was the male factor. Now the greatest limitation to treating a couple with infertility is diminished ovarian reserve of the female. This limitation has been studied extensively since investigators began describing dramatically lower success rates in in vitro fertilization (IVF) patients who have diminished ovarian reserve as reflected by an elevated day 3 serum FSH level. Strategies to improve outcomes have included increasing the dose of exogenous gonadotropins, decreasing the dosage of GnRH analogues, supplementing ovulation induction protocols with growth hormone, transferring back an increased number of embryos, and selective assisted hatching. Improvements in overall responsiveness have been demonstrated with virtually every protocol for some patients. Despite this fact, the incremental improvement in pregnancy rates has generally been small. These data continue to emphasize the importance of the qualitative changes in these patients’ oocytes, as many have sufficient improvements in the quantity of oocytes recovered to have routine numbers of embryos transferred.

For these reasons, it may not be sufficient simply to evaluate various treatment regimens by comparing peak E2 levels, the number of follicles that develop, the number of oocytes recovered, or the number of embryos available for transfer. Although pilot studies may legitimately compare ovarian responsiveness, any meaningful, definitive evaluation must also include an assessment of implantation and pregnancy rates.

Increased Gonadotropin Dosage The first and perhaps simplest approach to increasing the magnitude of the ovarian response is to increase circulating gonadotropin levels during stimulation. Higher circulating levels may reliable be achieved by increasing the quantity of gonadotropins being administered. Patients who responded poorly to low doses (150 IU FSH; 2 ampules per day) may commonly produce more follicles when given 300 IU or 450 IU per day.40 These enhanced responses lead to an increase in the number of oocytes obtained and the number of embryos transferred; and a significant number of pregnancies have been attained. Despite improvements in some patients, there are clear limits on the effectiveness of this strategy. At some point saturation kinetics are attained, and the ovarian response is determined more by the number of follicles available for recruitment than the circulating gonadotropin levels. This point is particularly important because low responders generally have markedly diminished numbers of follicles available for recruitment. It has been demonstrated that doses above 450 IU per day rarely produce a meaningful improvement in ovarian response or the ensuing pregnancy rates. Land et al. found no improvement in pregnancy rates with doses above 225 IU per day.40 Although the dose necessary to optimize ovarian responsiveness varies from patient to patient and should certainly be optimized, it is likely that clinically meaningful improvements are only rarely obtained with doses over 450 IU per day (6 ampules). It remains to be seen whether the introduction of recombinant FSH can alter the pregnancy rate for women with diminished ovarian reserve.

GnRH Agonist Down-Regulation The introduction of stimulation protocols containing GnRH agonists during the late 1980s provided new opportunities to stimulate patients who previously had limited responses to gonadotropins.41 Initial reports indicated that some low responders were stimulated better following luteal phase adminis-

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tration of a GnRH agonist.41 Subsequent clinical experience has provided disappointing results. In fact, many patients who are low responders may be completely refractory to stimulation after being down-regulated with a GnRH agonist.42 Whereas concurrent use of a GnRH agonist approaches being the standard for follicular stimulation in most ART programs, the enhancement of peak E2 levels, oocytes obtained, and pregnancy rates generally reflect the near-elimination of premature LH surges and the longer and more aggressive stimulation protocols that are possible. The fact that these are usually not the limiting factors in low responders may explain the generally unfavorable clinical results obtained with these protocols. There has been some question as to the direct impact of GnRH-a on ovarian responsiveness. GnRH receptors have been demonstrated in the ovary, although their role in follicular development is not understood. Feldberg et al. demonstrated increased ovarian responsiveness in low responders with elevated day 3 serum FSH levels who were maintained on lower doses of GnRH-a following pituitary suppression (minidose GnRHa).43 Although these preliminary data are provocative, prospective randomized dose response studies are clearly needed to address the issue of GnRH-a dose and ovarian performance adequately. Experience in our center continues to demonstrate that a number of patients are refractory to stimulation following down-regulation with GnRH-a at any dose (R.T. Scott et al., unpublished data). It is obvious that low responders represent a heterogeneous population of patients, and responses to various protocols are likely to vary widely.

GnRH Agonist Flare Because one goal in optimizing stimulation in women with diminished ovarian reserve was to increase the quantity of circulating gonadotropins, several investigators administered GnRH agonists to their patients beginning during the early follicular phase.44–46 The endogenous gonadotropin flare that occurred in response to the GnRH agonist was used to augment the exogenous gonadotropins. The duration of this endogenous gonadotropin flare has not been completely characterized, but pituitary desensitization is generally achieved within 5 days of initiating therapy. Therefore the patients are still protected from premature LH surges. Although many patients demonstrated an enhanced ovarian responsiveness using flare-up protocols, these protocols had some drawbacks. Some patients produced degenerate or low quality oocytes. Others

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rescued the corpus luteum from their prior cycle and produced large levels of progesterone during the early follicular phase. The impact of these elevations on folliculogenesis, endometrial development, and subsequent implantation rates has not been adequately studied. Finally, the overall impact on pregnancy rates has been mixed. Although flareup protocols are certainly not as successful for the average ART patient as the luteal phase suppression protocols, they do offer an opportunity to obtain controlled ovarian hyperstimulation in some patients who cannot be stimulated with other protocols.42

Microdose GnRHa Flare-up There have been no reported dose-response studies of the pharmacodynamics of GnRH agonists during flare-up ovulation induction cycles. The doses have generally been taken from treatment protocols for men with prostate cancer, where minimizing the duration and effect of the endogenous gonadotropin flare would be desirable. Navot et al. reported in 1991 that the rate of pituitary desensitization and ovarian down-regulation was significantly prolonged using 1% of the normal dose of histerelin.47 They subsequently extended their findings in the primate model by demonstrating that the pituitary could respond with supraphysiologic gonadotropin release in response to low doses of GnRH-a for prolonged intervals without inducing desensitization. These data demonstrated that the rate of pituitary desensitization to GnRH-a stimulation may be dose-dependent. These investigators did not evaluate the potential clinical impact of those findings to determine if they could be used to alter or enhance ovarian responsiveness during controlled ovarian hyperstimulation cycles. Scott et al. studied the impact of microdose GnRH agonist administration by giving patients who were low responders 20 g of leuprolide acetate (1/50 the normal dose) every 12 hours beginning on cycle day 2 and continuing until the administration of human chorionic gonadotropin (hCG).48 These patients also received exogenous gonadotropins beginning on cycle day 4. Most patients demonstrated a marked improvement in ovarian responsiveness, as indicated by higher peak E2 levels, an increase in the number of developing follicles, and recovery of more oocytes at the time of retrieval. Pituitary sensitivity was not serially tested, but it is likely that densensitization was attained by the completion of the stimulation because none of the patients had detectable premature LH surges. Of more importance is that sev-

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eral pregnancies were attained in this previously refractory group. We have extended this study. The protocol has been modified, and we now use leuprolide acetate 50 g bid with the onset of exogenous gonadotropins on day 3. These patients almost uniformly achieve higher peak E2 levels and require fewer ampules of gonadotropins. Additionally, in 85% a larger number of follicles are recruited. Pregnancy results have been mixed. Patients who are low responders but who have normal ovarian reserve screening have clinical pregnancy rates of 40%. In sharp contrast, patients with abnormal FSH levels generally have higher peak E2 levels and may produce additional follicles, but pregnancy rates are still poor (5%). Thus it appears that a microdose agonist flare-up protocol may increase the quantitative follicular response in many patients, but it may not significantly enhance the quality of the developing cohort of oocytes. Schoolcraft et al. reported their results using a modification of the microdose protocol.49 The authors evaluated 32 patients (mean age 36.8 years) who were cancelled in a prior IVF cycle secondary to a poor response. By using leuprolide acetate 40 g bid with the onset of exogenous gonadotropins 3 days after discontinuing oral contraceptive pills (taken for 21 days), adding 4 IU of growth hormone per day until hCG administration, and performing assisted hatching on all the transferred embryos, the authors showed a marked improvement in ovarian response with a higher E2 level on day 5, higher peak E2, more oocytes retrieved, an implantation rate of 25% (3.7 embryos/ET), and a pregnancy rate of 50%. The cancellation rate was 12.5%.49 The authors claimed that pretreatment with oral contraceptives was a significant factor in their successful outcomes by eliminating a corpus luteum rescue prior to the initiation of gonadotropins. The role of growth hormone (GH) supplementation is controversial (see below). These results are encouraging despite being based on a small number of patients. Larger series addressing the role of microdose GnRH are clearly needed.

Growth Hormone A detailed discussion of the GH–IGF–insulin-like growth factor-binding protein (IGFBP) axis is beyond the scope of this chapter, but, there are now extensive data demonstrating the critical importance of the IGF-IGFBP family (growth factors IGF-I and IGF-II and their binding proteins) to follicular development.50,51 In particular, IGF-I is GHdependent and is involved in potentiating the effect of FSH. This led several investigators to evaluate

the effect of GH administration as an adjunct during follicular stimulation. GH most likely acts directly on GH receptors in granulosa cells (GCs) rather than through augmentation of follicular IGFI,52 as IGF-I mRNA and receptors are not expressed in GCs of the dominant follicles (IGF-II mRNA and receptors are, however, expressed abundantly in the dominant follicle, the significance of which needs further investigation because IGF-II is not GH-dependent).53 Early trials were promising, with some reporting substantial improvements in follicular responsiveness and pregnancy rates. Other studies also suggested benefit.54,55 Unfortunately, follow-up studies have been less encouraging, and some controlled studies have been unable to demonstrate clinical benefit.56–59 Considering the large expense and the discouraging results in controlled trials, it must be concluded that there is no well established clinical role for GH in the treatment of low responders at the current time. Further studies directed at defining the dose of GH and determining if select populations can benefit from treatment (e.g., hypogonadotropic and polycystic ovary patients) are currently ongoing.

Increasing Number of Embryos at Time of Transfer A retrospective study found that a subset of women 40 years undergoing in vitro fertilization/ embryo transfer (IVF/ET) would respond to ovarian stimulation well enough to result in four or more embryos available for transfer. In such cases, pregnancy rates were similar to that observed in young patients (34.4% vs. 47.7% per embryo transfer), although delivery rates were higher among women 40 years old compared with women 40 years old (38% vs. 21%). The multiple gestation rate was lower in women 40 than in those 40 years old (7.5% vs. 32%), and all multiple births were twins in the older group. Spontaneous miscarriage rates often mitigated the pregnancy rates, as women 40 years enrolled in this study had a miscarriage rate of 44.8% compared to 22.0% in those 40 years old. Selective reduction is a possible option in the unlikely event that more than two embryos implant. However, prospective studies are needed to realize whether multiple-order embryo transfer is a credible option for women with diminished ovarian reserve.60

Increased Luteal Phase Progesterone Support Meldrum reported correction of impaired uterine receptivity in infertile women 40 years old under-

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going oocyte donation using increased progesterone replacement.61 Despite the same mean age of donors and recipients and same duration of infertility, women over age 40 receiving progesterone 100 mg per day had a marked increase in successful pregnancies similar to that observed in women under age 40 receiving 50 mg per day (54% of 35 women over age 40 receiving progesterone 100 mg per day had pregnancies compared with 21% of 24 women over age 40 receiving 50 mg progesterone and 46% of 28 women under age 40 receiving 50 mg progesterone. The use of luteal phase progesterone support as an effective adjunct in improving outcomes in women with diminished ovarian reserve awaits further well designed studies.

Assisted Hatching Some of the treatments designed to enhance pregnancy rates in low responders have not been directed toward improving ovarian responsiveness. Cohen et al. reported in 1992 that the use of selective assisted hatching in women with borderline FSH levels improved their implantation and ongoing pregnancy rates.62 This work was extended by Schoolcraft et al., who specifically studied patients previously identified as low responders.63 They found substantially higher pregnancy rates among the women whose embryos were hatched. Hu and coworkers applied nonselective assisted hatching in 258 consecutive patients.64 In women older than 38 years the authors achieved a live birth rate of 24% (10/42) for couples with no male factor and 14% (1/7) for couples with male factor infertility. These numbers are small, but most ART programs performing assisted hatching use this technique in older women. These data indicate that the embryos from women who are low responders may have impaired ability to produce a hatching enzyme (the putative factor responsible for dissolving an opening in the zona pellucida at the time of natural hatching), or their zona pellucida may be hardened or thickened. In either event, the data available at this time indicate that some benefit may be obtained through application of this technique.

Future Treatment It is now clear that women with diminished ovarian reserve have quantitative factors (e.g., low number of oocytes, peak E2 levels) and qualitative factors (e.g., reduced implantation rate per embryo transferred) that limit their reproductive performance. Although efforts to increase the number of

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follicles available for recruitment and development during any given treatment cycle will undoubtedly continue, it is also logical to assume that future treatments will be directed toward correcting the intrinsic intracellular processes that limit the reproductive potential of the individual oocytes that do develop. Although no treatment directed at the qualitative deficiencies are currently available, there are a number of interesting (but untested) possibilities. The first deals with the high incidence of aneuploidy in the oocytes of women who have diminished ovarian reserve. Because aneuploidy is generally the result of an abnormal first meiotic division, the oocyte is already abnormal by the time of retrieval. Future treatments may require that we replace the chromosomal complement of the oocyte with an appropriate haploid complement (possibly some form of pronuclear transposition). In vitro maturation of immature oocytes with supplementation of deficient factors may seem rational if we consider that the granulosa cells that accompany older oocytes are compromised in their production of growth factors, steroids, and glycoproteins; and they lack proper “nutritional” support for their sibling germ cells. Many such factors (e.g., mitochondria or certain messenger RNAs that have been related to changes in reproductive competence65,66) could be replaced initially by cytoplasmic donation and later by replacement of any specific factors (i.e., glycoproteins or growth factors) that have been identified and characterized. Abnormal meiotic spindles have also been noted in older women, leading to altered temporal and spatial changes in chromosomal movement and alteration of specific regulatory elements during the early phases of meiosis.67 Although these areas are being actively investigated at the current time, their potential for improving the efficiency of reproduction in women with diminished ovarian reserve remains clinically untested.

Acknowledgment This chapter has been adapted and modified from an article by Sharara, FI, Scott, RT, Seifer DB: The detection of diminished ovarian reserves in infertile women. Am J Obstet Gynecol 1998;179:804– 812.

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2. Scott RT, Hofmann GE. Prognostic assessment of ovarian reserve. Fertil Steril 1995;63:1–11. 3. Cameron IT, O’Shea FC, Rolland JM, et al. Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations. J Clin Endocrinol Metab 1988;67: 1190–1194. 4. Pearlstone AC, Fournet N, Gambone JC, Pang SC, Buyalos RP. Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age. Fertil Steril 1992;58:674–679. 5. Scott RT, Toner JF, Muasher SJ, et al. Follicle stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989; 51:651–654. 6. Toner JP, Philput CB, Jones GS, Muasher SJ. Basal follicle stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil Steril 1991;55:784–791. 7. Lenton EA, Sexton L, Lee S, Cooke ID. Progressive changes in LH and FSH and LH:FSH ratio in women throughout reproductive life. Maturitas 1988;10:35– 43. 8. Reyes FI, Winter JSD, Faiman C. Pituitary-ovarian relationships preceding the menopause. I. A crosssectional study of serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone levels. Am J Obstet Gynecol 1977;129: 557–564. 9. Sherman BM, West JH, Korenman SG. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab 1976;42: 629–636. 10. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 1975;55:699–706. 11. Batista MC, Cartledge TP, Zellmer AW, et al. Effects of aging on menstrual cycle hormones and endometrial maturation. Fertil Steril 1995;64:492–499. 12. Klein NA, Battaglia DE, Fujimoto VY, et al. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab 1996;81:1038–1045. 13. Klein NA, Illingworth PJ, Groome NP, et al. Decreased inhibin-B secretion is associated with the menotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin-A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 1996;81:2742–2745. 14. Seifer DB, Gardiner AC, Ferreira KA, Peluso JJ. Apoptosis as a function of ovarian reserve in women undergoing in vitro fertilization. Fertil Steril 1996; 66:593–598. 15. Muasher SJ, Oehninger S, Simonetti S, et al. The value of basal and/or stimulated serum gonadotropin levels in prediction of stimulation response and in vitro fertilization outcome. Fertil Steril 1988;50: 298–307.

16. Hughes EG, Robertson DM, Handlesman DJ, et al. Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J Clin Endocrinol Metab 1990;70:358–364. 17. McClachlan RI, Healy DL, Robertson DM, de Kretser DM, Burger HG. Plasma inhibin levels during gonadotropin induced ovarian hyperstimulation for IVF: a new index of follicular function? Lancet 1986;1:1233–1234. 18. Seifer DB, Gardiner AC, Lambert-Messerlian G, Schneyer AL. Differential secretion of dimeric inhibin in cultured luteinized granulosa cells as a function of ovarian reserve. J Clin Endocrinol Metab 1996;81:736–739. 19. Seifer DB, Lambert-Messerlian G, Hogan JW, et al. Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil Steril 1997;67: 110–114. 20. Scott RT, Hofmann GE, Oehninger S, Muasher SJ. Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization. Fertil Steril 1990;53:297–302. 21. Martin JSB, Nisker JA, Tummon IS, et al. Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle-stimulating hormone levels. Fertil Steril 1996;65:1238–1240. 22. Hansen LM, Batzer FR, Gutmann JN, et al. Evaluating ovarian reserve: follicle stimulating hormone and oestradiol variability during cycle days 2–5. Hum Reprod 1996;3:486–489. 23. Khalifa E, Toner JP, Muasher SJ, Acosta AA. Significance of basal follicle-stimulating hormone levels in women with one ovary in a program of in vitro fertilization. Fertil Steril 1992;57:835–839. 24. Licciardi FL, Liu HC, Rosenwaks Z. Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 1995;64:991–994. 25. Smotrich DB, Widra EA, Gindoff PR, et al. Prognostic value of day 3 estradiol on in vitro fertilization outcome. Fertil Steril 1995;64:1136–1140. 26. Mukherjee T, Copperman AB, Lapinski R, et al. An elevated day three follicle-stimulating hormone: luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation. Fertil Steril 1996;65:588–593. 27. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet 1987;2: 645–647. 28. Loumaye E. Billion JM, Mine JM, et al. Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil Steril 1990;53:295–301. 29. Tanbo T, Dale PO, Ludne O, Norman N, Abyholm T. Prediction of response to controlled ovarian hyperstimulation: a comparison of basal and clomiphene citrate-stimulated follicle stimulating hormone levels. Fertil Steril 1990;53:295–301.

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3. Detection and Therapeutic Approaches to Age-Related Infertility 30. Scott RT, Leonardi MR, Hofmann GE, et al. A prospective evaluation of clomiphene citrate challenge test screening in the general infertility population. Obstet Gynecol 1993;82:539–545. 31. Scott RT, Opsahl MS, Leonardi MR, et al. Life table analysis of pregnancy rates in a general infertility population relative to ovarian reserve and patient age. Hum Reprod 1995;10:1706–1710. 32. Adeno M, Gallagher H. Cigarette smoking and the age of menopause. Ann Hum Biol 1982;9:121–130. 33. Jick H, Porter J, Morrison AS. Relationship between smoking and age of natural menopause. Lancet 1997;1:1354–1354. 34. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RT. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test (CCCT). Fertil Steril 1994;62:257–262. 35. Hughes EG, Yeo J, Claman P, et al. Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action. Fertil Steril 1994;62:807–814. 36. Sterazik K, Strehler E, De Santo M, et al. Influence of smoking on fertility in women attending an in vitro fertilization program. Fertil Steril 1996;65:810–814. 37. Hershlag A, Lesser M, Montefusco D, et al. Interinstitutional variability of follicle-stimulating hormone and estradiol levels. Fertil Steril 1992;58:1123–1126. 38. Seifer DB, Canick JA, Seltman HJ, Frishman GN, Berk CA. Abstract P368. In: 39th Annual Meeting of the Society for Gynecologic Investigation, San Antonio, TX, 1993. 39. Syrop CH, Dawson JD, Husman KJ, Sparks AE, Van Voorhis BJ. Ovarian volume may predict assisted reproductive outcomes better than follicle hormone concentration on day 3. Hum Reprod 1999;14:1752. 40. Land JA, Yarmolinskaya MI, Dumoulin JCM, Evers JLH. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril 1996;65:961– 965. 41. Droesch K, Muasher ST, Brzyski R, et al. Value of suppression with a GnRH-a prior to gonadotropin stimulation for in vitro fertilization. Fertil Steril 1989;51:292–295. 42. Muasher SJ. Treatment of low responders. J Assist Reprod Genet 1993;10:112–114. 43. Feldberg D, Farhi J, Ashkenazi J, et al. Minidose gonadotropin-releasing hormone agonist is the treatment of choice in poor responders with high folliclestimulation hormone levels. Fertil Steril 1994;62: 343–346. 44. Garcia JE, Padilla SL, Bayati J, Baramki TA. Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization. Fertil Steril 1990;53:302–305. 45. Padilla SL, Bayati J, Garcia JE. Prognostic value of the early serum estradiol response to leuprolide acetate in in vitro fertilization. Fertil Steril 1990; 53:288–294.

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46. Padilla SL, Dugan K, Maruschak V, Shalika S, Smith RD. Use of the flare-up protocol with high dose human follicle stimulating hormone and human menopausal gonadotropins for in vitro fertilization in poor responders. Fertil Steril 1996;65:796–799. 47. Navot D, Rosenwaks Z, Anderson F, Hodgen GD. Gonadotropin releasing hormone agonist-induced ovarian hyperstimulation: low dose side effects in women and monkeys. Fertil Steril 1991;55:1069– 1075. 48. Scott RT, Navot D. Enhancement of ovarian responsiveness with micro-doses of GnRH-agonist during ovulation induction for in vitro fertilization. Fertil Steril 1994;61:880–885. 49. Schoolcraft W, Schlenker T, Gee M, Stevens J, Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil Steril 1997;67:93– 97. 50. Adashi EY, Resnick CE, Hernandez ER, et al. Insulin like growth factor I as an intra-ovarian regulator: basic and clinical implications. Ann NY Acad Sci 1991;626:161–167. 51. Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev 1992;13:641– 669. 52. Sharara FI, Nieman LK. Identification and cellular localization of growth hormone receptor gene expression in the human ovary. J Clin Endocrinol Metab 1994;79:670–672. 53. El-Roiey A, Chen X, Roberts VJ, et al. Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. J Clin Endocrinol Metab 1993;77:1411–1418. 54. Menashe Y, Lunenfeld B, Pariente C, Frenkel Y, Mashiach S. Can GH increase after clonidine administration predict the dose of human menopausal hormone needed for induction of ovulation. Fertil Steril 1990;53:432–435. 55. Shoham Z, European and Australian Multicenter study. Cotreatment with growth hormone and gonadotropin for ovulation induction in hypogonadotropic patients: a prospective, randomized, placebo-controlled, dose-response study. Fertil Steril 1995;64: 917–923. 56. Bergh C, Hillensjo T, Wikland M, et al. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril 1994;62:113–120. 57. Owen EJ, West C, Mason BA, Jacobs HS. Co-treatment with growth hormone of suboptimal responders in IVF-ET. Hum Reprod 1991;6:529–533. 58. Younis JS, Simon A, Koren R, et al. The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized, placebo controlled double blind study. Fertil Steril 1992; 58:575–580. 59. Suikkara AM, MacLachlan V, Koistinen R, Seppala M, Healy DL. Double-blind placebo controlled

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study: human biosynthetic growth hormone for assisted reproductive technology. Fertil Steril 1996; 65:800–805. 60. Wildra EA, Gindoff PR, Smotrich DB, Stillman RJ. Achieving multiple-order embryo transfer identifies women over 40 years of age with impaired in vitro fertilization outcome. Fertil Steril 1996;65:103–108. 61. Meldrum DR. Female reproduction aging-ovarian and uterine factors. Fertil Steril 1993;59:1–5. 62. Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. Implantation enhancement by selective assisted hatching using zona drilling of embryos with poor prognosis. Hum Reprod 1992;7:685–691. 63. Schoolcraft WB, Schlenker T, Gee M, Jones GS, Jones HW. Efficacy of assisted hatching in poor prognosis IVF candidates. Fertil Steril 1994;62:551–554. 64. Hu Y, Hoffman DI, Maxson WS, Ory SJ. Clinical application of non-selective assisted hatching of human embryos. Fertil Steril 1996;66:991–994. 65. Flood JT, Chillik CF, van Uem JFHM, Iritani A, Hodgen GD. Ooplasmic transfusion: prophase germinal vesicle oocytes made developmentally competent by microinjection of metaphase II egg cytoplasm. Fertil Steril 1990;53:1049–1054. 66. Keefe DL, Niven-Fairchild T, Powell S, Buradagunta S. Mitochondrial deoxyribonucleic acid deletion in oocytes and reproductive aging in women. Fertil Steril 1995;64:577–583. 67. Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assem-

bly in oocytes from naturally cycling women. Hum Reprod 1996;11:2217–2222.

Suggested Reading Chang M, Chiang C, Hsich T, et al. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998;69:505. Hoffman G, Danforth D, Seifer D. Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 1998;69:474. Reuss M, Kline J, Santos R, et al. Age and the ovarian follicle pool assessed with transvaginal ultrasonography. Am J Obstet Gynecol 1996;174:624. Santoro N, Tovaghogol A, Skurnick J. Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women. Fertil Steril 1999;71:658. Seifer D, Scott R, Bergh P, et al. Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin-B prior to a rise in day 3 FSH. Fertil Steril 1999;72:63. Sharara F, McClamrock H. The effect of aging on ovarian volume measurements in infertile women. Obstet Gynecol 1999;94:57. Sharara F, Seifer DB. New Methods for Assessing Ovarian Reserve. OBG Management Volume 12, issue 10, pages 61–69, 2000. Welt C, McNicholl D, Taylor A, Hall J. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999;84:105.

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4 Role of Ultrasonography in Infertility Theresa Widrich

Ultrasonography was first used in obstetrics and gynecology in 1958 by Donald, and it has undergone several developments since then. Both transabdominal and transvaginal ultrasonography (TVUS) are used in gynecology. The transabdominal approach gives a more panoramic view of the pelvis, but TVUS offers several advantages in gynecology. With TVUS the shorter distance of the ultrasound probe to the pelvic organs makes it possible to achieve a detailed delineation of the uterus with the cervix, uterine wall, and endometrium, ovaries, and fallopian tubes, even in obese patients. It does not require a full bladder, and so is more comfortable for the patient. Because of the proximity to the pelvic organs, high frequency transducers (5.0 or 7.5 MHz) may be used resulting in higher resolution and clearer images than transabdominal US. The combination of the pelvic examination and TVUS provides excellent information to the gynecologist. As a tool, TVUS has become indispensable for diagnosis and for selected treatments of infertility, such as evaluating the female pelvis, monitoring ovulation, and transvaginal oocyte pickup for in vitro fertilization.

Equipment Most ultrasound machines have B-mode (gray scale) imaging, M-mode (motion) and Doppler US (flow measurement at a single point of a vessel). Some machines also offer color Doppler making it possible to study the blood flow in a specific area. Various ultrasound probes are available. For TVUS there are mechanical probes with one oscillating element and electronic probes with phased

array or curvilinear transducers. Frequencies for TVUS are usually between 5.0 and 7.5 MHz and the angle of view may be between 60° and 360° (average 90°–150°) for endovaginal US. Smaller sectors make it possible to visualize details, such as small vessels and the heartbeat during early pregnancy. Wider angles allow an overview of the entire pelvis.

Technique of TVUS The patient must be informed about the procedure. Ideally she is positioned in the dorsal lithotomy position in stirrups. A bimanual examination precedes the US examination. The TVUS transducer is wiped with a disinfectant and is covered with a condom filled with gel. Coupling gel is placed on the tip of the transducer to ensure uninterrupted passage of the ultrasound waves from the probe into the pelvis. When scanning infertility patients at mid-cycle, one should be aware that some ultrasound gels and latex condoms have a spermicidal effect. In these cases polyethylene bags and paraffin oil can be used as an alternative. The transducer is inserted into the vaginal canal and images of the pelvic organs in the longitudinal and transverse plane are obtained. To get a 360° overview of the pelvis the US probe is rotated. Then the movement of the pelvic organs towards each other is tested. The examiner slightly moves the ultrasound probe and places his/her other hand on the abdominal wall and gently pushes towards the probe (like a bimanual exam using the ultrasound probe instead of one hand). If the pelvic organs do not slide this is an indirect sign of adhesions.

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Diagnosis of Infertility by TVUS

Endometrium

The first structures to be scanned are the uterus and cervix. It is useful to have performed a bimanual examination prior to this point to determine the position of the uterus (e.g. anteverted or retroverted). Its characteristic landmark is the endometrial stripe, surrounded by the homogeneous muscular layer of myometrium. Position and size of the uterus are noted (Fig. 4–1). Myomas are the most common pathology of the uterus and cervix. Smaller ones can be seen as round structures with high echogenicity on US. Larger ones distort the shape of the uterus or the endometrial stripe. Sometimes calcifications are seen within a myoma. When a leiomyoma is larger than 5 cm, the view obtained with TVUS may be obscured and in such cases it is more effective to carry out abdominal US. The position of the fibroid is important. Submucous myomas extend into the uterine cavity and may distort it, thereby inhibiting implantation of pregnancy. Müllerian abnormalities are estimated to occur in 2–3% of women. On TVUS a uterine septum can be seen as two endometrial stripes separated by a myometrial layer. The septum can result in inhibition of implantation and may be removed hysteroscopically. A bicornuate uterus is best discovered in transverse view; in the longitudinal view the intermediate myometrial layer is not continuous.

Circulating estrogen and progesterone influence the endometrial thickness and texture. US can clearly depict cyclic changes of texture and may indicate whether the appearance of the endometrium is related to the day of the menstrual cycle or to a suspected functional problem. During and shortly after menses the endometrium appears as a thin echogenic line. During the proliferative phase it thickens and becomes isoechoic. Toward ovulation the endometrium becomes more echogenic and develops a multilayered pattern. There is a thin hyperechoic line in the middle, surrounded by an inner hypoechoic layer and an outer echogenic layer that is secondary to stromal edema. This pattern seems necessary for normal pregnancy to develop (Fig. 4–2). Several studies have attempted to correlate endometrial thickness at the time of ovulation with pregnancy rates. It is now generally acknowledged that in the natural cycle, a thickness of 5 mm or less results in poor pregnancy rates, whereas 10 mm or more provides a good possibility of conception (Fig. 4–3). During the secretory phase the endometrium continues to thicken, reaching up to 14 mm, and becomes homogenic and hyperechoic on US. Beginning menstruation toward the end of the cycle may be seen as minimal hypoechoic spots in the endometrium. Polyps and other endometrial abnormalities may pose a problem. Endometrial polyps vary in size from less than a millimeter to several centimeters in diameter. Large polyps may interfere with implantation of the embryo and cause infertility. On

FIGURE 4–1. Saline infusion sonohysterography. Submucous myoma protrudes into the uterine cavity. Hysteroscopic removal is not possible in this case because the intramural part of the myoma is more than 50%.

FIGURE 4–2. Three layer pattern of the endometrium as seen around ovulation. (Courtesy of the Department of Gynecologic Endocrinology, University Hospital of Vienna, Austria.)

Conventional TVUS Uterus and Cervix

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FIGURE 4–3. Secretory endometrium prepared for conception. This patient had a positive pregnancy test one day after this scan was performed. (Courtesy of W. Feichtinger, Institute for Sterility Treatment, Vienna, Austria.)

US, endometrial polyps typically appear as an unusually high degree of thickening of the endometrium and are best diagnosed early in the menstrual cycle when the proliferative endometrium is still thin.

Ovaries As many as 10–30% of women investigated for infertility do not ovulate regularly. TVUS can be used to monitor ovulation. Follicles can be observed on TVUS when they reach a diameter of 2–3 mm. During the natural cycle, a dominant follicle typically appears during days 8–12. Its growth is linear, about 2 mm per day, and it reaches a size of 18–24 mm before ovulation (mean 21.5 mm). It is rare for other follicles to be present during the natural cycle, but in such cases they usually do not exceed 14 mm in diameter, nor do they ovulate. The size of the dominant follicle correlates with the serum estrogen level, and its size is more predictive of ovulation than serum estrogen levels, although a combination of the two gives the best accuracy. E2 levels at ovulation are between 150 and 400 pg/ml. Ultrasonography can be useful to detect ovulation itself; or in cases of tubal damage on one side, it can help determine on which side ovulation will occur if intrauterine insemination is planned. Moreover, the shape of a follicle helps determine whether it will ovulate. Fukuda et al. showed that a healthy (type A) follicle contains a cloud in the shape of a cone. The base is positioned at the follicle wall; the tip points into the center of the follicle and has a light spot assumed to be the oocyte-cumulus complex (Fig. 4–4). This can be

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seen when the follicle is in excess of 15 mm. Type B follicles show an echo free space and become atretic. Ovulation occurs 36–38 hours after the peak serum luteinizing hormone (LH) surge and is seen as a rapid reduction of follicle size. In most cases fluid is detected in the cul-de-sac. This may also be present before ovulation because of transudation. A corpus luteum is present from 45 minutes after ovulation, and on US appears as a round cystic structure with an irregular pattern due to blood clots. It changes rapidly over time. Polycystic ovary disease (PCO) is a type of menstrual dysfunction with anovulation, elevated androgens, and inappropriate gonadotropin secretion. Several causes lead to anovulation, and persistent anovulation leads to polycystic ovaries. Clinically, Balen et al. showed that obesity is associated with hirsutism and an elevated serum testosterone concentration; it is also correlated with increased rates of infertility and cycle disturbance. The rates of infertility and cycle disturbance also increase with serum LH concentrations 10 IU/L. A rising serum concentration of testosterone is associated with an increased risk of hirsutism, infertility and cycle disturbance. Sonographically, polycystic ovaries appear to be enlarged with a volume usually greater than 12 cm3. Several small follicles less than 10 mm are lined up under a thickened capsule. PCO indicates an increased risk of ovarian hyperstimulation syndrome, and in such cases US can play an important role in assessing the treatment plan. Endometriosis is a very common cause of infertility. Its prevalence is as high as 10% in the repro-

FIGURE 4–4. A healthy follicle in natural cycle shortly before ovulation. (Courtesy of the Department of Gynecologic Endocrinology, University Hospital of Vienna, Austria.)

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ductive age group and in 25–35% of infertile women. Common symptoms are secondary dysmenorrhea, secondary dyspareunia, diffuse or localized pelvic pain and low back pain, although women with endometriosis can be asymptomatic. On physical examination a retroverted, fixed uterus is suggestive of endometriosis. Nodularity in the cul-de-sac region or the sacrouterine ligaments is found in one-third of patients with endometriosis. Small foci of endometriosis can only be detected by laparoscopy but larger endometriomas are easily seen on TVUS. The classic sonographic appearance is the so called chocolate cyst, which appears homogenic and has the echogenicity of a fetal liver or lung. Some cysts are also partially solid and partially cystic. It can be difficult to differentiate between a corpus luteum cyst and an endometrioma. Often they can be distinguished only after several weeks: a corpus luteum cyst changes and eventually disappears.

Fallopian Tubes A healthy fallopian tube cannot be depicted sonographically unless there is some fluid around it, which, in a healthy woman may be present around ovulation or be due to ascites or inflammation. US may be helpful for detecting pelvic inflammatory disease (PID) or the chronic changes after PID, leading to the possible cause of infertility. Acute inflammation of the tube leads to thickening of the wall and free fluid in the pelvis. The tube is tender to the probe touch. Polycystic ovaries may be an indirect sign of acute PID. Chronic inflammation is seen as an accumulation of fluid in the tube and presents itself as an irregular, elongated mass filled with fluid or pus. It may initially appear circular like a stimulated follicle in one plane, but if the probe is turned through 90° the elongated structure becomes visible. The wall is thin and stretched. A tuboovarian abscess can be seen on TVUS as a conglomerate consisting of a complex cyst in the ovary surrounded by a dilated, fluid filled tube that is often tender on examination. Adhesions can seldom be depicted by ultrasound unless there is free fluid in the pelvis. They are suspected when there is no sliding of the uterus and ovaries, either to each other or in relation to the pelvic wall.

Fluid Enhanced TVUS Saline Infusion Sonohysterography One of the most exciting developments in vaginal sonography in recent years is the use of contrast agents. In 1993 Parsons and Lense developed the

technique of using saline as a negative contrast agent in the uterine cavity. Since then it has become widely used and mostly referred to as saline infusion sonohysterography (SIS). The technique is valuable for detecting any structural abnormalities, such as submucous myomas, endometrial polyps, and endometrial adhesions. The technique of SIS is as follows. After performing conventional TVUS the ultrasound probe is removed and an open-sided vaginal speculum is inserted. The cervix is cleansed with an antiseptic solution. Using a sterile uterine packing forceps, a small catheter is placed in the cervical os under direct visualization until the uterine fundus is reached. After removing the speculum a plastic syringe containing sterile saline is attached to the catheter. The ultrasound probe can then be reintroduced and saline is slowly infused into the uterus while observing for uterine distension. The uterine cavity can then be reevaluated. Submucous myomas can be defined as such after the instillation of saline and the relation of a fibroid to the uterine wall can be seen (Fig. 4–1). SIS also helps determine a suitable course of treatment because myomas with an intracavitary portion of more than 50% can be resected hysteroscopically. Submucous fibroids may also be diagnosed by hysteroscopy, but it is not possible to visualize the intramural part using this technique. Polyps when outlined by intracavitary fluid are seen as echogenic masses in the uterine cavity originating from the endometrium with a small or broad base. Adhesions or a septum are also easily seen when the uterine cavity is distended and they are outlined by the contrast agent. Several studies published over the last few years highlight some important advantages of using SIS. There are consistent findings that visualization of structural abnormalities is improved when saline is used, the procedure causes minimal discomfort and a low rate of complications. Two recent studies evaluated SIS for infertility patients: Soares et al. evaluated the diagnostic accuracy of SIS in uterine cavity diseases in 65 infertile patients, comparing its results with those of hysterosalpingography (HSG) and TVUS. Hysteroscopy was the gold standard and SIS had the same diagnostic accuracy for polypoid lesions and endometrial hyperplasia, with no equivocal diagnosis. For uterine malformations, SIS had a sensitivity of 77.8% and intrauterine adhesions a sensitivity of 75%. Gronlund et al. assessed the diagnostic value of SIS in an evaluation of metrorrhagia and infertility using hysteroscopy as the standard. The overall sensitivity and specificity for SIS was 90.9% and 100%, respectively. When examining the met-

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rorrhagia and infertility groups separately the sensitivity and specificity and predictive values were 100% for all parameters in cases of infertility.

Hysterosalpingo-Contrast Sonography In 15% of cases the inability to conceive is due to tubal occlusion. The gold standard for evaluating the tubes is laparoscopy, but this has risks associated with general anesthesia. Another method is HSG, however this has the disadvantage of exposing the ovaries to radiation. A relatively new technique for assessing the status of fallopian tubes is hysterosalpingo-contrast sonography (HyCoSy). Deichert and Schlief first described this technique in 1989. Technique: An echogenic contrast medium (most authors use Echovist®) is administered through the cervix into the uterus using a balloon catheter, and its flow through the fallopian tubes observed in real time sonography. Each tube must be examined separately, and the flow of contrast media should be observed in three segments of the tube: isthmic, ampullary and fimbrial. The contrast agent will also become visible in the Cul-de-Sac region. Several studies have compared HyCoSy with HSG and Chromolaparoscopy. The results of HyCoSy are equal or slightly better than HSG; discomfort is comparable with about 10% of the patients reporting severe discomfort. Compared with laparoscopy the concordance was about 85%. Results become better when it is combined with Doppler flow studies in each tube (91% concordance). These results indicate that, if carried out by an experienced ultrasonographer, HyCoSy is a suitable first line procedure in patients with infertility disorders.

Monitoring Treatment of Infertility Ovulation Induction Normally more than one follicle appears during stimulated cycles. In this situation several follicles contribute to the level of serum estrogen. TVUS is used to assess the number and size of stimulated follicles (Fig. 4–5). Clomiphene citrate (CC) has a weak estrogenic effect and leads to increased secretion of follicle stimulating hormone (FSH) and LH through activation of the hypothalamic pituitary axis. Its main indication is absent or infrequent ovulation. Usually a CC dose of 50 mg PO is given on cycle days 5–9. In case of failure, the dosage may be increased up to 150 mg per day. Ultrasonography can be used to monitor the growth and number of follicles. When the dominant follicle reaches at least 20 mm in diameter, human chorionic gonadotropin (hCG)

FIGURE 4–5. Hyperstimulated ovary with several follicles at IVF oocyte harvesting. The tip of the suction needle can be seen in the collapsing follicle in the middle. (Courtesy of the Department of Gynecologic Endocrinology, University Hospital of Vienna, Austria.)

can be administered to trigger ovulation. Follicles larger than 14 mm may ovulate as well, whereas those less than 14 mm usually become atretic after administration of hCG. At 36 hours after hCG injection ovulation occurs, and intrauterine insemination (IUI) or intercourse should be scheduled 24–48 hours later. Arici et al. demonstrated that this timing can achieve higher pregnancy rates. The endometrial thickness after CC administration is usually less than in natural cycles (5–9 mm). Beneventi et al. observed that endometrial maturation is slower after application of CC for about 3 days. Controlled ovarian hyperstimulation with FSH can be used to achieve ovulation if CC treatment fails or if there is known malfunction of the hypothalamus or pituitary gland. Follicle stimulation is achieved by daily intramuscular injections through 7–14 days. Serum estrogen levels and frequent TVUS examinations are recommended to assess when hCG should be administered to induce ovulation. Usually a size of 18 mm for the dominant follicle is recommended. TVUS gives better information for the timing than estrogen levels because a larger number of small follicles may also produce a significant increase in serum estrogen levels. An estrogen level of 1000–1500 pg/ml is optimal; at a level over 2000 pg/ml, hCG should not be given because of the risk of ovarian hyperstimulation syndrome. Early signs of ovarian hyperstimulation on US are enlarged ovaries and free fluid in the pelvis.

In Vitro Fertilization More than 20 years have passed since the first child was conceived through IVF. Today indications not only include tubal disease and resistant anovulation

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but also male factor infertility, unexplained infertility, endometriosis, immunologic causes of infertility, cervical factor and some cases of premature ovarian failure. More follicles are stimulated with IVF than during controlled ovarian hyperstimulation. Several different protocols exist using FSH to induce follicular growth and GnRH Analogs to prevent premature LH surges. TVUS alone or in conjunction with serum estrogen level measurements is used to monitor the ovarian response and a linear growth of follicles of 2 mm per day can be expected. When at least two or three follicles reach 16–18 mm diameter, 5000 or 10,000 IU of hCG is administered to induce follicular maturation. Oocytes are harvested 34 to 36 hours later by fine needle aspiration.

Technique of Follicle Measurements It is usually easy to locate stimulated ovaries by directing the US probe lateral to the uterus. Follicles have an elliptic shape and should be measured in 3 dimensions and the mean diameter calculated. In the natural cycle and after stimulation with FSH, a follicle is considered mature from a diameter of 16–18 mm. After stimulation with CC a minimum of 20 mm is required. Measuring all 3 dimensions is also necessary to rule out that other structures are confused with follicles. A large vessel or a hydrosalpinx may appear round on one plane but will be identified when rotating the probe by 90°.

Endometrium in Stimulated Cycles In contrast to the natural cycle there is now general agreement that endometrial thickness cannot be used as a predictive factor for pregnancy rates in stimulated cycles. De Gruyter et al. found that pregnancy rates of assisted reproductive procedures are influenced only marginally by the degree of endometrial proliferation and treatment should not be cancelled because of inadequate endometrial thickness. Endometrial echogenicity is a more reliable parameter in stimulated cycles. Fanchin et al. found in a prospective study that when the endometrial echogenicity is measured objectively by a computer assisted system on the day of hCG administration, pregnancy and implantation rates fell progressively and significantly from the low echogenicity to the high echogenicity group in IVF cycles.

FIGURE 4–6. An early gestational sac has developed in the uterus. (Courtesy of W. Feichtinger, Institute for Sterility Treatment, Vienna, Austria.)

TVUS at the time of the missed menstrual period and grows rapidly reaching approximately 10 mm 40 days after the last menstrual period (Fig. 4–6). The presence of a yolk sac confirms the development of embryonic structures. Fetal cardiac activity may be observed on TVUS after the fifth week following the last menstruation. It usually confirms a normal intrauterine pregnancy. First trimester abortion is less than 2% after documentation of a heartbeat, although one study found that from a maternal age of 35 years or older there is a fivefold risk of early pregnancy loss even after a fetal heartbeat is documented. If correlated to serum hCG levels using the first international standard preparation, a gestational sac is visible on TVUS in all normal pregnancies above 1000 mIU/ml hCG, a yolk sac above 7200 mIU/ml and a visible embryo with a heartbeat with an hCG level greater than 10800 mIU/ml. With ectopic pregnancies, a pseudogestational sac may appear in the endometrium but does not develop embryonic echoes or a yolk sac. Also -hCG levels do not double every 2–3 days as they should with a normal pregnancy. If the fallopian tubes are carefully scanned, sometimes the ectopic pregnancy can be visualized, and even a heartbeat seen on US.

Treatment of Infertility Using TVUS

Early Pregnancy

Ultrasound-Assisted Puncture of Follicles During IVF

Serum measurements of hCG and US imaging are used to track the development of early pregnancy. A gestational sac of 2 mm becomes visible on

In the early years of IVF, oocytes were retrieved laparoscopically, exposing women to risks of general anesthesia and surgery. In 1982 Lenz and Lau-

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ritzen were the first to report ultrasonographically guided transabdominal puncture for oocyte harvesting. The technique was then modified by Feichtinger and Kemeter to a transvesical and later a transvaginal approach. Needle guided vaginal puncturing for oocyte retrieval has now become the method of choice. Its advantages are the short distance to the ovaries with less probability of bowel injury or bleeding, better visualization of follicles, no adhesions to inhibit visualization of the follicles, no need for general anesthesia, an ambulatory setting for the procedure, and relatively few complications. Technique The entire procedure can be carried out in an outpatient setting. General anesthesia is not required; a sedative can be given if the patient is anxious but is not required in 50% of the cases. The patient is placed in the dorsal lithotomy position, and sterile drapes cover the legs and perineal area. The US probe is covered with a sterile condom or polyethylene bag, and a needle guide is attached to it. The vagina is cleansed with saline solution or IVF culture medium. Disinfecting solutions may be potentially harmful for the fertilization rate, and US gel on the outside of the transducer should also be avoided. The US probe is placed in the vagina and a biopsy line is generated on the US screen targeting the first stimulated follicle. A long 16 or 18 gauge needle is rapidly advanced through the vaginal wall into the follicle. The tip of the needle can be seen on the screen. The follicular fluid is aspirated under visualization and pulled into a collection chamber. The follicle collapses. Without withdrawing it, the needle is then carefully placed in the next follicle and suction is performed again. Some authors flush each follicle with medium, others do not. At the end of the procedure the pelvis is scanned to rule out bleeding.

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Another application is US guided multifetal pregnancy reduction and salpingocenteses in cases of ectopic pregnancies. In both cases toxic substances (methotrexate or KCl) are injected to the gestational sac with a US-guided needle.

Recent Developments Doppler, Color Doppler and Color Power Angiography Doppler ultrasound allows measurements of blood flow by measuring the change of frequency that occurs when the ultrasound beam is reflected by moving erythrocytes. Spectral Doppler displays the frequency shift in waveform and allows the measurement of absolute velocity and resistance to flow (pulsatility index) at a certain point of the vessel (Fig. 4–7). Color Doppler (CD) displays the blood flow in an area and its direction: blood flow towards the ultrasound transducer is usually red, away from it is displayed as blue. Color power angiography (CPA) uses the amplitude of Doppler signals which represent the density of erythrocytes in the vessel being studied. This provides a more accurate display of tissue perfusion but gives no information about the direction of the flow. Doppler ultrasonography cannot yet be used to monitor stimulated cycles, nor can it be used to predict pregnancy outcome. There is growing evidence that studies of perifollicular vascularity will predict the development of a healthy oocyte. There is still dispute about a significant difference in the pulsatility index of the uterine artery between those women who became pregnant and those who did not after IVF treatment. This relationship has not been identified by all authors and Zaidi et al. offer a possible expla-

Risks Compared with laparoscopic oocyte harvesting, the complication rate using the transvaginal aspiration technique is low. Occasional bleeding from puncture sites or damage to the iliac vessels can lead to complications. Pelvic inflammation has also been seen after oocyte harvesting.

Other Uses of TVUS Needle aspiration can also be performed to reduce ovarian cysts. Even when carried out before oocyte harvesting, it does not seem to have an adverse influence on the pregnancy outcome.

FIGURE 4–7. Doppler measurement of the right ovarian artery in a stimulated ovary. (Courtesy of W. Feichtinger, Institute for Sterility Treatment, Vienna, Austria.)

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through very tortuous tubes which may improve our ability to assess tubal patency.

Conclusion

FIGURE 4–8. Three-dimensional-ultrasonography. A uterus duplex is displayed using multiplanar mode and Color Doppler. (Courtesy of A. Lee, Department of Prenatal Diagnosis and Treatment, University Hospital of Vienna, Austria.)

nation for this: They have been able to demonstrate a circadian rhythm of the pulsatility index in the uterine artery indicating that uterine perfusion is better in the morning. Future work may help standardize results. CD Ultrasound has been proven to be very useful in assessing tubal patency as described above.

Three Dimensional US A transvaginal three-dimensional scan has been developed that amplifies diagnostic potential (Fig. 4–8). Several two-dimensional images (slices) are taken and the three-dimensional picture is then calculated by the machine. When the volume is obtained it can be analysed in three different ways: reslicing, volume measurements and surface rendering. Reslicing has an advantage over two dimensional ultrasound because slices can be in any angle to the ultrasound probe. Jurcovic et al. have demonstrated the usefulness of this technique for displaying congenital abnormalities of the uterus. Volume measurements are gaining more importance in the measurement of the endometrium. Yaman et al. have demonstrated the reproducibility of endometrial volume measurements and Raga et al. have shown that the volume of the endometrium at implantation may predict pregnancy rates better than two dimensional thickness measurements. Surface rendering gives very impressive pictures of embryos and fetuses. Sladkevicius has also demonstrated its use in gynecology. By combining CPA with three-dimensional US he could obtain accurate pictures of the flow of contrast agent even

Ultrasonography and especially TVUS have become indispensable tools for the gynecologic infertility work-up as well as for monitoring and treating infertility. The use of contrast medium enhances its possibilities, making it possible to avoid laparoscopy and hysteroscopy in selected cases. Color Doppler, CPA, and three-dimensional US are the most recent developments with very promising possibilities although are yet to be evaluated in terms of their usefulness for infertility patients.

References and Suggested Reading Alatas C, Aksoy E, Akarsu C, et al. Evaluation of intrauterine abnormalities in infertile patients by sonohysterography. Hum Reprod. 1997;12:487–490. Ayida G, Chamberlain P, Barlow D, et al. Is routine diagnostic laparoscopy for infertility still justified? A pilot study assessing the use of hysterosalpingo-contrast sonography and magnetic resonance imaging. Hum Reprod. 1997;12:1436–1439. Bakos O, Lundkvist O, Wide L, Bergh T. Ultrasonographical and hormonal description of the normal ovulatory menstrual cycle. Acta Obstet Gynecol Scand. 1994;73:790–796. Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod. 1995;10:2107–2111. Beneventi F, Sampaolo P, Polatti F, et al. Ultrasonography endometrial patterns in different hormonal treatments to induce ovulation. Radiol Med (Torino). 1995; 90:278–283. Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal sonography versus serum human chorionic gonadotropin in early detection of pregnancy. Am J Obstet Gynecol. 1988;158:608–612. Blumenfeld Z, Yoffe N, Bronshtein M. Transvaginal sonography in infertility and assisted reproduction. Obstet Gynecol Surv. 1991;46:36–49. Bree RL, Edwards M, Bohm-Velez M, et al. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with HCG level. Am J Roentgenol. 1989;153:75–79. Buttram VC Jr, Gibbons WE. Müllerian anomalies: a proposed classification. (An analysis of 144 cases). Fertil Steril. 1979;32:40–46. de Crespigny L, Kuhn R, McGinnes D. Saline infusion sonohysterosalpingography, an underutilized technique. Aust N Z J Obstet Gynaecol. 1997;37:206–209. De Geyter C, Schmitter M, De Geyter M, et al. Prospective evaluation of the ultrasound appearance of the

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4. Role of Ultrasonography in Infertility endometrium in a cohort of 1,186 infertile women. Fertil Steril. 2000;73:106–113. DeCherney AH, Laufer N. The monitoring of ovulation induction using ultrasound and estrogen. Clin Obstet Gynecol. 1984;27:993–1002. Deichert U, Schlief R, van de Sandt M, Juhnke I. Transvaginal hysterosalpingo-contrast-sonography (Hy-CoSy) compared with conventional tubal diagnostics. Hum Reprod. 1989;4:418–424. Dickey RP. Doppler ultrasound investigation of uterine and ovarian blood flow in infertility and early pregnancy. Hum Reprod Update. 1997;3:467–503. Dijkman AB, Mol BW, van der Veen F, et al. Can hysterosalpingocontrast-sonography replace hysterosalpingography in the assessment of tubal subfertility? Eur J Radiol. 2000;35:44–48. Fanchin R, Righini C, Ayoubi JM, et al. New look at endometrial echogenicity: objective computer-assisted measurements predict endometrial receptivity in in vitro fertilization-embryo transfer. Fertil Steril. 2000; 74:274–281. Feichtinger W. Follicle aspiration with interactive threedimensional digital imaging (Voluson): A step toward real-time puncturing under three-dimensional ultrasound control. Fertil Steril. 1998;70:374–377. Feichtinger W. Results and complications of IVF therapy. Curr Opin Obstet Gynecol. 1994;6:190–197. Feichtinger W. Current technology of oocyte retrieval. Curr Opin Obstet Gynecol. 1992;4:697–701. Fleischer AC. Sonographic assessment of endometrial disorders. Semin Ultrasound CT MR. 1999;20:259– 266. Fukuda M, Fukuda K, Yding Andersen C, Byskov AG. Healthy and atretic follicles: vaginosonographic detection and follicular fluid hormone profiles. Hum Reprod. 1995;10:1633–1637. Fukuda M, Shimizu T, Fukuda K, et al. Transvaginal hysterosonography for differential diagnosis between submucous and intramural myoma. Gynecol Obstet Invest. 1993;35:236–239. Goldstein SR, Timor-Tritsch IE: Ultrasound in Gynecology 1st Ed. Churchill Livingstone Inc. 1995. Gronlund L, Hertz J, Helm P, Colov NP. Transvaginal sonohysterography and hysteroscopy in the evaluation of female infertility, habitual abortion or metrorrhagia. A comparative study. Acta Obstet Gynecol Scand. 1999;78:415–418. Grunfeld L. The uterus and endometrium. Clin Obstet Gynecol. 1996;39:175–187. Hackeloer BJ. Ultrasound scanning of the ovarian cycle. J In Vitro Fert Embryo Transf. 1984;1:217–220. Jurkovic D, Gruboeck K, Tailor A, et al. Ultrasound screening for congenital uterine anomalies. Br J Obstet Gynaecol 1997;104:1320–1321. Nicolaides KH, Kleinkauf-Houcken A, Huneke B, Lindner C, Braendle W. Combining B-mode ultrasound with pulsed wave Doppler for the assessment of tubal patency. Hum Reprod. 1997;12:2457–2460. La Torre R, De Felice C, De Angelis C, et al. Transvaginal sonographic evaluation of endometrial polyps:

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a comparison with two dimensional and three dimensional contrast sonography. Clin Exp Obstet Gynecol. 1999;26:171–173. Lande IM, Hill MC, Cosco FE, Kator NN. Adnexal and cul-de-sac abnormalities: transvaginal sonography. Radiology. 1988;166:325–332. Laughead MK, Stones LM. Clinical utility of saline solution infusion sonohysterography in a primary care obstetric-gynecologic practice. Am J Obstet Gynecol. 1997;176:1313–1316. Lee A, Sator M, Kratochwil A, et al. Endometrial volume change during spontaneous menstrual cycles: volumetry by transvaginal three-dimensional ultrasound. Fertil Steril 1997;68:831–835. Orsini LF, Venturoli S, Lorusso R, et al. Ultrasonic findings in polycystic ovarian disease. Fertil Steril. 1985; 43:709–714. Parson AK, Lense JJ: Sonohysterography for endometrial abnormalities: preliminary results. J Clin Ultrasound 1993;21:87–95. Raga F, Bonilla-Musoles F, Casan EM, et al. Assessment of endometrial volume by three-dimensional ultrasound prior to embryo transfer: clues to endometrial receptivity. Hum Reprod. 1999;14:2851–2854. Schlief R, Deichert U. Hysterosalpingo-contrast sonography of the uterus and fallopian tubes: results of a clinical trial of a new contrast medium in 120 patients. Radiology. 1991;178:213–215. Schwimer SR, Rothman CM, Lebovic J, Oye DM. The effect of ultrasound coupling gels on sperm motility in vitro. Fertil Steril. 1984;42:946–947. Shalev J, Meizner I, Bar-Hava I, et al. Predictive value of transvaginal sonography performed before routine diagnostic hysteroscopy for evaluation of infertility. Fertil Steril. 2000;73:412–417. Sladkevicius P, Campbell S. Advanced ultrasound examination in the management of subfertility. Curr Opin Obstet Gynecol. 2000;12:221–225. Smith KE, Buyalos RP. The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity. Fertil Steril. 1996;65:35–40. Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril. 2000;73: 406–411. Sohaey R, Woodward P. Sonohysterography: technique, endometrial findings, and clinical applications. Semin Ultrasound CT MR. 1999;20:250–258. Speroff L, Glass RH, Kase NG. The polycystic ovary. In: Clinical Gynecologic Endocrinology and Infertility. 6th Edition, Baltimore: Williams & Wilkins 1999. Strandell A, Bourne T, Bergh C, et al. The assessment of endometrial pathology and tubal patency: a comparison between the use of ultrasonography and X-ray hysterosalpingography for the investigation of infertility patients. Ultrasound Obstet Gynecol. 1999;14:200– 204. Strandell A, Bourne T, Bergh C, Granberg S, Thorburn J, Hamberger L. A simplified ultrasound based infer-

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tility investigation protocol and its implications for patient management. J Assist Reprod Genet. 2000; 17(2):87–92. Timor-Tritsch IE, Rottem S. Transvaginal ultrasonographic study of the fallopian tube. Obstet Gynecol. 1987;70:424–428. Ubaldi F, Wisanto A, Camus M, et al. The role of transvaginal ultrasonography in the detection of pelvic pathologies in the infertility workup. Hum Reprod. 1998;13:330–333. Van der Auwera I, D’Hooghe TM. Ultrasound covers and sonographic gels are embryo-toxic and could be replaced by non-toxic polyethylene bags and paraffin oil. Hum Reprod. 1998;13:2234–2237.

Widrich T, Bradley LD, Mitchinson AR, Collins RL. Comparison of saline infusion sonography with office hysteroscopy for the evaluation of the endometrium. Am J Obstet Gynecol. 1996;174:1327–1334. Wolman I, Groutz A, Gordon D, et al. Timing of sonohysterography in menstruating women. Gynecol Obstet Invest. 1999;48(4):254–258. Wu MH, Tang HH, Hsu CC, et al. The role of threedimensional ultrasonographic images in ovarian measurement. Fertil Steril. 1998;69:1152–1155. Yaman C, Sommergruber M, Ebner T, et al. Reproducibility of transvaginal three-dimensional endometrial volume measurements during ovarian stimulation. Hum Reprod. 1999;14:2604–2608.

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5 Coping with Infertility: Practical Psychosocial Issues Dorothy A. Greenfeld

Three questions obsess infertile patients. “Am I ever going to be pregnant?” is heard with great frequency by physicians working with this population. Though patients may dread the answer, their longing for pregnancy and their fears that parenthood is forever out of reach compel them to ask the question. The other two questions are usually unspoken but are fueled by the ceaseless distress and anxiety patients suffer because of their inability to conceive: “Am I losing my mind?” and even more frightening “Is the distress that I feel preventing me from getting pregnant?” Physicians working with infertile individual(s) serve their patients well when they anticipate all three questions and when they include psychological support and counseling as an integral part of a comprehensive treatment plan. It has long been a common idea that infertility is “all in the mind,”1–3 so it is not surprising that patients fear they are the cause of their own infertility. Despite the long-standing myth that infertility has a psychiatric basis, studies on the psychological aspects of infertility have consistently demonstrated that infertile individuals are psychologically “normal” and that the experience of infertility rarely results in severe psychological sequelae or disabling psychiatric disorders.4–6 The emotional experience of infertility and its treatment, however, is generally concluded to be difficult and can have a profound impact on affected individuals and couples.6–8 Moreover, clinical data support the notion that participants in infertility treatment can benefit from psychological support and counseling, and that there is an important role for the mental health professional in this milieu.6,9,10 This chapter focuses on what clinicians who work with infertile patients can learn from studies

on the psychological aspects of infertility and how they can help patients cope with the typical psychosocial stressors associated with infertility. Some of the psychologically and ethically complex treatment decisions faced by infertile patients and the role of the mental health professional are discussed here. The chapter concludes with recommendations for clinicians dealing with couples and individuals faced with these difficult problems.

What Have We Learned from Research? Historically, infertility was thought to be a “woman’s problem,” and her psychological state was considered to be at the root of the problem. Indeed, papers on medical and psychological aspects of infertility from the first half of the twentieth century were generally in agreement that by unconsciously rejecting pregnancy, childbirth, and motherhood women caused their own infertility.1–3 This simplistic (and sexist) notion began to change during the late 1960s and early 1970s as studies appeared in the psychiatric and gynecologic literature that compared data from infertile women with data from matched controls (fertile women) and found no differences in their psychological state.11,12 At the same time, clinical reports began to emerge suggesting that there were certain predictable emotional responses to infertility and that infertile patients could benefit from psychological counseling and support.9,13–16 Studies using standard psychological measures have found that there are no differences in the psy-

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chological state between infertile couples and fertile controls.4,17,18 Nevertheless, these studies have continued to demonstrate that, although psychologically normal, infertile patients experience a high degree of emotional dysphoria and euphoria as a result of infertility and its treatment.5,6 For example, in a study of 59 infertile women, Downey et al. reported that 76% of the subjects through that infertility caused them serious psychological consequences.19 In another study of 63 infertile women and 37 infertile men, Mahlstedt et al.7 reported that subjects felt hopeless and depressed. In a study of 200 couples entering in vitro fertilization (IVF) treatment, Freeman et al.8 reported that 48% of the women and 15% of the men described infertility as the “worst experience of their lives.” Researchers have also considered whether patients’ coping strategies—how they cope with life in general—may serve as a predictor for how they endure a failed cycle of infertility treatment. For example, Litt et al.20 and Newton et al.21 reported that patients who demonstrated pretreatment depressive symptoms and pretreatment anxiety symptoms were more likely to have a poor emotional response to a failed cycle of IVF. The coping strategies that employ psychologically “distancing” oneself from the treatment appear to be the least effective. For example, in Litt et al.’s study the patients who had the most difficulty after a failed cycle were women who used “escape” as a coping strategy.20 In a similar report, Hynes et al. studied 100 infertile women and found that the women who used “avoidance” as a coping strategy were more likely to experience psychological distress after a failed treatment cycle.22 What can we learn from this research? Over the course of their infertility and its treatment patients typically experience a range of emotional responses, including guilt, anxiety, depression, and grief. These responses, which vary from patient to patient, are a normal part of the process. Although at times causing stress and symptoms, they do not in themselves suggest a psychologically unstable individual. The quality and content of the experience of infertility for most couples change over time.23 Nevertheless, there are certain practical psychosocial issues with which couples must cope as they go through the process—issues clinicians should keep in mind as they consider what is best for their patients. Such issues include the impact of the diagnosis, the impact of the treatment, gender differences in response to infertility and how they affect the way couples cope with the process, and coming to the decision to end treatment.

Practical Psychosocial Issues Impact of the Diagnosis Most people take their fertility for granted. In fact, a common complaint from individuals and couples when they have difficulty conceiving is “we were so careful to avoid pregnancy until we were ready.” Thus in what is commonly described as a “life crisis”10,16 couples go in short order from an assumption of assured fertility to one of absolute dismay at what is experienced as unfair and wholly unexpected infertility. The initial denial and “this can’t be happening to me” feelings may later change to intense remorse. The intensively painful experience of finding oneself defined as infertile in what appears to be a highly fertile world leads to feelings of isolation and guilt and the inevitable questions: “Why me”? Rosenthal24 described guilt as a primary emotional response common to many couples diagnosed with infertility: guilt about waiting too long to start a family, guilt about previous life events such as pregnancy termination or a sexually transmitted disease. The guilt can exacerbate feelings of remorse, leading to acute anxiety. Frequently the experience is to go from taking fertility for granted directly to an all-out aggressive attempt to achieve pregnancy—an emotional juxtaposition that forces entry into a world heretofore completely unknown to them. Infertile patients frequently complain that their lives have been completely “taken over” by their infertility, pervading their marital relationships, their sexual life, their relationships with their families, their social relationships (where everyone around them is getting pregnant and having babies). Once they begin treatment, infertility also can have a devastating effect on their financial life. The oftused phrase “the emotional roller coaster of fertility” aptly describes the euphoria and dysphoria so often associated with their experience. Over time, these feelings can become chronic23 as the length of the typical struggle with infertility and its treatment can lead to a growing sense of losing control of the process. All to often the result is a profound decline in the individual’s sense of integrity, competence, and feelings of self-worth. Mahlstedt described eight common losses associated with infertility.25 1. 2. 3. 4.

Loss Loss Loss Loss

of of of of

a (potential) relationship health status or prestige self-esteem

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5. Loss of self-confidence 6. Loss of security 7. Loss of a fantasy or hope of fulfilling an important fantasy 8. Loss of something or someone of great symbolic value

Impact of Treatment In addition to the emotional impact of infertility are the rigorous, expensive, and often humiliating demands of the medical treatment. By its nature, the treatment necessarily involves a prolonged intrusion into the most intimate aspects of the infertile couple’s life. The charting of basal body temperatures, the precise timing of sexual intercourse, and the need to perform “sex on demand” to optimize the possibility of conception are only the first and most benign of these intrusions. Later requirements may include invasive surgical procedures, taking ovulation-enhancing hormones by injection, undergoing intrauterine inseminations, and ultimately, for some, participation in assisted reproduction techniques such as IVF. Clearly, the pace and scope of treatment varies from one couple to the next, but the experience for all feels lengthy. The extended and repetitive nature of what to the physician may seem like innocuous treatments can have a devastating cumulative impact on the couples’ sexual and marital relationship. The couple must try to maintain a semblance of normal life while trying to accommodate a grueling, often hectic treatment schedule—all at a time when they feel in a “limbo” of uncertainty about whether any of the efforts will succeed. Some patients jokingly say, “I have learned more about the reproductive system than I ever imagined I would need to,” whereas for others the treatment regimens are confusing and difficult to understand. Already socially isolated from their fertile family members and friends, they find themselves feeling intimidated and anxious about broaching questions to the treatment staff. As the treatment becomes more complex, couples may be distressed to find themselves unprepared but contemplating a treatment prohibited by their religion or one they find ethically troubling. For example, couples are asked to decide whether to freeze, destroy, or donate excess embryos, whether they would tolerate a risky multifetal pregnancy, or whether they would consider fetal reductions (aborting one or more of the fetuses) to increase the likelihood of survival of the remaining reduced number of fetuses.

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Gender Differences in Response to Infertility As though the social, sexual, and financial impact of prolonged treatment on their relationship were not enough with which to contend, infertile couples must also confront the fact that they as individuals may have different responses to infertility and its treatment—differences related to gender. Without education and preparation to help them understand that this is normal, couples are often frightened by these differing responses and fear that it means they are losing everything, including their relationship. In fact, it is often quite the opposite. The experience of infertility often brings couples closer, strengthening the bonds between them. Because it is often true that they have different coping skills, the closeness resulting from the challenge of infertility can make them stronger as a team, although in the short run these differences can add to the couples’ difficulties.

Female Response to Infertility Many women worry about and doubt their fertility long before they try to conceive. When they are diagnosed as infertile they typically experience it as evidence of personal failure. (Interestingly, this is a typical reaction from women even when it is their male partner who is infertile.) Women typically see infertility as a punishment for their imagined previous “sins” (such as an abortion early in life). They frequently ruminate about time lost, time wasted, or experiences they “should not have had.” At the beginning of the workup phase, women are more likely to question their sexuality, to have increasing self-doubt, and to experience greater emotional distress than men.25–27 After prolonged infertility treatment women often report a decrease in sexual satisfaction and a loss of libido.23 Women are also typically much more affected by outside influences, such as who among their friends, relatives, and acquaintances is pregnant. No matter what the diagnosis, women report more feelings of role failure and diminished self-esteem. Though potentially more psychologically vulnerable to the “fertile world around them,” women nonetheless tend to show better coping skills in terms of reaching out to develop social networks with family and friends. It is often the woman who initiates and seeks out psychological support from a mental health professional and support groups.27

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Male Response to Infertility Men tend to assume that infertility is “a woman’s problem,” an assumption often reinforced by their female partners’ willingness to take on responsibility for the problem. This assumption may be inadvertently further compounded by the medical treatment team, who may not bother to perform a semen analysis until long after the female partner has been subjected to invasive diagnostic procedures. Men are less likely than women to question their fertility prior to treatment, and in many cases it comes as a shock to a man to learn that he is the infertile partner. These men report feelings of loss, diminished self-esteem, and a sense of being stigmatized.28 Nonetheless, their distress is generally not as severe as that of women. Men report feeling sad and disappointed but not devastated. In general, men appear to be more accepting of possible childlessness and are more willing then women to consider an end to treatment when infertility is due to a male factor. As a result, the man is usually the partner who is more reluctant to participate in an assisted reproductive technology program. (Women may interpret this reluctance as a lack of interest or a lack of agreement about family goals.) Whoever is the infertile partner, men more often tend to use distancing strategies to mute the intensity of their feelings of loss while at the same time remaining especially sensitive to their partner’s distress.27

Ending Treatment As treatment continues, the litany of anxieties and concerns among the infertile increasingly includes the question: “When is enough enough?” Obviously, at a time when it seems that the treatment possibilities are endless (i.e., the advent of advanced maternal age as a result of treatment with donated oocytes) this question is not easily answered. Infertile couples address this issue in many ways. For example, some couples go to the “end of the earth” to seek treatment and technology, and others decline any treatment. For some these decisions are made based on financial constraints, and for others they are based on religious or cultural taboos; but for all its worth attention from the treatment team. Though patients may hesitate, they want and appreciate discussion and guidance on this matter from their clinicians. Physicians can be most helpful when they give an ongoing honest assessment of the diagnosis, plan, and prognosis. Patients may raise their concerns about stop-

ping treatment as a way of putting the issue on the table; but merely raising the issue does not mean they are ready to stop immediately. Other patients want to have a plan for closure: for example, “We will try two more cycles of intrauterine inseminations and then we stop.” For all patients, stopping treatment involves a decision-making process and careful consideration. Some consider other options for parenthood such as adoption. Others explore third party reproduction, such as oocyte donation or a gestational surrogate. They also may consider not having children at all. The physician can be most helpful by taking a careful, guiding, but scrupulously neutral approach. What is not helpful is a statement such as, “You ought to consider adoption” as a euphemism for “This treatment is not going anywhere.”

Special Considerations of Pregnancy After Infertility Though the above practical psychological issues are experienced to some degree by everyone going through infertility treatment, not all patients need to spend a great deal of time looking at other options. After all, some do get pregnant. It might seem that, having achieved their goal, they would be pleased, grateful, and free of stress. Pregnancy itself, however, raises some specific issues that challenge the formerly infertile woman. All pregnant women worry about pregnancy loss and the health of their unborn child. These worries are often accentuated for the formerly infertile.

Pregnancy The issue of pregnancy is on the minds of these infertile women much if not most of the time. The result is a repetitive pattern of mood fluctuation with each menstrual cycle. During part of the cycle they are excited and optimistic, almost certain that this time conception has occurred. During this period they are completely focused on each bodily change, each nuance that may indicate the earliest stage of pregnancy. This heightened expectation of pregnancy is often compounded by symptoms caused by the infertility medications that mimic pregnancy (what Sandelowski et al. referred to as a “drug-induced pseudocyesis”).29 For example, these medications may cause patients to experience nausea, weight gain, and sore breasts or delayed menses, all of which can be interpreted as early signs or symptoms of pregnancy. Once menses

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occurs, the patient’s mood plunges. She is not pregnant and, she fears, never will be. What happens when, after infertility, pregnancy is clearly documented? Olshansky described an “identity shift” experience by the formerly infertile woman. At first, while anxiously straddling the fence between infertility and pregnancy, she may have difficulty seeing herself as a “normal pregnant woman.”30 Bernstein et al. described the normal ambivalence and questions about competence that affects all pregnant women. The author stated that these questions and anxieties are typically intensified in the newly pregnant (formerly infertile) patient who may voice doubts about her self-worth and her competence as a mother.31 The anxiety associated with infertility and its treatment may carry over and continue into the pregnancy. Concerns about “defective reproductive machinery” may extend to fears about potential problems with the pregnancy or subsequent delivery. When in fact there are prenatal or neonatal problems, women tend to feel guilt and shame, which they associate with their former infertility. Lind et al. described the impact of prior infertility on parents whose newborn children required treatment in the newborn intensive care unit. Even when the child’s illness had no connection whatsoever with the infertility, the mothers experienced a profound sense of loss and grief that they associated with their “defective” state.32

Pregnancy Loss Many imagine that miscarriage would be the worst thing that could happen to patients who have finally conceived after a long, difficult effort. In fact, that is not what the evidence shows. Women who are lucky enough to conceive after infertility treatment often report feeling vulnerable and often worry intensely about losing the pregnancy (some preparation and much reassurance is called for at this point). However, if that pregnancy results in a miscarriage, the disappointment is lessened because the women are frequently relieved to know they can achieve pregnancy and they at least have had that experience. Harris et al. described the paradox that infertile couples grieving after a miscarriage may simultaneously experience a kind of relief, an “emotional gain” that is the result of just knowing that they were able, if only for a short while, to be a part of “the fertile world.”33 Nevertheless, pregnancy loss following infertility merits special consideration. One study reported increased levels of depression in women following pregnancy loss, and most at risk were the childless women.34

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Multiple Pregnancy and Multifetal Pregnancy Reduction Rapid advances in the methods of assisted reproduction have led to an increase in multiple pregnancies.35 Patients who have been trying to conceive for years may not know that their medical treatment causes an increased risk of multiple pregnancy; and even if they are aware of that risk, they may welcome it, hoping to have more than one child.36 They may not fully understand the risks associated with multiple pregnancy, such as prematurity and infant mortality. In fact, pregnancies involving three or more fetuses constitute such a significant risk that it has led to the development of another treatment: multifetal pregnancy reduction. Because of the ethically complex issues associated with this treatment—one that may involve aborting one or more fetuses to save one or more fetuses—has raised concerns among clinicians. Two studies have considered the long-term psychological consequences of multifetal pregnancy reduction and have concluded that although women undergoing this procedure become distressed and suffer some short-term depression, most accept it as a painful necessity and report that they would willingly undertake it again.37,38

Pregnancy Following Treatment with Donor Gametes Although artificial insemination with donor sperm has been available to infertile couples for nearly a century, treatment of women with donor oocytes has been available only since 1984. Though conceptually similar, these treatments are significantly different. Treatment with donor oocytes is a more complicated, invasive, and expensive procedure than donor insemination. Furthermore, it has introduced a new cohort of patients into treatment, such as women with premature ovarian failure, women who have had surgically lost ovaries because of serious illness, and women of advanced reproductive age. Whether the couple is utilizing donor sperm or donated oocytes, however, the pretreatment preparation and many of the counseling issues remain the same. The couple must mourn the loss entailed by the fact that one of the parents is not genetically related to the potential child. The couple must also deal with the difficult decision as to whether they will utilize an anonymous or a known donor. Couples are also faced with questions about what to tell the potential child. What (if anything) and when should they tell the child about his or her conception?

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Role of the Mental Health Professional The identified psychological stresses of infertility treatment, the need to cope with demanding treatment protocols, and the expanding array of ethically complex issues have led to a steadily increasing appreciation of the role of the mental health professional on the infertility treatment team. Mental health professionals are utilized to assess and evaluate participants in infertility treatments, provide psychotherapeutic intervention and support, and serve as educators in a difficult and complex milieu.

Psychological Consultation and Evaluation Ideally, the mental health practitioner is an integral part of an interdisciplinary treatment team. In this context, routine evaluation by the mental health professional gives the patient the message that the demanding nature of the treatment requires a degree

of counseling, education, and support. Its routine nature suggests that the psychological stresses of treatment are “normal and expected.” Psychological consultation and evaluation give the patient an opportunity to express concerns he or she may have about the treatment as it allows the clinician an opportunity to form a picture of the participant. A medical practitioner with a small practice or who is incorporating infertility treatment into a gynecologic practice may not have a mental health practitioner available as part of the on-site team. In these instances it is important to obtain a thorough history that could include recommendations for referral to a mental health practitioner when appropriate. The assessment should be designed to determine whether further psychological evaluation is necessary. There are several models for the content of such an assessment. One such document is The Comprehensive History of Infertility (CPHI), developed by Burns and Greenfeld (1990) for the Mental Health Professional Group of the American Society for Reproductive Medicine (Table 5–1). The CPHI contains the reproductive history, psy-

TABLE 5–1. Comprehensive Psychosocial History of Infertility 1990 Reproductive History Infertility Current infertility: primary or secondary History of past infertility Pregnancy Living children (stepchildren, adopted, donor offspring, placed for adoption) Therapeutic abortion(s) Spontaneous abortion(s) Other perinatal loss: SIDS, death of child High-risk pregnancy History of genetic/chromosomal abnormalities Cancer of the reproductive tract and/or chemotherapy DES exposure Congenital abnormalities of the reproductive tract Family history of genetic disorders Mental Status Psychiatric history Hospitalization for psychiatric illness Psychiatric treatment Treatment with psychotropic medication Substance abuse Current mental status Symptoms of depression Symptoms of anxiety/panic attacks Symptoms of obsession Current use of psychotropic medications Current problem with substance abuse/addiction Change in mental status Exacerbation of prior psychiatric symptoms

Sexual History Frequency and response Function/dysfunction Religious or cultural influence on sexual patterns or procreation beliefs Sexual history Function/dysfunction Sexually transmitted disease Prior sperm donor/surrogate mother/consideration of use of donor gametes Homosexual or ambisexual patterns History of rape or incest Changes in any sexual patterns secondary to infertility or medical treatment. Relationship Status Marital History of marriages/divorces History of marital discord/therapy Extramarital relationships Current satisfaction/dissatisfaction Ambivalence about medical treatment and reproductive technologies Familial History of dysfunctional family of origin Recent deaths or births in family History of numerous familial losses Social Available support system Career disruptions or pressures History of or current legal problems Criminal conduct

(Reproduced from Burns LH, Greenfeld DA, for the Mental Health Professional Group. CPHI: Comprehensive Psychosocial History for Infertility. Birmingham, AL: American Society for Reproductive Medicine, 1990.)

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chological history, marital history, sexual history, and social history. Findings suggesting that referral to a mental health professional is appropriate include a history (past and present) of psychiatric illness, a history of pregnancy complications and loss, a history of sexual abuse, past or current chemical abuse or dependence, or a chaotic social or familial situation. Of course, any patient who requests such a referral should be provided one.39 Many programs of assisted reproductive technology require pretreatment evaluation and assessment of patients to determine if they are prepared for the rigors of the treatment, if they understand and are able to give informed consent to the treatment, if they are psychologically stable. One such program developed a set of guidelines for psychological evaluation.40 The following is a checklist of areas for consideration during the pretreatment evaluation and assessment of participants in treatment. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Patient reliability Ability to provide informed consent Stability of the couple’s relationship Psychological issues for the infertile partner Expectations of infertility treatment Understanding the impact of the technology Current and past sexual functioning Level of social support Religious and cultural considerations Psychiatric status Legal history

Psychological Support and Counseling For patients who have a seriously troubled history or who are in immediate psychological distress, a referral for psychotherapy is indicated. Even the large number of patients who do not merit referral are likely to be reassured that psychological support is available if needed. Several modalities of psychotherapeutic intervention have been effective for treatment of infertile individuals and couples. Therapeutic sessions may be conducted individually, with the couple (or family) together, or with one or both partners as participants in a group treatment. The focus of therapy may be alleviation of distress and control of psychological symptoms, sex therapy, or grief management. The techniques may include supportive, cognitive, or psychodynamically oriented treatment. Most of the referrals are for brief treatment involving crisis intervention designed to provide short-term support and symptom relief. The choice of modality usually depends

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on the nature of the problem, the patient(s) preferences, and the availability of each option. Though it is an individual’s or couple’s choice about the treatment modality, it is usually up to the referring clinician to initiate the referral, explaining the rationale for the recommendation. Whatever the choice of treatment focus or modality, one thing is clear: Gone are the days when physicians referred their infertile patients to psychotherapists for the purpose of helping them “work through unresolved conflicts impeding their changes for pregnancy.” Nowadays, the goal of psychotherapeutic intervention is to recognize that infertility is highly stressful and that dealing with it can enhance one’s ability to cope with the psychological and physical stresses of the problem.

Individual Therapy Many patients prefer individual treatment. It is the most private, secure, and common treatment modality, one that is likely to be most familiar and acceptable. When a patient has a clear preference for individual treatment, it should generally be honored unless there is a clear indication that another modality is indicated.

Couples Therapy Menning described the problem of infertility, no matter who is responsible for the diagnosis, as one that always affects the couple’s marriage, their friendship, and their sexual relationship.15 Hence couples treatment is often the most useful for infertile couples. It provides a safe forum where they can deal with conflicts, listen to each other, and deal with gender differences in response to the problem.

Group Therapy Many couples find group therapy especially useful. Groups of infertile couples can provide support, education, and the kind of empathy available only to those who are experiencing the same stresses. The experience of talking with others in the same predicament can help “normalize” the experience and provide a level of reassurance that makes the experience more tolerable. A prospective study of the effectiveness of support groups for the infertile concluded that they are “a highly acceptable and effective intervention in self-referred patients in alleviating psychological distress related to infertility.”40

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Recommendations for Physicians Infertile patients are surrounded by family and friends who advise them to “relax and you’ll get pregnant” (which of course only adds to their anxiety and distress). Obviously, it is helpful to patients when the medical team does not participate in that sort of advice. It is especially helpful to patients when their physicians reassure them that their anxiety is not preventing them from becoming pregnant. Moreover, physicians serve their infertile patients well when they communicate the fact that psychological stress is a temporary but inevitable part of the process. Physicians who have an indepth understanding of the psychological and emotional aspects of this complex problem can reassure and support patients, recognize when they need additional support, and help them find and use that support. Kingsberg41 listed the following recommendations for physicians treating infertile patients. 1. Educate and inform couples at each visit about their diagnosis, prognosis, and treatment options, even if it seems redundant. 2. Acknowledge and normalize the emotional aspects of these treatment options. 3. Encourage couples not to rush their decision about treatment. 4. Encourage couples to consult with a mental health professional.

References 1. Deutsch H (1944) The Psychology of Women. New York: Grune & Stratton. 2. Fisher IC. Psychogenic aspects of sterility. Fertil Steril 1953;4:466–471. 3. Benedek T. Infertility as a psychosomatic defense. Fertil Steril 1952;3:527–535. 4. Downey J, McKinney M. The psychiatric status of women presenting for infertility evaluation. Am J Orthopsychiatry 1992;62:196–205. 5. Berg BJ, Wilson JF. Psychiatric morbidity in the infertile population: a reconceptualization. Fertil Steril 1990;53:654–661. 6. Mazure CM, Greenfeld DA. Psychological studies of in vitro fertilization/embryo transfer participants. J In Vitro Fert Embryo Transfer 1989;6:242–49 7. Mahlstedt PP, MacDuff S, Bernstein J. Emotional factors and the in vitro fertilization and embryo transfer process. J In Vitro Fert Embryo Transfer 1987; 4:232–236. 8. Freeman EW, Boxer AS, Rickels K, et al. Psychological evaluation and support in a program of in vitro. Fertil Steril 1985;43:48–53.

9. Berger DM. The role of the psychiatrist in the reproductive biology clinic. Fertil Steril 1977;28:141– 145. 10. Covington SN. Psychosocial evaluation of the infertile couples: implications for social work practice. J Soc Work Hum Sexuality 1987;6:21–36. 11. Mai FM, Munday RM, Rump EE. Psychiatric interview comparisons between infertile and fertile couples. Psychosom Med 1972;12:46–59. 12. Noyes RW, Chapnick EM. Literature on psychology and infertility. Fertil Steril 1964;15:543–548. 13. Menning BE. The infertile couple: a plea for advocacy. Child Welfare 1975;54:545–560. 14. Menning BE. Resolve: a support group for infertile couples. Am J Nurs 1976;76:258–259. 15. Menning BE. Counseling infertile couples. Contemp Obstet Gynecol 1979;13:101–108. 16. Menning BE. The emotional needs of infertile couples. Fertil Steril 1980;34:313–319. 17. Adler JD, Boxley RL. The psychological reactions to infertility: sex roles and coping styles. Sex Roles 1985;12:271–279. 18. Connolly KJ, Edelmann RJ, Cooke ID, et al. The impact of infertility on psychological functioning. J Psychosom Res 1992;36:459–468. 19. Downey J, Yingling S, McKinney M, et al. Mood disorders, psychiatric symptoms, and distress in women presenting for infertility evaluation. Fertil Steril 1989;52:425–432. 20. Litt MD, Tennen H, Affleck G, et al. Coping and cognitive factors in adaptation to in vitro failure. J Behav Med 1992;15:171–187. 21. Newton C, Hearn M, Yuzpe A. Psychological assessment and follow up after in vitro fertilization: assessing the impact of failure. Fertil Steril 1990;54: 879–886. 22. Haynes GJ, Callan VJ, Terry DJ, et al. The psychological well-being of infertile women after a failed IVF attempt: the effects of coping. BMJ 1992;65: 269–278. 23. Berg BJ, Wilson JF. Psychological functioning across stages of treatment for infertility. J Behav Med 1991; 14:11–26. 24. Rosenthal MB. Psychiatric aspects of infertility and assisted reproductive technologies. Infertil Reprod Med Clinics of North Am 1993;4:471–482. 25. Mahlstedt PP. The psychological component of infertility. Fertil Steril 1985;43:335–346. 26. Daniluk JC. Strategies for counseling infertile couples. J Counsel Dev 1991;69:317–320. 27. Abbey A, Andrews FM, Halman LJ. Gender’s role in responses to infertility. Psych Women Q 1991;15: 295–316. 28. Natchtigall RD, Becker G, Wozny M. The effects of gender-specific diagnosis on men’s and women’s response to infertility. Fert Steril 1992;57:113–121. 29. Sandelowski M, Harris BG, Holditch-Davis D. Pregnant moments: the process of conception in infertile couples. Res Nurs Health 1990;13:273–282. 30. Olshansky EF. Psychosocial complications of preg-

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5. Coping with Infertility: Practical Psychosocial Issues nancy after infertility. NAACOGS Clin Issu Perinat Womens Health Nurs 1990;1:342–347. 31. Bernstein J, Mattox JH, Kellner R. Psychological status of previously infertile couples after a successful pregnancy. J Obstet Gynecol Neonatal Nursing 1988; 12:404–408. 32. Lind RF, Pruitt RL, Greenfeld DA. Previously infertile couples and the newborn intensive care unit. Health Soc Work 1989;14:127–144. 33. Harris BG, Sandelowski M, Holditch-Davis D. Infertility: a new interpretation of pregnancy loss. Mat Child Nurs 1991;16:217–220. 34. Neugebauer R, Kline J, Shrout P, et al. Major depressive disorder in the 6 months after miscarriage. JAMA 1997;277:383–388. 35. Berkowitz R, Lynch L, Chitkara U, et al. Selective reduction of multifetal pregnancies in the first trimester. N Engl J Med 1988;16:318. 36. Lieblum SR, Kemmann E, Taska L. Attitudes toward multiple births and pregnancy concerns in infertile and noninfertile women. J Psychosom Obstet Gynaecol 1990;11:197. 37. Shreiner-Engel P, Walther VN, Mindes J, et al. Firsttrimester multifetal pregnancy reduction: acute and persistent psychologic reactions. Am J Obstet Gynecol 1995;172:541–547. 38. McKinney M, Downey J, Timor-Tritsch I. The psychological effects of multifetal pregnancy reduction. Fertil Steril 1995;64:51–61. 39. Burns LH, Greenfeld DA. The Comprehensive Psy-

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chosocial History of Infertility (CPHI). Birmingham, AL: American Society for Reproductive Medicine, 1990. 40. Stewart DE, Boydell KM, McCarthy K, et al. A prospective study of the effectiveness of brief professionally-led support groups for infertility patients. Int J Psychiatry Med 1992;22:173–182. 41. Kingsberg SA. Assisted reproductive techniques and male factor infertility: psychological perspectives on the treatment recommendations of IUI, IVF, and ICSI. Syllabus from the course Male Infertility: The Medical and Psychological Team Approach to Treatment, sponsored by the American Society for Reproductive Medicine, 1996.

Suggested Reading Klock SC, Greenfeld DA. Psychological status of in vitro fertilization patients during pregnancy: a longitudinal study. Fertil Steril 2000;73:1159–1164. Milad MP, Klock SC, Moses S, et al. Stress and anxiety do not result in pregnancy wastage. Hum Reprod 1998; 13:2296–2300. Schover LR. Psychosocial aspects of infertility and decisions about reproduction in young cancer survivors: a review. Med Pediatr Oncol 1999;33:53–59. Infertility Counseling: A Comprehensive Handbook for Clinicians. Edited by Linda Hommer Kurns, Sharon N. Covington. New York: Parthenon Publishing Group, 1999.

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6 Impact of Managed Care on Office-Based Infertility Practice Richard E. Blackwell

When young couples begin forming a family, they do not anticipate problems with reproduction.1 Often the patients who attend reproductive endocrine infertility clinics are educated, are highly motivated, and have yet to confront an adversity in life that could not be overcome with perseverance. Therefore they may present to the reproductive endocrinologist in a frustrated, angry, confused state. Their view of reproductive medicine may be tainted by articles in the news, sensational press releases, and magazine articles with titles such as, “The Frightening Future of Baby Making” or “High Tech Baby Making.” They see newspaper headlines showing quadruplet gestations with their family members, news articles indicating that gametes have been switched in the laboratory or perhaps sold commercially, and infertility treatment resulting in malignancy or other disease processes.2 There is tabloid exposure in places such as grocery store check-out lines touting titles such as “Animal and Human Sperm Bank Mix-up” and “Tragic Dog Baby Born: Hospital Orders Cover-up.” Although most of these concerns may have questionable relevance to reproductive endocrine practice, they do hit on many sensitive social issues. Perhaps these situations contribute to the fact that 43% of infertile couples never seek help, with approximately 12% seeking care per year. It should also be remembered that this type of lay press is not totally ignored by the insurance industry. Most of these articles confirm the executives’ worst fear about liability in the case of gamete mix-up, the cost of multiple births, and the risk of increasing the insured cancer population.3–8 In other words, it is safe to say that infertility does not exist in a social or political vacuum. Furthermore, infertility does not exist in a vacuum from a medical point of view, although several attempts have been made nationally to seg58

regate the infertility benefit from other disease processes for simplification and ease of projecting risk. Essentially three types of proposal have been presented for dealing with infertility: a capitated plan such as the one implemented by U.S. HealthCare, the infertility protocol presented by Bates Consulting,9 and the Lewin VHI algorithm.10,11 Under the U.S. HealthCare model, the basic infertility workup can be carried out by anyone designated a primary provider. It consists of a semen analysis, postcoital test, hysterosalpingography, and some assessment of ovulation (typically a midluteal progesterone or endometrial biopsy). When most patients have finished this segment of the workup they are referred directly to a limited number of reproductive endocrinologists, completely bypassing the obstetrician/gynecologist. Patients may visit two reproductive endocrine practices and at that juncture choose their tertiary care provider. A capitated arrangement is reached between the corporate entity and the provider, which is in the mid-four-figure region. Any means may be used to achieve conception, such as laparoscopic surgery, intrauterine insemination, gonadotropins, gamete intrafallopian transfer, or in vitro fertilization (IVF). The provider has 2 years to achieve the pregnancy and must maintain a low 20th percentile pregnancy rate to remain eligible for the plan. If conception occurs early during the workup, the provider receives the remainder of the capitated payment. The algorithm presented by Bates Consulting Company involves an initial evaluation of the history, physical examination, semen analysis, hormone evaluation in 35% of the patients, and hysterosalpingography in 30%. One-third of the patients are thought to have disorders of ovulation; this problem is treated by correcting body weight (if 95% or

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130% of ideal) and/or therapy with clomiphene citrate, bromocriptine, or prednisone for six cycles as indicated. If no pregnancy results, 30% of the patients undergo office hysteroscopy and then three cycles of IVF. Thirty percent of the patients have ovulatory disorders, and 24% of them undergo operative laparoscopy. Half are thought to have a good prognosis. They attempt pregnancy for 6 months; if no pregnancy results, approximately 40% undergo three cycles of IVF. If they are poor-prognosis patients (50% with extensive tubal disease), they undergo three cycles of IVF. Forty percent of the couples have male factor infertility; 80% are oligospermic, and varicocelectomy is used sparingly. If no pregnancy occurs following surgery, three cycles of IVF are carried out. The azoospermic patient (20%) undergoes six cycles of therapeutic donor insemination. If no pregnancy results, two cycles of IVF are attempted. It should be noted that in this algorithm the patient pays the cost of laboratory evaluation, the cost of all medications including gonadotropins, an additional charge for the IVF cycle, and the cost of donor insemination. The algorithm designed by Lewin VHI was prepared by a panel of infertility experts using a literature review and a modified delphi approach. Infertility was treated as being the result of a variety of disease processes including such entities as a pituitary tumor, central nervous system dysfunction, diabetes mellitus, other systemic disorders, endometriosis, fibroids, adhesions, and eating disorders, among others. The algorithm further depends on a working relationship between the obstetrician/ gynecologist and the reproductive endocrinologist, functioning together as a network. It continuously evolves based on an outcome analysis. It sets boundaries on therapy based on a literature review and outcome analysis. This algorithm is entirely different from a protocol concept, which is derived from an individual anecdotal practice experience that often leads to failure, increased cost, dissatisfied subscribers, and ultimately litigation. Algorithms can be used to improve care, control cost, use resources efficiently, and increase the availability of coverage because it allows the payer to predict the worst case scenario, which generally falls in the range of 0.40 to 0.50 per member per month. This is much lower than is generally thought by the insurance industry. The algorithm also has as its basis a number of facts that influence reproduction. Approximately 54 million women in the United States age 15–45 years who are trying to conceive show subfertility

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rates in the range of 8.5–25.0%. Infertility acts against a background of changing age in both men and women, with the age of menopause normally ranging between 35 and 57 years (mean 51.4 years) in the U.S. population. By age 35 there is an exponential fall in the fecundity rate, with the fertility rate being approximately 100 per 1000 people at age 40.12 Furthermore, the number of clinically recognized trisomies rises exponentially at age 35, and by age 40 it represents approximately 25% of pregnancies.13 Likewise, the spontaneous miscarriage rate rises exponentially after age 35, and by age 40 it is approximately 30%.13 Ectopic pregnancies rise from 15% per 1000 pregnancies at age 25–34 to nearly 20% at age 35–44.14 In fact, every complication of pregnancy—including abortion, ectopic pregnancy, congenital malformations, prematurity, intrauterine growth retardation, macrosomia, perinatal mortality, fetal death, neonatal death, infant mortality, placenta previa, abruptio placentae, pregnancy-induced hypertension, chronic hypertension, diabetes labor dysfunction, cesarean section, maternal mortality, and maternal morbidity— increases markedly beyond age 35. In addition, the likelihood of conception is associated with agerelated male sexual dysfunction. The conception rate with partners under age 25 with 6 months of unprotected intercourse is 48.5%; at age 40 and over it is 22.7%. The frequency of intercourse decreases with age; and with intercourse occurring less than once per week, the conception rate is 16.7% over 6 months; at more than four times a week the conception rate is 83.3%. Finally, there is an exponential decrease in the number of orgasms per week and an exponential rise in the number of episodes of impotence, which begins at around age 35. All of these factors result in increased cost, decreased productivity of the couple, depression, marital discord, family discord, and isolation of the couple. These factors make powerful arguments for presenting an infertility benefit to providers. Furthermore, as a way of reducing cost, the algorithm stresses over and over again the use of accurate diagnosis, the maximization of pregnancy using low technology therapy, the appropriate use of laparoscopic surgery, and the appropriate use of assisted reproductive technology (ART) early during the workup if need be, all of which is cost-effective. Such an algorithm helps codify a standard of practice; it controls cost, limits other costs such as other surgery as for ectopic pregnancies, predicts outcome, and makes therapy finite. For example, clomiphene citrate ovulation induction is used for five ovulatory cycles, gonadotropin ovulation induction is used for six cycles, IVF is used for four

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to six cycles. An infertility algorithm also sets the referral pattern; that is, move the patient to the reproductive endocrinologist early during the workup, which is again cost-effective.15

Payment for Services Payment for infertility services generally falls into three general categories: capitation, discounted fee for service, and self-pay. Most reproductive endocrine practices operate with some form of these payments. There is little experience with capitated plans in the area of infertility, and to my knowledge no prospective data have been presented. Our own prospective payment plan, designed for the VIVA program [University of Alabama at Birmingham (UAB)], uses the Lewin VHI algorithm to form the basis of the proposal. A figure of 0.47 per member per month was used to project our expenses and revenues. Eleven months into the first year this figure appears to be correct. The plan covers a semen analysis, postcoital test, hysterosalpingography or sonohysterography, hormone assays, and follicular monitoring by ultrasonography. It also covers surgical procedures to diagnose or treat infertility, ovulation induction including clomiphene and gonadotropin therapy, artificial insemination by donor or husband, and assisted reproductive technology including IVF and gamete intrafallopian transfer. There are exclusions, limitations, and stipulations including a maximum lifetime coverage of nine ovulation induction cycles of clomiphene, six gonadotropin cycles, three artificial insemination cycles, and four ART cycles. In addition to standard co-pay, any service related to hospitalization or outpatient surgical procedures has a 40% co-pay; any drug such as clomiphene, gonadotropins, and gonadotropin-releasing hormone (GnRH) analogues used for treating infertility has a 40% co-pay; and sterilization reversals are excluded under this plan. Our experience over less than a year suggests that there is not an unfavorable selection bias.16 Most of us are familiar with discounted fee for service. Currently, many practitioners receive between $0.30 and $0.50 on the dollar for services rendered. Other than in states that have mandated coverage for ART services, many commercial carriers discontinue therapy at the level of gonadotropins plus intrauterine insemination or following a limited number of treatment cycles with this mode of therapy. Many reproductive endocrinologists favor out-of-pocket payment. Such a philosophy pushes infertility services farther into the boutique

nitch, and it might be that this form of therapy will enjoy the same market dynamics as a cosmetic surgery.

Database and Outcome Analysis Following publication of the article, “Are we exploiting the infertile couple?”17 Congress began to focus effort on standardizing not only infertility but laboratory services. Subsequently, an outcome database was established by the Society for Reproductive Technology; and the Clinical Laboratories Improvement Act (CLIA) regulations were modified. At the same time, following the Clinton failed health care initiative, a marketplace-driven revolution in managed care occurred. Carriers began to insist on accurate databases and outcome analysis. The concept of disease management was simultaneously introduced by both the insurance and pharmaceutical industries. This concept insists that diseases are treated in an incremental manner with the most cost-effective therapy based on a literature review and outcome analysis.18–22 Although these concepts appeal to some and are rejected by others, they raise many difficult issues. We have all seen databases manipulated and outcomes skewed by patient selection and exclusion. Pregnancy rates are clearly diagnosis- and agedependent; and advanced therapies often yield impressive results when applied to those who perhaps do not need them. Furthermore, disease management raises licensure issues, for instance the criminal indictment of a physician-benefits manager by the state of Florida who was charged with practicing medicine in that state without a license. Although this particular physician was licensed to practice in another state, his direction of patient care in Florida was viewed by the courts as a licensure violation. The same issues have been raised with regard to satellite offices, various satellite affiliations, and telemedicine. Likewise, advertisements appearing on the web may fall under the same constraints.

Credentialing Another area that will undoubtedly come under intense focus involves licensure and credentialing. Individuals who practice medicine in any state, regardless of the form, will most likely be required to apply for a license in that state, be networked with physicians who are physically in the location, and be appropriately certified, particularly as we

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enter the area of virtual reality in the surgical arena. Certification in reproductive endocrinology will most likely be a requisite for a payment by insurance companies, and failure to be certified will probably result in deselection, as has already been seen in some communities. Payment for sonography will probably be dependent on being certified by the American Registry of Diagnostic Medical Sonographers (ARDMS, 600 Jefferson Plaza, Suite 360, Rockville, MD 20852). Laboratories will have to be certified by both CLIA and The American College of Pathology to be competitive for contract bids.

Networks Networking is one of the most difficult social and legal issues facing reproductive endocrinologists. For instance, many of us practice broad-based reproductive medicine, which means we function as primary, secondary, and tertiary providers for some of our patients. The issue of self-referral from one role to the other is perilous and is being watched intensely by the insurance industry and government. The whole area of networking creates a special dilemma for those of us in academic medicine, as plans such as that presented by U.S. HealthCare seem to strike at the very purpose of a residency training program because the better programs prepare residents to manage broad-based reproductive medicine and infertility problems, up to the stage of assisted reproductive technology utilization. To bypass the skills of so many of our colleagues seems to be an inefficient use of resources. The most efficient treatment of the patient with complex reproductive medicine problems seems to be an initial referral of this patient directly to the obstetrician/gynecologist by the primary care provider, who would work up the patient guided by algorithms and disease management concepts. He or she would consult frequently with the reproductive endocrinologist during the workup and refer the patient who fails to conceive to the reproductive endocrinologist in a timely manner. These steps seem to limit cost and maximize outcome.15 However, in this intense era of competition, the formation of working networks between the reproductive endocrinologist and the obstetrician/gynecologist is at times difficult because problems of ego, training, and practice often interfere with the successful function of these networks. The future of reproductive medicine will be dictated by the use of algorithms, which are no more than a codification of the guidelines of practice advocated by the sub-

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specialty division of the American Board of Obstetrics and Gynecology. Another issue with which one must deal in networking is antitrust violation and the percentage of market control. Informal networks seem to attract the least attention from government antitrust forces. Under such arrangements individuals could be members of a number of networks, and admission to one would not exclude another. Networks have been described by Foy23,24 in these terms: “The effectiveness of a network is inversely proportional to its goal. A network needs to have a focus not a goal. A network needs a spider at the center, not a chairman. A network needs a note or a newsletter, not a journal. A network needs a good list of members more than a set of bylaws. A network needs groups, not committees. A network needs a phone number, not a building.” In other words, it is an informal network of providers who are willing to come together under a common philosophy and agree to treat patients accordingly. Such an organization, if made up of a strong group of obstetrician/gynecologists and reproductive endocrinologists, would have great appeal to insurance carriers looking for providers for their subscribers. Such networks would also allow the accumulation of enough data to furnish the payers meaningful outcome analyses. This process will always be dynamic as the pendulum of managed care swings to and fro, whether we are dealing with the extremes of capitation or the medical savings account. Those groups who will do well in such an environment will continue to strive to hone their clinical skills, question their every practice, and discard those practices that do not stand close analysis. These groups (and only these groups) will be able to compete in the medicine of the future.

References 1. Page H. Estimation of the prevalence and incidence of infertility in a population: a pilot study. Fertil Steril 1989;51:571–577. 2. Stephen EH. Projections of impaired fecundity among women in the United States: 1995 to 2020. Fertil Steril 1996;66:205–209. 3. Shushan A, Paltiel O, Iscovich J, et al. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13–18. 4. Callahan TL, Hall JE, Ettner SL, et al. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med 1994;331:244–249. 5. Collins JA, Bustillo M, Visscher RD, et al. An estimate of the cost of in vitro fertilization services in the United States in 1995. Fertil Steril 1995;64:1–8.

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6. Hecht BR. Iatrogenic multifetal pregnancy. Assist Reprod Rev 1993;3:75–87. 7. Wilcox LS, Kiely JL, Melvin CL, et al. Assisted reproductive technologies: estimates of their contribution to multiple births and newborn hospital days in the United States. Fertil Steril 1996;65:361–366. 8. Neumann PJ, Gharib SD, Weinstein MC. The cost of a successful delivery with in vitro fertilization. N Engl J Med 1994;331:239–243. 9. Bates GW, Bates SR. The economics of infertility: developing an infertility managed-care plan. Am J Obstet Gynecol 1996;174:1200–1207. 10. Blackwell RE. A proposed algorithm for evaluation and treatment of infertility. Update Infertility Reprod Med UAB 1995;7:1–8. 11. Blackwell RE. Clinical treatment of infertility: a practical algorithm. Drug Benefit Trends 1996;8:17– 22. 12. Stein ZA. Reviews and commentary: a woman’s age: childbearing and child rearing. Am J Epidemiol 1985;121:327–342. 13. Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet 1985;70:11–17. 14. Chow W-H, Daling VR, Cates WJ, et al. Epidemiology of ectopic pregnancy. Epidemiol Rev 1987;9:70– 94. 15. Gleicher N, Vanderlaan B, Karande V, et al. Infertility treatment dropout and insurance coverage. Obstet Gynecol 1996;88:289–293. 16. Eddy DM. Benefit language: criteria that will improve quality while reducing costs. JAMA 1996;275: 650–657. 17. Blackwell RE, Carr BR, Chang JR, et al. Are we exploiting the infertile couple? Fertil Steril 1987;48: 25–29. 18. Pittaway DE, Takacs P, Bauguess P. Laparoscopic adnexectomy: a comparison with laparotomy. Am J Obstet Gynecol 1994;171:385–391.

19. Vilos GA, Pispidikis JT, Botz CK. Economic evaluation of hysteroscopic endometrial ablation versus vaginal hysterectomy for menorrhagia. Obstet Gynecol 1996;88:241–245. 20. Brumsted JR, Blackman JA, Badger GJ, et al. Hysteroscopy versus hysterectomy for the treatment of abnormal uterine bleeding: a comparison of cost. Fertil Steril 1996;65:310–316. 21. Danese MD, Powe NR, Sawin CT, et al. Screening for mild thyroid failure at the periodic health examination. JAMA 1996;276:285–292. 22. Clancy CM. Evidence-based medicine meets costeffectiveness analysis. JAMA 1996;276:329–330. 23. Foy N. The Yin and Yang of Organizations. London: Grant McIntyre, 1981. 24. Handy C. Gods of Management. The Changing Work of Organizations. Oxford University Press, New York, 1995.

Suggested Reading Blackwell RE, Team WM. Hidden costs of infertility treatment in employee health benefits plans. Am J Obstet Gynecol 2000;182:891–895. Bron MS, Salmon JW. Infertility services and managed care. Am J Manag Care 1998;4:715–720. Griffin M, Pana WF. The economic cost of infertilityrelated services: an examination of the Massachusetts infertility insurance mandate. Fertil Steril 1998;70: 22–29. Tabbush V, Gambone JC. Managed health care coverage for infertility services: understanding adverse selection. Curr Opin Obstet Gynecol 1998;10:341–346. VanderLaan B, Karande V, Krohm C, et al. Cost considerations with infertility therapy: outcome and cost comparison between health maintenance organization and preferred provider organization care based on physician and facility cost. Hum Reprod 1998;13: 1200–1205.

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7 Basics of Laboratory Setup in the Office Dean E. Morbeck

Establishment of a pregnancy via in vitro fertilization (IVF) is a multifactorial process with several steps critical to its success. Important components include procurement of a reasonable number of good-quality mature eggs, proficiency of microassisted fertilization when needed, laboratory culture conditions that are noninhibitory and conducive to the fertilization and development of the resulting embryos, and finally a smooth and efficient transfer of high-quality embryos. A breakdown in any of these areas is sure to limit the success of a program. The design and function of the laboratory is thus of paramount importance. What makes a good IVF laboratory? The quality of the laboratory and the success of a program are dependent on a competent laboratory director and staff, and the design of the laboratory is of critical importance as well. Even a program with the best laboratory director cannot be successful if the air around the embryos is of poor quality. The director can control most of the factors that influence an embryo’s development, from the type of media to the amount of time the embryos are exposed to atmospheric air, room temperature, and various light sources. Air quality is a fixed component that is best addressed during the design of the facility. As IVF centers continue to move into private practice settings, it is becoming increasingly important that the reproductive endocrinologist and laboratory director know as much as possible about the need for adequate laboratory design. Unlike in a hospital or medical center, where specialized engineers and contractors design and build clean rooms and operating rooms on a routine basis, the private setting is subject to misrepresentation and lack of sufficient knowledge to meet the special needs of laboratory design. Having dealt with a “residential” engineer and contractor who promised

specifications that were never met, let me offer this advice: Check all plans and be sure in your mind that the design is capable of providing you with the environment you desire. If you are not sure, get a second opinion. The purpose of this chapter is to detail the important components of laboratory design, with minimal discussion of specialized IVF equipment and protocols. This chapter is not meant to be a howto manual on running an IVF laboratory. Rather, it is a guide for someone responsible for designing and building a new IVF laboratory.

Air Delivery System Specifications At this writing, no government agency or any other organization has developed specific guidelines for the quality of air and performance of the airhandling system in an IVF laboratory. This is fortunate for most of the laboratories presently used, as their designs vary greatly, and few would meet strict guidelines such as those for an operating room. Conversely, it presents a challenge to individuals building a laboratory from “scratch” because it is unclear what is necessary or optimal. Operating rooms (ORs) and clean rooms are two rooms for which there are published specifications that can serve as a framework for IVF laboratories. The specifications for these room types overlap considerably, as they both require ultra-clean environments. Specifications for these rooms are published by the American Society of Heating, Refrigeration and Air Conditioning Engineers (ASHRAF) every 4 years. The specifications for an OR are listed in Table 7–1. 63

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TABLE 7–1. 1995 ASHRAE Specifications for an Operating Room Positive pressure relative to adjacent areas by supplying 15% excess air 100% Outside air Minimum of 15 air changes per hour All air exhausted directly outdoors No air recirculated in room units Filter efficiency of 99.97% for particles  0.3 m Variable range temperature capability of 68°–76°F Relative humidity 50–60%

In addition to the items in Table 7–1, the handbook states that an increase in the total air exchanges to 25 per hour while decreasing the percent of outside air to 20% is an acceptable energysaving alternative. Reducing the amount of outside air would also be advantageous in areas with exceptionally poor quality outside air. Similar to the OR, specifications for clean rooms (1991 ASHRAE Applications Handbook) concentrate on filtration, pressurization, and temperature and humidity control. The main difference between the two is the different degrees of filtration required for the different classes of clean rooms and a greater emphasis on the direction of airflow, not only in the placement of ducts but also the air pattern (i.e., unidirectional versus multidirectional flow). For all practical purposes, meeting the specifications of the OR is sufficient for an IVF laboratory. Making the IVF laboratory a class 100 or even class 1000 clean room would be expensive, laborious, and unnecessary. However, much can be learned by studying clean room design and incorporating some of the concepts into the IVF laboratory design. For example, placement of supply and return ducts influences the direction and velocity of airflow in the room. Substantial airflow over a work surface would be undesirable, as the rate of evaporation of solutions would increase, affecting the osmolarity in addition to the temperature and pH. The opposite situation would likewise be suboptimal, as no airflow over an area would increase the chance of particulate or microbial contamination.

HVAC Design The heating, ventilating, and air conditioning (HVAC) system, along with the air filters and controls, is the foundation of the IVF laboratory. When considering a facility for an IVF center, any office building would suffice if it were not for the needs

of the laboratory and its special HVAC system. This is not to say that IVF cannot be done in a preexisting office building with a standard HVAC system. On the contrary, many laboratories currently exist in a suboptimal environment, and their programs are successful. The purpose of the OR-type HVAC system in an IVF laboratory is contamination prevention. Most environments are not inherently detrimental to fertilization and embryo development, although the potential exists for acute or chronic air quality changes that can adversely influence embryo quality. This is similar to the fact that surgery can be performed successfully outside an OR, even in a mobile army surgical hospital (MASH) unit in a tent. Although on average surgery is successful, the morbidity and mortality rates are higher than would be expected in a controlled environment, such as in an OR. The difference between an office building and an OR is not nearly as dramatic, but the principle is the same. Controls are needed to minimize chances of contamination by microbes or noxious gases. The role of the HVAC system is fourfold: Deliver clean air to the room, remove contaminants from sources within the room, pressurize the room, and control temperature and humidity. The following aspects of HVAC design are integral to the attainment of this goal.

Outside Air Delivery A laboratory director’s two worst fears related to the ventilation system are microbial contamination of a patient’s sample and introduction of toxic air. In general, outside air is much “cleaner” than indoor air with respect to microbes. Nosocomial infections in hospitals illustrate this phenomenon. By using 100% outside air the “contaminated” room air is not recirculated, thereby avoiding the classic “airplane” effect of concentrating and redistributing bacteria and viruses. Most particulate and microbial contaminants are generated within the room from personnel. In contrast, outside air contains few microbial contaminants relative to inside air, so 100% outside air should keep bacterial or viral concentrations at a minimum. In general, neither nosocomial nor outside air introduction of microbes should be a concern so long as adequate filtration is in place. Because HEPA 1000 filters are routinely used and recommended for ORs and thus IVF laboratories, the contamination with the greatest potential to do harm is the amount of toxic gases. Gaseous contaminants

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can arise from many sources, both indoors and outside. Thus the decision on the amount of outside air used should be based on the knowledge of outdoor air quality, location of air intakes, and the return air quality. These parameters vary by location. ASHRAE has two recommendations for the amount of outside air in operating rooms. Where codes require it, 100% outside air is used with 15 air exchanges per hour. Because using all outside air substantially increases operating costs, it is recommended that heat recovery devices be installed. If the code does not require 100% outside air, 20% outside air with 25 air exchanges per hour is acceptable. The amount of outside air used is one-third that when 100% is used. The major disadvantage to using 100% outside air is the unpredictable and uncontrollable nature of air pollution, which is mainly gaseous in nature. Placement of the air intake duct is critical and, according to ASHRAE, “should be located as far as practical (on directionally different exposures) but not less than 30 ft from combustion equipment, stack exhaust outlets, ventilation exhaust outlets from the hospital or adjoining buildings, medicalsurgical vacuum systems, cooling towers, plumbing vent stacks, and areas that may collect vehicular exhaust and other noxious fumes. The bottom of outdoor air intakes serving central systems should be located as high as practical but not less than 6 ft above ground level or, if installed above the roof, 3 ft above the roof level.” If the building housing the IVF laboratory is a single story high, the major concern should be vehicular exhaust and likewise if the laboratory is located in a busy downtown area. One would think that tall hospital buildings might be less subject to adverse conditions so long as the ASHRAE guidelines were met, but at least one hospital had to install an expensive air filtration system because the outdoor air intake for the OR was located next to a helicopter launch pad. It is important to analyze critically the concept of 100% outside air. First, what controls are in place if there is a major change in either the amount of contamination generated within the room or in the quality of outside air? If a filtration system is in place that can effectively remove hydrocarbons and other noxious gases from outside air, 100% outside air is preferred. However, most systems cannot guarantee that level of filtration. Will recirculation result in an increased chance of microbial or gaseous contamination? Probably, although HEPA 1000 filtration should counter any increased chance of microbial contamination due to recirculation.

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Regarding microbial contamination, even more important than recirculation is the sterile technique of the laboratory personnel and the length of culture. As more laboratories are culturing embryos for 3 days instead of 2 days and even some doing only blastocyst stage transfers, the chance of contamination increases. The other issue with recirculating air in the system is the potential for concentrating gases. Equipment in the laboratory off-gases continuously owing to the oil and lubricants used in most motors, so removal of this air is an important component of the ventilation system. Recirculating this air may increase the concentrations of off-gased compounds to an undesirable level. Additionally, there is the potential that gases from other parts of the building enter the IVF laboratory suite and thus could be concentrated in a recirculating air system. Verifying positive pressure relative to neighboring rooms is paramount to avoiding the movement of unwanted air into the laboratory. An extreme example of this phenomenon is the case reported by Cohen et al. in 1997 where anesthesia gases from a surgical suite located down the hall were being detected in the air of the IVF laboratory. Lack of adequate positive pressure and proper sealing was responsible for allowing the contaminants into the room. There are two types of air contaminant: particulate and gaseous. Both are serious and are dependent on the amount and quality of the outside air being used. Regardless of the amount of outside air used, appropriate filtration can rectify most air quality problems.

Air Filtration Filtration provides a security blanket for the HVAC system in an IVF laboratory, whether the laboratory uses 100% outside air or 100% recirculated air. Even though contaminants are generated in the laboratory, it is expected that they will not become concentrated in the system but, rather, be removed by the filter. Likewise, particulates and gases from outside air should be removed if adequate filtration is in place. The most common type of filtration used in HVAC systems is HEPA filtration, which removes particulates. Less common, but in some instances more critical, is the use of filters for removing gaseous substances. HEPA Filtration The HEPA filters are probably the most common type of filtration used in IVF laboratories, primar-

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ily because of their prevalence in the HVAC systems in ORs. HEPA filters do not filter via small pore size; rather, small particles adhere to the numerous glass fibers that make up the filter. The rate of airflow over the filter is thus important, as the particles need time to interact with the fibers. Van der Waals forces, mechanical entrapment, or electrical effects retain solid particles. Liquid droplets are also retained by surface tension force. The filters are rated based on their ability to remove 0.3 m particles, with minimum efficiency of 99.97%. Because the rate of airflow is important to the function of the filter, a properly sized blower is required to ensure adequate flow. The feet per minute (fpm) requirement at the filter face varies based on placement of the HEPA filter. There are two options for placing the HEPA filter. First, the filter can be positioned directly after the blower and heating and cooling coils of the HVAC. This system is advantageous in that there is only one filter to monitor, and it allows easy monitoring and changing. The drawback to this system is if particulates are generated in the ducts they will make their way into the rooms. The other option is to install terminal filters at the duct faces in the room. This system gives the most complete filtration and is the preferred method, but it does not allow for easy monitoring and a filter is required for each duct opening. For good performance and economy, a cleanroom filter system should include a 90–95% prefilter upstream of the HEPA filter. The prefilter should be changed on a frequent basis (monthly, depending on the quality of the outside air) to prolong the life of the expensive HEPA filter. How often must a HEPA filter be changed? It depends on several factors but most importantly on how well the prefilters do their job. The biggest advantage to the single filter system positioned immediately after the HVAC is the ability to monitor the pressure drop across the filter. One criterion used for determining if a filter needs to be changed is if the pressure drop rises from the typical new filter pressure drop of 25 mm H2O to a level of 50 mm H2O. Given this parameter, and with efficient use of pre-

filters, tests have indicated that filters last 8–13 years. On average, investment in a new filter every other year accompanied by diligent changing of prefilters should be more than sufficient for an IVF laboratory. Given the importance of HEPA filtration, the ability to monitor the pressure drop is valuable for ensuring that the filter is functioning properly. A manometer placed at the filter allows determination of the pressure difference, which can be readily viewed and incorporated into the daily, weekly, or monthly quality control routine. Gas Filtration Two types of gas common to indoor air are corrosive gases and organic gases. The most common gases one can expect from outside air are the corrosive gases, which include sulfur oxides and carbon monoxide from automobile exhausts and ozone. Organics in outside air include chloroform and several other vapors from petrochemical plants. Gas contaminants generated inside a facility are primarily organic, as is ozone. Contaminants can arise in the room from lubricants that vaporize if a motor or bearing is overheated. Because a major source of contaminants is new materials (e.g., new car smell), it is important to give the rooms time to off-gas. Tests have shown that concentrations of some volatile organic vapors, such as aromatic and aliphatic hydrocarbons, can be as much as five to six times higher in new buildings than in old ones. The sources of these chemicals are common building materials, including latex caulking, telephone cable materials, particleboard partition materials, paint, and adhesives. Some polymers that are formulated with plasticizers emit vapors for long periods. Plasticized polyvinyl chloride is a common product for flexible tubing and thus can continue to emit vapors even after the facility is no longer new. An example of the impact building materials can have on embryo development is shown in Table 7–2. During construction in a suite adjoining one laboratory there was a dramatic effect of linoleum

TABLE 7–2. Ability of One-Cell Mouse Embryos to Develop to Blastocysts During Construction of an Adjoining Suite Date

Construction activity in neighboring space

Blastocysts (%)

6/26 7/3 7/7

Twelve days after use of water-based paint During installation of floor tiles After installation of in-room air purifier

100 6.8 89

Source: Adapted from Cohen et al., 1997.

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tile adhesive on the development of one-cell mouse embryos. This effect was overcome with an inroom filtration unit. Interesting, none of the events that affected mouse embryo development altered the fertilization rate.

Pressurization Pressurization is one of the two most important components, the other being filtration, for development and maintenance of high quality indoor air in the IVF laboratory. Like filtration, the need for positive pressure in the laboratory is influenced to a certain extent by the quality of the surrounding air. In this regard, air surrounding the laboratory is similar to outside air in that it is beyond the control of the staff in the laboratory; hence positive pressure is again a preventive measure designed to keep undesirable gases and particles from moving from surrounding areas into the laboratory. The ASHRAE guidelines for operating rooms state that positive pressure should be maintained by supplying at least 15% more air to the OR in relation to adjacent rooms. The IVF laboratory presents a rather unique situation, however, in that in most centers there is an OR for performing egg retrievals adjacent to the laboratory, and it also requires positive pressure. Which room has priority? Although equal pressure between the two rooms would result in a minimum amount of air movement into the laboratory, conventional wisdom is that the laboratory should receive preferred treatment and therefore the pressure should be positive relative to that in the OR. This approach results in a gradient of pressures, with the laboratory receiving 15% more air than the OR and the OR receiving 15% more air than the hallway or adjacent rooms. The ability of a system to maintain positive pressure is important. First, though, let us note the different designs of air delivery systems. The system designed for the facility shown in Fig 7–1 was a VVT system, which stands for variable volume and temperature. With such a system, each room had its own thermostat and called for heating or cooling whenever its temperature fell outside the thermostat limits. With all rooms on the same system, the order in which rooms received heating or cooling was determined on a first-come first-served basis. If a room did not need heating or cooling, its damper closed and the room received nothing. Even though the IVF laboratory was designed to receive sufficient airflow to maintain positive pressure when the damper was open, if the room temperature was satisfied the damper closed and the room would go into negative pressure. Instead of a VVT

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system, it should have been a constant volume system. This is a variable temperature system, where all rooms get the same volume of air all the time, regardless of their heating or cooling needs. The other critical component for maintaining positive pressure is the degree of sealing between rooms and the ceiling. Door sweeps and gaskets on pass-throughs are important to allow the room to pressurize fully. Once a door is opened, the fact that the room was pressurized adequately ensures that the movement of air is out of the room and not back in. Openings in the ceiling can be equally critical. Ceilings harbor both large amounts of dirt and offgassed contaminants that can leak into a room if positive pressure is not maintained. Ensuring that a tight seal exists on all light fixtures, duct faces, and access doors prevents movement of ceiling air into the room.

Airflow Air turbulence in the room should be kept to a minimum to avoid mixing of dirty and clean air. Proper placement of supply vents and return ducts help maintain a relatively steady stream of clean, filtered air in the room. An effective style used extensively in clean rooms is unidirectional airflow, whereby the air supply is spread evenly over one surface of the room, and the opposite surface is the air return (e.g., ceiling and floor). Although this would be the ideal, it requires a more intensive duct system that is only required for the cleanest of clean rooms. Multidirectional airflow suffices for most laboratories, although supply and return vents should still be placed in a way to minimize the number of “dead” zones or high velocity areas. Supply vents should be of the laminar flow type, where air from the duct goes into a mixing box and then is pushed evenly through pinhole-size openings. This results in a relatively gentle introduction of air into the room. As the air moves down to the floor, it should be directed by the pull of return ducts located close to the floor. This design results in a steady movement of most of the air in one direction.

Air Volume Calculating the amount of air required for a facility is best left to an engineer. Awareness of what factors are involved with this computation is helpful for verifying that the job is being approached correctly. An inappropriately sized system can result in a multitude of factors, not least of which is the inability to deliver an adequate amount of air to maintain positive pressure in the laboratory. Other factors involved with air volume require-

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FIGURE 7–1. Laboratories at a reproductive center. HVAC, heating, ventilation, and air-conditioning; P, pass-through; TV, television monitors; 1, chemistry analyzer; 2, immunoassay equipment; 3, hematology analyzer; 4, refrigerator; 5, 80° freezer; 6, computer; 7, compound microscope; 8, centrifuge; 9, CO2 incubator; 10, laminar flow hood; 11, fume hood; 12, LS-160 liquid nitrogen supply tank; 13, microtool preparation equipment; 14, programmable freezer; 15, liquid nitrogen storage tanks; 16, stereo microscope; 17, K-system hood; 18, dual-stacked CO2 incubators; 19, inverted microscope with micromanipulators; 20, video equipment for microscopes; 21, balance; 22, osmometer; 23, pH meter; 24, oven; 25, autoclave.

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ments include the number of air exchanges required per hour, and indirectly, the filtration system employed. The HVAC must be sized to deliver the desired number of air exchanges to the room, which in most cases is 15–25. In addition to the blower size, the duct size is important for this factor, as a limit is reached regarding the amount of deliverable air. An undersized system can also result in insufficient airflow across the HEPA filter and consequently inadequate filtration. This has more to do with pressure at the filter face. Because there is such a dramatic drop in pressure across the filter, the fact that high efficiency filters are in place is important when calculating how large the system must be to deliver enough air to pressurize the room and provide the necessary exchanges.

Temperature and Humidity Control Relative to filtration and positive pressure, temperature and humidity control are secondary and have more to do with technician comfort. This fact should not be taken lightly, however, as the ability of the individuals in the laboratory to perform optimally is affected by their environment. A case can also be made for the importance of temperature and humidity in regard to how it affects specimens while they are in the incubators and while being exposed to room air. A balance must be struck between what is best for the gametes and embryos and what is comfortable for the staff. Certainly removing embryos from the incubator exposes them to lower temperatures and humidity in the room, as the incubators maintain a temperature of 37°C with high humidity (80%). The best scenario for the embryos would be the same conditions in the room. (To take it one step farther, 5% CO2 would make the room one large incubator.) Because this is unrealistic, a compromise must be reached. The ASHRAE guidelines for ORs state that the HVAC system should be able to maintain room temperatures of 68°–76°F and 50–60% relative humidity. Temperature control is relatively straightforward, although the ability to control the temperature in each room is usually desired. To deliver individual-room temperature control in a system that provides a constant air volume, each room must have its own HVAC system (e.g., mounted on the roof above each room), or the HVAC must produce air at a constant temperature (usually 55°C) that is then tempered by duct heaters located just upstream from the room duct. In most facilities the latter system is the only one that is practical.

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Heating and cooling needs are influenced by several factors and must be considered during the design of the system. If the system is engineered to deliver 100% outside air, a much larger number of heaters and cooling coils/condensers are needed compared to a system that uses only 15% outside air. The other primary factor to consider, particularly for cooling needs, is the heat load of the facility. Variables that must be considered are the location of the rooms relative to direct sun, the number of individuals working in the facility, and the cumulative heat production of the equipment and lights in the rooms. If an HVAC engineer does not ask for these data, expect the laboratories to be hot during the summer. Humidity control is much less straightforward and not as commonly addressed by IVF laboratories. The goal of a humidity control system should be to provide 50% relative humidity throughout the year. To do this, a system must be able to dehumidify during the summer months and humidify during the winter months (although this is largely dependent on climate). Why 50% relative humidity? A 50% humidity level takes into consideration the comfort of the staff and the optimal conditions for the specimens. Humidity levels that drop significantly below 50% (e.g., 35%) are undesirable for a number of reasons. First, the amount of static electricity increases. Because shoe covers are usually standard fare for IVF laboratories the staff become easily charged and is shocked throughout the day. Second, low room humidity results in a faster reduction in humidity in the incubators, especially when the doors are opened repeatedly during oocyte retrieval or an intracytoplasmic sperm injection (ICSI) case. This is a concern for two reasons. If the culture is an open system (i.e., without oil overlay), evaporation occurs more rapidly. Also, the CO2 content in the incubator is a function of the amount of CO2 added, the relative humidity, and to a small extent the temperature. If the humidity decreases drastically owing to repeated opening of the door in a low humidity room, most incubators cannot compensate for the lower humidity and thus take longer to recover to the set-point CO2 level. There are several methods for increasing the humidity in a laboratory. A direct approach is to put humidifiers in the room. This approach is feasible though not without drawbacks. First, a large humidifier is required if a large room is to be used, and it then requires its own purified water supply. In addition to the size of the room, the fact that the air changes 15–25 times per hour and is dry due to heating adds to the capacity requirements of the

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humidifier. Thus if a small room is in need of humidification, an in-room humidifier offers a viable alternative to central humidification. It is important to keep in mind that a humidifier can be a breeding ground for microbes and thus must be monitored closely (preferably added to the daily quality control checklist). The most common approach to humidification is placement of a humidifier directly in the HVAC unit. Humidification can be accomplished with ultrasonic, electronic steam canister, and nozzle (air and water mixed) type humidifiers. Although steam generation is probably the most common largely due to its broad availability, techniques such as ultrasonic humidification offer an alternative with several advantages. For instance, steam generation is an energy-intensive process, as water must be heated to boiling to generate the steam. Ultrasonic humidification uses less than one-tenth the energy to produce the same amount of humidity. Ultrasonic humidification also produces a fine mist of approximately 1 m diameter that is quickly absorbed into the air stream. This system minimizes the amount of water that condenses on the duct work. Water in the duct work provides a site for microbial growth and causes rust if the duct is not constructed of stainless steel. Small particle sizes of water are necessary to minimize these undesirable side effects of humidification. Although humidification requires the addition of components to the HVAC system or in the room itself, dehumidification is usually accomplished by the basic components of the HVAC units. High humidity (65%) is undesirable because it makes conditions uncomfortable for the laboratory staff, and it provides an environment that increases the chance of microbial growth on walls and other surfaces. If the HVAC system is sized appropriately, dehumidification should occur automatically, without the need for additional equipment, much like the dehumidification obtained with air conditioning in homes. Although air conditioning alone can dehumidify adequately in most cases, there are instances where cooling is not needed but humidity is high outside (e.g., a cool, rainy day) and so the room air may become overly humid. A system that allows complete control of humidity, both increasing or decreasing it at will is preferred. The general approach to centralized dehumidification is to cool air more than normal (45°F) and then reheat it to 55°F, which is the temperature of the air in the duct. Of course, to obtain the correct temperature and humidity, a balance must be reached between this heating and cooling cycle, and this is usually controlled electronically.

Each room in the laboratory should have individual temperature control and either particulate (HEPA) filtration on each duct face or in the main system (along with gas-phase filtration). In addition, the HVAC system should have the capacity to humidify and dehumidify, and there should be a control panel where these parameters can be viewed and modified if necessary. At least one person working in the laboratory should have working knowledge of the HVAC system and its control components. In lieu of central HVAC that can perform the necessary filtration, there are a few inroom purifiers available commercially or that can be made to order.

Room Construction and Design The goal of constructing an IVF laboratory is to build an environment that has few if any factors that might directly affect gamete/embryo viability. It is critical to consider each component used when building the rooms and evaluate each for its potential effect on the quality of the environment.

Floors, Walls, Ceilings, Cabinets A primary concern during construction of the physical structure of the laboratory is to avoid the use of materials that will off-gas for an extended period following completion of the construction. Given the propensity for construction to run behind schedule, most programs are ready to start doing IVF cases as soon as the building is complete. Depending on the materials used, it is possible that the room will contain unacceptable levels of noxious gases for months following the completion of construction. Because it is unlikely that the managers of the program would agree to wait 3–6 months to allow the room to off-gas, it is best to choose materials wisely. All walls and ceilings should be constructed of plaster and painted with an epoxy paint or baked enamel polyester. This serves two purposes. First, the finished surface of the walls and ceiling are smooth, nonshedding, easy to clean, and chip-resistant. This minimizes the amount of particulates that shed from the surface or become attached. This is particularly important for the ceiling, as drop ceilings are a source of dirt and dust. Second, epoxy paint does not off-gas appreciably and thus is not a concern for its effect on air quality. Cabinets can be another source of gaseous pollutants, particularly those made of manufactured wood products such as particleboard. Cabinets

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should be constructed of either solid wood or metal. In the case of wood, certain varieties such as oak, birch, and beech off-gas acetic acid, aldehydes, and alcohol. The amount of glue and adhesives should be kept to a minimum during construction. Both wood and metal cabinets should be painted with epoxy or baked enamel polyester. Counter tops must also be easy to clean, be chipresistant, and must not have the propensity for haboring contaminants. For this reason, the counter of choice is corian or similar material. One should stay away from the black counters found in many research laboratories, as they tend to shed their charcoal components. The preferred flooring is seamless sheet vinyl or epoxy. The floor surface should have an integral base flashed up the wall at least 4 inches. This allows for complete cleaning of the floor with minimal amounts of water seepage into cracks. The floor should also be flashed onto the cabinets so water cannot seep under the cabinets and become a source of microbial contamination.

Lighting It has long been known that visible light can be detrimental to in vitro cultured cells, including gametes and embryos. In a classic study on the effects of various wavelength light on the ability of hamster eggs to complete meiosis and develop pronuclei normally, Hirao and Yanagimachi found that light with wavelengths shorter than 470–480 nm (e.g., fluorescent light) inhibited eggs from completing meiosis and undergoing normal pronuclear development (Table 7–3). A reduction in normal development was seen with 15 minutes of exposure to fluorescent lights, whereas incandescent lights were without effect at this duration of

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exposure. In the same study, the effects of fluorescent light were prevented with proper filtering. The mechanism of action appears to be photoxidative products produced by the fluorescent light, which results in the production of reactive oxygen species such as H2O2 in the presence of atmospheric oxygen. These products then act on DNA to cause chromatid breaks and exchanges. Studies with mammalian cells have confirmed this hypothesis, as inhibiting these reactions chemically or enzymatically prevents DNA damage in cells exposed to fluorescent light. Given the strong evidence for effects of light on eggs and embryos, fluorescent light should be avoided in the laboratory. It goes without saying that there should be no windows in the laboratory. Incandescent lights with dimmer controls are the ideal and should be kept as dim as possible while gametes and embryos are handled. Some argue that the relatively brief exposure time typical in IVF laboratories makes lighting a moot point. Regardless, the potential exists, particularly as eggs and embryos are exposed to light for longer periods during micromanipulation.

Special Equipment Most laboratory directors have a good idea of the equipment they need to furnish the laboratory adequately. Nonetheless, there are a few items that are worth mentioning because of their special requirements. Whenever gametes and embryos are viewed microscopically, they should be placed on a warmed microscope stage. Because all of the most popular microscope brands have heated stages or can have them added, availability and source are not issues. An alternative to a heated stage is the use of a Hoffman K-System laminar flow hood with a heated

TABLE 7–3. Comparison of the Detrimental Effect of Light from Four Light Sources % Eggs undergoing normal meiosis and pronuclear development Length of irradiation (min) 0.25 1.0 1.5 5 10 15 30 60

Incandescent lamp

Fluorescent lamp

UV lamp

Sun 43.0 7.5 0

100.0 69.8 35.5

84.5 16.0 0

66.7 51.0 10.0 4.1 0

Source: Adapted from: Hirao Y, Yanagimachi R. Detrimental effect of visible light on meiosis of mammalian eggs in vitro. J Exp Zool 1978;206:365–370.

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bench. A water bath/circulator moves warm water through the work surface to give a large, homogeneously heated work surface that is especially useful during egg retrievals. During the design and construction of the laboratory it is important to consider placement of the hood and other laminar flow hoods (e.g., those for making media) and the ability to move the hoods into the room. One may find that once the cabinets are installed in the rooms space is not adequate for moving in a 6 foot long hood. Therefore planning an installation schedule is important. If flammable or volatile liquids are to be used, which is necessary for histology, a fume hood is needed. There are portable units that are suitable if the facility has limitations in putting in a permanent hood. Ideally, a fume hood should be installed with its own exhaust duct that goes directly outdoors. If the blower on the hood is used frequently, the HVAC engineer should be alerted that there will be a need for makeup air in that room.

Laboratory Design Design of the laboratory is dictated largely by the personal preference of the laboratory director within the constraints of the space allocated. Figure 7–1 illustrates one laboratory design. Similar to any building venture, there are always things that post de facto would be done differently; nonetheless it represents a good example of a working laboratory. The space shown comprises roughly onethird of the facility. Several aspects of the design presented in Figure 7–1 are worth discussing. Embryology and andrology combined comprise approximately 750 sq ft. Although both procedure rooms are 12  12 feet, the transfer room is oversized and could have been considerably smaller. The HVAC room is 9  20 feet and could have been larger. It contains three air-handling units with one dedicated strictly for IVF and procedures. It also includes the vacuum pump. Across the hall from the HVAC room is the gas room containing manifolds for oxygen, CO2, mixed gas, and medical air if needed. This room is located next to an outside door so tanks can be changed with minimal traffic inside the building. In most IVF centers, a separate chemistry laboratory may not be necessary if only hormone assays are performed on a single machine. The chemistry laboratory in this facility served a general obstetrics/gynecology program and thus required its own space for hematology, serology, and chemistry equipment.

Salient features in andrology include a passthrough to the collection room bathroom, a biologic cabinet for the preparation of sperm for either intrauterine insemination (IUI) or IVF, a fume hood for histology, and a 80°C freezer for storage of serum and frozen reagents. The laboratory includes two microscope stations on opposite sides of the room, a computer for data management and report writing, and a CO2 incubator. Although entry to the andrology laboratory is from the inside corridor, there are two rooms adjacent to it: a liquid nitrogen storage room and the cryolaboratory/microtool preparation laboratory. This was specifically designed in this manner to allow the cryolaboratory to act as a buffer between the “dirty” andrology laboratory and the HEPA filtered IVF laboratory, which includes the cryolaboratory. The Ln2 storage room is positioned to allow direct supply of liquid nitrogen into the cryolaboratory through the wall plus direct access outside for deliveries. The HEPA-filtered HVAC system in this facility ventilates four rooms: the cryolaboratory, embryology including media preparation, and the adjoining two procedure rooms. Air volume is set so embryology has the highest pressure, followed by the two procedure rooms and the cryolaboratory, with andrology and the hallway the lowest pressure areas. This gives the desired waterfall effect of air movement out of the critical areas. Embryology has two pass-throughs to each procedure room and a media preparation room within it. A 6-foot Hoffman K-system hood houses one stereoscope used during oocyte retrievals and for loading embryos for transfer. The goal of the design of this area of the laboratory is to provide the shortest distance between the culture dish and the patient for egg retrievals or embryo transfers. A second stereoscope located on the counter on the opposite side of the room is used for freezing and thawing embryos. The inverted scope with micromanipulators is positioned next to the hood and includes a shelf for audiovisual equipment. In the middle of embryology is a partition that houses the gas lines that supply the incubators. The media preparation room contains equipment needed for making media, including an osmometer, pH meter, and balance. There is also a 3-foot laminar flow hood and a refrigerator for media storage. The middle corridor of the building houses a large supply room, technician office space, and clean and dirty utility rooms where the oven and autoclave are located. All are within a short distance and at most two doors away from the laboratories.

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Plumbing: Gas and Water One of the biggest advantages of constructing a new IVF laboratory is the ability to place gas outlets and distilled/deionized water outlets strategically throughout the laboratory. This is particularly true in reference to gas outlets, as the ability to have a centralized gas room obviates the need for cylinders in the laboratory proper.

Gas Supply for Incubators and Benchtop The major focus of the earlier section on the HVAC system was on air quality. Although room air quality is important, even more important is the quality of the air in the incubators. This is true because more than 97% of an egg/embryo’s time in the laboratory is spent in the incubator, which places enormous importance on the source of air. There are at least three ways to supply air to the incubators. This discussion focuses on the delivery of air to the incubators where the mixture of gases in the incubators is 95% air and 5% CO2. Reducing the oxygen tension in the incubators is an alternative approach, which presents its own set of challenges (not discussed here). Most commercial incubators are designed to obtain air from the room via a pump and CO2 from a gas cylinder. In nearly all cases the gas line going into the incubator is fitted with a 0.2 m pore size filter for sterilization purposes. This system relies on the HVAC system to purify the air and provide enough air exchanges to remove contaminants that build up in the room over time. This system is at the mercy of the function of the HVAC system, which in turn is influenced greatly by the quality of outside or return air. If gas phase filtration is not used, this setup is particularly vulnerable to the wide fluctuations of air quality in urban environments where vehicular exhaust is a major pollutant. However, given an appropriately designed HVAC system with adequate filtration and verification procedures, room air can be a good source for incubator air. An alternative to room air is the use of air lines that deliver air from a medical air compressor directly to the location of the incubators in the laboratory. A medical air compressor is designed to exclude oil from the air stream and compression chamber and does not add any toxic or flammable contaminants to the compressed air. According to the National Fire Protection Association (NFPA) “Standard for Healthcare Facilities,” 1999 Edition, medical air must comply with the following: Liq-

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uid hydrocarbons must be nondetectable and gaseous hydrocarbons present at 25 ppm, pressure dew point at 50 psig must be 4°C, and the amount of permanent particulates must be 5 mg/m3 at 1 m size or greater. In addition to these basic requirements of a medical grade compressor system, other factors merit consideration. Similar to the HVAC system, the quality of medical grade air fluctuates based on the supply of ambient air to the compressor unless there is adequate gas phase filtration. In addition, the design of the system requires that the air go directly from a gas supply line to the incubators, bypassing the air pump that is normally used for room air. Air pressure delivered to the incubators must be 5–15 psi, depending on the brand of incubator. This design requires the security of having a backup compressor to ensure there is no breach in the delivery of air to the incubators should one compressor fail. This point is critical because in contrast to a compressor for medical air, CO2 is most commonly supplied to incubators via compressed air tanks and would not be influenced by a compressor failure. This situation would then result in a rapid increase in the CO2 concentration in the incubator if no backup compressor is in place. An alternative to room air and compressor air is medical grade air supplied in compressed air tanks. The advantage of this approach is primarily shortterm cost compared to a duplex compressor system equipped with adequate filtration. Other advantages include the fact that it requires less space than a duplex compressor, is not prone to failure, and does not require adding more components to the HVAC system (which in most cases requires a large amount of space). The major disadvantage to this system is that the quality of the air within the tanks is controlled by the individuals and the systems providing the air from the tanks, for which there are no guarantees of consistency. Although by definition medical grade air must meet the guidelines set forth by the NFPA, it is possible that tank-to-tank variation can occur and that an individual tank can contain contaminants. For this reason, it is a good idea to install line-filters of charcoal and potassium permanganate to remove any gaseous contaminants. The same can be said for medical grade CO2. However, because CO2 comprises only 5% of the air in the incubator it is not as much a factor if the remaining air is supplied from the room or from a generator. Finally, the other major drawback to using compressed air tanks for the incubators is the labor-intensive nature of switching tanks to keep the supply current.

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The best supply of air for incubators is from a duplex compressor with gas phase filtration. Most hospitals have a system of this type and can deliver this air directly to the laboratory. Because this can be both cost and space prohibitive in the private setting, the next best system is the use of room air with gas phase filtration on the HVAC and at least 15 air exchanges per hour. In the event that none of the aforementioned options is possible, there are commercially available in-room purifiers that can remove gas contaminants via activated charcoal filtration. The final type of gas plumbing that is useful in an IVF laboratory is supply of tri-gas (95% air with 5% CO2) directly to the benchtop for gassing culture dishes during procedures. Most laboratories use this type of gas, although many keep the tank in the room near the point of use. Providing a separate room for CO2 and 95/5 tank storage and having pipes deliver the gas to the locations needed avoids the problems associated with storing and exchanging dirty tanks in the laboratory proper. One final note is needed on the CO2 supply (and medical grade air from cylinders, if used). The preferred configuration for maintaining a constant supply of CO2 is use of a dual manifold. The manifold keeps two separate supplies of gas: a current one and a reserve supply. Once the pressure from the current supply side drops below a certain level, the manifold switches to the other tanks so the supply is automatically continued. Once this switch occurs, an alarm is set that notifies the laboratory the tanks have switched. The empty tanks can then be replaced.

Vacuum A vacuum line system is desirable if the laboratory director prefers to make media in-house. The vacuum is used for filtering media. Because many laboratories now use premade media, this may not be necessary; however, most facilities require a vacuum system for patient care. Thus running additional lines to strategic locations in the laboratory could prove useful in the future.

Water Purification High purity water is required in the IVF laboratory for media preparation. Pure water should also be used to wash glassware and to fill waterbaths and humidity pans from the incubators. Because it is possible to purchase high quality water and premade media, a water purification system is needed only if the laboratory director wants one.

The grade of water to use for media preparation is the National College for Clinical Laboratory Standards (NCCLS) type I water. In addition to using the highest purity standards of the water grades, the water should be used immediately after production to avoid its inevitable degradation to a lower type of water. Because pure water leaches components out of storage vessels (e.g., lead from glass), it should not be stored. Once it is used to prepare media, its osmolarity precludes these changes in quality due to storage. This is not to say that all purchased water is bad. On the contrary, there are several good sources of water for IVF; and because the water is stored in a relatively inert plastic or glass bottle the water maintains its quality. The main problem with buying water is unless you have an established program you have no way of testing the water against proven high quality media. So even if the water passes all quality control standards, there are no guarantees that it will perform well in IVF. If a water purification system is used, it should be located by the sink where dishwashing is done and close to the media preparation area. Most systems include pretreatment of water using reverse osmosis (or deionization) followed by ultrafiltration. The first phase of treatment, reverse osmosis, is a broad-based purification technique that removes more than 93% of inorganic ions, more than 99% of dissolved organics over 300 MW, more than 99% of particles, and more than 99% of microorganisms. The ultrafiltration process removes the remaining microorganisms and results in two- to four-log reduction of pyrogens. The final product of these two purification steps is 18 megohm-cm resistivity water that is ideal for IVF.

Electrical System and Device Monitoring Much of the equipment in the IVF laboratory is electronically controlled and therefore should have protection against power surges, fluctuations in power quality, and power outages. A system that rapidly notifies someone if there is a device malfunction is critical for IVF laboratories.

Power Reliability, Quality, and Backup Any equipment that contains a computer is subject to abrupt, periodic loss of function as a result of changes in electrical current. Although it is now commonplace to have all personal computers on

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some sort of surge protector or even an uninterruptible power supply (UPS), it is probably even more important to protect laboratory equipment that has microprocessors and performs essential functions. The two types of equipment that may be the most critical to protect are controlled-rate freezers and infrared-CO2 sensor incubators. If there is a power surge or a variation in current during a programmed embryo freeze, the rate of freezing is altered, which may affect the viability of the embryos. This can be prevented with a UPS. A similar situation exists with infrared sensor incubators. This type of incubator gives more reliable and rapid adjustment of CO2 concentrations than incubators that use timed injections of CO2. However, it is prone to failure owing to power fluctuations that would not affect other incubators. A failure in the CO2 sensor results in rapid loss of the proper CO2 concentration and incapacitates the incubator until the sensor board is replaced, at a substantial cost. If a facility has several incubators, failure of this type would be manageable unless it occurred at night, at which point it would provide a major inconvenience. This loss of function can be prevented in most cases with a UPS. Complete power outages due to a variety of causes are not uncommon and thus require alternative power supplies. In most cases a propane- or natural gas-operated generator is used to supply backup power. The challenge in a private setting is determining which outlets and systems should be powered by the generator to allow continued function of vital systems and equipment yet minimizing the size and cost of the generator. In general, all outlets and lights in the IVF laboratory and procedure rooms should be on backup power. If an ICSI case or a retrieval is being performed at the time a power outage occurs, rapid restoration of power is essential. Likewise, if a power outage occurs that lasts a few hours in the middle of the night, it is critical that the incubators are able to maintain temperature and CO2 content. It should be noted, however, that generator power backup is not immediate and thus can influence some systems, such as a programmable freezer. This is one more reason to use a UPS with certain equipment to prevent power fluctuations. Given the size of the HVAC system, determining if it should be on backup power is not easy due to the amount of energy it uses. In general, if an HVAC system is included in the emergency power setup, the size of the generator is twice that if it is not included. The job of the HVAC system is filtering, ventilating, and pressurizing the laboratory

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as well as controlling temperature and humidity. A short power outage would have a minimal effect on these factors, as would a long outage during nonworking hours. Given that the incubators are on backup power, they continue to function and function normally if they have a good air source. If the incubators obtain their air from the room, however, the quality of the air is critical, especially during a prolonged power outage. The final decision about putting the HVAC system on backup power should be made when considering the history of power reliability to the area and the likelihood of a major outage.

Instrument Monitoring A state-of-the-art monitoring system provides some peace of mind for the laboratory director. There are two main functions the system can perform: a switch for out-of-normal-limit detection and analogue values for continuous monitoring of actual levels. In both cases the system notifies someone if a value is beyond its set-point. The equipment that should be monitored and the degree of monitoring are listed in Table 7–4. The importance of monitoring these devices and being notified immediately, by phone or beeper, goes without saying. The utility of analogue measurements in the incubator is the ability to determine recovery times and the effects of varying amounts of use (i.e., door opening frequency). If this level of monitoring is not desired, a switch on incubator temperature and CO2 can be used instead.

Security Systems Several security systems are available. A security system should be in place for the entire building, including window break detectors, motion detectors, and door opening sensors. This establishes the general security that is essential for not only the TABLE 7–4. Laboratory Systems Monitored by a Simple Out-of-Range Switch or Analogue Detectors Switch Room temperature Room humidity Refrigerator and freezer temperatures Liquid nitrogen levels in tanks CO2 line pressure Medical air line pressure (if used) Analogue detector Incubator temperature Incubator CO2 concentration Incubator humidity

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laboratory but the entire building. Entrance into the building should require a key and a code to disarm the security system. The most important area in terms of security is the IVF laboratory and the location of the liquid nitrogen tanks. Separate locks with access limited to key personnel are important to maintain the security of incubating and stored embryos. This gives one additional layer of defense should a break-in occur, plus it should prevent someone with general access to the building from entering the laboratory (i.e., cleaning personnel).

Computer Capabilities No new facility should be built without the latest technologies of computer interconnectivity and wiring. Every room should have telephone and data jacks for computers. Even if a practice does not have a large computer network or even plans to install one, being prepared is worth the minimal expense involved. Several IVF computer programs are on the market that are networkable and allow data entry from many terminals. This is important for IVF given the need to report data to the Centers for Disease Control (CDC). Placing laptops or desktop computers in the laboratory allows convenient entry of data that otherwise would have to wait until a more suitable time. In addition to the ability to access the database, much of the equipment in laboratories now has the ability to export directly to a personal computer or be monitored by one. Thus the issue of wiring is an important one.

Audiovisual System The ability to project images from the laboratory and procedure rooms to other parts of the building is useful for educational purposes and patient involvement. A cable system in the building makes this possible. Thus ultrasonographic images from eggs or embryos can be broadcast. We typically do this during egg retrievals and embryo transfers; for the latter, patients can view their embryos being loaded into the catheter. A video film of the embryos can also be prepared to show patients more detail than the printed pictures, and they provide a more complete picture of the embryos for future reference. The audio portion of the system includes a standard sound system for music in every room with volume controls. In addition, a wireless microphone setup for the physician and laboratory staff

proves useful for discussing progress during an egg retrieval. Although such a system can be added at any time, it is best to plan ahead and have it in place during the construction of the building.

Conclusions This chapter describes most of the critical components of laboratory design and construction, including specifications that at this time are neither standard nor regulated for IVF laboratories. Knowledge of these factors is essential for the reproductive endocrinologist or laboratory director planning a new facility or redesigning an existing one. Without question, the single most important component of a new or redesigned facility is the indoor air quality for the IVF laboratory and the incubators. Indoor air quality is influenced by nearly all major design components of the laboratory, including the HVAC system, engineering of the system for proper pressurization, temperature and humidity control, physical layout and construction quality of the laboratory to maintain pressurization, and choice of building materials to minimize off-gassing of noxious fumes. Although many of the important design decisions can be arrived at intuitively, fundamental knowledge of the workings of an HVAC system and related variables offers a measure of security. This security translates into the ability to make an educated assessment of the validity of the construction and design plans, or if nothing else, the ability to recognize when a second opinion is in order.

Suggested Reading American Society of Heating and Refrigerating and Air Conditioning Engineering. Clean spaces. In: 1995 Applications Handbook. Atlanta: ASHRACE, 1995. American Society of Heating and Refrigerating and Air Conditioning Engineering. Health care facilities. In: 1995 Applications Handbook. Atlanta: ASHRACE, 1995. Cohen J, Gilligan A, Esposito W, Schimmel T, Dale B. Ambient air and its potential effects on conception in vitro. Hum Reprod 1997;12:1742–1749. Cooper EC. Laboratory Design Handbook. Boca Raton: CRC Press, 1994. Lieberman A. Contamination Control and Cleanrooms. Problems, Engineering Solutions, and Applications. New York: Van Nostrand Reinhold, 1992. May JV, Hanshew K. Organization of the in vitro fertilization and embryo transfer laboratory. In: Keel BA, Webster BW (eds) CRC Handbook of the Laboratory Diagnosis and Treatment of Infertility. Boca Raton: CRC Press, 1990:291–327.

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8 Anesthesia in the Office Angeline N. Beltsos

The advent of outpatient surgery revolutionized the medical world during the last century and added new dimensions to both surgery and anesthesia. Ancient Greeks and Egyptians routinely practiced outpatient anesthesia; they used alcohol and opioids for pain relief in the home. In 1842 Crawford Long made a major contribution to surgery by utilizing ether for the first clinical general anesthesia case, which interestingly occurred in the outpatient setting. Most surgeries were then performed in the inpatient hospital. By the early 1900s the first outpatient centers opened, and over the next 60–70 years ambulatory surgicenters, separate from the hospital operating room, began to appear. Outpatient surgery initially was performed on healthy patients and expected to be uncomplicated and brief. As experience has expanded it now includes less healthy patients and longer, more difficult procedures. The consequential development of ambulatory surgery has provided a major tool to do more with less for many surgical specialties including infertility. Furthermore, with the explosion of resources and technologies for the treatment of infertility, most of these procedures can be performed in the outpatient setting. Advanced reproductive technology (ART) centers provide treatment for infertility that may include in vitro fertilization (IVF), encompassing care for both male and female infertility. Oocyte retrieval using transvaginal ultrasonography is frequently performed allowing visualization of follicle borders without blind entry into follicular spaces as occurs with a laparoscopic approach. In addition, less anesthesia can be given, which may decrease oocyte exposure to anesthetics. The increased success of IVF and its decreased invasiveness (usually no laparoscopy required) have made this the more popular ART. Moreover, ultrasound-

guided follicle aspiration can be performed easily in the outpatient setting.

Types of Anesthesia General Anesthesia General anesthesia involves hypnosis, amnesia, analgesia, and possibly muscle relaxation. Induction should be pleasant and rapid (one arm–brain circulation time). Sedative, hypnotic, or opioid drugs given beforehand may help relax the anxious patient but may also prolong recovery from the general anesthesia. In the ART setting, some choose not to give anything preoperatively so as to minimize oocyte exposure and allow speedier recovery. Induction of anesthesia is usually accomplished with rapid-acting intravenous (IV) anesthesia such as barbiturates (thiopental, thiamylal, methohexital), ketamine, propofol, or etomidate. The opioids fentanyl, sufentanyl, and alfentanil can induce anesthesia, but when used at higher doses to induce unconsciousness they may cause complications (chest wall rigidity, delayed recovery, postoperative respiratory depression, nausea). For patients undergoing a tubal transfer procedure [gamete or zygote intrafallopian tube transfer (GIFT, ZIFT) Tubal Embryo Transfer (TET)], decreasing the incidence of emesis is important so as not to disturb the transferred products. Maintenance of anesthesia can be done by continuing the intravenous medicine with intermittent boluses or continuous drip or by adding inhaled anesthetics. Inhaled agents include nitrous oxide, isoflurane, desflurane, or sevoflurane. Analgesics for pain relief include opioids such as fentanyl, sufentanil, or alfentanil, which can be given for bal77

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anced anesthesia (balance of different medications). Muscle relaxants, if used in outpatient setting, must have a rapid onset and short duration of action. Succinylcholine is ultra-short-acting and frequently used. Newer agents popular in the outpatient setting include mevacurium and cisatracurium (nondepolarizing).

Regional Anesthesia: Epidural or Spinal Regional anesthesia includes epidural or spinal anesthesia. Advantages of regional anesthesia include postoperative pain relief, maintenance of the patient’s own airway, and decreased incidence of nausea and vomiting. The expertise of the anesthesia personnel is an important determining factor when choosing regional anesthesia in the outpatient setting. At L2-3, L3-4, or L4-5 of the lumbar spine, a small-gauge needle is placed in the epidural space for epidural anesthesia (19-gauge needle) or into the subarachnoid space for spinal anesthesia (26- or 27gauge needle). The epidural space lies between the spinal meninges (maters) and the vertebral canal, which is a series of discontinuous compartments that become continuous with the injection of air or fluid. The subarachnoid space is defined as the area under the dura mater and arachnoid mater. Epidural anesthesia may involve use of lidocaine, 2-chloroprocaine, or mepivacaine. Lidocaine, marcaine, or tetracaine may be utilized for spinal blockade. Other advantages of spinal anesthesia in the ART setting is the faster onset of anesthesia and the need for less equipment. Frequently, the patient is premedicated with a sedative such as midazolam (Versed). During regional anesthesia, oxygen may be given on an as-needed basis or routinely depending on the facility’s protocols or preference of anesthesia.

Monitored Anesthesia Care The American Society of Anesthesiologists (ASA) stated that monitored anesthesia care (MAC) includes (1) the usual noninvasive cardiocirculatory and respiratory monitoring, (2) administration of

TABLE 8–1. Necessary Points for Administering Anesthesia Person administering anesthesia must: 1. Be cardiac pulmonary resuscitation (CPR) certified 2. Be Advanced Cardiac Life Support (ACLS) certified 3. Understand the anesthetic agents being administered 4. Know the antidotes and have them available (see Appendix C. Antidotes) 5. Be prepared to handle general anesthesia/intubation 6. Have crash cart available and know how to use it 7. Have other team members available for help if needed

oxygen when indicated, and (3) intravenous administration of sedatives, anxiolytics, antiemetics, and other medicines. Levels of sedation vary from analgesia (pain relief), local anesthesia (pain relief to one part of body), conscious sedation (depressed level of consciousness but responsive), and deep sedation or hypnosis (unconscious and unresponsive). Sedation (drug-induced tranquility) and anxiolysis (relaxation) provide relief during procedures. Benzodiazepines, propofol, opioids (fentanyl, alfentanyl), and inhalation agents are used. Anesthesia personnel include an anesthesiologist or certified registered nurse anesthetist (CRNA) from the department of anesthesia. In some settings (e.g., procedures by dentists, radiologists, gastroenterologists) conscious sedation is frequently administered by the attendant nurse or doctor who is properly qualified. In all cases, a physician is always available. Nonetheless, whoever is administering the anesthetic must meet the criteria in Table 8–1. Other members of the team must know how to respond to emergencies and have emergency phone numbers close at hand (e.g., 911). In the ART setting, MAC usually involves conscious sedation with anesthesia personnel administering intravenous medicine and monitoring the patient. Some centers use a member of the ART team to administer the anesthesia. In a review of anesthesia practices in the United States, Ditkoff et al. found that 95% of IVF centers use conscious sedation and 56–68% use anesthesia personnel for MAC (Table 8–2).

TABLE 8–2. Common ART/IVF Anesthesia Scenarios Parameter Who administers anesthesia (MAC) Cost Usual medicines used

Anesthesia personnel Academic program 56% Private program 68% $391  $15 Midazolam (Versed) and/or diprivan (Propofol) with fentanyl

IVF team personnel

p

36% $157  $11 Meperidine (Demerol) and midazolam (Versed)

Source: Ditkoff et al., 1997. ART, assisted reproductive technology; IVF, in vitro fertilization; MAC, monitored anesthesia care.

0.05

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Local Anesthesia Local anesthetics act by interfering with the excitation-conduction process in the nerve membrane causing conduction blockade (see Appendix A). They can be used as infiltration for a peripheral nerve block or for a regional block (including spinal or epidural anesthesia). These substances cause a reversible blockade of nerve function and fall into two major categories: amino esters and amino amides. The discovery of cocaine as a benzoic ester led to the synthesis of amino esters derived from benzoic acid ester, which include benzocaine, procaine, tetracaine, and chloropaine. Lidocaine was developed in 1943 as the first amino amide and differed because it was essentially free of allergic reactions. Prilocaine, mepivacaine, and bupivacaine are other types from this category. Paracervical block is an option for anesthesia during ART procedures to decrease the discomfort of needle penetrance into the vagina but is infrequently used. Manipulation of the ovaries and entrance into the peritoneal cavity may require further intravenous sedation.

Studies on Anesthesia and ART/IVF Anesthetic agents have been found to accumulate quickly in follicular fluid after an intravenous bolus. For this reason, oocytes have been tested in an animal model to determine if increasing exposure of anesthetic agents affects oocyte quality and the ability to create a pregnancy. The mouse oocyte/ embryo is a frequently utilized model to examine the potential deleterious effects of toxins and for laboratory quality assurance. Depypere et al. found that exposing the mouse oocyte to increasing doses of propofol decreased fertilization rates from 84.7% in controls to 22.7% in the highest concentration (10.0 g/ml) and that increasing the time of propofol exposure decreased the fertilization rates from 92.0% in controls to 46.9% in oocytes exposed to propofol 1 g/ml for 40 minutes. Blastocyst development was not affected by either parameter. More recently, Janssenswillen et al. found that increasing concentrations of propofol affected the ability of the oocyte to fertilize and the blastocyst to develop. Furthermore, in this study increasing the dose and duration of exposure to propofol appeared to activate the oocytes parthenogenetically. Parthenogenesis can be elicited in oocytes by exposing them to a variety of agents including ethanol, heat-cold shock, and anesthetics; it also occurs in vivo, as in teratomas.

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Anesthetic options in ART programs have also been evaluated in regard to human pregnancy outcome. Pierce et al. compared thiopental sodium to propofol given for induction of anesthesia during 282 GIFT cycles. Pregnancy rates of 24.6% and 25.8% for the thiopental and propofol groups, respectively, were not significantly different. Palot et al. found that the use of nitrous oxide with and without halothane caused a decrease in cleavage rates when used for general anesthesia during oocyte retrievals. Regional anesthesia has also been evaluated and has the potential advantages of lower serum drug levels and a lower incidence of nausea and vomiting. Lefebre et al. found that transvaginal retrieval under epidural anesthesia had a higher cleavage rate than did laparoscopic retrieval with general anesthesia. Confounding variables color the interpretation of these results. Another study, by Botta et al., compared epidural anesthesia to propofol/nitrous oxide (mask-assisted ventilation) and found no difference in fertilization, cleavage, or pregnancy rates between the two groups. In a study from Beltsos et al., oocytes recovered early, compared to those recovered later, did not differ in rates of fertilization, cleavage, or pregnancy. Imoedemhe et al. also studied propofol and found no difference in oocytes retrieved from the beginning versus the end of a case when followed through pregnancy occurrence. This is in contrast to the earlier reports of Boyers et al. and Hayes et al., who found that fertilization and cleavage were decreased with anesthesia exposure, but the latter studies used general anesthesia and laparoscopic retrieval. What remains unclear is which anesthetic medicines are best for optimizing ART pregnancy outcomes. It appears that decreasing exposure to general anesthesia may be helpful. To study the effects of anesthesia, the murine model or the ART setting can be used. Whether parallels can be drawn between phylogenetically similar models or less similar mammalian systems such as the murine and human models is a constant issue in science. The ART arena is limited because it would be difficult to have a pure negative control, as some level of sedation is required. Certainly continued efforts to evaluate this subject in a prospective form will be welcomed to maintain ART success while providing the optimum in anesthesia care.

Indications and Purpose Institutional, local, or regional regulations and policies may govern the preoperative evaluation.

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TABLE 8–3. Preoperative Laboratory Tests for Women Based on Age Test recommended by age Laboratory test CBC/hemoglobin Electrolyte panel hCG (positive after hCG injection for ART) Chest radiography Electrocardiogram

40 years

40–49 years

50–59 years

60–69 years

70 years

✓

✓ (✓) —

✓ (✓) —

✓ ✓ —

✓

✓

✓ ✓ — ✓ ✓

—

CBC, complete blood count; hCG, human chorionic gonadotropin.

Preoperative Screening

Premedication

A careful history and physical examination by the physician and anesthesia team must be performed. As an initial screen in the office the patient is offered tests for human immunodeficiency virus (HIV) and hepatitis B surface antigen, a rubella titer, and rapid plasma reagin/Veneral Disease Research Laboratory (RPR/VDRL) testing. Consider screening for ethnicrelated diseases (e.g., thalassemia, sickle cell disease, Tay-Sachs disease). Table 8–3 indicates minimum preoperative screening considerations based on age and assuming a healthy woman. Appendix D is the American Society of Anesthesiologists’ (ASA) statement on routine preoperative laboratory and diagnostic screening. If the patient has medical problems, further testing should be focused on their disease. If significant disease exists, consider medical clearance not only for the surgery but also for preconception counseling. Suggestions for tests based on disease are provided in Table 8–4.

Anxiolytics Anxiolytics provide relaxation and amnesia. The most commonly used anxiolytic is midazolam (Versed); others are diazepam (Valium) and triazolam (Halcion). Considerations include careful dosing to prevent hypotension, a changing heart rate, and respiratory depression. There is concern that there may be deleterious effects on the oocyte with potential effects on fertilization. In light of this, preoperative anxiolytics should be administered as close to the time of the procedure as possible to decrease oocyte exposure; they should not be used if the patient is not anxious.

Protection Against Aspiration It has been noted that 25 ml of solutions of pH  2.5 if aspirated may lead to aspiration pneumonitis. This condition is defined as gastric contents

TABLE 8–4. Testing Recommendations for Various Diseases Disease Cardiac disease Hypertension Renal disease Diabetes

Asthma Steroid use History of irradiation

Testing and treating BUN, creatinine, chest radiography, ECG. Patient given antihypertensives the morning of surgery with a sip of water. If taking diuretic, check electrolytes. Electrolytes, BUN, creatinine. Electrolytes, BUN, creatinine, blood glucose, urinalysis, and possibly ECG. May need an insulin drip and q1h blood glucose assay. NPO after midnight and adjust morning insulin (usually take half of regular morning insulin). Patient uses nebulizer the morning of surgery. Also use inhaler prior to surgery. Take the medicine with the patient to the OR. Electrolytes, blood glucose level. May have falsely elevated WBC count. Give stress-dose steroids (e.g., hydrocortisone 100 mg IVPB). WBC, radiography, ECG.

ECG, electrocardiography; BUN, blood urea nitrogen; NPO, nothing by mouth; OR, operating room; WBC, white blood cell; IVPB, intravenous piggyback.

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entering the pulmonary tract via emesis or reflux, causing a life-threatening lung condition. Preoperatively, sodium citrate, metoclopramide (Reglan), or an H2-receptor antagonist can be given for women who are at risk for aspiration, such as those with a hiatal hernia or who are obese. Patients difficult to intubate or who will be masked are also candidates for prophylaxis (the mask can also insufflate the stomach, increasing the likelihood of reflux). The length of the fast should be at least 4–6 hours. Preoperative instructions should be in written form, signed by the patient, and a copy kept in her chart (see Appendix G and Appendix H). If the ART patient is not compliant and presents with a recent ingestion, she must be carefully counseled regarding the risk of aspiration pneumonitis. Recent liquid intake is less significant than food. Obesity and the history of a hiatal hernia increase the patient’s risk. Because the ART procedure is timed by human chorionic gonadotropin (hCG) injection, a delay may result in ovulation, which would make the ART procedure impossible. The window of time is evaluated from the hCG injection and last meal for considering if there is potential for delaying the case. Some might cancel the procedure to avoid potential medical and legal ramifications. Others advocate that this procedure is “necessary enough” (time, resources, money spent) to proceed. Proceeding at the scheduled time should involve written consent and assumption of responsibility by the patient for her error. Anesthetic choices include spinal anesthesia (because the patient can maintain her own airway) or general anesthesia, securing the airway with gastric suctioning. H2-receptor antagonists, sodium citrate, and metoclopramide should also be considered. MAC/conscious sedation is an alternative, but the medicine used should induce the least amount of nausea and vomiting and allow the patient to protect her own airway.

Upper Respiratory Infection at the Time of the Procedure If the patient has a bacterial upper respiratory infection (URI), consider antibiotic treatment as soon as the infection is recognized to improve her condition prior to surgery. Fever, congestion auscultated (wheezes, rales, rhonchi) by stethoscope, or significant malaise or lethargy at the time of surgery are factors that must be considered when cancelling a case. Some, nonetheless, would proceed with the procedure because it is considered “urgent” though not emergent.

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Prophylaxis Against Postoperative Nausea and Vomiting Patients who had significant nausea and vomiting with previous anesthesia or who have problems with motion sickness may require attention. Droperidol (before anesthesia), transdermal scopolamine (given the night before surgery), or ondansetron HCl (Zofran) may be considered in this situation.

Prophylactic Antibiotics Pelvic Inflammatory Disease The ART protocol frequently include oral antibiotics (doxycycline for possible Chlamydia trachomatis coverage) before the cycle begins. The American College of Obstetrics and Gynecology (ACOG) considers antibiotic prophylaxis to reduce the incidence of surgical site infection by contamination with lower genital tract flora. It is frequently used in women having a hysterectomy or cesarean section. In regard to ART with needle penetrance from the vagina into the peritoneal cavity to the ovary, the possibility of infection exists. For the routine patient without a history of pelvic infections, a single dose of a cephalosporin may be used. The choice of agent is based on the institution’s microbiology reports and hospital formulary. Arguments against treating the routine patient include the increasing number of resistant organisms, increased cost with unknown benefit, and oocyte exposure. If there is a history of PID, hydrosalpinx, or abscess, prophylactic intravenous antibiotics (cefotetan 1–2 g IVPB and doxycycline 100 mg IVPB) are an appropriate consideration. Oral antibiotics before and after the procedure comprise another option for this type of patient. Subacute Bacterial Endocarditis For subacute bacterial endocarditis (SBE) prophylaxis, the American Heart Association 1997 recommendations depended on the severity of the disease: high risk, moderate risk, negligible risk. High risk patients includes those with prosthetic valves, previous bacterial endocarditis, complex congenital heart disease, or surgically corrected systemic pulmonary shunts or conduits. The moderate risk group includes those with mitral valve prolapse with regurgitation. Prophylaxis is optional and is used only in the high risk patients undergoing vaginal hysterectomy or vaginal delivery. Dilation and curettage, sterilization procedures, and intrauterine device (IUD)

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placements or removals do not require prophylaxis. Extrapolating these recommendations to the ART patient with possible peritoneal contamination from the vagina, SBE prophylaxis might be indicated but only in high risk patients. SBE prophylaxis would include, at 30 minutes before the procedure, giving ampicillin 2 g IVPB and gentamicin 80 mg IVPB. At 6 hours after the procedure amoxicillin 1.5 g PO is given. For penicillin allergy, give vancomycin 1 g over 1 hour with gentamicin 80 mg IVPB. SBE prophylaxis does not appear to be indicated for embryo transfers.

(Demerol) to keep the patient in conscious sedation and comfortable. Other specialty operations are performed by the physician, who also supervises or directly gives the anesthetic such as for percutaneous radiologic and dental procedures. This is becoming a more popular option with ART procedures in the current health care environment of cost consciousness. Care must be taken not to have a surgeon who is concentrating on a procedure or an unqualified person be the responsible party for monitoring the patient under intravenous sedation.

Additional Local Anesthesia SBE and PID For both SBE and PID antibiotic prophylaxis, consider a combination of ampicillin 2 g IVPB, gentamicin 80 mg IVPB, and doxycycline 100 mg IVPB 30 minutes prior to the procedure and amoxicillin 1.5 g PO 6 hours later.

Anesthesia Options Based on the ART Procedure Ultrasound-Guided Follicle Aspiration MAC With Anesthesia Personnel Present The advent of ultrasound-guided follicle aspiration (USFA) has allowed retrievals to be done with MAC using intravenous or conscious sedation. As mentioned above, many programs use an anesthesiologist or CRNA to administer the medicine and monitor the patient (see Types of Anesthesia, above). In this setting it is common to use intravenous midazolam (Versed), diprivan (Propofol), and/or fentanyl. Opioid anesthesia must be used at the point of distribution (where it has been delivered) because of its classification, so traveling anesthesia personnel who come to one’s office may not have this form available for use. Anesthesia personnel must be prepared for possible general anesthesia and have all necessary equipment with them (see Anesthesia Equipment, below).

MAC Without Anesthesia Personnel Present Some programs have taken on the responsibility of MAC themselves and have an IVF team member administering the anesthetics. Usually a registered nurse (RN) or a physician administers midazolam (Versed) or fentanyl via intravenous infusion with intravenous fluids running. Others merely place a heplock and administer enough meperidine

Topical application of local anesthetics such as plain lidocaine or bupivacaine is a consideration at the site of the needle insertion site. It is usually not used, however, as the intravenous sedation is adequate, and the application requires an additional needlestick. If used, be sure to aspirate prior to injection to avoid intravascular injection, which can produce significant complications.

Regional Anesthesia If spinal or epidural is used, the USFA can be done with less intravenous anesthesia but is usually too involved for this simple procedure. It is a consideration for the patient who has had a recent ingestion. It is more frequently used with microlaparoscopic GIFT.

Fallopian Tube Transfer Procedures Via Laparoscopy MAC/General Anesthesia Oocytes are still retrieved via USFA under conscious sedation; general anesthesia can then be given for the laparoscopic transfer. Aside from the technical advantage and ease of USFA, another advantage of this setup is that in the event there are no eggs the patient has not undergone an unnecessary general anesthetic. The laparoscopic retrieval may be performed when the ovary is transvaginally inaccessible, and this requires either regional or general anesthesia. Local injection of port sites with 0.25–0.50% bupivacaine (Marcaine) prior to the incision has been found to decrease postoperative pain. The need to intubate the patient for laparoscopy depends on her size, the ability to establish an airway without difficulty, and the experience and speed of the surgeon. Asthmatics and singers are examples of patients in whom avoidance of intubation is advantageous. Mask anesthesia during

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laparoscopy with abdominal insufflation in steep Trendelenburg position can be arduous. Gastric distension resulting from a partially obstructed airway can increase to the point that the trocard is inserted into the stomach. Also, gastric distension increases reflux and possible aspiration.

trained and able to handle. Do not overextend yourself to cover areas where you and your staff are not capable of providing the full standard of care.

Regional Anesthesia

Patient

With regional anesthesia, both the USFA and the laparoscopic transfer is done with an epidural or spinal block. Microlaparoscopy, where the instruments are as small as 2 mm, can easily be done under regional block.

If the patient has a serious medical condition, preoperative and preconception counseling should be undertaken. Other steps include informed consent (see Appendix I); ovulation induction (or can be spontaneous cycle); and NPO after midnight prior to the procedure with written instructions that are signed, with the office keeping a copy (see Appendix G or H).

Percutaneous or Open Testicular Biopsy for Sperm Collection Local anesthetic with or without intravenous sedation can be used for a percutaneous sperm aspiration or an open testicular biopsy. It can be done with the anesthesia personnel present or in the office with the physician administering the local agent, with staff assistance to administer some intravenous conscious sedation.

Special Preparation

Nurse The nurse counsels the patient regarding the expected procedure and what will occur; completes the preoperative checklist (see Appendix F); assists in coordinating the surgeon, anesthesia, laboratory, and family; and assists in the discharge of the patient.

Doctor

Contraindications to Anesthesia in the Office In-office anesthesia is not an option for every patient. The patient with significant medical conditions or a history of anesthesia-related complications may be better off in an inpatient setting. An unstable/uncontrolled medical problem requiring inpatient treatment or a patient with ASA physical status III or IV should be treated in a full operating suite. Pulmonary or cardiac conditions that require invasive monitoring with a Swan-Ganz catheter (e.g., pulmonary hypertension) must not be treated in the office. Patients who may require prolonged intravenous treatment (increased nausea/ emesis or antibiotic prophylaxis overnight) should be in a facility prepared for overnight care. Patients susceptible to malignant hyperthermia (acetylcholinesterase deficiency) also must be in an inpatient setting. Recent exposure to diet pills or monoamine oxidase (MAO) inhibitors can result in a complicated anesthetic reaction, so anesthesia should be administered cautiously and in an inpatient facility (see Special Considerations, Diet Pills, below). The salient message is that one should provide care in a setting for which health care providers are

The physician obtains the patient’s history and performs a physical examination; reviews the preoperative laboratory results and any preoperative consults; reviews the accessibility of the ovaries prior to the day of the surgery by transvaginal ultrasonography; obtains informed consent after it is explained to the patient and possibly the significant other (see Appendix I); and writes preoperative instructions and an explanation of the USFA procedure and anesthesia given to patient (see Appendix G or H).

Anesthesia Equipment It is recommended that, no matter what type of anesthesia is given, the team be prepared for general anesthesia including intubation and the possible use of crash cart. Table 8–5 indicates what is necessary for patient care during anesthesia. The anesthesia personnel may already be part of an operating room staff in an outpatient surgery center or in a hospital where the procedures are performed. Some centers perform ART in their office procedure room, and anesthesia personnel (frequently a CRNA supervised by an off-site anesthesiologist) come to the office with portable equipment (Fig. 8–1). This is usually a private company

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A.N. Beltsos TABLE 8–5. Necessary Anesthesia Equipment Equipment

Always on patient   

Blood pressure measurement device Cardioscope tracing Pulse oximetry/oxygenation Stethoscope Oxygen available Stethoscope Thermometer Ambubag and intubation tray Crash cart: epinephrine, atropine, shock pads, ECG leads Expired carbon dioxide (capnography)

Always available

Helpful

      

A

B

C

D

FIGURE 8–1. Portable anesthesia equipment commonly used in the office setting. (A) Equipment stored and carried in wheeled luggage. (B) Full crash cart equipment. (C) Mandatory equipment for monitored anesthesia care: blood pressure cuff, pulse oximeter, electrocardiography leads for cardiac tracing. (D) Intubation equipment and ambubag must also be at hand.

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certified and staffed for this particular type of work. Other centers, in an effort to decrease expenses, have their own anesthesia equipment and administer anesthesia themselves as mentioned.

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billing must be well educated and continually updated on this ever-changing topic. Errors in billing can have legal consequences.

Outline of Steps Special Considerations Latex Allergy As many as 20% of health care workers have developed allergies to latex, which can involve an anaphylactic reaction. If a patient has latex allergy, care must be taken to protect the patient against exposure to latex products (transvaginal probe, surgeon’s gloves). This problem must also take into account the nonlatex products that have been found to be oocyte- and embryo-toxic.

Diet Pills If the patient has been exposed to diet pills such as Fen-Phen (fenfluramine-phenteramine), a thorough cardiac physical examination and an echocardiogram should be performed to ensure that no cardiac defects occurred as a result of these medicines. Furthermore, recent exposure to these medicines can have catecholamine-depleting effects, and therefore anesthesia must be administered with extreme caution. These patients are best treated in the inpatient setting where instant resuscitative measures are available.

Billing In the current health care milieu, careful attention to current procedural terminology (CPT) and International Classification of Diseases, 9th Revision (ICD-9) coding is imperative. Because these specific items continue to change every day, refer to the most current publications regarding the anesthesia and procedure performed. Some carriers do not want the anesthesia code but the surgical code. The time spent on anesthesia is usually needed on the claim and may be requested in either minutes or units (units are calculated in 15-minute intervals). Other carriers, particularly Medicare and Medicaid, want to know if the anesthesia was personally performed by an anesthesiologist or a CRNA. If CRNAs are being utilized, the number of CRNAs per supervising anesthesiologist may be requested information. If a nonanesthesiologist physician is providing the anesthesia, a different code is submitted. The staff responsible for the

Procedure 1. Preoperative counseling forms and written instructions (see Appendix G or H) are signed, with a copy given to the patient; the original goes in the chart. 2. Informed consent is signed by patient and surgeon (see Appendix I). The surgeon should always obtain the consent from the patient. Include the possibility of bleeding with potential need for blood transfusion; infection; injury to internal organs (female organs, intestines, bladder, major blood vessels); thromboembolic phenomenon; anesthetic complications; possible laparoscopy/laparotomy; and death. 3. Patient changes into a gown, and valuables are left with the family, in the car, or at home. Clothing is placed in a secured locker. 4. An identification bracelet is placed on the patient. 5. Baseline vital signs including height, weight, blood pressure, pulse, respiratory rate, and temperature are recorded. 6. Surgeon and anesthesia specialist perform the history and physical examination. Chart is checked for current medications, allergies, medical/surgical history, previous anesthesia and complications, and medical clearance if requested. The anesthesia specialist should also examine the patient’s airway and conduct a cardiac and pulmonary examination. 7. Patient is taken to the procedure room, and an intravenous infusion is started. 8. Blood pressure cuff, pulse oximeter, and cardiac monitor are placed. 9. Proceed to the anesthesia of choice. 10. Go through the postoperative checklist (see Appendix J).

Discharge Prior to discharge the patient must be observed after anesthesia and the procedure. Recommendations for the anesthesia specialist includes a minimal duration of observation of the following. MAC: 1 hour General: 2 hours Regional: until sensation returns

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The patient should also meet the requirements below. 1. No vomiting. 2. Tolerates oral fluids or intake (not absolutely necessary). 3. Voiding; if unable, catheter should be in place or patient should be instructed on self-catheterization (see Potential Complications, below). 4. State of hydration normal. 5. Medical condition stable. 6. Distance between home and ambulatory facility is not far or there is a nearby hospital. 7. Available responsible adult. 8. Anticipation of whether the patient is likely to suffer any complications if little or no intake (e.g., diabetes). 9. Postoperative pain relief may include acetaminophen for USFA or at most a mild analgesic such as acetaminophen with codeine. For laparoscopy, acetaminophen (Tylenol) with codeine or an equivalent should suffice. If more than this is needed, further evaluation is indicated to ensure that there is no significant intraperitoneal injury. 10. Review postoperative instructions (see Appendix K or L). Once signed, a copy is given to the patient; original goes in the chart. 11. Consider calling the patient the day after surgery to make sure she is recovering well.

Potential Complications 1. Nausea and vomiting. 2. Pain: Immediately after operation, particularly after laparoscopy, pain relief is important. After USFA, pain should be manageable with minimal medicine. If the pain is significant, further evaluation for possible complications is required. 3. Postoperative hypertension: commonly a preexisting condition. Patient should take their medications before surgery with sips of water. 4. Hypotension and syncope: Causes include hypovolemia, position changes, anesthetics, and a full bladder. Other possibilities include pulmonary embolus and myocardial infarction. 5. Aspiration pneumonitis. 6. Respiratory arrest/apnea: ASA recommends the same standards for basic intraoperative MAC as for regional or general anesthesia. The anesthesia team, physicians, or nurses administering the anesthesia should follow the same standards. Personnel should always be in charge of observing the patient for untoward reactions.

With heavy sedation or an involved procedure, this should not be the person performing the procedure. Avoid fixed drug combinations; rather, incrementally dose the patient to the point of sedation. Be aware that the patient could go from conscious sedation to deep or general sedation quickly, and antidotes should be on hand (see Appendix C) 7. Arrhythmia/cardiac arrest. 8. Hemorrhage: Large-bore intravenous access should be initiated immediately if significant bleeding occurs. Surgeon must be able to perform a laparoscopy or laparotomy if needed. Blood must be immediately accessible for transfusion as needed. Disseminated intravascular coagulation (DIC) is another complication if significant bleeding has occurred. 9. Allergic reaction. 10. Urinary retention (especially with spinal anesthesia). Catheterize the patient and allow an attempt to void. If unsuccessful, teach selfcatheterization for 1–2 days or leave a Foley catheter in place for 1–2 days with bladder training to be initiated afterward. 11. Postdural headache (1–10%). Needle and technique selection are important. Treat with an epidural blood patch. 12. Hypoxic events. 13. Thromboembolic phenomena. 14. Malignant hyperthermia: Treatment is dantrolene sodium. 15. Death: Incidence of anesthetic deaths is 0.7–3.7 per 10,000 inpatients receiving anesthetics. In the ambulatory care setting this may be 0.012– 0.15 deaths per 10,000. 16. Unanticipated hospital admissions: Overall incidence of hospital admission ranges from 0.68% to 4.10%.

Conclusions Outpatient anesthesia has developed into a sophisticated arena where high-tech care can be delivered in one’s office. Precautions must be taken to protect the patient when administering potent agents in settings away from a hospital, and only formally trained personnel should be responsible for this care. The least amount of anesthesia necessary to maintain patient comfort should be administered. Oocyte exposure to anesthetic agents is a recent concern, as it is found in the follicular fluid and may affect oocyte fertilization and ultimately pregnancy rates.

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Suggested Reading Accreditation Manual for Hospitals. Joint Commission on Accreditation of Healthcare Organizations, 1988. American College of Obstetricians and Gynecologists. Antibiotics and Gynecologic Infections. Educational Bulletin 237. Washington, DC: ACOG, 1997. American Society of Anesthesiologists. Standards, Guidelines and Statements, Park Ridge, IL: ASA, 1997. Barash PG, Cullen BF, Spoetling RK. Clinical Anesthesia, 3rd ed. Philadelphia: Lippincott-Raven, 1997. Baylor-Pridham DD, Reshef E, Drury K, et al. Follicular fluid lidocaine levels during transvaginal oocyte retrieval. Fertil Steril 1990;53:171–173. Beltsos A, Oldham L, Mahendra S, Basuray R, Williams D. Propofol exposure in ART cycles. In: Abstracts of the Pacific Coast Fertility Society, 1996. Botta G, D’angelo A, D’ari G, et al. Epidural anesthesia in an in vitro fertilization and embryo transfer program. J Assist Reprod Genet 1995;12:187–190. Boyers SP, Lavy G, Russell JB, DeCherney AH. A paired analysis of in vitro fertilization and cleavage rates of first- versus last-recovered preovulatory human oocytes exposed to varying intervals of 100% CO2 pneumoperitoneum and general anesthesia. Fertil Steril 1987; 48:969. Chetkowski RJ, Nass TE. Isoflurane inhibits early mouse embryo development in vitro. Fertil Steril 1988;49: 171. Coetsier T, Dhont M, De Sutter P, et al. Propofol anesthesia for ultrasound guided oocyte retrieval: accumulation of the anesthetic agent in follicular fluid. Hum Reprod 1992;10:1422–1424. Coombs DW. Aspiration pneumonia prophylaxis. Anesth Analg 1983;62:1055. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997;277:1794–1801. Degueldre M, Puissant F, Camus M, et al. Effects of carbon dioxide insufflation at laparoscopy on the gas phase in oocyte recovery fluids. J In Vitro Fertil Embryo Transfer 1984;1:106. Depypere HT, Dhont M, De Sutter P, Vanderkerckhove D. The influence of propofol on in vitro fertilization in mice [abstract]. Hum Reprod 1991;127(suppl): 151. De Sutter P, Dhont M, Merchiers E, et al. Effect of sequence of oocyte retrieval on oocyte fertilizability [abstract P483]. Hum Reprod 1991;127(suppl 1): 340. Ditkoff EC, Plumb J, Selick A, Sauer MV. Anesthesia practices in the United States common to in vitro fertilization (IVF) centers. J Assist Reprod Genet 1997; 14:145–147. Hayes MF, Sacco AG, Savoy-Moore RT, et al. Effect of general anesthesia of fertilization and cleavage of human oocytes in vitro. Fertil Steril 1987;48:975. Imoedemhe DAG, Sigue AB, Ghani IA, Aboezeid MA, Halim MSA. An evaluation of the effect of the anes-

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thetic agent propofol (‘Diprivan’) on the outcome of human in vitro fertilization. J Assist Reprod Genet 1992;9:488–491. Janssenswillen C, Christaens F, Camu F, Van Steirtegham A. The effect of propofol on parthogeneic activation, in vitro fertilization and early development of mouse oocytes. Fertil Steril 1997;67:769–774. Keenan RL. Anesthetic Disasters: Causes, Incidence, Preventability. Refresher Course Lectures, American Society of Anesthesiologists 242. Philadelphia: Lipincott, 1988. Lefebre G, Vauthier D, Seebacher J, et al. In vitro fertilization: a comparative study of cleavage rates under epidural and general anesthesia-interest for gamete intrafallopian tube transfer. J In Vitro Fertil Embryo Transfer 1988;5:305. Palot M, Visseaux H, Harika G, Carre-Pigeon F, Rendoing J. Effects of nitrous oxide and/or halothane on cleavage rate during general anesthesia for oocyte retrieval. Anesthesiology 1990;73:A930. Pierce RD, Syrope CH, Van Voorhis BJ, et al. An evaluation of the effect of anesthetic technique on reproductive success after laparoscopic pronuclear stage transfer. Anesthesiology 1995;83:352–358. Positions on Monitored Anesthesia Care. Park Ridge, IL: American Society of Anesthesiologists, 1986. Shapira SC, Chrubasik S, Hoffmann A, et al. Use of alfentanil of in vitro fertilization oocyte retrieval. J Clin Anesth 1996;8:282–285. Teaubeaut JR. Aspiration of gastric contents: an experimental study. Am J Pathol 1952;28:51. Warren RJ, Shaw B, Stainkampf MP. Effects of nitrous oxide on preimplantation mouse embryo cleavage and development. Biol Reprod 1990;43:158. White P. Outpatient Anesthesia. New York: Churchill Livingstone, 1990.

Additional Readings Kim WO, Kil HK, Koh SO, Kim JI. Effects of general and locoregional anesthesia on reproductive outcome for in vitro fertilization: a meta-analysis. J Korean Med Sci. 2000 Feb;15(1):68–72. Casati A, Valentini G, Zangrillo A, Senatore R, Mello A, Airaghi B, Torri G. Anaesthesia for ultrasound guided oocyte retrieval: midazolam/remifentanil versus propofol/ fentanyl regimens. Eur J Anaesthesiol. 1999 Nov; 16(11):773–8. Stener-Victorin E, Waldenstrom U, Nilsson L, Wikland M, Janson PO. A prospective randomized study of electro-acupuncture versus alfentanil as anaesthesia during oocyte aspiration in in-vitro fertilization. Hum Reprod. 1999 Oct;14(10):2480–4. Bokhari A, Pollard BJ. Anaesthesia for assisted conception: a survey of UK practice. Eur J Anaesthesiol. 1999 Apr;16(4):225–30. Martin R, Tsen LC, Tzeng G, Hornstein MD, Datta S. Anesthesia for in vitro fertilization: the addition of

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fentanyl to 1.5% lidocaine. Anesth Analg. 1999 Mar; 88(3):523–6. Bokhari A, Pollard BJ. Anaesthesia for assisted conception. Eur J Anaesthesiol. 1998 Jul;15(4):391–6. Trout SW, Vallerand AH, Kemmann E. Conscious sedation for in vitro fertilization. Fertil Steril. 1998 May; 69(5):799–808. Gorgy A, Meniru GI, Naumann N, Beski S, Bates S, Craft IL. The efficacy of local anaesthesia for percutaneous

epididymal sperm aspiration and testicular sperm aspiration. Hum Reprod. 1998 Mar;13(3):646–50. Christiaens F, Janssenswillen C, Van Steirteghem AC, Devroey P, Verborgh C, Camu F. Comparison of assisted reproductive technology performance after oocyte retrieval under general anesthesia (propofol) versus paracervical local anaesthetic block: a casecontrolled study. Hum Reprod 1998 Sep;13(9): 2456–60.

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Appendix A: Types of Local Anesthetic Agents Agent

Duration

Use

Procaine Tetracaine Chloroprocaine Lidocaine Mepivicaine Prilocaine Bupivacaine

Short Short Short Moderate Moderate Moderate Long

Infiltration/peripheral block Topical mucous membrane/spinal Infiltration/peripheral block/epidural Infiltration/peripheral block/spinal/epidural Not for topical use Intravenous regional Infiltration/peripheral block MAC

Appendix B: Commonly Used Medicines Trade name

Generic name

Alfentanyl Ancef Anectine Atracurarium Atropine Brevital Demerol Diazepam D-TC Edrophonium Fentanyl Inapsine Ketamine Labetalol Norcuron Pavulon Pentathol Propofol Reglan Robinol Romazicon Toradol Valium Versed Xylocaine Zofran

Alfenta Cefazolin Succinylcholine Tracrium Methohexital Meperidine Benzodiazepine d-Tubocararine Acetylcholinesterase agent inhibitor Droperidol Vecuronium Pancuronium Thiopental Diprivan Metoclopramide Glycopyrrolate Flumazenil Ketoralac Diazepam Midazolam Lidocaine Ondansetron HCl

Mechanism of action Opioid analgesic Cephalosporin antibiotic Depolarizing muscle relaxant Nondepolarizing muscle relaxant Anticholinergic General anesthetic Analgesic Sedative Muscle relaxant Neuromuscular reversal Opioid analgesic Neuroleptic agent Sedative-hypnotic Antihypertensive Nondepolarizing agent Neuromuscular blocade IV Anesthetic IV Anesthetic Dopamine antagonist/GI motility Anticholinergic Receptor antagonist/reversal agent NSAID Sedative Analgesic, amnesic Local anesthetic Antiemetic

GI, gastrointestinal; IV, intravenous; NSAID, nonsteroidal antiinflammatory drug.

Appendix C: Antidotes for Most Commonly Used IV Sedation Medications Drug name Narcotic analgesic: fentanyl, meperidine (Demerol) Diprivan (Propofol) Midazolam (Versed)

Antidote Naloxone HCl (Narcan) None Flumazenil (Romazicon)

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Appendix D: American Society of Anesthesiologists Statement on Routine Preoperative Laboratory and Diagnostic Screening (Approved by House of Delegates on October 14, 1987 and Last Amended on October 13, 1993) Preanesthetic laboratory and diagnostic testing is often essential; however, no routine* laboratory or diagnostic screening† test is necessary for the preanesthetic evaluation of patients. Appropriate indications for ordering tests include the identification of specific clinical indicators or risk factors (e.g., age, preexisting disease, magnitude of the surgical procedure). Anesthesiologists, anesthesiology departments, or health care facilities should develop appropriate guidelines for preanesthetic screening tests in selected populations after considering the probable contribution of each test to patient outcome. Individual anesthesiologists should order test(s) when, in their judgment, the results may influence decisions regarding risks and manage-

ment of the anesthesia and surgery. Legal requirements for laboratory testing where they exist should be observed. The results of tests relevant to anesthetic management should be reviewed prior to initiation of the anesthetic. Relevant abnormalities should be noted and action taken, if appropriate. *Routine refers to a policy of performing a test or tests without regard to clinical indications in an individual patient. †Screening

means efforts to detect disease in unselected populations of asymptomatic patients. Source: ASA, 520 N. Northwest Highway, Park Ridge, IL 60068-2573. Reprinted with permission.

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Appendix E: American Society of Anesthesiologists Guidelines for Nonoperating Room Anesthetizing Locations (Approved by House of Delegates on October 19, 1994) ASA endorses and supports the concept of Ambulatory Surgery and Anesthesia and encourages the anesthesiologist to play a role of leadership in both the hospital and freestanding setting. I. An ambulatory surgical facility may be hospital-affiliated or freestanding. The facility is established, equipped, and operated primarily for the purpose of performing outpatient surgical procedures. II. ASA Standards, Guidelines, and Policies should be adhered to in all areas except where they are not applicable to outpatient care. III. A licensed physician, preferably an anesthesiologist, must be in attendance in the facility at all times during patient treatment, recovery, and until medically discharged. IV. The facility must be established, equipped, constructed, and operated in accordance with applicable local, state, and federal laws. V. Staff shall be adequate to meet patient and facility needs and consist of: A. Professional Staff 1. Physicians and other practitioners who are duly licensed and qualified. 2. Nurses who are duly licensed and qualified. B. Administration Staff C. Housekeeping and Maintenance Staff VI. Physicians providing medical care in the facility should be organized into a Medical Staff

which assumes responsibility for credentials review, delineation of privileges, quality assurance, and peer review. VII. Personnel and equipment shall be on hand to manage emergencies. The facility must have an established policy and procedure concerning unanticipated patient transfer to an acute care hospital. VIII. Minimal patient care shall include: A. Preoperative instructions and preparation. B. An appropriate history and physical exam by a physician prior to anesthesia and surgery. C. Preoperative studies as medically indicated. D. Anesthesia shall be administered by anesthesiologists, other qualified physicians, or medically directed nonphysician anesthetists. E. Discharge of the patient is a physician responsibility. F. Patients who receive other than unsupplemented local anesthesia must be discharged to the company of a responsible adult. G. Written postoperative and follow-up care instructions. H. Accurate, confidential, and current medical records. Source: ASA, 520 N. Northwest Highway, Park Ridge, IL 60068-2573. Reprinted with permission.

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Appendix F: Preoperative Checklist  Patient notified of time and location of procedure.  Notified of procedure: 

Operating room  Office



Lab



 Anesthesia 



Surgeon

Nurses

Sonographer

 Patient given Preop Instruction sheet, signed and a copy retained for chart [see Appendix G or H].  Patient signed surgical consent [see Appendix I].  Physician history and physical completed.  Anesthesia history and physical completed.  OR equipment checked and in stock.  Preop. lab results  reviewed and  on chart.  Address any medical problems.  Review current medicines.  Allergies:  Order antibiotics if indicated for PID and/or SBE prophylaxis.  Consents also signed for  ART,  micromanipulation/ICSI,  embryo freezing.  ID band on patient.  Hospital gown given and clothes in locker.  Prosthesis removed and secured. Teeth Glasses Contact lens Artificial limb Other  Time of last meal: ___________  Have patient void.  Preop vitals: Temp ______ BP ______

Height ______

Pulse ______

RR ______

Weight ______

 Preop meds given. Medicine __________________

Method ______

Time ________

By whom ___________

Medicine __________________

Method ______

Time ________

By whom ___________

Medicine __________________

Method ______

Time ________

By whom ___________

Signature of RN ________________________________ Date ________________

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Appendix G: Preoperative Instructions for Ultrasound-Guided Follicle Aspiration This surgery involves transvaginal ultrasonography similar to what you have undergone already to measure the follicles. A needle is attached to the probe, which goes from the vagina to the ovary and aspirates (sucks out) the eggs. You will be made comfortable for this procedure with anesthesia, which will allow you to essentially sleep through it. Afterward you will be allowed to go hom, where you must rest. 1. The evening before surgery you may have a regular dinner. 2. After midnight, you cannot eat or drink anything. You may brush your teeth and rinse your mouth. No candy or gum is allowed. 3. Take a shower or bath the morning of surgery. 4. Come to the place where the laparoscopy/oocyte retrieval will be performed. Please arrive at the ______________________. Attached is a map and phone number. Date __________ Time __________ 5. Do not take aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) or naproxen (Alleve) starting 10 to 14 days before the procedure. 6. If you are taking a blood thinner such as heparin, please discuss this with the doctor prior to surgery. 7. If you have any medical conditions or problems and are taking medicine every day (example: insulin or antihypertensive), on the day of surgery you should:

8. After the procedure, you may have some cramping which acetaminophen (Tylenol) should help make better. 9. A responsible adult must accompany you and remain there during the surgery as well as drive you home. A responsible adult must also be with you at home after the surgery. You cannot drive home the day of the procedure. 10. Please do not bring children with you. 11. Be sure to bring any medicine that you take for a medical condition (such as asthma inhalers or high blood pressure pills) with you on the day of surgery. 12. If you have a cold, flu, or fever, contact our office immediately so we can evaluate you before surgery. 13. Wear comfortable clothes that are easy to put on and take off. Do not bring valuables to the surgery. You will be given a gown to wear and a place to put your belongings. If you wear dentures, a partial plate, eyeglasses, contact lenses, a hearing aid, or any other prosthesis, you will be asked to remove them prior to surgery. 14. Do not wear any cosmetics, including nailpolish or eye makeup. 15. Have a blanket and pillow in your car to be used for the ride home. Do not bring them into the facility. 16. If you have any questions about these instructions or the procedure, please contact our office. Phone number: ____________________

Signed __________________________________

Date ___________________

Witness _________________________________

Date ___________________

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Appendix H: Preoperative Instructions for a Laparoscopic Procedure This surgery involves transvaginal ultrasonography similar to what you underwent already to measure the follicles. A needle is attached to a probe, which goes from the vagina to the ovary and aspirates (sucks out) the eggs. Once the eggs are retrieved, a laparoscopy is performed, which involves small incisions made at your bellybutton, pubic bone, and side. Through these small incisions, small instruments are used to place the eggs and sperm into the tube. 1. The evening before surgery you may have a regular dinner. 2. After midnight, you cannot eat or drink anything. You may brush your teeth and rinse your mouth. No candy or gum is allowed. 3. Take a shower or bath the morning of surgery. 4. Come to the place where the laparoscopy/oocyte retrieval will be performed. Please arrive at the ______________________. Attached is a map and phone number. Date __________ Time __________ 5. Do not take aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) or naproxen (Alleve) starting 10 to 14 days prior to the surgery. 6. If you are taking a blood thinner such as heparin please discuss this with the doctor prior to surgery. 7. If you have any medical conditions or problems and are taking medicine every day (example: insulin or antihypertensive), on the day of surgery you should: 8. After the procedure, you may have some pain at the incisions or cramping, which the pain medicine prescription or acetaminophen (Tylenol) should help make better. 9. A responsible adult must accompany you and remain during the surgery as well as drive you home. A responsible adult must also be with you at home after the surgery. You cannot drive home the day of the procedure. 10. Please do not bring children with you. 11. Be sure to bring any medicine that you take for a medical condition (such as asthma inhalers or high blood pressure pills) with you on the day of surgery. 12. If you have a cold, flu, or fever, contact our office immediately so we can evaluate you before surgery. 13. Wear comfortable clothes that are easy to put on and take off. Do not bring valuables to the surgery. You will be given a gown to wear and a place to put your belongings. If you wear dentures, a partial plate, eyeglasses, contact lenses, a hearing aid, or any other prosthesis, you will be asked to remove them prior to surgery. 14. Do not wear any cosmetics, including nailpolish or eye makeup. 15. Have a blanket and pillow in your car to be used for the ride home. Do not bring them into the facility. 16. If you have any questions about these instructions or the procedure, please contact our office. Phone number: ____________________

Signed __________________________________

Date ___________________

Witness _________________________________

Date ___________________

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Appendix I: Consents Any consent for surgery should be evaluated by risk management or added to the current document to ensure proper language.

Consent for Procedure/Anesthesia: Ultrasound-Guided Follicle Aspiration PATIENT ________________________________________ AGE ______________ DATE _____________ TIME _________ PLACE ____________ I hereby authorize (doctor) _________________________________, M.D. and whomever he/she may designate as the assistants to administer such treatment as may be necessary for and/or to perform upon myself the following procedure: ULTRASOUND-GUIDED FOLLICLE ASPIRATION [Transvaginal ultrasonography is performed with a needle attached to aspirate (“suck out”) the eggs.] If any unforeseen condition arises during the course of the procedure, calling, in his or her judgment, for procedures in addition to, or different from those contemplated, I further request and authorize (a) the administration of blood during and immediately after the operation as deemed necessary by the surgeon and/or anesthesiologist; (b) disposal of any tissue removed from my body in a manner customary to the facility; and (c) taking photographs as deemed desirable by the attending physician and/or anesthesiologists. The nature and the purpose of the procedure includes retrieving the eggs as described above. Usually, fertility medicine has been utilized to make many follicles (cysts that contain the eggs), which can also make the ovaries swollen. This can be uncomfortable and is called ovarian hyperstimulation syndrome (OHSS). OHSS can make a woman feel bloated, can cause weight gain, and can lead to fluid collecting in the abdomen or lungs, which may require hospitalization for close monitoring. OHSS can also make the blood “thicker” so that it clots too easily (hypercoagulability). Possible alternatives include obtaining the eggs through a laparoscopic approach, which requires more anesthesia. Risks include infection; bleeding; injury to internal organs including the female organs, bladder, intestines, and major blood vessels; thromboembolic phenomenon (blood clots); complications from anesthesia; need for further surgery such as laparoscopy or laparotomy; and death. I acknowledge that no guarantee or assurance has been made as to the results that may be obtained. Sometimes an estimate of the number of eggs expected is given, but it can be more or less than that number, including zero. I consent to the administration of an anesthetic to be given by or under the direction of the anesthesiology department or company, or the surgeon, or whomsoever he/she may designate, using anesthetics as may be deemed desirable with the exception of __________________________ [if none, state]. The anesthesia may be intravenous medicine to make me sleepy; general anesthesia; or epidural or spinal anesthesia. I CERTIFY THAT I HAVE READ AND FULLY UNDERSTAND THE ABOVE CONSENT TO TREATMENT AND/OR OPERATION AND/OR PROCEDURE, THAT THE EXPLANATIONS THEREIN REFERRED TO WERE MADE, THAT ALL BLANKS OR STATEMENTS REQUIRING INSERTION OR COMPLETION WERE FILLED IN, AND THAT INAPPLICABLE PARAGRAPHS, IF ANY, WERE STRICKEN AND INITIALIZED BY ME BEFORE I SIGNED. SIGNATURE ____________________________________ DATE ________________ WITNESS ______________________________________ DATE ________________

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Consent for Procedure/Anesthesia: Ultrasound-Guided Follicle Aspiration with Laparoscopic Surgery with Tubal Transfer PATIENT __________________________________ AGE _________ DATE _______________ TIME ____________ PLACE ______________ I hereby authorize (doctor) _________________________________, M.D. and whomever he/she may designate as the assistants to administer such treatment as may be necessary for and/or to perform upon myself the following procedure: ULTRASOUND-GUIDED FOLLICLE ASPIRATION WITH LAPAROSCOPIC SURGERY WITH TUBAL TRANSFER [Transvaginal ultrasonography is performed with a needle attached to aspirate (“suck out”) the eggs. Then laparoscopy is performed to place the egg and sperm in the tube.] If any unforeseen condition arises during the course of the procedure, calling, in his or her judgment, for procedures in addition to, or different from those contemplated, I further request and authorize (a) the administration of blood during and immediately after the operation as deemed necessary by the surgeon and/or anesthesiologist; (b) disposal of any tissue removed from my body in a manner customary to the facility; and (c) taking photographs as deemed desirable by the attending physician and/or anesthesiologists. The nature and the purpose of the procedure includes retrieving the eggs as described above. Usually, fertility medicine has been utilized to make many follicles (cysts that contain the eggs), which can also make the ovaries swollen. This can be uncomfortable and is called ovarian hyperstimulation syndrome (OHSS). OHSS can make a woman feel bloated, can cause weight gain, and can lead to fluid collecting in the abdomen or lungs, which may require hospitalization for close monitoring. OHSS can also make the blood “thicker” so that it clots too easily (hypercoagulability). Possible alternatives include obtaining the eggs through a laparoscopic approach, which requires more anesthesia. Risks include infection; bleeding; injury to internal organs including the female organs, bladder, intestines, and major blood vessels; thromboembolic phenomenon (blood clots); complications from anesthesia; need for further surgery such as laparoscopy or laparotomy; and death. I acknowledge that no guarantee or assurance has been made as to the results that may be obtained. Sometimes an estimate of the number of eggs expected is given, but it can be more or less than that number including zero. I consent to the administration of an anesthetic to be given by or under the direction of the anesthesiology department or company, or the surgeon, or whomsoever he/she may designate, using anesthetics as may be deemed desirable with the exception of __________________________ (if none, state). The anesthesia may be intravenous medicine to make me sleepy; general anesthesia; or epidural or spinal anesthesia. I CERTIFY THAT I HAVE READ AND FULLY UNDERSTAND THE ABOVE CONSENT TO TREATMENT AND/OR OPERATION AND/OR PROCEDURE, THAT THE EXPLANATIONS THEREIN REFERRED TO WERE MADE, THAT ALL BLANKS OR STATEMENTS REQUIRING INSERTION OR COMPLETION WERE FILLED IN, AND THAT INAPPLICABLE PARAGRAPHS, IF ANY, WERE STRICKEN AND INITIALIZED BY ME BEFORE I SIGNED. SIGNATURE ____________________________________ DATE ________________ WITNESS ______________________________________ DATE ________________

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Appendix J: Postoperative Checklist Check off list as indicated or completed.  Patient recovered in recovery room for appropriate time. Recommendations for the anesthesia includes minimal durations of observation of: MAC: 1 hour GENERAL: 2 hours REGIONAL: until sensation returns  Received necessary antibiotics.  When time has ended and if no nausea or emesis, attempt oral intake.  When tolerating oral intake and/or no nausea or vomiting is present, discontinue IVF.  Voiding without difficulty.  Count from sponge, instruments, needles was correct at end of case.  Operative complications: No: _____ Yes: _____  If yes: ______________________________________________________  Anesthesia complications: No: _____ Yes: _____  If yes: ______________________________________________________  If any complications, what (if any) follow-up is necessary? ________________________________________________________________________________  Waiting husband or significant other notified that surgery is complete.  Operative report signed by surgeon as indicated.  Anesthesia report is signed by anesthesia specialist as indicated.  If laparoscopy, prescription for pain medicine given.  If SBE prophylaxis, prescription for postoperative antibiotic given.  Discharge instructions reviewed with patient and significant other is signed; copy given to patient and original put in chart.  Any other medical condition addressed as needed.  Patient given instructions for progesterone post-ART procedure as indicated.

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Appendix K: Discharge Instructions for Ultrasound-Guided Follicle Aspiration 1. No driving for 24 hours; therefore someone must drive you home. 2. A responsible adult should be with you when you go home today. 3. No tampons, intercourse, or douching for 2 weeks or when allowed by physician. 4. Rest at home the day of surgery. 5. You may increase your activity as tolerated the day after surgery and return to work if you desire. Stairs are okay if you are able. 6. You may shower or bathe the day of surgery with assistance. Do not bathe or shower if you are groggy from anesthesia. 7. Exercise may be attempted a few days after surgery if you feel up to it and if it is okay with your doctor. If your ovaries are swollen from the fertility medicines (“ovarian hyperstimulation syndrome”), you should not exercise until given the okay from the doctor. 8. You may eat or drink as you feel up to it. Avoid alcohol until your doctor says it is okay. 9. If you do not have a bowel movement within 2 days after the surgery, try a laxative or an enema. 10. For pain, you may take acetaminophen (Tylenol). If this does not help, call your doctor. 11. If you have: Heavy vaginal bleeding Fever over 100.5°F, 6 hours apart or over 101.0°F at any time Persistent nausea or vomiting Significant abdominal pain Inability to urinate Swelling or pain of your leg(s) Difficulty breathing Chest pain Persistent drainage of fluid or blood from your incisions Any urgent questions or problems Call the office immediately at phone number _____________________________ 12. The day of surgery you should take progesterone as instructed by the ART nurse. Day of surgery: ______________________________________ Starting the day after surgery (date __________), take _____________________________. 13. You may be asked to have tests done following surgery. Date: ______________________ Test: ___________________________________________ Date: ______________________ Test: ___________________________________________ Date: ______________________ Test: ___________________________________________ Signature ________________________________________ Date _______________________ Witness ______________________________________________ Date _______________________

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Appendix L: Discharge Instructions for a Laparoscopic Procedure 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13.

14.

15.

16.

No driving for 24 hours; therefore someone must drive you home. A responsible adult should be with you when you go home today. No tampons, intercourse, or douching for 2 weeks or when allowed by physician. Rest at home the first few days following surgery. You may increase your activity as tolerated the day after surgery and return to work if you desire. Stairs are okay if you are able. This does not include exercise. You may shower or bathe the day of surgery with assistance. Do not bathe or shower if you are groggy from anesthesia. Exercise may be attempted 2–4 weeks after surgery if you feel up to it and if it is okay with your doctor. If your ovaries are swollen from the fertility medicines (“ovarian hyperstimulation syndrome”), you should not exercise until given the okay from the doctor. You may return to work within 2–3 days if you feel up to it and it is not physically challenging. No heavy lifting for 2–4 weeks. You may eat or drink as you feel up to it. Avoid alcohol until your doctor says it is okay. If you do not have a bowel movement within 2 days after the surgery, try a laxative or an enema. For pain, you may take the pain medicine from the prescription or acetaminophen (Tylenol). If this does not help, call your doctor. You may have a sore throat from the surgery and anesthesia. Gargle with warm salt water and drink hot tea with real lemon. You may have shoulder pain from the surgery (“referred pain”). Hot tea with lemon can be helpful. Also curl up with a pillow, face down, with knees curled up under you. It may alleviate some of the discomfort. If you have: Heavy vaginal bleeding Fever over 100.5°F, 6 hours apart or over 101.0°F at any time Persistent nausea or vomiting Significant abdominal pain Inability to urinate Swelling or pain of your leg(s) Difficulty breathing Chest pain Persistent drainage of fluid or blood from your incisions Any urgent questions or problems Call the office immediately at phone number _____________________________ The day of surgery you should take progesterone as instructed by the ART nurse. Day of surgery: ______________________________________ Starting the day after surgery (date __________), take _____________________________. You may be asked to have tests done following surgery. Date: ______________________ Test: ___________________________________________ Date: ______________________ Test: ___________________________________________ Date: ______________________ Test: ___________________________________________

Signature ________________________________________ Date _______________________ Witness ______________________________________________ Date _______________________

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9 Ovulation Induction and Controlled Ovarian Hyperstimulation with Intrauterine Insemination Robert L. Collins

Ovulation induction with human pituitary gonadotropins (hPG) was first achieved in 1958. Subsequently, urinary menopausal gonadotropins (hMG) were successful in the treatment of anovulatory infertile women. Clomiphene citrate was first reported in 1961 to be successful in ovulation induction and conception. Since then, ovulation induction using exogenous gonadotropins has been successful in amenorrheic women with functional ovarian tissue, and fecundity rates of 15–30% are now expected. Women with chronic anovulation and women who fail to ovulate with clomiphene citrate may also be candidates for treatment with exogenous gonadotropins. Initially, functional disorders of the pituitary gland causing amenorrhea were successfully treated with exogenous gonadotropins. Now indications for treatment include other chronic anovulatory disorders, luteal phase dysfunction, cervical factor, and idiopathic (unexplained) infertility. Exogenous gonadotropins have also been given to normal ovulatory women to improve follicular stimulation and oocyte harvesting during assisted reproductive technologies. In this chapter we review the indications for treatment with exogenous gonadotropins and patient selection. Methods to monitor patient response to improve efficacy and ultimately avoid complications are discussed. Complications of therapy are mentioned and addressed in greater detail in Chapter 19. We review expected outcomes of treatment and introduce the recombinant products currently available. In the latter section, we review the indications and rationale for controlled ovarian hyperstimulation in conjunction with intrauterine insemination (COH/IUI) in apparently ovulatory women with unexplained infertility.

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Physiology Gonadotropins, whether derived from pituitary glands, extracted from postmenopausal urine, or developed using recombinant technology, have similar receptor binding characteristics and stimulatory effects in the ovary yielding similar results. Preparations contain varying quantities and ratios of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or no LH. Current dogma suggests that both FSH and LH are required to stimulate folliculogenesis and result in ultimate ovulation (Table 9–1). The amount of LH required appears to be low, as evidenced by successful ovulation in patients using pure FSH products. According to the two-cell theory, FSH is necessary for recruitment of the follicles and stimulation of the granulosa cells, and it is most likely responsible for selecting the dominant follicle. LH stimulates the thecal cells to produce androgens, which are subsequently aromatized to estrogens by granulosa cells under the influence of FSH stimulation. This synergistic action of FSH and LH results in rising estrogen levels in the follicular fluid. These estrogens in turn influence the rate of follicular growth and the differentiation of follicular cells through the stimulation of gonadotropin receptor synthesis. Ovulation results when appropriate physiologic FSH/LH ratios are secreted from the pituitary gland. The pituitary gland is dependent on the pulsatile delivery of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Significant alterations of either pulsatile GnRH secretion or pituitary gonadotropin secretion patterns result in anovulation. Abnormal gonadotropin pulsatility can cause excessive circulating LH, which leads to elevated androgens and creation of an androgenic milieu.

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9. Ovulation Induction and Intrauterine Insemination TABLE 9–1. Mechanisms of Action of FSH and LH Follicle-stimulating hormone (FSH) Granulosa cell membrane binding Activation of adenylate cyclase system Synthesis of cytochrome P450 aromatase Induction of luteinizing hormone (LH) receptors Enzyme activation for P synthesis Luteinizing hormone Provides androgen substrate for FSH-induced aromatase Resumption of oocyte meiosis Cumulus oöphorus maturation Follicular rupture Corpus luteum formation and support

This androgenic environment promotes follicular atresia, which is not conducive to normal folliculogenesis. This condition is most commonly seen in conjunction with polycystic ovarian disease (PCO). The administration of gonadotropins can override normal ovulatory mechanisms for ovarian folliculogenesis, as evidenced by the use of these agents in normogonadotropic women undergoing in vitro fertilization (IVF) treatments. The timing of the administration of gonadotropins is critical. Significantly more follicles are recruited and selected if hMG is administered early in the follicular phase. Therefore the number of follicles recruited and selected are dependent on both the timing of gonadotropin administration and the FSH content of the gonadotropin preparation. Luteinizing hormone continues to determine the steroidogenic pattern and the final maturation of the dominant follicle. Subsequent ovulation is induced by a surge of spontaneous LH activity (after adequate exposure of the pituitary gland to estrogens) or by the administration of an LH-like material such as human chorionic gonadotropin (hCG). Because the occurrence of a spontaneous endogenous LH surge is infrequent during gonadotropin therapy, LH or hCG is necessary for ovulation to occur after gonadotropin-induced follicular growth and, more importantly, for maintenance of the corpus luteum. The corpus luteum is dependent on continued LH

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or hCG support; and without the luteotropic effects of hCG or LH, a truncation of menstrual cycle length is observed. Short luteal phase lengths, premature menstruation, and early pregnancy wastage occurs without the provision of continued luteotropic support. This co-dependence led to the now widely used combination of gonadotropins and hCG or LH for ovulation induction.

Drugs Pharmaceutical preparations of gonadotropins play an important role in the treatment of infertility. They are used to stimulate follicular development in anovulatory women and for stimulating multiple follicular developments in women undergoing assisted reproductive techniques (ARTs). In men, FSH is utilized to initiate and maintain spermatogenesis in those with hypogonadotropic hypogonadism. It is usually administered in combination with LH. Gemzell first used human FSH in women in 1960 to treat anovulatory infertility, and pregnancies were reported. This human FSH was derived from human pituitaries. Subsequently, gonadotropins were extracted from postmenopausal urine (hMG); hMG contains a mixture of FSH and LH. They were quite effective, and for the next 30 years they became the standard for therapy. Since then, there have been many efforts to develop more purified urinary products. These products were subject to LH antibody treatment to remove the LH content from the final product (Table 9–2). Up to now, hCG has been derived from the urine of pregnant women. Until recently gonadotropins were of urinary origin. This source implies a number of disadvantages and concerns. One concern is the small risk of transmitting infectious agents such as viruses, as reported in some pituitary-derived growth hormone products. This has not been reported with the use of the urinary products. The disadvantages include low purity, no absolute source control, cumbersome collection of urine, some LH contamination even

TABLE 9–2. Preparation of Human Gonadotropins Preparation hMG uFSH uFSH-HP rFSH

Source

FSH activity (IU)

LH activity (IU)

Urine Urine Urine CHO cells

75 75 75–150 75–150

75 0.7 0.001 None

hMG, human menopausal gonadotropin; u, urinary; HP, highly purified; CHO, Chinese hamster ovary; rFSH, recombinant FSH.

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in pure FSH products, and low specific activity. The recently developed recombinant products are nearly 100% pure, devoid of contamination, and demonstrate batch-to-batch consistency. Through the application of recombinant DNA technology, it is now possible to produce human gonadotropins (hFSH, hLH, hCG) for medical use without having to extract them from human fluids. These recombinant products are produced in vitro by genetically engineered mammalian cells [Chinese hamster ovary (CHO) cells]. The technical description of the development of the products is beyond the scope of this chapter. The production of these products by recombinant (r) technology results in the formulation high specific activity, consistent batch to batch products suitable for clinical use. Several studies have demonstrated similar pharmacokinetic characteristics between the recombinant FSH (rFSH) and urinary FSH (uFSH) preparations. The bioavailability is approximately 60% and is comparable after both subcutaneous and intramuscular administration. After subcutaneous administration the apparent half-life is FSH is approximately 37 hours. For clinicians, this means that rFSH can be administered using doses and schedules previously utilized in their urinary gonadotropin protocols. Many studies have assessed the clinical usefulness and overall safety of these recombinant products. Routes of administration—subcutaneous, intravenous, intramuscular—have been compared, and no differences have been found. The usefulness of rFSH in patients with LH excess, such as those with PCO and those almost devoid of endogenous LH) has been demonstrated. Comparisons have been made between rFSH and uFSH in (OI) protocols as well as in ART, with or without agonists or antagonists. It is clear that FSH-induced steroidogenesis was not jeopardized after GnRH agonists induced pituitary suppression. In one study that summarized several papers, involving more than a 1000 ART treatment cycles, comparisons were made between uFSH and rFSH products. It indicated that after rFSH treatment significantly more oocytes were retrieved, more embryos were obtained, and more pregnancies resulted.

Patient Selection Ovulatory dysfunction is usually a symptom of an underlying disease process. Patients should be evaluated to include an assessment of the overall health. Thyroid dysfunction, hyperprolactinemia, and other endocrinopathies should be considered

and ruled out. Evaluations should exclude other causes of amenorrhea and anovulation treatable by other direct means, such as hyperprolactinemia. Patients with hyperprolactinemia, either idiopathic or secondary to small pituitary microadenomas, can be considered candidates for gonadotropin therapy if they were unresponsive or intolerant to primary therapy, such as dopamine agonists (i.e., bromocriptine). All patients should undergo a basic infertility investigation to rule out other causes. Pretreatment studies should include a semen analysis to verify that the man does not have severe oligospermia, azoospermia, or another gross abnormality. The uterine and tubal factors should be investigated by hysterosalpingography, saline infusion sonography (SIS), or office flexible hysteroscopy. Diagnostic laparoscopy with chromopertubation should be considered prior to initiation of treatment to assess completely and possibly treat tubal or peritoneal factors. These pretreatment procedures ensure that there are no contraindications to therapy. Extensive counseling of the couple regarding side effects, risks, expenses, logistics of treatment, and prognosis should be done before therapy. The impact of pregnancy on their health or any underlying medical condition should be considered. Risks such as ovarian hyperstimulation, multifetal pregnancies, and treatment cycle cancellation due to hyperstimulation should be discussed with the patient. Because high order pregnancies can result, selective fetal reduction procedures, although controversial and highly sensitive, should be given special attention. Counseling should be based on scientific and factual data. The duration of treatment should be discussed beforehand. The couple should be advised that the chance of conceiving during any one course is approximately 25%, and the average number of treatment courses needed to achieve a pregnancy is three. Overall, 60% of couples conceive within 4 months. All anovulatory patients may be classified as having (1) hypogonadotropic hypogonadism, (2) euestrogenic normogonadotropic euprolactinemic ovulatory dysfunction, or (3) hypergonadotropic hypogonadism. The categories correspond with World Health Organization (WHO) classes 1, 2, and 3, respectively. Patients with hypogonadotropic hypogonadism have signs and symptoms of estrogen deficiency including amenorrhea and failure to respond to progestin withdrawal, low concentrations of gonadotropins, and low serum estrogen levels. Women in this group include those with stress- or exercise-induced amenorrhea, lowweight-related amenorrhea, pituitary adenomas,

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isolated gonadotropin deficiency, and hypothalamic amenorrhea. The next classification group is called euestrogenic normogonadotropic ovulatory dysfunction. Women in this diagnostic category have serum concentrations of gonadotropins in the normal range and in some cases slightly elevated LH. Included in this group of disorders are polycystic ovary syndrome and luteal phase defect. Women with hypergonadotropic hypogonadism have elevated serum concentrations of FSH and LH and abnormally low concentrations of estrogen. This group includes women with premature ovarian failure, which may be idiopathic or induced by autoimmunity, surgery, chemotherapy, or irradiation. These disorders are characterized by endogenous gonadotropin elevation, and these patients do not benefit from additional exogenous gonadotropins. Ideal candidates for ovulation induction with gonadotropins have functional ovarian tissue and low endogenous gonadotropin secretion patterns that are amenorrheic or anovulatory (Table 9–3). These patients (i.e., normoprolactinemic eugonadotropic anovulation, or hypogonadotropic hypogonadism) may also be candidates for pulsatile GnRH treatment. Prior to treatment it is necessary to document the presence of functional ovarian follicles. Women responsive to a progesterone challenge, who present clinically with severe oligomenorrhea or amenorrhea, are presumed to have endogenous estrogen secretion and therefore have functioning follicles. Women with primary or secondary amenorrhea who do not have uterine bleeding after progesterone administration are presumed to be estrogen-deficient, and these patients should undergo further evaluation. Measurement of the serum FSH level is indicated. Elevated FSH concentration (hypergonadotropic hypogonadism) is consistent with ovarian failure, and these women are usually not candidates for treatment with ovulatory drugs.

TABLE 9–3. Clinical Indications for Gonadotropin Therapy Hypothalamic amenorrhea Hypogonadotropic hypogonadism Chronic anovulation (clomiphene citrate failure) Luteal phase dysfunction Cervical factor Timing artificial insemination Unexplained infertility Follicular development during ART ART, assisted reproductive technologies.

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There are rare instances where exogenous gonadotropins are reported to have induced ovulation in hypergonadotropic hypogonadal patients with suspected premature ovarian failure or resistant ovary syndrome (Savage syndrome). Patients who are clomiphene failures (both conception and ovulatory failures) may also be candidates for gonadotropin therapy. The use of gonadotropin in women with cervical factor infertility after failed conventional therapy has been successful. Despite the fact that gonadotropins can also be associated with induction of a luteal phase defect, gonadotropin stimulation protocols have also been used to correct a preexisting luteal phase defect. Unexplained (idiopathic) infertility is another indication for gonadotropins.

Clinical Monitoring Proper monitoring of the patient’s ovarian response is mandatory to determine dosage of drugs, optimize therapeutic benefits, time hCG administration, and minimize risks. Without proper monitoring gonadotropins may cause severe adverse reactions including superovulation, multiple pregnancies, and the ovarian hyperstimulation syndrome (OHSS). Early experiences with induction of ovulation with human gonadotropins demonstrated the dual risk of OHSS and the occurrence of multiple gestations. Monitoring should involve serial serum estradiol determinations and ultrasonic follicular measurements. Clinical monitoring is less precise and insensitive for achieving the above goals. The clinical assessment of early investigators utilized careful assessment of cervical mucus production and monitoring of preovulatory ovarian size by pelvic examination. However, it became apparent that there were significant variations in the responsive cervical mucus production among the individuals. A major source of this difficulty lay in the fact that the cervical mucus response was insensitive to subtle estrogen changes and maximum at the estrogen concentrations that optimized the pregnancy rate. There was no room for an increased response to signal ovarian hyperstimulation. Previously, the detection of preovulatory ovarian enlargement by pelvic examination was the only other parameter available to signal hyperstimulation. The impreciseness of the bimanual examination limited its ability to predict accurately the development of OHSS. Also, the lack of ovarian enlargement did not exclude the hyperstimulation syndrome. Because of the limitations of the clini-

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cal parameters experienced by earlier investigations, their use alone today for the purpose of monitoring ovarian response is inappropriate. Taymor reported data indicating the successful use of 24-hour serial urinary estrogen determinations for monitoring ovulation induction. Urinary determinations of estradiol, estrone, estriol, and pregnanediol have all been used to monitor the ovarian response. Determination of a specific estrogen was not found to be superior to determination of the total urinary estrogen secretion. An optimal excretion rate of total urinary estrogen was determined to be 50–60 g per day, with the upper safe limits of total urinary estrogens being variably established as 100–150 g per day. The above estrogen ranges are consistent with maximum conception rates, and the incidence of hyperstimulation and multiple births is reduced. There is no significant effect of injection time on the urinary estrogen result so along as the injections are given once daily. The difficulty of collecting complete 24-hour samples and the availability of a rapid radioimmunoassay for plasma estradiol led investigators to abandon urinary estrogen determinations. Because plasma estradiol was determined on a single sample of blood, the timing of the sampling relative to the previous injection of gonadotropin became a critical variable. A study of the plasma estradiol concentrations over the 24-hour period following injection of the gonadotropin demonstrated that although the 24-hour plasma estradiol value correlated with the level of ovarian stimulation, plasma estradiol concentrations were maximum during the 8- to 10-hour postinjection interval. At midcycle in normal ovulatory women, the serum estradiol concentration varies between 200 and 400 pg/ml. Higher levels of estradiol are necessary to increase the probability of conception, and Tredway concluded that raising the estradiol level from 500 to 1000 pg/ml could increase the rate of ovulation. Associated with these higher plasma estradiol levels were increased rates of ovulation, pregnancy, and OHSS. Despite later experiments, no uniformity has been established, and there has been a tendency to allow higher levels of estrogen prior to hCG. This can be accomplished when ultrasonography is used to follow follicular development. Consequently, the estrogen level above which hCG is withheld to minimize the development of OHSS has varied greatly (from more than 500 pg/ml to more than 2000 pg/ml). It is important to use threshold estradiol values that correspond to your laboratory and to individualize patient management in cases that exceed this threshold.

Transvaginal ovarian ultrasonography (TVUS) is performed serially to determine the number of follicles being stimulated and to monitor follicular sizes to time hCG administration (Fig. 9–1). The addition of follicular ultrasonographic scanning to the clinical monitoring protocol has allowed the use of gonadotropins in a safer environment. Difficult patients can be pushed harder, and extremely brittle patients with rapid estradiol rises can be monitored more accurately with ultrasonography. Improvements in ultrasound equipment and the development of vaginal probes with superior imaging qualities have provided exquisite details of follicular development. Ultrasonography has been used to observe follicular growth during normal menstrual cycles and during gonadotropin treatments. Follicular growth was noted to be linear during the ultrasonic examination, and there appeared to be strong correlations between follicular growth and estradiol measurements. Furthermore, it became possible to observe the development of multiple follicles and to assess the risk of multiple gestations or the occurrence of OHSS. Sonographic visualization may also be used to discriminate between single and multiple follicular growth, and it may therefore aid in clarifying the source of estradiol. Because the prevailing evidence suggests that follicles with diameters of 16–22 mm will ovulate, sonography may be a more precise predictor of the subsequent development of OHSS and may become a more precise indicator for determining the time of hCG administration to cause ovum release. Ultrasonic monitoring of follicular growth during ovulation induction is discussed in greater detail in Chapter 4. Ultrasonography has also been used to document and observe morphologic changes in the cervix

FIGURE 9–1. Multiple follicles in polycystic ovarian disease.

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FIGURE 9–2. Multilayered endometrial pattern.

and endometrial cavity and canal during ovulation induction. TVUS endometrial assessment has been used as a noninvasive marker of endometrial receptivity. Two parameters were suggested to evaluate the endometrium: endometrial thickness and endometrial pattern. Several patterns have been described in the literature, but they have been reduced to two grades: nonmultilayered or multilayered. A triple-line multilayered pattern may be the sonographic parameter that most reflects endometrial receptivity (Fig. 9–2). Endometrial thickness measurement has been used as a clinical tool to predict implantation following ovulation induction in both IVF and non-IVF treatment cycles. In many reports conception cycles had a significantly higher mean endometrial thickness than did the nonconception cycles. An ideal range for endometrial thickness has not been established, although Dickey et al. observed more biochemical pregnancies when the

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endometrial thickness was 9 mm or 13 mm during IVF treatment cycles. This relation was not seen following ovulation induction during non-IVF treatment cycles. Yet there may be a minimal endometrial thickness that is associated with conception; in fact, this concept of a minimal endometrial thickness is becoming widely accepted. The minimal endometrial thickness varies between 5 and 8 mm when measured during the late proliferative to early luteal phase. It must be emphasized that ultrasonography should not replace serum estradiol determinations. The results of ultrasound scanning of follicular growth are complementary to the estradiol data. Serum estradiol levels coupled with ultrasonic findings provide the most information on each individual’s ovarian response and subsequent risks for OHSS and multifetal pregnancies (Fig. 9–3).

Typical Treatment Cycle A physician trained and experienced in the technique should supervise ovulation induction. Such physicians should be skilled in the methods of monitoring and interpreting ovarian and endometrial ultrasound scans. The availability of rapid estradiol and progesterone assays is critical. The ability to interpret the assays is essential for safe and successful management of these high risk medications. The physician should also be experienced in the management of OHSS, which clinically varies from mild bloating and weight gain to hospitalization secondary to hemoconcentration, electrolyte imbalance, ascites, coagulation defects, and oliguria. Each patient responds uniquely and individually to gonadotropins. Although multiple gonadotropin dosages and treatment schedules have been advocated, only the individualized regimen can be considered the most commonly used dosage schedule (Table 9–4). The amount of medication and the duration of therapy vary not only among patients but also from one treatment cycle to another in the TABLE 9–4. Gonadotropin Dosage Schedules Level Gradual increase Intermittent therapy Initial step-up, then step-down Sequential estrogen-gonadotropins Individualized based on response Sequential clomiphene-gonadotropins Sequential GnRH agonist-gonadotropins (down-regulation) Simultaneous GnRH agonist-gonadotropin (flare)

FIGURE 9–3. Ovarian hyperstimulation syndrome.

GnRH, gonadotropin-releasing hormone.

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same patient. Therefore it is imperative to monitor the patient carefully each cycle to determine when a mature follicle is present, to time hCG administration, and to assess the risk of OHSS. The patient is usually begun on two ampules of gonadotropins (75 IU of both FSH and LH per ampule) daily early in the follicular phase or after a progestin-induced menstrual period. A preparation containing FSH only may be preferred in patients with PCO or who manifest other types of ovulatory dysfunction. A systematic flow sheet or a plot of the logarithm of the plasma estradiol versus linear days is useful for following the ovulatory response to gonadotropins and for predicting the day of hCG injection. Slow or no rise in the serum estradiol level indicates that the gonadotropin dose should be increased in increments, and these incremental rises should be maintained a minimum of 72 hours prior to further increases. Ideally, one should aim for a follicular length of approximately 9–12 days. Pregnancy rates are low in patients given hCG before day 6. Follicular development should be monitored with frequent ultrasound studies. Ultrasonography plays a critical role in assessing the response to gonadotropins and timing the hCG administration. A baseline ultrasound scan is suggested during the early follicular phase to determine the presence or absence of persistent cysts. A blood estradiol level is determined at baseline. If the estradiol is less than 80 pg/ml and no ovarian cysts are present, therapy is begun. When the estradiol level significantly increases, ultrasound imaging should be repeated every 2–3 days. Scanning becomes more frequent when the follicle reaches 14 mm or more. When follicles 16–18 mm or more are identified, gonadotropins are discontinued and hCG is given 24 hours after the last gonadotropin dosage to cause ovum release approximately 36 hours later. Usually 5000–10,000 IU of hCG is given to trigger ovulation. To maintain corpus luteum function, a supplemental dose of 5000 IU of hCG is given approximately 5 days after the initial ovum release injection. Some prefer multiple small injections of hCG (1500 IU every 3 days) or progesterone suppositories for luteotropic support. If there are signs of ovarian enlargement, the estradiol level exceeds 1000 pg/ml, or pelvic/abdominal tenderness is present, the supplemental dosage of hCG (5000 IU) is withheld. Progesterone suppositories may be substituted for luteotropic support without additional stimulation from supplemental hCG. If multiple (more than six) mature follicles more than 16–18 mm are present or estradiol is excessive, hCG is withheld and intercourse is discouraged. Complications such as OHSS are thus avoided.

If intrauterine insemination (IUI) is not planned, the patient is instructed to have intercourse on the night of the hCG injection and again on the following two nights (minimally). If IUI is planned, the couple is advised to have relations on the night of hCG administration and then to abstain until the IUI specimen is obtained. After hCG she is instructed to record her weight every other day, and any total weight gain of 10 lb or more or 3 lb in 24 hours is to be reported. A serum pregnancy test is obtained approximately 14–20 days after the initial hCG injection if no menstrual bleeding has occurred. If the patient’s hCG is positive, ultrasonography should be undertaken 2 weeks later (4 weeks following the hCG injection) to determine the number and location of fetuses present. This timely ultrasound scan allows early recognition of multiple fetuses and gives time to plan for the special care necessary for these high risk pregnancies or to plan for other possible options such as selective reduction. Ectopic pregnancies can also be diagnosed early by ultrasound scans before tubal rupture and damage. Early recognition of ectopic gestations allows outpatient laparoscopic or medical management and enhances the opportunity for conservative surgical procedures to preserve the functional capacity of the fallopian tube. A typical treatment cycle is summarized in Table 9–5.

Clinical Results The results of a survey of several large series of patients given gonadotropin therapy from several institutions over the past 30 years indicate that gonadotropin therapy is successful and has become widely accepted. Success rates up to 30% per cycle have been reported. One survey included approximately 12,619 treatment cycles given to approximately 5000 patients resulting in more than 2100 TABLE 9–5. Typical Gonadotropin Treatment Protocol Baseline estradiol and transvaginal ovarian ultrasonography Initiate therapy by cycle day 3 Individualized/graduated dosage starting at 2 ampules per day Initial estradiol and scan by day 4–5, then every 2–3 days More frequent estradiol and ultrasonography when leading follicle  14 mm Postcoital test when appropriate Continue scans until leading follicle  16–18 mm Give 10,000 units hCG 24 hours after last gonadotropin dosage Supplemental 5000 hCG 5 days later Intrauterine insemination 36 hours after hCG (if necessary) Serum hCG in 14 days after hCG Ultrasonic scan 4 weeks after ovulation if pregnant

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pregnancies. Patients were stratified into two groups: hypothalamic pituitary failure (group I) or hypothalamic pituitary dysfunction (group II). Group I patients were hypoestrogenic, characterized by low or absent endogenous GnRH pulsatility. Group II patients had some endogenous GnRH pulsatility, albeit aberrant or dysfunctional. They were also estrogenized and progestin-responsive. Patients with clomiphene failure were more likely to be among the group II patients. The results of these series, summarized by Blankstein et al., showed higher ovulatory and pregnancy rates in the group I subjects. Of the 279 patients in group I, an 82% conception rate occurred in patients receiving gonadotropin treatments. The cumulative pregnancy rates for the group I patients was 91.2% after six cycles of treatment, which is approximately 30% higher than the cumulative pregnancy rate in the normal nulliparous population. In contrast, of the 117 patients with hypothalamic pituitary dysfunction who failed to conceive following clomiphene citrate (group II), the pregnancy rate following gonadotropins was only 21.4% and the ovulation rate significantly less at 42.0%. Consequently, the success rates were 60.6% in group I versus 11.5% in group II in terms of the percentage of people who took home at least one living child. The mean number of ampules of gonadotropins likewise differed between groups: 40.0 for group I versus 18.2 ampules in group II. Among the patients who conceived, 94% did so within five cycles of treatment. These findings suggest that among the patients with endogenous gonadotropin pulsatility (group II) there is greater patient variability and they tend to be more difficult to manage. This group also had a higher risk of ovarian hyperstimulation and treatment cancellation. The poorer performance of patients in group II who have hypothalamic pituitary dysfunction led investigators to consider the use of GnRH agonists to create a temporary, func-

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tional hypophysectomy to reduce circulating LH and to mimic the group I pituitary failure patient. By abolishing the endogenous source of gonadotropin pulsatility, the investigators hopefully would achieve a more uniform patient response, reduce individual variability, and consequently reduce the risk of ovarian hyperstimulation.

Complications Complications include OHSS, multifetal pregnancy, pregnancy wastage, and an increased incidence of heterotopic pregnancies. A major complication associated with the use of gonadotropins is the occurrence of OHSS. All complications of gonadotropin therapy are essentially related to the degree of ovarian stimulation during ovulation induction. Fortunately, with careful clinical, ultrasonographic, and biochemical monitoring, the degree of severity and the frequency of complications can be reduced significantly. Theoretically, by controlling the degree of ovarian stimulation, the other complications of multiple pregnancy and pregnancy wastage can likewise be reduced. There are no reported ovulation induction stimulation protocols that reduce the risk of ovarian hyperstimulation to zero.

Ovarian Hyperstimulation The clinical presentation of OHSS is variable. The syndrome is characterized by ovarian enlargement, ascites, hydrothorax, electrolyte imbalance, hypovolemia, and oliguria. In the severe forms hemoconcentration, increased viscosity of blood, thromboembolic phenomena, and hypovolemic shock may occur and death may ensue. The incidence of OHSS is 3–23% for the mild form and 0.4–4.0% for the severe and potentially lethal form (Table 9–6). OHSS is discussed thoroughly in Chapter 19.

TABLE 9–6. Incidence of OHSS After Gonadotropin Therapy Study Brown Caspi Ellis Spadoni Thompson Lunenfeld Total

Treatment cycles (no.)

Mild OHSS (%)

Severe OHSS (%)

222 343 322 225 2,798 3,646

3.2 6.0 5.0 4.4 3.1

? 1.20 0.60 1.80 1.30 0.25

11,343

3.4

0.84

Source: Modified from Blankstein et al., 1986. OHSS, ovarian hyperstimulation syndrome.

a

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One study investigated risk factors and prognostic variables in the development of OHSS. Significantly higher levels of estradiol and prolactin were seen during the follicular phase in the treatment group when compared to controls. Also, there was a tendency for more follicular recruitment with significantly smaller follicles (12–14 mm) present on day 0 for all grades of OHSS. Among 22 variables identified, an increased risk is seen only in the young, lean patient. Using a mathematic model for predicting ovarian hyperstimulation, the authors in the above study suggested that three parameters (age, estradiol level on day 0, basal prolactin levels) had a combined predictive value that could not be improved with additional parameters. A proposed clinical profile of the patient at greatest risk for the development of the syndrome is young and lean, receives few ampules of gonadotropins but has rapidly increasing estradiol levels, and subsequently develops multiple small follicles. Therapy for moderate to severe hyperstimulation requires hospitalization and active management. Patients should be on bed rest with avoidance of pelvic examinations until the size of the ovaries decreases. Baseline and serial blood chemistry profiles and coagulation studies should be performed. Treatment is directed at maintaining vital signs, correcting electrolyte imbalances, and maintaining adequate hydration. Patients who become severely oliguric or anuric require renal hemodialysis. An intake–output balance should be carefully maintained to prevent overhydration. Only fluid lost should be replaced.

Pregnancy Wastage Other complications of gonadotropin-induced ovulation include an increased spontaneous abortion rate, which has been reported to range from 12% to 31%. In the series of patients reported by Blankstein et al., the overall abortion rate was 25.2% with no significant differences between patients belonging to group I or group II. However, a significant difference in abortion rate was observed in consecutive pregnancies (Table 9–7). During the

initial pregnancy cycle following gonadotropin treatment, the abortion rate was 28%. In contrast, during a subsequent pregnancy cycle the abortion rate was only 12%, which is comparable to the abortion rate in the normal population. The factors operative in the increased abortion rate observed in those patients were not identified, but ovarian hyperstimulation was suspected because approximately 50% of the patients with hyperstimulation ultimately aborted.

Multiple Births The incidence of multiple births increases after gonadotropin therapy. In an early report by Gemzell, prior to the prospective use of estrogen data, the rate of multiple gestations was equal to the rate of single gestations. By controlling the degree of ovarian stimulation using plasma estrogen determinations coupled with frequent monitoring by ultrasonography, the incidence of multiple births has decreased. The reported incidence of multiple birth ranges from 11% to 44%, with most of the multiple gestations being twins. Multiple gestations are to be avoided because of the obstetric complications. Apart from the increased incidence of spontaneous abortions and the increased obstetric risks associated with multiple gestations, the outcome of pregnancies following ovulation induction using gonadotropins appears normal. In summary, careful monitoring has reduced the incidence of hyperstimulation, but the incidence of twins and triplets has not been significantly reduced because they occur spontaneously in the population. The frequency of births of more than triplets appears to be reduced but not totally eliminated by carefully monitoring the patient’s ovulatory response to exogenous gonadotropins (Table 9–8).

Gender Ratios The incidence of male children in single pregnancies following gonadotropins therapy was 51.8%. The incidence of twins was 53.8% and triplets 66.7%. The expected ratio is 1.06. The increased

TABLE 9–7. Pregnancy Wastage After Gonadotropins

TABLE 9–8. Multiple Gestations (n  162)

Condition

Wastage (%)

Pregnancies

28 12 13 50

Singleton Twins Triplets Quadruplets

First conception Second conception No treatment after gonadotropins Hyperstimulation Source: Modified from Blankstein et al., 1986.

Source: Bettendorf et al., 1981.

Total no. 113 41 5 3

(69.8%) (25.3%) (3.1%) (1.8%)

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incidence of male births in Bettendorf et al.’s series is probably due to the small numbers involved in the study. In reviewing the literature, the expected gender ratio is approximated when several series are combined. There is no increased tendency in either direction. In a large series of patients reported by Ben-Rafael et al., 256 children were born in 195 births to 176 women; the secondary gender ratio was 50% male and 50% female. The same trend was observed for singletons and twin gestations.

induced ovulation induction are at any greater risk of malformations than the general population (Table 9–9).

Spontaneous Conception After Gonadotropin Therapy

Controlled ovarian hyperstimulation (COH) is the intentional induction of multiple ovulation to increase the number of eggs ovulated in an otherwise normally ovulating woman. COH is often carried out with intrauterine insemination (IUI) with washed sperm. Sperm washing allows selection of sperm with the most normal morphology and motility and with the absence of antibodies, white blood cells, and infectious organisms. IUI avoids cervical problems such as poor mucus, cervical antibodies, and infection. The rationale for COH/IUI is that the IVF pregnancy rate varies as the number of embryos transferred are increased, and the IVF fertilization rate varies with the number of sperm present; therefore increasing the number of eggs and the number of sperm creates a possible improvement in the number of sperm at the fertilization site and sperm capacitation. Follicular endocrine function and oocyte release may be affected; and tubal oocyte capture, secretory function, and transport may be improved. Endometrial receptivity may also be improved because of increased estrogen and progesterone levels. Placing a large number of sperm close to a large number of eggs empirically results in higher pregnancy rates.

Few studies have reported on spontaneous pregnancy rates after gonadotropin-induced pregnancies. Gonadotropin treatment does not cure the patient permanently of her ovulatory disorder. A larger series reported by Ben-Rafael et al. showed that among 141 women who had previously conceived using gonadotropin therapy the cumulative spontaneous pregnancy rate was 30.4% after 5 years. The miscarriage rate was 29.0% in gonadotropin-induced pregnancy, whereas the subsequent pregnancy enjoyed a miscarriage rate of 8.8%. The cumulative pregnancy rate of 30.4% was much lower than that in a group of normal parous women. Another study, by Lam et al., indicated a much lower spontaneous conception rate of 66.4% at 115 months when compared to the 88.6% at 23 months during the first course of gonadotropin therapy. They concluded that women receiving gonadotropin therapy have an 11-fold better chance of conceiving in a given cycle. The baseline estrogen and FSH levels, diagnosis, previous result of gonadotropin therapy, age, and menstrual pattern did not affect their fertility potential. This contrasted with Ben-Rafael et al.’s study, which found a lower cumulative spontaneous pregnancy rate in patients with low baseline gonadotropin and estrogen levels.

Congenital Anomalies The clinical data available in the literature do not indicate that babies born as a result of gonadotropin-

Controlled Ovarian Hyperstimulation and Intrauterine Insemination Mechanism of Action

Indications and Contraindications The COH/IUI option is indicated in women with unexplained infertility, prolonged subinfertility, cervical factor infertility, or stage I or II endometriosis and in women with two ovaries and one

TABLE 9–9. Congenital Anomalies After Gonadotropin-Induced Conceptions Study Thomspon et al. Schwartz et al. Hack et al. Spadoni et al. March Total

Infants (no.)

Anomalies (no.)

358 211 115 36 63 783

Source: Modified from March CM. Clin Obstet Gynecol 1984;27:966–974.

5 2 4 2 1 14

(1.4%) (0.9%) (3.1%) (5.5%) (1.6%) (1.8%)

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TABLE 9–10. Candidates for Controlled Ovarian Hyperstimulation/Intrauterine Insemination Unexplained infertility Minimal endometriosis Immunologic infertility Luteal phase defects Oligoasthenospermia Cervical factor infertility

fallopian tube (Table 9–10). Contraindications for COH/IUI include ovarian failure, significant presence of male factor, significant tubal adhesions or tubal dysfunction, or significant uterine abnormalities. Intrauterine insemination is not necessary for insemination of normal women with normal semen, but it has been shown to be definitely effective for insemination of normal women with cryopreserved semen. It is probably effective for cervical factor infertility, men with semen anti-sperm antibodies or retrograde ejaculation, and as an adjunct to superovulation. It is probably not effective for male factor infertility.

Administration Patients may be treated with gonadotropins, as described. Ovarian stimulation to induce superovulation is carried out in a fashion similar to that in women with ovulatory dysfunction. IUI is performed 36 hours after hCG is given.

Sperm Preparation Fresh Semen The method for sperm selection and separation for the placement of sperm directly into the uterus is left to the discretion of the clinician or andrologist. The preparation yielding the largest population of highly motile cells free of other cellular and chemical components of the seminal plasma is preferred. The choice of technique is based on the initial quality of the sample. The most commonly used methods are the standard swim-up and density gradient preparations. The swim-up (SU) procedure separates the motile sperm from other components of the ejaculate by allowing the sperm to swim up and out of the ejaculate. Recovery of motile sperm is usually poor with the SU method, and therefore only samples of low viscosity and with a high concentration/ large percentage of motile sperm should be used (Appendix A).

The density gradient technique employs solutions of high molecular weight, inert compounds that establish a density gradient through which the semen contents are centrifuged. The gradient is constructed in a way that allows most of the morphologically normal sperm to sediment to the bottom of the tube, whereas the abnormal forms, nonsperm cells, and cellular debris float in the upper parts of the gradient. Sperm recovery is usually much better with this technique. (Figure 9–4). Another, less desirable technique is direct sperm washing (SW). SW is a common method used in many physicians’ offices, as it is simple and can be performed in a minimum amount of time; however, it offers no improvement of sample motility and permits contamination of the uterus with extracellular material and nonsperm cells. Sperm washing should be used only when the semen sample is relatively clear of debris, bacteria, and round cells or where there are so few motile cells that any other separation technique would harm the sample. See Appendix A for a complete description of each technique.

Frozen Sperm The use of frozen semen for IUI is relatively common for a variety of infertility diagnoses. It is highly successful in initiating pregnancy among the normal female population, and inseminations are commonly performed one of two ways: intracervical (ICI) or intrauterine (IUI). Frozen sperm is purchased by the patient from any of the approved cryobanks. Thawing procedures are recommended by the supplier and must be followed to not jeopardize any warranties provided in the purchase.

FIGURE 9–4. Sperm prep for IUI by density gradient centrifugation.

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Intracervical inseminations with frozen sperm are the simplest and in most cases do not require extensive laboratory preparation other than thawing. Refer to the procedure by the respective supplier. The IUI procedure involves more detailed processing aimed chiefly at creating a clean sample free from any proteins or seminal fluids. IUIs require the sperm to be deposited directly into the uterine cavity, eliminating cell selection by cervical mucus. The procedure requires use of a clean sample. Many cryoprotectants and seminal fluid components create severe cramping when put into the uterus and are extremely painful to the woman. Some suppliers provide samples prepared and labeled for direct IUI use. Further processing is not necessary and would void any guarantee. Andrologists must identify the sperm supplier and use the recommended thawing protocol. The protocol described in Appendix B is to be used as additional processing to prepare an intravaginal or intracervical frozen specimen for IUI use.

Results There is a wide range of success reported: cycle fecundity after clomiphene citrate/IUI, increasing from 25% to 100% and after gonadotropins increasing from 50% to 300%. Cycle fecundity may range from 4% per cycle with male factor infertility to 25–30% per cycle for minimal endometriosis in women less than 30 years of age. Multiple pregnancies with approximately 25% twins, 5% triplets, and 2% quadruplets occur, which is similar to the results of ovulation induction without IUI. Ectopic pregnancy occurs in up to 5–10% of patients. Most of the pregnancies occur within two to four cycles of treatment. Birth defects are the same as those in the general population. Recently, a trial of controlled superovulation with gonadotropins/hCG in combination with IUI has been advocated for couples with unexplained infertility. Pregnancy rates comparable to gamete intrafollicular transfer (GIFT) have been reported. We have used a similar protocol for couples who completed the evaluation and have a diagnosis of unexplained infertility. We attempt controlled superovulation combined with IUI therapy prior to in vitro fertilization (IVF) and in couples previously demonstrating successful fertilization during IVF therapies who did not become pregnant.

Side Effects and Complications Side effects and complications of COH/IUI are the same as those seen with gonadotropin therapy in

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non-IUI cycles. Concerns have also been raised about the possible production of anti-sperm antibodies, although data do not conclusively demonstrate any clinically significant problems with this procedure.

Ongoing Management Generally, three or four cycles of COH/IUI are clinically appropriate. A maximum number is four cycles of hMG/IUI in selected patients. Some controversy exists as to the optimal number of inseminations per cycle. Data generally support one well timed IUI when adequate numbers of sperm are present. In addition, at least 3 million total motile sperm should be available for IUI. Any number lower than this results in lower pregnancy rates. Pregnancy rates increase slightly with 5 million total motile sperm per inseminate and increase only minimally with more than 5 million total motile sperm per inseminate. Pregnancy rates that approach the fecundity of normal women and that equal or exceed the pregnancy rates reported for IVF and GIFT have been reported. If the rationale for GIFT is delivery of increased numbers of gametes at the site of fertilization in normal fallopian tubes, the combination of gonadotropin/hCG superovulation and IUI can accomplish that goal without the expense and risk of operative intervention. Cycle fecundities of 0.17 for endometriosis, 0.29 for cervical factor, and 0.19 for idiopathic infertility have been reported and seem to justify the expense and risks of COH/IUI. The major criticism of that study was that it was an uncontrolled, retrospective analysis. Prospective, controlled comparisons of IVF, GIFT, and superovulation with IUI are still lacking. Nonetheless, the data suggest that the provision of multiple gametes and correction of subtle ovulatory dysfunction may be the mechanism(s) of the improved fertilization and pregnancy rates.

Suggested Reading Ben-Rafael Z, Dor J, Mashiach S, et al. Abortion rate in pregnancies following ovulation induced by human menopausal gonadotropin/human chorionic gonadotropin. Fertil Steril 1983;39:157–161. Ben-Rafael Z, Mashiach S, Oelsner G, et al. Spontaneous pregnancy and its outcome after human menopausal gonadotropin/human chorionic gonadotropin-induced pregnancy. Fertil Steril 1981;36:560–564. Ben-Rafael Z, Matalon A, Blankstein J, et al. Male to female ratio after gonadotropin-induced ovulation. Fertil Steril 1986;45:36–40. Bettendorf G, Braendle W, Sprotte C, et al. Overall

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results of gonadotropin therapy. In: Insler V, Bettendorf G (eds) Advances and Diagnosis in Treatment of Infertility. New York: Elsevier North-Holland, 1981: 21–34. Blankstein J, Mashiach S, Lunenfeld B. Induction of ovulation with gonadotropins. In: Ovulation Induction and In Vitro Fertilization. Chicago: Year Book, 1986:131–154. Blankstein J, Shalev J, Saadon T, et al. Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil Steril 1987;47: 597–602. Corsan GH, Kemmann E. The role of superovulation with menotropins in ovulatory infertility: a review. Fertil Steril 1991;55:468–477. Couzinet B, Lestrat N, Brailly S, et al. Stimulation of ovarian follicular maturation with pure follicle-stimulating hormone in women with gonadotropin deficiency. J Clin Endocrinol Metab 1988;66:552–556. Dickey RP, Olar TT, Taylor SN, et al. Relationship of biochemical pregnancy to preovulatory endometrial thickness and pattern in patients undergoing ovulation induction. Hum Reprod 1993;7:418–421. Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991;55:457–467. Fleischer AC, Pittaway DE, Beard LA, et al. Sonographic depiction of endometrial changes occurring with ovulation induction. J Ultrasound Med 1984;3:341–346. Friedler S, Schenker JG, Herman A, et al. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod Update 1996;2:323–335. Gemzell C. Induction of ovulation with human gonadotropins. Recent Prog Horm Res 1965;21:179–197. Gemzell CA, Diczfalusy E, Tillinger KG. Clinical effect of human pituitary follicle stimulating hormone (FSH). J Clin Endocrinol Metab 1958;18:1333–1348.

Insler V, Melmed H, Mashiach S, et al. A functional classification of patients selected for gonadotropic therapy. Obstet Gynecol 1968;32:620–626. Jones KP, Ravnikar VA, Schiff I. Results of human menopausal gonadotropin therapy at the Boston Hospital for Women (1979–1981). Int J Fertil 1987;32:131–134. Kurachi K, Aono T, Suzuki M. Results of gonadotropinshCG therapy in 1096 treatment cycles of 2166 Japanese women with anovulatory infertility. Eur J Obstet Gynecol Reprod Biol 1985;19:43–52. Lam SY, Baker G, Pepperell R, et al. Treatment-independent pregnancies after cessation of gonadotropin ovulation induction in women with oligomenorrhea and anovulatory menses. Fertil Steril 1988;50:26– 30. Lunenfeld B, Insler V. Gonadotropins. In: Diagnosis and treatment of functional infertility. Berlin: Grosse Verlag, 1978:76–89. March CM, Davajan V, Mishell DR Jr. Ovulation induction in amenorrheic women. Obstet Gynecol 1979;53: 8–11. Out HJ, Mannaerts BM, Driessen SG, et al. Recombinant follicle stimulating hormone (rFSH; Puregon) in assisted reproduction: more oocytes, more pregnancies; results from five comparative studies. Hum Reprod 1996;2:162–171. Seibel MM, McArdle CR, Thompson IF, et al. The role of ultrasound in ovulation induction: a critical appraisal. Fertil Steril 1981;36:573–577. Shoham Z, Insler V. Recombinant technique and gonadotropins production: new era in reproductive medicine. Fertil Steril 1996;66:187–201. Silverberg KM. Ovulation induction in the ovulatory woman. Semin Repro Endocrinol 1996;14:339–344. Tricomi V, Ferrd M, Solish G. The ratio of male and female embryo as determined by the sex chromosome. Am J Obstet Gynecol 1960;75:504–509.

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Appendix A: Techniques Modified Swim-Up Technique The swim-up procedure is used to separate motile sperm from nonmotile sperm and extracellular debris. It is particularly useful and the preferred method for separating samples that have large amounts of gelatinous material or debris and otherwise normal parameters. The swim-up procedure is performed for one of two purposes. The first, for diagnostic reasons, is to evaluate the recovery of a motile population from a given sample. It is important to have an estimate of the expected yield from a sample for intrauterine insemination (IUI) purposes. The second purpose is to harvest a population of highly motile cells for use in a therapeutic IUI. When a separation is performed for immediate patient use the sample must be aseptically prepared. There are many acceptable methods used to perform a swim-up in the andrology community; all yield comparable results. The sample can be processed on the benchtop at room temperature or in a 37°C incubator. Other variations include use of a sodium bicarbonate-buffered medium and incubation at 37°C in a 5% CO2 atmosphere.

Materials 1. Sterile 5 ml round bottom tubes: Falcon No. 2001. 2. Sterile disposable transfer pipettes (Coning Scientific Corporation, 1050 Arroyo Avenue, San Fernando, CA 91340-1822; distributed by Baxter Scientific, cat. no. 222-105). 3. Pipettors. 4. Disposable pipette tips. 5. Sterile pasteur pipettes and clean bulbs. 6. Makler chamber. 7. Sperm washing medium (manufactured and distributed by Irvine Scientific, Santa Ana, CA, 92705, cat. no. 9983).

Procedure 1. Perform a semen analysis. Record the volume, concentration, motility, progressive motility, normal morphology, viscosity, liquefaction, and debris. 2. “Wet” the bottom and sides of several sterile 5 ml round-bottom tubes. 3. Add 0.25–0.50 ml of the liquefied semen to each of the tubes. 4. Layer 1.0–1.5 ml of modified human tubal fluid (MHTF) on top of the semen. Tightly cap the tubes.

5. Place in a 37°C incubator and incubate 45–60 minutes. 6. Remove as much of the supernatant as possible while leaving the semen–media interface intact. 7. Pool the supernatants into one or two 5-ml sterile test tubes. 8. Centrifuge at 600g for 5 minutes. 9. Resuspend the pellet to 0.3–0.5 ml with MHTF. 10. Record the concentration, motility, progressive motility, and incubation time used. Compute and record the concentration of motile sperm and total number of motile sperm. 11. Transport sperm and data to the clinician for the IUI.

Density Gradient Centrifugation Technique Density gradient preparation of sperm for IUI takes advantage of the natural buoyant density properties of sperm. The gradient described below is designed to allow the morphologically normal sperm to migrate to the bottom of the tube, and the abnormal forms and nonsperm cells “float” in the upper parts of the gradients. The major advantage of this type of preparation is that it yields a high concentration of morphologically normal, motile sperm for the insemination.

Materials 1. PureSperm (manufactured by NidaCon International AB, Gothenburg, Sweden; distributed by genX International 170 Fort Path Road, Madison, CT 06433, cat no. PS0250). 2. Sperm washing medium (manufactured and distributed by Irvine Scientific, Santa Ana, CA, 92705, cat. no. 9983). 3. Conical centrifuge tubes (Falcon no. 352099). 4. Sterile disposable transfer pipettes (manufactured by Coning Scientific Corporation, 1050 Arroyo Avenue, San Fernando, CA 91340-1822, distributed by Baxter Scientific, cat. no. 222-105). 5. Sterile 5 ml round-bottom tubes (Falcon no. 2001).

Equipment 1. Clinical centrifuge capable of spinning samples at 600–700g. 2. Makler chamber. 3. Phase-contrast microscope.

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Solutions PureSperm Gradient: gradient dilutions can be stored up to 2 weeks at 4°C. 1. Label three sterile tubes with today’s date and 95% PureSperm, 70% PureSperm, and 40% PureSperm, respectively. 2. To tube labeled 95%, add 9.5 ml of stock PureSperm and 0.5 ml of sperm wash medium. 3. To tube labeled 70%, add 7.0 ml of stock PureSperm and 3.0 ml of sperm wash medium. 4. To tube labeled 40%, add 4.0 ml of stock PureSperm and 6.0 ml of sperm wash medium. 5. Label two sterile conical centrifuge tubes with the patient’s name. Rinse the tubes with 2–3 ml of sperm wash medium. Gently add 0.5 ml of 95% PureSperm to the bottom of the tube. Next gently layer 0.5 ml of 70% PureSperm on top of the 95% layer. Follow with layering 0.5 ml of the 40% PureSperm.

Procedure 1. Perform semen analysis as per the standard protocol. Record the results. 2. Layer up to 2–3 ml of liquefied semen to each of the gradient tubes. (Split the ejaculate as evenly as possible so you can use the tubes as each other’s counterbalance.) 3. Centrifuge the tubes at 600–700g for 20–25 minutes. 4. Using a sterile Pasteur pipette or other narrow sterile pipette (i.e., 1 ml serologic), remove the pellet and transfer to a labeled sterile 5 ml round-bottom tube. 5. Dilute the pellet with 3 ml of sperm wash medium and thoroughly suspend. 7. Centrifuge at 600g for 5 minutes. 8. Carefully remove the supernatants and resuspend the pellet in 3 ml of sperm wash medium. 9. Centrifuge at 600g for 5 minutes. 10. Carefully remove the supernatant and resuspend the pellet in 0.3–0.5 ml of sperm wash medium. 11. Aseptically remove 0.005 ml of sperm suspension and place it on a Makler chamber.

12. Determine cell count, motility, and progression. Record the results. 13. Take the sperm suspension and all appropriate documentation to the clinician for the IUI.

Sperm Wash Materials 1. Sterile 5 ml round-bottom tubes (Falcon no. 2001). 2. Sterile disposable transfer pipettes (manufactured by Coning Scientific Corporation, 1050 Arroyo Avenue, San Fernando, CA 91340-1822; distributed by Baxter Scientific, cat. no. 222105). 3. Pipettors. 4. Disposable pipette tips. 5. Sterile pasteur pipettes and clean bulbs. 6. Makler chamber. 7. Sperm washing medium (manufactured and distributed by Irvine Scientific, Santa Ana, CA, 92705, cat. no. 9983).

Procedure 1. Perform the semen analysis as per the standard procedure. Record volume, concentration, motility, progressive motility, abnormal morphology, viscosity, liquefaction, and debris. 2. Aliquot 2.5 ml of ejaculate into a clean 5.0 ml tube. Repeat as necessary until the entire ejaculate is aliquotted. 3. Aliquot 2.5 ml of medium into each tube and mix thoroughly. 4. Centrifuge at 200g for a minimum of 5 minutes. 5. Aspirate supernatant and resuspend pellet in 0.5 ml medium. 6. Pool all resuspended pellets into a single tube and make up the volume to 4.5 ml with clean medium. 7. Repeat steps 4 and 5. 8. Perform a cell count. Record concentration, motility, progressive motility, and final volume. 9. Transport sperm and data to the clinician for the IUI.

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Appendix B: Preparation of Intravaginal or Intracervical Frozen Specimen for IUI Materials 1. Frozen semen. 2. Sterile 5 ml round-bottom tubes (Falcon no. 2001). 3. Sterile disposable transfer pipettes (manufactured by Coning Scientific Corporation, 1050 Arroyo Avenue, San Fernando, CA 91340-1822; distributed by Baxter Scientific, cat. no. 222105). 4. Pipettors. 5. Disposable pipette tips. 6. Sterile Pasteur pipettes and clean bulbs. 7. Makler chamber. 8. Sperm washing medium (manufactured and distributed by Irvine Scientific, Santa Ana, CA 92705, cat. no. 9983).

Procedure 1. Begin thawing approximately 1.5–1.0 hour before the sample is needed for use. 2. Check the inventory books and tank to verify the correct sample and the storage location. Note the total number of samples remaining for this patient. 3. Thaw the sample as directed by the appropriate supplier.

4. Perform a semen analysis. Record volume, concentration, motility, progression, and abnormal morphology. Record viscosity, liquefaction, and debris as “NA.” 5. Maintain sterile technique for the duration of the IUI preparation. Gently pipette the thawed sample from the cryo-vial into a 5 ml test tube labeled with the sperm and patient’s identity. 6. Using the same pipette, add medium one drop at a time, shaking between additions to slowly change the osmolality of the sperm solution. Adding medium too quickly results in lysis of the sperm cells. 7. Continue adding medium dropwise until the volume has tripled. 8. Cap the tube tightly and centrifuge at 300g (half-speed) for 5 minutes. 9. Aspirate supernatant and discard. Resuspend pellet in 4.0 ml of clean medium and repeat step 8. 10. Aspirate supernatant and discard. Resuspend pellet in 0.5 ml of clean medium. 11. Perform a final count. Report volume, concentration, motility, and progressive motility. Compute and record concentration of motile sperm and number of motile sperm. 12. Load the insemination catheter.

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10 Diagnostic and Therapeutic Hysteroscopy in the Office David A. Grainger, Bruce L. Tjaden, and Arjav Shah

The clinical presentation of gynecologic patients often mandates evaluation of the uterine cavity. Symptoms requiring evaluation include menorrhagia, intermenstrual bleeding, postmenopausal bleeding, and infertility, particularly those preparing for in vitro fertilization (IVF). Techniques for uterine evaluation include endometrial biopsy, vaginal ultrasonography, sonohysterography, hysterosalpingography, and hysteroscopy. Dating back to its introduction by Bazzini during the early 1800s, hysteroscopic evaluation has added to the elucidation of uterine factors for infertility, which may account for 10–15% of cases.1,2 Infertility is defined as 1 year of unprotected intercourse without conception. It is estimated that 10–15% of couples at reproductive age are infertile (Table 10–1).3 Uterine factors, which include structural and developmental defects (müllerian anomalies) account for 10% of infertility cases (Table 10–2).4,5 Hysterosalpingography (HSG) has been the time-honored modality for uterine evaluation. The procedure has diagnostic limitations, however, and is not useful as a treatment modality. Nonetheless, HSG remains a useful tool with relatively high sensitivity and specificity. Indeed, recent publications have confirmed the continuing value of HSG. Sonohysterography (sonoHG, sometimes termed hysterosonography) has been developed and may play a significant role in the evaluation of the uterine cavity.6 Hysteroscopy does not necessarily replace HSG or sonoHG but, rather, augments these modalities. The major advantage of hysteroscopy is direct visualization of the uterine cavity. Most importantly, hysteroscopy—and with advances in equipment, office hysteroscopy—can be utilized to diagnose and treat intrauterine lesions at a single session. 116

Traditionally, hysteroscopy has been a hospital or outpatient surgery center procedure, usually necessitating a major anesthetic (general anesthesia or regional block). With the advent of better optics smaller instrumentation became available, reducing the need for major anesthesia; officebased hysteroscopy became a reality. Publications have confirmed the safety, efficacy, and utility of office-based hysteroscopy.7,8 This chapter focuses on the use of in-office hysteroscopy for diagnostic and therapeutic purposes in the management of infertility patients. Indications for office hysteroscopy are reviewed, as are techniques for performing this procedure. We review also some emerging technology that will provide new options for the clinician in his or her office. Lastly, economic considerations for the clinician regarding the cost of equipment (capitalization) versus potential economic benefit are explored.

Indications The indications for hysteroscopy are listed in Table 10–3. Endometrial curettage has been the standard procedure for evaluating the endometrial cavity

TABLE 10–1. Causes of Infertility Cause of Infertility Male Female Ovulatory dysfunction Tubal Uterine Cervical Unexplained

% 40–45 40–50 40–45 40–45 10–20 1–2 5–10

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10. Diagnostic and Therapeutic Hysteroscopy in the Office TABLE 10–2. Uterine Factors as a Cause of Infertility Study

%

Rock DeCherney Diamond

5 7 4

Source: Li and Cook4 and Rock and Murphy.5

(specifically, endometrial histology) for many years. Several studies have demonstrated the inadequacies of dilatation and curettage (D&C), including inadequate sampling, missed lesions (including large polyps), and, most concerning, missed diagnosis of endometrial carcinoma.9,10 Hysteroscopy offers the distinct advantage of direct visualization and directed sampling (biopsy). Loeffer has demonstrated the value of negative hysteroscopic results in women with abnormal bleeding. With a normal hysteroscopic evaluation, he (and others) have shown that histologic evaluation is abnormal in fewer than 3% of patients.10,11

Intrauterine Masses Endometrial polyps are occasionally suspected on sonography and can usually be confirmed by HSG or sonoHG. The diagnosis can be confirmed and a definitive diagnosis established with hysteroscopy. (This is just one example of the complementary nature of HSG or sonoHG and hysteroscopy.) Pathophysiologic characteristics of these polyps include their origination as a focal hyperplastic process of the basalis, which develops into a benign overgrowth of endometrial tissue containing glands, stroma, and vasculature. The estimated prevalence of endometrial polyps in the general population is 2–4%.12 For some patients polyps are a source of infertility, presumably acting as an intrauterine device (IUD). Many of these patients present with abnormal uterine bleeding in addition to infertility.

TABLE 10–3. Indications for Hysteroscopy Abnormal uterine bleeding Menorrhagia Intracycle bleeding Postmenopausal bleeding Intrauterine mass(es) Asherman syndrome “Lost” intrauterine device (IUD) Foreign object Abnormal hysterosalpingography (HSG) or sonohysterography (sonoHG) Before artificial reproductive therapy (pre-ART)

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The occurrence of carcinoma in seemingly benign polyps is reported to be less than 0.5%.13 Even though some polyps can be removed with blind curettage, many are missed during the process because of their mobility. Polyps are often morphologically described as broad-based and sessile, pedunculated, or attached to endometrium by a slender stalk. Clinical implications lie with categorization of polyps into one of three broad areas: hyperplastic, atrophic, or functional. Hyperplastic polyps often populate the endometrial cavity diffusely. Malignant tumors are more likely to develop from these polyps secondary to their source (the baseline), which is much less responsive to progesterone than estrogen. Atrophic polyps are found in postmenopausal patients and may represent the process of regressive changes in a hyperplastic or functional polyp. Functional polyps resemble the surrounding endometrium in that they respond to hormonal changes during the menstrual cycle. Virtually any size polyp can be removed in the office.14 Scissors or cautery are utilized to incise the attachment of the polyp from the uterine wall. Large broad-based sessile polyps may require follow-up treatment in the operating room with the resectoscope. The polyps are excised under direct visualization. Functional polyps are identified as those with a lining identical to the surrounding endometrium. Nonfunctional polyps are noted to be white protuberances that are covered with branching surface vessels. All removed polyps should be sent to the pathology laboratory for histologic evaluation. Approximately 20% of uteri removed for endometrial carcinoma have additional pathology, including benign polyps.14 Leiomyomas of the uterus are the most common uterine neoplasms. In hysterectomy specimens, 75% of uteri have histologic evidence of leiomyoma.15 They are more common in black women than white women. Myomas arise often during the third and fourth decade, thus affecting reproductive performance. Myomas arise from the myometrium and are thought to be a clonal tumor. Indeed, approximately 60% of uterine fibroids are karyotypically abnormal.16,17 These tumors shrink with gonadotropin-releasing hormone (GnRH) analogue treatment but generally return to their pretreatment size within 3 months of discontinuing the therapy.18 Submucous fibroids tend to cause problems with abnormal bleeding or early pregnancy loss(es); large myomas may cause pressure symptoms or obstruction of labor, or they may inhibit palpation of adnexal structures.19 Myomas are classified by their location: subserosal, intramural, submucosal, or pedunculated (into the uterine or peritoneal cav-

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ities). Treatment for leiomyomas is indicated if they are symptomatic, interfere with fertility, enlarge rapidly, or pose diagnostic problems. The definitive diagnosis of submucosal leiomyoma is made by hysteroscopy and excisional biopsy. They appear as white spherical masses covered with a fragile, thin-walled vasculature. Myomas can be sessile or pedunculated. Hysteroscopic resection of myomas is often relatively simple when the tumor diameter is less than 2 cm.14 For larger submucous fibroids, pretreatment with GnRH analogues should be considered. Maximal shrinkage occurs after 3 months of therapy.18 This therapy results in a decrease in size and may also decrease the bleeding by reducing the vasculature of the tumor.

Müllerian Anomalies Congenital abnormalities of the uterus are uncommon and appear to be transmitted by a polygenic or multifactorial pattern of inheritance. Based on retrospective studies, the incidence of these abnormalities appears to be 2–3%. Uterine anomalies are found in 4% of infertile women and in 10–15% of women with recurrent abortion.20 Spontaneous abortion and obstetric complications such as premature labor and abnormal fetal presentation are the most common reproductive symptoms in patients with uterine anomalies.21 Uterine defects are not a proven primary cause of infertility, and most authors agree that müllerian anomalies are more commonly associated with pregnancy wastage (Table 10–4). The septate uterus is the most common uterine abnormality (30%) associated with recurrent early spontaneous abortion.22 The septum is a product of the persistence of the fused müllerian ducts with failure of resorption of the intervening wall. Hysteroscopic metroplasty has been the mainstay of therapy for the uterine septum. Though originally described as a procedure necessitating laparotomy, metroplasty is now most commonly done via hysteroscopy. Hysteroscopic metroplasty has traditionally been performed in a minor surgery set-

TABLE 10–4. Müllerian Anomalies Associated with Poor Reproductive Performance Septate uterus Unicoruate uterus Bicornuate uterus Uterine didelphys

ting, often with laparoscopic visualization to establish the diagnosis (septate uterus versus bicornuate uterus). Using imaging techniques such as magnetic resonance imaging, laparoscopy may not be required to confirm the diagnosis. Furthermore, many hysteroscopic surgeons are comfortable treating the known uterine septum without laparoscopic visualization. Thus the procedure is amenable to use in an office setting with proper instrumentation. Pregnancy outcomes appear to be quite good for patients with recurrent pregnancy loss secondary to a uterine septum after metroplasty (85% pregnant with a 75% delivery rate). It is less clear what relation a uterine septum may have with infertility.23 Treatment with estrogens after resection of the septum may help with reepithelialization of the raw surfaces of the endometrial cavity. Additionally, an intrauterine balloon or IUD may be left in the uterine cavity to help reduce the chance of intrauterine adhesions. The transcervical approach, whether in the operating room or the office, is less invasive and avoids the risk of pelvic adhesions associated with abdominal procedures.

Asherman Syndrome Intrauterine synechiae (Asherman syndrome) most commonly develop after curettage is performed during the postpartum or postabortal period. The concurrent presence of an intrauterine infection raises the probability of synechia formation. The clinical presentation may consist of hypomenorrhea or amenorrhea and infertility. The diagnosis is made by HSG or hysteroscopy. Hysteroscopic examination reveals bands of fibrous tissue or smooth muscle, without significant inflammation, that traverse the endometrial cavity. The treatment lies in identifying the adhesions and dividing them with scissors or cautery. The office setting often is utilized for dividing central synechiae, which do not need to be excised, just divided.14 Lateral and diffuse adhesions are probably best lysed in the operating room with concomitant laparoscopic guidance. Upon restoration of normal intrauterine anatomy, or IUD or a pediatric Foley catheter is generally placed in the uterine cavity. The catheter is removed in 7–10 days; the IUD may be left in for 1–3 months. Patients are placed on conjugated estrogen (1.25 mg per day) for 1 month. Hysterography or office hysteroscopy can be done for follow-up within 1–3 months of surgery. Reproductive outcomes are related to the extent of preoperative endometrial damage and are summarized in Table 10–5.24–29

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TABLE 10–5. Reproductive Outcomes Following Treatment of Intrauterine Adhesions No. of pregnancies/study population Study March24 Valle25 Lancet26 Caspi27 Oelsner28 Total

Pretreatment

Posttreatment

14/84 8/266 189/484 40/122 9/57 260/1013 (25.7%)

33/38 85/95 77/113 28/33 14/20 237/299 (79.3%)

Other Indications Retrieval of an IUD often can be attempted using the office hysteroscope prior to obtaining radiographic imaging. Transvaginal ultrasonography can be utilized to identify the location of the device in the endometrial cavity that is not readily found on palpation with a uterine sound. If the IUD has partially perforated the abdominal cavity, hysteroscopic removal with concurrent laparoscopy may provide the safest means.30 Postpartum or postabortal bleeding may be a result of retained products of conception. Such persistent bleeding can be evaluated and treated by hysteroscopy-guided removal of the retained products. After completion of the procedure, antibiotic therapy is generally recommended.

Hysteroscopy Prior to In Vitro Fertilization Detectable uterine abnormalities have been noted in up to 45% of the patients undergoing IVF.31 These abnormalities include endometrial polyps, submucous leiomyomas, uterine malformations, and cervical stenosis. Shamma et al. studied patients who underwent office hysteroscopy under paracervical block prior to IVF.32 Twenty-eight

patients were studied, all having had normal HSGs prior to enrollment. Twelve patients (43%) had abnormal hysteroscopic findings, including small uterine septa, small submucous fibroids, uterine hypoplasia, and cervical ridges. Significant differences in the clinical pregnancy rates were found in patients with abnormal and normal findings by hysteroscopy (8.3% vs. 37.5%). The above indications for office hysteroscopy deal with correcting abnormalities of the cavity in an attempt to improve pregnancy outcomes. Indications for office hysteroscopy for patients attempting conception who have a normal cavity include transcervical transfer of gametes or embryos. One review summarized the experience with hysteroscopic replacement of gametes and embryos.31 Overall, the pregnancy rates from these procedures do not appear to offer any advantage to ultrasoundguided transfers and are comparable to the pregnancy rates after transcervical intrauterine embryo transfer (see Table 10–6).

Contraindications In concordance with the relative safety and ease of office hysteroscopy, absolute contraindications are cervical carcinoma, acute pelvic infection, and pregnancy. If pelvic infection occurs with an unretrievable IUD, office hysteroscopy may be per-

TABLE 10–6. Outcome of Transcervical GIFT Using Hysteroscopy or Ultrasonography Outcome Procedure Ultrasound-guided Hysteroscopy SART; IVF in 1994

Cycles (no.)

Pregnancy

Ectopic

173 131 31,000

36 (20.1%) 25 (19%) 21%

2 (6%) NR 4%

GIFT, gamete intrafollopian transfer; SART, Society for Assisted Reproductive Technology; IVF, in vitro fertilization.

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formed to remove the device. The patient would then undergo an antibiotic regimen to complete the treatment for pelvic infection. Relative contraindications include extensive intrauterine adhesions, leiomyomas larger than 2 cm, severe medical disorders (diabetes, asthma, blood dyscrasias), and excessive uterine bleeding (restricting the hysteroscopic view).14 Gestations with an IUD in place can be managed by hysteroscopic removal of the device.

Equipment The uterine cavity is a potential space and must be distended to allow complete visualization for adequate diagnosis and treatment. Optical systems must provide adequate light and resolution, and there must be a means of delivering energy to the areas requiring therapy (mechanical energy, thermal energy, laser energy). We discuss each of these three areas separately as they apply to office hysteroscopy.

Distension of the Cavity Carbon dioxide gas has been used most commonly to distend the uterine cavity in an office setting. The insufflators are relatively inexpensive, use low rates of flow, and are easy to maintain. Visualization using CO2 is excellent and for strictly diagnostic purposes provides an adequate means of distending the cavity. CO2 is rapidly absorbed into the bloodstream and cleared by the lungs. There are several disadvantages. The CO2 often leaks around the hysteroscope, making distension of the cavity difficult. Furthermore, it is inadequate for operative procedures as it tends to form bubbles when mixed with blood. Care must be taken to use only insufflators specifically designed for hysteroscopy for CO2 delivery. Laparoscopic insufflators are designed for high flow rates, and deaths have been reported using laparoscopic insufflators for hysteroscopy (high flow, leading to CO2 embolism). Fluid distension media include high-molecularweight dextran (Hyskon), electrolyte solutions, and non-ionic solutions (sorbitol, mannitol, glycine). Hyskon is used relatively infrequently for several reasons. It is messy, with a consistency of syrup, and if not cleaned from instruments quickly results in immobilization of moving parts. It provides excellent visualization, particularly if there is any bleeding present. We have found the easiest delivery system to be a 50 cc syringe, intravenous extension tubing, and a strong nurse or medical student. Generally, the amount of Hyskon used should not

exceed 500 ml as there is significant risk of pulmonary edema. Furthermore, rare adverse reactions including anaphylaxis and disseminated intravascular coagulation have been reported. Overall, this medium is unlikely to find a useful place in office hysteroscopy. Low viscosity fluids are easier to use in an office setting. They include ionic fluids (electrolytecontaining, such as normal saline or lactated Ringer’s) and non-ionic fluids (such as sorbitol, mannitol, or glycine). The electrolyte-containing solutions are advantageous in that their absorption, even in relatively large amounts, poses little risk to the patient. However, they cannot be used with traditional monopolar electrosurgery. The non-ionic solutions may be used with monopolar electrosurgery but carry the risk of water intoxication if absorbed in large amounts. Therefore, it is critical that accurate measurements of fluid absorption be maintained throughout the procedure. In the office setting, this is less likely to pose significant problems, as the more difficult and extensive hysteroscopic procedures should be performed in an ambulatory surgery center or in the hospital. Visualization of the endometrial cavity is best accomplished using continuous flow of distension medium. Office hysteroscopes with dual channels for inflow and outflow are readily available and are preferred for both diagnostic and therapeutic use.

Light and Optics: Flexible, Micro, or Rigid Hysteroscopes? Although advances in fiberoptics, light sources, and delivery systems have occurred, it is the authors’ opinion that the visual clarity of rigid hysteroscopic systems remains superior at the present time. Additionally, rigid systems are more adaptable to therapeutic usage. We profile some of the more common systems, including one flexible hysteroscope (Olympus), one microhysteroscope (Imagyn), and one rigid system (Wolf). Many other products are available and are adequate or perhaps superior, but these systems give the reader an idea of what is available currently.

Flexible Hysteroscopy The advantages of a flexible hysterocope is its small size, resulting in improved tolerance by the patient. Most patients do not require anesthesia or cervical dilation. The Olympus hysterofiberscope (Fig. 10–1) provides an ergonomic design and singlehanded control. Minor surgical procedures may be

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Rigid Hysteroscopy

FIGURE 10–1. Microhysteroscope.

performed through this hysteroscope, including directed biopsy or excisional biopsy of small polyps.

Rigid hysteroscopes range from 3 to 5 mm outside diameter and can be configured for continuous flow and operative procedures (Fig. 10–3). The optical resolution with these systems is excellent and approaches or exceeds that of the large resectoscopes utilized in the operating room. The hysteroscopes are generally inserted with no dilation of the cervix; if dilation is required, a paracervical block is used. Operating channels allow introduction of semirigid instruments or bipolar electrodes (Versapoint). The resolution obtained with these instruments, combined with the increased “firepower” obtained by using bipolar technology in physiologic distension media, should add greatly to the therapeutic benefits of office hysteroscopy.

Energy Sources Microhysteroscopy Imagyn Medical (Laguna Niguel, CA) has introduced the MicoSpan hysteroscopy system (Fig. 10–2), which has as an integral component a 1.6 mm offset microhysteroscope with enhanced microoptics. The outside diameter, when used with the sheath, is approximately the size of a Pipelle, yet the fused image fiber and the microoptics provides 150% of the illumination and up to three times the resolution of similar-size hysteroscopes. This system is used in combination with the MicroSpan Sheath, which has an expandable working channel that accepts 2 mm semirigid instruments for biopsy or excision. The sheath also allows continuous flow or distension medium, with controls for inflow and outflow optimizing visualization of the cavity.

Mechanical Energy Mechanical energy in the form of biopsy instruments is the most common application of “energy” in the office. These instruments are small (2 mm)

A

FIGURE 10–2. Flexible hysteroscope appropriate for performing minor surgical procedures including directed biopsy or excisional biopsy of small polyps.

B FIGURE 10–3. A, B. Rigid hysteroscope.

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and semirigid, allowing them to pass down the operating channels of most office hysteroscopes. These instruments can be used to obtain directed biopsies, transect the base of polyps, or cut uterine septa.

Unipolar Energy Generators producing unipolar energy use the patient as a conductor, with the source of energy being the active electrode, and the ground plate being the receiver of the electrons. Thus conductive distension solutions may not be used, as the energy is dissipated in the medium, extinguishing any meaningful tissue interaction. These forms of energy are commonly conducted via electrodes designed to be used for endometrial ablation, resection of large fibroids or polyps, or metroplasty. Non-ionic solutions are used (glycine, sorbitol, mannitol); it is incumbent on the surgeon to maintain accurate measurements of fluid absorption (infused minus recovered). Several devices have been designed to aid in the accurate measurement of fluid absorption. The experienced hysteroscopist recognizes situations in which fluid absorption is likely (bleeding from ablation or resection of fibroids). However, one must always be alert to the problem of excessive fluid absorption, even with seemingly benign cases, as fluid overload with these solutions can have serious sequelae.

Bipolar Energy A new hysteroscopic energy delivery system has been introduced. Traditionally, unipolar energy is utilized through loops, bars, or other types of ablative electrode, which requires the use of non-ionic solutions with the attendant risks of water intoxication and hyponatremia. Versapoint (Gynecare, Menlo Park, CA) is a bipolar electrosurgery system that employs at least three distinct advantages: (1) normal saline may be used as a distension medium; (2) the electrodes are small and pass easily through a 5 mm hysteroscope; and (3) instantaneous tissue vaporization eliminates resection chips (Fig. 10–4). The generator delivers energy to the active electrode, creating a “vapor pocket,” which causes instantaneous cellular rupture upon contact with tissue. This bipolar energy source also provides excellent hemostasis and is useful for treating submucus leiomyoma or endometrial polyps. Versapoint may also be used as an adjunct to endometrial ablation, either traditional rollerball or using

FIGURE 10–4. Bipolar electrosurgery system (Versapoint). (Courtesy of Gynecare)

one of the emerging thermal therapies such as ThermaChoice, shown in Figure 10–5 (Gynecare).

Procedure Timing the Examination Especially for the novice, hysteroscopy is best performed during the early to mid-proliferative phase of the cycle. Bleeding has stopped, but the endometrium has not grown to the point that it obscures the view. With insertion of the hysteroscope, strips of late proliferative or secretory endometrium can be elevated and easily confused with polyps. If therapeutic procedures such as ablations are performed in the office, endometrial preparation with either danazol (Danocrine) or GnRH analogues can provide thinning of the endometrium, allowing excel-

FIGURE 10–5. ThermaChoice system. (Courtesy of Gynecare)

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lent visualization and perhaps more efficacious treatment.

Medications The patient should be given nonsteroidal antiinflammatory drugs (NSAIDs) approximately 30–60 minutes prior to the procedure. Some of these medications are available as rectal suppositories and are effective within 15–30 minutes of administration. The procedure is generally well tolerated with no further medications being given. The occasional patient benefits from a mild sedative or tranquilizer (e.g., the patient who does not tolerate an endometrial biopsy). These medications should also be administered 30–60 minutes prior to the procedure. Most of these procedures are performed without intravenous access; therefore, if any narcotic medications are required, they are usually administered intramuscularly. This situation arises only in rare patients in our experience.

Patient Position The patient is placed in the dorsal lithotomy position, and a bimanual examination is performed to make certain no adnexal tenderness is present and to determine uterine size and position. Ideally, an adjustable electric bed with leg rests is available for patient comfort. As the examinations are brief, it has been our experience that the procedure is well tolerated even with a normal examination table. If video equipment is available, the patient is positioned such that she can view the screen. Involvement of the patient with the ongoing procedure is beneficial for both educational purposes and patient comfort (distraction).

Cervical Preparation After placing a bivalved speculum, the cervix is cleansed with povidone-iodine solution. The bivalved speculum allows for its easy removal after the uterine cavity has been entered with the hysteroscope. Removing the speculum allows more range of motion with the hysteroscope and thus more complete inspection of the cavity.

Paracervical Block The use of a paracervical block is controversial. In general, with small hysteroscopes (3.5–5.0 mm) no cervical dilation is necessary to introduce the instrument. A prospective randomized comparison of paracervical blocks with anesthetic versus no injection revealed no significant difference in pain

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perception scores by the patients.33 This study evaluated 177 women undergoing outpatient hysteroscopy. Paracervical block consisted of 10 cc of 1% mepivacaine hydrochloride solution (87 patients) or no block (90 patients). The pain scores for the treated group were 4.2  2.0 and for the untreated group 5.2  2.1, which were not significantly different. It is probably more important to pretreat patients with nonsteroidal medications 30–60 minutes prior to the procedure. Occasional patients do not tolerate office hysteroscopy (e.g., those who do poorly with an endometrial biopsy may tolerate diagnostic hysteroscopy but probably not do well with therapeutic procedures). Several techniques may be used for a paracervical or intracervical block. We prefer to inject 0.25% bupivicaine into the cervix through a 20-gauge spinal needle, using 5 cc at the 4 and 8 o’clock positions. Bupivicaine has a little longer onset of action but provides longer relief after the procedure.

Insertion of the Hysteroscope The hysteroscope is gently inserted through the external cervical os, and the endocervical canal is inspected. Insufflation medium (CO2 or liquid) is injected, allowing visualization of the cavity, which appears as a dark spot (the location of this “dark spot” depends on the angle of scope and the position of the uterus). The hysteroscope is directed toward this dark spot until the cavity is entered. The flow of medium is adjusted so the cavity is adequately distended. Systematic inspection of the cavity is performed and should include examination of the fundus, anterior and posterior walls, lateral walls, both tubal ostia, and the lower uterine segment. The findings should be recorded on hard copy, which is kept with the patient’s record.

Complications Inadequate Visualization Inadequate visualization is the most common “complication” of hysteroscopy, and the most common cause of inadequate visualization is lack of flow of the distension medium. Increasing the flow rate by raising the bag of medium, increasing pressure on the syringe, or increasing the flow rate on the CO2 insufflator may resolve the problem. If the cervical canal is narrow, it may be gently dilated prior to inserting the hysteroscope. Blood in the cavity, obscuring the view, generally responds to increasing flow rate. If blood continues to obscure the field, high-molecular-weight dextran may be

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used. This medium is immiscible with blood but has the potential complications listed above. If CO2 is used and leakage is occurring at the external cervical os, the tenaculum may be adjusted to narrow the canal. Downward traction on the tenaculum is often useful for the anteverted or retroverted uterus.

Perforation of the Uterus If the hysteroscope advances easily, and the cavity is not visualized, uterine perforation should be suspected and the procedure terminated. Likewise, insufflation of large amounts of distension medium with little return indicates perforation. These perforations are generally midline and require no further therapy. Exceptions include perforation of the uterus with a monopolar or bipolar device, or if there is any suspicion of bowel injury. These patients should undergo a laparoscopic evaluation of the pelvis, with possible laparotomy if indicated.

the procedure. The discussion in this chapter has focused on an office-based system. One should recognize that a state of the art system is expensive ($15,000–$20,000) as it includes light sources, hysteroscopes, video equipment, and hysteroscopic instruments. Additional costs may include bipolar instrumentation, the modality that allows true therapeutic efficacy in the office. It becomes clear that so long as physician reimbursement is unaffected by the site of the procedure (i.e., a traditional feefor-service system), there is no incentive for the capitalization costs. However, in a managed care environment (capitated or global fee), the hospital portion of the expense falls to the physician. This may run $1000–$2000 per procedure. It therefore requires few procedures to justify the expenditure for the equipment. This, combined with the overall patient satisfaction and improvements in technology, may result in more of these procedures being performed in-office.

Infection Infection following hysteroscopy is rare. Careful selection of patients by bimanual examination and careful inspection of the cervical discharge prior to the procedure prevents infectious sequelae. Prophylactic antibiotics should be administered to patients with mitral valve prolapse per recommendations of the American Heart Association.

Bleeding Bleeding following office hysteroscopy is rare. As more therapeutic procedures are performed in an office setting, the risk of bleeding increases. Bleeding can occur from the cervix (laceration from the tenaculum). The cervix should be carefully inspected at the end of the procedure, and if a laceration is present it should be repaired using a figure-of-eight suture. Intracavitary bleeding due to resection of polyps or fibroids, the septum, or after ablation may be controlled by placing a Foley catheter with a 30 cc balloon in the uterus and inflating with 10–30 cc of saline. The catheter acts as both a tamponade and a drain and is left in place for 24 hours. Antibiotic prophylaxis should be provided for patients in whom a catheter is left in the uterus.

Summary Assessing the endometrial cavity is an integral part of the infertility evaluation. Traditionally, it was accomplished using HSG. Although HSG continues to be utilized, along with sonoHG, it appears that hysteroscopy is the most sensitive method for examining the endometrial cavity. Whether the small lesions identified at hysteroscopy that are missed with other evaluations are clinically significant is not known. The advances in optics has allowed much smaller hysteroscopes to be utilized; and combined with advances in energy delivery this has made other diagnostic and therapeutic hysteroscopy feasible. The cost of the equipment (and reimbursement constraints) remains a barrier to more widespread use of this effective therapy. Furthermore, many clinicians are easily frustrated when beginning to use hysteroscopy and abandon the procedure, to the detriment of their patients. Educational efforts directed at both clinicians and third-party payers may increase utilization of this extremely beneficial, cost-effective procedure.

Economic Considerations

Options for the Next Step in the Treatment Algorithm

After recognizing the benefits of hysteroscopy from both a diagnostic and therapeutic viewpoint, the clinician must then decide in which setting to perform

Evaluation of the uterine cavity is an important step in the evaluation of the infertile couple. Office hysteroscopy is a valuable technique that is probably

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more sensitive than HSG or sonoHG in detecting small lesions (for some of which the clinical significance is not well established). The next steps include evaluation of tubal patency and function (HSG or falloposcopy).

References 1. Russell JR. History and development of hysteroscopy. Obstet Gynecol Clin North Am 1988;15: 1–11. 2. Pellicer A. Hysteroscopy in the infertile women. Obstet Gynecol Clin North Am 1988;15:99–105. 3. Mosher WB, Pratt WF. Fecundity and infertility in the United States: incidence and trends. Fertil Steril 1991;56:192–193. 4. Li TC, Cooke ID. Uterine factors in infertility. Curr Opin Obstet Gynecol 1992;4:212–219. 5. Rock JA, Murphy AA. Anatomic abnormalities. Clin Obstet Gynecol 1986;29:886–911. 6. Parsons AK, Lense JJ. Sonohysterography for endometrial abnormalities: preliminary results. J Clin Ultrasound 1993;21:87–95. 7. Valle RF. Future growth and development of hysteroscopy. Obstet Gynecol Clin North Am 1988;15: 111––126. 8. Chambers JT, Chambers SK. Endometrial sampling: When? Where? Why? With What? Clin Obstet Gynecol 1992;35:28–39. 9. Gimpelson RJ, Rappold HO. A comparative study between panoramic hysteroscopy with directed biopsies and dilatation and curettage: a review of 276 cases. Am J Obstet Gynecol 1988;158:489–492. 10. Loeffer FD. Hysteroscopy with selective endometrial sampling compared with D & C for abnormal uterine bleeding: the value of a negative hysteroscopic view. Obstet Gynecol 1989;73:16–20. 11. Fraser IS. Hysteroscopy and laparoscopy in women with menorrhagia. Am J Obstet Gynecol 1990;162: 1264–1269. 12. Van Bogaert LJ. Clinicopathologic findings in endometrial polyps. Obstet Gynecol 1988;71:771–773. 13. Pettersson B, Adami HO, Lindgren A. Endometrial polyps and hyperplasia as risk factors for endometrial carcinoma. Acta Obstet Gynecol Scand 1985; 64:653–659. 14. Gimpleson RJ. Office hysteroscopy. Clin Obstet Gynecol 1992;35:270–281. 15. Cramer SF, Patel D. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:435–438. 16. Fletcher AJ, Morton CC, Pavelka K, Lage JM. Chromosome aberrations in uterine smooth muscle tumors: potential diagnostic relevance of cytogenetic instability. Cancer Res 1990;50:4092–4097. 17. Meloni AM, Surti U, Contento AM, Davare J. Uterine leiomyomas: cytogenetic and histologic profile. Obstet Gynecol 1992;80:209–217. 18. Stewart EA, Friedman AJ. Steroidal treatment of myomas: preoperative and long-term medical therapy. Semin Reprod Endocrinol 1992;10:344–350.

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19. Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology and management. Fertil Steril 1981;36:433–445. 20. Valle RF. Hysteroscopy in the evaluation of female infertility. Am J Obstet Gynecol 1980;137:425–431. 21. Rock JA, Schlaff WD. The obstetrical consequences of utero-vaginal anomalies. Fertil Steril 1985;43: 681–692. 22. Heinonen PK, Saarikoski S, Pystynen P. Reproductive performance of women with uterine anomalies. Acta Obstet Gynecol Scand 1982;61:157–162. 23. Hassiakos DK, Zourlas PA. Transcervical division of uterine septa. Obstet Gynecol Surv 1990;45:165– 173. 24. March CM, Israel R. Gestational outcome following hysteroscopic lysis of adhesions. Fertil Steril 1981; 36:455–459. 25. Valle RF, Sciarra JJ. Intrauterine adhesions: classification, treatment and reproductive outcome. Am J Obstet Gynecol 1988;158:1459–1470. 26. Lancet M, Kessler I. A review of Ashermans syndrome, and results of modern treatment. Int J Fertil 1988;33:14–24. 27. Caspi E, Peripinal S. Reproductive performance after treatment of intrauterine adhesions. Int J Fertil 1975; 20:249–252. 28. Oelsner G, David A, Insler V, et al. Outcome of pregnancy after treatment of intrauterine adhesions. Obstet Gynecol 1974;44:341–344. 29. Schlaff WD, Hurst BS. Preoperative sonographic measurement of endometrial pattern predicts outcome of surgical repair in patients with severe Asherman’s syndrome. Fertil Steril 1995;63:410–413. 30. Thompson JD, Rock JA. Te Linde’s Operative Gynecology. Philadelphia: Lippincott, 1992, pp 385–409. 31. Balmaceda JP, Ciuffardi I. Hysteroscopy and assisted reproductive technology. Obstet Gynecol Clin North Am 1995;22:507–518. 32. Shamma FN, et al. The role of office hysteroscope in in vitro fertilization. Fertil Steril 1992;58:1237– 1239. 33. Vercillini P, Colombo A, Mauro A, et al. Paracervical anesthesia for outpatient hysteroscopy. Fertil Steril 1994;62:1083–1085.

Suggested Readings Lindheim SR, Kavic S, Shulman SV, et al. Operative hysteroscopy in the office setting. J Am Assoc Gynecol Laparosc 2000;7:65–69. Zullo F, Pellicano M, Stigliano CM, DiCarlo C, Fabrizio A, Nappi C. Topical anesthesia for office hysteroscopy. A prospective randomized study comparing two modalities. J Reprod Med 1999;6:331–6. Pal L, Lapensee L, Toth TL, Isaacson KB. Comparison of office hysteroscopy, transvaginal ultrasonography, and endometrial biopsy in evaluation of abnormal uterine bleeding. J Soc Laparaoendosc Surg 1997;1:125– 30. Valli E, Zupi E, Marconi D, Solima E, Nagar G,

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Romanini C. Outpatient diagnostic hysteroscopy. J Am Assoc Gynecol Laparosc 1998;5:397–402. Saidi MH, Sadler RK, Theis VD, Akright BD, Farhart SA, Villanueva GR. Comparison of sonography, sonohysterography, and hysteroscopy for evaluation of abnormal uterine bleeding. J Ultrasound Med 1997; 16:587–591.

Ross JW. Numerous indications for office flexible minihysteroscopy. J Am Assoc Gynecol Laparosc 2000;7: 221–226. Marrello F, Bettochi S, Greco P, Ceci O, Vimercati A, Di Venere R, Loverro G. Hysteroscopic evaluation of menopausal patients with sonographically atrophic endometrium. J Am Assoc Gynecol Laparosc 2000;7:197–200.

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11 Endoscopic Evaluation of the Fallopian Tube Eric S. Surrey

The human fallopian tube plays a vital role in the reproductive process. Its functions include sperm transport, ovum pickup, and embryo transport. The tube is the site for sperm capacitation, oocyte fertilization, and early embryo development and maintenance. Tubal ovum and embryo transport are dependent on a rich interplay between the endocrine milieu, cilial function, muscular contractions, and adrenergic innervation. Vascular perfusion studies have demonstrated the presence of fluid in the tubal lumen with high concentrations of metabolic substrates. Substances secreted in the tube include trypsin inhibitors, prostaglandins, immunoglobulins (particularly IgA), bicarbonate, and such cytokines as transforming growth factor- (TGF). These substances may play a role in zona pellucida dispersion and provide sustenance to the oocyte and early embryo. Studies suggest compromise of implantation and pregnancy rates after attempted in vitro fertilization (IVF) in women with hyrosalpinges. This suggests that inflammatory tubal fluid may have a direct deleterious effect on the uterine environment as well. Investigators have reported that in a population of infertile patients 11–16% present with various tubal factors. Significant prognostic factors include a history of pelvic infection, sexually transmitted diseases, tubal or ovarian surgery, endometriosis, or use of various intrauterine devices. Distal tubal disease most commonly stems from prior infection or as a response to inflammatory insults (e.g., prior pelvic surgery, endometriosis). Proximal disease may result from inflammation or infection as well but may also stem from salpingitis isthmica nodosa, spasm, amorphous casts, or extrinsic compression due to adenomyosis, endometriosis, or leiomyomas. These disorders may result in total tubal

occlusion or in more subtle dysfunction in the presence of patent fallopian tubes. Thus it is clear that the fallopian tube plays a much greater role in the reproductive process than that of a passive conduit between ovary and uterus. The primary means of assessing the fallopian tube have traditionally included hysterosalpingography (HSG) and laparoscopy. The accuracy of HSG findings when compared to laparoscopic findings has been debated. Investigators from a multicenter World Health Organization (WHO) trial reported that only 55% of 125 women undergoing both laparoscopy and HSG had similar findings. In an investigation in which HSG was performed the day prior to laparoscopy, the sensitivity of HSG was noted to be only 0.54. In contrast, Opsahl and colleagues reported that HSGs that were interpreted as “normal,” as would be the case in women with unexplained infertility, were confirmed at surgery in 96.6% of cases, but in only 63.1% of patients with HSGs were they interpreted as “suspicious.” Swart and colleagues performed a meta-analysis of 20 previously published papers comparing the accuracy of the diagnosis of tubal patency or peritubal adhesions by HSG in comparison to laparoscopy. Point estimates for tubal patency of 0.65 and 0.83 (sensitivity and specificity, respectively) were calculated. This means that although tubal disease is highly likely in the presence of an abnormal HSG, tubal patency on HSG does not rule out pathology. In addition, the diagnosis of peritubal adhesions by HSG was completely unreliable based on the findings of this study. Neither HSG nor laparoscopy allow the clinician to differentiate between true proximal occlusion and spasm at the uterocornual ostium or the presence of occlusive mucous plugs. Selective salpingography, a procedure involving 127

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transcervical catheterization of the fallopian tube under fluoroscopic guidance with subsequent imaging and canalization, has been proposed as a secondary measure when proximal tubal occlusion is initially appreciated at HSG. Hydrostatic pressure due to dye infusion or direct placement of the catheter in the case of selective salpingography may dislodge debris and mucous plugs or lyse intraluminal adhesions. Letterie and Sakas reported that 93% of resected tubal segments demonstrated true pathology, such as fibrosis or salpingitis isthmica nodosa, if obstruction persisted after selective salpingography. More recently, transvaginal sonography has been employed to assess tubal patency. Saline, air, and echo enhancing agents have been injected into fallopian tubes transcervically as transvaginal sonography is performed. The patency of each tube is assessed by the escape of air bubbles, color Doppler flow patterns, or the progressive collection of fluid in the cul-de-sac. Concordance with laparoscopic findings is variable, and this technique requires further development before it can be generally accepted as part of the routine evaluation of the fallopian tube. Unfortunately, none of these imaging studies provides a truly accurate assessment of tubal anatomy. A patent tube is not necessarily a normal tube. A radiologic or sonographic finding of tubal occlusion or other luminal defect does not confirm the presence of a true disease state or define the nature of the lesion, only its location. Evaluation of the endothelial lining or nonobstructive defects cannot be performed. Thus more direct visualization would be ideal.

Endoscopic Techniques Laparoscopy has traditionally served as the gold standard for diagnosing tubal and peritubal pathology. Tubal obstruction can be assessed by chromopertubation: transcervical infusion of diluted indigo carmine or methylene blue dye. The extent of peritubal adhesions can be assessed along with the remainder of the pelvic cavity. Various findings at laparoscopy have been employed to predict tubal function in cases of suspected distal disease: wall thickness, ampullary dilation, extent of peritubal adhesions, and fimbrial mucosal appearance. However, laparoscopy provides little information regarding the tubal lumen itself in that access can be achieved only to the most distal aspect. Laparoscopy is even less helpful for assessing a presumed proximal occlusion, as a true causative factor can-

not be visualized, although secondary factors such as endometriosis or leiomyomas can be assessed. A patent tube with normal-appearing fimbriae may still harbor unrecognized luminal defects that may impair fertility. As a result, various investigators have attempted to assess more accurately the nature of the fallopian tubal lumen by direct visualization. Advances in fiberoptic technology have made this possible. “Salpingoscopy” is defined as endoscopic visualization of the tubal lumen from the ampullary– isthmic junction to the fimbria employing transfimbrial access. “Falloposcopy” represents endoscopic evaluation of the fallopian tube from the uterotubal ostium to the fimbria employing transcervical access.

Indications and Contraindications The primary indication for performance of falloposcopy is assessment of the infertile woman with suspected proximal tubal disease after HSG or in whom HSG is contraindicated (Table 11–1). The poor correlation between findings at HSG and surgery particularly with regard to proximal tubal occlusion has been reported. Prior to subjecting a patient to microsurgical anastomosis at laparotomy or tubal bypass employing assisted reproductive technologies (ART), a thorough assessment of the tubal lumen may reveal such findings as spasm of the uterotubal ostium, intraluminal polyps, or mucous plugs, which may lend themselves to less invasive therapy. Similarly, the finding of an irreparably damaged tubal lumen may allow the patient to avoid laparoscopy altogether and be referred directly for in vitro fertilization-embryo transfer (IVF-ET). The patient with hydrosalpinges diagnosed radiologically may benefit from falloposcopy or sal-

TABLE 11–1. Indications and Contraindications for Tubal Endoscopy Indications Suspected proximal tubal occlusion Suspected distal tubal occlusion Unexplained infertility Contraindication to hysterosalpingography (contrast dye allergy) Gamete and/or zygote transfer? Contraindications Active pelvic infection Active uterine bleeding Allergic reaction to local anesthetic agents Extensive uterine synechiae or submucous myomas

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pingoscopy. Salpingoscopy, which is performed during concomitant laparoscopy, provides information regarding both the tubal lumen and the peritubal environment. Although falloposcopy provides no information regarding peritubal disease, should the endothelial lining prove to be damaged beyond repair, further surgical investigation would be unwarranted. In contrast, a patient with a less severely damaged endothelial lining noted at falloposcopy would require a concomitant or subsequent laparoscopic procedure to assess the extent of peritubal disease with the potential need to undergo endoscopic tubal reconstruction. A third indication is the patient with otherwise unexplained infertility after a standard evaluation. Patients with normal findings at HSG and laparoscopy have been noted to have intraluminal adhesions and abnormal endothelial vascular patterns during tubal microendoscopy. In addition, the use of falloposcopic visualization of the tubal lumen to confirm appropriate catheter placement prior to transcervical gamete transfer on an outpatient basis has been reported. Contraindications to tubal endoscopy are displayed in Table 11–1. This procedure should not be performed in the presence of active pelvic infection or uterine bleeding or in patients unable to tolerate local anesthetic agents if the procedure is to be undertaken in an office setting. Patients with such endometrial pathology as synechiae or a submucous myoma, preventing visualization and access to the uterotubal ostium, are poor candidates for falloposcopy as well.

Salpingoscopy: Equipment and Technique Transfimbrial salpingoscopy, performed during laparoscopy, is a means of visualizing the tubal lumen from the ampullary–isthmic junction to the fimbria. Flexible fiberoptic or rigid salpingoscopes with camera attachments and outer diameters ranging from 1.8 to 2.8 mm (Olympus, Lake Success, NY; Karl Storz, Culver City, CA) are introduced into the peritoneal cavity through an accessory 5 mm trochar with a 3 mm reducer (Fig. 11–1). The fallopian tube to be evaluated is stabilized by placing an atraumatic grasping forceps on the antimesenteric serosal border just proximal to the fimbria. The fimbrial ostium is cannulated by the salpingoscope until a point of resistance is met or until the ampullary–isthmic junction is reached (Fig. 11–2). In the event of total distal occlusion, a small

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FIGURE 11–1. Flexible salpingoscope with irrigating channel. (Courtesy of Olympus, Lake Success, NY)

neosalpingostomy incision is made with microscissors or laser to allow tubal cannulation. This incision serves as the start of a potential full distal neosalpingostomy procedure should the tube be deemed repairable. If necessary, this site can also be subsequently sealed. Visualization is performed in a retrograde fashion as the tubal lumen is distended with Ringer’s lactate solution to which heparin 5000 U/L has been added. Although this procedure must be performed during laparoscopy, a general anesthetic may not be necessary when salpingoscopy is combined with microlaparoscopy employing outpatient conscious sedation techniques. Dripping 1% lidocaine on the tubal serosa makes the procedure more easily tolerated in this setting. Although this procedure was initially designed to assess the potential for successful repair of the distally occluded fallopian tube, several investigative teams have assessed the role of salpingoscopy in the patient with patent tubes. Surrey and Surrey noted a strong correlation between laparoscopic and salpingoscopic findings in 40 tubes believed to have moderate to severe disease at laparoscopy. In marked contrast, no correlation was noted between findings derived from these two techniques in 51 tubes noted to be normal or to have minimal disease at laparoscopy. In the latter group, 35.7% were shown to have moderate to severe luminal abnormalities at salpingoscopy. Marconi and colleagues reported that 37% of patients described as having normal tubes at laparoscopy had endothelial abnormalities appreciated only by salpingoscopy. Shapiro et al. reported a 23.5% discordance in findings between the two procedures. Of 151 normalappearing tubes at laparoscopy, Antony and co-

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E.S. Surrey FIGURE 11–2. Cannulation of the fallopian tube with a flexible salpingoscope. The distal serosal edge is stabilized by atraumatic grasping forceps.

workers reported that 39 (25.8%) had no mucosal lesions appreciated at salpingoscopy. Discrepancies between salpingoscopic and HSP findings have also been reported. Numerical salpingoscopy scores have been shown to be highly predictive of pregnancy by several investigative teams (Fig. 11–3). The ability to visualize mucosal abnormalities directly may therefore provide valuable information that would not otherwise be obtained by employing more traditional techniques.

FIGURE 11–3. Estimated cumulative spontaneous intrauterine pregnancy rates from the time of surgery based on mean salpingoscopy scores based on results of lifetable analysis. Circles, patients (n  18) with mean scores 12 (mean  SEM) (follow-up 11.7  2.3 months). Squares, patients (n  24) with mean scores 12 (mean  SEM) (follow-up 14.6  1.9 months). †p  0.038 vs. patients with scores 12. (From Surrey and Surrey, 1996, with permission.)

Falloposcopy: Equipment and Technique One of the disadvantages of transfimbrial salpingoscopy is the need for concomitant laparoscopy and the inability to access regions of the fallopian tube proximal to the ampullary–isthmic junction. Kerin and colleagues initially reported successful transcervical microendoscopy of the entire tubal lumen from the uterotubal ostium to the fimbria, a procedure termed “falloposcopy.” A variety of falloposcopes have been developed as modifications of fiberoptic angioscopes. These flexible instruments measure approximately 1.5 m in length and 0.45–0.5 mm in outer diameter (Conceptus, San Carlos, CA; Medical Dynamics, Englewood, CO; Intramed, San Diego, CA; Olympus) (Fig. 11–4). Two basic techniques for performing falloposcopy have been described: a coaxial approach and a linear everting catheter approach. With the coaxial approach, the uterotubal ostium (UTO) is first visualized by introducing a flexible hysteroscope into the endometrial cavity under video monitoring to achieve a long axis view within 1–2 mm of the tubal ostia. Cervical dilation is rarely required and is avoided if possible to prevent leakage. A variety of hysteroscopes with 1.5–2.0 mm o.d. and a single operating channel have been employed (Olympus; Intramed; Mitsubishi Cable Industries, Itami, Japan). Lactated Ringer’s solution is infused as a distension medium through extension tubing connected to one arm of an

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FIGURE 11–4. Coaxial falloposcope with 0.45 mm OD and camera attachments. (Courtesy of Conceptus, San Carlos, CA)

attached Tuohy-Borst type Y-connector (Cook Ob/Gyn, Spencer, IN). A flexible platinum-tipped tapered guidewire of 0.3–0.8 mm o.d. (Target Therapeutics, San Jose, CA; Conceptus; Cook Ob/Gyn; Glidewire Medi-Tech, Watertown, NH) is then introduced into the UTO through the second arm of the Y-connector and advanced until either a point of resistance, increased patient discomfort, or a distance of 15 cm is reached. Care should be taken to avoid passage of the wire through the UTO during a period of ostial spasm. It should be noted that although the intramural segment of the fallopian tube is fairly straight over its 1.5–2.5 cm length it may form an acute angle with the cavity. A gentle torque motion may facilitate guidewire passage through this region. Once the wire has been introduced, a Tefloncoated catheter with 1.2–1.3 mm o.d. (Target Therapeutics; Conceptus; Cook Ob/Gyn) is introduced over the wire for a similar distance. The guidewire is then withdrawn. A second Tuohy-Borst Y-connector is then attached to the proximal end of the catheter. The falloposcope is introduced through the straight arm of the second Y-connector. This allows protection for the atraumatic leading end of the highly flexible falloposcope, which measures 120–130 cm in length and 0.3–0.5 mm o.d. (Olympus; Mitsubishi; Intramed; Medical Dynamics, Englewood, CO). The coaxial system is displayed in Figure 11–5. Lactated Ringer’s solution is infused through the angled arm of this second Y-connector. A xenon light source, a camera chip, and a high resolution video monitor are required. The tubal lumen is visualized in a retrograde fashion taking care to main-

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FIGURE 11–5. Coaxial falloposcopy. Falloposcope has been placed through the straight arm of a Y-connector into a Teflon over-the-wire catheter.

tain the falloposcope flush with the distal opening of the catheter. A white-out occurs if the lens directly touches the tubal endothelial lining. Dual video monitoring of hysteroscopy and falloposcopy is helpful. This approach allows simultaneous diagnosis and potential therapy of visualized lesions with the subsequent use of stiffer wires or balloon catheters. This technique is summarized in Table 11–2. The linear everting catheter system (Imagyn, Laguna Niguel, CA) represents an alternative approach for transcervical cannulation and visualization of the fallopian tube lumen. The linear everting catheter (LEC) consists of an outer and an inner catheter body that is joined distally by a balloon (Fig. 11–6). This balloon everts by pressurization of a joining membrane, which slowly unrolls the catheter tip as the inner body is advanced. The UTO is visualized by introducing the falloposcope through the distal lumen of the catheter, obviating the need for use of a separate hysteroscope. The balloon is pressurized and the catheter slowly everted. This catheter system allows the balloon to conform to the tortuous path of the falloTABLE 11–2. Coaxial Falloposcopy: Summary of Technique Visualization of uterotubal ostium (UTO) with flexible hysteroscope Guidewire cannulation of UTO Over-the-wire catheter placement Removal of guidewire Introduction of falloposcope through catheter Retrograde visualization

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FIGURE 11–6. Linear everting catheter system (Imagyn, Laguna Niguel, CA). (A) Instrument. (B) Diagram of the instrument. (From Pearlstone et al., 1992, with permission)

pian tube more accurately while eliminating lateral shear forces. Once the tube has been completely catheterized to the point at which resistance is met or until the catheter is advanced for a distance of 15 cm, the 0.5 mm o.d. falloposcope is subsequently introduced through the everted catheter. Falloposcopy is performed in a retrograde fashion. Office-based falloposcopy has been described with use of the LEC system in only several published series to date. Scudamore and coworkers were able to perform bilateral tubal endoscopic visualization successfully in 18 of 19 patients with a mean operating time of 35 minutes (range 25–50 minutes). Epithelial characteristics were appreciated in 34 of 37 tubes visualized. No complications were reported. Bauer and colleagues performed outpatient falloposcopy in eight tubes in seven patients prior to intratubal insemination. No irrigation was employed in the tube, and falloposcopy was performed solely to confirm catheter location in the tube. Catheterization was successfully performed in all patients without complications. Dunphy and colleagues reported that in-office falloposcopy induced significantly less intense pain than HSG. Rapid eversion, cannulation, and flushing near the UTO were associated with the most severe discomfort in this series.

Normal Anatomy and Pathologic Findings The endothelial lining of the intramural portion of the fallopian tube is 0.8–1.0 mm in diameter and is marked by several flattened folds. The isthmic region extends for 2–3 cm with a 1–2 mm diameter, and it is marked by four to six longitudinal folds with a more delicate vascular pattern (Fig. 11–7). The ampulla rapidly increases in diameter from 1.5–4.0 mm proximally to 8–10 mm distally. Its variable length is 5–10 cm. As one progresses distally, a radial pattern of primary folds 4 mm in height, which increase in number, are visualized (Fig. 11–8). Delicate secondary folds that incorporate a fine vascular pattern are appreciated as one reaches the more distal aspects of the ampullary region. A variety of pathologic findings in the tubal lumen have been effectively visualized with the aid of tubal endoscopy. Distally, one is able to assess the extent of inflammatory vascular patterns, mucosal atrophy, and loss of primary endothelial folds characteristic of hydrosalpinges (Fig. 11–9). More proximal lesions that can be appreciated include varying degrees of stenoses, nonocclusive intraluminal adhesions, tubal polyps, mucous

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FIGURE 11–7. Falloposcopic image of the normal tubal isthmus obtained with the linear everting catheter. (From Pearlstone et al., 1992, with permission)

plugs, and the endothelial diverticula associated with salpingitis isthmica nodosa. Kerin and coworkers developed a classification system to standardize and quantify findings at falloposcopy. Point scores are attributed for patency, dilation, vascular patterns, epithelial quality, and intraluminal adhesions. As has been shown with salpingoscopy, findings at falloposcopy correlate poorly with findings at HSG. In a large series of falloposcopies performed on 112 tubes in 75 women who had a presumptive diagnosis of prox-

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FIGURE 11–9. Hydrosalpinx visualized with a linear everting catheter system. Note the flattened fibrotic endothelial lining. (From Pearlstone et al., 1992, with permission)

imal tubal occlusion based on laparoscopic or radiologic findings, no abnormalities were noted in 46%. Venezia and colleagues noted that HSG and LEC falloposcopy findings failed to correlate in 40% of tubes visualized. Another small series reported that 9 of 12 tubes described as proximally occluded as seen by HSG were normal at falloposcopy. We have reported that 40% of visualized tubes in patients with otherwise unexplained infertility and normal HSG had abnormalities appreciated only at falloposcopy. The likelihood of HSG or chromo per tubation depicting normal tubes when abnormalities were detected at falloposcopy was 22.7% in this study. Management changes were made in 52.4% of patients in this series as a result of falloposcopic findings. A clear correlation between falloposcopic findings and conception has been described.

Complications

FIGURE 11–8. Image of the normal tubal ampulla obtained with a flexible salpingoscope.

The primary risk of falloposcopy is that of tubal perforation, the incidence of which is extremely low. Exaggerated acute angles formed by the junction of the intramural portion of the tube with the uterotubal ostium, peritubal adhesions limiting tubal flexibility, and narrowing of the lumen due to fibrotic obstruction predispose to perforation. No perforations that occurred during procedures we performed have been associated with significant sequelae. Gentle manipulation and a keen aware-

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TABLE 11–3. Fallopian Tube Evaluation Techniques Parameter Tubal access Patency confirmed Access entire tube Confirm obstruction site Visualize lumen Overcome UTO spasm OR setting/conscious sedation Visualize nonobstructive lesions Assess peritubal disease

HSG

Selective salpingography

Laparoscopy/ chromoperturbation

Salpingoscopy

Falloposcopy

Cervical   /     

Cervical        

Cervical/fimbrial   / Extreme distal only /   

Fimbrial        

Cervical      /  

HSG, hysterosalpingography; OR, operating room.

ness of tubal anatomy represents a crucial means of avoiding this complication. A low incidence of guidewire dissection between the endothelium, without sequelae, has also been reported. Aside from the standard risks of laparoscopy, no complications attributed to salpingoscopy per se have been reported. Evaluation of the fallopian tube in the infertile woman by standard HSG or laparoscopy may not represent a completely accurate means of ruling out underlying pathology. Advances in fiberoptic catheter technology allow the investigator to visualize the tubal lumen directly. The relative merits of the techniques employed to assess the fallopian tube are summarized in Table 11–3. Whether tubal endoscopy after selective salpingography should represent a standard part of the infertility evaluation shall come from the results of larger ongoing clinical trials.

Management Decisions Proximal Disease Patients with intraluminal mucous plugs or debris may best be managed with aquadissection techniques. Intraluminal endometriosis and endosalpingiosis may perhaps best be treated medically with a trial of gonadotropin-releasing hormone (GnRH) agonist or danazol therapy, although minimal intraluminal adhesions may be more appropriately approached with gentle guidewire dissection. Denser adhesions or mild stenoses may also be approached employing balloon dilation techniques. These procedures may someday be performed in an office setting, once sufficient data addressing safety and patient tolerance have been reported. Increased analgesic requirements and the inability to avoid tubal perforation by performing

concomitant laparoscopy may prove to be limiting factors. Patients with dense fibrotic obstruction require tubal bypass with IVF or resection and microsurgical anastomosis as appropriate.

Distal Disease The patient with suspected hydrosalpinges is managed in a different fashion. If a grossly dilated tube with no functional endothelial lining or extensive intraluminal adhesions is noted at falloposcopy, further surgical intervention may prove unnecessary, or salpingectomy may be performed if appropriate. The patient should be referred directly for IVF. If the lining appears only minimally compromised, laparoscopic assessment of peritubal disease with the potential for neosalpingostomy should be performed. IVF would be appropriate in the presence of extensive peritubal disease or more advanced maternal age. This management paradigm is summarized in Table 11–4.

TABLE 11–4. Management Based on Findings at Falloscopy/Salpingoscopy Normal lumen: treat as unexplained infertility; perform laparoscopy if indicated Suspected proximal occlusion Mucous plugs, debris: aquadissection Endometriosis, endosalpingiosis: medical suppression Nonobstructive adhesions: guidewire dissection Moderate adhesions, stenosis: guidewire dissection or directed balloon tuboplasty Dense obstruction: IVF/ET vs. resection and microsurgical anastomosis Suspected distal occlusion Severe disease: IVF/ET, possible salpingectomy Mild to moderate disease: IVF/ET vs. laparoscopy, possible neosalpingostomy depending on patient’s age and extent of peritubal disease IVF/ET, in vitro fertilization–embryo transfer.

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Falloposcopy and salpingoscopy represent exciting new and evolving technologies that allow visualization of the tubal lumen in a minimally invasive fashion. This procedure clearly lends itself to performance in an office setting with minimal anesthesia. As a result, management decisions can now be made based on visualization of the pathologic findings. As experience and technology progress, tubal endoscopy may become a standard part of the outpatient evaluation of the infertile patient with suspected tubal disease. Acknowledgments. Special thanks to John F. Kerin, M.D., Ph.D. and Mark W. Surrey, M.D. for their vision and guidance.

Suggested Reading Andersen A, Yue Z, Meng F, Patersen K. Low implantation rate after in vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum Reprod 1994;9:1935–1938. Antony A, Slanger T, van Herendael BJ. Salpingoscopy is an important part of the infertility work-up. J Am Assoc Gynecol Laparosc 1996;3:369–374. Bauer O, Diedrich K, Bacich S, et al. Transcervical access and intra-lumenal imaging of the fallopian tube in the non-anesthetized patient: preliminary results using a new technique for fallopian access. Hum Reprod 1992;7(suppl):7–11. Boer-Meisel M, te Velde E, Habbema J, Kardaun J. Predicting the pregnancy outcome in patients treated for hydrosalpinx: a prospective study. Fertil Steril 1986; 45:23–29. Brosens I, Boackx W, Delattin P, Puttemans P, Vasquez G. Salpingoscopy: a new preoperative diagnostic tool in tubal infertility. Br J Obstet Gynaecol 1987;94: 768–773. Cummings DC, Taylor PJ. Historical predictability of abnormal laparoscopic findings in the infertile woman. J Reprod Med 1979;23:295–298. De Bruyne F, Hucke J, Willers R. The prognostic value of salpingoscopy. Hum Reprod 1997;12:266–271. Dechaud H, Daures JP, Hedon B. Prospective evaluation of falloposcopy. Hum Reprod 1998;13:1815–1818. Dickens CJ, Maguiness SD, Conur MT, et al. Human tubal fluid: formation and composition during vascular perfusion of the fallopian tube. Hum Reprod 1995; 10:505–508. Dor J, Homburg R, Rabau E. An evaluation of etiologic factors and therapy in 665 infertile couples. Fertil Steril 1977;28:718–722. Dubuisson J, Chapion C, Morice P, et al. Laparoscopic salpingostomy: fertility results according to the tubal mucosal appearance. Hum Reprod 1994;9:334–339. Dunphy B, Greene C. Falloposcopic cannulation, oviductal appearances and prediction of treatment independent intrauterine pregnancy. Hum Reprod 1995;10: 3313–3316.

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Dunphy B, Tawzer P, Bultz B, et al. A comparison of pain experienced during hysterosalpingography and in-office falloposcopy. Fertil Steril 1994;62:62–70. Dunphy BC. Office falloposcopy assessment in proximal tubal disease. Fertil Steril 1994;61:168–170. Gordts S, Campo R, Romhauts L, Brosens I. Transvaginal hydrolaparoscopy as an outpatient procedure for infertility investigation. Hum Reprod 1998;13:99–103. Grow DR, Coddington CC, Flood JF. Proximal tubal occlusion by hysterosalpingogram: a role for falloposcopy. Fertil Steril 1993;60:170–174. Guerriero S, Ajoosa S, Mais V, Paoletti AM, Melis GB. The screening of tubal abnormalities in the infertile couple. J Assist Reprod Genet 1996;13:407–412. Henry-Suchet J, Loffredo V, Tesuier L, Pez J. Endoscopy of the tube ( tuboscopy): its prognostic value for tuboplasties. Acta Eur Fertil 1985;16:139–145. Heylen SM, Brosens IA, Puttemans P. Clinical value and cumulative pregnancy rates following rigid salpingoscopy during laparoscopy for infertility. Hum Reprod 1995;11:2913–2916. Katz E, Akman MA, Damewood MD, Garcia JE. Deleterious effect of the presence of hydrosalpinx on implantation and pregnancy rates with in vitro fertilization. Fertil Steril 1996;66:122–125. Kerin J, Daykhovsky L, Grundfest W, Surrey E. Falloposcopy: a microendoscopic transvaginal technique for diagnosing and treating endotubal disease incorporating guide wire cannulation and direct balloon tuboplasty. J Reprod Med 1990;35:606–612. Kerin J, Daykhovsky L, Segalowitz J, et al: Falloposcopy: a microendoscopic technique for visual exploration of the human fallopian tube from the uterotubal ostium to the fimbria using a transvaginal approach. Fertil Steril 1990;54:390–400. Kerin J, Williams D, San Roman G, et al. Falloposcopic classification and treatment of fallopian tube lumen disease. Fertil Steril 1992;57:731–741. Kerin JF, Pearlstone AJ, Surrey ES. Tubal microendoscopy: salpingoscopy and falloposcopy. In: Keye WR Jr, Chang RJ, Rebar RW, Soules MR (eds) Infertility: Evaluation and Treatment. Philadelphia: Saunders, 1995:372–386. Letterie GS, Sakas EL. Histology of proximal tubal obstruction. Fertil Steril 1991;56:831–835. Mage G, Pouly J-L, de Joliniere J, et al. A preoperative classification to predict the intrauterine and ectopic pregnancy rates after distal tubal microsurgery. Fertil Steril 1986;46:807–810. Marana R, Catalano GF, Muzii L, et al. The prognostic role of salpingoscopy in laparoscopic tubal surgery. Hum Reprod 1999;14:2991–2995. Marana R, Rizzi M. The role of salpingoscopy and falloposcopy in infertility. Curr Opin Obstet Gynecol 1996;8:257–260. Marana R, Rizzi M, Muzii L, et al. Correlations between the American Fertility Society classifications of adnexal adhesions and distal tubal occlusion, salpingoscopy, and reproductive outcome in tubal surgery. Fertil Steril 1995;64:924–929.

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Marconi G, Auge L, Sojo E, Young E, Quintana R. Salpingoscopy: systematic use in diagnostic laparoscopy. Fertil Steril 1992;57:742–746. Opsahl MS, Miller B, Klein TA. The predictive value of hysterosalpingography for tubal and peritoneal infertility factors. Fertil Steril 1993;6:444–448. Pearlstone AC, Surrey ES, Kerin JF. The linear everting catheter: a nonhysteroscopic transvaginal technique for access and microendoscopy of the fallopian tube. Fertil Steril 1992;58:854–857. Puttemans P, Brosens I, DeLattis P, Vasquez G, Boeckx W. Salpingoscopy versus hysterosalpingography in hydrosalpinges. Hum Reprod 1987;2:535–540. Puttemans PJ, De Bruyne F, Heylen SM. A decade of salpingoscopy. Eur J Obstet Gynecol Reprod Biol 1998;81:197–206. Savada T, Tsukada K, Satoh M, Kawakami S. Correlation between salpingoscopic score and subsequent pregnancy outcome in patients with tubal infertility. J Assist Reprod Genet 1997;14:562–565. Scudamore IW, Dunphy BC, Cooke ID. Outpatient falloposcopy: intralumenal imaging of the fallopian tube by trans-uterine fiberoptic endoscopy as an outpatient procedure. Br J Obstet Gynaecol 1992;99:829–835. Shapiro B, Diamond M, de Cherney A. Salpingoscopy: an adjunctive technique for evaluation of the fallopian tube. Fertil Steril 1988;49:1076–1079. Sulak P, Letterie G, Coddington C, et al. Histology of proximal tubal obstruction. Fertil Steril 1991;56: 831–835. Surrey ES. Falloposcopy. Obstet Gynecol Clin North Am 1999;26:53–62, vi.

Surrey ES. Microendoscopy of the human fallopian tube. J Am Assoc Gynecol Laparosc 1999;6:383–389. Surrey ES, Surrey MW. Correlation between salpingoscopic and laparoscopic staging in the assessment of the distal fallopian tube. Fertil Steril 1996;65:267– 271. Surrey ES, Adamson GD, Surrey MW, et al. Introduction of a new coaxial falloscopy system: a multicenter feasibility study. J Am Assoc Gynecol Laparosc 1997;4:473–78. Surrey ES, Surrey MW, Kerin JF. Salpingoscopy and falloposcopy. In: Adamson GD, Martin DC (eds) Endoscopic Management of Gynecologic Disease. Philadelphia: Lippincott-Raven, 1996:345–358. Swart P, Mol BWJ, Van der Veen F, et al. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1995;64:486– 491. Swolin K, Rosencrantz M. Laparoscopy vs. hysterosalpingography in sterility investigations, a comparative study. Fertil Steril 1972;23:270–273. Thurmond AS, Novy M, Uhcida BT, Rösch J: Fallopian tube obstruction: selective salpingography and recanalization. Radiology 1987;163:511–514. Venezia R, Zangara C, Knight C, Cittadini E. Initial experience of a new linear everting falloposcopy system in comparison with hysterosalpingography. Fertil Steril 1993;60:771–725. World Health Organization. Comparative trial of tubal insufflation, hysterosalpingography, and laparoscopy with dye hydrotubation for assessment of tubal patency. Fertil Steril 1980;46:1101–1107.

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12 Transcervical Tubal Cannulation Jacek W. Graczykowski and David B. Seifer

Bilateral or unilateral proximal tubal obstruction (PTO) is a common finding on a hysterosalpingogram (HSG) obtained as a part of the infertility workup. The traditional management of this radiologic finding is laparoscopic assessment of the oviducts. If no spill of transcervically injected contrast is noted from the fimbriated end of the fallopian tube, microsurgical resection of the obliterated segment of the oviduct and anastomosis is performed. HSG alone has a nearly 40% falsepositive rate, and PTO is often overdiagnosed. Laparoscopic evaluation of PTO does not eliminate the false-positive rate. Serious pathology is found in only 40% of the microsurgically resected tubal segments, and amorphous casts, calcifications, or a patent lumen are the findings in the remaining 60% of the excised oviducts. Therefore the need for major abdominal surgery can be questioned in such cases. The need for accurate diagnosis of PTO has led to the development of several diagnostic modalities: (1) selective fluoroscopically guided salpingography; (2) transcervical tubal cannulation; and (3) transfimbrial or transcervical salpingoscopy. The advent of assisted reproductive techniques (ARTs) contributed another treatment option to the management of PTO-related infertility. Both microsurgical anastomosis and ART are invasive, laborious, and costly. Transcervical tubal cannulation (TCTC), which provides a diagnostic and therapeutic modality, has become an attractive approach to the management of PTO. TCTC offers less expensive, less invasive restoration of tubal patency and can be performed as an outpatient office procedure under minimal anesthesia. The success of recanalization of the affected oviduct depends on the etiology of the obstruction and the extent of the blocked segment. When TCTC fails to recanalize the oviduct, serious pathology is found in 93% of

microsurgically resected segments, justifying more invasive management. The etiology of PTO varies widely. Intraluminal factors such as muscular spasm, amorphous debris, and mucous plugs are the most common reasons for obstruction and can be easily removed by tubal cannulation. Other conditions such as obliterative fibrosis (most likely secondary to inflammatory changes), chronic salpingitis, and salpingitis isthmica nodosa do not easily respond to cannulation. Rare etiologies of PTO have also been reported, including parasitic infection, tuberculosis, and hyalinized ectopic pregnancy. If PTO develops after a surgical tubal anastomosis, tubal cannulation is rarely successful, and tubal wall perforation or fistula may occur. The success of TCTC is measured not only by passing a catheter along the oviduct but also by maintaining the patency and achieving an intrauterine pregnancy. The reproductive success following an effective tubal cannulation depends on multiple factors: the etiology of the obstruction, functioning of the tubal muscularis and the mucosa, status of the distal portion of the oviduct, the presence of peritubal adhesions, age, and the presence of other independent infertility factors (male and female). Overall, 82% of all catheterized tubes become patent, and 68% of them remain open; 24% patients achieve an intrauterine pregnancy, and the ectopic pregnancy rate is 6%.

Indications/Purpose The TCTC procedure is performed to reestablish tubal patency of a proximally obstructed oviduct(s) in women who desire a pregnancy. Assessment of tubal status is an essential part of the infertility

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workup. If PTO is suspected during the initial HSG procedure, selective salpingography should be performed to confirm the diagnosis. A TCTC setup may be available at the same time; and if selective salpingography fails to image a patent oviduct, careful cannulation can be attempted. Not all women who have evidence of PTO on prior HSG may benefit from TCTC. The selection of candidates for TCTC and selection of the method of cannulation should be undertaken carefully. Women under the age of 40 with minimal risk of distal tubal disease according to their history, no filling defects in the uterine cavity on HSG, and an absence of severe male factor are excellent candidates for office fluoroscopically guided selective salpingography combined with TCTC. If distal tubal damage is strongly suspected (history of salpingitis, high seropositive titer for Chlamydia trachomatis), selective salpingography and TCTC could be performed at the time of a diagnostic laparoscopy, which allows simultaneous assessment of the distal segment of the oviduct. Women with intrauterine radiographic filling defects may be served better by a hysteroscopically guided TCTC, which allows concomitant assessment of the endometrial cavity. An algorithm for PTO is summarized in Fig. 12–1.

(which can be performed at the same time), a pregnancy test, and a semen analysis. A Chlamydia trachomatis antibody [immunoglobulin G and M (IgG, IgM)] titer and Chlamydia and gonorrhea cervical cultures are also recommended. Prophylactic antibiotics (doxycycline 100 mg PO bid  6 days) may be started 2 days prior to the procedure. Counseling before the procedure should be individualized, based on the results of the workup, and should include an explanation of the technique, its effectiveness and anticipated pregnancy chance, possible complications, and finally other management options. Patient should sign an informed consent prior to the procedure.

Equipment There are several TCTC systems available. If the procedure is performed in the physician’s office or at the time of HSG, the oviducts can be cannulated under fluoroscopic guidance. The hysteroscopic

Contraindications The TCTC procedure should be avoided in women who are pregnant or have a history of recent or active salpingitis. Any suspicion of pelvic infection must be clarified prior to cannulation. An adnexal mass also warrants a workup to rule out a pelvic abscess prior to cannulation. Advanced tubal damage and loss of normal function is a contraindication to TCTC. Unblocking the proximal segment in bipolar tubal disease may increase the woman’s chance of an ectopic pregnancy, not an intrauterine implantation. Such patients should be referred directly for ART. In vitro fertilization is also a better choice for couples with severe male factor infertility.

Special Preparation The TCTC is best performed during the early follicular phase of the menstrual cycle when the endometrium is thin and the patient is unlikely to be pregnant. Heavy menstrual bleeding may interfere with accurate assessment of the uterine cavity and the oviducts. The workup prior to TCTC should include HSG

FIGURE 12–1. Algorithm for proximal tubal obstruction (PTO) management. HSG, hysterosalpingography; ART, assisted reproductive technology.

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12. Transcervical Tubal Cannulation

approach using a distension medium and cervical dilatation requires an operating room. The best results are obtained when a coaxial catheter system is used, and the oviduct is penetrated by a thin platinum wire and a 3 French (3F) Teflon catheter advanced over the wire. A double-lumen plastic catheter (7.5F to 12.0F; Cook Ob/Gyn, Spencer, IN) with a balloon is placed in the endometrial cavity via the cervical canal, and the balloon is inflated. One lumen of the catheter allows injection of the radiographic contrast, and the larger port is used to pass other catheters. A 5.5F radiopaque curved catheter (40 cm long, Cook Ob/Gyn) can be used for selective salpingography and as an introducer a curved T-J wire (0.89 mm diameter, 90 cm long, ended with a 1.5 mm Safe-T-J tip, Cook Ob/Gyn) or a 3F catheter (65 cm long, Cook Ob/Gyn) containing a steel wire ended with a platinum tip (0.38 mm diameter, 90 cm long, Cook Ob/Gyn). The exact choice equipment depends on the surgeon’s preference. TCTC with a wire alone yields less effective results followed by lower pregnancy rates. Catheters ended with inflatable balloons for tubal dilatation have also been described. The TCTC catheter system described below is the most practical and widely used in an outpatient setting. It consists of a coaxial catheter system, which is placed in the oviduct under direct fluoroscopy guidance.

Steps 1. Perform HSG. 2. Perform selective salpingography under fluoroscopy. 3. Introduce the coaxial catheter system into the uterine cavity under fluoroscopic guidance. 4. Cannulate radiographically the nonfilling oviduct(s) under fluoroscopic guidance. 5. Assess the radiographic image of the distal portion of the oviduct.

Detailed Description of the Procedure The initial HSG is performed in the usual fashion. Local anesthesia is administered (paracervical block using 1% solution of lidocaine). Additional intravenous conscious sedation with midazolam HCl and fentanyl citrate is recommended. If a double-lumen balloon cannula was used to perform HSG, a 5.5F (40–65 cm long) curved guid-

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ing radiopaque catheter is advanced via the cervical cannula and positioned under fluoroscopic guidance in the uterine cornu with the blocked oviduct. A syringe with radiographic contrast is attached to the end of the cervical catheter, and small amounts of contrast can be injected periodically to improve visualization of the endometrial cavity. If the oviduct fails to fill after direct injection of the contrast during selective salpingography, a T-J wire can be introduced via the 5.5F guiding cannula and placed into the tubal ostium to open it up. Then the T-J wire can be replaced with the inner catheter (3F) containing a guidewire ended with a platinum tip; it is threaded via the outer guiding catheter (5.5F), and the wire tip is then advanced into the tubal ostium. Once this is accomplished, the inner 3F catheter is gently introduced into the isthmus over the guidewire. Advancement of the catheter can be monitored by fluoroscopy. Successful cannulation is signified by the distal oviduct filling with contrast. The procedure is then repeated on the contralateral side when indicated.

Complications Complications with TCTC are relatively rare. The most serious is pelvic infection and salpingitis, which may lead to sepsis. Infection is most likely a flare of a subclinical inflammatory process that was not detected prior to the procedure. Aggressive infectious workup of any febrile episode following TCTC, hospitalization, and administration of therapeutic intravenous doses of broad-spectrum antibiotics may contain the spread and severity of the infectious process. The use of prophylactic antibiotics may reduce the risk of this complication. Perforation of the oviduct with the guidewire has also been described. The surgeon should pay close attention to the direction of the wire while advancing it along the blocked area of the oviduct. Any outpouching of the radiographic contrast may be consistent with an oviduct wall perforation, a false track, or a fistula. Although this complication is relatively rare, it has been observed during laparoscopy performed by a second team during tubal cannulation. The sequelae of tubal perforation during the cannulation procedure are difficult to assess. Excessive exposure to radiation should be avoided. The surgeon should keep track of the total time of x-ray exposure during fluoroscopy and should not extend beyond a total of 10 minutes of exposure.

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TABLE 12–1. Three Methods for Proximal Tubal Obstruction Management. Parameter Cost Hospitalization Technical difficulty Distal oviduct and pelvis evaluation Evaluation of tubal lumen Subsequent fertility Long-term retained tubal patency Subsequent cumulative intrauterine pregnancy rate Risk of ectopic pregnancy Possible complications

Microsurgical anastomosis

IVF

TCTC

Expensive Inpatient Technically difficult and requires hi-tech equipment Gives opportunity to evaluate and correct distal oviduct and pelvis Unable to evaluate the status of tubal lumen Restores long-term fertility 70%

Expensive Outpatient Technically difficult and requires hi-tech equipment No need to correct distal oviduct

Inexpensive Outpatient Technically not difficult

No need to evaluate tubal status Fertility “on-demand” only Not applicable

Unable to evaluate and correct distal oviduct and pelvis Provides information on status of tubal lumen Restores long-term fertility 70%

60%

80%

25–40%

15% Adhesion formation, surgical risks, anesthesia risks

8% Hyperstimulation syndrome, multiple pregnancies

6–10% Oviduct perforation infection

IVF, in vitro fertilization; TCTC, transcervical tubal cannulation.

Conclusion The TCTC procedure is an easy, practical diagnostic and therapeutic procedure for management of PTO. The technical simplicity, low cost, high effectiveness, and low rate of complications make TCTC an attractive alternative to more invasive and expensive laparoscopy or microsurgery (Table 12–1). Each infertility patient with a suspicion of PTO should be offered selective salpingography combined with TCTC as the first-line approach. This approach may eliminate the need for more invasive and costly procedures in many women. The future developments of new instrumentation (e.g., transcervical salpingoscopy, sometimes called falloposcopy; everted catheters; transcervical balloon tuboplasty) may expand and improve the results obtained with TCTC.

Suggested Reading American Fertility Society [presently American Society for Reproductive Medicine]. Guideline for Practice. Tubal Disease. Birmingham, AL: AFS, February 15, 1993. Lang EK. The efficacy of transcervical recanalization of

obstructed postoperative fallopian tubes. Eur Radiol 1998;8:461–465. Letterie GS, Sakas EL. Histology of proximal tubal obstruction in cases of unsuccessful tubal canalization. Fertil Steril 1991;56:831–835. Novy MJ, Thurmond AS, Patton P, Uchida BT, Rosch J. Diagnosis of cornual obstruction by transcervical fallopian tube cannulation. Fertil Steril 1988;50:434– 440. Osada H, Kiyoshi Fujii T, Tsunoda I. Outpatient evaluation and treatment of tubal obstruction with selective salpingography and balloon tuboplasty. Fertil Steril 2000;73:1032–1036. Risquez F, Confino E. Transcervical tubal cannulation, past, present, and future. Fertil Steril 1993;60:211– 226. Thurmond AS, Rosch J. Nonsurgical fallopian tube recanalization for treatment of infertility. Radiology 1990;174:371–374. Thurmond AS. Pregnancies after selective salpingography and tubal recanalization [editorial]. Radiology 1994;190:11–13. Woolcott R. Proximal tubal occlusion: a practical approach. Hum Reprod 1996;11:1831–1833. Woolcott R, Petchpud A, O’Donnell P, Stanger J. Differential impact on pregnancy rate of selective salpingography, tubal catheterization and wire-guided recanalization in the treatment of proximal fallopian tube obstruction. Hum Reprod 1995;10:1423–1426.

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13 Microlaparoscopy for Infertility in the Office Steven F. Palter

Infertility remains a problem of significant magnitude today. In that a major life function, the ability to biologically reproduce, is compromised, this disease represents a major disability to those affected. Moreover, significant secondary psychological trauma often results. Current surveys estimate that approximately 10% of the U.S. population suffer from infertility.1 One of the major etiologic factors in infertility is a pelvic abnormality resulting in tubal blockage. Tubal factor infertility is estimated to be present in 30–40% of women with infertility.2,3 Salpingitis, endometriosis, and postoperative adhesions remain the primary causes.3 For decades gynecologists have searched for accurate, well tolerated, inexpensive methods to determine tubal patency in the office setting. Historically, the first method widely used was the Rubin test, initially described in 1920.4 Here CO2 gas is insufflated through the cervix and uterus and ultimately the fallopian tubes if patent. Patency was determined via measurements of gas pressure or documentation of subdiaphragmatic gas on radiographs. Unfortunately, the test is significantly painful and provides information only on the patency of the tube. This test was later replaced by hysterosalpingography (HSG), also initially described by Rubin.5 Microlaparoscopy in the office under local anesthesia is the most recent technique available for tubal assessment and represents the intersection of two technologies. The first, microlaparoscopy, is the use of sub-5-mm laparoscopes and accessory instrumentation. The second is a technique to perform laparoscopy under local anesthesia, often in nontraditional (i.e., nonoperating room) settings, such as the hospital procedure room or a physician’s office.6–17 The technique of office laparoscopy under local anesthesia is especially suited to meet the current

pressures of quality versus cost in an era of managed care. It is likely that this technique will soon become a major part of the practicing general gynecologist’s diagnostic and operative armamentarium. Office microlaparoscopy under local anesthesia is especially well suited to the evaluation of patients with infertility. Laparoscopy is the preferred diagnostic and therapeutic tool utilized by gynecologists to evaluate peritoneal and tubal factor infertility. This approach allows visualization of the entire abdominal cavity with far less morbidity and risk of adhesion formation than laparotomy.18,19 Common findings in patients with infertility at laparoscopy are endometriosis, adhesions, and evidence of acute or chronic pelvic inflammatory disease. Unfortunately, the basic evaluation of the female pelvis has changed little over the last decade. Currently, evaluation of the status of the fallopian tubes is a standard component of the infertility investigation, and laparoscopy remains the gold standard against which all methods are judged. A survey of practice patterns of nearly 400 board-certified reproductive endocrinologists in the United States confirmed the high prevalence of evaluating tuboperitoneal factors during the infertility evaluation.20 About 96% of practitioners indicated that they always, or almost always, ordered HSG during the infertility workup for new couples seeking fertility treatment. Similarly, the same group of respondents always or almost always performed laparoscopy more than 89% of the time. This represented the third and fourth most commonly performed procedures for evaluating new couples seeking fertility treatment, following only semen analysis and assessment of ovulation. Also indicated by this sample was the almost universal performance of both HSG and laparoscopy for any given couple. Recently, attention 141

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has focused on the cost-effectiveness of each aspect of the evaluation and treatment of the couple with infertility. As such, there has been a general trend to delay or exclude the one test of greatest expense and invasiveness—laparoscopy. As early as 1980 Hulka et al. wrote on the standardization of the infertility workup to “balance the cost-effectiveness of certain empiric treatment trials with the need for the physician to know the nature of the underlying disease.”21 They recommend, among other tests, HSG during initial evaluation of the patient. If any tubal pathology is discovered, laparoscopy was indicated. Otherwise, laparoscopy was delayed until after at least four cycles of successfully induced ovulation. Hulka et al. emphasized that “laparoscopy is indicated at the end of the routine of infertility survey.”21 Again, laparoscopy was to be performed at least 6 months after HSG. They similarly stated that the low incidence of positive findings on routine endoscopy should relegate laparoscopy to the end of the infertility evaluation.21 They concluded, however, that the low cost, minimal invasiveness, and high tolerance of the Rubin test made it preferable to laparoscopy. Today, these same benefits may be realized by office laparoscopy without compromising diagnostic accuracy and maintaining some corrective potential. The primary motivating factor justifying a delay in performing laparoscopy is the belief that what is perceived to be a small yield may not justify the relatively large cost of the procedure or the risks (primarily anesthesia-related). Others believe that alternative, nearly equivalent information can be obtained by less expensive and less invasive tests. Finally, it has been suggested that the era of surgical repair of structurally damaged fallopian tubes is over, replaced by assisted reproductive technologies of presumably higher (at least monthly) fecundity rates. Therefore any evaluation of the role of laparoscopy in the evaluation and treatment of couples with infertility must address the following points: (1) What is the prevalence of tuboperitoneal disease diagnosed by laparoscopy? (2) What is the effectiveness of laparoscopy in treating such disease? (3) What alternative methods of diagnosis are available? (4) What is the comparative sensitivity and specificity of these methods? (5) What is the cost-effectiveness of the decision to include or exclude laparoscopy in the evaluation? Office microlaparoscopy under local anesthesia shifts the cost-benefit balance in favor of the early performance of laparoscopy versus late or no laparoscopy, as demonstrated by an analysis of the “number needed to treat” (NNT).22 Calculation of

the NNT allows economic calculations to be made with regard to the cost of achieving a pregnancy when laparoscopy is performed for unexplained infertility. It has been estimated that the cost per pregnancy is approximately $10,000 for clomiphene administration and intrauterine inseminations, $17,000 for gonadotropin therapy with intrauterine inseminations, and $40,000–$50,000 for assisted reproductive technologies.6 When evaluating the cost of any given therapy the total cost of treatment must be calculated. This includes the physician professional component, anesthesia- and anesthesiologist-related charges, and hospital operating room time and supply charges. Currently, anesthesia and hospital room charges are billed in time intervals. In fact, charges of $10–$20 per minute for hospital room charges alone are not uncommon. Total global charges for diagnostic infertility laparoscopies routinely range from $6,000 to $10,000. At $8000, the total cost per pregnancy would rise to $24,000–$80,000. If office laparoscopy under local anesthesia is performed for a total global fee of $3000, the cost per pregnancy drops to $9,000–$30,000.22 Even at a cost per procedure of $5000 (more than double our current cost), the cost per pregnancy is $9,000–$30,000. When compared to the $15,000–$50,000 for other interventions, office laparoscopy is a cost-effective technique. Currently, HSG remains the most frequent initial screening test used to evaluate tuboperitoneal factors. Unfortunately, there is a large body of literature demonstrating the limited sensitivity and specificity of this test. A study of 433 patients with primary infertility was performed in which all patients underwent HSG and laparoscopy.23 Almost 50% of the population showed some abnormality by either one or both diagnostic methods. Thirty percent of the time the findings on HSG and laparoscopy were discordant. The single most frequent discrepancy (19%) was an abnormality found on laparoscopy that was missed on HSG. A meta-analysis by Swart et al. of 20 retrospective comparisons of HSG and laparoscopy determined point estimates of 0.65 sensitivity and 0.83 for specificity for the evaluation of tubal patency by HSG.24 Swolin and Rosencrantz simultaneously performed laparoscopy and HSG and determined a sensitivity of 0.54 and a specificity of 0.83.25 Opsahl et al. however, demonstrated that even in the normal HSG group a high likelihood (16%) of moderate to severe pelvic disease was found.26 The two most common causes of tuboperitoneal disease are prior pelvic surgery and prior pelvic inflammatory disease (PID). Unfortunately, the his-

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tory and physical examination alone have been shown to be poor predictors of who has such disease. A retrospective study by Rosenfeld et al. of more than 650 laparoscopies for infertility found a poor predictive value of historical risk factors or the physical examination.27 Only 25% of patients with laparoscopically documented chronic PID recollected a prior episode of acute PID. Similarly, the physical examination was equally poor in predicting PID-related adhesive disease. In fact, clinical examination is poorly able to diagnose even acute PID accurately. Studies have demonstrated that nearly one-third of patients with a clinical diagnosis of acute PID had another diagnosis or no disease at all.28–30

History of Laparoscopy Under Local Anesthesia The first reported case of laparoscopy in a human patient was by Jacobaeus of Sweden in 1910 using a Nitze cystoscope.31 The endoscopy took place after establishing a pneumoperitoneum using room air. The first American laparoscopy followed shortly thereafter in 1920, by Orndoff, using a modified thoracoscope passed through a customized trocar. It was a remarkable publication by Short in the British Medical Journal in 1925 that was the first described laparoscopy under local anesthesia outside a traditional medical setting.32 That report described a technique whereby the disadvantages and dangers of laparotomy are avoided by inspecting the abdominal viscera through a cystoscope. The scope is inserted through an infraumbilical incision under strict local anesthesia. It is uncanny how accurately present-day advantages of office laparoscopy under local anesthesia were predicted in that early publication. As Short described32: In a certain number of cases, not many perhaps, there is a far less formidable alternative [to laparotomy]: this is to distend the abdomen with air, which can be done without serious discomfort under a local anaesthetic through a tiny incision, and to inspect the viscera with a cystoscope. . . . The advantages of coelioscopy over exploratory laparotomy are: (1) it can be done without discomfort under novocaine; (2) the incision is so small that it is only necessary to keep the patient in bed for a day or two; (3) no special instruments are needed; (4) it can be done at the patient’s own house; (5) it is available when it would be dangerous to perform laparotomy.

Contrary to common beliefs, this report of laparoscopy under local anesthesia is not an isolated anomaly, and there is a long history in support of

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the safety, feasibility, and advantages of laparoscopy under local anesthesia.10,11,33 Laparoscopy was largely developed as a procedure under local, not general, anesthesia. Perhaps the greatest wealth of literature related to laparoscopy under local anesthesia was published during the 1970s in conjunction with the development of laparoscopic methods of female sterilization. Most early American endoscopists learned the technique of laparoscopy while performing tubal sterilization procedures. Virtually all of the currently employed methods of tubal sterilization were developed as procedures under local anesthesia. More than 80% of the initial procedures using monopolar cautery, bipolar cautery, Silastic bands, and mechanical clips were performed under local anesthesia.12,14,34–36 More dramatic is a combined series of more than 250,000 women who were sterilized in rural camps in India under local anesthesia.6 Despite an average operating time of 6 minutes per patient, sterilization of equipment with boiling water, and make-shift accommodations (often auditoriums or tents), complication and failure rates rival that of standard Western techniques during the same period. Many common procedures have increasingly become outpatient and office-based. Laparoscopy also has been performed in office-based settings under local anesthesia and has been shown to be safe and well tolerated; moreover, it offers many advantages over traditional hospital-based procedures.12,17 Similarly, office laparoscopy using traditionally sized instrumentation under local anesthesia was reported to be associated with a reduction in cost, time, and patient discomfort.12 Refinements in fiberoptic technology have allowed creation of a new generation of microlaparoscopes with diameters less than 5 mm that maintain the optical quality and diagnostic abilities of traditional laparoscopes.37 Faber and Coddington performed a direct comparative study of the diagnostic accuracy of a 1.98 mm fiberoptic laparoscope versus a traditional 10 mm rod-lens scope for diagnostic laparoscopy under general anesthesia.38 Here, diagnostic laparoscopy was performed using the microlaparoscope, and all operative findings were reported. The surgical team was then changed, and subsequent traditional 10 mm diagnostic laparoscopy was performed. Operative findings reported by each surgeon using the microlaparoscopic equipment correlated with the operative findings reported using the traditionally sized equipment. Scores for both endometriosis and adhesions did not differ in any statistically significant way. Direct comparative studies under local anesthesia remain to be performed.

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TABLE 13–1. Results of Office Microlaparoscopy Under Local Anesthesia. Parameter

ALL

CPP

INF

p

Age (years) Gravidity Operating time (min) Recovery time (min) Fentanyl (g) Versed (mg) Pain Scale Score (0–10) 30-Minutes postop pain (0–10) Time to normal activity (days) Time to return to work (days) Time to resume intercourse (days) Postop. meds. usage (tablets ibuprofen)

35.33 0.96 20.85 51.65 81.48 3.20 5.87 1.48 1.88 1.70 4.61 4.88

36.45 1.55 23.91 51.64 90.91 4.00 7.00 3.17 1.73 2.23 5.42 9.45

34.56 0.56 18.75 51.67 75.00 2.66 5.04 0.53 2.01 1.29 4.21 1.53

NS 0.05 NS NS 0.05 0.05 0.05 0.005 NS 0.05 NS 0.005

ALL; CPP, chronic pelvic pain; INF, infertility.

Office Microlaparoscopy for Infertility Infertility is especially suited for the application of office microlaparoscopy in that it has a relatively high incidence of negative or minimal findings. In 1980 it was noted that “by far the largest segment of an unscreened group will reveal either local or absent findings on routine endoscopy.”21 In fact, a physician’s own personal rate of pathology encountered at laparoscopy must be assessed when deciding on the setting in which to perform laparoscopy under local anesthesia. In our center, approximately 20% of patients undergoing laparoscopy have pathology of significant enough magnitude to warrant repeat surgical intervention. It is not uncommon for a general practice to have negative or minimal pathology rates of 10–40%. Selected specialty referral practices, however, may have rates of only 10%. Obviously, this must be taken into consideration when counseling patients. In this regard, some practitioners choose to perform diagnostic microlaparoscopy under local anesthesia in the operating room as a preoperative adjunct to traditional operative laparoscopy. Diagnostic microlaparoscopy is then performed under local anesthesia in the operating room. If no pathology is visualized, the procedure is completed under local anesthesia. If pathology is visualized, however, the patient can then be put under general anesthesia and a formal operative laparoscopy performed. We performed a cohort study on all patients requiring diagnostic laparoscopy as part of their general infertility evaluation (n  27) to determine whether a complete laparoscopic infertility evaluation (including chromopertubation) could be performed under local anesthesia in an office setting.16

Here, office microlaparoscopy under local anesthesia is performed with one or two secondary 2or 3-mm punctures. The pelvis and abdomen are inspected in the same fashion as for traditional laparoscopy. A dilute solution of indigo carmine dye is then injected via the uterine manipulator. Care must be taken to inject the dye slowly to avoid the risk of tubal spasm and false-positive findings. This potential is being investigated on ongoing trials, although initial experience suggests that the occurrence of tubal spasm and false-positive dye perfusion studies is similar to that seen with HSG. This would be expected for laparoscopy under local anesthesia, as the muscle-relaxing effects of general anesthesia are not available. All of these patients reported that they were highly satisfied with the procedure; 96% would repeat the procedure in the office under local anesthesia, and 93% preferred the office laparoscopy to a previous traditional operating room-based laparoscopy. There were no procedures that could not be performed owing to patient or equipment failure, and no procedures required general anesthesia. All aspects of the infertility investigation could be successfully performed including chromopertubation, biopsy of endometriosis, and inspection of all areas of the pelvis and abdomen. The average procedure duration was 18 minutes (range 8–50 minutes). Furthermore, patients were stable enough for discharge within less than 50 minutes. The average patient required minimal to no postoperative medication and fully returned to her usual activities within 24 hours. Analysis of costs demonstrated an approximately 75% reduction in charges compared with traditional laparoscopy. These results suggest that the use of office microlaparoscopy might allow diagnostic laparoscopy to be considered earlier in the infertility investigation. For those who perform

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laparoscopy-guided assisted reproduction technology (ART) procedures such as [gamete or zygote intrafallopian transfer (GIFT, ZIFT) or (TET)], office laparoscopy under local anesthesia can significantly improve the scheduling difficulties and reduce the cost of these procedures. Our experience has indicated that diagnostic laparoscopies performed for the evaluation of infertility are the most well tolerated office laparoscopic procedures.17 This is independent of the presence of associated pathology such as endometriosis or adhesions.

References 1. Sauer MV. Investigation of the female pelvis. J Reprod Med 1993;38:269–276. 2. Witt B. Pelvic factors and infertility. Infertil Reprod Clin North Am 1991;2:371. 3. Trimbos-Kemper T, Trimbos B, van Hall E. Etiological factors in tubal infertility. Fertil Steril 1982;37: 384–388. 4. Rubin I. Nonoperative determination of patency of fallopian tubes in sterility: intrauterine insufflation with oxygen and production of subphrenic pneumoperitoneum: preliminary report. JAMA 1920;75:661. 5. Rubin I. Roentgendiagnostik der uterus tumorens mit hilfe von intrauterine Collargol injecktionen: Vorlaeufige Mitteilung. Zentralbl Gynaekol 1914;38: 658. 6. Metha P. A total of 250,136 laparoscopic sterilizations by single operator. Br J Obstet Gynaecol 1989; 96:1024–1034. 7. Childers J, Hatch K, Surwit E. Office laparoscopy and biopsy for evaluation of patients with intraperitoneal carcinomatosis using a new optical catheter. Gynecol Oncol 1992;47:337–342. 8. Steege J. Repeated clinic laparoscopy for the treatment of pelvic adhesions: a pilot study. Obstet Gynecol 1994;83:276–279. 9. Snabes M, Poindexter A III. Laparoscopic tubal sterilization under local anesthesia in women with cyanotic heart disease. Obstet Gynecol 1991;78:437– 440. 10. Peterson H, Hulka J, Spielman F, Lee S, Marchbanks P. Local vs. general anesthesia for laparoscopic sterilization: randomized study. Obstet Gynecol 1987; 70:903–908. 11. Brown D, Fishburne J, Roberson V, Hulka J. Ventilatory and blood gas changes during laparoscopy with local anesthesia. Am J Obstet Gynecol 1976; 124:741–745. 12. Wheeless C Jr. Outpatient laparoscopic sterilization under local anesthesia. Obstet Gynecol 1972;39:767– 770. 13. Alexander G, Goldrath M, Brown E, Smiler B. Outpatient laparoscopic sterilization under local anesthesia. Am J Obstet Gynecol 1973;116:1065–1068.

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14. Fishburne J, Omran K, Hulka J, Mercer J, Edelman D. Laparoscopic tubal clip sterilization under local anesthesia. Fertil Steril 1974;25:762–766. 15. Fishburne JJ. Office laparoscopic sterilization with local anesthesia. J Reprod Med 1977;18:233–234. 16. Palter S, Olive D. Office laparoscopy under local anesthesia for infertility: utility, acceptance, and costbenefit/outcome analysis. Fertil Steril 1995;64:S8. 17. Palter S, Olive D. Office laparoscopy under local anesthesia for chronic pelvic pain. J Am Assoc Gynecol Laparosc 1996;3:359–364. 18. Lundberg W, Wall J, Mathers J. Laparoscopy in evaluation of pelvic pain. Obstet Gynecol 1973;42:872– 876. 19. Diamond M, Daniell J, Johns D, et al. Postoperative adhesion development after operative laparoscopy: evaluation at early second look procedures. Fertil Steril 1991;55:700–704. 20. Glatstein IZ, Harlow BL, Hornstein MD. Practice patterns among reproductive endocrinologists: the infertility evaluation. Fertil Steril 1997;67:443–451. 21. Hulka J, Israel R, Hoffman J. During the infertility survey, at which period do you feel endoscopy is indicated? Open forum. Int J Fertil 1980;25:1–6. 22. Taylor HS OD. Unexplained infertility: the role of laparoscopy. 1997. 23. Portuondo JA, Pena Irala J, Ibanez E, Echanojauregui AD. Clinical selection of infertile patients for laparoscopy. Int J Fertil 1984;29:234–238. 24. Swart P, Mol BW, van der Veen F, et al. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1995; 64:486–491. 25. Swolin K, Rosencrantz RM. Laparoscopy vs. hysteroscopy in sterility investigations, a comparative study. Fertil Steril 1972;23:270–273. 26. Opsahl MS, Miller B, Klein TA. The predictive value of hysterosalpingography for tubal and peritoneal infertility factors. Fertil Steril 1993;60:444–448. 27. Rosenfeld DL, Seidman SM, Bronson RA, Scholl GM. Unsuspected chronic pelvic inflammatory disease in the infertile female. Fertil Steril 1983;39:44– 48. 28. Jacobson L. Differential diagnosis of acute pelvic inflammatory disease. Am J Obstet Gynecol 1980; 138:1006. 29. Jacobson L, Westrom L. Objectivized diagnosis of acute pelvic inflammatory disease. Am J Obstet Gynecol 1969;105:1088. 30. Bartsich E, Dillon T. Acute pelvic inflammatory disease: laparoscopic assessment. NY State J Med 1981; 81:25. 31. Gunning J. The history of laparoscopy. J Reprod Med 1974;12:222–226. 32. Short A. The use of celioscopy. BMJ 1925;2:254. 33. Rothfusz E, Kitz D, Andrews R, et al. O2sat HR, MAP among patients receiving local anesthesia. Anesth Analg 1988;67:S189. 34. Penfield A. Laparoscopic sterilization under local anesthesia. Obstet Gynecol 1974;12:251.

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35. Yoon I, King T. A preliminary and intermediate report on a new laparoscopic tubal ring procedure. J Reprod Med 1975;15:54–56. 36. Hulka J, Omran K, Phillips JJ, et al. Sterilization by spring clip: a report of 1000 cases with a 6-month follow-up. Fertil Steril 1975;26:1122–1131. 37. Molloy D. The diagnostic accuracy of a microlaparoscope. J Am Assoc Gynecol Laparosc 1995;2: 203–206. 38. Faber BM, Coddington CC III. Microlaparoscopy: a comparative study of diagnostic accuracy. Fertil Steril 1997;67:952–954.

Suggested Reading Group OLS. Postoperative adhesion development after operative laparoscopy: evaluation at early second-look procedures. Fertil Steril 1991;55:700–704. Jansen R. Early laparoscopy after pelvic operations to prevent adhesions: safety and efficacy. Fertil Steril 1988;49:26–31. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217–222.

Palter SF. Microlaparoscopy under local anesthesia and conscious pain mapping for the diagnosis and management of pelvic pain. Curr Opin Obstet Gynecol 1999;11:387–393. Palter SF. Office microlaparoscopy under local anesthesia. Obstet Gynecol Clin North Am 1999;26:109–120, vii. Palter S. Office laparoscopy under local anesthesia. In: Azziz R, Murphy A (eds). New York: Springer, 1997. Perez R-D. Second-look laparoscopy adhesiolysis: the procedure of choice for preventing adhesion recurrance. J Reprod Med 1991;36:700–702. Raj S, Hulka J. Second-look laparoscopy in infertility surgery: therapeutic and prognostic value. Fertil Steril 1982;38:325–329. Rosser J, Olive D, Zreik T, et al. Decreased performance of skilled laparoscopic surgeons at microlaparoscopy versus traditional laparoscopy. J Am Assoc Gynecol Laparosc 1996;3:S44. Rosser JC Jr, Palter SF, Rodas EB, et al. Minilaparoscopy without general anesthesia for the diagnosis of acute appendicitis. J Soc Laparoendosc Surg 1998;2:79–82. Steege J, Stout A. Resolution of chronic pelvic pain after laparoscopic lysis of adhesions. Am J Obstet Gynecol 1991;165:278–283. Tulandi T, Murray C, Guralnick M. Adhesion formation and reproductive outcome after myomectomy and secondlook laparoscopy. Obstet Gynecol 1993;82:213–215.

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14 Treatment of Cervical Stenosis Gary N. Frishman

Cervical stenosis is a condition in which the cervix becomes narrowed and constricted. Although there is no one accepted diagnosis in the literature, the inability to pass a fine probe, endocervical brush, or cotton-tipped applicator and the retention of dye in the uterus following hysterosalpingography (HSG) are acceptable diagnostic tests. Cervical stenosis may follow a cone biopsy or laser surgery for dysplastic changes in the cervix, with reported rates ranging from 1% to 29%.1,2 Higher incidences of stenosis may reflect more aggressive treatment required because of larger, deeper lesions or an earlier learning curve with any given surgical technique. In addition, treatment of intraepithelial neoplasia in a patient with diethylstilbestrol or in a menopausal woman may be more likely to result in cervical stenosis. Inherited conditions and müllerian anomalies may also be etiologic agents. Cervical stenosis is associated with many gynecologic conditions, including dysmenorrhea related to the increased uterine pressure necessary to achieve menstrual flow. The stenosis may also predispose the patient to endometriosis secondary to retrograde menstruation. The stenotic cervix can have a negative impact on fertility. It may compromise the mucus-producing glands and adversely affect the survival of sperm as reflected in a postcoital test. If the transfer of gametes or embryos through the cervix is indicated, the stenosis may lead to an inability to perform these procedures. Finally, poor visualization of the endocervix may lead to inadequate colposcopy, necessitating a cone biopsy, which in and of itself may further potentiate this condition.

Purpose The purpose of treating the stenotic cervix is usually to reverse the preexisting condition. However, prophylactic treatment has been described as well, via placing a temporary cervical stent following a cone biopsy.3

Indications for Treatment of Cervical Stenosis Indications for treatment include non-fertilityrelated issues such as amenorrhea and dysmenorrhea. The inability to view or sample the endocervix (in conjunction with colposcopy) or the endometrium (in conjunction with an endometrial biopsy or dilatation and curettage) are additional indications. From the perspective of fertility, the inability to evaluate the uterus (i.e., to perform HSG) or to transfer gametes or embryos mandate consideration for treatment of any cervical stenosis.

Contraindications Contraindications for treatment of cervical stenosis include active cervical or lower genital tract infection, the presence of a desired preterm pregnancy, or concern about the upper reproductive tract anatomy (i.e., possible previous supracervical hysterectomy or a müllerian anomaly).

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Equipment The following equipment is needed for cervical dilatation. Tenaculum Anesthetic (Xylocaine) Spinal needle Syringe 10 cc Small set of dilators Open-sided speculum To maintain cervical patency, a stem pessary can be considered.4 Although stem pessaries are no longer made, many hospitals (or older gynecologists) may have some available. The Word Catheter (Vioteque, Langhorn, PA) serves as a useful alternative. A suturing tray and 2-0 monofilament permanent suture (Prolene, Nylon) are required for fixation of the stent.

Procedure For initial entry into the uterus for dilation, consideration may be given to concomitant ultrasonography should the cervical canal be obliterated.5 During any procedure to dilate the stenotic cervix, it may be easier to locate the cervical os if the patient comes in during her menstrual period. A paracervical block along with a nonsteroidal medication may help reduce any discomfort. Once the cervix is dilated, the stem pessary may be placed. When the pessary is to be sutured into the cervix, it may be easier to first place the sutures through the pessary, then suture the cervix at the desired location, and finally pass the pessary down along the sutures (similar to a gondola) into the cervical canal. This technique is easier than attempting to pass a needle in the confined space of the vaginal fornix through the pessary when it is already in place in the cervix. The stem pessary should be left in for approximately 6 weeks. The patient is placed on prophylactic antibiotics (doxycycline 100 mg PO bid) during this time. If the patient is actively trying to conceive she can be counseled that, although not the standard of care, it is probably acceptable to become pregnant during this time. If the cervix cannot be cannulated, a laser should be considered to evert the cervix. A CO2 laser with a small fixed spot size at a power density setting of 20 watts/cm2 is used to remove a 1 cm cylinder along the site of the obliterated os. It may be facilitated by passage of a extremely fine sound or

probe. Treatment is continued along the probe to a depth below which the stenosis is no longer present. Topical estrogen supplementation may be considered in menopausal women. Alternative techniques for the stenotic cervix depend on the specific goal. For visualizing the uterus as part of an infertility evaluation, consideration may be given to HSG using a modified technique. A 3.5 French (3.5F) Tom Cat catheter (Sherwood Medical, St. Louis, MO) is passed through the usual acorn tip, permitting installation of dye through this more narrow aperture.6 Alternatively, the acorn tip may be shaved down with a tenaculum placed on either side of the cervix to allow a good approximation and seal, following which the dye usually finds its way up into the uterus. If the goal is to perform adequate cervical sampling, consideration may be given to using a moist urethral swab. This swab is on a stiff wire stem and is supplied with some chlamydial culture sets (VIDAS Chlamydia Collection Kit; Medical Packaging Corporation, Camarillo, CA). The urethral swab’s small size often permits entry into the cervix. It may also be used as a malleable probe, as the wire can be bent. If colposcopy is necessary when there is an inability to visualize the endocervical canal (despite use of an endocervical speculum), consideration may be given to placing an extra thin laminaria.7,8 When using a Laminaria japonica, moistening it before insertion speeds the dilation process. Regardless of the type of laminaria used, it should be able to be removed 30 minutes to several hours following placement with adequate dilatation achieved for visualizing the endocervix. Cervical stenosis may also present during menopause as an endometrial fluid collection. If this accumulation results from a stenotic cervix, the fluid is likely to be a benign condition if the endometrial stripe is less than 3 mm.9

Complications Complications principally relate to perforation of the uterus during dilation. If this occurs, the patient should be followed for bleeding and infection. Some patients experience a vasovagal reaction to cervical manipulation. Although failure to complete the procedure is not generally considered a complication, the patient should be counseled about the possibility of an unsuccessful procedure. Should the cervix not be able to be dilated adequately as a single procedure in the office, options include serial progressively

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aggressive dilations with or without an extra thin laminaria or taking the patient to the operating room. Although reocclusion of the os is also not a complication, the patient should be followed up 4–6 weeks following removal of the stent or after any dilatation to make sure the cervix is still patent. Serial cervical dilations can subsequently be performed in the office if there is a concern about restenosis.

Conclusions The stem pessary or Word Catheter is useful for treating cervical stenosis. Following completion of this procedure and confirmation of the maintenance of cervical patency, the patient may undergo intrauterine insemination or embryo transfer as indicated. Some techniques exist to assist in the performance of HSG. Dysmenorrhea, if resulting from cervical stenosis, should be relieved. Adequate cervical sampling and colposcopy can often be performed in women with cervical stenosis. If so, it avoids a cone biopsy and the likelihood of progression of this condition.

References 1. Baggish MS, Dorsey JH, Adelson M. A ten year experience treating cervical intraepithelial neoplasia with the CO2 laser. Am J Obstet Gynecol 1989;161:60–68. 2. Byrne GD. Cone biopsy: a survey of 100 cases. Aust NZ J Obstet Gynaecol 1966;6:266–270. 3. Luesley DM, Redman CWE, Buxton EJ, et al. Prevention of post-cone biopsy cervical stenosis using a temporary cervical stent. Br J Obstet Gynaecol 1990; 97:334–337.

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4. Frishman GN. The use of the stem pessary to facilitate transcervical embryo transfer in women with cervical stenosis. J Assoc Reprod Genet 1994;11:225–228. 5. Hornstein MD, Osathanondh R, Birnholz JC, et al. Ultrasound guidance for selected dilatation and evacuation procedures. J Reprod Med 1986;31:947–950. 6. Rosenwaks Z, Sultan KM, Davis OK. A novel technique for cervical cannulation during hysterosalpingography. Fertil Steril 1993;59:1329–1330. 7. Stern JL. Preventing cervical conization by achieving satisfactory colposcopy with hygroscopic cervical dilators. Am J Obstet Gynecol 1990;163:176–177. 8. Johnson N, Crompton AC, Wyatt J, et al. Using Lamicel to expose high cervical lesions during colposcopic examinations. Br J Obstet Gynaecol 1990;97:46–52. 9. Goldstein SR. Postmenopausal endometrial fluid collections revisited: look at the doughnut rather than the hole. Obstet Gynecol 1994;83:738–740.

Suggested Reading Baldauf JJ, Dreyfus M, Ritter J. Risk of cervical stenosis after large loop excision or laser conization. Obstet Gynecol 1996;88:933–938. Barbier RL. Stenosis of the external cervical os: an association with endometriosis in women with chronic pelvic pain. Fertil Steril 1998;70:571–573. Glatstein IZ, Pang SC, McShane PM. Successful pregnancies with the use of laminaria tents before embryo transfer for refractory cervical stenosis. Fertil Steril 1997;67:1172–1174. Groutz A, Lessing JB, Wolf Y, et al. Cervical dilatation during ovum pick-up in patients with cervical stenosis: effect on pregnancy outcome in an in vitro fertilizationembryo transfer program. Fertil Steril 1997;67:909– 911. Noyes H. Hysteroscopic cervical canal shaving: a new therapy for cervical stenosis before embryo transfer in patients undergoing in vitro fertilization. Fertil Steril 1999;71:965–966.

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15 Treatment of Male Reproductive Dysfunction in the Office Hossein Sadeghi-Nejad and Robert Oates

Increased awareness of fertility issues and technologic advances in the field of infertility have resulted in a major increase in the number of couples seeking treatment. Proper assessment and correction of male factors contributing to infertility is required as part of the complete evaluation for the infertile couple. A male factor can be identified in almost 50% of infertile couples. This chapter reviews some of the foundations of diagnosis and treatment for male factor infertility. Procedures that are more optimally performed in the operating room with anesthesia monitoring are briefly discussed. Treatment modalities that can be performed efficiently in the office setting are reviewed in more detail.

History A thorough history helps elucidate the etiology of reproductive dysfunction before initiating a treatment regimen. Surgical and nonsurgical causes of infertility should be assessed (Table 15–1). In patients with oligospermia or oligoasthenospermia (decreased sperm count and motility) various risk factors should be considered and the offending agents eliminated if possible. See Chapter 3 for a more complete discussion.

Physical Examination A careful physical examination is crucial for determining diagnosis and directing therapy. Obvious findings include the number, location, size, texture, and consistency of the testes; the presence or absence of vasa deferentia; the presence or absence and the grade of varicoceles; and the penile/ure150

thral anatomy. Small testes with a soft consistency are typically indicative of compromised spermatogenesis. Inability to palpate the vasa is the hallmark of congenital bilateral absence of the vas deferens (CBAVD.) Subtle findings center around delicate palpation of the epididymis to describe its length and degree of fullness. An indurated or engorged vas deferens or epididymis may be indicative of a distal obstructive process. Varicocele refers to dilated veins of the pampiniform plexus and is seen in approximately 40% of infertile men. Varicoceles may affect the quantity and quality of spermatogenesis and are left-sided in 80% of patients (18% are bilateral).

Laboratory Evaluation The semen analysis provides valuable clues during assessment of the infertile man. Low semen volume (1 ml) in an azoospermic patient typically points to ejaculatory duct obstruction (EDO) or vasal aplasia/anomaly. Examples of the latter include CBAVD, in which mesonephric duct developmental pathology also affects seminal vesicle formation and hence seminal volume. EDO may be secondary to congenital causes such as midline prostatic cysts of müllerian origin or acquired causes such as previous prostatic inflammatory/infectious processes. Normal semen volume azoospermia usually implies abnormal spermatogenesis or an obstructive process blocking the flow of sperm. Etiologies of ductal occlusion include prior vasectomy, postinflammatory tubular stenosis, and Young syndrome. Nonobstructive azoospermia is typically accompanied by elevated follicle-stimulating hormone (FSH) values and has a variety of causes, both genetic (e.g., Klinefelter syndrome, XX male syndrome, deletion of the

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15. Treatment of Male Reproductive Dysfunction in the Office TABLE 15–1. Risk Factors for Male Reproductive Dysfunction Cryptorchidism Testicular trauma, torsion, cancer Sexually transmitted diseases Epididymitis Adult-onset mumps Alcohol, drug, or tobacco abuse Spinal cord injury Scrotal irradiation Pediatric hernia repair Chemotherapy Prostatitis Urinary tract anomalies Medications Environmental toxin exposure Retroperitoneal surgery Systemic medical illness

DAZ gene cluster on the Y chromosome) and acquired (e.g., chemotherapy, viral orchitis, radiotherapy).

Basic Review of Male Reproductive Physiology Spermatogenesis The production of mature spermatozoa from spermatogonia in the seminiferous tubule is termed spermatogenesis. Two meiotic reduction divisions take spermatogonia through the primary and secondary spermatocyte stages to the haploid spermatid. Spermiogenesis is a morphologic alteration of the spermatid to form the mature spermatozoan. Nuclear elongation and flattening, acrosome formation, and shedding of residual cytoplasm are some of the events that comprise spermiogenesis.

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at its distal end (the ampulla) before joining the duct of the seminal vesicle to form the ejaculatory duct. The ejaculatory duct pierces the prostatic capsule and finally opens up at the verumontanum.

Ejaculatory Neurophysiology Emission, bladder neck closure, and antegrade propulsion constitute the three phases of ejaculation. Emission consists of seminal fluid deposition into the posterior urethra and is under sympathetic control (T12–L2). Bladder neck closure is the second phase of ejaculation and prevents reflux of the ejaculate into the bladder. It is also dependent on sympathetic innervation. The final phase of ejaculation, antegrade propulsion, which involves urethral expulsion of the ejaculate by contraction of the periurethral musculature, is mediated by somatic efferents from S2–4. These processes and inputs from higher cerebral locations and various sensory stimuli are integrated at the ejaculatory reflex center (T12–L2). This controls the temporal sequence of neuronal firing during the ejaculatory event.

Treatment Strategies for Male Reproductive Dysfunction Nonmedical treatment of the infertile male patient may be subdivided into those procedures that can be performed in the office setting and those that are generally done in the operating room. Although most surgical procedures for male infertility can be accomplished with local anesthesia, the use of mild intravenous sedation and monitoring in the operating room is recommended for certain procedures, as follows.

Ductal System Sperm Transport Once sperm are produced in the seminiferous tubules in the parenchyma of the testis, continuous fluid flow moves the newly released sperm into the intratesticular rete testis. Arising from the rete testis, six to eight efferent ducts emerge from the testicular capsule to form the caput epididymis. The individual efferent ducts coalesce into a single, highly coiled epididymal tubule that forms the corpus and cauda epididymis. The tubule acquires a thicker muscularis and becomes the convoluted vas deferens, which gradually straightens out to form the vas deferens proper. The vas travels up and out of the scrotum and turns back at the internal inguinal ring to enter the pelvis. The vas corkscrews

Varicocelectomy Operative approaches for varicocelectomy include standard inguinal, subinguinal, retroperitoneal (high ligation), and laparoscopic approaches. Regional or general anesthesia is typically required for the laparoscopic, high ligation, and standard inguinal approaches. The subinguinal incision may be easily performed with local anesthesia and a small amount of intravenous sedation. Patient comfort is clearly enhanced when the latter is employed. We recommend use of the operating microscope to minimize the chances of testicular artery or lymphatic injury. Clips or ties may be used to occlude the dilated venous segments. It should be men-

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tioned that varicoceles may also be treated with percutaneous venous embolization performed by an interventional radiologist. Vein occlusion is achieved by means of coils or detachable balloons.

Microsurgical Reconstruction Microsurgical reconstruction with local anesthesia and intravenous sedation is performed in previously vasectomized patients and those with congenital or postinflammatory epididymal obstruction. The success of vasectomy reversal depends on the surgeon’s skill and the number of years elapsed since the vasectomy. Patency rates are superior to pregnancy rates because the latter may be adversely affected by female factors and sperm quality. Although some surgeons insist on observing viable spermatozoa at the anastomotic site (hence moving proximal to the epididymis in some cases for vasoepididymostomy), others perform vasovasostomy even if no fluid/sperm is observed in the proximal vasal limb. For congenitally obstructed patients, microsurgical reconstruction usually entails vasoepididymostomy because the level of occlusion to sperm flow is typically found in the epididymis. Although it is possible to use local anesthesia alone, the patient is required to be perfectly still for prolonged periods of time. In addition, the operating microscope is not an item that most surgeons have in an office setting, dictating that this procedure be carried out in an operating room environment.

Transurethral Resection for EDO Transurethral resection for EDO (TURED) involves TUR of the dilated intraprostatic ejaculatory ducts or of midline cystic structures. It must be performed in the operating room under general or regional anesthesia after the obstructing anatomy has been carefully defined with transrectal ultrasonography (TRUS). Whereas complete EDO presents as low-volume azoospermia, severe oligoasthenospermia may be seen in partial forms of EDO. Cyst unroofing at the level of the verumontanum allows decompression of the cyst and relieves ductal obstruction. Ejaculatory duct incision is carried out in cases where no cyst is identified. If TRUS demonstrates fibrosed, nondilated ducts, TUR is not likely to be helpful. Transrectal-guided aspiration of the seminal vesicles (into which sperm has collected secondary to downstream blockage of the ejaculatory duct) or the vasal ampullae has been reported as a treatment for these situations. In gen-

eral, this sperm is of poor quality, and even its use in conjunction with intracytoplasmic sperm injection (ICSI) results in few pregnancies. When TURED is not an appropriate option, microsurgical sperm aspiration from the proximal ductal system with cryopreservation is the most direct treatment strategy to consider to obtain viable sperm.

Office Procedures Penile Vibratory Stimulation Penile vibratory stimulation (PVS) is the first-line treatment modality in spinal cord injury patients suffering from anejaculation. It is used to provide a semen specimen via stimulation of the ejaculatory reflex center (Fig. 15–1).

Indications Spinal cord injury patients whose lesion is above or at T10 and who have active lower extremities are candidates for penile vibratory stimulation. These patients usually have intact sympathetic outflow and thus normally innervated vasal ampullae, prostate, seminal vesicles, and bladder neck. Because of the high level of injury, the ejaculatory integration center at T12–L1 and its associated tracts are typically not affected, nor are the sensory afferent or efferent nerves entering and exiting the cord at S2–4. Inactivity of the lower cord, demonstrated by an atonic bladder or flaccid lower extremities, is correlated with low PVS success rates. PVS success/failure rates are illustrated in Figure 15–2.

Contraindications Severely dysreflexic patients who are unable to be easily controlled pharmacologically should not have PVS. Autonomic dysreflexia stimulated by ejaculation is seen in patients with lesions above the T6 neurologic level. Dysreflexia occurs when sympathetic nervous system activation induced as part of the ejaculatory event is poorly regulated and incompletely controlled. Hypertension, pounding headache, diaphoresis, and a vagal counterresponse bradycardia are clinical signs of significant autonomic dysreflexia. Head elevation and cessation of the vibratory stimulus usually ends the dysreflexic episode. Pretreatment with calcium channel blockers prior to PVS is needed in certain circumstances.

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FIGURE 15–1. Ejaculatory reflex neurophysiology. The motor division of the pudendal nerve carries efferent fibers from the sacral cord to the perineal and periurethral musculature. The sensory division of the pudendal nerve contains the afferent fibers responsible for transmission of stimuli to the sacral cord. Integration of ejaculatory events is performed by the ejaculatory reflex center near T12. Seen exiting the thoracolumbar cord are the sympathetic neurons innervating the vasal ampullae (VA), seminal vesicles (SV), and the bladder neck. BC, bulbocavernosus muscle; IC, ischiocavernosus muscle. (From Seffel et al., 1991, with permission)

Equipment A hand-held vibrating massage unit with a conical tip is satisfactory for most patients (Fig. 15–3). Vibrators with these features are readily available in retail specialty stores. The small surface area of the conical contact point ensures high stimulation to the frenulum. Large, round-headed vibrators are not as effective.

Procedure

FIGURE 15–2. Penile vibratory stimulation (PVS) success/failure rates with regard to the level of injury.

The bladder must be catheterized and emptied before stimulation. A small volume of medium appropriate for sperm survival may be left in the bladder, although most stimulations result in antegrade ejaculate flow. The vibrator tip is gently pressed against the frenular area on the undersur-

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of the vasal ampullae and seminal vesicles. The sample may then be processed for IUI, in vitro fertilization (IVF), or ICSI.

Indications FIGURE 15–3. Hand-held vibrating massage unit with a conical tip for penile vibratory stimulation.

face of the glans penis and moved slowly from side to side. Abdominal muscle spasticity or a sudden increase in the tumescence and rigidity of the reflex erectile response indicates that the vibrator is correctly placed and heralds impending ejaculation. The antegrade seminal fluid discharged is collected into a sterile container for analysis and possible processing. Once deemed successful and safe, the couple is instructed about how to perform the technique so all subsequent specimen collections do not require the assistance of the original practitioner. If the couple is using the semen for home selfinsemination, PVS is carried out by the couple themselves during the ovulatory window. If intrauterine insemination (IUI) or in vitro technologies are being employed, the man simply collects the seminal fluid and presents it to the reproductive laboratory at the appropriate time.

Comments Complications include autonomic dysreflexia, as described above. In summary, PVS is a simple, inexpensive, safe modality for treating anejaculation in spinal cord-injured patients with lesions above T10. It is less effective in those with lower cord lesions as various limbs of the reflex arc are disrupted. The best aspect is that the patient and his partner can be taught how to collect the samples themselves, divorcing them from the requirement of medical intervention. For the anejaculatory patient in whom PVS has failed, rectal probe electroejaculation (EEJ) and direct sperm harvesting should be considered. In patients who are insensate in the rectal area, EEJ may be done in the office setting without anesthesia. It is the next logical treatment modality.

Rectal Probe Electroejaculation Rectal probe electroejaculation (RPE) is used to provide a semen specimen by induction of electrically mediated contractions of the smooth muscle

The RPE procedure provides the means for semen retrieval in spinal cord-injured patients in whom PVS has failed, regardless of the level of their lesion, above or below T10. It is also employed in patients with testicular cancer who have undergone retroperitoneal lymph node dissection and are anejaculate due to disruption of the periaortic sympathetic chain, which innervates the vasal ampullae and seminal vesicles. Other candidates include patients with transverse myelitis, multiple sclerosis, diabetes mellitus, or myelodysplasia who also suffer from an inability to initiate emission. The only patients who are appropriate candidates for office RPE are those spinal cord-injured men who are insensate in the rectal area and who do not demonstrate uncontrollable autonomic dysreflexia upon stimulation.

Contraindications The RPE procedure is strictly contraindicated in men with ongoing anorectal pathology that is potentially exacerbated by electrical stimulation or that precludes easy insertion of the rectal probe. Diabetic men with calcification of the distal vasa and ejaculatory ducts usually do not respond to external electrical stimuli with a contraction as the smooth muscle in the walls of the target structures is nonfunctional. RPE should not be performed in the office setting in patients who have sensation in the rectal area or who have uncontrollable autonomic dysreflexia and require intravenous pharmacotherapy.

Equipment An RPE unit developed by Seager and associates (National Rehabilitation Hospital) is typically employed (Fig. 15–4). A similar computerized version has been developed by others to deliver electrical pulses rhythmically to the target area. The Seager model consists of a rectal probe attached to a power unit with a transformer that allows changes in the current and voltage output. Three electrodes deliver and pick up the current. A thermometer embedded into the rectal probe helps monitor the rectal temperature to avoid thermal injury. The delivered current is displayed on the power unit and can be modified accordingly with the power knobs by the

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Comments

FIGURE 15–4. Rectal probe electroejaculator unit developed by Seager and associates, National Rehabilitation Hospital.

operator. The safety profile of this series of units is excellent when used with proper instruction.

Procedure With the patient in the dorsal lithotomy or lateral decubitus position, the bladder is catheterized and emptied. Further washing is done with 20–25 ml of buffered solution; another 25 ml aliquot is left indwelling in the bladder for later sperm retrieval, if necessary. The lubricated 1.25 inch rectal probe is gently inserted into the anorectum such that the electrodes are facing anteriorly toward the prostate and the seminal vesicles (Fig. 15–5). Smaller probes may be employed if the rectum is contracted and defunctionalized. Some authors recommend anoproctoscopy to examine the rectal mucosa prior to probe insertion. Gradually increasing pulsatile stimulations to a maximum voltage of 20 V and a maximum current density of 400 mA are delivered while monitoring the rectal temperature. The latter should not rise above 39°C. A sterile container is used to collect the antegrade seminal fluid, which usually simply drips from the meatus. There is no periurethral muscular contraction, only electrically induced emission. The bladder neck is probably stimulated as well to coapt and prevent retrograde flow. More semen is occasionally obtained by catheterizing the bladder at the end of the procedure and collecting any retrograde fraction. This necessarily occurs if the patient has had a prior transurethral resection of the bladder neck. The specimens are then used for IUI, IVF, or ICSI. The choice of which adjunctive technique to employ depends not only on the semen parameters but also on any concomitant female and financial issues.

Complications include autonomic dysreflexia, as described above. Preprocedure treatment with calcium channel blockers can prevent the onset of autonomic dysreflexia or blunt its severity in those prone to its development. However, aborting the procedure and removing the rectal probe is still the best way to resolve an acute situation most expeditiously. Other complications include minor anorectal burns and lacerations, urinary retention, and rectal perforation, all of which are potential problems but in actuality are seen only rarely. The RPE procedure is a safe, highly effective treatment for anejaculation secondary to upper motor neuron and lower motor neuron dysfunction. The result of stimulation is an electrically induced contraction of the vasal ampullae and seminal vesicles. In this way, semen can be harvested for use with a variety of adjunctive reproductive techniques. Direct epididymal sperm aspiration is the next appropriate therapeutic maneuver in patients who have failed RPE. Table 15–2 lists pregnancy rates and adjunctive reproductive techniques employed in couples in whom the male partner is spinal cordinjured.

FIGURE 15–5. Patient positioning and insertion of the rectal probe electroejaculator. (From Goldstein, 1995, with permission)

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TABLE 15–2. Pregnancy Rates and Adjunctive Reproductive Techniques Employed in Couples in whom the Male Partner is Spinal Cord-Injured: PVS and RPE Technique

Total no. of cycles

Successful couples/total (no.)

Pregnancy rate/cycle (%)

—

5/8

—

11 6 19 9 5

0/6 1/4 4/8 5/6 2/7

0 17 21 56 29

Self-insemination Intrauterine insemination Natural cycle Clomiphene citrate Human menopausal gonadotropin Gamete intrafallopian transfer In vitro fertilization

Source: Adapted from Nehra et al. J Urol 1996;155:554–559. PVS, penile vibratory stimulation; RPE, rectal probe electroejaculation.

Analysis and Processing of Retrograde Ejaculates The purpose of analyzing retrograde ejaculates is to diagnose retrograde ejaculation and treat it by means of sperm retrieval from the postejaculate urine.

Indications Patients with retrograde ejaculation who have failed pharmacologic induction of bladder neck coaptation can have their retrograde specimens optimized for use with any one of a number of adjunctive reproductive techniques. Table 15–3 lists various anatomic and neuropathic etiologies of retrograde ejaculation. In all of these circumstances emission is intact, so vasal and seminal vesicle contraction occurs and seminal fluid is deposited into the prostatic urethra. During the rhythmic periurethral muscular contraction, however, the circular muscle fibers of the bladder neck do not coapt to prevent retrograde flow of the seminal fluid. Anatomic causes of retrograde ejaculation include those surgical procedures that, as a direct consequence of their intent, permanently fix the

bladder neck in an open position. Transurethral resection of the prostate or the bladder neck and prior Y-V-plasty of the bladder neck are some of the anatomic causes of retrograde ejaculation, but it should be noted that most of these patients are able to void on their own and there is no need for catheterization to obtain the postejaculate urine. It is only when alkalinization through oral bicarbonate therapy or postejaculatory voiding into an appropriate buffer solution does not successfully provide an optimal sperm specimen that the need arises for instillation of buffer/medium into the bladder prior to ejaculation to establish the best possible mileu that can be achieved.

Contraindications Patients with acute bacterial prostatitis should not be catheterized, as the infection may become systemic and more severe. Although severe meatal anomalies or urethral stricture may preclude successful catheterization, these conditions are not strict contraindications for bladder catheterization.

Equipment The equipment required includes a Foley catheter and sperm medium.

TABLE 15–3. Etiology of Retrograde Ejaculation Neurologic causes Spinal cord injury S/P retroperitoneal lymph node dissection Diabetes mellitus Transverse myelitis Multiple sclerosis Pharmacologic (-sympatholytic medications) Idiopathic Anatomic causes Prior Y-V-plasty of the bladder neck Transurethral resection of the prostate Transurethral resection of the bladder neck

Procedure Retrograde ejaculation is diagnosed by microscopically evaluating the postejaculate urine specimen. The patient should void to completion, ejaculate, and void again as soon as possible after ejaculation. In this way only a small amount of urine comes into contact with the seminal fluid when it travels in a retrograde fashion. In addition, processing of the specimen is made easier because of the reduced volume. It should be spun down and

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the pellets joined and resuspended to 1 ml final volume. Sperm density and motility are then determined. To optimize the milieu of the sperm when they are used for IUI or other assisted reproductive technology, it is necessary to alkalinize the urine component by having the patient ingest bicarbonate (650 mg tablets  4) approximately 1 hour prior to the anticipated ejaculation. This often maximizes the motility by reducing the harmful effects of urine acidity. If the pH is in the normal range of 7.0–8.5 and the motility is still poor, it may be worthwhile to instill 30 ml of an approved sperm-processing medium into the bladder via catheter prior to ejaculation. Addition of an albumin source can further stabilize the sperm membrane and may add to improved sperm vitality. If the patient is able to initiate voiding on his own, the urine/medium/semen mixture is processed as soon as it is available from the patient, usually within 10–15 minutes following ejaculation.

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In an obviously obstructed circumstance, the preliminary testis biopsy is not required prior to undertaking definitive reconstructive microsurgery. In the clearly nonobstructive azoospermic man, a preliminary biopsy serves only to prove that spermatogenesis is deficient; it does not prove that sperm will or will not be found at the time of testicular sperm extraction (TESE). Therefore testis biopsy is rarely indicated as a sole, separate procedure. For the purposes of this chapter, the focus is on performance of a testis biopsy in the office setting when testis tissue is being harvested for analysis, processing, and possible cryopreservation or simultaneous use as the sperm source for ICSI. It can be performed in nonobstructed and obstructed patients. Of importance is the concept that when reconstructive microsurgery is a possibility for the obstructed patient, it should always be viewed as the first option, as it gives the couple many more choices and affords them the opportunity to achieve pregnancy through natural means. There are both open and percutaneous approaches.

Complications This is a minimally invasive procedure where the only possible complications are those associated with bladder catheterization.

Comments Urine processing for retrieval of postejaculate sperm in patients with retrograde ejaculation in whom -sympathomimetic medication does not restore antegrade sperm flow is safe and minimally invasive. Many such patients are able to achieve pregnancies in conjunction with adjunctive reproductive techniques. To optimize the condition of the sperm, rare patients benefit from instillation of sperm-processing medium with albumin directly into the bladder prior to ejaculation, which requires catheterization.

Testicular Biopsy/Testicular Tissue Extraction for Azoospermia A biopsy of the testis has long been the traditional mode of evaluating spermatogenic potential in the azoospermic patient. The histologic pattern seen upon pathologic review allows one to differentiate between obstructive and nonobstructive causes of azoospermia. However, many clinical clues allow the same assessment to be made without the need for an invasive biopsy, including the physical characteristics of the testes, vasa, and epididymides and the hormonal values, most specifically FSH.

Indications In the obstructed patient, if testicular tissue must be harvested, it is retrieved at the time of reconstruction. In the patient with spermatogenic failure as the etiology of azoospermia, testis biopsy (for histologic analysis) can be performed at the same time as testicular tissue extraction for the purpose of identifying individual whole spermatozoa for use with ICSI. Although a small amount of intravenous sedation nicely supplements local anesthesia, this procedure may be carried out in the office setting where only local anesthesia is available. Certain patients are not appropriate candidates for this approach (see below). If tissue is being harvested for use with ICSI that day or for analysis and cryopreservation (if sperm are found) for use with ICSI at a later date, coordination with the embryology laboratory is of the utmost importance. If there has been no prior documentation that the patient with nonobstructive azoospermia actually has whole spermatozoa in his spermatogenic epithelium, it is not wise to schedule a simultaneous ICSI procedure. In the event no sperm are found, the physical and fiscal investment the couple has made to get to that point is all for naught. It is best to extract the tissue prior to an ICSI cycle and cryopreserve it. If sperm are found in sufficient quantity, the frozen–thawed sample can serve as the sperm source for a subsequent ICSI. Alternatively, a fresh sample can be obtained on the day of oocyte harvest, secure in the knowledge that

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there have been sperm found at an earlier date and that there is tissue available to supply that sperm should no sperm be found that day. Open approaches are favored in patients with nonobstructive azoospermia because the volume of tissue obtained is much greater, an important consideration when spermatogenesis is so limited.

Contraindications Although not strictly a contraindication, in the patient with exceedingly small testes or a small solitary testis, care must be taken to preserve enough testicular tissue to support adequate testosterone production by the Leydig cells located in the interstititum between the seminiferous tubules. It would be a drastic outcome if the patient were left hypoandrogenic and required life-long testosterone replacement. Certain patients are not good candidates for office-based scrotal procedures. They tend to pull up on their testes and are extremely uncomfortable. With testicular compression, a vagal response may be elicited resulting in severe bradycardia. Each case must be individualized in terms of the man’s ability to have his operation in a setting away from monitored anesthesia care.

Procedure For an open biopsy, if it is combined with TESE, the procedure must be coordinated with the embryology laboratory for tissue processing. Local anesthesia is obtained by instilling bupivacaine 0.25% (7–10 cc) into the spermatic cord near the pubic tubercle. Approximately 5 cc of the anesthetic is injected subcutaneously along the intended incision line. Standard skin preparation and draping are performed, followed by a small (approximately 1.5 cm) transverse skin incision while the assistant holds the testicle taut against the overlying skin (Fig. 15–6). The tunica vaginalis is similarly incised; the skin, dartos layer, and tunica vaginalis edges are held apart with an eyelid retractor. A no. 11 blade is used to make a 0.5 cm transverse incision into the tunica albuginea on the anterior surface of the testis. Gentle compression of the testis helps extrude and expose an adequate tissue sample, which is subsequently grasped with jewelers forceps and excised using iris scissors. A drop of sperm medium is placed on a glass slide, and the excised tissue is blotted on its surface for “wet

Equipment The equipment requirements differ depending on whether an open or percutaneous approach is selected. Open approach: bupivacaine 0.25% (7 cc); 25gauge needle; sterile preparation kit; scalpels (11 and 15 blades); eyelid retractor; jewelers’ forceps; small, sharp tissue scissors; glass microscope slides; cytofixative; phase contrast microscope with 400 magnification; Bouin’s solution (picric acid, acetic acid, formaldehyde); test yolk buffer (TYB; Irvine Scientific, Santa Ana, CA); 12 ml conical tubes; cauterizing instrument; catgut suture (4-0) Percutaneous approach: bupivacaine 0.25% (7 cc); 25-gauge needle; sterile preparation kit; glass microscope slides; cytofixative; phase contrast microscope with 400 magnification; Bouin’s solution (picric acid, acetic acid, formaldehyde); test yolk buffer (TYB; Irvine Scientific); 12 ml conical tubes; Vim Silverman needle, Tru-Cut needle, Biopty gun (Bard Urological), or other self-designed instruments for tissue extraction/ aspiration.

FIGURE 15–6. Testicular positioning and incision for open biopsy. (From Goldstein, 1995, with permission)

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prep” analysis. If no sperm are seen, a second specimen may be similarly excised from a different location on the ipsilateral testicle. Lack of sperm in this sample mandates contralateral TESE because there is no guarantee that the embryology laboratory will be more successful in finding testicular sperm despite a more extensive and intensive search. For therapeutic purposes, the tissue is minced into small segments and placed in a conical tube containing 1 ml of TYB for laboratory analysis and possible cryopreservation. A 0.3 mm piece is placed in Bouin’s solution for formal histologic analysis. The percutaneous biopsy is performed by injecting 2–3 cc of local anesthetic into the scrotal skin in the intended biopsy area. The scrotal skin may be incised for a tiny distance prior to the actual firing of the biopsy device to prevent inclusion of skin in the final specimen. It is important to consider the trajectory of the needle device (lateral to medial) such that the epididymis is not accidentally injured. Tissue is processed as above for the wet preparation, formal histologic analysis, and therapeutic uses. The biopsy site is compressed for 5–10 minutes for hemostasis.

Comments Incisional or biopsy site bleeding/hematoma may be encountered. Temporarily decreased sperm density has been reported but has not been clinically significant. Blood contamination of the specimen is a potential problem and makes processing and sperm extraction more difficult in cases where ICSI is planned. Testicular biopsy is a safe, well tolerated procedure that may be performed in the office setting and may be combined with therapeutic TESE. Because of the larger specimen size for histologic analysis and use with ICSI, the open technique is superior to a blind percutaneous biopsy in most instances. If no sperm are retrieved from the testicular tissue, donor insemination or adoption may be considered.

Percutaneous Epididymal Sperm Aspiration The purpose of percutaneous epididymal sperm aspiration (PESA) is to recover spermatozoa from the epididymis using a percutaneous technique for use with advanced reproductive techniques such as ICSI.

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Indications The PESA procedure is used in the treatment of obstructive azoospermia. It should be emphasized that sperm aspiration, with an open or a percutaneous approach, is not the first option if reconstruction is possible. Extraction of epididymal spermatozoa from patients with conditions not amenable to repair is best performed as an open approach, as sufficient quantities of fluid and sperm are routinely collected to ensure adequate supplies for cryopreservation into numerous vials, each of which can serve as the sperm source for an ICSI cycle at a later date. Percutaneous extraction does not require use of an operating microscope but may compromise the ability of the couple to achieve pregnancy if no sperm are easily obtained.

Contraindications Bleeding diatheses may lead to intrascrotal hematoma formation. If the testis is small and the epididymis is soft, there may be little intraepididymal fluid, making percutaneous aspiration difficult.

Equipment The equipment required includes a 21-gauge butterfly needle, 3 cc syringe, sterile conical tube, buffered culture medium, and local anesthetic.

Procedure After initiating a local spermatic cord block and infiltrating the skin where the puncture will be made, a 21-gauge needle is directed toward the epididymal corpus or head while the assistant immobilizes the testis. Gentle traction on the aspirating syringe connected to the needle results in the appearance of epididymal fluid in the connector tubing between the butterfly needle and the syringe. The needle is then gradually withdrawn, and the tubing is occluded to prevent spillage. Compression is applied to the scrotum.

Comments Bleeding may occur at the aspiration site, and blood contamination of the specimen hampers processing for ICSI. In cases where no epididymal fluid is obtained or if no sperm are noted in the aspirated epididymal fluid, the blind nature of the procedure may seriously jeopardize the success of open microscopic epididymal sperm aspiration by injuring the epididymal tubules. The PESA procedure is safe and may be per-

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formed in the office setting using a percutaneous approach. Despite its advantages of a shorter operating time and minimal patient discomfort, it typically yields less epididymal fluid and less usable sperm than microscopic epididymal sperm aspiration (MESA). The success of MESA may be adversely affected by tubular damage during PESA. Failure to obtain sperm using PESA entails moving on to an open procedure for microscopic epididymal sperm retrieval (MESA).

Suggested Reading Brackett NL. Semen retrieval by penile vibratory stimulation in men with spinal cord injury. Hum Reprod Update 1999;5(3):216–222. Craft I, Tsirigotis M, Bennet V, et al. Percutaneous epididymal sperm aspiration and intracytoplasmic sperm injection in the management of infertility due to obstructive azoospermia. Fertil Steril 1995;63:1038– 1042. Devroey P, Liu J, Goossens A, et al. Pregnancies after testicular sperm extraction and intracytoplasmic sperm injection in nonobstructive azoospermia. Hum Reprod 1995;10:1457–1460. Dohle GR, Ramos L, Pieters MH, et al. Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia. Hum Reprod 1998;13:620–623. Goldstein M. Surgery of Male Infertility, 1st ed. Philadelphia: Saunders, 1995. Kamischke A, Nieschlag E. Treatment of retrograde ejaculation and anejaculation. Hum Reprod Update 1999; 5(5):448–474. Levine LA, Lisek EW. Successful sperm retrieval by percutaneous epididymal and testicular sperm aspiration. J Urol 1998;159:437–440. Lipshultz L, Howards S. Infertility in the Male, 3rd ed. New York: Mosby, 1997. Mercan R, Urman B, Alata C, Aksoy S, Nuhoglu A, Isiklar A, Balaban B. Oucome of testicular sperm retrieval procedures in non-obstructive azoospermia: percutaneous aspiration versus open biopsy. Hum Reprod 2000;15(7):1548–1551.

Mulhall JP, Burgess CM, Cunningham D, et al. Presence of mature sperm in testicular parenchyma of men with nonobstructive azoospermia: prevalence and predictive factors. Urology 1997;49:91–96. Oates RD, Lobel SM, Harris DH, et al. Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved epididymal spermatozoa. Hum Reprod 1996;11:133–138. Phillipson GT, Petrucco GM, Matthews CD. Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Hum Reprod 2000;15:431–435. Rosenlund B, Westlander G, Wood M, et al. Sperm retrieval and fertilization in repeated percutaneous epididymal sperm aspiration. Hum Reprod 1998;13: 2805–2807. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod 1999;14(1):131–135. Seftel AD, Oates RD, Krane RJ. Disturbed sexual function in patients with spinal cord disease. Neurol Clin 1991;9:757–778. Sheynki YR, Ye Z, Menendez S, et al. Controlled comparison of percutaneous and microsurgical sperm retrieval in men with obstructive azoospermia. Hum Reprod 1998;13:3086–3089. Silber SJ. Microsurgical TESE and the distribution of spermatogenesis in non-obstructive azoospermia. Hum Reprod 2000;15(11):2278–2284. Silber SJ. New concepts in operative andrology: a review. Int J Androl 2000;23(suppl):66–76. Silber SJ, Nagy Z, Devroey P. The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. Hum Reprod 1997;12:2693–2700. Silber SJ, Nagy Z, Liu J, et al. The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: the genetic implications for male infertility. Hum Reprod 1995;10:2031–2043. Takihara H. The treatment of obstructive azoospermia in male infertility: past, present, and future. Urology 1998;51(suppl 5A):150–155. Tournaye H. Surgical sperm recovery for intracytoplasmic sperm injection: which method is to be preferred? Hum Reprod 1999;14 Suppl 1:71–81.

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16 In Vitro Fertilization in the Office Setting Bradford L. Bopp and Glen K. Adaniya

Since the birth of the first child conceived using the process of in vitro fertilization (IVF) in 1978, many thousands of children have been born worldwide through this fascinating procedure. In the early days of IVF, only a few highly specialized centers around the world were prepared to perform the dramatic surgical procedure involving the recovery of oocytes. At the same time, behind the scenes a highly skilled team of biologists waited patiently to receive and prepare the oocytes for in vitro insemination. Although the emotional intensity involved with each IVF procedure performed remains constant, over time the process itself has been greatly simplified. In fact, over the past 20 years, IVF has become increasingly successful, all the while becoming less expensive and less invasive. A comparison of statistics reported by the Society for Assisted Reproductive Technology (SART) supports the use of IVF over alternative forms of assisted reproduction. For instance, in 1989 SART reported statistics based on the national registry for assisted reproductive technologies (ART) performed in the United States during the 1987 calendar year. IVF accounted for approximately 80% of ART procedures, with the remaining 20% being gamete intrafallopian transfer (GIFT). The success rate for IVF was 16%, whereas the success rate for GIFT was 25%. The main advantage of IVF over GIFT is that it does not require laparoscopy and therefore is less invasive and less expensive, but one could not ignore the difference in success rates of the two procedures during that period. Over the past decade, embryo culture techniques and embryo transfer techniques have improved dramatically and so have IVF success rates. As a result, today IVF and GIFT success rates are similar and approximately 95% of ART procedures performed annu-

ally involve IVF. Although there is still a role for alternative forms of ART, such as GIFT, IVF has many advantages, including a transvaginal approach to follicle aspiration permitting minimal (if any) anesthesia, confirmation of fertilization, and control of the number of embryos being delivered to the uterus. For these reasons, hundreds of centers worldwide offer highly successful and minimally invasive IVF procedures performed in the office setting.

Purpose The desire to have a child is one of the most powerful, innate drives of most men and women. Despite this desire, approximately 15% of couples actively trying to conceive for 1 year remain infertile. These couples do demonstrate subfertility. Yet when expectantly managed, nearly one-half of the remaining couples conceive over the next year. At the end of 2 years a couple’s fecundity is reduced. At some point in time along the way, many couples seek assistance. A variety of factors adversely affect fertility rates. For example, advancing maternal age has a profound negative impact on fertility rates; and with women delaying childbearing for a number of socioeconomic reasons, the percentage of couples presenting for evaluation of infertility is increasing. As more couples seek evaluation and treatment of infertility, IVF is being used more frequently. For many of these couples, IVF is a minimally invasive, cost-effective means to increase their statistical chance of achieving a pregnancy. Ultimately, this is the true purpose of IVF.

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Indications As couples undergo evaluation and treatment of infertility, IVF is the first line of therapy in certain situations. For instance, in women with tubal occlusion, IVF may be the only option available for the couple. On the other hand, for couples with unexplained infertility IVF may represent one of the final therapeutic options available. In both situations, IVF ultimately increases the couple’s chance of achieving a pregnancy. The causes of infertility justifying the use of IVF as a therapeutic option include tubal disease, tubal occlusion, unexplained infertility, endometriosis, ovulatory dysfunction, cervical factor, pelvic adhesions, a combination of factors, and sperm abnormalities. The latter includes even severe sperm abnormalities now that intracytoplasmic sperm injection (ICSI) is available. All of the aforementioned factors involve either an unfavorable environment for egg–sperm interaction or an inability of a given egg and sperm to unite and fertilize. The principal advantage of IVF is that in certain couples it allows the rescue of eggs and sperm from unfavorable conditions, provides a more favorable environment for egg–sperm interaction, confirms fertilization, and ensures delivery of the embryo to the uterus. Today IVF is carried out routinely in the office setting at hundreds of facilities worldwide. Yet we must not forget that, although minimally invasive and cost-effective, facilities offering IVF must ensure staffing by appropriately trained physicians and laboratory personnel.

Contraindications Although IVF provides an excellent option for many couples seeking treatment for impaired fertility, it is not indicated for some couples. For instance, women with significantly diminished ovarian reserve or ovarian failure do not benefit from IVF. Additionally, some couples do not benefit from IVF for physiologic reasons that complicate the procedure. For example, some women have cervical abnormalities that preclude embryo transfer. Other women have undergone ovarian transfixation, thereby making a transvaginal approach to follicle aspiration difficult if not impossible. For these women, an alternative technique involving a laparoscopic approach such as GIFT or zygote intrafallopian transfer (ZIFT) may be more appropriate. In couples with severe sperm abnormalities, IVF may be ineffective unless performed in con-

junction with ICSI. Another equally important contraindication rests with religious beliefs. Some religious doctrine does not permit fertilization outside the human body and therefore does not allow IVF as a treatment option. All of these factors must be considered with each couple preparing for IVF.

Special Preparation Needed by Patient and Physician Once a couple has been thoroughly evaluated and in some instances failed more conservative treatment, IVF may be appropriate. IVF abounds with ethical dilemmas for many couples, and these must be addressed before proceeding. First, the couple must be fully educated as to the techniques involved in manipulating their gametes. Issues such as fertilization occurring outside the body may ultimately preclude some couples from proceeding. In addition, whether a couple elects to cryopreserve embryos is of great significance. Likewise, the number of embryos a couple elects to have transferred may create an uncomfortable situation if all the embryos implant and result in a multiple gestation. These issues should be discussed and documented using consent forms that conform to local, state, and federal legal precedence. Our consent forms contain several pages of discussion regarding the medication risks, procedural risks, pregnancy risks, multiple pregnancy risks, failure possibilities, financial responsibilities, and more. We require that all consent forms are either notarized or are witnessed by appropriate members of our office staff prior to initiating a cycle. When preparing couples for IVF, a thorough history and physical examination should be performed and a normal Papanicolaou smear confirmed. A normal endometrial cavity should be confirmed with either a hysterosalpingogram or a sonohysterogram. In addition, we frequently perform a trial embryo transfer during the follicular phase of the cycle preceding stimulation to document catheter placement and ease of the transfer. We identify blood types and screen for infectious diseases including human immunodeficiency virus (HIV), hepatitis B and C, syphilis (rapid plasma reagin, RPR), Chlamydia trachomatis, and rubella. A recently obtained semen analysis should be documented. In women over 38 years of age, we often assess ovarian reserve with a clomiphene citrate challenge test (CCCT), and in women over 40 years of age a normal mammogram should be documented. If clinically indicated, we have a low threshold for additional testing such as a chest radi-

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ography or electrocardiography. Because IVF is an elective process, ensuring maternal well-being is essential prior to initiating therapy.

Equipment Clinical Preparation Follicle Aspiration The following list contains the basic instrumentation needed for follicle aspiration. The disposable equipment, including the gloves, is tested for embryo toxicity. The nondisposable equipment is prepared as a kit and sterilized. 12-Well heating block in a dry bath incubator Round-bottom test tubes, 17  100 mm Dulbecco’s phosphate-buffered saline (DPBS) (Life Technologies, Baltimore, MD), 20 ml Modified human tubal fluid (mHTF) with 500 units heparin sodium, 50 ml (Irvine Scientific, Santa Ana, CA) Bivalved speculum Datascope Echotip Norfolk XS ovum aspiration needle, 16gauge, 30 cm (Cook IVF, Spencer, IN) Flexible tubing Sterile gown Needle guide designed specifically for the transvaginal probe Packet of sterile sponges Pioneer Pro Pump suction apparatus with a foot pedal control (Pioneer Medical, Madison, CT) Powder-free gloves Ring forceps Sterile aquasonic 100 ultrasound transmission gel (Parker Laboratories, Fairfield, NJ) Sterile endocavity ultrasound cover kit (CIVCO Medical Instruments, Kalona, IA) Ultrasound machine with a transvaginal probe

Embryo Transfer Minimal equipment is required for the embryo transfer. The disposable equipment is tested for embryo toxicity prior to use. The nondisposable instruments are sterilized and stored in an incubator maintained at 37°C. Syringe, 1 cc Syringe, 10 cc Preimplantation stage one (P1) culture medium, 20 ml (Irvine Scientific, Santa Ana, CA) Bivalved speculum Sterile gown

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Large cotton swabs Powder-free gloves Ring forceps Tenaculum Wallace catheter, 23 cm (Cooper Surgical, Shelton, CN)

Laboratory Preparation The following is a comprehensive list of the equipment needed in an assisted reproductive laboratory to perform IVF procedures. The number of items required, such as incubators, depend on the number of cycles performed. 37°C Incubator Alarm timers Alarms for incubators and liquid nitrogen storage tank Camera for inverted microscope CO2 incubators Compound microscope Dial-out equipment for alarm system Dry bath heater with 12-well heating block Environmental chamber for inverted microscope Heating stage for inverted microscope Inverted phase contrast microscope Isolette Laminar flow hood Liquid nitrogen storage tank Pipettors Programmable embryo freezer with computer Refrigerator Slide warmer Sperm counter Stereo dissecting microscope Swinging bucket centrifuge Thermometers In addition, the following items are required if the laboratory intends to perform intracytoplasmic sperm injection (ICSI). Antivibration table Coarse and fine micromanipulators Holding pipettes ICSI injection needles Microinjectors Disposable items include the following. Syringe filters, 0.2 m Syringes, 1 cc, 3 cc, and 10 cc Plastic pipettes, 1 ml, 5 ml, 10 ml, and 25 ml Plastic round-bottom test tubes, 12  75 mm and 17  100 mm Conical plastic test tubes, 15 ml and 50 ml

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Tissue culture flasks, 50 ml and 250 ml Tissue culture dishes, 60 mm and 100 mm Aluminum canes for cryopreservation Borosilicate glass Pasteur pipettes Cardboard sleeves for canes Cryovials Gloves Microcells (Conception Technologies, San Diego, CA) Organ culture dishes Pipette tips Tuberculin syringes Wallace catheter The media/solutions needed are as follows: 1,2-Propanediol (PrOH) (Sigma, St. Louis, MO) Blastocyst medium (Irvine Scientific, Santa Ana, CA) Dulbecco’s phosphate-buffered saline (DPBS) Glycerol (Sigma) Hyaluronidase (Sigma) Isolate (Irvine Scientific) Mineral oil (Sigma) Modified human tubal fluid (mHTF) P1 medium Polyvinylpyrrolidone (PVP) (Irvine Scientific) Serum substitute supplement (SSS) (Irvine Scientific)

Brief Outline of Steps Clinical Steps Initial history, physical examination, testing, consent Ovarian suppression using luteal phase gonadotropinreleasing hormone agonist (GnRHa) or antagonist Ovulation induction using follicle-stimulating hormone (FSH), either recombinant or urinary products Human chorionic gonadotropin (hCG) administration and scheduling follicle aspiration Transvaginal oocyte aspiration Luteal phase progesterone support and possibly hCG boosters Embryo transfer Pregnancy test 15 days after follicle aspiration

Laboratory Steps Identification and grading of oocytes Sperm preparation Oocyte insemination/ICSI Fertilization assessment Embryo culture Embryo transfer Embryo cryopreservation

Procedures The justification for each of the procedures described below are beyond the scope of this chapter. They reflect a carefully selected combination of protocols based on a review of the literature that, in our hands, result in success rates well above that of the national average reported by SART. Please refer to the Suggested Reading list for some of the references. We conform to SART reporting guidelines, and our results are based on an average of 2.9 embryos transferred to a patient population similar to that of an average IVF facility. Factors that influence the number of embryos we transfer include patient age, embryo quality, previous history, and diagnosis. Only in the most unusual circumstances do we transfer more than three embryos. Fortunately, as we increase the frequency of use of blastocyst transfers, the number of embryos we transfer on average continue to decrease toward 2.0, thereby eliminating the triplet risk for most couples undergoing IVF.

Clinical Procedures Preparation From the start of the GnRHa down-regulation, about 5 weeks pass before a couple finds out the result of their pregnancy test. We typically begin GnRHa on menstrual cycle day 21 or the equivalent luteal phase day. In anovulatory women, oral contraceptive pills or a progestational agent may be used in combination with the GnRHa. Menses typically begin as normally expected and on cycle day 1, 2, or 3 a baseline ultrasound scan is performed to assess the ovaries for cysts or pathology. In addition, a blood sample is drawn to measure the serum estradiol, which indicates the efficacy of GnRHa ovarian suppression. If appropriately suppressed, we reduce the GnRHa dose by one-half and initiate controlled ovarian stimulation using gonadotropins in an a.m. and p.m. divided dosing interval. We adjust our dosing according to age, menstrual characteristics, and if available response to previous gonadotropin stimulation. After 5 days of completed gonadotropin therapy, the ovarian response is monitored with sequential ultrasound scans and serum estradiol levels. Typically, when two lead follicles reach 18–20 mm in size, hCG is administered. Factors such as follicle quantity, follicle size, and serum estradiol levels vary widely in every individual, so a precise guideline is difficult to recommend. For “poor” responders and “high” responders we use modified protocols. When a cohort of follicles demonstrate adequate quantity, size, and

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serum estradiol production, hCG is administered to induce oocyte maturation. At 36 hours after hCG administration, we schedule the follicle aspiration.

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vital signs with continuous pulse oximetry, electrocardiography, and blood pressure assessment.

Follicle Aspiration Anesthesia The type of anesthetic a patient chooses determines the location where we perform the follicle aspiration. Women opting for no anesthetic, oral narcotic medication, or intramuscular narcotic medication undergo their procedure in our transfer suite, thereby avoiding operating room and anesthesiology charges. A Datascope is used during the procedure to monitor pulse and oxygen saturation and the blood pressure. The procedure room should be equipped with a resuscitation cart, and the staff must be appropriately trained to respond to an emergency. To conform to local standards of care, we follow the same postoperative guidelines used for our ambulatory surgery patients. Oxygen saturation and pulse are continuously monitored using a Datascope for 1 hour after follicle aspiration while assessing blood pressure every 15 minutes. Most women in our practice opt for intravenous sedation, and we provide an anesthesiologist. Prior to the procedure, the anesthesiologist reviews the history and performs a physical examination. Anesthetic consent forms are signed. The anesthesiologist then administers an intravenous combination of propofol, midazolam, and fentanyl. Oxygen is provided via nasal cannula. The anesthesiologist maintains the patient’s airway, and monitors her

FIGURE 16–1. In vitro fertilization suite containing the ultrasonography machine, equipment table, Pioneer Pro Pump aspiration device, Datascope, and procedure table. In the background is the pass-through window containing the dry well incubator.

The IVF suite is adjacent to the laboratory, and a small pass-through window connects the two rooms (Fig. 16–1). The pass-through window can be seen in the background. The 12-well heating block in the dry bath incubator sits in the window. The instrument tray is positioned along the back wall, and a procedure light is mounted to the back wall. Proceeding from left to right in the foreground is the ultrasound machine, the Pioneer Pro Pump suction apparatus, the Datascope, and the procedure table. The laboratory is located on the other side of the pass-through window (Fig. 16–2). Proceeding from left to right in Figure 16–2 is the laminar flow hood, isolette, incubators, liquid nitrogen storage tank, and inverted microscope. Once adequate sedation has been administered, the patient’s legs are positioned in stirrups, and she is draped in a sterile fashion. The sterile instrumentation used for the follicle aspiration is shown in Figure 16–3. Proceeding from left to right is the Echotip Norfolk Needle, bivalved speculum, ring forceps, needle guide, an endocavity ultrasound cover kit, aquasonic ultrasound gel, two rubber bands, round-bottom test tubes, rubber tubing, and sponges. A bivalved speculum is inserted in the vagina to expose the cervix. The vagina and cervix are prepared using 20 ml of DPBS soaked on ster-

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B.L. Bopp and G.K. Adaniya FIGURE 16–2. Assisted reproductive technology laboratory with the passthrough window located in the background. In the foreground, proceeding from left to right, is the laminar flow hood, Isolette, incubators, liquid nitrogen storage tank, and inverted microscope.

ile sponges. The instruments are removed. Using a sterile draped vaginal probe, real-time ultrasonography is performed. The ovaries are visualized, and the endometrium is characterized. An Echotip Norfolk XS ovum aspiration needle should be tested using the foot pedal to activate the Pioneer Pro Pump suction apparatus and aspirate modified HTF,

from a round-bottom test tube. The suction pressure should be adjusted to 100 mmHg. Suction pressures over 100 mmHg may be associated with an increased risk of oocyte trauma, such as a fractured zona pellucida. The needle is then inserted in the vaginal probe guide, the vaginal apex is punctured, and the first

FIGURE 16–3. Follicle aspiration tray. Proceeding from left to right, the Echotip Norfolk Needle, bivalved speculum, ring forceps, needle guide, Endocavity Ultrasound Cover, Aquasonic Ultrasonic Gel, two rubber bands, round-bottom test tubes, rubber tubing, and sponges.

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ovarian follicle is entered. Using the foot pedal, 100 mmHg suction pressure is then applied to tubing equipped with a test tube trap mechanism, and the first follicle begins to decompress. The fluid is aspirated into a round-bottom test tube containing approximately 1 ml of modified HTF. As the follicle approaches total collapse, the needle is spun around its long axis until all of the fluid has been drained. Next, an adjacent follicle is directly entered, and all of the follicles are aspirated sequentially in a similar fashion. Continuous pressure should be maintained. After aspirating the last follicle, the pressure is released and the needle removed from the ovary and vagina. The needle is flushed with modified HTF. Repeat the process on the contralateral ovary. With each follicle aspirated, the volume remaining in the test tube is evaluated prior to decompressing the next follicle. Avoid aspirating a follicle that requires interrupting the pressure during decompression to change test tubes. As each test tube fills with fluid a new test tube is connected, and the full test tube is capped and immediately taken to the window opening into the laboratory. The test tube is placed in a 12-well heating block located in a dry bath incubator maintained at a temperature of 37°C. The reproductive biologists then scan the fluid for oocytes. When both ovaries have been decompressed, the ultrasound probe is removed and the vaginal wall puncture sites visually inspected for hemostasis. If needed, pressure is applied or a suture placed at the bleeding site. In some women, it is appropriate to aspirate the free fluid from the cul-de-sac as oocytes may be recovered from the fluid obtained. In situations where low oocyte recovery is anticipated, a double-lumen needle (Follicle Aspiration Set; Swemed Lab, Billdal, Sweden) may be used to flush the follicles immediately after aspiration. In this instance, a 10 ml syringe containing modified HTF is connected to the tubing provided with the double-lumen needle. The follicle is decompressed in the usual fashion; and upon completion, 1–3 ml of fluid is injected into the follicle to force reexpansion, thereby causing turbulence in the follicle and potentially dislodging an oocyte for aspiration. Oocyte recovery rates are similar for both single-lumen and double-lumen aspiration, but physician anxiety may be reduced and multiple attempts can be made to find an oocyte from each follicle with the double-lumen tube.

Embryo Transfer Now that blastocyst transfer has gained increasing popularity and success, many patients are sched-

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uled for day 3 and day 5 transfers. In most instances luteal phase progesterone support is initiated on the evening before the follicle aspiration or on the evening of the follicle aspiration. The precise timing of initiating luteal phase progesterone and the best delivery system to be used remains to be determined. Regardless, on the third or fifth day after follicle aspiration, the couple returns for embryo transfer. We prescribe Valium and indomethacin 1 hour prior to the transfer. The decision concerning the number of embryos to transfer either has been predetermined or will be modified at the time of transfer depending on the embryo quality. Upon entering the transfer suite, the patient’s identity is confirmed by the reproductive biologist, and the patient is then positioned on an examination table in close proximity to the laboratory window. This minimizes the manipulation of the embryos prior to the transfer. The sterile instrument pack consists of a bivalved speculum, ring forceps, tenaculum, large cotton swabs, sponges, and a towel sterilized and stored in an incubator at 37°C. The pack is opened at the time of the transfer. The physician reviews the trial transfer notes or past transfer notes and confirms the number of embryos to be transferred. Minimal instruments are needed for the embryo transfer (Fig. 16–4). Proceeding from left to right, there is a bivalved speculum, tenaculum, ring forceps, large cotton swabs, 10 cc syringe, 1 cc syringe, Wallace catheter, and sponges. The physician scrubs and uses embryo-tested, powder-free gloves. The speculum is placed in the vagina, and the cervix is centered. The vagina is prepared using P1 medium, and the exocervix is wiped with mediumsoaked swabs. P1 medium (10 ml) is then connected to a Wallace catheter outer sheath, and the outer sheath tip is inserted in the cervical os to approximately 1 cm. The endocervix is gently irrigated to flush the cervical mucus from the canal. Often a bubble of mucus protrudes from the canal and can be easily wiped away from the cervix. A tuberculin syringe is then inserted in the external os, and suction is applied to aspirate additional mucus. A trial transfer is performed using a sterile Wallace catheter inserting either the inner catheter or the sheath alone to just beyond the internal cervical os. The embryos are loaded into a sterile Wallace catheter and handed to the physician through the pass-through window. The Wallace catheter is then inserted into the cervix and advanced to a point on the catheter corresponding to 6.5–7.0 cm. The embryos are expelled, and after approximately 30 seconds the catheter is rotated and slowly withdrawn. The catheter is passed back to the repro-

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B.L. Bopp and G.K. Adaniya FIGURE 16–4. Embryo transfer tray. Proceeding from left to right, a bivalved speculum, tenaculum, ring forceps, large cotton swabs, a 10 cc syringe, 1 cc syringe, Wallace catheter, and sponges.

ductive biologist, who flushes the catheter and the sheath with equilibrated P1 medium. If the flush is clear, the transfer is complete. If one is retained, the embryo is reloaded into a sterile Wallace catheter and the transfer is repeated. With increasing frequency ART facilities are using ultrasound guidance to perform embryo transfer. It provides visual confirmation of embryo placement and may lead to enhanced success rates. The patient is taken to a holding area and asked to recline for 1 hour prior to discharge. Over the next 2 weeks hCG boosters may be administered along with progesterone support. The pregnancy test is scheduled for 15 days after follicle aspiration.

Laboratory Procedures Quality Control It is critically important that a strict, comprehensive quality control program be followed in the ART laboratory to ensure success. Daily temperature checks of incubators, refrigerators, slide warmers, heated microscope stages, Isolettes, heating blocks, and dry incubators are performed and recorded. In addition, daily monitoring of incubator and Isolette CO2 levels must be performed. All laboratory disposable items that come into contact with the embryos or spermatozoa must be tested for toxicity, including such items as petri dishes, flasks, test tubes, pipettes, pipette tips,

transfer catheters, gloves, and media. Toxicity testing is usually done with a bioassay such as the mouse one-cell assay, the mouse two-cell assay, the hamster sperm survival test, or the human sperm survival test. The use of cryopreserved one-cell or two-cell mouse embryos (Conception Technologies, San Diego, CA) eliminates the need for maintaining a mouse colony. If the semen analysis and preparation of the semen sample are done in the ART laboratory, the laboratory is considered to be performing high complexity testing and is subject to the Clinical Laboratory Improvement Amendments of 1988 (CLIA ‘88) guidelines. The guidelines are extensive and cover such areas as proficiency testing, patient test management, quality control, quality assurance, personnel, and the inspection process. The laboratory must undergo the inspection process and receive a CLIA certificate to be in compliance. The reader is encouraged to examine the guidelines, which may be found in the Suggested Reading list.

Media A wide variety of media have been used for ART procedures during the past 20 years. Some examples are Ham’s F10, Ham’s F12, human tubal fluid (HTF), and Eagle’s medium. Historically, the medium was prepared in the ART laboratory, allowing each laboratory to have control over media

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preparation. Today, there are many choices of commercially available media that may be utilized by ART laboratories. We conducted studies comparing a commercial medium (P1) with the P1 medium produced by our ART laboratory and found that the two media produced similar fertilization rates and embryo development. The advantages of purchasing media are convenience and decreased utilization of technician time. An additional advantage is that the medium arrives with embryo bioassay and endotoxin results. The end user has the option of using those results as their quality control testing, which would save both time and money. However, because there is uncertainty regarding the conditions to which the medium was exposed between the time it was tested at the medium production facility and the time it arrives in the laboratory, testing it at the ART laboratory is recommended. One of the developments in culture media is the new sequential medium, which takes into account the various metabolic requirements of the developing embryo. These media have allowed ART laboratories to grow embryos to the blastocyst stage without the use of co-culture before performing the embryo transfer. ART programs are thus able to decrease the number of transferred embryos owing to the higher implantation potential of blastocysts. This has led to a dramatic decrease in the number of higher-order multiple gestations.

IVF Procedure Day Prior to Oocyte Retrieval Culture dishes are prepared the day before oocyte retrieval and placed in a CO2 incubator overnight to equilibrate. Make a 10% serum substitute supplement (SSS) with P1 medium, and filter it using a syringe filter. Label the appropriate number of 60 mm petri dishes (depending on the number of follicles) with the patient’s name. Pipette five 35 l drops into the petri dishes and overlay with 5 ml of mineral oil. Prepare dishes to rinse the oocyte cumulus complexes by pipetting 5 ml of the P1 medium into petri dishes labeled with the patient’s name. Finally, prepare the sperm-washing medium by making 20 ml of P1 with 10% SSS in a tissue culture flask. Place the culture dishes, rinse dishes, and sperm-washing medium (making sure the cap is loose) into an incubator at 37°C and 5% CO2 in air. Additionally, pour 20 ml of Dulbecco’s phosphate-buffered saline into a tissue culture flask and let it sit at room temperature overnight. This is used for preparation of the vagina prior to the ultra-

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sound-guided vaginal retrieval. Finally, prepare 50 ml of modified HTF by adding 500 units of heparin and place in the 37°C incubator overnight.

Oocyte Retrieval Preparation of the Isolette is the first step in preparing for oocyte retrieval. Place the culture and rinse dishes into the Isolette just prior to the start of the retrieval. In addition, label an appropriate number of 100 mm petri dishes and place them in the Isolette. Finally, place a sterile glass Pasteur pipette with an aspiration bulb attached in a sterile test tube sitting in a test tube rack located in the Isolette. Follicular aspirates are suctioned into round-bottom test tubes and passed through the access window into the ART laboratory. These tubes are then placed in a rack located in the Isolette, which has been calibrated to 37°C and 5% CO2. Aspirates are poured into the large petri dishes, and the test tubes are discarded. Using the dissecting microscope located in the Isolette, locate the oocyte-cumulus complex (OCC). Aspirate the OCCs with the Pasteur pipette, rinse them thoroughly in the rinse dishes to remove excess red blood cells, and place them in the culture dishes. Repeat with the remainder of the aspirates until all the OCCs have been collected. Place all the culture dishes in the culture incubator.

Semen Preparation A wide variety of sperm preparation techniques are currently available. The goal of any preparation method should be to remove both the immotile and morphologically abnormal spermatozoa, to remove any bacteria and cellular debris, and to retain as many of the motile spermatozoa as possible. Some sperm preparation techniques are sperm washing, migration methods such as the swim-up and swimdown techniques, adherence methods such as glass wool filtration, and density gradient centrifugation. The density gradient centrifugation technique is performed as follows. Remove an aliquot from the liquefied sample, load it onto a Microcell, and perform an initial semen analysis. Place the semen on top of a density gradient column consisting of 1 ml of 45% Isolate over 1 ml of 90% Isolate in a 15 ml conical test tube. Centrifuge at 200g for 15 minutes and then aspirate all the fluid above the sperm pellet. Resuspend the pellet in 5 ml of sperm washing medium and centrifuge at 200g for 5 minutes. Remove the supernatant and resuspend the pellet; wash again for 5 minutes. Finally, remove the supernatant and resuspend in the minimum appropriate volume. Take an aliquot and determine the

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concentration and motility. Calculate the volume of the sample required to inseminate the oocytes at a concentration of 100,000 motile spermatozoa/ml, then place the sample in the incubator at 37°C and 5% CO2 until the time of insemination.

Insemination Approximately 4–6 hours after oocyte retrieval, place the sperm sample and the oocytes in the Isolette. Verify the identity of the gametes and record on the patient’s verification form. Have a second biologist verify the gametes prior to insemination to ensure proper identification. Resuspend the spermatozoa, as some settling occurs while sitting in the incubator. Add the predetermined amount of spermatozoa to each oocyte and observe the culture drops microscopically to confirm the approximate number of spermatozoa per oocyte. Return the oocytes to the incubator until the fertilization check.

Intracytoplasmic Sperm Injection Extra equipment is needed in laboratories performing ICSI (Fig. 16–5). As shown, the equipment includes an inverted microscope positioned on an antivibration table, course and fine micromanipulators, and microinjectors. ICSI has become the standard insemination method for couples with male factor infertility and couples with poor or failed fer-

tilization during a previous cycle. It is beyond the scope of this chapter to describe the ICSI procedure in detail, so the reader is encouraged to review the suggested readings on ICSI. Briefly, use two 1 cc syringes with needles to mechanically strip away most of the cumulus cells surrounding the oocytes. Place the oocytes in a hyaluronidase solution 80 IU/ml to help dislodge the remainder of the cumulus and corona cells. Use a finely drawn sterile glass Pasteur pipette to help remove the cells by carefully aspirating the oocyte in and out of the pipette. Once the cells are removed, rinse the oocytes in equilibrated P1  10% SSS. Observe the oocyte using the inverted microscope to check for the presence of a polar body, the indicator of oocyte maturity. Set up the holding and injection pipettes on the ICSI microscope and aspirate a 10% polyvinylpyrrolidone (PVP) solution into the injection pipette to aid in control of the spermatozoa. Prepare an oocyte injection dish by placing four 5 l drops of modified HTF  10% SSS around a central 5 l drop of PVP. Cover the drops with mineral oil. Add approximately 1 l of the processed sperm sample to the PVP drop. The volume of sperm added may need to be adjusted according to the sperm concentration. Add the mature oocytes to the modified HTF drops and bring the dish to the ICSI microscope. Immobilize a motile spermatozoon with the injection pipette and then aspirate it into the pipette

FIGURE 16–5. Intracytoplasmic sperm injection setup. Equipment includes the inverted microscope positioned on an antivibration table, coarse and fine micromanipulators, and microinjectors.

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tail first. Secure the oocyte with the holding pipette, positioning the oocyte so injection does not take place into the area of polar granularity, which usually means orienting the polar body at either the 12 or 6 o’clock position. With the spermatozoon at the tip of the injection pipette, insert the pipette into the oocyte at the 3 o’clock position. Aspirate the spermatozoon and the cytoplasmic organelles into the injection pipette, break the oolemma, and inject the spermatozoon and organelles slowly back into the cytoplasm. Withdraw the needle and repeat for the remainder of the mature oocytes. Return the injected oocytes back to the incubator until fertilization assessment the following day.

Fertilization Assessment The oocytes are checked for the presence of pronuclei, which are the indicators of fertilization, approximately 14–18 hours after insemination. This is accomplished with the aid of a finely drawn sterile glass Pasteur pipette attached to a small pipette bulb. The oocyte is usually located among the dispersed cumulus cells on the bottom of the petri dish. Gently aspirate the oocyte in an out of the glass pipette to dislodge the attached cells. This is done to aid in visualizing the pronuclear structures. Sometimes the surrounding cells have formed a tight clump of cells, and the oocyte must be gently removed from the clump by careful dissection with the aid of two 1 cc syringes with 27-gauge needles. Observe the oocyte microscopically for the presence of two pronuclei, and place the fertilized oocytes into fresh equilibrated P1. If more than two pronuclei are observed, the polypronuclear embryos should be discarded immediately, as they are capable of apparently normal-looking cell division. Once the fertilization assessment is completed, return the fertilized and unfertilized oocytes to the incubator. Check the unfertilized oocytes again in the afternoon for signs of late fertilization.

Embryo Culture The embryos of patients undergoing a day 3 transfer remain in the P1 until the day of transfer. For patients scheduled for a blastocyst transfer, move the embryos from P1 to equilibrated blastocyst medium  10% SSS on day 3 and return the embryos to the incubator until the day 5 transfer. On the day prior to the scheduled blastocyst transfer, prepare new culture dishes with blastocyst medium  10% SSS and equilibrate overnight. Transfer new embryos that require extended culture past day 5 to the fresh blastocyst medium  10% SSS.

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Preparation for Embryo Transfer On the day prior to the embryo transfer prepare a 50% transfer dish by pipetting 2 ml of a 50% SSS in P1 solution into the inner well of a 3037 organ culture dish. Add 4 ml of P1 to the outer well and incubate overnight at 37°C and 5% CO2. In addition, add approximately 20 ml of P1 to a test tube and equilibrate overnight. This will be used to help remove any cervical mucus while performing the embryo transfer. On the day of the transfer, separate the embryos to be transferred from those that are of suitable quality for cryopreservation. Move the embryos to be transferred into the 50% transfer dish within 1 hour of the scheduled transfer time and move the 50% dish and the cervix rinse into the Isolette. When the patient is properly prepared for the transfer, aspirate the embryos into the transfer catheter in no more than a 30 l volume. Pass the catheter through the access door to the physician. Once the transfer is complete, the catheter is passed back to the ART laboratory, and the catheter is rinsed thoroughly with P1/SSS to check for the presence of residual embryos. If none is present, the transfer is complete. Otherwise, reload the retained embryos into a new transfer catheter and repeat the transfer procedure.

Embryo Cryopreservation The addition of embryo cryopreservation has greatly enhanced the overall pregnancy rates per fresh cycle for patients who have frozen embryos. Cryopreservation has allowed multiple attempts to achieve pregnancy from only one stimulated cycle. Many embryo cryopreservation protocols are available, such as those utilizing the cryoprotectant glycerol, dimethylsulfoxide (DMSO), or 1,2-propanediol (PrOH). We currently use a combination of PrOH and sucrose to freeze/thaw pronuclear and cleavagestage embryos and a protocol utilizing glycerol for freezing and thawing blastocysts. Only the PrOH protocol is presented here. The reader is encouraged to examine the Suggested Reading list for more detail on both cleavage-stage embryo freezing and blastocyst freezing. Briefly, prepare the following solutions. 0.5 M PrOH in Dulbecco’s phosphate buffered saline (DPBS) 1.0 M PrOH in DPBS 1.5 M PrOH in DPBS 1.5 M PrOH  0.2 M sucrose in DPBS Place the embryos in 0.5 M PrOH for 5 minutes, followed by 5 minutes in 1.0 M PrOH and then 10

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minutes in 1.5 M PrOH. Finally, place the embryos in the 1.5 M PrOH  0.2 M sucrose solution for 5 minutes and then into a labeled cryovial containing 1 ml of 1.5 M PrOH  0.2 M sucrose. Load the embryos into an embryo freezer, such as the Planer Kryosave (T.S. Scientific, Perkasie, PA) and initiate the freezing program. 1. Ramp from room temperature to 7.0°C at 2.0°C/min. 2. Hold for 5 minutes, then manually seed the vial to induce ice formation. 3. Continue to hold at 7.0°C for 15 minutes. 4. Ramp from 7.0°C to 35.0°C at 0.3°C. 5. At the end of the cryopreservation program, quickly place the vials on a labeled freezing cane, place a labeled cardboard sleeve over the cane, and plunge the cane into a small Dewar filled with liquid nitrogen. Transfer the cane into a liquid nitrogen storage tank.

Embryo Thawing The embryos should be thawed quickly to avoid the generation of ice damage in the embryo. Briefly, prepare the following solutions and bring them to room temperature. 1.0 M PrOH  0.2 M sucrose in DPBS 0.5 M PrOH  0.2 M sucrose in DPBS 0.2 M sucrose in DPBS Fill a large beaker of water with water and bring the temperature to 37°C. Remove the cryovial from the cane and plunge it into the 37°C water. After the vial is thawed, pipette the contents into a 3037 petri dish and locate the embryos. Move the embryos into 1.0 M PrOH  0.2 M sucrose for 5 minutes. Transfer the embryos to the 0.5 M PrOH  0.2 M sucrose solution for 5 minutes. Finally, move the embryos into DPBS  0.2 M sucrose for 5 minutes before placing the embryos in a culture dish containing microdrops of P1 medium. Observe the embryos microscopically for evidence of ice damage. The embryo is judged to be viable if fewer than 50% of the blastomeres exhibit ice damage. Place the embryos in the incubator and transfer on the appropriate day.

Complications Complications occur with any intervention; but when related to elective procedures, they seem more significant. Fortunately, IVF is a safe procedure, and significant complications are uncommon. An exception is, arguably, high-order multiple ges-

tations. Complications can be categorized by those related to the stimulation, the procedure, and the outcome of the cycle. Complications related to the stimulation itself include reactions to medications and ovarian hyperstimulation. Severe ovarian hyperstimulation syndrome complicates about 1–2% of cycles, and management strategies should be clearly understood when this complex, potentially lethal complication is encountered. Procedure-related complications include anesthesia reactions, traumatic organ injury, and postprocedure complications. Anesthesia-related complications include nausea, vomiting, adverse drug reactions, malignant hyperthermia, airway obstruction, airway injury, and aspiration pneumonia. Traumatic injury includes bowel perforation, blood vessel laceration, and ovarian hemorrhage. Postprocedure complications include ovarian abscess, pyosalpinges, endomyometritis, ovarian torsion, hydrosalpinges, and pelvic hematoma. Outcome-related complications are most commonly related to multiple gestations. Complications due to multiple gestations include both fetal and maternal adverse outcomes. Multiple gestations account for 30–35% of the pregnancies achieved through IVF, and up to 10% are triplets or more. Spontaneous abortion, premature labor, preeclampsia, and cesarean delivery are only a few of the potential complications associated with multiple gestations. Potential neonatal complications are numerous and are typically related to prematurity. Equally important to the issue of multiple gestation is that of ectopic gestation. Despite the use of IVF, in which the fallopian tubes are bypassed, ectopic pregnancies occur with an incidence of approximately 3%. Additionally, heterotopic pregnancies also occur, with a reported incidence of 0.1–0.3%. Early pregnancies resulting from IVF must be intensely monitored, and gestation location must be confirmed as early as possible. Sound judgment and careful monitoring of patients minimize the incidence of all of the mentioned complications.

Conclusions The evolution of IVF has been rapid and significant. Once available to only a few couples around the world, IVF is now a viable therapeutic option for thousands of couples. No longer considered experimental, IVF has become a routine part of infertility treatment protocols. Success rates continue to improve, and costs continue to decrease. As advances in technology continue to simplify

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IVF procedures, IVF is rapidly becoming a routine part of infertility treatment in the office.

Suggested Reading Adashi E, Rock J, Rosenwaks Z (eds). Reproductive Endocrinology, Surgery, and Technology. Philadelphia: Lippincott-Raven, 1996. Behr B, Pool T, Milki A, et al. Preliminary clinical experience with human blastocyst development in vitro without co-culture. Hum Reprod 1999;14:454–457. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology, RESOLVE. The National Fertility Association. 1997 Assisted Reproductive Technology Success Rates. Atlanta: CDC, 1999:41. CLIA ‘88 Final Rules: A Summary of Major Provisions of the Final Rules Implementing the Clinical Laboratory Improvement Amendments of 1988. Northfield, IL: College of American Pathologists, February 1992. Clinical Laboratory Improvement Amendments of 1988; Final Rule. Federal Register 1992;57:7002–7298. Coroleu B, Carreras O, Veiga A, et al. Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization. Hum Reprod 2000;15:616– 620. Edwards R, Brody S. Principles and Practice of Assisted Reproduction. Philadelphia: Saunders, 1995. Fluker M, Copeland J, Yuzpe A. An ounce of prevention: outpatient management of the ovarian hyperstimulation syndrome. Fertil Steril 2000;73:821–824. Gardner D. Development of serum-free media for the culture and transfer of human blastocysts. Hum Reprod 1998;13:218–225. Gardner D, Schoolcraft W, Wagley L, et al. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod 1998;13: 3434–3440. Glass K, Green C, Fluker M, et al. Multicenter randomized controlled trial of cervical irrigation at the time of embryo transfer [abstract no. O-085]. In: 2000 Annual Meeting Program Supplement of the 56th Annual Meeting of the American Society for Repro-

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ductive Medicine. San Diego, CA: American Society for Reproductive Medicine, 2000:S30. Hammitt D, Barud K, Galanits T, et al. Post-ICSI culture of oocytes in G1.2 versus HTF-SSS—fertilization, embryo quality and pregnancy outcomes [abstract no. P-025]. In: 2000 Annual Meeting Program Supplement of the 56th Annual Meeting of the American Society for Reproductive Medicine. San Diego, CA: American Society for Reproductive Medicine, 2000:S103. Keel BA, May JV, DeJonge CJ. Handbook of the Assisted Reproduction Laboratory. Boca Raton: CRC Press, 2000. May J, Hanshew K. Organization of the in vitro fertilization/embryo transfer laboratory. In: Keel B, Webster B (eds) CRC Handbook of the Laboratory Diagnosis and Treatment of Infertility. Boca Raton: CRC Press, 1990:291–327. Medical Research International, The American Fertility Society Special Interest Group. In Vitro Fertilization. Embryo Transfer in the United States: 1987 Results from the National IVF-ET Registry. Fertil Steril 1989;51:13–20. Menezo Y, Nicollet B, Herbaut N, et al. Freezing cocultured human blastocysts. Fertil Steril 1992;58:977– 980. Palermo G, Cohen J, Alikani M, et al. Intracytoplasmic sperm injection: a novel treatment for all forms of male factor infertility. Fertil Steril 1995;63:1231–1240. Sallam H, Farrag A, Ezzeldin F, et al. Vigorous flushing of the cervical canal prior to embryo transfer—A prospective randomized study [abstract no. P-345]. In: 2000 Annual Meeting Program Supplement of the 56th Annual Meeting of the American Society for Reproductive Medicine. San Diego, CA: American Society for Reproductive Medicine, 2000:S203. Surrey E, Schoolcraft W. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive technologies. Fertil Steril 2000;73:667–676. Veeck LZ (eds) Cryopreservation of embryos/eggs. In: Adashi E, Rock J, Rosenwaks Z (eds) Reproductive Endocrinology, Surgery, and Technology, vol 2. Philadelphia: Lippincott-Raven, 1996:2353–2365. Wood E, Batzer F, Go K, et al. Ultrasound-guided soft catheter embryo transfers will improve pregnancy rates in in-vitro fertilization. Hum Reprod 2000;15:107–112.

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17 Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation Phillip E. Patton and Don P. Wolf

Unstimulated or natural cycle in vitro fertilization (IVF), and in vitro maturation (IVM-IVF) of immature oocytes are two new and potentially important adjuncts to conventional IVF involving ovarian stimulation. Both procedures offer significant advantages over conventional IVF, but because the pregnancy rates with these procedures remain low few centers have introduced unstimulated IVF or IVM-IVF into routine clinical practice. The application of the novel techniques and approaches involved in IVF without gonadotropins will likely have a major impact on practitioners of the assisted reproductive technologies and on the laboratory during the next few years. The purpose of this review is to focus, for the practicing clinician, on the fundamental principles of unstimulated IVF and IVM-IVF of oocytes.

Unstimulated In Vitro Fertilization On July 25, 1978, a baby girl was born as a result of IVF performed during an unstimulated menstrual cycle. Use of an unstimulated cycle was not based on concerns of cost, the complexity of ovarian stimulation protocols, or problems in endometrial receptivity induced by gonadotropins; rather, it was used because protocols using exogenous gonadotropins were largely disappointing, resulting in no live births in the initial series of 77 women. Steptoe and Edwards provided the first evidence that unstimulated IVF was a legitimate, effective option to protocols using ovarian stimulation. With experience, the initial enthusiasm of unstimulated IVF was dampened for several reasons. Monitoring follicular development was complex and laborintensive. At the time, multiple blood and urine samples were required on a daily basis. Further-

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more, oocyte retrieval required operative laparoscopy, often at inconvenient times during the night. In the initial 79 cases of unstimulated IVF reported in 1980, preovulatory oocytes were recovered in 45 of 68 cycles. The probability of a live birth per procedure was only 0.029. The disappointing low fecundity rate with unstimulated IVF provoked a reexamination of protocols using ovarian stimulants. Initially, protocols using clomiphene citrate and ultimately protocols employing menotropins exclusively or a combination of menotropins and gonadotropin-releasing hormone (GnRH) agonists largely replaced unstimulated IVF when pregnancy rates were proved superior. During the late 1980s practitioners of the assisted reproductive technologies observed the reemergence of unstimulated IVF. In part, this rejuvenation occurred secondary to two well recognized technologic advances. The development of transvaginal ultrasound-guided follicle aspiration was a key component, as oocyte retrieval was taken out of the operating room and into the outpatient setting. Because the technique could be performed in an outpatient setting, a significant cost savings was also realized. Transvaginal oocyte retrieval proved superior in women with well recognized risk factors for laparoscopic surgery. Moreover, the fear of failed oocyte retrieval secondary to ovarian scaring or premature ovulation was largely avoided with transvaginal techniques. Along with the advances in oocyte retrieval systems, the industry observed the advent of reliable, sensitive kits to measure urinary luteinizing hormone (LH) and less costly immunoassay methods for measuring serum estradiol. As a result of these improvements, unstimulated IVF reemerged as an attractive alternative to IVF with ovarian stimulation.

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Patient Selection Initially, unstimulated IVF was used in ovulatory women of all ages and with disparate diagnoses. With experience, however, it became apparent that women in specific diagnostic categories did poorly. Examples include couples with male factor infertility, in whom pregnancy rates are extremely low in the presence of oligozoospermia or asthenozoospermia. It is also likely that men with high titers of sperm antibodies do poorly and should consider other reproductive options. A second group that has done poorly is women over age 40. In most reported series of unstimulated IVF, women over 40 years of age have been excluded from analysis. The true fecundity rate from a single IVF cycle for this subgroup is still ill-defined; Nevertheless, the limited reported results in women over age 40 have been discouraging. Women who respond poorly to gonadotropins may be candidates for unstimulated IVF. This group can be identified by tests of ovarian reserve. Serum follicle-stimulating hormone (FSH) testing performed on the third day of the menstrual cycle is one such test of ovarian reserve (a decreased reserve in young women is associated with poor egg quality and low pregnancy rates). Low serum FSH (10 IU/ml) correlate with successful IVF. A cycle day 3 FSH value may in fact predict outcome better than age. Nevertheless, a single blood test during a single menstrual cycle may miss detecting women with diminished ovarian reserve. As a result of this concern, the clomiphene citrate challenge test (CCCT) was developed, and has been examined in a variety of infertility populations. With the CCCT, baseline FSH (day 3) and stimulated FSH (day 10) values are obtained following administration of clomiphene citrate. FSH testing before and after clomiphene citrate may be a superior screening tool when compared to baseline FSH testing alone. Based on extensive but preliminary studies, the CCCT appears to be predictive of outcome in both the general infertility population and with assisted reproductive technologies. Women with elevated day 3 FSH levels or stimulated (day 10) FSH levels may be poor candidates for unstimulated IVF.

Cycle Monitoring In the initial unstimulated IVF series, Steptoe and Edwards carefully monitored the LH surge because fertilization rates were known to be dependent on a critical length of exposure of the follicle to cir-

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culating LH. Monitoring serial blood and urine samples for initiation of the LH surge was at times cumbersome, costly, and unreliable. Because the onset of the LH surge can occur at variable times throughout the day, some oocyte retrievals were scheduled during the night to avoid problems associated with monitoring the LH surge. Modern protocols for unstimulated IVF use injectable human chorionic gonadotropin (hCG) to mimic the effects of LH on follicle development. Administration of hCG has several important advantages over a spontaneous LH surge. First, hCG can serve as a surrogate to LH by allowing the ovarian oocyte to complete the first maturation division and become fertilizable. Second, night-time administration of hCG allows predictable morning oocyte retrieval. Accurate timing of the hCG injection is a critical component for unstimulated IVF. To best determine the timing of hCG, three important aspects of the menstrual cycle must be monitored. 1. Follicular maturity using pelvic ultrasonography. During the unstimulated cycle, pelvic ultrasonography can be used to track the development of the preovulatory follicle initiated at least 3–4 days before the predicted LH surge. Follicular growth rates average 2.0–2.5 mm per day, and mature oocytes may be obtained in follicles as small as 15 mm (mean diameter). However, follicle size must be correlated with serum estradiol testing because of the significant interpatient variability. Generally, two or three ultrasound scans are required to track the rate of growth of the preovulatory follicle adequately. 2. Serum estradiol. The mature preovulatory follicle cannot be identified by ultrasonographic parameters alone. The second component in determining oocyte maturity involves serum estradiol testing with one of a variety of commercially available immunoassay kits. Because of between-kit variations in measured estradiol levels, determination of a threshold value that predicts follicular maturity is difficult. Programs that are contemplating unstimulated IVF should establish their own correlations between estradiol levels and follicular dimensions by monitoring a control group of fertile women with serial ultrasound scans and estradiol levels. Paulson and coauthors have established approximate guidelines for defining follicular maturity on the basis of both follicle size and serum estradiol (Table 17–1). It should be noted that these guidelines represent maximal diameters as measured with a General Electric 5 MHz vaginal transducer and not mean measurements of fol-

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TABLE 17–1. Follicle Maturity Criteria as Indication for hCG Administration During Unstimulated IVF Cycles Follicle size (mm)

Serum estradiol (pg/ml)a

 20  18  15

 200  250  300

Source: Adapted from Paulson et al., 1990, with permission. hCG, human chorionic gonadotropin; IVF, in vitro fertilization. aPantex extraction kit.

licle size. When serum estradiol levels measured in a morning blood sample meet criteria that correspond to follicle dimensions, hCG (10,000 IU) is administered during the evening of that day. Routinely, oocyte aspiration is performed approximately 34–36 hours following the hCG injection. 3. Luteinizing hormone testing. The onset of the LH surge is abrupt and occurs usually within the same 24 hour interval as the peak preovulatory estrogen level. In most cases the LH surge can be detected in serial urine specimens collected during the periovulatory period. It is advisable to collect a minimum of three urine samples daily, assaying for LH using commercially available immunoassays (e.g., OvuQUICK; Monoclonal Antibodies, Sunnyvale, CA). The last specimen should be collected immediately before hCG injection. The LH surge most commonly occurs during the early morning (3–7 a.m.); urine samples test positive several hours later as determined by semiquantitative assay. When both mid-day and evening urine samples are tested, the LH surge is detected 95% of the time. The occurrence of a surge before hCG administration is not uncommon even when relatively conservative criteria for follicular maturity are met. In our series, LH surges were detected during 25% of the cycles prior to hCG injection. Previous studies have shown that the best results occur during surge cycles when oocytes are collected at a time near spontaneous ovulation (roughly 36 hours from the serum LH surge onset or 28 hours after urinary detection). Reasonably good outcomes can be achieved during retrieval cycles in which a premature LH surge has occurred. Nevertheless, the results are unpredictable, and the work is labor-intensive because of the possible need for evening retrievals. Therefore cycle cancellation is often recommended when an LH surge is detected by standard urinary assays.

Follicle Aspiration The techniques of follicle aspiration for unstimulated IVF are similar to those used for conventional IVF. Prior to oocyte retrieval, prophylactic antibiotics (doxycycline 100 mg twice daily and continued for 2–5 days) are frequently recommended. Approximately 34–36 hours after hCG injection, transvaginal sonography is performed to identify the preovulatory follicle and to confirm that premature rupture has not occurred. After the follicle is identified, the patient can be given analgesics, but we have found that most patients require only minimal sedation and analgesia. Special care must be exercised when directing the aspiration needle toward the single preovulatory follicle. It is probably best to first puncture the peritoneum before puncturing the follicle in a two-step process because any unanticipated motion from the patient could compromise successful aspiration. Following peritoneal puncture, the needle is directed slowly toward the single preovulatory follicle, usually toward the largest dimensions of the follicle. When the follicle is entered from an acute angle or from the side, the chances of a successful aspiration are reduced. Both single-lumen and double-lumen aspiration needles can be used for unstimulated IVF. Secondary follicles can also be aspirated and may improve the outcome, if additional oocytes are recovered, because of the ability to transfer multiple embryos.

Culture and Embryo Transfer The culture conditions for unstimulated IVF are similar to those for conventional IVF. Cleaving embryos (day 2 or 3) can be transferred to the uterine fundus using techniques identical to those described for conventional IVF.

Pros and Cons of Unstimulated IVF Unstimulated IVF offers several advantages over IVF with ovarian stimulation (Table 17–2). Ethical, moral, and legal difficulties associated with embryo cryopreservation are largely avoided; and because ovarian stimulants are not required, the cost of unstimulated IVF is significantly less. Furthermore, the morbidity secondary to ovarian stimulation or multiple pregnancy is essentially nonexistent. Despite the absence of conclusive data, women are worried about the potential link between repeated exposure to ovarian stimulation and ovarian cancer.

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17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation TABLE 17–2. Advantages and Disadvantages of Unstimulated IVF and IVF with Ovarian Stimulation Stimulated IVF Advantages Embryos for cryopreservation Infrequent failed oocyte retrieval Low cycle cancellation rate Multiple embryo transfer Disadvantages Altered endometrial receptivity Frequent monitoring High cost Labor intensive Multiple pregnancy Ovarian hyperstimulation ? Ovarian cancer Unstimulated IVF Advantages Easy monitoring Low cost No multiple pregnancy No ovarian hyperstimulation No ovarian stimulants required Disadvantages Monovular cycles Possible LH surge cycles High cancellation rate Rigid patient selection criteria

GnRH analogues are used. The cost of a passed cycle ($500–$600) for single-egg IVF is not insignificant, particularly when cycles are canceled because of an LH surge. Failed oocyte retrieval or failed fertilization probably occurs more frequently with unstimulated IVF. Finally, the laboratory costs with unstimulated IVF are similar to those with conventional IVF. Although only a single oocyte is manipulated by laboratory personnel, the time required for preparation, processing the oocyte at the time of retrieval, and culture and transfer is only slightly less than for conventional IVF.

Success Rates with Unstimulated IVF

Unstimulated IVF represents a legitimate option to women with a strong family history of ovarian cancer or women who are fearful of the risks of exogenous gonadotropin exposure. In many cases, unstimulated IVF is less labor-intensive. The time used by office personnel for teaching sessions and office procedures is reduced compared to conventional IVF. There are several well recognized limitations with unstimulated IVF. Because GnRH analogues are not used, the timing of oocyte retrieval is unpredictable. The vagaries of the menstrual cycle make it difficult to predict the timing of office procedures and laboratory use. Detection of an LH surge during a monitored cycle is common and generally leads to cycle cancellation. In contrast, LH surge activity is rarely seen with stimulated IVF when

The reported success rates with unstimulated IVF are highly variable. Some of the major reported series are summarized in Table 17–3. As with many innovative technologies, early success was met with enthusiasm. However, in the past two reported series from the In Vitro Fertilization Registry the success rates with unstimulated IVF have been disappointing. In 1993 an overall clinical pregnancy rate of 4.9% per retrieval was reported for 481 cycles. Nearly one-third of the cycles were canceled, and only one pregnancy during 122 initiated cycles was reported in women over age 40. As a group women under age 40 did the best, with a 7% clinical pregnancy rate per retrieval (6.3% deliveries/retrieval). The 1994 data were similar, with an overall clinical pregnancy rate per retrieval of 10%, but no women over age 40 delivered a viable pregnancy. Women under 40 years of age had a 15.0% clinical pregnancy rate per retrieval and a 10.2% live birth rate per retrieval. A staggering 50% of cycles were canceled. The discrepancies in reported pregnancy rates between the early series and those that are more recent are perplexing. In part, some of the differences could be due to the careful selection and screening of patients and the intense monitoring that is inevitably associated with new clinical protocols. Nevertheless, the results of more recent data suggest that the widespread application of unstim-

TABLE 17–3. Success Rates with Unstimulated IVF Study Foulot et al., 1989 Paulson et al., 1989 Patton et al., 1989 IVF Registry, 1993 IVF Registry, 1994

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Cycles initiated 71 36 27 481 460

Cancellation rate 3/71 11/36 15/27 155/481 206/410

(4%) (30%) (55%) (32%) (50%)

Clinical pregnancy rate per embryo transfer 17/53 5/25 2/8 16/203 22/157

(32%) (20%) (25%) (8%) (14%)

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ulated IVF is ill-advised, and clinicians should carefully select candidates for this procedure in an effort to maximize pregnancy rates.

potential candidates from the pool of couples considering assisted reproductive technology.

Maximizing Pregnancy Rates with Unstimulated IVF

In Vitro Maturation

Unfortunately, there are no scientifically tested criteria developed for selecting candidates for unstimulated IVF. Based on the collected published data, we recommend the following guidelines for patient selection. Unstimulated IVF would best serve women under age 40 with regular, predictable menstrual cycles and without any evidence of a male factor. Women who are poor responders to conventional ovarian hyperstimulation protocols but who have normal tests of ovarian reserve are also potential candidates. Prior to any procedure, we recommend ultrasonography and endocrine testing during the menstrual cycle to exclude the possibility of aberrant folliculogenesis or luteal dysfunction. A mock cycle that indirectly assesses follicular dynamics and luteal function in women contemplating unstimulated IVF may be helpful. Women with menstrual cycles exhibiting low serum estradiol levels at the time of follicular maturity (Table 17–1) are not ideal candidates. Luteal problems identified by serial luteal phase progesterone values or endometrial biopsies can also be used as exclusion criteria. Women with recurrent pregnancy loss or endocrinopathies are not good candidates for unstimulated IVF. Previous laboratory testing that provided evidence of endocrine dysfunction during the menstrual cycle must be carefully reviewed. If convincing, an alternate option for fertility is recommended. In all, this leaves a small subset of

In contrast to unstimulated IVF, which may be appropriate for only a small percentage of infertility couples, in vitro maturation (IVM), or the process of maturing oocytes harvested from an unstimulated ovary, has the potential to serve a large population of patients. Advantages include elimination of gonadotropin use for ovarian stimulation and the small but theoretic risk of ovarian cancer or ovarian hyperstimulation syndrome. There is also significant cost reduction when compared to conventional IVF. With IVM, overall costs may be decreased by at least 50% by eliminating exposure to gonadotropins, reducing monitoring costs, and decreasing costs of IVF personnel. In vitro maturation of mammalian oocytes is based on the recognition that oocytes released from antral follicles resume meiosis spontaneously under appropriate culture conditions in vitro. In most mammals, meiosis is initiated during fetal development but is arrested at prophase of the first meiotic division by the time of birth [termed the germinal vesicle (GV) stage] (Fig. 17–1). Meiotic arrest, in nearly all of the several million oocytes present in the infant human ovary, is maintained in the primordial or preantral follicle throughout reproductive life. Thus only a few oocytes escape arrest and are destined for release at ovulation each month during the menstrual cycle, with the remainder perhaps never completing meiosis but, rather, undergoing degeneration secondary to follicular atresia. Completion of the first meiotic division

FIGURE 17–1. Immature, germinal vesicle (GV)-intact, rhesus monkey oocyte (left) and mature, metaphase II oocyte (right).

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occurs only after the oocyte and the ovarian follicle that encompasses it have undergone extensive growth and exposure to LH. During a normal menstrual or stimulated cycle, the resumption of meiosis is triggered in oocytes contained in mature, antral follicles by the preovulatory surge of LH or hCG injection, respectively. GV breakdown and chromatin condensation occurs with completion of the first meiotic division followed in several hours by a second meiotic arrest (MII, Fig. 17–1), this time at metaphase of the second meiotic division. Meiosis is completed only after sperm penetration triggers oocyte activation. Control of meiosis during the oocyte’s tenure in the ovary is complex, involving communication between the oocyte and the surrounding cumulus/granulosa cell mass. Cell processes from supporting cells extend through the zona pellucida and establish intimate contacts in the form of gap junctions with oocyte surface microvilli. Cycle 3,5adenosine monophosphate has been implicated in the maintenance of meiotic arrest as oocytes released from the follicular environment can be held in the GV-intact state by agents that promote high intracellular levels of this second messenger. The effect of the gonadotropin surge on meiosis may be exerted through disruption of the cumulus–oocyte communication system. The aspect of oocyte maturation just discussed focuses on nuclear progression. Another component of oocyte maturation concerns cytoplasmic events. Indeed, cytoplasmic changes may well control nuclear events. Changes in cytoplasmic levels of metaphase-promoting factor (MPF) are thought to control meiosis. MPF is a complex between cyclin B and a 34 kDa protein, homologous to the product of the cdc2 gene in fission yeast and therefore referred to as p34cdc2. This protein is a serine/threonine kinase whose state of phosphorylation and association with cyclin B determines MPF activity. High levels of MPF are associated with maturation arrest, whereas low or decreasing levels are correlated with release of the meiotic block. Once MPF levels fall, phosphorylation–dephosphorylation cascades are activated that culminate in additional cytoplasmic events prerequisite to fertilization and the activation of development, such as chromosome condensation and nuclear laminin breakdown.

Animal Studies The mouse has served as a convenient and useful model for IVM based on access to large numbers of oocytes and the efficiency and speed in which

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GV-intact oocytes mature to MII. As long ago as 1935, in classic experiments conducted by Pincus and Enzmann, it was recognized that oocytes isolated from graafian follicles and placed in culture would resume meiosis spontaneously. In 1984 Schroeder and Eppig demonstrated that the developmental capacity of in vitro matured mouse oocytes was normal. Systems are now established for the recovery of oocytes from preantral follicles that are capable of completing growth and maturation in vitro and subsequently undergoing fertilization and development to term following transfer to a surrogate. Remarkably, this capability has also been demonstrated for oocytes isolated from primordial follicles. A major effort has also focused on IVM in domesticated species such as the bovine species, where a trip to the local abattoir can provide hundreds of ovaries with the potential to conduct experiments involving thousands of oocytes. Although the overall efficiency of producing calves following IVM-IVF is low, improvements in individual components or steps in IVM protocols will undoubtedly be forthcoming.

Nonhuman Primate Studies Nonhuman primate studies of IVM are of theoretic interest to the clinical arena because of similarities to human reproductive processes. Follicular development, hormone secretion, and luteal function are similar to those in humans, supporting the nonhuman primate as a model for investigating regulation of the menstrual cycle. An advantage of the model is the ability to conduct invasive experimentation without the ethical limitations attendant to clinical research. Although the model is not robust enough to support systematic or extensive molecular level approaches, conditions for the harvest of ovarian oocytes and their subsequent maturation in culture have been defined in the rhesus monkey. In studies from Alak and Wolf, IVM was conducted in TALP, a simple medium composed of balanced salts, lactate, and pyruvate, supplemented in this case with 20% fetal calf serum and human gonadotropins. The highest yield and quality of oocytes was associated with ovaries excised during the early follicular phase from unstimulated animals. Most (55%) of the oocytes surrounded by two or more layers of cumulus and at least 100 m in diameter underwent germinal vesicle breakdown (GVBD) with 40% maturing to MII. The presence of exogenous human FSH and LH improved GVBD and MII levels in a way that was dependent on the

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stage of the menstrual cycle. The fertilization rate for in vitro matured oocytes was 32% (16/50). The authors concluded that IVM in the rhesus monkey can be enhanced by more rigorous selection of meiotically competent oocytes isolated from ovarian oocyte pools using follicular size, oocyte size, and the appearance of the OCC as selection criteria. In a follow-up study, Alak and coworkers demonstrated that the regulatory peptides inhibin and activin or their combination could significantly improve the success rate of IVM in the rhesus monkey. Such findings may ultimately play a major role in directing the development of clinical protocols.

Evolution of Clinical IVM Technology Studies on the maturation of human ovarian oocytes (Table 17–4) date back to the 1960s with the pioneering work of Edwards and coworkers in Cambridge. Edwards noted that maturation can occur upon follicular release in several animal species and humans. The application of this knowledge within the context of ongoing conventional IVF and the production of viable pregnancies, however, did not occur for decades, with a report from the Jones Clinic in Norfolk. In this case, oocytes were recovered and matured from patients undergoing ovarian stimulation, presumably from the inadvertent aspiration of small antral follicles, a relatively infrequent and unpredictable event. It probably occurs more commonly than at first appreciated because GV-intact oocytes may not be surrounded by a large cumulus mass and hence are difficult to find. Moreover, those that are recovered in cumulus may not be examined closely until long after collection, such that their status at pickup would be unknown. A second, more recent report confirmed the clinical usefulness of immature oocytes collected from patients during ovarian stimulation and matured over a time course of 30 hours. The first pregnancy success following IVM of oocytes collected from a nonstimulated patient was reported by Cha and coworkers in 1991. In the

context of an oocyte donation program, ovarian tissue was obtained from biopsied or whole excised ovaries, and oocytes were aspirated with a 21-gauge needle from 2- to 5-mm follicles. IVM was conducted in modified Hams’ F10 medium with 20% fetal calf serum (FCS) or 50% follicular fluid (FF) for up to 48 hours of culture. Of the 270 oocytes recovered (11.7 per ovary), 76.7% appeared healthy, 56% matured to MII in the presence of follicular fluid, and 36% did so in medium supplemented with FCS. The authors examined the results as a function of stage of the menstrual cycle and concluded that the percentage of healthy oocytes was unrelated to cycle phase. The number of collected oocytes did, however, decline significantly with increasing age of the donor. The only recipient in whom embryos were transferred, conceived, and delivered. The oocytes were recovered from a 28-year-old patient 13 days from her last menstrual period from a single ovary yielding 11 healthy oocytes. Among the seven resulting embryos, five were transferred on day 18 of steroid replacement to a 33-year-old woman with premature ovarian failure. A triplet pregnancy ensued. The first robust experience showing promise of widespread clinical utility was reported in 1994. Although only one pregnancy was reported following IVM-IVF, an efficient recovery method was described whereby erythrocytes were first removed from aspirates by ultrafiltration facilitating oocyte identification and recovery. Oocyte maturation, fertilization, and development rates for patients with and without polycystic ovarian syndrome (PCOS) were compared. A larger number of oocytes were obtained from PCOS patients. Two culture methods and maturation time intervals were also examined. A more aggressive approach to handling IVM oocytes was introduced in a follow-up report by this group. Intracytoplasmic sperm injection (ICSI) was employed rather than conventional insemination, and the resultant embryos were cultured to blastocyst stage and hatched before transfer. This approach produced one pregnancy, with the birth of a girl.

TABLE 17–4. Development of Clinical IVM-IVF Study Edwards, 1965 Veeck et al., 1983 Cha et al., 1991 Trounson et al., 1994 Barnes et al., 1995

Development Human oocytes mature spontaneously in vitro IVM in stimulated cycle results in pregnancy IVM-IVF in unstimulated cycle results in pregnancy Improved collection techniques for IVM ICSI and assisted hatching with IVM-IVF

IVM-IVF, in vitro oocyte maturation–in vitro fertilization; ICSI, intracytoplasmic sperm injection.

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The relatively poor pregnancy success rate for IVM-IVF led Barnes and coworkers to evaluate the influence of ovulatory function (regular, anovulatory, or irregular PCOS patients) on IVM outcome and embryo quality. Oocytes from regularly cycling patients gave optimum results: 82% maturation rate in 48 hours in TCM199 medium supplemented with 10% FCS, recombinant hFSH, hCG, pyruvate, penicillin, and streptomycin. When compared to in vivo matured oocytes, IVM-IVF-produced embryos showed a higher arrest rate during cleavage and a slower cleavage rate. IVM-IVF embryos from regularly cycling patients also performed better than did those from anovulatory or irregular PCOS patients. These findings suggest that clinical outcome may well depend on patient selection, which reflects the quality of the primary oocyte recovered and placed in culture for IVM.

Steps in IVM-IVF Follicular Monitoring Pelvic ultrasonography is initiated within the first 2–3 days of the unstimulated cycle to assess the number of oocytes available for harvest. Many protocols use the information from a second ultrasound scan (cycle days 5–7) to schedule oocyte retrieval (cycle days 7–14). Determination of peripheral steroid concentration is not required. Exogenous oral or intramuscular estrogen has been used to promote endometrial development in IVM protocols. Theoretically, supplemental estrogen may be necessary to stimulate endometrial growth suitable for implantation. Preliminary results using estrogen hold promise; but the optimal dose, timing, and method of administration require further testing.

Oocyte Collection Collection occurs during the mid- to late-follicular phase by transvaginal ultrasound-guided aspiration of 0.4- to 2.0-cm (diameter) follicles using a 30 cm needle (17 gauge with a short bevel). Removal of erythrocytes and follicular cells from the aspirates can be accomplished by ultrafiltration. The flush medium employed is probably not critical to success and may involve heparinized human tubal fluid (HTF) or phosphate-buffered saline (PBS). The number of oocytes collected from PCOS patients averaged approximately 15 and from non-PCOS patients 3.

Oocyte Maturation Maturation is undoubtedly related to oocyte quality, which should be assessed at recovery. A high

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quality oocyte is fully grown (100 m), enclosed by more than two layers of cumulus cells, and has a homogeneous, evenly colored ooplasm. Atretic oocytes are dark or discolored and may contain vacuoles. Successful maturation is usually measured by cumulus expansion, GVBD or disappearance of the germinal vesicle, and the appearance of a first polar body. Maturation to PB1 should occur within 48 hours of recovery for oocytes obtained from nonstimulated patients and within 30 hours for patients subjected to ovarian stimulation with gonadotropins. The medium employed for IVM varies from simple TCM199 or HTF to the relatively complex solutions such as Ham’s F10 or Menezo’s B2. Typically these media are supplemented with a protein source, such as serum, follicular fluid or a commercially available serum derivative (SSS or Plasmanate), hormones or growth factors (FSH, hMG, hCG, -estradiol, activin), pyruvate, antibiotics, and bicarbonate to provide buffering in 5% CO2 in air. Experience to date indicates that most (approximately 55%) primary oocytes mature to MII within 48 hours.

IVM-IVF In vitro fertilization following maturation initially involved conventional insemination, with highly variable fertilization levels (around 30–40%). More recent reports have incorporated intracytoplasmic sperm injection (ICSI) into the protocol with fertilization levels in the 60–70% range. This difference, if significant, may result because adverse alterations in the zona pellucida can occur during prolonged culture, which in turn may reflect precocious release of the oocyte’s cortical granules.

Embryo Culture For the culture of embryos produced by conventional IVF and presumably those from IVM-IVF, a number of media and culture durations have been employed successfully. Usually for short-term culture (up to 3 days) a simple medium supplemented with a serum product is adequate (e.g., HTF with 10% serum or serum substitute). For longer culture (4 days or more) a complex medium such as Gardners G1 or G2 with a serum product would be favored or perhaps co-culture on Vero cells.

Embryo Transfer Embryo transfer mimics conventional IVF. Assisted hatching may be appropriate depending on the experience of the ART program providing the service.

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Conclusions The development of IVM-IVF technology, which at first glance may seem slow, is gaining momentum and in our opinion will soon be an integral part of every ART program. Concomitant with the application of this technology will be increased reliance on a quality laboratory. Prolonged culture times, increased reliance on ICSI, and assisted hatching require an added time commitment from laboratory personnel. On a research and development level, it is possible that the technology could benefit from improvements in the initial selection of oocytes and their quality evaluation, with attention focused on cytoplasmic and nuclear maturation. These are areas where model animal studies may ultimately provide useful guidance. When IVM-IVF does become a part of our armamentarium of technologies, the storage of follicular oocytes at low temperatures may represent an alternative to frozen embryo storage, as it avoids the ethical objections of the latter.

Suggested Reading Alak BM, Coskun S, Friedman CI, et al. Activin A stimulates meiotic maturation of human oocytes and modulates granulosa cell steroidogenesis in vitro. Fertil Steril 1998;70:1126–1130. Alak BM, Smith GD, Woodruff TK, et al. Enhancement of primate oocyte maturation and fertilization in vitro by inhibin A and activin A. Fertil Steril 1996;66:646. Alak BM, Wolf DP. Rhesus monkey oocyte maturation and fertilization in vitro: roles of the menstrual cycle and of exogenous gonadotropins. Biol Reprod 1994; 51:879. Barnes FL, Crombie A, Gardner DK, et al. Blastocyst development and birth after in vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching [case report]. Hum Reprod 1995;10:3243. Barnes FL, Kausche A, Tiglias J, et al. Production of embryos from in vitro matured primary human oocytes. Fertil Steril 1996;65:1151. Burry KA, Hickok LR, Patton PE, et al. Preliminary experience with natural cycle in vitro fertilization [abstract 0-001]. In 39th Annual Meeting of the Pacific Coast Fertility Society, April 10–14, 1991, Indian Wells, CA. Cha KY, Koo JJ, Ko JJ, et al. Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil Steril 1991; 55:109. Edwards RG. Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature 1965;208:349. Edwards RG, Steptoe PC, Purdy JM. Establishing fullterm human pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol 1980;87:737.

Eppig JJ, O’Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod 1996; 54:197. Foulot H, Ranoux C, Dubuisson J-B, et al. In vitro fertilization without ovarian stimulation: a simplified protocol applied in 80 cycles. Fertil Steril 1989;52:617. Kasper KC, Rodrick-Highberg G, Lankford JC. OvuSTICK Kit for Semiquantitative Analysis of Human Luteinizing Hormone in Urine. Technical Report No. 6. Sunnyvale, CA: Monoclonal Antibodies, 1986. Loumaye E, Billion JM, Mine JM, et al. Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil Steril 1990;53:295. Patton PE, Burry KA, Wolf DP et al. The use of oral contraceptives to regulate oocyte retrieval. Fertil Steril 1988;49:716. Paulson RI, Sauer MV, Francis MM, et al. In vitro fertilization in unstimulated cycles: a clinical trial using hCG for timing of follicle aspiration. Obstet Gynecol 1990;76:788. Scott RT, Leonardi MR, Hofmann GE, et al. A prospective evaluation of clomiphene citrate challenge test screening in the general fertility population. Obstet Gynecol 1993;82:539. Scott RT, Toner JF, Muasher SJ, et al. Follicle stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651. Smitz J, Cortvrindt R. Oocyte in-vitro maturation and follicle culture: current clinical achievements and future directions. Hum Reprod 1999;14(suppl 2):145–161. Tanbo T, Dale PO, Lunde O, et al. Prediction of response to controlled ovarian hyperstimulation: a comparison of basal and clomiphene citrate-stimulated folliclestimulating hormone levels. Fertil Steril 1992;57:819. Thornton MH, Francis MM, Paulson RJ. Immature oocyte retrieval: lessons from unstimulated IVF cycles. Fertil Steril 1998;70:647–650. Toner JP, Philput CB, Jones GS, et al. Basal follicle stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil Steril 1991; 55:784. Trounson A, Wood C, Hausche A. In vitro maturation and the fertilization and developmental competence of oocytes recovered from untreated polycystic ovarian patients. Fertil Steril 1994;62:353. Veeck LL, Wortham JW Jr, Witmyer J, et al.: Maturation and fertilization of morphologically immature human oocytes in a program of in vitro fertilization. Fertil Steril 1983;39:594–602. Whitacre KS, Seifer DB, Friedman CI, et al. Effects of ovarian source, patient age, and menstrual cycle phase on in vitro maturation of immature human oocytes. Fertil Steril 1998;70:1015–1021.

Additional Reading Beckers NG, Pieters MH, Ramos L, et al. Retrieval, maturation, and fertilization of immature oocytes obtained from unstimulated patients with polycystic ovary syndrome. J Assist Reprod Genet 1999;16:81–6.

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17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation Cahill DJ, Wardle PG, Harlow CR, et al. Expected contribution to serum oestradiol from individual ovarian follicles in unstimulated cycles. Hum Reprod 2000; 15:1909–12. Cha KY, Han SY, Chung HM, et al. Pregnancies and deliveries after in vitro maturation culture followed by in vitro fertilization and embryo transfer without stimulation in women with polycystic ovary syndrome. Fertil Steril 2000;73:978–83. Chian RC, Buckett WM, Too LL, et al. Pregnancies resulting from in vitro matured oocytes retrieved from patients with polycystic ovary syndrome after priming with human chorionic gonadotropin. Fertil Steril 1999; 72:639–42. Chian RC, Buckett WM, Tulandi T, et al. Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome. Hum Reprod 2000;15:165–70.

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Chung HM, Hong SW, Lim JM, et al. In vitro blastocyst formation of human oocytes obtained from unstimulated and stimulated cycles after vitrification at various maturational stages. Fertil Steril 2000;73:545– 51. Cobo AC, Requena A, Neuspiller F, et al. Maturation in vitro of human oocytes from unstimulated cycles: selection of the optimal day for ovum retrieval based on follicle size. Hum Reprod 1999;14:1864–8. Mikkelsen AL, Smith S, Lindenberg S. Impact of oestradiol and inhibin A concentrations on pregnancy rate in in vitro oocyte maturation. Hum Reprod 2000;15: 1685–90. Nogueira D, Staessen C, Van de Velde H, et al. Nuclear status and cytogenetics of embryos derived from in vitro-matured oocytes. Fertil Steril 2000;74:295–8. Thornton MH, Francis MM, Paulson RJ. Immature oocyte retrieval: lessons from unstimulated IVF cycles. Fertil Steril 1998;70:647–50.

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18 Intratubal Gamete Transfer Kristin Sinnock Friel and Alan S. Penzias

In 1978 the birth of the first human conceived in vitro and delivered to her mother’s uterus through the cervix astounded the world and electrified fertility specialists. Old assumptions, paradigms, and treatment algorithms were shaken; and a new era in the management of infertility emerged. In vitro fertilization (IVF), the first of the assisted reproductive technologies (ART), burst onto the world stage and the race was on to match the feat. With progress there is doubt; nonetheless, IVF centers proliferated, each attempting to duplicate and improve on the technique. Just 2 years later, gamete intrafallopian transfer (GIFT) was introduced when the technique was successfully carried out in primates. The first human GIFT procedures were performed by Asch et al. in 1984, and the study was reported in 1986. In their cohort of 10 couples, four patients achieved a clinical pregnancy and two of those took home viable infants. The American Fertility Society formed the Society for Assisted Reproductive Technology (SART), which in turn developed a national ART registry. The first registry report summarized the data for 1987. That year the number of ART procedures performed in the United States topped 10,000 (Fig. 18–1). The summary success rate for IVF was 16% per initiated cycle in contrast to a 25% rate for GIFT. The apparent discrepancy in the success rates spurred further interest in the GIFT procedure; and like IVF, GIFT grew in popularity. In 1987 a total of 1968 GIFT procedures were performed. This number nearly tripled in just 5 years when in 1992 there were 5767 GIFT cases. It is worthy to note that 1992 was the year in which GIFT peaked in popularity (Fig. 18–2). The reasons for the decline in the popularity of GIFT have little to do with its rate of success. The pregnancy rates have held relatively 184

steady since 1991, with a reported rate of 28.4% in 1994. Rather, it seems that the rising success of IVF (Fig. 18–3), coupled with its less invasive approach, has increased the frequency with which IVF is chosen over GIFT. In 1987 approximately 80% of all ART procedures were IVF with 20% GIFT. In 1994 the proportion was nearly 90% IVF with 10% GIFT. Despite the decline, GIFT remains a viable, important therapeutic option for select couples with primary or secondary infertility.

Purpose of GIFT Since the late 1980s the technical steps used in the GIFT procedure have evolved, but the theory behind its application has not changed. The purpose of GIFT is to transfer mature, preovulatory oocytes and concentrated, motile, washed sperm into one or both fallopian tubes to place gametes at their “natural site of fertilization.” The mechanism of the enhanced pregnancy rate per treatment cycle in women with normal pelvic anatomy is the increase in the number of sperm and oocytes that have the opportunity to interact in the ampulla of the fallopian tube. It is generally believed that couples in the general population conceive at a rate of 20–25% per month. If a couple has not succeeded in achieving pregnancy after 1 year despite adequate frequency of unprotected intercourse, it is presumed that their cycle fecundity is lower than that of the general population. There is some debate as to the actual fecundability of these couples but it is clearly less than that of the fertile population. After a comprehensive evaluation, some couples are found to have a discernible, treatable cause of their infertility. These couples are directed to specific therapies

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FIGURE 18–3. Total number of IVF procedures reported to the SART registry along with the crude delivery rate by year. FIGURE 18–1. Total number of ART procedures reported to the Society of Assisted Reproductive Technologies (SART) registry, by year.

meant to address their particular problem. However, experience has demonstrated that relative to their native chances for conception without treatment the GIFT procedure does increase the cycle fecundity among couples who have been completely evaluated for primary or secondary infertility.

Why Is GIFT Better? It is known that fallopian tubes actively secrete a host of substances, including growth factors, prostaglandins, and glycoproteins, which serve a variety of tubal functions. Although IVF has shown us that the fallopian tube itself is not absolutely necessary for successful fertilization of a human oocyte

or for the early development of an embryo that leads to pregnancy, each factor secreted by the fallopian tube may have intrinsic properties important to the ultimate success of fertilization. Presumably, the ampulla of the fallopian tube is an ideal environment for human conception, and to this end many of the culture media used in the assisted reproductive technologies have attempted to recapitulate the tubal environment by mimicking the concentrations of certain elements and substances in the tube. In addition, some evidence suggests that the proximity of the tube and ovary may allow intravascular or intercellular communication between these two organs. Such substances, though yet to be specifically defined, may also contribute to the success of fertilization. Anecdotally, placement of the gametes in the tube proximal to the ovary with the greatest number of corpora lutea improves the chances for success. This as yet unsubstantiated impression suggests that local exchange of substances in the vascular arcade between the ovary and fallopian tube somehow exerts a positive influence over the events leading to fertilization and, ultimately, tubal transport of early embryos into the uterus. Therefore by placing gametes directly into the fallopian tube the ovarian-tubal communication may be preserved.

Indications for GIFT FIGURE 18–2. Total number of GIFT (Gamete Intrafallopian Transfer) procedures reported to the SART (Society of Assisted Reproductive Technology) registry along with the crude delivery rate by year.

One infertility problem that GIFT corrects is a mechanical defect in ovum pickup. In highly fertile women each tube has only about a 63% efficiency rate at picking up an ovum released by a

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TABLE 18–1. Indications for GIFT Pelvic adhesions unrelated to pelvic inflammatory disease Endometriosis Cervical factor infertility Oligoanovulatory infertility Idiopathic infertility Religious principles GIFT, gamete intrafallopian transfer.

given ovary. A number of other species are much more efficient at the process of ovum capture. In these species the ovary is surrounded by a bursa connected to the fallopian tube. This bursa limits the migration of the extruded oocyte to within a few millimeters of the fimbria thereby ensuring nearly 100% efficiency in the capture of ovulated oocytes. The anatomic relation between the human fallopian tube and ovary is highly susceptible to the intrusive effects of mechanical distortion. Table 18–1 lists the conditions that make a patient a candidate for GIFT. Because the GIFT procedure can overcome inefficiencies of ovum pickup, candidates for GIFT include women with a history of pelvic adhesions unrelated to pelvic inflammatory disease. These individuals lack the ability to capture efficiently the oocytes released from the ovary spontaneously. Clearly, there is the need for surgical judgment in these cases. Adhesions that severely distort the pelvic anatomy make the process of oocyte retrieval at laparoscopy difficult. Because the ovaries have been stimulated by gonadotropins to raise multiple follicles, they are particularly sensitive to excess manipulation. Bleeding can be induced with greater ease than when manipulating unstimulated ovaries. Furthermore, at the time of laparoscopy it is expected that all preovulatory oocytes will be aspirated. Mechanical limitations that prevent complete aspiration of all preovulatory follicles can therefore place the patient at greater risk for the ovarian hyperstimulation syndrome. Limiting GIFT to patients with mild pelvic adhesive disease may be prudent, but another caveat is the absence of intratubal damage. Patients with adhesions and a history of upper genital tract infections should not undergo the GIFT procedure. These patients are at significantly greater risk for ectopic pregnancy, as the microvillous ovum transport system in the fallopian tube may be compromised. In summary, patients with adhesions resulting from endometriosis or past abdominal surgery are candidates for GIFT in select circumstances. Those whose pelvic adhesions were

caused by infectious processes stand a greater risk for ectopic pregnancy and should be steered toward IVF. Infertility patients with a history of minimal and mild endometriosis are good candidates for GIFT. Evidence of improved cycle fecundity with the laparoscopic treatment of stage I and II endometriosis suggests that this condition in some way inhibits the process of sperm–egg interaction and transport. Placing the gametes directly into the fallopian tube removes them from the peritoneal milieu influenced by the endometriosis. Cervical factor infertility is difficult to define in absolute terms. Previously, this diagnosis was limited to patients with “hostile” cervical mucus. The inhospitable mucus is thought to act as a barrier to sperm entry, which decreases cycle fecundity. With the advent of IVF, cervical factor infertility takes on a new dimension. Atraumatic transfer of embryos to the endometrium is crucial to the success of IVF. In many patients, embryo transfer can be done with ease owing to the current generation of embryo transfer catheters. Some patients, however, have cervical anatomy that is challenging. In these patients, ultrasound-guided embryo transfer has been proposed to observe the path of the catheter and assist in guiding it atraumatically into the endometrium. Although this is useful in some circumstances, particularly where there is sharp anteflexion or retroflexion of the uterus, it does not correct the anatomy when odd configurations are encountered. In these women, difficulty transferring embryos atraumatically may pose the greatest challenge to inducing pregnancy. Although distortion of the normal cervical anatomy should not pose a barrier to sperm transport to the uterus following intercourse, those couples who remain infertile despite less aggressive conventional therapies sometimes progress to the assisted reproductive technologies. GIFT may be an ideal alternative for these individuals with normal tubal anatomy. The transfer of gametes to the fallopian tube may prove a better route for giving embryos across to the uterus than further attempts at transcervical embryo transfer. Women with a history of oligoanovulation may also be candidates for GIFT. If conception has not occurred with the use of less aggressive treatments, including ovulation induction with intrauterine insemination, GIFT may be used. Likewise, patients with idiopathic infertility may become pregnant with GIFT. Following a comprehensive evaluation and lacking success with more conservative methods in the treatment algorithm, GIFT may be

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an effective next step. There is some debate about the place of diagnostic laparoscopy in the evaluation of idiopathic infertility. Some practitioners believe that in the absence of a history suggesting pelvic adhesive disease or endometriosis, combined with a normal hysterosalpingogram, ovulation induction may be prescribed without performing diagnostic laparoscopy. Others believe that a combination procedure, the diagnostic GIFT, should be performed. This can benefit the patient with unexplained infertility, as the normal findings on laparoscopy can be treated at that time by placing gametes into the fallopian tubes. If laparoscopy reveals distorted pelvic anatomy not amenable to laparoscopic ovum capture or intratubal gamete transfer, the procedure can be converted. The conversion would include transvaginal oocyte retrieval followed by traditional IVF and transcervical embryo transfer. The GIFT procedure enables fertilization to occur in the patient’s body. At least one major religion that prohibits IVF (partly on the basis of conception occurring outside a woman’s body) permits GIFT. Therefore some couples may choose GIFT when presented with the option of assisted reproductive technology.

Contraindications to GIFT If the fallopian tubes are compromised, GIFT is not an appropriate therapeutic choice. Table 18–2 is a list of contraindications to GIFT. During the initial investigation of the infertile couple, attention should be paid to the fallopian tubes in more detail than simply noting whether the structure is patent. The tubes should be examined carefully for the presence of salpingitis isthmica nodosum. This finding, indicative of intrafallopian damage, mitigates against performing the GIFT procedure. Likewise, a history of documented pelvic inflammatory disease (PID) should be used to guide patients away from this therapeutic option. Undocumented cases of PID pose a significant dilemma. It is important to obtain maximum anatomic information about

TABLE 18–2. Contraindications to GIFT History of pelvic inflammatory disease Known tubal abnormalities Severe male factor infertility Any known contraindication to laparoscopy

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these patients before proceeding. Studies including hysterosalpingography and diagnostic laparoscopy should be carried out prior to choosing GIFT. In such cases, even perfectly normal-appearing pelvic anatomy does not guarantee normal function. Patients who have undergone tubal anastomosis following reversal of tubal sterilization make poor GIFT candidates. These individuals have a significantly increased risk for ectopic pregnancy and should be steered towards IVF. For GIFT to succeed, the sperm must be capable of fertilizing an oocyte. Unlike IVF, there is no direct proof that fertilization takes place following gamete placement. Some indirect evidence can be gleaned. When supernumerary oocytes are obtained they can be placed in culture with sperm and the resulting embryos frozen for the patient’s later use. If the fertilization rate among these excess oocytes is good, many assume that the transferred gametes would likely have shared the same fate. If pregnancy occurs, the suspicion is confirmed. When it does not, the question remains open. Therefore when selecting patients for GIFT one must be reasonably certain that fertilization could occur. Normal semen parameters including normal sperm concentrations, motility, and morphology are a good start Should there be a question about the ability of sperm to penetrate the eggs, or should there be no fertilization among the supernumerary eggs of an unsuccessful GIFT cycle, consideration should be given to alternate methods. Finally, any patient with a contraindication to laparoscopy should be ruled out for the GIFT procedure. As techniques for laparoscopy under local anesthesia and gasless laparoscopy emerge, the number of patients for whom laparoscopy is contraindicated may decline. Zygote intrafallopian transfer (ZIFT) is an alternate methodology whereby fertilization is first observed in vitro, after which the zygotes are transferred laparoscopically to the fallopian tubes. Much like GIFT in concept, ZIFT differs in that oocytes are retrieved vaginally and then fertilized in vitro. In cases where a male factor may reduce the likelihood of fertilization, intracytoplasmic sperm injection (ICSI) can be performed and the resultant embryos returned to the patient the next day, following confirmation of fertilization. ZIFT, as an analogue to GIFT, extends the range of intrafallopian transfer to patients with male factor infertility. One drawback to this approach is the need for two surgical procedures: the first wherein the oocytes are retrieved and the second at which the zygotes are returned to the fallopian tubes laparoscopically.

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Equipment The equipment required to perform GIFT consists of laparoscopic instruments and laboratory equipment. In our setting we perform the GIFT procedure under general endotracheal anesthesia. Therefore our equipment and procedures reflect this practice preference. Table 18–3 is an itemized checklist used to prepare for the GIFT procedure. The laparoscopic equipment includes a video system, a CO2 insufflator, a fiberoptic light source and fiberoptic cable, and a pedal-activated Rocket suction pump. These items are all stored on a mobile vertical cart that can be rolled into position for the procedure (Fig. 18–4). In the background the proximity of the laboratory to the operating room is apparent. In addition to a window through which tubes of follicular aspirates can be passed, there is an access door into the operating room. The embryologist uses this door to enter the operating room with the loaded GIFT catheter at the appropriate time. The laboratory, contiguous to the operating room, is equipped with a Nikon inverted 10 dissecting microscope with heated stage. A warming tray containing two 12-well heating blocks sits adjacent to the laboratory to maintain the temperature of the conical tubes containing the follicle aspirates while they await evaluation by the embryologist.

FIGURE 18–4. Video system, insufflator, and suction apparatus mounted on a portable cart in the operating room. Note the proximity of the laboratory to the operating room immediately behind the portable cart.

TABLE 18–3. Itemized Checklist Used to Prepare for the GIFT Procedure Laparotomy pack One 4-0 Vicryl suture Power-free (PF) gloves for physician PF gloves for scrub nurse One steri-drape Light handle One camera drape 10 Raytech sponges Rocket needle Glass syringe, 30 cc Modified HTF medium, 100 cc Conical Falcon tubes, 15 ml Drape sheet Gowns (3) PF gloves for embryologist One no. 11 blade One sterile plastic bowl One set of 0.5-inch Steri-strips One 7 mm laparoscope Suprapubic trochar, 5 m GIFT aspiration needle Fenestrated aspirator, 5 mm Pyrex beaker, 250 ml Polypropylene tubing, 18 g

Procedure The steps for performing GIFT are similar to those of standard IVF protocols. Initially, the ovaries are stimulated by intramuscular or subcutaneous administration of gonadotropins most often in combination with gonadotropin-releasing hormone (GnRH) agonist. The ovaries are then monitored for follicular growth with transvaginal ultrasonography and serum estradiol levels. Human chorionic gonadotropin (hCG) is administered when three or more follicles exceed 16 mm in greatest diameter. The precise combination of follicle quantity, follicle size, and estradiol level is difficult to render, but an adequate responder should produce at least six mature follicles in response to stimulation. When the follicle quantity and size in combination with the serum estradiol level is adequate, hCG is administered. A laparoscopic oocyte retrieval is

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scheduled to occur 36 hours after the intramuscular hCG administration. Upon arrival at the ART center, the patient is identified and interviewed by a staff anesthesiologist, and anesthesia consent is obtained. The physician performing the GIFT procedure then interviews the patient and reviews her cycle flow sheet. The flow sheet contains vital information about her history, including the status of her fallopian tubes and any comments regarding the GIFT procedure the patient’s personal physician may have written. The flow sheet also reflects the number of oocytes to be placed in one or both fallopian tubes. The quantity of oocytes to transfer is agreed upon in advance of the procedure by the couple and their personal physician. There has been some controversy in the literature regarding the number of oocytes to transfer at the time of GIFT. This has become an increasingly important issue as efforts are under way to limit the incidence of multiple pregnancy. At the same time, there is increased economic pressure to limit the expense of the procedure and improve the ratio of dollars spent per pregnancy. In addition, religious reasons for selecting GIFT aside, excess oocytes obtained at GIFT can be inseminated and the resulting embryos frozen for a patient’s later use. If subsequent transfer of these embryos is done transvaginally to the uterus, the savings relative to another stimulated cycle are high. We looked at the success rates of GIFT as a function of the number of oocytes transferred. We found that women who received four or more oocytes were three times more likely to achieve clinical pregnancy compared to those who received three or less. There was a marginal advantage to receiving five versus four oocytes, but any more than six showed no statistically significant difference with respect to clinical pregnancy rates. It seems, therefore, that there is a limit to the success of GIFT that may not simply be overcome by increasing the number of eggs transferred. Our routine transfer recommendations are listed in Table 18–4. The physician performing the procedure reviews the previously signed and witnessed consent forms and verbalizes the previously agreed-on fate of any

TABLE 18–4. Recommended Number of Oocytes to Transfer at GIFT Age (years)

Oocytes (no.)

30 31–34 35–39 40

3 4 5 6

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oocytes obtained in excess of those transferred. Verbalization of the previously agreed-on fate of the supernumerary oocytes is particularly useful to ensure that the patient understands exactly what will happen to each of her eggs. In our program we commonly offer the patient “mini-IVF” for spare oocytes. This procedure is IVF of the excess oocytes with cryopreservation of those that meet predetermined quality criteria. Those couples who, for religious or personal reasons, choose not to have “mini-IVF” performed can choose to have the eggs discarded. We do not permit concurrent egg donation with spare oocytes. The patient is brought to the operating room where the embryologist who will perform the gamete manipulation greets her and confirms her identity. General endotracheal anesthesia is applied, and the patient is prepared in the supine position. An instrument table is laid out (Fig. 18–5) containing the necessary equipment for the procedure. With the patient in position, heating blocks and a 250 ml beaker containing modified human tubal fluid (HTF) are placed on a Mayo stand. The conical Falcon tubes are filled with 1 cc of heparinized modified HTF and placed in sterilized heating blocks (Fig. 18–6). A Veress needle is used to insufflate the abdomen with CO2, and the gas pressure is limited to 15 mmHg. The laparoscope is placed infraumbilically, and a 5 mm port is placed suprapubically in midline. The Rocket needle is placed midway between the two ports for manipulation of the GIFT retrieval needle followed by the transfer catheter (Fig. 18–7). Follicle aspiration is carried out under direct laparoscopic vision, and all visible follicles are aspirated. The follicles are aspirated into 15 ml conical Falcon tubes that contain 1 cc of heparinized modified HTF medium. The GIFT needle is flushed with medium at the conclusion of the retrieval portion of the case and passed off the field. The glass syringe is used to wash the pelvis with modified HTF medium. The physician then chooses a fallopian tube for transfer and grasps the fimbriated portion. A practice catheter is passed into the distal end of the fallopian tube, and once entry is confirmed it is removed. A question that arises with GIFT is whether to transfer the gametes to one tube or two. In 1991 we evaluated 399 GIFT cycles. In 133 of these cycles, gametes were transferred to one fallopian tube, and the rest had bilateral transfer. The clinical pregnancy rate for the unilateral group was 25.6% and for the bilateral transfer group it was 23.3%. The lack of a significant difference in pregnancy rates enabled us to conclude that there was

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K. Sinnock Friel and A.S. Penzias FIGURE 18–5. From left to right: scalpel, Veress needle, 7 mm reusable laparoscopic trocar, a 35 cm 18 gauge GIFT needle with polypropylene tubing and rubber stopper, a Rocket needle, a reusable 5 mm laparoscopic trocar, a blunt probe, a trial transfer catheter, and a glass syringe attached to a hollow suction wand.

no advantage to bilateral tubal transfer. We were able to reduce the total operating time by performing the transfer in a single tube. When choosing the tube for transfer, we considered the dominance of the ipsilateral ovary and the general appearance of the tube. Tubal patency, absence of adhesions, and easy manipulation may be more important factors than simply the state of the ipsilateral ovary. It is thought that the tubes themselves have an intrinsic role in the success of fertilization. In addition, there is a countercurrent blood flow exchange mechanism between the tube and the ovary. This countercurrent flow exchange mechanism may facilitate the flow of substances that influence fer-

tilization, embryo transport, and ultimately success. The countercurrent mechanism has demonstrated that the ovarian vein, which contains ovarian secretions, can transfer these substances to the ovarian artery, suggesting that a fraction of the products of the ovary are returned to the ovary in a short loop feedback system. In addition, the distal portion of the fallopian tube is supplied by the ovarian artery. Thus ovarian secretions directly influence the ampulla of the fallopian tube proximal to it through a short feedback loop. Because the tube is influenced hormonally by the proximal ovary through the short loop feedback mechanism, initially it was thought to be most advantageous to transfer

FIGURE 18–6. Adjusting the suction pressure by aspirating medium from the 250 ml beaker just prior to commencing the procedure.

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FIGURE 18–7. Abdominal placement of instruments. The laparoscope is at left and the 5 mm blunt probe at right. In the center is the Rocket needle containing the GIFT aspiration needle.

gametes into the tube next to the ovary with the most follicles to simulate the natural, physiologic state. In 1994 Ransom et al. in retrospectively analyzed the effect of gamete transfer to the tube next to the ovary with the greater number of follicles. A total of 144 GIFT cycles were examined, and indeed a higher pregnancy rate was reported for those transfers to the ipsilateral rather than the contralateral tube of the ovary with the greater number of dominant follicles. The embryologist examines all follicular aspirates and places the oocytes identified in Irvine P1 medium. During the interval between the aspiration and the transfer, the oocytes in the tissue culture plate are incubated at 37°C in 5% CO2 in air. At the conclusion of the aspiration procedure the embryologist selects the predetermined number of oocytes for transfer. The scientist then scrubs and puts on a gown. Upon returning to the laboratory, the embryologist, with the aid of another scientist, draws up a small pocket of fluid containing oocytes surrounded on either side by a small pocket of fluid, each with 50,000–100,000 sperm. The embryologist then delivers the gametes to the surgeon for tubal cannulation. The tip of the catheter is then placed at approximately 4 cm depth in the ampulla of the fallopian tube. The issue of how far into the tube the gametes should be placed was answered in 1989. Yee et al. followed 246 consecutive GIFT cycles over an 18month period. A standard ovarian stimulation protocol was used. Likewise, a standard method of oocyte retrieval and gamete transfer were used.

Each fallopian tube was sounded, and the transfer catheter was marked at distances of 2, 3, and 4 cm from the distal end. Both tubes received gametes, but a maximum of four eggs were transferred. The overall pregnancy rate in this group was 35.4%, with a clinical pregnancy rate of 30.9%. In general, the pregnancy rate increased with the number of eggs transferred and with the depth of the distal tubal lumen. For tubal transfer of less than 3 cm, the rate was 16.7%; for transfers at 3–4 cm the rate was 28.1%; and for those at more than 4 cm the pregnancy rate was 36.4%. After depositing the gametes the catheter is returned to the laboratory to confirm that it is indeed empty. The instruments and CO2 are removed from the patient’s body, and the incisions are closed. The patient then spends 30–60 minutes in the supine position in our two-bed recovery room followed by 30 minutes in a reclining chair in our two-chair step-down unit.

Anesthesia During the early work on GIFT, egg retrievals and transfers were performed under general anesthesia via a minilaparotomy or laparoscopy. General anesthesia itself comes with a series of risk factors: aspiration pneumonia, airway trauma, reactive airway disease, malignant hyperthermia, nausea, vomiting, and a significant time for recovery. The potential embryotoxic effect from general anesthesia is an additional theoretic risk. In 1995 Silva et al. reported on the technique of spinal anesthesia for GIFT. Spinal anesthesia was administered at a level

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between L3 and S1 at the time of laparoscopy. Intravenous midazolam and fentanyl were used as adjuncts, and intraoperative monitoring included electrocardiography (ECG), end-tidal CO2, blood pressure, and pulse oximetry. Of the 68 GIFT cycles in which spinal anesthesia was used, clinical pregnancy rates overall were 49/%, with a delivery rate of 37%. There was only one observed anesthesia-related complication. One patient suffered from a mild spinal headache, which resolved on its own without requiring a blood patch or further medical intervention. In 1996 Padilla et al. proposed the use of local anesthesia plus intravenous sedation for GIFT procedures. Intravenous sedatives included midazolam, fentanyl, inapsine, and propofol. Oocyte retrieval was performed using transvaginal ultrasonography aspiration. Just prior to laparoscopy 0.5% bupivacaine was infiltrated at the laparoscopic incision sites. A 5 mm endoscope was used, and the intraabdominal pressure was held at 8–12 mmHg. Catheter transfer of gametes was then carried out in the usual fashion. Patients were monitored for up to 2 hours in the recovery room. The average operating room time was 64  12 minutes and the recovery time 92  30 minutes. The clinical pregnancy rate per transfer was 39% with an ongoing pregnancy rate of 32%. There were no intraoperative or postoperative complications. Only two patients reported nausea, and only one required additional intravenous narcotic sedation. General anesthesia by endotracheal tube is used in our practice. The patients receive an intravenous combination of fentanyl and propofol. The gases administered include O2 and N2O. The patient’s vital signs are monitored intraoperatively with continuous ECG, end-tidal CO2 quantitation, blood pressure determination, and pulse oximetry.

Laparoscopic Versus Transvaginal Transfer The question of anesthesia type is also a factor in the decision whether to proceed with gamete transfer laparoscopically or transvaginally. Early transfer technique relied solely on laparoscopy and minilaparotomy for gamete transfer for which general anesthesia was required. The push to enable assisted reproductive technologies to be carried out in the outpatient ambulatory setting prompted investigation of less invasive techniques or retrieval and transfer. In 1993 Jansen et al. developed and reported on the use of a catheter system for cannulating the fallopian tubes through the vagina. In an early series of 20 patients who underwent GIFT

via the transvaginal technique there were four pregnancies. Among 60 matched controls who underwent laparoscopic transfer there were 21 pregnancies. In this report, pregnancy rates for transvaginal transfers were no more than-two thirds of those with laparoscopic GIFT. Woolcott and Stanger in 1994 reported 83 patients who underwent transvaginal GIFT. The clinical pregnancy rate in this cohort was 27.7%. This group emphasized that the physics behind transferring gametes vaginally was inherently different from those governing laparoscopic transfer. There is concern that transperitoneal migration is a risk with vaginal transfer. The fluid dynamics of retrograde tubal gamete deposition may play a role such that low volumes and slow rates of injection may be important factors for preventing transperitoneal migration. There is also concern that the currently available techniques for transvaginal gamete transfer may damage the endometrium in the process. At the present time, there is active research into designing better systems for transvaginal gamete transfer.

Complications Anesthetic complications during GIFT have been reported but are fortunately rare. Like all procedures where general anesthesia is applied, adequate safety measures must be taken. Critical to this is having trained personnel administer the anesthesia in a setting equipped with instruments essential to monitoring vital functions. Backup procedures, including mechanisms for treating malignant hyperthermia, should be in place. Intraoperative complications reported during the GIFT procedure include bowel injury, blood vessel damage, and ovarian hemorrhage. Ordinary techniques used to avoid these complications in other laparoscopic procedures are applied in GIFT as well. In the outpatient setting, however, it is necessary to develop protocols to handle such unanticipated events. Personnel should be trained to react to these rare events and immediate operative repair begun or appropriate transfer to a local inpatient hospital setting enacted. To further limit the risks of both anesthetic and intraoperative complications, we require a preoperative anesthesia consultation for women with a history of an anesthetic complication or a body mass index (BMI) above 28. In our outpatient setting we limit the performance of GIFT to women with a BMI below 28. The risk of ovarian injury can be minimized by gentle handling of the gonad

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during the procedure. We favor use of a blunt probe to elevate and fix the ovary against the side wall above the level of the ovarian blood supply. Direct visualization of the ovary and path of the retrieval needle is critical. Keeping the needle still during aspiration is important because excessive pulling or tension can cause rents in the ovarian cortex. When picking up the fallopian tube for gamete transfer we take care to limit the tension placed so as to avoid inadvertent avulsion of fimbria. Whole blood in an inhibitor of sperm–egg interaction, so it is also important to avoid repeated cannulation of the fallopian tube prior to transfer. Postoperative complications include ovarian hyperstimulation syndrome (OHSS). There is functionally no difference between the reported rates of OHSS with GIFT and IVF. Bear in mind that follicle aspiration reduces the risk of OHSS relative to the same number of follicles and estradiol level during routine ovulation induction cycles where intrauterine insemination will occur. Therefore it is important to empty all follicles even in couples who do not plan to generate embryos for cryopreservation with supernumerary oocytes. Like all patients with stimulated ovaries, there is an increased risk of ovarian torsion. Postoperative instructions should include advice to avoid strenuous physical activity and to enumerate the warning symptoms of ovarian torsion. These warnings signs include sharp intermittent or unrelenting pain accompanied by nausea or vomiting (or both). Infection following GIFT is rare but possible. Patients with multiple corpora lutea who are using supplemental progesterone may have a somewhat elevated temperature; fever above 100°F should be reported. Outcome-related complications are primarily related to pregnancy. The risk of ectopic pregnancy has been reported to range from 5% to 8%. There is also an increased risk of heterotopic pregnancy: from one in 30,000 spontaneous conceptions to as many as one in 1000 GIFT pregnancies. Patients with significant risk factors for ectopic pregnancy are not ideal GIFT candidates, but it should be noted that IVF does not preclude the development of an ectopic pregnancy.

Conclusions Development of the GIFT procedure represented a major advancement in the assisted reproductive technologies. The popularity of GIFT grew over time owing to its exceptional success rates. The improvements in IVF technology, which have increased its success, has taken back from GIFT

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many patients who could have undergone this somewhat less invasive procedure. Still, GIFT is an excellent option for many infertile couples. Future developments may see the resurgence of GIFT, especially in the area of transcervical fallopian transfer. The ability to make this technique nonlaparoscopic with the reliable, atraumatic transfer of gametes to the fallopian tubes will certainly enable more patients to take advantage of the technique and will allow more centers to offer the procedure.

Suggested Reading Abramovici H, Dirnfeld M, Bornstein J, Lissak A, Gonen Y. Gamete intrafallopian transfer: an overview. J Reprod Med 1993;38:698–702. Asch RH, Balmaceda JP, Ellsworth LR, Wong PC. Preliminary experiences with gamete intrafallopian transfer (GIFT). Fertil Steril 1986;45:366–371. Assisted reproductive technology in the United States and Canada: 1991 results from the Society for Assisted Reproductive Technology generated from the American Fertility Society Registry. Fertil Steril 1993;59: 956–962. Assisted reproductive technology in the United States and Canada: 1992 results generated from the American Fertility Society/Society for Assisted Reproductive Technology Registry. Fertil Steril 1994;62:1121– 1128. Assisted reproductive technology in the United States and Canada: 1993 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 1995;64:13–21. Assisted reproductive technology in the United States and Canada: 1994 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 1996;66:697–705. Bauer O, Diedrich K. Transcervical tubal transfer of gametes and embryos. Curr Opin Obstet Gynecol 1994;6:178–183. Beilin Y, Bodian CA, Mukherjee T, Andres LA, Vincent RD Jr, Hock DL, Sparks AE, Munson AK, Minnich ME, Steinkampf MP, Christman GM, McKay RS, Eisenkraft JB. The use of propofol, nitrous oxide, or isoflurane does not affect the reproductive success rate following gamete intrafallopian transfer (GIFT): a multicenter pilot trial/survey. Anesthesiology 1999;90: 36–41. Bendz A. The anatomical basis for a possible counter current exchange mechanism in the human adnexa. Prostaglandins 1977;13:355–362. Cramer DW, Liberman RF, Powers D, Hornstein MD, McShane P, Barbieri RL. Recent trends in assisted reproductive techniques and associated outcomes. Obstet Gynecol 2000;95:61–6. Dawood MY. In vitro fertilization, gamete intrafallopian transfer, and superovulation with intrauterine insemi-

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nation: efficacy and potential health hazards on babies delivered. Am J Obstet Gynecol 1996;174:1208–1217. Driscoll GL, Tyler JP, Clark L, Bernstein J. Transfer of gametes into the fallopian tubes—is choice of side important? Hum Reprod 1996;11:1881–1883. Guirgis RR, al Shawaf T, Craft I. Ovarian torsion: a complication of GIFT: a report on two cases and literature review. Hum Reprod 1992;7:967–969. In vitro fertilization/embryo transfer in the United States: 1987 results from the National IVF-BT Registry. Fertil Steril 1989;51:13–19. In vitro fertilization-embryo transfer in the United States: 1988 results from the IVF-ET Registry. Medical Research International, Society for Assisted Reproductive Technology, American Fertility Society. Fertil Steril 1990;53:13–20. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1989 results from the IVF-ET Registry. Medical Research International, Society for Assisted Reproductive Technology, The American Fertility Society. Fertil Steril 1991;55:14–22; discussion 22– 23. In vitro fertilization-embryo transfer (IVF-BT) in the United States: 1990 results from the IVF-BT Registry, Medical Research International, Society for Assisted Reproductive Technology (SART), The American Fertility Society. Fertil Steril 1992;57:15–24. Jansen RP, Anderson JC. Transvaginal versus laparoscopic gamete intrafallopian transfer: a case-controlled retrospective comparison. Fertil Steril 1993;59:836– 840. Kenny DT. The impact of maternal age on clinical pregnancy and spontaneous abortion in women undergoing in vitro fertilization and gamete intra-fallopian transfer. Aust NZ J Obstet Gynaecol 1994;34:443–448. Kenny DT. In vitro fertilisation and gamete intrafallopian transfer: an integrative analysis of research, 1987– 1992. Br J Obstet Gynaecol 1995;102:317–325. Mastroyannis C. Gamete intrafallopian transfer: ethical considerations, historical development of the procedure, and comparison with other advanced reproductive technologies. Fertil Steril 1993;60:389–402. Milki AA, Tazuke SI. Comparison of carbon dioxide and air pneumoperitoneum for gamete intrafallopian transfer under conscious sedation and local anesthesia. Fertil Steril 1998;69:552–4. Padilla SL, Dugan K, Maruschak V, Smith RD, Zinder H. Laparoscopically assisted gamete intrafallopian transfer with local anesthesia and intravenous sedation. Fertil Steril 1996;66:404–407.

Penzias AS, Alper MM, Oskowitz SP, Berger MJ, Thompson IB. Gamete intrafallopian transfer: assessment of the optimal number of oocytes to transfer. Fertil Steril 1991;55:311–313. Penzias AS, Thompson IB, Alper MM, Oskowitz SP, Berger MJ. Successful use of gamete intrafallopian transfer does not reverse the decline in fertility in women over 40 years of age. Obstet Gynecol 1991; 77:37–39. Penzias AS, Alper MM, Oskowitz SP, Berger MJ, Thompson LB. Comparison of unilateral and bilateral tubal transfer in gamete intrafallopian transfer (GIFT). J In Vitro Fert Embryo Transfer 1991;8:276–278. Ransom MX, Corsan GH, Garcia AJ, Doherty KA, Kemmann B. Tubal selection for gamete intrafallopian transfer. Fertil Steril 1994;61:386–389. Schenker JG, Ezra Y. Complications of assisted reproductive techniques. Fertil Steril 1994;61:411–422. Silva PD, Kang SB, Sloane KA. Gamete intrafallopian transfer with spinal anesthesia. Fertil Steril 1993; 59:841. Silva PD, Meisch AL, Meisch JK, Kang SB, Rooney B. Factors associated with improving success rates with gamete intrafallopian transfer under thin-needle spinal anesthesia. J Assist Reprod Genet 1995;12:569–573. Silva PD, Olson KL, Meisch JK, Silva DE. Gamete intrafallopian transfer. A cost-effective alternative to donor oocyte in vitro fertilization in women aged 40–42 years. J Reprod Med 1998;43:1019–22. Swisher ED, Wobster R, Armstrong A. Age-related pregnancy rates in GIFT patients. Mil Med 1998;163: 449–50. Woolcott R, Stanger J. The fluid dynamics of injection: variables as they relate to transvaginal gamete intrafallopian transfer and tubal embryo transfer. Hum Reprod 1994;9:1670–1672. Woolcott R, Stanger J, Cohen R, Silber S. Refinements in the methodology of injection for transvaginal gamete intrafallopian transfer. Hum Reprod 1994;9: 1466–1468. Yee B, Barnes RB, Vargyas JM, Marrs RP. Correlation of transabdominal and transvaginal ultrasound measurements of follicle size and number with laparoscopic findings for in vitro fertilization. Fertil Steril 1987;47:828–832. Yee B, Rosen GF, Chacon RR, Soubra S, Stone SC. Gamete intrafallopian transfer: the effect of the number of eggs used and the depth of gamete placement on pregnancy initiation. Fertil Steril 1989;52:639– 644.

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19 Complications of Ovulation Induction Janee A. Fonslick and David B. Seifer

Over 2 million women age 15–44 years are estimated to have taken fertility drugs in the United States. This number will continue to increase as more women seek treatment for infertility, and many undergo treatment with ovulation induction agents. Thus it is important to be aware of the possible complications associated with superovulation so we can adequately counsel, diagnose, and treat our patients appropriately. We discuss here several iatrogenic complications associated with the use of ovulation induction agents, including ovarian hyperstimulation syndrome, multifetal gestations, preterm delivery, heterotopic/ectopic pregnancy, spontaneous abortion, and the theoretic risk of a possible increase in the incidence of ovarian cancer.

developed the other form, which suggests two distinct mechanisms of OHSS.

Ovarian Hyperstimulation Syndrome

The late form of OHSS is thought to be induced by endogenous hCG and is seen in women who become pregnant with one or more gestational sacs. The number of gestational sacs, serum hCG, and serum progesterone and estradiol levels 11–13 days after hCG are predictive of late OHSS.

As the number of women undergoing in vitro fertilization (IVF) techniques increases, it is anticipated that the number of cases of ovarian hyperstimulation syndrome (OHSS) will increase. When human menopausal gonadotropin (hMG) is used for ovarian hyperstimulation, even with close monitoring of estradiol levels and the use of ultrasonography the incidence of OHSS is 4%, including the moderate and severe types. Lyons et al. in 1994 identified two distinct presentations of OHSS: early and late. This study was a retrospective analysis of 592 IVF cycles during 1988–1993. Six (1%) of the cohort had moderate or severe OHSS presenting 3–7 days after human chorionic gonadotropin (hCG) administration (early OHSS), whereas four (0.7%) had severe OHSS presenting 12–17 days after hCG. None of the patients who developed early or late OHSS

Early OHSS The early form of OHSS is believed to be due to the acute effect of exogenous hCG administration, usually administered 35 hours before egg retrieval. As implied, it presents earlier than the late form, and it can occur in patients who do not become pregnant. The increased number of oocytes and elevated estradiol concentration on the day hCG is given are predictors of early OHSS.

Late OHSS

Pathogenesis of OHSS The exact etiology of OHSS is unknown, but it is hypothesized to result from a substance produced by the ovary. It is possible that this substance is stimulated by hCG. OHSS can exist in a mild or severe form. The signs and symptoms of severe OHSS are listed below. Marked ovarian enlargement Ascites Pleural effusion Nausea and vomiting Acute respiratory distress syndrome (ARDS) Thromboembolic phenomena

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Hematocrit 45% White blood cell (WBC) count 15,000/mm3 with left shift Elevated liver function tests Creatinine 1.5 mg/dl Increased plasma renin and aldosterone Sodium retention and oliguria Potentially lethal aspects of OHSS include hypotension, renal failure, thromboembolic phenomena, and ARDS. This increased vascular permeability, mainly of the ovarian vessels, results in leakage of large amounts of fluid into the peritoneal space with resultant acute reduction of the intravascular volume. The clinical picture is similar to that of a large surface area burn or a patient with severe pancreatitis where a large amount of third spacing of intravascular fluid occurs. This leads to severe hypotension, decreased preload, and tachycardia. The decreased preload may also be due in part to tense ascites compressing the inferior vena cava. The increased permeability is mediated through prostaglandins and histamine by the ovaries and an activated follicular renin-angiotensin system. Activation of renin and angiotensin leads to increased antidiuretic hormone (ADH) from the kidney, eventually leading to hemoconcentration and oliguria. Vascular permeability factor (VPF) has been implicated in playing a role in this mechanism.

Vascular Permeability Factor The VPF causes vascular leakage and is present in the corpus luteum. Investigators have compared the concentrations of VPF in serum, peritoneal fluid, and follicular fluid in women who developed OHSS to that in women who did not. They found a 100fold increase in follicular fluid compared to serum and peritoneal fluid, suggesting that the ovary is a significant source of VPF. Serum concentrations of VPF on day 14 after hCG revealed that patients who developed severe OHSS had significantly higher serum VPF concentrations (15.2 vs. 0.7 pg/ ml) than those who did not develop the syndrome. Interestingly, age, serum estradiol, and the number of follicles 13 mm on the day of hCG administration were not statistically different between the two groups. Three of four patients who developed severe OHSS had positive serum hCG values 14 days after administration, whereas the patients who did not develop severe OHSS had negative hCG values. Krasnow et al. postulated that “the hCG that rescues the corpus luteum results in an increase in ovarian VPF secretion, which in turn causes an exacerbation of OHSS.”

Patients at Risk The OHSS is more frequent in young patients and patients with polycystic ovaries, conception cycles (particularly related to either endogenous or exogenous hCG), high estradiol levels, and multiple second-degree follicles. When a gonadotropinreleasing hormone (GnRH) analogue is used in combination with hMG administration, patients exhibit higher estradiol levels without the interference of endogenous luteinization; therefore high estradiol levels in this type of protocol put patients into a significantly higher risk group, according to Ron et al. Also, luteal phase supplementation with hCG leads to a higher incidence of OHSS.

Treatment Treatment is empiric. The initial decision is whether to hospitalize the patient. If the hematocrit is less than 45% and signs and symptoms are restricted to a swollen abdomen, nausea, and mild dyspnea, treatment is mainly bed rest with increased fluid intake to maintain urine output. If the patient goes home, it is important that she fulfills the following requirements. 1. Remains well hydrated: drink 12 oz every 2 hours during waking hours 2. Weighs herself daily with the same scale (needs to inform physician if she gains 3–5 lb/day) 3. Performs daily abdominal girth measurements in the same manner 4. Avoids exercise, intercourse 5. Incurs no pelvic examinations by other health care workers 6. Consumes a diet low in potassium with high protein If the hematocrit is 45% or symptoms include ascites and patient discomfort, tachypnea, vomiting, or diarrhea, treatment requires hospital admission, with close monitoring of plasma electrolytes, and renal and liver function. Intravenous crystalloids, usually 5% dextrose in normal saline (D5NS), are administered just enough to perfuse the kidneys (sometimes only 500 ml per day) with close monitoring of body weight, fluid balance, abdominal girth, respiratory rate, hematocrit, and electrolytes. It is important to avoid hypotonic solutions, especially lactated Ringer’s (LR), which contains potassium. Dextran, fresh frozen plasma, and albumin encourage third spacing and further formation of ascites with increased abdominal pressure, de-

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creased venous return, decreased cardiac output, and oliguria with a resultant increase in creatinine. Paracentesis performed in a slow gravitational manner can result in immediate improvement marked by diuresis.

Prevention Multiple steps that can be taken toward preventing OHSS. It may be as simple as using a reduced dosage of gonadotropins. Withholding hCG administration should be considered when the estradiol level exceeds 2000 pg/ml in the presence of many second degree follicles and during induction of ovulation or a non-IVF cycle. GnRH analogues may be used for triggering ovulation if they have not been used for initial down-regulation. It is also important to avoid hCG supplementation of the luteal phase if the cycle is thought to be high risk for development of OHSS; progesterone supplementation can be used alternatively. Other alternatives for avoiding OHSS during an IVF cycle include cryopreserving all embryos for later transfer during an unstimulated cycle. Some have described preventing OHSS in high risk cases by administering 50 g of intravenous albumin during oocyte recovery and immediately afterward.

Multifetal Gestations The incidence of multiple pregnancies during cycles induced with hMG is 10–20%. The hCG in doses less than 5000 IU resulted in fewer multiple pregnancies compared with doses of more than 6000 IU. Thompson and Hansen reported that their multiple pregnancy rate was 25% when hCG overlapped hMG therapy during the last few days, whereas when given 1–3 days after the last injection the rate was 19%. The number of preovulatory follicles are probably a better parameter than the estradiol level, as the latter is also a reflection of the number of second degree follicles (14 mm in diameter), and these follicles are probably not involved in conception. Combined clomiphene citrate–hMG reduces the incidence of multiple pregnancies to 7.7–10.0% probably because the selection phase is over once hMG is introduced; the exogenous gonadotropins propel the follicles to the preovulatory size. The cohort of follicles is believed to be smaller than with hMG alone yet significantly higher than with clomiphene citrate alone.

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Incidence with Assisted Reproductive Technology The incidence of multifetal gestations among pregnancies achieved with assisted reproductive technology (ART) depends on the number of embryos transferred. Series in which up to six embryos were transferred yielded multiple pregnancy rates of about 38%, with four embryos 18%, and with three embryos 12%. Similarly, with gamete intrafallopian transfer (GIFT), multifetal gestations occurred at a rate of 43% with nine or ten oocytes transferred, 39% with seven or eight oocytes, and 15% with four oocytes. Age also affects the multiple gestation rate in ART pregnancies. One series reported a 28.5% rate in women age 35–39 and 16.4% in women over age 40. A reported series on zygote intrafallopian transfer (ZIFT) reported a multifetal gestation rate of 17.6% when three zygotes were transferred.

Prevention Steps for prevention of multifetal gestations include the following. Withholding hCG when the estradiol level is higher than 4000 pg/ml or when there are four or more follicles at 15 mm diameter or greater. Also, it is imperative to be conservative with polycystic ovary syndrome (PCOS) patients starting with low doses of hMG. Because with in vitro fertilization (IVF) multiple gestations are controlled by the number of transferred embryos (discussed above), it is recommended that three or fewer embryos be placed if the patient is less than 35 years old, whereas four-embryo placement is acceptable for patients more than age 35. Although the clinical impact of these guidelines for reducing multiple gestations remains to be demonstrated, recent modification of embryo cultures are allowing programs to transfer two blastocysts on day 5 after oocyte retrieval while maintaining pregnancy rates and meaningfully reducing the birth of three or more babies. Treatment of higher-order multiple gestations (i.e., three or more) can be accomplished by selective reduction, with up to 90% success rates reported in experienced hands.

Selective Reduction: Transcervical, Transvaginal, Transabdominal The transcervical method of selective reduction involves gradual dilatation of the cervix and aspirating the lowest sac(s) or crushing the embryo with a biopsy forceps. Typically, it is done up to week

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9 of the pregnancy. The transvaginal method uses a 25 cm long 16-gauge needle inserted into the sac closest to the vaginal wall. Aspiration is done up to week 7 of the gestation; alternatively, potassium chloride can be injected into the fetal thorax. The transabdominal approach is most commonly used. An 18-gauge needle is inserted transabdominally into the fetal thorax, and demise is achieved by trauma or an injection of saline or potassium chloride. This is usually done during weeks 9–11. The transabdominal approach is believed to be safer, with fewer infections and fewer abortions.

Preterm Delivery There is evidence that pregnancies conceived by ART are more likely to result in preterm delivery. Many studies have focused on the role of relaxin in this phenomenon. The major biologic action of relaxin in mammals is allowing accommodation of pregnancy and remodeling of connective tissues. In vitro, relaxin affects collagen synthesis. Studies have shown that administration of relaxin intravaginally or intracervically can effect cervical softening, effacement, and dilatation and can decrease the time to delivery. Relaxin is not necessary for delivery of pregnant patients who conceive with donor oocytes without producing relaxin, as the corpus luteum is absent. Relaxin is normally produced by the corpus luteum, and concentrations are highest during the first trimester. After 12 weeks of pregnancy, levels remain fairly stable in a given individual, as there is no diurnal secretion pattern, pulsatility, or minute-to-minute variation. It has been shown that multiple gestations and ovarian stimulation cause increased relaxin concentrations. Studies have been performed to determine whether high peripheral relaxin concentrations contribute to preterm delivery. A study by Weiss et al. demonstrated that elevated first trimester serum relaxin concentrations in pregnant women following ovarian stimulation were predictive of increased prematurity. This study involved comparisons between two groups of women; those who became pregnant with ovarian stimulation (hMG and hCG with and without GnRH agonists, clomiphene citrate with and without hCG, IVF, and clomiphene citrate with hMG and hCG) and those who became pregnant without the use of fertility drugs. Excluded from this study were those at risk for preterm labor, including patients with a history of diethylstilbestrol (DES) exposure, a history of more than one major operative cervical procedure,

or uterine anomalies. Preterm delivery was defined as delivery before 37 weeks estimated gestational age for singletons and 34 weeks for multiple gestations. The study group consisted of 114 patients: 76 singletons, 31 multiple gestations including three triplets, and 7 vanishing fetuses. The pregnancies were divided into good and bad outcomes. Good outcomes were defined as uneventful births, and poor outcomes were births with either preterm labor or cervical incompetence requiring cerclage. Hyperrelaxinemia was defined as mean values more than 3 SD above the normal mean. Overall, there were 74 patients with hyperrelaxinemia and 40 with normal relaxin. The patients in the hyperrelaxinemic group had a significantly higher prematurity risk or preterm delivery than the group with normal relaxin (31.0% vs. 7.5%). When this group was divided into multiple gestations and singletons, the differences observed in the multiple gestation group retained statistical significance only with hyperrelaxinemia remaining associated with increased prematurity risk or preterm delivery. Logistic regression analysis of the singleton data demonstrated this trend as well. The authors concluded that “in women who became pregnant after ovarian stimulation, first trimester hyperrelaxinemia identifies a group of high risk women who can be monitored more closely to detect and potentially treat early cervical dilation of premature labor, perhaps with cervical cerclage.”

Heterotopic/Ectopic Pregnancies Spontaneous heterotopic pregnancy incidence is estimated between 1:4000 and 1:10,000 compared with an incidence of ectopic pregnancy of 1% in the general population. With the use of gonadotropins, the incidence of heterotopic pregnancy increases to 1%, and the incidence of ectopic pregnancy is 3%. Because tubal disease and pelvic surgery are more common among patients treated with IVF-embryo transfer (IVF-ET) the incidence of ectopic pregnancies is expected to be higher; it is estimated to be 4.5%. The incidence of heterotopic pregnancies among IVF-ET gestations is similar to that for gonadotropin-induced pregnancies (about 1%).

Signs and Symptoms Symptoms include abdominal pain (present in 80%) and hypovolemic shock with abdominal tenderness (in 10%). It is important to remember that

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signs and symptoms of ovarian hyperstimulation may present with a similar picture, but tenderness is usually unilateral with an ectopic pregnancy and bilateral with ovarian hyperstimulation. Vaginal bleeding may or may not be present (found in up to 50% of cases), creating possible confusion with threatened abortion. About 40% can be diagnosed by ultrasonography with the remaining 60% by laparotomy or laparoscopy. Approximately 70% are diagnosed at 5–8 weeks’ gestation and approximately 10% after 11 weeks. Treatment options included salpingectomy, salpingostomy, KCl injection, or expectant management. Systemic methotrexate is a less than ideal treatment, as it aborts both the tubal and the intrauterine pregnancy.

Pregnancy Outcome Two-thirds of intrauterine pregnancies are delivered alive. One-third abort early during the first trimester.

Theories Sex steroids have been suggested to alter the contractility of the tube musculature or effect endosalpingeal proliferation, thereby controlling embryo transport through the tube. Joupilla et al. showed significantly lower estradiol E2 and progesterone levels in ectopic than intrauterine pregnancies. With ovulation induction or ART the preovulatory estradiol is supraphysiologic and remains high during the luteal phase because of multiple corpora lutea. Molling et al. and McBain found a correlation between ectopic pregnancies and high late follicular phase estradiol levels after treatment with menotropins. Luteal phase progesterone levels after ovulation induction and ART are higher than during normal cycles because of multiple corpora lutea and early progesterone supplementation. Progesterone has a slowing effect on tubal contractility and ciliary beat, which may contribute to ectopic pregnancies by affecting tubal transport.

Spontaneous Abortion In contrast to earlier reports no increase in the spontaneous abortion rate in clomiphene citrate (CC)treated patients. In contrast, hMG-treated patients continue to be associated with a higher rate of spontaneous abortion (25%) than the general population. This high incidence is attributed partly to the increased age of patients using this medication

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and hence an increased prevalence of chromosomal aberrations such as trisomies. In addition, the higher rate of multiple pregnancies can result in increased pregnancy loss. Finally, there is earlier recognition of these pregnancies as abortions as they are often followed from the time of conception with close surveillance. Bohrer and Kemman performed a retrospective analysis comparing women treated with gonadotropins resulting in spontaneous abortion and women treated with gonadotropins who delivered a viable infant to determine if there were factors predictive of women likely to miscarry. Factors they examined included age, history of past miscarriages, duration of infertility, diagnostic category, weight, body surface area, duration and weight-corrected dose of gonadotropin administration, maximum estradiol level, estradiol pattern, hCG dose, presence or absence of hCG support during the luteal phase, results of postcoital testing, methods of insemination, and results of the husband’s semen analysis. The only significant difference between the two study groups was weight and advanced age. The increased risk of miscarriage with advancing age is consistent with the general experience of increased miscarriage rates in older women. The increased rate seen with obesity is independent of age and estradiol level at ovulation and increases with increasing weight. It is unclear whether obese women in the general population have higher miscarriage rates. The observed association between weight and miscarriage may be partly the result of an increase in peripheral conversion to estrone and an increased estrone/estradiol ratio, which may affect endogenous gonadotropins. Also, baseline androgen levels are relatively increased in obese women; androgen levels are further augmented with hMG therapy secondary to thecal cell stimulation by hMG. Therefore, the altered steroid milieu could alter the endometrium or developing ovum or conceptus. A higher miscarriage rate in hMG-treated was shown in women who had endogenous gonadotropin activity than in those who were hypogonadotropic. It is not clear if these women were obese. The authors concluded that “obese women weighing more than 81.8 kg should make every effort to lose weight before beginning gonadotropin therapy.”

Ovarian Cancer Several case reports of ovarian carcinoma and tumors of low malignant potential in women undergoing treatment for infertility generated concern

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over the possible relation between ovulationinducing medication and ovarian tumors. During 1992–1993 a series of publications gave widespread attention to the possibility of this association. This discussion reviews the theories of the development of ovarian cancer based on risk factors. It also reviews the epidemiologic studies considering this association. An undisputed risk factor for the development of ovarian cancer is low parity, whereas high parity is protective. It has been theorized that protection is due to suppression of ovulation, so it follows that this may be the mechanism by which oral contraceptives are protective against ovarian cancer. Therefore infertility and incessant ovulation are risk factors. It has been further speculated that ovarian hyperstimulation produced by fertility drugs can increase this risk. In 1971 Fathalla suggested that “with each ovulation the ovarian surface (epithelium) incurs minor trauma, and the cumulative effect of repetitive surface injury contributes to the development of ovarian neoplasms.” Five case-control studies and two retrospective cohort studies examined this issue as well as one pooled reanalysis of three of these case-control studies. A large study by Venn et al. (discussed later), did not find evidence that ovulation induction contributed to ovarian cancer risk, whereas studies by Cramer, Nasca, Hartge et al., and Rossing et al. did find evidence supporting the role of ovulation induction in ovarian cancer risk. The Collaborative Ovarian Cancer Group (COCG) pooled data from the Cramer, Nasca, and Hartge et al. studies because studies were determined to be the only ones of ovarian cancer during 1956–1986 for which fertility drug exposure were available and met other criteria (i.e., defining cases as women newly diagnosed with invasive epithelial ovarian cancer at a U.S. hospital). (COCG) investigators excluded women who never married, those who may have undergone bilateral oophorectomy, data provided by surrogates, women with borderline tumors, and nonwhites (due to insufficient data among nonwhites). Data on infertility and fertility drug exposure were available for 622 women and their 1101 controls. Among these women, 96 cases and 135 controls were infertile (15% and 12%, respectively). After adjusting for age, parity, breast feeding, and oral contraceptive use, women who had used fertility drugs had nearly three times the risk of invasive epithelial ovarian cancer as women lacking a history of infertility [odds ratio (OR) 2.8; 95% confidence interval (CI) 1.3–6.1]. This results from the 20 cancer cases who had used fertility drugs com-

pared to only 11 controls. Among nulligravidas, the OR was 27 and the 95% CI 2.3–316 based on only 12 exposed infertile cancer cases and 1 infertile control. In a separate analysis of borderline ovarian cancer, the adjusted OR among all women regardless of gravidity was 4.0 (95% CI 1.1–13.9). A study by Ron et al. suggested an association between infertility and ovarian cancer. Kaufman et al. recalculated these data using infertile women as the reference group. This reduced the crude OR for the nulligravid women from 17 to 12, still demonstrating an increased OR. Limitations of the Ron et al. study include the relatively small number of women who had been exposed to fertility drugs and the wide 95% CIs, with lower limits as low as 1.3. In addition, there was a lack of information on the etiology of the infertility, ovarian cancer histology, and family history of cancer. Moreover, the specific drug therapy used was unknown for 16 of 20 exposed cases and 8 of 11 exposed controls, and there was no information regarding recall bias confounding this study such as dosage, duration, and concomitant use of multiple agents. Cancer patients may have remembered their exposure history more thoroughly than did the controls, thereby exaggerating the observed ORs. More recently the results of a retrospective casecohort study were reported by Rossing et al. Instead of identifying ovarian cancer cases and comparing their fertility drug exposure history to a set of controls, they identified a cohort of infertile women, determined which of them subsequently developed ovarian cancer, and compared their fertility drug usage to a subcohort of 135 women chosen at random from a larger group of 3837 women. Cancer cases were obtained from the Seattle tumor registry. Infertility records were obtained for specific information on infertility type, reproductive history, and specific drug exposures. Eleven ovarian cancers were found: four invasive epithelial, five borderline, and two granulosa cell tumors. All were diagnosed in women ages 24–43. The subgroup of clomiphene users for at least 12 cycles had a risk ratio of 11.1. Duration of use less than 1 year was not associated with increased risk. This risk was seen regardless of gravidity. The limitations of this study included the lack of consideration of oophorectomy rates, incomplete information regarding drug exposure before enrollment, the small number of cancer cases, and the fact that the group largely used clomiphene whereas only 4% of the subcohort was exposed to Pergonal. The strengths of the Rossing et al. study included the mean time (7 years) from enrollment to diag-

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nosis (unlikely for the risk elevation to be due to preexisting tumors that led to infertility and subsequent fertility drug exposure). Moreover, 9 of 11 cases were diagnosed after the patient had stopped being cared for by fertility specialists; therefore detection was probably not due to a surveillance bias related to infertility workups. The authors had access to extensive information on infertility subtype, fertility drug class, and number of induction cycles. Recall bias was reduced because exposure data were collected before the tumor was diagnosed. Venn et al. examined the incidence of ovarian, breast, and uterine cancer in a cohort of 10,358 women in Australia referred for IVF between 1978 and 1992. The exposed group consisted of 5564 patients. The agents used depended on the period of treatment; until 1987 CC  hMG followed by hCG was used; in 1987 GnRH agonists (leuprolide, buserelin) replaced CC to prevent an untimely surge of LH; and finally during 1990–1992 GnRH agonist was used in combination with hMG or follicle-stimulating hormone (FSH) followed by hCG. The unexposed group of 4794 were registered for IVF but did not receive ovarian stimulation and had “natural cycle” IVF only. There was no apparent increase in the risk associated with the level of exposure to stimulated treatment cycles. The median number of cycles was two; 77.0% of women had three or fewer cycles; and 1.9% of women had ten or more cycles. Seventyfour percent of cancers occurred in women having only one or two stimulated cycles. There was also no association between infertility type and breast cancer or exposure to IVF. In the charts of none of the women with ovarian cancer was an ovarian disorder recorded as the cause of infertility. For both ovarian and uterine cancer an unexpectedly large number of women had unexplained infertility recorded; the standardized incidence ratio of ovarian cancer was 6.9, and the standardized incidence ratio of uterine cancer was 8.3. Cancers of the ovary, breast, and uterus and all cancers combined were not associated with exposure to stimulated IVF cycles. A study by Gross et al. in 1994 examined the incidence of ovarian cancer among oral contraceptive users and nonusers considering combined data from the Cancer and Steroid Hormone (CASH) study; the Surveillance, Epidemiology, and End Results (SEER) network; and published reports of epidemiologic studies. They demonstrated that increasing duration of oral contraceptive use decreased the incidence of ovarian cancer in all groups. In fact, 10-year use of oral contraceptives

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by women with a family history of ovarian cancer reduced their risk to below that of never-users whose family history was negative for ovarian cancer. Furthermore, oral contraceptive use appears to protect against the development of ovarian cancer with an average risk reduction of up to 80% for users compared to nonusers (RR  0.2). Protection from ovarian cancer increases with increasing duration of use and persists for up to 20 years following discontinuation. The speculation that ovulation-inducing agents cause ovarian cancer is based on the incessant ovulation theory that repeated trauma to the ovarian epithelium promotes cell division in the context of elevated gonadotropin levels noted in postmenopausal women. Two studies, however, refute these theories. Schildkraut et al. found that patients with PCOS (who are oligoovulatory) have an increased risk (2.5-fold) of ovarian cancer. Helzlsouer et al. found that mean FSH levels were lower among patients with ovarian cancer than in controls and that increasing levels were associated with significantly lower risk. The possibility that fertility drugs increase the risk of ovarian cancer requires additional investigation. Physicians should consider informing women about what is and what is not known regarding this possible association. Currently studies funded by the National Institutes of Health and the National Cancer Institute are under way to answer these questions.

Conclusions There are numerous possible complications associated with the use of ovulation induction agents. As more and more women are undergoing superovulation, it is important to be well informed of these risks so we may adequately counsel our patients, take steps to minimize these risks, and know how to manage such complications when they occur.

Suggested Reading Antsaklis AJ, Drakakis P, Vlazakis GP, et al. Reduction of multifetal pregnancies to twins does not increase obstetric or perinatal risks. Hum Reprod 1999;14: 1338–1340. ASRM Practice Committee Report. Guidelines on Number of Embryos Transferred, November 1999. ASRM Practice Committee Report. Multiple Pregnancy Associated with Infertility Therapy, November 2000. Bohrer M, Kemmann E. Risk factors for spontaneous abortion in menotropin-treated women. Fertil Steril 1987;48:571–575.

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Bristow RE, Karlan BY. Ovulation induction, infertility, and ovarian cancer risk. Fertil Steril 1996;66:499–507. Bristow RE, Karlan BY. The risk of ovarian cancer after treatment for infertility. Curr Opin Obstet Gynecol 1996;8:32–37. Fisch JD, Milki AA, Behr B. Sibling embryo blastocyst development correlates with the in vitro fertilization day 3 embryo transfer pregnancy rate in patients under age 40. Fertil Steril 1999;71:750–752. Fluker MR, Copeland JE, Yuzpe AA. An ounce of prevention: outpatient management of the ovarian hyperstimulation syndrome. Fertil Steril 2000;73:821– 824. Gross TP, Schlesselman JJ. The estimated effect of oral contraceptive use on the cumulative risk of epithelial ovarian cancer. Obstet Gynecol vol. 83 p. 619–626, 1996. Haning RV Jr, Canick JA, Goldsmith LT, et al. The effect of ovulation induction on the concentration of maternal serum relaxin in twin pregnancies. Am J Obstet Gynecol 1996;174:227–232. Hartge P, Schiffman MH, Hoover R, et al. A case control study of epithelial ovarian cancer. Am J Obstet Gynecol 1989;161:10–16. Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926–1930. Hock DL, Seifer DB. Ovarian hyperstimulation syndrome. Infertil Reprod Med Clin North Am 2000; 11:399. Houmard BS, Seifer DB. Infertility treatment and informed consent: current practices of reproductive endocrinologists. Obstet Gynecol 1999;93:252–257. Krasnow JS, Berga SL, Guzick DS, Zeleznik AJ, Yeo K-T. Vascular permeability factor and vascular endothelial growth factor in ovarian hyperstimulation syndrome: a preliminary report. Fertil Steril 1996;65: 552–555. Lyons CA, Wheeler CA, Frishman GN, et al. Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 1994;9:792–799. Mathur RS, Akande AV, Keay SD, et al. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril 2000;73:901–907.

McElhinney B, McClure N. Ovarian hyperstimulation syndrome. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:103–122. Ron EL, Lunenfeld B, Menczer J, et al. Cancer incidence in a cohort of infertile women. Am J Epidemiol 1987; 125:780–790. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331:771–776. Schenker, et al. Complications of assisted reproductive techniques. Fertil Steril 1994;61:411–422. Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996; 88:554–559. Sherwood OD. Relaxin. In: Knobil E, Neill (eds) The Physiology of Reproduction. New York: Raven, 1988: 585–673. Shu XO, Brinton LA, et al. Population-based case-control study of ovarian cancer in Shanghai. Cancer Res 1989;49:3670–3674. Spirtas R, Kaufman SC, Alexander NJ. Fertility drugs and ovarian cancer: red alert or red herring? Fertil Steril 1993;59:291–293. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999;71:282–286. Tal J, Haddad S, Gordon N, Timor-Tritsch I. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Steril 1996;66:1–12. Venn A, Watson L, Lumley J, et al. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346:995–1000. Weiss G, Goldsmith LT, Sachdev R, et al. Elevated firsttrimester serum relaxin concentrations in pregnant women following ovarian stimulation predict prematurity and preterm delivery. Obstet Gynecol 1993;82: 821–828. Whelan J III, Vlahos N. The ovarian hyperstimulation syndrome. Fertil Steril 2000;73:883. Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. Part II. Am J Epidemiol 1992;136:1184–1203.

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Index

Abnormalities, Müllerian detecting with ultrasound, 40 spontaneous abortion associated with, 118 Abortion, spontaneous and age, 24 and gonadotropin-induced ovulation, 108 in ovarian induction, 199 Adhesions, intrauterine, outcomes of treatment of, 118–19 Age and fertility, 24–38 and multifetal gestations, with assisted reproductive technology, 197 and prediction of pregnancy, and the clomiphene citrate challenge test, 29–30 and reproduction, 7–8, 161 Air compressor, medical, 73 Air delivery system for an in vitro fertilization laboratory, 63–72 outside air delivery, 64–66 Airflow, directing, in the laboratory, 67 Air quality, in the laboratory, 76 Air volume, 67–68 American Board of Obstetrics and Gynecology, 61 American Registry of Diagnostic Medical Sonographers, 61 American Society of Anesthesiologists (ASA) guidelines for nonoperating room anesthetizing locations, 91 on monitored anesthesia care, 78 on routine preoperative laboratory and diagnostic screening, 90 American Society of Heating, Refrigeration and Air Conditioning Engineers (ASHRAF), specification for operating rooms, 63 Amoxicillin, prophylactic administration of, after surgery, 82 Ampicillin, prophylactic administration of, before surgery, 82 Analysis, of retrograde ejaculates, 156–57 Anatomy defects leading to infertility, 3–5

findings from falloposcopy, 132–33 Andrology, laboratory design features, 72 Anejaculation, treating, 2–21 Anesthesia for gamete intrafallopian transfer, 191–92 in the office, 77–99 reaction to, as a complication of in vitro fertilization, 172 for in vitro fertilization, 165 Aneuploidy, and diminished ovarian reserve, 35 Antibiotics, prophylactic, prior to surgery, 81–82 Antibodies anti-sperm, 13–14 therapy for, 19–20 on sperm, 2 Antidotes, for sedation medications, 89 Antral follicles, relationship of count of with assisted reproductive therapy outcomes, 31 Anxiolytics, preoperative administration of, 80 Asherman syndrome, development of, after curettage, 118 Aspiration, protecting against, with premedication, 8–81 Assay, variability of, immunoassays of luteinizing and follicle-stimulating hormones, 31–35 Assisted hatching, 35 Assisted reproductive technology (ART), 20, 77, 145 effects of inhibin levels on success of, 26 gamete technologies, 6 gonadotropins used in, 101–2 for male factor infertility, 22 for managing proximal tubal obstruction, 137 multifetal gestations in, 197–98 ultrasound guidance for embryo transfer at, 168 Audiovisual system, educational, for the laboratory, 76 Azoospermia, testicular biopsy for evaluating, 157–59 Basal body temperature (BBT) chart, 3 Basal follicle-stimulating hormone ratio to luteinizing hormone, 27–28 Bates Consulting Company, model for infertility treatment, 58–59 203

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204

Index

Benzocaine, 79 Billing, descriptive terminology used in, 85 Biopsy, of the testis, 17–18 Bleeding, after hysteroscopy, 124 Body mass index, and gamete intrafallopian transfer in an office setting, 192–93 British Medical Journal, early description of laparoscopy in, 143 Bromocriptine, for treating pituitary tumors, 19 Bupivacaine (Marcaine), administration during fallopian tube transfer, 82 Capitated payment, in fertility treatment, 58 Carbon dioxide, for uterine cavity distension, 120 Cefotetan, prophylactic administration of, before surgery, 81 Centers for Disease Control (CDC), reporting data to with computers, 76 Centrifugation, density gradient, for sperm preparation, 113–14 Cervical mucus, interaction with sperm, 14 Cervical stenosis, treatment of, 147–49 Checklist for in-office surgery with anesthesia, 85–86 postoperative, 97 preoperative, for in-office surgery with anesthesia, 92 Chocolate cyst, in endometriosis, 42 Chromosomal anomalies Down syndrome, 7 male reproductive dysfunction accompanying, 15–51 risk for, as a function of age, 7 Cisatracurium, 78 Clean rooms, specifications for, 64 Clinical results, of ovulation induction, 106–7 Clomiphene citrate (Clomid) gonadotropins for treating anovulation, 100 for treating anovulation, 7 for treating oligospermia, 19 Clomiphene citrate challenge test (CCCT), 28–31 Coaxial falloposcopy, 13–31 Color power angiography (CPA), 45–46 Complications of falloposcopy, 133–34 of gamete intrafallopian transfer, 192–93 of hysteroscopy, 123–24 of ovulation induction, 100, 195–202 with gonadotropin therapy, 107, 111 of penile vibratory stimulation, 154 postoperative, in gamete intrafallopian transfer, 193 of pregnancy, and age, 59 of processing of retrograde ejaculates, 157 of rectal probe electroejaculation, 155 of transcervical tubal cannulation, 139–40

of treatment for cervical stenosis, 148–49 of in vitro fertilization, 172 Comprehensive History of Infertility, The (Burns and Greenfeld), 54–55 Computers, capability of, 76 Conception, spontaneous, after gonadotropin-induced pregnancies, 109 Confirmation, of infertility, 1 Congenital anomalies adrenal hyperplasia androgen excess in, 15 androgen excess in, treating, 19 after gonadotropin therapy, studies, 109 See also Genetic abnormalities Congenital bilateral absence of the vas deferens (CBAVD), 150 Consent forms, for ultrasound-guided follicle aspiration, 94–95 Contraindications to anesthesia in the office, 83 to controlled ovarian hyperstimulation, 109–10 to falloposcopy, 128–29 to gamete intrafallopian transfer, 187 to hysteroscopy in the office, 119–20 to penile ejaculatory stimulation, 152 to percutaneous epididymal sperm aspiration, 159 to rectal probe electroejaculation, 154 to retrograde ejaculate processing, 156 to testicular biopsy, 158 to transcervical tubal cannulation, 138 to treating cervical stenosis, 147 to in vitro fertilization, 162 Contrast agents, in sonography, 42–43 Controlled ovarian hyperstimulation, 43 and intrauterine insemination, 10–115 See also Ovarian hyperstimulation syndrome Coping, with infertility, psychosocial issues, 49–57 Costs of hysteroscopy, justifying in managed care, 124 of microlaparoscopy justifying in managed care, 141–42 versus other procedures, 142 versus traditional laparoscopy, 144 of transcervical tubal cannulation, versus microsurgical anastomosis and ART, 137 of unstimulated in vitro fertilization, 176–77 of in vitro maturation, 178 Counseling, about ovulation induction, 102–3 Couples therapy, in infertility, 55 Credentialing, of professionals, 6–61 Cryopreservation, of embryos, 171–72 Cryptorchidism, effect on the germinal epithelium, 10 Culture, of embryos, for in vitro maturation, 181 Cumulative probability of pregnancy, 7

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Index Current procedural terminology (CPT), 85 Cystic fibrosis, family history of, and male infertility, 11 Database analysis, 60 Design, of a laboratory, 72 Diabetes, effect on potency and ejaculatory function, 11 Diagnosis of infertility by transabdominal and transvaginal ultrasonography, 4–46 studies of male infertility, 16–18 Diazepam (Valium), premedication with, in surgery, 80 Diet pills, allergy to, special considerations in surgery, 85 Discharge instructions for a laparoscopic procedure, 99 for ultrasound-guided follicle aspiration, 98 Disease accompanying ovulatory dysfunction, evaluating, 102–3 screening for, prior to surgery, 80 Distension, of the uterine cavity, for hysteroscopy, 120 Doppler ultrasound, 45–46 Down syndrome (trisomy 21), risk of, as a function of age, 7 Doxycycline prophylactic administration of, before surgery, 81 for treating distal tubal occlusion, 4 for treating pyospermia, 20 Droperidol, for reducing nausea and vomiting, 81 Drugs, preparations of gonadotropins, 101–2. See also Medications Ductal system, sperm transport in, 151 Duration, of therapy, initial counseling about, 102–3 Ectopic gestation, 198–99 management of, 106, 172 rate of, in gamete intrafallopian transfer, 193 Ejaculatory duct obstruction (EDO), 15–51 Ejaculatory function effect on potency and ejaculatory function, 11 neurophysiology of, 151 Electrical system, for the laboratory, 74–76 Embryos culture of, 171 number of, for in vitro fertilization/embryo transfer, 34 thawing of, 172 Embryo transfer equipment for, 163 preparation for, 171 procedure for, 167–68, 181 Empiric therapy, for male infertility, 19 Endometriosis, 41–42

205

Endometrium biopsy of, in the secretory phase, 3 ultrasonography for evaluating, 4–41, 105 in stimulated cycles, 44 Endoscopy for evaluating the fallopian tube, 127–36 for evaluating the pelvic anatomy, 5 Energy, for humidification, 70 Energy sources, for hysteroscopy, 121–22 Epidural anesthesia, advantages of, 78 studies, 79 Equipment for anesthesia, in an office setting, 83–85 for cervical dilatation, 148 energy sources for hysteroscopy, 121–22 for gamete intrafallopian transfer, 188 hysteroscopes, structure variations, 12–21 for an office laboratory, 71–72 for penile vibratory stimulation, 153 for percutaneous epididymal sperm aspiration, 159 for rectal probe electroejaculation, 154–55 for retrograde ejaculate processing, 156 for testicular biopsy, 158–59 for transcervical tubal cannulation, 138–39 for in vitro fertilization, 163–64 Estradiol, levels of and basal follicle-stimulating hormone levels, 27–28, 106 and ovarian stimulation, 104 and timing for oocyte aspiration, 175–76 Estrogen, urinary determination of, for monitoring ovulation induction, 104 Etiology of cervical stenosis, 147 of ejaculatory duct obstruction, 15–51 Euestrogenic normogonadotropic ovulatory dysfunction, 103 Evaluation of the female for infertility, 1–9 laboratory, for male infertility, 12–18, 15–51 of the male factor in infertility, 1–2, 1–23 results, 18 uterine, hysteroscopic, 116 Fallopian tube endoscopic evaluation of, 127–36 ultrasonography of, 42 Fallopian tube transfer, anesthesia during, 82–83 Falloposcopy, equipment and technique, 13–34 Fecundity and age, 59 defined, 7 Fentanyl, administration in surgery, without anesthesia personnel present, 82

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206 Fertility rate, in the United States, 1 Fertilization assessment, for in vitro fertilization, 171 Fever, effect on testicular function, 11 Fiberoptic technology, microlaparoscopy using, 143 Fibroids, submucous, hysteroscopic diagnosis of, 42 Filtration, of air, 65–66 Follicle aspiration equipment for, 163 procedures, 165–67, 176 ultrasound-guided anesthesia during, 82 preoperative instruction, 93 Follicles functional ovarian, documenting the presence of, 103 maturity of, evaluating, 175 monitoring, for in vitro maturation/in vitro fertilization, 181 puncture of, in vitro fertilization, 44–45 Follicle-stimulating hormone (FSH) administration in ovulation induction, 10–101 and age, 24–28 assay of, to evaluate male infertility, 15–16 basal levels of, intercycle and intracycle variability of, 26–27 to initiate and maintain spermatogenesis, 101 Follicular fluid, a1ccumulation of anesthetic agents in, 79 Freezers, for the in vitro laboratory, 75 Frozen semen, for intrauterine insemination, 11–11 Fructose, seminal, for evaluating ejaculatory duct obstruction, 13 Future, of treating age-related infertility, 35 Gamete intrafallopian transfer (GIFT), 184–94 anesthesia for, 77 comparison with controlled superovulation, 111 multifetal gestations with, 197 success rate of, comparison with in vitro fertilization, 161 Gametes, donor, pregnancy following treatment with, 53–54 Gamete technologies. See Assisted reproductive technology (ART) Gaseous pollutants, from construction materials, 7–71 Gas supply, in a laboratory, 73–74 Gender, and response to infertility, 51–52 Gender ratios, after gonadotropin therapy, 108–9 General anesthesia, 77–78 Genetic abnormalities screening for, and recommendation for preconception counseling, 80 testing for, in male evaluation, 16 See also Chromosomal anomalies; Congenital anomalies

Index Gentamicin, prophylactic administration of, before surgery, 82 Glucocorticoids, for treating congenital adrenal hyperplasia, 19 Gonadotoxins, list of, 11 Gonadotropin-releasing hormone, agonists to, downregulation with, and ovarian responsiveness, 32–33 Gonadotropins administration of, in gamete intrafallopian transfer, 188–89 dosage of, in treating diminished ovarian reserve, 32 exogenous, indications for treatment with, 10–115 See also Human chorionic gonadotropin (hCG); Human menopausal gonadotropin (hMG); Human pituitary gonadotropin (hPG) Gonadotropin therapy, outcomes of, 106–7 Group therapy, in infertility, 55 Growth hormone, role in follicular development, 34 Guidelines for nonoperating room anesthetizing locations, American Society of Anesthesiologists, 91 Guilt, as a response to infertility, 50 Heating, ventilating and air conditioning (HVAC) system, design of, 64–66 Heterotopic pregnancies, 198–99 Histerelin, response of the pituitary to, 33 History medical risk factors for aspiration after anesthesia, 81 of the infertile male, 1–11, 150 of outpatient surgery laparoscopy under local anesthesia, 143–44 modern, 77 tests for tubal patency, 141 of in vitro fertilization, 161–73 Hood, placement of, in planning a laboratory, 72 Hormones medical therapy for male infertility related to, 18–19 screening for, in male evaluation, 15–16 Human chorionic gonadotropin (hCG) early ovarian hyperstimulation syndrome and, 195 timing of administration, and patient preparation, 81 Human menopausal gonadotropin (hMG) ovulation induction with, 100 rate of ovarian hyperstimulation syndrome and, 195 spontaneous abortion rate with use of, 199 for treating hypogonadotrophic hypogonadism, 7 Human pituitary gonadotropin (hPG), ovulation induction with, 100 Humidity, control of, in a laboratory, 69–70 Hydrogen receptor antagonist, preoperative administration of, to prevent aspiration, 81

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Index

207

Hypergonadotropic hypogonadism, symptoms of, 103 Hyperprolactinemia symptoms of, 15 treating, 18–19 Hypogonadism, sources of androgen excess inducing, 15–16 Hypogonadotropic hypogonadism medical treatment of, 18–19 symptoms of, 102–3 Hypothalamic pituitary dysfunction outcomes of gonadotropin therapy in, 107 Hypothalamic pituitary failure, outcomes of gonadotropin therapy in, 107 Hyskon, for uterine distension, advantages and risks of using, 120 Hysterosalpingo-contrast sonography, 43 Hysterosalpingography (HSG), 4 for fallopian tube evaluation, 127 for tubal patency evaluation, 141–42 for uterine evaluation, 116 Hysteroscopy, diagnostic and therapeutic, 116–26

Intrauterine masses, identifying with hysteroscopy, 117–18 Intravasation syndrome, following oil-based contrast material use in hysterosalpingography, 4 Intubation, during laparoscopy, contraindications to, 82–83 In vitro fertilization (IVF), 43–44, 161–73 hysteroscopy prior to, 119–22 laboratory for, 63–76 outcomes of, and intercycle variability in folliclestimulating hormone levels, 27 sperm-bound antibodies as a contraindication to, 20 unstimulated, 174–83 In Vitro Fertilization Registry, 177 In vitro maturation (IVM), 178–79

Identity shift, on achieving pregnancy, 53 Immunobead test, for anti-sperm antibodies, 14 Incubators, air supply to, 73 Indications for controlled ovarian hyperstimulation, 109–10 for falloposcopy, 128–29 for gamete intrafallopian transfer, 185–87 for gonadotropin therapy, 103 for hysteroscopy, 116–19 for penile ejaculatory stimulation, 152 for percutaneous epididymal sperm aspiration, 159 for processing retrograde ejaculates, 156–57 for rectal probe electroejaculation, 154 for testicular biopsy, 157–58 for transcervical tubal cannulation, 137–38 for treating cervical stenosis, 147 for in vitro fertilization, 162 Individual therapy, in infertility, 55 Indomethacin, administration prior to embryo transfer, 167 Infection, after hysteroscopy, 124 Infertility, defined, 116 Inguinal surgery, reproductive effects of, 11 Inhibin, changes in levels of with age, 25–26 Insemination, for male factor treatment, outcomes of, 6 Instruments, monitoring system for the laboratory, 75 International Classification of Diseases, 85 Intracytoplasmic sperm injection (ICSI), 17–18 procedure for, 17–71 Intratubal gamete transfer, 184–94 Intrauterine insemination and controlled ovarian hyperstimulation, 10–115 technique, 115

Laboratory in the office evaluation for male infertility, 12–18 preparation for in vitro fertilization, 163–64, 168–69 setup basics, 63–76 tests for evaluation of male infertility, 15–51 tests recommended for women, based on age, 80 Laparoscopic procedure, discharge instructions, 99 Laparoscopic transfer versus transvaginal transfer, 192 Laparoscopy for diagnosing tubal and peritubal pathology, 128 diagnostic, in idiopathic infertility, 187 for fallopian tube evaluation, 127 preoperative instructions, 94 Latex, allergy to, special considerations in surgery, 85 Layout, model laboratory, in a reproductive center, 68 Leiomyomas, identification and treatment of, 117–18 Leukocytes, in semen, 13 Leuprolide acetate, ovarian responsiveness and pregnancy rate after administration of, 34 Lewin VHI, algorithm for fertility treatment, 59 Lidocaine, 79 Lighting, effect on in vitro cell cultures, 71 Linear everting catheter falloposcopy, 131–32 Line filters, for commercial compressed air tanks, 73 Local anesthesia, 79 for gamete intrafallopian transfer, 192 for laparoscopy, history of, 143 list of agents for, 89 for microlaparoscopy, 141 with ultrasound-guided follicle aspiration, 82 Loss associated with infertility, 5–51 of pregnancy, 53

Jacobaeus of Sweden, historic laparoscopy by, 143 Kallmann syndrome medical treatment for, with human chorionic gonadotropic, 18–19 symptoms of, 15

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208

Index

Luteinizing hormone (LH) administration of, in ovulation induction, 10–101 assay of to evaluate male infertility, 15–16 in unstimulated in vitro fertilization, 174, 176 Male response to infertility, 52 treating reproductive dysfunction of, 15–60 Managed care, effect on office-based infertility practice, 58–62, 141 Management of fallopian tube problems, 134–35 ongoing, in controlled ovarian hyperstimulation, 111 of proximal tubal obstruction, table, 140 Mechanism of controlled ovarian hyperstimulation/intrauterine insemination, 109–11 Media, for assisted reproductive technology, 168–69 Medical therapy, for male infertility, 18–21 Medications amoxicillin, 82 ampicillin, 82 benzocaine, 79 bromocriptine, 19 bupivacaine (Marcaine), 82 cefotetan, 81 cisatracurium, 78 clomiphene citrate (Clomid), 7, 19, 100 doxycycline, 4, 20, 81 droperidol, 81 fentanyl, 82 gentamicin, 82 histerelin, 33 before hysteroscopy, 123 indomethacin, 167 leuprolide acetate, 34 lidocaine, 79 meperidine (Demerol), 82 metoclopramide (Reglan), 81 mevacurium, 78 midazolam (Versed), 78, 80, 82 ondansetron (Zofran), 81 triazolam (Halcion), 80 valium, 167 vancomycin, 82 Medicines, names and mechanism of action, 89 Meiosis, control of, 178–79 Mental health professional, role in infertility treatment, 54–55 Meperidine (Demerol), administration in surgery, without anesthesia personnel present, 82 Metoclopramide (Reglan), preoperative administration of, to prevent aspiration, 81

Metroplasty, hysteroscopic, for treating uterine septum, 118 Mevacurium, 78 Microlaparoscopy, 141 Microsurgical epididymal sperm aspiration (MESA), 22, 160 Microtubular obstructive disease, surgical treatment of, 22 Midazolam (Versed) administration in surgery, without anesthesia personnel present, 82 premedication with, in surgery, 78, 80 Miscarriage rate, after in vitro fertilization, and age, 34 Monitored anesthesia care (MAC), 78 in ultrasound-guided follicle aspiration, 82 Monitoring clinical, of ovarian response, 103–5 cycle, in unstimulated in vitro fertilization, 175 Morphologic tests, of ovarian responsiveness, 31 Müllerian abnormalities detecting with ultrasound, 40 spontaneous abortion associated with, 118 Multifetal gestations in assisted reproduction, complications of, 172 in ovulation induction, 197–98 risk of with human chorionic gonadotropin administration, 103, 108 in assisted reproduction, 53 Mumps, postpubertal, 11 Muscle relaxants, for outpatient use, 78 Myomas, ultrasound for detecting, 40, 42 National College for Clinical Laboratory Standards (NCCLS), 74 National Fire Protection Association (NFPA), 73 Networks, social and legal issues in, for reproductive endocrinologists, 61 Nonsteroidal antiinflammatory drugs (NSAIDs) before hysteroscopy, 123 for treating pyospermia, 20 Number needed to treat (NNT), evaluative tool for economic calculations, 142 Nurse, preparation for anesthesia and surgery in the office, 83 Obstruction, ejaculatory duct, treating, 21–22 Ondansetron (Zofran), for reducing nausea and vomiting, 81 Oocyte-cumulus complex (OCC), harvesting, 169 Oocytes collection of, for in vitro maturation/in vitro fertilization, 181 maturation of, 178–79 for in vitro maturation/in vitro fertilization, 181

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Index minimizing exposure to anesthesia, 77–78 minimizing exposure to medication, 80 preparation for retrieval for in vitro fertilization, 169 Open biopsy, testicular, 158–59 Operating rooms, specifications for, air delivery systems, 63 Opioid anesthetics, 77–78 Oral contraceptives, pretreatment with, 34 Outcomes of assisted reproductive technology, effects of inhibin levels on, 25 of controlled ovarian hyperstimulation, 111 database for analysis of, 60 of pregnancies, with ovarian induction, 198–99 of unstimulated in vitro fertilization, success rates, 177–78 of in vitro fertilization, 27 complications involving, 172 Ovarian cancer, risk of, in ovulation induction, 199–201 Ovarian hyperstimulation syndrome (OHSS), 195–96 as a complication to gamete intrafallopian transfer, 193 as a complication to in vitro fertilization, 172 risk of, with human chorionic gonadotropin administration, 103 risks accompanying, 105–9 therapy for, 108 See also Controlled ovarian hyperstimulation Ovarian reserve diminished as a contraindication to in vitro fertilization, 162 and reproduction, 24, 28–29 evaluating during patient selection for unstimulated in vitro fertilization, 175 Ovarian torsion, risk of, with stimulated ovaries, 193 Ovaries basal follicle-stimulating hormone screening with one only, 27 sonography for evaluating, 41–42 Ovulation assessment of, 2–3 defects in, 6 induction of, 43, 10–115 complications of, 195–202 verifying the occurrence of, 3 Parthenogenesis, induction by propofol, 79 Pathogenesis, of ovarian hyperstimulation syndrome, 195–96 Pathology, of the tubal lumen, 132–33 Patient preparation for anesthesia and surgery in the office, 83 preparation for hysteroscopy, 123

209

selection of for gamete intrafallopian transfer, 186 for ovulation induction, 102–3 for unstimulated in vitro fertilization, 178 for in vitro fertilization, 175 for in vitro maturation, 181 Payment, insurance for infertility services, 60 Pelvic inflammatory disease (PID) considerations in prophylactic administration of antibiotics before surgery, 81 ultrasonographic identification of, 42 Penile vibratory stimulation (PVS), to obtain a semen specimen, 152 Percutaneous biopsy, testicular, 158–59 Percutaneous epididymal sperm aspiration, 159–60 Personnel, for anesthesia administration, 78 traveling, 82 Physical examination of the male, 11–12 in treating male reproductive dysfunction, 150 Physicians preparation for anesthesia and surgery in the office, 83 recommendations for, in managing psychosocial issues, 56 Physiology of ovulation induction, 10–101 reproductive, of the male, 151 Pituitary tumor, excluding, in hyperprolactinemia, 18–19 Plumbing, for a laboratory, 73 Polycystic ovary disease (PCO), 41 Polyps, endometrial association with infertility, 117 ultrasonography for evaluating, 4–42 Power, reliability of, for the laboratory, 74–75 Pregnancy early, ultrasound images in, 44 after infertility, special considerations in, 52–53 rate of, and basal follicle-stimulating hormone levels, 25–26 wastage in gonadotropin-induced ovulation, 108 See also Multifetal gestations Preparation for clinical procedures, in vitro fertilization, 164–65 for office surgery, 83 for transcervical tubal cannulation, 138 for in vitro fertilization, 162–63 Pressurization, in the air delivery system, 67 Preterm delivery, as a complication of assisted reproductive technology, 198 Prevention of multifetal gestations, 197 of ovarian hyperstimulation syndrome, 197 Primary care, evaluation of women with infertility in, 1

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210

Index

Primate studies, of in vitro maturation, 179–80 Procedure in cervical dilatation, 148 in gamete intrafallopian transfer, 188–91 in hysteroscopy, 122–23 in penile vibratory stimulation, 153–54 in percutaneous epididymal sperm aspiration, 159 in processing retrograde ejaculates, 156–57 in rectal probe electroejaculation, 155 in transcervical tubal cannulation, 139 in vitro fertilization, 164–72 Progesterone, luteal phase serum levels of, 3 and pregnancy rate in women over forty, 34–35 Prophylaxis, against postoperative nausea and vomiting, 81 Propofol, experimental administration to mice, effect on fertilization rate, 79 Proximal tubal obstruction (PTO), evaluation and management of, 137 Psychological evaluation, 54–55 Psychosocial issues, in coping with infertility, 49–57, 141 Pyospermia, treatment of, 20 Quality control, in the laboratory, for in vitro fertilization, 168 Recombinant DNA technology, production of gonadotropins using, 102 Recommendations, for ovarian reserve screening, 31–32 Reconstruction, microsurgical, in epididymal obstruction, 152 Rectal probe electroejaculation, 154–56 Regional anesthesia, 78 with ultrasound-guided follicle aspiration, 82–83 Relaxin, levels of, and risk of preterm delivery, 198 Retrograde ejaculation, treatment of, 20 Risk factors for development of sperm-bound antibodies, 14 for ovarian hyperstimulation syndrome, 108, 196–97 Room construction, for a laboratory, 7–72 Rubin test, for tubal patency, 141 Saline infusion sonohysterography (SIS), 42–43 Salpingoscopy, equipment and technique, 129–30 Scopolamine, transdermal, for reducing nausea and vomiting, 81 Screening with the clomiphene citrate challenge test, 29 for disease, prior to surgery, 80 for genetic diseases, 80 ovarian reserve recommendations for, 31–32 threshold values, 3–35

preoperative, 80 routine, American Society of Anesthesiologists (ASA) on, 90 See also Patient, selection of Security systems, for the laboratory, 75–76 Selective fetal reduction, 53 counseling about, 102 in multifetal gestations, 197–98 Semen adjunctive studies of, 13–14 analysis of, 2, 12–13 preparing for in vitro fertilization, 169–70 Septate uterus, and pregnancy wastage, 118 Sex hormone-binding globulin (SHBG), effect of, on measurement of unbound testosterone, 15 Side effects, in controlled ovarian hyperstimulation, 111 Smoking, and age at menopause, 30 Society for Assisted Reproductive Technology (SART), statistics on advantages of in vitro fertilization, 161 Sodium citrate, preoperative administration of, to prevent aspiration, 81 Sonography, for detecting uterine structural lesions, 5 Sperm, preparation of, for controlled ovarian hyperstimulation, 11–11 Spermatogenesis, physiology of, 151 Sperm capacitation index (SCI), 14 Sperm function penetration assay, 14–15 tests of, 14–15 Sperm washing (SW), 110 technique, 114 Spinal anesthesia, advantages of, 78 Spinal cord injury, adjunctive techniques in, and pregnancy rates, 155–56 Strategy for coping, and response to a failed treatment cycle, 50 for infertility testing, 1 female evaluation, 5 Subacute bacterial endocarditis (SBE), risk evaluation and prophylactic antibiotic administration, 81–82 Succinylcholine, 78 Superovulation, risk of, with human chorionic gonadotropin administration, 103 Support, psychological, 55 Surgery, retroperitoneal lymph node dissection, 1–11 Surgical therapy, for male infertility, 21–22 Swim-up (SU) procedure, for sperm preparation, 110, 113 Symptoms of ectopic pregnancy, 198–99 of ovarian hyperstimulation syndrome, 197

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Index Technology fiberoptic, microlaparoscopy using, 143 of in vitro maturation, 18–81 Temperature, control of, in a laboratory, 69–70 Testicle, undescended, 1–11 Testicular biopsy for evaluating azoospermia, 157–59 sedation during, 83 Testicular sperm extraction (TESE), 157–59 Testosterone, serum levels of, 15 Three dimensional scan, transvaginal ultrasound, 46 Timing of human chorionic gonadotropic injection, 175–76 of hysteroscopy, 122–23 Transcervical microendoscopy, of the tubal lumen, 13–34 Transcervical tubal cannulation, 137–40 Transfimbrial salpingoscopy, 129–30 Transrectal ultrasonography (TRUS), for detecting ejaculatory duct obstruction, 13, 16–17 Transurethral resection, for ejaculatory duct obstruction, 152 Transvaginal transfer versus laparoscopic transfer, 192 Transvaginal ultrasonography (TVUS), 39–48 advantage of, for oocyte retrieval, 77 for assessing tubal patency, 128 in follicle aspiration, and unstimulated in vitro fertilization, 174 to monitor follicular size, before human chorionic gonadotropin administration, 104 Treatment cycle of, typical, 105–6 of diminished ovarian reserve, 32–35 ending, decisions about, 52 of infertility, emotional impact of, 51 of male factor infertility, 6, 18–22 monitoring, 43–44 strategy for, 5–6 in male reproductive dysfunction, 151–52 Triazolam (Halcion), premedication with, in surgery, 80 Tubal disease, treatment and outcomes, 6 Tubal Embryo Transfer (TET), anesthetics selected for use in, 77–78

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Ultrasonography for monitoring changes in the cervix and endometrial cavity, 104–5 for following ovulation induction, 106 role in infertility evaluation, 39–48 scrotal, 16 transrectal, for evaluating male infertility, 16 Ultrasound-guided follicle aspiration, discharge instructions for, 98 Upper respiratory infection, factors affecting decisions about surgery in the presence of, 81 Urinalysis, postejaculate, 17 Urinary tract infections, and male infertility, 13 U.S. HealthCare, infertility treatment model of, 58 Uterus, perforation of, as a complication of hysteroscopy, 124 Vacuum line, for the laboratory, 74 Valium, administration prior to embryo transfer, 167 Vancomycin, substitution for penicillin in patients with allergy, 82 Varicocele gonadal function in the presence of, 12 surgery for, 21 Varicocelectomy, 151–52 Vasal aplasia, 15–51 Vascular permeability factor (VPF), in ovarian hyperstimulation syndrome, 196 Vas deferens, congenital absence of, 12, 150 surgical treatment in, 22 Vasectomy, reversal of, 152 VIVA program, prospective payment plan in, 60 Water, purification of, for the laboratory, 74 Women, response to infertility, 51 World Health Organization (WHO), hysterosalpingography versus laparoscopy study, 127 Zygote intrafallopian transfer (ZIFT), 187 anesthesia for, 77–78 multifetal gestation rate in, 197