IVF in the Medically Complicated Patient: A Guide to Management

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Prelims

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IVF in the medically complicated patient: a guide to management

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IVF in the medically complicated patient: a guide to management

Edited by Nick S Macklon Department of Reproductive Medicine University Medical Centre Utrecht Utrecht The Netherlands

LONDON AND NEW YORK

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© 2005 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2005 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park Abingdon, Oxon OX14 4RN, UK Tel.: Fax.: E-mail: Website:

+44 (0) 20 7017 6000 +44 (0) 20 7017 6699 [email protected] http://www.tandf.co.uk/medicine

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. British Library Cataloguing in Publication Data Data available on application Library of Congress Cataloging-in-Publication Data Data available on application ISBN 1-84184-428-4 Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel.: 800 272 7737; Fax.: 800 374 3401 Outside Continental USA Tel.: 561 994 0555; Fax.: 561 361 6018 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0) 1264 332424 E-mail: [email protected] Composition by Parthenon Publishing Printed and bound by Scotprint, Haddington, UK

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Contents

Contributors

vii

Foreword

xiii

Introduction Section 1

xv

The IVF patient with medical problems

1.

The patient at risk of thrombosis NS Macklon

2.

The patient with endocrine disease JSE Laven

19

3.

The patient with malignant disease RA Anderson

41

4.

The patient with systemic lupus erythematosus Z Blumenfeld

51

5.

The couple discordant for human immunodeficiency virus MV Sauer

61

6.

The couple with sexual dysfunction WL Gianotten

73

7.

The obese patient B Ola and WL Ledger

87

Section 2

3

The IVF patient with gynecological problems

8.

The patient with endometriosis T Gurgan and A Demirol

103

9.

The patient with hydrosalpinx A Strandell

117

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IVF IN THE MEDICALLY COMPLICATED PATIENT

10. The patient with fibroids JH Check and JW Krotec

139

11. The patient with congenital uterine abnormalities PK Heinonen

159

Section 3

The successful and unsuccessful IVF patient

12. Preparing for pregnancy: preconception care EAP Steegers and HIJ Wildschut

181

13. The poor responder SD Keay

205

14. The patient with recurrent miscarriage R Rai

221

15. Giving bad news: ‘It’s time to stop’ J Boivin, J Takefman and A Braverman

233

Index

241

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Contributors

RA Anderson MD PhD MRCOG Division of Reproductive and Developmental Science MRC Human Reproductive Science Unit Centre for Reproductive Biology The University of Edinburgh Chancellor’s Building 49 Little France Crescent Edinburgh EH16 4SB UK Z Blumenfeld MD Reproductive Endocrinology Department of Obstetrics and Gynecology Rambam Medical Center Technion-Faculty of Medicine Haifa 31096 Israel J Boivin PhD School of Psychology Cardiff University Tower Building, Park Place Cardiff CF10 3AT UK AM Braverman PhD Psychological and Complementary Care Reproductive Medicine Associates of New Jersey 111 Madison Avenue Morristown, NJ 07960 USA

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JH Check MD PhD Division of Reproductive Endocrinology and Infertility University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Camden, NJ 08103 USA A Demirol MD CLINIC of Women’s Health Infertility and IVF Center Ankara Turkey BCJM Fauser MD PhD Department of Reproductive Medicine University Medical Centre Utrecht 3508 GA Utrecht The Netherlands WL Gianotten MD NVVS Centre for Reproduction Erasmus Medical Center 3000 CA Rotterdam The Netherlands T Gurgan MD Hacettepe University Department of Obstetrics and Gynecology IVF and Infertility Unit Ankara Turkey PK Heinonen MD Medical School University of Tampere and Department of Obstetrics and Gynecology University Hospital of Tampere 33014 Finland

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CONTRIBUTORS

SD Keay MD MRCOG Department of Biological Sciences University of Warwick Gibbet Hill Road Coventry CV4 7AL and Centre for Reproductive Medicine University Hospitals Coventry and Warwickshire NHS Trust Coventry CV2 2DX UK JW Krotec MD Endoscopic Surgery Cooper Institute for Reproductive Hormonal Disorders Marlton, NJ 08053 USA JSE Laven MD PhD Department of Obstetrics and Gynaecology Erasmus Medical Center PO Box 2040 3000 CA Rotterdam The Netherlands WL Ledger MA DPhil (Oxford) FRCOG Academic Unit of Reproductive and Developmental Medicine Obstetrics and Gynaecology Level 4, Jessop Wing University of Sheffield Tree Root Walk Sheffield S10 2SF UK NS Macklon MB ChB MD MRCOG Infertility and Periconceptional Medicine Department of Reproductive Medicine University Medical Centre Utrecht 3508 GA Utrecht The Netherlands

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B Ola MBBS PGCME MD MRCOG Obstetrics and Gynaecology Level 4, Jessop Wing University of Sheffield Tree Root Walk Sheffield S10 2SF UK

FWACS

R Rai BSc MD MRCOG Department of Obstetrics and Gynaecology Imperial College London St Mary’s Hospital South Wharf Road London W2 1PG UK MV Sauer MD Department of Obstetrics and Gynecology College of Physicians and Surgeons Columbia University Division of Reproductive Endocrinology Columbia Presbyterian Medical Center New York, NY 10032 USA EAP Steegers MD PhD Obstetrics and Prenatal Medicine Erasmus University Medical Center 3000 CA Rotterdam The Netherlands A Strandell MD PhD Department of Obstetrics and Gynecology Göteborg University Sahlgrenska University Hospital S-413 45 Göteborg Sweden

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CONTRIBUTORS

J Takefman PhD Psychological Services McGill Reproductive Centre McGill University Health Centre Royal Victoria Hospital Montreal Quebec H3A 1A1 Canada HIJ Wildschut MD PhD Obstetrics and Prenatal Medicine Erasmus University Medical Center 3000 CA Rotterdam The Netherlands

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Foreword

IVF in the Medically Complicated Patient is a unique book, in both its focus and its format. As the chief editor indicates, IVF patients increasingly present with health conditions that have a potential impact on treatment outcomes (i.e. chances for success and complications). A number of medical areas potentially relevant for IVF are covered in this book. Information provided is clinically relevant and up-to-date. The fixed format for each chapter is especially helpful in rendering IVF in the Medically Complicated Patient easy to read. The reader will quickly find the information required for a given patient. The summary sections at the end of each chapter are particularly helpful in this respect. This book also underlines the current trend in infertility therapies to address attention beyond a positive pregnancy test. Chances for pregnancy without major complications and the subsequent birth of healthy children are closely related to both the condition of the patient before treatment and the chosen treatment modality itself. The reader may find the chapter concerning preconception care especially informative. Patients will certainly benefit from the more integrated perspective of the period before and after conception. This book is comprehensive without being exhaustive. I am convinced that IVF in the Medically Complicated Patient will find its way to the fertility specialist involved in everyday patient care. Bart CJM Fauser

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MD PhD

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Introduction

The majority of women entering an in vitro fertilization (IVF) program are fit and healthy. Care is therefore primarily focused on helping the couple to achieve their reproductive ambitions. However, the increasing tendency to delay childbirth means that a greater proportion of women embarking on IVF are presenting with a concurrent condition that may have implications for IVF management and outcomes. While a large body of data is now available, it is not always readily accessible to the busy fertility specialist in the clinic. The aim of this book is to provide a concise but authoritative guide to the preparation, management and follow-up of IVF patients presenting with one or more of a broad range of potential complications encountered in contemporary practice. To this end, all the chapters follow a similar format in which the author addresses the impact of the condition on IVF outcomes and vice versa before providing didactic information designed to guide the management. The modern fertility specialist has an important role in preparing the couple for pregnancy, and counselling those who fail to conceive. These two areas of contemporary practice are also addressed. I hope that the busy clinician will find this book a useful aid, and I am grateful to all the authors for their expert contributions. Nick S Macklon

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Section 01

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Section 1 The IVF patient with medical problems

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Chapter 1

The patient at risk of thrombosis NS Macklon

INTRODUCTION The clinical association between venous thromboembolism (VTE) and in vitro fertilization (IVF) arises primarily within the context of ovarian hyperstimulation syndrome (OHSS), in which thromboembolic complications may have fatal consequences. Occasionally, patients presenting for IVF treatment may have a previous history of VTE, or be considered to be at increased risk of developing thromboembolic complications as a result of undergoing IVF treatment. VTE is a rare complication of ovarian stimulation for IVF. Recent data point to an incidence of 1.6 events per 100 000 cycles/woman,1 and the majority of cases of VTE reported in the literature are associated with the presence of risk factors for thromboembolic disease.2 Given the thrombophilic nature of ovarian stimulation and the potentially catastrophic effects of VTE, it is important to identify women at increased potential risk of this complication, so as to provide appropriate counseling and allow preventive steps to be taken where necessary. While fortunately rare in this patient group, venous thrombosis is a potentially serious disorder, which may often lead to post-thrombotic syndrome causing chronic morbidity. In one study of long-term complications, 74% of women with upper-extremity deep venous thrombosis (DVT) had residual disability up to 6 years later in the form of persistent discomfort, exercise-induced cramp, cold hands and weakness.3 Since women undergoing IVF are on the whole young and active, this may afflict their lives for many years. In this chapter, the mechanisms thought to increase the risk of thrombogenesis during IVF treatment are reviewed, strategies for identifying the at-risk patient are discussed and management options aimed at reducing the risk are summarized.

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THE IMPACT OF IVF ON THE RISK OF THROMBOEMBOLIC DISEASE The pathogenesis of venous thrombosis is complex and not completely understood. The classic triad of predisposing mechanisms described by Virchow – hypercoagulability, venous stasis and vascular damage – is still of value in understanding circumstances that may lead to DVT in the context of IVF. Ovarian stimulation results in a hyperestrogenic state, which has been associated with hypercoagulability and increased risk of DVT following oral contraceptive pill use and pregnancy. Evidence for estrogens as causes of thrombosis is provided by the reduction in the incidence of DVT associated with lower doses of estrogens in oral contraceptive pills.4 The supraphysiological levels of estrogen that arise during ovarian stimulation for IVF would therefore appear to cause an increase in the risk of VTE. However, in recent years, a number of studies have shown changes in coagulation parameters during IVF treatment to be modest.5–7 During IVF treatment, the action of coagulation factors seems to be associated less with the level of serum estradiol concentrations (which may reach levels ten times higher than in physiological cycles) than with the biochemical changes that occur after the triggering of final oocyte maturation with human chorionic gonadotropin (hCG). Taken together, these data suggest that hyperestrogenism related to ovarian stimulation is not associated with the coagulation abnormalities observed with high-estrogen-content oral contraceptives, and therefore does not significantly increase the potential for thrombus formation. During down-regulation and luteal support, the changes in plasma levels of anticoagulant proteins are virtually negligible. The only coagulation parameter that may change considerably during IVF treatment is the activated protein C (APC) resistance. In its activated form, protein C plays a central role in fibrinolysis. During ovarian stimulation, levels of APC actually appear to increase in association with rising estradiol levels. At the same time, factor VIII and protein S levels are diminished. This slight increase in APC associated with raised estradiol levels might be considered as a protective mechanism against thrombosis during periods of estrogen excess. Indeed, patients resistant to APC have been shown to be at greater risk of thrombosis during ovarian stimulation. The possibility that ovarian stimulation for IVF treatment increases susceptibility to thrombosis by inducing APC resistance has been suggested. Most of the studies that failed to show such an association employed an APC resistance test that quantifies the effect of APC on the intrinsic coagulation pathway. This pathway is much less sensitive to changes in sex

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THE PATIENT AT RISK OF THROMBOSIS

steroids than the tissue factor-based extrinsic coagulation pathway. The extrinsic pathway is initiated by the release of tissue factor, which is released after tissue damage, and stimulated monocytes.8 The tissue factorbased APC resistance test used in investigations of the effect of oral contraceptive pills is sensitive to changes in estrogens, and does reveal changes during hyperstimulation. In a study in which the effect of ovarian stimulation on the extrinsic pathway was measured, APC sensitivity ratios (APCsr) increased slightly at down-regulation, increased more strongly during hyperstimulation and remained high during the luteal phase. The plasma levels of anticoagulant proteins, protein C and protein S, did not change significantly.9 However, since thrombin formation is unchanged during ovarian stimulation, increases in tissue plasminogen activator (tPA) are unlikely to be a major concern.10 Increases in blood viscosity associated with an increase in hemoglobin (Hb), hematocrit (hct) and mean cell volume (MCV) are associated with a greater risk of thrombosis. In this situation, blood flow becomes slow and platelets and neutrophils in the blood circulation adhere easily to the vascular wall, resulting in contact activation of the blood coagulation cascade system. However, studies have indicated that activation of the coagulation system occurs before hemoconcentration can be clinically recognized, a finding inconsistent with the concept that hemoconcentration during IVF is the principal trigger of the coagulation cascade. Increases in parameters of hemoconcentration have been reported to occur during the period of down-regulation with gonadotropin releasing hormone (GnRH) agonists prior to commencing ovarian stimulation.9 During stimulation, these variables were observed to return to baseline, and in the luteal phase they dropped to values below baseline. The changes in hematocrit were relatively minor. Given the modest effects of IVF on hemoglobin, hematocrit, platelets and the plasma levels of the proteins involved in the protein C pathway, it seems reasonable to conclude that ovarian stimulation itself (prior to the administration of hCG to trigger final oocyte maturation) induces only marginal changes in hemostatic parameters. In contrast, the period following hCG administration reveals clinically significant alterations in the coagulation and fibrinolytic systems. The changes in these factors before and after hCG administration are summarized in Table 1. Following hCG administration, fibrinogen and factors II, V, VII, VIII and IX are elevated.5 In one study, activation of the coagulation cascade system was observed to occur within 2 days after hCG, reaching a maximum approximately 8 days following hCG administration.11 Activation of these systems was observed to continue for more than 3 weeks when pregnancy was established.11

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Table 1 Overview of effects of ovarian stimulation on hemostatic parameters compared with baseline levels and data from nonstimulated cycles (data derived from references 5, 9, 11–13) Parameter

Pre-hCG

Post-hCG ↓ ↓ =

Whole blood parameters

Hemoglobin Hematocrit Platelet count

= = ↓

Coagulation inhibitors

Antithrombin Protein S total Protein S free Protein C activity Protein C antigen Protein C inhibitor APCsr

↓ ↓ = = = = ↑/=

↓/= ↓/= = ↓/= = = ↑/=

Measures of hemostasis

PT APTT

↑ =

↓ ↓/=

Clotting factors

Factor I (fibrinogen) Factor II (prothrombin) Factor V Factor VII Factor VIII Factor IX Factor X

= = = = = = =

↑/= ↑ ↑ ↑ ↑/= ↑ =

APCsr, activated protein C sensitivity ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; hCG, human chorionic gonadotropin; =, no effect; ↓, decreases; ↑, increases

Fibrinolysis also increases after hCG administration, indicated by elevated plasminogen concentration, decreased α2-plasmin inhibitor and increased concentrations of fibrinomers (D-dimers).14 However, the fibrinolytic phenomena only occur several days after the thrombotic phenomena have appeared, consistent with a prothrombotic state in the early luteal phase.

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Ovarian hyperstimulation syndrome Severe forms of thrombosis following ovarian stimulation for IVF have been reported in women with concomitant signs of OHSS.2,11,15 Indeed, a severe feature of OHSS is VTE, for which a prevalence of 1/128 (0.78%) has been reported and which accounts for most deaths associated with the syndrome.16 It is unclear, however, how OHSS increases this risk, and why only a few women seem to be predisposed to developing such complications. Whether thrombosis arises as a result of blood modifications secondary to the clinical OHSS itself or as a consequence of the major changes in the steroid milieu induced by gonadotropin stimulation has been a matter of debate. The assumption that hemoconcentration and hyperviscosity resulting from extravascular sequestration of fluid in OHSS might increase the incidence of thrombotic events is not supported by cases of severe thromboembolic events reported following gonadotropin therapy without clinical manifestations of OHSS.17–19 Moreover, no correlation appears to exist between hematocrit and hemostasis parameters during OHSS.20 A specific role for biochemical hyperestrogenism associated with OHSS could be postulated on the basis of the hyperestrogenic state that exists in pregnancy and in users of oral contraceptives. However, as stated earlier, the association between increased estrogen levels and abnormal parameters of hemostasis during IVF is weak. Indeed, no correlation was found between estrogen and changes in coagulation factors observed in women with OHSS.6,20 Moreover, thromboembolic events associated with OHSS usually occur some time after the expected peak estradiol concentration.2 While the mechanism behind thrombogenesis during OHSS is uncertain, the increased risk that arises in association with this complication of IVF is clear. Careful monitoring and the judicious use of measures to avoid OHSS such as ‘coasting’ are particularly important in patients at risk of thrombosis. Adequate hydration and thromboprophylaxis during treatment for OHSS are vital if life-threatening complications are to be avoided. The further management of OHSS is addressed elsewhere.21

PREPARING THE PATIENT FOR IVF TREATMENT: ASSESS THE RISK All patients proceeding to IVF treatment should be individually assessed for their risk of thrombotic complications. Women who should be considered at increased risk include those with congenital or acquired

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Table 2 Increased risk of deep venous thrombosis (DVT) associated with specific thrombophilias (adapted from reference 22)

Thrombophilia

General population

Patients with DVT

AT deficiency

0.02–0.17

1.1

85% by age 50

PC deficiency

0.14–0.05

3.2

50% by age 5

PS deficiency

—

2.2

50% by age 50

APC resistance

3.6–6.0

Prothrombin G20210A

1.7–3.0

21 6.2

Risk of DVT

3–7-fold increase 2.8-fold increase

AT, antithrombin; PC, protein C; PS, protein S; APC, activated protein C

thrombophilias, those who develop OHSS, those over 40 years of age and smokers (Table 2). Congenital thrombophilia, or tendency to thrombosis, consists of a group of inherited disorders that include deficiencies in protein C, protein S and antithrombin; resistance to APC due to a point mutation (Arg506Gln) in the factor V gene (the factor V Leiden mutation); and a 677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR 677T). Renewed interest in the role of thrombophilias as important determinants of thombotic risk occurred with the discovery in 1993 of APC resistance.23 Resistance to APC is an autosomal dominant trait caused by a mutation in the coagulation factor V gene. This mutation results in a replacement of arginine residue 506 with a glutamine at one of the factor V cleavage sites for APC. The factor V Leiden mutation that results in APC resistance has a high prevalence in Caucasians of 4–5%,24 but is rare among Asians and Africans.25 The prevalence of hyperhomocysteinemia in individuals with venous thrombosis has also been found to be high, and this represents an additional independent risk factor for DVT.26 A cause of moderate hyperhomocysteinemia is a relatively frequent mutation in the gene encoding 5,10methylenetetrahydrofolate reductase (MTHFR). Until recently, data relating to the impact of these factors on the prevalence of thrombosis following assisted reproductive technologies (ART) were scarce. In a study of women hospitalized for severe OHSS, 85% had

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one or more positive markers of thrombophilia compared with 27% of a control subjects who had undergone IVF without developing severe OHSS.27 The prevalence of MTHFR 677T and antithrombin and protein S deficiencies, but not the antiphospholipid syndrome or protein C deficiency, was significantly increased in women with severe OHSS. Consistent with previous reports,28 all the clinically significant thrombotic events reported in this study occurred in women with more than one marker of thrombophilia. Several case reports have been published describing women who developed venous thrombosis during IVF treatment and who were found to be APC resistant.29,30 In a recent study of 305 women undergoing 747 cycles, 4% carried the factor V Leiden mutation (all heterozygotes), 6.2% the factor II A20210 gene variant and 17.7% the TT (homozygous variant) MTHFR genotype.1 Frequencies were similar to those reported in the general population.24 Of 31 women with factor V Leiden or factor II A20210 mutation undergoing IVF, none developed a thrombotic event during ovulation induction. In contrast, the combination of age > 39 years and plasma total homocysteine (tHcy) > 97.5th centile conferred a risk of thrombotic events 14–15-fold higher. The authors also assessed the prevalence of acquired thrombophilias in this cohort, and found 5% to test positive for lupus anticoagulant.1 Acquired thrombophilias include the antiphospholipid syndrome, which is the presence of anticardiolipin antibodies or circulating lupus anticoagulants, deficiencies of antithrombin and protein S and acquired protein C resistance. The overall prevalence of anticardiolipin antibodies and lupus anticoagulants in the general population has not been established with certainty, but rates of 1–5% have been estimated.31 The thrombotic risk associated with these antibodies, particularly in young healthy women, is unclear, but VTE rates of 6–8% in healthy subjects with lupus anticoagulant have been reported (Table 2).32 Additional risk factors that should be assessed prior to commencing IVF treatment include the following.

Prior VTE Women with a previous episode of VTE are at greatly increased risk for recurrence, particularly when exposed to high-risk conditions. In an observational study of 1231 consecutive patients with VTE, 19% had had at least one previous clinically recognized episode.33 In a case–control study, patients with a history of VTE were around 16 times more likely to develop a new episode during a subsequent high-risk period compared with patients without a history of DVT or pulmonary embolism (PE).34

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Age A number of studies support an association between increasing age and a higher incidence of VTE.22 Patients aged > 40 years are at significantly increased risk.22,35 In a recent study of 305 women undergoing ovarian stimulation, thrombotic events were observed in 4/747 cycles, with a prevalence of 0.5% corresponding to 1.6 per 100 000 cycles. Age over 39 years was associated with a 15.2-fold (95% confidence interval (CI) 2–115) increase in risk of thrombosis during IVF treatment.1 In this series only one thrombotic event occurred, in a woman under 39 years of age, and this subject had antiphospholipid antibodies and mild hyperhomocysteinemia.1

Obesity Although obesity has long been cited as a risk factor for VTE, a number of studies have found no association.36 While risk may be increased, the association appears to be weak. The implications of obesity in IVF treatment are dealt with in detail in Chapter 7.

Screening for thrombophilias There is currently little evidence to support universal screening for thrombophilia in pregnancy or prior to IVF for the prevention of VTE.37 However, screening for thrombophilia should be considered in women with a history of recurrent miscarriage, or personal or family history of VTE. Thrombophilia is associated with a high risk of developing OHSS,27 and this has been proposed as an additional reason for screening for thrombophilia in women with a family or personal history of thrombosis prior to undergoing ovarian stimulation, and in women who have developed OHSS (Table 3). However, a recent study failed to show an increase in the prevalence of thrombophilia in women with severe OHSS, and the costeffectiveness of screening for thrombophilias in this context of IVF could not be demonstrated.38 Screening for thrombophilias should include plasma antithrombin, proteins S and C, antiphospholipid antibodies, and testing for factor V Leiden mutation and MTHFR 677T.

Management of the IVF cycle Patients deemed to be at additional risk of thrombosis should be advised as to the importance of avoiding the development of OHSS. Milder

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Table 3

When to consider screening for thrombophilia

Positive personal or family history for thrombosis Patients with severe ovarian hyperstimulation syndrome (OHSS) Women aged over 40 years

stimulation protocols in combination with a reduced dose of hCG (5000 IU or less) for triggering final oocyte maturation may reduce the risk without compromising chances of pregnancy.39,40 Judicious use of ‘coasting’ and the use of progesterone rather than hCG for luteal support have been shown to reduce the risk of OHSS.21 The decision whether or not to prescribe thromboprophylaxis in a given patient will depend on an individual assessment of the risk/benefit of treatment in each patient. The presence or absence of the risk factors addressed in this chapter should direct treatment. Management of the woman with a single previous VTE has been controversial, but recent data from studies of pregnancy may guide therapy in the context of IVF. In a woman with a previous VTE that was not related to pregnancy or oral contraceptive use, and in whom no thrombophilia or other additional risk factor is present, thromboprophylaxis probably need not be prescribed.37 However, in women with a previous VTE and underlying thrombophilia, or where the VTE was idiopathic or related to pregnancy or the pill, or where additional risk factors are present, pharmacological prophylaxis should be considered (Table 4). Prophylactic therapy is probably not necessary during ovarian stimulation, when the risk of thrombosis is minimal.41 Given the rarity of occurrence of VTE prior to hCG, and the increased risk of significant intraabdominal bleeding that may occur following oocyte pick-up, medical thromboprophylaxis should be delayed until after this procedure has been carried out. Evidence from large-scale randomized controlled studies is not available to guide therapy. However, the available data support the following approach. Low-molecular-weight heparin (LMWH) remains the first-line pharmacological method. Daily subcutaneous dalteparin (5000 IU) or enoxaparin (40 mg) should be commenced 24 h after oocyte pick-up. The dose may need to be adjusted in women with very low or very high body weight. At a low body weight (< 50 kg or body mass index (BMI) < 20 kg/m2), lower doses may be required (e.g. 20 mg enoxaparin or 2500 IU dalteparin daily).42 In obese patients (BMI > 30), higher doses

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Table 4

When to consider thromboprophylaxis

Previous deep venous thrombosis (DVT) Ovarian hyperstimulation syndrome (OHSS) requiring hospital admission Acquired or hereditary thrombophilia in combination with age over 40 years and/or smoking

may be required. The platelet count should be checked before and 1 week after commencing LMWH to detect heparin-induced thrombocytopenia. Treatment should continue for 3 weeks. In patients who develop OHSS, a longer period of treatment should be considered. In those who conceive, long-term prophylaxis may be indicated. While the clinical approach described here is also appropriate to pregnancy, specialist advice should be sought. Unfractionated heparin and LMWH do not cross the placenta and are not associated with teratogenesis or fetal hemorrhage. The disadvantages usually associated with long-term use are osteoporosis, heparininduced thrombocytopenia and allergy.43 Compression stockings may also be useful. By stopping overdistension of the veins, they prevent endothelial damage and exposure to subendothelial collagen.44 Low-dose (60–75 mg) aspirin has been widely used in pregnancy to prevent preeclampsia and in IVF in attempt to improve implantation. It is well tolerated and has few side-effects. Data from a recent study in the context of orthopedic surgery suggest that it may be effective in preventing venous thrombosis. Concerns exist as to risks of perioperative hemorrhage, but insufficient data are available to assess this risk in IVF. Its effectiveness in pregnancy and IVF remains to be established, but it is likely to be less than that of LMWH.37 Finally, in women with hyperhomocysteinemia, the risk of developing VTE may be reduced by folic acid supplementation.45 Women planning a long-haul flight after IVF may be at increased risk of developing DVT as a result of dehydration and immobility associated with the so-called ‘economy class syndrome’. Although VTE is rare after air travel, patients should probably be advised against long-haul flights within 6 weeks of IVF treatment as the thrombogenic influence of even mild ovarian hyperstimulation syndrome may take several weeks to resolve. Those who elect to travel in this period should consider wearing compression stockings, and should be advised to carry out frequent leg movements and ensure adequate hydration during the flight.46

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POST-IVF FOLLOW-UP Clinical reports of DVT occurring following IVF treatment indicate that it most frequently presents in early pregnancy,47 between 5 and 10 weeks after hCG administration.2 This has implications for both the duration for which prophylaxis should be administered in high-risk patients, and the duration for which clinical surveillance should be maintained, in order to ensure early detection and treatment. Many reported cases of DVT following IVF are in sites other than the lower limb, but this may simply reflect publication bias. The jugular vein appears to be a relatively frequent site, with the majority of thromboses occurring here being associated with hormonal ovarian stimulation.47 It should be emphasized that clinical diagnosis for DVT is highly unreliable.48 Early recourse to objective diagnosis of DVT is advised, particularly in the at-risk patient. Compression and duplex Doppler ultrasound techniques have been demonstrated to be reliable non-invasive means of diagnosing or excluding DVT, and are readily available.47 Recent case reports have demonstrated the value of ultrasound in the diagnosis of upper-extremity and neck-vein DVT.49 The management of venous VTE is comprehensively dealt with elsewhere.42

SUMMARY OF MANAGEMENT OPTIONS (1) DVT occurring after IVF is a rare but potentially life-threatening complication of IVF. (2) There is little evidence that increased estradiol levels underlie the increased risk associated with IVF treatment. (3) In the period following hCG administration, considerable changes in the coagulation and fibrinolytic systems are observed. (4) All patients beginning IVF should be subjected to an individual risk assessment prior to commencing treatment. (5) Screening for thrombophilias should be considered in women who have had a previous thrombotic event or a family history of thrombosis, in women who have developed OHSS and in women over 40 years of age. (6) Thromboprophylaxis should be considered in women with a previous DVT, in women who develop OHSS and in women over 40 years with a thrombophilia. In addition, women who develop serious

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infections or immobilization due to surgery should receive thromboprophylaxis. (7) Compression stockings and low-molecular-weight heparin constitute first-line thromboprophylaxis. (8) Thromboprophylaxis should normally be commenced 48 h after oocyte pick-up to reduce the risk of hemorrhagic complications. This should be extended throughout the first trimester. In cases where thrombophilia has been detected, consideration should be given to extending prophylaxis throughout pregnancy. (9) Clinical diagnosis of DVT is unreliable. Objective testing should be carried out before instituting or withdrawing anticoagulative therapy with heparin.

REFERENCES 1. Grandone E, Colaizzo D, Cappuci F, et al. Age and homocysteine plasma levels are risk factors for thombotic complications after ovarian stimulation. Hum Reprod 2004; 19: 1796–9 2. Stewart JA, Hamilton PJ, Murdoch AP. Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum Reprod 1997; 12: 2167–73 3. Tilney ML, Griffiths HJ, Edwards EA. Natural history of major venous thrombosis of the upper extremity. Arch Surg 1970; 101: 792–6 4. Speroff L, DeCherney A. Evaluation of a new generation of oral contraceptives. The Advisory Board for the New Progestins. Obstet Gynecol 1993; 81: 1034–47 5. Lox C, Canez M, DeLeon F, et al. Hyperestrogenism induced by menotropins alone or in conjunction with leuprolide acetate in in-vitro fertilization cycles: the impact on hemostasis. Fertil Steril 1995; 63: 566–70 6. Biron C, Galtier-Dereure F, Rabesandratana H, et al. Hemostasis parameters during ovarian stimulation for in-vitro fertilization: results of a prospective study. Fertil Steril 1997; 67: 104–9 7. Lox C, Canez M, Prien S. The influence of hyperestrogenism during in vitro fertilization on the fibrinolytic mechanism. Int J Fertil 1998; 43: 34–9 8. Østerud B. Activation pathways of the coagulation system in normal haemostasis. Scand J Haematol 1984; 32: 337–45 9. Curvers J, Nap AW, Thomassen MC, et al. Effect of in-vitro fertilization treatment and subsequent pregnancy on the protein C pathway. Br J Haematol 2001; 115: 400–7 10. Montgomery VC, Richard-Davis G, Saleh AA, et al. Fibrinolytic parameters in women undergoing ovulation induction. Am J Obstet Gynecol 1993; 169: 1549–53

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11. Kodama H, Fukuda J, Karube H, Matsui T et al. Status of the coagulation and fibrinolytic systems in ovarian hyperstimulation syndrome. Fertil Steril 1996;66:417-424 12. Aune B, Øian P, Østerud B. Enhanced sensitivity of the extrinsic coagulation system during ovarian stimulation for in-vitro fertilization. Hum Reprod 1993; 8: 1349–52 13. Ricci G, Cerneca F, Simeone R, et al. Impact of highly purified urinary FSH and recombinant FSH on haemostasis : an open-label, randomized, controlled trial. Hum Reprod 2004; 19: 838–48 14. Golan A, Ron-el R, Herman A, et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430–40 15. Baumann P, Diedrich K. Thromboembolic complications associated with reproductive endocrinologic procedures. Hematol Oncol Clin North Am 2000; 14: 431–443 16. Delvigne A, Demoulin A, Smitz J, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features. Hum Reprod 1993; 8: 1353–60 17. Aurousseau MH, Samama MM, Belhassen A, et al. Risk of VTE in an in-vitro fertilization programme: three case reports. Hum Reprod 1995; 10: 94–97 18. Aboulghar MA, Mansour RT, Serour GI, Amin YM. Moderate ovarian hyperstimulation syndrome complicated by deep cerebrovascular thrombosis. Hum Reprod 1998; 13: 2088–91 19. Loret de Mola JR, Kiwi R, Austin C, Goldfarb JM. Subclavian deep vein thrombosis associated with the use of recombinant follicle-stimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome. Fertil Steril 2000; 73: 1253–6 20. Pride SM, James CS, Yuen B. The ovarian hyperstimulation syndrome. Semin Reprod Endocrinol 1990; 8: 247 21. Practice Committee of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril 2004; 82 (Suppl 1): S81–6. 22. Anderson FA Jr, Spencer FA. Risk factors for venous VTE. Circulation 2003; 107 (Suppl 1): I9–16 23. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004–8 24. Reese DC, Cox M, Clegg JB. World distribution of factor V-Leiden. Lancet 1995; 348: 1133–4 25. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222–31 26. Den Heijer M, Koster T, Blom HJ. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759–62 27. Dulitzky M, Cohen SB, Inbal A, et al. Increased prevelance of thrombophilia among women with severe ovarian hyperstimulation syndrome. Fertil Steril 2002; 77: 463–7

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28. Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297–301 29. Horstkamp B, Lübke M, Kentenich H, et al. Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in-vitro fertilization. Hum Reprod 1996; 11: 280–2 30. Brechmann J, Unterberg C. Superior vena cava thrombosis after in vitro fertilization. Dtsch Med Wochenschr 2000; 125: 1429–32 31. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000; 15: 145–51 32. Bick RL, Baker WF Jr. The antiphospholipid and thrombosis syndromes. Med Clin North Am 1994; 78: 667–84 33. Anderson FA Jr, Wheeler HB. Physician practices in the management of venous VTE: a community-wide survey. J Vasc Surg 1992; 16: 707–14 34. Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415–20 35. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scot Med J 1996; 41: 83–6 36. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case–control study. Arch Intern Med 2000; 160: 809–15 37. Greer IA. Inherited thrombophilia and venous VTE. Best Pract Res Clin Obstet Gynaecol 2003; 17: 413–25 38. Fábregues F, Tàssies D, Reverter JC, et al. Prevalence of thrombophilia in women with severe ovarian hyperstimulation syndrome and cost-effectiveness of screening. Fertil Steril 2004; 81: 989–95 39. Macklon N, Fauser BC. Regulation of follicle development and novel approaches to ovarian stimulation for IVF. Hum Reprod Update 2000; 6: 307–12 40. Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 2003; 88: 166–73 41. Ludwig M, Felberbaum RE, Diedrich K. Deep vein thrombosis during administration of HMG for ovarian stimulation. Arch Gynecol Obstet 2000; 263: 139–41 42. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258–65 43. Macklon NS, Greer IA, Reid AW, Walker ID. Thrombocytopenia, antithrombin deficiency and extensive VTE in pregnancy: treatment with low-molecular weight heparin. Blood Coagul Fibrinolysis 1995; 6: 672–5 44. Macklon NS, Greer IA. Technical note: compression stockings and posture: a comparative study of their effects on the proximal deep veins of the leg at rest. Br J Radiol 1995; 68: 515–18

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45. D’Angel A, Selhub J. Homocysteine and thrombotic disease. Blood 1997; 90: 1–11 46. Gallus AS, Goghlan DC. Travel and venous thrombosis. Curr Opin Pulm Med 2002; 8: 372–8 47. Arya R, Shehata HA, Patel RK, et al. Internal jugular vein thrombosis after assisted conception therapy. Br J Haematol 2001; 115: 153–5 48. Macklon NS. Diagnosis of deep venous thrombosis and pulmonary embolism in pregnancy. Curr Opin Pulm Med 1999; 5: 233–7 49. Jesudason WV, Small M. Internal jugular vein thrombosis following ovarian hyperstimulation. J Laryngol Otol 2003; 117: 222–3

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Chapter 2

The patient with endocrine disease JSE Laven

INTRODUCTION The female reproductive system is a dynamic system with morphological, biochemical and functional states, with a long-term (monthly) rhythm as well as short-term (minute to minute) fluctuations. Complex (neuro-)regulatory mechanisms are involved in the interplay between the pituitary and the ovary. This system is generally referred to as the hypothalamic– pituitary–ovarian axis (HPO axis). The hypothalamus and its neuroendocrine communications constitute the central regulatory organ in the HPO axis. Recent evidence suggests that gonadotropin releasing hormone (GnRH) neurons are endowed with receptors for neurotransmitters that are responsive to GnRH, catecholamines, steroids and thyroid hormones as well as growth factors. This in turn implies that disturbances in other HPO axis end-organs might induce disturbances upstream in the axis. Pregnancy may occur in the setting of endocrine diseases or may reveal these conditions for the first time. Management of pregnancy in these circumstances is challenging and requires a high degree of vigilance on the part of treating physicians. Optimizing care and preparation prior to pregnancy, and adopting a multidisciplinary approach, can improve outcomes in these patients. In this chapter, common endocrine disturbances which require attention in the patient embarking on in vitro fertilization (IVF) treatment are reviewed.

GROWTH HORMONE–SOMATOSTATIN SYSTEM Growth hormone (GH) affects the ovary both indirectly through the gonadotropins and insulin-like growth factor I (IGF-I), and directly through

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its effect on steroidogenesis. GH acts on the ovary, affecting oogenesis and steroidogenesis through a modulatory effect on gonadotropin-dependent and -independent functions. It also affects the maturation of the follicle and gamete, and thereby plays a facilitative role in fertility.1 Our understanding of the role of GH in ovulation has in recent years been enhanced by the study of patients with loss of GH function. An example of such an ‘experiment of nature’ is the infertile patient suffering from a GH deficiency (Oliver–McFarlane syndrome). In one reported case, adjuvant GH did not influence the ovarian response to exogenous gonadotropins.2 In Laron-type dwarfism, where low IGF-I and normal GH levels are observed, with a deficiency of GH receptors, spontaneous and assisted reproductive technology (ART) pregnancies have been reported.3,4 Recently, ovulation induction and succesful pregnancy following gonadotropin therapy was reported in two women with combined pituitary hormone deficiency (CPHD) secondary to Prop1 gene mutations.5 In these women, none of GH, IGF-I or prolactin appeared necessary for ovulation, embryonic development or normal pregnancy outcome. These data serve to illustrate the redundancy evident in the endocrine and paracrine control of follicular development and function. GH excess (acromegaly) is a rare disease, occurring with a population prevalence of 60 per million and an incidence of 3–4 per million per year. Males and females appear to be equally affected, with an average age at presentation of 44 years. Younger patients may have more aggressive tumors and higher GH concentrations.6 The development of efficacious surgical and medical therapies for pituitary adenomas as well as the improvement of hormone therapy for ovulation induction has made pregnancy possible for women harboring pituitary tumors. Bromocriptine can be used in acromegaly, but results are generally disappointing. Somatostatin analogs have been used in acromegaly even during pregnancy with uneventful outcomes, but their safety has yet to be established.7

Impact of IVF on GH disturbances Whether acromegaly might be influenced by ovarian hyperstimulation is unknown. Data addressing this issue are lacking.

Preparing the patient for IVF When preparing the patient with acromegaly for IVF treatment, the clinician should be aware of the spectrum of endocrine disturbances associated with this condition. In addition to elevated GH levels, patients with acromegaly frequently demonstrate elevated IGF-I levels and modestly elevated prolactin levels. The GnRH and thyrotropin releasing hormone

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THE PATIENT WITH ENDOCRINE DISEASE

(TRH) response is inappropriate, and serum gonadotropin levels are usually low. Glucose intolerance (decreased glucose/insulin ratio) and hyperinsulinemia are found in nearly all acromegalic patients, and this should be tested and glucose status optimized prior to commencing IVF.7 Serum phosphate, urinary calcium and creatinine clearance may be increased. Cardiac function (arrhythmias, decreased contractility) may be be compromised as well as pulmonary function (increased lung volume and upper airway obstruction). In addition to the laboratory findings, ophthalmologic examination and magnetic resonance imaging (MRI) of the pituitary should be considered to assess the state of disease progression.8,9 The primary approach to treating pituitary tumors causing hypersecretion of GH is trans-sphenoidal surgery. Should the tumor not be completely removed, additional radiotherapy is sometimes employed. Medical treatments aimed at optimizing the hormonal status of women with acromegaly prior to IVF include bromocriptine and somatostatin analogs. While both of these have been used in pregnancy with uneventful outcomes, their impact is limited, and, as mentioned above, the safety of the latter is yet to be demonstrated.8,9

Managing the IVF cycle Since most acromegalic patients have had trans-sphenoidal resection, the majority will be hypogonadotropic. In these patients, combined luteinizing hormone (LH) and follicle stimulating hormone (FSH) preparations should be used in ovarian hyperstimulation.10 Human chorionic gonadotropin (hCG) does not seem to affect the course of the disease.

Follow-up Acromegaly may increase maternal morbidity (gestational diabetes, hypertension), and fetal morbidity and mortality especially, during pregnancy. Similarly, gestational risks due to the possibility of tumor growth or necrosis during pregnancy, mainly in women with macroadenomas, raise concern. However, in most cases, acromegaly will not have a detrimental effect on pregnancy outcome.11

HYPOTHALAMIC–PITUITARY–ADRENAL AXIS The hypothalamic–pituitary–adrenal (HPA) axis and the female reproductive system are intertwined, exhibiting a complex relationship and

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exerting profound, mostly inhibitory effects on the reproductive axis. Corticotropin releasing hormone (CRH) and CRH-induced propiomelanocortin peptides inhibit hypothalamic GnRH secretion, and glucocorticoids inhibit pituitary LH and ovarian estrogen and progesterone secretion. These effects are responsible for the ‘hypothalamic’ amenorrhea of stress, depression and eating disorders, and the hypogonadism of Cushing’s syndrome. Several components of the HPA axis and their receptors are present in reproductive tissues and may participate in the inflammatory processes of the ovary, i.e. ovulation and luteolysis, and of the endometrium, i.e. implantation and menstruation. Cushing’s disease and Cushing’s syndrome need to be controlled to allow for conception.12,13 Although hypofunction of the adrenal cortex may be caused by various mechanisms, the common clinical feature is inadequate cortisol secretion. Adrenal insufficiency usually presents as shock in a previously undiagnosed patient with Addison’s disease. However, chronic adrenal insufficiency varies from complete failure of the cortex to modest impairment. The principal signs and symptoms are weakness, weight loss, nausea, vomiting, hyperpigmentation and hypotension. Loss of hair, especially in females, is occasionally found. Menstrual disorders are found in more than 25% of cases. Some patients have regular ovulatory cycles. Development of amenorrhea is frequently associated with premature ovarian failure involving low estrogen and high gonadotropin levels.14 Fertility appears to be reduced in women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.15 Compared with a non-CAH female population, pregnancy and live-birth rates are severely reduced in salt-wasting patients, mildly reduced in simple virilizing patients and normal in non-classical patients. Several endocrine factors have been suggested to contribute to the impaired fertility in CAH females, mostly due to adrenal or ovarian overproduction of androgens and progestins (17-hydroxyprogesterone and progesterone). In classical CAH, menarche or regular menses does not normally occur until plasma testosterone concentrations are within normal limits. Such patients have a good prognosis for normal fertility. Improving endocrine, surgical and psychological management could also contribute to improving fertility chances in non-classical CAH patients.15

Impact of IVF on hypothalamic–pituitary–adrenal disease During ovarian hyperstimulation, the associated supraphysiological levels of estrogens and progestogens may result in normalization of hypocortisolism. In contrast, in patients with hypercortisolemia, the situation can

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deteriorate.12 Ovarian hyperstimulation potentiates basal and adrenocorticotropic hormone (ACTH)-perturbed adrenal dehydroepiandrosterone sulfate (DHEAS) secretion.16 Estrogens directly stimulate the CRH gene, which may explain the slight hypercortisolism of females and the preponderance of depression, anxiety and eating disorders, as well as Cushing’s disease, in women. Should the patient conceive, hypercortisolism may be exacerbated by the high levels of placenta-derived CRH in the maternal plasma that occur in the latter half of pregnancy. This hypercortisolism causes a transient adrenal suppression in the postpartum period, which may explain the postpartum blues/depression and autoimmune phenomena of this period. It should be realized that pregnancy is itself a transient, but physiologic, period of hypercortisolism. Maternal pituitary ACTH secretion and plasma ACTH levels rise during pregnancy, remaining within normal limits. These changes parallel the rise of plasma cortisol levels. Hence, the maternal adrenal glands during pregnancy gradually become hypertrophic.13

Preparing for IVF treatment Prior to commencing IVF treatment, the presence of hypercortisolism can be demonstrated by testing 24-h urinary free-cortisol excretion. The 24-h 17-hydrosteroid excretion level (corrected for creatinine excretion) gives an indirect measure of cortisol secretion. An overnight 1-mg dexamethasone suppression test is also a useful screening test. Although these tests have a high false-positive rate, if all three tests are normal, Cushing’s syndrome is excluded. Since a correct diagnosis of Cushing’s disease is of utmost importance to initiate the proper treatment, all cases in which the diagnosis is suspected should be referred to an endocrinologist. Definitive diagnosis of Cushing’s syndrome may be extremely difficult, particularly in obese patients with mild hypercortisolism, hirsutism, hypertension or depression. The hypercortisolism in pseudo-Cushing’s states is believed to be mediated through increased hypothalamic secretion of CRH in the context of a HPA axis that is appropriately restrained by negative feedback. In contrast, hypothalamic CRH secretion is completely suppressed by the hypercortisolism of true Cushing’s syndrome, which is less responsive to negative feedback of exogenous glucocortioids. The endocrinologist has an important role in optimizing management of oversecretion syndromes such as Cushing’s disease, in order to allow pregnancy to proceed without undue maternal and fetal morbidity.13 The diagnosis of adrenal insufficiency is a medical emergency. Hence, the diagnosis should not be delayed by elaborate diagnostic testing. Low

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serum sodium concentration with elevated potassium levels strongly suggests adrenal insufficiency. Cortisol serum measurements are useful during a crisis. If the serum cortisol is above 18 µg/dl, the diagnosis can be ruled out. Additional testing includes blood glucose, urea nitrogen and calcium. Lymphocytosis and eosinophilia are often present. If features are compatible with pituitary disease, MRI might be useful.12 In classical CAH, the key measurement is represented by the serum 17-hydroxyprogesterone level. There is no overlap between normal individuals and classical CAH patients. The non-classical forms might be diagnosed by ACTH stimulation tests, in which they all show moderately to severely elevated 17-hydroxyprogesterone levels within 60 min after ACTH administration.15 When an ACTH-secreting tumor is present, intervention prior to IVF is warranted. The primary treatment modality is surgery. In cases of incomplete surgical removal or recurrent tumor, radiation therapy is indicated. Laparoscopic adrenalectomy is reserved for patients with persistent disease despite surgical and medical treatment of the pituitary tumor. Medical treatment with the adrenalytic agent mitotane is indicated in those patients who have failed surgical treatment, for preoperative treatment aiming at diminishing the impact of cortisol on tissue damage and as an adjunct to radiotherapy. The largest experience with medical treatment for Cushing’s disease involves metyrapone, a steroidogenesis inhibitor, without descriptions of congenital abnormalities. In ACTH-independent Cushing’s syndrome, a progestogen antagonist (mifepristone) may be used to treat the undesirable sequelae of excessive cortisol production. This will have minimal or no effect on the lesions of the adrenal or pituitary. The adverse effects of the long-term use of mifepristone, are slight to moderate, and reflect antiglucocorticoid effects. During treatment with mifepristone, one should be aware of the possibility that the patient might develop an Addison-like syndrome in the face of elevated blood ACTH and cortisol levels. Prior to IVF, due to its antiprogestogenic nature, the drug should be stopped.17 In adrenal insufficiency, corticoid substitution constitutes the primary goal. Although immunotherapy with corticosteroids with or without IVF may be successful in limited cases where several follicles are present, oocyte donation with IVF may be the best option for the patient seeking fertility, particularly in the absence of ovarian follicles. Cryopreservation of ovarian tissue may offer hope to affected unmarried young women.14,18 In CAH patients, single daily dexamethasone regimens restore normal menstrual cyclicity. The onset of regular, ovulatory menstrual cycles, as judged by daily salivary progesterone profiles, was achieved within 2–3 years of menarche using this treatment regimen.15

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Managing the IVF cycle In ACTH-independent Cushing’s syndrome, progestogen antagonists should be discontinued prior to IVF. Of essential importance is the replacement of lost adrenal cortical function by the regular administration of physiological doses of hydrocortisone. During IVF (a high-stress situation), the hydrocortisone dose must be increased significantly, and if necessary given parenterally. Gonadal function is replaced with gonadotropins, either with LH and FSH, in cases where the pituitary has been removed, or with FSH only, in those patients in whom basal gonadotropin levels are normal.19

Follow-up Most cases of Cushing’s disease are due to microadenomas, and therefore neurosurgical problems seldom occur. In pregnant women with Cushing’s disease, premature labor, hypertension and gestational diabetes are common. Recent reviews show that Cushing’s syndrome may increase maternal morbidity (gestational diabetes, hypertension) and fetal morbidity and mortality. Intervention is warranted to remove a tumor that secretes ACTH during pregnancy, to reduce the risk of fetal loss. However, literature regarding these issues is scant.13,20 In pregnant women, cortisol requirements appear not to be increased during pregnancy, since the kidney produces large amounts of deoxycortisone from progesterone. Although deoxycortisone is a much weaker corticosteroid and mineralocorticosteroid compared with cortisol, addisonian crises are unusual during pregnancy. In contrast, their incidence is increased during the postpartum period. Adrenal crises require treatment, and in patients undergoing elective surgery, stress regimens should be used.21 In cases of classical CAH in the mother or father, or in those cases in which the mother has previously given birth to an affected child, dexamethasone treatment should be initiated as soon as pregnancy is diagnosed. Chorionic villus sampling should then be performed between 8 and 10 weeks of gestation. If there is a male fetus, treatment might be discontinued. If there is a female fetus, DNA analysis might show whether the fetus is affected. In the latter case, dexamethasone treatment is continued throughout pregnancy.22

HYPOTHALAMIC–PITUITARY–THYROID AXIS Deficiency as well as an excess of thyroid hormone induces significant changes in the metabolism and interconversion of androgens and estrogens.

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Hence, chronic anovulation with or without dysfunctional uterine bleeding may result from inappropriate feedback in women with thyroid disease.23 Hyperthyroidism has marked metabolic effects such as increased oxygen consumption and thermogenesis, as well as increased lipolysis, all of which are factors that promote weight loss. In most women, cycles are anovulatory, although some have ovulatory cycles. In the latter, inadequate mid-cycle LH surges might be responsible for the reduced fertility. Thyrotoxicosis influences reproductive function, especially in women. Anovulation with oligomenorrheic or amenorrheic cycles is frequently found in these women. Hypothyroidism is commonly associated with ovulatory dysfunction such as reduced libido and anovulation. These changes might be due to deficient LH secretion.23,24

Impact of IVF treatment on disorders of the hypothalamic–pituitary–thyroid axis After ovarian stimulation, free thyroxine (T4) levels seem to decrease, whereas thyroid stimulating hormone (TSH), T4-binding globulin (BG) and total T4 and tri-iodothyronine (T3) levels increase. Low maternal free T4 and elevated maternal TSH levels during early gestation have been reported to be associated with impaired psychomotor development in the offspring.25,26 Women with hypothyroidism should receive particular attention, to ensure euthyroid status prior to embarking on pregnancy. Exogenous administration of hCG used to induce follicular maturation in IVF patients undergoing ovarian hyperstimulation results in lower circulating hCG concentrations than seen in pregnancy, and shows no effects on thyroxine or thyrotropin levels. Under clinical conditions of controlled ovarian hyperstimulation for assisted reproduction, exogenous hCG appears not to affect the hypothalamic–pituitary–thyroid axis.27 However, recently it has been reported that ovarian hyperstimulation induces mild changes in thyroid function, especially during the luteal phase and in early pregnancy.26

Preparing the patient for IVF In patients approaching IVF therapy who have suspected thyroid dysfunction, TSH serum levels should be determined in combination with free T4 levels. Hyperthyroidism should be suspected in cases where T4 and T3 levels are elevated with low TSH levels. Just 5% of patients with hyperthyroidism show only elevated T3 levels in conjunction with normal T4 levels. When the patient is adequately substituted, TSH levels are low whereas free T4 levels are within the normal range. Patients treated for their

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hyperthyroidism should be regularly checked by their endocrinologist, since they are at risk of developing iatrogenic hypothyroidism. Recently, data have been presented showing a positive effect of intravenous immunoglobulin immunotherapy on the IVF outcome in patients positive for antithyroid antibodies.28 Considering the possible side-effects of these treatment schedules, and the possible association of these organspecific antibodies in relation to early implantation failure, further investigations are needed before this therapy is introduced into clinical practice in IVF.

Managing the IVF cycle In hyperthyroidism, the naturally occurring mid-cycle LH surge is altered. However, since the introduction of GnRH agonists and antagonists, this is not of any clinical importance. Similarly, during natural-cycle IVF, in cases where ovulation is induced using hCG, reduced LH levels are compensated. Hypothyroidism is associated with decreased plasma concentrations of estrogens and androgens, whereas the free fractions are increased (because of the decreased binding capacity of sex hormone binding globulin (SHBG)). LH secretion might be decreased in cases of hypothyroidism, which might affect luteal phase characteristics during an IVF cycle. However, if the patient is in the euthyroid state, these derangements are corrected completely. Hence, no additional measurements have to be taken during ovarian hyperstimulation and IVF in these patients. In ovulatory women presenting for IVF with tubal factor infertility, recent data indicate that routine screening with a TSH test does not yield a significantly higher proportion of abnormal results than that expected from the reference laboratory normal values.29 However, the incidence of thyroid antibodies in euthyroid women with recurrent IVF failure appears to be significantly increased. Since these autoantibodies seem to be distinct and independent markers for reproductive failure, their identification provides the opportunity to identify women at risk for an adverse outcome in IVF.30

Follow-up Pregnancy has profound effects on the regulation of thyroid function and, hence, on thyroid dysfunction. Alterations of maternal thyroid function have important implications for fetal and neonatal development. Hyperthyroidism is altered during pregnancy, with a tendency for exacerbation during the first trimester, and amelioration during the second and

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third trimesters. The natural history of the disorder must be considered when treating patients, since antithyroid drugs cross the placenta and can directly affect fetal thyroid function.31 Replacement of lost thyroid function should be done by the administration of L-thyroxine. With regard to potential repercussions affecting the offspring, recent evidence suggests that hypothyroidism is associated with an impairment of fetal brain development due to insufficient transfer of maternal thyroid hormones to the fetoplacental unit.32

HYPERSECRETION OF PROLACTIN Hyperprolactinemia resulting from inappropriate prolactin (Prl) secretion is a common clinical entity. There are many causes for this condition; some reflect serious pathology whereas others are a consequence of reversible functional disorders. Hyperprolactinemia and microprolactinoma are frequent findings in young women, and excessive Prl secretion impairs ovarian function, causing anovulatory subfertility.33,34 Prl-secreting tumors cause hyperprolactinemia, galactorrhea, headache and bitemporal loss of vision. Tumors are arbitrarily classified as microprolactinoma (< 1 cm) and macroprolactinomas (> 1 cm), the latter being associated with higher serum levels of Prl. The diagnosis is usually made using MRI of the pituitary. Most tumors are located in the lateral wings of the anterior pituitary.33 Inappropiate Prl secretion induces adrenal androgen secretion and inhibits 5α-reductase activity, which converts androgens into dihydrotestosterone. Furthermore, hyperprolactinemia induces hyperinsulinemia. Elevated Prl levels exert an inhibitory effect on GnRH neurons, probably by interference with dopaminergic and opioidergic systems. Treatment of hyperprolactinemia is indicated because of the consequences of infertility.33,34

Impact of IVF on disease Estrogen significantly promotes the release of Prl by the pituitary, probably through stimulation of the estrogen and TRH receptors on the lactotroph cells. Furthermore, estrogens decrease the ability of dopamine to inhibit Prl secretion. Finally, progesterone induces an acute release of Prl, probably through an increase in GnRH. Prl and estradiol levels increase during ovarian hyperstimulation. However, the onset of hyperprolactinemia cannot be predicted.35 Transitory hyperprolactinemia seems to be associated with an increase in

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the numbers of larger (> 12 mm) follicles and with more mature oocytes and better IVF success rates.36 Transient hyperprolactinemia is also positively associated with intracytoplasmic sperm injection (ICSI) outcome, in particular with oocyte quality and fertilization rate.37

Preparing the patient for IVF Physiological causes of hyperprolactinemia (nipple stimulation, stress, exercise, dehydration) should be ruled out. Sometimes repetitive determinations can be helpful in these instances. Thyroid function tests along with gonadotropin serum levels and estrogen and progestogen determinations are helpful, since they are rarely abnormal in cases of microadenomas. MRI is the method of choice in delineating the sellar contents. Prolactin serum levels should be within the normal range prior to initiation of the IVF cycle. Attention should be given to the fact that after preceding ovarian hyperstimulation, Prl levels might be increased. Dopamine agonists are effective in normalizing Prl levels in more than 90% of patients, but long-term treatment may be required in some patients. Bromocriptine therapy is the first-line treatment. However, more recently, newer specific D2 dopamine agonists (e.g. cabergoline) have become available that have fewer side-effects and are also long-acting. Prolactin-lowering drugs do not increase the incidence of multiple pregnancies or early pregnancy loss.33 Trans-sphenoidal surgery is usually indicated in those patients in whom medical therapy fails or cannot be tolerated, or in patients who harbor macroprolactinomas. In the vast majority of hyperprolactinemic women, pregnancy is safe, and could be beneficial.34 In ovulatory women presenting for IVF with tubal factor infertility, data indicate that routine Prl screening yields a significantly higher proportion of abnormal results than that expected from the reference laboratory normal values.38

Managing the IVF cycle During ovarian hyperstimulation, prolactin levels increase and might cause transient hyperprolactinemia in a previously normoprolactinemic individual. Hyperprolactinemia exerts an inhibitory effect on GnRH release from the hypothalamus. Furthermore, it stimulates adrenal androgen synthesis and blocks steroid synthesis by the gonads. However, no data are available concerning how to compensate during IVF cycles for this phenomenon. Moreover, elevated prolactin levels are associated with a better outcome in IVF.36,37

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Follow-up The pituitary enlarges during pregnancy due to estrogen stimulation of the lactotropic cells. In addition, prolactin levels increase during normal pregnancy, and hence Prl determinations are not particularly helpful during this time. This complicates the evaluation of these patients. However, the experience of treated patients is reassuring. In patients with previous microadenomas, enlargement to the point of symptom occurrence is very rare, and hence most patients can be followed expectantly with regular examination of visual fields. In patients with macroadenomas, symptomatic growth is more common, and reinstitution of bromocriptine therapy may be necessary to treat such an increase in tumor size. Bromocriptine has been used during pregnancy, and has not been linked to teratogenicity. Cabergoline is the most effective and tolerated of the antiprolactinemic drugs.20,34

PANHYPOPITUITARISM Panhypopituitarism is a disease complex with variable clinical manifestations. Recent studies have improved our understanding of its pathophysiology, particularly in patients with pituitary adenomas. In that setting, hypopituitarism was previously considered a permanent and irreversible process, requiring lifelong hormone replacement therapy. While this could be true in some instances, recent data have demonstrated recovery of pituitary function in a large number of patients with hypopituitarism following surgical decompression. Understanding the pathophysiology of hypopituitarism and recognizing the probability for recovery of function should be emphasized in the management of patients with this disease. An important aspect of the management is patients’ education about their disease, including the use of ‘medic alert’ identification. The managing physician should appreciate the variable clinical manifestations of the disease and the possible occurrence of other associated neuroendocrine, neurological and neuroophthalmologic signs and symptoms. Treatment of hypopituitarism should not be rigid, but instead always individualized. Management should take into consideration the patient’s age, sex, education, original disease process and clinical history.39

Impact of IVF on disease Because these patients lack functional pituitary tissue, ovarian hyperstimulation does not induce hypercortisolism.16 Similarly, thyroid function might not be affected in these women through ovarian hyperstimulation, since they generally lack TSH.26

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Preparing the patient for IVF Replacement therapy in cases of hypopituitarism in the adult has improved outcomes dramatically in the past decade. After initial detailed investigation of the extent of hormone deficiency, replacement therapy is tailored to the particular needs of the individual. Of essential importance is the replacement of lost adrenal cortical and thyroid function by the regular administration of physiological doses of hydrocortisone and thyroxine. Over-replacement with glucocorticoids must be avoided. Diabetes insipidus should be treated with sufficient amounts of antidiuretic hormone. Altered body composition and well-being is reversible with GH therapy, emphasizing the importance of GH in the adult.40

Managing the IVF cycle Replacement of gonadal steroids is simpler than the induction of fertility. Gonadal function is replaced with both gonadotropins LH and FSH.19 Recent reports suggest that co-administration of conjugated estrogens might be useful However, this has not been confirmed in larger trials.41 During IVF (a high-stress situation), the hydrocortisone dose must be increased significantly, and if necessary given parenterally.

Follow-up Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies, with the application of particularly strict criteria to avoid twin pregnancies. Early elective Cesarian section is probably warranted in this group.42

DIABETES MELLITUS Diabetes mellitus, especially when poorly controlled and associated with poor nutrition, can lead to growth failure and sexual infantilism and irregular cycles. Cumulative rates of pregnancies and involuntary infertility are similar to those in non-diabetics. Diabetic women, however, have fewer pregnancies and births than controls, and relatively more diabetic women are nulliparous. Only half of all diabetic pregnancies are planned. In one study, diabetic women reported that their condition had a negative influence on their attitude towards having children.43 It seems that patients with insulin-dependent diabetes mellitus (IDDM) have conventional responses to gonadotropin stimulation for IVF,

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and their follicular milieu resembles that of non-IDDM (NIDDM) patients. Nevertheless, in view of the significant advantages of preconceptional diabetes control in regard to pregnancy outcome, they should be allowed to participate in IVF programs only after tight preconception metabolic control has been obtained. Type 2 diabetes is perhaps the most visible obesity-related problem. Present in at least 14 million Americans, it leads to serious complications and premature death. It is largely caused by obesity, and is generally cured by weight loss. The quality of life of the obese is markedly reduced, and the costs to health-care systems are great. Preventive programs have yet to affect the rising prevalence, and an effective solution remains elusive.43

Impact of IVF on the disease Ovarian hyperstimulation is associated with a significant increase in ovarian steroid hormone production. Such high levels of sex steroids may affect lipid metabolism leading to decreased total cholesterol, triglycerides and low-density lipoprotein (LDL) cholesterol levels, while high-density lipoprotein (HDL) cholesterol levels remain the same. It has been shown that free fatty acid levels are elevated following ovarian hyperstimulation. However, treated women show no increase in cardiovascular risk, since their lipoprotein lipid levels are not affected.44 On the other hand, ovarian hyperstimulation induces supraphysiological estrogen and progestogen serum levels, which in turn might worsen the insulin resistance and hence might induce hypo- or hyperglycemic episodes in these patients.44,45

Preparing the patient for IVF IDDM should be meticulously regulated using insulin injection or pumps. Daily repetitive glucose determinations are a necessity. In NIDDM, oral glucose tolerance testing might be used to evaluate the effect of weight loss and dietary measures.43 Short-term weight loss has been consistently successful in reducing insulin resistance and restoring ovulation and fertility. However, problems arise with maintaining weight loss and precisely quantifying the associated long-term benefits of risk factor change. Recent research has shown that modest long-term life-style changes can reduce the extent of impaired glucose tolerance and delay the conversion to diabetes mellitus. Current conservative treatment should emphasize sustainable weight loss through dietary modification and exercise. Modifying additional life-style factors, including alcohol consumption, psychosocial stressors and smoking, is also

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crucial in long-term treatment of diabetics. Insulin sensitizers are widely used to decrease insulin intolerance. Initially they reduce body weight, but this seems to be just a temporary effect.46

Managing the IVF cycle Metformin is a common treatment for women who have insulin resistance manifesting as NIDDM. In both IDDM and NIDDM, adjustment of carbohydrate metabolism as well as the use of insulin sensitizers seems to decrease the amount of exogenous FSH needed in ovarian hyperstimulation.47

Follow-up The goal of treatment in NIDDM and IDDM is tight control of blood glucose levels and to adjust diet, exercise and insulin to achieve tight control of carbohydrate metabolism. By doing so, the major risks associated with diabetes mellitus and pregnancy can be effectively reduced.43 Although the data are somewhat limited, available studies indicate that the rate of adverse maternal and fetal outcomes is at least as great, if not greater, for NIDDM than for IDDM. It has been postulated that some of the excess risk is due to the fact that women with NIDDM are older, heavier, less likely to seek early prenatal care and generally in less satisfactory glycemic control.46

SUMMARY OF MANAGEMENT OPTIONS (TABLE 1) GH excess (1) Acromegaly is associated with a spectrum of endocrine disturbances as well as with cardiac and pulmonary disease. This should be tested for, and glucose status should be optimized prior to commencing IVF. (2) Hyperstimulation should make use of combined gonadotropin (LH and FSH) therapy, and in itself does not seem to affect the disease. (3) Acromegaly is associated with increased maternal morbidity (gestational diabetes, hypertension, tumor growth or necrosis), and fetal morbidity and mortality especially, during pregnancy.

HPA axis (1) Hypocortisolism may ameliorate during IVF hyperstimulation, and therefore careful control and substitution of adrenal function is a necessity.

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Table 1

Principal risks and issues Risks

Issues

Acromegaly

Associated endocrinopathy Cardiac and pulmonary disease Tumor progression Increased maternal morbidity and mortality

Combined LH and FSH therapy

HPA axis

Amelioration of hypocortisolism Exacerbation of hypercortisolism Salt-wasting Hyperandrogenism and virilization Premature labor, hypertension, gestational diabetes

Adequate substitution of gluco- and mineralocorticoids Adrenalytic treatment Surgery Adaptation to increased stress LH and FSH treatment after hypophysectomy

HPT axis

Amelioration of hypothyroidism Exacerbation of hyperthyroidism Iatrogenic hypothyroidism Thyroid antibodies

Euthyroid status Substitution or suppression through regular control of thyroid function Reduced luteal phase LH levels

Hyperprolactinemia

Tumor increase Tumor necrosis Hyperandrogenism Hyperinsulinemia

Exacerbation of symptoms

Continued

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Table 1

Continued Risks

Issues

Panhypopituitarism

Associated endocrinopathies High-risk pregnancies Increased maternal morbidity and mortality

Singleton pregnancies Adequate replacement therapy LH and FSH Conjugated estrogens

Diabetes mellitus

Exacerbation of insulin resistance Increased maternal and fetal morbidity and mortality

Tight daily metabolic control Insulin sensitizers Life-style modification

HPA, hypothalamic–pituitary–adrenal; HPT, hypothalamic– pituitary–thyroid; LH, luteinizing hormone; FSH, follicle stimulating hormone

(2) Hypercortisolism may exacerbate during IVF and the subsequent pregnancy, and hence adrenal function should be monitored regularly. Medical or surgical treatment should be considered prior to commencing IVF. (3) In congenital adrenal hyperplasia, hyperandrogenism should be corrected prior to initiating IVF treatment. During pregnancy, special attention should be paid to the sex of the fetus and whether glucocorticoid treatment is indicated.

HPT axis (1) Since hypothyroidism may ameliorate and hyperthyroidism might exacerbate during ovarian stimulation, close and tight control of thyroid function is a necessity during IVF and the subsequent pregnancy. The final goal of such an approach should be a euthyroid status. Hyperthyroid patients especially are prone to iatrogenic hypothyroidism, which is associated with fetal maldevelopment and mortality.

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(2) During ovarian hyperstimulation, one might encounter reduced luteal phase LH serum levels. Moreover, ovarian hyperstimulation induces mild changes in thyroid function especially during the luteal phase and in early pregnancy. Hypothyroidism is associated with an impairment of fetal brain development due to insufficient transfer of maternal thyroid hormones to the fetoplacental unit. (3) Screening for thyroid antibodies in euthyroid women with recurrent IVF failure appears to make sense, since these autoantibodies seem to be distinct and independent markers for reproductive failure.

Hyperprolactinemia (1) Excessive prolactin secretion impairs ovarian function, causing anovulatory subfertility. Hyperprolactinemia might be more frequent in infertile women. (2) Prolactin serum levels should be within the normal range prior to initiation of the IVF cycle, and this can be accomplished through either medical or surgical treatment. Ovarian hyperstimulation during IVF induces transient hyperprolactinemia, which is associated with a better treatment outcome. (3) Prolactin determinations are not particularly helpful during pregnancy. In patients with previous microadenomas, enlargement to the point of symptom occurrence is very rare, in contrast to patients with macroadenomas, in whom symptomatic growth is more common, and reinstitution of bromocriptine therapy may be necessary.

Panhypopituitarism (1) Panhypopituitarism is associated with a spectrum of endocrine disturbances, which should be tested for, and subsequent substitution is mandatory prior to commencing IVF. (2) Ovarian hyperstimulation should make use of FSH as well as LH. Cotreatment with conjugated estrogens might be worth considering. Fertility treatment must strive for singleton pregnancies, with application of particularly strict criteria to avoid twin pregnancies. (3) Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Early elective Cesarean section is probably warranted in this group. Finally, pregnancy in women suffering from this disease is associated with an increased risk for maternal morbidity and mortality.

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Diabetes mellitus (1) Tight control of blood glucose levels and adjustment of diet, exercise and insulin to normalize carbohydrate metabolism is mandatory prior to IVF treatment. (2) In both IDDM and NIDDM, adjustment of carbohydrate metabolism and insulin sensitizers decrease the amount of exogenous FSH needed in ovarian hyperstimulation. Ovarian hyperstimulation might worsen the insulin resistance, and hence might induce hypo- or hyperglycemic episodes in these diabetic patients. (3) Normalization of blood glucose levels reduces the major risks associated with diabetes mellitus and pregnancy. The rate of adverse maternal and fetal outcomes is greater in NIDDM compared with IDDM.

REFERENCES 1. Chandrashekar V, Zaczek D, Bartke A. The consequences of altered somatotropic system on reproduction. Biol Reprod 2004; 71: 17–27 2. Shaker AG, Fleming R, Jamieson ME, et al. Ovarian stimulation in an infertile patient with growth hormone-deficient Oliver–Mcfarlane syndrome. Hum Reprod 1994; 9: 1997–8 3. Menashe Y, Sack J, Mashiach S. Spontaneous pregnancies in two women with Laron-type dwarfism: are growth hormone and circulating insulin-like growth factor mandatory for induction of ovulation? Hum Reprod 1991; 6: 670–1 4. Dor J, Seidman DS, Amudai E, et al. Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebocontrolled double-blind study. Hum Reprod 1995; 10: 40–3 5. Voutetakis A, Sertedaki A, Livadas S, et al. Ovulation induction and successful pregnancy outcome in two patients with Prop1 gene mutations. Fertil Steril 2004; 82: 454–7 6. Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999; 2: 29–41 7. Holdaway IM. Treatment of acromegaly. Horm Res 2004; 62 (Suppl 3): 79–92 8. Arosio M, Cannavo S, Epaminonda P, et al. Therapy for the syndromes of GH excess. J Endocrinol Invest 2003; 26 (Suppl 10): 36–43 9. Paisley AN, Trainer PJ. Medical treatment in acromegaly. Curr Opin Pharmacol 2003; 3: 672–7 10. Schoot DC, Coelingh Bennink HJ, Mannaerts BM, et al. Human recombinant follicle-stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency. J Clin Endocrinol Metab 1992; 74: 1471–3

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11. Bronstein MD, Salgado LR, Castro Musolino NR. Medical management of pituitary adenomas: the special case of management of the pregnant woman. Pituitary 2002; 5: 99–107 12. Magiakou MA, Mastorakos G, Webster E, et al. The hypothalamic–pituitary–adrenal axis and the female reproductive system. Ann NY Acad Sci 1997; 816: 42–56 13. Molitch ME. Pituitary tumors and pregnancy. Growth Horm IGF Res 2003; 13 (Suppl A): S38–44 14. Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease 2001. J Clin Endocrinol Metab 2001; 86: 2909–22 15. Hagenfeldt KB. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency – the adult woman. Growth Horm IGF Res 2004; 14 (Suppl A): S67–71 16. Casson PR, Kristiansen SB, Umstot E, et al. Ovarian hyperstimulation augments adrenal dehydroepiandrosterone sulfate secretion. Fertil Steril 1996; 65: 950–3 17. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5: 77–82 18. Connell JM, Fraser R, Davies E. Disorders of mineralocorticoid synthesis. Best Pract Res Clin Endocrinol Metab 2001; 15: 43–60 19. Schoot DC, Harlin J, Shoham Z, et al. Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women. Hum Reprod 1994; 9: 1237–42 20. Molitch ME. Evaluation and management of pituitary tumors during pregnancy. Endocr Pract 1996; 2: 287–95 21. Ambrosi B, Barbetta L, Morricone L. Diagnosis and management of Addison’s disease during pregnancy. J Endocrinol Invest 2003; 26: 698–702 22. Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update 2004; 10: 469–85 23. Poppe K, Velkeniers B. Female infertility and the thyroid. Best Pract Res Clin Endocrinol Metab 2004; 18: 153–65 24. Adlersberg MA, Burrow GN. Focus on primary care. Thyroid function and dysfunction in women. Obstet Gynecol Surv 2002; 57 (Suppl 3): S1–7 25. Muller AF, Verhoeff A, Mantel MJ, et al. Decrease of free thyroxine levels after controlled ovarian hyperstimulation. J Clin Endocrinol Metab 2000; 85: 545–8 26. Poppe K, Glinoer D, Tournaye H, et al. Impact of ovarian hyperstimulation on thyroid function in women with and without thyroid autoimmunity. J Clin Endocrinol Metab 2004; 89: 3808–12 27. Foulk RA, Musci TJ, Schriock ED, et al. Does human chorionic gonadotropin have human thyrotropic activity in vivo? Gynecol Endocrinol 1997; 11: 195–201 28. Sher G, Maassarani G, Zouves C, et al. The use of combined heparin/aspirin and immunoglobulin G therapy in the treatment of in vitro fertilization patients with antithyroid antibodies. Am J Reprod Immunol 1998; 39: 223–5

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29. Zollner U, Lanig K, Steck T, et al. Assessment of endocrine status in patients undergoing in-vitro fertilization treatment. Is it necessary? Arch Gynecol Obstet 2001; 265: 16–20 30. Bussen S, Steck T, Dietl J. Increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in-vitro fertilization failure. Hum Reprod 2000; 15: 545–8 31. Neale D, Burrow G. Thyroid disease in pregnancy. Obstet Gynecol Clin North Am 2004; 31: 893–905, xi 32. Kaplan MM. Management of thyroxine therapy during pregnancy. Endocr Pract 1996; 2: 281–6 33. Crosignani PG, Bianchedi D, Riccaboni A, et al. Management of anovulatory infertility. Hum Reprod 1999; 14 (Suppl 1): 108–19 34. Liu JK, Couldwell WT. Contemporary management of prolactinomas. Neurosurg Focus 2004; 16: E2 35. Piekos MW, Binor Z, Rawlins RG, et al. Effects of induced hyperprolactinemia on in vitro fertilization cycles. Fertil Steril 1995; 63: 371–6 36. Mendes MC, Ferriani RA, Sala MM, et al. Effect of transitory hyperprolactinemia on in vitro fertilization of human oocytes. J Reprod Med 2001; 46: 444–50 37. Doldi N, Papaleo E, De Santis L, et al. Treatment versus no treatment of transient hyperprolactinemia in patients undergoing intracytoplasmic sperm injection programs. Gynecol Endocrinol 2000; 14: 437–41 38. Hofmann GE, Denis AL, Scott RT, et al. The incidence of transient hyperprolactinemia in gonadotropin-stimulated cycles for in vitro fertilization and its effect on pregnancy outcome. Fertil Steril 1989; 52: 622–6 39. Arafah BM. Medical management of hypopituitarism in patients with pituitary adenomas. Pituitary 2002; 5: 109–17 40. Sonksen PH. Replacement therapy in hypothalamo-pituitary insufficiency after childhood: management in the adult. Horm Res 1990; 33 (Suppl 4): 45–51 41. Hayashi M, Tomobe K, Hoshimoto K, et al. Successful pregnancy following gonadotropin therapy in a patient with hypogonadotropic hypogonadism resulting from craniopharyngioma. Int J Clin Pract 2002; 56: 149–51 42. Overton CE, Davis CJ, West C, et al. High risk pregnancies in hypopituitary women. Hum Reprod 2002; 17: 1464–7 43. Anonymous. Standards of medical care in diabetes. Diabetes Care 2004; 27 (Suppl 1): S15–35 44. Brizzi P, Dessole S, Tonolo G, et al. Effect of ovarian stimulation on plasma lipid and apolipoprotein concentrations in a population of infertile women undergoing IVF/embryo transfer. Reprod Biomed Online 2003; 7: 309–12 45. Tadmor OP, Kleinman Y, Barr I, et al. Side effects of ovarian hyperstimulation: hormonal and lipid profile changes. Int J Fertil Menopausal Stud 1994; 39: 105–10 46. Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale

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and strategies. A statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Am J Clin Nutr 2004; 80: 257–63 47. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003; 327: 951–3

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Chapter 3

The patient with malignant disease RA Anderson

INTRODUCTION Patients with cancer present particular challenges to the in vitro fertilization (IVF) unit. Many will be struggling to deal with the new diagnosis, and may be unwell with their underlying disease. A second group will be cancer survivors, for whom the issues will be more focused on assessment of the impact of their cancer treatment on their fertility. Some of this group will also have concerns about the potential effect of IVF and subsequent pregnancy on their cancer, for example those women with breast cancer. Cancer is diagnosed in approximately 650 000 women each year in the USA. Some conditions that affect women of reproductive age are becoming more common.1 As treatment of previously uniformly fatal diseases such as the acute leukemias has improved, so has the number of young women survivors, whose fertility may have been compromised in a number of ways. Increasing recognition of the adverse effects of cancer treatment on fertility of both men and women together with this increasing survival has shifted emphasis from treatment and cure at any cost to a greater interest in preserving fertility. Patients of both sexes may therefore be referred to IVF units for discussion of the implications of their cancer treatment on their fertility, and for consideration of ways to ameliorate any adverse effects. Such patients are of an increasingly wide age range, and now include the prepubertal, generating fresh challenges for their carers. Approximately 1 in 5000 adolescents are affected with cancer, with an overall cure rate of 75%.2,3

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IMPACT OF MALIGNANT DISEASE ON IVF Patients with malignant disease may have reduced fertility as a result of their condition. This has long been recognized for men, with approximately 70% of men with Hodgkin’s disease having impaired semen quality.4 Infrequent ejaculation as a result of illness (e.g. pyrexia), anxiety and loss of sexual interest may contribute to this. A possible adverse effect of reduced sexual activity with a prolonged ejaculatory interval should also be taken into consideration in assessment of the healthy male partner of the cancer patient. Non-specific effects of cancer may also influence female fertility: a reduction in oocyte quality and fertilization rates has been reported.5 Men and women newly diagnosed with cancer and wishing to have children have markedly different options. Cryopreservation of semen, despite the caveats regarding quality mentioned above, is now routinely considered and widely available, although there is often little time available between diagnosis, referral to a storage center and the need to initiate treatment.6 The risk of loss of fertility will be related to the treatment proposed, but the relative ease of semen cryostorage means it is much better to store unnecessarily than miss the opportunity. Patients will be faced with the need to consider the fate of any stored samples in the event of their death; this may be distressing, as patients may have been unwilling or unable to face the reality of their condition prior to that point. Competence to give consent will need to be assessed in adolescent patients.7 Staff at the storage center may not have appropriate experience, and this issue should be specifically addressed by the pediatric oncology team before referral. Age-specific patient information can be of great value under such circumstances. Subsequent usage of cryopreserved sperm will be determined by couple-specific factors as in any couple seeking fertility treatment, but with due attention to both the spermatogenic function of the man at that time (which may have recovered to normal) and the quality and quantity of the stored samples, which will inform decisionmaking as to the appropriate treatment modality. Only approximately 10–25% of men who store sperm under these conditions subsequently use it.8,9 If chemotherapy has already been started, consideration should be given as to whether semen storage is still appropriate; it is generally thought not to be, on the basis of animal data showing significant adverse effects on progeny from the use of sperm exposed to chemotherapeutic agents. Women have no equivalent option for fertility preservation. Potential options that should be discussed with the woman and her partner, if any,

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THE PATIENT WITH MALIGNANT DISEASE

include taking no specific action, urgent IVF with embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. The latter is outwith the remit of this chapter, but is the subject of considerable recent advances10 and comprehensive review.11 The need to consider urgent IVF will be in part determined by the treatment the woman is about to undergo, as the invasiveness of the procedure and the inherent delay change the basis for decision-making, compared with semen cryostorage. The option to do nothing should be explored, bearing in mind the patient’s age, diagnosis and prognosis, and proposed treatment. The option for future use of donated oocytes as an established treatment should be clearly explained. It should also be made clear that there is considerable interindividual variability in the gonadotoxic effects of different anticancer regimens, making accurate estimates of the risk of, for example, premature ovarian failure, difficult. In general, alkylating agent-based chemotherapy (e.g. cyclophosphamide, chlorambucil and busulfan) is markedly more gonadotoxic than that using agents such as doxorubicin, cisplatin and Adriamycin, while methotrexate, vincristine and bleomycin have low gonadotoxicity. Alkylating agents are, however, widely used in the treatment of conditions such as leukemia and lymphoma, which are the commoner malignancies of the relevant age group. Oncologists are increasingly using regimens without alkylating agents, such as the ABVD regimen doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine), with reduced gonadotoxicity, but there is the risk of cardiotoxicity with anthracycline agents. However, it should be recognized that there may be no dose of agents such as cyclophosphamide that is not toxic to the follicle, with the age of menopause being more subtly influenced at low doses and such patients being at risk of premature ovarian failure even if regular menstruation is resumed. Radiotherapy is also very damaging to the ovary, but can have adverse effects on other parts of the reproductive axis, including the hypothalamus, pituitary and uterus. This is of importance to the patient considering IVF, as total body or local irradiation may damage the uterus, resulting in increased risk of miscarriage, premature delivery and low birth weight.12,13 Multiple pregnancy is therefore a particular risk in these women. IVF requires sperm, so further difficulties arise with the need for a male partner. The existence of a long-term relationship does not necessarily imply that the man wishes to have children with the woman, but he may be under considerable pressure, not necessarily expressed, to be part of the treatment. The raising of the issue may lead to relationship difficulties, and the need for support for both partners should be considered and readily available. The use of donated sperm may be appropriate. Semen analysis may reveal hitherto undetected reproductive dysfunction, with

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implications for both the immediate treatment cycle and his future fertility. He will need to give his explicit consent for the use of his sperm, and both will need to consider the fate of the embryos in the event of death of either partner, although this will be predominantly directed towards the female cancer patient. Should the woman not have a (male) partner, some of these issues are in fact simplified by the need to use donated sperm. An alternative option is oocyte cryopreservation, which avoids issues surrounding fertilization. Live birth following this procedure was first reported in 1986, but it remains much less widely used, and generally pregnancy rates per oocyte have been very low.14 The use of less mature oocytes has also been described,15 and vitrification appears to improve oocyte survival,16 but few pregnancies have resulted. There may be issues specific to particular diagnoses. One example is the patient with cervical cancer. Transvaginal oocyte aspiration following ovarian stimulation may not be appropriate because of the risk of bleeding from the tumor, and transabdominal aspiration may need to be considered. Women who are about to undergo hysterectomy may consider ovarian cryopreservation with later autotransplantation, but will need surrogacy. Conservative surgery such as radical trachelectomy may be feasible in some centers for selected patients; experience of fertility in these patients is limited,17 although it may be preserved. Some, however, may be subfertile due to deficiencies in the cervical mucus. Such patients will have very little cervical tissue, thus putting them at risk of premature delivery should conception be successful.

IMPACT OF IVF ON MALIGNANT DISEASE The main concerns regarding whether IVF will impact adversely on the patient with cancer relate to the potential delay in starting the patient’s treatment (e.g. chemotherapy) or any possible effects of the hormonal changes on the disease. Some delay is inevitable, and its impact and magnitude should be discussed with the patient and her oncologist. Considerations for planning the treatment cycle include usual factors such as the patient’s normal menstrual cycle, but she may also be using hormonal contraception. Oral contraception is of little consequence, and of course frequently used to regulate menstrual cycles prior to IVF. The use of depot medroxyprogesterone acetate results in significant hypogonadotropic hypogonadism (i.e. the patient is already down-regulated), but this will be overcome by the administration of exogenous gonadotropins, and its suppressive effects on the endometrium are irrelevant in this context as all embryos will be

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cryopreserved. The use of gonadotropin releasing hormone (GnRH) antagonists is probably the most effective way to shorten the IVF cycle if that is of paramount importance. In an initial report of the use of GnRH antagonist, the median duration of treatment was 12 days, including luteolysis when necessary.18 Breast cancer is the most common malignant disease in women of reproductive age, and approximately 15% of breast cancer occurs in women under the age of 40. There may be time to perform IVF with embryo cryopreservation or ovarian cryopreservation, although some do not recommend the latter because of the potential for pre-existing metastases in the ovary.19 This is, however, rare in the absence of other, detectable, metastases.20 Superovulation exposes the patient to high estradiol concentrations, if only for a few days. This has raised concerns where the cancer is estrogen-dependent, most clearly in breast and endometrial cancers. The use of an antiestrogen, widely employed in the treatment of breast cancer, for ovarian stimulation has been suggested and successfully demonstrated,21 but the magnitude of the risk over such a short period of time is unclear. Furthermore, such manipulations are not necessary in breast cancers not expressing estrogen receptors. In the less common situation of a woman with endometrial cancer, tamoxifen is contraindicated due to its stimulatory effects on the endometrium, but aromatase inhibitors can be used in both conditions.

PREPARING THE PATIENT FOR IVF For the woman with newly diagnosed malignancy, it is of prime importance that the patient has adequate time to consider whether she (and her partner) wish to proceed with IVF, despite the urgency of the situation. Factors to consider include potential family pressures, relationship issues and whether the woman is considering the potential of fertility preservation to divert her own attention from dealing with the main issue: her diagnosis and impending treatment. The need for adequate time to consider her options is essential, yet clearly very limited. Independent counseling will be invaluable in some cases. Issues regarding the welfare of the child that IVF is being undertaken to create should be raised in the context of long-term prognosis. Specific pretreatment investigations should be considered in women undergoing IVF who have been treated for cancer in the past. Early follicular phase follicle stimulating hormone (FSH) measurement should be performed in women who have undergone any chemotherapy previously, no matter how little gonadotoxicity the oncologist claimed it to have. Even

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minimal gonadotoxicity may have been significantly deleterious in a woman with an already modest ovarian reserve from being at the lower extreme of normal biological variation, yet masked by normal menstrual cycles. Other biochemical measures have been clearly demonstrated to be of predictive value in a research setting: basal serum anti-Müllerian hormone and stimulated (i.e. following FSH administration) inhibin B correlate well with the number of oocytes that will be recovered, but are not widely available.22,23 Ovarian volume and antral follicle count are also useful measures of ovarian reserve, and it appears most useful to assimilate several different tests. The effects of radiation may be manifest in uterine size, uterine artery blood flow and endometrial development. Uterine growth during childhood is arrested by radiation;24 thus, size may be normal in the eugonadal patient irradiated post-pubertally, although abnormalities of uterine blood flow may also be detected holm re. These patients are at significant risk of pregnancy complications including miscarriage, growth retardation and premature delivery,13,25 and consideration should be given to singleembryo transfer to prevent multiple pregnancy. Endometrial development in response to endogenous or exogenous steroid treatment can be readily monitored by ultrasound. Prolonged estrogen treatment may be appropriate if the uterus appears small or endometrial development inadequate, but the likelihood of improvement is low.

MANAGING THE IVF CYCLE One of the clearest indications for the use of GnRH antagonists is in patients requiring IVF as a matter of urgency. IVF cycles using GnRH antagonists generally start in the spontaneous follicular stage of the cycle, to make use of the normal intercycle rise in gonadotropins.26 If the patient is in the late follicular phase or luteal phase at the time of presentation, a small dose of GnRH antagonist can be used to cause follicular regression or luteolysis, allowing gonadotropin administration to start just a few days later. Any asynchrony of the endometrium is not relevant, as all embryos will be cryopreserved in these patients. Alternatively, if the patient is using hormonal contraception, this can be continued until immediately before gonadotropin administration is scheduled to start, with the addition of a GnRH antagonist from day 6. As discussed above, estrogen-dependent cancers raise specific concerns regarding the potential for stimulation of the malignancy by the elevated estrogen concentrations induced by superovulation. The main conditions in which this is a concern are breast and endometrial cancers. In patients

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with breast cancer, the use of tamoxifen without exogenous gonadotropin has been demonstrated to result in a modest increase in the number of oocytes and embryos recovered.21 The use of aromatase inhibitors in these patients has been advocated.11 Similar to antiestrogen administration, the resulting reduction in estrogen concentrations will have the added advantage of increasing endogenous FSH concentrations, and this has been shown to reduce the dosage of exogenous FSH required.27 There was no evidence for a reduction in pregnancy rate associated with the use of the aromatase inhibitor letrozole in patients treated with superovulation and intrauterine insemination, although there are no data on IVF outcomes.

POST-IVF FOLLOW-UP Many patients having ‘emergency’ IVF will move on to their definitive treatment rapidly after embryo cyopreservation, and will therefore often not be clinically followed up by the IVF center. Clearly, it is essential to ensure that no immediate adverse effects have occurred, but this can be achieved by telephone contact. Similarly, the patient should be informed as to the final outcome of treatment, and provided with a written record of the number of embryos stored. It may be valuable for this written record to restate the conditions of storage (e.g. time limitations), as such considerations may well have been forgotten or not clearly discussed or appreciated in the lead up to treatment. The details of long-term follow-up should be clearly recorded. Where embryos or sperm are cryopreserved and there are restrictions on whether the IVF unit can contact the patient’s other medical carers, as in the UK, a plan and appropriate consents should be in place. Some patients will not survive their disease, and it is much more appropriate that this be detected by regular follow-up, for example by annual contact with the patient, their primary-care physician or the physician caring for their malignancy, than only some years after death. Formal systems should be in place for this not to be missed. Issues surrounding posthumous use or destruction of cryopreserved embryos will have been covered pretreatment, but it may be appropriate for the final summary to document this.

SUMMARY OF MANAGEMENT OPTIONS Tables 1 and 2 list the options for fertility preservation and treatment in patients with malignant disease.

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Table 1

Options for fertility preservation in women

Option

Advantages

Disadvantages

Ovarian cryopreservation

Possible in prepubertal women

Experimental risk of transmission of malignancy

Oocyte cryopreservation

Does not require fertilization

Poor pregnancy rates

IVF/embryo preservation

Established technology

Duration of treatment, requires fertilization

IVF, in vitro fertilization

Table 2

Summary of principal treatment considerations

Newly diagnosed malignancy Assessment of impact of proposed treatment on fertility Discussion of options for patient/partner Consideration of prognosis for patient and consequences of patient’s death Assessment of involvement of partner Impact of specific diagnosis Breast, endometrial, cervical cancer Influence on treatment cycle Use of GnRH antagonist, aromatase inhibitor Risks to patient of IVF treatment Previously treated malignancy Assessment of ovarian compromise hormone measurement, ultrasound Assessment of uterine function if post-radiotherapy Risk of relapse/long-term survival GnRH, gonadotropin releasing hormone; IVF, in vitro fertilization

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REFERENCES 1. Weir HK, Thun MJ, Hankey BF, et al. Annual report to the nation on the status of cancer, 1975–2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 2003; 95: 1276–99 2. Stiller C. Epidemiology of cancer in adolescents. Med Pediatr Oncol 2002; 39: 149–55 3. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19: 3163–72 4. Rueffer U, Breuer K, Josting A, et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann Oncol 2001; 12: 1307–11 5. Pal L, Leykin L, Schifren JL, et al. Malignancy may adversely influence the quality and behaviour of oocytes. Hum Reprod 1998; 13: 1837–40 6. Tomlinson MJ, Pacey AA. Practical aspects of sperm banking for cancer patients. Hum Fertil (Camb) 2003; 6: 100–5 7. Grundy R, Larcher V, Gosden RG, et al. Fertility preservation for children treated for cancer (2): ethics of consent for gamete storage and experimentation. Arch Dis Child 2001; 84: 360–2 8. Kelleher S, Wishart SM, Liu PY, et al. Long-term outcomes of elective human sperm cryostorage. Hum Reprod 2001; 16: 2632–9 9. Blackhall FH, Atkinson AD, Maaya MB, et al. Semen cryopreservation, utilisation and reproductive outcome in men treated for Hodgkin’s disease. Br J Cancer 2002; 87: 381–4 10. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 364: 1405–10 11. Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update 2004; 10: 251–66 12. Sanders JE, Hawley J, Levy W, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: 3045–52 13. Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus – review of the effects of treatment of childhood cancer. Hum Fertil (Camb) 2002; 5: 61–6 14. Tucker M, Morton P, Liebermann J. Human oocyte cryopreservation: a valid alternative to embryo cryopreservation? Eur J Obstet Gynecol Reprod Biol 2004;113 (Suppl 1): S24–27 15. Wu J, Zhang L, Wang X. In vitro maturation, fertilization and embryo development after ultrarapid freezing of immature human oocytes. Reproduction 2001; 121: 389–93 16. Yoon TK, Kim TJ, Park SE, et al. Live births after vitrification of oocytes in a stimulated in vitro fertilization–embryo transfer program. Fertil Steril 2003; 79: 1323–6 17. Plante M, Renaud MC, Francois H, et al. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol Oncol 2004; 94: 614–23

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18. Anderson RA, Kinniburgh D, Baird DT. Preliminary evidence of the use of a gonadotrophin releasing-hormone antagonist in superovulation/IVF prior to cancer treatment. Hum Reprod 1999; 14: 2665–8 19. Kim SS. Ovarian tissue banking for cancer patients. To do or not to do? Hum Reprod 2003; 18: 1759–61 20. Gagnon Y, Tetu B. Ovarian metastases of breast carcinoma. A clinicopathologic study of 59 cases. Cancer 1989; 64: 892–8 21. Oktay K, Buyuk E, Davis O, et al. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003; 18: 90–5 22. Yong PTK, Baird DT, Thong KJ, et al. Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle number at different stages of the normal menstrual cycle and after pituitary down-regulation. Hum Reprod 2003; 18: 35–44 23. Van Rooij IA, Broekmans FJ, Te Velde ER, et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17: 3065–71 24. Bath LE, Critchley HOD, Chambers SE, et al. Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement. Br J Obstet Gynaecol 1999; 106: 1265–72 25. Larsen EC, Loft A, Holm K, et al. Oocyte donation in women cured of cancer with bone marrow transplantation including total body irradiation in adolescence. Hum Reprod 2000; 15: 1505–8 26. Olivennes F, Cunha-Filho JS, Fanchin R, et al. The use of GnRH antagonists in ovarian stimulation. Hum Reprod Update 2002; 8: 279–90 27. Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Invest 2004; 11: 406–15

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Chapter 4

The patient with systemic lupus erythematosus Z Blumenfeld

INTRODUCTION Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of uncertain cause that can affect many organs of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies, characterize the disease. The clinical course of SLE is highly variable. Long periods of remission may alternate with chronic or acute relapses. Women in the reproductive age group are particularly affected, and may suffer from multiple symptoms arising from inflammatory involvement that can affect almost every organ.1,2 The reported prevalence of SLE in the population is 40–50 cases per 100 000.1 Due to improved detection of mild disease, the incidence has increased in recent years.2 Moreover, the impact of modern therapies on future fertility has been clarified. The effect of SLE treatment on subsequent fertility and improvements in the prognosis of SLE have led to an increase in the number of women with SLE presenting for infertility therapy. In this chapter, the potential risks of exacerbating the condition under fertility treatment, and the possible impact of SLE on in vitro fertilization (IVF) outcomes and subsequent pregnancy, are reviewed. Management options aimed at optimizing outcomes in this potentially difficult group of patients are proposed.

IMPACT OF SLE ON IVF OUTCOMES Fertility is estimated to be almost normal in female patients with SLE, except for amenorrhea accompanying severe flare-ups, renal insufficiency-related

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hypofertility and ovarian failure secondary to cyclophosphamide therapy. Cyclophosphamide administration is significantly associated with premature ovarian failure (POF) and hypergonadotropic amenorrhea. In women with lupus nephritis, POF was reported in half of those treated with cyclophosphamide pulse therapy (CPT), affecting the majority of those older than 30 years, about 50% of patients between 20 and 30 years and only 13% of women < 20 years.3 Amenorrhea was experienced by 71% of patients after oral cyclophosphamide, versus 45% of those receiving intravenous CPT. More recently, Liu and colleagues4 have concluded that pulse cyclophosphamide therapy in fertile women with SLE is associated with an increased rate of sustained amenorrhea, and the older is the patient, the higher is the risk for sustained amenorrhea. Whereas several investigators found a reduced or no risk of POF after CPT, others have found an incidence of 26–54% of POF in CPT.5 Other studies, which employed dosages of 1–4 mg/kg/day of oral cyclophosphamide for 4–4.3 years, have reported higher rates of POF in approximately 53–71% of patients.6 In a retrospective cohort study by Mok and colleagues,7 of the 70 women treated with cyclophosphamide, 18 (26%) developed POF, with a higher rate in patients who had received oral cyclophosphamide, 30%, versus intravenous cyclophosphamide, 13%. In this study, the cumulative dose of cyclophosphamide and age were independent risk factors for POF. In the group with ovarian failure, the cumulative dose of cyclophosphamide was higher than in the group without gonadal insufficiency (28.8 vs. 15.4 g). The preservation of ovarian function despite gonadotoxic chemotherapy has been the focus of extensive clinical efforts and scientific endeavors in the past decade (see also Chapter 3). Following our preliminary encouraging experience in women with lymphoma,8–10 in which the temporary induction of a prepubertal hormonal milieu during chemotherapy was associated with a significantly decreased risk of POF, we administered a monthly injection of gonadotropin releasing hormone agonist (GnRH-a) to 18 young SLE women in parallel with alkylating agent chemotherapy.8–10 A monthly intramuscular depot injection of 3.75 mg D-tryptophan-6 (D-Trp6)-GnRH-a was administered after informed consent to young female patients with autoimmune, severe connective-tissue diseases (17 SLE patients and one woman with nephrotic syndrome) in parallel with chemotherapy, for up to 6 months. The treated patients (study group) were compared with a group of nine women similarly treated by CPT or chlorambucil for SLE/connective tissue disease, but who were not referred for the GnRH-a adjuvant treatment. Whereas none of the 18 women receiving GnRH-a in parallel with alkylating agent chemotherapy (cyclophosphamide (n = 17) or chlorambucil (n = 1)) suffered POF and hypergonadotropic amenorrhea, five of the nine patients treated by alkylating agents (cyclophosphamide (n = 8) or

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THE PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS

chlorambucil (n = 1)) experienced POF. Our experience suggests that the beneficial effect of GnRH-a co-treatment may have a role in the preservation of future fertility and ovarian function in young women of reproductive age exposed to gonadotoxic chemotherapy such as alkylating agents. Similar experience has been presented by McCune and colleagues,11 whereby their GnRH agonist-treated SLE patients had a significantly better chance of having preserved cyclic ovulatory ovarian function and fertility, as compared with the matched control group (odds ratio (OR) > 11; p < 0.05). The groups were individually matched for age, race, disease duration, mean cyclophosphamide dose and indication for therapy by an investigator not involved in patient care and blinded to outcome. In those women with SLE presenting for IVF in whom ovarian function is sufficient to provide an adequate response to ovarian stimulation, the chance of achieving a live birth appears to be reduced. In a study of IVF outcomes in women with SLE, 18 pregnancies generated nine live-births, four fetal deaths and five embryonic losses.12 The majority of poor outcomes were reported in those women who underwent IVF and embryo transfer (IVF–ET) in the context of multiple follicular development during a planned ovulation-induction cycle as treatment for anovulation. In contrast, live-births were achieved in six out of seven pregnancies after ‘planned’ IVF–ET.12 However, the small size of this study requires that it be interpreted with caution. It has been suggested that the presence of antinuclear antibody (ANA) might reduce pregnancy rates after IVF–ET. However, the mechanism of implantation failure by ANA has not yet been clarified. In a recent study, the impact of ANA on pregnancy rate after IVF–ET was investigated, as was the necessity of specific medication for infertile women who have ANA in their sera.13 In this study of 108 infertile women using IVF–ET or intracytoplasmic sperm injection (ICSI)–ET, the implantation rate per embryo transferred in the first treatment cycle was 14.8% (8/54) in women with ANA as compared with 32.4% (33/102) in healthy controls (p < 0.05).13 The pregnancy rate per ET in the first treatment cycle was 28% (7/25) for women with ANA and 54.2% (26/48) in the healthy controls. The pregnancy rate difference between the two groups was also statistically significant (p < 0.05). Afterwards, treatments with IVF–ET or ICSI–ET were repeatedly performed for unsuccessful patients, without any specific medication for ANA. The average number of IVF cycles resulting in ET was 1.80 ± 1.13 and 1.27 ± 0.54, in women with and without ANA, respectively. The cumulative pregnancy rates per patient were 68% (17/25) and 55.6% (35/63), respectively. There was no significant difference in the overall pregnancy rate between the two groups. These findings suggest that ANA might have an impact on implantation failure in women

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treated by IVF–ET or ICSI–ET. ANA reduced the pregnancy rate in the first IVF–ET or ICSI–ET cycles, but not the cumulative pregnancy rate without medication.13 These data indicate that the mechanisms of implantation failure by ANA may be amenable to treatment. Patients with SLE with long-lasting established disease may have poorer pregnancy outcomes than women with later-onset disease.14 Active renal disease and maternal hypertension are important predictors of fetal loss and premature birth, respectively.14 Placental pathology in SLE patients is characterized by decidual vasculopathy and infarction, and in antiphospholipid syndrome (APS) patients, infarction can be extensive.14 Maternal anti-52-kDa SSA/Ro by immunoblot continues to be an important risk factor for having a child with heart block.14 The risk of having a subsequent child with congenital heart block ranges between 12% and 16%.14 Childhood morbidity with heart block is high, with 63% eventually requiring pacemakers.14 In APS, anti-β2-glycoprotein-I (anti-β2-GP-I) antibodies can play a significant role in the diagnosis, especially when the traditional assays for anticardiolipin (aCL) antibodies and lupus anticoagulant (LAC) are negative.14 Although some obstetricians have found that intravenous immunoglobulin (IVIG) may improve the birth rate in antiphospholipid (aPL) antibody-positive women who have recurrent spontaneous abortions after IVF,14 this therapeutic modality remains of equivocal value and therefore controversial. In a series of women conceiving after IVF, pregnancy complications included pre-eclamptic toxemia,15 SLE flare-up and gastrointestinal hemorrhage due to the Mallory–Weiss syndrome, multiple gestations and gestational diabetes. Postpartum complications included nephritis flare, costochondritis and suicidal depression. Five of the 16 cycles (31%) in seven SLE patients, five of 48 cycles (10%) in ten primary-APS patients and none of five cycles in two women with aPL antibodies (without SLE or primary APS) resulted in live-born children, including multiple gestations (three twin sets with four surviving infants, and two triplet sets with three surviving infants). Fifty per cent of the living children (seven of 14) were premature, three had neonatal lupus and one had pulmonic stenosis. Five surviving infants (36%) had complications unrelated to prematurity. This study concluded that although IVF–ET can be successful in SLE and primaryAPS patients, the rates of fetal and maternal complications are high.

IMPACT OF IVF ON SLE The exponential rise in serum estradiol concentration associated with assisted reproductive technologies (ART) and controlled ovarian

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hyperstimulation (COH) may occur irrespective of the ovulationinduction protocol used, possibly causing SLE flare-up and thromboembolic phenomena. Le Thi Huong and colleagues12 have published their experience with 114 cycles of ovulation induction in 21 SLE patients and women with APS. Complications such as fetal loss, SLE flare-up or thromboembolic phenomena led to diagnosis of the underlying disease in eight women. Two patients suffered thrombophlebitis after COH using gonadotropins. An SLE flare-up appeared after 13 out of 62 cycles, with a flare-up rate higher after COH using gonadotropins (27% per cycle) than after clomiphene citrate therapy (6%), and after an unplanned (30%) compared with a planned IVF cycle (10%). These investigators concluded that ovulation induction can reveal undiagnosed SLE or APS. In another study, the risks of COH in SLE patients and women with APS were reported.15 Nineteen women who had undergone 68 cycles of IVF were studied by interview and retrospective chart review. Four IVF cycles (25%) in SLE patients resulted in SLE flare-up and two (13%) in the ovarian hyperstimulation syndrome (OHSS). One patient with primary APS who had been treated with heparin during multiple cycles developed osteopenia. No thromboembolic complications were reported.

TO SCREEN OR NOT TO SCREEN? Since SLE is a chronic disease with a broad spectrum of clinical and immunological manifestations, this condition may be frequently misdiagnosed.16 A recent study conducted to determine the prevalence of undiagnosed SLE among a cohort of infertile women undergoing ART treatment employed a screening protocol using sequential (two-stage) testing, which included a self-completed questionnaire followed by an ANA test.16 The questionnaire was distributed to 143 consecutive infertile patients, aged 24–42 years (mean 33.6 ± 4.7 years), who were to be treated by IVF. Patients who completed the questionnaire with three or more positive answers were sent for ANA testing; those who tested positive were referred to the Clinical Immunology Unit for anti-double-stranded DNA (dsDNA) antibody test and clinical assessment. A total of 136 women (95.1%) completed the questionnaire. Thirteen patients (9.6%) answered positively to three or more questions. Of these, five patients (3.8%) were ANA-positive and two (1.5%) had undiagnosed SLE. The investigators concluded that a 1.5% prevalence of undiagnosed SLE may be found in a cohort of infertile women. Given this low prevalence, routine screening is not warranted at present.

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aPL antibodies are an established cause of recurrent pregnancy loss. As defective embryonic implantation is a common link between unexplained infertility and recurrent miscarriage, interest has focused on the potential relationship between aPL antibodies and implantation failure after IVF–ET.17 Although most studies have reported an increased prevalence of aPL antibodies among women undergoing IVF–ET, prospective studies examining their effect on the outcome of IVF–ET demonstrate that these antibodies do not significantly affect either the implantation or ongoing pregnancy rates.17 The increased prevalence of aPL antibodies among women with infertility is therefore likely to be part of a generalized autoimmune disturbance associated with infertility.17,18 Hence, routine screening for aPL antibodies among women undergoing IVF–ET is not warranted, and therapeutic interventions should be used only in welldesigned randomized controlled trials.17

PREPARING THE PATIENT FOR IVF Pregnancy should be avoided during active disease (especially with significant organ impairment) owing to the high risk of miscarriage and exacerbation of SLE. Women with SLE should be counseled not to become pregnant until the disease has been quiescent for at least 6 months. It is important that the patient be prepared for IVF in close collaboration with her immunologist. The prinicipal drugs employed in treating SLE include non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, glucocorticoids and, as mentioned earlier, immunosuppressive agents such as cyclophosphamide. Attention should be given to stabilizing the condition and rationalizing drug use to those considered safe in pregnancy (see Chapter 12). Advice should also be given regarding life-style changes that may improve the chances of a successful outcome. A well-balanced diet, regular exercise and stopping cigarette-smoking have all been shown to improve SLE.19

MANAGING THE IVF CYCLE When gonadotropin therapy is considered, a preventive anti-inflammatory therapy should be discussed with the SLE patient, in conjunction with heparin and/or antiaggregate therapy for those with asymptomatic aPL antibodies or prior thrombotic events12 (see Chapter 1). There are some data suggesting that sulfonamides and penicillin (but not the semisynthetic

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penicillins) may cause exacerbations and should therefore be avoided during IVF treatment.

POST-IVF FOLLOW-UP Following IVF treatment, the patient with SLE should be followed in order to minimize longer-term complications. While this will normally be done in collaboration with an immunologist, reproductive endocrinologists and infertility-care providers should be aware of the principal areas in which they may have the leading management role. The risk of osteoporosis in long-term users of glucocorticosteroids is a very serious problem in these young women, where estrogen replacement therapy (ERT) or estrogen treatment may be relatively contraindicated owing to the possible risk of a flare-up effect of estrogen on lupus activity.20 Estrogens may exert various stimulatory effects on the immune system, including an increase of prolactin secretion, which has a proinflammatory role and may play a role in SLE activity.21 Oral contraceptives (OCs) are generally not prescribed for women with SLE due to the widely held view that they may activate disease. Therefore, intuitively, every possible effort should be made to prevent POF and the need for ERT or hormone replacement therapy (HRT). The reported evidence regarding a deleterious effect of combined oral contraceptives (COCs) upon the activity of SLE or on thromboembolism in SLE has been reviewed,20 together with an examination of osteoporosis prevention. It has been argued that while SLE is a hormonally driven disease, multiple hormones, and not just estrogen, may possibly play a pathophysiologic role.20 Estrogen use as either COCs or HRT has not been systematically studied before, and therefore neither quantification of the risk nor identification of high-risk groups can be accurately and definitively substantiated.22 Recently, Bhattoa and colleagues23 studied the effect of 1-year transdermal ERT on bone mineral density (BMD) and biochemical markers of bone turnover in osteopenic postmenopausal SLE women in a randomized, double-blind, placebo-controlled trial. Both groups received 5 mg continuous oral medroxyprogesterone acetate, 500 mg calcium and 400 IU vitamin D3.23 Lumbar spine, femoral and hip BMD were measured at baseline and at 6 and 12 months. Serum osteocalcin and degradation products of C-terminal telopeptides of type-I collagen levels were also measured.23 Whereas a significant difference in the change of lumbar spine BMD at 6 months between the two groups was detected, there was no significant difference in SLE disease activity index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology

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(ACR) damage index and corticosteroid dose during the study period.23 This study concluded that transdermal ERT may prevent bone loss in postmenopausal SLE patients, without increasing the risk of flare-up and disease activity. The effects of progestins on bone have been studied,24 concluding that progestins neither add nor subtract much of the protective action of estrogens on bone. Another recommended examination in these patients is an annual regular Papanicolaou smear. A previous retrospective study has found an increased risk of uterine cervical atypia in women with SLE who have been treated with cytotoxic drugs. We found a significantly higher incidence of cervical atypia in SLE patients (35.9%) compared with non-SLE control groups (< 5%; p < 0.01).25 No significant difference was found between the incidence of atypia in patients previously treated by cytotoxic medications such as cyclophosphamide pulses or methotrexate (4/9), compared with SLE women not receiving cytotoxic drugs (10/30).25 Colposcopically directed biopsies revealed three cases of cervical intraepithelial neoplasia (CIN) I–III (21%) among the cases with atypia.25 We concluded, therefore, that SLE patients should have regular cytologic cervical Papanicolaou smears due to a significantly increased incidence of atypia, regardless of previous cytotoxic therapy.25

SUMMARY OF MANAGEMENT OPTIONS Whereas IVF and other versions of ART are possible and applicable to SLE patients and those with APS and other autoimmune diseases, and normal offspring can be generated, the serious and possible life-threatening complications should be discussed with patients. Childhood morbidity with heart block is high for the offspring of gestations in SLE patients with antiSSA/Ro antibodies, with more than half of newborns eventually requiring pacemakers. The serious risk of postpartum flare-up and eventual lupus nephritis should be considered. In an attempt to minimize this serious risk, ART treatment should be indicated and performed only in patients with normal creatinine, after complete remission of the autoimmune disease for at least 1–2 years.

ACKNOWLEDGMENTS The help and co-operation of Professor M. Nahir, MD, Mrs Naomi Schultz, MSc and all staff of the Rheumatology Department at Rambam Medical Center, Haifa, Israel, are gratefully acknowledged.

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REFERENCES 1. Von Feldt JM. Systemic lupus erythematosus. Recognizing its various presentations. Postgrad Med 1995; 97: 79, 83, 86 2. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1993; 72: 113–24 3. Langevitz P, Klein L, Pras M, Many A. The effect of cyclophosphamide pulses on fertility in patients with lupus nephritis. Am J Reprod Immunol 1992; 28: 157 4. Liu G, Chen Y, Wang L, et al. The risk of sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Hua Xi Yi Ke Da Xue Xue Bao 2001; 32: 294–5, 306 5. McDermott EM, Powell RI. Incidence of ovarian failure in systemic lupus erythematosus after treatment with pulse cyclophosphamide. Ann Rheum Dis 1996; 55: 224–9 6. Medeiros MM, Silveira VA, Menezes AP, Carvalho RC. Risk factors for ovarian failure in patients with systemic lupus erythematosus. Braz J Med Biol Res 2001; 34: 1561–8 7. Mok CC, Lau CS, Wong RWS. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum 1998; 41: 831–7 8. Blumenfeld Z, Shapiro D, Shteinberg M, et al. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus 2000; 9: 1–5 9. Blumenfeld Z. Gynecologic concerns for young women exposed to gonadotoxic chemotherapy. Curr Opin Obstet Gynecol 2003; 15: 359–70 10. Blumenfeld Z. Ovarian cryopreservation versus ovarian suppression by GnRH analogues: primum non nocere. Hum Reprod 2004; 19: 1924–5 11. McCune WJ, Christman G, et al. Use of leuprolide for ovarian protection during cyclophosphamide therapy. Annual Meeting of the American College of Rheumatology, September 2001. Arthritis Rheum 2001; 44: S387 (abstr 2006) 12. Le Thi Huong D, Wechsler B, Piette JC. Ovulation induction therapy and systemic lupus erythematosus. Ann Med Interne (Paris) 2003; 154: 45–50 13. Kikuchi K, Shibahara H, Hirano Y, et al. Antinuclear antibody reduces the pregnancy rate in the first IVF–ET treatment cycle but not the cumulative pregnancy rate without specific medication. Am J Reprod Immunol 2003; 50: 363–7 14. Meng C, Lockshin M. Pregnancy in lupus. Curr Opin Rheumatol 1999; 11: 348–51 15. Guballa N, Sammaritano L, Schwartzman S, et al. Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum 2000; 43: 550–6

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16. Geva E, Lerner-Geva L, Burke M, et al. Undiagnosed systemic lupus erythematosus in a cohort of infertile women. Am J Reprod Immunol 2004; 51: 336–40 17. Backos M, Rai R, Regan L. Antiphospholipid antibodies and infertility. Hum Fertil (Camb) 2002; 5: 30–4 18. Gleicher N. Some thoughts on the reproductive autoimmune failure syndrome (RAFS) and Th-1 versus Th-2 immune responses. Am J Reprod Immunol 2002; 48: 252–4 19. Formica MK, Palmer JR, Rosenberg L, McAlindon TE. Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women’s Health Study. J Rheumatol 2003; 30: 1222 20. Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum 1997; 40: 797–803 21. Krause I, Blumenfeld Z, Malchinsky M, et al. Anti-endothelial cell antibodies in the sera of hyperprolactinemic women. Lupus 1998; 7: 377–82 22. Quint EH, Breech L, Blumenfeld Z. Case 2005: ovarian suppression with chemotherapy in adolescents. J Pediatr Adolesc Gynecol 2004; 17: 413–16 23. Bhattoa HP, Bettembuk P, Balogh A, et al. The effect of 1-year transdermal estrogen replacement therapy on bone mineral density and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Osteoporos Int 2004; 15: 396–404. 24. Thijssen JH. Overview on the effects of progestins on bone. Maturitas 2003; 46 (Suppl 1): S77–87 25. Blumenfeld Z, Lorber M, Yoffe N, Scharf Y. Systemic lupus erythematosus: predisposition for uterine cervical dysplasia. Lupus 1994; 3: 59–61

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Chapter 5

The couple discordant for human immunodeficiency virus MV Sauer

INTRODUCTION Human immunodeficiency virus (HIV) infects nearly 40 million people worldwide. It affects women and men equally, although in the USA the majority of cases are found in reproductive-aged men.1 Significant advancements in medical treatment using highly active antiretroviral therapy (HAART) have improved survivorship, and for individuals compliant with therapy the illness is now considered a chronic ailment rather than a terminal disease. However, a diagnosis of HIV remains a devastating blow to an individual’s expectations for a normal adult life. Couples in whom one or both partners are infected with HIV are counseled against pregnancy for fear of both horizontal and vertical transmission of the virus. Providing fertility care to couples in whom one partner is known to be HIV-seropositive remains a subject of intense controversy.2,3 Traditionally, reproductive options for HIV-serodiscordant couples have been limited. Donor sperm insemination and adoption represent the only recommended ‘safe’ options for the partners of HIV-seropositive men. However, reproductive drive is very strong, and patients are known to take unreasonable risks in order to have a baby. It is therefore not surprising that seroconversions of uninfected women have occurred as a result of timed intercourse without a condom.

IMPACT OF HIV INFECTION ON IVF OUTCOMES The impact of HIV on in vitro fertilization (IVF) per se is negligible. However, in general, patients who are HIV-seropositive have not been

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granted access to fertility care. In side-by-side comparisons with HIVseronegative men, men with HIV undergoing intracytoplasmic sperm injection (ICSI) have performed similarly with respect to fertilization in vitro, embryo quality, embryo implantation and pregnancy outcome.4

Impact of IVF on HIV infection and disease Sperm washing with swim-up separates motile sperm from seminal plasma and non-motile cells (the compartment in which HIV resides). Success rates are largely dependent on factors that limit pregnancy outcomes for conventional patients undergoing infertility treatment, with the age of the female partner being the most significant prognostic indicator.5 To date, there is no evidence to suggest that undergoing either IVF or intrauterine insemination (IUI) alters the course of the underlying disease.

IUI or IVF There are advantages and disadvantages to using either IUI or IVF approaches. Although more cases of IUI have been reported, it remains unclear as to whether one approach is superior, and there are no randomized controlled trials to compare efficacy and safety. IUI is technically easier, less expensive and, with repetitive applications, approaches the efficacy of IVF in well-selected patients. However, IUI therapy requires millions of sperm cells to be placed above the natural immunological barrier of the cervix. It is difficult to ensure that all lymphocytes and macrophages are eliminated from the ‘washed’ preparation. Since infection has been reported following IUI, and washed specimens may harbor virus, most centers recommend that all IUI specimens be tested for HIV prior to use. Viral testing adds complexity to the method and cost. Furthermore, men with chronic HIV infection often have abnormal semen profiles.6 In such instances, IUI therapy may be less effective, since pregnancy success is generally reduced in men with persistently abnormal semen analyses. IVF with or without ICSI is commonly performed to treat male factor infertility, and is available at centers providing assisted reproduction.7 Similar to preparing sperm for IUI, discontinuous density gradient centrifugation techniques are utilized prior to IVF and ICSI, and only motile sperm found in the supernatant following swim-up are selected. Many fewer sperm are necessary for IVF, and typically fewer than 20 sperm are selected per case of IVF–ICSI. There are also distinct disadvantages to IVF, as the cost is significantly greater in terms of both time and money. Patients undergo ovarian

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hyperstimulation prior to egg harvest, necessitating more monitoring. Oocyte aspiration is invasive and requires anesthesia. Ovarian hyperstimulation syndrome may occur, and multiple births further complicate many pregnancies.8

PREPARING THE PATIENT FOR IVF HIV-infected patients should be under active medical surveillance for their illness by infectious disease specialists, and, where appropriate, they should be prescribed antiviral medications. Plasma HIV RNA viral counts and CD4 status should be ascertained prior to beginning treatment. Table 1 lists recommendations and pretreatment tests performed prior to entry into our clinical program. Partners should be HIV tested and be seronegative. Couples must remain compliant with safe sex practices and agree to use condoms. Women receive thorough pelvic examinations including Papanicolaou smears and cervical cultures, and serum estradiol and follicle stimulating hormone (FSH) levels are measured in order to evaluate the appropriateness of IVF therapy. HIV-seropositive women should receive prophylactic antibiotics prior to uterine cavity assessment (hysterosalpingography or sonohysterography), and medications should be extended for 7–10 days following the procedure. Physicians should try to avoid examining HIVseropositive women during their menstrual cycle to minimize blood contamination of examination rooms and ultrasound equipment. When blood is present, a thorough cleaning of exposed surfaces with a mild bleach solution is necessary to eradicate virus.

MANAGING THE IVF CYCLE Standard protocols for ovarian hyperstimulation are prescribed. Needle aspiration of oocytes occurs 34–36 h following human chorionic gonadotropin (hCG) injection. A fresh semen sample is requested for ICSI. The use of semen preparation techniques, commonly referred to as ‘sperm washing’, has been recommended as a means of reducing the likelihood of horizontal transmission of HIV for nearly 15 years.9 Results are encouraging, with reasonable pregnancy rates reported in more than 3600 published attempts and no seroconversions occurring in treated women or children.10 Most of this work has taken place in Europe, as there are few practitioners in the USA willing to offer therapy, presumably for fear of infecting the seronegative partner and child. The US Centers for Disease Control and

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Table 1 Medical and reproductive pretreatment recommendations and tests Female patient Age < 42 years Day 2–3 FSH < 15 mIU/ml Day 2–3 estradiol < 65 pg/ml Informed consent (risks, benefits and alternatives explained and documented) Absence of opportunistic infections or prophylaxis Infectious disease tests HIV-1 and HIV-2 (viral counts if HIV-seropositive) hepatitis A, B and C (HCV viral RNA counts if seropositive) syphilis (RPR) cervical cultures for gonorrhea and chlamydia Hysterosalpingogram or saline infusion sonohysterogram (SIS) Papanicolaou smear Assessment of need for vaccinations Genetic tests as appropriate cystic fibrosis, hemoglobin electrophoresis, Tay–Sachs Complete blood count (CBC) with platelets CD4 counts (in HIV-seropositive women) Thyroid stimulating hormone (TSH) SMA-12 with liver functions (in HIV- or HCV-infected women) Blood type (Rh/ABO) Medical clearance letter from internist dispensing HIV treatment Medical clearance by maternal–fetal medicine Male patient Semen analysis (if HIV- or HCV-seropositive must have adequate total motile count to perform ICSI) Infectious disease tests HIV-1 and HIV-2 (viral counts in seropositive men) hepatitis A, B and C (HCV viral RNA counts in seropositive men)

Continued

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Table 1

Continued

syphilis (RPR) Genetic tests cystic fibrosis, hemoglobin electrophoresis, Tay–Sachs Blood type (Rh/ABO) CD4 counts (HIV-infected men) Absence of opportunistic infections Informed consent (risks, benefits and alternatives explained and documented) SMA-12 and liver functions in HIV- and HCV-infected men Medical clearance letter from internist dispensing HIV treatment FSH, follicle stimulating hormone; HIV, human immunodeficiency virus; HCV, hepatitis C virus; RPR, rapid plasma regain; SMA-12, sequential multiple analysis (12-channel biochemical profile); Rh, rhesus; ICSI, intracytoplasmic sperm injection

Prevention (CDC) published recommendations against treating HIVserodiscordant couples after HIV seroconversion occurred in a woman following IUI therapy with sperm from her HIV-seropositive husband.11 Table 2 details the method used at Columbia University for sperm preparation. Embryo transfers are typically scheduled on the third or fifth day. Assisted hatching is not performed on the embryos of HIV patients.

POST-IVF FOLLOW-UP Serial blood testing (ultrasensitive HIV-RNA polymerase chain reaction (PCR)) is repeated throughout pregnancy at the beginning of each trimester. At delivery and 3 months postpartum, mothers are tested using assays sensitive enough to detect virus to the level of < 50 copies per ml of blood. Newborns are tested at birth and 3 months of age. Patients failing to become pregnant or women who experience spontaneous abortion are asked to repeat HIV tests 3 and 6 months later. Table 3 details the initial 103 cycles of treatment in HIV-seropositive men.12 Couples with fertility problems that are associated with poor IVF

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Table 2 Semen processing for in vitro fertilization–intracytoplasmic sperm injection (IVF–ICSI) Fresh semen sample collected at time of oocyte aspiration Sample handled using strict sterile technique in a class II biological safety cabinet Sample transferred to clean, sterile 15-ml centrifuge tube Semen evaluated visually for sperm concentration, motility and extraneous cells Semen centrifuged through a discontinuous density gradient as follows: 1.5 ml of the lower (90%) layer pipetted into one (or more, depending on semen volume) tube 1.5 ml of the upper (47%) layer carefully pipetted on top of this, and 1–2 ml of semen pipetted directly on top of the upper layer Gradient tube(s) centrifuged for 10–20 min at 300g Following spin, pellet(s) transferred to a clean tube and diluted with 5 ml of modified human tubal fluid (HTF) supplemented with 5% (v/v) human serum albumin (HSA) Sperm centrifuged for a maximum of 10 min at 300g and supernatant (wash number 1) removed Pellet resuspended in 3 ml of fresh modified HTF–HSA and spun again for a maximum of 5 min Supernatant (wash number 2) removed and the pellet resuspended in a small volume of modified HTF–HSA Sperm allowed 45-min period for ‘swim-up’ Only sperm from final motile fraction selected for ICSI

success rates should be counseled regarding their prognosis prior to undergoing treatment, given the unknown risk of HIV transmission that accompanies therapy.

The special needs of HIV-seropositive women The prognosis for pregnant women with HIV has greatly improved with the introduction of HAART, which increases survival and enhances quality

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Table 3 Clinical results of the first 103 consecutive treatment attempts using in vitro fertilization–intracytoplasmic sperm injection (IVF–ICSI) in human immunodeficiency virus type 1 (HIV-1)serodiscordant couples12 Number of couples treated number of initiated cycles number of attempts per couple

54 103 1.9 + 1.1 (1–6)

Cancellation rate due to poor ovarian response

12.6%

Number of oocytes aspirated per retrieval

16.8 + 9.8 (2–47)*

Number of fertilized oocytes per ICSI case

9.1 + 5.5 (0–24)*

Number of embryos transferred per attempt

3.6 + 1.1 (1–8)*

Percentage of couples with cryopreserved embryos

32.2%

Overall clinical pregnancy rate per embryo transfer

39.5%

Ongoing and delivered pregnancy rate per embryo transfer

33.7%

Cumulative pregnancy rate for couples over repeated attempts

50.0%

Number of seroconversions in treated women

0

Number of seroconversions in delivered offspring

0

*Mean ± SD (range)

of life while reducing the risk of vertical transmission of HIV to the fetus from approximately 25% to < 2%.13 Many women with HIV desire to have children and seek professional help. In some cases the serodiscordant couple’s fertility potential is presumed to be normal, and instruction on self-insemination may be all that is required. Often, other coexisting factors require medical assistance,

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particularly in cases of tubal disease. There remains little published experience relating to IVF services for HIV-seropositive women.14

Patient selection and methods of treatment of HIV-seropositive women Table 1 lists the requirements for HIV-seropositive women interested in participating in fertility services. Patients are commonly referred by consultants in infectious disease. Most require HAART to suppress HIV levels to low or preferably undetectable values. Patients are given the option of self-insemination using semen collected in a sterile container by masturbation and drawn up into a 5-ml Bectin–Dickerson syringe for easy placement into the lower vagina. If women are discovered to have either tubal occlusion or severe abnormalities of their partner’s semen then they are triaged to IVF–ICSI. IVF–ICSI is preferred to standard IVF in order to remove all adherent blood from the egg and surrounding cumulus. Prior to beginning treatment, the patient’s infectious disease consultant should attest to her clinical status and compliance with medications. Patients meet with a specialist in maternal–fetal medicine experienced with HIV. At this consultation, the management of the upcoming pregnancy, the need for careful surveillance for drug interactions and toxicity, and a plan for delivery and aftercare are reviewed. In women over the age of 35 years, chorionic villus sampling or amniocentesis is not recommended in order to minimize risk of infection in the fetus. Mothers do not breast-feed, and receive bromocriptine postpartum to suppress lactation.

Additional considerations Women with HIV have unique needs, and require subspecialty care to optimize outcomes. With respect to infectious disease, it is imperative that viral counts be maximally suppressed. Transmission risk to the fetus is known to correlate directly with HIV counts in the mother. The best results are in women with persistently low (< 1000 copies) and preferably undetectable values. Certain medications, such as stavudine and efavirenz, are contraindicated for use during pregnancy, and in some cases adjustments to medications will be necessary prior to fertility treatment.15 Separate work-stations and incubation and embryo storage facilities are necessary for handling the HIV-seropositive patient in order to minimize risk of viral contamination in the embryology laboratory. Pre-cycle consultation with anesthesiology is provided to review the drugs used during the aspiration.

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All couples initially consult with a social-worker, and are encouraged to follow-up for support during the pregnancy. The stigmatism of HIV infection often leads to isolation and depression. Substance abuse is also common, as patients self-medicate with alcohol or drugs. It is essential to the success of any program that ongoing systems be in place to evaluate and treat psychosocial disorders.

SUMMARY OF MANAGEMENT OPTIONS It remains to be seen whether health-care providers in the field of assisted reproduction embrace the HIV-infected patient. Despite statements by the American Society for Reproductive Medicine,16 the American College of Obstetricians and Gynecologists17 and the European Society of Human Reproduction and Embryology18 encouraging physicians to provide care to HIV-seropositive men and women, few programs are known to be openly compliant. Although patients cannot be discriminated against under US law and are protected by the Americans with Disability Act,19 care-givers often claim conscientious-objector status and refer patients to programs that accept and treat. In our experience, the integration of HIV-infected patients into our clinical practice has not created undue hardships. Collaboration with infectious disease, maternal–fetal medicine, pediatrics and social services provides patients with a unique highly focused and specialized team of health-care providers to attend to their multiple needs and the needs of their baby. This unusually high level of surveillance positively reinforces the importance of compliance with medicines and physician directives. The purpose of all clinical trials involving assisted reproduction is to provide HIV-serodiscordant couples with an opportunity to have a child without risk of viral transmission. Various techniques have been suggested as preventive measures to avoid infection in HIV-serodiscordant couples intent on reproducing. The commonly accepted principles of health-care ethics include consideration of respect for autonomy, non-maleficence, beneficence, fidelity and justice.20 Each of these tenets should be individually considered in deciding whether or not to treat. Informed and rational decision-making must occur in every case of intervention. A lengthy discussion of the natural history of HIV infection, and the biology of transmission, should precede treatment. Alternatives, including artificial insemination with donor sperm, adoption and childless living, should also be offered. A balanced and non-prejudicial view towards treatment is requisite, and typically mandates that professionals outside of the IVF team be involved. Patients must act intentionally and without controlling

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influences that would prejudice against a free and voluntary act. Most important, women need to understand that no procedure is risk-free, and all carry a small possibility for infection in themselves and their babies.

REFERENCES 1. Centers for Disease Control and Prevention. 2001 HIV/AIDS Surveillance Report. Atlanta, GA: CDC, 2001; 13: 1–41 2. Englert Y, Van Vooren JP, Place I, et al. ART in HIV-infected couples. Has the time come for a change in attitude? Hum Reprod 2001; 16: 1309–15 3. Anderson DJ. Assisted reproduction for couples infected with the human immunodeficiency virus type 1. Fertil Steril 1999; 72: 592–4 4. Sauer MV, Chang PL. Establishing a program to assist HIV-1 seropositive men to have children using IVF–ICSI. Am J Obstet Gynecol 2002; 186: 627–33 5. Chu MC, Pena JE, Thornton MH, et al. Assessing the efficacy of IVF and ICSI in HIV-1 serodiscordant couples. Reprod Biomed Online 2005; 10: 130–4 6. Gilling-Smith C, Frodsham LCG, Tamberlin B, et al. Reducing reproductive risks in HIV infected couples: a comprehensive programme of care. Hum Reprod 2003; 18: 581–7 7. Dale B, Elder K, eds. Micromanipulation techniques. In In Vitro Fertilization. Cambridge: Cambridge University Press, 1997: 150–76 8. Pena JE, Thornton MH, Sauer MV. Complications of IVF–ICSI in HIV serodiscordant couples. Arch Gynecol Obstet 2003; 268: 198–201 9. Semprini AE, Levi-Setti P, Bozzo M, et al. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet 1992; 340: 1317–19 10. Sauer MV. Sperm washing techniques address the fertility needs of HIVseropositive men: a clinical review. Reprod Biomed Online 2005; 10: 135–40 11. Anonymous. HIV-1 infection and artificial insemination with processed semen. Morbid Mortal Weekly Rep 1990; 39: 249, 255–6 12. Pena JE, Thornton MH, Sauer MV. In vitro fertilization with intracytoplasmic sperm injection to prevent viral transmission in HIV-1 serodiscordant couples: report of 113 consecutive cycles. Fertil Steril 2003; 80: 356–62 13. The International Perinatal Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1. N Engl J Med 1999; 340: 977–87 14. Ohl J, Partisani M, Wittemer C, et al. Assisted reproduction techniques for HIV serodiscordant couples: 18 months of experience. Hum Reprod 2003; 18: 1244–9 15. Al-Khan A, Colon J, Palta V, et al. Assisted reproductive technology for men and women infected with human immunodeficiency virus type 1. Clin Infect Dis 2003; 36: 195–200

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16. Ethics Committee of the ASRM. HIV and infertility treatment. Fertil Steril 2002; 77: 218–22 17. American College of Obstetricians and Gynecologists. HIV: Ethical Guidelines for Obstetricians and Gynecologists, April 2001. ACOG Committee Opinion 255. Washington, DC: ACOG, 2001 18. The ESHRE Ethics and Law Task Force. Task Force 8: Ethics of medically assisted fertility treatment for HIV positive men and women. Hum Reprod 2004; 19: 2454–6. 19. Annas GJ. Protecting patients from discrimination – the Americans with Disabilities Act and HIV infection. N Engl J Med 1998; 339: 1255–9 20. Sauer MV. Providing assisted reproductive care to HIV-serodiscordant couples: time to re-examine healthcare policy. Am J Bioethics 2003; 3: 33–40

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Chapter 6

The couple with sexual dysfunction WL Gianotten

INTRODUCTION Various types of sexual dysfunction can interfere with natural conception, and not conceiving can negatively influence both the pleasure of sex and sexual function. Although in the process of assisted reproduction the pleasure factor becomes less important, other aspects of sexual functioning become increasingly important. In this context, it is vital that sperm are produced at the right time and that the vagina can receive the ultrasound transducer and speculum. In this chapter, various types of sexual dysfunction that can interfere with the outcome of assisted reproduction and in vitro fertilization (IVF) are scrutinized and management options provided. Meanwhile, some attention is given to possible long-term deleterious emotional and sexual side-effects of our interventions.

IMPACT OF SEXUAL DYSFUNCTION ON THE IVF PROCEDURE AND OUTCOME Sexual dysfunction categories are described in ascending order of disturbing the process of IVF.

Premature ejaculation Only a few men cannot impregnate because of always ejaculating before penetration. This particular group of premature-ejaculation patients usually cannot masturbate either. However, premature ejaculation does not seriously disturb the IVF process.

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Low desire Low desire in the woman does not interfere with IVF. In the man, it can cause low arousal with difficulty in keeping an erection and subsequent ejaculation.

Hypertonic pelvic floor If it causes painful vaginal examinations, this can be a precursor of vaginismus when the procedures become more stressful.

Erectile dysfunction By itself, erectile dysfunction (ED) does not interfere with IVF, but it can complicate the process of orgasm and ejaculation. Most causes of ED are not directly related to the wish to conceive. However, in some instances, this may be the case, such as when performance failure is caused by the high pressure to produce sperm on demand, or if there is ambivalence about a pregnancy.

Post-traumatic stress disorder The occurrence of sexual abuse in the past is not always sufficiently investigated and treated prior to embarking on IVF treatment. Post-traumatic stress disorder (PTSD) related to previous sexual abuse can cause sudden emotional breakdown in situations resembling the former sexual abuse situation. The stress of IVF combined with pelvic examination may provide such circumstances.

Orgasm dysfunction Female orgasm is not necessary for conception. Male orgasm (or actually ejaculation) is, since no ejaculation means no conception. In one study, inhibited male orgasm was prevalent in 5.7% of males presenting with sexual dysfunction.1 Some orgasm dysfunction (OD) cases are caused by ambivalence regarding pregnancy. Other men have OD only during intercourse, but can masturbate and deliver an ejaculate when required. Lifelong anejaculation, frequently resulting from a combination of character- and religious-based sexual inhibitions, is more difficult to overcome during IVF treatment.

Vaginismus This sexual dysfunction is found in 0.5–1% of the female population,2 but is probably more frequent among women with an unfulfilled wish for a

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child. Many couples with vaginismus continue for years in a relationship without having intercourse. While seeking fertility treatment, they often do not intend to acquire the ability to have intercourse, but only to become pregnant. However, since vaginismus can seriously hamper intravaginal interventions such as vaginal examination and ultrasound, or embryo transfer, the wish to conceive by IVF may provide the motivation finally to institute and accept treatment.3

IMPACT OF IVF ON SEXUAL (DYS-)FUNCTION In many couples, sexuality has already been compromised before entering IVF treatment because of failure to conceive, and the subsequent medical interventions.4 The invasion of the couple’s physical and emotional privacy during fertility treatment can further reduce sexual desire in both partners and damage the relationship.5 In one study of patients awaiting assisted reproduction treatment, sexual function and sexual pleasure were frequently disturbed, and around 25% suffered from depression.6 In anxious women, the pain or perceived pain of vaginal procedures can exacerbate a tense hypertonic pelvic floor, resulting in a complete ‘closing’ of the vagina. In women with a history of sexual or physical abuse that has received insufficient attention, various aspects of the procedure can cause violent flashbacks (re-experiencing traumas). Since this can seriously interfere with the procedure, the possibility of previous abuse should be investigated before commencing IVF treatment. Men are also sensitive to the stress of the IVF treatment process. This can be due to a diminished sense of male self-esteem. In one study, 10% of men were observed to experience sexual dysfunction of a psychogenic nature in response to the diagnosis of infertility.7 It has also been shown that the emotional stress to the man enrolled in an IVF program can negatively affect the quality of semen.8 Moreover, the ‘superstress’ of the moment (the ‘this is the night’ syndrome), with the necessity to perform, can deteriorate sexual performance, expressing itself as erectile or orgasmic failure.

PREPARING THE PATIENT FOR IVF Careful history-taking is an important tool in preparation and prevention of problems. When we come across poor sexual functioning in men, with imminent or real erectile or orgasmic failure, a thorough differential

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diagnosis is needed. In a case of performance failure due to the stress of the moment, additional (sexological) counseling should be considered, and the potential benefits of back-up procedures (such as availability of cryosemen) and pharmacological and visual-erotic support should be explained and offered. When there is evidence that ambivalence towards fatherhood or the relationship itself is affecting sexual function, the decision to proceed with assisted reproduction should clearly be reconsidered. Serious sexual dysfunction affecting the chance of conception should be addressed before entering IVF treatment. It may then be possible to prevent additional emotional damage to the couple, and frustration for the medical team. In less serious dysfunction, the stress can be reduced when its impact is explained and when back-up procedures (so called ‘in case of’ scenarios) are explained and offered. Indeed, when counseling was offered in an IVF program setting, the semen quality of the vast majority of patients studied did not appear to be significantly affected by the superstress of participation in the day of oocyte recovery.9 Since the IVF procedure can be seriously disturbed by violent flashbacks due to previous abuse, this possibility should be investigated before embarking on IVF treatment. When sexual violence has previously occurred that has not yet been sufficiently addressed, a thorough assessment is needed by a psychiatrist or psychotherapist experienced in sexual violence. Several types of trauma are distinguished (Table 1).10 In type I trauma, where a relatively short treatment process is needed, it seems advisable first to treat the aftermath of the sexual abuse. In type II trauma, treatment can be advised also, and, depending on the amount of damage, it is recommended to delay fertility treatment. Assisted reproduction should not be started without counseling by an experienced therapist, who can also address the practical aspects of the fertility procedures. To reconsider the need to conceive by IVF is even more obvious in cases of type III trauma, where the damage is most serious. When expecting ‘superstress’ in the woman as a result of insufficiently resolved vaginismus or sexual violence, additional preparation is needed. In such situations, it is advisable to build a relationship based on trust, with always the same (usually female) professional. This approach may also be extended to having all vaginal interventions performed by one trusted member of the fertility team. In other cases, the process can be facilitated when the woman is counseled by a female psychosomatic professional who can advise beforehand how to handle the stress, who recognizes the patient’s reaction pattern and who will be present during all procedures. Being conscious of having control over the process and interventions

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Table 1

Various types of trauma and trauma-related disorders

Type I trauma

Single shocking experience causing post-traumatic stress disorder (PTSD); this trauma includes full, detailed memories, ‘omens’ and misperceptions

Type II trauma

Chronic traumatic experiences causing not only PTSD but also more complex and diverse consequences including denial and numbing, dissociation and rage

Type III trauma

After extreme sadistic violence, or sexual violence in groups at a very young age, resulting in usually untreatable dissociative disorders

can prevent emotional breakdown in some of these women. One way for the woman to have control is, for instance, to insert the speculum or vaginal ultrasound probe herself.

FIRST DO NO HARM Modern techniques make it possible for the sexually confrontational aspects of IVF to be minimized, by, for instance, harvesting sperm by epididymal aspiration and transferring the embryo under general anesthesia. But is this always wise? A strong urge to conceive can blind couples against the potential damage that can be caused by fertility interventions. Some couples may focus purely on achieving a pregnancy by a ‘quick fix’, when a longer-term approach to solving sexual problems may result not only in pregnancy but also in other relational benefits. The anorgasmic man who ‘loses’ half a year undergoing treatment, but then can ejaculate by himself, will most probably be much happier in the longer term than the man who undergoes epididymal aspiration. Similarly, the woman with PTSD who ‘loses’ a year to treatment, but then is able to undergo the procedures fully conscious, without much stress and without loss of control, may be much happier and less damaged than the woman who becomes pregnant through vaginal procedures under general anesthesia.

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It should be recognized that IVF treatment alone, while offering the ‘quick fix’ that some couples seek for their fertility problem, is more likely to exacerbate rather than help the couple’s sexual problems. In those who elect to undergo IVF, the challenge is to minimize these negative effects.

MANAGING THE IVF CYCLE Here, attention is paid to handling difficulties arising from erectile problems, ejaculation problems, vaginismus and PTSD.

Erectile dysfunction In the assisted reproduction process, ED has to be taken seriously, since diminished sexual excitement can disturb ejaculation. This is a good indication for one of the phosphodiesterase 5 (PDE5) inhibitors, to be taken approximately 1 h before masturbation. Neither sildenafil11 nor tadalafil12 has an adverse effect on sperm function or ejaculate quality. Discuss and give consideration to other ways of sexual stimulation to enhance excitement and erection, for example the presence of the wife, or the use of fantasies and sexually explicit videos or magazines. Men are sensitive to visual sexual stimulation, especially moving pictures. They are obviously a facilitating factor when the patient ‘has to’ produce semen.13 Since most men will know what turns them on, they should be told to make use of that possibility (and let them, for instance, bring their own X-rated movie or magazine). It is obvious that the fertility unit should have a room for masturbation (‘production’) where the man cannot be disturbed, with a proper erotic environment and with video and/or DVD facilities. The erotic material should not only be available when the man needs it (which can be embarrassing to request), but always present in the room. In many units, the material is regularly stolen from the production room. When a batch with X-rated material is available only at the reception desk, it should be handed out automatically to every man.

Retrograde ejaculation In retrograde ejaculation (RE), sperm quality is often impaired and the clinical process will be complicated. Pharmacological treatment, being the least invasive option, should be tried first. Imipramine and chlorpheniramine with phenylpropanolamine show the best reversal rates in RE.14 In spinal cord-injured men, usually vibration and electroejaculation procedures are needed. By using a silicone balloon catheter to tamponade the

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bladder neck, antegrade ejaculation can be collected without urine contamination.15 The combination of vibration and a silicone balloon catheter could be tried as well in cases where pharmacological treatment of RE has failed. Alternatively, sperm can be retrieved from urine produced after masturbation.

Orgasm dysfunction Anejaculation is a major problem, since ejaculate is needed for conception. The majority of men with this dysfunction will fit within four groups: anejaculation due to neurological damage; medication-induced; lifelong emotionally inhibited; and situational (performance failure).

Due to neurological damage Over 80% of young men suffering from spinal cord injury can ejaculate with strong penile vibratory stimulation. One approach is to apply the FertiCare vibrator, at a frequency of 100 Hz and a peak-to-peak amplitude of 2.5 mm.16 Rectal electroejaculation should be reserved for failures.17 In men who have type 1 diabetes mellitus or have undergone retroperitoneal or intrapelvic operations, the results of penile vibration will probably be less favorable.

Medication-induced A high percentage of anorgasmia is due to medication, the selective serotonin reuptake inhibitor (SSRI) antidepressants being most notorious. Serotonin changes are responsible for delayed orgasm in 57% and no orgasm in 45% of patients using SSRIs or venlafaxine.18 Various strategies can be used to induce orgasm/ejaculation.19 The serotonin changes can be counteracted with antidotes, for example the antiserotonergic cyproheptadine (4–16 mg, 1 h before intercourse or masturbation). For orgasm per se, the dopaminergic amantadine can be used. However, there is a case report where amantadine seemed to impair gamete function during IVF–embryo transfer (IVF–ET).20 Other recommended antidotes are bupropion (150 mg, 3 h before), methylphenidate (5 mg, 1 h before) and sildenafil (100 mg, 1 h before). In the case of SSRIs with a short half-life, the serotonergic action can be counteracted by not taking the drug for 72 h. Sexual function will then have returned to normal in most men, usually without impairment of the antidepressive or antianxiety action.21 When a man taking paroxetine experiences symptoms of acute withdrawal, halving the dose for 72 h can be tried. Because of the long half-life, this ‘drug holiday’ strategy is not possible with fluoxetine.

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Lifelong emotionally inhibited Being lifelong, this is poorly amenable to acute treatment. However, with properly applied treatment, the results are reasonable.22 To prevent aggressive procedures such as electroejaculation or testis biopsy, one could try to harvest and cryopreserve the nocturnal emission. This usually happens more easily after ‘sexual priming’ (administering before sleep as much erotic stimulation as is acceptable). Some of these men eventually learn to ejaculate with a strong vibrator (FertiCare), combined with pharmacological support. Although there is some clinical experience with antiserotonergics (cyproheptadine), dopaminergics (amantadine) and stimulants (methylphenidate), convincingly effective treatments are not yet available.15 It is obvious that one should aim at both relaxation (‘let it go’) and sexual excitement. However, in practice, many of these men are not amenable to the use of erotic imagination, visual stimulation, etc.

Situational In this case, the man fails to ejaculate because of the stress of the moment. The approach basically consists of diminishing the insecurity and performance failure and increasing the stimulation. Insecurity can be partially reduced by information on back-up solutions (‘If you don’t succeed, don’t worry, we have several other solutions!’). For instance, having a cryopreserved sperm sample (even if the quality is not that good) can diminish performance failure. Stimulation can be increased by combining the use of a PDE5 inhibitor, a vibrator and visually explicit erotic stimulation.

Poor ejaculate When the ejaculate is of poor quality, one can try to improve this on the day of oocyte pick-up. High sexual stimulation during masturbation with X-rated videos resulted in recovery of spermatozoa of greater fertilizing potential in both normozoospermic and cryptozoospermic men.23 This sometimes can obviate the need for testicular biopsy. Another way to enhance the ejaculate quality is by extending the excitement phase. The duration of pre-ejaculatory sexual arousal is an important predictor of ejaculate quality for specimens produced by masturbation.24 This can be troublesome in busy departments. A further room, well adapted for this purpose, could diminish the stress for both the man and the department.

Vaginismus For many couples wishing to conceive, vaginismus is no longer a problem when they realize that it can be solved by self-insemination. However,

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when vaginal ultrasound, intrauterine insemination or embryo transfer are inevitable, vaginismus becomes a major obstacle. Of course, it is best to treat the vaginismus before assisted reproduction is started. Treatment is usually based on a combination of systematic desensitization and psychosexual education, sometimes supplemented with cognitive behavioral therapy and hypnosis25 and specialized pelvic-floor physiotherapy. Unfortunately, fertility departments are regularly caught in the ‘Catch 22’ situation, where treatment is promised or started and the woman’s vaginismus threatens to disturb the process. What strategies can be employed to overcome this?

General anesthesia This seemingly logical solution is very threatening to many women with vaginismus. The clinical experience is that the anxiety increases and the ‘vaginistic behavior’ is prolonged because of the loss of control.

Self-hypnosis, self-relaxation and imagery Self-hypnosis techniques can usually be learned in a short period of time.26 The woman learns induction, then deepening and then proceeding to ‘a safe place’. Improving the positive imagery capacities is another way of coping with pain and other threatening moments.27 One may expect good results when these strategies are combined with self-management.

Self-management Having control over the situation is a very important item. For some women, a feeling of self-competence is more important than a bit of pain. Many women can learn to introduce the speculum or vaginal probe themselves. This is much easier when a woman is always attended by the same fertility professional (if possible a very patient female).

Medication Psychiatrists have tried anxiolytics and gynecologists have tried muscle relaxants, and usually none of these women have resolved their vaginismus. For some women, losing control under medication can be a rather threatening experience. Something should be said here about botulinum toxin. In Iran, this was injected in the muscles inside the vagina of women with vaginismus, while they were either lightly sedated or under general anesthetic. The majority of

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these women were able to have pain-free intercourse after one or two treatment sessions, and none of them experienced any side-effects.28 This approach will neither appeal to nor be understood by most Western professionals. We believe that we can offer some explanation. In our hospital in Rotterdam, we treat many Islamic women with vaginismus. In a small percentage, their problem was solved once the husband had penetrated his wife when she was sound asleep. This was arranged with her full consent and with a strong dose of sleeping tablets. It was astonishing to find that after the first intercourse the woman had no more fear. We call these cases defloration phobia instead of penetration phobia. It will be clear that such cases will be found mainly in societies or groups with a very high premium on virginity.

The aftermath of trauma and post-traumatic stress disorder When harboring memories of sexual trauma, the vaginal interventions of assisted reproduction can be very threatening. The combination of being undressed, laying down, having someone standing between her legs (especially when male), experiencing the stress of the situation (‘Will I become pregnant?’), having items inserted in her vagina and eventually suffering pain can suddenly break the woman’s resistance and cause vivid flashbacks and memories. With the patient anxious, screaming or crying, with the husband confused or angry and with the physician confused, angry and maybe guilty, one could call this an acute emergency. Such situations have to be prevented. Unfortunately, there is no ‘quick-fix’ approach such as general anesthesia or anxiolytics, since this can easily revictimize the woman because she loses control again. Being aware of traumatic histories, it is best to put treatment strategies in place prior to intervention. However, often one cannot wait until that process is ready. Besides, some patients do not need a full trauma treatment and can learn in some sessions to handle the stress of assisted reproduction. So what can be done?

Treatment strategies Not losing control is a most important principle here. Ahead of the intervention, the woman should know exactly what will happen, and she should be allowed (as far as is feasible) to have control during the various steps of a procedure, for example by saying ‘stop’ or ‘I need a break’, etc. Dealing with this technique has to be learned also by the physician. With these patients in particular, the professional should always be the same person and preferably female (if the patient was abused by a male). For moments when control is not feasible, the patient should learn how to handle the emotions that may surface during that temporary lack of control.

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During this explanation and learning stage, she should again and again be able to reconsider her decision. Depending on the seriousness of the emotional disturbance, such counseling and developing of skills to deal with the intervention can be done by a therapist, by a fertility nurse or by the physician. Depending on his emotional capacities, the partner should be used, since his support can be of utmost importance. Tools that may be useful for preparing women to undergo these interventions are self-hypnosis (‘going to a safe place’), imagery exercises, relaxation exercises (breathing exercises), and using meditation music and transitional objects (e.g. a cuddly toy) to help the woman feel that this time no harm will be done to her.27 Additionally, control can be increased when the woman or her partner can carry out part of the procedure, as in vaginismus (such as introducing the speculum or vaginal probe).

Medication Medication is regularly used in the course of a full PTSD treatment.29 The important function is to relax the patient sufficiently so that she can pass through the psychotherapy process. So why not try an anxiolytic (maybe with an amount of retrograde amnesia) as a way to deal with the woman’s stress? Unfortunately, this strategy usually diminishes the sense of control. Medication may numb the woman’s body or disconnect her from her body. The situation becomes more tricky in the woman who experienced dissociation during her abuse, because this comes close to recreating the abuse. It becomes plainly disastrous in the woman who has been doped during her abuse. Hence, medication is frequently inappropriate. There are, however, patients for whom medication can help. Some women have learned to use a fast-acting anxiolytic when starting to feel anxious. That experience should become integrated into the counseling in such a way that the woman knows that she is in control of that medication, and if and when to use it. In an integrated approach, some women benefit from learning how to use and handle their own anxiolytic. Using an unknown preparation is far more risky.

In real emergencies Sometimes, in spite of supposed proper preparation, the patient collapses emotionally – and this can also happen out of the blue. What should one do when things really go wrong? Depending on the situation, one has to decide the best strategy: administer a strong anxiolytic and continue the procedure; stop the procedure and try to calm the woman before continuing;

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or announce stopping the procedure completely. Usually, the partner will know how the patient can be calmed, for example when she is held by her partner or by a nurse. Whatever strategy is followed, afterwards ample time and attention are needed to sort out exactly what happened, how to proceed and eventually how this can be prevented next time.

POST-IVF FOLLOW-UP Optimal continuation of the sexual relationship deserves our attention, especially when assisted reproduction has contributed to a disturbed sexual life. For couples leaving treatment without a child, sex can be the vital element in continuing their relationship. For couples with a baby, sex is needed both to preserve the ‘lover’ aspects of their relationship and to cope with the hassles of parenthood. All that is required is to inquire whether their sexual life is satisfactory and without problems, and, if not, refer them to a good sex therapist.

SUMMARY OF MANAGEMENT OPTIONS (1) Be aware that, in assisted reproduction, the procreative aspects of sex can easily harm or even destroy the recreational and relationship aspects of sex and, as such, the quality of life. (2) Spend extensive time on thorough sexual history-taking, and so anticipate the various reactions to the stress of assisted reproduction such as ejaculatory performance failure and re-experienced sexual abuse. (3) In the case of erectile or ejaculatory failure, spend time motivating the man as much as possible into maximum sexual stimulation (vibrator, X-rated movies, PDE5 inhibitor, etc.). (4) Ensure that the fertility unit has a room optimally equipped and maintained for masturbation with vibrator and visual stimulation available, where the man can spend time undisturbed. (5) In the case of a history of insufficiently addressed sexual abuse, ask for assessment by a professional experienced in sexual violence. If possible, put treatment strategies in place prior to intervention. (6) In the case of vaginismus (and sexual abuse experience), spend time during preparation on self-management strategies and let all procedures be done by the same team.

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(7) In the case of a history of sexual abuse (when keeping control is very elementary for the woman), spend much time on counseling both the couple and the team in how to handle the stress of the situation. Use anxiolytic medication only within such a combined approach.

REFERENCES 1. Dekker J. Inhibited male orgasm. In O’Donohue W, Geer JH, eds. Handbook of Sexual Dysfunctions. Assessment and Treatment. Boston: Allyn & Bacon, 1993 2. Simons JS, Carey MP. Prevalence of sexual dysfunctions: results from a decade of research. Arch Sex Behav 2001; 30: 177–219 3. Drenth JJ. Vaginismus and the desire for a child. J Psychom Obstet Gynecol 1988; 9: 125–38 4. Coëffin-Driol C, Giami A. L’impact de l’infertilité et de ses traitements sur la vie sexuelle et la relation de couple: revue de la littérature [The impact of infertility and its treatment on sexual life and marital relationships: review of the literature]. Gynecol Obstet Fertil 2004; 32: 624–37 5. Leiblum SR, Aviv A, Hamer R. Life after infertility treatment: a long-term investigation of marital and sexual function. Hum Reprod 1998; 13: 3569–74 6. Oddens BJ, Tonkelaar den I, Nieuwenhuyse H. Psychosocial problems in women facing fertility problems. Hum Reprod 1999; 13: 255–61 7. Saleh RA, Ranga GM, Raina R, et al. Sexual dysfunction in men undergoing infertility evaluation: a cohort observational study. Fertil Steril 2003; 79: 909–12 8. Ragni G, Caccamo A. Negative effect of stress of in vitro fertilization program on quality of semen. Acta Eur Fertil 1992; 23: 21–3 9. Drudy L, Harrison R, Verso J, et al. Does patient semen quality alter during an in vitro fertilization (IVF) program in a manner that is clinically significant when specific counseling is in operation? J Assist Reprod Genet 1994; 11: 185–8 10. Terr LC. Childhood traumas: an outline and overview. Am J Psychiatry 1991; 148: 10–20 11. Purvis K, Muirhead GJ, Harness JA. The effects of sildenafil on human sperm function in healthy volunteers. Br J Clin Pharmacol. 2002; 53 (Suppl 1): 53S–60S 12. Hellstrom WJ, Overstreet JW, Yu A, et al. Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 2003; 170: 887–91 13. van Roijen JH, Slob AK, Gianotten WL, et al. Sexual arousal and the quality of semen produced by masturbation. Hum Reprod 1996; 11: 147–51 14. Kamischke A, Nieschlag E. Update on medical treatment of ejaculatory disorders. Int J Androl 2002; 25: 333–44

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15. Lim TC, Mallidis C, Hill ST, et al. A simple technique to prevent retrograde ejaculation during assisted ejaculation. Paraplegia 1994; 32: 142–9 16. Sonksen J, Biering-Sorensen F, Kristensen JK. Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. Paraplegia 1994; 32: 651-60 17. Ohl DA, Sonksen J, Menge AC, et al. Electroejaculation versus vibratory stimulation in spinal cord injured men: sperm quality and patient preference. J Urol 1997; 157: 2147–9 18. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry 2001; 62: 10–21 19. Zajecka J. Strategies for the treatment of antidepressant-related sexual dysfunction. J Clin Psychiatry 2001; 62 (Suppl 3): 35–43 20. Cowan BD, Lucas JA 3rd, Sopelak VM, et al. Failed fertilization during an in vitro fertilization cycle after oral ingestion of amantadine hydrochloride. J In Vitro Fert Embryo Transf 1988; 5: 282–5 21. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995; 152: 1514–16 22. Apfelbaum B. Retarded ejaculation. In Leiblum SR, Rosen RC, eds. Principles and Practice of Sex Therapy, 3rd edn. New York: Guilford Press, 2000: 205–41 23. Yamamoto Y, Sofikitis N, Mio Y, et al. Influence of sexual stimulation on sperm parameters in semen samples collected via masturbation from normozoospermic men or cryptozoospermic men participating in an assisted reproduction programme. Andrologia 2000; 32: 131–8 24. Pound N, Javed MH, Ruberto C, et al. Duration of sexual arousal predicts semen parameters for masturbatory ejaculates. Physiol Behav 2002; 76: 685–9. 25. McGuire H, Hawton K. Interventions for vaginismus. Cochrane Database Syst Rev 2003; (1): CD001760 26. O’Neill LM, Barnier AJ, McConkey K. Treating anxiety with self-hypnosis and relaxation. Contemp Hypnosis 1999; 16: 68–80 27. Zolbrod AP. Men, Women and Infertility. Intervention and Treatment Strategies. New York: Lexington Books, 1993 28. Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004; 104: 922–5 29. Yehuda R, Marshall R, Penkower A, et al. Pharmacological treatments for posttraumatic stress disorder. In Nathan PE, Gorman JM, eds. A Guide to Treatments that Work, 2nd edn. New York: Oxford University Press, 2002: 411–55

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Chapter 7

The obese patient B Ola and WL Ledger

INTRODUCTION Obesity can be defined as an excessive amount of body fat, leading to physical ill-health or adverse effects on socioeconomic or psychological well-being. Obesity is thought to result from a combination of environmental and genetic factors. There are several methods for estimating body fatness in adults; these include total body weight, waist circumference and hip circumference. Several indices of obesity have been derived from these measurements, including body mass index (BMI), waist-to-hip ratio (WHR), abdominal volume index (AVI), abdominal visceral adiposity (measured by magnetic resonance imaging) and body fat content. However, BMI is the most widely used index of body fatness in relation to body weight and height. BMI is defined as the weight (in kilograms) divided by the square of the height (in meters). Obesity is a growing problem in many parts of the world. However, that this condition is a problem is not uniformly acknowledged. Sociocultural and ethnic factors redefine what may be considered pathological weight gain in some parts of the world, but may be regarded as acceptable or desirable or even considered a hallmark of beauty and social wellbeing in other parts. The World Health Organization (WHO) described health as ‘a state of complete physical, mental, and social well-being, and not merely the absence of disease or infirmity’;1 yet, it offered a blanket definition for being overweight (BMI 25–29.9) or obese (BMI ≥ 30).2 The WHO may therefore appear to contradict itself by advocating a broad definition for good health, but a restrictive classification for overweight and obese people without consideration of geographic, social or psychological determinants of ill-health. This point has been variously debated.

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Whereas some researchers have not found ethnic influences in BMI measurements between black and white volunteers,3 others have suggested lower BMI cut-offs in Chinese and Asians,4 and in yet another study African–Americans responded by choosing a larger ideal body size than Caucasians and Asians in the same environment.5 This lack of consensus has prompted the WHO to reopen the debate, leading to a consultation document on whether geographical factors should be allowed to influence BMI cut-offs.6 Notwithstanding societal and cultural views, the clinical use of BMI as a predictor of risk of morbidity carries a good evidence base (Table 1). BMI > 25 is associated with an increased risk of type 2 diabetes mellitus, gallbladder disease, essential hypertension, hypercholesterolemia, coronary heart disease, asthma and osteoarthritis.7 In another study, obesity, cigarette-smoking and hypertension were found to be independent risk factors for pulmonary embolism.8 Similarly, a BMI > 26 has been found to increase significantly the odds of developing thrombotic stroke compared with women with BMI < 21.9

OBESITY AND POLYCYSTIC OVARIAN SYNDROME Polycystic ovarian syndrome (PCOS) is a multisystemic endocrine disorder affecting about 5% of women in the developed world. It is characterized by infrequent ovulation or anovulation, clinical and/or biochemical features of hyperandrogenism, and polycystic ovaries appearance on transvaginal ultrasonography – a diagnosis strengthened by the exclusion of lateonset congenital adrenal hypertrophy (LoCAH), Cushing’s syndrome or adrenal tumors. PCOS has been associated with genomic variants linked with increased oxidative stress, hyperandrogenemia, obesity, insulin resistance and/or type 2 diabetes mellitus.10 Furthermore, the metabolic syndrome, comprising central obesity, impaired glucose tolerance, hypertension and dyslipidemia, is associated with PCOS, and carries increased risk of type 2 diabetes mellitus and ischemic heart disease.11

OBESITY AND REPRODUCTIVE PERFORMANCE Overweight and obese women appear to have compromised reproductive performance. This was demonstrated by Jensen and colleagues12 who compared women with BMI > 25 with those with BMI between 19 and 25. After adjusting for confounding variables, they found an odds ratio (OR) for fecundability of 0.77 (95% confidence interval (CI) 0.70–0.84). This

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Table 1 Medical and reproductive disorders commonly associated with obesity Medical diseases worsened by obesity

Reproductive disorders associated with obesity

Type 2 diabetes mellitus

Menstrual irregularity

Gallbladder disease

Anovulation

Essential hypertension

Delay to pregnancy

Hypercholesterolemia

Reduced fecundity

Coronary heart disease

Miscarriages

Asthma Osteoarthritis Venous thromboembolic disorders

reduction in fecundability might be explained by infrequent ovulation and menstrual irregularity, leading to delay to pregnancy. The pathogenesis is uncertain, but may be related to elevated leptin secretion from adipose tissue, which acts via neuropeptide Y secreted by the hypothalamus.13 Neuropeptide Y has recently been linked with regulation of the onset of menstruation at puberty; and abnormal secretion of leptin has been implicated in the pathogenesis of precocious or delayed puberty, anovulation in underweight women and PCOS.13–15 The value of weight loss to the infertile obese patient has been repeatedly shown in many studies. Weight loss improves the chances of spontaneous or stimulated ovulation and facilitates interventions including laparoscopy and transvaginal scanning. All women with raised BMI should have (well-documented) counseling regarding weight loss, and be offered support in a weight-loss program. The fertility specialist may, however, face the dilemma of the aging patient who has repeatedly been unable to lose weight. Since advancing age from mid-30s onwards has such a deleterious effect on in vitro fertilization (IVF) performance, a point may be reached at which a decision to proceed with IVF treatment despite persistent obesity may be safer and more likely to lead to a live birth than further delay.

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IMPACT OF OBESITY ON IVF OUTCOMES Pregnancy rates after IVF and intracytoplasmic sperm injection (ICSI) among obese (BMI 30–35) and very obese (BMI > 35) women appear to be reduced compared with normal and moderately overweight women.16 This is particularly so in women with a WHR > 0.8.17 IVF is also more problematic in obese women. They are more likely to have menstrual and ovulatory disorders and therefore it is more difficult to plan the start of their treatments. Furthermore, failure to down-regulate the pituitary adequately may lead to an increased cancellation rate at this stage. More follicle stimulating hormone (FSH) may then needed for adequate ovarian stimulation in obese, non-PCOS, normogonadotropic women compared with normal-weight women,18–20 although other studies have not demonstrated this association between obesity and increased FSH requirements for IVF.21,22 Obesity may lead to complications at oocyte collection. Laparoscopic oocyte collection is difficult or impossible in obese women, but this approach has largely been superseded by transvaginal ultrasoundguided oocyte collection. Extreme obesity may make ultrasound identification of follicles difficult, although good-quality equipment can largely overcome this obstacle. Fertilization rates after IVF or ICSI do not appear to be affected by obesity.20 A further compromised variable affecting IVF outcome in the obese patient is the ease of embryo transfer. The success of IVF partly depends on a good embryo transfer technique. However, in the very obese woman, despite adequate anticipation and preparation, the cervix may recede behind folds of vaginal skin, making the transfer procedure unduly prolonged and difficult, resulting in reduced pregnancy rates.

PREGNANCY OUTCOME IN OBESE PATIENTS Overweight and obese women are more prone to adverse pregnancy outcomes (Table 2). Obesity is also associated with increased risk of firsttrimester and recurrent miscarriages in IVF pregnancies,20,23 supporting earlier findings linking obesity with an increased tendency to miscarry.24,25 Pre-pregnancy obesity also carries increased risk of fetal macrosomia and maternal hypertensive disease, impaired glucose tolerance, diabetes mellitus and venous thromboembolic disorders antenatally. Obese women are at risk of difficult delivery with shoulder dystocia, are more likely to require cesarean section for failure to progress in labor and are prone to a higher rate of postnatal venous thromboembolic and respiratory complications.26

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Table 2

Poor obstetric and perinatal outcomes associated with obesity

Poor obstetric performance associated with obesity

Poor perinatal outcomes associated with obesity

Maternal hypertensive disease

Neural tube defects

Impaired glucose tolerance and diabetes mellitus

Omphaloceles

Venous thromboembolic disorders

Ophthalmic anomalies

Difficult delivery with shoulder dystocia due to fetal macrosomia

Esophageal defects

Increased Cesarean section rate for failure to progress in labor

Intestinal defects

Increased rate of wound infection and wound dehiscence Postnatal respiratory complications

Heart defects

Cardiac anomalies Urogenital anomalies Limb defects Multiple fetal anomalies

A large American case–control study27 showed that obese and overweight women, compared with normal-weight women, were more likely to have babies with neural tube defects (OR 3.5, 95% CI 1.2–10.3), omphaloceles (OR 3.3, 95% CI 1.0–10.3), heart defects (OR 2.0, 95% CI 1.2–3.4) and multiple anomalies (OR 2.0, 95% CI 1.0–3.8). Proposed explanations for these findings include hyperglycemia, hyperinsulinemia or coexisting diabetes mellitus, and dietary vitamin deficiencies, all of which are associated with birth defects. Other studies have also linked obesity with ophthalmic, esophageal, cardiac, intestinal, urogenital and limb defects.28–31

WELFARE OF THE CHILD Obese women are more likely to give birth to large-for-dates or macrosomic infants, who are at increased risk of subsequent childhood and adolescent obesity. Some have proposed that such babies may inherit their parent’s tendency to insulin resistance and may develop childhood type 2

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diabetes mellitus, or suffer hypertensive and coronary heart diseases in adulthood.32 On the contrary, Barker’s hypothesis of fetal origins of adult disease suggests that it is small-for-gestational-date infants that are at increased risk of coronary heart disease, hypertension, impaired glucose tolerance and hypercholesterolemia.33 We do not believe that at present there is sufficient evidence of harm in childhood to justify withholding assisted conception treatment from infertile couples solely on ‘welfare of the child’ grounds.

PSYCHOLOGICAL ASPECTS OF OBESITY In many Western communities, being overweight or obese may be associated with low self-esteem, particularly among adolescents. Exposure to adverse childhood experiences such as child abuse, bullying, poor parenting and poor diet can initiate or worsen obesity-related depression.34,35 It has also been demonstrated that women are more likely than men to become depressed as a result of obesity.34 Being overweight or obese may not, however, always be regarded as depressing or socioculturally undesirable.36,37 In the USA, white Americans were more likely than African-Americans to choose a lower body mass as ideal, whereas the latter group were less likely to consider themselves ‘obese’ but may rather consider a larger body mass as a mark of beauty.38 Further research is needed to determine reproductive outcome in this group of ‘obese’ women with good self-esteem, to try to dissociate societal values leading to behavioral causes of subfertility (e.g. reduced frequency of intercourse, delay in finding a lifetime partner until advanced female age) from the physiological effects of obesity on reproduction.

SHOULD A ‘CUT-OFF’ BMI BE IMPOSED FOR WITHHOLDING IVF TREATMENT? There is a lack of consensus on the adverse effects of obesity on the outcome of assisted conception treatment. Whilst some reports link obesity with an increased risk of reproductive disorders and reduced fecundity in the infertile population,16,17,20 others have not found a significant negative effect of being overweight on IVF pregnancy rate,39 or an adverse affect of being overweight or obese on superovulation and IVF treatments.21 Furthermore, Wang and colleagues40 recently reported increased pregnancy rates in obese and overweight women who underwent stimulated intrauterine insemination treatments, compared with non-obese and

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underweight women. The results of retrospective studies must be treated with caution: although such studies may contain large groups of patients, they may lack adequate control groups, leading to erroneous comparisons of outcomes. Dosage of FSH, for example, may merely reflect the prescribing clinician’s belief that obese women require higher doses of gonadotropins. The only means of resolving these controversies is by prospective randomized controlled trials. Clinical guidelines on fertility assessment and treatment for people with fertility problems in the UK were commissioned by the National Institute for Clinical Excellence (NICE) and published in 2004. The guideline development group adopted the WHO definitions for obese and overweight women. Their recommendation is that ‘BMI outside 19–30 is likely to reduce the success of assisted reproduction procedures’ based on evidence from four retrospective studies.39,41–44 However, the conclusion that withholding assisted conception treatment from moderately obese women can be justified on grounds of the reduced pregnancy rate is open to question. Table 3 summarizes the evidence from various studies linking obesity with pregnancy outcomes. Although Wang and colleagues16 and Fedorcsak and associates44 demonstrated significantly lower cumulative clinical pregnancy rates (CPR) and live-birth rates (LBR) per cycle of IVF treatment in overweight/obese women, respectively, other studies contradict these findings.21,40 It is also significant that CPR and LBR figures quoted for obese women by Wang and colleagues16 and Fedorcsak and associates44 are higher than the published average figures for the UK.45 The evidence used by the NICE guideline development group was largely taken from retrospective studies that were conducted outside the UK, from countries in which treatment protocols and IVF practices may differ significantly. Not surprisingly, those studies that featured prominently in the NICE guidelines39,42–44 all reported pregnancy rates that are very different from those in the UK, and may not be directly generalizable to UK practice.

SUMMARY OF MANAGEMENT OPTIONS IVF treatment has become commonplace in the Western world, and is a growing part of health-care in many parts of the Middle and Far East also. Careful selection of patients of high IVF fecundity, i.e. young slim women with short infertility history, with cause of infertility attributable to tubal blockage without hydrosalpinx, male factor infertility (± ICSI) or unexplained infertility, has allowed some assisted reproductive technologies (ART) centers to achieve impressively high pregnancy rates after IVF.

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Study characteristics

Small prospective cohort study Location: Sweden n = 190 IVF cycles

Retrospective study Location: UK n = 333 women

Large retrospective study Location: Australia n = 3145 women

Retrospective study Location: France n = 248 IVF cycles

Wass et al.,17 1997

Lashen et al.,21 1999

Wang et al.,16 2000

Wittemer et al.,39 2000

LBR = 15.2% per cycle

Very obese (BMI ≥ 35)

CPR = 40% after 2.1 cycles OR = 0.73 (0.57–0.95)

Continued


CPR = 23.7 per cycle for BMI ≥ 28 p = 0.69

LBR = 14.3% per cycle for BMI ≥ 25 p = 0.99


CPR = 20% per cycle for BMI < 28

CPR = 48% after 2.3 cycles

Obese (BMI = 30–34.5)

CPR = 14.7% per cycle for BMI ≥ 25 p = 0.14

Overweight (BMI = 25–29.9)

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CPR = 28.9% per cycle

Normal (BMI = 20–24.9)

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Authors and year of study

Table 3 Summary of studies comparing pregnancy outcomes in normal women and overweight and obese women undergoing in vitro fertilization (IVF)

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Retrospective study Location: Norway n = 383

Retrospective study Location: USA n = 180 IVF cycles

Meta-analysis of 5 experimental and observational studies n = 369 women

Retrospective study Location: USA n = 420 cycles

Fedorcsak et al.,44 2000

Loveland et al.,43 2001

Mulders et al.,19 2003

Nichols et al.,42 2003

Obese (BMI = 30–34.5)

OPR = 24.7% per cycle for BMI ≥ 25 p = 0.13

CPR = 35.2% per cycle for BMI ≥ 28 p = 0.1

Pooled OR = 1.22 (0.77–1.93) for BMI = 25–30

CPR = 52.1% per cycle for BMI 20–27.9


LBR = 63.3% per cycle for BMI ≥ 25


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OPR = 50.6% per cycle

LBR = 75% per cycle


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Continued


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LBR = 19.0% per cycle for BMI = 25–29.9 cum LBR = 44.9% after 3 cycles

LBR = 20.7% per cycle for BMI = 18.5–24.9 cum LBR = 50.3% after 3 cycles



cum LBR = 41.4% after 3 cycles p† = 0.3

LBR = 16.9% per cycle for BMI > 30 * p = 0.3

Obese (BMI = 30–34.5)

p* as derived by authors for linear trend in four groups, inclusive of 134 cycles in underweight women with body mass index (BMI) < 18.5 (not shown in this table) with live-birth rate (LBR) = 21.3%; p† as calculated by authors using Kaplan–Meier for cumulative live-birth rates (cum LBR) in four groups, inclusive of underweight women (not shown in this table) with cum LBR = 46.6%; CPR, clinical pregnancy rate; OPR, ongoing pregnancy rate

Large retrospective study Location: Norway n = 4944 cycles

Fedorcsak et al.,20 2004


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Continued

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Table 3

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However, in the ‘real world’, not all patients fit into the ‘high IVF fecundity’ group, but still present with problems of infertility and request treatment with IVF. Whether to offer treatment to these patients is a philosophical question. Basic biology holds some of the answers: IVF treatment is probably pointless for an amenorrheic 50-year-old with FSH of 40 IU/l, unless donor oocyte treatment is available. However, although moderately obese women may have suboptimal IVF outcomes and may present particular management problems during IVF and through pregnancy, it is incorrect to label them as untreatable. Careful management of obese obstetric patients in a ‘high-risk’ clinical setting should lead to a good outcome. Provided that obese patients are carefully advised at the outset about problems that may be encountered during IVF treatment and in pregnancy, and that they give informed consent that they wish to proceed under these circumstances, refusal of treatment may be deemed unethical. Whilst obese women are more prone to many medical and reproductive disorders, the reproductive risks of moderate obesity are not great. Denying access to funded assisted conception treatment simply because the female partner is overweight may be considered a violation of Articles 12 (the right to marry and found a family) and 14 (prohibition of discrimination) of the Human Rights Act.46 Article 17 (prohibition of abuse of rights) prohibits the abuse of human rights ‘on any ground such as sex, race, colour, language, religion, political or other opinion, national or social origin, association with a national minority, property, birth or other status’. It is therefore plausible that, in time, such policies may be subject to legal challenge.

REFERENCES 1. World Health Organization. Constitution of the World Health Organization. 1948 http://policy.who.int 2. World Health Organization. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Consultation. WHO Technical Report Series Number 854. Geneva: WHO, 1995 3. Gallagher D, Visser M, Sepulveda D, et al. How useful is body mass index for comparison of body fatness across age, sex, and ethnic groups? Am J Epidemiol 1996; 143: 228–39 4. Ko GT, Tang J, Chan JC, et al. Lower BMI cut-off value to define obesity in Hong Kong Chinese: an analysis based on body fat assessment by bioelectrical impedance. Br J Nutr 2001; 85: 239–42 5. Gluck ME, Geliebter A. Racial/ethnic differences in body image and eating behaviors. Eat Behav 2002; 3: 143–51

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6. World Health Organization Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363: 157–63 7. Must A, Spadano J, Coakley EH, et al. The disease burden associated with overweight and obesity. JAMA 1999; 282: 1523–9 8. Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642–5 9. Rexrode KM, Hennekens CH, Willett WC, et al. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 1997; 277: 1539–45 10. San Millan JL, Corton M, Villuendas G, et al. Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab 2004; 89: 2640–6 11. Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 2004; 89: 2601–7 12. Jensen TK, Scheike T, Keiding N, et al. Fecundability in relation to body mass and menstrual cycle patterns. Epidemiology 1999; 10: 422–8 13. Goumenou AG, Matalliotakis IM, Koumantakis GE, Panidis DK. The role of leptin in fertility. Eur J Obstet Gynecol Reprod Biol 2003; 106: 118–24 14. Kopp W, Blum WF, von Prittwitz S, et al. Low leptin levels predict amenorrhea in underweight and eating disordered females. Mol Psychiatry 1997; 2: 335–40 15. Licinio J, Mantzoros C, Negrao AB, et al. Human leptin levels are pulsatile and inversely related to pituitary–adrenal function. Nat Med 1997; 3: 575–9 16. Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 2000; 321: 1320–21 17. Wass P, Waldenstrom U, Rossner S, Hellberg D. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilization–embryo transfer. Hum Reprod 1997; 12: 2057–60 18. Soderstrom-Anttila V, Foudila T, Hovatta O. A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme. Hum Reprod 1996; 11: 1864–70 19. Mulders AG, Laven JS, Eijkemans MJ, et al. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. Hum Reprod Update 2003; 9: 429–49 20. Fedorcsak P, Dale PO, Storeng R, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod 2004; 19: 2523–8 21. Lashen H, Ledger W, Bernal AL, Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization. Hum Reprod 1999; 14: 712–15 22. Loh S, Wang JX, Matthews CD. The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients. Hum Reprod 2002; 17: 1207–11

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23. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case–control study. Hum Reprod 2004; 19: 1644–6 24. Hamilton-Fairley D, Kiddy D, Watson H, et al. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotropin. Br J Obstet Gynaecol 1992; 99: 128–31 25. Bellver J, Rossal LP, Bosch E, et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003; 79: 1136–40 26. Sheiner E, Levy A, Menes TS, et al. Maternal obesity as an independent risk factor for caesarean delivery. Paediatr Perinat Epidemiol 2004; 18: 196–201 27. Watkins ML, Rasmussen SA, Honein MA, et al. Maternal obesity and risk for birth defects. Pediatrics 2003; 111: 1152–8 28. Waller DK, Mills JL, Simpson JL, et al. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol 1994; 170: 541–8 29. Queisser-Luft A, Kieninger-Baum D, Menger H, et al. [Does maternal obesity increase the risk of fetal abnormalities? Analysis of 20 248 newborn infants of the Mainz Birth Register for detecting congenital abnormalities.] Ultraschall Med 1998; 19: 40–4 30. Moore LL, Singer MR, Bradlee ML, et al. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 2000; 11: 689–94 31. Mikhail LN, Walker CK, Mittendorf R. Association between maternal obesity and fetal cardiac malformations in African Americans. J Natl Med Assoc 2002; 94: 695–700 32. Deckelbaum RJ, Williams CL. Childhood obesity: the health issue. Obesity Res 2001; 9 (Suppl 4): 239S–43S 33. Barker DJ, Hales CN, Fall CH, et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36: 62–7 34. Carpenter KM, Hasin DS, Allison DB, Faith MS. Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. Am J Public Health 2000; 90: 251–7 35. Faith MS, Matz PE, Jorge MA. Obesity–depression associations in the population. J Psychosom Res 2002; 53: 935–42 36. Forestell CA, Humphrey TM, Stewart SH. Is beauty in the eye of the beholder? Effects of weight and shape on attractiveness ratings of female line drawings by restrained and nonrestrained eaters. Eat Behav 2004;5: 89–101 37. Baskin ML, Ahluwalia HK, Resnicow K. Obesity intervention among AfricanAmerican children and adolescents. Pediatr Clin North Am 2001; 48: 1027–39 38. Stevens J, Kumanyika SK, Keil JE. Attitudes toward body size and dieting: differences between elderly black and white women. Am J Public Health 1994; 84: 1322–5

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39. Wittemer C, Ohl J, Bailly M, et al. Does body mass index of infertile women have an impact on IVF procedure and outcome? J Assist Reprod Genet 2000; 17: 547–52 40. Wang JX, Warnes GW, Davies MJ, Norman RJ. Overweight infertile patients have a higher fecundity than normal-weight women undergoing controlled ovarian hyperstimulation with intrauterine insemination. Fertil Steril 2004; 81: 1710–12 41. National Institute for Clinical Excellence. Factors affecting the outcome of in vitro fertilisation treatments. In: Moody J, ed. Fertility Assessment and Treatment for People with Fertility Problems. Guideline Developed by the National Collaborating Centre for Women’s and Children’s Health. London: RCOG Press, 2004: 96 42. Nichols JE, Crane MM, Higdon HL, et al. Extremes of body mass index reduce in vitro fertilization pregnancy rates. Fertil Steril 2003; 79: 645–7 43. Loveland JB, McClamrock HD, Malinow AM, Sharara FI. Increased body mass index has a deleterious effect on in vitro fertilization outcome. J Assist Reprod Genet 2001; 18: 382–6 44. Fedorcsak P, Storeng R, Dale PO, et al. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand 2000; 79: 43–8 45. Human Fertilisation and Embryology Authority. The national data statistics for IVF clinics. London: HFEA, 2001. http://www.hfea.gov.uk/ForPatients/ PatientsGuidetoIVFClinics/NationalDataStatistics 46. Human Rights Act 1998, Chapter 42. London: HMSO, 1998

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Section 2 The IVF patient with gynecological problems

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The patient with endometriosis T Gurgan and A Demirol

INTRODUCTION Endometriosis is one of the most frequently encountered benign diseases in gynecology. This progressive and recurrent disease, mainly affecting women of reproductive age, is an important cause of pelvic pain, dysmenorrhea and dyspareunia, and infertility. Complete resolution of endometriosis is not yet possible, but therapy has essentially three main objectives: to delay recurrence for as long as possible, to reduce pain and to increase the possibility of pregnancy. Endometriosis affects 2.5–3% of women of reproductive age,1 and is diagnosed in 20–68% of women with infertility.2,3 It is likely that endometriosis occurs in most women at some stage in their reproductive years. The etiology and pathogenesis of endometriosis are beyond the scope of this chapter. However, while agreement exists as to the major factors that may lead to endometriosis, such as menstrual regurgitation and high exposure to menstruation and estrogen, many aspects regarding etiology and pathogenesis remain unsolved.

ENDOMETRIOSIS AS A CAUSE OF SUBFERTILITY The link between endometriosis and infertility is demonstrated by women with infertility showing an increased rate of endometriosis, while women with endometriosis have a higher rate of infertility. The mechanisms linking the two are complex and controversial. Numerous studies have reported alterations in the peritoneal environment in women with endometriosis, and have suggested that these changes may have an adverse effect on fertility.4 It has been proposed that secretory products of the

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ectopic endometrial and/or immune cells interfere with ovulation, endocrine function, gamete and embryo transport, oocyte fertilization, and embryo development and implantation.5 Substances implicated as having an antifertility effect have been variously identified. Extensive endometriosis may simply impair fertility by mechanical means. However, the main visible features of the minimal and mild stages of endometriosis are peritoneal or ovarian endometriotic implants and filmy adhesions on the Fallopian tubes or ovaries, and the causal link between these cases and infertility is much debated.6–8 Many treatments have been proposed for endometriosis-associated infertility, such as medical therapy, surgery or a combination of both. Surgical ablation or removal of the implants has been employed for many years. However, there is no convincing evidence that this treatment promotes a significant improvement in fertility.9,10 More recently, Marcoux and colleagues11 have demonstrated a significant improvement in pregnancy rates after ablation of endometriotic implants in patients with minimal or mild endometriosis. In cases of extensive endometriosis such as endometrioma when surgery is often indicated, it is important to consider the risks of treatment. Not only adhesion formation, but also the diminished ovarian reserve that may result from surgical removal of ovarian tissue or as a result of electrocautery may have a far more negative impact on in vitro fertilization (IVF) outcome that outweighs any benefit of surgery.

THE IMPACT OF ENDOMETRIOSIS ON IVF OUTCOME After male factor infertility and tubal factor infertility, endometriosis is the third most common indication for assisted reproductive technologies (ART). Problems of oocyte pick-up or transportation of the fertilized oocyte to the uterine cavity are indications for ART. Although both surgical and medical management of endometriosis have been associated with a reduction in symptoms, both have resulted in only a minimal increase in fertility.12,13 It is clear that some of these putative mechanisms of infertility in endometriosis may be corrected by controlled ovarian hyperstimulation with intrauterine insemination (COH–IUI), but in failed cases with this therapy IVF has provided a powerful therapeutic tool.12 In some patients with endometriosis, particularly in advanced disease, IVF should be considered as the first line of treatment. The IVF procedure corrects not only the endocrine and ovulatory dysfunction but also replaces abnormal ovum pick-up and gamete transport mechanisms, compensates for abnormal

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fertilization and may reduce the exposure of the oocyte to potentially adverse effects of the intraperitoneal environment. Theoretically, IVF provides the opportunity to study the impact of endometriosis on critical steps such as fertilization and implantation. Unfortunately, studies in this area remain controversial and difficult to interpret, due to the presence of several confounding factors. One major factor is the problem of an appropriate control group. Frequently, women with tubal disease and unexplained infertility are used as control groups. Both groups are probably invalid, because reduced efficiency of fertilization and implantation may be present in these groups. Also, patients with severe male factor infertility may not have been thoroughly investigated with laparoscopy in ART centers for the diagnosis of minimal or mild endometriosis. Second, the interpretation of studies involving ART is also problematic, because dysfunctions that contribute to subfertility in the natural cycle in endometriosis patients may be corrected by the use of gonadotropin releasing hormone (GnRH) agonist, ovarian stimulation, oocyte retrieval, IVF, and embryo culture and transfer. Several investigators have observed lower pregnancy rates in women with endometriosis, while others have found no difference between endometriosis patients and control groups. The impact of endometriosis on IVF is therefore likely not to act primarily via the lesions per se, but rather by more subtle dysfunctions that may be empirically overcome by the IVF treatment. IVF offers the highest pregnancy rates for endometriosis patients, but the question of whether the presence of endometriosis affects the outcome of women undergoing IVF has not been resolved. Recent studies have provided contradictory data. While some studies show no effect of endometriosis on IVF outcome,12,14 others have suggested negative effects on fertilization. Fertilization rates in patients with minor endometriosis were found to be significantly reduced in natural-cycle IVF compared with unexplained and tubal infertility.15 Moreover, there were significantly reduced fertilization rates in women with endometriosis undergoing stimulated IVF treatment.16–18 However, other studies have not found a difference in fertilization rates for women undergoing IVF treatment for endometriosis.14,19 Several studies have suggested an impairment of implantation in patients with endometriosis.19 On the other hand, this might be due to intrinsic deficiencies within the endometrium, as manifested by the aberrant uterine response to sex steroid hormones, or because of impaired oocyte/embryo quality.20 Further studies have pointed to low response and low fertilization rates but no difference in pregnancy rates compared with other indications.21 In contrast, other studies did indeed reveal lower pregnancy rates in patients with endometriosis.12,22,23

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Altered embryo development24 and higher rates of embryo arrest25 in women with endometriosis have been described, compared with healthy controls. It seems that the impairment found in embryos can be induced by previous defects in folliculogenesis. Moreover, clinical data regarding oocyte donation programs seem to support the theory of impaired quality of oocytes from ovaries of endometriosis-affected women.23 To achieve successful implantation, pregnancy and subsequent birth, in addition to adequate embryo quality, an appropriate endometrium is mandatory. The endometrium should be able to accept embryo attachment and development. Although there is no general agreement, some alterations have been found in the eutopic endometrium of women with endometriosis that could be responsible, at least in part, for the subfertility shown by these women.26 The factors directly implicated in the crosstalk between the embryo and endometrium preceding implantation have not yet been extensively studied in this group of women.23 It is possible that they could militate against adequate implantation. Concerning the effect of the severity of endometriosis on IVF outcome, some studies have shown a lower fertilization rate and lower pregnancy rate in severe endometriosis stages III and IV compared with stages I and II.13,27,28 Other studies demonstrated diminished ovarian reserve (higher follicle stimulating hormone (FSH) and estradiol level) on day 3 and reduced follicles) in advanced-stage endometriosis.29,30 On the other hand, there are some studies showing no impact of endometriosis stage on IVF outcome.9

EFFECTS OF PREVIOUS OVARIAN SURGERY FOR ENDOMETRIOSIS ON THE OUTCOME OF IVF Controversy remains concerning the effect of surgery in patients with endometriosis on the future response and IVF outcome. Ovarian cystectomy, a term that denotes the excision of an intraovarian cyst, necessitates in most cases resection of healthy ovarian cortex with follicles, and might not be the most appropriate approach for function-preserving surgery. The main concern of ovarian surgery is the risk of destruction of healthy ovarian tissue, which can result in a poor response during IVF and diminished ovarian reserve resulting in early menopause.31,32 Evaluation of the extent of ovarian damage during endometriotic surgery requires an accurate description of the pathology and the surgical techniques used. The outcome of surgery on ovarian function is determined by the extent of deep coagulation used for hemostasis during excision, and the proximity of the lesion to the hilus of the ovary.

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The impact of the type of surgery (ablation or excision) in the hands of experienced surgeons seems to be comparable.33,34 On the other hand, cystectomy can result in extensive damage when performed by an inexperienced surgeon. The impact of ovarian endometriomas on ART outcomes is similarly controversial.33,35–38 It has been suggested that the presence of an ovarian endometriotic cyst might impair oocyte quality in the ipsilateral ovary, and that the response to controlled ovarian hyperstimulation (COH), as well as fertilization and implantation rates, might be decreased.39–41 For patients with endometriomas who have undergone ovarian cystectomy, studies have shown conflicting results for ovarian response, with some patients showing a detrimental effect35,36 and others showing no adverse effect.33,38,39 The classic doctrine that ovarian endometriomas require surgery in infertile women is unproven. In fact, several retrospective studies have reported reduced responses to gonadotropins after cystectomy for ovarian endometriomas in young women.42–45 Such findings suggest that at least some of the adverse effects of endometriomas on fertility outcomes might derive from prior surgical interventions rather than the endometriosis itself. For example, in the study of Tinkanen and Kujansuu,45 the effects of operative treatment of recurrent ovarian endometriosis on the pregnancy rate in IVF were evaluated. They compared 45 patients with ovarian endometriosis during IVF treatment, 36 of the cases being recurrences after previous operation. The control group included 55 patients who had endometriomas and had undergone surgery without recurrence. Patients with endometriomas had significantly more embryos for transfer compared with women without endometriomas. The clinical pregnancy rate was 38% in the endometrioma group compared with 22% in the no-endometrioma group. This was probably because of the more extensive radical surgery in the control group. Radical surgery resulted in no recurrence but at the same time it caused diminished ovarian response. Similarly, Williams and colleagues46 reported better pregnancy rates in women with endometriomas during IVF compared with those who had undergone ovarian cystectomy. In the study of Garcia-Velasco and associates,47 the effect of conservative surgery on ovarian endometriomas before the IVF cycle was evaluated. They compared ART cycle outcome in 133 women treated by laparoscopic cystectomy for an endometrioma > 3 cm in size with the outcome in 56 women with an ovarian endometriotic cyst of a similar size who had not previously undergone conservative ovarian surgery. The IVF cycle was started within 12 months of surgery. There was no difference in terms of number of oocytes, fertilization rate, number of embryos transferred, implantation rate and clinical pregnancy rate between the groups.

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Controversial data were reported after laparoscopic cystectomy on the ovarian response during ovarian stimulation for IVF. Surgical treatment of endometriosis suggested that cystectomy may induce loss of follicular reserve during IVF,46 and ovarian cystectomy could provoke loss of normal ovarian tissue either by removing ovarian stroma with oocytes together with the capsule or by the thermal damage provoked by coagulation.48 Pagidas and co-workers42 compared the outcome of reoperation of stage III or IV endometriosis-related infertility versus IVF. The cumulative pregnancy rate at 9 months after surgery was 24.4%; on the other hand, 33.4% and 69.6% cumulative pregnancy rates were achieved after one cycle of IVF and two cycles of IVF, respectively. They concluded that if the initial surgery fails to restore fertility in patients with stage III and IV endometriosis, IVF is more effective than reoperation. Aboulghar and colleagues22 performed a case–control study to evaluate the effectiveness of IVF in patients with advanced endometriosis and previous surgical treatment, and this group was compared with a tubal factor group. The mean number of oocytes retrieved, and the mean number of embryos transferred, were significantly lower in the endometriosis group than in the other group. Implantation and pregnancy rates were significantly lower in the endometriosis group, too.

OVARIAN STIMULATION FOR IVF IN PATIENTS WITH ENDOMETRIOSIS Use of GnRH agonists The IVF outcome in patients with endometriosis pretreated or not with GnRH agonists has been evaluated in several studies.49–52 Oehninger and colleagues49 compared the IVF outcome in 12 patients with endometriosis treated or not treated with GnRH agonist. GnRH agonist was started on day 21 of the menstrual cycle, and gonadotropin was started when pituitary suppression was achieved. A higher pregnancy rate was observed when GnRH agonist was used (41.6% vs. 16.6%). In another study,50 the IVF outcome of patients with endometriosis was evaluated. One group of patients (29 patients) were treated with GnRH agonist starting on day 1 of the cycle; pituitary desensitization was achieved after at least 14 days of agonist treatment. The other group (144 patients) were not pretreated with GnRH agonist, and gonadotropin therapy was given with or without clomiphene citrate (CC). The cumulative pregnancy rate was 87.9% and 50.3% for GnRH agonist-treated and -non-treated groups, respectively.

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Chedid and associates51 evaluated treatment with GnRH agonist analog for 3 weeks, in comparison with a non-treated group, in endometriosis patients undergoing IVF. There was a tendency for a higher pregnancy rate in the agonist-treated group (38.9% vs. 22.6%). In the study of Olivennes and co-workers,52 294 IVF cycles with treatment using a long-protocol GnRH agonist and gonadotropins, or gonadotropins only, were evaluated. A significant increase in the number of oocytes retrieved and the pregnancy rate achieved per cycle was achieved in the GnRH agonist-treated group (9.1 vs. 3.3 and 38.4% vs. 6.7%, respectively). No prospective randomized study has evaluated GnRH agonist treatment in IVF cycles with endometriosis, but from these retrospective studies it can be concluded that reproductive outcome is enhanced with GnRH agonist treatment.

Short and long GnRH agonist protocols There is no prospective study comparing the IVF outcome in endometriosis patients using the short and long protocols. Tan and colleagues50 compared the cumulative conception rates among patients treated with short, ultrashort and long protocols. A higher rate with the long protocol was achieved than with the short or ultrashort protocol (50.3% vs. 8.3%).

Prolonged down-regulation with GnRH agonist prior to ovulation induction for IVF Prolonged down-regulation means extending the usual 2–3-week period of agonist administration. The rationale behind prolonged down-regulation is to control the disease prior to starting IVF treatment by inactivation or neutralization of the endometriotic activity. Dicker and colleagues53 reported a 30% pregnancy rate per transfer in 40 cycles (31 patients) with stage III and IV endometriosis in IVF treatment. GnRH agonist therapy was given for 6 months. They reported no pregnancies in women who had not received prolonged agonist treatment in 48 cycles previously. In another retrospective study,54 there was a significantly higher pregnancy rate in 21 patients with various stages of endometriosis undergoing IVF who received GnRH agonist for 60 days or more before stimulation, in comparison with standard mid-luteal down-regulation with GnRH agonist in 11 patients (67% vs. 27%). In a prospective study,55 the use of GnRH agonist for 6 months prior to stimulation (35 patients, 48 cycles) resulted in a higher pregnancy rate compared with gonadotropin stimulation only (25% vs. 3.9%). In another prospective study,56 84 patients with endometriosis stage III and IV were

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previously treated for ≥ 2 months, and a significantly higher pregnancy rate was achieved than with short or ultrashort GnRH agonist treatment (34.7% vs. 10.7%). However, in the prospective study of Remorgida and co-workers,57 the IVF outcome was not different between the prolongedagonist-treatment and short-treatment groups (50% vs. 30%).

POST-IVF Recent epidemiologic studies have demonstrated that patients with unexplained infertility, including endometriosis-associated infertility, are at higher risk of pregnancy complications, such as spontaneous miscarriage, preterm delivery and small-for-gestational-age infants.58 Other studies have suggested that impaired uterine remodeling during the conception cycle might predispose to defective deep placentation, thereby providing an explanation for the association between the type of infertility and impaired pregnancy outcome after IVF.59,60

SUMMARY OF MANAGEMENT OPTIONS (1) Several investigators have reported significantly reduced fertilization rates in women with endometriosis undergoing IVF treatment.16–18 However, other studies have not found a difference in fertilization rates for women undergoing IVF treatment for endometriosis.14,19 Several studies have suggested an impairment of implantation in patients with endometriosis.19 On the other hand, this might be due to intrinsic deficiencies within the endometrium, as manifested by the aberrant uterine response to sex steroid hormones, or because of impaired oocyte/embryo quality.20 (2) For infertile women who have stage III/IV endometriosis and have previously had one or more infertility operations, IVF–embryo transfer (IVF–ET) is often a better therapeutic option than another infertility operation.42 But, there is no sufficiently powered prospectively randomized trial evaluating the effect on pregnancy outcome of surgical treatment followed by IVF–ET versus IVF–ET alone. (3) The impact of ovarian endometriomas on ART outcomes is controversial.33,35–38 (4) It is important to realize that the first attempt at surgical treatment for ovarian endometriosis in a young woman might determine her

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reproductive future. Because of this, the patient should know the limitations of surgery in improving or restoring fertility and the potential risks. (5) For patients with endometriomas who have undergone ovarian cystectomy, studies have reported conflicting results for ovarian response, with some patients showing a detrimental effect35,36 and others showing no adverse effect.33,37–38 There is no prospective randomized trial in patients with endometriomas who have undergone surgical treatment versus those who have not to evaluate the effectiveness of removal prior to IVF. (6) On the basis of retrospective studies, the reproductive outcome of patients with endometriosis appears to be enhanced if down-regulation with GnRH agonists is used before ovarian stimulation for IVF.51,52 (7) There are no prospective comparative studies in the literature between the long and short GnRH agonist protocols in patients with endometriosis. (8) There is evidence to suggest that the use of prolonged GnRH agonist down-regulation is beneficial in patients with endometriosis.53–55 (9) It has not been demonstrated that there is any benefit of suppression with gestrinone or danazol prior to ovarian stimulation for IVF. (10) There is a lack of data relating to patients with endometriosis treated with GnRH antagonist. (11) Substantial advances in the clinical management of endometriosis are likely to depend on the development of non-invasive diagnostic biochemical markers of the disease.

REFERENCES 1. Houston DE, Noller KL, Melton LJ III, et al. Incidence of pelvic endometriosis in Rochester, Minnesota, 1970–1979. Am J Epidemiol 1987; 125: 959–69 2. Koninckx PR, Meuleman C, Demeyere S, et al. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 1991; 55: 759–65 3. Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod 1991; 6: 544–9 4. Haney AF. Endometriosis-associated infertility. Reprod Med Rev 1997; 6: 154–61

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5. Illera MJ, Juan L, Stewart C, et al. Effects of peritoneal fluid from women with endometriosis on implantation in the mouse model. Fertil Steril 2000; 74: 41–8 6. Olive DL, Schwartz LB. Endometriosis. N Engl J Med 1993; 328: 1759–69 7. Thomas EJ. Endometriosis, 1995 – confusion or sense? Int J Gynaecol Obstet 1995; 48: 149–55 8. Davies JA. Endometriosis: a scientific and clinical challenge. Br J Obstet Gynaecol 1994; 101: 267–8 9. Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. Laparoscopic endometriosis treatment: is it better? Fertil Steril 1993; 59: 35–8 10. Hughes EG, Fedorkow DM, Collins JA. Quantitative overview of controlled trials in endometriosis-associated infertility. Fertil Steril 1993; 59: 963–70 11. Marcoux S, Maheusx R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997; 337: 217–22 12. Evers JLH. The role of surgery in the treatment of pelvic endometriosis in subfertile patients. Middle East Fertil Soc J 2001; 4: 19–21 13. Azem F, Lessing JB, Geva, E et al. Patients with stages III and IV endometriosis have a poorer outcome on in vitro fertilization–embryo transfer than patients with tubal infertility. Fertil Steril 1999; 72: 1107–9 14. Olivennes F, Feldberg D, Liu HC, et al. Endometriosis: a stage by stage analysis – the role of in vitro fertilization. Fertil Steril 1995; 64: 392–8 15. Cahill DJ, Wardle PG, Maile LA, et al. Pituitary–ovarian dysfunction as a cause for endometriosis-associated and unexplained infertility. Hum Reprod 1995; 10: 3142–6 16. Hull MG, Willams JA, Ray B, et al. The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoa. Hum Reprod 1998; 13: 1825–30 17. Bergendal A, Naffah S, Nagy C, et al. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J Assist Reprod Genet 1998; 15: 527–9 18. Harlow CR, Cahil DJ, Maile LA, et al. Reduced preovulatory granulosa cell steroidogenesis in women with endometriosis. J Clin Endocrinol Metab 1996; 81: 426–9 19. Arici A, Oral E, Bukulmez O, et al. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo program. Fertil Steril 1996; 66: 858–9 20. Simon C, Gutierrez A, Vidal A, et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 1994; 9: 725–9 21. Bergendal A, Naffah S, Nagy C, et al. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J Assist Reprod Genet 1998; 15: 530–4

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22. Aboulghar AM, Mansour TR, Serour GI, et al. The outcome of in vitro fertilization in advanced endometriosis with previous surgery: a case-controlled study. Am J Obstet Gynecol 2003; 188: 371–5 23. Garrido N, Navarro J, Remohi J, et al. Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update 2000; 6: 67–74 24. Brizek CL, Schlaff S, Pellegrini VA, et al. Increased incidence of aberrant morphological phenotypes in human embryogenesis – an association with endometriosis. J Assist Reprod Genet 1995; 12: 106–12 25. Pellicer A, Oliveira N, Ruiz A, et al. Exploring the mechanism(s) of endometriosis-related infertiliy: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod 1995; 10 (Suppl 2): 91–7 26. Garcia-Velasco JA, Arici A. Is the endometrium or oocyte/embryo affected in endometriosis? Hum Reprod 1999; 14 (Suppl 2): 77–89 27. Pal L, Shifren JL, Isaacson KB, et al. Impact of varying stages of endometriosis on the outcome of in vitro fertilization–embryo transfer. J Assist Reprod Genet 1998; 15: 27–31 28. Chillick CF, Acosta AA, Garcia JE, et al. The role of in vitro fertilization in infertile patients with endometriosis. Fertil Steril 1985; 44: 56–61 29. Pellicer A, Ardiles G, Neuspiller F, et al. Evaluation of the ovarian reserve in young low responders with normal basal FSH using three-dimensional ultrasounography. Fertil Steril 1998; 70: 671–5 30. Maneschi F, Marasa L, Incandela S, et al. Ovarian cortex surrounding benign neoplasm: histologic study. Am J Obstet Gynecol 1993; 169: 388–93 31. de Boer EJ, den Tonkelaar I, te Velde ER, et al., OMEGA-Project group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003; 18: 1544–52 32. Brosens I. Endometriosis and the outcome of in vitro fertilization. Fertil Steril 2004; 81: 1198–200 33. Canis M, Pouly JL, Tamburro S, et al. Ovarian response cystectomy for endometriotic cysts of >3 cm in diameter. Hum Reprod 2001; 16: 2583–6 34. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril 2001; 76: 662–5 35. Tinkanene H, Kujansuu E. In vitro fertilization in patients with ovarian endometriomas. Acta Obstet Gynecol Scand 2000; 79: 119–22 36. Ho H, Lee RK, Hwu Y, et al. Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet 2002; 19: 507–111 37. Loh FH, Tan AT, Kumar J, Ng SC. Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 1999; 72: 316–21

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38. Marconi G, Vilela M, Quintana R, et al. Laparoscopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotropin stimulation. Fertil Steril 2002; 78: 876–8 39. Mahutte NG, Arici A. New advances in the understanding of endometriosis related infertility. J Reprod Immunol 2002; 55: 73–83 40. Nisolle M. Ovarian endometriosis and peritoneal endometriosis: are they different entities from a fertility perspective? Curr Opin Obstet Gynecol 2002; 14: 283–8 41. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77: 1148–55 42. Pagidas K, Falcone T, Hemmings R, Miron P. Comparison of reoperation for moderate (stage III) and severe (stage IV) endometriosis-related infertility with in vitro fertilization–embryo transfer. Fertil Steril 1996; 65: 791–5 43. Loh FH, Tan AT, Kumar J, Ng SC. Ovarian response after laparoscopic ovarion cystectomy for endometriotic cysts in 132 monitored cycles Fertil Steril 1999; 72: 316–21 44. Al-Azemi M, Bernal AL, Steele J, et al. Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosis. Hum Reprod 2000; 15: 72–5 45. Tinkanen H, Kujansuu E. In vitro fertilization in patients with ovarian endometriomas. Acta Obstet Gynecol Scand 2000; 79: 119–22 46. Williams CM, Ho Yuen B, Klein NA, et al. Ovarian endometriomas during IVF treament: do they affect outcomes? Fertil Steril 1998; 70 (Suppl 19): 0–49 47. Garcia-Velasco JA, Mahutte NG, Corona J, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case–control study. Fertil Steril 2004; 81: 1194–7 48. Donnez J, Nisolle M, Gillet N, et al. Large ovarian endometriomas. Hum Reprod 1996; 11: 641–6 49. Oehninger S, Bryski RG, Muasher SJ, et al. In-vıtro fertilization and embryo transfer in patients with endometriosis: impact of a gonadotrophin releasing hormone agonist. Hum Reprod 1989: 4: 541–4 50. Tan SL, Maconochie N, Doyle P, et al. Cumulative conception and live-birth rates after in vitro fertilization with and without the use of long, short, and ultrashort regimens of the gonadotropin-releasing hormone agonist buserelin. Am J Obstet Gynecol 1994; 171: 513–20 51. Chedid S, Camus M, Simitz J, et al. Comparison among different ovarian stimulation regimens for assisted procreation procedures in patients with endometriosis. Hum Reprod 1995: 10: 2406–11 52. Olivennes F, Feldberg D, Liu HC, et al. Endometriosis: a stage by stage analysis – the role of in vitro fertilization. Fertil Steril 1995; 64: 392–8 53. Dicker D, Goldman GA, Ashkenazi J, et al. The value of pre-treatment with gonadotrophin releasing hormone (GnRH) analogue in IVF–ET therapy of severe endometriosis. Hum Reprod 1990; 5: 418–20 54. Nakamuro K, Oosawa M, Kondou I, et al. Menotropin stimulation after prolonged gonadotropin releasing hormıne agonist pretreatment for in vitro

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fertilization in patients with endometriosis. J Assist Reprod Genet 1992; 9: 113–17 55. Dicker D, Goldman JA, Levy T, et al. The impact of long-term gonadotropinreleasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization–embryo transfer. Fertil Steril 1992; 57: 597–600 56. Marcus SF, Edwards RG. High rates of pregnancy after long term down-regulation of women with severe endometriosis. Am J Obstet Gynecol 1994; 171: 812–17 57. Remorgida V. Anserini P, Croce S, et al. Comparison of different ovarian stimulation protocols for gamete intrafallopian transfer in patients with minimal and mild endometriosis. Fertil Steril 1990; 53: 1060–3 58. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome. Hum Reprod 2001; 16: 2593–7 59. Brosens JJ, Pijnenborg R, Brosens I. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies. Am J Obstet Gynecol 2002; 187: 1416–23 60. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implication for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003; 69: 1–7

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Chapter 9

The patient with hydrosalpinx A Strandell

INTRODUCTION Tubal factor infertility was the original indication for which in vitro fertilization (IVF) was first performed. During the past decade, it has become evident that tubal infertility in general and hydrosalpinx in particular carry a worse prognosis than other infertility factors. The first report from 1994 showed a reduced pregnancy rate and an increased rate of miscarriage in hydrosalpinx patients, as compared with patients with other tubal infertility,1 and it has been followed by numerous retrospective studies. Initially, theories focused on the hydrosalpinx fluid, its content and also the possibility of wash-out of embryos through leakage of fluid through the uterine cavity. A lot of research has been devoted to investigate the hydrosalpinx fluid for possible embryotoxic components and growth-inhibiting factors, but the mechanism through which a hydrosalpinx exerts its negative effects is still obscure. Several reports have demonstrated inhibitory effects on embryo growth in mice2,3 but not in humans,4 while other studies have shown growth-promoting properties of the hydrosalpinx fluid.5 Secondary to the hydrosalpinx fluid’s influence on the endometrium, the environmental prerequisite for implantation has been studied. The roles of integrins and several cytokines have been elucidated, but the main question as to why embryos do not implant or develop properly has not yet been answered.6–8 There is certainly a lack of knowledge, and not even the detailed course from the original tubal infection to the fimbrial closing and exudation of fluid into the tubal lumen is completely understood. Despite the lack of knowledge of the mechanism, several treatments with the intention to dispose of the hydrosalpingeal fluid have been

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suggested. The effect of salpingectomy has been thoroughly investigated in randomized trials, while other treatment options such as tubal occlusion, salpingostomy and transvaginal aspiration have been subjected to study designs of less validity.

IMPACT OF HYDROSALPINX ON IVF OUTCOMES Several retrospective studies have reported the adverse IVF outcome in hydrosalpinx patients.1,9–21 As seen from the data in Table 1, all but one study demonstrated lower pregnancy rates among hydrosalpinx patients compared with controls without hydrosalpinx. The overall effect of hydrosalpinx is a reduction by half in pregnancy rate per fresh embryo transfer, as demonstrated by one meta-analysis of ten retrospective studies resulting in a common odds ratio (OR) of 0.57 (95% confidence interval (CI) 0.48–0.68).22 The common OR in Table 1 is 0.45 (95% CI 0.39–0.53), which can be explained by the addition of two studies published after the meta-analysis and the fact that specific cycles with poor prognosis have been identified and included. Also, frozen–thawed cycles are impaired in hydrosalpinx patients; the common OR is 0.39 (95% CI 0.16–0.94) based on two studies.1,14 The same meta-analysis demonstrated a doubled risk for miscarriage in hydrosalpinx patients: common OR 2.3 (95% CI 1.56–3.48).22 Ectopic pregnancies have also been investigated, but only two small studies have demonstrated a significantly increased risk among hydrosalpinx patients.17,21 All other retrospective studies show similar rates of ectopic pregnancy in patients with tubal infertility whether or not hydrosalpinx is present. Table 2 summarizes the retrospective studies presenting ectopic pregnancy rates. The overall negative impact of hydrosalpinx on IVF outcome is summarized in Figure 1.

IMPACT OF HYDROSALPINX TREATMENT ON IVF OUTCOME The overwhelming evidence for the negative influence of hydrosalpinx on IVF outcome started an intense debate about treatment options, most of which focused on surgical methods to dispose of the hydrosalpingeal fluid. Laparoscopic salpingectomy is the only method that has been properly evaluated in a randomized controlled trial, while all other methods have to be judged, taking into account the lower level of evidence.

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THE PATIENT WITH HYDROSALPINX

Salpingectomy A Scandinavian multicenter study randomized 204 patients to laparoscopic salpingectomy or no intervention prior to the first cycle of IVF.24 Of special interest were the groups with bilateral and/or ultrasound-visible hydrosalpinges, which were previously shown to have a worse prognosis.18,19 Patients with ultrasound-visible hydrosalpinges were the ones who benefited most from salpingectomy: live-birth rate 40% vs. 17% (p = 0.04) without any surgical intervention.24 The main results from these poorprognosis groups are shown in Figure 2. This study constitutes the major part in a systematic review, including two additional smaller trials of salpingectomy,25 showing a statistically significant increase in live-birth rate if salpingectomy preceded IVF (OR 2.1, 95% CI 1.2–3.6) in all hydrosalpinx patients. However, the Scandinavian study could demonstrate that the effect was entirely due to the positive effect among those with hydrosalpinges that were enlarged enough to be seen on ultrasound.26 The recommendation of salpingectomy has raised concern about unnecessary removal of tubes that might be suitable for salpingostomy and spontaneous conception. The optimal management is of course that the Fallopian tube and its mucosal status can be evaluated at the time of laparoscopy, and the immediate decision can be taken whether the tube should be removed or reconstructed. The prerequisite for the latter scenario is surgical/laparoscopic competence for distal tubal repair, and also postoperative time to allow for spontaneous conception. Also, in cases of salpingectomy for unilateral hydrosalpinx, time for spontaneous conception should be considered, since several case series have demonstrated the occurrence of spontaneous pregnancies after surgery.27–29

Tubal occlusion Proximal occlusion of the Fallopian tube has been suggested as an alternative to salpingectomy, in particular when dense adhesions complicate an intended salpingectomy. Occlusion of the tube serves the purpose of interrupting the passage of fluid to the endometrial cavity but leaves the hydrosalpinx in place, where it might interfere with the aspiration of oocytes. The procedure can be combined with distal fenestration of the hydrosalpinx, but the opening frequently reoccludes. The method has in three small retrospective studies yielded results comparable to those after salpingectomy and improved outcome as compared with no intervention.21,30,31 Table 3 presents the available studies of the alternative surgical treatments of proximal occlusion and neosalpingostomy.

119

120

Blazar et al.,16 1997

1996 HSG/laparoscopy

Sonography/ HSG/laparoscopy

HSG/laparoscopy

Katz et al.,13 1996

Fleming and


Akman et al.,14 1996

Hull,15

HSG/laparoscopy

HSG/laparoscopy

HSG/laparoscopy

Sonography

Sharara et al.,12 1996

1995

1994

Vandromme et

Kassabji et

al.,11

1994

Andersen et

al.,10

HSG/laparoscopy

Strandell et al.,1 1994

35/161 (21.7)

18/77 (23.4)

16/95 (16.8)

1/14 (7.1)

27/103 (26.2)

7/69 (10.1)

41/234 (17.5)

9/91 (9.9)

14/121 (11.6)*

105/385 (27.3)

63/212 (29.7)

467/1268 (36.8)

24/98 (24.5)

30/89 (33.7)

14/61 (23.0)

70/223

(31.4)†

224/744 (30.1)

89/367 (24.2)

Controls without hydrosalpinx (n/cycles (%))

Continued

0.74 (0.48–1.15)

0.72 (0.39–1.32)

0.35 (0.20–0.60)

0.24 (0.03–1.91)

0.70 (0.38–1.30)

0.38 (0.14–1.01)

0.46 (0.30–0.72)

0.25 (0.13–0.52)

0.41 (0.22–0.75)

Odds ratio (95% CI)

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al.,9

Diagnostic method

Hydrosalpinx patients (n/cycles (%))

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Author, publication year

Table 1 Summary of retrospective studies; clinical pregnancy rates after fresh and frozen–thawed in vitro fertilization (IVF) cycles in hydrosalpinx patients and controls1,9–21

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Continued

223/1343 (16.6)

4/47 (8.5)

13/45 (28.9)

13/115

(11.3)§

9/41 (22.0)

1322/4318 (30.6)

56/145 (38.6)

51/88 (58.0)

66/326 (20.2)

11/92 (12.0)

52/220 (23.6)

Controls without hydrosalpinx (n/cycles (%))

0.47 (0.40–0.56)

0.45 (0.39–0.53)

0.15 (0.05–0.43)

0.29 (0.14–0.64)

0.50 (0.27–0.95)

2.07 (0.78–5.47)

0.45 (0.25–0.83)

Odds ratio (95% CI)

hydrosalpinx with marked distension of one or both tubes; †patients with bilateral salpingectomy; ‡including patients with bilateral hydrosalpinges; §including hydrosalpinx visible by ultrasound; χ2 test for heterogeneity (13 df) = 29.13 (p = 0.006); HSG, hysterosalpingography; CI, confidence interval

*Including

Pooled (Cochran–Mantel–Haenzsel)

Total

HSG/surgery

Murray et al.,21 1998

Sonography/ HSG/laparoscopy Sonography/ HSG/laparoscopy

1998

Freeman et al.,20 1998

de Wit et

HSG/laparoscopy

Ng et al.,17 1997

16/130 (12.3)‡


11:00 am

al.,19


Diagnostic method

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Wainer et al.,18 1997


Table 1

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121

122

Total Pooled (Cochran–Mantel–Haenzsel)

70/3630 (1.9)

6/367 (1.6) 19/744 (2.6) 0/223† 0/89 1/98 (1.0) 30/1268 (2.4) 4/190 (2.1) 0/92 4/326 (1.2) 5/88 (5.7) 1/145 (0.7) 0.53 0.085

0.90 1.0 0.52 0.57 1.0 0.70 1.0 0.056 0.21 0.67 0.02

p Value

1.19 (0.75–1.89) 1.60 (0.95–2.70)

0.50 (0.06–4.21) 0.86 (0.20–3.74) — — — 0.44 (0.06–3.25) 1.24 (0.22–6.91) — 2.60 (0.75–8.98) 0.38 (0.04–3.33) 13.40 (1.46–123.0)

Odds ratio (95%CI)

hydrosalpinx with marked distension of one or both tubes; †patients with bilateral salpingectomy; ‡including hydrosalpinx visible by ultrasound; χ2 test for heterogeneity (10 df) = 18.27 (p = 0.051); CI, confidence interval

25/1092 (2.3)

Strandell,1 1994 Andersen,9 1994 Kassabji,10 1994 Sharara,12 1996 Akman,14 1996 Katz,13 1996 Fleming,15 1996 Ng,17 1997 de Wit,19 1998 Freeman,20 1998 Murray,21 1998

Controls (n/cycles (%))

11:00 am

*Including

1/121 (0.8)* 2/91 (2.2) 2/234 (0.9) 2/103 (1.9) 0/14 1/95 (1.1) 2/77 (2.6) 3/41 (7.3) 7/224 (3.1)‡ 1/45 (2.2) 4/47 (8.5)


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Table 2 Summary of retrospective studies; ectopic pregnancy rates after fresh and frozen–thawed in vitro fertilization (IVF) cycles in hydrosalpinx patients and controls with other type of tubal infertility1,9,10,12–15,17,19–21

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Clinical pregnancy 0.47 (0.40–0.56) Implantation 0.50 (0.43–0.58) Miscarriage 1.49 (1.08–2.05) Ectopic pregnancy 1.60 (0.95–2.70) Delivery 0.43 (0.35–0.53) 0.1

1.0

2.0

Figure 1 Meta-analyses of retrospective studies comparing outcomes of in vitro fertilization (IVF) in patients with uni- and bilateral hydrosalpinges and controls, showing common odds ratios and 95% confidence intervals, calculated using data from articles included in the latest published metaanalysis and two additional studies20,21,23

70

p = 0.019

60 Live-birth rate (%)

Chapter 09

50 40

55% p = 0.040 p = 0.057

40%

33%

30 20

15%

17%

16%

10 0 Bilateral

Salpingectomy

Ultrasoundvisible

Bilateral and ulrasound-visible No intervention

Figure 2 Live-birth rates in the Scandinavian randomized trial of pre-in vitro fertilization (IVF) salpingectomy, in groups of patients with bilateral and/or ultrasound-visible hydrosalpinges24

Transvaginal aspiration Ultrasound-guided transvaginal aspiration has been advocated as a treatment option to remove the hydrosalpingeal fluid. If the procedure is performed prior to stimulation, the fluid always reaccumulates. Even if it is

123

124

9/23

7/15

16/28

Murray et al.,21 1998

Stadtmauer et al.,30 2000

Surrey and Schoolcraft,31 2001

n/n

57

47

39

%

7/15

22/30

9/15

n/n

47

73

60

%

Tubal occlusion

—

—

3/7

n/n

—

—

43

%

Neosalpingostomy

%

— —

—

2/15 13 p < 0.05

4/47 8.5 p < 0.05

n/n

No surgery

11:00 am

Salpingectomy

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Table 3 Clinical pregnancy rates per embryo transfer in three retrospective studies comparing tubal occlusion, neosalpingostomy and salpingectomy with no surgery in hydrosalpinx patients, prior to in vitro fertilization (IVF)21,30,31

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done at the time of oocyte retrieval, the risk of recurrence is already high at the time of transfer. Of two small retrospective studies evaluating this procedure, one showed a benefit (Table 4).32,33 However, the small sample size indicates the risk of a type I error being present. Further studies are certainly required.

Medical treatment The use of antibiotics has been introduced as a simple treatment to overcome the negative effects of hydrosalpinx. However, antibiotic treatment has never been prospectively evaluated, and to date, there is only one small retrospective study, which has suggested that extended doxycycline treatment during an IVF cycle would minimize the detrimental effect of hydrosalpinx.34

Other suggested management The use of the natural cycle with the intention to avoid ovarian hyperstimulation and subsequent enlargement of hydrosalpinges has been described in one retrospective study.35 Patients with hydrosalpinges undergoing IVF in a natural cycle (n = 72) demonstrated significantly higher pregnancy rates compared with patients who received controlled ovarian hyperstimulation (n = 49) (18% vs. 7%, p < 0.05). This result may be biased by the selection of patients to the different treatments. Furthermore, the demonstrated impaired outcome in frozen–thawed cycles contradicts a potential benefit of natural cycles. Any advantage of this method has to be proved in additional studies before it can be considered as an appropriate alternative, taking into account the obvious disadvantages with natural cycles. The suggestion of increasing the number of replaced embryos to counteract the adverse effect of hydrosalpinges has not been proved effective, and should not be considered in times when efforts are made to decrease the rate of multiple pregnancy.

IMPACT OF IVF ON HYDROSALPINX What happens to the hydrosalpinges when patients undergo IVF? In untreated patients, the hydrosalpinges may enlarge during stimulation and may possibly disturb the oocyte retrieval procedure. The hydrosalpinx can be accidentally but also intentionally punctured. The risk of infection is described, but is not of frequent occurrence. Of greater importance is the

125

126

Pregnancy Birth

Pregnancy Birth

Sowter et al.,32 1997

Van Voorhis et al., 33 1998

CI, confidence interval

Outcome

5/16 5/16

6/30 5/30

n/n

31.3 31.3

20.0 16.7

%

Aspiration

1/18 0/18

3/18 3/18

n/n

5.6 —

16.7 16.7

%

No aspiration

0.13 0.01

1.0 1.0

p Value

7.73 (0.79–75.3) —

1.25 (0.27–5.77) 1.0 (0.21–4.80)

Odds ratio (95% CI)

11:00 am


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Treatment group

Table 4 Summary of two retrospective studies of transvaginal aspiration of hydrosalpingeal fluid prior to in vitro fertilization (IVF), including only first cycle32,33

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case when distally occluded tubes are not detected prior to stimulation, but enlarge and become visible by ultrasound before the aspiration of oocytes. That patient has probably not been informed about the bad prognosis associated with hydrosalpinges, and if the ongoing cycle fails, a discussion of salpingectomy should be initiated. The sign of endometrial fluid during an IVF cycle has in a few case reports and comparative studies been associated with tubal factor infertility, and described as a very bad-prognosis sign.36–38 In two retrospective series including patients with all types of infertility factors, clinical pregnancy rates were significantly impaired if endometrial fluid appeared during ovarian hyperstimulation.37,38 A summary of studies of endometrial fluid is given in Table 5. There is no use in aspirating the endometrial fluid prior to transfer, because of the rapid recurrence of fluid.39 Instead, freezing of all embryos and transfer of thawed embryos after salpingectomy should be suggested. Another related clinical symptom is hydrorrhea, claimed to be associated with a poor pregnancy rate after IVF.36

IMPACT OF IVF ON HYDROSALPINX TREATMENT In patients who are surgically treated for their hydrosalpinges, there are a few case reports from which some experience should be acknowledged. Dehiscence at the tubal corners after bilateral salpingectomy has resulted in expulsion of fetuses from the uterine cavity.40 From this experience, one can learn that the tube should not be excised too close to the uterus. Another report describes adnexal torsion after tubal occlusion for a unilateral hydrosalpinx.41 Concern has been raised regarding the potential hazard of disturbing the circulation and innervation to the ovary by performing a radical salpingectomy. Studies have not been able to show a significant reduction in the number of oocytes retrieved after salpingectomy,42–46 although one study demonstrates impairment of the ovarian response, ipsilateral to the salpingectomy.47 This finding stresses the importance of a meticulous surgical technique. A summary of studies of ovarian function is presented in Table 6.

PREPARING THE PATIENT FOR IVF Once a hydrosalpinx has been detected during the infertility work-up, by hysterosalpingography (HSG), ultrasound or laparoscopy, careful consideration of further management has to be made. Bearing in mind the poor

127

128

All factors (tubal 50%)

All factors (tubal 40%)

Levi et al.,37 2001

Chien et al.,38 2002

CI, confidence interval

Hydrosalpinx

Andersen et al.,36 1996

Infertility factor

2/35 (5.7)

15/57 (26.3)

0/3

193/711 (27.1)

333/786 (42.4)

7/34 (20.6)

No endometrial fluid (n/cycles(%))

0.003

0.02

1.0

p Value

0.16 (0.04–0.68)

0.49 (0.26–0.89)

—

Odds ratio (95% CI)

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Endometrial fluid present (n/cycles(%))

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Table 5 Summary of retrospective studies comparing the effect of endometrial fluid on clinical pregnancy rate after in vitro fertilization (IVF)36,38

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prognosis without any intervention prior to IVF, information and discussion with the patient is mandatory. The first step is to evaluate the hydrosalpinx regarding its characteristics. If it is a distally occluded tube with intraluminal adhesions and without any fluid, it can be left without any further interventions. This type of pathology is not suitable for repair, nor does it affect IVF outcome. In practice, this evaluation can be done through transvaginal ultrasound in most cases, taking into account the information from previous examinations. If the prior examinations revealed fluid-filled tubes, a discussion of laparoscopic salpingectomy should be initiated with the patient. Psychologically, it is very distressing for the infertile patient to be recommended salpingectomy, in particular if she has bilateral pathology. Bilateral salpingectomy would leave her without any possibility of spontaneous conception and she would have to rely solely on IVF. On the other hand, in the presence of bilateral hydrosalpinges, her chances of conceiving and giving birth after IVF are small. The acceptance of salpingectomy is higher in cases of unilateral hydrosalpinx. If the contralateral tube is patent, she may conceive spontaneously and she has also improved her chances of pregnancy and live birth after IVF.

Pre-IVF treatment If the patient with ultrasound-visible hydrosalpinx consents to laparoscopy prior to her first IVF cycle, she should be informed about different possible outcomes such as salpingectomy, tubal occlusion and even salpingostomy. In the ideal situation, the tube can be opened distally and the mucosa inspected and evaluated. If more than half of the mucosa is healthy, the prognosis for spontaneous conception after surgical reconstruction is good.48 If the interior tube is without any mucosal folds, salpingectomy is the optimal procedure. The original infection causing the hydrosalpinx may also result in adhesions that firmly attach the tube to the peritoneal surfaces and the bowel. Lysis of the hydrosalpinx may carry a high risk of complications with injuries to the adjacent organs, and the salpingectomy procedure may then be replaced by proximal occlusion of the Fallopian tube or a smaller tubal resection. Fenestration of the remaining hydrosalpinx may temporarily dispose of the fluid, but the opening reoccludes with the reaccumulation of fluid, which becomes visible by ultrasound. After salpingectomy or tubal occlusion, it is recommended to wait at least 2 months for the endometrial environment to restore, before starting controlled ovarian hyperstimulation. In the Scandinavian multicenter

129

130

26 vs. 134

29 vs. 73

139 vs. 139

26

15 vs. 34

Lass et al,47 1998

Bredkjaer et al., 1999

Dar et al.,44 2000

Stadtmauer et al.,30 2000

Hydrosalpinx

Ectopic pregnancy after IVF

Hydrosalpinx

Ectopic pregnancy

Ectopic pregnancy, hydrosalpinx, sterilization

Reason for surgery

Not studied

6.1 vs. 5.3 NS

Not studied

3.8 vs. 6.0 p < 0.01

Not studied

Ipsilateral vs. contralateral

14.0 vs. 12.9 NS

11.1 vs. 9.7 NS

9.3 vs. 9.1 NS

9.9 vs. 9.1 NS

11.2 vs. 11.2 NS

Overall (two ovaries)

Continued

Retrospective cohort

Analysis before and after surgery

Case–control

Case–control

Case–control

Study design

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Verhulst et al.,42 1994

Number of patients

Number of oocytes

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Table 6 Summary of eight studies examining the effect of salpingectomy on ovarian function by measuring the number of retrieved oocytes after controlled ovarian hyperstimulation.30,31,42–47 Controls are the same patient before surgery, the contralateral ovary or patients without previous tubal surgery

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32 vs. 35

26 vs. 52

Surrey and Schoolcraft31 2001

Tal et al.,46 2002

NS, not significant

26

Number of patients

Ectopic pregnancy

Hydrosalpinx

Hydrosalpinx

Reason for surgery

6.3 vs. 6.2 NS

Not studied

Not studied

Ipsilateral vs. contralateral

8.6 vs. 8.4 NS

16.2 vs. 17.5 NS

9.4 vs. 8.7 NS

Overall (two ovaries)

Number of oocytes

Case–control

Retrospective cohort

Analysis before and after surgery

Study design

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Strandell et al. 2001


Continued

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Table 6

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study, the median time from surgery to embryo transfer was 140 days (range 50–690 days).24

MANAGING THE IVF CYCLE Routine stimulation protocols can be applied to hydrosalpinx patients with or without them having undergone any surgical intervention prior to the start. However, it is known that patients with tubal factor infertility may require a higher dose of gonadotropin, possibly depending on the engagement of the ovary and the subsequent damage from the original infection. The patient pretreated with salpingectomy can be monitored in the routine program. If tubal occlusion has been performed, the hydrosalpinx will still be visible at sonography and should be recognized during stimulation, and puncture avoided at oocyte retrieval. Since communication to the uterine cavity is interrupted, the chance of implantation should possibly not be impaired. Patients who have not undergone any surgical intervention prior to IVF may require additional ultrasound monitoring, to evaluate the enlargement of a previously seen hydrosalpinx or to determine whether previously undetectable tubes have become fluid-filled. At the time of oocyte retrieval, aspiration of the hydrosalpingeal fluid under antibiotic cover can be considered. If any endometrial fluid is detected, freezing of all embryos can be considered and transfer postponed until a laparoscopic salpingectomy has been carried out.

POST-IVF FOLLOW-UP If the first cycle in patients without any pretreatment for hydrosalpinx does not result in a pregnancy, or a spontaneous abortion occurs, further discussion of salpingectomy should be initiated before starting a new cycle. In the Scandinavian study of salpingectomy, one-third of the patients originally randomized to no intervention prior to their first cycle had a salpingectomy performed after one or two failed cycles. This group achieved the same live-birth rate of 55% when cumulative results were calculated, although they had to undergo more cycles compared with the group who had a salpingectomy before their first cycle. Controls during pregnancy in patients with hydrosalpinx may draw attention to the possible risk for pelvic infection. Although tubo-ovarian abscesses during pregnancy are rare, cases have been described in which the combination of IVF treatment and hydrosalpinx in patients has been

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elucidated as a possible risk factor.49 This risk scenario supports the recommendation of pre-IVF salpingectomy.

SUMMARY OF MANAGEMENT OPTIONS Patients with hydrosalpinx have a poor prognosis after IVF and are less likely to conceive and give birth without any pretreatment, compared with patients who have undergone surgical intervention prior to IVF. A treatment protocol is presented in Figure 3. Each statement is accompanied by a grade of recommendation based on the evidence level of the reference studies (Table 7).50

Hydrosalpinx visible by ultrasound before start

Laparoscopy

Accessible hydrosalpinx

Evaluate mucosa if indicated

Extensive adhesions

Hydrosalpinx not visible by ultrasound before start

Patient wishes no surgery

Visible during stimulation

Transvaginal aspiration at ovum pick-up + antibiotics

Transvaginal aspiration at ovum pick-up + antibiotics

Failed cycle No surgery

Proximal occlusion + distal drainage Failed cycle

Salpingostomy

Non-visible during stimulation

Discuss surgery again before next cycle

No endometrial fluid

Transfer

Salpingectomy

Failed cycle

Endometrial fluid detected

Cancel transfer Freezing of embryos Laparoscopy for intended salpingectomy Frozen–thawed transfer

Laparoscopy

Figure 3 Treatment protocol for patients with hydrosalpinx undergoing in vitro fertilization (IVF). A–D correspond to grades of recommendation based on evidence levels (Table 7)50

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Table 7 ation50 Level of evidence 1a 1b 2a 2b

Strength of evidence corresponding to grade of recommend-

Type of study/source

Grade of recommendation

Systematic review and meta-analysis of randomized controlled trials At least one randomized controlled trial

A

At least one well-designed controlled study without randomization At least one other type of well-designed quasi-experimental study

B

A

B

3

Well-designed non-experimental descriptive studies, such as comparative studies, correlation studies or case studies

C

4

Expert committee reports or opinions and/or clinical experience of respected authorities

D

(1) Patients with hydrosalpinx large enough to be visible by ultrasound should be recommended laparoscopic salpingectomy prior to IVF, which will double their chance of having a child (evidence level 1a). (2) In cases of severe adhesions to the hydrosalpinx, proximal occlusion of the tube and distal drainage can be performed (level 2). (3) At laparoscopy, a hydrosalpinx with healthy mucosa can be repaired by salpingostomy, and function for spontaneous conception with a fairly good prognosis (level 3). (4) Salpingectomy for a unilateral hydrosalpinx increases the chance of spontaneous conception (level 3). (5) Transvaginal aspiration of the hydrosalpingeal fluid at the time of oocyte retrieval can be performed in patients who have not had any surgical pretreatment (level 4). (6) The presence of endometrial fluid is a poor-prognosis sign, and embryo transfer can be canceled, embryos frozen and transfer postponed until a laparoscopic salpingectomy has been performed (levels 3–4).

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(7) Respect should be given to an individual’s choice not to undergo salpingectomy for psychological reasons (level 4). (8) Failure of one cycle should imply a new discussion of salpingectomy in order to increase the chance of a live birth (level 1b).

REFERENCES 1. Strandell A, Waldenström U, Nilsson L, et al. Hydrosalpinx reduces in-vitro fertilization/embryo transfer rates. Hum Reprod 1994; 9: 861–3 2. Mukherjee T, Copperman AB, McCaffrey C, et al. Hydrosalpinx fluid has embryotoxic effects on murine embryogenesis: a case for prophylactic salpingectomy. Fertil Steril 1996; 66: 851–3 3. Beyler SA, James KP, Fritz MA, et al. Hydrosalpingeal fluid inhibits in-vitro embryonic development in a murine model. Hum Reprod 1997; 12: 2724–8 4. Strandell A, Sjögren A, Bentin-Ley U, et al. Hydrosalpinx fluid does not adversely affect the normal development of human embryos and implantation in vitro. Hum Reprod 1998; 13: 2921–5 5. Sawin SW, Loret de Mola JR, Monzon-Bordonaba F, et al. Hydrosalpinx fluid enhances human trophoblast viability and function in vitro: implications for embryonic implantation in assisted reproduction. Fertil Steril 1997; 68: 65–71 6. Meyer WR, Castelbaum AJ, Somkuti S, et al. Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod 1997; 12: 1393–8 7. Barmat LI, Nasti K, Yang X, et al. Are cytokines and growth factors responsible for the detrimental effects of hydrosalpingeal fluid on pregnancy rates after in vitro fertilization–embryo transfer? Fertil Steril 1999; 72: 1110–12 8. Strandell A, Thorburn J, Wallin A. The presence of cytokines and growth factors in hydrosalpingeal fluid. J Assist Reprod Genet 2004; 21: 241–7 9. Andersen AN, Yue Z, Meng FJ, et al. Low implantation rate after in-vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum Reprod 1994; 9: 1935–8 10. Kassabji M, Sims JA, Butler L, et al. Reduced pregnancy outcome in patients with unilateral or bilateral hydrosalpinx after in vitro fertilization. Eur J Obstet Gynecol Reprod Biol 1994; 56: 129–32 11. Vandromme J, Chasse E, Lejeune B, et al. Hydrosalpinges in in-vitro fertilization: an unfavourable prognostic feature. Hum Reprod 1995; 10: 576–9 12. Sharara FI, Scott RT Jr, Marut EL, et al. In-vitro fertilization outcome in women with hydrosalpinx. Hum Reprod 1996; 11: 526–30 13. Katz E, Akman MA, Damewood MD, et al. Deleterious effect of the presence of hydrosalpinx on implantation and pregnancy rates with in vitro fertilization. Fertil Steril 1996; 66: 122–5 14. Akman MA, Garcia JE, Damewood MD, et al. Hydrosalpinx affects the implantation of previously cryopreserved embryos. Hum Reprod 1996; 11: 1013–14

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15. Fleming C, Hull MGR. Impaired implantation after in vitro fertilization treatment associated with hydrosalpinx. Br J Obstet Gynaecol 1996; 103: 268–72 16. Blazar AS, Hogan JW, Seifer DB, et al. The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro fertilization. Fertil Steril 1997; 67: 517–20 17. Ng EH, Yeung WS, Ho PC. The presence of hydrosalpinx may not adversely affect the implantation and pregnancy rates in in vitro fertilization treatment. J Assist Reprod Genet 1997; 14: 508–12 18. Wainer R, Camus E, Camier B, et al. Does hydrosalpinx reduce the pregnancy rate following in vitro fertilization? Fertil Steril 1997; 68: 1022–6 19. de Wit W, Gowrising CJ, Kuik DJ, et al. Only hydrosalpinges visible on ultrasound are associated with reduced implantation and pregnancy rates after invitro fertilization. Hum Reprod 1998; 13: 1696–701 20. Freeman MR, Whitworth CM, Hill GA. Permanent impairment of embryo development by hydrosalpinges. Hum Reprod 1998; 13: 983–6 21. Murray DL, Sagoskin AW, Widra EA, et al. The adverse effect of hydrosalpinges on in vitro fertilization pregnancy rates and the benefit of surgical correction. Fertil Steril 1998; 69: 41–5 22. Zeyneloglu HB, Arici A. Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization–embryo transfer. Fertil Steril 1998; 70: 492–9 23. Camus E, Poncelet C, Goffinet F, et al. Pregnancy rates after IVF in cases of tubal infertility with and without hydrosalpinx: meta-analysis of published comparative studies. Hum Reprod 1999; 14: 1243–9 24. Strandell A, Lindhard A, Waldenström U, et al. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999; 14: 2762–9 25. Johnson N, Mak W, Sowter M. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev 2004; (3): CD002125 26. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Hydrosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod 2001; 16: 2403–10 27. Choe J, Check JH. Salpingectomy for unilateral hydrosalpinx may improve in vivo fecundity. Gynecol Obstet Invest 1999; 48: 285–7 28. Aboulghar MA, Mansour RT, Serour GI. Spontaneous intrauterine pregnancy following salpingectomy for a unilateral hydrosalpinx. Hum Reprod 2002; 17: 1099–100 29. Sagoskin AW, Lessey BA, Mottla GL, et al. Salpingectomy or proximal tubal occlusion of unilateral hydrosalpinx increases the potential for spontaneous pregnancy. Hum Reprod 2003; 18: 2634–7 30. Stadtmauer LA, Riehl RM, Toma SK, Talbert LM. Cauterization of hydrosalpinges before in vitro fertilization is an effective surgical treatment associated with improved pregnancy rates. Am J Obstet Gynecol 2000; 183: 367–71

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31. Surrey ES, Schoolcraft WB. Laparoscopic management of hydrosalpinges before in vitro fertilization–embryo transfer: salpingectomy versus proximal tubal occlusion. Fertil Steril 2001; 75: 612–17 32. Sowter MC, Akande VA, Williams JA, et al. Is the outcome of in-vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of a hydrosalpinx? Hum Reprod 1997; 12: 2147–50 33. Van Voorhis BJ, Sparks AE, Syrop CH et al. Ultrasound-guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in-vitro fertilization cycles. Hum Reprod 1998; 13: 736–9 34. Hurst BS, Tucker KE, Awoniyi CA, Schlaff WD. Hydrosalpinx treated with extended doxycyclin does not compromise the success of in vitro fertilization. Fertil Steril 2001; 75: 1017–19 35. Lindheim SR, Hellner D, Ditkoff EC, Sauer MV. Ovarian hyperstimulation compounds the deleterious effect of hydrosalpinx on outcome during IVF–ET. Assist Reprod Rev 1997; 7: 64–6 36. Andersen AN, Lindhard A, Loft A, et al. The infertile patient with hydrosalpinges – IVF with or without salpingectomy. Hum Reprod 1996; 11: 2081–4 37. Levi AJ, Segars JH, Miller BT, Leondires MP. Endometrial cavity fluid is associated with poor ovarian response and increased cancellation rates in ART cycles. Hum Reprod 2001; 16: 2610–15 38. Chien LW, Au HK, Xiao J, Tzeng CR. Fluid accumulation within the uterine cavity reduces pregnancy rates in women undergoing IVF. Hum Reprod 2002; 17: 351–6 39. Hinckley MD, Milki AA. Rapid reaccumulation of hydrometra after drainage at embryo transfer in patients with hydrosalpinx. Fertil Steril 2003; 80: 1268–71 40. Inovay J, Marton T, Urbancsek J, et al. Spontaneous bilateral cornual uterine dehiscence early in the second trimester after bilateral laparoscopic salpingectomy and in-vitro fertilization: case report. Hum Reprod 1999; 14: 2471–3 41. LaCombe J, Ginsburg F. Adnexal torsion in a patient with hydrosalpinx who underwent tubal occlusion before in vitro fertilization. Fertil Steril 2003; 79: 437–8 42. Verhulst G, Vandersteen N, Van Steirteghem AC, et al. Bilateral salpingectomy does not compromise ovarian stimulation in an in-vitro fertilization/embryo transfer programme. Hum Reprod 1994; 9: 624–8 43. Bredkjaer HE, Ziebe S, Hamid B, et al. Delivery rates after in-vitro fertilization following bilateral salpingectomy due to hydrosalpinges: a case control study. Hum Reprod 1999; 14: 101–5 44. Dar P, Sachs GS, Strassburger D, et al. Ovarian function before and after salpingectomy in artificial reproductive technology patients. Hum Reprod 2000; 15: 142–4 45. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Prophylactic salpingectomy does not impair the ovarian response in IVF treatment. Hum Reprod 2001; 16: 1135–9

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46. Tal J, Paltieli Y, Korobotchka R, et al. Ovarian response to gonadotropin stimulation in repeated IVF cycles after unilateral salpingectomy. J Assist Reprod Genet 2002; 19: 451–5 47. Lass A, Ellenbogen A, Croucher C, et al. Effect of salpingectomy on ovarian response to superovulation in an in vitro fertilization–embryo transfer program. Fertil Steril 1998; 70: 1035–8 48. Vasquez HB, Arici A, Olive D, et al. Prospective study of tubal mucosal lesions and fertility in hydrosalpinges. Hum Reprod 1995; 10: 1075–8 49. Matsunaga Y, Fukushima K, Nozaki M, et al. A case of pregnancy complicated by the development of a tubo-ovarian abscess following in vitro fertilization and embryo transfer. Am J Perinatol 2003; 20: 277–82 50. National Collaborating Centre for Women’s and Children’s Health. Fertility Assessment and Treatment for People with Fertility Problems. London: RCOG Press, 2004. (http://www.rcog.org.uk/guidelines.asp?PageID=108&GuidelineID=64)

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Chapter 10

The patient with fibroids JH Check and JW Krotec

INTRODUCTION Uterine fibroids occur in over 30% of women.1 Fibroids may adversely affect fertility and pregnancy outcome. Submucosal fibroids probably have the most negative impact, but other types of fibroids may also unfavorably affect these results. There are about 145 genes involved in fibroid formation from uterine smooth muscle. Theoretically, fibroids may decrease fertility for several reasons. They may obstruct the corneal portion of the tube,2 cause dysfunctional uterine contractility which could interfere with ovum transport, nidation and sperm migration, and impair blood supply to the endometrium, or cause atrophy and ulceration of the endometrium3–8. In vitro fertilization (IVF)–embryo transfer (ET) is an expensive procedure and is not without risk, e.g. ovarian hyperstimulation syndrome. Thus, it is important to make the circumstances as conducive as possible for successful embryo implantation. For example, the presence of a hydrosalpinx, whether bilateral or unilateral, seems to reduce implantation rates following ET.9 Evidence suggests that the removal of these hydrosalpinges improves subsequent implantation rates following ET.10,11 Even in light of all the potential problems that fibroids may cause, the consensus about whether to treat them in preparation for an IVF–ET cycle is not as one-sided as that for performing salpingectomy for hydrosalpinges. Historically, treatment options for fibroids related to infertility have been surgical. This chapter summarizes existing data concerning the effects of uterine fibroids on IVF outcome. Furthermore, the chapter presents data concerning benefits and risks of the surgical treatment options. Hopefully, this will

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allow the reader to formulate their own opinion about whether to treat fibroids in preparation for a given IVF–ET cycle. Finally, the authors present the published experience and explain the general plan adopted by the Cooper Center for IVF.

TYPES OF FIBROIDS AND DIAGNOSTIC MODALITIES Fibroids are categorized by their position on the uterus. They can be pedunculated, subserosal, intramural, cervical and submucosal (Figure 1). Intramural and subserosal fibroids are further defined by either their propensity for distorting the endometrial cavity (intramural) or the fraction of the fibroid that is actually in the cavity (submucosal type 0, 1 and 2). Submucosal ‘type 0’ are totally in the cavity, ‘type 1’ 50% or more and ‘type 2’ less than 50%. Rarer types (not associated with fertility) are parasitic, ovarian and broad-ligament, but these are not germane to this

Pedunculated

Intramural Subserosal

Type 0 submucosal

Subserosal causing tubal occlusion

Type 1 submucosal

Cervical

Figure 1

140

Diagram showing various types of fibroids

Intramural causing compression of cavity

Type 2 submucosal

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THE PATIENT WITH FIBROIDS

discussion. Terms such as calcified, degenerated, firm, soft, etc. are also used to describe fibroids. Of course, these definitions are somewhat arbitrary, as the distinctions between types may be subjective. The diagnosis of fibroids can be made in several different ways, and the method can shed light on the potential effect on implantation and pregnancy. Perhaps, as discussed later in the chapter, submucosal fibroids have the greatest impact on implantation and pregnancy. These can be presumptively diagnosed by hysterosalpingography (HSG). Abnormal findings can be confirmed, and possibly treated, by hysteroscopy. Hysteroscopy can help the physician to distinguish between fibroids, polyps and synechiae. HSG can also suggest tubal occlusion, hydrosalpinx and distortion of the cavity caused by other fibroids. Other less invasive and relatively inexpensive diagnostic modalities include ultrasound, sonohysterography and three- and four-dimensional ultrasound. These can all be done in an office setting and, together with findings from HSG, can help define the type, size and position of the fibroids (Figure 2). Ultrasound with simultaneous Doppler flow studies can differentiate fibroids from adenomyosis (Figure 3). Computed tomography (CT) scan and magnetic resonance imaging (MRI) are much more costly and require special facilities, but they can help to define the size and position and also help to differentiate adenomyosis. However, neither of these methods can easily define tubal patency, hydrosalpinx and distortion of anatomy. As suggested above, visual diagnosis via hysteroscopy and concurrent laparoscopy can afford very accurate evaluation and subsequent treatment of submucosal, subserosal and some intramural fibroids. Unfortunately, many intramural fibroids cannot be appreciated accurately by these techniques, and are better evaluated by the other methods.

EVIDENCE SUGGESTING AN ASSOCIATION OF FIBROIDS AND INFERTILITY There are no controlled studies that definitively prove the association of fibroids and infertility. The evidence is more anecdotal, with a mixture of small series on ‘unexplained infertility’ achieving various success rates following myomectomy. Fibroids are found in 1–2.4% of women with unexplained infertility.12 For example, a review of seven published studies of patients with unexplained infertility following abdominal myomectomy found a 53.9% pregnancy rate.13 Another study found a 44.4% pregnancy rate following laparoscopic myomectomy.14 However, these studies lacked expectant controls.

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a

b Figure 2 Submucosal fibroids (arrows) identified by: (a) transvaginal sonography; (b) sonohysterography; (c) four-dimensional sonohysterography; (d) hysterosalpingography

TYPE OF FIBROID IN RELATIONSHIP TO EFFECT ON INFERTILITY Submucosal fibroid Alhough studies are still lacking in expectant controls, the submucosal fibroid is the most likely location associated with subfertility. Very convincing pregnancy rates ensue following hysteroscopic or laparoscopic

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c

d Figure 2

Continued

removal.15–20 Even if one questions the improvement in pregnancy rates because of lack of controls, there is little doubt that the miscarriage rate is considerably increased without surgical treatment.6 The submucosal fibroid is usually very accessible by minimally invasive out-patient surgery. Thus, there is little debate that, when detected, submucosal fibroids should be confirmed by hysteroscopy and be removed by a skilled surgeon through hysteroscopic resection21 (Figure 4).

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a

b Figure 3 Differentiation of fibroids from adenomyosis using color Doppler imaging: (a) fibroid (arrow) with peripheral vessels and no internal flow seen; (b) in adenomyosis (arrow), central vessels are seen

INTRAMURAL FIBROID AND PREGNANCY RATES FOLLOWING IVF–ET One study evaluating the effect of fibroids on IVF outcome concluded that smaller fibroids not compressing the uterine cavity decreased implantation rates.22 This study included both intramural and subserosal fibroids.22 However, another study found that any submucosal and intramural fibroids not compressing the uterine cavity decreased implantation rates, but that subserosal fibroids had no effect.23

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a

b

c Figure 4 Types of submucosal fibroids as seen by hysteroscopy: (a) type 0 (open arrow) and type 2 (solid white arrow) seen in the same patient; (b) type 1 (black arrow); (c) type 0 (open arrow)

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Farhi and colleagues24 presented data suggesting that intramural fibroids may be associated with a lower implantation rate, but only when there is uterine cavity distortion. Finally, at the other extreme of conclusions, another study did not find any effect on implantation rates of intramural or subserosal fibroids < 7 cm (Figure 5).25 A more recent study by Surrey and colleagues26 found a lower implantation rate in women with intramural fibroids, but only a trend for lower live-delivery rates. However, the implantation rates were sufficiently high

a

b Figure 5 Intramural fibroids: (a) compressing endometrial cavity; (b) no compression of endometrial cavity

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in the group with fibroids that the authors concluded that surgical intervention could not be justified.26 We have also evaluated the effect of intramural fibroids < 5 cm on implantation rates using a matched-control study.27 Although we did not find a significant difference between the two groups (p = 0.08), there was a definite trend for lower implantation rates in those with intramural fibroids (20.2% vs. 13.6%)27 (Table 1). There are data suggesting that the drugs used for controlled ovarian hyperstimulation may have an adverse effect on implantation rates.32–34 We considered the possibility that whatever these medications do to lower implantation rates, it could be magnified by the presence of fibroids. To test this hypothesis, we evaluated the effect of intramural fibroids on implantation rates in donor-oocyte recipients.35 We found no difference in implantation rates, 29.9% vs. 27.4%, suggesting that the presence of intramural fibroids may exacerbate the adverse effect that controlled ovarian hyperstimulation has on implantation.35

THE LOCATION OF FIBROIDS AND PREGNANCY OUTCOME Stovall and colleagues22 noted in their study that 93% of fibroids were in the fundus. However, in our study, only half of the fibroids were in the fundus. Although the pregnancy rate was respectable at 38.7% when fibroids were in the fundus, there was a trend for higher pregnancy rates when they were found only in the lower uterine segment (46.7%).27 The data are similarly conflicting if one considers the location of fibroids in women not

Table 1 Studies of effect of smaller intramural fibroids not distorting the uterine cavity on implantation rates following embryo transfer Lower rates

No adverse effect

Stovall et al.22

Farhi et al.24

Eldar-Geva et al.23

Ramzy et al.29

Healy28

Jun et al.30 Surrey et al.26 Dietterich et al.31 Check et al.27

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a

b Figure 6 Posterior subserosal fibroid (arrow) seen by (a) transvaginal sonography and (b) laparoscopy

necessarily undergoing IVF–ET. Some studies demonstrated no influence of fibroid location.36,37 One study found lower pregnancy rates with posterior fibroids (Figure 6).

FIBROIDS AND MISCARRIAGE Ramzy and colleagues25 concluded that uterine-corporal myomota < 7 cm and not encroaching on the uterine cavity did not increase miscarriage

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rates. However, most other studies demonstrate an increased miscarriage rate. This is especially true with submucosal fibroids, but also with intramural fibroids.26,27 Although our study of donor-egg recipients found no decrease in implantation rates, there was an increase in miscarriage rates in those women with fibroids.35 Thus, the effect on miscarriage does not seem in any way to be related to the controlled ovarian hyperstimulation regimen. A recent study presented by Hartmann and colleagues38 at the 2004 Society for Gynecologic Investigation was provocative. They found a fourfold risk of miscarriage among women who had fibroids < 3 cm in diameter that were entirely intramural during the early first trimester. In contrast, patients with fibroids > 3 cm had no increased risk of miscarriage. Although it is difficult to hypothesize how a smaller fibroid is more risky for miscarriage than a larger one, it is suspected that this difference was fortuitous, or affected by confounding variables. Nevertheless, the study must make one consider that some fibroids may lead to greater risk of miscarriage in some other manner than those mechanisms previously proposed. The study by Hartmann and colleagues38 found an odds ratio of any size submucosal fibroid, compared with the no-fibroid group, of 2.34, as opposed to 1.67 for intramural fibroids. These data would be similar to the conclusions reached by Bajekal and Li,39 after reviewing the world literature. They reported that submucosal fibroids were the type most responsible for miscarriage (and infertility also) and that the subserosal type had the least effect. Intramural fibroids played an intermediate role39 (Figure 7).

EFFECT OF TREATMENT ON PREGNANCY OUTCOME The question whether or not to treat The type of fibroid that has the most negative effect on pregnancy outcome is the submucosal fibroid.39 Since this type is easily accessible hysteroscopically by a skilled surgeon, there seems little question that it should be removed prior to the patient undergoing the expensive and relatively risky procedure of IVF–ET (Figures 8 and 9). The only debate could be whether there is some minimal size at which they could be treated only with ‘careful vigilance and benign neglect’. One controlled study found a benefit in hysteroscopically removing submucosal myomas > 2 cm.40 Subserosal types and pedunculated fibroids seem to have the least impact on outcome, and, in general, probably should be left alone. In certain specific instances, such as fibroids growing quickly during pregnancy

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a

b Figure 7 Sonograms of types of fibroids found to have the least impact on outcome: (a) subserosal fibroid (S); (b) pedunculated fibroid (P) with stalk seen (arrow)

or late first-trimester or early second-trimester miscarriages (especially more than one), surgical intervention may be considered. Intramural fibroids are the type about which there is a diversity of opinions regarding whether or not to remove them surgically. The larger they are (i.e. > 7 cm), and if they distort the uterine cavity, the more evidence exists that the patient would be advised to have a prophylactic myomectomy before undergoing IVF–ET. However, even though we agree with that approach in general, the patient must be advised of the potential risks involved. She must be made aware that there are no

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a

b Figure 8 Hysteroscopic surgery demonstrating (a) submucosal fibroid (arrow) and (b) endometrium after successful resection

definitive studies proving that surgery will improve outcome. It is also possible that she could have a normal pregnancy following IVF–ET even without surgery.

Evidence supporting surgical removal of fibroids A literature search found only one study comparing spontaneous conception in infertile women with and without myomas where other infertility factors were excluded.41 The study found an 11% vs. 2.5% pregnancy rate

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a

b Figure 9 Transvaginal sonography demonstrating (a) submucosal fibroid (+ and x, calipers) and (b) the same endometrial cavity post-resection

per cycle in those with and without fibroids (p < 0.002).41 These authors claimed a 42% pregnancy rate in those patients undergoing myomectomy, compared with only 25% for those women without fibroids and only 11% for those with fibroids, during a 9-month observation period.41 The study investigated fibroids in all locations, including submucosal fibroids and those distorting the uterine cavity. A meta-analysis was performed of 46 studies of pregnancy following myomectomy.42 After hysteroscopic surgery, pregnancy rates varied from 16.7% to 78.9%. Following laparoscopic removal or excision by laparotomy,

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Prospective evaluation of myomectomy

Table 2 Author(s)

Type of surgery

Pregnancy rate (%)

Starks15

Laparotomy

62.5

Vollen-Hover et al.8

Laparotomy

46

Laparotomy

75

Laparotomy

61.5

Laparotomy

50

Liu et

al.43

Tulandi et

al.44

Abramovici et Dubuisson et

al.45

al.14

Laparoscopy

33.3

al.46

Laparoscopy

73.1

Campo and Garcea47

Laparoscopy

54.1

Serracchioli et al.48

Laparotomy and laparoscopy

54.8

Miller et

the pregnancy rate varied from 9.6 to 75%. Overall, the pregnancy rate was 48% with all surgeries combined vs. 45% for hysteroscopic myomectomy vs. 49% for laparoscopic or abdominal myomectomy.42 There were only nine prospective studies in this group of 46, as seen in Table 2. The pregnancy rates varied from 33.3% to 75% (Table 2) in these studies. To date, there are no controlled studies of implantation rates in patients undergoing IVF–ET evaluating the effect of myomectomy for fibroids < 7 cm not distorting the uterine cavity. Probably such a study could only be performed by those IVF centers producing data suggesting lower implantation rates with intramural fibroids.22,23,28 Table 2 summarizes studies evaluating the effect of smaller intramural fibroids not distorting the uterine cavity on implantation rates following ET.

SUMMARY OF MANAGEMENT OPTIONS In this chapter, we have seen that there are as yet no incontrovertible studies about the effect of fibroids on fertility. There are conflicting data about almost all aspects of the role of fibroids on implantation, pregnancy rates, miscarriage rates and pregnancy outcome. In view of the lack of controlled studies (for the most part), we must rely on anecdotal reports and experience. Below is our philosophy about treatment.

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IVF–ET is expensive and somewhat risky. If a woman is trying naturally to conceive, the only thing lost is time by not treating fibroids. However, if the presence of a fibroid in a given woman will reduce the chance of conception following IVF–ET, the decision for surgery should be considered earlier than for a couple not requiring IVF–ET. The data certainly support hysteroscopic removal of submucosal fibroids > 2 cm. Intramural fibroids distorting the uterine cavity or those < 7 cm probably warrant surgical intervention. Nevertheless, because major surgery is necessary and permanent damage precluding future pregnancies is possible, patients must be properly informed as to potential risks and benefits. Although there seems to be a possible trend for lower implantation rates with smaller intramural fibroids not compressing the uterine cavity, there seems to be an acceptable pregnancy rate with these fibroids present to warrant at least two or three ETs before considering surgery. This philosophy is also based on the fact that there are no studies to date showing that surgery under these conditions improves outcome. Since the data strongly suggest that certain fibroids increase miscarriage rates, we would recommend surgery if there was at least one previous miscarriage, as long as it was not found to be of genetic origin. Previously, we may have used a minimum size to suggest surgery, but, based on recent data, even the size may not be a factor.39 Of course, patients must be informed that one cannot prove that the fibroid was the cause, or that removing it would necessarily help. The final decision should be up to the patient. Subserosal and pedunculated fibroids would, in general, favor a nonsurgical approach. Exceptions may be a very large fibroid or multiple ones coupled with unexplained failure to conceive despite several ETs, or recurrent pregnancy loss of unknown cause.

REFERENCES 1. Verkauf BS. Myomectomy for fertility enhancement and preservation. Fertil Steril 1992; 58: 1–15 2. Ingersoll FM. Fertility following myomectomy. Fertil Steril 1963; 14: 596–602 3. Jacobson FN, Enzer N. Uterine myomas and endometrium. Obstet Gynecol 1956; 7:206–10 4. Deligdish L, Lowenthal M. Endometrial changes associated with myomata of the uterus. J Clin Pathol 1970; 23: 676–80 5. Hunt JE, Wallach EE. Uterine factor in infertility: an overview. Clin Gynecol 1974; 17: 44–64

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6. Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981; 36: 433–45 7. Iosif CS, Akerland M. Fibromyomas and uterine activity. Acta Obstet Gynecol Scand 1983; 62: 165–7 8. Vollen-hoven BJ, Lawrence AS, Healy DL. Uterine fibroids: a clinical review. Br J Obstet Gynaecol 1990; 97: 285–98 9. Strandell A, Waldenstrom U, Nilsson L, Hamberger L. Hydrosalpinx reduces in vitro fertilization/embryo transfer pregnancy rates. Hum Reprod 1994; 9: 861–3 10. Choe J, Check JH. Salpingectomy for unilateral hydrosalpinx may improve in vivo fecundity. Gynecol Obstet Invest 1999; 48: 285–7 11. Kiefer DG, Check JH. Salpingectomy improves outcome in the presence of a unilateral hydrosalpinx in a donor oocyte recipient: a case report. Clin Exp Obstet Gynecol 2001; 28: 71–2 12. Check ML, Check JH, Wilson C, et al. Outcome of in vitro fertilization–embryo transfer according to age in poor responders with elevated baseline serum follicle stimulation hormone using minimal or no gonadotropin stimulation. Clin Exp Obstet Gynecol 2004; 31: 183–4 13. Dubuisson JB, Chapron C. Laparoscopic myomectomy today: a good technique when correctly indicated. Hum Reprod 1996; 11: 934–5 14. Dubuisson JB, Chapron C, Chavet X, Gregorakis SS. Fertility after laparoscopic myomectomy of large intramural myomas: preliminary results. Hum Reprod 1996; 11: 518–22 15. Starks GC. CO2 laser myomectomy in an infertile population. J Reprod Med 1988; 33: 184–6 16. Rosati P, Bellati U, Exacoustos C, et al. Uterine myoma in pregnancy: ultrasound study. Int J Gynecol Obstet 1989; 28: 109–17 17. Narayan R, Rajat R, Goswamy K. Treatment of submucous fibroids and outcome of assisted conception. J Am Assoc Gynecol Laparosc 1994; 1: 307–11 18. Goldenberg M, Sivan E, Sharabi Z, et al. Outcome of hysteroscopic resection of submucous myomas for infertility. Fertil Steril 1995; 64: 714–16 19. Ubaldi F, Tournaye H, Camus M, et al. Fertility after hysteroscopic myomectomy. Hum Reprod Update 1995; 1: 81–90 20. Seinera P, Farina C, Todros T. Laparoscopic myomectomy and subsequent pregnancy: results in 54 patients. Hum Reprod 2000; 15: 1993–6 21. Check JH. Multiple follicles in an unstimulated cycle despite elevated gonadotropins in a perimenopausal female. Gynecol Obstet Invest 1992; 33: 190–2 22. Stovall DW, Parrish SB, Van Voorhis BJ, et al. Uterine leiomyomas reduce the efficacy of assisted reproduction cycles: results of a matched follow-up study. Hum Reprod 1998; 13: 192–7 23. Eldar-Geva T, Meagher S, Healy DL, et al. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil Steril 1998; 70: 687–91

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24. Farhi J, Ashkenazi J, Feldberg D, et al. Effect of uterine leiomyomata on the results of in-vitro fertilization treatment. Hum Reprod 1995; 10: 2576–8 25. Ramzy AM, Sattar M, Amin Y, et al. Uterine myomata and outcome of assisted reproduction. Hum Reprod 1998; 13: 198–202 26. Surrey ES, Lietz AK, Schoolcraft WB. Impact of intramural leiomyomata in patients with a normal endometrial cavity on in vitro fertilization–embryo transfer cycle outcome. Fertil Steril 2001; 75: 405–10 27. Check JH, Choe JK, Lee G, Dietterich C. The effect on IVF outcome of small intramural fibroids not compressing the uterine cavity as determined by a prospective matched control study. Hum Reprod 2002; 17: 1244–8 28. Healy DL. Impact of uterine fibroids on ART outcome. Environ Health Perspect 2000; 108 (Suppl 5): 845–7 29. Ramzy AM, Satta M, Amin Y, et al. Uterine myomata and outcome of assisted reproduction. Hum Reprod 1998; 13: 198–202 30. Jun SH, Ginsburg ES, Racowsky C, et al. Uterine leiomyomas and their effect on in vitro fertilization outcome: a retrospective study. J Assist Reprod Genet 2001; 18: 139–43 31. Dietterich C, Check JH, Choe JK, et al. The presence of small uterine fibroids not distorting the endometrial cavity does not adversely affect conception outcome following embryo transfer in older patients. Clin Exp Obstet Gynecol 2000; 27: 168–70 32. Check JH, O’Shaughnessy A, Lurie D, et al. Evaluation of the mechanism for higher pregnancy rates in donor oocyte recipients by comparison of fresh with frozen embryo transfer pregnancy rates in a shared oocyte programme. Hum Reprod 1995; 10: 3022–7 33. Check JH, Choe JK, Katsoff D, et al. Controlled ovarian hyperstimulation adversely affects implantation following in vitro fertilization–embryo transfer. J Assist Reprod Genet 1999; 16: 416–20 34. Check JH, Choe JK, Nazari A, et al. Fresh embryo transfer is more effective than frozen for donor oocyte recipients but not for donors. Hum Reprod 2001; 16: 1403–8 35. Wang W, Check JH. Effect of corporal fibroids on outcome following embryo transfer in donor-oocyte recipients. Clin Exp Obstet Gynecol 2004; 31: 263–4 36. Ancien P, Querada F. Abdominal myomectomy: results of a simple operative technique. Fertil Steril 1996; 65: 41–51 37. Sudik R, Husch K, Steller J, Daume E. Fertility and pregnancy outcome after myomectomy in sterility patients. Eur J Obstet Gynecol Reprod Biol 1996; 65: 209–14 38. Hartmann et al. Presented at the Society for Gynecologic Investigation, 2004 39. Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update 2000; 6: 614–20 40. Varasteh NN, Neuwirth RS, Levin B, Keltz MD. Pregnancy rates after hysteroscopic polypectomy and myomectomy in infertile women. Obstet Gynecol 1999; 94: 168–71

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41. Bulletti C, DeZiegler D, Polli V, et al. The role of leiomyomas in infertility. J Am Assoc Gynecol Laparosc 1999; 6: 441–5 42. Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002; 17: 1424–30 43. Liu CH, Lin YS, Lin CC, et al. Medical treatment of uterine myoma with longacting gonadotropin-releasing hormone agonist prior to myomectomy. J Formos Med Assoc 1993; 92: 536–9 44. Tulandi T, Murray C, Guralnick M. Adhesion formation and reproductive outcome after myomectomy and second-look laparoscopy. Obstet Gynecol 1993; 82: 213–15 45. Abramovici H, Dirnfeld M, Auslander R, et al. Pregnancies following treatment by GNRH-a (Decapeptyl) and myomectomy in infertile women with uterine leiomyomata. Int J Fertil Menopausal Stud 1994; 39: 150–5 46. Miller CE, Johnston M, Rundell M. Laparoscopic myomectomy in the infertile woman. J Am Assoc Gynecol Laparosc 1996; 3: 525–32 47. Campo S, Garcea N. Laparoscopic myomectomy in premenopausal women with and without preoperative treatment using gonadotrophin-releasing hormone analogues. Hum Reprod 1999; 14: 44–8 48. Seracchioli R, Rossi S, Govoni F, et al. Fertility and obstetric outcome after laparoscopic myomectomy of large myomata: a randomized comparison with abdominal myomectomy. Hum Reprod 2000; 15: 2663–8

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Chapter 11

The patient with congenital uterine abnormalities PK Heinonen

INTRODUCTION Abnormal fusion of the Müllerian ducts and failure of absorption of the septum cause varying degrees of congenital uterine malformations ranging from uterine aplasia to a complete double uterus.1 The etiology of uterine anomalies is unknown, but may be multifactorial or polygenic in character.2 Diethylstilbestrol (DES) exposure in utero is one factor known to cause uterine malformations (T-shaped uterus).3 Uterine anomalies have been reported to occur in 5% of the general female population, in 2–3% of fertile women, in 3% of infertile women and in 5–10% of patients with recurrent miscarriage.4 Improvement in uterine imaging techniques and especially routine use of transvaginal ultrasound have increased the frequency of their diagnosis. Many uterine anomalies are found incidentally before the first pregnancy. Congenital uterine malformations are more often associated with poor obstetric performance than with infertility. About 20–25% of patients with uterine anomalies have serious reproductive problems.5 Recurrent pregnancy wastage, including abortion and premature labor, is the most common clinical manifestation of these disorders, although the majority of such subjects reproduce efficiently.2,6,7 Uterine malformations are rarely a single cause of primary infertility, except for absence of the uterus or cervical atresia.8 Primary infertility associated with uterine anomalies may be attributed to related disorders such as endometriosis, pelvic adhesive disease or ovulatory dysfunction. Assisted reproductive treatment is therefore also indicated in some cases with uterine malformations treated by in vitro fertilization (IVF). Tubal damage has been the most common etiological factor in assisted

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reproduction, about half of the patients with uterine anomalies having this background. Unexplained infertility has been found in 6–29% of patients with uterine anomalies treated with IVF.9–11

IMPACT OF UTERINE MALFORMATIONS ON IVF OUTCOMES A number of studies have shown that uterine anomalies are associated with lowered rates of embryo implantation.10,11 However, in one report of 24 patients with a malformed uterus, implantation rates per embryo transfer were similar to that in the general infertile population.9 It is thus possible that other factors such as quality of embryos, number of embryos transferred and technical aspects of the technology of assisted reproduction may affect implantation rates. Surveys published on these topics are so small that conclusions remain invalid. The classification of the American Fertility Society divides uterine anomalies into main groups, although variation between groups is possible (Figure 1).1 The distribution of these disorders ranges according to population, but complete or partial septate uterus is the most common (Table 1). The main groups of uterine malformations are characterized by specific features that determine the prognosis for achieving an ongoing pregnancy, and the possible benefits of treatment prior to assisted reproduction. Each main group of anomalies is therefore addressed separately.

Unicornuate uterus A unicornuate uterus can be present alone or with a rudimentary horn on the opposite side.12 A non-communicating rudimentary horn is the most common, the communicating type being found very rarely. The rudimentary horn may have a cavity, hematometra then being possible (Figure 2) A functional endometrium in the rudimentary horn is rare, but the prevalence of endometriosis is increased compared with other Müllerian anomalies.13 High numbers of ectopic pregnancies and fetal survival rates of 55–61% have been reported in patients with a unicornuate uterus.14,15 Most of these patients have only one patent tube adjacent to a functional uterine cavity. Occlusion or removal of this tube means infertility and the need for assisted reproductive treatment.14 Marcus and associates9 used IVF–embryo transfer (IVF–ET) to treat six (25%) patients with unicornuate uterus out of 24 with uterine anomalies, and Heinonen and associates11 treated eight (47%) of 17 patients. Implantation rates per embryo were 13.2% and 9.6% and the pregnancy

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THE PATIENT WITH CONGENITAL UTERINE ABNORMALITIES

I

IIA

IIB

III

IVA

IVB

VA

IVC

VB

Figure 1 Classification of uterine malformations: I, uterine agenesis or cervical atresia; IIA, unicornuate uterus; IIB, unicornuate uterus with rudimentary horn; III, didelphic uterus; IVA, complete bicornuate uterus; IVB, partial bicornuate uterus; IVC, arcuate uterus; VA, septate uterus; VB, subseptate uterus. Diethylstilbestrol (DES) drug-related (T-shaped) uterus is not shown. Reprinted from reference 1, copyright (1988) with permission from the American Congress of Rehabilitation Medicine and the American Society for Reproductive Medicine

rates per patient were 83% and 75%, respectively. Ectopic pregnancy occurred in three, miscarriage in two, preterm delivery in one and term delivery in five of 11 pregnancies after IVF.9,11 Pregnancy in the rudimentary horn has also been reported after IVF.16 The unicornuate uterus is associated with a low implantation rate and a risk of ectopic pregnancy in assisted reproductive treatment.

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Table 1 Distribution of uterine anomalies among 441 patients in Tampere University Hospital, Finland, between 1963 and 1997 Uterine anomaly

%

Aplasia

12

Unicornuate

10

Didelphic

11

Complete bicornuate

3

Partial bicornuate

13

Septate

17

Subseptate

29

Didelphic uterus This uterine anomaly develops when fusion of the Müllerian ducts is completely lacking, with duplication of corpus and cervix (Figure 3). A longitudinal vaginal septum is found in these patients, and is mostly the first indication for additional diagnostic procedures.17 A didelphic uterus is as common as the unicornuate type (Table 1). Fetal survival rates have been 56–75% in retrospective studies.15,17 Only six patients with a didelphic uterus treated with IVF–ET have been reported.9,11 Marcus and associates9 had four patients, three of whom delivered after assisted reproduction, and one of these was preterm. Heinonen and associates11 treated two patients; one of them had a pregnancy after IVF–ET, which ended in miscarriage. Implantation rates per embryo were 27.3% and 6%, respectively. The fact that only a few women with a didelphic uterus have been treated with assisted reproduction would imply that infertile patients in this group can be treated mostly by conventional methods, and assisted reproduction is rarely needed. Operative unification of both hemiuteri is not necessary, and this operation should be avoided.

Bicornuate uterus In the past, the bicornuate uterus constituted the largest group of uterine anomalies, hysterosalpingography (HSG) being the main diagnostic tool. HSG may not accurately distinguish a bicornuate from a septate uterus

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a

c

b

Figure 2 (a) Unicornuate uterus without rudimentary horn; (b) unicornuate uterus with noncommunicating rudimentary horn with no cavity; and (c) unicornuate uterus with non-communicating rudimentary horn and cavity. Reprinted from reference 12, copyright (1983) with permission from the International Federation of Gynecology and Obstetrics

Figure 3 Laparoscopic view showing didelphic uterus. The rectovesical ligament is between the hemiuteri

(Figure 4). Recent experiences with endoscopic and ultrasound diagnostic techniques indicate that many anomalies once considered bicornuate may in fact be septate. This anomaly is associated with repeated abortion and preterm delivery.6,15 Classic abdominal metroplasty according to

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Figure 4 Hysterosalpingography shows a divided uterine cavity at first regarded as bicornuate uterus. Laparoscopy and hysteroscopy confirmed the presence of the uterine septum

Strassmann is the recommended therapeutic approach in cases with habitual abortions.5 This operation is very rarely necessary. Nine patients with a bicornuate uterus treated by IVF have been reported.9 The implantation rate per embryo was 11.6% and the pregnancy rate per patient 44.4%. There were no full-term deliveries among five pregnancies; one was ectopic, one ended in miscarriage and three were preterm deliveries. Guirgis and Shrivastav18 treated 14 patients with bicornuate uterus by gamete intrafallopian transfer (GIFT); eight (57.1%) achieved a pregnancy after a mean of 2.1 attempts per patient. Assisted reproduction after Strassmann metroplasty of a bicornuate uterus or patients with arcuate uterus have not been reported.

Septate uterus Partial and complete septate uteri are the most common types of uterine anomalies (Table 1).7 Transvaginal ultrasound easily reveals the presence of a uterine septum (Figure 5). The anatomy of the uterine septum varies widely, and hysteroscopic and laparoscopic investigations are often necessary to exclude a bicornuate uterus. A complete uterine septum sometimes extends through to the cervical canal and a longitudinal vaginal septum is found. This anomaly is associated with the poorest reproductive outcome, with low fetal survival rates and a high rate of first-trimester miscarriage.15,19 Primary infertility is usually not associated with the uterine

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Figure 5 Transvaginal ultrasound showing in transverse view the septum dividing the uterine cavity

septum, and the indications for assisted reproduction are similar to those without a malformed uterus. Although there have been no controlled studies to confirm attempts to manage the uterine septum, its treatment seems to improve the prognosis of pregnancy after assisted reproduction. Lavergne and associates10 reported 16 cases of septate uterus treated with assisted reproduction. Nine of these women had operative treatment of the uterine septum before IVF–ET and seven had no treatment. The implantation rate was higher (10.5%) than in untreatable uterine anomalies (4.7%). There were no differences between the groups concerning response to stimulation, quality of embryos or quality of transfers. The authors recommended hysteroscopic treatment of the uterine septum before any attempts at assisted reproduction.10 Grimbizis and associates20 have reported successful results: eight (72.7%) of 11 patients undergoing hysteroscopic septum resection conceived after assisted reproductive treatment. In another study, seven patients with a subseptate uterus had undergone hysteroscopic incision of the subseptum prior to IVF–ET.11 The implantation rate per embryo was 8.3%, while the pregnancy rate per embryo was 19.0% and per patient 42.9%.11 Three out of four pregnancies ended in term delivery and one ectopic pregnancy occurred. These results reflect the situation after surgical repair rather than that in the intact subseptate uterus. Another study from Bourn Hall, UK, involved five women with septate uterus and no surgical treatment. The implantation rate was 22.5% and the pregnancy rate

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per patient 35.7%. Three out of five pregnancies ended in first-trimester miscarriages, one was preterm delivery and only one was full-term.9 Hysteroscopic metroplasty does not counter infertility, but can improve the prognosis of pregnancy after assisted reproduction. The maturational defects of the septal endometrium found in natural cycles may impair the malformed uterine cavity and prevent reception of the fertilized ovum.21 Removal of the septum thus not only eliminates an unsuitable site for implantation but may also improve endometrial function21. Table 2 summarizes outcomes of assisted reproductive treatments and pregnancies in women with uterine abnormalities according to two studies.9,11

DES drug-related uterus Abnormalities such as a T-shaped and hypoplastic uterus have been reported in 70% of DES-exposed women according to HSG studies.3 These patients have had more failures in implantation in an IVF program,

Table 2 Outcome of treatment by assisted reproduction in women with uterine anomalies summarized from two studies of 41 patients and 30 pregnancies Marcus et al.9

Heinonen et al.11

Total

Number of patients

24

17

41

Implantation rate per embryo (%)

17.5

8.8

13.1

Pregnancy rate per embryo transfer (%)

37.3

18.0

26.8

Pregnancy rate per patient (%)

70.8

58.8

65.9

Number of pregnancies

19

11

30

Ectopic pregnancy (%)

10

27

13

Miscarriage (%)

21

27

20

Preterm delivery (%)

32

0

27

Term delivery (%)

37

47

40

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in particular in cases of a T-shaped uterus.22 Hysteroscopic treatment may improve the prognosis of pregnancy.23 This group is expected to decline in importance as most of these women pass their reproductive years.2

IMPACT OF IVF ON UTERINE MALFORMATIONS The development and availability of assisted reproduction have greatly improved the prognosis for conceiving a pregnancy in some rare uterine abnormalities. For certain anomalies, pregnancy was not possible prior to the era of IVF.24

Cervical atresia Cervical atresia is an uncommon Müllerian malformation possibly associated with vaginal aplasia.25 Canalization procedures are performed initially to relieve symptoms related to hematometra and retrograde menstruation.26 Hysterectomy should be avoided to preserve fertility. The chance of a spontaneous pregnancy is reduced even after successful reconstruction of the genital tract due to severe endometriosis, as well as cervical and tubal factors. Case reports of pregnancies after IVF and an ultrasound-guided transmyometrial embryo transfer have been published.27

Uterine aplasia Uterovaginal aplasia is found in 1 per 5000 females.2 The condition causes primary infertility. Assisted reproduction has been reported in such women. Surrogate women have been used to transfer the embryo, and results have been comparable to those with conventional IVF.28 Beski and associates29 treated six patients with gestational surrogacy. The pregnancy rate per embryo transfer was 21.4% and the pregnancy rate per patient 50%. Petrozza and associates30 reported 32 women diagnosed with congenital absence of the uterus and vagina undergoing IVF with subsequent transfer of embryos to a surrogate uterus. They found that congenital absence of the uterus and vagina is not commonly inherited in a dominant fashion. In vitro surrogacy is controversial and is not accepted in some countries.

PREPARING THE PATIENT FOR IVF Accurate diagnosis of the malformed uterus is necessary prior to assisted reproduction.

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Transvaginal ultrasound, hysterosonography and hysteroscopy have replaced conventional HSG as a first-line diagnostic tool. These constitute adequate means to diagnose septate and didelphic uteri (Figures 5 and 6). They are not always adequate to detect a rudimentary horn associated with a unicornuate uterus, or to confirm a bicornuate uterus. Three-dimensional ultrasound and magnetic resonance imaging (MRI) are more accurate techniques for detection of the anomaly.31,32 Laparoscopy makes it possible to evaluate the uterine structure within the abdominal cavity. Endometriosis is frequently associated with many uterine anomalies, and its treatment before assisted reproduction is recommended. A rudimentary horn associated with a unicornuate uterus has been reported to be associated with endometriosis in 50%.13 Removal of the rudimentary uterine horn may improve the chances of a successful pregnancy. A longitudinal vaginal septum is found most often in women with a complete septate and didelphic uterus.33,34 It is mostly asymptomatic. Its incision may facilitate embryo transfer in that visualization of the uterine cervix is improved. Ultrasound scanning of the kidneys is important, as renal malformations are found in 15–25% of women with uterine anomalies. Unilateral renal agenesis is the most common renal anomaly and is associated with the unicornuate and didelphic uterus.35

Figure 6 Hysterosonography can be used to visualize a uterine septum and to measure its length and thickness

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Many authors recommend hysteroscopic metroplasty of a uterine septum prior to assisted reproduction treatment.10,11,20 Hysteroscopic incision of the uterine septum is a fairly simple and safe procedure involving low morbidity.19 Excessively radical incision may damage the uterine muscular wall and incur a risk of rupture of the uterus during pregnancy.19 Fedele and associates36 have reported that a septal remnant less than 1 cm is as good as complete septal incision (Figure 7). Incision of the cervix septum is not necessary.

a

b Figure 7 (a) Hysterosalpingography shows preoperatively a complete uterine septum and (b) the same uterine cavity after hysterosocopic incision of the septum

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Abdominal metroplasty for a bicornuate or didelphic uterus is nowadays very rarely necessary before assisted reproduction. Only patients with recurrent miscarriages and a need of assisted reproduction may indicate Strassmann metroplasty before treatment.

MANAGING THE IVF CYCLE Ovarian stimulation, cycle monitoring by serial ultrasound scanning, sperm preparation and embryo culture are standard IVF methods, and do not differ in patients with uterine anomalies. Intracytoplasmic sperm injection (ICSI) has been used in cases with low or failed fertilization in conventional IVF or primary male factor.11 Ombelet and associates37 reported that a unicornuate uterus was associated with an undescended ovary when MRI was performed after clomiphene citrate ovarian stimulation. This is worthy of consideration when follicles are aspirated after ovarian stimulation in patients with a unicornuate uterus. Embryo transfer is preferably made to the hemiuterus that shows a more suitable endometrium according to ultrasound scanning, in patients with a didelphic or complete bicornuate uterus. The cavity of the hemiuterus is often directed markedly laterally, and this may hinder the gentle direction of the transfer catheter into the uterine cavity. Ultrasound may be useful in estimating the location of the cavity. Pregnancy has been located more commonly (76%) in the right hemiuterus than in the left.17 Mor and associates38 have suggested that use of tubal embryo transfer may improve results in certain cases. They report a per embryo implantation rate of 33% among seven patients. Many of the published studies in this field cover the period when three embryos were normally transferred, with the concomitant increased risk of multiple pregnancy. Among 24 women with uterine malformations, the multiple pregnancy rate in the group of patients who had three embryos transferred was 40%, compared with 0% in those receiving one or two embryos.9 It was therefore recommended that patients with uterine anomalies should not have more than two embryos transferred, to minimize the risks of multiple pregnancy and preterm labor.9 In current practice, single-embryo transfer is recommended to reduce the risk of multiple pregnancy, and thus the combined risks of a malformed uterus and multiple pregnancy. Although twin pregnancies, even triplets, have been described in malformed uteri, both are risk factors for preterm labor, and using single-embryo transfer it is possible to reduce these

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risks.9,11,39 Transfer of cryopreserved–thawed embryos is effected during natural cycles or after artificial hormonal endometrial preparation. Table 3 summarizes some of the options that may be involved in assisted reproductive treatment of patients with uterine anomalies.

POST-IVF FOLLOW-UP If pregnancy follows after assisted reproductive treatment in a malformed uterus, it needs meticulous follow-up. This pregnancy carries at least the same risks as in cases of conception during the normal cycle. It is of prime importance to confirm the site of pregnancy using transvaginal ultrasound (Figure 8). Ectopic pregnancy has been reported in all types of malformed uterus after IVF, but is most common in women with a unicornuate uterus.14 First-trimester abortions are associated with a septate uterus, but incision of the septum prior to assisted reproduction improves the prognosis of pregnancy.10,11,20 Preterm delivery has occurred in 15–45% of all deliveries in women with a malformed uterus.6,7,15 Pregnancy after assisted reproduction also carries a risk of preterm delivery, even in a single pregnancy in a normal uterine cavity.40,41 Thus, both factors may increase the number of preterm deliveries. Prophylactic cervical cerclage has been used in women with uterine anomalies to prevent preterm delivery.42,43 The relevant data are mostly from retrospective studies. Patients who have had second-trimester miscarriage or extremely preterm delivery may benefit from the application of cervical cerclage. Transvaginal ultrasound may be useful in assessing the length of the cervical canal and the appropriate point of application. Unilateral renal agenesis predisposes women with uterine anomalies to gestational hypertension and pre-eclampsia.35 The condition is often mild, but may indicate treatment and delivery earlier than planned. Marcus and associates9 reported that four (36.4%) of 11 deliveries after IVF were complicated by pre-eclampsia, although the presence of renal malformations was not reported. The Cesarean section rates in patients with uterine anomalies delivered after assisted reproduction have been 60–77%.9,11,18 This is attributed to prematurity and fetal malpresentations, and also a history of infertility may have lowered the threshold for intervention. High frequencies of breech presentation and Cesarean section are often associated with malformed uteri. Normal vaginal delivery is possible after hysteroscopic incision of a uterine septum.44

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Unicornuate Didelphic, bicornuate All

Oocyte retrieval Embryo transfer Embryo transfer

Ultrasound, pyelography

All

During ART

Ultrasound, endoscopies, MRI Laparoscopic treatment of endometriosis Removal of rudimentary horn Incision of vaginal septum Incision of uterine septum

All All Unicornuate Didelphic, septate Subseptate–septate

Continued

Undescended ovaries make it difficult ET to better hemiuterus Only 1–2 embryos

Precise diagnosis of the malformed uterus To improve prognosis of pregnancy To improve prognosis of pregnancy To facilitate embryo transfer To improve implantation rate and prognosis of pregnancy To detect renal anomalies

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Process

Main options in patients with uterine malformations before, during and after assisted reproductive treatment

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Transvaginal ultrasound Ultrasound Ultrasound: measurement of endocervix Ultrasound Ultrasound, toxemia tests

MRI, magnetic resonance imaging; ET, embryo transfer

Unicornuate Septate All All Solitary kidney

After ART

Process

Risk of ectopic pregnancy Risk of first-trimester abortion Cervical incompetence (cervical cerclage) Fetal malpresentation, Cesarean section Risk of pre-eclampsia

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Figure 8 Transvaginal ultrasound image of a didelphic uterus with pregnancy in the patient’s left hemiuterus

SUMMARY OF MANAGEMENT OPTIONS (1) Accurate diagnosis of the malformed uterus is important before assisted reproduction. (2) Hysteroscopic incision of the uterine septum improves implantation rates and prognosis of pregnancy. (3) Laparoscopic treatment of endometriosis and rudimentary horn may improve the prognosis of pregnancy after assisted reproduction. (4) Transfer of one or at most two embryos is highly recommended to prevent multiple pregnancy. (5) The risk of miscarriage and preterm labor is associated with a malformed uterus, and preterm labor is also associated with assisted reproduction per se. (6) Cervical cerclage may be useful if ultrasound shows cervical incompetence.

REFERENCES 1. The American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Müllerian anomalies and intrauterine adhesions. Fertil Steril 1988; 49: 944–55

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2. Lin PC, Bhatnagar KP, Nettleton GS, Nakajima ST. Female genital anomalies affecting reproduction. Fertil Steril 2002; 78: 899–915 3. Goldberg JM, Falcone T. Effect of diethylstilbestrol on reproductive function. Fertil Steril 1999; 72: 1–7 4. Acién P. Incidence of Müllerian defects in fertile and infertile women. Hum Reprod 1997; 12: 1372–6 5. Jones HW Jr. Reproductive impairment and the malformed uterus. Fertil Steril 1981; 36: 137–48 6. Heinonen PK, Saarikoski S, Pystynen P. Reproductive performance of women with uterine anomalies. An evaluation of 182 cases. Acta Obstet Gynecol Scand 1982; 61: 157–62 7. Raga F, Bauset C, Remohi J, et al. Reproductive impact of congenital Müllerian anomalies. Hum Reprod 1997; 12: 2277–81 8. Heinonen PK, Pystynen PP. Primary infertility and uterine anomalies. Fertil Steril 1983; 40: 311–16 9. Marcus S, Al-Shawaf T, Brinsden P. The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. Am J Obstet Gynecol 1996; 175: 85–9 10. Lavergne N, Aristizabal J, Zarka V, et al. Uterine anomalies and in vitro fertilization: what are the results? Eur J Obstet Gynecol Reprod Biol 1996; 68: 29–34 11. Heinonen PK, Kuismanen K, Ashorn R. Assisted reproduction in women with uterine anomalies. Eur J Obstet Gynecol Reprod Biol 2000; 89: 181–4 12. Heinonen PK. Clinical implications of the unicornuate uterus with rudimentary horn. Int J Gynaecol Obstet 1983; 21: 145–50 13. Fedele L, Bianchi S, Di Nola G, et al. Endometriosis and nonobstructive Müllerian anomalies. Obstet Gynecol 1992; 79: 515–17 14. Heinonen PK. Unicornuate uterus and rudimentary horn. Fertil Steril 1997; 68: 224–30 15. Grimbizis GF, Camus M, Tarlatzis BC, et al. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 2001; 7: 161–74 16. Tang R, Sheng Y, Chen ZJ. Rupture of pregnancy in a communicating rudimentary uterine horn after in vitro fertilization and embryo transfer. Int J Gynecol Obstet 2004; 86: 394–5 17. Heinonen PK. Clinical implications of the didelphic uterus: long-term followup of 49 cases. Eur J Obstet Gynecol Reprod Biol 2000; 91: 183–90 18. Guirgis RR, Shrivastav P. Gamete intrafallopian transfer (GIFT) in women with bicornuate uteri. J In Vitro Fert Embryo Transfer 1990; 7: 283–4 19. Homer HA, Li T-C, Cooke ID. The septate uterus: a review of management and reproductive outcome. Fertil Steril 2000; 73: 1–14 20. Grimbizis G, Camus M, Clasen K, et al. Hysteroscopic septum resection in patients with recurrent abortions or infertility. Hum Reprod 1998; 13: 1188–93

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21. Fedele L, Bianchi S, Marchini M, et al. Ultrastructural aspects of endometrium in infertile women with septate uterus. Fertil Steril 1996; 65: 750–2 22. Kerjean A, Poirot C, Epelboin S, Jouannet P. Effect of in-utero diethylstilboestrol exposure on human oocyte quality and fertilization in a programme of invitro fertilization. Hum Reprod 1999; 14: 1578–81 23. Garbin O, Ohl J, Bettahar-Lebugle K, Dellenbach P. Hysteroscopic metroplasty in diethylstilboestrol-exposed and hypoplastic uterus: a report on 24 cases. Hum Reprod 1998; 13: 2751–5 24. Thjissen RFA, Hollanders JMG, Willemsen WNP, et al. Successful pregnancy after ZIFT in a patient with congenital cervical atresia. Obstet Gynecol 1990; 76: 902–4 25. Rock JA, Carpenter SE, Wheeless CR, Jones HW Jr. The clinical management of maldevelopment of the uterine cervix. J Pelvic Surg 1995; 1: 129–33 26. Deffarges JV, Haddad B, Musset R, Paniel BJ. Utero-vaginal anastomosis in women with uterine cervix atresia: long-term follow-up and reproductive performance. A study of 18 cases. Hum Reprod 2001; 16: 1722–5 27. Anttila L, Penttilä T-A, Suikkari A-M. Successful pregnancy after in-vitro fertilization and transmyometrial embryo transfer in a patient with congenital atresia of cervix. Hum Reprod 1999; 14: 1647–9 28. Goldfarb JM, Austin C, Peskin B, et al. Fifteen years experience with an in-vitro fertilization surrogate gestational pregnancy programme. Hum Reprod 2000; 15: 1075–8 29. Beski S, Gorgy A, Venkat G, et al. Gestational surrogacy: a feasible option for patients with Rokitansky syndrome. Hum Reprod 2000; 15: 2326–8 30. Petrozza JC, Gray MR, Davis AJ, Reindollar RH. Congenital absence of the uterus and vagina is not commonly transmitted as a dominant genetic trait: outcomes of surrogate pregnancies. Fertil Steril 1997; 67: 387–9 31. Fedele L, Dorta M, Brioschi D, et al. Magnetic resonance evaluation of double uteri. Obstet Gynecol 1989; 74: 844–7 32. Woelfer B, Salim R, Banerjee S, et al. Reproductive outcomes in women with congenital uterine anomalies detected by three-dimensional ultrasound screening. Obstet Gynecol 2001; 98: 1099–103 33. Heinonen PK. Longitudinal vaginal septum. Eur J Obstet Gynecol Reprod Biol 1982; 13: 253–8 34. Haddad B, Louis-Sylvestre C, Poitout P, Paniel B-J. Longitudinal vaginal septum: a retrospective study of 202 cases. Eur J Obstet Gynecol Reprod Biol 1997; 74: 197–9 35. Heinonen PK. Gestational hypertension and preeclampsia associated with unilateral renal agenesis in women with uterine malformations. Eur J Obstet Gynecol Reprod Biol 2004; 114: 39–43 36. Fedele L, Bianchi S, Marchini M, et al. Residual uterine septum of less than 1 cm after hysteroscopic metroplasty does not impair reproductive outcome. Hum Reprod 1996; 11: 727–9 37. Ombelet W, Grieten M, DeNeubourg P, et al. Undescended ovary and unicornuate uterus: simplified diagnosis by the use of clomiphene citrate ovarian

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stimulation and magnetic resonance imaging (MRI). Hum Reprod 2003; 18: 858–62 38. Mor E, Bayrak A, Tourgeman DE, et al. Embryo implantation in women with Müllerian anomalies: role of tubal embryo transfer. Fertil Steril 2004; 81 (Suppl 3): 22–3 39. Gerris J, Eulaers E, Joostens M, et al. Successful triplet pregnancy in a patient with a unicornuate uterus with a cavitary communicating rudimentary horn. Hum Reprod 1993; 8: 338–41 40. Koudstaal J, Braat DDM, Bruinse HW, et al. Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals. Hum Reprod 2000; 15: 1819–25 41. Wang JX, Norman RJ, Kristiansson P. The effect of various infertility treatment on the risk of preterm birth. Hum Reprod 2002; 17: 945–9 42. Wajntraub G, Milwidsky A, Weiss D. Prevention of premature delivery in a unicornuate uterus by cervical cerclage. Acta Obstet Gynecol Scand 1975; 54: 497–8 43. Golan A, Langer R, Wexler S, et al. Cervical cerclage – its role in the pregnant anomalous uterus. Int J Fertil 1990; 35: 164–70 44. Heinonen PK. Reproductive performance of women with uterine anomalies after abdominal or hysteroscopic metroplasty or no surgical treatment. J Am Assoc Gynecol Laparosc 1997; 4: 311–17

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Section 3 The successful and unsuccessful IVF patient

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Chapter 12

Preparing for pregnancy: preconception care EAP Steegers and HIJ Wildschut

INTRODUCTION Despite continuing efforts to improve antenatal care, the incidence of a number of adverse pregnancy outcomes, including low birth weight, preterm delivery and birth defects, has not diminished in recent years. Furthermore, during recent decades maternal mortality has failed to decline substantially in developed countries such as The Netherlands. This may in part be attributed to an increased number of women of advanced age at the time of their first pregnancy, an increased number of multiple pregnancies and a relatively increased number of high-risk pregnancies among women with a chronic medical condition. In women with medical disorders who require assisted reproductive technologies (ART) treatment, it is of utmost importance that before ART is considered, it is evaluated whether such therapy is sensible in view of possible maternal and perinatal morbidity and mortality. This requires extensive counseling. The most critical stages of embryonic development, i.e. up to 56 days after conception, largely occur before a woman is aware of her pregnancy. The first antenatal visit usually takes place after organogenesis and early placentation have been completed and, therefore, is too late to have a substantial impact on reproductive outcome. Hence, risk factors for adverse pregnancy outcome should be addressed before conception. The opportunity for primary prevention, to address and reduce risk factors for adverse pregnancy outcome before conception, has led many to believe that a shift from antenatal care to preconception care could be the most effective strategy to improve maternal and fetal outcome.1 The principal goal of preconception care is to maximize the quality of fetal, newborn and infant life through primary prevention. This can be

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achieved by promoting healthy habits, the education of women on pregnancy planning and the need for antenatal care and the identification and reduction of (modifiable) risk factors before conception. Intrauterine growth and development are increasingly regarded as important determinants of health in later life. Furthermore, pregnancy complications such as severe pre-eclampsia and gestational diabetes are related to cardiovascular and diabetic disease of the same woman in later life. Common underlying risk factors are probably involved. Preconception care can therefore contribute to the prevention of both abnormal pregnancy outcome and chronic disease of both mother and child in later life. Preconception care should not be restricted to women; their partners should also be involved for the evaluation of paternal risk factors for adverse pregnancy outcome. Preconception care is always indicated in populations at high risk of adverse pregnancy outcome, and should be actively offered by health-care providers. High-risk populations include women with complicated obstetric histories, chronic medical disorders, history of malignant disease or morbid obesity and those using medication. Increasingly more women who have birth defects themselves (such as congenital cardiac anomalies) or who have a history of organ transplantation wish to have children. Some immigrant subpopulations may be classified as high-risk as well, for example with respect to hemoglobinopathies and consanguinity. This type of care should be concentrated at university and large peripheral hospitals, with a co-ordinating role of an obstetrician. Figure 1 illustrates how the out-patient clinic for preconception care is organized at the Erasmus University Medical Center, Rotterdam, The Netherlands So far, no international consensus exists as to which low-risk populations should be offered preconception care. Should all couples contemplating pregnancy receive preconception care or should preconception care be aimed at all individuals of reproductive age? Preconception care for low-risk populations, i.e. the population at large, should be organized by cooperation between community-care institutions and peripheral hospitals. Nurses, general practitioners or family physicians, midwives, internists, clinical geneticists, pediatricians, and health professionals at family planning clinics have all been suggested as potentially eligible health-care workers to deliver preconception care. Hollingsworth and colleagues1 proposed that a preconception clinic should be run collaboratively by an internist, perinatologist, geneticist, nurse-clinician and a nutritionist. General practitioners and community midwives consider preconception care to belong to their professional domain, but consider themselves insufficiently trained to deliver this.2 Preconception care has been shown to improve pregnancy outcome in women with diabetes mellitus,3 those with phenylketonuria4 and those

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PRECONCEPTION CARE

OUT-PATIENT CLINIC FOR PRECONCEPTION CARE from within hospital Own initiative or referral externally Referral letter

1st visit

Medical history Description of specific problem

2 months

To gain additional information from doctors involved Consultation of other specialities Search of international literature Additional diagnostic procedures

2nd visit

To draw up to a multidisciplinary preconceptional, ante- and postnatal plan of management Written report (for referring specialist, own files and couple) Archiving

Follow-up of pregnancy outcome Figure 1

Organization of preconception care in a university center

taking potentially teratogenic drugs.5 A recent meta-analysis by Ray and colleagues6 demonstrated a pooled major congenital anomaly rate (from 14 cohort studies) of 2.1% in diabetic women who had received preconception care versus 6.5% in diabetic women who had not (relative risk (RR) 0.36). Furthermore, it was shown that after preconception counseling, diabetic women planned their pregnancies better, had lower mean glycohemoglobin (HbA1c) values in pregnancy, were less often hospitalized and had less perinatal morbidity.7 Evaluation of the preconception care clinic in Glasgow also illustrated that preconception counseling improved the outcome of a subsequent pregnancy among women with chronic disease, particularly women with diabetes and hypertension.8 The use of folic acid supplements during the periconceptional period has also been shown to reduce the risk of bearing a child with a neural tube defect.9,10 There are no adverse psychological effects attributable to preconception counseling. It has been shown that preconception counseling does not result in increased anxiety among an out-patient hospital population, and

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even decreases anxiety in couples at high risk of an adverse pregnancy outcome.11 Furthermore, looking at folic acid supplementation and cutting down of smoking as examples, compliance to advice given seems to be rather good.12,13

COMPONENTS OF PRECONCEPTION CARE Preconception care should encompass the following four components: (1) Risk assessment: the systematic evaluation and identification of risk factors for adverse pregnancy outcome. This may require additional screening, diagnostic tests and consultation with other specialists. (2) Health promotion: couples are informed and educated on a variety of health-promotion issues, including periconceptional folic acid supplement use, avoidance of alcohol, tobacco and other drugs, and proper nutrition. (3) Intervention in order to modify or eliminate risk factors. (4) Counseling: adequate information and counseling allow couples to make an informed choice on whether to refrain from child-bearing or opt for pregnancy.

Risk assessment Risk assessment encompasses screening for and evaluation of risk factors through assessing the woman’s history, which should include an evaluation of obstetric and medical history, infectious disease history, family history, smoking, alcohol and drug use, teratogen exposure at home or at work, medication use, and dietary habits. Table 1 provides an overview of risk factors to be considered for the evaluation for each of these categories.14,15 Preconception care should also include risk assessment of the partner, as there is increasing evidence of paternal influence on pregnancy outcome.16 Furthermore, as men may also carry or pass on genetic risks to their offspring, it is of equal importance to evaluate the family history of both prospective parents. Several screening instruments have been developed in order to facilitate the provision of preconception care. A self-administered screening tool named the ‘Preconceptional Health Appraisal’ was developed in Chapel Hill, North Carolina. It was shown that screening can be performed

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Table 1 Preconceptional history: items covered in a validated screening questionnaire Screening items Medical history Diabetes Thyroid disease Asthma Heart disease High blood pressure Deep venous thrombosis Kidney disease SLE Epilepsy Sickle cell anemia Cancer Reproductive history Uterine or cervical abnormalities Two or more first-trimester miscarriages Preterm delivery (14–28 weeks’ GA) One or more intrauterine death(s) Prior infant < 2750 g at birth Prior infant admitted to neonatal ICU Prior infant with birth defect Operative delivery Nutritional history Vegetarianism/veganism Frequent consumption of snacks/pica History of bulimia/anorexia nervosa Special diet Vitamin supplement use Intolerance for milk

Infectious disease history STD Herpes simplex Chlamydia infection Human papillomavirus Viral hepatitis (or risk behavior) HIV (or risk behavior) Occupational exposure to blood Blood transfusion Own/work with cats Immunity to rubella Family history Birth defects/genetic diseases Related to partner Race Social history/behavior risks Alcohol use (per day) Tobacco use (per day) Marijuana, cocaine or other drug use Chemical use at home/work Exposure to radiation at work Participation in sports Age ≥ 34 years Medication history Use of prescription medication Use of over-the-counter medication

SLE, systemic lupus erythematosus; GA, gestational age; ICU, intensivecare unit; STD, sexually transmitted disease; HIV, human immunodeficiency virus

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efficiently and reliably using such a questionnaire, and that its use could save providers much time by filtering out relevant problems that need to be further addressed.15 An internet version of such a preconception screening checklist was released in The Netherlands (www.zwangerwijzer.nl). It also contains explanations and recommendations for every item or domain that has been filled out by the respondent. Depending on the first assessment, additional testing often includes laboratory tests and other diagnostic examinations, where indicated. In order to do this, referral to specialized out-patient clinics may be indicated. Blood analyses may include hemoglobin and hematocrit, blood type and antibody screening, liver and kidney function tests, rubella titer, screening for (carriership of) phenylketonuria, hemoglobinopathies, sickle cell anemia and Tay–Sachs disease, and infectious diseases including sexually transmitted diseases such as hepatitis and human immunodeficiency virus (HIV). A search for inherited thrombophilias, analyses of vitamin profiles, thyroid function, autoimmune factors and karyotype of both partners may also be performed. We believe that routine thrombophilia screening should not be performed as yet in women with histories of recurrent miscarriage, pre-eclampsia, intrauterine growth restriction or intrauterine fetal death. Published studies show inconsistent results, in part due to differences in design and methodological shortcomings. Furthermore, no proven preventive treatment is available for subsequent pregnancies as there are no completed trials to determine the effects of heparin on pregnancy outcomes for women with thrombophilia. Other diagnostic examinations may include a Papanicolaou smear, tuberculosis skin test, urine screening for protein and glucose, and an ultrasound examination of the uterus, tests for cervical incompetence, hysteroscopy, hysterosalpingography or laparoscopy if uterine disorders are suspected.

Health promotion Preconception health promotion should focus on the use of periconceptional use of folic acid. In healthy women without uncomplicated past histories, 400 µg daily is advised. In women with a previous child with a neural tube defect, 5 mg should be advised (in some countries, this is also routine policy in women who have a neural tube defect (NTD) themselves, or have a first-degree relative with a NTD, have celiac disease or take antiepileptic medications). Health promotion is also directed to stop or reduce smoking, alcohol intake and illicit substances, reduce exposure to possible detrimental environmental factors at work as well as at home, prevent infections such as toxoplasmosis and Listeria, and bring attention

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to vaccination status (such as rubella), healthy diet and life-style factors such as stress, physical activity, high-risk behavior and working conditions. The encouragement of procreating in the optimal reproductive period (20–35 years of age) becomes increasingly important. Finally, couples can be educated on the need for antenatal-care services and in what way and when they should be accessed.

Alcohol Ethanol is the most common human teratogen. Heavy drinking during pregnancy can result in serious adverse outcomes for the fetus. The fetal alcohol syndrome (FAS) is a triad characterized by pre- and postnatal growth impairment, brain damage and typical facial dysmorphology, including a smooth philtrum. Mental retardation is common, as is hyperactivity, extreme nervousness and poor attention span. With the exception of only the most severe cases, recognition that a child has been affected by antenatal exposure to alcohol is extremely difficult and may remain so up to 4 years of age.17 Although women tend to decrease their alcohol consumption during pregnancy, their actual level of drinking depends to a large extent on their drinking habits prior to conception. In many cases, the fetus is exposed to the teratogenic effects of ethanol during the critical period of organogenesis, before pregnancy is confirmed. The majority of drinking women are not aware of their pregnancy until the fourth week after conception.18 The ways in which ethanol affects biochemical processes and cellular structures are poorly understood despite extensive research. It is postulated that ethanol-induced cell injury is the result of the sequelae of oxidative stress and the formation of oxygen free radicals.18 Others have suggested that nutritional deficiencies that are associated with alcohol abuse may be important risk factors for FAS.19 As it is difficult to determine how much alcohol puts a fetus at risk and at what stages of pregnancy the fetus is affected, it is not known whether drinking any amount of alcohol is safe. The safest course at present, therefore, is to advise women to abstain from drinking alcoholic beverages during pregnancy and while breast-feeding.20

Tobacco Cigarette smoking is a major modifiable risk factor for pregnancy-related complications, including spontaneous abortion, preterm birth, low birth weight, placental abruption and perinatal mortality.21–23 Nevertheless, many women continue to smoke throughout pregnancy. Prevalence studies

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in the 1990s show that 20–30% of pregnant women in developed countries report smoking.24 Intensive educational efforts by governments, public health officials and others have contributed to increased awareness of the harmful consequences of maternal smoking. As a result, a reduction in the prevalence of smoking has been documented in several countries, notably Norway, Sweden, Canada and the USA. In addition to the overall reduction in smoking prevalence, around a third of women smokers give up smoking at the some stage of their pregnancy.25,26 However, a substantial number of women who stopped smoking during pregnancy will resume smoking following childbirth.27 Failure to stop smoking will have a detrimental effect on long-term maternal and child health. Smoking cessation can have considerable effects on health outcomes.28,29 Although effective cessation interventions exist, their overall effect is modest, and they do not reach many high-risk smokers.

Vaccines Pregnancy should not deter a woman from receiving vaccines that are safe and will protect both her health and that of her child. However, care must be taken to avoid inappropriate administration of certain vaccines that could be hazardous to her unborn child. This is particularly true for live vaccines. Following the recommendations of the World Health Organization (WHO), active vaccination with live attenuated measles, mumps, rubella, bacillus Calmette–Guérin (BCG) and yellow fever virus vaccines should be avoided in pregnancy.

Counseling Couples should be counseled on the specific risks of pregnancy based on the presence of other risk factors, which may include genetic issues or the recurrence risk of previous obstetric complications. In recent years, more and more women who have previously been told or who have assumed that they could never bear a child because of a (severe) congenital anomaly, or chronic disease (and medication use) or organ transplantation, are opting for pregnancy. Preconception care in women with chronic medical conditions requires special knowledge, training and organization (Figure 1). This deals with the optimal timing of pregnancy and balancing of maternal and fetal/neonatal well-being and prognosis. During this counseling process, it should be realized that pregnancy is accompanied by substantial changes in many systems that also alter physiological values (Figure 2). Pregnancyspecific values have to be used as baselines. Preconception advice should focus on the following components:

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50 Cardiac output

Percentage change

Chapter 12

40

Plasma volume

30

GFR

20 10 PNa

0

Posm

–10

Ppr Palb

–20

Pcrcat TSR

–30

Purea –40 –50 NP

10

20

30

40

Weeks Figure 2 Adaptations to pregnancy. GFR, glomerular filtration rate; PNa, plasma sodium; Posm, plasma osmolality; Ppr, plasma prorenin; Palb, plasma albumin; Pcreat, plasma creatinine; TSR, total systemic resistance; Purea, plasma urea; NP, not pregnant. From reference 30, with permission

(1) Evaluation of the severity of the disease: effective contraception is important until full assessment has been completed, and to enable subsequent optimal timing of pregnancy; (2) Possible effects of pregnancy on the disorder and related risk of maternal morbidity and even mortality; (3) Effects of the disorder on the outcome of pregnancy; risks should be discussed regarding miscarriage, immature or preterm (iatrogenic) delivery, intrauterine growth restriction, intrauterine fetal death and operative procedures during gestation as well as delivery; (4) Risks of occurrence of a parental chronic/genetic disease in the child; (5) Teratogenic risks of medication; (6) Clear (often multidisciplinary) written management policies for the periconceptional, antenatal, peripartum and puerperial periods: these should be easily accessible any time of day for all physicians who may have to deal with the patient.

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Intervention The goal of a preconceptional intervention is to modify or eliminate risk factors in order to minimize the risk of an adverse outcome. The best known example is the initiation of folic acid (or multivitamin) supplementation to reduce the first occurrence10,31 of NTD. Smoking cessation, treatment of infections (i.e. urinary tract infection, Chlamydia or other sexually transmitted disease), vaccination against rubella, and dietary modification in order to gain or lose weight are additional examples of common interventions that may improve outcome. Interventions may also encompass a change of (potentially) teratogenic drug therapy to a safer agent for women on chronic medication (i.e. anticoagulation, antihypertensive drugs), improved control of preconceptional blood glucose levels in diabetic women, correction of vitamin deficiencies or anemia, and treatment of eating disorders. Large epidemiological studies have demonstrated that women with a history of a pregnancy complicated by pre-eclampsia, intrauterine growth restriction or gestational diabetes are shown to be at increased (2–7-fold) risk to develop cardiovascular disease and type 2 diabetes in later life.21–36 This concept of pregnancy as a cardiovascular and metabolic challenge test offers new opportunities for health risk assessment and secondary preventive interventions at a relatively young age.

Specific drugs and agents Drugs may pose dangers throughout pregnancy, but they are especially of concern during the first trimester when the vital organs and systems are developing. The pharmacological effect of a medication may have important ramifications for the unborn infant. The primary prevention of druginduced teratogenic exposure should be an important part of preconception care. A teratogenic exposure can be defined as one that may produce a permanent abnormality of structure or function in an organism exposed during embryonic or fetal life.37 Several surveys suggest that more than 80% of pregnant women use a drug at some stage in gestation. A recent study in The Netherlands showed that 86% of 7500 pregnant women had used at least one drug during pregnancy and 69% when folic acid, iron preparations and vitamins were not taken into account.38 More than half of them used three or more different drugs. Forty-five per cent, 57% and 70% of women had taken medication in the first, second and third trimester, respectively. The most frequently used drugs in the first trimester were folic acid (8%), iron (8%), amoxicillin (4%), meclozine with cyclozine, miconazole-gyn (3%), antacids (2%), triamcinolone-derm (2%), lactulose (2%) and salbutamol (1%).

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The prescription of drugs often represents a therapeutic dilemma. Although most medication is given for the treatment of a maternal disorder, drugs can reach the embryo and exert teratogenic effects via the yolk sac and amniotic fluid and subsequently the fetus through placental transfer. However, ‘therapeutic nihilism’ should also be avoided. Chronic diseases not properly treated can also adversely affect pregnancy outcome. For example, reducing anticonvulsants could result in breakthrough seizures, which are more harmful for the fetus than properly managed continued use of these known teratogenic drugs. For most chronic diseases, there are guidelines on how to modify management when the patient becomes pregnant.39 Since fetal safety is a major concern, widely utilized drugs that have been in use for long periods are preferable to newer drugs, where safety has not yet been established.40 In the case of chronic disorders, women should be preconceptionally counseled about the risks of medication during pregnancy, and the first trimester of pregnancy in particular. Consideration should be made to stop the medication, lower the dosage or change to another drug. Knowledge of possible teratogenic effects of medication is therefore of critical importance. Medication should only be prescribed because of strict indications and only after proper evaluation of its safety in pregnancy. The severe consequences of insufficient knowledge of risks became clear after the thalidomide and diethylstilbestrol (DES) disasters. There are several reasons why it is often very difficult to determine whether a specific drug or environmental agent is teratogenic:40,41 (1) Most studies of teratogenic effects of drugs have focused on major anatomic malformations. It is much more difficult to assess a biologically plausible cause-and-effect relationship between a particular exposure and the more subtle reproductive outcomes such as minor anatomic malformations, growth restriction, developmental and cognitive impairments, neurobehavioral changes, and germ-cell toxicity, including premature ovarian senescence in the offspring. (2) Most toxicology data concerning drug exposure in pregnancy are based on experimental animal models. Formal clinical studies of the effects of drugs on pregnancy outcomes are relatively scarce. They are usually limited to observational data, case reports and anecdotal data that are prone to potential bias in patient selection and ascertainment of outcomes and exposure. In particular, case–control studies are prone to recall bias. The latter can lead to false associations of drug therapy and adverse pregnancy outcome, as women who have given birth to malformed infants tend to remember more clearly the course of their pregnancies than do women who have given birth to healthy children.

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(3) The response to exposure of potentially teratogenic drugs is dose- and time-related. The first 3 months of pregnancy are the most vulnerable period in fetal life for injury to organs from potentially teratogenic agents. (4) The extent of placental transfer of drugs and other environmental agents varies. Factors affecting placental transfer include dosage, resorption, maternal plasma concentration, clearance and metabolism, blood flow through the placenta, plasma protein binding, molecular weight and lipid solubility, mechanism of placental transfer (diffusion, active transport), maternal pH, and interactions with other drugs. (5) Most pregnant women are exposed to more than one drug, but the extent of drug prescription and the types of drugs prescribed are difficult to ascertain. (6) A potentially teratogenic drug may be administrated for a maternal condition that itself is associated with an increased frequency of fetal malformations, such as diabetes. (7) Most congenital malformations occur rarely, and many teratogens, even when known to be associated with an increased risk of a given malformation, do not affect the great majority of exposed fetuses. To guide physicians in interpretation of the teratogenic risk associated with prescription drugs, the US Food and Drug Administration (FDA) has established a system that classifies drugs on the basis of data from studies in animals and humans. Classified drugs range from class A, which are considered safe for use during pregnancy, to class X, which are contraindicated during pregnancy because of proven teratogenicity (Table 2). Currently, only 40% of drugs in the Physician’s Desk Reference are thus listed.42 In a review of the risks associated with fetal exposure to drugs, Koren and colleagues40 published a list of drugs with proven teratogenicity (Table 3). There are several limitations to the FDA risk classification system. The risk classification is not always up to date, and information on the magnitude of risk is often lacking. Teratogen information services are independent counseling services often linked to state health departments, universities or genetic counseling services. These services provide up-to-date information to pregnant women and/or health-care providers on the risk of exposure to various drugs, biological products and environmental agents. Some of these services follow women to determine pregnancy outcomes after a particular exposure.

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Table 2 Pregnancy categories issued by the US Food and Drug Administration Category A Studies in human-beings have not shown an increased risk of fetal abnormalities if administered during pregnancy. The possibility of fetal harm appears remote. Advice: Because studies cannot rule out the possibility of harm, the drug should be used during pregnancy only if clearly needed. Category B Animal reproduction studies have not revealed evidence of impaired fertility or harm to the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Or, animal reproduction studies have shown an adverse effect but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Advice: Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Category C The drug has been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Or, there are neither animal reproduction studies nor adequate and well-controlled studies in humans. Advice: The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Category D From animal and human studies, there is evidence that the drug can cause fetal harm when administered to a pregnant woman. Advice: If this drug is used during pregnancy, or if this patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Category X From animal and human studies, there is clear evidence that the drug causes fetal harm when administered to a pregnant woman. The drug is contraindicated in women who are or may become pregnant. However, if this drug is used during pregnancy, or if this patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

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Table 3 Clinically used drugs with proven teratogenic effects in humans40 Drug(s)

Teratogenic effect

Methotrexate

CNS and limb malformations

ACE inhibitors

Prolonged renal failure in neonates, decreased skull ossification, renal tubular dysgenesis

Anticholinergic drugs

Neonatal meconium ileus

Antithyroid drugs (propylthiouracil and hypothyroidism, methimazole)

Fetal and neonatal goiter and aplasia cutis

Carbamazepine

Neural tube defects

Cyclophosphamide

CNS malformations, secondary cancer

Danazol and other androgenic drugs

Masculinization of female fetuses

Diethylstilbestrol

Vaginal carcinoma and other genitourinary defects in female and male offspring

Hypoglycemic drugs

Hypoglycemia in neonates

Lithium

Ebstein’s anomaly

Misoprostol

Moebius sequence (6th and 7th nerve palsies), limb defects

Non-steroidal antiinflammatory drugs

Constriction of the ductus arteriosus, necrotizing enterocolitis

Phenytoin

Growth restriction, CNS defects

Psychoactive drugs (e.g. barbiturates, opioids and benzodiazepines)

Neonatal withdrawal syndrome when drug is taken in late pregnancy

Continued

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Table 3

Continued

Drug(s)

Teratogenic effect

Retinoids

CNS, craniofacial, cardiovascular and other defects

Tetracycline

Anomalies of teeth and bone

Thalidomide

Limb-shortening defects, internal organ defects

Valproic acid

Facial and CNS defects

Warfarin

Skeletal and CNS defects, Dandy–Walker syndrome

ACE, angiotensin-converting enzyme; CNS, central nervous system

In both animal and human studies, there is growing evidence that paternal toxic exposure is associated with abnormal reproductive outcome.16 However, there is hardly any information on drug utilization of men around the time of conception. Pharmacy dispensing data from Denmark and The Netherlands showed that one-third of all fathers had taken up prescriptions for at least one drug in the half year before conception.43 At least 5% of all fathers used three or more types of drugs. The main drugs purchased were antibiotics (about 9%), analgesics (7%), antihistamines (2%) and anti-ulcer drugs (2%). The fact that a large proportion of fathers used a drug around the time of conception stresses the importance of safety information on drugs with respect to potential paternal teratogenicity.

PREVENTION OF BIRTH DEFECTS A birth defect is any type of structural, functional or metabolic abnormality determined largely by factors operating before birth, i.e. in utero. The causes of birth defects may be genetic, environmental or mixed. The birth prevalence of congenital anomalies is affected by the natural history of the underlying disorder, as some are lethal in early fetal life, while others can become clinically evident days or months after birth or even much later in

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life. An estimated 5% of children are born with a congenital or genetically determined anomaly. Most women of child-bearing age have little or no experience with genetic or congenital disorders, and may not be aware that they are at risk of transmitting them to their children. Prevention of birth defects and congenital abnormalities is best accomplished at the primary health-care level, starting with the assessment of genetic and environmental risk factors for adverse pregnancy outcome. This includes a positive family history of a birth defect or a genetic disorder, poor medical or obstetric history (e.g. recurrent miscarriage or a previous child with a congenital anomaly), carrier detection of a recessive trait frequent in the community, advanced maternal age and exposure to teratogens. Couples at increased genetic risk should have access to relevant genetic services for prepregnancy counseling. They should also have access to laboratory tests, including cytogenetic or DNA studies, where indicated.44 The huge technological progress in medical genetics in the past decades has enabled the implementation of a relatively new form of prevention that is based on reproductive choice.45 The goal of the latter is to optimize the chances that individuals at increased risk of affected offspring will have children free of the specific congenital or genetically determined anomalies. However, the emphasis on personal autonomy in reproductive decision-making has been subject to criticism, in particular regarding issues of sex selection and the prevention of late-onset disease, such as familial breast and ovarian cancer.46,47 On the other hand, in a number of countries, there is potential for coercive pressure from the government, society and family members in genetic testing programs.48 For instance, in some countries, it is mandatory to have a test for thalassemia before getting married.49 In this context, it is stressed that testing should always remain voluntary, and the couples themselves should decide whether or not to be tested, thereby taking into account their personal and moral values. Due attention should also be given to informing prospective parents about the implications, the potential benefits and the limitations of first- and second-trimester prenatal screening for Down’s syndrome and neural tube defects. Prepregnancy counseling programs should be established to increase awareness of the potential environmental and genetic risks and modes of prevention.

Genetically determined abnormalities Genetically determined anomalies encompass chromosome abnormalities, single-gene disorders and other genetic aberrations, mitochondrial disorders, and multifactorial conditions of gene–environment interaction. Genetic disorders can be inherited, that is transmitted from parents to

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offspring, or arise de novo, as the result of a new mutation. In accordance with the laws of Mendel, the typical patterns of inheritance depend on whether the mutant gene is located on one of the autosomal chromosomes (autosomal dominant or recessive pattern of inheritance) or on the X chromosome (X-linked pattern of inheritance). In pedigrees with a dominant trait, the expressivity is sometimes so low that the mutation is clinically hardly detectable. When this is the case, the trait is said to have low penetrance. OMIM, Online Mendelian Inheritance in Man, is a comprehensive database that contains useful textual information on the three categories of genetic disorders. This database can be retrieved free of charge from the internet (www.ncbi.nlm.nih.gov/omim). Chromosomal abnormalities are characterized by an excess or deficiency of genetic material (aneuploidy). Most of these conditions are caused by random errors of cell division (non-disjunction) in the formation of gametes. They are usually sporadic, not hereditary. The most common aneuploidy is trisomy 21 or Down’s syndrome, which is characterized by 47 chromosomes, the extra one being chromosome 21. The risk of its occurrence increases with maternal age.50,51 Deletions are characterized by loss of a part of a chromosome, which may be as small as a single base or as large as one or more genes. Hence, (micro-)deletions may not be sufficiently large to be seen on routine cytogenetic analysis. Special targeted techniques are needed to detect (micro-)deletion. The clinical spectrum of deletions varies with the nature and size of the DNA segment involved. For instance, a microdeletion in the Y chromosome is associated with infertility.52 Other forms of chromosomal aberrations include translocations, inversions and duplications, which refer to rearrangements, of chromosome segments. Translocations and inversions may be balanced, i.e. rearrangement without loss of genetic material, or unbalanced, resulting in either excess or deficiency of chromosomal material. When one of the parents is a carrier of a balanced structural chromosome aberration, the pregnancy may result in one of three types of chromosomal pattern: normal chromosomal pattern; the balanced chromosome rearrangements, which do not usually cause any obvious phenotypic features; or the unbalanced structural chromosome pattern, which will lead to a spontaneous miscarriage or an infant with multiple congenital anomalies and/or mental retardation. Risk rates for unbalanced progeny vary considerably, ranging from 50% to an almost negligible risk.53 The risk of unbalanced progeny depends on the type of chromosome rearrangement, and the nature and size of the chromosomal segment involved. Given the complexity of determining individual risk estimates in couples with balanced structural chromosome aberrations, it is advised to refer them for genetic counseling before pregnancy.

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Chromosome polymorphisms are natural structural chromosome variants that occur relatively frequently in the general population. Chromosome polymorphisms have no effect on the individual phenotype. Single-gene disorders are caused by mutations in a single major gene. Their clinical manifestations are quite variable, depending on the function of the normal gene. Typical examples are inborn errors of metabolism, such as those associated with cystic fibrosis and congenital bilateral absence of the vas deferens (CBAVB) due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.52 Single-gene disorders are inherited following patterns of dominant, recessive, autosomal or Xlinked inheritance. Individual single-gene disorders range in frequency from 1 per 2500 to 1 per 25 000 births. Other genetic aberrations include uniparental disomy, which refers to the situation where two homologous chromosomes or chromosome segments come from one parent while neither is inherited from the other parent. This can produce rare congenital disorders, such as Prader–Willi syndrome, which is associated with the absence of the paternal contribution to a specific segment on chromosome 15 (15q11.2–q13), Angelman’s syndrome, which is associated with a loss of function of the maternally derived allele of chromosome 15, and Beckwith–Wiedemann syndrome, which is associated with paternal isodisomy of chromosome 11 (www.geneclinics.org). These disorders may also be the result of genomic imprinting. Genomic imprinting is a process that results in allele-specific differences in transcription, DNA methylation and DNA replication timing.54 From recent studies, it is suggested that births involving assisted reproductive technology have an increased risk of imprinting disorders.55,56 Extrachromosomal inheritance refers to mitochondrial inheritance. Mitochondria contain their own distinct genome. Mutations in mitochondrial DNA are typically inherited from the mother, since ova contain mitochondria whereas sperm do not. Pathogenic mitochondrial DNA mutations are responsible for rare defects of the common final pathway of mitochondrial energy metabolism, i.e. oxidative phosphorylation.57 The clinical presentation of mitochondrial disorders in childhood is highly variable, with non-specific encephalopathy as the most common finding.58 Unlike nuclear chromosomal rearrangements, the occurrence of sporadic pathogenic mitochondrial DNA mutations does not increase with maternal age, and unaffected mothers are unlikely to have more than one affected child.59 Multifactorial conditions are due to the interaction of several genes and/or environmental factors. The genetic factors confer an inborn predisposition to the development of a particular condition in interaction with environmental factors. Examples of conditions in this category are some

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common congenital malformations, including cleft lip and palate, neural tube defects and congenital heart defects. Other examples include insulindependent diabetes mellitus, coronary heart disease, epilepsy, asthma and some cancers. Environmental causes of birth defects are those that interfere with normal embryonic or fetal development, and include physical agents (e.g. radiation, hyperthermia), chemicals (e.g. some medications, alcohol, tobacco and drugs, both legal and illicit) and infections (e.g. syphilis, rubella, toxoplasmosis and cytomegalovirus infection).

Preimplantation diagnosis For a number of genetic conditions, a reliable diagnosis can be accomplished by biopsy of the eight-cell embryo. Diagnostic tests are conducted on one or two cells (blastomeres) before they are implanted, allowing the selection of genetically unaffected embryos before a pregnancy has been established.60 The issue of pregnancy termination is thus circumvented. Preimplantation diagnosis may be indicated in couples at substantial risk of a genetic disorder as an alternative to prenatal diagnosis by chorionic villus sampling or amniocentesis. The technique has been applied to the analysis of numerical and structural chromosomal abnormalities that can result in handicap or recurrent miscarriage, the identification of sex to prevent transmission of X-linked disease and the detection of specific serious single-gene disorders.61 However, the acceptability and safety of preimplantation diagnosis need yet to be determined with respect to both pregnancy rate and the occurrence of congenital anomalies.60,62

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6. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. Q J Med 2001; 94: 435–44 7. Herman WH. Diabetes and pregnancy. Preconception care, pregnancy outcomes, resource utilization and costs. J Reprod Med 1999; 44: 33–8 8. Cox M, Whittle MJ, Byrne A, et al. Prepregnancy counseling: experience from 1075 cases. Br J Obstet Gynaecol 1992; 99: 873–6 9. Czeizel AE, Dudás I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–5 10. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–7 11. De Weerd S, van der Bij AK, Braspenning JCC, et al. Psychological impact of preconception counseling: assessment of anxiety before and during pregnancy. Community Genet 2001; 4: 129–33 12. De Weerd S, Thomas CMG, Cikot RJLM, et al. Preconception counseling improves folate status of women planning pregnancy. Obstet Gynecol 2002; 99: 45–50 13. De Weerd S, Thomas CMG, Kuster JETG, et al. Variation of serum and urine cotinine in passive and active smokers and applicability in preconceptional smoking cessation counseling. Environ Res 2002; 90: 119–24 14. Cefalo RC, Moos MK. Preconceptional Health Care: A Practical Guide, 2nd edn. St Louis: Mosby Year Book, 1995 15. De Weerd S, van der Bij AK, Cikot RJLM, et al. Preconception care: a screening tool for health assessment and risk detection. Prev Med 2002; 34: 505–11 16. Trasler JM, Doerksen T. Teratogen update: paternal exposures – reproductive risks. Teratology 1999; 60: 161–72 17. Adams J, Bittner P, Buttar HS, et al. Statement of the Public Affairs Committee of the Teratology Society on the Fetal Alcohol Syndrome. Teratology 2002; 66: 344–7 18. Cohen-Kerem R, Koren G. Antioxidants and fetal protection against ethanol teratogenicity. I. Review of the experimental data and implications to humans. Neurotoxicol Teratol 2003; 25: 1–9 19. Dreosti IE. Nutritional factors underlying the expression of the fetal alcohol syndrome. Ann NY Acad Sci 1993; 678: 193–204 20. Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343: 118–26 21. Kramer MS, Seguin L, Lydon J, Goulet L. Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol 2000; 14: 194–210 22. Pollack HP, Lantz PM, Frohna JG. Maternal smoking and adverse birth outcomes among singletons and twins. Am J Public Health 2000; 90: 395–400 23. Bouckaert A. Smoking during pregnancy: foetal growth retardation and other risks for the newborn. Stat Med 2000; 19: 239–54

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24. Lumley J, Oliver S, Waters E. Interventions for promoting smoking cessation during pregnancy (Cochrane Review). In The Cochrane Library, Issue 1. Oxford: Update Software, 2003 25. Cnattingius S, Lindmark G, Meirik O. Who continues to smoke while pregnant? J Epidemiol Community Health 1992; 46: 218–21 26. Owen L, McNeill A, Callum C. Trends in smoking during pregnancy in England, 1992–7: quota sampling surveys. BMJ 1998; 317: 728 27. Pickett KE, Wakschlag LS, Dai L, Leventhal BL. Fluctuations of maternal smoking during pregnancy. Obstet Gynecol 2003; 101: 140–7 28. Fiore MC. A clinical practice guideline for treating tobacco use and dependence. A US health service report. JAMA 2000; 283: 3244–54 29. Lancaster T, Stead LF. Individual behavioural counselling for smoking cessation (Cochrane Review). In The Cochrane Library, Issue 1. Oxford: Update Software, 2002 30. Baylis C, Davidson JM. The urinary system. In Chamberlin G, Broughton Pipkin F, eds. Clinical Physiology in Obstetrics. Oxford: Blackwell Science, 1998: 263–307 31. Czeizel AE, Dudás I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–5 32. Irgens HU, Reisaeter L, Irgens LM, Tie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001; 323: 1213–17 33. Smith GCS, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study. Lancet 2001; 357: 2002–6 34. LinneY, Barkeling B, Rossner S. Natural course of gestational diabetes mellitus: long term follow up in the SPAWN study. Br J Obstet Gynaecol 2002; 109: 1227–31 35. WCS. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 2003; 326: 845–52 36. Haaukkamaa L, Salminen M, Laivuori H, et al. Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol 2004; 93: 805–8 37. Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol 2002; 100: 465–73 38. Schirm E, Meijer WM, Tobi H, de Jong-van den Berg LTW. Drug use by pregnant women and comparable non-pregnant women in The Netherlands with reference to the Austrlian classification system. Eur J Obstet Gynecol Reprod Med 2004; 114: 182–8 39. Harambu F, Miremont-Salamé G, Moore N. Good and bad drug prescription in pregnancy. Lancet 2000; 356: 1704 40. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128–37

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41. Naeye RL, Tafari N. Risk factors in pregnancy and disease of the fetus and newborn. Baltimore: Williams & Wilkins, 1983: 95–18 42. Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmocother 2001; 35: 1485–9 43. Schirm E, Pedersen L, Tobi H, et al. Drug use among fathers around time of conception: two register based surveys from Denmark and The Netherlands. Pharmacoepidemiol Drug Safe 2004; 13: 609–13 44. Kinmonth AL, Reinhard J, Bobrow M, Pauker S. The new genetics. Implications for clinical services in Britain and the United States. BMJ 1998; 316: 767–70 45. Asch DA, Hershey JC, Pauly MV, et al. Genetic screening for reproductive planning: methodological and conceptual issues in policy analysis. Am J Public Health 1996; 86: 684–90 46. Parker M. Public deliberation and private choice in genetics and reproduction. J Med Ethics 2000; 26: 160–5 47. Wagner TM, Ahner R. Prenatal testing for late-onset diseases such as mutations in the breast cancer gene 1 (BRCA1). Just a choice or a step in the wrong direction? Hum Reprod 1998; 13: 1125–6 48. Chadwick R, ten Have H, Husted J, et al. Genetic screening and ethics: European perspectives. J Med Philos 1998; 23: 255–73 49. Atkin K, Ahmad WI. Genetic screening and haemoglobinopathies: ethics, politics and practice. Soc Sci Med 1998; 46: 445–58 50. Snijders RJM, Sundberg K, Holzgreve W, et al. Maternal age- and gestationspecific risk for trisomy 21. Ultrasound Obstet Gynecol 1999; 13: 167–70 51. Morris JK, Wald NJ, Mutton DE, Alberman E. Comparison of models of maternal age-specific risk for Down syndrome live births. Prenat Diagn 2003; 23: 252–8 52. Dohle GR, Halley DJJ, Van Hemel JO, et al. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod 2002; 17: 13–16 53. Daniel A, Hook EB, Wulf G. Risks of unbalanced progeny at amniocentesis to carrier of chromosome rearrangements: data from United States and Canadian laboratories. Am J Med Genet 1989; 33: 14–53 54. Mannens M, Alders M. Genomic imprinting: concept and clinical consequences. Ann Med 1999; 31: 4–11 55. Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 2003; 361: 1975–7 56. Lucifero D, Chaillet JR, Trasler JM. Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology. Hum Reprod Update 2004; 10: 3–18 57. Zeviani M, Di Donato S. Mitochondrial disorders. Brain 2004; 127: 2153–72 58. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr 2003; 42: 703–10

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59. Chinnery PF, DiMauro S, Shanske S, et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet 2004; 364: 592–6 60. Van de Velde H, De Vos A, Sermon K, et al. Embryo implantation after biopsy of one or two cells from cleavage-stage embryos with a view to preimplantation genetic diagnosis. Prenat Diagn 2000; 20: 1030–7 61. Pickering S, Braude P. Further advances and uses of assisted conception technology. BMJ 2003; 327: 1156–8 62. European Society of Human Reproduction and Embryology PGD Consortium Steering Committee. ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001). Hum Reprod 2002; 17: 233–46

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The poor responder SD Keay

INTRODUCTION Poor ovarian response to exogenous follicle stimulating hormone (FSH) stimulation is a major problem in clinical practice, accounting for up to 26% of cycles started.1 Definitions of poor response or the poor responder vary but the definition is of practical importance. A distinction should be drawn between failure to reach a threshold for multifollicular development and those individuals with intrinsically reduced ovarian reserve who fail to recruit preovulatory follicles, despite high daily gonadotropin doses. This latter group present specific challenges in that most strategies to date have met with limited success in improving treatment outcome, whereas the former usually respond satisfactorily to an increase in gonadotropin dose. It is recognized that both female fecundity and ovarian responsiveness to gonadotropin prior to in vitro fertilization (IVF) decline with age.2 Women are born with their full complement of germ cells after reaching a peak in utero. Their effective biological ovarian age may be in advance of their chronological age if their follicle number declines more rapidly, or they have fewer to begin with. This early ovarian aging is a disadvantage for IVF.2 FSH regulates ovarian steroidogenesis and follicular development, but numerous glycosylated isoforms of FSH exist in the circulation with varying bioactivity. FSH’s potency depends on the extent and site of glycosylation and signals through the FSH receptor, which is a transmembrane G-coupled protein. Naturally occurring mutations have been detected, and studies have reported that the ovarian response to exogenous FSH is at least in part determined by the receptor genotype.3

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The interval between incipient ovarian failure (usually defined as elevated basal FSH levels) and the menopause has been calculated at around 13 years.4 For the majority of women who are not undergoing fertility treatment, the process proceeds unrecognized until the late stages of menstrual irregularity or vasomotor symptoms. Women undergoing assisted reproductive technologies (ART), however, will normally have ovarianreserve testing undertaken prior to their first cycle or following a poor ovarian response. Factors associated with poor response include those listed in Table 1. The age-related decline in fecundity is an important social issue in Western populations, as we are seeing more women delaying child-bearing. Figures from The Netherlands suggest that 25% of pregnancies will be in women over the age of 35 by 2009.5 The extent to which IVF can compensate for the age-related decline in natural fecundity has been studied, and computer modeling suggests that IVF will compensate for 50% of the decline in delaying from 30 to 35 years, but only by one-third in women delaying from 35 to 40.6 There are concerns about poor responders’ reproductive outcome, as diminished ovarian reserve has been associated with not only lower pregnancy rates but also increasing miscarriage rates.7 It is therefore important to consider outcomes in terms of live-birth rates per cycle started when considering the available evidence on which change in standard IVF practice is recommended.

IMPACT OF POOR RESPONSE ON IVF OUTCOME The number of embryos available influences IVF success rates,8 and poor ovarian response reduces pregnancy rates in both the index and subsequent IVF cycles.9 Furthermore, simply using higher gonadotropin doses may increase follicular recruitment but does not necessarily translate into higher pregnancy rates.10 The inverse relationship between total gonadotropin dose used and IVF success is well established,11,12 but the threshold at which the decline in implantation and pregnancy rates occurs is not. The observation that young women with normal ovarian reserve who recruited few follicles achieved pregnancy rates that were broadly similar to those in women with a higher response13 suggests that a low oocyte yield, in itself, is not necessarily detrimental if the woman is young and has a normal ovarian reserve. However, a low yield in response to high gonadotropin dosages is associated with a much worse outcome.12 The stimulation dose used may therefore be important in considering any

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Table 1

Factors associated with poor response

Advanced female age Previous ovarian surgery Endometriomas High body mass index Previous pelvic infection Interbatch variability (urinary gonadotropin preparations) Functional ovarian cysts

definition of poor response. The relationship between ovarian reserve and oocyte quality is more difficult to study, but the increasing aneuploidy rates and reduced natural fecundity in the late 30s and early 40s point toward an association between the numbers of follicles remaining and their quality.

IMPACT OF REPEATED IVF ON OVARIAN RESPONSE There is no evidence to suggest that repeated controlled ovarian stimulation cycles are associated with an acceleration in the natural rate of follicle loss and an earlier menopause. Similarly, the suppression of ovulation by the combined oral contraceptive pill or during pregnancy does not inhbit the process. The factors controlling the rates of follicle loss are largely unknown, but apoptosis may be inhibited, or accelerated, by factors as diverse as gonadotropins, steroid hormones, cytokines and growth factors acting through putative gene families such as bcl-2.

PREPARING THE PATIENT FOR IVF Additional investigations It would be helpful to identify ‘poor’ responders prior to gonadotropin stimulation to ensure that they receive optimal management and appropriate counseling. A variety of simple and dynamic tests have been used to help predict ovarian response prior to treatment.

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Antral follicle count and basal serum FSH may, if not already performed, identify women with diminished reserve. It is important to remember that fluctuating basal (days 2–4) FSH concentrations are a pointer to impaired ovarian reserve, and that a single serum sample may mislead and give false reassurance. Antral follicle count14 would be expected to be less prone to such fluctuations. A number of other screening tests, including ovarian volume,15 inhibin 16 B, Müllerian inhibitory substance (MIS),17 insulin-like growth factor I (IGF-I)18 and growth hormone,19 have been used, but are not in widespread everyday practice. Women with high basal FSH concentrations should be warned about the risk of a low oocyte yield, although younger women are less disadvantaged than older women. Women over 40 years with abnormal FSH concentrations have a very poor outlook, and oocyte donation represents their best chance of conceiving.20 It has to be acknowledged that the perfect screening test does not exist, and that the actual response to gonadotropins is the best dynamic test of ovarian reserve.

Pre-IVF Functional ovarian cysts associated with elevated estradiol levels occur in at least 5% of cycles and are detrimental to ovarian stimulation.21 Functional ovarian cysts disturb the response to gonadotropin, and can be detected by ultrasound prior to commencing ovarian stimulation. Their incidence is reduced by progestogen pretreatment. Using the combined contraceptive pill in poor responders has been advocated, but there is a paucity of evidence to support this approach when live-birth rates are considered.

MANAGING THE IVF CYCLE The lack of a uniform definition of ‘poor response’ makes it difficult to compare treatment outcomes or, indeed, develop and assess protocols for prevention and management.22 A variety of different approaches have been used to try to improve the outcome in poor responders. Intracytoplasmic sperm injection (ICSI) in poor responders is no more effective than standard insemination at IVF, and should not be performed solely because of low oocyte numbers. Natural-cycle IVF has given acceptable pregnancy rates in some series, and avoids the use of expensive gonadotropins.23 A preliminary case series of in vitro maturation of immature oocytes from poor responders has been reported, with acceptable pregnancy and implantation rates, and is

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suggested by the authors to be an alternative to cycle cancellation.24 Larger controlled studies are required to determine whether live birth rates are satisfactory, and this report should be regarded as preliminary.

Stimulation regimen changes If a response to ovarian stimulation is suboptimal, it may lead to cycle cancellation, but even in cases that reach oocyte retrieval the prognosis may be reduced. It has been suggested that the greater is the total dose of gonadotropins required to reach oocyte retrieval, the lower is the pregnancy rate.11,25 An initial ‘poor’ response identifies a group of patients who are less likely to respond well in subsequent attempts. Despite increased gonadotropin stimulation on subsequent stimulation attempts, these patients show a high cancellation rate varying between 24% and 68%.1 Young patients with a normal basal FSH canceled because of a ‘poor’ response did poorly compared with normal responders, but more recently, women < 35 years with normal ovarian reserve despite producing only a few follicles achieved satisfactory pregnancy rates.13

FSH dose Although it is tempting to believe that ‘poor’ ovarian response may be overcome simply by increasing the dose of gonadotropin, the literature suggests that this is not the case. Manzi and colleagues27 observed that increasing from 225 to 375 IU FSH daily significantly increased the number of follicles recruited, but pregnancy rates remained poor. Women who eventually responded well to the higher gonadotropin dose achieved significantly lower pregnancy rates than women with a good initial response to the lower gonadotropin dose (5% vs. 16.5%, respectively), despite comparable follicle numbers and serum estradiol levels. Similarly, Land and associates10 observed that significantly more follicles were recruited when the daily stimulation dose was doubled to 450 IU FSH following a ‘poor’ response to 225 IU FSH, but that the pregnancy rate was very low (3.2% per IVF cycle). Hofmann and co-workers28 suggested that increasing ovarian stimulation from 300 IU FSH to 450 IU FSH daily in ‘poor’ responders might reduce cancellation rates, but Karande and colleagues29 found that increasing the stimulation dose did not result in higher IVF pregnancy rates. It is thus important to consider carefully before increasing the dose of FSH beyond at most 300 IU FSH daily, as this may lead to a false impression of improvement. It is imperative that during treatment we do not forget that the aim of treatment is a live birth, and not the achieving of an oocyte pick-up.

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A study of poor response to recombinant (rec)FSH (300 IU/day) investigated whether substituting 150 IU recFSH for 150 IU human menopausal gonadotropin (hMG) was better than increasing the stimulation dose of recFSH. The hMG group produced significantly more oocytes than the control group, who received an increased dose of recFSH (375 IU/day), suggesting that, in a small proportion of unexpected poor responses, changing the composition of the stimulation regimen rather than the dose is beneficial.30

GnRH agonists in poor responders Gonadotropin releasing hormone (GnRH) agonists reduce premature luteinization, but their use is also associated with higher gonadotropin requirements. Standard practice has been to commence GnRH agonists in the mid-luteal phase, but, in poor responders especially, there may be benefit in reducing the GnRH agonist dose or altering the time in the cycle it is started. This has resulted in numerous variations on the theme of reducing agonist dose. Despite this theoretical basis, there is a paucity of evidence from prospective controlled studies to support the use of a short or flare protocol (wherein FSH and agonist are commenced simultaneously) over the long protocol.31 Reducing the GnRH agonist dose in a microdose flare protocol reduced the incidence of repeat cancellation for poor response, and improved pregnancy rates, without a concomitant increase in luteinizing hormone (LH) or progesterone in the follicular phase.32 Luteal agonist administration was stopped at the onset of menses in a series of over 200 IVF cycles, with only a single case of premature luteinization and a reduced repeat-cancellation rate.33 Although small series such as these point to potential benefits of adjusting GnRH agonist protocols, no good evidence exists to support increased pregnancy rates.

GnRH antagonists in poor responders Given the concerns that GnRH agonists may dampen the ovarian response, the use of GnRH antagonists has been proposed as a means of avoiding this whilst effectively preventing premature LH surges. Equivalent pregnancy rates were reported in a small study of 48 poor responders, despite significantly fewer oocytes being retrieved in the antagonist group compared with a flare regimen.34 A controlled study compared high-dose FSH (600 IU FSH/day) and delaying antagonist

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administration until the lead follicle reached 16 mm with a standard long protocol, and observed a significant reduction in cycle cancellation (4.8% vs. 34%, respectively) and a higher pregnancy rate.35 Larger, properly randomized, trials are required to determine whether there is a role for the antagonist in the management of poor response, and, if so, whether delaying administration is helpful, but at present there is no convincing evidence to support its use in this context.

Oral contraceptive pill pretreatment Suppressing endogenous FSH concentrations prior to ovarian stimulation by using the combined contraceptive pill or progestogens has been employed in the hope of enhancing responsiveness. There is some evidence to suggest that this may be helpful,36 but, as with so much of the management of poor response, adequate trials are lacking to draw firm conclusions.

Adjuvant treatments A number of clinical trials using different adjuvant treatments have been conducted.

Growth hormone and growth hormone releasing hormone The somatotropic axis affects ovarian function and follicular development. Endogenous growth hormone (GH) secretion correlates with oocyte number and serum estradiol levels during IVF.37 GH may act directly through ovarian receptors or indirectly through hepatic IGF-I secretion, which augments the granulosa cell response to FSH in vitro.38 Recombinant GH has consistently failed to show an improvement in poor responders with elevated basal FSH concentrations,39 but a systematic review identified an overall higher live-birth rate in poor responders receiving GH.40 The review concluded that GH should be submitted to further investigation, given the findings of the three small studies analyzed. However, a large multicenter randomized, double-blind, placebocontrolled study of poor responders showed no improvement in follicular recruitment.41 The available evidence from randomized controlled trials suggests a possible role for adjuvant GH in poor responders, but further work is required to confirm this and to identify specific groups of poor responders who may benefit from GH.

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L-Arginine

It has been hypothesized that adding L-arginine, a nitric oxide precursor, may improve perifollicular vascularity and hence ovarian response. In a small randomized trial of poor responders, L-arginine was associated with significantly fewer cancellations and a higher egg yield.42 Whilst appearing to sensitize the ovary, no ongoing pregnancy or live-birth resulted. However, a subsequent study by the same authors concluded that Larginine had a detrimental effect on embryo quality and pregnancy rates when used in their general IVF population,43 and hence it now appears unwise to consider the use of this agent.

Pyridostigmine Pyridostigmine, an acetylcholinesterase inhibitor, increases acetylcholine and GH secretion. In a randomized controlled trial of 70 poor responders, significantly less FSH was required, and more oocytes were retrieved with pyridostigmine, compared with placebo.44 Serum GH and intrafollicular GH and IGF-I levels were significantly higher in the treatment group compared with the placebo group. It is not known whether pyridostigmine may have a direct effect on the endometrium or ovary, and no other studies have been reported using this drug in poor responders.

Glucocorticoids Studies of adjuvant glucocortioids have predominantly been used in general IVF populations rather than poor responders. Prednisolone co-treatment resulted in a higher pregnancy rate in non-pituitary-desensitized cycles,45 but in a small study of pituitary-desensitized cycles no difference between dexamethasone and controls was detected.46 That glucocorticoids appear to sensitize the ovary to gonadotropins is suggested by a randomized controlled study of women with polycystic ovarian syndrome (PCOS) undergoing IVF.47 The trial showed a trend toward higher oocyte numbers (mean 13 vs. 8 in the placebo group) and lower gonadotropin requirements with prednisolone, compared with placebo. This is consistent with our observation of a reduction in cancellation for poor response in a standard IVF population with low-dose dexamethasone, compared with placebo.48 Incorporating dexamethasone into standard long-protocol regimens may optimize multifollicular development. This study was unable to determine whether critically defined poor-responder patients would benefit from co-treatment, but pilot data from a small randomized controlled trial

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of unselected poor responders showed a trend toward lower repeat cancellation.49 A larger placebo-controlled randomized study of sufficient power is required to determine whether strictly defined poor responders’ outcome is improved.

Aspirin Interest in adjuvant aspirin was raised by the findings of a randomized placebo-controlled trial of 298 patients that reported increased oocyte number, embryo implantation and clinical pregnancy rate50 and a lower cancellation rate. However, in poor responders, there appeared to be no benefit compared with placebo.51

Dehydroepiandrosterone A small case series of poor responders undergoing repeat intrauterine insemination (IUI) were given dehydroepiandrosterone (DHEA) daily for 2 months prior to ovarian stimulation52 with higher serum estradiol levels This contrasts with studies of other adjuvant treatments where administration is limited to the stimulation cycle, and raises the possibility that prolonged exposure to the adjuvant drugs may improve ovarian sensitivity to FSH.

Letrozole (aromatase inhibitor) Aromatase inhibitors block the terminal step in estradiol synthesis; they have been used for estradiol suppression in postmenopausal breast-cancer patients. In anovulatory PCOS women, overall gonadotropin requirement was significantly reduced with letrozole.53 In a preliminary study of 12 patients who responded poorly in 25 previous stimulation cycles prior to IUI (< 3 follicles recruited), there was evidence of an improved ovarian response to FSH with letrozole 2.5 mg/day and a reduced requirement for FSH.54 A subsequent controlled trial in 38 women observed a reduction in total FSH dosage and an equivalent pregnancy rate.55 The study group comprised women > 35 years with between one and three unsuccessful IVF cycles. It is imperative that the effectiveness of adjuvant drugs be demonstrated in prospective, double-blind, placebo-controlled trials. Trials may need to be multicenter in order to recruit sufficient patients. It is important that the definition of poor response, and thereby the entry criteria for the trials, is consistent, and demonstrated to be of prognostic significance.

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POST-IVF FOLLOW-UP Repeating ovarian reserve testing is worthwhile, as an abnormal result may explain the poor response and help in deciding on further stimulation attempts. The daily stimulation dose should be increased to 300 IU FSH daily, however, there is little evidence to support an increase in daily stimulation beyond this, when livebirth rates are considered, and patients should be aware of this. The decision either to pursue further IVF treatment using the patient’s own oocytes or to discontinue treatment or opt for oocyte donation is a difficult one. Oocyte donation is a successful treatment, although the supply of donor eggs depends on local circumstances, and in the UK, despite egg-sharing programs, there remains a shortage. Using donated gametes will be unacceptable to some or outwith the financial reach of others. Follow-up of poor responders has demonstrated an earlier age at menopause,56,57 which is unsurprising given the continuum between normal ovarian reserve, incipient ovarian failure and complete ovarian failure. Poor responders (450 IU FSH/day with < 4 oocytes retrieved or cycle cancellation because < 3 follicles developed) were six times more likely to reach the menopause within 10 years than women with raised basal FSH levels, and 23 times more likely than controls.58

SUMMARY OF MANAGEMENT OPTIONS Poor response continues to present a major challenge in contemporary IVF practice (Table 2). Some progress has been made in defining poor response, taking into account what stimulation dose is used. Young women with normal ovarian reserve, by either endocrine or biophysical assessment, have a reasonable prospect of conceiving even if few oocytes are obtained. Increasing the stimulation dose to 300 IU FSH daily will result in a response sufficient to justify oocyte pick-up in most women. However, little evidence is available to show that such a policy will increase pregnancy rates. For the remainder, particularly if they have abnormal reserve tests or are older than 35 years, their chances of IVF success are diminished. The decision to move to oocyte donation can be difficult for couples, particularly those who continue to produce embryos in low numbers. Identification of women at risk of early biological ovarian aging would provide them with information about the risks of delaying attempts at conceiving. However, if the management of poor response can be

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Table 2

Main issues in management of poor response

Definition

Consider FSH dose and ovarian reserve Low oocyte numbers in response to < 300 IU FSH/day may simply need higher daily dose

FSH preparation

If unresponsive to high-dose recFSH, consider providing some FSH as hMG

Maximum FSH dose

300 IU FSH Beyond this, no evidence of benefit Maximum 450 IU FSH flare-up

OCP pretreatment

Possible benefit but evidence from small studies

GnRH agonist Flare regimen: some evidence may be helpful GnRH antagonist

Role to be determined

Adjuvant treatment

Aspirin: no benefit Glucocorticoids: no clear benefit Growth hormone: may be beneficial in select groups

Decline in Poor responders with impaired reserve – lower oocyte quality implantation rates. Need to consider live-birth outcomes FSH, follicle stimulating hormone; OCP, oral contraceptive pill; GnRH, gonadotropin releasing hormone; rec, recombinant; hMG, human menopausal gonadotropin

advanced, it will only be by conducting adequately powered prospective randomized controlled trials where there are uniform and widely accepted entry criteria.

REFERENCES 1. Keay SD, Liversedge NH, Mathur RS, et al. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol 1997; 104: 521–7

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2. Akande VA, Fleming CF, Hunt LP, et al. Biological versus chronological ageing of oocytes, distinguishable by raised FSH levels in relation to the success of IVF treatment. Hum Reprod 2002; 17: 2003–8 3. Perez Mayorga M, Gromoll J, Behre HM, et al. Ovarian response to folliclestimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab 2000; 85: 3365–9 4. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis: detection and clinical relevance. Hum Reprod 2003; 18: 1137–9 5. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002; 8: 141–54 6. Leridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 2004; 19: 1548–53 7. Levi AJ, Raynault MF, Bergh PA, et al. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril 2001; 76: 666–9 8. Templeton A, Morris JK, Parslow W. Factors that affect outcome of in-vitro fertilisation treatment. Lancet 1996; 348: 1402–6 9. Jenkins JM, Davies DW, Devonport H, et al. Comparison of ‘poor’ responders with ‘good’ responders using a standard buserelin/human menopausal gonadotropin regime for in-vitro fertilization. Hum Reprod 1991; 6: 918–21 10. Land JA, Yarmolinskaya MI, Dumoulin JC, et al. High-dose human menopausal gonadotrophin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril 1996; 65: 961–5 11. Stadtmauer L, Ditkoff EC, Session D, et al. High doses of gonadotropins are associated with poor pregnancy outcomes after in vitro fertilization–embryo transfer. Fertil Steril 1994; 61: 1058–64 12. Kailasam C, Keay SD, Wilson P, et al. Defining poor ovarian response during IVF cycles, in women aged < 40 years, and its relationship with treatment outcome. Hum Reprod 2004; 19: 1544–7 13. Lashen H, Ledger W, Lopez-Bernal A, et al. Poor responders to ovulation induction: is proceeding to in-vitro fertilization worthwhile? Hum Reprod 1999; 14: 964–9 14. Chang MY, Chiang CH, Hsieh TT, et al. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998; 69: 505–10 15. Lass A, Skull J, McVeigh E, et al. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization can predict poor response. Hum Reprod 1997; 12: 294–7 16. 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: 110–14 17. Seifer DB, MacLaughlin DT, Christian BP, et al. Early follicular serum müllerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77: 468–71

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18. Keay SD, Liversedge NH, Akande VA, et al. Serum insulin-like growth factor 1 concentrations following pituitary desensitisation do not predict the ovarian response to gonadotrophin stimulation prior to IVF. Hum Reprod 2003; 18: 1797–801 19. Potashnik G, Lunenfield E, Shwartz I, et al. Endogenous plasma growth hormone and the occurrence of pregnancies in patients undergoing in-vitro fertilization and embryo transfer with ovarian stimulation. Hum Reprod 1995; 10: 1065–9 20. Akande VA, Keay SD, Hunt LP, et al. The practical implications of a raised serum FSH and age on the risk of IVF treatment cancellation due to a poor ovarian response. J Assist Reprod Genet 2004; 21: 257–62 21. Jenkins JM, Davies DW, Anthony FW, et al. The detrimental influence of functional ovarian cysts during in-vitro fertilization cycles. Hum Reprod 1992; 7: 776–80 22. Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000; 73: 667–76 23. Bassil S, Godin PA, Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders. Hum Reprod 1999; 14: 1262–5 24. Liu J, Lu G, Qian Y, et al. Pregnancies and births achieved from in vitro matured oocytes retrieved from poor responders undergoing stimulation in in vitro fertilization cycles. Fertil Steril 2003; 80: 447–9 25. Shulman A, Ghetler Y, Fejgin M, et al. Relationship between the threshold of ovarian sensitivity to human menopausal gonadotrophin stimulation and invitro fertilization treatment outcome. Hum Reprod 1995; 10: 3198–201 26. Van Rysselberge M, Puissant F, Barlow P, et al. Fertility prognosis in IVF treatment of patients with cancelled cycles. Hum Reprod 1989; 4: 663–6 27. Manzi DL, Thornton KL, Scott LB, et al. The value of increasing the dose of human menopausal gonadotropins in women who initially demonstrate a poor response. Fertil Steril 1994; 62: 251–6 28. Hofmann GE, Toner JP, Muasher SJ, et al. High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low responder patients for in vitro fertilization. J In Vitro Fert Embryo Transfer 1989; 6: 285–9 29. Karande VC, Jones GS, Veeck LL, et al. High-dose follicle-stimulating hormone stimulation at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients. Fertil Steril 1990; 53: 486–9 30. De Placido G, Mollo A, Alviggi C, et al. Rescue of IVF cycles by HMG in pituitary down-regulated normogonadotrophic young women characterized by a poor initial response to recombinant FSH. Hum Reprod 2001; 16: 1875–9 31. Tarlatzis BC, Zepiridis L, Grimbizis G, et al. Clinical management of low ovarian response to stimulation for IVF; a systematic review. Hum Reprod Update 2003; 9: 61–76 32. Surrey ES, Bower JA, Hill DM. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998; 69: 419–24

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33. Faber BM, Mayer J, Cox B, et al. Cessation of gonadotrophin-releasing hormone agonist therapy combined with high-dose gonadotrophin stimulation yields favorable pregnancy results in low responders. Fertil Steril 1998; 69: 826–30 34. Akman MA, Erden HF, Tosun SB, et al. Comparison of agonistic flare-up protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod 2001; 16: 868–70 35. D’Amato G, Caroppo E, Pasquadibisceglie A, et al. A novel protocol of ovulation induction with delayed gonadotropin-releasing hormone antagonist administration combined with high-dose recombinant follicle-stimulating hormone and clomiphene citrate for poor responders and women over 35 years. Fertil Steril 2004; 81: 1572–7 36. Biljan MM, Mahutte NG, Dean N, et al. Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. Fertil Steril 1998; 7: 1063–9 37. Stone BA, Marrs RP. Ovarian responses to menopausal gonadotrophins in groups of patients with differing basal growth hormone levels. Fertil Steril 1992; 58: 32–6 38. Adashi EY, Resnick CE, D’Ercole A, et al. Insulin-like growth factors as intraovarian regulators of granulosa cell function. Endocr Rev 1985; 6: 400–20 39. Homburg R, Ostergaard H. Clinical applications of growth hormone for ovarian stimulation. Hum Reprod Update 1995; 1: 264–75 40. Harper K, Proctor M, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev 2003; (3): CD000099 41. Howles CM, Loumaye E, Germond M, et al. Does growth hormone-releasing factor assist follicular development in poor responder patients undergoing ovarian stimulation for in-vitro fertilization ? Hum Reprod 1999; 14: 1939–43 42. Battaglia C, Salvatori M, Maxia N, et al. Adjuvant L-arginine treatment for invitro fertilization in poor responder patients. Hum Reprod 1999; 14: 1690–7 43. Battaglia C, Regnani G, Marsella T, et al. Adjuvant L-arginine treatment in controlled ovarian hyperstimulation: a double-blind, randomized study. Hum Reprod 2002; 17: 659–65 44. Kim C-H, Chae H-D, Chang Y-S. Pyridostigmine cotreatment for controlled ovarian hyperstimulation in low responders undergoing in vitro fertilization–embryo transfer. Fertil Steril 1999; 71: 652–7 45. Kemeter P, Feichtinger W. Prednisolone supplementation to Clomid and/or gonadotrophin stimulation for in-vitro fertilization – a prospective randomized trial. Hum Reprod 1986; 1: 441–4 46. Bider D, Amoday I, Tur-Kaspa I, et al. The addition of a glucocorticoid to the protocol of programmed oocyte retrieval for in-vitro fertilization – a randomized study. Hum Reprod 1996; 11: 1606–8 47. Fridstrom M, Carlstrom K, Sjoblom P, et al. Effect of prednisolone on serum and follicular fluid androgen concentrations in women with polycystic ovarian syndrome undergoing in-vitro fertilization. Hum Repro 1999; 14: 1440–4

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48. Keay SD, Lenton EA, Cooke ID, et al. Low-dose dexamethasone augments the ovarian response to exogenous gonadotrophins leading to a reduction in cycle cancellation rate in a standard IVF programme. Hum Reprod 2001; 16: 1861–5 49. Jenkins JM, Gadd SC, Anthony FW, et al. Corticosteroids may act via IGF-1 to improve the response to ovarian stimulation in IVF ‘poor’ responders. Br J Obstet Gynaecol 1994; 101: 269–70 50. Rubinstein M, Marazzi A, Polak de Fried E. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertil Steril 1999; 71: 825–9 51. Lok IH, Yip SK, Cheung LP, et al. Adjuvant low-dose aspirin therapy in poor responders undergoing in vitro fertilization: a prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril 2004; 81: 556–61 52. Casson PR, Lindsay MS, Pisarska MD, et al. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000; 15: 2129–32 53. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002; 77: 776–80 54. Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Invest 2004; 11: 406–15 55. Goswami SK, Das T, Chattopadhyay R, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004; 19: 2031–5 56. Nikolaou D, Lavery S, Turner C, et al. Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure? Hum Reprod 2002; 17: 1106–11 57. de Boer EJ, den Tonkelaar I, te Velde ER, et al. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003; 18: 1544–52 58. Lawson R, El-Toukhy T, Kassab A, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003; 18: 527–33

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The patient with recurrent miscarriage R Rai

INTRODUCTION Miscarriage is the commonest complication of pregnancy. It is estimated that between 10% and 15% of clinically recognized pregnancies miscarry. In contrast, recurrent miscarriage, the loss of three or more consecutive pregnancies, is relatively uncommon, affecting between 1% and 2% of couples trying to conceive.1 Whilst the most common cause for any single miscarriage is a sporadic fetal chromosome abnormality, the incidence of which increases with advancing maternal age, women who repeatedly miscarry tend to lose euploid as apposed to aneuploid fetuses.2,3 This suggests that some women with recurrent miscarriage have a persistent underlying cause to account for their pregnancy losses. These causes, which can be simply divided into those that are embryological in origin, such as aneuploidies, and those that are related to the maternal environment, are shown in Table 1.

Table 1

Recognized causes of recurrent miscarriage

Defect

Prevalence (%)

Thrombophilic defects Antiphospholipid syndrome Uterine abnormalities Insulin resistance Paternal karyotype abnormalities

30 15 5 Up to 27 4

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Whilst couples with recurrent miscarriage have by definition been fertile, assisted conception techniques may be offered to them for one of two reasons: either because they have developed secondary infertility, which has been reported to occur in up to 32% of those with recurrent miscarriage,4 or in an attempt to improve the chances of a successful pregnancy. With respect to the latter reason, it should be borne in mind that amongst those with unexplained recurrent miscarriage, the chance of a future successful pregnancy with supportive care alone is in the region of 65–70%.5

IMPACT OF A HISTORY OF RECURRENT MISCARRIAGE ON IVF OUTCOME Few studies have examined the outcome of in vitro fertilization (IVF) amongst women with unexplained recurrent miscarriage. Raziel and colleagues6 compared the outcome of 42 IVF cycles amongst 20 women with a history of unexplained recurrent miscarriage and secondary infertility with that of a control group of 20 women of similar age with no history of miscarriage. Whilst those with a history of recurrent miscarriage had a similar pregnancy rate (33%/cycle) compared with the control group (29%/cycle), their miscarriage rate was significantly higher (7/14; 50%) compared with that of the controls (1/12; 8%). In a recent retrospective examination of the German IVF registry, Kupka and colleagues7 were able to demonstrate clearly an association between the number of previous miscarriages a woman had experienced and the risk of miscarriage following IVF (Figure 1). Similar data were reported from an analysis of the US assisted reproductive technologies (ART) registry of 62 000 clinical pregnancies resulting from ART procedures performed between 1996 and 1998.8

IMPACT OF IVF ON MISCARRIAGE Whether the miscarriage rate is increased amongst pregnancies conceived after IVF compared with those conceived spontaneously is questionable. Whilst initial studies reported an increased rate of miscarriage following IVF, more recent data do not support such a relationship. Interpretation of the data is hampered by fundamental differences in methodologies and terminologies used in different studies. Definitions of clinical pregnancy and miscarriage differ between studies, some of which have not accounted for recognized factors such as maternal age, which is known to affect miscarriage rates.

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THE PATIENT WITH RECURRENT MISCARRIAGE

45

IVF

Miscarriage rate (%)

40

ICSI

35 30 25 20 15 10 5 0 0

1

2

3

Number of previous miscarriages

Figure 1 Miscarriage rate per clinical pregnancy after in vitro fertilization (IVF) is influenced by the number of previous miscarriages after spontaneous/assisted conception. ICSI, intracytoplasmic sperm injection. After reference 7

35

Freshly fertilized embryos

30 Miscarriage rate (%)

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Cryopreserved embryos

25 20 15 10 5 0 20–29

30–34

35–37

38–40

41–43

Female age (years)

Figure 2 Miscarriage rate after in vitro fertilization (IVF) of freshly fertilized vs. cryopreserved embryos according to patient age. After reference 8

Analysis of the US ART registry reported the spontaneous miscarriage rate to be 14.7% amongst ART pregnancies, compared with 14.1% amongst those enrolled in the National Survey of Family Growth, a population-based survey of women aged 15–44 years.8 Amongst those undergoing ART, the miscarriage rate increased with advancing maternal age and was also increased amongst those using cryopreserved embryos (Figure 2) and ovarian stimulation protocols using clomiphene citrate, and after zygote intrafallopian transfer. As one might expect, there was no relationship between maternal age and miscarriage rate amongst those using donor oocytes and freshly fertilized embryos.

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IVF versus ICSI Both the US study and data from the German registry reported an insignificant increase in the miscarriage rate after intracytoplasmic sperm injection (ICSI) compared with conventional IVF.7,8 This might, however, mask a true difference between the two techniques, as couples needing IVF for factors other than male-factor infertility may have other potential reasons for miscarriage, such as uterine fibroids and poor oocyte quality. It has recently been reported that the rate of fetal aneuploidy was significantly higher in the products of first-trimester miscarriage of couples who underwent ICSI (16/21; 76%) compared with an age-matched cohort of those who had undergone conventional IVF (16/22; 41%: p < 0.01).9 This may be related to either factors associated with the processes involved with ICSI or to increased sperm aneuploidy rates amongst those with an impaired semen analysis. The miscarriage rate is increased in ICSI pregnancies after testicular sperm extraction (TESE),10,11 and indeed there appears to be an increased incidence of sperm chromosome abnormalities amongst the male partners of couples with recurrent miscarriage.12

PREPARING THE PATIENT FOR IVF All women with a history of recurrent miscarriage should be investigated prior to commencement of an IVF cycle for a recognized cause of their pregnancy losses. In essence, a woman should be screened for antiphospholipid antibodies (lupus anticoagulant and both the immunoglobulin G (IgG) and IgM classes of anticardiolipin antibodies), factor V Leiden and activated protein C resistance (as a global test of the protein C/S coagulation pathway).13 Those with polycystic ovaries should have their insulin resistance status determined, and all should have an assessment of uterine anatomy. In addition, both partners should have their peripheral blood karyotype determined. The following variations on a conventional IVF cycle should also be discussed.

Preimplantation genetic diagnosis for those with reciprocal translocations In approximately 4% of couples with recurrent miscarriage, one partner carries either a balanced reciprocal translocation, in which there is an exchange of two terminal segments from different chromosomes, or a Robertsonian translocation, in which there is centric fusion of two acrocentric chromosomes.4

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Whilst carriers of a balanced reciprocal translocation are phenotypically normal, abnormal segregation at meiosis leads to between 50% and 70% of their gametes and hence embryos being unbalanced. Thus, appropriate ovarian stimulation regimens to obtain a large number of embryos may be more important than with conventional IVF for those with unexplained recurrent miscarriage. The patient clearly has to be counseled that she may not reach the stage of embryo transfer due to the absence of normal or balanced embryos. Hence, the live-birth rate/cycle for those with a reciprocal translocation undergoing preimplantation genetic diagnosis (PGD) is lower than would be hoped: between 29%/oocyte retrieval rising to 38%/embryo transfer.14 This has to be compared with the live-birth rate amongst those with a reciprocal translocation who persevere with spontaneous conception, where the chance of a successful pregnancy even after three miscarriages is between 50% and 65%.15

Preimplantation genetic screening for those with unexplained recurrent miscarriage The European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium includes unexplained recurrent miscarriage amongst the inclusion criteria for preimplantation genetic screening (PGS).16 The basis for this recommendation is the significant contribution that recurrent fetal aneuploidy makes to the etiology of recurrent miscarriage. Rubio and colleagues,17 using three rounds of fluorescence in situ hybridization (FISH) screening for chromosomes 13, 16, 18, 21, 22, X and Y, performed aneuploidy screening in 71 couples with two or more miscarriages and 28 couples undergoing PGD for sex-linked diseases (the control group). The percentage of abnormal embryos was significantly higher amongst those with miscarriage (70.7%) compared with controls (45.1%). This difference was most marked amongst those women aged < 37 years (miscarriage cohort 70.7% abnormal vs. 33.3% amongst the control cohort). This study also reported that all the embryos were abnormal in 22% of cycles amongst those with miscarriage, and further cycles yielded a similar rate of abnormality. An important caveat with the use of PGS amongst women with unexplained recurrent miscarriage is whether it improves the live-birth rate over and above the 75% achieved with spontaneous conception alone.5 In Rubio’s study, one pregnancy amongst those with miscarriage was trisomic for chromosome 15 (which was not screened for). Until the more widespread introduction of techniques that examine the whole chromosome content of a cell, such as comparative genomic hybridization, an important practical question is how many chromosomes should be

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screened for using FISH. Wilding and associates18 reported that five-color FISH screening for chromosomes 13, 16, 18, 21 and 22 is indicated for those with recurrent miscarriage, compared with three-color FISH for those with implantation failure following IVF. Despite aneuploidy screening, miscarriage of a chromosomally normal pregnancy does occur.17 This highlights the importance of also considering maternal factors that contribute to miscarriage and how they may be overcome.

Surrogacy Gestational surrogacy as a treatment for recurrent miscarriage is only recently being explored. The rationale for such treatment is that the cause of pregnancy loss amongst some couples lies with an abnormal maternal environment and not with an abnormal embryo. Raziel and colleagues6 reported the case of a 36-year-old woman who had experienced 24 unexplained consecutive miscarriages with the same partner, despite the use of a variety of agents including aspirin, heparin, progesterone and intravenous immunoglobulin. A conventional IVF cycle with transfer of two goodquality embryos to the surrogate resulted in the birth of an appropriately grown male infant at term. Whilst there are no reports of the outcome of a series of patients with recurrent miscarriage who have used surrogacy, this treatment option should be considered for the small number of couples with recurrent miscarriage who continue to miscarry despite comprehensive investigation and treatment of an underlying cause. The argument in favor of gestational surrogacy is enhanced if it is demonstrated that the couple repeatedly lose chromosomally normal pregnancies.

MANAGING THE IVF CYCLE Management of the cycle is similar to that of those having IVF with no previous history of recurrent miscarriage. However, it is relevant to consider the use of adjuvant therapy for certain conditions associated with recurrent miscarriage.

Adjuvant therapy during the IVF cycle Antiphospholipid syndrome Approximately 15% of women with recurrent miscarriage have the antiphospholipid syndrome (APS).19 The accepted treatment for these

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women during pregnancy is aspirin together with heparin.20 Recent data have allowed us to escape from the restrictive concept of reproductive failure associated with antiphospholipid antibodies (aPLs) being thrombosis of the uteroplacental vasculature. Current concepts now emphasize the adverse effect of these antibodies on implantation. aPLs have been shown to impair decidualization, increase trophoblast apoptosis and inhibit syncytialization of the trophoblast.21,22 Interestingly, these effects are reversed, at least in vitro, by low-molecular-weight heparin (LMWH).23 It is our practice to treat women with APS with LMWH (enoxaparin 20 mg daily) commencing 6 h post-oocyte retrieval, and commence low-dose aspirin (75 mg daily) once the pregnancy test is positive. Both aspirin and heparin should be continued until 24 completed weeks of pregnancy.

Thrombophilia Using thromboelastography, which is an assessment of whole-blood hemostasis, and by assaying the level of thrombin–antithrombin complexes, we have reported that 30% of women with recurrent miscarriage are in a hypercoagulable state outside of pregnancy.13,24 However, less than 5% of these women have had a previous systemic thrombosis.4 As women undergoing controlled ovarian hyperstimulation as part of their IVF cycle are at increased risk for thromboembolic disease, it is our practice to prescribe heparin thromboprophylaxis to that small cohort of women with a history of previous systemic thrombosis. We do not routinely prescribe thromboprophylaxis to those women with a congenital or acquired thrombophilic defect who have never had a systemic thrombosis. In cases of ovarian hyperstimulation syndrome amongst women with recurrent miscarriage, early resort to thromboprophylaxis is even more important.

Insulin resistance and metformin The prevalence of polycystic ovaries is significantly higher amongst women with recurrent miscarriage (40%) compared with women with no history of reproductive failure (22%).25 The overwhelming majority of women with recurrent miscarriage who have polycystic ovaries are spontaneously ovulatory and have a normal body mass index (BMI). However, even amongst this cohort, there is an increased prevalence of insulin resistance (27%), which has been reported to be associated with both recurrent miscarriage and recurrent implantation failure following IVF.26,27 A recent randomized study reported that amongst those women who are insulinresistant and who have a normal BMI, pretreatment with metformin until

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the time of human chorionic gonadotropin (hCG) administration improves the pregnancy rate.28

Low-dose aspirin There is no evidence base for the use of low-dose aspirin amongst those women with unexplained recurrent miscarriage.29 Indeed, animal data and limited human data suggest that prenatal use of aspirin may be associated with increased bleeding tendency, congenital malformations, and cognitive and behavioral defects, including schizophrenia in the offspring.30

Natural killer cells and steroids The relationship between peripheral blood natural killer (NK) cells and reproductive outcome is one of the most controversial fields in reproductive medicine. NK cells are lymphocytes that are part of the innate immune system. They may be divided into those found in peripheral blood and those present in the uterine decidua. There are important phenotypic and functional differences between NK cells present at the two sites. Unlike peripheral blood NK cells, uterine NK cells have little killing ability. Microarray analysis combined with flow cytometric and reverse transcriptase– polymerase chain reaction (RT–PCR) studies have demonstrated that the phenotype of uterine NK cells is different from that of NK cells in peripheral blood.31 Whilst some centers have advocated the use of glucocorticoids as adjuvant therapy in women with raised peripheral NK-cell levels, there is no evidence base to support this. Indeed, glucocorticoids themselves during pregnancy are associated with an increased risk of preterm delivery secondary to rupture of membranes, and the development of pre-eclampsia and gestational diabetes.32 Importantly, glucocorticoid receptors are present in the stromal compartment of the endometrium, thus suggesting that they play an important role in decidualization.33 The effect of exogenous glucocorticoid therapy on the endometrial gene expression profile during decidualization has not been examined.

POST-IVF FOLLOW-UP If miscarriage should occur, it is important to obtain fetal tissue for cytogenetic analysis. The importance of this is that if the fetal karyotype was abnormal, this would not only explain the cause of pregnancy loss but also

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be a guide for the prognosis of a future pregnancy. Women who lose a pregnancy with an abnormal fetal karyotype have a higher chance of a future successful pregnancy, compared with those who lose a pregnancy with a normal karyotype.34

SUMMARY OF MANAGEMENT OPTIONS The indications for IVF amongst women with recurrent miscarriage are either because they have developed secondary infertility or in order to decrease their risk of miscarriage and simultaneously improve their chances of a successful pregnancy. All women should be comprehensively investigated to exclude the presence of an underlying treatable cause for their pregnancy failures. In the presence of such a cause, adjuvant therapy during a cycle would be indicated. In the absence of such a cause and if the fetal karyotypes are known to have been abnormal, PGS is currently being explored as a treatment option. Amongst women losing pregnancies with a normal chromosome complement, the cause of pregnancy failure lies with the host maternal environment and IVF is unlikely to be of benefit.

REFERENCES 1. Stirrat GM. Recurrent miscarriage. Lancet 1990; 336: 673–5 2. Sullivan AE, Silver RM, LaCoursiere DY, et al. Recurrent fetal aneuploidy and recurrent miscarriage. Obstet Gynecol 2004; 104: 784–8 3. Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case–control study. Hum Reprod 2002; 17: 446–51 4. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994; 9: 1328–32 5. Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997; 12: 387–9 6. Raziel A, Friedler S, Schachter M, et al. Successful pregnancy after 24 consecutive fetal losses: lessons learned from surrogacy. Fertil Steril 2000; 74: 104–6 7. Kupka MS, Dorn C, Montag M, et al. Previous miscarriages influence IVF and intracytoplasmatic sperm injection pregnancy outcome. Reprod Biomed Online 2004; 8: 349–57 8. Schieve LA, Tatham L, Peterson HB, et al. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003; 101: 959–67 9. Lathi RB, Milki AA. Rate of aneuploidy in miscarriages following in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril 2004; 81: 1270–2

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10. Borges E Jr, Rossi-Ferragut LM, Pasqualotto FF, et al. Testicular sperm results in elevated miscarriage rates compared to epididymal sperm in azoospermic patients. Sao Paulo Med J 2002; 120: 122–6 11. Anderson AR, Wiemer KE, Weikert ML, Kyslinger ML. Fertilization, embryonic development and pregnancy losses with intracytoplasmic sperm injection for surgically-retrieved spermatozoa. Reprod Biomed Online 2002; 5: 142–7 12. Rubio C, Gil-Salom M, Simon C, et al. Incidence of sperm chromosomal abnormalities in a risk population: relationship with sperm quality and ICSI outcome. Hum Reprod 2001; 16: 2084–92 13. Rai R, Tuddenham E, Backos M, et al. Thromboelastography, whole-blood haemostasis and recurrent miscarriage. Hum Reprod 2003; 18: 2540–3 14. Braude P, Pickering S, Flinter F, Ogilvie CM. Preimplantation genetic diagnosis. Nat Rev Genet 2002; 3: 941–53 15. Carp H, Feldman B, Oelsner G, Schiff E. Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril 2004; 81: 1296–301 16. Thornhill AR, Dedie-Smulders CE, Geraedts JP, et al. ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)’. Hum Reprod 2005; 20: 35–48 17. Rubio C, Simon C, Vidal F, et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod 2003; 18: 182–8 18. Wilding M, Forman R, Hogewind G, et al. Preimplantation genetic diagnosis for the treatment of failed in vitro fertilization–embryo transfer and habitual abortion. Fertil Steril 2004; 81: 1302–7 19. Rai RS, Regan L, Clifford K, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995; 10: 2001–5 20. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253–7 21. Sebire NJ, Fox H, Backos M, et al. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod 2002; 17: 1067–71 22. Mak IY, Brosens JJ, Christian M, et al. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 2002; 87: 2581–8 23. Bose P, Black S, Kadyrov M, et al. Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro. Am J Obstet Gynecol 2004; 191: 2125–31 24. Vincent T, Rai R, Regan L, Cohen H. Increased thrombin generation in women with recurrent miscarriage. Lancet 1998; 352: 116 25. Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage – a reappraisal. Hum Reprod 2000; 15: 612–15

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26. Craig LB, Ke RW, Kutteh WH. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril 2002; 78: 487–90 27. Cano F, Garcia-Velasco JA, Millet A, et al. Oocyte quality in polycystic ovaries revisited: identification of a particular subgroup of women. J Assist Reprod Genet 1997; 14: 254–61 28. Kjotrod SB, von During V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod 2004; 19: 1315–22 29. Rai R, Backos M, Baxter N, et al. Recurrent miscarriage – an aspirin a day? Hum Reprod 2000; 15: 2220–3 30. Daya S. Recurrent spontaneous early pregnancy loss and low dose aspirin. Minerva Ginecol 2003; 55: 441–9 31. Koopman LA, Kopcow HD, Rybalov B, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003; 198: 1201–12 32. Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337: 148–53 33. Henderson TA, Saunders PT, Moffett-King A, et al. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab 2003; 88: 440–9 34. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000; 73: 300–4

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Giving bad news: ‘It’s time to stop’ J Boivin, J Takefman and A Braverman

INTRODUCTION Medical training focuses on treating a patient until the medical issue is resolved. Unfortunately, infertility treatment does not always resolve the medical issue in favor of a pregnancy. Consequently, medical professionals will encounter regularly the need to counsel a patient that their chances of success are so low that it is in their best interest to discontinue treatment. However, because there is no clear end-point for the cessation of unsuccessful fertility treatment, as there is always some probability of success inherent in further attempts, the physician may have difficulty in justifying his/her best advice to patients. Similarly, from the couple’s point of view, being able to walk away from treatment involves significant psychological tasks. For instance, the couple must accept that treatment has failed despite the odds, begin decision-making about the next steps, and emotionally deal with such losses as wish-fulfillment, a potential genetic offspring, etc. From an evidence-based perspective, there is limited research carried out directly on this specific doctor–patient communication. Thus, the following sections are based on both relevant clinical theories and indirect research. Physicians can best support couples in this ‘end of treatment’ consultation by being able to recognize: (1) Psychological factors that make this process difficult for couples; (2) Risk factors that contribute to some patients suffering greater distress during this transition; (3) Specific skills that can facilitate the consultation process for both physician and patient.

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THE EMOTIONAL CHALLENGES EVOKED BECAUSE OF THE ‘END OF TREATMENT’ CONSULTATION A review of the literature reveals three main emotional challenges that make ending treatment difficult for couples: fear of not being able to cope; an inability to imagine a life without children; and concerns over survival of the partnership.

Fear of not being able to cope with ending treatment The hope produced by being in treatment keeps at bay the full sorrow of never having your own children. When there is no further possibility of conceiving, these feelings surface completely and can feel like they are too much to bear. Daniluk1 proposed that one of the main factors preventing couples from ending treatment is the fear that such feelings will be overwhelming and impossible to cope with. For most couples, ending treatment is a process rather than an event, with the mental transition from ‘not yet pregnant’ to ‘not going to be pregnant’ being gradual.2 Although this process is distressing, it is manageable, because it gradually allows couples to adapt to the possibility of treatment failure. Thus, couples will move from being certain that they want further treatments, to being ambivalent about biopsychosocial and financial costs versus chances of success, to eventually being comfortable in their decision to end treatment. The acceptability of advice about ending treatment will therefore vary as a function of where couples find themselves in this transition process.

An inability to imagine a life without (one’s own) children Many couples persist with treatment because they cannot imagine a satisfying and happy life without their own children. For these couples, being told that treatment is over is tantamount to having no future. During the transition from ‘not yet pregnant’ to ‘never going to be pregnant’, couples must construct a new future for themselves. However, parenting is such an important organizing principle for how people see their futures that this task can seem insurmountable. Add to this society’s emphasis on parenthood as the major developmental milestone in adulthood, and one can understand why the future looks so bleak to these couples. Part of this pessimism is due to a lack of knowledge. Research shows that couples who remain child-free eventually fare well, in the sense that they can achieve a contented life, and they can interpret their infertility experience in terms of its positive impact on their life, for example on their commitment as a couple.3,4 Despite this positive growth, the sadness of

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infertility is not entirely forgotten, and this traumatic life experience continues to have effects. For example, studies have shown that many years later women still report intrusive thoughts about their fertility,5 and still report fertility-problem stress.6

Fear concerning survival of the marital relationship For many couples, the basis for committing to a relationship is the eventuality of forming a family with children. The end of treatment may cause people to question the basis for their marriage. Furthermore, the diagnosed partner may have fears that their partner may not wish to continue in a childless relationship. Strauss and colleagues7 found that couples who felt their union would be threatened by a lack of children were the ones most likely to persist with treatment and/or be reluctant to end treatment. Thus, the recommendation to end treatment may trigger marital issues that have lain dormant, or threaten the viability of the marriage.

FACTORS THAT INFLUENCE PATIENTS’ REACTIONS TO THE ‘END OF TREATMENT’ CONSULTATION How a person or couple reacts to advice about ending treatment will differ according to a variety of factors. Thus, couples will enter the ‘end of treatment’ consultation with different mental agendas, from being prepared to hear that it is time to give up to being completely unprepared. It is important to know in advance the factors that may influence how people will react to advice about ending treatment, as this will influence the physician’s expectations for the consultation.

Demographic factors Gender is critical to decision-making about further treatments. Women are more likely to initiate treatment, want to try new treatments and want to continue with treatment compared with men, and men tend to be willing to end treatment sooner than their partners.8 This gender difference can produce significant conflict and disagreement between spouses about ending treatment and/or pursuing alternatives. Although age does not seem to be a predictor of treatment persistence, parity has been found to be a significant predictor of withdrawal.9 Couples who have children are more likely to accept the end of treatment.10 On the basis of these findings, one can expect that women, particularly childless women, will receive advice about ending treatment with more difficulty, and possibly more resistance, than their partners.

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Emotional and relational factors One of the most consistent findings in the infertility literature is that patients overestimate their chances of success. This ‘optimistic bias’ is well documented, and understood from a theoretical perspective as being an important factor in determining positive adjustment.11 Several studies have shown that optimism plays a part in the initiation of treatment10 and the maintenance of treatment efforts.7 Indeed, Callan and colleagues9 found that those who were willing to end treatment had become less optimistic that in vitro fertilization (IVF) would help them achieve their goal of parenthood. Based on these studies, we could predict that those who remain highly optimistic about IVF success will have a harder time accepting the end of treatment. Ironically, these same people will be more optimistic with regard to third-party alternatives such as egg donation and adoption. As noted previously, couples who believe that their marriage needs children to survive will be more resistant to ending treatment.7 However, those who believe that treatment has had a negative impact on their marriage and their personal lives will be more open to ending treatment,12 and less likely to seek treatment for a second child.13 In a longitudinal evaluation of adaptation to treatment termination, it was reported that 10% of couples ended treatment because of the strain that treatment was putting on their partnership.4 Similarly, people experiencing much psychological distress are more likely and/or willing to end treatment, as shown by high stress-related drop-out rates.14 These findings suggest that people who are at the ‘end of their tether’ or emotionally worn out by treatment may more easily accept recommendations to end treatment.

Cognitive factors The way that people think about or evaluate their treatment experiences and alternatives to treatment will also determine how they will react to the ‘end of treatment’ consultation. People who feel that they have not done enough to become pregnant will have more difficulty ending treatment.1 A central issue in accepting advice about ending treatment is dealing with the possibility that more or other kinds of treatments could, in theory, lead to a pregnancy: ‘What if this new treatment works? What if one more cycle works? What if we use a different stimulation protocol?’ Couples are more likely to accept advice about ending treatment if they can achieve a sense of ‘having done enough’.1,12 People who are more open-minded about different ways to form a family will likely react more favorably to advice to end treatment, as the end of treatment will not automatically mean childlessness. A Dutch study

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found that life-satisfaction scores among people at the end of treatment were higher than population norms, but only for long-term infertile couples who were also exploring alternative options to natural pregnancy.15 Similarly, choosing to adopt was the main factor accounting for lower emotional distress in those who had experienced treatment failure.16 Finally, it has been shown that divergence between partners on their willingness to pursue other parenting options is associated with a more difficult transition when treatment ends.4

SPECIFIC SKILLS THAT CAN FACILITATE THE ‘END OF TREATMENT’ CONSULTATION PROCESS FOR BOTH PHYSICIAN AND PATIENT Establishing aims of the consultation At the beginning of the consultation, the physician should set the agenda for the meeting as well as exploring what agenda or approach the patient brings. Stating what the physician wants to accomplish, for example reviewing the patient’s treatment and discussing future treatments, prevents the patient from having concerns or anxiety about what to expect. Sometimes it is helpful to ask the patient directly if he or she has any expectations about what the physician might say. The second task is to inquire about the patient’s agenda. By asking for the patient’s agenda and expectations, the physician can ascertain the patient’s level of preparedness for hearing the recommendation to end treatment. It is essential to arrive at a ‘shared understanding’ of the problem at hand for the consultation to proceed successfully. Research has shown that patient-centered consultations that involve more open-ended questions, with greater scope for patients to raise their own concerns and express emotions, are preferred by patients in medical situations that are uncontrollable and unpredictable like the ‘end of treatment’ consultation.17

Setting the context for the recommendation to end treatment The physician can begin to review the patient’s medical history and treatment cycle as a foundation upon which to build his or her recommendation. If the patient is informed about the reasoning behind the recommendation and is reassured that the physician has fully evaluated the couple’s unique medical situation, then they may be more willing to accept the physician’s opinion. It is at this point that the physician should encourage patients to reflect on what they have done to achieve a pregnancy, so that

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they too can feel they have ‘done enough’. Physicians can help patients come to this belief by asking them to reflect on whether they believe that they have received the best treatment, followed well the recommendations of their specialists during each treatment trial and given each treatment option their best effort.

Ensuring supportive follow-up The consultation should also include enough time for the patient to ask any questions. and physicians should encourage patients to call or come back once the information is processed. Patients’ feelings of disappointment or of being overwhelmed should be normalized. It is critical that patients leave the consultation not feeling abandoned, and with the understanding that this is a process not an end-point. A recent study showed that insufficient information, poor comprehension of medical advice and lack of empathy expressed by medical staff were key contributing factors to patients evaluating fertility centers poorly.18

Stating the positive aspects Depending on where the couple is in the transition process from ‘not yet pregnant’ to ‘not going to be pregnant’, pointing out some of the positive aspects of ending treatment may be appropriate at this time. Some of these might include: (1) Relief about ending constant treatments; (2) Climbing off the emotional roller coaster; (3) Life no longer being ‘on hold’ or in limbo; (4) Feeling more ‘in control’ than ‘out of control’; (5) Privacy reintroduced into the relationship; (6) End of financial considerations; (7) Opportunity to explore other options for family building with better success rates; (8) Opportunity to focus on other life pursuits.

Preparing the couple for the future beyond IVF The physician should ask the couple whether they want to explore alternatives to IVF at this point, or come back at a later date. Their decision will

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GIVING BAD NEWS

depend on where they are in the transition process and the many risk factors noted previously. Patients’ needs for this information can best be met at a time when they are ready to receive it. It might be outside the mandate of a medical person to counsel further those patients who will not be pursuing medical alternatives, because this mainly involves addressing psychological and emotional issues. In either case, the physician may want to end the consultation by referring the couple to a mental-health counselor or by recommending reading material on alternatives to parenthood, including living child-free. It is important not to overwhelm the patient with information, and to pay attention to how much the patient is actually taking in.

SUMMARY OF MANAGEMENT OPTIONS In summary, it is possible to deliver the bad news of ending treatment in such a manner as to minimize stress and commence the process of healing and recovery for a couple. Overall, during the consultation, physicians should ensure that patients assimilate accurately the information conveyed and its ramification, without provoking denial or overwhelming emotional distress. In an empathetic manner, physicians should help patients to disclose their concerns about ending treatment, express their associated feelings and decide whether they want to review different options. The long-term benefits of such effective physician–patient communication are better coping, improved patient self-management, better recovery, psychological adjustment and increased patient satisfaction.17 The guiding principles for the ‘end of treatment’ consultation should be: (1) Build a case based on their treatment history before presenting the recommendations and options. (2) Help couples to reflect on all they have done to achieve a pregnancy so that they can more easily accept the evidence provided and feel that they have done enough. (3) Allow patients to express concerns and feelings and listen with empathy, as the end of treatment will undoubtedly trigger such emotional responses. (4) Let the patient set the agenda once the advice is conveyed. (5) Reassure patients of continued attention and care. (6) Ensure that the patient has assimilated any hopeful news along with the bad news.

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REFERENCES 1. Daniluk JC. The Infertility Survival Guide. California: New Harbinger Publications, 2001 2. Throsby K. No-one will ever call me Mummy: making sense of the end of IVF treatment. New Working Paper Series. London: Gender Institute, London School of Economics and Political Science, 2001; issue 5 3. Brew T. Benefit finding in women’s lives following unsuccessful infertility treatment. Dissertation, Cardiff University, Cardiff, Wales, 2002 4. Daniluk JC. Reconstructing their lives: a longitudinal, qualitative, analysis of the transition to biological childlessness for infertile couples. J Counsel Dev 2001; 79: 439–49 5. Sundby JS. Long-term psychological consequences of infertility: a follow-up study of former patients. J Women’s Health 1992; 1: 209–17 6. Abbey A, Andrews FM, Halman LJ. Infertility and parenthood: does becoming a parent increase well-being? J Consult Clin Psychol 1994; 62: 398–403 7. Strauss B, Hepp U, Staeding G, Mettler L. Psychological characteristics of infertile couples: can they predict pregnancy and treatment persistence. J Comm Appl Soc Psychol 1998; 8: 289–301 8. Greil AL. Infertility and psychological distress: a critical review of the literature. Soc Sci Med 1997; 45: 1679–704 9. Callan VJ, Kloske B, Kashima Y, Hennessey JF. Toward understanding women’s decisions to continue or stop in vitro fertilisation: the role of social, psychological and background factors. J In Vitro Fert Embryo Transfer 1988; 5: 363–9 10. Fortier C, Wright J, Sabourin S. Soutien social et abandon de la consultation médicale en clinique de fertilité. J Int Psychol 1992; 27: 33–48 11. Taylor SE. Adjustment to threatening events: a theory of cognitive adaptation. Am Psychol 1983; 38: 1161–73.12 12. Blenner JL. Passage through infertility treatment: a stage theory. Image J Nurs Sch 1990; 22: 153–8 13. Daniluk JC. Factors related to couples’ decisions to attempt in vitro fertilization. J Assist Reprod Genet 1993; 10: 310–16 14. Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 2004; 81: 258–61 15. Van Balen F, Trimbos-Kemper TCM. Long-term infertile couples: a study of their well being. J Psychosom Obstet Gynaecol 1993; 14: 53–60 16. Bryson CA, Sykes DH, Traub AI. In vitro fertilization: a long-term follow-up after treatment failure. Hum Fertil 2000; 3: 214–20 17. Weinman J. Doctor–patient communication. In Baum A, Newman S, Weiman J, et al. Cambridge Handbook of Psychology, Health and Medicine. Cambridge: Cambridge University Press, 1997: 282–7 18. Schmidt L, Holstein B, Boivin J, et al. High ratings of satisfaction with fertility treatment are common: findings from the Copenhagen Multi-centre Psychosocial Infertility (COMPI) Research Programme. Hum Reprod 2003; 18: 2638–46

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abuse, sexual and physical 75–6 acromegaly 20, 33, 34 activated protein C (APC) resistance 4–5, 9 sensitivity ratios (APCsr) 5 adrenal insufficiency 23–4, 35 adrenal tumors 88 adrenocorticotropic hormone (ACTH) 23, 24 ACTH stimulation test 24 alcohol use 187 alkylating agents in chemotherapy 43 amantadine 79 amenorrhea 22, 51–2 American Fertility Society 160, 161, 162 androgen overproduction 22, 28, 29 anti-β2-glycoprotein-1 (anti-β2-GP-1) 54 anti-Müllerian hormone 46 antinuclear antibody (ANA) 53–4 antiphospholipid antibodies (aPLs) 54, 56, 227 antiphospholipid syndrome (APS) 54, 226–7 antithrombin 9 antral follicle count 46, 208 L-arginine 212 aromatase inhibitors 47, 48, 213 aspirin 213, 227, 228

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bad news, presenting to couples 233–9 Barker’s hypothesis, fetal origin of adult disease 92 T4-binding globulin (BG) 26 birth defects, prevention 195–9 body mass index (BMI) 87–93 ‘cut-off’ in obese patients? 92–3 bone mineral density (BMD) 57 botulinum toxin 81–2 breast cancer 45 bromocriptine 20, 29 celiac disease 186 cervical atresia 159, 167 cervical atypical smear 58 cervical cancer 44 chemotherapy alkylating agents 43 gonadotoxicity 43, 45–6 in male patients 42 clinical pregnancy rate (CPR) 93, 94–6, 107, 118, 120–1, 124, 128 clomiphene citrate 170 ‘coasting’ 7, 11 combined pituitary hormone deficiency (CPHD) 20 compression stockings 12 computed tomography (CT) scan 141 congenital adrenal hyperplasia (CAH) 22–4 congenital uterine abnormalities 159–74 American Fertility Society classification 160, 161 ART options 172–3 bicornuate uterus 161, 162–4, 168 cervical atresia 159, 167 didelphic uterus 161, 162, 163 embryo implantation rate 160 fetal survival rates 160 hypoplastic uterus 166 septate uterus 161, 164–6 T-shaped uterus 166 treatment outcomes 166 unicornuate uterus 160–1, 163, 168 uterine aplasia 167 see also tubal factor infertility connective tissue disease 52

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controlled ovarian hyperstimulation (COH) 55, 104, 107, 125, 129 with IUI 104 corticotropin releasing hormone (CRH) 22 CRH gene 23 cryopreservation conditions for storage 44, 47 embryo 45, 48 ovarian tissue 24, 45, 48 semen 42, 76 Cushing’s syndrome and disease 22–4, 25, 88 cyclophosphamide therapy oral 52 pulse (CPT) 52 cystectomy 107–8 dalteparin 11 deep venous thrombosis (DVT) 3, 8–9 ‘defloration phobia’ 82 dehydroepiandrosterone (DHEA) 213 dehydroepiandrosterone sulfate (DHEAS) 23 dexamethasone 23–4, 25, 212 suppression test 23 diabetes mellitus 31–3, 35, 37 insulin dependent (IDDM) 31, 37 non-insulin dependent (NIDDM) 32, 37 diethylstilbestrol (DES) 159, 166, 191 dihydrotestosterone 28 dopamine agonists 29 doxorubicin, ABVD regimen 43 ectopic pregnancy 118, 122, 130–1, 160–1 ejaculate, poor quality 80 embryo arrest rate 106 embryo transfer (ET) 53–6, 105, 124, 139–40, 148–54, 170 ‘end of treatment’ consultation emotional challenges 234–5 coping without treatment 234 life without children 234–5 facilitating the process 237–9 couple’s future beyond IVF 238–9 establishing aims 237 positive aspects 238

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setting the context 237–8 supportive follow-up 238 factors influencing patients’ reactions 235–7 cognitive 236–7 demographic 235 emotional and relational 236 endocrine disease 19–37 endometrial cancer 45 endometriosis 103–11, 168 clinical pregnancy rate 107 effects of previous ovarian surgery 106 ovarian stimulation 108–10 subfertility 103–4 treatments 104 enoxaparin 11, 227 epilepsy 186 erectile dysfunction (ED) 74, 75, 78 estrogen replacement therapy (ERT) 57 estrogens 4, 7, 22, 46, 57, 63 European Society of Human Reproduction and Embryology (ESHRE) 225 extrachromosomal inheritance 198 factor II A20210 mutation 9 factor V Leiden mutation 9 fetal alcohol syndrome (FAS) 187 fetal origin of adult disease 92 fibroids 139–54 clinical studies 147 diagnosis 140–1, 144, 146 location 147–8 miscarriage rates 148–9 myomectomy evaluation 153 treatment outcomes 149–53 types 140–1, 142–7 fluorescence in situ hybridization (FISH) screening 225–6 folic acid supplementation 12, 186 follicle stimulating hormone (FSH) 21, 45, 47, 63, 90 see also poor responders follow-up acromegaly 21 congenital uterine abnormalities 170–1

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Cushing’s disease 25 diabetes 33 endometriosis 110 HIV 65–6 hydrosalpinx 132–3 hyperprolactinemia 30 hypopituitarism 31 malignant disease 47 poor responders to FSH 214 recurrent miscarriage 228–9 sexual dysfunction 84 systemic lupus erythematosus 57 thyroid dysfunction 27–8 trauma and PTSD 84 venous thromboembolism VTE 13 Food and Drug Administration (FDA) classification, teratogenic drugs 192, 193 gamete intrafallopian transfer (GIFT) 164 genetic abnormalities 195–9 Down’s syndrome 197 extrachromosomal inheritance 198 Online Mendelian Inheritance in Man (OMIM) database 197 preimplantation diagnosis 199 genetic screening, preimplantation 224–6 glucocorticoids 212–13 glucose intolerance 21 anti-β2-glycoprotein-1 (anti-β2-GP-1) 54 gonadotoxicity, chemotherapy 43, 45–6, 52 gonadotropin releasing hormone antagonists 45, 46, 48, 105 poor responders to FSH 210–11 gonadotropin releasing hormone (GnRH) 19, 20, 21, 22, 29 gonadotropin releasing hormone agonists (GnRH-a) 52–3, 108–10 long versus short protocols 109 poor responders to FSH 210 prolonged down-regulation 109–10 growth hormone (GH) 19–21, 33, 208, 211 growth hormone–somatostatin system 19–21 health, WHO definition 87 hematocrit (hct) 5, 6, 7 hematometra 160

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hemoglobin 5, 6 hemostatic parameters 5, 6, 7 heparin-induced thrombocytopenia 12 highly active antiretroviral therapy (HAART) 61, 68 HIV seropositive women patient selection 64–5, 68 special needs 66–9 transmission risk to fetus 68 treatment methods 68 Hodgkin’s disease 42 hormone replacement therapy (HRT) 57 human chorionic gonadotropin (hCG) 4, 5, 11, 21, 26, 63 human immunodeficiency virus (HIV) 61–70 clinical precautions 63, 66, 68 clinical results 67 legal and social considerations 69–70 pretreatment recommendations and tests 64–5, 68 seropositive women, special needs 66–9 transmission risk to fetus 68 ultrasensitive HIV-RNA polymerase chain reaction 65 US CDC recommendations 63 Human Rights Act 97 hydrosalpinx 117–35 clinical studies 118, 120–1, 122, 123, 124, 126, 128, 130–1 ectopic pregnancy rates 118, 122 fluid properties 117–18 versus other tubal factors 117–18 salpingectomy 119, 123, 124, 127, 129, 130–1 transvaginal aspiration 123–5, 126 tubal occlusion 119, 124, 127, 129 17-hydrosteroid excretion level 23 hypercoagulability 4, 5, 7 hypercortisolemia 22–3, 30, 35 hyperhomocysteinemia 8 hyperinsulinemia 28 hyperprolactinemia 28–30, 34, 36 hypertension 54 hyperthyroidism 26, 35 hypertonic pelvic floor 74 hypogonadotropic hypogonadism 44 hypopituitarism 30–1, 35, 36 hypothalamic–pituitary–adrenal (HPA) axis 21–5, 33, 34

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hypothalamic–pituitary–ovarian (HPO) axis 19 hypothalamic–pituitary–thyroid (HPT) axis 25–8, 34, 35 hypothyroidism 26, 35 hysterosalpingography (HSG) 127, 141, 143, 159, 162, 164, 166, 169 hysteroscopy 143, 145, 151, 164–5, 168 inhibin B 46, 208 insulin-like growth factor I (IGF-I) 19–20, 208 insulin resistance 227–8 intracytoplasmic sperm injection (ICSI) 53–4, 62, 63, 90, 170, 208, 224 intrauterine insemination (IUI) with controlled ovarian hyperstimulation 104 versus IVF for HIV couples 62 ‘It’s time to stop’ 233–9 late-onset congenital adrenal hypertrophy (LoCAH) 88 letrozole 213 leukemia 43 live-birth rate (LBR) 93, 94–6, 119 long-haul flight, DVT risk 12 low desire 74 low-molecular-weight heparin (LMWH) 11–12, 227 luteinizing hormone (LH) 21, 26 lymphoma 43 magnetic resonance imaging (MRI) 21, 141 malignant disease 41–8 principal treatment considerations 48 Mallory–Weiss syndrome 54 management of cycle acromegaly 21 congenital adrenal hyperplasia 25 congenital uterine abnormalities 170–1 diabetes 33 ‘end of treatment’ consultation 239 fibroids 153–4 human immunodeficiency virus 63–4 hydrosalpinx 125, 132, 133–5 hyperprolactinemia 29 hypopituitarism 31 malignant disease 46–7 poor responders to FSH 208–13, 214–15

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recurrent miscarriage 226–8, 229 sexual dysfunction 78–84 systemic lupus erythematosus 56–7 thyroid dysfunction 27 venous thromboembolism 10–12 mean cell volume (MCV) 5 medroxyprogesterone 44 metformin 33, 227–8 5,10-methylenetetrahydrofolate reductase (MTHFR) 8–9 metroplasty 163, 166, 169 mifepristone 24 miscarriage, recurrent 159, 163, 166, 221–9 adjuvant therapy during IVF 226–8 causes 221 genetic screening 226–6 surrogacy 226 miscarriage rates 222, 223 Müllerian inhibitory substance (MIS) 208 National Institute for Clinical Excellence (NICE) guidelines on fertility assessment 93 National Survey of Family Growth (US) 223 natural killer (NK) cells 228 neural tube defect (NTD) 186 non-steroidal anti-inflammatory drugs (NSAIDs) 56 obesity 8, 10, 32, 87–97 birth weights 91–2 BMI ‘cut-off’? 92–3 clinical studies of pregnancy rates and LBR 93, 94–6 diabetes 32, 88 ethnic/geographic variations 88 indices 87 medical disorders 89 NICE guidelines on fertility assessment 93 polycystic ovarian syndrome (PCOS) 88 pregnancy outcomes 90–1 psychological aspects 92 reproductive disorders 88–9 venous thromboembolism risk 8, 10 Oliver–McFarlane syndrome 20 Online Mendelian Inheritance in Man (OMIM) database 197

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oocyte retrieval 105 ophthalmologic examination 21 oral contraceptives 4–5, 57, 211 orgasm dysfunction (OD) 74, 75, 79–80 lifelong emotionally inhibited 80 medication induced 79 neurological damage 79 situational 80 ovarian hyperstimulation syndrome (OHSS) 3, 7–9, 10–12, 55 ovarian stimulation 108–10 ovarian volume 46, 208 panhypopituitarism 30–1, 35, 36 Papanicolaou smear 58 phosphodiesterase 5 (PDE5) inhibitors 78 plasma HIV RNA viral counts 63 plasma total homocysteine (tHcy) 9 plasminogen concentration 6 platelet count 6, 12 polycystic ovarian syndrome (PCOS) 88, 212 poor responders to FSH 205–15 adjuvant treatments 211–12 age related decline 205–6 factors associated 207 FSH dose 209–10, 214 GnRH agonists 210 GnRH antagonists 210–11 management issues 215 oral contraceptives 211 stimulation regimen change 209 post-thrombotic syndrome 3 post-traumatic stress disorder (PTSD) 74, 76, 77, 82–4 medication 83 trauma types 76, 77 treatment strategies 82–3 preconception care 181–99 birth defects, prevention 195–9 care components 184 counseling 183–4, 188–9 health promotion 186–8 intervention 190–5 out-patient organization 182, 183

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‘Preconceptional Health Appraisal’ 184–5 risk assessment 184–6 screening checklist, internet 186 see also genetic abnormalities ‘Preconceptional Health Appraisal’ 184–5 pregnancy physiological adaptations to 189 preimplantation genetic diagnosis (PGD) 199, 225–6 preimplantation genetic screening (PGS) 224–6 premature ejaculation 73 premature ovarian failure (POF) 52, 57 preparing the patient acromegaly 20–1 assessing thrombosis risk 7–12 congenital uterine abnormalities 167–70 diabetes 32 HIV 63 hydrosalpinx 127–9 hypercortisolemia 23–4 hyperprolactinemia 29 hypopituitarism 31 malignant disease 45–6 poor responders to FSH 207–8 sexual dysfunction 75–7 systemic lupus erythematosus 56 thyroid dysfunction 26–7 preterm delivery 159, 161, 163 pretreatment recommendations and tests 64–5 progestin levels 22 prolactin (Prl) 28, 35 Prop 1 mutation 20 protein S deficiency 9 pulmonary embolism (PE) 9 pyridostigmine 212 radiotherapy 43 reciprocal translocations 224–5 5α-reductase 28 renal disease 53–4 renal malformation 168 retrograde ejaculation (RE) 78–9

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salpingectomy 119, 123, 124, 127, 129, 130–1 selective serotonin reuptake inhibitor (SSRI) antidepressants 79 semen processing for HIV patients 66 sexually dysfunctional couples 73–85 ‘first do no harm’ 77–8 smoking, tobacco 8, 88, 187–8 social considerations HIV 69–70 sexually dysfunctional couples 74, 75–7, 78 somatostatin 20 sperm washing 62, 63 steroids 228 surrogacy 226 systemic lupus erythematosus (SLE) 51–8 screening 55–6 tamoxifen 47 teratogenic drugs 190–5 clinically used drugs 194–5 drug use by fathers 195 FDA classification 192, 193 first trimester 190 testicular sperm extraction (TESE) 224 thalidomide 191 thrombophilia DVT risk 8–9 recurrent miscarriage 227 screening 10, 11 thrombosis 3–14 thyroid stimulating hormone (TSH) 26 thyroxine (T4) 26 tri-iodothyroxine (T3) 26 tobacco 8, 88, 187–8 trans-sphenoidal surgery 21, 29 transvaginal aspiration for hydrosalpinx 123–5, 126 trauma related disorders 74, 76, 77, 82–4 emergencies 83 medication 83 treatment strategies 82–3 tri-iodothyroxine (T3) 26 D-tryptophan-6-gonadotropin releasing hormone agonist (D-Trp6-GnRH-a) 52

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tubal factor infertility 117–18 tubal occlusion 119, 124, 127, 129 ultrasensitive HIV-RNA polymerase chain reaction 65 ultrasound imaging 141, 142–3, 150, 152, 165, 168, 174 unfractionated heparin 12 urinary free–cortisol excretion level 23 US Centers for Disease Control and Prevention (CDC) recommendations for HIV 63 uterine abnormalities American Fertility Society classification 160, 161, 162 see also congenital uterine abnormalities uterine cavity assessment 63 uterine fibroids see fibroids vaccines 188 WHO recommendations 188 vaginismus 74–5, 80–2 anesthesia 81 medication 81–2 self-hypnosis/relaxation 81 self-management 81 vascular damage 4 venlafaxine 79 venous stasis 4 venous thromboembolism (VTE) incidence 3, 7 risk factors 3–12 Virchow, predisposing mechanisms for DVT 4 World Health Organization (WHO) obesity definitions 87, 93 vaccination during pregnancy, recommendations 188

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