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Help your patients through the maze of infertilitytreatments Infertility is suffered by around 1 in 7 couples and can be asource of confusion for both partners, providing high stress onrelationships. 25% of cases are explained through male Infertility,50% through female Infertility, whilst 25% are generallyunexplained. The possible causes and solutions are many andcomplex. Infertility, one of the first in the new Gynecology in Practiceseries, assists gynecologists and family practitioners to bettercare for their patients who have trouble conceiving. The authorsprovide a strong focus on effective diagnosis and management.Following a review of the factors that affect fertility,Infertility takes a practical approach to: * Evaluation of fertility * Management and treatment * Complications * Pre-implantation screening * Fertility preservation Gynecology in Practice The Gynecology in Practice series provides clinical 'in theoffice' or 'at the bedside' guides to effective patient care forgynecologists. The tone is practical, not academic, with authorsoffering guidance on what might be done and what should be avoided.The books are informed by evidence-based practice and feature: * Algorithms and guidelines where they are appropriate * ''Tips and Tricks' boxes - hints on improvingoutcomes * 'Caution' warning boxes - hints on avoidingcomplications * 'Science Revisited' - quick reminder of the basic scienceprinciples * Summaries of key evidence and suggestions for furtherreading

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Table of Contents

Cover

Table of Contents

Half title page

Title page

Copyright page

Series Foreword

Preface

Contributors

1 Factors Affecting Fertility

Weight

Age

Smoking

Caffeine

Alcohol

Summary

2 Evaluation of the Infertile Couple

Introduction

Evaluation of the female

Evaluation of the male

Additional testing of the infertile couple

Summary

3 Diagnosis and Management of Tubal Factor Infertility

Introduction

Diagnosis of tubal infertility

Management of tubal infertility

Tubal surgery versus in-vitro fertilization and embryo transfer

Summary

4 Diagnosis and Management of Uterine Infertility

Introduction

Evaluation of the uterus

Congenital abnormalities

Acquired anomalies

Summary

5 Diagnosis and Management of Infertility Due to Endometriosis

Introduction

Clinical presentation

Pathogenesis of endometriosis

Diagnosis of endometriosis

Imaging techniques

Treatment

Summary

6 Diagnosis and Management of Infertility Due to Anovulation

Introduction

Classification of anovulation

Diagnosis of anovulation

Treatment of ovulatory disorders

Summary

7 Diagnosis and Management of Infertility Due to Diminished Ovarian Reserve

Introduction

Ovarian physiology and the ovarian follicle pool

Female reproductive aging

Diminished ovarian reserve: oocyte quantity versus quality

Diagnosis of diminished ovarian reserve

Treatment of diminished ovarian reserve

Summary

8 Diagnosis and Management of Male Infertility

Introduction

Investigating the infertile male

Treating male infertility: the role of non-ART treatments

Treating male infertility by assisted reproductive techniques

Surgical sperm recovery for treating male infertility

Summary

9 Diagnosis and Management of Unexplained Infertility

Introduction

Basic fertility work-up in subfertile couples

Prognosis of unexplained subfertility

Management

ART

Summary

10 Endocrine Disorders and Infertility

Pituitary disorders that affect reproduction

Hyperprolactinemia and prolactinomas

Acromegaly

Thyroid disorders: hyperthyroidism and hypothyroidism

Adrenal disorders: Cushing syndrome and congenital adrenal hyperplasia

Summary

11 Physiologic Basis of Ovulation Induction

Introduction

Physiological basis of ovulation

WHO classification of anovulation

Injectable gonadotropin preparations

Clomiphene citrate

Aromatase inhibitors

Summary

12 Intrauterine Insemination

Introduction

Indications for IUI see Table 12.1

Work-up before IUI

Contraindications

Natural cycles or controlled ovarian hyperstimulation?

Semen parameters and processing

IUI in practice: description of the procedure

IUI protocols

Intrauterine versus other forms of artificial insemination

Risks and complications of IUI see Table 12.2

Outcomes, benefits, and limits

Summary

13 In-vitro Reproductive Technologies

Introduction

Laboratory procedures after stimulation

Assessment of the embryo

Embryo freezing

Summary

14 Egg Donation and Surrogacy

Introduction

Recipients

Donors

Cycle management

Clinical results

Ethics

Surrogacy

Summary

15 Complications of Infertility Treatment

Introduction

Acute complications

Long-term complications

Summary

16 Preimplantation Genetic Diagnosis

Introduction

Embryo biopsy

PGD for monogenic disorders

HLA typing

Chromosomal rearrangements

Preimplantation genetic screening

Ethical aspects of PGD

Advances in PGD and future perspectives

Summary

17 Fertility Preservation

Introduction

Fertility preservation options involving cryopreservation of embryos or oocytes

Surgical approach to fertility preservation

Medical approach to fertility preservation

Individualization of fertility preservation

Logistics of fertility preservation

Summary

18 Infertility Treatment: Varying Approaches Across Continents

Introduction

Utilization and availability of ART

Reimbursement of ART

Regulation of ART

ART outcome monitoring and success rates

Summary

Index

Infertility

This edition first published 2011, © 2011 by Blackwell Publishing Ltd

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The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Infertility / edited by Emre Seli.

p. ; cm.—(Gynecology in practice)

Includes bibliographical references and index.

ISBN 978-1-4443-3353-4 (pbk. : alk. paper)

 1. Infertility. I. Arici, Aydin. II. Series: Gynecology in practice.

[DNLM: 1. Infertility–diagnosis. 2. Infertility–therapy. 3. Reproductive Techniques, Assisted. WP 570]

RC889.S448 2011

616.6′92–dc22

2010039156

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF 9781444393934; Wiley Online Library 9781444393958; ePub 9781444393941

Series Foreword

In recent decades, massive advances in medical science and technology have caused an explosion of information available to the practitioner. In the modern information age, it is not unusual for physicians to have a computer in their offices with the capability of accessing medical databases and literature searches. On the other hand, however, there is always a need for concise, readable, and highly practicable written resources. The purpose of this series is to fulfill this need in the field of gynecology.

The Gynecology in Practice series aims to present practical clinical guidance on effective patient care for the busy gynecologist. The goal of each volume is to provide an evidence-based approach for specific gynecologic problems. “Evidence at a glance” features in the text provide summaries of key trials or landmark papers that guide practice, and a selected bibliography at the end of each chapter provides a springboard for deeper reading. Even with a practical approach, it is important to review the crucial basic science necessary for effective diagnosis and management. This is reinforced by “Science revisited” boxes that remind readers of crucial anatomic, physiologic or pharmacologic principles for practice.

Each volume is edited by outstanding international experts who have brought together truly gifted clinicians to address many relevant clinical questions in their chapters. The first volumes in the series are on Chronic Pelvic Pain, one of the most challenging problems in gynecology, Disorders of Menstruation, Infertility, and Contraception. These will be followed by volumes on Sexually Transmitted Diseases, Menopause, Urinary Incontinence, Endoscopic Surgeries, and Fibroids, to name a few. I would like to express my gratitude to all the editors and authors, who, despite their other responsibilities, have contributed their time, effort, and expertise to this series.

Finally, I greatly appreciate the support of the staff at Wiley-Blackwell for their outstanding editorial competence. My special thanks go to Martin Sugden, PhD; without his vision and perseverance, this series would not have come to life. My sincere hope is that this novel and exciting series will serve women and their physicians well, and will be part of the diagnostic and therapeutic armamentarium of practicing gynecologists.

Aydin Arici, MD

Professor

Department of Obstetrics, Gynecology, and Reproductive Sciences

Yale University School of Medicine

New Haven, USA

Preface

The rapid pace of scientific and technological discovery has greatly influenced the care of the infertile couple. Diagnostic and therapeutic options for infertile couples have undergone dramatic evolution in the past three decades, touching the lives of couples for whom few options existed previously. More than 30 years after the birth of the first child conceived by assisted reproductive technologies, we are now able to stimulate ovaries to obtain multiple oocytes, extract sperm from testes of men with severe infertility, inject sperm into oocytes to achieve fertilization, and biopsy embryos for diagnostic purposes. With increasingly complex modalities available for diagnosing and treating infertility comes the need for a clear, concise, readable, and practical text to serve as a resource for providers.

This text has been written with the aim of providing a clinical “in the office” or “at the bedside” guide for effective patient care for obstetrician gynecologists and trainees. Written by experts in the field of reproductive endocrinology and infertility, this book provides cutting-edge and evidence-based suggestions regarding common and important clinical problems in reproductive medicine. A standard format is adopted throughout the text, intended to streamline access to critical information. Practical guidance is provided through the use of sensible algorithms and treatment guidelines. Key evidence is summarized in “Evidence at a Glance” boxes; “Tips & Tricks” boxes provide hints on improving outcomes, and “Caution” boxes offer suggestions for avoiding potential problems and pitfalls. In addition, “Science Revisited” boxes provide quick reminders of the basic scientific principles necessary to more fully understand the clinical issues at hand.

The overall format of the volume is similarly aimed at facilitating access to information. Following a discussion of factors affecting fertility and an overview of the evaluation of the infertile couple, the diagnosis and management of specific causes of infertility are presented. Treatment options available for infertile couples (including ovulation induction, intrauterine insemination, in-vitro reproductive technologies, and oocyte donation/gestational surrogacy) and complications of infertility treatments are then discussed. Finally, up-to-date reviews of preimplantation genetic screening/diagnosis and fertility preservation are provided; two areas of extensive research in the field of infertility. The volume concludes with a chapter comparing the different approaches to diagnosis and treatment of infertility in different parts of the world, emphasizing that there are differences among practices and resources across continents (and that there is often “more than one way to skin a cat”).

I would like to thank all the authors for their outstanding contributions. I would also like to thank Martin Sugden, Lewis O’Sullivan, and Michael Bevan from Wiley, who made this book possible. I hope the readers will find the book a useful and concise review of a rapidly evolving field of medicine.

Emre Seli

New Haven

1 September 2010

Contributors

Ashok Agarwal, PhD, Director, Center for Reproductive Medicine; Professor, Lerner College of Medicine, Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio, USA

Baris Ata, MD, Clinical and Research Fellow in Reproductive Endocrinology and Infertility, McGill Reproductive Centre, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, McGill University, Montreal, Canada

Robert F. Casper, MD, Division of Reproductive Sciences, University of Toronto, Canada; Camille Dan Family Research Chair in Translational Cell Biology and Senior Scientist, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Medical Director, Toronto Centre for Advanced Reproductive Technologies, Tornonto, Canada

Deirdre A. Conway, MD, Fellow, Reproductive Endocrinology and Infertility, University of California, Los Angeles, California, USA

Alan B. Copperman MD, Director, Division of Reproductive Endocrinology and Infertility; Vice-Chairman and Clinical Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, Mount Sinai Medical Center, New York; Co-Director, Reproductive Medicine Associates of New York, New York, USA

Luisa Delle Piane, MD, Reproductive Medicine and IVF Unit, University of Turin, Torino, Italy

Juan Antonio Garcia Velasco, MD, PhD, Associate Professor of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid; Director, IVI-Madrid, Spain

Alfredo Guillén Anton Instituto Valenciano de Infertilidad, IVI Madrid, Madrid, Spain.

Amanda N. Kallen Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA

Caleb B. Kallen, MD, PhD, Assistant Professor, Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Emory University School of Medicine, Atlanta, Georgia, USA

Sonya Kashyap, MD, MSc Epi, Reproductive Endocrinology and Infertility, University of California San Francisco, California, USA

Joshua U. Klein, MD, Clinical Fellow, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Columbia University, New York, USA

Pinar H. Kodaman, MD, PhD, Assistant Professor, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, New Haven, Connecticut, USA

Maria D. Lalioti, PhD, Assistant Professor, Department of Obstetrics, Gynecology and Reproductive Sciences,Yale University School of Medicine, New Haven, Connecticut, USA

Cornelis B. Lambalk, MD, PhD, Scientific Director, Department of Reproductive Medicine, VU University Medical Center, Amsterdam, The Netherlands; Guest Professor Gynecology and Urology, University of Gent, Belgium

Janelle Luk, MD, Clinical Fellow, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA

Michelle L. Matthews, MD, Associate Director, Reproductive Endocrinology, Carolinas Medical Center, Charlotte, North Carolina, USA

Samuel A. Pauli, MD, Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, Emory University School of Medicine, Atlanta, Georgia, USA

Beth W. Rackow, MD, Assistant Professor, Reproductive Endocrinology and Infertility, Yale University School of Medicine, New Haven, Connecticut, USA

Alberto Revelli, Reproductive Medicine and IVF Unit, University of Turin, Torino, Italy

Paolo Rinaudo, MD, PhD, Reproductive Endocrinology and Infertility, University of California San Francisco, California, USA

Mitchell Rosen, MD, HCLD, Reproductive Endocrinology and Infertility, University of California San Francisco, California, USA

Joelle Safi, MD, Intern, Center for Reproductive Medicine, Cleveland Clinic, Cleveland, Ohio, USA

Denny Sakkas, PhD, Associate Professor, Director of ART Laboratories, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine; Chief Scientific Officer, Molecular Biometrics Inc., New Haven, Connecticut, USA

Mark V. Sauer, MD, Professor and Vice Chairman, Department of Obstetrics and Gynecology, College of Physicians & Surgeons, Columbia University, Chief Division of Reproductive Endocrinology, Columbia University Medical Center, New York, USA

Emre Seli, MD, Associate Professor of Obstetrics, Gynecology, and Reproductive Sciences, Associate Director for Research, Division of Reproductive Endocrinology and Infertility, Director, Oocyte Donation and Gestational Surrogacy Program, Yale University School of Medicine, New Haven, Connecticut, USA

Mousa I. Shamonki, MD, FACOG, Director, In Vitro Fertilization and Assisted Reproduction, University of California, Los Angeles, California, USA

Rakesh K. Sharma, MD, Center for Reproductive Medicine, Glickman Urological & Kidney Institute, and Ob/Gyn and Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio, USA

Enrique Soto, MD, Fellow, Division of Gynecologic Minimally Invasive Surgery, Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, USA

Pieternel Steures, MD, PhD, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, the Netherlands

Hugh S. Taylor, MD, Professor of Obstetrics, Gynecology, and Reproductive Sciences; Director, Division of Reproductive Endocrinology and Infertility, Yale University School of Medicine, New Haven, Connecticut, USA

Herman Tournaye, MD, PhD, Professor of Developmental Biology and Reproductive Sciences, Centre for Reproductive Medicine, VUB University Hospital, Brussels, Belgium

Bulent Urman MD, Head, Obstetrics and Gynecology, American Hospital, Istanbul, Turkey

Jan Willem van der Steeg, MD, PhD, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, the Netherlands

1

Factors Affecting Fertility

Enrique Soto1 and Alan B. Copperman2

1Mount Sinai School of Medicine, New York, NY, USA

2Mount Sinai Medical Center and Reproductive Medicine Associates, New York, NY, USA

In order to take optimal care of patients who seek preconceptional counseling and of patients who present with infertility, the treating physician needs to have an extensive knowledge of the multiple factors that influence human reproduction.

Fecundability and time to pregnancy (TTP) are used in the literature as markers of fertility. Fecundability is defined as the probability of conceiving in a single menstrual cycle while TTP is the length of time in months that it takes a couple to conceive. Infertility is defined as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse in a woman under the age of 35 years and 6 months without success in a woman 35 or older.

Although the current literature describes a number of factors that are likely to play a role in the ability that a patient or couple has to conceive, it is important to highlight that evidence from randomized controlled trials is lacking for the majority of these regarding quantification and certainly causality of each factor.

In this chapter we summarize the most relevant factors that affect fertility, making evidence-based recommendations where appropriate to better counsel our patients to improve their ability to conceive. Our recommendations will include the practice committee opinions of the American Society for Reproductive Medicine (ASRM) and the American College of Obstetricians and Gynecologists (ACOG) as leading institutions in reproductive medicine and women’s health in the United States.

Weight

Body mass index (BMI) is used in the literature as an objective marker to classify underweight, overweight and obesity in adults. BMI is a calculated measurement that compares a person’s weight and height and it is defined as the weight in kilograms divided by the square of the height in meters (kg/m2). Even though there is a growing debate on the possible need to develop different BMI cut-off points for each ethnic group, BMI is applicable to all ethnic groups, is the same for both sexes and is age-independent.

The World Health Organization (WHO) and the National Institutes of Health (NIH) describe underweight as a BMI < 18.5, normal weight as BMI 18.5–24.9, overweight as BMI 25–29.9 and obesity as BMI > 30.

TIPS & TRICKS

Always calculate and document your patient’s BMI in the first office visit (weight in kilograms divided by the square of the height in meters) and determine if she falls under the category of underweight (BMI < 18.5), normal weight (BMI 25–29.9), overweight (BMI 25–29.9) or obese (BMI > 30). Appropriate counseling should follow.

BMI should then be calculated in the follow-up visits to determine any changes as well as to track response to treatment or interventions.

Fecundability has been found in multiple studies to be lower at the extremes of BMI in patients trying to conceive spontaneously. This finding was confirmed in a recent prospective cohort study by Wise et al., in which a longer TTP was seen in women who were overweight, obese and very obese (BMI ≥ 35), compared with normal weight women. Additionally being underweight (BMI < 20) was associated with reduced fecundability among nulliparous women.

Although some authors have linked male obesity with subfecundity, the evidence is not compelling and there are no randomized controlled studies to address this association. Male obesity was not linked to subfecundity in the recent prospective cohort study by Wise et al.

The direct effect of being overweight and obese on assisted reproduction technologies (ART) is less clear than for spontaneous pregnancies. In a meta-analysis by Maheshwair et al., women with a BMI ≥ 25 had a lower chance of pregnancy following in vitro fertilization (IVF) [odds ratio (OR) 0.71], required a higher dose of gonadotropins and had an increased miscarriage rate (OR 1.33) in comparison to women of normal weight. In a recent study by Bellver et al., implantation, pregnancy and live birth rates were lower in obese women; in fact, pregnancy and live birth rates were reduced progressively with each unit of BMI, independent of embryo quality, suggesting an alteration in the uterine environment as a likely factor in these patients.

Evidence is accumulating that suggests that effective treatment of women with elevated BMI may improve reproductive outcome. Nonsurgical treatment for patients with overweight and polycystic ovary syndrome (PCOS) was shown to improve fertility in patients that lost at least 5% of their weight in a small prospective study by Crosignani. Surgical treatment may show benefit as well, as evidenced by a recent meta-analysis by Merhi which concluded that although “the majority of the present data tend toward reporting an improvement in fertility status after surgical weight loss, it remains unclear whether this is a direct result of the significant weight reduction per se”.

Recommendations

All patients should be advised to follow a healthy diet according to the United States Department of Agriculture (USDA) guidelines. Patients should consume a variety of nutrient-dense foods and beverages within and among the basic food groups while choosing foods that limit the intake of saturated and trans fats, cholesterol, added sugars, salt and alcohol.

ACOG recommends folic acid supplementation of 400 µg/day on all women capable of becoming pregnant, since it has shown to reduce the occurrence and recurrence of neural tube defects.

Weight loss and exercise should be advised for all women who are overweight or obese for all the associated health benefits.

There is not enough evidence to recommend surgical treatment for obesity on the ground of fertility improvement. Patients who wish to pursue bariatric surgery should have appropriate medical management with an expert in the field to monitor possible nutritional deficiencies and other complications.

TIPS & TRICKS

Refer your patients to the USDA website to obtain detailed information on following a healthy diet with help of the USDA Food Guide and the DASH Eating Plan:

http://www.health.gov/DietaryGuidelines/dga2005/document/

Age

The incidence of infertility increases with advancing maternal age. In a prospective study by Dunson et al., the percentage of infertility was 8% for women aged 19–26 years, 13–14% for women aged 27–34 years and 18% for women aged 35–39 years.

There is also evidence that the age of the male partner may affect fertility after the age of 35 years. In the study by Dunson et al., the proportion of couples failing to spontaneously conceive within 12 cycles increased from 18% when the male partner was 35 years old to 28% when the male partner was 40.

There is a similar decline in the success of IVF as the age of patient increases. In 2007, the percentage of transfers of fresh embryos from nondonor oocytes resulting in live births in the United States was 46.1 for patients <35 years of age and showed a progressive decline to 16.4 in patients 41–42 years of age.

Recommendations

Although according to the ASRM guidelines a patient is diagnosed with infertility after 12 months or more of being unable to achieve a successful pregnancy, earlier evaluation and treatment may be justified based on medical history and physical findings and is warranted after 6 months for women over age 35 years.

The ASRM additionally states that “times to conception increases with age. For women over age 35 years, consultation with a reproductive specialist should be considered after 6 months of unsuccessful efforts to conceive.”

Important reproductive potential and ovarian reserve tests that are commonly performed by specialists include a sonogram to assess general pelvic anatomy and basal antral follicular count (BAFC) as well as the day 3 serum biomarkers follicle stimulating hormone (FSH) and estradiol.

As part of the counseling process for treatment of infertility, the reproductive specialist should be familiar with the new and innovative options that are available for each individual patient, including options that halt the reproductive aging process such as oocyte cryopreservation.

Smoking

Approximately 30% of reproductive age women and 35% of reproductive age men in the United States smoke, and up to 13% of infertility may be attributable to cigarette smoking. Most studies that address the effect of active smoking of the female partner on fertility to date report a decreased fecundability independent of other confounding influences. In the largest available population study by Hull et al., the increasing delay to conception correlated with increasing daily numbers of cigarettes smoked.

In a meta-analysis by Waylen et al., which included 22 studies, patients who smoked had significantly lower odds of live birth per cycle (OR 0.54), significantly lower odds of clinical pregnancy per cycle (OR 0.56), significantly higher odds of spontaneous abortion (OR 2.65) and significantly higher odds of ectopic pregnancy (OR 15.69).

The ASRM in the Practice Committee Opinion on Smoking and infertility concluded that smoking (1) appears to accelerate the loss of reproductive function, (2) may advance the time of menopause by 1–4 years and (3) is associated with an increased risks of spontaneous abortion, ectopic pregnancy and gamete mutagenesis. Additionally, smokers require nearly twice the number of IVF attempts to conceive as nonsmokers.

A definite causality between male partner smoking and infertility has not been proven but there are data that suggest that there may be adverse effects in male smokers, as well. Smokers have an average 23% decrease in sperm concentration and 13% decrease in sperm motility in comparison to nonsmokers.

The largest meta-analysis to date on the effect of female and male smoking on IVF included 22 studies and despite the variations in results between studies, there was compelling evidence that smoking had a negative influence on IVF outcome.

Recommendations

The United States Public Health Service (USPHS) guidelines recommend that advice to quit and brief counseling be done at all or nearly all office visits by a smoker, regardless of the reason for the visit.

TIPS & TRICKS

The USPHS and ACOG recommend using the “5 A’s” algorithm for brief counseling in the office:

Ask about smoking status

Advise smokers to quit

Assess their readiness to quit

Assist them with their smoking cessation effort

Arrange follow-up visits or contact

TIPS & TRICKS

Be familiar with the different tools available to help your patient quit, including:

Telephone counseling (1–800-QUITNOW)Pharmaceutical aids:*

Nonprescription aids:

Nicotine replacement therapy [pregnancy class D]:

Gum, lozenge and transdermal patch

Prescription aids: Nicotine replacement therapy (nasal spray and oral inhaler [pregnancy class D]), bupropion (pregnancy class C) and varenicline (pregnancy class C)

Computer programsWebsites:

http://www.smokefree.gov/

http://www.cdc.gov/tobacco/

* ACOG states that “The use of nicotine replacement products or other pharmaceuticals for smoking cessation aids during pregnancy and lactation have not been sufficiently evaluated to determine their efficacy or safety. Nicotine gum, lozenges, patches, inhalers, and special-dose antidepressants that reduce withdrawal symptoms, such as bupropion, should be considered for use during pregnancy and lactation only when nonpharmacologic treatments (e.g., counseling) have failed.”

Caffeine

Caffeine consumption is common in women of reproductive age, as shown in a recent study of women between the ages of 16 and 45 where the mean consumption of caffeine was 173.95 mg/day (1 cup of coffee is approximately equivalent to 100 mg of caffeine). Eighteen percent of women exceeded caffeine guidelines and consumed 300 mg or more of caffeine.

Subfertility has been linked to heavy caffeine consumption (>500 mg). A European multicenter study that controlled for potential confounding factors (e.g. smoking) found a significantly increased OR (OR 1.45) for subfecundity among women that consumed more than 500 mg per day of caffeine (>5 cups of coffee/day), which represented an increase in the TTP of 11%. The OR was even higher in patients who also smoked (OR 1.56).

A meta-analysis by Klonoff-Cohen on the effect of female and male caffeine consumption on IVF found only one study that directly examined the effect of female and male caffeine consumption on IVF. In this study, female caffeine consumption had an effect on spontaneous abortions (OR range from 6.2 to 19.8, depending on the dose and timing of consumption), failure on achieving a live birth (OR 2.9–3.9) and infant gestational age (OR decreases of 3.5–3.8 weeks). Male consumption of caffeine did not have an effect on sperm, IVF or neonatal endpoints.

Given the limitations of available data, more studies are needed to further evaluate this possible association.

Recommendations

Patients attempting to conceive naturally or through ART who consume more than 500 mg of caffeine/day (>5 cups of coffee/day) should be advised to limit consumption to 100–200 mg of caffeine/day (1–2 cups of coffee or equivalent).

The ASRM states in their Committee Opinion that “moderate caffeine consumption (1–2 cups of coffee/day or equivalent) before or during pregnancy has no apparent adverse effects on fertility or pregnancy outcomes.”

Alcohol

The data reflecting the effect of alcohol on fertility have shown conflicting results. The most recent prospective study on 18 555 women addressing this possible effect, by Chavarro et al., did not find an association between alcohol consumption and infertility after adjusting for other possible confounding factors (e.g. smoking, parity), confirming the findings of a prior prospective trial by Florack et al., where the level of alcohol consumption in the female partner was not related to fecundability. In the study by Chavarro et al., an even split on the results of the available prospective trials is reported (three positive and three null studies).

In the meta-analysis on the effect of female and male alcohol consumption on ART by Klonoff-Cohen, the author found one study that examined female and male alcohol consumption as a primary risk factor for ART. In this study, female alcohol consumption was associated with a 13% decrease in the number of oocytes retrieved (OR 0.87), a decrease in pregnancy rate (OR 2.86), and an increased risk of spontaneous abortion (OR 2.2). Additionally, male alcohol consumption (1 drink) during the IVF cycle was associated with increased risk of spontaneous abortions, compared with men who did not drink 1 month before the IVF attempt (OR 2.7), or up to 1 week before sperm collection (OR 38.04).

Additional studies are needed to further assess the relationship between alcohol consumption and ART.

TIPS & TRICKS

Assess if your patient has an alcohol-drinking problem by following the simple CAGE questionnaire in the first office visit:

Have you ever felt the need to cut down on drinking?Have you ever felt annoyed by criticism of your drinking?Have you ever had guilty feeling about your drinking?Do you ever take a morning eye opener (a drink first thing in the morning to steady your nerves or get rid of a hangover)?

One positive response to any of these questions suggests suggest the need for closer assessment; two or more positive responses are very suggestive of alcoholism.

Recommendation

Patients who report heavy consumption of alcohol or who test positive to alcohol consumption questionnaires should be referred to a substance abuse specialist.

Patients attempting to conceive naturally or through ART who consume alcohol should be advised to avoid consumption of more than 2 drinks/day.

The ASRM states in their Committee Opinion “higher levels of alcohol consumption (≥2 drinks/day) probably are best avoided when attempting pregnancy, but there is no evidence to indicate that more moderate alcohol consumption adversely affects fertility.”

Alcohol consumption should cease completely once pregnancy is established, since the level of alcohol consumption that is safe during pregnancy is not known. In fact, the U.S. Surgeon General’s advisory on alcohol use in pregnancy advises women who are pregnant or considering becoming pregnant to abstain from using alcohol.

Summary

Factors that play an important role in fertility include the age and weight of the patient, as well as maternal consumption of tobacco, caffeine or alcohol.

Weight

Fecundability has been found in multiple studies to be lower at the extremes of BMI in patients trying to conceive spontaneously. The direct effect of being overweight and obese on ART is less clear than for spontaneous pregnancies. In a recent prospective cohort study, male obesity was not linked to subfecundity.

Age

The incidence of infertility increases with advancing maternal age, as does the likelihood of success with ART. There is some evidence that the age of the male partner may affect fertility after the age of 35 years.

Smoking

Smoking is associated with an increased risk of spontaneous abortion, ectopic pregnancy and gamete mutagenesis. Additionally, smokers require nearly twice the number of ART attempts to conceive as nonsmokers.

A definite causality between male partner smoking and infertility has not been proven.

Caffeine

Subfertility has been linked to heavy caffeine consumption (>500 mg/day). Female caffeine consumption has been linked to an increased risk of spontaneous abortion, failure to achieve a live birth and a decrease in gestational age of the infant. Male consumption of caffeine has not been proven to have a deleterious effect on fertility.

Alcohol

The data reflecting the effect of alcohol on fertility have shown conflicting results. A recent prospective study did not find an association between alcohol consumption and infertility.

Recommendations

The following advice should be given to patients attempting to conceive spontaneously or through ART:

follow a healthy diet according to USDA guidelines (including folic acid supplementation of 400 µg/day)quit smokinglimit caffeine consumption to 1–2 cups of coffee/day or equivalentavoid alcohol consumption greater than 2 drinks/day (quit completely once pregnancy confirmed).

Additionally, weight loss and exercise should be advised for all women who are overweight or obese, for all the associated health benefits. Evidence is accumulating to suggest that effective treatment of women with elevated BMI may improve reproductive outcome.

Although the diagnosis of infertility is established until 12 months of not being able to conceive, earlier evaluation and treatment may be justified in some patients based on medical history and physical findings and is warranted after 6 months for women over the age of 35 years.

Selected Bibliography

ACOG Committee Opinion #316: Smoking cessation during pregnancy. Obstet Gynecol 2005;106:883.

ACOG Practice Bulletin #44: Neural tube defects. Obstet Gynecol 2003;102:203–13.

Bellver J, Busso C, Pellicer A, et al. Obesity and assisted reproductive technology outcomes. Reprod Biomed Online 2009 Jan 24.

Bolúmar F, Olsen J, Rebagliato M, et al. Caffeine intake and delayed conception: A European multicenter study on infertility and subfecundity. Am J Epidemiol 1997;145:324.

Chavarro JE, et al. Caffeinated and alcoholic beverage intake in relation to ovulatory disorder infertility. Epidemiology 2009;20:374–81.

Crosignani PG, et al. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod 2003;18:1928–32.

Derbyshire E, Abdula S. Habitual caffeine intake in women of childbearing age. J Hum Nutr Diet 2008;21:159–64.

Dunson DB, Baird DD, Colombo B. Increased infertility with age in men and women. Am J Obstet Gynecol 2004;103:51–6.

Florack EI, Zielhuis GA, Rolland R. Cigarette smoking, alcohol consumption, and caffeine intake and fecundability. Prev Med 1994;23:175–80.

Hull MG, et al. Delayed conception and active and passive smoking: The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertil Steril 2000;74:725–33.

Klonoff-Cohen H. Female and male lifestyle habits and IVF: what is known and unknown. Hum Reprod Update 2005;11:179–203.

Klonoff-Cohen H, Bleha J, Lam-Kruglick P. A prospective study of the effects of female and male caffeine consumption on the reproductive endpoints of IVF and gamete intra-Fallopian transfer. Hum Reprod 2002;17:1746–175.

Klonoff-Cohen H, Lam-Kruglick P, Gonzalez C. Effects of maternal and paternal alcohol consumption on the success rates of in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 2003;79:330–9.

Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology—a systematic review. Hum Reprod Update 2007;13:433–44.

Merhi ZO. Impact of bariatric surgery on female reproduction. Fertil Steril 2009;92:1501–8.

Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008;90(5 Suppl):S60.

Practice Committee of the American Society for Reproductive Medicine Smoking and infertility. Fert Steril 2008;90(Suppl 3).

Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Reproductive Endocrinology and Infertility. Optimizing natural fertility. Fertil Steril 2008;90:S1–6.

U.S. Department of Health and Human Services. U.S. Surgeon General releases advisory on alcohol use in pregnancy. Washington, DC: U.S. Department of Health and Human Services, 2005.

Vine, MF. Smoking and male reproduction: a review. Int J Androl 1996;19:323.

Waylen AL et al. Effects of cigarette smoking upon clinical outcomes of assisted reproduction: a meta-analysis. Hum Reprod Update 2009;15:31–44.

Wise L, Rothman KJ, Mikkelsen EM, et al. An internet-based prospective study of body size and time-to-pregnancy. Hum Reprod 2010;25:253–64.

Websites

http://www.health.gov/DietaryGuidelines/dga2005/document/

http://www.smokefree.gov/

http://www.cdc.gov/tobacco/

http://www.sart.org/

2

Evaluation of the Infertile Couple

Michelle L. Matthews

Carolinas Medical Center, Charlotte, North Carolina, USA

Introduction

It is estimated that approximately 15% of couples will seek assistance for fertility issues during their reproductive years. This number is increasing as more women elect to delay childbearing and patients are increasingly aware of testing and treatment options. Infertility is generally defined as 1 year of unprotected intercourse without conception. It may take longer to conceive as women age; therefore, it is appropriate to initiate an evaluation after 6 months of infertility for women over the age of 35 years or for women with a history of oligomenorrhea or amenorrhea, a partner who is known to be subfertile, or known uterine/tubal disease or endometriosis.

The basic evaluation of infertility, regardless of patient age, includes a thorough history and examination, assessment of ovulation, a semen analysis, and assessment of the uterine cavity and tubal patency. Additional testing may be warranted based on the patient’s history and may include laparoscopy to evaluate the pelvic and ovarian reserve testing (Table 2.1). The recommendations for appropriate testing have been revised over time as the causes of infertility have been investigated and tests to detect these underlying etiologies have been evaluated. Evaluation should be tailored to the patient’s history, age and duration of infertility, and should be cost-effective and evidence-based.

Table 2.1 Evaluation of the infertile couple

HysterosalpingogramPerformed in the follicular phase of the cycle (day 7–12) to evaluate uterine cavity and fallopian tube patencyAdditional assessment of the uterus and/or uterine cavity may be performed with transvaginal ultrasound or SISSemen analysisAssessment of sperm quality and quantityThe man should abstain from ejaculation for 2–3 days prior to semen analysisSemen analysis should be repeated and patient should be referred to a urologist if preliminary testing indicates abnormalitiesAssessment of ovulationBBTOVTSerum progesterone assay (timed 7 days after LH surge or 7 days before expected menses)Luteal phase progesterone assay is the most accurate of the tests;however, any are acceptable to determine ovulationAdditional hormonal testingTSH and prolactin: Only necessary if patient is oligoovulatoryOvarian reserve testing:Day 3 FSH and E2AMHAFCTesting of ovarian reserve is indicated for women >35 years of age, or with a single ovary, a history of prior ovarian surgery or prior poor response to exogenous gonadotropin stimulationNo single test of ovarian reserve has been found to be most predictive of fertility potential but increasing evidence suggests that AMH and antral follicle counts may be more predictive than FSH and E2 aloneLaparoscopyPeritoneal factors such as endometriosis and pelvic/adnexal adhesions should be evaluated with a laparoscopy only if there is a strong clinical suspicion of these conditions or before considering aggressive empirical treatments with significant cost and/or risks

AFC, antral follicle count; AMH, antimüllerian hormone; BBT, basal body temperature charting; E2, estradiol; OVT, ovulation predictor testing; SIS, saline instilled sonography.

Evaluation of the Female

History and Physical Examination

Approximately 40% of infertility can be attributed to female fertility factors which may be elicited from patient history. A thorough history should include both childhood and pubertal development, as these may influence future menstrual function and fertility. A detailed menstrual history is an integral part of the evaluation. Age at menarche as well as length, frequency and amount of menstrual flow should be noted. A history of irregular cycles, menorrhagia or intermenstrual bleeding can indicate an ovulatory disorder or an anatomic condition of the uterus warranting further evaluation. Any complaints of neck tenderness, masses or galactorrhea may indicate a thyroid or prolactin abnormality. Any chronic pelvic pain, pain with menses (dysmenorrhea) or with intercourse (dyspareunia) may indicate pelvic pathology such as infection or endometriosis. Prior Pap smear abnormalities and subsequent treatments (i.e. ablative or excision procedures) should be noted. Other pertinent reproductive history includes prior pregnancies and their outcomes.

A detailed medical history includes ongoing medical conditions, prior illnesses and infections, surgeries (particularly pelvic surgeries), medications and social habits such as tobacco and alcohol consumption. Any family history of reproductive difficulties, birth defects or genetic diseases should also be elicited. Exposure to any toxic environmental agents should be noted, but are not known to be a common cause of infertility in most patients. Physical examination should include assessment of the thyroid for enlargement, masses or tenderness. A breast exam for masses or secretions may reveal galactorrhea. Ay signs of hirsutism, male pattern baldness or acne may indicate the possibility of polycystic ovary syndrome (PCOS). An abdominal/pelvic exam may reveal uterine or ovarian masses, vaginal or cervical abnormalities, or pelvic tenderness suggestive of endometriosis.

Assessment of Ovulation

Ovulatory infertility will be detected in approximately 30% of infertile women and is the most common etiology for female factor infertility. There are several methods for evaluating ovulation including menstrual history, ovulation predictor kits, basal body temperature charting, ultrasound, endometrial biopsy and midluteal serum progesterone. Menstrual history is often all that is required to reveal an ovulatory dysfunction. Infrequent or absent menstrual cycles often indicates an ovulatory disorder.

Methods to more specifically evaluate for an ovulatory disorder include home assessment with ovulation detection test (OVT) or basal body temperature (BBT) charting. OVTs include kits for assessing urinary luteinizing hormone (LH) at midcycle and are approximately 90–95% accurate. Other more elaborate electronic monitors that incorporate other factors such as menstrual cycle length tracking are not clearly more effective for most patients than urinary OVT alone.

Ovulation may also be assessed by BBT charting performed by the patient. BBT tracking is performed by measuring temperature each morning before rising and is based on the principle that temperature rises in response to the presence of serum progesterone after ovulation. Baseline temperature during the follicular phase of the cycle prior to ovulation is 97.0–98.0 °F (36.1–36.7 °C) and increases approximately 0.5 °F (0.25 °C) or more after ovulation in the luteal phase. Since progesterone rises after ovulation, BBT is not helpful in an individual cycle to determine the most appropriate time for intercourse but rather is used retrospectively to determine a range of days in which ovulation generally occurs.

Perhaps the easiest and more accurate way to assess ovulation is a midluteal serum progesterone assay. Serum progesterone is generally low (1 ng/mL or less) in the early follicular phase, rises slightly on the day of the LH surge to approximately 1–2 ng/mL, and then peaks in the midluteal phase approximately 7 days after ovulation. There is no specific quantitative value of progesterone that indicates the quality of ovulation, however, a value >3–4 ng/mL indicates that ovulation occurred. Serum progesterone testing is best scheduled approximately 7 days after an LH surge detected with an OVT. Serum progesterone is otherwise evaluated on cycle day 21–23 in a patient with a 28-day cycle, or approximately 7 days prior to expected menses in a patient with longer cycles (i.e. cycle day 28 in a patient with 35-day cycles). It is important to remember that menstrual cycle lengths may vary and the serum progesterone assessment will not be accurate if not timed properly.

Other methods for assessing ovulation have been suggested such as serial ultrasound and endometrial biopsy. Serial transvaginal ultrasound is useful prior to ovulation to detect the size and number of preovulatory follicles and the growth of the endometrium in response to estradiol production from the ovary. Findings of a collapsed follicle or development of a corpus luteum are presumptive of ovulation; however, these signs are not particularly helpful in establishing the timing of ovulation. In addition, serial ultrasounds are not as cost-effective as other options and are generally not warranted.

Endometrial biopsy is often described as the “gold standard” to assess ovulation. Histologic evidence of secretory endometrial changes indicates a progesterone effect on the endometrium and confirms ovulation. This test has the disadvantages of patient discomfort and increased cost compared to other methods; its use is therefore not indicated in the general infertility evaluation.

In summary, there are several methods for assessing ovulation and the choice of method should be individualized to the patient. If a diagnosis of ovulatory infertility is established, further investigation into the underlying etiology is warranted. Common etiologies for anovulation include thyroid disease, PCOS, hyperprolactinemia, eating disorders, perimenopause and pituitary or hypothalamic conditions. Further evaluation will depend on patient history but will often include a TSH, prolactin, follicle stimulating hormone (FSH) and estradiol to determine the underlying etiology. An ovarian ultrasound may also be used in the diagnosis if PCOS is suspected based on menstrual history and/or signs of hirsutism. Polycystic ovaries are found on ultrasound if multiple small (<10 mm) follicles are crowded along the periphery of the ovary.

Fallopian Tube Assessment

Tubal disease is responsible for approximately 15% of female infertility. The two primary methods for determining fallopian tube patency are hysterosalpingography (HSG) and laparoscopy with fallopian tube chromopertubation. Laparoscopy has a higher risk of complications, so HSG is preferred unless the patient is otherwise undergoing surgery for another consideration. HSG is able to detect uterine cavity abnormalities such as uterine polyps, müllerian anomalies and fibroids. HSG is also valuable to assess fallopian tube architecture and abnormalities such as salpingitis isthmica nodosum (SIN), polyps, hydrosalpinges and peritubal adhesions. There are two contraindications for HSG: current pelvic infection and pregnancy. Allergy to iodine is also a consideration if agents containing iodine are used for fallopian tube instillation.

There are a variety of instruments to instil dye into the uterine cavity including acorn-top catheters, uterine balloon and cervical cap. The choice of instrument is generally based on operator preference and there is no clear advantage of one instrument over another. There are two types of dye used for instillation into the uterus and fallopian tubes: water soluble and oil based. A water soluble dye is generally preferred as it provides improved visualization of subtle abnormalities. Fluoroscopic images are obtained intermittently to evaluate the uterus and tubes during slow instillation of dye.

The HSG should be scheduled during cycle days 7–12 to avoid the possibility of pregnancy. No medications are required prior to performing the procedure; however, anti-inflammatories may be recommended an hour prior to HSG or within 30 minutes after to decrease the risk of cramping. Various other agents such as paracervical block and topical analgesia have been evaluated with no conclusive evidence of benefit for pain reduction. Antibiotics are not universally recommended but may be considered in patients with a prior history of pelvic infection or findings of hydrosalpinges on HSG.

HSG is valuable for evaluating both the uterine cavity and fallopian tube architecture. There should be free spill of contrast material into the peritoneal cavity during the HSG if there is no occlusion of the fallopian tubes. The fallopian tubes have three segments visualized on HSG: the interstitial or cornual region attaching the tube to the uterus, the isthmic portion and the ampullary portion nearest the ovary. Tubal abnormalities can be due either to occlusion from prior infection or surgery, or to spasm of the tube in reaction to the contrast material. Proximal spasm of the tube at its junction with the uterus can occur as the cornual portion of the tube is encased by smooth muscle of the uterus. This is difficult to distinguish from a pathologic condition resulting in occlusion. The HSG should be repeated or a laparoscopy performed to differentiate spasm from actual occlusion.

Obstruction of the fallopian tubes in the isthmic (Fig. 2.1) or distal ampullary tube is more likely to be pathologic. SIN may be visualized in the isthmic segment as several small diverticulum of contrast and is secondary to prior infection. Distal tubal obstruction can be secondary to peritubal adhesions or hydrosalpinx (Fig. 2.2) which is identified by significant dilation of the fallopian tube and absence of spill of contrast into the peritoneal cavity.

Figure 2.1 HSG with normal uterine cavity, midtubal occlusion of the right fallopian tube, and patency of the left tube.

Figure 2.2 HSG with bilateral hydrosalpinges.

Fibroids, polyps and uterine synechiae manifest as filling defects on HSG and can have a variety of appearances depending on their size and location. Small abnormalities are best visualized during early contrast filling of the uterus as they may be obscured when the uterus is completely opacified. This provides the most accurate assessment of the architecture of the abnormality to determine the most likely diagnosis. Uterine fibroids and polyps are generally well demarcated with smooth borders, in contrast to adenomyosis and uterine synechiae. Adenomyosis is a condition in which endometrium extends into the myometrium of the uterus. This may be seen on HSG as small diverticula with contrast material extending into the myometrium. If adenomyosis is suspected, MRI is more commonly used to confirm the diagnosis. Uterine synechiae may be present from prior endometritis or uterine surgery such as myomectomy, cesarean section, endometrial ablation or dilation and curettage. This will manifest as an irregular contour within the cavity of the uterus. Further assessment of any abnormality with transvaginal ultrasound, saline instilled sonography (SIS) and/or hysteroscopy is often needed for further assessment.

Alternatives to HSG have been recommended for evaluation of tubal patency including chlamydia antibody titers, sonohysterography (SHG) or hysterosalpingo-contrast sonography (HyCoSy), and salpingoscopy. Chlamydia antibody titers have been suggested as a cost-effective, noninvasive test of fallopian tube status since chlamydia is the primary cause of pelvic inflammatory disease (PID) and subsequent tubal damage. However, other etiologies of possible tubal damage (i.e. gonorrhea, prior tubal surgery, endometriosis) will not be detected with this assay. More direct methods of assessing fallopian tube status include injecting saline (SHG) or air-contrast (HyCoSy) through the uterus and fallopian tubes and observing for presence in the cul-de-sac by ultrasound observation. Benefits of these techniques may include improved patient comfort, decreased cost, and avoidance of radiation exposure, however, the location of tubal blockage cannot be determined if present. Salpingoscopy is assessment of the interior architecture of the fallopian tube by endoscopy. It has the advantage of direct assessment of the tubal mucosa, but is not able to evaluate external tubal anatomy including peritubal adhesions. These alternatives are discussed in more detail in Chapter 3.

Evaluation of the Uterus

There are several anatomic abnormalities of the uterus that may impact fertility potential. Abnormalities of the uterine cavity include both developmental abnormalities (unicornuate, biocornuate, didelphic and septate) as well as acquired ones (polyps, fibroids, synechiae), as mentioned previously. Generally, congenital abnormalities may increase the risk of complications during pregnancy (i.e. preterm labor, preterm delivery, breech presentation) but do not significantly impact the risk of infertility. However, these findings should be noted for appropriate preconceptual counseling.

Evaluation of acquired uterine abnormalities such as uterine polyps and fibroids is warranted, although their overall contribution to infertility is debatable. Evidence suggests that submucous and large intramural (≥4 cm) fibroids may impact fertility and miscarriage risk. Polyps are more likely to impact fertility potential if they are larger (≥2 cm), or causing abnormal uterine bleeding. Uterine synechiae (i.e., areas of scarring) are another acquired abnormality that may impact embryo implantation. Uterine synechiae should be suspected in patients were there is a suspicion of intracavitary abnormality and a history of prior endometritis, endometrial curettage or surgery for fibroids/polyps. Thorough assessment and treatment of these conditions may improve fertility potential based on individual findings.

The uterine cavity may be assessed by HSG, transvaginal ultrasound or SIS. Either transvaginal ultrasound or SIS has the advantage of assessing the uterine myometrium for other pathologic conditions such as fibroids or adenomyomas in addition to assessing the uterine cavity for adhesions, fibroids or polyps. HSG is most effective for assessing both the uterine cavity and fallopian tube patency. Assessment should be tailored to the patient’s history and examination. Most patients are able to be assessed by HSG and transvaginal ultrasound. Generally, SIS is reserved for more thorough evaluation of abnormalities visualized on standard transvaginal ultrasound or HSG.

SIS enhances endovaginal ultrasound examination of the uterine cavity with minimal patient discomfort. SIS consists of using transvaginal ultrasound to image the uterine cavity while sterile saline is instilled into the cavity. This allows detection of abnormalities within the uterine cavity.

TIPS & TRICKS

Saline instilled sonography (SIS; sonohysterography) enhances endovaginal ultrasound examination of the uterine cavity with minimal patient discomfort. SIS consists of using transvaginal ultrasound to image the uterine cavity while sterile saline is instilled into the cavity. This allows detection of abnormalities within the uterine cavity. SIS is performed by first cleansing the cervix with an antiseptic solution. A small intrauterine insemination catheter purged of any air bubbles is inserted through the cervix into the uterine cavity. Sterile saline is flushed through the catheter as the uterus is scanned in the long axis and coronal planes. Water appears dark and tissue is light so that filling defects such as polyps, fibroids and adhesions are easily visualized.

If traditional methods for assessing uterine pathology are indeterminant, MRI can used for more detailed evaluation of the uterus. MRI is particularly helpful in differentiating leiomyomas from andenomyosis. It is also considered the standard evaluation for uterine anomalies such as bicornuate and septate uteri. It is particularly useful before considering invasive surgery to more clearly define uterine architecture in patients with uterine anomalies or suspected andenomyosis or adenomyomas.

Evaluation of the Pelvic Peritoneum

Laparoscopy has traditionally been considered the gold standard for evaluation of the pelvis for intra-abdominal causes of infertility and tubal pathology. Laparoscopy was traditionally considered part of a standard fertility evaluation until those recommendations were revised. Current recommendations from the American Society for Reproductive Medicine (ASRM) indicate that peritoneal factors such as endometriosis and pelvic/adnexal adhesions should be evaluated with a laparoscopy only if there is a strong clinical suspicion of these conditions (i.e. history, physical exam, pelvic ultrasound or HSG suggests endometriosis or pelvic pathology) or before considering aggressive empirical treatments with significant cost and/or risks.

It should be noted that laparoscopy may detect pelvic pathologies that HSG may not identify, specifically pelvic adhesions and endometriosis. However, the risk versus benefit of laparoscopy should be considered on an individual patient basis considering her risk factors and the likelihood of benefit from the surgery. While laparoscopy may identify endometriosis which otherwise would not be detected without surgery, the likelihood of ablative surgery for minimal endometriosis significantly increasing absolute pregnancy rates is relatively small. It is important to consider whether the findings on laparoscopy would change the management plan for an individual patient given her presentation and other fertility factors.

CAUTION

There are two contraindications for HSG: current pelvic infection and pregnancy. Allergy to iodine is also a consideration if agents containing iodine are used for fallopian tube instillation. The exam should be scheduled during days 7–12 of the cycle to avoid the possibility of pregnancy and thickened endometrium which will interfere with most effective imaging of the uterine cavity. Antibiotics are not universally recommended but may be considered in patients with a prior history of pelvic infection or findings of hydrosalpinges on HSG.

Cervical Factors

Cervical factors are a relatively infrequent cause of infertility. Abnormalities of cervical mucus are a presumptive cause of infertility for some patients but are difficult to identify. The postcoital test was developed to assess the ability of the sperm to penetrate cervical mucus and assess the quality of the mucus for conception. However, the test results were found to be highly variable and did not clearly correlate with outcomes. This test is not recommended for routine screening in couples and perhaps the only utility is to assess for sperm presence after intercourse in men who are otherwise unable to produce a sperm sample for semen analysis.

Ovarian Reserve Testing

The most recent U.S. data indicate that the number of women having children after 30 years of age is increasing. Between 1980 and 2002, the percentage of women in the U.S. giving birth at age 30–34 years has increased from 8.4% to 14.2%. An increase in birth rate from 2.2% to 5.9% has also been documented for women age 35–39 years, with a small increase as well from 0.3 to 1.3% for women age 40–44 years. Ovarian reserve testing is recommended to assess a woman’s reproductive potential if over 35 years of age, or for women with a single ovary, a history of prior ovarian surgery or prior poor response to exogenous gonadotropin stimulation. The purpose of ovarian reserve testing is to evaluate oocyte quality and quantity to provide information of reproductive potential beyond the likelihood of successful pregnancy based on chronologic age alone.

Several endocrinologic markers have been evaluated as a marker of ovarian reserve including FSH, inhibin B, estradiol and antimüllerian hormone (AMH), in addition to ultrasonographic techniques such as antral follicle count (AFC), ovarian volume and vascular resistance. Provocative tests have also been utilized such as the clomiphene citrate challenge test (CCCT) and the exogenous FSH ovarian reserve test (EFORT). These tests are often helpful in assessing the ability of a patient to respond to ovulation induction agents, but their utility in assessing likelihood of pregnancy is limited.

Serum Endocrinologic Assays

Basal FSH values drawn during menstrual day 2–3 have been routinely utilized as a marker of ovarian reserve. As FSH values increase, ovarian responsiveness decreases. The cut-off value used to define a “normal” FSH may vary between laboratories. An FSH value of 10–15 IU/L is generally considered borderline, and values over 15 IU/L are considered significantly elevated and have been correlated with decreased likelihood of conception with fertility treatments. It is important when assessing FSH values to also evaluate basal estradiol as an elevation may suppress FSH and give a falsely reassuring value. A normal basal estradiol may vary between laboratories, but typically is less than 60 pg/mL.

FSH values may fluctuate widely between cycles as age increases. It is important for patients and healthcare providers not to be falsely reassured by a single normal FSH result. A normal FSH level in a 40–45 year old woman with regular menstrual cycles will be elevated in a preceding or subsequent cycle about 30–50% of the time. In addition, a normal FSH level does not negate the impact of age on fertility. Although basal FSH testing is often used as a marker of ovarian responsiveness to gonadotropins, controversy exists regarding its utility as a predictor of spontaneous pregnancy.

Inhibin B is produced by the granulosa cells and levels diminish with age due to a reduction of the recruited cohort of the antral follicle pool. However, both baseline estradiol and inhibin B levels have not been consistently correlated with ovarian response. Estradiol levels rise in the early follicular phase in later reproductive years, and then eventually decrease, but no consistent cut-off value have been correlated with ovarian responsiveness. A fall in inhibin B results in the increase in FSH, but the inhibin B assay is not routinely commercially available and has not been shown to have added benefit to the FSH value alone.