Recurrent Pregnancy Loss E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: GIP - Gynaecology in Practice
• Sprache: Englisch

Seitenzahl: 402

Veröffentlichungsjahr: 2013

Beschreibung

Recurrent Pregnancy Loss

Edited by

Ole B Christiansen, MD, D.M.Sc., Rigshospitalet, Copenhagen and AalborgUniversityHospital, Aalborg, Denmark

Recurrent Pregnancy Loss is a silent problem for many women

The spontaneous loss of a pregnancy in the first 22 weeks is often not recorded as the mother needed no medical or surgical treatment. Women who repeatedly suffer this tragedy can go unheard as a result. Gynecologists can feel unable to help.

But they can help. Research is showing how to identify women who suffer recurrent pregnancy loss and which treatments might prevent a further recurrence. Gynecologists are learning how to monitor subsequent pregnancies for the early signals of problems.

Recurrent Pregnancy Loss provides a practical approach to this hidden clinical challenge. The highly experienced, international author team explores:

• How to obtain a relevant history
• Which investigations to order
• The physiological reasons behind recurrent pregnancy loss
• The best approach to treatment
• How to monitor patients in subsequent pregnancies

Clinical in approach, practical in execution, with the patient at the centre, Recurrent Pregnancy Loss guides you as you support your patients.

Leseprobe

Contents

Copyright page

Series Foreword

Contributors

Preface to the First Edition

1 Obtaining the Relevant History

Introduction

Demographic data

Reproductive history

Disease history

Family history

Conclusions

Bibliography

2 Which Investigations Are Relevant?

Introduction

Thrombophilia tests

Screening for thrombophilia in women with recurrent miscarriage

Conclusions

Parental and fetal karyotyping

Testing

Reproductive consequences of carrier status

Treatment or prevention

Fetal karyotype

Tests for diagnosing uterine anomalies

Diagnosis of uterine anomalies

Prognosis of pregnancy outcome

Conclusion

Thyroid function tests

Summary

Bibliography

3 NK Cells in Peripheral Blood and the Endometrium

Introduction

NK cells and reproduction

Methods of assessment

NK cell analysis in recurrent miscarriage

NK cell testing in practice

Targeted immune therapy

Immune therapy caution

When to offer NK cell testing

Bibliography

4 Cytokines and Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss

Introduction – Cytokines and pregnancy: basic concepts

Interactions between Treg cells, Th17 cells, and cytokines and normal pregnancy and RPL

Cytokine gene polymorphisms and RPL – an overview

Practical evaluation of cytokines for the diagnostic of RPL

Bibliography

5 How to Assess the Prognosis after Recurrent Miscarriage

Introduction

Method of study

Specific causes of RPL and prognosis

Prognosis in pregnancy

Classification of prognosis

Conclusions

Bibliography

6 Which Treatments Should be Offered? PGD/PGS, Allogeneic Lymphocyte Immunization, Intravenous Immunoglobulin

Introduction

Preimplantation genetic testing

Active and passive immunization using lymphocyte immunization and IvIg

Bibliography

7 Which Treatment Should be Offered? Heparin/Aspirin, Progesterone, Prednisolone

Introduction

Heparin and aspirin

Clinical data

Progesterone

Future research

Prednisolone

Other treatment options

Estrogen

Conclusion

Bibliography

8 Which Treatment Should be Offered: Metformin, hCG, GM-CSF/G-CSF, TNF-α Inhibitors, Standard IVF/ICSI

Introduction

Metformin

hCG

GM-CSF/G-CSF

TNF-α inhibitors

IVF/ICSI without PGD

Bibliography

9 Talking to Patients about Lifestyle, Behavior, and Miscarriage Risk

Introduction

The importance of information following miscarriage

Timing

Discussing the causes of miscarriage

Questions may include:

Discussing the concept of risk

Setting realistic expectations

Advice for the best possible chance of a healthy pregnancy

Risk and cause

Talking to patients you have advised, after another miscarriage

The importance of good care

Sources of information and support

When the trying stops

Summary

Further sources of information and support

Bibiliography

10 Endocrine and Ultrasonic Surveillance of Pregnancies in Patients with Recurrent Miscarriage

Introduction

The role of endocrine surveillance

Prediction of miscarriage

The role of ultrasound surveillance

Prediction of miscarriage

Subchorionic hematoma

Vanishing twin syndrome

First trimester screening

Second trimester screening

Progesterone to prevent pregnancy loss

Further assessment

Supportive care

Conclusion

Bibliography

11 Obstetric Complications in Patients with Recurrent Miscarriage – How Should they be Monitored in the Third Trimester?

Introduction

Tests of fetal well-being in the third trimester – what are they and what do they mean

Prediction of spontaneous preterm labor

Prevention of adverse effects of prematurity

Management of preterm prelabor rupture of membranes (PPROM)

Management of third trimester pregnancy in diagnostic categories of recurrent miscarriage

Endocrine disorders

Prothrombotic conditions

Inherited thrombophilia

Unexplained recurrent miscarriage

Bibliography

12 Recurrent Miscarriage after ART:A Double Challenge

Introduction

Two subsets of RM patients with a need for ART

RM after OI with or without IUI

RM after IVF/ICSI

Treatment

Bibliography

13 How to Cope with Stress and Depression in Women with Recurrent Miscarriage

Stress and depression in women with recurrent miscarriage

Decision making and its relation to stress and depression

How can clinicians assist in decision processes and improve coping?

Conclusions

Bibliography

14 Recurrent Miscarriage and the Risk of Autoimmune Disease and Thromboembolic Disease

Introduction

RM and autoimmunity

RM and aPL

RM and other autoantibodies

RM and thromboembolic disease

15 How to Organize and Run an Early Pregnancy Unit/Recurrent Miscarriage Clinic

Introduction

Setting the scene

Standards of practice

Early pregnancy loss

Management of early pregnancy loss

Contraindications to medical management

Protocol for medical management of miscarriage

Surgical management of miscarriage

Expectant management of miscarriage

Ectopic pregnancy

Recurrent miscarriage

Staffing and training implications

Opportunities for specialist training

Audit and research issues

Bibliography

16 How to Organize an Early Pregnancy Unit/Recurrent Miscarriage Clinic – American Perspective

Introduction

Patient population at RPL special clinic

Interprofessional approach

Roles of healthcare providers

How to manage patient flow at special RPL clinic?

What to offer other than medical care?

Physical facility for the special RPL clinic

Ultrasound unit

Conclusion

Bibliography

17 Case Studies

Introduction

Bibliography

Index

This edition first published 2014 © 2014 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Recurrent pregnancy loss / edited by Ole B. Christiansen.        p. ; cm.–(Gynecology in practice)    Includes bibliographical references and index.

    ISBN 978-0-470-67294-5 (pbk. : alk. paper) – ISBN 978-1-118-74901-2 – ISBN 978-1-118-74903-6 (eMobi) – ISBN 978-1-118-74918-0 (ePub) – ISBN 978-1-118-74932-6 (ePdf)I. Christiansen, Ole B., editor of compilation. II. Series: Gynecology in practice.    [DNLM: 1. Abortion, Habitual–prevention & control. WQ 225]    RG648    618.3′92–dc23

2013017940

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

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: Insert: © Authors Chapter 10: A. Appiah and J. Johns.Cover designed by Sarah Dickinson

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, MDProfessor, Department of Obstetrics, Gynecology, and Reproductive SciencesYale University School of MedicineNew Haven, CT, USA

Contributors

Muhammad A. AkhtarClinical Research Fellow, Reproductive Medicine UnitUniversity Hospitals Coventry and Warwickshire NHS TrustUniversity of Warwick, Coventry, UKAdjoa AppiahClinical Research FellowEarly Pregnancy and Gynaecology Assessment UnitKing’s College HospitalLondon, UKJuan BalaschInstitute Clínic of Gynecology, Obstetrics and NeonatologyBarcelona, SpainRuth Bender AtikNational DirectorThe Miscarriage AssociationWakefield, UKEmmy van den BoogaardCenter for Reproductive MedicineDepartment of Obstetrics and GynecologyAcademic Medical CenterAmsterdam, The NetherlandsHoward J.A. CarpDepartment of Obstetrics and GynecologySheba Medical CenterTel Hashomer & Tel Aviv UniversityTel Hashomer, IsraelRicard CerveraDepartment of Autoimmune DiseasesInstitute Clínic of Medicine and DermatologyHospital ClínicBarcelona, SpainOle B. ChristiansenProfessor, Unit for Recurrent MiscarriageFertility Clinic 4071RigshospitaletCopenhagen, Denmark; andDepartment of Obstetrics and GynaecologyAalborg University HospitalAalborg, DenmarkSilvia DaherDepartment of ObstetricsSão Paulo Federal University (UNIFESP)São Paulo, SP, BrazilAnnMaria EllardNurse SpecialistMiscarriage ClinicLiverpool Women’s HospitalLiverpool, UKRoy G. FarquharsonGynaecologistMiscarriage ClinicLiverpool Women’s HospitalLiverpool, UKDida FleisigDepartment of Behavioral SciencesThe College of Management Academic StudiesRishon Le-Zion, IsraelMariëtte GoddijnCenter for Reproductive MedicineDepartment of Obstetrics and GynecologyAcademic Medical CenterAmsterdam, The NetherlandsAe-Ra HanReproductive MedicineDepartment of Obstetrics and GynecologyDepartment of Microbiology and ImmunologyThe Chicago Medical School at Rosalind Franklin University of Medicine and ScienceVernon Hills, IL, USABarbara E. Hepworth-JonesTrustee, The Miscarriage AssociationWakefield, UKShehnaaz JivrajConsultant Obstetrician and GynaecologistJessop Wing, Sheffield Teaching Hospitals TrustHonorary Senior LecturerUniversity of SheffieldSheffield, UKJemma JohnsConsultant Obstetrician and GynecologistEarly Pregnancy and Gynaecology Assessment UnitKing’s College HospitalLondon, UKPaulien G. de JongDepartment of Vascular MedicineAcademic Medical CenterAmsterdam, The NetherlandsClaudia KowalikDepartment of Obstetrics and GynecologyAcademic Medical CenterAmsterdam, The NetherlandsJoanne Kwak-KimReproductive MedicineDepartment of Obstetrics and GynecologyDepartment of Microbiology and ImmunologyThe Chicago Medical School at Rosalind Franklin University of Medicine and ScienceVernon Hills, IL, USAElisabeth C. LarsenUnit for Recurrent MiscarriageFertility Clinic 4071RigshospitaletCopenhagen, DenmarkM. Angeles Martínez-ZamoraInstitute Clínic of Gynecology, Obstetrics and NeonatologyBarcelona, SpainRosiane MattarDepartment of ObstetricsSão Paulo Federal University (UNIFESP)São Paulo, SP, BrazilSaskia MiddeldorpDepartment of Vascular MedicineAcademic Medical CenterAmsterdam, The NetherlandsHenriette Svarre NielsenDepartment of Obstetrics and GynaecologyUniversity of CopenhagenCopenhagen, DenmarkKuniaki OtaReproductive MedicineDepartment of Obstetrics and GynecologyDepartment of Microbiology and ImmunologyThe Chicago Medical School at Rosalind Franklin University of Medicine and ScienceVernon Hills, IL, USASiobhan QuenbyProfessor of ObstetricsDirector of the Biomedical Research Unit in Reproductive HealthWarwick Medical SchoolUniversity of Warwick, Coventry, UKGavin SacksAssociate Professor, University of New South WalesSt George HospitalSydney, NSW, Australia; andClinical Director, IVF AustraliaHunter Valley, NSW, AustraliaKeren ShakharDepartment of Behavioral SciencesThe College of Management Academic StudiesRishon Le-Zion, IsraelMaria Regina TorloniDepartment of ObstetricsSão Paulo Federal University (UNIFESP)São Paulo, SP, BrazilRosa VissenbergCenter for Reproductive MedicineDepartment of Obstetrics and GynecologyAcademic Medical CenterAmsterdam, The Netherlands

Preface to the First Edition

Recurrent pregnancy loss (RPL), which is almost synonymous with recurrent miscarriage (RM), is defined as a minimum of three (or two) spontaneous losses of intrauterine pregnancies before gestational week 22. It is a cause of involuntary childlessness that among physicians and in the general population is much less recognized than childlessness due to failure to conceive (infertility) or stillbirth. This is mainly due to the fact that whereas there are many established public and private IVF clinics taking care of couples with infertility, as well as many clinics specialized in obstetrics and fetomaternal medicine that take care of women with stillbirths, most women with RPL are being managed in clinics of general gynecology by physicians who often have their main interest in gynecological surgery. A second reason for the invisibility of RPL is that many patients with very early miscarriages or biochemical pregnancies are not coming into contact with hospitals or gynecologic specialists because they have no need for surgical or medical treatment and therefore remain unknown to the secondary and tertiary health-care system. A third reason for the invisibility of RPL may be that since very few treatment options with documented efficacy exist, few physicians feel motivated to take care of these patients. In my experience, only well-­educated psychologically strong patients will be able to mobilize the mental energy required to consult one of the few (often distantly located) clinics that have specialized in RPL management. The majority of RPL patients become stuck in the system because few recognize their problems and even fewer can offer them treatments.

Since only a minority of RPL cases are fully recognized by the secondary and tertiary health-care system, no valid registration of the size of the problem exists. Estimates showing that 1% of all women suffer RPL are based on studies conducted 30 years earlier at a time when detecting early pregnancy loss had limited possibilities (no high-resolution vaginal ultrasound, insensitive hCG tests). The real and current prevalence of RPL may be considerably higher than 1% and is also dependent on how the condition is defined: two or more losses versus three or more.

The main goal of this book is to highlight the condition and to help practitioners and gynecologists cope with patients in clinical practice. All chapters are written by specialists who have taken care of patients with RPL in clinical practice and have done recognized research. The reader may be confused by the different opinions put forward by the contributing specialists: some find specific investigations and treatments sufficiently validated to use them or recommend their use in RPL whereas others discourage their use due to limited documentation. In my opinion, this disagreement primarily reflects the fact that there is an urgent need for further specialization and high-quality research in this area. However, the disagreement also reflects the different conditions under which the specialists meet RPL patients: those from private clinics dependent on charging the patients will often have a more liberal approach to tests and treatments while specialists from public clinics who do not charge patients will typically adhere to a more conservative approach to tests and treatments.

As part of the publisher’s Gynecology in Practice series, the aim of the book is to ­provide gynecologists in practice or in training with a clinical guide for use in the office or at the bedside.

Therefore, the contributors of the chapters have been asked to write in a practical and concise tone with few references to facilitate easy readability.

I thank all the authors for contributing excellent chapters covering their areas of expertise and for their efforts to write in the expected practical style. I hope that the book will be helpful for improving the management of RPL in clinical practice and for creating public awareness on this hidden cause of childlessness.

Ole B. ChristiansenProfessor, DMScUnit for Recurrent MiscarriageFertility Clinic 4071, Rigshospitalet, Copenhagen, DenmarkandDepartment of Obstetrics and GynaecologyAalborg University Hospital, Aalborg, Denmark

1

Obtaining the Relevant History

Ole B. Christiansen1,2

1 Unit for Recurrent Miscarriage, Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark2 Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark

Introduction

In most clinics, patients referred with a diagnosis of recurrent miscarriage (RM) will normally come to a first consultation with a physician where information about the reproductive history and other medical information are collected, blood samples are taken, and other relevant investigations are carried out or planned.

Whereas authors in the area of RM often spend plenty of space in their articles to list the abundance of investigations undertaken in their clinic: hysteroscopy, endometrial biopsy, parental or fetal karyotyping, screening for thrombophilia, autoantibodies and microbiobes in addition to endocrine investigations, they spend very little space (if any) to describe the stringency and accuracy through which information has been obtained from the patients themselves or their hospital records. This reflects the modest emphasis most authors lay on reproductive and disease history compared with information obtained from other kind of investigations.

In this chapter, I will review information that we aim to collect at the first consult­ation at my clinic because we (i) find it important for assessing the spontaneous ­prognosis for live birth and (ii) it can often point toward etiological factors before any results from ultrasonic and laboratory investigations are obtained.

The relevant information achievable from the patients themselves or their case records can be divided into demographic data, reproductive history, disease ­history, and family history. The information should be obtained from both partners but the information concerning the women must be considered the most important.

Demographic data

The most important demographic data are information about parental age, body mass index (BMI), lifestyle, social class, and occupational factors in addition to information about the partner.

Parental Age

High maternal age is one of the strongest negative prognostic factors known. Maternal age over 41–42 years will be decisive for a conservative treatment approach since the dominant risk factor for miscarriage in this age group is embryonal ­aneuploidy (especially trisomies), which can only be actively treated by IVF with egg donation. The impact of high paternal age on risk of miscarriage and RM is difficult to study since parental ages are strongly correlated and the only couples that are really informative are those few comprising a young woman and an elderly male. The ­evidence provided so far suggests that high paternal age per se indeed increases the risk of miscarriage, although much less than high maternal age.

BMI

The patients should be weighted and the height measured at the first consultation to obtain a reliable BMI since both BMI below 20 and over 30 have in some studies been reported to decrease the prognosis for live birth in women in the background population and among RM patients. However, a recent study from my clinic showed that high BMI did not exhibit any impact on subsequent miscarriage rate in RM patients with regular menstrual cycles who can conceive spontaneously. BMI may therefore only have an impact on subsequent miscarriage rate in patients with ­polycystic ovary syndrome who normally only can conceive after ovulation induction. Whether normalization of an abnormal BMI will improve the pregnancy prognosis in terms of miscarriage rate in these patients is still to be documented, but clearly, weight loss will decrease the risk of gestational diabetes and other late ­pregnancy complications.

Lifestyle Factors

The most important lifestyle factors of importance for RM are consumption of coffee, alcohol, and tobacco in addition to the extent of leisure-time exercise during ­pregnancy. Drug abuse is rare in RM women but should be monitored. Whereas information about coffee consumption is trustworthy, information about alcohol and tobacco use will probably be underestimated. In my clinic we tell patients that daily consumption of four or more cups of coffee (and tea and cola with an equivalent caffeine content) during pregnancy should be avoided since several studies have reported that this increases the risk of miscarriage in the ­general population.

Any use of alcohol at least in the first half of pregnancy should be strongly ­discouraged since just one to two drinks a week in the first trimester have been shown to double the miscarriage risk and there is also an increased risk of fetal alcohol syndrome.

Whereas there is no good proof that tobacco use increases the risk of early ­miscarriage, the patients should try to reduce smoking, primarily to diminish the risk of late pregnancy complications such as intrauterine growth retardation, preterm birth, and placental abruption – conditions strongly associated with both RM and smoking.

Information should be obtained about leisure-time exercise since recent research suggests that some kinds of high-impact exercise, defined as exercise more than 75 min a week, may increase miscarriage risk <14th week significantly with relative risks of 3.6–4.2 in pregnant women from the general population. Therefore, patients should be interviewed specifically about what kind of exercise they perform and for how many hours a week. If it is estimated that the patient practises too much “­dangerous” exercise, she should be encouraged to reduce its intensity and duration.

Social Class

Low social class and low educational level are risk factors for perinatal complications such as preterm birth, which can only partly be explained by a more unhealthy ­lifestyle (high BMI, smoking, drinking) among low social class women. In my clinic, we ask the couples about their occupation and this information will in most instances provide a rough estimate of their social status. Whereas the social factors cannot be changed by interventions at the RM clinic, extra surveillance in the third trimester should be provided for some of these patients due to the higher risk of late pregnancy complications.

Occupational Factors

Patients should be interviewed in details about their working situation. Is their working situation very stressful? Are they standing many hours a day or are they lifting heavy burdens? Do they have changing working times including night work? Are they working with hazardous chemicals or radiation? Although the documentation that improvement of working conditions indeed improves perinatal outcome is poor, RM patients with risky work conditions should be encouraged to change the conditions and support be provided to implement the changes (letters to the employers, etc.). Patients with night work may be encouraged to only work by day time in the next pregnancy, diminish working load, or get pregnancy leave.

Partner

Patients with RM are almost always married or live in an established partnership. In my clinic, the husband is asked whether he has fathered pregnancies in previous relationships and about the outcome of these pregnancies. In addition, he is asked about health status with particular focus on congenital or testicular disorders and intake of medicine.

An increasing number of our RM couples are immigrants from the Middle East, with tradition for inter-cousin marriages. Therefore, it is important to obtain information about whether the couples are related. There may be an increased risk of miscarriage in first-cousin marriages and definitely an increased risk of malformations and autosomal recessive diseases in the offspring. This may be an indication for closer-than-normal ultrasonic fetal monitoring during pregnancy. If a first-cousin couple with RM continues to miscarry in spite of other treatments, the possibility of offering insemination with donor sperm should be mentioned to the couple, but due to culture and religion, this offer will rarely be accepted.

CAUTION

Most published studies put little emphasis on lifestyle and occupational factors, although these may affect pregnancy outcome more than factors found by blood tests.   Too much emphasis should not be put on the importance of a moderately increased BMI since its impact on miscarriage risk in RM is unclear and the effect of weight loss on miscarriage risk is undocumented.   Many patients with RM seek an explanation for their miscarriages in some self-inflicted factor, for example, intake of a specific food ingredient, a stressful event, a jump, or a heavy lift. Such self-guilt can be enhanced if the importance of lifestyle factors for RM is over-exaggerated when talking with the patients.

Reproductive history

Clinical Appearance of Pregnancy Losses

In my clinic, considerable time is spent to get valid information about the patients’ reproductive history, especially about the gestational ages at the time of previous fetal demise and the ultrasonographic and hormonal measurements undertaken in each pregnancy. This information is obtained from questionnaires sent to the patients before the first consultation in order to give them time to collect relevant data from hospital records and other documents and to recall events.

At the first consultation, every effort is done to integrate information from written records and the patients’ own information in order to answer four main questions relating to each pregnancy: (i) was it confirmed by a urinary pregnancy test or serum-hCG measurement? (ii) were there signs of intrauterine pregnancy by ultrasound (intrauterine gestational sac, yolk sac, or embryonal echo with or without fetal heart action)? (iii) were chorionic villi detected by histology after uterine curettage? and (iv) at which gestational age had the fetal demise probably happened?

Other information relating to previous pregnancies is also thoroughly collected: mode of conception, results from karyotyping of miscarriages, identity of the partner for each pregnancy, and perinatal data relating to pregnancies progressing to the ­second/third trimester. Any treatment attempts in each pregnancy are also registered.

We also found that primary RM patients with a history of exclusively PULs exhibit a very high (16%) frequency of clinical tubal pregnancy at some time point in their reproductive history. This may indicate that the pregnancy losses in many of these patients may be spontaneously resorbed ectopic pregnancies due to tubal damage rather than intrauterine losses. We suspect that these patients have a subtotal tubal damage and as a consequence, we offer them IVF treatment in the next pregnancy – providing them with a good chance for live birth (see Chapters 8 and 17).

CAUTION

Some patients exaggerate the number of pregnancy losses in order to qualify for being referred to a dedicated RM clinic and qualify for active treatment at the clinic. These patients can be identified by doing an extensive collection of information from files from hospitals and general practitioners.

Gestational Age of Pregnancy Losses

Information about time of fetal demise, not to confound with the time of discovery of fetal death, is important, especially when we are dealing with pregnancy losses in the early second trimester (13th–18th week gestation). It has been reported in several studies that when fetal death is documented to have happened after 13th week, it is associated with a much higher risk of new second trimester miscarriage or extreme early birth compared with an early miscarriage (see Chapter 5). Some miscarriages detected by ultrasound in the second trimester have, evaluated from the size of the dead fetus, probably happened in the first trimester. Since the impact of a “real” second trimester loss on the risk of new late loss or preterm birth seems to be much greater than the impact of a first trimester loss, in my clinic much efforts are done to collect relevant information in order to distinguish between “real” and “false” second trimester losses in the history.

TIPS AND TRICKS

Questionnaires requesting information about time and place for previous ­pregnancy losses and about investigations undertaken in each pregnancy should be mailed to new patients 3 weeks prior to initial consultation.

Perinatal Data

Information about outcome of previous births or stillbirths is important to obtain. Our studies have shown that in patients with secondary RM, the birth of a boy ­compared with a girl prior to RM decreases the prognosis for live birth in the first ­pregnancy after referral by 22% corresponding to an OR for birth of 0.37 (95% CI 0.2–0.7). If the firstborn boy was born preterm or had birth weight <2500 g, the prognosis seems to be reduced even more.

Figure 1.1 Pedigree showing the reproductive histories of a woman (proband) with secondary recurrent miscarriage after the birth of a slightly growth-retarded boy and her mother. Information about autoimmune diseases and screening for risk factors for recurrent miscarriage are also given. MBL, mannose-binding lectin.

The patient database at my clinic indicates that women with secondary RM ­significantly more often than expected had given birth to a firstborn child with some congenital disorder or malformation. In these cases, many efforts are done to achieve information about the exact diagnosis of the child and together with experts in genetics and ultrasound to make a plan for surveillance in the next pregnancy, including prenatal screening and, if possible, offer treatment with IVF combined with preimplantation genetic diagnosis (see Chapter 6).

Information about perinatal complications when the patients themselves were born can provide information about the prognosis for birth since women being born with a low own birth weight (<2900 g) will have a high risk of experiencing multiple (≥5) miscarriages in their later reproductive life (Figure 1.1).

SCIENCE REVISITED

In the majority of published studies in RM, little emphasis is put on getting a comprehensive reproductive history with documentation of pregnancy losses being biochemical, early clinical miscarriages, or “real” second trimester miscarriages.    Detailed information about the time of fetal demise in previous pregnancy losses and perinatal outcome in previous ongoing pregnancies is important for assessing the risk of new miscarriage and late pregnancy complications.

Disease history

A thorough history of disease must be obtained. We focus in particular on autoimmune diseases, which are clearly overrepresented in RM women. The endocrine and metabolic changes associated with some autoimmune diseases such as type I diabetes and hypothyreosis may in theory directly interfere with trophoblast invasion and growth; alternatively, the increased inflammatory cytokine response and breakage of immunological tolerance characterizing autoimmune disease is predisposing to miscarriage and RM. Whatever autoimmune disease a patient has, its presence strengthens the belief that immunological disturbances are causing the miscarriages also in patients negative for the limited panel of autoantibodies investigated in most RM clinics. The patients should also be asked about previous thromboembolic ­episodes; presence of such will strengthen the suspicion that the patient has a ­thrombophilic disorder even though the routine screening for thrombophilic factors is normal.

Family history

Collecting a family history, especially from RM women, has high priority in my clinic. During a period of 20 years, we have asked our patients for information about the reproductive histories of siblings and mothers and we found that also in families of patients with normal karyotypes, sisters, brothers’ wives and mothers all displayed miscarriage rates that were almost doubled compared with the background population. In addition, we found that first-degree relatives had an increased prevalence of a series of autoimmune diseases. A high frequency of miscarriages, perinatal complications, and autoimmune disease among first-degree relatives may suggest that the patient origins from a family carrying genes for poor trophoblast development and genes predisposing to breakage of immunological tolerance and proinflammatory responses (Figure 1.1). Carriage of such genetic factors is probably associated with a diminished prognosis for live birth. An accumulation of miscarriage and autoimmune disease among the first-degree relatives should alert the general practitioner or nonspecialized gyne­cologist and lead to referral to a specialized RM clinic already after two or three ­miscarriages. A burdened family history should lead the physicians of the RM clinic to monitor the patients more closely during early and late pregnancy since the risk of miscarriage and perinatal complications in the patients’ next pregnancy may be increased. A family history of early onset autoimmune or thromboembolic disease should alert the physician in the RM clinic about a possible immunological or thrombophilic etiology in spite of normal routine blood screening and this may warrant extended blood testing.

Information about repeated miscarriages among first-degree siblings or their mothers increases the chance that the patients carry a balanced translocation and based on this finding it has been proposed only to investigate karyotypes in younger RM patients with a family history of repeated miscarriages to save costs (see Chapter 2).

However, it must be emphasized that no study has so far attempted to quantify the impact of a family history of miscarriage, perinatal complications, or early onset autoimmune and thromboembolic disease for the risk of new miscarriage in patients with RM. When such a study has been undertaken, it will hopefully be possible to include family information in a more exact way when estimating the prognosis in patients with RM.

PEARLS TO TAKE HOME

A family history of repeated miscarriages or autoimmune or early onset thromboembolic disease should alert the physician of a diminished spontaneous prognosis, which should lead to referral to a dedicated RM clinic already after few (2–3) miscarriages.

Conclusions

As reviewed earlier, it is rewarding to spend efforts and time to get a comprehensive history from the patients. I think that a thorough reproductive history with detailed knowledge about whether the pregnancy loses had been PULs or clinical miscarriages, whether miscarriages had been before or after gestational week 13, and whether there had been perinatal complications associated with previous births is paramount for estimating the prognosis as exact as possible and thus will help in the decision taking regarding whether to treat or not. A reliable estimate of the number of previous pregnancy losses and their gestational ages is also important for assessing the risk of perinatal complications in subsequent ongoing pregnancies, which will influence the level of monitoring that should be offered in late pregnancy. Sometimes the reproductive history per se can be decisive for offering the patients IVF treatment or other kinds of assisted reproduction.

Clearly, if risk factors for miscarriages in the patients’ lifestyle or occupation are identified, this should result in improvement of lifestyle and working conditions.

Information about autoimmune or thromboembolic disease among the patients themselves or their first-degree family members can often raise suspicion about a possible immunological or thrombophilic etiology of miscarriages in spite of normal routine blood screening, and this may lead to extended biochemical testing.

Figure 1.1 illustrates the value of obtaining a thorough disease and reproductive history concerning a RM patient and her first-degree family members. The patient was referred to our clinic after having experienced six early miscarriages after the birth of a growth-retarded boy. It was planned to offer her treatment with intravenous immunoglobulin (IvIg) in her next pregnancy but unfortunately 3 years after referral, she had not yet managed to conceive in spite of assisted reproductive technology (ART), probably due to advanced age (now 42 years). Her history with own low-birth weight, the birth of a growth-retarded boy in the first pregnancy, symptoms of autoimmune disease (ulcerous colitis), and her mother’s history of several unexplained stillbirths (of growth-retarded boys), RM and autoimmune disease (hyperthyreosis) suggest that the family carries genetic variants that predispose both to autoimmunity and impaired trophoblast growth or function and points to a poor prognosis. We found that both the patient and her mother had very low plasma levels of mannose-binding lectin (MBL), which is determined by genetic polymorphisms on chromosome 10. Low MBL levels predispose to RM with reduced prognosis, late fetal death, and low-birth weight. The clinical information about the patient and her family was not very useful at the time when the patient was finally referred to our clinic because at that time she had become candidate for our most extensive therapy (IvIg), exclusively due to the high number of miscarriages. However, she did not get the chance to benefit from this treatment due to advanced age. If the information regarding the patient and her mother had been collected and taken seriously already when she had suffered her third miscarriage, she would have been referred at a time when she was still able to conceive and benefit from the possible effect of IvIg treatment (see Chapter 6).

Overall, a valid and detailed information about all the relevant factors that can be achieved from talking with the patients and reading their hospital records will, in conjunction with results from blood tests and investigations of uterine anatomy, provide the best basis for assessing the patients’ prognosis, in terms of chance of life birth and risk of perinatal complications, and will help taking the decision about when and how to treat.

PATIENT ADVICE

If a risk factor for RM is identified in a patient, it is important to tell her that this is probably not the full explanation for the disorder but a piece in the jig jaw puzzle and eliminating or treating this factor is no guaranty for pregnancy success.

Bibliography

Christiansen, O.B., Steffensen, R., Nielsen, H.S. and Varming, K. (2008) Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecologic Obstetric Investigation, 66, 257–267.

Edlow, A.G., Srinivas, S.K. and Elovitz, M.A. (2007) Second trimester loss and subsequent ­pregnancy outcomes: what is the real risk?American Journal of Obstetrics Gynecology, 197, 581e1–581e6.

Kolte, A.M., Nielsen, H.S., Moltke, I. et al. (2011) A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic link. Molecular Human Reproduction, 17, 379–385.

Nielsen, H.S., Andersen, A.M., Kolte, A.M. et al. (2008) A first born boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage – a confirmatory study. Fertility and Sterility, 89, 907–911.

2

Which Investigations Are Relevant?

Paulien G. de Jong,1 Emmy van den Boogaard,2 Claudia R. Kowalik,3 Rosa Vissenberg,2 Saskia Middeldorp1 and Mariëtte Goddijn2

1 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands2 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, The Netherlands3 Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, The Netherlands

Introduction

Potential risk factors for a subsequent miscarriage can be identified in women with preceding recurrent miscarriage (RM). The strength of the association with RM is not clear for all risk factors. The question thus remains which diagnostic tests should be used in daily clinical practice. Ideally, diagnostic tests should only be ­carried out if the test can either give insight in the prognosis of the individual patient or if the established cause can be treated effectively.

In clinical practice, the decision to perform diagnostic investigations follows upon a detailed history with regard to the prior miscarriages and a further medical, obstetric, lifestyle, and family history.

Women with RM are often in great despair, and it is not uncommon that diagnostic investigations are being performed and treatments are being described despite a lack of evidence. It has been shown that too many diagnostic investigations and unproven treatments are performed in women with RM since doctors find it difficult to resist insistent women.

New medical tests should be thoroughly evaluated before they are introduced in routine clinical practice, this way avoiding erroneous diagnoses or alternatively, the initiation of unproven potentially harmful therapy. In addition, increasing costs of healthcare have been calling for the elimination of ineffective medical testing.

Presently, many diagnostic interventions for women or couples with RM are controversial because there is no information available with regard to prognosis and lack of evidence of potential treatment options in case of positive test results. There is a high need for prospective cohort studies for prognostic purposes and randomized, adequately powered trials to test the beneficial effects and absence of harmful effects of treatment interventions. Only after elucidating the prognosis for individual women and/or establishing a beneficial safe treatment effect, diagnostic investigations should be performed on a routine basis in clinical practice.

Chapter 2 of this book deals with the diagnostic investigations testing for thrombophilia, chromosome abnormalities, uterine abnormalities, and thyroid autoimmunity in women with RM.

EVIDENCE AT A GLANCE

ESHRE guideline “recurrent miscarriage,” 2006RCOG guideline “recurrent miscarriage, investigation and treatment of couples,” 2011ACCP guideline “VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy” 2012

Thrombophilia tests

The term thrombophilia is used to describe a disorder associated with an increased tendency to venous thromboembolism (VTE). It can be acquired, as in women with malignant disease or antiphospholipid syndrome, as well as inherited. Traditionally, possible features are a family history of thrombosis, thrombosis at an unusual ­location or thrombosis at young age, but a large proportion of carriers of thrombophilic defects remains asymptomatic throughout life. In addition to these features, thrombophilia is also associated with an increased risk of both sporadic miscarriage and RM. Severe preeclampsia is also associated with ­thrombophilia; for other adverse pregnancy ­outcomes, including placental ­abruption and intrauterine growth restriction, the presence of an association is controversial.

Tests

The antiphospholipid syndrome is diagnosed in women if they test positive for lupus anticoagulant (nonspecific inhibitor), have moderate or high titre IgG or IgM anticardiolipin antibodies (>40 GPL or MPL or >99th percentile) or moderate or high titre IgG or IgM β2glycoprotein I antibodies (>99th percentile) on two occasions at least 12 weeks apart and suffer from at least one clinical criteria such as unexplained fetal death (later than 10 weeks of gestation), three or more unexplained consecutive miscarriages (before 10 weeks of gestation), or one or more premature births of a ­morphologically normal neonate before the thirty-fourth week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency.

These criteria for diagnosis were decided at a consensus conference in Sydney in 2006 but as of yet, still more evidence-based data are needed to sharpen the criteria.

Inherited thrombophilias are diagnosed by laboratory testing if a factor V Leiden mutation or prothrombin gene mutation (G20210A) is present or if a ­deficiency of antithrombin, protein C, or protein S is present on two separate occasions and ­measured outside of pregnancy, combined oral contraceptive use, or significant liver disease.

CAUTION

Antiphospholipid syndrome and inherited thrombophilia are associated with RM. Guidelines do not advise to test for all forms of thrombophilia, since a positive test result will not always alter clinical management.    Antiphospholipid syndrome is diagnosed if tested positive, one two occasions at least 12 weeks apart, for:

lupus anticoagulant ormoderate or high titre IgG or IgM anticardiolipin antibodies (>40 GPL or MPL or >99th percentile) ormoderate or high titre IgG or IgM β2glycoprotein I antibodies (>99th percentile) on two occasions at least 12 weeks apartand RM (three or more losses <10 weeks’ gestation and or one or more losses >10 weeks’ gestation)

Coagulation Cascade, Regulatory Mechanisms

Inherited thrombophilia can be explained by decreased levels of anticoagulant ­proteins or altered functions of coagulation factors due to mutations. The effects of the currently known inherited thrombophilic defects on fibrin formation are explained in Figure 2.1. The process of coagulation is activated and regulated in several ways, in which thrombin (factor IIa) plays a key role. It converts fibrinogen to fibrin; the main component of a hemostatic plug. Second, it activates coagulation factors V, VIII, XI, leading to increased thrombin formation, and factor XIII, which crosslinks fibrin strands. Coagulation is physiologically regulated by protein C and protein S. Protein C is activated to activated Protein C (APC) by thrombin in the presence of thrombomodulin. APC inactivates factors Va and VIIIa, and protein S serves as a cofactor in this process, indirectly decreasing thrombin formation. A third natural anticoagulant is antithrombin; it inhibits thrombin directly, but can also inactivate factors Xa, IXa, VIIa and plasmin, thereby indirectly inhibiting thrombin formation.

Inherited Thrombophilia

Two forms of inherited thrombophilia are the gain of functional mutations called factor V Leiden and prothrombin gene mutation (G20210A). Factor V Leiden results from a substitution of adenine for guanine at the 1691 position of the factor V gene. This leads to the substitution of glutamine for arginine at position 506 in the factor V polypeptide. As a consequence, factor Va is resistant to degradation by APC, which results in less downregulation of thrombin, compared to normal factor Va.

The prothrombin gene mutation results from a mutation in the promotor region of the prothrombin gene (G20210A), which leads to slightly elevated prothrombin levels, which is associated with an increased risk of thrombo­embolism.

Deficiencies of the natural anticoagulants antithrombin, protein C and protein S lead to increased thrombin generation and are relatively rare forms of inherited thrombophilia.

Prevalence of Inherited Thrombophilia

Altogether, the different forms of inherited thrombophilia are not rare, but the ­frequency varies considerably within healthy populations. Heterozygosity for factor V Leiden is the most prevalent inherited thrombophilic defect, occurring in 5% of Caucasians; however, it is rare in Asians and Africans. The mutation in the ­prothrombin gene is present in approximately 2–3% of Caucasians, but is also less common in Asians and Africans. Homozygosity for these two mutations is rare, with a prevalence of 0.02% for factor V Leiden and 0.014% for prothrombin gene mutation (G20210A). Deficiencies of Protein C, Protein S, and antithrombin are much rarer than factor V Leiden or prothrombin gene mutation (G20210A); their combined ­prevalence is approximately 1%.

Figure 2.1 Blood coagulation and fibrinolysis.Simplified scheme of coagulation and fibrinolysis. Coagulation is initiated by a tissue factor (TF)–factor VIIa complex that can activate factor IX or factor X, leading to formation of the key enzyme thrombin (factor IIa). Tissue factor-dependent coagulation is rapidly inhibited by tissue factor pathway inhibitor (TFPI). Coagulation is maintained through the activation of factor XI by thrombin. Through the intrinsic tenase complex (factors IXa and VIIIa) and the prothrombinase complex (factors Xa and Va), the additional thrombin required to downregulate fibrinolysis is generated by the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). The coagulation system is regulated by the protein C pathway. Thrombin activates protein C in the presence of thrombomodulin. Together with protein S (PS), activated protein C (APC) is capable of inactivating factors Va and VIIIa, which results in a downregulation of thrombin generation and consequently in an upregulation of the fibrinolytic system. The activity of thrombin is controlled by the inhibitor antithrombin (AT). The solid arrows indicate activation and the broken arrows inhibition.

Pathophysiological Mechanisms Leading to Pregnancy Loss