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OVARIAN HYPERSTIMULATION SYNDROME




Ovarian Hyperstimulation Syndrome (OHSS) is a condition that can occur
in women undergoing in vitro fertilization, after having follicle stimulating
hormone (FSH) injections to stimulate egg growth and maturation. Some
patients respond excessively to the drug and dose given. If large numbers of
eggs mature, the high hormone levels coming out of the hyperstimulated
ovaries, combined with the increased size of the ovaries, can cause extremely
serious, and sometimes lethal, side effects. Moderate-to-severe OHSS requires
admission to a hospital. Dr. Rizk is one of the world™s top experts on managing
OHSS.

This is the ¬rst published book dedicated to all aspects of OHSS. The
pathophysiology, prevention and management of this syndrome have been
revolutionized over the past decade, and it is important for reproductive
practioners and infertility specialists to understand the latest ¬ndings about this
potentially deadly condition. The author reviews in depth the classi¬cation,
epidemiology, pathophysiology, complications, and prediction, prevention and
treatment options for OHSS. This book is intended for infertility specialists,
reproductive medicine specialists and assisted reproduction specialists.

Botros R. M. B. Rizk is Professor and Chief, Division of Reproductive Endo-
crinology and Infertility, Department of Obstetrics and Gynecology at the
University of South Alabama School of Medicine. He is also Medical and
Scienti¬c Director of the University of South Alabama in vitro fertilization
program.
OVARIAN
HYPERSTIMULATION
SYNDROME

Epidemiology, Pathophysiology, Prevention and Management




BOTROS R. M. B. RIZK
University of South Alabama
School of Medicine
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521857987

© Botros Rizk 2006


This publication is in copyright. Subject to statutory exception and to the provision of
relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.
First published in print format 2006

eBook (NetLibrary)
ISBN-13 978-0-511-22130-9
ISBN-10 0-511-22130-4 eBook (NetLibrary)
hardback
ISBN-13 978-0-521-85798-7
hardback
ISBN-10 0-521-85798-8

paperback
ISBN-13 978-0-521-68149-0
paperback
ISBN-10 0-521-68149-9

Cambridge University Press has no responsibility for the persistence or accuracy of urls
for external or third-party internet websites referred to in this publication, and does not
guarantee that any content on such websites is, or will remain, accurate or appropriate.
This book is dedicated to my very dear and beloved parents, Dr. Isis Mahrous Rofail, my mother,
and Mitry Botros Rizk, my father. Their unlimited true love, genuine sacrifice, care and support
have filled my life with happiness, fulfilment and gratitude. Their memories, wisdom and
thoughts will stay with us forever to guide us.
CONTENTS




Foreword by Robert G. Edwards page ix

Preface xiii

I Classi¬cation of Ovarian Hyperstimulation Syndrome 1

II Epidemiology of Ovarian Hyperstimulation Syndrome:
Iatrogenic and Spontaneous 10

III Pathophysiology of Ovarian Hyperstimulation Syndrome 43

IV Genetics of Ovarian Hyperstimulation Syndrome 79

V Complications of Ovarian Hyperstimulation Syndrome 92

VI Prediction of Ovarian Hyperstimulation Syndrome 119

VII Prevention of Ovarian Hyperstimulation Syndrome 130

VIII Treatment of Ovarian Hyperstimulation Syndrome 200

Index 227

Color plate section, follows page 82




vii
FOREWORD




A COMPLICATED COMPLICATION

The subject of this book continues to attract serious medical attention. Ovarian
hyperstimulation was a problem from before the days of in vitro fertilization
(IVF), when it was noted by an Israeli group among their patients being
stimulated for ovulation induction. It also emerged when IVF created the need
to apply ovarian stimulation to produce, say, 10 mature oocytes for fertilization
in vitro. Today, the condition is well known and heavily researched as it spreads
with every practising IVF centre, where there is a constant need to produce a
medium number of follicles per patient. Unfortunately, as originally discovered
in laboratory animals, there is a very weak correlation between the dose of
gonadotrophins and the number of ovulated oocytes, indicating that unknown
numbers of follicles may begin their growth and expansion. Numerous
attempts have been made to introduce useful therapies for this condition,
and these are effective to varying degrees of ef¬ciency.
Botros (Peter) Rizk is highly talented and presents a text that is well
balanced between the description of OHSS, its causes and effects, and means of
controlling its very serious complications. His own opinions come through very
clearly and will help professionals involved in assisted reproduction to keep
up-to-date with current therapies. Available therapies are assessed in detail,
which is certain to be of help to many clinicians. He gives his own clear
opinions on the risks and the means of prevention. Since he writes simply and
informatively, it is a pleasure to read the various sections of this book. The clear
layout, good illustrations and numerous references in the book should help
to clarify the causes of this condition. Every point made in the book has
several associated references, providing clear pointers to further reading.
The numerous illustrations help to carry the reader through this exhaustive
evaluation of the causes of and, hopefully, cures for OHSS. Overall, the text is
so clear and authoritative that attention must be given in this Foreword to the
aspects of ovarian hyperstimulation covered.
Successive chapters cover the classi¬cation of the syndrome, its
epidemiology, pathophysiology and genetics. These are followed by chapters
on the complications of hyperstimulation, its prediction and patient education
to help with this disorder. The book is completed with chapters on the
prevention and treatment of hyperstimulation. The layout is very simple
and attractive, such as in the opening classi¬cation where the objectives of
classi¬cation are considered, including a description of its ¬rst classi¬cation


ix
x FOREWORD




by Rabau et al. in 1967, followed by successive modi¬cations (e.g. the division
of its symptoms into mild, moderate and severe as successive investigators
modi¬ed the original protocol), until workers today go into such detail as
suspecting hypothyroidism or FSH receptors may be involved. Discussing the
epidemiology of ovarian hyperstimulation, the author stresses the effects of
IVF on our understanding of ovarian hyperstimulation, the need for milder
treatments, the relationships with polycystic ovarian disease and the roles of
hyperinsulinism. The accompanying endocrine revolution led to the introduc-
tion of human menopausal gonadotrophin (hMG) and then recombinant
preparations of gonadotrophins and the introduction of GnRH, its agonists and
antagonists. The complex problems of the short luteal phase in relation to the
use of ovarian stimulation in cyclic women is discussed in detail and assessed
for spontaneous and recurrent situations.
Extensive attention is naturally paid to the pathophysiology of hyper-
stimulation and its associated massive ovarian enlargement and circulatory
disorders. These highly serious conditions have, fortunately, attracted the
attention of many investigators who have steadily characterized their successive
stages. A glance at the work of Van Beaumont in 1872 introduces the problems
of osmoregulation, capillary permeability, the roles of various steroids and the
ovarian renin“angiotensin system. This section also stresses the genetic nature
of OHSS, with references to the actions of prostaglandins, Von Willebrand
factor and of vascular endothelial growth factor (VEGF) as an agent affecting
capillary permeability. Its actions in follicular ¬‚uid are presented in detail and
in relation to the ratio between total and free VEGF. Analyses of the roles of
interleukins, selectins and intercellular adhesion molecule (ICAM) follow in
succession.
Not surprisingly, the genetics of OHSS occupies the succeeding chapter,
opening with descriptions of recent work on the follicle stimulating hormone
(FSH) receptor, its mutations and the origin of spontaneous OHSS. Extensive
detail is considered in this and the previous chapter, as the slow but cer-
tain clari¬cation of the background genetics is assessed. Reaching the
molecular level is certain to open new leads, such as the higher sensitivity
to human chorionic gonadotrophin (hCG) to speci¬c forms of the FSH
receptor mutants. This polymorphic system may determine the severity of
many systems reliant on FSH activity and the threshold effects of the various
mutants.
The complications of OHSS also attract, quite correctly, the detailed
attention of the author. Fatalities are very rare, yet nevertheless have attracted
considerable attention ever since the ¬rst case was described by Lunenfeld
and his colleagues. Cerebrovascular complications include thromboembolic
complications and hypercoaguable states, and their early and later effects are
assessed. The detailed discussion of these states and their related effects leads
to a most authoritative analysis by the author. Family histories, rare vascular
complications, myocardial infarction and respiratory complications are all
described. The details of these complications are so numerous as to demand a
close reading of this chapter. Predicting OHSS is not easy, and is considered in
xi
FOREWORD




Chapter VI. Classical appproaches involve estrogen assays, yet their value is still
questioned today despite exhaustive studies. The author discusses the value of
assessing the rising levels of VEGF from granulosa cells and in blood. Assays for
Von Willebrand factor, especially near the time of implantation, and for inhibin
are mentioned, together with the use of ultrasound for scoring the sizes of the
numerous follicles, measuring ovarian volume and low intravascular ovarian
resistance. Risk factors include rapidly rising plasma oestrogen levels and young
women with polycystic ovaries with excessive follicular response, especially
soon after the hCG injection (early OHSS).
The author clari¬es the risks to patient health and provides help to increase
awareness of this distressing disorder. ˜Ten Commandments™ for preventing
OHSS initiate Chapter VII, and these are soon doubled. The ¬rst set includes
the use of low doses of stimulatory gonadotrophins, and ovarian diathermy
prior to stimulation. The second list proposes delaying hCG, avoiding it by
using GnRH to induce ovulation and progesterone for luteal phase support.
Risks of polycystic ovary syndrome (PCOS), the use of metformin and
weight reduction are essential reading, although the consequences of changing
gonadotrophin levels have always been somewhat unpredictable, while results
with metformin, aromatase inhibitors, pentoxyfylline and other formulations
require much more analysis. Ovarian drilling and the use of GnRH antagonists
are discussed at some length, although more data are clearly needed. Likewise,
by using natural cycle IVF, single-embryo transfer may help, although the
author concludes that no single protocol has yet proved effective.
Adjusting the effects of ovarian stimulation by ˜˜coasting™™ HCG has been in
use for many years now, and the author gives much space to its practice.
Summarizing numerous reports, he concludes there is still a paucity of
randomized trials, and that coasting risks decreases in oocyte numbers and
pregnancy rates. Using GnRH antagonists, and recombinant luteinizing
hormone (rLH) does not lead to ¬rm conclusions, although rLH may offer
the best alternative. Injecting albumim or starch are of doubtful value, and
reducing follicle numbers, or cryopreserving oocytes for a later cycle seem to
offer little. The author suggests a combined approach is best, involving
decreasing gonadotrophins, coasting, reducing HCG levels to induce ovulation,
and giving progesterone for luteal support.
The ¬nal chapter deals with treatments for OHSS. This has attracted
detailed attention and the author recommends thorough check-up and follow-
up. Moderate forms may be treated on an outpatient basis, with ultrasound,
blood counts, liver function and coagulation monitoring, and perhaps too
with rehydration, culdocentesis and albumin injections. Severe forms involve
aspirating ascitic ¬‚uid, giving intravenous ¬‚uids, hydration, paracentesis, liver
function tests, investigating respiratory compromise, anticoagulants to preserve
renal function, and also treating many other symptoms. Ascitic ¬‚uid and
pleural effusions may be aspirated, many clinicians considering this a matter of
priority. Abdominal paracentesis has been questioned but is now regarded as
essential. The author covers the basics of these studies and concludes by
describing novel forms of blocking VEGFR-2.
xii FOREWORD




This book has several very attractive advantages. It is well written and
maintains a momentum that carries the reader with the text. It is clearly
authoritative and written by a clinician with considerable experience. The
detailed references set the scene for further reading, give credit to workers in the
¬eld and display the immense amounts of effort put into hyperstimulation
research. It will be a very handy tome on a clinician™s bookshelf, and should
also attract the attention of non-clinical scientists and researchers and those
practising IVF. And in the future, it could be updated fairly quickly as the saga
of ovarian hyperstimulation enters new ¬elds of scienti¬c awareness.
Professor Robert G. Edwards, C.B.E., Ph.D., D.Sc., F.R.C.O.G., F.R.S.
Emeritus Professor, Cambridge University, Cambridge, England
Editor-in-Chief, Reproductive Biomedicine Online
PREFACE




Ovarian hyperstimulation syndrome (OHSS) presents a unique challenge in
the practice of medicine in general and reproductive medicine in particular.
There is no other situation where a ˜˜healthy™™ patient seeks medical assistance
and may end up with serious medical complications. About 20 years ago,
when I was working at Northwick Park Hospital in London, UK, a young
patient presented to the emergency department a few days after a Gamete
Intra-Fallopian Transfer (GIFT) procedure with severe OHSS, shortly followed
by stroke. Amazingly, she completely recovered and delivered a healthy girl.
The acute developments in this patient had an extraordinary effect on me, and
since then I have dedicated a signi¬cant part of my career to this iatrogenic
complication.
Worldwide, more than 500 000 in vitro fertilization (IVF) cycles are
performed every year, and ¬ve to six times this number of superovulation cycles
are performed. Therefore, severe OHSS will be encountered in small numbers
by individual centers, although large numbers of cases will occur worldwide.
This has led to lack of expertise in dealing with the myriad of complications
of OHSS, especially because of their multisystem effects. Furthermore, the
emphasis has been on how to maximize the success of IVF. This emphasis
should shift to how to maximize its safety, and this is the ultimate goal of
this book.
Writing this book, I was driven by a desire to provide a clinical guide that
will help those practicing in the ¬eld of assisted reproduction and infertility.
Both clinicians and scientists were in my mind. The infertility specialist will ¬nd
the book a resource on how to evaluate patients before starting fertility
treatment, with keen attention on to how to avoid the development of OHSS by
a series of well-chosen decisions. The success of this book should be judged by a
decline in the incidence and severity of OHSS seen in IVF centers and by
infertility specialists. The scientist reading this book will immediately realize
that recent discoveries in receptor mutations emphasize that only systematic
scienti¬c research can provide real understanding of the pathophysiology of
OHSS and the potential for change. I hope this book boosts their enthusiasm to
make further discoveries. The IVF nurse coordinator who is directly involved in
ovarian stimulation will ¬nd this book helps her understand what is going
through the minds of the IVF team during the cycle, and so helps her to serve
her patients better.




xiii
xiv PREFACE




The structure of the book is simple, with eight chapters covering all
important areas. It was essential to start with classi¬cation in Chapter I “
categorizing patients makes it possible to decide who can be treated as an out-
patient and who needs to be admitted to hospital or intensive care. Chapter II
on epidemiology emphasizes which groups of patients are at risk, taking
into consideration patient characteristics and treatment protocols. The call to
establish an international registry should be a priority of the American Society
for Reproductive Medicine and the European Society for Human Reproduction
and Embryology. The pathophysiology of OHSS is where all the recent research
developments have occurred, and in Chapters III and IV in-depth discussion
of the molecular biology research over the last decade complements our
understanding. These developments should stimulate basic science researchers
to advance our knowledge not only of hyperstimulation but also of routine
ovulation induction. In Chapter V the detailed discussion of the complications of
OHSS should prepare clinicians for dif¬culties they may encounter. Prediction,
prevention and treatment are covered in the ¬nal three chapters. There has
been an extraordinary effort to prevent OHSS. Eventually, this should mean
that we all have extensive experience of prevention and less experience of
treatment. Chapter VIII focuses on outpatient and inpatient treatment, as well as
intensive care and novel medical therapies that we may see in the next few years.
The work presented in this book has been the result of tremendous
research and contributions from clinicians and scientists all over the world.
The ¬ght against OHSS has been global, with important contributions from
Europe, the USA and the Middle East. While early work is quoted in detail
in this book, the recent advances in the last ¬ve years are emphasized. The
wonderful stimulation, leadership and guidance provided by Bob Edwards has
been extraordinary and could have never been replaced. I have also greatly
enjoyed my extensive collaboration over the last two decades with Dr. Johan
Smitz from Belgium, Dr. Mohamed Aboulghar from Egypt, and Dr. Melanie
Davies, Dr. Charles Kingsland and Dr. Sam Abdalla from the UK. I would also
like to thank Dr. Bridgett Mason and Professor Howard Jacobs from London
and Professor Steve Smith from Cambridge for the magni¬cent opportunities
they gave me in those two great cities in the UK. Working with skilled
clinicians, such as Dr. Dudley Mathews from Kent and Dr. Roger Martin and
Simon Crocker from Norwich provided great enjoyment. I thank Miss Julie
Hazelton for her dedication and assistance in typing the manuscript of this
book. I believe that our collaboration with investigators from Spain, Greece and
Italy will open the way to more innovations. I have tried my best to present
impartially the evidence on every issue that is open for debate, while making
my personal views clear. I hope that clinicians will identify much useful
experience, and that scientists will maintain their eagerness for research that
will enlighten our understanding; and ultimately that our patients will bene¬t
from all our efforts.

Botros Rizk, M.D., M.A., F.R.C.O.G., F.R.C.S.(C.), H.C.L.D., F.A.C.O.G., F.A.C.S.
Alabama 2006
I

CLASSIFICATION OF OVARIAN
HYPERSTIMULATION SYNDROME


Ovarian hyperstimulation syndrome (OHSS) is characterized by bilateral,
multiple follicular and thecal lutein ovarian cysts (Figure I.1) and an acute shift
in body ¬‚uid distribution resulting in ascites (Figure I.2).


THE PURPOSE OF OVARIAN HYPERSTIMULATION
SYNDROME CLASSIFICATIONS

The objectives of all OHSS classi¬cations are three-fold (Aboulghar and
Mansour, 2003). The ¬rst objective is to compare the incidence of OHSS.
The second objective is to evaluate the ef¬cacy of the different approaches for
prevention of the syndrome. The ¬nal objective is to plan the management of
OHSS, according to its severity and the presence or absence of complications.


OVERVIEW OF OHSS CLASSIFICATIONS

There has been no unanimity in classifying OHSS, and divergent classi¬cations
have made comparisons between studies dif¬cult (Rizk, 1993). Aboulghar and

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