3051_Seifer_00FM 11/27/01 3:41 PM Page i

Office-Based
Infertility Practice
3051_Seifer_00FM 11/27/01 3:41 PM Page ii
3051_Seifer_00FM 11/27/01 3:41 PM Page iii

David B. Seifer, M.D. Robert L. Collins, M.D.

Director, Division of Reproductive Endocrinology Medical Director, The Reproductive Center
and Infertility Youngstown, Ohio
and and
Professor and Vice-Chair of Academic Affairs Associate Professor
Department of Obstetrics, Gynecology and Department of Obstetrics and Gynecology
Reproductive Sciences Northeast Ohio University College of Medicine
UMDNJ-Robert Wood Johnson Medical School Rootstown, Ohio
New Brunswick, New Jersey

Editors

Office-Based
Infertility Practice

With 58 Figures
3051_Seifer_00FM 11/27/01 3:41 PM Page iv

David B. Seifer, M.D. Robert L. Collins, M.D.

Director, Division of Reproductive Medical Director
Endocrinology and Infertility Reproductive Endocrinologist
and The Reproductive Center
Professor and Vice-Chair of Academic Affairs Youngstown, OH 44514, USA
Department of Obstetrics, Gynecology and and
Reproductive Sciences Associate Professor
UMDNJ-Robert Wood Johnson Medical Department of Obstetrics and Gynecology
School Northeast Ohio University College of Medicine
303 George Street Rootstown, OH 44272, USA
New Brunswick, NJ 08901, USA

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

Library of Congress Cataloging-in-Publication Data

Office-based infertility practice / editors, David B. Seifer, Robert L. Collins
p. cm.
Includes bibliographical references and index.
ISBN 0-387-98390-2 (hbk : alk. paper)
1. Infertility. 2. Office practice. 3. Human reproductive technology. I. Seifer, David
B., 1955– II. Collins, Robert L.
RC889 .O35 2001
616.6.9206—dc21 00-053200

Printed on acid-free paper.

© 2002 Springer-Verlag New York, Inc.

All rights reserved. This work may not be translated or copied in whole or in part without the
written permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York,
NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use
in connection with any form of information storage and retrieval, electronic adaptation, computer
software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.
The use of general descriptive names, trade names, trademarks, etc., in this publication, even if the
former are not especially identified, is not to be taken as a sign that such names, as understood by
the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone.
While the advice and information in this book are believed to be true and accurate at the date of
going to press, neither the authors nor the editors nor the publisher can accept any legal responsi-
bility for any errors or omissions that may be made. The publisher makes no warranty, express or
implied, with respect to the material contained herein.

Production managed by Jenny Wolkowicki; manufacturing supervised by Joseph Quatela.

Typeset by Matrix Publishing Services, Inc., York, PA.
Printed and bound by Edwards Brothers, Inc., Ann Arbor, MI.
Printed in the United States of America.

9 8 7 6 5 4 3 2 1

ISBN 0-387-98390-2 SPIN 10660187

Springer-Verlag New York Berlin Heidelberg

A member of BertelsmannSpringer Science+Business Media GmbH
3051_Seifer_00FM 11/27/01 3:41 PM Page v

This book is dedicated to our children Ben Joseph Seifer, Charlie

Max Seifer, Denise Collins, and Robbie Collins, for the joy, love
and promise they represent.
This page intentionally left blank
3051_Seifer_00FM 11/27/01 3:41 PM Page vii

Preface

The practice of clinical reproductive medicine has practice in the era of managed care and coordinat-
gradually moved from its initial 1980–90 hospital ing ancillary offsite medical personnel.
base to its present (circa 2001) office site of oper- The objective of this text is to assist in this ongo-
ation. With this transition have been improvements ing endeavor by presenting in a clear, concise man-
in efficiency of practice often in response to ner many of the topics relevant to contemporary
increased pressure to provide the most patient sat- office-based infertility practice. The initial half of
isfaction. An added challenge of office-based prac- this text addresses topics which focus upon general
tice has been taking on many of the responsibili- concepts of infertility evaluation and practice. The
ties of what had been traditionally the hospital’s latter half is a practical approach to the execution
domain. Some of these new responsibilities have of specific office-based infertility procedures. We
included the ordering of operative supplies and hope this book will assist all medical personnel who
equipment, the establishment of quality control dedicate their clinical effort in achieving what is
programs, construction and maintenance of special most coveted by our patients, the birth of a healthy
laboratory spaces, redesigning efficient methods of newborn.

DAVID B. SEIFER, M.D.

UMDNJ-Robert Wood Johnson Medical School
ROBERT L. COLLINS, M.D.
The Reproductive Center, Youngstown, Ohio

October 2001

vii
This page intentionally left blank
3051_Seifer_00FM 11/27/01 3:41 PM Page ix

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

1 Evaluation of the Female for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Bryan D. Cowan
2 Evaluation of the Male for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Kevin A. Spear
3 Detection and Therapeutic Approaches to Age-Related Infertility . . . . . . . . . . . . . . . . . . . . 24
Fady I. Sharara, Richard T. Scott, Jr., and David B. Seifer
4 Role of Ultrasonography in Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Theresa Widrich
5 Coping with Infertility: Practical Psychosocial Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Dorothy Greenfeld
6 Impact of Managed Care on Office-Based Infertility Practice . . . . . . . . . . . . . . . . . . . . . . 58
Richard E. Blackwell
7 Basics of Laboratory Set-Up in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Dean E. Morbeck
8 Office Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Angeline N. Beltsos
9 Ovulation Induction and Controlled Ovarian Hyperstimulation with
Intrauterine Insemination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Robert L. Collins
10 Diagnostic and Therapeutic Hysteroscopy in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
David A. Grainger, Bruce l. Tjaden, and Arjav Shah
11 Endoscopic Evaluation of the Fallopian Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Eric S. Surrey
12 Transcervical Tubal Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Jacek W. Graczykowski and David B. Seifer
13 Microlaparoscopy for Infertility in the Office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Steven F. Palter
14 Treatment of Cervical Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Gary N. Frishman
15 Treatment of Male Reproductive Dysfunction in the Office . . . . . . . . . . . . . . . . . . . . . . . . 150
Hossein Sadeghi-Nejad and Robert Oates

ix
3051_Seifer_00FM 11/27/01 3:41 PM Page x

x Contents

16 In Vitro Fertilization in the Office Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Glen K. Adaniya and Bradford L. Bopp
17 Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation . . . . . . . . . . . . . . . . . . 174
Phillip E. Patton and Don P. Wolf
18 Intratubal Gamete Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Kristin Sinnock Friel and Alan S. Penzias
19 Complications of Ovulation Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Janee A. Fonslick and David B. Seifer
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
3051_Seifer_00FM 11/27/01 3:41 PM Page xi

Contributors

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

xi
3051_Seifer_00FM 11/27/01 3:41 PM Page xii

xii Contributors

Alan S. Penzias, M.D., Boston IVF, 40 Second Avenue Suite 300, Waltham MA 02451, USA
Hossein Sadeghi-Nejad, Director, Center for Male Reproductive Medicine, UMD-New Jersey Medical
School and Hackensack University Medical Center, 20 Prospect Ave, Suite 711, Hackensack NJ 07601,
USA
Richard T. Scott, Jr., M.D., Reproductive Medicine Associates, 111 Madison Avenue Suite 100, Morris-
town, NJ 07962, USA
David B. Seifer, M.D., Director, Division of Reproductive Endocrinology and Infertility, and Professor
and Vice-Chair of Academic Affairs, Department of Obstetrics, Gynecology and Reproductive Sci-
ences, UMDNJ–Robert Wood Johnson Medical School, 303 George Street, Suite 250, New Brunswick
NJ 08901, USA
Arjav Shah, M.D., Orange Park Medical Center, 1605 Kinsley Avenue, Orange Park, FL 32073, USA
Fady I. Sharara, M.D., The Fertility and Reproductive Health Center, 4316 Evergreen Lane, Annandale,
VA 22003, USA
Kevin A. Spear, M.D., Advanced Urology Associates, Professional Center North, 75 Arch Street, Suite
101, Akron, OH 44304, USA
Eric S. Surrey, Colorado Center for Reproductive Medicine, 799 East Hampden Ave. Suite 300, Engle-
wood, CO 80110, USA
Bruce L. Tjaden, M.D., Center for Reproductive Medicine, 2903 E. Central, Wichita, KS 67214, USA
Theresa Widrich, M.D., Department of Obstetrics and Gynecology, Landeskrankenhaus Mödling, Sr. M.
Restitutag 12, A-2340, Mödling, Austria
Don P. Wolf, Ph.D., Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505
NW 185th Avenue, Beaverton, OR 97006-3448, USA
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 1

1
Evaluation of the Female for Infertility
Bryan D. Cowan

Evaluation of women with infertility is an increas- duction, and female tuboperitoneal diseases.
ingly important part of the primary care practi- Although the distribution of these defects varies
tioner’s role. Reproductive dysfunction affects with infertility populations, it is convenient to con-
more than 2 million married couples during their sider that about 40% of couples have male factor
reproductive lives, and approximately 10–15% of dysfunction, ovulatory dysfunction occurs in 20%,
women between the ages of 25 and 45 seek office and anatomic abnormalities are present in 30%
consultation concerning reproductive dysfunction. (Table 1–1). Ten percent of couples have no iden-
As a perspective, the fertility rate in the United tifiable cause of their reproductive dysfunction after
States has remained nearly constant for more than a thorough infertility evaluation.
a decade at 2.1 live births per reproductive-age
female. This is coincident with the ideal fertility
rate that maintains a population profile consistent Strategy for Infertility Testing
with “zero population growth.” Because our soci-
ety has this population growth philosophy, there is Once the diagnosis of infertility is confirmed, a
great pressure on couples to have their families at thorough evaluation correctly classifies the cause
a time that is convenient for them personally and of infertility in 85–90% of patients. Most of the
professionally. Thus many couples seek fertility evaluation is conducted in an office environment
services to overcome acquired diseases, enhance and usually requires no more than 60–90 days to
natural decreasing fertility associated with age, and complete. The timing of the tests is generally coor-
accommodate life style agendas. dinated with the female ovarian menstrual cycle.
Figure 1–1 illustrates the hormone levels during the
menstrual cycle. It is usually convenient to sched-
Confirmation of Infertility ule tests throughout the course of two cycles to
avoid disruption of the ovarian menstrual cycle and
Infertility is established when a couple attempts a potential errors in interpretation if tests conflict.
pregnancy for 12 months or longer and conception
fails. It is important to remember that the natural
fertility rate is expressed in two ways. The overall Male Factor Evaluation
cumulative pregnancy rate is the expected proba-
bility of conception within a population when all The history from the male partner should include
the pregnancies have occurred. The second impor- important information concerning a history of pre-
tant factor to consider is the occurrence of preg- viously fathered pregnancies, testicular trauma or
nancy with each opportunity (ovulation) for con- infection, environmental exposure to toxins or heat,
ception. In young, unencumbered couples, this and coital and sexual performance. If a physical
fecundity rate is approximately 20% per month. examination can be performed, the genitalia are
Three important factors are associated with infer- inspected and the developmental stage classified.
tility. They are represented by major disturbances The scrotum is evaluated for masses, varicocele, or
in male gamete production, female gamete pro- inguinal hernia.

1
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 2

2 B.D. Cowan

TABLE 1–1. Causes of Infertility TABLE 1–2. Semen Analysis Parameters

Cause % Volume 2 ml
pH 7.2–8.0
Male factor 40 Concentration 20  106 spermatozoa/ml
Ovulation defect 20 Count 40  106 spermatozoa/ejaculate
Pelvic diseases 30 Motility 50% forward progression or
Unexplained 10 25% rapid progression
Morphology 30% normal forms
Vitality 75% live

Semen analysis is the single most important lab- Source: WHO, 1992.
oratory test for male factor evaluation. Although
many parameters can be measured, the volume,
total number of ejaculated sperm, percent motility
tration, zona binding assays, cervical mucus pene-
of the sperm, and percent normal forms (Table 1–2)
tration assays, and seminal antibody detection.
represent the major and most important parameters.
Detecting antibody on sperm has been associated
It is important to remember that the time required
with the prediction of infertility, particularly if the
to complete a cycle of sperm production is 70–80
antibody is recognized to be a head-to-head agglu-
days. Thus if antecedent illness, stress, or injury
tinating antibody of the immunoglobulin G class.
has occurred, it is advisable to repeat the semen
Unfortunately, except for antibody testing, other
analysis after an appropriate interval of time has
adjunctive tests are less helpful, difficult to per-
elapsed that would ensure measurement of an unaf-
form, and expensive. In particular, most authorities
fected sperm cycle.
recommend that routine use of the postcoital test
Adjuncts to the traditional semen analysis have
be abandoned. This test is difficult to interpret and
been sought to assess the fertilizing capability of
dependent on female cervical mucus production
the semen or the fertility of the man. These adjuncts
during the ovarian menstrual cycle; moreover, uni-
include a postcoital test, zona-free hamster pene-
form norms have not been established. Addition-
ally, critical evaluation of reported case series
reveal an inability of the test to predict fertility.
Thus we believe that semen analysis represents
the single and most important test for evaluating the
man. When necessary, this test should be repeated
at 2- to 3-week intervals to encompass a complete
70- to 80-day sperm cycle. Other than seminal anti-
sperm antibodies, other routine adjunctive tests of
sperm function are not justifiable and should be used
only for special indications.

Assessment of Ovulation
The history of the female partner should include
the time of menarche, the interval between men-
strual cycles, the presence or absence of molimina,
the duration of menstrual flow, and the presence or
absence of dysmenorrhea. Women with regular,
predictable cycles (26–34 days) can be predicted to
be ovulatory with a high degree of certainty
FIGURE 1–1. Hormone levels during the menstrual cycle. (99.8%). In perspective, only two to three of every
During the proliferative phase (days 1–14) estrogen lev- 1000 women who offer a history of regular, pre-
els progressively rise. Ovulation (day 14) is preceded by
an increase in the gonadotropins and is signaled by a
dictable cycles are discovered to be anovulatory.
sharp rise in luteinizing hormone (LH). During the secre- It is important to remember that the menstrual
tory phase (days 15–28) the corpus luteum produces history reflects subjective information, and confir-
increasing levels of progesterone. In the absence of fer- mation of ovulatory status should be determined
tilization, menstruation (days 1–5) occurs as the endo- by appropriate laboratory tests. Three office-based
metrium is shed. procedures are used to confirm that ovulation has
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 3

1. Evaluation of the Female for Infertility 3

TABLE 1–3. Assessment of Ovulatory Status ng/ml indicates about luteal function, but it clearly
Test Timing means that ovulation has occurred.
Endometrial biopsy is typically performed during
BBT Complete cycle
Serum progesterone Mid-luteal the late luteal phase to classify the morphologic
Endometrial biopsy Late luteal transformation of the secretory endometrium. The
Sonography Late follicular “luteal phase defect” has been defined as endo-
LH testing Late follicular metrium that is more than 48 hours “out of phase”
BBT, basal body temperature; LH, luteinizing hormone.
with the cycle. The proper interpretation of this test
requires three pieces of information: (1) the date the
test was performed; (2) the date natural menstrua-
occurred, and two additional office-based proce- tion occurred; and (3) the morphologic dating of the
dures are used to determine that ovulation will endometrial specimen. For example, a specimen
occur in the immediate future. obtained on day 26 of a 28-day cycle that was inter-
To determine that ovulation has occurred, most preted as consistent with day 23 endometrium would
clinicians use basal body temperature (BBT) chart be considered out of phase, but a specimen obtained
monitoring, luteal phase serum progesterone meas- 6 days before the onset of menstruation consistent
urements, or secretory phase endometrial biopsy. with day 23 secretory endometrium would be con-
BBT chart monitoring typically reveals a tempera- sidered in phase. Finally, interest has emerged con-
ture below 98°F during the follicular phase (Table cerning adjunctive measurement of endometrial pep-
1–3). After ovulation the temperature rises 0.2°– tides. In particular, some integrins are known to be
0.6°F and is sustained for 9–13 days during the expressed at unique times during the secretory phase.
luteal phase. Immediately before or coincident with Measurement of these factors may increase the accu-
the onset of menses, the temperature falls below racy of properly classifying endometrial specimens.
98°F. This typical “biphasic” profile is demon- Endometrial biopsy is inconvenient to the pa-
strated repeatedly in ovulatory women. tient, is associated with mild discomfort, and is
Use of BBT chart monitoring to determine dys- approximately four to six times more expensive
functional ovulation (in contrast to the absence of than serum progesterone measurements. Unfortu-
ovulation) is generally not helpful. Unfortunately, nately, there is a mixed degree of agreement regard-
parameters such as the number of temperature-ele- ing serum progesterone measurements and endo-
vated days and the magnitude of the temperature metrial maturity. Hence these two tests currently
rise have correlated with other measures of luteal stand at the “discretion of the practitioner” as inde-
function (progesterone, endometrial biopsy) and pendent but not correlated tests.
have not been used reliably to initiate therapy. Thus Follicular measurements (sonography) have
BBT chart monitoring can establish ovulation but been used to predict ovulation. In general, a natu-
is unable to determine the presence or absence of rally growing follicle expands at approximately 2–3
ovulatory disturbances. mm per day and ruptures after the follicular diam-
Serum progesterone concentrations are higher eter approaches 20–22 mm. In contrast, a clomi-
than 5 ng/ml during the luteal phase. Most clini- phene citrate-stimulated follicle ruptures when the
cians use the luteal phase progesterone level to diameter approaches 24–26 mm. After rupture the
establish both ovulation and the quality of ovula- follicle generally collapses, and fluid collects in
tion. If the serum progesterone is higher than 5 the cul-de-sac. Commonly, a luteal structure can be
ng/ml, ovulation is confirmed. This measurement observed in the ovary. Finally, urinary measure-
can apply to any day of the luteal phase. When more ments of mid-cycle luteinizing hormone (LH) can
rigorous criteria are set for the time of progester- detect the preovulatory LH surge. Because urinary
one measurement (6–8 days prior to the onset of LH measurements are done infrequently (usually
menses—typically day 20–22 of the cycle), several once or twice daily), it is reasonable to estimate
investigators have reported that the “quality” of that ovulation will occur 24–36 hours after detec-
ovulation can be determined. The precise threshold tion of the surge.
value of progesterone is controversial, but most
agree that a mid-luteal progesterone level of less
than 10 ng/ml is consistent with luteal dysfunction. Anatomic Defects
Additionally, most authors agree that a serum pro-
gesterone level higher than 20 ng/ml is consistent Figure 1–2 reviews the anatomy of the female
with adequate luteal function. There is no consen- pelvic organs. Two principal anatomic defects
sus on what a serum progesterone level of 10–20 deserve evaluation for couples with infertility. Uter-
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 4

4 B.D. Cowan

TABLE 1–4. Assessment of Tuboperitoneal/

Anatomic Status
Test Comment
Hysterosalpingography High false-negative rate
Laparoscopy Confirms peritoneal disease
Hysteroscopy Confirms intrauterine disease
Sonohysterography Visualizes mural and
intrauterine lesions
Sonography Identifies uterine and
endometrial contour

Currently, both aqueous and oil-based contrast

solutions are available for use.
Studies have provided evidence concerning the
value of hysterosalpingography. If the hysterosal-
pingogram is normal (normal uterine contour with
bilateral tubal fill and spill), it has a negative pre-
dictive value of only about 60%. This is principally
because the infertility population has a high inci-
dence of endometriosis, which typically represents
peritoneal disease but not tubal disease. Therefore
the tubes appear open on the hysterosalpingogram,
but the disease remains unrecognized by this lim-
ited study. Similarly, proximal tubal occlusion has
a 50% positive predictive value. At the time of fur-
ther diagnostic studies (below) proximal tubal
occlusion cannot be demonstrated, probably related
to the presence of tubal spasm or another technical
problem associated with the procedure. However,
the hysterosalpingogram has a high positive pre-
dictive value if distal tubal occlusion is detected.
When distal tubal occlusion is detected, un-
treated patients are at increased risk for pelvic
infection. Therefore these patients should be treated
with an outpatient course of antibiotics. We rec-
ommend doxycycline 100 mg bid for 5 days. The
FIGURE 1–2. Female pelvic organs. (A). The relations efficacy of antibiotic treatment for patients without
between uterus, bladder, colon, and great vessels are hydrosalpinx has not been demonstrated convinc-
noted in the transverse plane. (B) These relations are ingly. The presence of acute cervical or pelvic
emphasized in the sagittal plane. infections represents a contraindication.
Most clinicians use water-based contrast mate-
rial for hysterosalpingography. The use of oil-based
contrast material has been associated with an intra-
vasation syndrome. The oil-based droplets are ab-
ine abnormalities (malformations, uterine fibroids, sorbed into the circulation and then wedge in the
endometrial polyps) and tuboperitoneal factors microcapillary spaces throughout the body. This
(pelvic scarring from infection or prior surgery, syndrome presents as respiratory difficulty (pul-
endometriosis, congenital tubal abnormalities) can monary involvement) and changes in mental status
be evaluated by several techniques (Table 1–4). (cerebral involvement). The syndrome typically
A time-honored test for evaluating uterine and appears a few hours after the procedure. Deaths
tubal factors is hysterosalpingography. It is a con- have been reported. The diagnosis is relatively easy,
trast study performed under fluoroscopy, where usually based on a chest radiograph demonstrating
radiopaque solutions are injected into the uterus to contrast dispersed throughout the lung. Treatment
define the outline of the uterus and fallopian tubes. is supportive.
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 5

1. Evaluation of the Female for Infertility 5

Sonography is a valuable tool for detecting uter- major tests to evaluate male factor, tuboperitoneal
ine structural lesions such as uterine fibroids and status, and ovulation status. Invasive procedures
adnexal pathology. Although the role of sonogra- such as hysterosalpingogram and laparoscopy are
phy has been limited by its inability to evaluate scheduled during the proliferative phase of the
tubal status and subtle abnormalities of the endo- cycle to avoid the risk of a procedure during a con-
metrium (polyps, small fibroids), it is emerging as comitant pregnancy.
a relatively simple office-based procedure that can Serum progesterone measurements are timed for
provide the clinician with extra details concerning 6–8 days before the onset of menses, and endo-
the pelvic anatomy. The inclusion of sonohys- metrial biopsy is performed 2–3 days prior to the
terography has expanded our view of the endome- onset of menses. Semen analysis can be performed
trium to detect intrauterine abnormalities that may at any time during the cycle. In general, we rec-
go undetected. However, even with sonohysterog- ommend hysterosalpingography, serum progester-
raphy, demonstration of tubal patency is difficult. one, and semen analysis during the first month. An
Some authors have reported using special solutions, office visit can be scheduled at the conclusion of
adding microspheres, and color-flow Doppler to these studies to review the data and to advance to
demonstrate flow into the fallopian tubes. Despite laparoscopy based on any detected abnormalities
the problems, sonography and sonohysterography (below).
currently are best applied to the evaluation of the If no explanation is discovered after these initial
uterus and endometrium. studies, endoscopy (hysteroscopy and laparoscopy)
Endoscopy is currently considered the most thor- is performed to exclude endometriosis and nonob-
ough, comprehensive tool for evaluating pelvic structive tubal adhesions (found in approximately
anatomy. Laparoscopy allows visualization of the 50% of cases with negative basal studies) and occult
peritoneum to detect endometriosis and to assess intrauterine lesions (fewer than 1% of patients).
tubal status. Hysteroscopy can be used to evaluate
the endometrium and the tubal ostia. Additionally,
when disease is detected, therapy can be provided. Treatment
These therapies include adhesiolysis, neosalpin-
gostomy, and adnexal surgery. Treatment strategy is based on the level of clinical
care available for the couple. Three levels of care
have evolved, classified as basic, complex level I,
Evaluation Strategy and complex level II. The basic level of care is
based on treating anovulation. Patients with more
The strategy for female infertility evaluation has complex disorders are referred to higher levels. As
evolved into an efficient, cost-effective investiga- seen in Table 1–5, women more than 35 years of
tion that can usually be performed during two age should be considered to have a complex prob-
cycles. Figure 1–3 shows the usual timing of the lem and so be referred to a higher level of evalua-
tion. Only women less than 35 years of age with
ovulation dysfunction are candidates for basic
levels of treatment. If ovulation defects exist, clo-
miphene citrate is initiated for up to four cycles.
Thyroid and prolactin screening should exclude
correctable endocrine dysfunction.

TABLE 1–5. Levels of Complexity

of Reproductive Care
Basic level
35 years old
Anovulation
No male or tubal factors
Complex level I
35 years old
Tubal disease
FIGURE 1–3. Usual timing of fertility testing during the Male factor
female ovarian menstrual cycle. HSG, hysterosalpin- No conception at basic level
Complex level II
gogram; P, progesterone; Bx, endometrial biopsy; PCT, Gamete technologies
postcoital test; surgery, laparoscopy, and/or hysteroscopy.
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 6

6 B.D. Cowan

TABLE 1–6. Outcome of ART Procedures (1997*)

Procedure # of Cycles Deliveries (%) Ectopic (%)
IVF 33,032 28.4 0.9
IVF  ICSI 18,312 27.1 0.6
GIFT 1,943 30.0 1.0
ZIFT 1,104 28.0 1.2
Donor 4,616 35.7 0.5
Cryopreserved cycle 10,181 16.9 0.7

*Fertil Steril 2000;74:641–654.

Complex level I is a level of care designed to treat below) that ranges from 3% to 9% and a cumula-
diagnosis-related conditions of male gamete pro- tive probability of conception that approaches 30%
duction, tuboperitoneal disease, and complex anovu- over 8–12 inseminations. Donor insemination has
lation. Complex level I treatment facilities have the an expected fecundity of 12–18% and a cumulative
ability to treat couples with insemination, advanced success rate that approaches 70% after 8–10 treat-
follicular stimulation, and advanced endoscopic ment cycles. In special cases, retrograde ejacula-
management. It makes little sense to perform expen- tion, electrostimulatory ejaculation, and testicular
sive, time-consuming diagnostic procedures (e.g., aspiration/biopsy have allowed acquisition of
laparoscopy) if the operating surgeon does not have sperm for use in insemination or ART.
the skill to treat the conditions detected properly.
Complex level II facilities provide gamete tech-
nologies to correct infertility. An array of assisted Tubal Disease
reproductive technology (ART) (Table 1–6) can be
Pelvic adhesions and endometriosis represent dis-
used under the umbrella “gamete technologies.”
eases of the pelvis that impair fertility. Laparo-
Commonly, patients who receive these treatments
scopic adhesiolysis produces a pregnancy success
have failed conservative therapies at the basic and
rate of nearly 50%. On the other hand, women who
complex level I or are of advanced maternal age
require neosalpingostomy for hydrosalpinx have an
when seeking fertility treatment.
overall expected maximum probability of preg-
Therapeutic options are classified as diagnosis-
nancy of less than 20%.
related or empiric. Diagnosis-related treatments are
Endometriosis is classified into stages based on
provided for couples affected by disordered male fac-
the extent of disease. In women with early disease
tors, tubal factors, or ovulation defects. Empiric ther-
(stage I–II) the cumulative probability of pregnancy
apy is provided to couples with unexplained infertility.
is 60%. In contrast, women with stage III or IV dis-
ease benefit from surgery, but the cumulative prob-
ability of pregnancy is only 35% for these women.
Male Factor Treatment
Male factor treatment is principally insemination. Ovulation Defects
Two types of insemination are provided: homolo-
gous and donor. In general, homologous intrauter- Women with estrogenized/androgenized chronic
ine insemination has a per-cycle fecundity (see anovulation are typically treated successfully with

TABLE 1–7. Fecundity and Cumulative Probability of Conception for Various

Infertility Treatment Options
Cumulative
Treatment option Fecundity conceptions (%)
Unexplained and untreated 0.08 50
Anovulatory with clomiphene 0.12 65
Surgery for adhesiolysis 0.04 40
Surgery for neosalpingostomy 0.02 12
Surgery for stage I–II endometriosis 0.06 65
Surgery for stage III–IV endometriosis 0.06 35
hMG for hypothalamic amenorrhea 0.30 90
Normal 0.20 90

hMG, human menopausal gonadotropin.

3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 7

1. Evaluation of the Female for Infertility 7

these parameters. Two models are commonly used

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

Impact of Age on Reproduction

No discussion of female fertility would be com-
plete without considering ovarian maturity. Two
detrimental reproductive events affect oocyte devel-
opment over time. Increased occurrence of nondis-
FIGURE 1–4. Logistic regression demonstrating the cumu-
lative probability of conception for common infertility
junction leads to genetic abnormalities associated
conditions. with trisomy. Table 1–8 demonstrates the age-
dependent association of Down syndrome (trisomy
21). Reproductive efficiency is also dramatically
influenced by age. Two important examples must
clomiphene citrate: 85% of patients on this therapy
be considered. A 40-year-old population undergo-
ovulate. Of those who ovulate, 65% achieve a preg-
ing donor insemination demonstrated a 50% preg-
nancy within 4–6 months. Human menopausal
gonadotropin (hMG) (Metrodin, Pergonal, Hume-
gon, Fertinex) has been used to treat women with
hypogonadotrophic hypogonadism and estroge- TABLE 1–8. Age-Dependent Association of
nized/androgenized chronic anovulatory patients Down Syndrome
who fail to respond to clomiphene citrate. Curi- Risk for all
ously, those with hypogonadotrophic hypogonad- Maternal Risk of chromosome
ism have an excellent response to hMG therapy. age (years) Down syndrome abnormalities
Approximately 90% of these patients achieve a 20 1/1923 1/526
pregnancy within 6 months of therapy. This remark- 21 1/1695 1/526
able response represents the highest fertility treat- 22 1/1538 1/500
ment option available to clinicians. In contrast, 23 1/1408 1/500
24 1/1299 1/476
chronically anovulatory patients refractory to clo- 25 1/1205 1/476
miphene citrate fare much worse: Their expected 26 1/1124 1/476
maximum probability of pregnancy is only 30% 27 1/1053 1/455
despite the high ovulatory rates established with 28 1/990 1/435
hMG. 29 1/935 1/417
30 1/885 1/384
31 1/826 1/384
32 1/725 1/322
Measures of Fertility 33
34
1/592
1/465
1/285
1/243
Treatment Success 35 1/365 1/178
36 1/287 1/149
37 1/225 1/123
Fertility treatment measurements require an analy- 38 1/177 1/105
sis of time-dependent events. As such, two expres- 39 1/139 1/80
sions are used to discuss fertility success. Fecun- 40 1/109 1/63
dity is the measure of pregnancy occurrence per 41 1/85 1/48
single ovulatory cycle. The cumulative probability 42 1/67 1/39
43 1/53 1/31
of pregnancy represents the expectations of con- 44 1/41 1/24
ception in a population over time. That expectation 45 1/32 1/18
is time-dependent and may occur within 6 months 46 1/25 1/15
or 6 years, depending on the duration of the meas- 47 1/20 1/11
48 1/16 1/8
urement. 49 1/12 1/7
Analytic tools have been developed to assess
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 8

8 B.D. Cowan

technological gimmick or a clinical tool? J Soc Obstet

Gynecol Can 1993;15:25–32.
Eggert-Kruse W, Leinhos G, Gerhard I, et al. Prognostic
value of in vitro sperm penetration into hormonally
standardized human cervical mucus. Fertil Steril 1989;
51:317–323.
ESHRE Capri Workshop Group. Male sterility and sub-
fertility: guidelines for managements. Hum Reprod
1994;9:1260–1264.
Forti G, Krausz C. Clinical review 100: evaluation and
treatment of the infertile couple. J Clin Endocrinol
Metab 1998;83:4177–4188.
Griffith CS, Grimes DA. The validity of the postcoital
test. Am J Obstet Gynecol 1990;162:616–620.
Gwatkin RBL, Collins JA, Jarrell JF, et al. The value of
semen analysis and sperm function assays in predict-
ing pregnancy among infertile couples. Fertil Steril
1990;53:693–699.
Hanson MA, Dumesic DA. Initial evaluation and treat-
FIGURE 1–5. Historic population analysis of female fer- ment of infertility in a primary-care setting. Mayo Clin
tility rate by age from Morman genealogic data. Modi- Proc 1998;73:681–685.
fied from Mineau G and Trussell J, Demography, 1982. Hughes EG, Fedorkow DM, Collins JA. A qualitative
overview of controlled trials in endometriosis-associ-
ated infertility. Fertil Steril 1993;59:963–970.
Kremer J, Jager S. The significance of antisperm anti-
nancy occurrence and a 50% miscarriage rate, for bodies for sperm-cervical mucus interaction. Hum
a take-home pregnancy success rate of 25%. This Reprod 1992;7:781–784.
population was compared to a 30-year-old group Opsahl MS, Miller B, Klein TA. The predictive value of
who demonstrated an 80% chance of pregnancy and hysterosalpingography for tubal and peritoneal infer-
a 20% chance of miscarriage, resulting in a 65% tility factors. Fertil Steril 1993;60:444.
take-home pregnancy rate. Lastly, historic popula- Shalev J, Meizner I, Bar-Hava I, et al. Predictive value
tions have demonstrated profound aberrations of of transvaginal sonography performed before routine
diagnostic hysteroscopy for evaluation of infertility.
the fertility rate after age 35 (Fig. 1–5). Historic Fertil Steril 2000;73:412–417.
populations are of interest because contraception Taylor PJ, Lewinthal D, Leader A, et al. A comparison
was unknown, and in some (e.g., Mormans) large of dextran 70 with carbon dioxide as the distention
families were desired. medium for hysteroscopy in patients with infertility or
Thus women after age 35 are at increased risk requesting reversal of a prior tubal sterilization. Fertil
for nondisjunction events leading to trisomy and Steril 1987;47:861–863.
decreased reproductive efficiency. Fertility evalua- Wentz AC, Kossoy LR, Parker RA. The impact of luteal
tion and treatments become urgent in this popula- phase inadequacy in an infertile population. Am J
tion. Obstet Gynecol 1990;162:937–945.
Yoder IC, Hall DA. Hysterosalpingography in the 1990s.
AJR 1991;157:675–683.
Suggested Reading
Treatment
Diagnosis
Adamson GD, Pasta DJ. Surgical treatment of endome-
Baker HWG, Burger HG, de Krester DM, et al. Testicu- triosis-associated infertility: meta-analysis compared
lar vein ligation and fertility in men with varicoceles. with survival analysis. Am J Obstet Gynecol 1994;
BMJ 1985;291:1678–1680. 171:1488–1505.
Barnea ER, Holford TR, McInnes DRA. Long-term prog- American Fertility Society. The American Fertility Soci-
nosis of infertile couples with normal basic investiga- ety classification of adnexal adhesions, distal tubal
tions: a life-table analysis. Obstet Gynecol 1985;66: occlusion, tubal occlusion secondary to tubal ligation,
24–26. tubal pregnancies, müllerian anomalies and intrauter-
Barratt CLR. On the accuracy and clinical value of semen ine adhesions. Fertil Steril 1988;49:944–955.
laboratory tests. Hum Reprod 1995;10:250–252. Chung CC, Fleming R, Jamieson ME, et al. Randomized
Chalmers TC, Celano P, Sacks H, Smith H Jr. Bias in comparison of ovulation induction with and without
treatment assignment in controlled clinical trials. N intrauterine insemination in the treatment of unex-
Engl J Med 1983;309:1358–1361. plained infertility. Hum Reprod 1995;10:3139–3141.
Dunphy BC, Scudamore I, Cooke ID. Falloposcopy, a Collins JA, Burrows EA, Willan AR. The prognosis for
3051_Seifer_01_p1-9 11/5/01 3:04 PM Page 9

1. Evaluation of the Female for Infertility 9

live birth among untreated infertile couples. Fertil Pal L, Lapensee L, Toth TL, Isaacson KB. Comparison
Steril 1995;64:22–28. of office hysteroscopy, transvaginal ultrasonography,
Crosignani PG, Walters DE, Soliani A. The ESHRE mul- and endometrial biopsy in evaluation of abnormal uter-
ticentre trial on the treatment of unexplained infertil- ine bleeding. J Soc Laparoendosc Surg 1997;1:125–30.
ity: a preliminary report. Hum Reprod 1991;6:953– Reiss H. Management of tubal infertility in the 1990s.
958. Br J Obstet Gynaecol 1991;98:619–623.
Dlugi AM, Reddy S, Saleh WA, et al. Pregnancy rates Saidi MH, Sadler RK, Theis VD, Akright BD, Farhart
after operative endoscopic treatment of total (neosal- SA, Villanueva GR. Comparison of sonography, sono-
pingostomy) or near total (salpingostomy) distal tubal hysterography, and hysteroscopy for evaluation of
occlusion. Fertil Steril 1994;62:913–920. abnormal uterine bleeding. J Ultrasound Med 1997;
Edvinsson A, Forssman L, Milsom I, et al. Factors in the 16:587–91.
infertile couple influencing the success of artificial Saravelos, et al. Microsurgery versus laparoscopic adhe-
insemination with donor semen. 1990;53:81–87. siolysis for fertility. Hum Reprod 1995;10:2887–2928.
Friedman AJ, Juneau-Norcross M, Sedensky B, et al. Life Schlesinger MH, Wilets IF, Nagler HM. Treatment out-
table analysis of intrauterine insemination pregnancy come after varicocelectomy: a critical analysis. Urol
rates for couples with cervical factor, male factor, and Clin North Am 1994;21:517–529.
idiopathic infertility. Fertil Steril 1991;55:1005–1007. Society for Assisted Reproductive Technology and the
Gysler M, March CM, Mishell DR Jr, et al. A decade’s American Society for Reproductive Medicine. Assisted
experience with an individualization of clomiphene reproductive technology in the United States: 1997
treatment regimen including its effect on the postcoital results generated from the American Society for
test. Fertil Steril 1982;37:161–167. Reproductive Medicine/Society for Assisted Repro-
Haan G. Effects and costs of in-vitro fertilization. Int J ductive Technology Registry. Fertil Steril 2000;74:
Technol Assess Health Care 1991;7:585–593. 641–654.
Hammond MG, Hlame JK, Talbert LM. Factors affect- Speroff L. The effect of aging on fertility. Curr Opin
ing the pregnancy rate in clomiphene citrate induction Obstet Gynecol 1994;6:115–120.
of ovulation. Obstet Gynecol 1983;62:196–202. Toner JP, Glood JR. Fertility after the age of 40. Obstet
International Federation of Fertility Societies, Montpel- Gynecol Clin North Am 1993;20:261–272.
lier, pp 1–43. Valli E, Zupi E, Marconi D, Solima E, Nagar G,
International Working Group for Registers on Assisted Romanini C. Outpatient diagnostic hysteroscopy. J Am
Reproduction. World Collaborative Report 1993. Assoc Gynecol Laparosc 1998;5:397–402.
Lindheim SR, Kavic S, Shulman SV, Sauer MV. Opera- Van Steirteghem A, Liu J, Joris H, et al. Higher success
tive hysteroscopy in the office setting. J Am Assoc rate by intracytoplasmic sperm injection than by sub-
Gynecol Laparosc 2000;7:65–9. zonal insemination: report of a second series of 300
Mineau G, Trussell J. A specification of marital fertility consecutive treatment cycles. Hum Reprod 1993;8:
by parents’ age, age at marriage, and marital duration. 1055–1060.
Demography 1982;19:335–350. Zullo F, Pellicano M, Stigliano CM, DiCarlo C, Fabrizio
Office of Technology, US Congress. Infertility: Medical A, Nappi C. Topical anesthesia for office hysteroscopy.
and Social Choices. US Government Printing Office, A prospective randomized study comparing two
Washington, DC, pp 3–402. modalities. J Reprod med 1999;6:331–6.
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 10

2
Evaluation of the Male for Infertility
Kevin A. Spear

The purpose of this chapter is to give a concise but ther husband nor wife understands the menstrual
practical overview of the in-office evaluation of the cycle and does not know the optimal time for inter-
infertile man. Women have traditionally sought course. Because sperm survive in the female repro-
consultation and treatment for infertility, so the ductive tract for approximately 2 days, the most
focus of therapy for many years has been on female effective frequency of intercourse is every 48 hours
factors. Because approximately 40% of infertility around the ovulatory peak, which ensures that
cases involve male factors, it is imperative that the viable spermatozoa are present during the 12- to
couple be considered as a unit and the infertility 24-hour period when the egg is in the fallopian tube
evaluation proceed in a parallel manner. Also, sig- and capable of being fertilized.
nificant medical pathology can be uncovered by a Lubricant use should be investigated. Commonly
comprehensive infertility evaluation of the man. used substances such as K-Y Jelly, Lubifax, Surgi-
Additionally, with advances in the diagnosis and lube, Keri Lotion, and saliva have been shown to
treatment of male factor infertility, and the refine- decrease sperm motility in vitro. If lubricant use is
ment of assisted reproductive techniques, many necessary, couples should be instructed to use a
men whose problems were once untreatable are minimal amount of one that does not impair motil-
now excellent candidates for therapy. As economic ity. Substances that do not impair in vitro motility
issues are becoming increasingly important, it is include petroleum jelly, vegetable oil, and peanut
evident that treatment of male factor infertility is oil.
cost-effective. The man must not be ignored, and The history of an undescended testicle is signif-
the following is a guide to his evaluation. icant. In a patient with a history of unilateral cryp-
torchidism, regardless of the time of orchidopexy,
overall semen quality is considerably less than that
Evaluation found in normal men. Despite this fact, most men
with one undescended testis are able to initiate a
The initial workup begins whenever the patient pre- pregnancy without difficulty. Bilateral cryptorchi-
sents. This is predicated by the fact that the longer dism is extremely important. Progressive damage
a couple remains infertile the less chance there is occurs to the germinal epithelium if the testicle is
for cure. A rapid, noninvasive, cost-effective evalu- not in its proper position in the scrotum. It has been
ation is essential. shown that orchidopexy should be performed prior
to 2 years of age to maintain a significant level of
History spermatogenic function.
Any previous surgery of the retroperitoneum,
The cornerstone of the evaluation of the infertile bladder neck (prostate), pelvis, inguinal region, or
man is the history and physical examination. Table scrotum should be assessed. Retroperitoneal lymph
2–1 outlines the complete pertinent history. The node dissection with interruption of the sympathetic
sexual history is paramount. Some of the problems chain causes anejaculation with resultant azoosper-
most commonly encountered in this patient popu- mia. Today nerve-sparing techniques allow more
lation are related to the timing of intercourse, with than 90% of patients to retain ejaculatory function
it being too frequent or too infrequent. Often nei- after retroperitoneal lymph node dissection. Any

10
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 11

2. Evaluation of the Male for Infertility 11

TABLE 2–1. Infertility History A family history of cystic fibrosis is important

Sexual history owing to associated vasal agenesis and epididymal
Duration of infertility abnormalities. Finally, a history of anosmia (lack
Prior pregnancies, with present and any previous partners of smell) indicates the possibility of hypogo-
Previous treatments nadotropic hypogonadism. Galactorrhea, head-
Evaluation and treatment of female partner
Potency aches, and impaired visual fields suggest the pres-
Use of lubricants ence of a central nervous system tumor.
Timing and frequency of intercourse It is useful to use a preprinted history form filled
Frequency of masturbation out by the patient. It ensures that all pertinent his-
Past medical history, including childhood
Undescended testicles
torical data are obtained prior to the physical exam-
Testicular torsion ination.
Testicular trauma
Delayed puberty
Pelvic injury Physical Examination
Diabetes, multiple sclerosis
Previous or current therapy The physical examination must be thorough, with
Viral and febrile illness history special attention to the genitalia. Figure 2–1 depicts
Postpubertal mumps orchitis the pertinent male reproductive anatomy. The
Sexually transmitted diseases penile curvature and location of the urethral mea-
Urinary tract infections
Cystic fibrosis, or family history of it tus should be assessed, as abnormalities may result
Past surgical history in improper delivery of the ejaculate. Testicular size
Orchiectomy and consistency must be recorded, with the length
Orchidopexy
Retroperitoneal surgery
Pelvic, inguinal, or scrotal surgery
Herniorrhaphy
Medications and gonadotoxins
Chemotherapeutic agents
Therapeutic drugs: cimetidine, sulfasalazine, nitrofurantoin
Chemicals (pesticides)
Recreational drugs: smoking, marijuana, cocaine
Androgenic steroids
Thermal exposure (hot tubs)
Radiation

surgery on the bladder neck may cause retrograde

ejaculation. Inguinal surgery such as herniorrhaphy,
undertaken when an infant or an adult, may have
caused vasal occlusion or vascular insufficiency to
the testicle.
Fever can cause impaired testicular function. The
ejaculate may not be affected for more than 3
months after the event, as spermatogenesis takes
about 74 days. Therefore events that have occurred
during the previous 3–6 months are important.
Postpubertal mumps may cause mumps orchitis,
which results in an atrophic testis. Fifty percent of
patients with testicular cancer have subnormal
sperm densities prior to therapy. A history of dia-
betes or multiple sclerosis should raise questions
about potency and ejaculatory function.
Exposure to drugs and toxins should be detailed.
Withdrawal of the medications listed under gonado-
toxins in Table 2–1 may allow the return of normal FIGURE 2–1. Pertinent male reproductive tract anatomy
spermatogenesis. The routine use of hot tubs or in coronal view. Arrows depict flow of sperm and ejac-
saunas should be discontinued, as elevated tem- ulate. (By permission of the American Society of Repro-
peratures impair spermatogenesis. ductive Medicine)
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 12

12 K.A. Spear

testicle in the scrotum—must be identified (Fig.

2–3). A varicocele can cause abnormalities in
gonadal function. The scrotal contents should be
palpated with the patient in both the supine and
standing positions. Many varicoceles are not visi-
ble and may be discernible only when the patient
stands or performs a Valsalva maneuver. Varicoce-
les often result in a smaller testis on that side.
Ninety percent are left-sided, and any discrepancy
in size between the two testes should arouse sus-
picion of a varicocele.
A rectal examination is essential to assess
prostate size, evidence of infection, and the pres-
ence of midline cysts. Look carefully for signs of
hypogonadism, such as decreased body hair,
gynecomastia, infantile genitalia, and decreased
FIGURE 2–2. Measuring the length of a testicle with a muscular development.
Seager orchidometer. (From Goldstein, 1995, by per-
mission of W.B. Saunders)

Laboratory Evaluation
The laboratory is an integral part of a full-service
measured with calipers (Fig. 2–2) and the volume
infertility center. If an on-site laboratory is not
estimated with an orchidometer. Size is an impor-
available, specimens must be analyzed by a dedi-
tant indicator of spermatogenic capability, as 85%
cated infertility laboratory. Data from a reputable
of the testis is involved in sperm production. When
laboratory are critical. Unfortunately, the semen
there is damage to the testicular tubules, loss of
analysis must be done locally because the speci-
mass occurs. The normal length of the testis is more
men must be evaluated shortly after production.
than 4 cm and the volume more than 20 ml.
Most other studies can be sent out to any reputable
Epididymal induration and irregularities should
laboratory.
be noted. The presence of a vas must be docu-
mented, as 2% of infertile men have congenital
absence of the vas. Varicoceles—dilated spermatic
veins that present as a “bag of worms” above the Semen Analysis
The primary laboratory test is the semen analysis.
It must be emphasized that semen analysis is not a
test for fertility. It does not separate patients into
sterile and fertile groups; it does give diagnostic
information and allows a directed evaluation and
treatment. At least two semen analyses must be
obtained to establish a baseline. The specimen
should be collected with a consistent abstinence of
2–3 days. The specimen container must be clean,
not necessarily sterile, and wide-mouthed to mini-
mize collection error. The preferred technique of
collection is by masturbation, although coitus inter-
ruptus or use of a special condom devoid of sper-
matocidal agents may be used. The specimen must
be evaluated within 2 hours of collection.
The standard semen analysis allows evaluation
of semen volume, pH, density (sperm per milli-
liter), motility, measurement of forward progres-
sion of sperm, and sperm morphology. The semen
FIGURE 2–3. (A) Left visible (grade 3) varicocele. (B) is examined also for evidence of sperm agglutina-
dilated veins underneath the scrotal skin. tion, hyperviscosity, and the presence of white
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 13

2. Evaluation of the Male for Infertility 13

TABLE 2–2. WHO Criteria for Normal Semen Analysis are not always accurate, are labor- and cost-pro-
Semen parameter Value hibitive, and have not been shown to have a clini-
cal impact.
Volume 2.0–5.0 ml
Density 20 million/ml For the few patients with symptoms of urinary
Motility 50% or genital tract infections cultures should be pre-
Forward progression 2 (scale 1–4) pared. The specific cultures obtained depend on the
Morphology 30% normal forms individuals’ symptoms and examination but should
Leukocytes 1 million/ml
Agglutination None
include cultures of urine, expressed prostatic secre-
Hyperviscosity None tions, and a postprostatic massage urine sample. It
has been demonstrated that exotoxins of Esche-
Source: World Health Organization, 1992. richia coli can significantly affect sperm motility
and may also decrease sperm production. Common
sexually transmitted organisms such as Chlamydia,
blood cells. The World Health Organization (WHO) Mycoplasma, and Ureaplasma have been impli-
range of values for normal semen analysis is given cated in reproductive failure. Patients with active
in Table 2–2. prostatitis or other urinary tract infections fre-
Some laboratories use computer-assisted semen quently have decreased sperm count and motility.
analyses, which are of some value for measuring
sperm motility; however, they should be used only Fructose
as a source of supplemental information. Attention With low-volume oligospermia or low-volume
has been turned to a more accurate manual analy- azoospermia, one should be concerned about ret-
sis of sperm morphology. Using strict criteria rograde ejaculation and ejaculatory duct obstruc-
(Kruger criteria) for defining “normal” morphol- tion. The assessment for ejaculatory duct obstruc-
ogy, in patients undergoing in vitro fertilization tion may incorporate a test for seminal fructose, a
(IVF), a significantly higher fertilization rate may sugar produced in the seminal vesicles. Its absence
be achieved from semen specimens with more than may indicate the possible absence of the seminal
4% normal forms. vesicles or obstruction of the ejaculatory ducts.
Problematically, the fructose test is not entirely
Adjunctive Semen Studies accurate and hence is unreliable. The state of the
art now is transrectal ultrasonography (TRUS) to
White Blood Cell Staining detect ejaculatory duct obstruction or seminal vesi-
Leukocytes in semen have significant effects on cle aplasia.
sperm function. They modulate an autoimmune
Anti-sperm Antibodies
response, adversely affect motility and fertilizing
capacity, and deter sperm transport in the female Great attention has been focused recently on im-
reproductive tract. The semen of most men contains munologic infertility, resulting in a better under-
some immature sperm forms (round cells), which standing of the etiology and biology of anti-sperm
ordinarily cannot be distinguished from white antibodies. The incidence of anti-sperm antibodies
blood cells (WBCs). This often leads to an erro- in the infertile man range from 8% to 21%. In con-
neous diagnosis of pyospermia or infection. Spe- trast, only 0.9–4.0% of fertile men and women have
cial immunohistochemical stains identify WBCs. detectable antibodies. Aggregate evidence docu-
These stains should be employed if more than 1 ments that anti-sperm antibodies comprise signifi-
million round cells/ml or more than 1 million cant infertility factor. In men only antibodies pres-
WBCs/ml are reported on routine semen analysis. ent on the sperm surface are clinically important.
The peroxidase stain can be employed: It stains Anti-sperm antibodies have implications at var-
polymorphonuclear leukocytes brown. Monoclonal ious stages in the fertilization process. Clarke et al.
antibodies directed against the leukocyte CD45 or showed that sperm agglutination is significantly
HLE-1 antigen are the current “gold standard.” higher in men with positive immunobead tests.
Although more accurate, they are expensive and Thus sperm agglutination is a definite sign of anti-
labor-intensive. In most clinical cases, a cyto- sperm antibodies. Others have found that antibod-
chemical stain is sufficient. Semen cultures are not ies decrease motility. Poor sperm penetration into
indicated in asymptomatic patients, as they are cervical mucus has been noted in many of these
essentially always negative. Routine cultures for patients. Additionally, the acrosome reaction may
atypical organisms are unwarranted because they be impaired in patients with antibodies attached to
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 14

14 K.A. Spear

the sperm head. Of great importance is evidence tion. A specimen of cervical mucus, obtained
that anti-sperm antibodies may cause impairment within a few hours of intercourse, is examined
of zona binding and fertilization. In Zonari et al.’s under a microscope. More than 10 sperm per high
study, IVF cycles with no fertilization showed a power field, most of which demonstrate progres-
lack of zona binding and antibodies on the sperm sive motility, constitutes a normal study.
head. Witkin et al. studied unsuccessful IVF cycles Indications for postcoital testing include hyper-
and found a high correlation between sperm-bound viscous semen, unexplained infertility, and low-
antibodies and low fertilization rates. volume semen with good sperm density. This test
Risk factors for the development of sperm-bound is contraindicated for patients with poor quality
antibodies include previous testicular surgery, semen specimens. Inherent poor reproducibility
trauma, or infection, as does a history of torsion, and the fact that there are specimens from both par-
cryptorchidism, and genitourinary infections. Addi- ties make the study difficult to interpret. If an
tionally, obstructive azoospermia (possibly due to abnormal result is obtained, an in vitro cervical
obstruction from a previous hernia repair, congen- mucus penetration test may be performed. These
ital absence of the vas deferens, or vasectomy) can tests have been developed to standardize and iso-
induce sperm autoimmunity. No prevasectomy late semen factors.
reversal evaluation is required, as only serum anti- Several commercially available tests allow mea-
bodies can be assessed. Serum antibodies are non- surement of sperm migration and penetration
specific and cannot accurately predict postopera- through standard (usually bovine) cervical mucus.
tive results. An example of this type of test is the Penetrak
Selective testing for anti-sperm antibodies is (Serono Diagnostics, Braintree, MA). These test
important. Patients who should be evaluated in- results usually correlate with the quality of the
clude those with the previously mentioned risk fac- semen specimen, but there are patients who have
tors as well as those with sperm agglutination noted abnormal results and normal semen parameters. In
on semen analysis, low sperm motility, abnormal these individuals, look for the presence of anti-
cervical mucus penetration test, or multiple failed sperm antibodies. Currently, the definitive role of
intrauterine insemination (IUI) or IVF cycles, and cervical mucus penetration tests in the evaluation
couples with unexplained infertility. of the infertile male is not clear.
There is no good correlation between serum anti-
sperm antibodies and the presence of sperm-bound
antibodies. Additionally, it is the sperm-bound anti-
Sperm Penetration Assay
bodies that cause abnormalities in reproductive The sperm penetration assay is a sophisticated test
function, which is where testing should be focused. that measures the physiologic ability of the human
Direct assays measure sperm-bound antibodies. In- sperm to enter a zona-free hamster egg and begin
direct tests are serum studies. The preferred test is the fertilization reaction. The zona pellucida is the
the direct immunobead test (IBT), but it requires barrier to cross-species fertilization. When hamster
motile sperm. Results show the percent of sperm eggs are rendered zona-free and penetrated by
bound, the antibody isotype, and the binding loca- human spermatozoa in vitro, they serve as a sub-
tion. The clinically significant range is 20–50% stitute for human ova in a preliminary assessment
of sperm demonstrating immunobead binding. Im- of fertilizing capacity. For successful penetration,
munoglobulin G (IgG) and IgA antibodies are sperm must be able to undergo capacitation, the
assessed. It is unlikely that IgM immunoglobulin will acrosome reaction, fusion with the oolema, and
be found in the male genital tract, so testing for this incorporation into the ooplasm. Scoring is based on
subclass is unwarranted. In instances where this level the percentage of ova penetrated, or number of pen-
of sophisticated testing is not available or a screen- etrations per ovum. The lower limit of normal is
ing test is desired, Sperm Mar (Ortho Diagnostic 10–30% of ova penetrated. Results are expressed
Systems, Beerse, Belgium) is a commercially avail- as the mean number of penetrations per ovum,
able assay that does not require sperm processing. which Lipshultz’s laboratory has termed the sperm
capacitation index (SCI). An SCI of less than 5 is
abnormal. Although interpretation of this study is
Sperm Function Tests controversial, the results generally correlate with
IVF success rates. The test may be useful is if one
Sperm–Cervical Mucus Interaction
is contemplating IUI versus IVF/ICSI (intracyto-
The postcoital test assesses the sperm in the part- plasmic sperm injection) or IVF versus ICSI. If the
ner’s cervical mucus and the interaction between sperm penetration assay is normal, IUI would be
the two. The test is performed just prior to ovula- logical in the IUI versus IVF/ICSI case, and IVF
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 15

2. Evaluation of the Male for Infertility 15

would be indicated in the IVF versus ICSI case. individual to allow a cost-conscious, efficient eval-
Familiarity with the laboratory performing the uation. Fewer than 3% of infertility cases are due
assay is critical to allow proper interpretation. to a primary endocrinopathy. Sigman studied 1034
men to determine what hormonal workup should
be done and which patients should be studied. He
found that by limiting screening to men with sperm
Hormonal Screening densities less than 10 million/ml only one case of
A brief review of male reproductive endocrine endocrinopathy would have been missed. A higher
physiology is essential. The testes are dual organs. degree of confidence and detection results when
There is an endocrine (hormonal) component con- patients with higher sperm counts are screened,
sisting of Leydig cells, Sertoli cells, and germ although the likelihood of discovering a significant
(sperm) cells. This component is necessary for male abnormality is low.
sexual differentiation and maturation, normal What studies are appropriate? It is uncommon to
potency and ejaculatory capability, and spermato- find clinically important abnormalities in LH or
genic maturation. Endocrine and spermatogenic testosterone if the FSH is normal. In Sigman’s
compartments are anatomically and functionally study, no significant endocrine aberrance would
integrated. Proper hormone balance is initiated by have been missed by screening FSH and testos-
a pulsatile hypothalamic release of gonadotropin- terone alone. Evaluation of FSH and testosterone
releasing hormone (GnRH). This causes pituitary seems to be the most efficient, cost-effective, and
release of follicle-stimulating hormone (FSH) and revealing hormonal survey. If the FSH is abnormal,
luteinizing hormone (LH), which have a direct or the testosterone is low, the serum LH should be
action on the testis. FSH acts on Sertoli cells to pro- assayed. Also, consider a free testosterone assay
vide a favorable milieu for spermatogenesis. LH in equivocal cases or in clinical situations such as
stimulates the Leydig cell to secrete testosterone, obesity.
providing the locally high concentration required If the LH and testosterone levels are low, pro-
for spermatogenesis. lactin should be evaluated. Hyperprolactinemia
Serum testosterone reflects Leydig cell function causes LH suppression, which in turn lowers serum
and provides an indication of intratesticular testos- testosterone. Low serum testosterone decreases
terone. There is a diurnal rhythm, with the peak libido and may cause infertility.
during early morning. Consequently, it is optimal Certain patient historic factors raise suspicions
to perform serum testosterone evaluations in the of given entities. With hypogonadotropic hypogo-
morning. Additionally, when monitoring an indi- nadism, or Kallmann syndrome (congenital form),
vidual patient it is optimal if the tests are done at there is failure of GnRH secretion; clinical signs
a relatively consistent time of day. Serum testos- include anosmia (lack of smell) and delayed
terone includes both bound and unbound (free) puberty. Hyperprolactinemia may manifest with
fractions. The free fraction is the biologically impaired visual fields and severe headaches sec-
active component and comprises 2% of the total ondary to a prolactin-secreting pituitary tumor. The
testosterone. Alterations in the sex hormone-bind- patient may also complain of impotence. Be aware
ing globulin (SHBG) may give spurious estimates that gonadotropin production is inhibited by nega-
of the biologically active unbound testosterone, as tive feedback from estrogens and androgens at the
changes in SHBG are reflected in the total testos- hypothalamus and pituitary. A hypogonadal state is
terone. SHBG is increased by estrogens, thyroid induced by androgen excess, either exogenous or
hormone administration, and cirrhosis; it is de- endogenous. Exogenous sources include testos-
creased by androgens, growth hormone, and obe- terone supplementation and anabolic steroids, each
sity. For example, in obese men the total testos- of which has a contraceptive effect. Congenital
terone may be lowered secondary to a decrease in adrenal hyperplasia is the most common cause of
SHBG, whereas the free testosterone may be endogenous androgen excess. These patients have
within normal limits. Furthermore, testosterone is a history of precocious puberty, short stature, and
aromatized in peripheral tissue to estrogen. There underdeveloped testes. Urinary 17-ketosteroids
is increased aromatization in the presence of alco- should be measured in these individuals.
holism, chronic liver disease, testis tumors, and Of note is the fact that patients with hypothy-
obesity. Most importantly, if the serum testos- roidism do not present primarily with infertility,
terone does not correlate with the clinical situation and routine thyroid-stimulating hormone (TSH)
or is equivocal, the free testosterone should be screening is not indicated. Table 2–3 depicts the
assayed. various hormonal patterns and their corresponding
The endocrine workup should be tailored to the clinical entities.
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 16

16 K.A. Spear

TABLE 2–3. Hormonal Patterns and Corresponding Clinical Status

Clinical status FSH LH T
Normal Normal Normal Normal
Testicular failure Elevated Elevated Normal or low
Germinal aplasia Elevated Normal Normal
Hypogonadotropic hypogonadism Low Low Low

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

Genetic Testing nosis is based on a venous diameter of 3.5 mm or

more with the patient at rest so he can be scanned
Genetic testing should be considered in the man in the supine position. Subclinical varicoceles are
with severe oligospermia or azoospermia. This approximately 3 mm in diameter. Color flow
becomes important especially when ICSI is being Doppler allows determination of the direction and
contemplated. It has been demonstrated by Page magnitude of blood flow. To detect the change in
and others, that men with Y chromosome deletions, flow, or reflux, the patient must perform the Val-
such as AZFc, will likely transmit the deletion and salva maneuver and may require examination in the
infertility to their sons who were conceived by standing position. This positioning allows adequate
ICSI. Several laboratories proficient in this testing assessment of reflux in the testicular veins,
include Boston University School of Medicine although the accuracy and clinical significance are
Center for Human Genetics (617-638-7083) and the not absolute. Scrotal ultrasonography and color
Genetics and IVF Institute Molecular Genetics duplex Doppler are excellent adjuncts in patients
Laboratory in Fairfax, VA (800-654-4363) with equivocal examinations.
Genetic screening is mandated in patients with
bilateral congenital absence of the vas deferens.
Cystic fibrosis gene screening is required as dis- Transrectal Ultrasonography
cussed in this chapter.
In the past, evaluation of patients with low-volume
ejaculates, especially those with azoospermia,
included postejaculate urinalysis and subsequent
Diagnostic Studies vasography. Historically, surgical vasotomy with
vasography were required to image the seminal
Scrotal Ultrasonography vesicles and ejaculatory ducts to diagnose ejacula-
The use of ultrasonography to image organs and tory duct obstruction. Vasography is an invasive
vessels and to measure blood flow is beneficial dur- surgical procedure, and there is a risk of vasal scar-
ing evaluation of the infertile man. Its principal ring and obstruction.
application regarding male factor infertility is for Transrectal ultrasonography (TRUS) is now
the diagnosis of varicoceles. Varicocele is usually being used to detect varying degrees of ejaculatory
diagnosed by physical examination, although the duct obstruction. It is essentially a noninvasive,
physical examination is sometimes complicated by inexpensive office procedure that is readily avail-
body habitus and is sometimes equivocal. Some able. Patients do not require pre-TRUS preparation,
investigators believe that small varicoceles are as antibiotics, or enemas. Urologists are comfortable
important as large ones. Whether nonpalpable or with this technique, as it is used routinely for the
subclinical varicoceles are clinically significant evaluation and diagnosis of prostate carcinoma.
remains a subject of controversy. Transrectal images of the prostate and seminal vesi-
Several adjuncts in the diagnosis of varicocele cles are vastly superior to those obtained with trans-
are available. Portable, pencil-probe directional abdominal imaging. High-resolution images using
Doppler units can be utilized in the office to assist a 7.5 MHz rectal probe are produced in transverse
in varicocele detection. This modality detects and sagittal planes. Ejaculatory duct obstruction is
changes in blood flow (reflux) during a Valsalva easily diagnosed, and the results are highly accu-
maneuver, but the accuracy and reproducibility of rate when using TRUS in azoospermic patients with
this technique are limited. low ejaculate volume. Obstruction is documented
Standard scrotal ultrasonography is readily avail- by the presence of dilated seminal vesicles more
able, familiar to urologists and infertility clinicians, than 1.5 cm in diameter seen on transverse imag-
noninvasive, and relatively inexpensive. The diag- ing. Additional findings indicating obstruction
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 17

2. Evaluation of the Male for Infertility 17

technique. Patients are prepared with an oral fluo-

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

Postejaculate Urinalysis
A postejaculate urinalysis to detect retrograde
FIGURE 2–4. Transverse view of the prostate (within cur- ejaculation should be obtained in patients with an
sors) with a large midline cyst (hypoechoic lesion within ejaculation (no antegrade ejaculate), those with
prostate), as seen by transrectal ultrasonography (TRUS).
(From Goldstein, 1995, by permission of W.B. Saunders)
low-volume azoospermia, and all others with low-
volume semen samples, including those with oligo-
spermia and normal concentration. The patient
include midline intraprostatic cystic structures and voids to completion, produces anejaculate, and then
intraprostatic calcifications along the projected immediately voids into a specimen container. The
course of the ejaculatory ducts (Figs. 2–4, 2–5). unspun voided specimen is then evaluated. A diag-
The absence of seminal vesicles and ampulla of the nosis of retrograde ejaculation is confirmed when
vas is diagnostic of congenital abnormalities. Jarow more than 10 sperm are noted per high power field.
has demonstrated that sperm are not normally noted The sample is then centrifuged and evaluated, by
in the seminal vesicles in an unobstructed state semen analysis, to obtain concentration and motil-
immediately after ejaculation. Fluid can be aspi- ity values.
rated from the seminal vesicles via transrectal ultra-
sonic guidance to confirm ejaculatory duct obstruc- Testis Biopsy
tion. A 15-cm, 18- or 20-gauge disposable Echotip
Turner biopsy needle (Cook) is well suited for this Historically, testis biopsy has been used to diag-
nose a variety of impaired male fertility disorders.
With the advent of hormonal screening and nonin-
vasive imaging modalities, testis biopsy and oper-
ative vasography have assumed a limited role.
Testis biopsy is reserved for patients who have
azoospermia, essentially normal-size testes, palpa-
ble vas deferens and epididymis, and a normal vol-
ume of semen. In these cases, testis biopsy allows
the differentiation between patients with micro-
tubular obstructive disease who are candidates for
microsurgical repair and patients with disorders of
sperm development. In the age of intracytoplasmic
sperm injection (ICSI), testicular biopsy has taken
on an increased role.
Patients who were previously untreatable are
now candidates for extraction of testicular sperm.
In the past it was stated that if an individual has an
FSH level more than three times normal, testicular
FIGURE 2–5. Transverse view of the prostate with a cal- failure is present, and no treatment is available.
cification (arrow) in the region of the ejaculatory ducts, However, in 50% of patients with an elevated FSH
as seen by TRUS. (From Goldstein, 1995, by permission level up to three times the normal value, sperm
of W.B. Saunders) or spermatids are noted on testicular biopsy. The
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 18

18 K.A. Spear

sperm is extracted from the testicular tissue in the TABLE 2–4. Diagnoses After Evaluation
laboratory and used in conjunction with ICSI. Diagnosis Patients (%)
Testicular biopsy can be performed in the office
Varicocele 37–42
under local anesthesia. Plain 1% lidocaine is used Idiopathic 20–25
to infiltrate the anterior scrotal skin and dartos lay- Obstruction 6–14
ers. With the testicle firmly held in position and Anti-sperm antibodies 3–9
with the epididymis in a posterior position and the Testicular failure 1–9
Pyospermia/infection 1–5
anterior surface up against the scrotal wall, a 1 cm Ejaculatory dysfunction 1–3
incision is made down to the tunica vaginalis. Hold- Endocrinopathies 1
ing stitches are placed in the tunica vaginalis, and
it is opened sharply the length of the incision. An
eyelid retractor is placed and additional 1% lido-
caine is dripped on the tunica albuginia. A holding ners should be present during the initial visit and
stitch is placed in the tunica albuginia, which is any subsequent visit during which treatment deci-
then incised approximately 0.5–1.0 cm in length. sions are made. Each case must be individualized
Testicular tubules extrude from the opening and are with male partner issues, female partner issues, suc-
excised with tenotomy scissors. The tissue is placed cess rates for treatment options, costs, morbidities,
in support medium, such as human tubular fluid or and the couple’s expectations being addressed.
Hamm’s F-10, for transport to the laboratory. The In the office, various treatment options can be
biopsy is best done where intravenous sedation can initiated. In cases where surgery is indicated, expla-
be administered. nation of the procedure and its potential outcome
Testicular biopsy remains the gold standard in is required. The following is a review of the treat-
regard to diagnosis when one is searching for a ment for infertile males in the office environment.
small number of sperm. When extraction of testic-
ular sperm is to be utilized with ICSI, testicular
biopsy affords a better chance of obtaining sperm Treatment
than testicular aspiration. Furthermore, testicular
tissue can be frozen to be utilized in the future. ICSI Medical Therapy
pregnancies and good fertilization rates have been Hormonal Causes
reported using cryopreserved testicular sperm.
Testicular aspiration can be performed in the In patients with hypogonadotropic hypogonadism,
office setting. Start with 1% lidocaine local infil- treatment is highly effective. The congenital form,
tration at the puncture site. A spermatic cord block Kallman syndrome, is a result of failure of GnRH
may aid with anesthesia. The lidocaine is injected secretion. Thus FSH, LH, and testosterone are all
perivasally. A 23-gauge needle and the Fratzen low. Treatment consists of hCG 2000 IU given
apparatus for fine-needle aspiration is used. An intramuscularly three times a week. This dosage
alternative is a syringe with a three-pronged han- adequately virilizes the man, although spermato-
dle. The needle is inserted into the testicle, and neg- genesis proceeds to completion in only 20% of
ative pressure is exerted on the syringe (plunger is patients. In most patients, after 6 months one-half
pulled back) while moving the needle up and down of a 75 IU ampule of pergonal is administered three
within the testicle to obtain a sample. This tech- times a week to supply FSH. Sperm counts below
nique is limited because the chance of obtaining 10 million/ml, with good sperm motility, are usu-
sperm is low, the yield is low, and currently it must ally noted. Many of these patients are able to con-
be coordinated with egg retrieval. There are no ceive despite the decreased sperm density.
reports of cryopreserved aspirates resulting in ICSI Individuals with hyperprolactinemia require
pregnancies. Therefore, aspiration must be per- computed tomography (CT) or magnetic resonance
formed in a coordinated fashion with egg retrieval, imaging (MRI) of the head, with attention to the
and donor sperm are required for backup. sella turcica, to rule out a pituitary tumor. Patients
with mild elevations of prolactin need repeat test-
ing for prolactin to confirm a significant elevation,
Results of Evaluation as prolactin production is stress-related and levels
vary. Repeat studies are important in cases where
Evaluation of the infertile male categorizes patients. the prolactin level is less than 30 ng/ml. Serum pro-
Not only can diagnoses be made (Table 2–4), treat- lactin levels over 300 ng/ml are diagnostic of a pitu-
ment plans can be discussed and initiated. Both part- itary adenoma; a level of over 100 ng/ml is usually
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 19

2. Evaluation of the Male for Infertility 19

caused by an adenoma. If a pituitary tumor is found, Empiric Therapy

neurosurgery, irradiation, or bromocriptine is re-
quired. If a tumor cannot be delineated on imaging Despite extensive evaluation, as many as 25% of
studies or a microadenoma (10 mm) is found, infertile men have no obvious demonstrable cause
bromocriptine is the therapy of choice. Begin with for their infertility. Such patients are categorized as
a 1.25 mg dose by mouth at bedtime to minimize having “idiopathic” infertility. A variety of empiric
the side effects of nausea, vomiting, fatigue, nasal therapies have been utilized for these patients.
stuffiness, and postural hypotension. The dosage is There is no convincing evidence that any empiric
increased to an average of 2.5 mg twice a day. Pro- therapy is beneficial. Data from placebo-controlled
lactin levels return to normal in virtually all patients studies of clomiphene citrate show little or no
within days of achieving the full therapeutic dose, benefit.
which usually is 5.0–7.5 mg. Consequently, pro- Other agents have been assessed, including other
lactin levels should be monitored 4–7 days after antiestrogens such as tamoxifen, aromatase inhibi-
dosage changes to determine the therapeutic tors such as testolactone, gonadotropins, kallikrein,
response. The effects of bromocriptine are usually indomethacin, pentoxifylline, zinc, and antioxidants
not permanent, but one-sixth of patients maintain including vitamins C and E. There is a paucity of
normal prolactin levels after cessation of the drug. data to document the benefit of any of these agents
This is evident in patients with idiopathic hyper- in the idiopathic setting. Evaluation of treatment reg-
prolactinemia, when no tumor is noted. Bromocrip- imens for idiopathic infertility is complicated when
tine can be withdrawn yearly to determine if the many etiologies are classified together. Various drugs
abnormality persists. Testosterone levels rise in and dosages are utilized, placebo-controlled studies
about 3 months; and as with most therapy, semen are lacking, and various outcomes are assessed in-
analyses are delayed until 3 months after initiation cluding semen parameters and pregnancy rates. Ad-
to allow completion of spermatogenesis. ditionally, treatment-independent pregnancy rates
Congenital adrenal hyperplasia, the most com- must be considered.
mon cause of endogenous androgen excess, is usu- At this point there is no individual treatment that
ally detected prior to any infertility problems. It is can predictably improve sperm function or fertility
treated with glucocorticoids. in men with idiopathic infertility. Therefore empiric
In an oligospermic patient with low testosterone therapy for these patients is not recommended. If
and nonelevated LH, clomiphene citrate (Clomid) one chooses to attempt a trial of empiric therapy,
is beneficial. It is of note that if an individual has consideration of side effects, costs, and potential
a low LH level, a prolactin assay should be per- detriment to fertility must be considered.
formed. Clomiphene citrate is an antiestrogen– Anti-sperm Antibodies
estrogen receptor blocker that prevents negative
feedback of estrogens to the pituitary and hypo- Options for therapy are limited for those with anti-
thalamus. Estrogen is present in men, and it plays sperm antibodies. The washing and dilution tech-
an important role in the pituitary–hypothalamic– niques currently available are inadequate owing to
gonadal axis. Ablation of feedback inhibition the high affinity of antibodies. Corticosteroid ther-
causes augmentation of GnRH and of LH and FSH apy is controversial, and few controlled studies are
secretion. Increased LH stimulates the Leydig cell available. One controlled study showed benefit of
production of testosterone. Possibly, the increase in immunosuppression, but a definitive answer is lack-
FSH enhances sperm production. A clomiphene cit- ing. One problem is the risk profile of corticos-
rate dose of 25 mg daily is initiated. Serum testos- teroids, which includes mood changes, glucose
terone should be tested 2–4 weeks after initiation intolerance, ulcers, GI bleeding, and (most severe)
of treatment and every 3 months thereafter to avoid aspetic necrosis of the hip. Because of the contro-
excessive serum testosterone levels. Some authors versial nature of this treatment and the inherent
recommend monitoring estradiol levels, as testos- risks, it is not the treatment of choice.
terone is converted peripherally, and elevated estro- If one chooses to use this therapy, an appropri-
gens may be detrimental to sperm production. ate regimen consists of prednisolone 20 mg twice
Because the spermatogenic cycle takes 74 days, a day on days 1–10 of the partner’s cycle, followed
semen analysis is undertaken 3 months into ther- by a 5 mg dose twice a day on days 11 and 12. This
apy. Clomiphene citrate is well tolerated in men, treatment cycle should be continued for at least
and side effects such as gastrointestinal (GI) upset, 6 months. Hendry found statistically significant
changes in libido, weight gain, and visual distur- improvement in pregnancy rates between the treat-
bances are rare. ment and control arms after 6 months of treatment.
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 20

20 K.A. Spear

The other well controlled study, by Haas, had a a day. The drugs are taken for 10–14 days before
treatment period of 3 months, and no significant assessing their effectiveness. If one of the three
difference was noted. The longer, 6-month treat- compounds is ineffective, try imipramine (Tofranil)
ment may be advantageous and required. The best 25 mg twice a day. If this is not efficacious, try a
results are obtained when the regimen is used in combination of one of the first three drugs and
conjunction with stimulated IUI cycles. imipramine. This treatment is most effective in
In vitro fertilization is not a good therapeutic patients with diabetes.
option, as fertilization rates are markedly decreased If medical therapy fails, one can retrieve semen
when sperm-bound antibodies are present. The from a postejaculatory urine specimen to be used
treatment of choice is ICSI. Studies have shown in conjunction with an assisted reproductive tech-
excellent, standard fertilization rates and pregnancy nique (ART). To optimize the quality of the speci-
and birth rates. ICSI has an associated cost burden men, two methods are available: alkalization of
that must be factored into the assessment and plan. the urine and catheterization with instillation of
An additional modality is donor insemination. Cou- buffered solution.
ples should be counseled regarding their options, To alkalize the urine, administer sodium bicar-
along with risk/benefit and cost profiles. bonate tablets 650 mg four times a day or one or
two tablespoons of baking soda mixed in a glass of
Pyospermia water every 6 hours. This regimen should begin at
least 24 hours prior to sperm retrieval. Also, opti-
If a significant number of white blood cells (1 mize the urine osmolality in the range of 300–380
million/ml) are noted in a semen sample, treatment mosm/L, as it is in semen. This is accomplished by
is indicated. Treatment consists of: (1) frequent
increasing or restricting fluids. In general, the
ejaculation, once every other day; (2) doxycycline,
patient voids 1 hour prior to the planned ejacula-
100 mg twice a day; and (3) an over-the-counter
tion and then drinks 300–500 ml of fluid. The
nonsteroidal antiinflammatory drug (NSAID).
patient then ejaculates and voids into a container
Begin treatment at the start of the partner’s men-
with buffered medium.
strual cycle and discontinue it several days after
An additional method is to catheterize the indi-
ovulation. This regimen may be administered in a
vidual prior to ejaculation. Drain the bladder and
cyclic fashion. Treatment is monitored by semen
then instill 50–100 ml of a physiologic solution
analysis, with the sample given a few days after
such as human tubule fluid or Hamm’s F-10. The
ovulation or several days prior to a scheduled IUI.
patient then masturbates and urinates into a speci-
Studies indicate a marked decrease in leukocy-
men container. These specimens are processed and
tospermia with this regimen. In the few patients
used in the appropriate ART (i.e., IUI, IVF).
who have symptoms and positive cultures, appro-
priate antibiotics are employed. Nitrofurantoin
(Macrodantin) should be avoided because of Anejaculation
adverse affects on spermatogenesis.
Some patients who have undergone retroperitoneal
or pelvic surgery or who had a spinal cord injury
Retrograde Ejaculation
suffer from anejaculation, rather than retrograde
With retrograde ejaculation, incomplete closure of ejaculation, which is a total absence of ejaculatory
the bladder neck during ejaculation leads to ret- function. Although these patients occasionally
rograde flow of semen into the bladder. Patients respond to sympathomimetics such as pseudo-
present with low-volume semen, oligospermia ephedrine, with the regimen as described, most
(decreased sperm count), or azoospermia. This require vibratory stimulation, electroejaculation, or
condition commonly occurs in men with diabetes surgical extraction of sperm from the vas or epi-
mellitus or those who have undergone retroperi- didymis to obtain sperm for the ART procedure.
toneal or pelvic surgery that disrupts the sympa- Vibratory stimulation of ejaculation is easily per-
thetic nerves required for normal ejaculation. The formed in the office and is most successful in
condition is confirmed by finding large numbers patients with upper spinal cord lesions. This tech-
of sperm in the postejaculate urine. nique uses a vibrator, the commercial Acuvibe
These patients can be treated effectively with model 6001 or a small hand-held unit with a cone
sympathomimetic such as pseudoephedrine hydro- tip that is sold in drugstores as a foot/body mas-
chloride (Sudafed) 60 mg four times a day. Alter- sager. The unit is applied to the frenulum of the
native agents are ephedrine 25–50 mg four times a penis and then may be moved to the dorsum of the
day or phenylpropanolamine (Ornade) 75 mg twice glans. Patients who respond to this therapy do so
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 21

2. Evaluation of the Male for Infertility 21

within 5–10 minutes. Usually pelvic floor contrac- ligation, all of which are outpatient procedures.
tions, and possibly lower extremity contractions, Open surgical ligation, performed under local anes-
are demonstrated prior to ejaculation. Most patients thesia with or without intravenous sedation, is the
who respond exhibit antegrade ejaculation, but preferred method. A subinguinal incision is an
catheterization may be performed to retrieve the excellent approach. Its small size translates into
retrograde component. No anesthesia is required, superb patient comfort postoperatively. This tech-
but patients with lesions above T6 and those with nique is cost-effective and low risk. A microsurgi-
a history of autonomic dysreflexia are pretreated cal approach may be advocated so the vasal and
with 10 mg sublingual nifedipine. Additional pre- testicular arteries and the lymphatics are spared.
treatment includes one of the two methods de- The literature confirms that varicocelectomy
scribed, alkalization or catheterization, to optimize improves fertility rates. A compilation of controlled
the quality of the specimen obtained from the blad- studies demonstrates significantly improved preg-
der. Also, if the patient self-catheterizes, has a Foley nancy rates, and an international WHO study sup-
catheter, or has a history of voiding dysfunction, a ports the influence of varicoceles on fertility. A
urine culture should be obtained prior to therapy prospective, randomized, crossover study by Madgar
and antibiotics instituted. Patients who respond et al. clearly demonstrated significant improvement
consistently with an antegrade specimen can learn in fertility in patients undergoing varicocelectomy
to perform this technique with the aid of their part- versus patients who were simply observed.
ner. Pregnancies have been reported by utilizing
this technique with intravaginal insemination. Ejaculatory Duct Obstruction
Electroejaculation utilizes a rectal probe that
Ejaculatory duct obstruction can be treated with
electrically stimulates contraction of the seminal
transurethral resection of the ejaculatory ducts.
vesicles and vasal ampullae, resulting in discharge
Prior to treatment it is optimal if the obstruction is
of semen into the urethra. The model 12 electro-
verified by transrectal aspiration of the seminal
ejaculator, developed and refined by Seager, is dis-
vesicles or by vasography. These studies also con-
tributed by the National Rehabilitation Hospital,
firm the presence of sperm, ruling out proximal
Washington, DC. Electroejaculation can be per-
obstruction. Figure 2–6 illustrates potential sites of
formed in an office or procedure room in select
obstruction in the reproductive tract, including the
patients with spinal cord injuries. No anesthesia is
ejaculatory duct. Published results of treatment
required. Keep autonomic dysreflexia in mind for
show that one-half of patients have sperm in the
patients with lesions above T6. The sample is
ejaculate postoperatively, and 25% of all those
processed to be used in conjunction with IUI or
undergoing treatment contribute to a pregnancy.
IVF.
Complications include (1) impairment of semen
parameters due to urine pooling in the prostatic
Surgical Therapy
Although a concise description of surgical tech-
niques is beyond the scope of this chapter, an under-
standing of the breadth of corrective procedures
available is imperative. The major techniques uti-
lized are briefly addressed, with an emphasis on
outcomes and expectations.

Varicocele
A varicocele is an abnormal dilation of the testic-
ular veins in the scrotum. It is the most common
cause of male infertility, with a 15% incidence in
the general population and a 40% incidence in
infertile men. Among men with secondary infertil-
ity, there is an 80% incidence. Treatment results in
semen improvement in 70% of men and pregnan-
cies in 40% of couples. Repair is done by open sur- FIGURE 2–6. Sites of potential obstruction in the male
gical ligation of the vessels, transvenous emboliza- reproductive tract. Sagittal view. (By permission of Bayer
tion of the internal spermatic vein, or laparoscopic Corp.)
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 22

22 K.A. Spear

TABLE 2–5. Time Since Vasectomy Related to Results partners should undergo CF mutation analysis from
After Reversal a serum sample to estimate their risk of transmit-
Time since Sperm noted after Partners ting CF or congenital absence of the vas to off-
vasectomy (years) reversal (%) pregnant (%) spring. If the couple is at risk and proceeds with an
3 97 76 ART procedure, amniocentesis, chorionic villous
3–8 88 53 sampling, or preimplantation genetics should be
9–14 79 44 considered.
15 71 30
Assisted Reproductive Techniques
Source: Belker et al., 1991.
A variety of ART techniques have been used to treat
male factor infertility. It must be pointed out that
an ART should not be considered primary therapy
fossa and mixing with semen and (2) urinary reflux for male factor infertility. The most cost-effective
into the ejaculatory ducts. Many of these men have treatment with the highest success rate, combined
a yellow, watery ejaculate. They should dilute the with low patient morbidity, is the goal. An ART
urine by increasing fluid intake and alkalinizing the technique should be combined with treatment of
urine by taking sodium bicarbonate tablets (650 mg the infertile man to gain the highest possible preg-
four times a day) or Poly-citra (5 ml every 8 hours nancy rates. Schelegel has reported extensive cost
starting a day prior to planned ejaculation). analysis studies comparing varicocelectomy and
vasectomy reversal with primary ART. He con-
Microtubular Obstructive Disease vincingly showed the cost-effectiveness of treating
Between 5% and 10% of patients with normal- infertile men.
volume azoospermia have microtubular obstruc-
tion. Prior vasectomy and de novo epididymal
obstruction are the most common causes. Both of
Conclusions
these entities can be corrected with sophisticated Infertility is a major health concern for a large pro-
microsurgical techniques. The vasovasostomy portion of reproductive-age patients. Recognizing
study group demonstrated that the length of time this entity as a “couple” problem is essential to suc-
since vasectomy is the most important predictor of cessful treatment. Advances in the understanding,
success of a reversal (Table 2–5). Vasoepididy- diagnosis, and treatment of male factor infertility
mostomy results in an approximately 70% patency is advancing at a rapid pace. Health professionals
rate with pregnancy rates reported in the 30–50% treating the infertile man are an integral part of the
range. The average length of time before a preg- team addressing couple fertility.
nancy occurs after vasectomy reversal is 1 year.
Regarding vasoepididymostomy, most patients
have sperm in their ejaculate 3–6 months after sur- Suggested Reading
gery, but the surgery should not be considered a Acacio BD, Gottfried T, Israel R, et al. Evaluation of a
technical failure until 18 months postoperatively, as large cohort of men presenting for a screening semen
it may take that long for sperm to appear. analysis. Fertil Steril 2000;73:595–597.
Amer M, Haggar SE, Moustafa T, et al. Testicular sperm
Congenital Absence of the Vas Deferens extraction: impact of testicular histology on outcome,
number of biopsies to be performed and optimal time
Among azoospermic patients, 1.4% are found on for repetition. Hum Reprod 1999;14:3030–3034.
physical examination to have bilateral congenital Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of
absence of the vas deferens. Sperm can be obtained 1469 microsurgical vasectomy reversals by the Vaso-
from these patients by microsurgical epididymal vasostomy Study Group. J Urol 1991;145:505.
sperm aspiration (MESA). This procedure has the Chuang AT, Howards SS. Male infertility: evaluation and
best chance of success and highest yield. Percuta- nonsurgical therapy. Urol Clin North Am. 1998;25:
703–713.
neous epididymal or testicular aspiration has sev-
Clarke GN, Elliott PJ, Smaila C. Detection of sperm anti-
eral drawbacks, including inconsistent success, low bodies in semen using the immunobead test: a survey
yield, and inability to cryopreserve the sperm. The of 813 consecutive patients. Am J Reprod Immunol
sperm can be utilized with ICSI. Cystic fibrosis Microbiol 1985;7;118–123.
(CF) and congenital absence of the vas deferens are Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu
different ends of a phenotypic spectrum resulting B, Audrins P, Saunders D, Quinn F, deKretser D,
from deletions in the CF gene. Prior to MESA, both McLachlan R: Y chromosome analysis of infertile men
3051_Seifer_02_p10-23 11/27/01 3:43 PM Page 23

2. Evaluation of the Male for Infertility 23

and their sons conceived through intracytoplasmic McClure RD. Male infertility. In: Tanagho EA, Mc-
sperm injection: vertical transmission of deletions and Aninch JW (eds) General Urology. Norwalk, CT:
rarity of de novo deletions, Fertil Steril 74:909, 2000. Lange, 1992:669–695.
Goldenberg RL, White R. The effect of vaginal lubri- Muller CH. Rationale, interpretation, validation, and uses
cants on sperm motility in vitro. Fertil Steril 1975; of sperm function tests. J Androl 2000;21:10–30.
26:872. Ohl DA, Naz RK. Infertility due to antisperm antibod-
Goldstein M. Surgery of Male Infertility. Philadelphia: ies. Urology 1995;46:591–602.
Saunders, 1995. Schlesinger MS, Nagler HM. Treatment outcome after
Haas GC Jr, Manganiello P: A double-blind, placebo con- varicocelectomy. Urol Clin North Am 1994;21:517.
trolled study of the use of methylprednisolone in infer- Page DC, Silber S, Brown LG. Men with infertility
tile men with sperm-associated immunoglobulins, Fer- caused by AZFc deletion can produce sons by intra-
til Steril 47:295, 1987. cytoplasmic sperm injection, but are likely to transmit
Hellstrom WJ, Overstreet JW, Samuels SJ, et al. The rela- the deletion and infertility. Hum Reprod 14:1722,
tionship of circulating antisperm antibodies to sperm 1999.
surface antibodies in infertile men. J Urol 1980;140: Schlegel PN: Is assisted reproduction the optimal treat-
1039. ment for varicocele-associated male infertility? A cost-
Hendry WF: The significance of antisperm antibodies: effectiveness analysis. Urology, 49:83, 1997.
measurement and management, Clin Endocrinol 36: Sigman M, Howards SS. Male infertility. In: Walsh PC,
219, 1992. Retik AB, Stamey TA, Vaughan ED (eds) Campbell’s
Honig SC, Oates RD. Infertility. In: Krane RJ, Siroky Urology. Philadelphia: Saunders, 1992:661–705.
MB, Fitzpatrick IM (eds) Clinical Urology. Philadel- Sigman M, Lipshultz LI. Male infertility. In: Stein BS,
phia: Lippincott, 1994;1102–1142. Caldamone AA, Smith JA (eds) Clinical Urological
Honig SC, Lipshultz LI, and Jarow J. Significant med- Practice. New York: Norton, 1995:1219–1270.
ical pathology uncovered by a comprehensive male Silber SJ, Alagappan R, Brown LG, Page DC. Y chro-
infertility evaluation. Fertil Steril 62:1028, 1994. mosome deletions in azoospermic men undergoing
Jarow IP. Seminal vesicle aspiration of fertile men. J Urol intracytoplasmic sperm injection after testicular sperm
1996;156:1005–1007. extraction. Hum Reprod 13:3332, 1998.
Kamischke A, Nieschlag E. Analysis of medical treat- Witkin SS, David SS. Effect of sperm antibodies on preg-
ment of male infertility. Hum Reprod 1999;14(suppl nancy outcome in a subfertile population. Am J Obstet
1):1–23. Gynecol 1988;158:59–62.
Kleiman SE, Yogev L, Hauser R, Botcham A, Lessing Witkin SS, Viti D, David SS, et al. Relation between anti-
JB, Paz G, et al. Genetic evaluation of infertile men. sperm antibodies and the rate of fertilization of human
Hum Reprod 14:33, 1999. oocytes in vitro. J Assist Reprod Genet 1992;9:207–
Kruger TF, Acosta AA, Simmons KE, et al. Predictive 210.
value of abnormal sperm morphology in in vitro fer- World Health Organization. WHO Laboratory Manual
tilization. Fertil Steril 1988;49:112. for the Examination of Human Semen and Sperm-
Lamb EJ. Prognosis for the infertile couple. Fertil Steril Cervical Mucus Interaction, 3rd ed. New York: Cam-
1972;23:320. bridge University Press, 1992.
Lipschultz LI. Cryptoorchidism in the subfertile male. Yanagimachi R, Yanagimachi H, Rogers BJ. The use of
Fertil Steril 1976;27:609. zona-free animal ova as a test system for the assess-
Lipschultz LI, Howards SS. Infertility in the Male, 3rd ment of the fertilizing capacity of human spermato-
ed. St. Louis: Mosby-Year Book, 1996. zoa. Biol Reprod 1976;15:471.
Lubs HA Jr. Testicular size in Klinefelter’s syndrome in Zonari R, deAlmeida M, Rodrigues D, et al. Localiza-
men over fifty. N Engl J Med 1962;267:326. tion of antibodies on spermatozoa and sperm move-
Madgar I, et al. Controlled trial of high spermatic vein ment characteristics are good predictors of in vitro fer-
ligation for varicocele in infertile men. Fertil Steril tilization success in cases of male autoimmune
1995;63:120. infertility. Fertil Steril 1993;59:606–612.
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 24

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

Two social factors, delayed childbearing and an disappointing, they do represent realistic options
increase in the prevalence of divorce followed by for many couples. For couples unwilling to con-
remarriage, are contributing to a growing number sider these options, the next step may be to opti-
of women in their mid to late thirties who desire mize their treatment as much as possible. These
fertility at a time when fecundity is declining. One patients require more aggressive stimulation and
of the most difficult challenges is the evaluation treatment protocols and continue to have relatively
and treatment of these women, who desire fertility decreased pregnancy rates compared to women
but have diminished ovarian reserve. The latter is with undiminished ovarian reserve. This chapter
due to the fact that they frequently do not produce reviews various methods for ovarian reserve screen-
enough quality oocytes to take full advantage of the ing and considers treatment approaches for opti-
various options offered by assisted reproductive mizing chances for women with diminished ovar-
technologies. In addition, pregnancy rates during ian reserve to become a biologic parent.
natural and assisted cycles are dramatically re-
duced, and the rate of spontaneous miscarriages is
markedly increased. The challenge of increasing Follicle-Stimulating Hormone
miscarriages with diminished ovarian reserve was
highlighted in a retrospective study examining the Basal FSH Levels
influence of maternal age on pregnancy loss rates
after early documentation of fetal cardiac activity The traditional techniques used to estimate a
by transvaginal ultrasonography in women under- patients’ ovarian reserve are of limited clinical
going ovulation induction for infertility. A sponta- value because of poor predictive values, invasive-
neous abortion rate of 2% was observed for mater- ness, or expense. A parameter that is easily meas-
nal ages 35 years but increased to 16% for those urable, minimally invasive, and inexpensive and
36 years old following documentation of fetal that has good predictive value is needed. The basal
cardiac activity.1 follicle-stimulating hormone (FSH) level on cycle
The development of diminished ovarian reserve day 3 has been described by some as meeting these
generally reflects the age-related decline in repro- criteria.3–6
ductive performance.2 As such, diminished ovarian
reserve represents a natural physiologic occurrence Age-Related Changes in FSH Levels
noted in most women during their mid to late thir-
ties. This presents a particular challenge to the prac- A series of studies during the 1970s and 1980s
ticing clinician, who must attempt to identify those characterized the endocrinologic aspects of the
women with markedly reduced ovarian reserve transition through the climacteric.7–10 Sherman and
prior to embarking on expensive, invasive treat- colleagues documented that women with normal
ments. ovulatory cycles commonly begin to have subtle
If women have diminished ovarian reserve, they elevations in their FSH levels in their mid-
should be counseled to consider oocyte donation or thirties.9,10 Further studies confirmed these findings
adoption. Although these options frequently are and consistently demonstrated that the first eleva-

24
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 25

3. Detection and Therapeutic Approaches to Age-Related Infertility 25

tions occur during the early follicular phase.7,8 who was evaluating the relation between gonado-
Although these studies did not evaluate the relation tropin-releasing hormone (GnRH) stimulation test
between the FSH level and ovarian reserve, they results and the ovarian response to gonadotropins.15
documented that FSH levels increase at the same Evaluation of the pregnancy rates following in vitro
general time the incidence of diminished ovarian fertilization (IVF) cycles revealed high pregnancy
reserve increases. rates in groups in whom FSH levels were relatively
The physiologic basis for the increase in basal low, whereas no pregnancies occurred in groups in
FSH with aging has received renewed vigor. Batista whom the basal FSH values were higher. Although
et al. evaluated luteinizing hormone (LH), FSH, the small number of patients in the study precluded
17-estradiol inhibin, progesterone, PP-14, and a meaningful evaluation of basal FSH levels and
endometrial biopsies (EMBs) in young (age 20–30) pregnancy rates, it indicated the need for a larger,
and older (age 40–50) volunteers.11 FSH levels more detailed study.
were increased, and inhibin levels (Monash assay) Scott et al. found in a large retrospective study
were decreased in the older group. None of the of 758 IVF cycles that pregnancy rates decreased
other parameters were different; in particular, the markedly as FSH levels rose.5 Ongoing pregnancy
incidence of out-of-phase EMBs was similar rates were highest in women whose FSH levels
among the two groups. More recently, Klein and were 15 IU/L and fell to less than 5% in those
coworkers could not find any decrease in estradiol, whose basal FSH levels were over 25 IU/L. This
progesterone, LH, or total immunoreactive inhibin reduction in pregnancy rate was attributed to di-
(Monash assay) levels with reproductive aging.12 minished ovarian reserve, as these patients devel-
These investigators were able to show that the older oped fewer follicles, produced fewer oocytes, and
group (age 40–45) had accelerated follicular devel- had fewer embryos transferred. Significantly, age
opment leading to a shortened follicular phase com- would not have predicted the differences in clini-
pared to the younger group (age 20–25). The same cal response because the ages of the women in the
investigators also measured the 24-hour mean FSH various groups were equivalent (mean age approx-
and LH levels during the early follicular and mid- imately 35 years). Thus assessment of basal FSH
luteal phases of the cycle in both the younger and levels provided a means of predicting ovarian
older groups. The 24-hour mean FSH levels were responsiveness and eventual pregnancy rates prior
significantly higher in the older group during both to assuming the risks and expense of treatment.
phases of the cycle than in the younger group, Another study from the same center evaluated
whereas no differences were noted for LH. These the relative predictive values of basal FSH levels
investigators suggested that elevated FSH levels and age in 1478 consecutive IVF cycles. Although
seen with reproductive aging may represent a pri- there was a definable decline in pregnancy rate as
mary neuroendocrine change rather than an ovar- age increased, basal day 3 FSH levels provided
ian one. More recently the same investigators eval- much better predictive values for both pregnancy
uated the correlation between follicular FSH, and cancellation rates.6 This finding was confirmed
estradiol, and inhibin A and B using a newly devel- in other studies.
oped dimeric (bioactive) inhibin assay and found The precise physiologic basis for basal FSH
an inverse correlation between follicular FSH and screening is the subject of intense investigation.
inhibin B levels in the two groups of women de- Originally several researchers postulated that be-
scribed above (young versus older).13 This obser- cause these elevations occur when circulating estra-
vation suggests that reproductive aging is primarily diol levels are at their nadir, differences in FSH lev-
of ovarian origin. Furthermore, there are data to els could reflect differences in inhibin activity.
support the hypothesis that both diminished follic- Studies comparing inhibin levels in women of dif-
ular quantity and quality occur in women with ferent ages provide little support for that specific
diminished ovarian reserve, as is discussed in the mechanism. Hughes et al. found that although there
next section. These follicles have diminished was an age-related decline in peak inhibin levels
capacity for steroidogenesis and inhibin produc- during complex ovulation induction, those levels
tion; they have fewer cells, and these cells have a were not different earlier in the cycle (basal).16
good chance of undergoing apoptosis.14 Other authors found differences between inhibin
levels in high and low responders during complex
Basal FSH Levels and Pregnancy Rates ovulation induction cycles, but again basal levels
were not different.17 It is important to note that the
The earliest description of pregnancy rates and above studies used the Monash assay to measure
basal FSH levels was in a study by Muasher et al., total immunoreactive inhibin, which is based on a
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 26

26 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

heterologous double-antibody radioimmunoassay and a reduced probability of conceiving a clinical

based on purified 31-kDa bovine follicular fluid pregnancy through ART than women with high day
inhibin, which also binds to the free -subunit and 3 inhibin B. Danforth and coworkers evaluated
its precursors. Using a newly developed dimeric luteal phase inhibin A and follicular phase inhibin
inhibin assay, which measures specific forms of B levels and noted an inverse relation with advanc-
bioactive inhibins (A and B) by enzyme-linked ing age. Also noted was a decline in inhibin A and
immunosorbent assay, the rise in early follicular inhibin B before the monotropic FSH rise. Addi-
FSH with reproductive aging correlates with a fall tional data support the observation that day 3 serum
in inhibin B levels.13 Hopefully, introduction of this inhibin B levels decline before the monotropic FSH
assay will allow investigators to examine the rela- rise. Seifer and coworkers studied women under-
tive contributions of estradiol and inhibins A and going ART who demonstrated a poor response to
B to controlling FSH secretion. stimulation as measured by increased ampules of
It has been reported that luteinized granulosa gonadotropins for stimulation yielding a higher
cells from women with elevated day 3 FSH levels cancellation rate, a lower estradiol response, fewer
produce less steroids, are less viable in culture, oocytes retrieved, and lower clinical pregnancy
have a reduced mitotic index, and produce de- rate. They found that this group of women also had
creased quantities of insulin-like growth factor lower inhibin B levels than women undergoing
(IGF-I and IGF-II). Moreover, it has been demon- ART with normal ovarian responsiveness, despite
strated that preovulatory follicles from women with both groups having similar nonelevated day 3 FSH
diminished ovarian reserve contained fewer num- levels. In addition to confirming the inverse rela-
ber of luteinized granulosa cells and have a higher tion between declining inhibin levels and rising
percentage of cells undergoing apoptosis compared FSH levels, Santoro and colleagues demonstrated
with women with uncompromised ovarian reserve an increase in activin A, which may also contrib-
undergoing superovulation for in vitro fertiliza- ute to the FSH elevation.
tion–embryo transfer (IVF-ET).14 More impor- The results of these studies call for follow-up
tantly, these investigators reported that the secre- investigations with larger patient populations. If
tion of total and dimeric inhibin A (using a specific future investigations confirm the above findings,
assay) was lower in granulosa cell cultures obtained dimeric inhibin measurements along with day 3
at IVF from patients with high basal FSH, but no FSH may provide a better screening test than either
significant differences in either estradiol or pro- test alone.
gesterone concentrations were seen. This hopefully
provides one explanation for the long-sought phys- Intercycle and Intracycle Variability
iologic reason for the increase in basal FSH in
women with diminished ovarian reserve.18
in Basal FSH Levels
If basal FSH levels are to be used to counsel patients
regarding their chances for conception, a number of
Inhibin questions regarding the reproducibility of the test
Seifer et al.19 examined assisted reproductive tech- must be addressed. One is defining the magnitude
nology (ART) outcomes in women characterized as of the intercycle variation in basal FSH levels. Scott
having low or high day 3 serum inhibin B concen- et al. evaluated the intercycle variability in basal
trations (45 pg/ml vs. 45 pg/ml). Women with FSH levels in 81 women undergoing multiple IVF
low day 3 serum inhibin B demonstrated 70% of cycles.20 The mean deviation was 4.2  0.4 IU/L,
the estradiol response, 66% of the number of with a range that extended from 1 IU/L to 42 IU/L.
occytes retrieved, 28% of the clinical pregnancy However, the patients with normal basal FSH lev-
rate per initiated cycle and three times the cancel- els (15 IU/L) had low intercycle variations (mean
lation rate per initiated cycle than women with a 2.6  0.2 IU/L). In contrast, patients with elevated
day 3 inhibin B level 45 pg/ml. After controlling basal FSH levels had a much higher degree of vari-
for age, day 3 serum FSH, day 3 serum estradiol, ation (mean 7.4  0.9 IU/L). Scott et al. noted that
patient cycle number, and ART method, day 3 the intercycle variability in basal FSH levels gen-
serum inhibin B 45 pg/ml was noted to be prog- erally did not affect the patients’ prognostic cate-
nostic of the number of oocytes retrieved and the gory and therefore should have a minimal impact
clinical pregnancy rate. These data suggest that on clinical decision-making.
women with low day 3 serum concentrations of In the same study, 28 patients had an intercycle
inhibin B have less ovarian reserve, as demon- variability in basal FSH values that resulted in the
strated by a poor response to ovulation induction patient having a basal FSH value in the normal or
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 27

3. Detection and Therapeutic Approaches to Age-Related Infertility 27

intermediate range during one cycle and elevated Basal FSH Screening in Women
in another. If basal FSH levels reflect the overall with One Ovary
metabolic activity of the developing cohort of fol-
licles, it seemed possible that reproductive perfor- Because basal FSH level screening is believed to
mance would be enhanced during cycles when the reflect the activity of the developing cohort of fol-
basal FSH levels were lower. Perhaps patients licles as a whole, there was considerable concern
needed to be monitored from cycle to cycle and as to whether the predictive value of the test would
then stimulated during the cycle when their FSH be maintained in women with one ovary. There is
levels were normal. A paired analysis of the high a decrease in the size of the initial cohort of folli-
and low FSH cycles in these patients revealed no cles in these patients, but there is not necessarily a
differences in stimulation quality, number of corresponding decrease in their quality.
oocytes retrieved, or fertilization rates. Interest- Khalifa et al. compared the basal FSH levels in
ingly, the patients all behaved as low responders in women with one or two ovaries and evaluated the
both cycles. These data indicate that by the time predictive values of the test in each group.23 The
patients develop more variability in their basal FSH 162 women with one ovary had higher mean basal
concentrations they have already had a significant FSH levels and correspondingly had a poorer
diminution in ovarian reserve. Furthermore, it response to gonadotropin stimulation than the 1066
strongly suggests that serial screening of FSH lev- patients with two ovaries. After controlling for the
els to select the optimal cycle for stimulation would basal FSH level, however, there were no differences
be of limited clinical value. This study was limited, in gonadotropin responsiveness or pregnancy and
however, because information regarding pregnancy delivery rates. These data indicate that basal FSH
outcome was not available. Selection criteria for screening retains its predictive value in women with
entry into the study required patients to have had one ovary, even when using the same thresholds for
repeated ART cycles without successful pregnancy. defining an abnormal test.
Martin et al.21 examined the pregnancy outcomes
of four cohorts of couples regarding intercycle vari- Estradiol Levels and Basal
ability of the day 3 serum FSH level. More than Day 3 FSH Levels
1850 cycles of women who underwent IVF were
categorized as follows: only 20 mIU/ml; always The validity of FSH screening depend on the time
20 mIU/ml; current 20 mIU/ml but one previ- during the cycle the sample is collected. Timing is
ous 20 mIU/ml; and current 20 mIU/ml but two considered optimal when circulating estradiol (E2)
or more previous 20 mIU/ml. No pregnancies levels are at their nadir, which is typically around
occurred in 53 cycles with day 3 FSH only 20 cycle day 3. Some patients have inappropriately
mIU/ml. In 1750 women whose day 3 FSH levels high E2 levels on day 3, which suggests that they
were always 20 mIU/ml, the pregnancy rate per may be farther into their follicular phase than is
cycle was 16.5%. For 54 cycles in which day 3 FSH clinically apparent. In these circumstances, it is
was 20 mIU/ml one time only but 20 mIU/ml possible that the higher circulating E2 level is sup-
during the treatment cycle, the pregnancy rate as pressing FSH levels back into the normal range
5.6%. For 11 cycles where two or more previous even if the patient has diminished ovarian reserve.
FSH determinations were 20 mIU/ml but with a The original studies evaluating the relation
current day 3 FSH 20 mIU/ml, no pregnancy between basal E2 and FSH levels in an effort to
occurred. Based on these results the investigators determine if there was a threshold value above the
came to the conclusion that patients with day 3 predictive value of a normal FSH level was lost.5
serum FSH 20 mIU/ml should be strongly dis- No such threshold value could be identified. More
couraged from proceeding with IVF. The 5.6% recently, two investigators revisited this question.
pregnancy per cycle rate with one previously ele- Licciardi et al. determined that progressive in-
vated FSH supports the concept that once a patient creases in basal day 3 E2 levels were associated
has an elevated FSH level she is unlikely to be suc- with declining ovarian responsiveness and preg-
cessful during further IVF cycles regardless of what nancy rates.24 After controlling for FSH levels,
future day 3 FSH values may be. however, there was no difference in pregnancy rates
Another study examined intracycle variability in in women with normal or “elevated” basal E2 lev-
a healthy population of women with regular men- els. Thus the authors were unable to demonstrate
strual cycles. It noted serum FSH on days 2–5 to that the E2 levels added information beyond that
be similar.22 This result appears to have been con- seen with FSH levels alone.
firmed by other investigators.12 In contrast, Smotrich et al. demonstrated a sig-
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 28

28 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

nificant decline in pregnancy rates with elevated E2 by poor gonadotropin responsiveness and preg-
levels, even after controlling for the FSH levels.25 nancy rates in patients undergoing complex ovula-
These authors chose a higher threshold E2 value for tion induction or one of the assisted reproductive
defining a significant elevation (80 pg/ml compared technologies.5,6,15–18,20,23–25 The test is simple, inex-
to 45 pg/ml in Licciardi et al.’s paper), although no pensive, and routinely available. The studies per-
data regarding the comparability of the assays are formed to date are limited to clinical circumstances
available. requiring complex ovulation induction. No data are
In aggregate, these data suggest that patients with currently available to assess the predictive value of
elevated E2 levels may have reduced reproductive basal FSH screening during spontaneous ovulatory
potential. Further studies are needed to define more cycles or in women from a general infertility
clearly the appropriate threshold values and to population.
determine exactly how they should alter interpre-
tation of circulating FSH concentrations.
Clomiphene Citrate Challenge Test
Basal FSH/LH Ratios The clomiphene citrate (CC) challenge test (CCCT)
Although extensive data are available regarding the was described in 1987 by Navot et al. as a means
high level of specificity of basal FSH levels, the of assessing ovarian reserve in women 35 years of
fact remains that the test may have limited sensi- age and older.27 This simple test consists of meas-
tivity. Stated otherwise, patients with abnormal lev- uring serum FSH concentrations on cycle day 3
els are typically low responders with poor preg- (basal) and then again on cycle day 10 following
nancy rates (highly specific), but a substantial administration of 100 mg of CC on cycle days 5
group of patients have normal levels and still through 9. In the original study, reported prior to
respond poorly to stimulation with associated poor any of the studies addressing the value of basal FSH
pregnancy rates. This led some investigators to seek levels, an abnormal test was defined by an elevated
more sensitive tests (i.e., FSH/LH ratios, dimeric level in the day 10 sample. Obviously, an abnor-
inhibin, E2 as previously mentioned) to determine mal value on cycle day 3 also results in the test
if a given patient has diminished ovarian reserve. being considered abnormal.
Mukherjee et al. reported that patients with ele- Similar to the information regarding basal FSH
vated FSH/LH ratios (indicating disproportionally levels, the precise physiology of the CCCT has not
more FSH secretion) were low responders with been clearly defined. The premise of the test is that
lower peak E2 levels and fewer oocytes recovered.26 in women with normal ovarian reserve the overall
The authors evaluated 74 patients with normal basal metabolic activity of the developing follicles should
FSH and E2 who underwent IVF, 14 of whom had be able to overcome the impact of CC on the hypo-
an FSH/LH ratio 3.6. The cancellation rate in that thalamic-pituitary axis and suppress FSH levels
group was 12 of 14, compared to a significantly back into the normal range by cycle day 10. Addi-
lower cancellation rate of 6 of 60 if the FSH/LH tion of CC creates a “provocative” test that unmasks
ratio was 3.6. It is of note that pregnancy rate patients who might not be detected by basal FSH
in patients with an FSH/LH ratio 3.6 was 25% screening alone. Investigators have demonstrated
(neither of the two patients with an FSH/LH different serum inhibin B concentrations in normal
ratio 3.6 conceived). Obviously a larger sample versus abnormal CCCTs, supporting the concept
size is needed before this ratio can be used clini- that diminished granulosa cell inhibin B production
cally as a marker of diminished ovarian reserve. may be responsible for an abnormal CCCT.
In a review of the basal FSH/LH ratios and preg-
nancy outcome data from the Saint Barnabas Med-
ical Center program in Livingston, NJ, there were
CCCT and Pregnancy Rates
no definable differences in pregnancy or implanta- In its original description, the CCCT was used to
tion rates among 336 patients with normal basal evaluate 51 infertile women over age 35.27 All 51
FSH levels and varying FSH/LH ratios. More data of these women had normal basal FSH concentra-
are needed to determine if evaluation of this rela- tions, but 18 had elevated values following CC
tion can provide clinically meaningful information. administration and were categorized as having
diminished ovarian reserve. Demographically, the
patients with diminished reserve were similar to
Current Status of Basal FSH Screening those with adequate reserve at equivalent ages,
Elevated basal day 3 FSH concentrations are highly durations of infertility, and requirements for aug-
predictive of diminished ovarian reserve as defined mentation of ovulation. However, only 1 of the 18
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 29

3. Detection and Therapeutic Approaches to Age-Related Infertility 29

(6%) patients with diminished reserve conceived, followed for a minimum of 1 year had an abnor-
whereas 14 of 33 (42%) of the adequate reserve mal CCCT. The incidence of abnormal tests rose
group became pregnant. with age and was 3% when the woman was 30
Following this initial report, several groups eval- years, 7% at 30–34 years, 10% at 35–39 years, and
uated the predictive value of the CCCT for screen- 26% for women 40 years. Most importantly, the
ing patients participating in ART programs.28 pregnancy rates in the patients with diminished
Tanbo et al. studied 91 women over age 35 and ovarian reserve were markedly lower (9%) than
found abnormal CCCTs in 37.29 Of these 37 pa- those with adequate reserve (43%). The pregnancy
tients, 20 also had an elevated basal FSH concen- rates were still significantly decreased after con-
tration on cycle day 3. Only one patient had an trolling for age. It is of note that only 7 of the 23
abnormal value on day 3 and a normal value on day patients with abnormal tests had an elevated day 3
10. The predictive value of an abnormal test was FSH level, again suggesting that the CCCT may be
85% for cycle cancellation due to poor ovarian substantially more sensitive than screening with
responsiveness and 100% for failing to conceive. day 3 samples alone. An examination of the E2
In contrast, cancellation rates were much lower response between days 3 and 10 failed to reveal any
(31.5%) and the pregnancy rates much higher correlation differentiating those women with nor-
(11%) in patients with normal tests. Most signifi- mal or abnormal FSH responses.
cantly, approximately twice as many patients were Evaluation of the relation between the eventual
identified using the CCCT compared to basal FSH clinical diagnoses and CCCT results in these 236
screening alone. couples revealed a high incidence of abnormal tests
Loumaye et al. also evaluated the CCCT but in the patients with unexplained infertility. In fact,
defined an abnormal test by adding the day 3 and the incidence of abnormal CCCTs was highest
day 10 FSH values together.28 In their series of 114 among patients with unexplained infertility (38%)
patients a threshold effect was evident, with preg- and was unaffected by age.30 This finding suggests
nancy rates remaining equivalent until the summed that diminished ovarian reserve should be consid-
FSH concentrations exceeded 26 IU/L, when they ered an etiology of infertility, and that couples with
became zero. Here again the predictive value of an abnormal tests should no longer be considered to
abnormal test for failing to become pregnant was have unexplained infertility.
100%.
Predictive Value of Age and the CCCT
CCCT for Screening the General
Infertility Population The data from the studies described above clearly
define that the CCCT has been predictive values for
The data generated during the initial evaluation of pregnancy rates than does age alone. In clinical
the CCCT were similar to those obtained when practice both age and CCCT results are now avail-
evaluating basal FSH levels alone. The CCCT eval- able. Scott et al. performed a life-table analysis of
uates the predictive value of the test in ART pro- the pregnancy rates of 589 couples from the gen-
grams or for patients undergoing complex ovula- eral infertility population who were followed for up
tion induction. Although the test is clearly useful to 45 months.31 Analysis of the patients with
for identifying patients with a poor prognosis in abnormal CCCTs revealed that the pregnancy rates
that setting, the results may not be readily extrap- were uniformly poor independent of the patient’s
olated to the general infertility population. There age. This finding provides further support to the
were legitimate concerns that because the CCCT contention that diminished ovarian reserve is a spe-
reflected the inability of the developing cohort of cific etiology of infertility.
follicles to suppress FSH levels into the normal In contrast, evaluation of the patients with ade-
range, the test would be predictive only of the qual- quate ovarian reserve (normal tests) revealed a
ity of the cohort as a whole. If a single follicle in significant diminution in pregnancy rates with
a cohort has good reproductive potential (even if increasing age. This underscores the importance of
the others did not), the natural processes of recruit- considering the patients’ age when counseling them
ment and selection could lead to ovulation of the regarding their long-term chances for conception,
highest-quality follicle, and the predictive value of even when their CCCT results are normal. Pearl-
the CCCT would be diminished. stone et al. noted similar findings when evaluating
Scott et al. completed a long-term prospective the combined predictive value of age and basal FSH
evaluation of CCCT screening in women from the concentrations in women over age 40 who were
general infertility population.30 Approximately undergoing complex ovulation induction.4
10% of the 236 patients who were evaluated and The poor predictive value of a normal test result
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 30

30 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

in women over age 40 emphasizes that there are lation induction, and with IVF.27–30,34 Although the
changes in the reproductive system that are not test is specific, it has limited sensitivity, with a sig-
detected by a CCCT that may significantly limit the nificant age-related diminution in reproductive
reproductive potential of individual patients.2 As potential occurring even among women with nor-
noted previously, there are definable changes in the mal test results.2
nonovarian components of the reproductive system The CCCT may be superior to basal FSH screen-
that could theoretically account for some of the age- ing because it is two to three times more sensitive
related decline in reproductive potential. The fact than basal FSH screening alone. Although abnor-
that tubal transfer of donor eggs produces equiva- mal day 3 FSH values appear to be accompanied
lent pregnancy rates in all age groups suggests that by abnormal day 10 values in most cases, the cur-
the most significant component of the age-related rent literature does not contain enough data to rec-
decline in reproductive potential relates to gamete ommend omission of the day 3 sample, and the
quality. Taken in aggregate, it appears that the authors continue to screen patients with both day 3
development of an abnormal CCCT is in fact a late and day 10 FSH levels. Specific screening guide-
finding, and that a significant oocyte-related lines are described below.
diminution in reproductive potential occurs prior to
the development of an abnormal test. A test pre-
dicting oocyte quality would obviously be of sig-
nificant clinical importance. Ovarian Reserve Screening
Threshold Values
Smoking and the CCCT
When applying the tests to a given patient popula-
Women who smoke cigarettes go through meno- tion, the practicing clinician is critically dependent
pause 1–4 years earlier than nonsmokers, and a on the validity of the assay results and the thresh-
direct relation between the number of cigarettes old values used for counseling. The importance of
smoked and early menopause has been noted.32,33 validating any given assay system is described
It suggests that smokers deplete their pool of folli- below. The broader issue of selecting a threshold
cles at an accelerated rate, suggesting that these value for normal and abnormal is also important.
women may have an onset of diminished ovarian In some of the early reports, authors used the dis-
reserve at an earlier age. Sharara et al. examined tribution of results among healthy and apparently
the relation between cigarette smoking and the normal women to determine the 95% confidence
prevalence of diminished ovarian reserve.34 They interval of anticipated results. Values above this
evaluated women over age 35 because it is unlikely range were considered abnormal. Although this
that women at younger ages, even if they were approach is intuitively logical, it is not appropriate
depleting their pool of follicles at an accelerated for validation of this type of test result. For exam-
rate, would have depleted enough of their follicles ple, if the women screened were all in their early
to manifest diminished reserve. This was confirmed twenties, it would be illogical and probably incor-
in two studies where the mean age of smoking rect to assume that 5% of them had a degree of
women was 35.35,36 In our study, women who diminished ovarian reserve adequate to compro-
smoked cigarettes had a significantly higher preva- mise their fertility. Similarly, if a group of women
lence of abnormal CCCTs, implicating smoking in in their early forties were evaluated, the number
the loss of reproductive potential at an earlier age. with diminished ovarian reserve would greatly
It may be appropriate to add loss of reproductive exceed the 5%, which would be defined as abnor-
potential to the already long list of health hazards mal. Clearly, defining threshold values by creating
induced by smoking in reproductive-age women. a general population confidence interval is inap-
This information is of critical importance when propriate.
counseling smoking women. Other environmental The threshold values for normal and abnormal
and endogenous factors (e.g., galactosemia) that tests should be based on clinically defined end-
may affect ovarian reserve are being investigated. points. Because the specific changes that account
for the loss of reproductive potential remain unde-
fined, all the studies reported to date are observa-
Current Status of CCCT Screening tional in nature. The only way to determine a
An abnormal CCCT has excellent predictive value threshold value is to perform the screening test in
for diminished ovarian reserve and poor long-term a large group of women and then follow them clin-
pregnancy rates during natural cycles, during ovu- ically to determine who is able to conceive. An eval-
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 31

3. Detection and Therapeutic Approaches to Age-Related Infertility 31

uation of the distribution of these data may then be Seifer et al.38 reported a technique for quantita-
used to define normal and abnormal test results. For tively translating the results obtained at different
centers that do not have a large clinical volume or institutions. They derived an equation that allowed
that want to apply these screening tests without them to predict the values obtained in one system
waiting the required time to accumulate all the fol- based on the results obtained in the other (r 
low-up data, comparison of their assay system with 0.99). These data suggest that institutions may com-
those from one of the centers where the original pare their assay to those used at centers that have
research was done is indicated. validated their threshold levels based on clinical
performance.
Assay Variability
Immunoassays of LH and FSH are intrinsically dif- Morphologic Tests
ficult and imprecise, reflecting the fact that LH and
Investigators have attempted to quantify potential
FSH are glycoprotein hormones composed of a pro-
ovarian responsiveness using ultrasonographic
tein dimer backbone with variable degrees of gly-
measurements of various morphologic ovarian
cosylation. Because these hormones have a com-
characteristics. An example is correlating antral fol-
mon  chain, the specificity of their actions is
licle counts with ART outcomes. It has been
determined by the unique  chain. The amino acid
observed that the number of antral follicles detected
sequences of the  and  chains are believed to
by transvaginal ultrasonography decreases with
remain constant, although the degree of glycosyla-
advancing age. Antral follicle counts have been
tion varies substantially throughout the menstrual
found to correlate well with ovarian responsiveness
cycle. The different degrees of glycosylation affect
to stimulation and pregnancy outcomes.
the bioactivity and circulating half-lives of both LH
Transvaginal ultrasonographic ovarian volume
and FSH and may also substantially influence the
measurement represents another morphologic test
immunoassayability of these hormones. This is one
of ovarian reserve. Syrop and coworkers39 exam-
of the main factors that explains the varying dis-
ined ovarian volumes and noted that total ovarian
crepancy between bioassay and immunoassay hor-
volume and the volume of the smallest ovary were
mone levels in samples collected throughout the
predictive of a woman’s response to gonadotropin
menstrual cycle.
stimulation and ART success. Specifically, large
Differences in the antibodies used to measure
ovarian volumes were predictive of good ART out-
gonadotropin levels also contribute to the impreci-
come, whereas small ovarian volumes were asso-
sion of these assays. Most of the commercially
ciated with poor ART outcomes.
available assay systems use polyclonal antibody
systems that bind differently to different haptens on
the glycoprotein hormone. It is important to rec- Recommendations for Ovarian
ognize that immunoassays do not measure the total Reserve Screening
quantity of the glycoprotein present but, rather, the
overall number of binding sites recognized by the Based on the data currently available in the litera-
antibodies used in the system. Consequently, as ture, it is possible to recommend guidelines about
the distribution of the various isoforms changes who should be screened for evidence of diminished
throughout the menstrual cycle, the ability of any ovarian reserve. All infertile women over age 30
single assay to recognize the gonadotropins pres- should be screened because the rise in the incidence
ent may differ substantially. Obviously, this prob- of diminished ovarian reserve begins at approxi-
lem would be amplified when using another sys- mately that time. We believe that women should be
tem with different antibodies that may recognize a screened early in their overall infertility evaluation,
different set of haptens. as the test is simple and inexpensive, and it pro-
For all of these reasons, comparison of results vides valuable prognostic information. Addition-
among different assay systems may be difficult.37 ally, younger women with unexplained infertility
The problems go beyond simple calculation of pro- should be screened because the incidence of abnor-
portionality because an assay that reports a rela- mal tests approaches 50% among these patients
tively higher value with one set of isoforms could independent of their age.
present a lower value when measuring another. Perhaps the most important aspect of using the
Additionally, different assays may be calibrated various tools available for assessing ovarian reserve
against different reference preparations, adding fur- is the way in which the information is applied to
ther variability to the results reported. patient counseling. These tests do not have absolute
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 32

32 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

sensitivity or specificity. Patients with abnormal For these reasons, it may not be sufficient sim-
values should be counseled that their chances for ply to evaluate various treatment regimens by com-
conception are poor and that they may want to con- paring peak E2 levels, the number of follicles that
sider other options, such as oocyte donation or develop, the number of oocytes recovered, or the
adoption. These patients have excellent pregnancy number of embryos available for transfer. Although
rates in oocyte donation programs, indicating that pilot studies may legitimately compare ovarian
the remainder of their reproductive system usually responsiveness, any meaningful, definitive evalua-
functions normally. The results of these tests, how- tion must also include an assessment of implanta-
ever, should not be used to exclude patients from tion and pregnancy rates.
care. This information is similar in nature to that
provided by a semen analysis. Just as men with Increased Gonadotropin Dosage
severe oligoasthenospermia occasionally father a
The first and perhaps simplest approach to increas-
child, women with evidence of diminished ovarian
ing the magnitude of the ovarian response is to
reserve occasionally conceive. The information is
increase circulating gonadotropin levels during
best used to counsel patients regarding their indi-
stimulation. Higher circulating levels may reliable
vidual chances for conception. Decisions about how
be achieved by increasing the quantity of gonado-
to apply that information is a personal decision
tropins being administered. Patients who responded
made by the infertile couple and their clinician.
poorly to low doses (150 IU FSH; 2 ampules per
Finally, the absolute dependence of these tests
day) may commonly produce more follicles when
on clinically determined threshold values makes it
given 300 IU or 450 IU per day.40 These enhanced
imperative that clinicians have confidence in the
responses lead to an increase in the number of
significance of the results from their own labora-
oocytes obtained and the number of embryos trans-
tory. This may be achieved by evaluating clinically
ferred; and a significant number of pregnancies
defined endpoints in their own population or by par-
have been attained.
allel comparison with the results obtained in an
Despite improvements in some patients, there are
established laboratory.
clear limits on the effectiveness of this strategy. At
some point saturation kinetics are attained, and the
Treatment of Women with ovarian response is determined more by the num-
Diminished Ovarian Reserve ber of follicles available for recruitment than the
circulating gonadotropin levels. This point is par-
Prior to the advent of intracytoplasmic sperm injec- ticularly important because low responders gener-
tion (ICSI), it was believed that the major obstacle ally have markedly diminished numbers of follicles
to treatment of the infertile couple was the male available for recruitment. It has been demonstrated
factor. Now the greatest limitation to treating a cou- that doses above 450 IU per day rarely produce a
ple with infertility is diminished ovarian reserve of meaningful improvement in ovarian response or
the female. This limitation has been studied exten- the ensuing pregnancy rates. Land et al. found no
sively since investigators began describing dramat- improvement in pregnancy rates with doses above
ically lower success rates in in vitro fertilization 225 IU per day.40 Although the dose necessary to
(IVF) patients who have diminished ovarian reserve
optimize ovarian responsiveness varies from patient
as reflected by an elevated day 3 serum FSH level.
to patient and should certainly be optimized, it is
Strategies to improve outcomes have included
likely that clinically meaningful improvements are
increasing the dose of exogenous gonadotropins,
only rarely obtained with doses over 450 IU per
decreasing the dosage of GnRH analogues, sup-
day (6 ampules). It remains to be seen whether the
plementing ovulation induction protocols with
introduction of recombinant FSH can alter the preg-
growth hormone, transferring back an increased
nancy rate for women with diminished ovarian
number of embryos, and selective assisted hatch-
reserve.
ing. Improvements in overall responsiveness have
been demonstrated with virtually every protocol for GnRH Agonist Down-Regulation
some patients. Despite this fact, the incremental
improvement in pregnancy rates has generally been The introduction of stimulation protocols contain-
small. These data continue to emphasize the impor- ing GnRH agonists during the late 1980s provided
tance of the qualitative changes in these patients’ new opportunities to stimulate patients who previ-
oocytes, as many have sufficient improvements in ously had limited responses to gonadotropins.41 Ini-
the quantity of oocytes recovered to have routine tial reports indicated that some low responders were
numbers of embryos transferred. stimulated better following luteal phase adminis-
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 33

3. Detection and Therapeutic Approaches to Age-Related Infertility 33

tration of a GnRH agonist.41 Subsequent clinical rescued the corpus luteum from their prior cycle
experience has provided disappointing results. In and produced large levels of progesterone during
fact, many patients who are low responders may be the early follicular phase. The impact of these ele-
completely refractory to stimulation after being vations on folliculogenesis, endometrial develop-
down-regulated with a GnRH agonist.42 Whereas ment, and subsequent implantation rates has not
concurrent use of a GnRH agonist approaches been adequately studied. Finally, the overall impact
being the standard for follicular stimulation in most on pregnancy rates has been mixed. Although flare-
ART programs, the enhancement of peak E2 levels, up protocols are certainly not as successful for the
oocytes obtained, and pregnancy rates generally average ART patient as the luteal phase suppres-
reflect the near-elimination of premature LH surges sion protocols, they do offer an opportunity to
and the longer and more aggressive stimulation pro- obtain controlled ovarian hyperstimulation in some
tocols that are possible. The fact that these are usu- patients who cannot be stimulated with other pro-
ally not the limiting factors in low responders may tocols.42
explain the generally unfavorable clinical results
obtained with these protocols. Microdose GnRHa Flare-up
There has been some question as to the direct
impact of GnRH-a on ovarian responsiveness. GnRH There have been no reported dose-response studies
receptors have been demonstrated in the ovary, of the pharmacodynamics of GnRH agonists dur-
although their role in follicular development is not ing flare-up ovulation induction cycles. The doses
understood. Feldberg et al. demonstrated increased have generally been taken from treatment protocols
ovarian responsiveness in low responders with ele- for men with prostate cancer, where minimizing the
vated day 3 serum FSH levels who were maintained duration and effect of the endogenous gonadotro-
on lower doses of GnRH-a following pituitary sup- pin flare would be desirable. Navot et al. reported
pression (minidose GnRHa).43 Although these pre- in 1991 that the rate of pituitary desensitization and
liminary data are provocative, prospective random- ovarian down-regulation was significantly pro-
ized dose response studies are clearly needed to longed using 1% of the normal dose of histerelin.47
address the issue of GnRH-a dose and ovarian per- They subsequently extended their findings in the
formance adequately. Experience in our center con- primate model by demonstrating that the pituitary
tinues to demonstrate that a number of patients are could respond with supraphysiologic gonadotropin
refractory to stimulation following down-regulation release in response to low doses of GnRH-a for pro-
with GnRH-a at any dose (R.T. Scott et al., unpub- longed intervals without inducing desensitization.
lished data). It is obvious that low responders rep- These data demonstrated that the rate of pituitary
resent a heterogeneous population of patients, and desensitization to GnRH-a stimulation may be
responses to various protocols are likely to vary dose-dependent. These investigators did not evalu-
widely. ate the potential clinical impact of those findings
to determine if they could be used to alter or
GnRH Agonist Flare enhance ovarian responsiveness during controlled
ovarian hyperstimulation cycles.
Because one goal in optimizing stimulation in Scott et al. studied the impact of microdose
women with diminished ovarian reserve was to GnRH agonist administration by giving patients
increase the quantity of circulating gonadotropins, who were low responders 20 g of leuprolide
several investigators administered GnRH agonists acetate (1/50 the normal dose) every 12 hours
to their patients beginning during the early follic- beginning on cycle day 2 and continuing until the
ular phase.44–46 The endogenous gonadotropin flare administration of human chorionic gonadotropin
that occurred in response to the GnRH agonist was (hCG).48 These patients also received exogenous
used to augment the exogenous gonadotropins. The gonadotropins beginning on cycle day 4. Most
duration of this endogenous gonadotropin flare has patients demonstrated a marked improvement in
not been completely characterized, but pituitary ovarian responsiveness, as indicated by higher peak
desensitization is generally achieved within 5 days E2 levels, an increase in the number of developing
of initiating therapy. Therefore the patients are still follicles, and recovery of more oocytes at the time
protected from premature LH surges. Although of retrieval. Pituitary sensitivity was not serially
many patients demonstrated an enhanced ovarian tested, but it is likely that densensitization was
responsiveness using flare-up protocols, these pro- attained by the completion of the stimulation
tocols had some drawbacks. Some patients pro- because none of the patients had detectable pre-
duced degenerate or low quality oocytes. Others mature LH surges. Of more importance is that sev-
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 34

34 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

eral pregnancies were attained in this previously the effect of GH administration as an adjunct dur-
refractory group. ing follicular stimulation. GH most likely acts
We have extended this study. The protocol has directly on GH receptors in granulosa cells (GCs)
been modified, and we now use leuprolide acetate rather than through augmentation of follicular IGF-
50 g bid with the onset of exogenous gonadotro- I,52 as IGF-I mRNA and receptors are not expressed
pins on day 3. These patients almost uniformly in GCs of the dominant follicles (IGF-II mRNA
achieve higher peak E2 levels and require fewer and receptors are, however, expressed abundantly
ampules of gonadotropins. Additionally, in 85% a in the dominant follicle, the significance of which
larger number of follicles are recruited. Pregnancy needs further investigation because IGF-II is not
results have been mixed. Patients who are low GH-dependent).53 Early trials were promising, with
responders but who have normal ovarian reserve some reporting substantial improvements in follic-
screening have clinical pregnancy rates of 40%. In ular responsiveness and pregnancy rates. Other
sharp contrast, patients with abnormal FSH levels studies also suggested benefit.54,55 Unfortunately,
generally have higher peak E2 levels and may pro- follow-up studies have been less encouraging, and
duce additional follicles, but pregnancy rates are some controlled studies have been unable to dem-
still poor (5%). Thus it appears that a microdose onstrate clinical benefit.56–59 Considering the large
agonist flare-up protocol may increase the quanti- expense and the discouraging results in controlled
tative follicular response in many patients, but it trials, it must be concluded that there is no well
may not significantly enhance the quality of the established clinical role for GH in the treatment of
developing cohort of oocytes. low responders at the current time. Further studies
Schoolcraft et al. reported their results using a directed at defining the dose of GH and determin-
modification of the microdose protocol.49 The ing if select populations can benefit from treatment
authors evaluated 32 patients (mean age 36.8 years) (e.g., hypogonadotropic and polycystic ovary
who were cancelled in a prior IVF cycle secondary patients) are currently ongoing.
to a poor response. By using leuprolide acetate
40 g bid with the onset of exogenous gonadotro- Increasing Number of Embryos
pins 3 days after discontinuing oral contraceptive
at Time of Transfer
pills (taken for 21 days), adding 4 IU of growth
hormone per day until hCG administration, and per- A retrospective study found that a subset of
forming assisted hatching on all the transferred women 40 years undergoing in vitro fertilization/
embryos, the authors showed a marked improve- embryo transfer (IVF/ET) would respond to ovar-
ment in ovarian response with a higher E2 level on ian stimulation well enough to result in four or
day 5, higher peak E2, more oocytes retrieved, an more embryos available for transfer. In such cases,
implantation rate of 25% (3.7 embryos/ET), and a pregnancy rates were similar to that observed in
pregnancy rate of 50%. The cancellation rate was young patients (34.4% vs. 47.7% per embryo trans-
12.5%.49 The authors claimed that pretreatment fer), although delivery rates were higher among
with oral contraceptives was a significant factor in women 40 years old compared with women 40
their successful outcomes by eliminating a corpus years old (38% vs. 21%). The multiple gestation
luteum rescue prior to the initiation of gonadotro- rate was lower in women 40 than in those 40
pins. The role of growth hormone (GH) supple- years old (7.5% vs. 32%), and all multiple births
mentation is controversial (see below). These were twins in the older group. Spontaneous mis-
results are encouraging despite being based on a carriage rates often mitigated the pregnancy rates,
small number of patients. Larger series addressing as women 40 years enrolled in this study had a
the role of microdose GnRH are clearly needed. miscarriage rate of 44.8% compared to 22.0% in
those 40 years old. Selective reduction is a pos-
sible option in the unlikely event that more than
Growth Hormone
two embryos implant. However, prospective stud-
A detailed discussion of the GH–IGF–insulin-like ies are needed to realize whether multiple-order
growth factor-binding protein (IGFBP) axis is embryo transfer is a credible option for women with
beyond the scope of this chapter, but, there are now diminished ovarian reserve.60
extensive data demonstrating the critical impor-
tance of the IGF-IGFBP family (growth factors Increased Luteal Phase
IGF-I and IGF-II and their binding proteins) to fol-
Progesterone Support
licular development.50,51 In particular, IGF-I is GH-
dependent and is involved in potentiating the effect Meldrum reported correction of impaired uterine
of FSH. This led several investigators to evaluate receptivity in infertile women 40 years old under-
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 35

3. Detection and Therapeutic Approaches to Age-Related Infertility 35

going oocyte donation using increased progester- follicles available for recruitment and development
one replacement.61 Despite the same mean age of during any given treatment cycle will undoubtedly
donors and recipients and same duration of infer- continue, it is also logical to assume that future
tility, women over age 40 receiving progesterone treatments will be directed toward correcting the
100 mg per day had a marked increase in success- intrinsic intracellular processes that limit the repro-
ful pregnancies similar to that observed in women ductive potential of the individual oocytes that do
under age 40 receiving 50 mg per day (54% of 35 develop. Although no treatment directed at the
women over age 40 receiving progesterone 100 mg qualitative deficiencies are currently available,
per day had pregnancies compared with 21% of 24 there are a number of interesting (but untested) pos-
women over age 40 receiving 50 mg progesterone sibilities.
and 46% of 28 women under age 40 receiving 50 The first deals with the high incidence of aneu-
mg progesterone. The use of luteal phase proges- ploidy in the oocytes of women who have dimin-
terone support as an effective adjunct in improving ished ovarian reserve. Because aneuploidy is gen-
outcomes in women with diminished ovarian erally the result of an abnormal first meiotic
reserve awaits further well designed studies. division, the oocyte is already abnormal by the time
of retrieval. Future treatments may require that we
Assisted Hatching replace the chromosomal complement of the oocyte
with an appropriate haploid complement (possibly
Some of the treatments designed to enhance preg- some form of pronuclear transposition). In vitro
nancy rates in low responders have not been maturation of immature oocytes with supplemen-
directed toward improving ovarian responsiveness. tation of deficient factors may seem rational if we
Cohen et al. reported in 1992 that the use of selec- consider that the granulosa cells that accompany
tive assisted hatching in women with borderline older oocytes are compromised in their production
FSH levels improved their implantation and ongo- of growth factors, steroids, and glycoproteins; and
ing pregnancy rates.62 This work was extended by they lack proper “nutritional” support for their sib-
Schoolcraft et al., who specifically studied patients ling germ cells. Many such factors (e.g., mito-
previously identified as low responders.63 They chondria or certain messenger RNAs that have been
found substantially higher pregnancy rates among related to changes in reproductive competence65,66)
the women whose embryos were hatched. Hu and could be replaced initially by cytoplasmic donation
coworkers applied nonselective assisted hatching in and later by replacement of any specific factors
258 consecutive patients.64 In women older than 38 (i.e., glycoproteins or growth factors) that have
years the authors achieved a live birth rate of 24% been identified and characterized. Abnormal mei-
(10/42) for couples with no male factor and 14% otic spindles have also been noted in older women,
(1/7) for couples with male factor infertility. These leading to altered temporal and spatial changes in
numbers are small, but most ART programs per- chromosomal movement and alteration of specific
forming assisted hatching use this technique in regulatory elements during the early phases of
older women. meiosis.67 Although these areas are being actively
These data indicate that the embryos from investigated at the current time, their potential for
women who are low responders may have impaired improving the efficiency of reproduction in women
ability to produce a hatching enzyme (the putative with diminished ovarian reserve remains clinically
factor responsible for dissolving an opening in the untested.
zona pellucida at the time of natural hatching), or
their zona pellucida may be hardened or thickened.
In either event, the data available at this time indi- Acknowledgment
cate that some benefit may be obtained through This chapter has been adapted and modified from
application of this technique. an article by Sharara, FI, Scott, RT, Seifer DB: The
detection of diminished ovarian reserves in infer-
tile women. Am J Obstet Gynecol 1998;179:804–
Future Treatment 812.
It is now clear that women with diminished ovar-
ian reserve have quantitative factors (e.g., low References
number of oocytes, peak E2 levels) and qualitative 1. Smith KE, Buyalos RP. The profound impact of
factors (e.g., reduced implantation rate per embryo patient age on pregnancy outcome after early detec-
transferred) that limit their reproductive perfor- tion of fetal cardiac activity. Fertil Steril 1996;65:35–
mance. Although efforts to increase the number of 40.
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 36

36 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

2. Scott RT, Hofmann GE. Prognostic assessment of 16. Hughes EG, Robertson DM, Handlesman DJ, et al.
ovarian reserve. Fertil Steril 1995;63:1–11. Inhibin and estradiol responses to ovarian hyper-
3. Cameron IT, O’Shea FC, Rolland JM, et al. Occult stimulation: effects of age and predictive value for in
ovarian failure: a syndrome of infertility, regular vitro fertilization outcome. J Clin Endocrinol Metab
menses, and elevated follicle-stimulating hormone 1990;70:358–364.
concentrations. J Clin Endocrinol Metab 1988;67: 17. McClachlan RI, Healy DL, Robertson DM, de
1190–1194. Kretser DM, Burger HG. Plasma inhibin levels dur-
4. Pearlstone AC, Fournet N, Gambone JC, Pang SC, ing gonadotropin induced ovarian hyperstimulation
Buyalos RP. Ovulation induction in women age 40 for IVF: a new index of follicular function? Lancet
and older: the importance of basal follicle-stimulat- 1986;1:1233–1234.
ing hormone level and chronological age. Fertil Steril 18. Seifer DB, Gardiner AC, Lambert-Messerlian G,
1992;58:674–679. Schneyer AL. Differential secretion of dimeric
5. Scott RT, Toner JF, Muasher SJ, et al. Follicle stim- inhibin in cultured luteinized granulosa cells as a
ulating hormone levels on cycle day 3 are predictive function of ovarian reserve. J Clin Endocrinol Metab
of in vitro fertilization outcome. Fertil Steril 1989; 1996;81:736–739.
51:651–654. 19. Seifer DB, Lambert-Messerlian G, Hogan JW, et al.
6. Toner JP, Philput CB, Jones GS, Muasher SJ. Basal Day 3 serum inhibin-B is predictive of assisted repro-
follicle stimulating hormone level is a better predic- ductive technologies outcome. Fertil Steril 1997;67:
tor of in vitro fertilization performance than age. Fer- 110–114.
til Steril 1991;55:784–791. 20. Scott RT, Hofmann GE, Oehninger S, Muasher SJ.
7. Lenton EA, Sexton L, Lee S, Cooke ID. Progressive Intercycle variability of day 3 follicle-stimulating hor-
changes in LH and FSH and LH:FSH ratio in women mone levels and its effect on stimulation quality in in
throughout reproductive life. Maturitas 1988;10:35– vitro fertilization. Fertil Steril 1990;53:297–302.
43. 21. Martin JSB, Nisker JA, Tummon IS, et al. Future in
8. Reyes FI, Winter JSD, Faiman C. Pituitary-ovarian vitro fertilization pregnancy potential of women with
relationships preceding the menopause. I. A cross- variably elevated day 3 follicle-stimulating hormone
sectional study of serum follicle-stimulating hor- levels. Fertil Steril 1996;65:1238–1240.
mone, luteinizing hormone, prolactin, estradiol, and 22. Hansen LM, Batzer FR, Gutmann JN, et al. Evalu-
progesterone levels. Am J Obstet Gynecol 1977;129: ating ovarian reserve: follicle stimulating hormone
557–564. and oestradiol variability during cycle days 2–5. Hum
9. Sherman BM, West JH, Korenman SG. The meno- Reprod 1996;3:486–489.
pausal transition: analysis of LH, FSH, estradiol, and 23. Khalifa E, Toner JP, Muasher SJ, Acosta AA. Sig-
progesterone concentrations during menstrual cycles nificance of basal follicle-stimulating hormone lev-
of older women. J Clin Endocrinol Metab 1976;42: els in women with one ovary in a program of in vitro
629–636. fertilization. Fertil Steril 1992;57:835–839.
10. Sherman BM, Korenman SG. Hormonal characteris- 24. Licciardi FL, Liu HC, Rosenwaks Z. Day 3 estradiol
tics of the human menstrual cycle throughout repro- serum concentrations as prognosticators of ovarian
ductive life. J Clin Invest 1975;55:699–706. stimulation response and pregnancy outcome in
11. Batista MC, Cartledge TP, Zellmer AW, et al. Effects patients undergoing in vitro fertilization. Fertil Steril
of aging on menstrual cycle hormones and endome- 1995;64:991–994.
trial maturation. Fertil Steril 1995;64:492–499. 25. Smotrich DB, Widra EA, Gindoff PR, et al. Prog-
12. Klein NA, Battaglia DE, Fujimoto VY, et al. Repro- nostic value of day 3 estradiol on in vitro fertiliza-
ductive aging: accelerated ovarian follicular devel- tion outcome. Fertil Steril 1995;64:1136–1140.
opment associated with a monotropic follicle-stimu- 26. Mukherjee T, Copperman AB, Lapinski R, et al. An
lating hormone rise in normal older women. J Clin elevated day three follicle-stimulating hormone:
Endocrinol Metab 1996;81:1038–1045. luteinizing hormone ratio (FSH:LH) in the presence
13. Klein NA, Illingworth PJ, Groome NP, et al. De- of a normal day 3 FSH predicts a poor response to
creased inhibin-B secretion is associated with the controlled ovarian hyperstimulation. Fertil Steril
menotropic FSH rise in older, ovulatory women: a 1996;65:588–593.
study of serum and follicular fluid levels of dimeric 27. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic
inhibin-A and B in spontaneous menstrual cycles. J assessment of female fecundity. Lancet 1987;2:
Clin Endocrinol Metab 1996;81:2742–2745. 645–647.
14. Seifer DB, Gardiner AC, Ferreira KA, Peluso JJ. 28. Loumaye E. Billion JM, Mine JM, et al. Prediction
Apoptosis as a function of ovarian reserve in women of individual response to controlled ovarian hyper-
undergoing in vitro fertilization. Fertil Steril 1996; stimulation by means of a clomiphene citrate chal-
66:593–598. lenge test. Fertil Steril 1990;53:295–301.
15. Muasher SJ, Oehninger S, Simonetti S, et al. The 29. Tanbo T, Dale PO, Ludne O, Norman N, Abyholm
value of basal and/or stimulated serum gonadotropin T. Prediction of response to controlled ovarian hyper-
levels in prediction of stimulation response and in stimulation: a comparison of basal and clomiphene
vitro fertilization outcome. Fertil Steril 1988;50: citrate-stimulated follicle stimulating hormone lev-
298–307. els. Fertil Steril 1990;53:295–301.
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 37

3. Detection and Therapeutic Approaches to Age-Related Infertility 37

30. Scott RT, Leonardi MR, Hofmann GE, et al. A 46. Padilla SL, Dugan K, Maruschak V, Shalika S, Smith
prospective evaluation of clomiphene citrate chal- RD. Use of the flare-up protocol with high dose
lenge test screening in the general infertility popula- human follicle stimulating hormone and human
tion. Obstet Gynecol 1993;82:539–545. menopausal gonadotropins for in vitro fertilization in
31. Scott RT, Opsahl MS, Leonardi MR, et al. Life table poor responders. Fertil Steril 1996;65:796–799.
analysis of pregnancy rates in a general infertility 47. Navot D, Rosenwaks Z, Anderson F, Hodgen GD.
population relative to ovarian reserve and patient age. Gonadotropin releasing hormone agonist-induced
Hum Reprod 1995;10:1706–1710. ovarian hyperstimulation: low dose side effects in
32. Adeno M, Gallagher H. Cigarette smoking and the women and monkeys. Fertil Steril 1991;55:1069–
age of menopause. Ann Hum Biol 1982;9:121–130. 1075.
33. Jick H, Porter J, Morrison AS. Relationship between 48. Scott RT, Navot D. Enhancement of ovarian respon-
smoking and age of natural menopause. Lancet siveness with micro-doses of GnRH-agonist during
1997;1:1354–1354. ovulation induction for in vitro fertilization. Fertil
34. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott Steril 1994;61:880–885.
RT. Cigarette smoking accelerates the development 49. Schoolcraft W, Schlenker T, Gee M, Stevens J,
of diminished ovarian reserve as evidenced by the Wagley L. Improved controlled ovarian hyperstimu-
clomiphene citrate challenge test (CCCT). Fertil lation in poor responder in vitro fertilization patients
Steril 1994;62:257–262. with microdose follicle-stimulating hormone flare,
35. Hughes EG, Yeo J, Claman P, et al. Cigarette smok- growth hormone protocol. Fertil Steril 1997;67:93–
ing and the outcomes of in vitro fertilization: meas- 97.
urement of effect size and levels of action. Fertil 50. Adashi EY, Resnick CE, Hernandez ER, et al. Insulin
Steril 1994;62:807–814. like growth factor I as an intra-ovarian regulator:
36. Sterazik K, Strehler E, De Santo M, et al. Influence basic and clinical implications. Ann NY Acad Sci
of smoking on fertility in women attending an in vitro 1991;626:161–167.
fertilization program. Fertil Steril 1996;65:810–814. 51. Giudice LC. Insulin-like growth factors and ovarian
37. Hershlag A, Lesser M, Montefusco D, et al. Interin- follicular development. Endocr Rev 1992;13:641–
stitutional variability of follicle-stimulating hormone 669.
and estradiol levels. Fertil Steril 1992;58:1123–1126. 52. Sharara FI, Nieman LK. Identification and cellular
38. Seifer DB, Canick JA, Seltman HJ, Frishman GN, localization of growth hormone receptor gene ex-
Berk CA. Abstract P368. In: 39th Annual Meeting of pression in the human ovary. J Clin Endocrinol Metab
the Society for Gynecologic Investigation, San Anto- 1994;79:670–672.
nio, TX, 1993. 53. El-Roiey A, Chen X, Roberts VJ, et al. Expression
39. Syrop CH, Dawson JD, Husman KJ, Sparks AE, Van of insulin-like growth factor-I (IGF-I) and IGF-II and
Voorhis BJ. Ovarian volume may predict assisted the IGF-I, IGF-II, and insulin receptor genes and
reproductive outcomes better than follicle hormone localization of the gene products in the human ovary.
concentration on day 3. Hum Reprod 1999;14:1752. J Clin Endocrinol Metab 1993;77:1411–1418.
40. Land JA, Yarmolinskaya MI, Dumoulin JCM, Evers 54. Menashe Y, Lunenfeld B, Pariente C, Frenkel Y,
JLH. High-dose human menopausal gonadotropin Mashiach S. Can GH increase after clonidine admin-
stimulation in poor responders does not improve in istration predict the dose of human menopausal hor-
vitro fertilization outcome. Fertil Steril 1996;65:961– mone needed for induction of ovulation. Fertil Steril
965. 1990;53:432–435.
41. Droesch K, Muasher ST, Brzyski R, et al. Value of 55. Shoham Z, European and Australian Multicenter
suppression with a GnRH-a prior to gonadotropin study. Cotreatment with growth hormone and gonad-
stimulation for in vitro fertilization. Fertil Steril otropin for ovulation induction in hypogonadotropic
1989;51:292–295. patients: a prospective, randomized, placebo-con-
42. Muasher SJ. Treatment of low responders. J Assist trolled, dose-response study. Fertil Steril 1995;64:
Reprod Genet 1993;10:112–114. 917–923.
43. Feldberg D, Farhi J, Ashkenazi J, et al. Minidose 56. Bergh C, Hillensjo T, Wikland M, et al. Adjuvant
gonadotropin-releasing hormone agonist is the treat- growth hormone treatment during in vitro fertiliza-
ment of choice in poor responders with high follicle- tion: a randomized, placebo-controlled study. Fertil
stimulation hormone levels. Fertil Steril 1994;62: Steril 1994;62:113–120.
343–346. 57. Owen EJ, West C, Mason BA, Jacobs HS. Co-treat-
44. Garcia JE, Padilla SL, Bayati J, Baramki TA. Follic- ment with growth hormone of suboptimal responders
ular phase gonadotropin-releasing hormone agonist in IVF-ET. Hum Reprod 1991;6:529–533.
and human gonadotropins: a better alternative for 58. Younis JS, Simon A, Koren R, et al. The effect of
ovulation induction in in vitro fertilization. Fertil growth hormone supplementation on in vitro fertil-
Steril 1990;53:302–305. ization outcome: a prospective randomized, placebo
45. Padilla SL, Bayati J, Garcia JE. Prognostic value of controlled double blind study. Fertil Steril 1992;
the early serum estradiol response to leuprolide 58:575–580.
acetate in in vitro fertilization. Fertil Steril 1990; 59. Suikkara AM, MacLachlan V, Koistinen R, Seppala
53:288–294. M, Healy DL. Double-blind placebo controlled
3051_Seifer_03_p24-38 11/5/01 9:35 AM Page 38

38 F.I. Sharara, R.T. Scott, Jr., and D.B. Seifer

study: human biosynthetic growth hormone for bly in oocytes from naturally cycling women. Hum
assisted reproductive technology. Fertil Steril 1996; Reprod 1996;11:2217–2222.
65:800–805.
60. Wildra EA, Gindoff PR, Smotrich DB, Stillman RJ. Suggested Reading
Achieving multiple-order embryo transfer identifies
women over 40 years of age with impaired in vitro Chang M, Chiang C, Hsich T, et al. Use of the antral fol-
fertilization outcome. Fertil Steril 1996;65:103–108. licle count to predict the outcome of assisted repro-
61. Meldrum DR. Female reproduction aging-ovarian ductive technologies. Fertil Steril 1998;69:505.
and uterine factors. Fertil Steril 1993;59:1–5. Hoffman G, Danforth D, Seifer D. Inhibin-B: the physi-
62. Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. ologic basis of the clomiphene citrate challenge test for
Implantation enhancement by selective assisted ovarian reserve screening. Fertil Steril 1998;69:474.
hatching using zona drilling of embryos with poor Reuss M, Kline J, Santos R, et al. Age and the ovarian
prognosis. Hum Reprod 1992;7:685–691. follicle pool assessed with transvaginal ultrasonogra-
63. Schoolcraft WB, Schlenker T, Gee M, Jones GS, phy. Am J Obstet Gynecol 1996;174:624.
Jones HW. Efficacy of assisted hatching in poor prog- Santoro N, Tovaghogol A, Skurnick J. Decreased inhibin
nosis IVF candidates. Fertil Steril 1994;62:551–554. tone and increased activin A secretion characterize
64. Hu Y, Hoffman DI, Maxson WS, Ory SJ. Clinical reproductive aging in women. Fertil Steril 1999;71:658.
application of non-selective assisted hatching of Seifer D, Scott R, Bergh P, et al. Women with declining
human embryos. Fertil Steril 1996;66:991–994. ovarian reserve may demonstrate a decrease in day 3
65. Flood JT, Chillik CF, van Uem JFHM, Iritani A, Hod- serum inhibin-B prior to a rise in day 3 FSH. Fertil
gen GD. Ooplasmic transfusion: prophase germinal Steril 1999;72:63.
vesicle oocytes made developmentally competent by Sharara F, McClamrock H. The effect of aging on ovar-
microinjection of metaphase II egg cytoplasm. Fer- ian volume measurements in infertile women. Obstet
til Steril 1990;53:1049–1054. Gynecol 1999;94:57.
66. Keefe DL, Niven-Fairchild T, Powell S, Buradagunta Sharara F, Seifer DB. New Methods for Assessing Ovar-
S. Mitochondrial deoxyribonucleic acid deletion in ian Reserve. OBG Management Volume 12, issue 10,
oocytes and reproductive aging in women. Fertil pages 61–69, 2000.
Steril 1995;64:577–583. Welt C, McNicholl D, Taylor A, Hall J. Female reproduc-
67. Battaglia DE, Goodwin P, Klein NA, Soules MR. tive aging is marked by decreased secretion of dimeric
Influence of maternal age on meiotic spindle assem- inhibin. J Clin Endocrinol Metab 1999;84:105.
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 39

4
Role of Ultrasonography in Infertility
Theresa Widrich

Ultrasonography was first used in obstetrics and array or curvilinear transducers. Frequencies for
gynecology in 1958 by Donald, and it has under- TVUS are usually between 5.0 and 7.5 MHz and
gone several developments since then. Both transab- the angle of view may be between 60° and 360°
dominal and transvaginal ultrasonography (TVUS) (average 90°–150°) for endovaginal US. Smaller
are used in gynecology. The transabdominal ap- sectors make it possible to visualize details, such
proach gives a more panoramic view of the pelvis, as small vessels and the heartbeat during early
but TVUS offers several advantages in gynecology. pregnancy. Wider angles allow an overview of the
With TVUS the shorter distance of the ultra- entire pelvis.
sound probe to the pelvic organs makes it possible
to achieve a detailed delineation of the uterus with
the cervix, uterine wall, and endometrium, ovaries, Technique of TVUS
and fallopian tubes, even in obese patients. It does
not require a full bladder, and so is more comfort- The patient must be informed about the procedure.
able for the patient. Because of the proximity to the Ideally she is positioned in the dorsal lithotomy
pelvic organs, high frequency transducers (5.0 or position in stirrups. A bimanual examination pre-
7.5 MHz) may be used resulting in higher resolu- cedes the US examination. The TVUS transducer
tion and clearer images than transabdominal US. is wiped with a disinfectant and is covered with a
The combination of the pelvic examination and condom filled with gel. Coupling gel is placed on
TVUS provides excellent information to the gyne- the tip of the transducer to ensure uninterrupted
cologist. As a tool, TVUS has become indispensa- passage of the ultrasound waves from the probe into
ble for diagnosis and for selected treatments of the pelvis. When scanning infertility patients at
infertility, such as evaluating the female pelvis, mid-cycle, one should be aware that some ultra-
monitoring ovulation, and transvaginal oocyte sound gels and latex condoms have a spermicidal
pickup for in vitro fertilization. effect. In these cases polyethylene bags and paraf-
fin oil can be used as an alternative. The transducer
is inserted into the vaginal canal and images of the
Equipment pelvic organs in the longitudinal and transverse
plane are obtained. To get a 360° overview of the
Most ultrasound machines have B-mode (gray pelvis the US probe is rotated. Then the movement
scale) imaging, M-mode (motion) and Doppler US of the pelvic organs towards each other is tested.
(flow measurement at a single point of a vessel). The examiner slightly moves the ultrasound probe
Some machines also offer color Doppler making and places his/her other hand on the abdominal wall
it possible to study the blood flow in a specific and gently pushes towards the probe (like a biman-
area. Various ultrasound probes are available. For ual exam using the ultrasound probe instead of one
TVUS there are mechanical probes with one oscil- hand). If the pelvic organs do not slide this is an
lating element and electronic probes with phased indirect sign of adhesions.

39
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 40

40 T. Widrich

Diagnosis of Infertility by TVUS Endometrium

Circulating estrogen and progesterone influence the
Conventional TVUS endometrial thickness and texture. US can clearly
depict cyclic changes of texture and may indicate
Uterus and Cervix
whether the appearance of the endometrium is
The first structures to be scanned are the uterus and related to the day of the menstrual cycle or to a sus-
cervix. It is useful to have performed a bimanual pected functional problem. During and shortly after
examination prior to this point to determine the menses the endometrium appears as a thin echo-
position of the uterus (e.g. anteverted or retro- genic line. During the proliferative phase it thick-
verted). Its characteristic landmark is the endome- ens and becomes isoechoic. Toward ovulation the
trial stripe, surrounded by the homogeneous mus- endometrium becomes more echogenic and devel-
cular layer of myometrium. Position and size of ops a multilayered pattern. There is a thin hyper-
the uterus are noted (Fig. 4–1). echoic line in the middle, surrounded by an inner
Myomas are the most common pathology of the hypoechoic layer and an outer echogenic layer that
uterus and cervix. Smaller ones can be seen as is secondary to stromal edema. This pattern seems
round structures with high echogenicity on US. necessary for normal pregnancy to develop (Fig.
Larger ones distort the shape of the uterus or the 4–2). Several studies have attempted to correlate
endometrial stripe. Sometimes calcifications are endometrial thickness at the time of ovulation with
seen within a myoma. When a leiomyoma is larger pregnancy rates. It is now generally acknowledged
than 5 cm, the view obtained with TVUS may be that in the natural cycle, a thickness of 5 mm or
obscured and in such cases it is more effective to less results in poor pregnancy rates, whereas 10 mm
carry out abdominal US. The position of the fibroid or more provides a good possibility of conception
is important. Submucous myomas extend into the (Fig. 4–3). During the secretory phase the endo-
uterine cavity and may distort it, thereby inhibiting metrium continues to thicken, reaching up to 14
implantation of pregnancy. mm, and becomes homogenic and hyperechoic on
Müllerian abnormalities are estimated to occur US. Beginning menstruation toward the end of the
in 2–3% of women. On TVUS a uterine septum can cycle may be seen as minimal hypoechoic spots in
be seen as two endometrial stripes separated by a the endometrium.
myometrial layer. The septum can result in inhibi- Polyps and other endometrial abnormalities may
tion of implantation and may be removed hystero- pose a problem. Endometrial polyps vary in size
scopically. A bicornuate uterus is best discovered from less than a millimeter to several centimeters
in transverse view; in the longitudinal view the in diameter. Large polyps may interfere with im-
intermediate myometrial layer is not continuous. plantation of the embryo and cause infertility. On

FIGURE 4–1. Saline infusion sonohysterography. Submu- FIGURE 4–2. Three layer pattern of the endometrium
cous myoma protrudes into the uterine cavity. Hystero- as seen around ovulation. (Courtesy of the Department
scopic removal is not possible in this case because the of Gynecologic Endocrinology, University Hospital of
intramural part of the myoma is more than 50%. Vienna, Austria.)
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 41

4. Role of Ultrasonography in Infertility 41

seen when the follicle is in excess of 15 mm. Type

B follicles show an echo free space and become
atretic. Ovulation occurs 36–38 hours after the peak
serum luteinizing hormone (LH) surge and is seen
as a rapid reduction of follicle size. In most cases
fluid is detected in the cul-de-sac. This may also
be present before ovulation because of transuda-
tion. A corpus luteum is present from 45 minutes
after ovulation, and on US appears as a round cys-
tic structure with an irregular pattern due to blood
clots. It changes rapidly over time.
Polycystic ovary disease (PCO) is a type of men-
strual dysfunction with anovulation, elevated
androgens, and inappropriate gonadotropin secre-
FIGURE 4–3. Secretory endometrium prepared for concep- tion. Several causes lead to anovulation, and per-
tion. This patient had a positive pregnancy test one day sistent anovulation leads to polycystic ovaries.
after this scan was performed. (Courtesy of W. Feichtinger, Clinically, Balen et al. showed that obesity is asso-
Institute for Sterility Treatment, Vienna, Austria.) ciated with hirsutism and an elevated serum testos-
terone concentration; it is also correlated with
increased rates of infertility and cycle disturbance.
US, endometrial polyps typically appear as an un-
The rates of infertility and cycle disturbance also
usually high degree of thickening of the endome-
increase with serum LH concentrations 10 IU/L.
trium and are best diagnosed early in the menstrual
A rising serum concentration of testosterone is
cycle when the proliferative endometrium is still
associated with an increased risk of hirsutism,
thin.
infertility and cycle disturbance. Sonographically,
Ovaries polycystic ovaries appear to be enlarged with a vol-
ume usually greater than 12 cm3. Several small fol-
As many as 10–30% of women investigated for licles less than 10 mm are lined up under a thick-
infertility do not ovulate regularly. TVUS can be ened capsule. PCO indicates an increased risk of
used to monitor ovulation. Follicles can be ovarian hyperstimulation syndrome, and in such
observed on TVUS when they reach a diameter of cases US can play an important role in assessing
2–3 mm. During the natural cycle, a dominant fol- the treatment plan.
licle typically appears during days 8–12. Its growth Endometriosis is a very common cause of infer-
is linear, about 2 mm per day, and it reaches a size tility. Its prevalence is as high as 10% in the repro-
of 18–24 mm before ovulation (mean 21.5 mm). It
is rare for other follicles to be present during the
natural cycle, but in such cases they usually do not
exceed 14 mm in diameter, nor do they ovulate. The
size of the dominant follicle correlates with the
serum estrogen level, and its size is more predic-
tive of ovulation than serum estrogen levels,
although a combination of the two gives the best
accuracy. E2 levels at ovulation are between 150
and 400 pg/ml. Ultrasonography can be useful to
detect ovulation itself; or in cases of tubal damage
on one side, it can help determine on which side
ovulation will occur if intrauterine insemination is
planned. Moreover, the shape of a follicle helps
determine whether it will ovulate. Fukuda et al.
showed that a healthy (type A) follicle contains a
cloud in the shape of a cone. The base is positioned FIGURE 4–4. A healthy follicle in natural cycle shortly
at the follicle wall; the tip points into the center of before ovulation. (Courtesy of the Department of Gyne-
the follicle and has a light spot assumed to be the cologic Endocrinology, University Hospital of Vienna,
oocyte-cumulus complex (Fig. 4–4). This can be Austria.)
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 42

42 T. Widrich

ductive age group and in 25–35% of infertile technique of using saline as a negative contrast
women. Common symptoms are secondary dys- agent in the uterine cavity. Since then it has become
menorrhea, secondary dyspareunia, diffuse or widely used and mostly referred to as saline infu-
localized pelvic pain and low back pain, although sion sonohysterography (SIS). The technique is
women with endometriosis can be asymptomatic. valuable for detecting any structural abnormalities,
On physical examination a retroverted, fixed uterus such as submucous myomas, endometrial polyps,
is suggestive of endometriosis. Nodularity in the and endometrial adhesions.
cul-de-sac region or the sacrouterine ligaments is The technique of SIS is as follows. After per-
found in one-third of patients with endometriosis. forming conventional TVUS the ultrasound probe
Small foci of endometriosis can only be detected is removed and an open-sided vaginal speculum is
by laparoscopy but larger endometriomas are eas- inserted. The cervix is cleansed with an antiseptic
ily seen on TVUS. The classic sonographic appear- solution. Using a sterile uterine packing forceps, a
ance is the so called chocolate cyst, which appears small catheter is placed in the cervical os under
homogenic and has the echogenicity of a fetal liver direct visualization until the uterine fundus is
or lung. Some cysts are also partially solid and par- reached. After removing the speculum a plastic
tially cystic. It can be difficult to differentiate be- syringe containing sterile saline is attached to the
tween a corpus luteum cyst and an endometrioma. catheter. The ultrasound probe can then be reintro-
Often they can be distinguished only after several duced and saline is slowly infused into the uterus
weeks: a corpus luteum cyst changes and eventu- while observing for uterine distension. The uterine
ally disappears. cavity can then be reevaluated.
Submucous myomas can be defined as such after
Fallopian Tubes the instillation of saline and the relation of a fibroid
to the uterine wall can be seen (Fig. 4–1). SIS also
A healthy fallopian tube cannot be depicted sono-
helps determine a suitable course of treatment
graphically unless there is some fluid around it,
because myomas with an intracavitary portion of
which, in a healthy woman may be present around
more than 50% can be resected hysteroscopically.
ovulation or be due to ascites or inflammation. US
Submucous fibroids may also be diagnosed by hys-
may be helpful for detecting pelvic inflammatory
teroscopy, but it is not possible to visualize the intra-
disease (PID) or the chronic changes after PID,
mural part using this technique. Polyps when outlined
leading to the possible cause of infertility.
by intracavitary fluid are seen as echogenic masses
Acute inflammation of the tube leads to thicken-
in the uterine cavity originating from the endome-
ing of the wall and free fluid in the pelvis. The tube
trium with a small or broad base. Adhesions or a sep-
is tender to the probe touch. Polycystic ovaries may
tum are also easily seen when the uterine cavity is
be an indirect sign of acute PID. Chronic inflam-
distended and they are outlined by the contrast agent.
mation is seen as an accumulation of fluid in the
Several studies published over the last few years
tube and presents itself as an irregular, elongated
highlight some important advantages of using SIS.
mass filled with fluid or pus. It may initially appear
There are consistent findings that visualization of
circular like a stimulated follicle in one plane, but
structural abnormalities is improved when saline is
if the probe is turned through 90° the elongated
used, the procedure causes minimal discomfort and
structure becomes visible. The wall is thin and
a low rate of complications.
stretched. A tuboovarian abscess can be seen on
Two recent studies evaluated SIS for infertility
TVUS as a conglomerate consisting of a complex
patients: Soares et al. evaluated the diagnostic accu-
cyst in the ovary surrounded by a dilated, fluid filled
racy of SIS in uterine cavity diseases in 65 infer-
tube that is often tender on examination. Adhesions
tile patients, comparing its results with those of
can seldom be depicted by ultrasound unless there
hysterosalpingography (HSG) and TVUS. Hyster-
is free fluid in the pelvis. They are suspected when
oscopy was the gold standard and SIS had the same
there is no sliding of the uterus and ovaries, either
diagnostic accuracy for polypoid lesions and endo-
to each other or in relation to the pelvic wall.
metrial hyperplasia, with no equivocal diagnosis.
For uterine malformations, SIS had a sensitivity of
Fluid Enhanced TVUS 77.8% and intrauterine adhesions a sensitivity of
Saline Infusion Sonohysterography 75%. Gronlund et al. assessed the diagnostic value
of SIS in an evaluation of metrorrhagia and infer-
One of the most exciting developments in vaginal tility using hysteroscopy as the standard. The over-
sonography in recent years is the use of contrast all sensitivity and specificity for SIS was 90.9%
agents. In 1993 Parsons and Lense developed the and 100%, respectively. When examining the met-
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 43

4. Role of Ultrasonography in Infertility 43

rorrhagia and infertility groups separately the sen-

sitivity and specificity and predictive values were
100% for all parameters in cases of infertility.

Hysterosalpingo-Contrast Sonography
In 15% of cases the inability to conceive is due to
tubal occlusion. The gold standard for evaluating the
tubes is laparoscopy, but this has risks associated
with general anesthesia. Another method is HSG,
however this has the disadvantage of exposing the
ovaries to radiation. A relatively new technique for
assessing the status of fallopian tubes is hystero-
salpingo-contrast sonography (HyCoSy). Deichert
and Schlief first described this technique in 1989. FIGURE 4–5. Hyperstimulated ovary with several follicles
Technique: An echogenic contrast medium (most at IVF oocyte harvesting. The tip of the suction needle
authors use Echovist®) is administered through the can be seen in the collapsing follicle in the middle. (Cour-
cervix into the uterus using a balloon catheter, and tesy of the Department of Gynecologic Endocrinology,
its flow through the fallopian tubes observed in real University Hospital of Vienna, Austria.)
time sonography. Each tube must be examined sep-
arately, and the flow of contrast media should be can be administered to trigger ovulation. Follicles
observed in three segments of the tube: isthmic, larger than 14 mm may ovulate as well, whereas
ampullary and fimbrial. The contrast agent will also those less than 14 mm usually become atretic after
become visible in the Cul-de-Sac region. Several administration of hCG. At 36 hours after hCG
studies have compared HyCoSy with HSG and injection ovulation occurs, and intrauterine insem-
Chromolaparoscopy. The results of HyCoSy are ination (IUI) or intercourse should be scheduled
equal or slightly better than HSG; discomfort is 24–48 hours later. Arici et al. demonstrated that this
comparable with about 10% of the patients report- timing can achieve higher pregnancy rates. The
ing severe discomfort. Compared with laparoscopy endometrial thickness after CC administration is
the concordance was about 85%. Results become usually less than in natural cycles (5–9 mm). Ben-
better when it is combined with Doppler flow stud- eventi et al. observed that endometrial maturation
ies in each tube (91% concordance). These results is slower after application of CC for about 3 days.
indicate that, if carried out by an experienced ultra- Controlled ovarian hyperstimulation with FSH
sonographer, HyCoSy is a suitable first line proce- can be used to achieve ovulation if CC treatment
dure in patients with infertility disorders. fails or if there is known malfunction of the hypo-
thalamus or pituitary gland. Follicle stimulation is
achieved by daily intramuscular injections through
Monitoring Treatment of Infertility 7–14 days. Serum estrogen levels and frequent
Ovulation Induction TVUS examinations are recommended to assess
when hCG should be administered to induce ovu-
Normally more than one follicle appears during lation. Usually a size of 18 mm for the dominant
stimulated cycles. In this situation several follicles follicle is recommended. TVUS gives better infor-
contribute to the level of serum estrogen. TVUS is mation for the timing than estrogen levels because
used to assess the number and size of stimulated a larger number of small follicles may also produce
follicles (Fig. 4–5). a significant increase in serum estrogen levels. An
Clomiphene citrate (CC) has a weak estrogenic estrogen level of 1000–1500 pg/ml is optimal; at a
effect and leads to increased secretion of follicle level over 2000 pg/ml, hCG should not be given
stimulating hormone (FSH) and LH through acti- because of the risk of ovarian hyperstimulation syn-
vation of the hypothalamic pituitary axis. Its main drome. Early signs of ovarian hyperstimulation on
indication is absent or infrequent ovulation. Usu- US are enlarged ovaries and free fluid in the pelvis.
ally a CC dose of 50 mg PO is given on cycle days
5–9. In case of failure, the dosage may be increased In Vitro Fertilization
up to 150 mg per day. Ultrasonography can be used
to monitor the growth and number of follicles. More than 20 years have passed since the first child
When the dominant follicle reaches at least 20 mm was conceived through IVF. Today indications not
in diameter, human chorionic gonadotropin (hCG) only include tubal disease and resistant anovulation
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 44

44 T. Widrich

but also male factor infertility, unexplained infer-

tility, endometriosis, immunologic causes of infer-
tility, cervical factor and some cases of premature
ovarian failure. More follicles are stimulated with
IVF than during controlled ovarian hyperstimula-
tion. Several different protocols exist using FSH to
induce follicular growth and GnRH Analogs to pre-
vent premature LH surges. TVUS alone or in con-
junction with serum estrogen level measurements
is used to monitor the ovarian response and a lin-
ear growth of follicles of 2 mm per day can be
expected. When at least two or three follicles reach
16–18 mm diameter, 5000 or 10,000 IU of hCG
is administered to induce follicular maturation.
Oocytes are harvested 34 to 36 hours later by fine
needle aspiration. FIGURE 4–6. An early gestational sac has developed in
the uterus. (Courtesy of W. Feichtinger, Institute for
Technique of Follicle Measurements Sterility Treatment, Vienna, Austria.)

It is usually easy to locate stimulated ovaries by

directing the US probe lateral to the uterus. Folli-
cles have an elliptic shape and should be measured TVUS at the time of the missed menstrual period
in 3 dimensions and the mean diameter calculated. and grows rapidly reaching approximately 10 mm
In the natural cycle and after stimulation with FSH, 40 days after the last menstrual period (Fig. 4–6).
a follicle is considered mature from a diameter of The presence of a yolk sac confirms the develop-
16–18 mm. After stimulation with CC a minimum ment of embryonic structures. Fetal cardiac activ-
of 20 mm is required. Measuring all 3 dimensions ity may be observed on TVUS after the fifth week
is also necessary to rule out that other structures following the last menstruation. It usually confirms
are confused with follicles. A large vessel or a a normal intrauterine pregnancy. First trimester
hydrosalpinx may appear round on one plane but abortion is less than 2% after documentation of a
will be identified when rotating the probe by 90°. heartbeat, although one study found that from a
maternal age of 35 years or older there is a five-
Endometrium in Stimulated Cycles fold risk of early pregnancy loss even after a fetal
heartbeat is documented. If correlated to serum
In contrast to the natural cycle there is now gen-
hCG levels using the first international standard
eral agreement that endometrial thickness cannot
preparation, a gestational sac is visible on TVUS
be used as a predictive factor for pregnancy rates
in all normal pregnancies above 1000 mIU/ml hCG,
in stimulated cycles. De Gruyter et al. found that
a yolk sac above 7200 mIU/ml and a visible embryo
pregnancy rates of assisted reproductive procedures
with a heartbeat with an hCG level greater than
are influenced only marginally by the degree of
10800 mIU/ml. With ectopic pregnancies, a pseudo-
endometrial proliferation and treatment should not
gestational sac may appear in the endometrium but
be cancelled because of inadequate endometrial
does not develop embryonic echoes or a yolk sac.
thickness. Endometrial echogenicity is a more reli-
Also -hCG levels do not double every 2–3 days
able parameter in stimulated cycles. Fanchin et al.
as they should with a normal pregnancy. If the fal-
found in a prospective study that when the endo-
metrial echogenicity is measured objectively by a lopian tubes are carefully scanned, sometimes the
computer assisted system on the day of hCG admin- ectopic pregnancy can be visualized, and even a
istration, pregnancy and implantation rates fell heartbeat seen on US.
progressively and significantly from the low echo-
genicity to the high echogenicity group in IVF Treatment of Infertility Using TVUS
cycles.
Ultrasound-Assisted Puncture
Early Pregnancy of Follicles During IVF
Serum measurements of hCG and US imaging are In the early years of IVF, oocytes were retrieved
used to track the development of early pregnancy. laparoscopically, exposing women to risks of gen-
A gestational sac of 2 mm becomes visible on eral anesthesia and surgery. In 1982 Lenz and Lau-
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 45

4. Role of Ultrasonography in Infertility 45

ritzen were the first to report ultrasonographically Another application is US guided multifetal
guided transabdominal puncture for oocyte har- pregnancy reduction and salpingocenteses in cases
vesting. The technique was then modified by of ectopic pregnancies. In both cases toxic sub-
Feichtinger and Kemeter to a transvesical and later stances (methotrexate or KCl) are injected to the
a transvaginal approach. Needle guided vaginal gestational sac with a US-guided needle.
puncturing for oocyte retrieval has now become the
method of choice. Its advantages are the short dis-
tance to the ovaries with less probability of bowel Recent Developments
injury or bleeding, better visualization of follicles, Doppler, Color Doppler and
no adhesions to inhibit visualization of the folli- Color Power Angiography
cles, no need for general anesthesia, an ambulatory
setting for the procedure, and relatively few com- Doppler ultrasound allows measurements of blood
plications. flow by measuring the change of frequency that
occurs when the ultrasound beam is reflected by
Technique moving erythrocytes. Spectral Doppler displays the
frequency shift in waveform and allows the meas-
The entire procedure can be carried out in an out- urement of absolute velocity and resistance to flow
patient setting. General anesthesia is not required; (pulsatility index) at a certain point of the vessel
a sedative can be given if the patient is anxious but (Fig. 4–7). Color Doppler (CD) displays the blood
is not required in 50% of the cases. The patient is flow in an area and its direction: blood flow towards
placed in the dorsal lithotomy position, and sterile the ultrasound transducer is usually red, away from
drapes cover the legs and perineal area. The US it is displayed as blue. Color power angiography
probe is covered with a sterile condom or polyeth- (CPA) uses the amplitude of Doppler signals which
ylene bag, and a needle guide is attached to it. The represent the density of erythrocytes in the vessel
vagina is cleansed with saline solution or IVF cul- being studied. This provides a more accurate dis-
ture medium. Disinfecting solutions may be poten- play of tissue perfusion but gives no information
tially harmful for the fertilization rate, and US gel about the direction of the flow. Doppler ultra-
on the outside of the transducer should also be sonography cannot yet be used to monitor stimu-
avoided. The US probe is placed in the vagina and lated cycles, nor can it be used to predict pregnancy
a biopsy line is generated on the US screen target- outcome. There is growing evidence that studies of
ing the first stimulated follicle. A long 16 or 18 perifollicular vascularity will predict the develop-
gauge needle is rapidly advanced through the vagi- ment of a healthy oocyte. There is still dispute about
nal wall into the follicle. The tip of the needle can a significant difference in the pulsatility index of
be seen on the screen. The follicular fluid is aspi- the uterine artery between those women who
rated under visualization and pulled into a collec- became pregnant and those who did not after IVF
tion chamber. The follicle collapses. Without with- treatment. This relationship has not been identified
drawing it, the needle is then carefully placed in by all authors and Zaidi et al. offer a possible expla-
the next follicle and suction is performed again.
Some authors flush each follicle with medium, oth-
ers do not. At the end of the procedure the pelvis
is scanned to rule out bleeding.

Risks
Compared with laparoscopic oocyte harvesting, the
complication rate using the transvaginal aspiration
technique is low. Occasional bleeding from punc-
ture sites or damage to the iliac vessels can lead to
complications. Pelvic inflammation has also been
seen after oocyte harvesting.
Other Uses of TVUS
Needle aspiration can also be performed to reduce
ovarian cysts. Even when carried out before oocyte FIGURE 4–7. Doppler measurement of the right ovarian
harvesting, it does not seem to have an adverse artery in a stimulated ovary. (Courtesy of W. Feichtinger,
influence on the pregnancy outcome. Institute for Sterility Treatment, Vienna, Austria.)
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 46

46 T. Widrich

through very tortuous tubes which may improve our

ability to assess tubal patency.

Conclusion
Ultrasonography and especially TVUS have
become indispensable tools for the gynecologic
infertility work-up as well as for monitoring and
treating infertility. The use of contrast medium
enhances its possibilities, making it possible to
avoid laparoscopy and hysteroscopy in selected
cases. Color Doppler, CPA, and three-dimensional
US are the most recent developments with very
promising possibilities although are yet to be eval-
FIGURE 4–8. Three-dimensional-ultrasonography. A uated in terms of their usefulness for infertility
uterus duplex is displayed using multiplanar mode and
patients.
Color Doppler. (Courtesy of A. Lee, Department of Pre-
natal Diagnosis and Treatment, University Hospital of
Vienna, Austria.) References and Suggested Reading
Alatas C, Aksoy E, Akarsu C, et al. Evaluation of intra-
nation for this: They have been able to demonstrate uterine abnormalities in infertile patients by sonohys-
a circadian rhythm of the pulsatility index in the terography. Hum Reprod. 1997;12:487–490.
uterine artery indicating that uterine perfusion is Ayida G, Chamberlain P, Barlow D, et al. Is routine diag-
nostic laparoscopy for infertility still justified? A pilot
better in the morning. Future work may help stan- study assessing the use of hysterosalpingo-contrast
dardize results. CD Ultrasound has been proven to sonography and magnetic resonance imaging. Hum
be very useful in assessing tubal patency as de- Reprod. 1997;12:1436–1439.
scribed above. Bakos O, Lundkvist O, Wide L, Bergh T. Ultrasono-
graphical and hormonal description of the normal ovu-
Three Dimensional US latory menstrual cycle. Acta Obstet Gynecol Scand.
1994;73:790–796.
A transvaginal three-dimensional scan has been Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary
developed that amplifies diagnostic potential (Fig. syndrome: the spectrum of the disorder in 1741
4–8). Several two-dimensional images (slices) are patients. Hum Reprod. 1995;10:2107–2111.
taken and the three-dimensional picture is then cal- Beneventi F, Sampaolo P, Polatti F, et al. Ultrasonogra-
culated by the machine. When the volume is ob- phy endometrial patterns in different hormonal treat-
tained it can be analysed in three different ways: ments to induce ovulation. Radiol Med (Torino). 1995;
reslicing, volume measurements and surface ren- 90:278–283.
dering. Reslicing has an advantage over two dimen- Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal
sonography versus serum human chorionic gonado-
sional ultrasound because slices can be in any angle tropin in early detection of pregnancy. Am J Obstet
to the ultrasound probe. Jurcovic et al. have dem- Gynecol. 1988;158:608–612.
onstrated the usefulness of this technique for dis- Blumenfeld Z, Yoffe N, Bronshtein M. Transvaginal
playing congenital abnormalities of the uterus. Vol- sonography in infertility and assisted reproduction.
ume measurements are gaining more importance in Obstet Gynecol Surv. 1991;46:36–49.
the measurement of the endometrium. Yaman et al. Bree RL, Edwards M, Bohm-Velez M, et al. Transvagi-
have demonstrated the reproducibility of endome- nal sonography in the evaluation of normal early preg-
trial volume measurements and Raga et al. have nancy: correlation with HCG level. Am J Roentgenol.
shown that the volume of the endometrium at 1989;153:75–79.
implantation may predict pregnancy rates better Buttram VC Jr, Gibbons WE. Müllerian anomalies: a
proposed classification. (An analysis of 144 cases).
than two dimensional thickness measurements. Fertil Steril. 1979;32:40–46.
Surface rendering gives very impressive pictures of de Crespigny L, Kuhn R, McGinnes D. Saline infusion
embryos and fetuses. Sladkevicius has also dem- sonohysterosalpingography, an underutilized technique.
onstrated its use in gynecology. By combining CPA Aust N Z J Obstet Gynaecol. 1997;37:206–209.
with three-dimensional US he could obtain accu- De Geyter C, Schmitter M, De Geyter M, et al. Prospec-
rate pictures of the flow of contrast agent even tive evaluation of the ultrasound appearance of the
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 47

4. Role of Ultrasonography in Infertility 47

endometrium in a cohort of 1,186 infertile women. a comparison with two dimensional and three dimen-
Fertil Steril. 2000;73:106–113. sional contrast sonography. Clin Exp Obstet Gynecol.
DeCherney AH, Laufer N. The monitoring of ovulation 1999;26:171–173.
induction using ultrasound and estrogen. Clin Obstet Lande IM, Hill MC, Cosco FE, Kator NN. Adnexal and
Gynecol. 1984;27:993–1002. cul-de-sac abnormalities: transvaginal sonography.
Deichert U, Schlief R, van de Sandt M, Juhnke I. Trans- Radiology. 1988;166:325–332.
vaginal hysterosalpingo-contrast-sonography (Hy-Co- Laughead MK, Stones LM. Clinical utility of saline solu-
Sy) compared with conventional tubal diagnostics. tion infusion sonohysterography in a primary care
Hum Reprod. 1989;4:418–424. obstetric-gynecologic practice. Am J Obstet Gynecol.
Dickey RP. Doppler ultrasound investigation of uterine 1997;176:1313–1316.
and ovarian blood flow in infertility and early preg- Lee A, Sator M, Kratochwil A, et al. Endometrial vol-
nancy. Hum Reprod Update. 1997;3:467–503. ume change during spontaneous menstrual cycles:
Dijkman AB, Mol BW, van der Veen F, et al. Can hys- volumetry by transvaginal three-dimensional ultra-
terosalpingocontrast-sonography replace hysterosal- sound. Fertil Steril 1997;68:831–835.
pingography in the assessment of tubal subfertility? Orsini LF, Venturoli S, Lorusso R, et al. Ultrasonic find-
Eur J Radiol. 2000;35:44–48. ings in polycystic ovarian disease. Fertil Steril. 1985;
Fanchin R, Righini C, Ayoubi JM, et al. New look at 43:709–714.
endometrial echogenicity: objective computer-assisted Parson AK, Lense JJ: Sonohysterography for endome-
measurements predict endometrial receptivity in in trial abnormalities: preliminary results. J Clin Ultra-
vitro fertilization-embryo transfer. Fertil Steril. 2000; sound 1993;21:87–95.
74:274–281. Raga F, Bonilla-Musoles F, Casan EM, et al. Assessment
Feichtinger W. Follicle aspiration with interactive three- of endometrial volume by three-dimensional ultra-
dimensional digital imaging (Voluson): A step toward sound prior to embryo transfer: clues to endometrial
real-time puncturing under three-dimensional ultra- receptivity. Hum Reprod. 1999;14:2851–2854.
sound control. Fertil Steril. 1998;70:374–377. Schlief R, Deichert U. Hysterosalpingo-contrast sonog-
Feichtinger W. Results and complications of IVF ther- raphy of the uterus and fallopian tubes: results of a
apy. Curr Opin Obstet Gynecol. 1994;6:190–197. clinical trial of a new contrast medium in 120 patients.
Feichtinger W. Current technology of oocyte retrieval. Radiology. 1991;178:213–215.
Curr Opin Obstet Gynecol. 1992;4:697–701. Schwimer SR, Rothman CM, Lebovic J, Oye DM. The
Fleischer AC. Sonographic assessment of endometrial effect of ultrasound coupling gels on sperm motility
disorders. Semin Ultrasound CT MR. 1999;20:259– in vitro. Fertil Steril. 1984;42:946–947.
266. Shalev J, Meizner I, Bar-Hava I, et al. Predictive value
Fukuda M, Fukuda K, Yding Andersen C, Byskov AG. of transvaginal sonography performed before routine
Healthy and atretic follicles: vaginosonographic detec- diagnostic hysteroscopy for evaluation of infertility.
tion and follicular fluid hormone profiles. Hum Fertil Steril. 2000;73:412–417.
Reprod. 1995;10:1633–1637. Sladkevicius P, Campbell S. Advanced ultrasound exam-
Fukuda M, Shimizu T, Fukuda K, et al. Transvaginal ination in the management of subfertility. Curr Opin
hysterosonography for differential diagnosis between Obstet Gynecol. 2000;12:221–225.
submucous and intramural myoma. Gynecol Obstet Smith KE, Buyalos RP. The profound impact of patient
Invest. 1993;35:236–239. age on pregnancy outcome after early detection of fetal
Goldstein SR, Timor-Tritsch IE: Ultrasound in Gynecol- cardiac activity. Fertil Steril. 1996;65:35–40.
ogy 1st Ed. Churchill Livingstone Inc. 1995. Soares SR, Barbosa dos Reis MM, Camargos AF. Diag-
Gronlund L, Hertz J, Helm P, Colov NP. Transvaginal nostic accuracy of sonohysterography, transvaginal
sonohysterography and hysteroscopy in the evaluation sonography, and hysterosalpingography in patients
of female infertility, habitual abortion or metrorrhagia. with uterine cavity diseases. Fertil Steril. 2000;73:
A comparative study. Acta Obstet Gynecol Scand. 406–411.
1999;78:415–418. Sohaey R, Woodward P. Sonohysterography: technique,
Grunfeld L. The uterus and endometrium. Clin Obstet endometrial findings, and clinical applications. Semin
Gynecol. 1996;39:175–187. Ultrasound CT MR. 1999;20:250–258.
Hackeloer BJ. Ultrasound scanning of the ovarian cycle. Speroff L, Glass RH, Kase NG. The polycystic ovary. In:
J In Vitro Fert Embryo Transf. 1984;1:217–220. Clinical Gynecologic Endocrinology and Infertility.
Jurkovic D, Gruboeck K, Tailor A, et al. Ultrasound 6th Edition, Baltimore: Williams & Wilkins 1999.
screening for congenital uterine anomalies. Br J Obstet Strandell A, Bourne T, Bergh C, et al. The assessment of
Gynaecol 1997;104:1320–1321. endometrial pathology and tubal patency: a compari-
Nicolaides KH, Kleinkauf-Houcken A, Huneke B, Lind- son between the use of ultrasonography and X-ray hys-
ner C, Braendle W. Combining B-mode ultrasound terosalpingography for the investigation of infertility
with pulsed wave Doppler for the assessment of tubal patients. Ultrasound Obstet Gynecol. 1999;14:200–
patency. Hum Reprod. 1997;12:2457–2460. 204.
La Torre R, De Felice C, De Angelis C, et al. Trans- Strandell A, Bourne T, Bergh C, Granberg S, Thorburn
vaginal sonographic evaluation of endometrial polyps: J, Hamberger L. A simplified ultrasound based infer-
3051_Seifer_04_p39-48 11/5/01 9:36 AM Page 48

48 T. Widrich

tility investigation protocol and its implications for Widrich T, Bradley LD, Mitchinson AR, Collins RL.
patient management. J Assist Reprod Genet. 2000; Comparison of saline infusion sonography with office
17(2):87–92. hysteroscopy for the evaluation of the endometrium.
Timor-Tritsch IE, Rottem S. Transvaginal ultrasono- Am J Obstet Gynecol. 1996;174:1327–1334.
graphic study of the fallopian tube. Obstet Gynecol. Wolman I, Groutz A, Gordon D, et al. Timing of sono-
1987;70:424–428. hysterography in menstruating women. Gynecol
Ubaldi F, Wisanto A, Camus M, et al. The role of trans- Obstet Invest. 1999;48(4):254–258.
vaginal ultrasonography in the detection of pelvic Wu MH, Tang HH, Hsu CC, et al. The role of three-
pathologies in the infertility workup. Hum Reprod. dimensional ultrasonographic images in ovarian meas-
1998;13:330–333. urement. Fertil Steril. 1998;69:1152–1155.
Van der Auwera I, D’Hooghe TM. Ultrasound covers and Yaman C, Sommergruber M, Ebner T, et al. Repro-
sonographic gels are embryo-toxic and could be re- ducibility of transvaginal three-dimensional endome-
placed by non-toxic polyethylene bags and paraffin oil. trial volume measurements during ovarian stimulation.
Hum Reprod. 1998;13:2234–2237. Hum Reprod. 1999;14:2604–2608.
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 49

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

Three questions obsess infertile patients. “Am I on the psychological aspects of infertility and how
ever going to be pregnant?” is heard with great fre- they can help patients cope with the typical psy-
quency by physicians working with this population. chosocial stressors associated with infertility. Some
Though patients may dread the answer, their long- of the psychologically and ethically complex treat-
ing for pregnancy and their fears that parenthood ment decisions faced by infertile patients and the
is forever out of reach compel them to ask the ques- role of the mental health professional are discussed
tion. The other two questions are usually unspoken here. The chapter concludes with recommendations
but are fueled by the ceaseless distress and anxiety for clinicians dealing with couples and individuals
patients suffer because of their inability to con- faced with these difficult problems.
ceive: “Am I losing my mind?” and even more
frightening “Is the distress that I feel preventing me
from getting pregnant?” Physicians working with
infertile individual(s) serve their patients well when What Have We Learned
they anticipate all three questions and when they from Research?
include psychological support and counseling as an
integral part of a comprehensive treatment plan. Historically, infertility was thought to be a
It has long been a common idea that infertility is “woman’s problem,” and her psychological state
“all in the mind,”1–3 so it is not surprising that was considered to be at the root of the problem.
patients fear they are the cause of their own infer- Indeed, papers on medical and psychological
tility. Despite the long-standing myth that infertil- aspects of infertility from the first half of the twen-
ity has a psychiatric basis, studies on the psycho- tieth century were generally in agreement that by
logical aspects of infertility have consistently unconsciously rejecting pregnancy, childbirth, and
demonstrated that infertile individuals are psycho- motherhood women caused their own infertility.1–3
logically “normal” and that the experience of infer- This simplistic (and sexist) notion began to change
tility rarely results in severe psychological sequelae during the late 1960s and early 1970s as studies
or disabling psychiatric disorders.4–6 The emotional appeared in the psychiatric and gynecologic litera-
experience of infertility and its treatment, however, ture that compared data from infertile women with
is generally concluded to be difficult and can have data from matched controls (fertile women) and
a profound impact on affected individuals and cou- found no differences in their psychological
ples.6–8 Moreover, clinical data support the notion state.11,12 At the same time, clinical reports began
that participants in infertility treatment can benefit to emerge suggesting that there were certain pre-
from psychological support and counseling, and that dictable emotional responses to infertility and that
there is an important role for the mental health pro- infertile patients could benefit from psychological
fessional in this milieu.6,9,10 counseling and support.9,13–16
This chapter focuses on what clinicians who Studies using standard psychological measures
work with infertile patients can learn from studies have found that there are no differences in the psy-

49
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 50

50 D.A. Greenfeld

chological state between infertile couples and fer- Practical Psychosocial Issues
tile controls.4,17,18 Nevertheless, these studies have
continued to demonstrate that, although psycho- Impact of the Diagnosis
logically normal, infertile patients experience a
high degree of emotional dysphoria and euphoria Most people take their fertility for granted. In fact,
as a result of infertility and its treatment.5,6 For a common complaint from individuals and couples
example, in a study of 59 infertile women, Downey when they have difficulty conceiving is “we were
et al. reported that 76% of the subjects through that so careful to avoid pregnancy until we were ready.”
infertility caused them serious psychological con- Thus in what is commonly described as a “life cri-
sequences.19 In another study of 63 infertile women sis”10,16 couples go in short order from an assump-
and 37 infertile men, Mahlstedt et al.7 reported that tion of assured fertility to one of absolute dismay
subjects felt hopeless and depressed. In a study of at what is experienced as unfair and wholly unex-
200 couples entering in vitro fertilization (IVF) pected infertility. The initial denial and “this can’t
treatment, Freeman et al.8 reported that 48% of the be happening to me” feelings may later change to
women and 15% of the men described infertility as intense remorse. The intensively painful experience
the “worst experience of their lives.” of finding oneself defined as infertile in what
Researchers have also considered whether appears to be a highly fertile world leads to feel-
patients’ coping strategies—how they cope with life ings of isolation and guilt and the inevitable ques-
in general—may serve as a predictor for how they tions: “Why me”? Rosenthal24 described guilt as a
endure a failed cycle of infertility treatment. For primary emotional response common to many cou-
example, Litt et al.20 and Newton et al.21 reported ples diagnosed with infertility: guilt about waiting
that patients who demonstrated pretreatment too long to start a family, guilt about previous life
depressive symptoms and pretreatment anxiety events such as pregnancy termination or a sexually
symptoms were more likely to have a poor emo- transmitted disease. The guilt can exacerbate feel-
tional response to a failed cycle of IVF. The cop- ings of remorse, leading to acute anxiety. Fre-
ing strategies that employ psychologically “dis- quently the experience is to go from taking fertil-
tancing” oneself from the treatment appear to be ity for granted directly to an all-out aggressive
the least effective. For example, in Litt et al.’s study attempt to achieve pregnancy—an emotional jux-
the patients who had the most difficulty after a taposition that forces entry into a world heretofore
failed cycle were women who used “escape” as a completely unknown to them.
coping strategy.20 In a similar report, Hynes et al. Infertile patients frequently complain that their
studied 100 infertile women and found that the lives have been completely “taken over” by their
women who used “avoidance” as a coping strategy infertility, pervading their marital relationships,
were more likely to experience psychological dis- their sexual life, their relationships with their fam-
tress after a failed treatment cycle.22 ilies, their social relationships (where everyone
What can we learn from this research? Over the around them is getting pregnant and having babies).
course of their infertility and its treatment patients Once they begin treatment, infertility also can have
typically experience a range of emotional re- a devastating effect on their financial life. The oft-
sponses, including guilt, anxiety, depression, and used phrase “the emotional roller coaster of fertil-
grief. These responses, which vary from patient to ity” aptly describes the euphoria and dysphoria so
patient, are a normal part of the process. Although often associated with their experience. Over time,
at times causing stress and symptoms, they do not these feelings can become chronic23 as the length
in themselves suggest a psychologically unstable of the typical struggle with infertility and its treat-
individual. The quality and content of the experi- ment can lead to a growing sense of losing control
ence of infertility for most couples change over of the process. All to often the result is a profound
time.23 Nevertheless, there are certain practical psy- decline in the individual’s sense of integrity, com-
chosocial issues with which couples must cope as petence, and feelings of self-worth. Mahlstedt
they go through the process—issues clinicians described eight common losses associated with
should keep in mind as they consider what is best infertility.25
for their patients. Such issues include the impact of
the diagnosis, the impact of the treatment, gender 1. Loss of a (potential) relationship
differences in response to infertility and how they 2. Loss of health
affect the way couples cope with the process, and 3. Loss of status or prestige
coming to the decision to end treatment. 4. Loss of self-esteem
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 51

5. Coping with Infertility: Practical Psychosocial Issues 51

5. Loss of self-confidence Gender Differences in

6. Loss of security
7. Loss of a fantasy or hope of fulfilling an impor- Response to Infertility
tant fantasy
8. Loss of something or someone of great symbolic As though the social, sexual, and financial impact
value of prolonged treatment on their relationship were
not enough with which to contend, infertile cou-
ples must also confront the fact that they as indi-
Impact of Treatment viduals may have different responses to infertility
and its treatment—differences related to gender.
In addition to the emotional impact of infertility are Without education and preparation to help them
the rigorous, expensive, and often humiliating understand that this is normal, couples are often
demands of the medical treatment. By its nature, frightened by these differing responses and fear that
the treatment necessarily involves a prolonged it means they are losing everything, including their
intrusion into the most intimate aspects of the infer- relationship. In fact, it is often quite the opposite.
tile couple’s life. The charting of basal body tem- The experience of infertility often brings couples
peratures, the precise timing of sexual intercourse, closer, strengthening the bonds between them.
and the need to perform “sex on demand” to opti- Because it is often true that they have different cop-
mize the possibility of conception are only the first ing skills, the closeness resulting from the chal-
and most benign of these intrusions. Later require- lenge of infertility can make them stronger as a
ments may include invasive surgical procedures, team, although in the short run these differences
taking ovulation-enhancing hormones by injection, can add to the couples’ difficulties.
undergoing intrauterine inseminations, and ulti-
mately, for some, participation in assisted repro- Female Response to Infertility
duction techniques such as IVF.
Clearly, the pace and scope of treatment varies Many women worry about and doubt their fertility
from one couple to the next, but the experience for long before they try to conceive. When they are
all feels lengthy. The extended and repetitive nature diagnosed as infertile they typically experience it
of what to the physician may seem like innocuous as evidence of personal failure. (Interestingly, this
treatments can have a devastating cumulative is a typical reaction from women even when it is
impact on the couples’ sexual and marital relation- their male partner who is infertile.) Women typi-
ship. The couple must try to maintain a semblance cally see infertility as a punishment for their imag-
of normal life while trying to accommodate a gru- ined previous “sins” (such as an abortion early in
eling, often hectic treatment schedule—all at a time life). They frequently ruminate about time lost, time
when they feel in a “limbo” of uncertainty about wasted, or experiences they “should not have had.”
whether any of the efforts will succeed. At the beginning of the workup phase, women are
Some patients jokingly say, “I have learned more more likely to question their sexuality, to have
about the reproductive system than I ever imagined increasing self-doubt, and to experience greater
I would need to,” whereas for others the treatment emotional distress than men.25–27
regimens are confusing and difficult to understand. After prolonged infertility treatment women
Already socially isolated from their fertile family often report a decrease in sexual satisfaction and a
members and friends, they find themselves feeling loss of libido.23 Women are also typically much
intimidated and anxious about broaching questions more affected by outside influences, such as who
to the treatment staff. As the treatment becomes among their friends, relatives, and acquaintances is
more complex, couples may be distressed to find pregnant. No matter what the diagnosis, women
themselves unprepared but contemplating a treat- report more feelings of role failure and diminished
ment prohibited by their religion or one they find self-esteem. Though potentially more psychologi-
ethically troubling. For example, couples are asked cally vulnerable to the “fertile world around them,”
to decide whether to freeze, destroy, or donate women nonetheless tend to show better coping
excess embryos, whether they would tolerate a skills in terms of reaching out to develop social
risky multifetal pregnancy, or whether they would networks with family and friends. It is often the
consider fetal reductions (aborting one or more of woman who initiates and seeks out psychological
the fetuses) to increase the likelihood of survival of support from a mental health professional and sup-
the remaining reduced number of fetuses. port groups.27
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 52

52 D.A. Greenfeld

Male Response to Infertility ping treatment as a way of putting the issue on the
table; but merely raising the issue does not mean
Men tend to assume that infertility is “a woman’s they are ready to stop immediately. Other patients
problem,” an assumption often reinforced by their want to have a plan for closure: for example, “We
female partners’ willingness to take on responsi- will try two more cycles of intrauterine insemina-
bility for the problem. This assumption may be tions and then we stop.”
inadvertently further compounded by the medical For all patients, stopping treatment involves a
treatment team, who may not bother to perform a decision-making process and careful consideration.
semen analysis until long after the female partner Some consider other options for parenthood such
has been subjected to invasive diagnostic proce- as adoption. Others explore third party reproduc-
dures. Men are less likely than women to question tion, such as oocyte donation or a gestational sur-
their fertility prior to treatment, and in many cases rogate. They also may consider not having children
it comes as a shock to a man to learn that he is the at all. The physician can be most helpful by taking
infertile partner. These men report feelings of loss, a careful, guiding, but scrupulously neutral ap-
diminished self-esteem, and a sense of being stig- proach. What is not helpful is a statement such as,
matized.28 “You ought to consider adoption” as a euphemism
Nonetheless, their distress is generally not as for “This treatment is not going anywhere.”
severe as that of women. Men report feeling sad
and disappointed but not devastated. In general,
men appear to be more accepting of possible child-
lessness and are more willing then women to con- Special Considerations of
sider an end to treatment when infertility is due to Pregnancy After Infertility
a male factor. As a result, the man is usually the
partner who is more reluctant to participate in an Though the above practical psychological issues
assisted reproductive technology program. (Women are experienced to some degree by everyone going
may interpret this reluctance as a lack of interest through infertility treatment, not all patients need
or a lack of agreement about family goals.) Who- to spend a great deal of time looking at other
ever is the infertile partner, men more often tend to options. After all, some do get pregnant. It might
use distancing strategies to mute the intensity of seem that, having achieved their goal, they would
their feelings of loss while at the same time remain- be pleased, grateful, and free of stress. Pregnancy
ing especially sensitive to their partner’s distress.27 itself, however, raises some specific issues that
challenge the formerly infertile woman. All preg-
nant women worry about pregnancy loss and the
Ending Treatment health of their unborn child. These worries are often
accentuated for the formerly infertile.
As treatment continues, the litany of anxieties and
concerns among the infertile increasingly includes Pregnancy
the question: “When is enough enough?” Obvi-
ously, at a time when it seems that the treatment The issue of pregnancy is on the minds of these
possibilities are endless (i.e., the advent of infertile women much if not most of the time. The
advanced maternal age as a result of treatment with result is a repetitive pattern of mood fluctuation
donated oocytes) this question is not easily with each menstrual cycle. During part of the cycle
answered. Infertile couples address this issue in they are excited and optimistic, almost certain that
many ways. For example, some couples go to the this time conception has occurred. During this
“end of the earth” to seek treatment and technol- period they are completely focused on each bodily
ogy, and others decline any treatment. For some change, each nuance that may indicate the earliest
these decisions are made based on financial con- stage of pregnancy. This heightened expectation of
straints, and for others they are based on religious pregnancy is often compounded by symptoms
or cultural taboos; but for all its worth attention caused by the infertility medications that mimic
from the treatment team. Though patients may hes- pregnancy (what Sandelowski et al. referred to as
itate, they want and appreciate discussion and guid- a “drug-induced pseudocyesis”).29 For example,
ance on this matter from their clinicians. Physicians these medications may cause patients to experience
can be most helpful when they give an ongoing nausea, weight gain, and sore breasts or delayed
honest assessment of the diagnosis, plan, and prog- menses, all of which can be interpreted as early
nosis. Patients may raise their concerns about stop- signs or symptoms of pregnancy. Once menses
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 53

5. Coping with Infertility: Practical Psychosocial Issues 53

occurs, the patient’s mood plunges. She is not preg- Multiple Pregnancy and Multifetal
nant and, she fears, never will be. Pregnancy Reduction
What happens when, after infertility, pregnancy
is clearly documented? Olshansky described an Rapid advances in the methods of assisted repro-
“identity shift” experience by the formerly infertile duction have led to an increase in multiple preg-
woman. At first, while anxiously straddling the nancies.35 Patients who have been trying to con-
fence between infertility and pregnancy, she may ceive for years may not know that their medical
have difficulty seeing herself as a “normal pregnant treatment causes an increased risk of multiple preg-
woman.”30 Bernstein et al. described the normal nancy; and even if they are aware of that risk, they
ambivalence and questions about competence that may welcome it, hoping to have more than one
affects all pregnant women. The author stated that child.36 They may not fully understand the risks
these questions and anxieties are typically intensi- associated with multiple pregnancy, such as pre-
fied in the newly pregnant (formerly infertile) maturity and infant mortality.
patient who may voice doubts about her self-worth In fact, pregnancies involving three or more
and her competence as a mother.31 The anxiety fetuses constitute such a significant risk that it has
associated with infertility and its treatment may led to the development of another treatment: multi-
carry over and continue into the pregnancy. Con- fetal pregnancy reduction. Because of the ethically
cerns about “defective reproductive machinery” complex issues associated with this treatment—one
may extend to fears about potential problems with that may involve aborting one or more fetuses to
the pregnancy or subsequent delivery. When in fact save one or more fetuses—has raised concerns
there are prenatal or neonatal problems, women among clinicians. Two studies have considered the
tend to feel guilt and shame, which they associate long-term psychological consequences of multifetal
with their former infertility. Lind et al. described pregnancy reduction and have concluded that al-
the impact of prior infertility on parents whose though women undergoing this procedure become
newborn children required treatment in the new- distressed and suffer some short-term depression,
born intensive care unit. Even when the child’s ill- most accept it as a painful necessity and report that
ness had no connection whatsoever with the infer- they would willingly undertake it again.37,38
tility, the mothers experienced a profound sense of
loss and grief that they associated with their “defec- Pregnancy Following Treatment
tive” state.32 with Donor Gametes
Although artificial insemination with donor sperm
Pregnancy Loss has been available to infertile couples for nearly a
Many imagine that miscarriage would be the worst century, treatment of women with donor oocytes
thing that could happen to patients who have finally has been available only since 1984. Though con-
conceived after a long, difficult effort. In fact, that ceptually similar, these treatments are significantly
is not what the evidence shows. Women who are different. Treatment with donor oocytes is a more
lucky enough to conceive after infertility treatment complicated, invasive, and expensive procedure
often report feeling vulnerable and often worry than donor insemination. Furthermore, it has intro-
intensely about losing the pregnancy (some prepa- duced a new cohort of patients into treatment, such
ration and much reassurance is called for at this as women with premature ovarian failure, women
point). However, if that pregnancy results in a mis- who have had surgically lost ovaries because of
carriage, the disappointment is lessened because serious illness, and women of advanced reproduc-
the women are frequently relieved to know they can tive age.
achieve pregnancy and they at least have had that Whether the couple is utilizing donor sperm or
experience. Harris et al. described the paradox that donated oocytes, however, the pretreatment prepara-
infertile couples grieving after a miscarriage may tion and many of the counseling issues remain the
simultaneously experience a kind of relief, an same. The couple must mourn the loss entailed by
“emotional gain” that is the result of just knowing the fact that one of the parents is not genetically
that they were able, if only for a short while, to be related to the potential child. The couple must also
a part of “the fertile world.”33 Nevertheless, preg- deal with the difficult decision as to whether they will
nancy loss following infertility merits special con- utilize an anonymous or a known donor. Couples are
sideration. One study reported increased levels of also faced with questions about what to tell the poten-
depression in women following pregnancy loss, and tial child. What (if anything) and when should they
most at risk were the childless women.34 tell the child about his or her conception?
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 54

54 D.A. Greenfeld

Role of the Mental of counseling, education, and support. Its routine

nature suggests that the psychological stresses of
Health Professional treatment are “normal and expected.” Psychologi-
cal consultation and evaluation give the patient an
The identified psychological stresses of infertility opportunity to express concerns he or she may have
treatment, the need to cope with demanding treat- about the treatment as it allows the clinician an
ment protocols, and the expanding array of ethi- opportunity to form a picture of the participant.
cally complex issues have led to a steadily increas- A medical practitioner with a small practice or
ing appreciation of the role of the mental health who is incorporating infertility treatment into a
professional on the infertility treatment team. Men- gynecologic practice may not have a mental health
tal health professionals are utilized to assess and practitioner available as part of the on-site team. In
evaluate participants in infertility treatments, pro- these instances it is important to obtain a thorough
vide psychotherapeutic intervention and support, history that could include recommendations for
and serve as educators in a difficult and complex referral to a mental health practitioner when appro-
milieu. priate.
The assessment should be designed to determine
Psychological Consultation whether further psychological evaluation is neces-
and Evaluation sary. There are several models for the content of
such an assessment. One such document is The
Ideally, the mental health practitioner is an integral Comprehensive History of Infertility (CPHI), devel-
part of an interdisciplinary treatment team. In this oped by Burns and Greenfeld (1990) for the Men-
context, routine evaluation by the mental health tal Health Professional Group of the American
professional gives the patient the message that the Society for Reproductive Medicine (Table 5–1).
demanding nature of the treatment requires a degree The CPHI contains the reproductive history, psy-

TABLE 5–1. Comprehensive Psychosocial History of Infertility 1990

Reproductive History Sexual History
Infertility Frequency and response
Current infertility: primary or secondary Function/dysfunction
History of past infertility Religious or cultural influence on sexual patterns or
Pregnancy procreation beliefs
Living children (stepchildren, adopted, donor offspring, Sexual history
placed for adoption) Function/dysfunction
Therapeutic abortion(s) Sexually transmitted disease
Spontaneous abortion(s) Prior sperm donor/surrogate mother/consideration of use
Other perinatal loss: SIDS, death of child of donor gametes
High-risk pregnancy Homosexual or ambisexual patterns
History of genetic/chromosomal abnormalities History of rape or incest
Cancer of the reproductive tract and/or chemotherapy Changes in any sexual patterns secondary to infertility or
DES exposure medical treatment.
Congenital abnormalities of the reproductive tract Relationship Status
Family history of genetic disorders Marital
History of marriages/divorces
Mental Status History of marital discord/therapy
Psychiatric history Extramarital relationships
Hospitalization for psychiatric illness Current satisfaction/dissatisfaction
Psychiatric treatment Ambivalence about medical treatment and reproductive
Treatment with psychotropic medication technologies
Substance abuse Familial
Current mental status History of dysfunctional family of origin
Symptoms of depression Recent deaths or births in family
Symptoms of anxiety/panic attacks History of numerous familial losses
Symptoms of obsession Social
Current use of psychotropic medications Available support system
Current problem with substance abuse/addiction Career disruptions or pressures
Change in mental status History of or current legal problems
Exacerbation of prior psychiatric symptoms Criminal conduct

(Reproduced from Burns LH, Greenfeld DA, for the Mental Health Professional Group. CPHI: Comprehensive Psychosocial
History for Infertility. Birmingham, AL: American Society for Reproductive Medicine, 1990.)
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 55

5. Coping with Infertility: Practical Psychosocial Issues 55

chological history, marital history, sexual history, on the nature of the problem, the patient(s) prefer-
and social history. Findings suggesting that refer- ences, and the availability of each option. Though
ral to a mental health professional is appropriate it is an individual’s or couple’s choice about the
include a history (past and present) of psychiatric treatment modality, it is usually up to the referring
illness, a history of pregnancy complications and clinician to initiate the referral, explaining the
loss, a history of sexual abuse, past or current chem- rationale for the recommendation. Whatever the
ical abuse or dependence, or a chaotic social or choice of treatment focus or modality, one thing is
familial situation. Of course, any patient who clear: Gone are the days when physicians referred
requests such a referral should be provided one.39 their infertile patients to psychotherapists for the
Many programs of assisted reproductive tech- purpose of helping them “work through unresolved
nology require pretreatment evaluation and assess- conflicts impeding their changes for pregnancy.”
ment of patients to determine if they are prepared Nowadays, the goal of psychotherapeutic interven-
for the rigors of the treatment, if they understand tion is to recognize that infertility is highly stress-
and are able to give informed consent to the treat- ful and that dealing with it can enhance one’s abil-
ment, if they are psychologically stable. One such ity to cope with the psychological and physical
program developed a set of guidelines for psycho- stresses of the problem.
logical evaluation.40 The following is a checklist of
areas for consideration during the pretreatment
evaluation and assessment of participants in treat- Individual Therapy
ment. Many patients prefer individual treatment. It is the
most private, secure, and common treatment
1. Patient reliability modality, one that is likely to be most familiar and
2. Ability to provide informed consent acceptable. When a patient has a clear preference
3. Stability of the couple’s relationship for individual treatment, it should generally be hon-
4. Psychological issues for the infertile partner ored unless there is a clear indication that another
5. Expectations of infertility treatment modality is indicated.
6. Understanding the impact of the technology
7. Current and past sexual functioning
8. Level of social support Couples Therapy
9. Religious and cultural considerations
10. Psychiatric status Menning described the problem of infertility, no
11. Legal history matter who is responsible for the diagnosis, as one
that always affects the couple’s marriage, their
friendship, and their sexual relationship.15 Hence
couples treatment is often the most useful for infer-
Psychological Support and Counseling tile couples. It provides a safe forum where they
For patients who have a seriously troubled history can deal with conflicts, listen to each other, and
or who are in immediate psychological distress, a deal with gender differences in response to the
referral for psychotherapy is indicated. Even the problem.
large number of patients who do not merit referral
are likely to be reassured that psychological sup- Group Therapy
port is available if needed. Several modalities of
psychotherapeutic intervention have been effective Many couples find group therapy especially useful.
for treatment of infertile individuals and couples. Groups of infertile couples can provide support,
Therapeutic sessions may be conducted individu- education, and the kind of empathy available only
ally, with the couple (or family) together, or with to those who are experiencing the same stresses.
one or both partners as participants in a group treat- The experience of talking with others in the same
ment. The focus of therapy may be alleviation of predicament can help “normalize” the experience
distress and control of psychological symptoms, and provide a level of reassurance that makes the
sex therapy, or grief management. The techniques experience more tolerable. A prospective study of
may include supportive, cognitive, or psychody- the effectiveness of support groups for the infertile
namically oriented treatment. Most of the referrals concluded that they are “a highly acceptable and
are for brief treatment involving crisis intervention effective intervention in self-referred patients in
designed to provide short-term support and symp- alleviating psychological distress related to infer-
tom relief. The choice of modality usually depends tility.”40
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 56

56 D.A. Greenfeld

Recommendations for Physicians 9. Berger DM. The role of the psychiatrist in the repro-
ductive biology clinic. Fertil Steril 1977;28:141–
145.
Infertile patients are surrounded by family and
10. Covington SN. Psychosocial evaluation of the infer-
friends who advise them to “relax and you’ll get tile couples: implications for social work practice. J
pregnant” (which of course only adds to their anx- Soc Work Hum Sexuality 1987;6:21–36.
iety and distress). Obviously, it is helpful to patients 11. Mai FM, Munday RM, Rump EE. Psychiatric inter-
when the medical team does not participate in that view comparisons between infertile and fertile cou-
sort of advice. It is especially helpful to patients ples. Psychosom Med 1972;12:46–59.
when their physicians reassure them that their anx- 12. Noyes RW, Chapnick EM. Literature on psychology
iety is not preventing them from becoming preg- and infertility. Fertil Steril 1964;15:543–548.
nant. Moreover, physicians serve their infertile 13. Menning BE. The infertile couple: a plea for advo-
patients well when they communicate the fact that cacy. Child Welfare 1975;54:545–560.
14. Menning BE. Resolve: a support group for infertile
psychological stress is a temporary but inevitable couples. Am J Nurs 1976;76:258–259.
part of the process. Physicians who have an in- 15. Menning BE. Counseling infertile couples. Contemp
depth understanding of the psychological and emo- Obstet Gynecol 1979;13:101–108.
tional aspects of this complex problem can reassure 16. Menning BE. The emotional needs of infertile cou-
and support patients, recognize when they need ples. Fertil Steril 1980;34:313–319.
additional support, and help them find and use that 17. Adler JD, Boxley RL. The psychological reactions
support. to infertility: sex roles and coping styles. Sex Roles
Kingsberg41 listed the following recommenda- 1985;12:271–279.
tions for physicians treating infertile patients. 18. Connolly KJ, Edelmann RJ, Cooke ID, et al. The
impact of infertility on psychological functioning. J
1. Educate and inform couples at each visit about Psychosom Res 1992;36:459–468.
their diagnosis, prognosis, and treatment options, 19. Downey J, Yingling S, McKinney M, et al. Mood dis-
even if it seems redundant. orders, psychiatric symptoms, and distress in women
2. Acknowledge and normalize the emotional presenting for infertility evaluation. Fertil Steril
aspects of these treatment options. 1989;52:425–432.
20. Litt MD, Tennen H, Affleck G, et al. Coping and cog-
3. Encourage couples not to rush their decision
nitive factors in adaptation to in vitro failure. J Behav
about treatment. Med 1992;15:171–187.
4. Encourage couples to consult with a mental 21. Newton C, Hearn M, Yuzpe A. Psychological assess-
health professional. ment and follow up after in vitro fertilization: assess-
ing the impact of failure. Fertil Steril 1990;54:
879–886.
References 22. Haynes GJ, Callan VJ, Terry DJ, et al. The psycho-
logical well-being of infertile women after a failed
1. Deutsch H (1944) The Psychology of Women. New IVF attempt: the effects of coping. BMJ 1992;65:
York: Grune & Stratton. 269–278.
2. Fisher IC. Psychogenic aspects of sterility. Fertil 23. Berg BJ, Wilson JF. Psychological functioning across
Steril 1953;4:466–471. stages of treatment for infertility. J Behav Med 1991;
3. Benedek T. Infertility as a psychosomatic defense. 14:11–26.
Fertil Steril 1952;3:527–535. 24. Rosenthal MB. Psychiatric aspects of infertility and
4. Downey J, McKinney M. The psychiatric status of assisted reproductive technologies. Infertil Reprod
women presenting for infertility evaluation. Am J Med Clinics of North Am 1993;4:471–482.
Orthopsychiatry 1992;62:196–205. 25. Mahlstedt PP. The psychological component of infer-
5. Berg BJ, Wilson JF. Psychiatric morbidity in the tility. Fertil Steril 1985;43:335–346.
infertile population: a reconceptualization. Fertil 26. Daniluk JC. Strategies for counseling infertile cou-
Steril 1990;53:654–661. ples. J Counsel Dev 1991;69:317–320.
6. Mazure CM, Greenfeld DA. Psychological studies of 27. Abbey A, Andrews FM, Halman LJ. Gender’s role in
in vitro fertilization/embryo transfer participants. J In responses to infertility. Psych Women Q 1991;15:
Vitro Fert Embryo Transfer 1989;6:242–49 295–316.
7. Mahlstedt PP, MacDuff S, Bernstein J. Emotional 28. Natchtigall RD, Becker G, Wozny M. The effects of
factors and the in vitro fertilization and embryo trans- gender-specific diagnosis on men’s and women’s
fer process. J In Vitro Fert Embryo Transfer 1987; response to infertility. Fert Steril 1992;57:113–121.
4:232–236. 29. Sandelowski M, Harris BG, Holditch-Davis D. Preg-
8. Freeman EW, Boxer AS, Rickels K, et al. Psycho- nant moments: the process of conception in infertile
logical evaluation and support in a program of in couples. Res Nurs Health 1990;13:273–282.
vitro. Fertil Steril 1985;43:48–53. 30. Olshansky EF. Psychosocial complications of preg-
3051_Seifer_05_p49-57 11/5/01 3:13 PM Page 57

5. Coping with Infertility: Practical Psychosocial Issues 57

nancy after infertility. NAACOGS Clin Issu Perinat chosocial History of Infertility (CPHI). Birmingham,
Womens Health Nurs 1990;1:342–347. AL: American Society for Reproductive Medicine,
31. Bernstein J, Mattox JH, Kellner R. Psychological sta- 1990.
tus of previously infertile couples after a successful 40. Stewart DE, Boydell KM, McCarthy K, et al. A
pregnancy. J Obstet Gynecol Neonatal Nursing 1988; prospective study of the effectiveness of brief pro-
12:404–408. fessionally-led support groups for infertility patients.
32. Lind RF, Pruitt RL, Greenfeld DA. Previously infer- Int J Psychiatry Med 1992;22:173–182.
tile couples and the newborn intensive care unit. 41. Kingsberg SA. Assisted reproductive techniques and
Health Soc Work 1989;14:127–144. male factor infertility: psychological perspectives on
33. Harris BG, Sandelowski M, Holditch-Davis D. Infer- the treatment recommendations of IUI, IVF, and
tility: a new interpretation of pregnancy loss. Mat ICSI. Syllabus from the course Male Infertility: The
Child Nurs 1991;16:217–220. Medical and Psychological Team Approach to Treat-
34. Neugebauer R, Kline J, Shrout P, et al. Major depres- ment, sponsored by the American Society for Repro-
sive disorder in the 6 months after miscarriage. ductive Medicine, 1996.
JAMA 1997;277:383–388.
35. Berkowitz R, Lynch L, Chitkara U, et al. Selective Suggested Reading
reduction of multifetal pregnancies in the first tri-
mester. N Engl J Med 1988;16:318. Klock SC, Greenfeld DA. Psychological status of in vitro
36. Lieblum SR, Kemmann E, Taska L. Attitudes toward fertilization patients during pregnancy: a longitudinal
multiple births and pregnancy concerns in infertile and study. Fertil Steril 2000;73:1159–1164.
noninfertile women. J Psychosom Obstet Gynaecol Milad MP, Klock SC, Moses S, et al. Stress and anxiety
1990;11:197. do not result in pregnancy wastage. Hum Reprod 1998;
37. Shreiner-Engel P, Walther VN, Mindes J, et al. First- 13:2296–2300.
trimester multifetal pregnancy reduction: acute and Schover LR. Psychosocial aspects of infertility and deci-
persistent psychologic reactions. Am J Obstet sions about reproduction in young cancer survivors: a
Gynecol 1995;172:541–547. review. Med Pediatr Oncol 1999;33:53–59.
38. McKinney M, Downey J, Timor-Tritsch I. The psy- Infertility Counseling: A Comprehensive Handbook for
chological effects of multifetal pregnancy reduction. Clinicians. Edited by Linda Hommer Kurns, Sharon
Fertil Steril 1995;64:51–61. N. Covington. New York: Parthenon Publishing Group,
39. Burns LH, Greenfeld DA. The Comprehensive Psy- 1999.
3051_Seifer_06_p58-62 11/5/01 9:45 AM Page 58

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

When young couples begin forming a family, they regate the infertility benefit from other disease pro-
do not anticipate problems with reproduction.1 cesses for simplification and ease of projecting risk.
Often the patients who attend reproductive endo- Essentially three types of proposal have been
crine infertility clinics are educated, are highly presented for dealing with infertility: a capitated
motivated, and have yet to confront an adversity in plan such as the one implemented by U.S. Health-
life that could not be overcome with perseverance. Care, the infertility protocol presented by Bates
Therefore they may present to the reproductive Consulting,9 and the Lewin VHI algorithm.10,11
endocrinologist in a frustrated, angry, confused Under the U.S. HealthCare model, the basic infer-
state. Their view of reproductive medicine may be tility workup can be carried out by anyone desig-
tainted by articles in the news, sensational press nated a primary provider. It consists of a semen
releases, and magazine articles with titles such as, analysis, postcoital test, hysterosalpingography,
“The Frightening Future of Baby Making” or “High and some assessment of ovulation (typically a mid-
Tech Baby Making.” They see newspaper headlines luteal progesterone or endometrial biopsy). When
showing quadruplet gestations with their family most patients have finished this segment of the
members, news articles indicating that gametes workup they are referred directly to a limited num-
have been switched in the laboratory or perhaps ber of reproductive endocrinologists, completely
sold commercially, and infertility treatment result- bypassing the obstetrician/gynecologist. Patients
ing in malignancy or other disease processes.2 may visit two reproductive endocrine practices and
There is tabloid exposure in places such as grocery at that juncture choose their tertiary care provider.
store check-out lines touting titles such as “Animal A capitated arrangement is reached between the
and Human Sperm Bank Mix-up” and “Tragic Dog corporate entity and the provider, which is in the
Baby Born: Hospital Orders Cover-up.” Although mid-four-figure region. Any means may be used to
most of these concerns may have questionable rel- achieve conception, such as laparoscopic surgery,
evance to reproductive endocrine practice, they do intrauterine insemination, gonadotropins, gamete
hit on many sensitive social issues. Perhaps these intrafallopian transfer, or in vitro fertilization
situations contribute to the fact that 43% of infer- (IVF). The provider has 2 years to achieve the preg-
tile couples never seek help, with approximately nancy and must maintain a low 20th percentile
12% seeking care per year. It should also be remem- pregnancy rate to remain eligible for the plan. If
bered that this type of lay press is not totally conception occurs early during the workup, the
ignored by the insurance industry. Most of these provider receives the remainder of the capitated
articles confirm the executives’ worst fear about lia- payment.
bility in the case of gamete mix-up, the cost of mul- The algorithm presented by Bates Consulting
tiple births, and the risk of increasing the insured Company involves an initial evaluation of the his-
cancer population.3–8 In other words, it is safe to tory, physical examination, semen analysis, hormone
say that infertility does not exist in a social or polit- evaluation in 35% of the patients, and hysterosal-
ical vacuum. Furthermore, infertility does not exist pingography in 30%. One-third of the patients are
in a vacuum from a medical point of view, although thought to have disorders of ovulation; this problem
several attempts have been made nationally to seg- is treated by correcting body weight (if 95% or

58
3051_Seifer_06_p58-62 11/5/01 9:45 AM Page 59

6. Impact of Managed Care on Office-Based Infertility Practice 59

130% of ideal) and/or therapy with clomiphene rates in the range of 8.5–25.0%. Infertility acts
citrate, bromocriptine, or prednisone for six cycles against a background of changing age in both men
as indicated. If no pregnancy results, 30% of the and women, with the age of menopause normally
patients undergo office hysteroscopy and then three ranging between 35 and 57 years (mean 51.4 years)
cycles of IVF. in the U.S. population. By age 35 there is an expo-
Thirty percent of the patients have ovulatory dis- nential fall in the fecundity rate, with the fertility
orders, and 24% of them undergo operative lapa- rate being approximately 100 per 1000 people at
roscopy. Half are thought to have a good progno- age 40.12 Furthermore, the number of clinically rec-
sis. They attempt pregnancy for 6 months; if no ognized trisomies rises exponentially at age 35, and
pregnancy results, approximately 40% undergo by age 40 it represents approximately 25% of preg-
three cycles of IVF. If they are poor-prognosis nancies.13 Likewise, the spontaneous miscarriage
patients (50% with extensive tubal disease), they rate rises exponentially after age 35, and by age 40
undergo three cycles of IVF. it is approximately 30%.13 Ectopic pregnancies rise
Forty percent of the couples have male factor from 15% per 1000 pregnancies at age 25–34 to
infertility; 80% are oligospermic, and varicocelec- nearly 20% at age 35–44.14 In fact, every compli-
tomy is used sparingly. If no pregnancy occurs fol- cation of pregnancy—including abortion, ectopic
lowing surgery, three cycles of IVF are carried out. pregnancy, congenital malformations, prematurity,
The azoospermic patient (20%) undergoes six intrauterine growth retardation, macrosomia, peri-
cycles of therapeutic donor insemination. If no natal mortality, fetal death, neonatal death, infant
pregnancy results, two cycles of IVF are attempted. mortality, placenta previa, abruptio placentae,
It should be noted that in this algorithm the patient pregnancy-induced hypertension, chronic hyper-
pays the cost of laboratory evaluation, the cost of tension, diabetes labor dysfunction, cesarean sec-
all medications including gonadotropins, an addi- tion, maternal mortality, and maternal morbidity—
tional charge for the IVF cycle, and the cost of increases markedly beyond age 35. In addition, the
donor insemination. likelihood of conception is associated with age-
The algorithm designed by Lewin VHI was pre- related male sexual dysfunction. The conception
pared by a panel of infertility experts using a liter- rate with partners under age 25 with 6 months of
ature review and a modified delphi approach. Infer- unprotected intercourse is 48.5%; at age 40 and
tility was treated as being the result of a variety of over it is 22.7%. The frequency of intercourse
disease processes including such entities as a pitu- decreases with age; and with intercourse occurring
itary tumor, central nervous system dysfunction, less than once per week, the conception rate is
diabetes mellitus, other systemic disorders, endo- 16.7% over 6 months; at more than four times a
metriosis, fibroids, adhesions, and eating disorders, week the conception rate is 83.3%. Finally, there is
among others. The algorithm further depends on an exponential decrease in the number of orgasms
a working relationship between the obstetrician/ per week and an exponential rise in the number of
gynecologist and the reproductive endocrinologist, episodes of impotence, which begins at around age
functioning together as a network. It continuously 35. All of these factors result in increased cost,
evolves based on an outcome analysis. It sets decreased productivity of the couple, depression,
boundaries on therapy based on a literature review marital discord, family discord, and isolation of the
and outcome analysis. This algorithm is entirely couple. These factors make powerful arguments for
different from a protocol concept, which is derived presenting an infertility benefit to providers. Fur-
from an individual anecdotal practice experience thermore, as a way of reducing cost, the algorithm
that often leads to failure, increased cost, dissatis- stresses over and over again the use of accurate
fied subscribers, and ultimately litigation. Algo- diagnosis, the maximization of pregnancy using
rithms can be used to improve care, control cost, low technology therapy, the appropriate use of lap-
use resources efficiently, and increase the avail- aroscopic surgery, and the appropriate use of
ability of coverage because it allows the payer to assisted reproductive technology (ART) early dur-
predict the worst case scenario, which generally ing the workup if need be, all of which is cost-effec-
falls in the range of 0.40 to 0.50 per member per tive. Such an algorithm helps codify a standard of
month. This is much lower than is generally thought practice; it controls cost, limits other costs such as
by the insurance industry. other surgery as for ectopic pregnancies, predicts
The algorithm also has as its basis a number of outcome, and makes therapy finite. For example,
facts that influence reproduction. Approximately 54 clomiphene citrate ovulation induction is used for
million women in the United States age 15–45 five ovulatory cycles, gonadotropin ovulation in-
years who are trying to conceive show subfertility duction is used for six cycles, IVF is used for four
3051_Seifer_06_p58-62 11/5/01 9:45 AM Page 60

60 R.E. Blackwell

to six cycles. An infertility algorithm also sets the nitch, and it might be that this form of therapy
referral pattern; that is, move the patient to the will enjoy the same market dynamics as a cosmetic
reproductive endocrinologist early during the surgery.
workup, which is again cost-effective.15

Database and Outcome Analysis

Payment for Services
Following publication of the article, “Are we ex-
Payment for infertility services generally falls into ploiting the infertile couple?”17 Congress began to
three general categories: capitation, discounted fee focus effort on standardizing not only infertility
for service, and self-pay. Most reproductive endo- but laboratory services. Subsequently, an outcome
crine practices operate with some form of these database was established by the Society for Repro-
payments. There is little experience with capitated ductive Technology; and the Clinical Laboratories
plans in the area of infertility, and to my knowl- Improvement Act (CLIA) regulations were modi-
edge no prospective data have been presented. Our fied. At the same time, following the Clinton failed
own prospective payment plan, designed for the health care initiative, a marketplace-driven revolu-
VIVA program [University of Alabama at Birm- tion in managed care occurred. Carriers began to
ingham (UAB)], uses the Lewin VHI algorithm to insist on accurate databases and outcome analysis.
form the basis of the proposal. A figure of 0.47 per The concept of disease management was simulta-
member per month was used to project our neously introduced by both the insurance and phar-
expenses and revenues. Eleven months into the first maceutical industries. This concept insists that dis-
year this figure appears to be correct. The plan cov- eases are treated in an incremental manner with the
ers a semen analysis, postcoital test, hysterosalpin- most cost-effective therapy based on a literature
gography or sonohysterography, hormone assays, review and outcome analysis.18–22
and follicular monitoring by ultrasonography. It Although these concepts appeal to some and are
also covers surgical procedures to diagnose or treat rejected by others, they raise many difficult issues.
infertility, ovulation induction including clomi- We have all seen databases manipulated and out-
phene and gonadotropin therapy, artificial insemi- comes skewed by patient selection and exclusion.
nation by donor or husband, and assisted repro- Pregnancy rates are clearly diagnosis- and age-
ductive technology including IVF and gamete dependent; and advanced therapies often yield
intrafallopian transfer. There are exclusions, limi- impressive results when applied to those who per-
tations, and stipulations including a maximum life- haps do not need them. Furthermore, disease man-
time coverage of nine ovulation induction cycles of agement raises licensure issues, for instance the
clomiphene, six gonadotropin cycles, three artifi- criminal indictment of a physician-benefits man-
cial insemination cycles, and four ART cycles. In ager by the state of Florida who was charged with
addition to standard co-pay, any service related to practicing medicine in that state without a license.
hospitalization or outpatient surgical procedures Although this particular physician was licensed to
has a 40% co-pay; any drug such as clomiphene, practice in another state, his direction of patient
gonadotropins, and gonadotropin-releasing hor- care in Florida was viewed by the courts as a licen-
mone (GnRH) analogues used for treating infertil- sure violation. The same issues have been raised
ity has a 40% co-pay; and sterilization reversals are with regard to satellite offices, various satellite
excluded under this plan. Our experience over less affiliations, and telemedicine. Likewise, advertise-
than a year suggests that there is not an unfavor- ments appearing on the web may fall under the
able selection bias.16 same constraints.
Most of us are familiar with discounted fee for
service. Currently, many practitioners receive
between $0.30 and $0.50 on the dollar for services Credentialing
rendered. Other than in states that have mandated
coverage for ART services, many commercial car- Another area that will undoubtedly come under
riers discontinue therapy at the level of gonadotro- intense focus involves licensure and credentialing.
pins plus intrauterine insemination or following a Individuals who practice medicine in any state,
limited number of treatment cycles with this mode regardless of the form, will most likely be required
of therapy. Many reproductive endocrinologists to apply for a license in that state, be networked
favor out-of-pocket payment. Such a philosophy with physicians who are physically in the location,
pushes infertility services farther into the boutique and be appropriately certified, particularly as we
3051_Seifer_06_p58-62 11/5/01 9:45 AM Page 61

6. Impact of Managed Care on Office-Based Infertility Practice 61

enter the area of virtual reality in the surgical arena. specialty division of the American Board of Obstet-
Certification in reproductive endocrinology will rics and Gynecology.
most likely be a requisite for a payment by insur- Another issue with which one must deal in net-
ance companies, and failure to be certified will working is antitrust violation and the percentage of
probably result in deselection, as has already been market control. Informal networks seem to attract
seen in some communities. Payment for sonogra- the least attention from government antitrust forces.
phy will probably be dependent on being certified Under such arrangements individuals could be
by the American Registry of Diagnostic Medical members of a number of networks, and admission
Sonographers (ARDMS, 600 Jefferson Plaza, Suite to one would not exclude another. Networks have
360, Rockville, MD 20852). Laboratories will have been described by Foy23,24 in these terms: “The
to be certified by both CLIA and The American effectiveness of a network is inversely proportional
College of Pathology to be competitive for contract to its goal. A network needs to have a focus not a
bids. goal. A network needs a spider at the center, not a
chairman. A network needs a note or a newsletter,
not a journal. A network needs a good list of mem-
Networks bers more than a set of bylaws. A network needs
groups, not committees. A network needs a phone
Networking is one of the most difficult social and number, not a building.” In other words, it is an
legal issues facing reproductive endocrinologists. informal network of providers who are willing to
For instance, many of us practice broad-based come together under a common philosophy and
reproductive medicine, which means we function agree to treat patients accordingly. Such an organi-
as primary, secondary, and tertiary providers for zation, if made up of a strong group of obstetri-
some of our patients. The issue of self-referral from cian/gynecologists and reproductive endocrinolo-
one role to the other is perilous and is being gists, would have great appeal to insurance carriers
watched intensely by the insurance industry and looking for providers for their subscribers. Such
government. The whole area of networking creates networks would also allow the accumulation of
a special dilemma for those of us in academic med- enough data to furnish the payers meaningful out-
icine, as plans such as that presented by U.S. come analyses. This process will always be dynamic
HealthCare seem to strike at the very purpose of a as the pendulum of managed care swings to and fro,
residency training program because the better pro- whether we are dealing with the extremes of capi-
grams prepare residents to manage broad-based tation or the medical savings account. Those groups
reproductive medicine and infertility problems, up who will do well in such an environment will con-
to the stage of assisted reproductive technology uti- tinue to strive to hone their clinical skills, question
lization. To bypass the skills of so many of our col- their every practice, and discard those practices that
leagues seems to be an inefficient use of resources. do not stand close analysis. These groups (and only
The most efficient treatment of the patient with these groups) will be able to compete in the medi-
complex reproductive medicine problems seems cine of the future.
to be an initial referral of this patient directly to
the obstetrician/gynecologist by the primary care
provider, who would work up the patient guided by References
algorithms and disease management concepts. He 1. Page H. Estimation of the prevalence and incidence
or she would consult frequently with the reproduc- of infertility in a population: a pilot study. Fertil Steril
tive endocrinologist during the workup and refer 1989;51:571–577.
the patient who fails to conceive to the reproduc- 2. Stephen EH. Projections of impaired fecundity
tive endocrinologist in a timely manner. These steps among women in the United States: 1995 to 2020.
seem to limit cost and maximize outcome.15 How- Fertil Steril 1996;66:205–209.
ever, in this intense era of competition, the forma- 3. Shushan A, Paltiel O, Iscovich J, et al. Human meno-
tion of working networks between the reproductive pausal gonadotropin and the risk of epithelial ovar-
endocrinologist and the obstetrician/gynecologist is ian cancer. Fertil Steril 1996;65:13–18.
4. Callahan TL, Hall JE, Ettner SL, et al. The economic
at times difficult because problems of ego, train- impact of multiple-gestation pregnancies and the
ing, and practice often interfere with the success- contribution of assisted-reproduction techniques to
ful function of these networks. The future of repro- their incidence. N Engl J Med 1994;331:244–249.
ductive medicine will be dictated by the use of 5. Collins JA, Bustillo M, Visscher RD, et al. An esti-
algorithms, which are no more than a codification mate of the cost of in vitro fertilization services in
of the guidelines of practice advocated by the sub- the United States in 1995. Fertil Steril 1995;64:1–8.
3051_Seifer_06_p58-62 11/5/01 9:45 AM Page 62

62 R.E. Blackwell

6. Hecht BR. Iatrogenic multifetal pregnancy. Assist 19. Vilos GA, Pispidikis JT, Botz CK. Economic evalu-
Reprod Rev 1993;3:75–87. ation of hysteroscopic endometrial ablation versus
7. Wilcox LS, Kiely JL, Melvin CL, et al. Assisted vaginal hysterectomy for menorrhagia. Obstet Gy-
reproductive technologies: estimates of their contri- necol 1996;88:241–245.
bution to multiple births and newborn hospital days 20. Brumsted JR, Blackman JA, Badger GJ, et al. Hys-
in the United States. Fertil Steril 1996;65:361–366. teroscopy versus hysterectomy for the treatment of
8. Neumann PJ, Gharib SD, Weinstein MC. The cost of abnormal uterine bleeding: a comparison of cost. Fer-
a successful delivery with in vitro fertilization. N til Steril 1996;65:310–316.
Engl J Med 1994;331:239–243. 21. Danese MD, Powe NR, Sawin CT, et al. Screening
9. Bates GW, Bates SR. The economics of infertility: for mild thyroid failure at the periodic health exam-
developing an infertility managed-care plan. Am J ination. JAMA 1996;276:285–292.
Obstet Gynecol 1996;174:1200–1207. 22. Clancy CM. Evidence-based medicine meets cost-
10. Blackwell RE. A proposed algorithm for evaluation effectiveness analysis. JAMA 1996;276:329–330.
and treatment of infertility. Update Infertility Reprod 23. Foy N. The Yin and Yang of Organizations. London:
Med UAB 1995;7:1–8. Grant McIntyre, 1981.
11. Blackwell RE. Clinical treatment of infertility: a 24. Handy C. Gods of Management. The Changing Work
practical algorithm. Drug Benefit Trends 1996;8:17– of Organizations. Oxford University Press, New
22. York, 1995.
12. Stein ZA. Reviews and commentary: a woman’s age:
childbearing and child rearing. Am J Epidemiol Suggested Reading
1985;121:327–342.
13. Hassold T, Chiu D. Maternal age-specific rates of Blackwell RE, Team WM. Hidden costs of infertility
numerical chromosome abnormalities with special treatment in employee health benefits plans. Am J
reference to trisomy. Hum Genet 1985;70:11–17. Obstet Gynecol 2000;182:891–895.
14. Chow W-H, Daling VR, Cates WJ, et al. Epidemiol- Bron MS, Salmon JW. Infertility services and managed
ogy of ectopic pregnancy. Epidemiol Rev 1987;9:70– care. Am J Manag Care 1998;4:715–720.
94. Griffin M, Pana WF. The economic cost of infertility-
15. Gleicher N, Vanderlaan B, Karande V, et al. Infertil- related services: an examination of the Massachusetts
ity treatment dropout and insurance coverage. Obstet infertility insurance mandate. Fertil Steril 1998;70:
Gynecol 1996;88:289–293. 22–29.
16. Eddy DM. Benefit language: criteria that will im- Tabbush V, Gambone JC. Managed health care coverage
prove quality while reducing costs. JAMA 1996;275: for infertility services: understanding adverse selec-
650–657. tion. Curr Opin Obstet Gynecol 1998;10:341–346.
17. Blackwell RE, Carr BR, Chang JR, et al. Are we VanderLaan B, Karande V, Krohm C, et al. Cost consid-
exploiting the infertile couple? Fertil Steril 1987;48: erations with infertility therapy: outcome and cost
25–29. comparison between health maintenance organization
18. Pittaway DE, Takacs P, Bauguess P. Laparoscopic and preferred provider organization care based on
adnexectomy: a comparison with laparotomy. Am J physician and facility cost. Hum Reprod 1998;13:
Obstet Gynecol 1994;171:385–391. 1200–1205.
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 63

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

Establishment of a pregnancy via in vitro fertiliza- specifications that were never met, let me offer this
tion (IVF) is a multifactorial process with several advice: Check all plans and be sure in your mind
steps critical to its success. Important components that the design is capable of providing you with the
include procurement of a reasonable number of environment you desire. If you are not sure, get a
good-quality mature eggs, proficiency of microas- second opinion.
sisted fertilization when needed, laboratory culture The purpose of this chapter is to detail the impor-
conditions that are noninhibitory and conducive to tant components of laboratory design, with mini-
the fertilization and development of the resulting mal discussion of specialized IVF equipment and
embryos, and finally a smooth and efficient trans- protocols. This chapter is not meant to be a how-
fer of high-quality embryos. A breakdown in any to manual on running an IVF laboratory. Rather, it
of these areas is sure to limit the success of a pro- is a guide for someone responsible for designing
gram. The design and function of the laboratory is and building a new IVF laboratory.
thus of paramount importance.
What makes a good IVF laboratory? The qual-
ity of the laboratory and the success of a program
are dependent on a competent laboratory director
Air Delivery System
and staff, and the design of the laboratory is of crit- Specifications
ical importance as well. Even a program with the
best laboratory director cannot be successful if the At this writing, no government agency or any other
air around the embryos is of poor quality. The direc- organization has developed specific guidelines for
tor can control most of the factors that influence an the quality of air and performance of the air-
embryo’s development, from the type of media to handling system in an IVF laboratory. This is for-
the amount of time the embryos are exposed to tunate for most of the laboratories presently used,
atmospheric air, room temperature, and various as their designs vary greatly, and few would meet
light sources. Air quality is a fixed component that strict guidelines such as those for an operating
is best addressed during the design of the facility. room. Conversely, it presents a challenge to indi-
As IVF centers continue to move into private viduals building a laboratory from “scratch” be-
practice settings, it is becoming increasingly impor- cause it is unclear what is necessary or optimal.
tant that the reproductive endocrinologist and lab- Operating rooms (ORs) and clean rooms are two
oratory director know as much as possible about rooms for which there are published specifications
the need for adequate laboratory design. Unlike in that can serve as a framework for IVF laboratories.
a hospital or medical center, where specialized The specifications for these room types overlap
engineers and contractors design and build clean considerably, as they both require ultra-clean envi-
rooms and operating rooms on a routine basis, the ronments. Specifications for these rooms are pub-
private setting is subject to misrepresentation and lished by the American Society of Heating, Refrig-
lack of sufficient knowledge to meet the special eration and Air Conditioning Engineers (ASHRAF)
needs of laboratory design. Having dealt with a every 4 years. The specifications for an OR are
“residential” engineer and contractor who promised listed in Table 7–1.

63
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 64

64 D.E. Morbeck

TABLE 7–1. 1995 ASHRAE Specifications for of the laboratory and its special HVAC system. This
an Operating Room is not to say that IVF cannot be done in a preex-
Positive pressure relative to adjacent areas by supplying isting office building with a standard HVAC sys-
15% excess air tem. On the contrary, many laboratories currently
100% Outside air exist in a suboptimal environment, and their pro-
Minimum of 15 air changes per hour grams are successful.
All air exhausted directly outdoors
No air recirculated in room units The purpose of the OR-type HVAC system in an
Filter efficiency of 99.97% for particles  0.3 m IVF laboratory is contamination prevention. Most
Variable range temperature capability of 68°–76°F environments are not inherently detrimental to fer-
Relative humidity 50–60% tilization and embryo development, although the
potential exists for acute or chronic air quality
changes that can adversely influence embryo qual-
ity. This is similar to the fact that surgery can be
performed successfully outside an OR, even in a
In addition to the items in Table 7–1, the hand- mobile army surgical hospital (MASH) unit in a
book states that an increase in the total air tent. Although on average surgery is successful, the
exchanges to 25 per hour while decreasing the per- morbidity and mortality rates are higher than would
cent of outside air to 20% is an acceptable energy- be expected in a controlled environment, such as in
saving alternative. Reducing the amount of outside an OR. The difference between an office building
air would also be advantageous in areas with excep- and an OR is not nearly as dramatic, but the prin-
tionally poor quality outside air. ciple is the same. Controls are needed to minimize
Similar to the OR, specifications for clean rooms chances of contamination by microbes or noxious
(1991 ASHRAE Applications Handbook) concen- gases.
trate on filtration, pressurization, and temperature The role of the HVAC system is fourfold: Deliver
and humidity control. The main difference between clean air to the room, remove contaminants from
the two is the different degrees of filtration required sources within the room, pressurize the room, and
for the different classes of clean rooms and a greater control temperature and humidity. The following
emphasis on the direction of airflow, not only in aspects of HVAC design are integral to the attain-
the placement of ducts but also the air pattern (i.e., ment of this goal.
unidirectional versus multidirectional flow).
For all practical purposes, meeting the specifica-
tions of the OR is sufficient for an IVF laboratory. Outside Air Delivery
Making the IVF laboratory a class 100 or even class A laboratory director’s two worst fears related to
1000 clean room would be expensive, laborious, and the ventilation system are microbial contamination
unnecessary. However, much can be learned by of a patient’s sample and introduction of toxic air.
studying clean room design and incorporating some In general, outside air is much “cleaner” than
of the concepts into the IVF laboratory design. For indoor air with respect to microbes. Nosocomial
example, placement of supply and return ducts infections in hospitals illustrate this phenomenon.
influences the direction and velocity of airflow in By using 100% outside air the “contaminated”
the room. Substantial airflow over a work surface room air is not recirculated, thereby avoiding the
would be undesirable, as the rate of evaporation of classic “airplane” effect of concentrating and redis-
solutions would increase, affecting the osmolarity tributing bacteria and viruses. Most particulate and
in addition to the temperature and pH. The opposite microbial contaminants are generated within the
situation would likewise be suboptimal, as no air- room from personnel. In contrast, outside air con-
flow over an area would increase the chance of par- tains few microbial contaminants relative to inside
ticulate or microbial contamination. air, so 100% outside air should keep bacterial or
viral concentrations at a minimum.
HVAC Design In general, neither nosocomial nor outside air
introduction of microbes should be a concern so
The heating, ventilating, and air conditioning long as adequate filtration is in place. Because
(HVAC) system, along with the air filters and con- HEPA 1000 filters are routinely used and recom-
trols, is the foundation of the IVF laboratory. When mended for ORs and thus IVF laboratories, the con-
considering a facility for an IVF center, any office tamination with the greatest potential to do harm is
building would suffice if it were not for the needs the amount of toxic gases. Gaseous contaminants
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 65

7. Basics of Laboratory Setup in the Office 65

can arise from many sources, both indoors and out- Regarding microbial contamination, even more
side. Thus the decision on the amount of outside air important than recirculation is the sterile technique
used should be based on the knowledge of outdoor of the laboratory personnel and the length of cul-
air quality, location of air intakes, and the return air ture. As more laboratories are culturing embryos
quality. These parameters vary by location. for 3 days instead of 2 days and even some doing
ASHRAE has two recommendations for the only blastocyst stage transfers, the chance of con-
amount of outside air in operating rooms. Where tamination increases.
codes require it, 100% outside air is used with 15 The other issue with recirculating air in the sys-
air exchanges per hour. Because using all outside tem is the potential for concentrating gases. Equip-
air substantially increases operating costs, it is rec- ment in the laboratory off-gases continuously owing
ommended that heat recovery devices be installed. to the oil and lubricants used in most motors, so
If the code does not require 100% outside air, 20% removal of this air is an important component of the
outside air with 25 air exchanges per hour is accept- ventilation system. Recirculating this air may
able. The amount of outside air used is one-third increase the concentrations of off-gased compounds
that when 100% is used. to an undesirable level. Additionally, there is the
The major disadvantage to using 100% outside potential that gases from other parts of the building
air is the unpredictable and uncontrollable nature enter the IVF laboratory suite and thus could be con-
of air pollution, which is mainly gaseous in nature. centrated in a recirculating air system. Verifying
Placement of the air intake duct is critical and, positive pressure relative to neighboring rooms is
according to ASHRAE, “should be located as far paramount to avoiding the movement of unwanted
as practical (on directionally different exposures) air into the laboratory. An extreme example of this
but not less than 30 ft from combustion equipment, phenomenon is the case reported by Cohen et al. in
stack exhaust outlets, ventilation exhaust outlets 1997 where anesthesia gases from a surgical suite
from the hospital or adjoining buildings, medical- located down the hall were being detected in the air
surgical vacuum systems, cooling towers, plumb- of the IVF laboratory. Lack of adequate positive
ing vent stacks, and areas that may collect vehicu- pressure and proper sealing was responsible for
lar exhaust and other noxious fumes. The bottom allowing the contaminants into the room.
of outdoor air intakes serving central systems There are two types of air contaminant: particu-
should be located as high as practical but not less late and gaseous. Both are serious and are depen-
than 6 ft above ground level or, if installed above dent on the amount and quality of the outside air
the roof, 3 ft above the roof level.” being used. Regardless of the amount of outside
If the building housing the IVF laboratory is a air used, appropriate filtration can rectify most air
single story high, the major concern should be quality problems.
vehicular exhaust and likewise if the laboratory is
located in a busy downtown area. One would think Air Filtration
that tall hospital buildings might be less subject to
Filtration provides a security blanket for the HVAC
adverse conditions so long as the ASHRAE guide-
system in an IVF laboratory, whether the labora-
lines were met, but at least one hospital had to
tory uses 100% outside air or 100% recirculated
install an expensive air filtration system because the
air. Even though contaminants are generated in the
outdoor air intake for the OR was located next to
laboratory, it is expected that they will not become
a helicopter launch pad.
concentrated in the system but, rather, be removed
It is important to analyze critically the concept
by the filter. Likewise, particulates and gases from
of 100% outside air. First, what controls are in place
outside air should be removed if adequate filtration
if there is a major change in either the amount of
is in place.
contamination generated within the room or in the
The most common type of filtration used in
quality of outside air? If a filtration system is in
HVAC systems is HEPA filtration, which removes
place that can effectively remove hydrocarbons and
particulates. Less common, but in some instances
other noxious gases from outside air, 100% outside
more critical, is the use of filters for removing
air is preferred. However, most systems cannot
gaseous substances.
guarantee that level of filtration. Will recirculation
result in an increased chance of microbial or HEPA Filtration
gaseous contamination? Probably, although HEPA
1000 filtration should counter any increased chance The HEPA filters are probably the most common
of microbial contamination due to recirculation. type of filtration used in IVF laboratories, primar-
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 66

66 D.E. Morbeck

ily because of their prevalence in the HVAC sys- filters, tests have indicated that filters last 8–13
tems in ORs. HEPA filters do not filter via small years. On average, investment in a new filter every
pore size; rather, small particles adhere to the other year accompanied by diligent changing of
numerous glass fibers that make up the filter. The prefilters should be more than sufficient for an IVF
rate of airflow over the filter is thus important, as laboratory.
the particles need time to interact with the fibers. Given the importance of HEPA filtration, the
Van der Waals forces, mechanical entrapment, or ability to monitor the pressure drop is valuable for
electrical effects retain solid particles. Liquid ensuring that the filter is functioning properly. A
droplets are also retained by surface tension force. manometer placed at the filter allows determination
The filters are rated based on their ability to remove of the pressure difference, which can be readily
0.3 m particles, with minimum efficiency of viewed and incorporated into the daily, weekly, or
99.97%. Because the rate of airflow is important monthly quality control routine.
to the function of the filter, a properly sized blower
is required to ensure adequate flow. The feet per Gas Filtration
minute (fpm) requirement at the filter face varies
based on placement of the HEPA filter. Two types of gas common to indoor air are corro-
There are two options for placing the HEPA fil- sive gases and organic gases. The most common
ter. First, the filter can be positioned directly after gases one can expect from outside air are the cor-
the blower and heating and cooling coils of the rosive gases, which include sulfur oxides and car-
HVAC. This system is advantageous in that there bon monoxide from automobile exhausts and
is only one filter to monitor, and it allows easy mon- ozone. Organics in outside air include chloroform
itoring and changing. The drawback to this system and several other vapors from petrochemical plants.
is if particulates are generated in the ducts they will Gas contaminants generated inside a facility are
make their way into the rooms. The other option is primarily organic, as is ozone. Contaminants can
to install terminal filters at the duct faces in the arise in the room from lubricants that vaporize if a
room. This system gives the most complete filtra- motor or bearing is overheated.
tion and is the preferred method, but it does not Because a major source of contaminants is new
allow for easy monitoring and a filter is required materials (e.g., new car smell), it is important to
for each duct opening. give the rooms time to off-gas. Tests have shown
For good performance and economy, a clean- that concentrations of some volatile organic vapors,
room filter system should include a 90–95% pre- such as aromatic and aliphatic hydrocarbons, can
filter upstream of the HEPA filter. The prefilter be as much as five to six times higher in new build-
should be changed on a frequent basis (monthly, ings than in old ones. The sources of these chemi-
depending on the quality of the outside air) to pro- cals are common building materials, including latex
long the life of the expensive HEPA filter. How caulking, telephone cable materials, particleboard
often must a HEPA filter be changed? It depends partition materials, paint, and adhesives. Some
on several factors but most importantly on how well polymers that are formulated with plasticizers emit
the prefilters do their job. The biggest advantage to vapors for long periods. Plasticized polyvinyl chlo-
the single filter system positioned immediately ride is a common product for flexible tubing and
after the HVAC is the ability to monitor the pres- thus can continue to emit vapors even after the facil-
sure drop across the filter. One criterion used for ity is no longer new.
determining if a filter needs to be changed is if the An example of the impact building materials can
pressure drop rises from the typical new filter pres- have on embryo development is shown in Table
sure drop of 25 mm H2O to a level of 50 mm H2O. 7–2. During construction in a suite adjoining one
Given this parameter, and with efficient use of pre- laboratory there was a dramatic effect of linoleum

TABLE 7–2. Ability of One-Cell Mouse Embryos to Develop to Blastocysts During

Construction of an Adjoining Suite
Date Construction activity in neighboring space Blastocysts (%)
6/26 Twelve days after use of water-based paint 100
7/3 During installation of floor tiles 6.8
7/7 After installation of in-room air purifier 89

Source: Adapted from Cohen et al., 1997.

3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 67

7. Basics of Laboratory Setup in the Office 67

tile adhesive on the development of one-cell mouse system, it should have been a constant volume sys-
embryos. This effect was overcome with an in- tem. This is a variable temperature system, where
room filtration unit. Interesting, none of the events all rooms get the same volume of air all the time,
that affected mouse embryo development altered regardless of their heating or cooling needs.
the fertilization rate. The other critical component for maintaining
positive pressure is the degree of sealing between
rooms and the ceiling. Door sweeps and gaskets on
Pressurization
pass-throughs are important to allow the room to
Pressurization is one of the two most important pressurize fully. Once a door is opened, the fact that
components, the other being filtration, for devel- the room was pressurized adequately ensures that
opment and maintenance of high quality indoor air the movement of air is out of the room and not back
in the IVF laboratory. Like filtration, the need for in. Openings in the ceiling can be equally critical.
positive pressure in the laboratory is influenced to Ceilings harbor both large amounts of dirt and off-
a certain extent by the quality of the surrounding gassed contaminants that can leak into a room if
air. In this regard, air surrounding the laboratory is positive pressure is not maintained. Ensuring that
similar to outside air in that it is beyond the con- a tight seal exists on all light fixtures, duct faces,
trol of the staff in the laboratory; hence positive and access doors prevents movement of ceiling air
pressure is again a preventive measure designed to into the room.
keep undesirable gases and particles from moving
from surrounding areas into the laboratory. Airflow
The ASHRAE guidelines for operating rooms
Air turbulence in the room should be kept to a min-
state that positive pressure should be maintained by
imum to avoid mixing of dirty and clean air. Proper
supplying at least 15% more air to the OR in rela-
placement of supply vents and return ducts help
tion to adjacent rooms. The IVF laboratory presents
maintain a relatively steady stream of clean, filtered
a rather unique situation, however, in that in most
air in the room. An effective style used extensively
centers there is an OR for performing egg retrievals
in clean rooms is unidirectional airflow, whereby
adjacent to the laboratory, and it also requires pos-
the air supply is spread evenly over one surface of
itive pressure. Which room has priority? Although
the room, and the opposite surface is the air return
equal pressure between the two rooms would result
(e.g., ceiling and floor). Although this would be the
in a minimum amount of air movement into the lab-
ideal, it requires a more intensive duct system that
oratory, conventional wisdom is that the laboratory
is only required for the cleanest of clean rooms.
should receive preferred treatment and therefore the
Multidirectional airflow suffices for most labo-
pressure should be positive relative to that in the
ratories, although supply and return vents should
OR. This approach results in a gradient of pres-
still be placed in a way to minimize the number of
sures, with the laboratory receiving 15% more air
“dead” zones or high velocity areas. Supply vents
than the OR and the OR receiving 15% more air
should be of the laminar flow type, where air from
than the hallway or adjacent rooms.
the duct goes into a mixing box and then is pushed
The ability of a system to maintain positive pres-
evenly through pinhole-size openings. This results
sure is important. First, though, let us note the dif-
in a relatively gentle introduction of air into the
ferent designs of air delivery systems. The system
room. As the air moves down to the floor, it should
designed for the facility shown in Fig 7–1 was a
be directed by the pull of return ducts located close
VVT system, which stands for variable volume and
to the floor. This design results in a steady move-
temperature. With such a system, each room had
ment of most of the air in one direction.
its own thermostat and called for heating or cool-
ing whenever its temperature fell outside the ther- Air Volume
mostat limits. With all rooms on the same system,
the order in which rooms received heating or cool- Calculating the amount of air required for a facil-
ing was determined on a first-come first-served ity is best left to an engineer. Awareness of what
basis. If a room did not need heating or cooling, its factors are involved with this computation is help-
damper closed and the room received nothing. Even ful for verifying that the job is being approached
though the IVF laboratory was designed to receive correctly. An inappropriately sized system can
sufficient airflow to maintain positive pressure result in a multitude of factors, not least of which
when the damper was open, if the room tempera- is the inability to deliver an adequate amount of air
ture was satisfied the damper closed and the room to maintain positive pressure in the laboratory.
would go into negative pressure. Instead of a VVT Other factors involved with air volume require-
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 68

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

68
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 69

7. Basics of Laboratory Setup in the Office 69

ments include the number of air exchanges required Heating and cooling needs are influenced by sev-
per hour, and indirectly, the filtration system eral factors and must be considered during the
employed. The HVAC must be sized to deliver the design of the system. If the system is engineered
desired number of air exchanges to the room, which to deliver 100% outside air, a much larger number
in most cases is 15–25. In addition to the blower of heaters and cooling coils/condensers are needed
size, the duct size is important for this factor, as a compared to a system that uses only 15% outside
limit is reached regarding the amount of deliver- air. The other primary factor to consider, particu-
able air. larly for cooling needs, is the heat load of the facil-
An undersized system can also result in insuffi- ity. Variables that must be considered are the loca-
cient airflow across the HEPA filter and conse- tion of the rooms relative to direct sun, the number
quently inadequate filtration. This has more to do of individuals working in the facility, and the cumu-
with pressure at the filter face. Because there is such lative heat production of the equipment and lights
a dramatic drop in pressure across the filter, the fact in the rooms. If an HVAC engineer does not ask
that high efficiency filters are in place is important for these data, expect the laboratories to be hot dur-
when calculating how large the system must be to ing the summer.
deliver enough air to pressurize the room and pro- Humidity control is much less straightforward
vide the necessary exchanges. and not as commonly addressed by IVF laborato-
ries. The goal of a humidity control system should
be to provide 50% relative humidity throughout the
Temperature and Humidity Control
year. To do this, a system must be able to dehu-
Relative to filtration and positive pressure, temper- midify during the summer months and humidify
ature and humidity control are secondary and have during the winter months (although this is largely
more to do with technician comfort. This fact dependent on climate). Why 50% relative humid-
should not be taken lightly, however, as the ability ity? A 50% humidity level takes into consideration
of the individuals in the laboratory to perform opti- the comfort of the staff and the optimal conditions
mally is affected by their environment. A case can for the specimens.
also be made for the importance of temperature and Humidity levels that drop significantly below
humidity in regard to how it affects specimens 50% (e.g., 35%) are undesirable for a number of
while they are in the incubators and while being reasons. First, the amount of static electricity
exposed to room air. increases. Because shoe covers are usually standard
A balance must be struck between what is best fare for IVF laboratories the staff become easily
for the gametes and embryos and what is comfort- charged and is shocked throughout the day. Sec-
able for the staff. Certainly removing embryos from ond, low room humidity results in a faster reduc-
the incubator exposes them to lower temperatures tion in humidity in the incubators, especially when
and humidity in the room, as the incubators main- the doors are opened repeatedly during oocyte
tain a temperature of 37°C with high humidity retrieval or an intracytoplasmic sperm injection
(80%). The best scenario for the embryos would (ICSI) case. This is a concern for two reasons. If
be the same conditions in the room. (To take it one the culture is an open system (i.e., without oil over-
step farther, 5% CO2 would make the room one lay), evaporation occurs more rapidly. Also, the
large incubator.) Because this is unrealistic, a com- CO2 content in the incubator is a function of the
promise must be reached. amount of CO2 added, the relative humidity, and to
The ASHRAE guidelines for ORs state that the a small extent the temperature. If the humidity
HVAC system should be able to maintain room decreases drastically owing to repeated opening of
temperatures of 68°–76°F and 50–60% relative the door in a low humidity room, most incubators
humidity. Temperature control is relatively straight- cannot compensate for the lower humidity and thus
forward, although the ability to control the tem- take longer to recover to the set-point CO2 level.
perature in each room is usually desired. To deliver There are several methods for increasing the
individual-room temperature control in a system humidity in a laboratory. A direct approach is to
that provides a constant air volume, each room must put humidifiers in the room. This approach is fea-
have its own HVAC system (e.g., mounted on the sible though not without drawbacks. First, a large
roof above each room), or the HVAC must produce humidifier is required if a large room is to be used,
air at a constant temperature (usually 55°C) that is and it then requires its own purified water supply.
then tempered by duct heaters located just upstream In addition to the size of the room, the fact that the
from the room duct. In most facilities the latter sys- air changes 15–25 times per hour and is dry due to
tem is the only one that is practical. heating adds to the capacity requirements of the
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 70

70 D.E. Morbeck

humidifier. Thus if a small room is in need of Each room in the laboratory should have indi-
humidification, an in-room humidifier offers a vidual temperature control and either particulate
viable alternative to central humidification. It is (HEPA) filtration on each duct face or in the main
important to keep in mind that a humidifier can be system (along with gas-phase filtration). In addi-
a breeding ground for microbes and thus must be tion, the HVAC system should have the capacity to
monitored closely (preferably added to the daily humidify and dehumidify, and there should be a
quality control checklist). control panel where these parameters can be viewed
The most common approach to humidification is and modified if necessary. At least one person
placement of a humidifier directly in the HVAC unit. working in the laboratory should have working
Humidification can be accomplished with ultrasonic, knowledge of the HVAC system and its control
electronic steam canister, and nozzle (air and water components. In lieu of central HVAC that can per-
mixed) type humidifiers. Although steam generation form the necessary filtration, there are a few in-
is probably the most common largely due to its broad room purifiers available commercially or that can
availability, techniques such as ultrasonic humidifi- be made to order.
cation offer an alternative with several advantages.
For instance, steam generation is an energy-inten-
sive process, as water must be heated to boiling to Room Construction and Design
generate the steam. Ultrasonic humidification uses
less than one-tenth the energy to produce the same The goal of constructing an IVF laboratory is to
amount of humidity. Ultrasonic humidification also build an environment that has few if any factors
produces a fine mist of approximately 1 m diam- that might directly affect gamete/embryo viability.
eter that is quickly absorbed into the air stream. This It is critical to consider each component used when
system minimizes the amount of water that con- building the rooms and evaluate each for its poten-
denses on the duct work. Water in the duct work pro- tial effect on the quality of the environment.
vides a site for microbial growth and causes rust if
the duct is not constructed of stainless steel. Small Floors, Walls, Ceilings, Cabinets
particle sizes of water are necessary to minimize
these undesirable side effects of humidification. A primary concern during construction of the phys-
Although humidification requires the addition of ical structure of the laboratory is to avoid the use
components to the HVAC system or in the room of materials that will off-gas for an extended period
itself, dehumidification is usually accomplished by following completion of the construction. Given the
the basic components of the HVAC units. High propensity for construction to run behind schedule,
humidity (65%) is undesirable because it makes most programs are ready to start doing IVF cases
conditions uncomfortable for the laboratory staff, as soon as the building is complete. Depending on
and it provides an environment that increases the the materials used, it is possible that the room will
chance of microbial growth on walls and other contain unacceptable levels of noxious gases for
surfaces. months following the completion of construction.
If the HVAC system is sized appropriately, de- Because it is unlikely that the managers of the pro-
humidification should occur automatically, without gram would agree to wait 3–6 months to allow the
the need for additional equipment, much like the room to off-gas, it is best to choose materials
dehumidification obtained with air conditioning in wisely.
homes. Although air conditioning alone can dehu- All walls and ceilings should be constructed of
midify adequately in most cases, there are instances plaster and painted with an epoxy paint or baked
where cooling is not needed but humidity is high enamel polyester. This serves two purposes. First,
outside (e.g., a cool, rainy day) and so the room air the finished surface of the walls and ceiling are
may become overly humid. A system that allows smooth, nonshedding, easy to clean, and chip-resis-
complete control of humidity, both increasing or tant. This minimizes the amount of particulates that
decreasing it at will is preferred. The general ap- shed from the surface or become attached. This is
proach to centralized dehumidification is to cool air particularly important for the ceiling, as drop ceil-
more than normal (45°F) and then reheat it to 55°F, ings are a source of dirt and dust. Second, epoxy
which is the temperature of the air in the duct. Of paint does not off-gas appreciably and thus is not
course, to obtain the correct temperature and hu- a concern for its effect on air quality.
midity, a balance must be reached between this Cabinets can be another source of gaseous pol-
heating and cooling cycle, and this is usually con- lutants, particularly those made of manufactured
trolled electronically. wood products such as particleboard. Cabinets
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 71

7. Basics of Laboratory Setup in the Office 71

should be constructed of either solid wood or metal. exposure. In the same study, the effects of fluores-
In the case of wood, certain varieties such as oak, cent light were prevented with proper filtering.
birch, and beech off-gas acetic acid, aldehydes, and The mechanism of action appears to be photox-
alcohol. The amount of glue and adhesives should idative products produced by the fluorescent light,
be kept to a minimum during construction. Both which results in the production of reactive oxygen
wood and metal cabinets should be painted with species such as H2O2 in the presence of atmo-
epoxy or baked enamel polyester. spheric oxygen. These products then act on DNA
Counter tops must also be easy to clean, be chip- to cause chromatid breaks and exchanges. Studies
resistant, and must not have the propensity for with mammalian cells have confirmed this hypoth-
haboring contaminants. For this reason, the counter esis, as inhibiting these reactions chemically or
of choice is corian or similar material. One should enzymatically prevents DNA damage in cells
stay away from the black counters found in many exposed to fluorescent light.
research laboratories, as they tend to shed their Given the strong evidence for effects of light on
charcoal components. eggs and embryos, fluorescent light should be
The preferred flooring is seamless sheet vinyl or avoided in the laboratory. It goes without saying
epoxy. The floor surface should have an integral that there should be no windows in the laboratory.
base flashed up the wall at least 4 inches. This Incandescent lights with dimmer controls are the
allows for complete cleaning of the floor with min- ideal and should be kept as dim as possible while
imal amounts of water seepage into cracks. The gametes and embryos are handled. Some argue that
floor should also be flashed onto the cabinets so the relatively brief exposure time typical in IVF
water cannot seep under the cabinets and become laboratories makes lighting a moot point. Regard-
a source of microbial contamination. less, the potential exists, particularly as eggs and
embryos are exposed to light for longer periods dur-
ing micromanipulation.
Lighting
It has long been known that visible light can be Special Equipment
detrimental to in vitro cultured cells, including
gametes and embryos. In a classic study on the Most laboratory directors have a good idea of the
effects of various wavelength light on the ability of equipment they need to furnish the laboratory ade-
hamster eggs to complete meiosis and develop quately. Nonetheless, there are a few items that are
pronuclei normally, Hirao and Yanagimachi found worth mentioning because of their special require-
that light with wavelengths shorter than 470–480 ments. Whenever gametes and embryos are viewed
nm (e.g., fluorescent light) inhibited eggs from microscopically, they should be placed on a warmed
completing meiosis and undergoing normal pronu- microscope stage. Because all of the most popular
clear development (Table 7–3). A reduction in nor- microscope brands have heated stages or can have
mal development was seen with 15 minutes of them added, availability and source are not issues.
exposure to fluorescent lights, whereas incandes- An alternative to a heated stage is the use of a Hoff-
cent lights were without effect at this duration of man K-System laminar flow hood with a heated

TABLE 7–3. Comparison of the Detrimental Effect of Light from Four

Light Sources
% Eggs undergoing normal meiosis and pronuclear development
Length of Incandescent Fluorescent UV
irradiation (min) lamp lamp lamp Sun
0.25 43.0
1.0 7.5
1.5 0
5 66.7
10 51.0
15 100.0 84.5 10.0
30 69.8 16.0 4.1
60 35.5 0 0

Source: Adapted from: Hirao Y, Yanagimachi R. Detrimental effect of visible light on meio-
sis of mammalian eggs in vitro. J Exp Zool 1978;206:365–370.
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 72

72 D.E. Morbeck

bench. A water bath/circulator moves warm water Salient features in andrology include a pass-
through the work surface to give a large, homoge- through to the collection room bathroom, a biologic
neously heated work surface that is especially use- cabinet for the preparation of sperm for either
ful during egg retrievals. intrauterine insemination (IUI) or IVF, a fume hood
During the design and construction of the labo- for histology, and a 80°C freezer for storage of
ratory it is important to consider placement of the serum and frozen reagents. The laboratory includes
hood and other laminar flow hoods (e.g., those for two microscope stations on opposite sides of the
making media) and the ability to move the hoods room, a computer for data management and report
into the room. One may find that once the cabinets writing, and a CO2 incubator.
are installed in the rooms space is not adequate for Although entry to the andrology laboratory is
moving in a 6 foot long hood. Therefore planning from the inside corridor, there are two rooms adja-
an installation schedule is important. cent to it: a liquid nitrogen storage room and the
If flammable or volatile liquids are to be used, cryolaboratory/microtool preparation laboratory.
which is necessary for histology, a fume hood is This was specifically designed in this manner to
needed. There are portable units that are suitable if allow the cryolaboratory to act as a buffer between
the facility has limitations in putting in a perma- the “dirty” andrology laboratory and the HEPA fil-
nent hood. Ideally, a fume hood should be installed tered IVF laboratory, which includes the cryolabo-
with its own exhaust duct that goes directly out- ratory. The Ln2 storage room is positioned to allow
doors. If the blower on the hood is used frequently, direct supply of liquid nitrogen into the cryolabo-
the HVAC engineer should be alerted that there will ratory through the wall plus direct access outside
be a need for makeup air in that room. for deliveries.
The HEPA-filtered HVAC system in this facility
ventilates four rooms: the cryolaboratory, embry-
Laboratory Design ology including media preparation, and the adjoin-
Design of the laboratory is dictated largely by the ing two procedure rooms. Air volume is set so
personal preference of the laboratory director embryology has the highest pressure, followed by
within the constraints of the space allocated. Fig- the two procedure rooms and the cryolaboratory,
ure 7–1 illustrates one laboratory design. Similar to with andrology and the hallway the lowest pressure
any building venture, there are always things that areas. This gives the desired waterfall effect of air
post de facto would be done differently; nonethe- movement out of the critical areas.
less it represents a good example of a working lab- Embryology has two pass-throughs to each pro-
oratory. The space shown comprises roughly one- cedure room and a media preparation room within
third of the facility. it. A 6-foot Hoffman K-system hood houses one
Several aspects of the design presented in Fig- stereoscope used during oocyte retrievals and for
ure 7–1 are worth discussing. Embryology and loading embryos for transfer. The goal of the design
andrology combined comprise approximately 750 of this area of the laboratory is to provide the short-
sq ft. Although both procedure rooms are 12  12 est distance between the culture dish and the patient
feet, the transfer room is oversized and could have for egg retrievals or embryo transfers. A second
been considerably smaller. The HVAC room is 9  stereoscope located on the counter on the opposite
20 feet and could have been larger. It contains three side of the room is used for freezing and thawing
air-handling units with one dedicated strictly for embryos. The inverted scope with micromanipula-
IVF and procedures. It also includes the vacuum tors is positioned next to the hood and includes a
pump. Across the hall from the HVAC room is the shelf for audiovisual equipment. In the middle of
gas room containing manifolds for oxygen, CO2, embryology is a partition that houses the gas lines
mixed gas, and medical air if needed. This room is that supply the incubators. The media preparation
located next to an outside door so tanks can be room contains equipment needed for making
changed with minimal traffic inside the building. media, including an osmometer, pH meter, and bal-
In most IVF centers, a separate chemistry labo- ance. There is also a 3-foot laminar flow hood and
ratory may not be necessary if only hormone a refrigerator for media storage.
assays are performed on a single machine. The The middle corridor of the building houses a large
chemistry laboratory in this facility served a gen- supply room, technician office space, and clean and
eral obstetrics/gynecology program and thus re- dirty utility rooms where the oven and autoclave are
quired its own space for hematology, serology, and located. All are within a short distance and at most
chemistry equipment. two doors away from the laboratories.
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 73

7. Basics of Laboratory Setup in the Office 73

Plumbing: Gas and Water uid hydrocarbons must be nondetectable and gas-
eous hydrocarbons present at 25 ppm, pressure
One of the biggest advantages of constructing a dew point at 50 psig must be 4°C, and the amount
new IVF laboratory is the ability to place gas out- of permanent particulates must be 5 mg/m3 at 1 m
lets and distilled/deionized water outlets strategi- size or greater.
cally throughout the laboratory. This is particularly In addition to these basic requirements of a med-
true in reference to gas outlets, as the ability to have ical grade compressor system, other factors merit
a centralized gas room obviates the need for cylin- consideration. Similar to the HVAC system, the
ders in the laboratory proper. quality of medical grade air fluctuates based on the
supply of ambient air to the compressor unless there
Gas Supply for Incubators and Benchtop is adequate gas phase filtration. In addition, the
design of the system requires that the air go directly
The major focus of the earlier section on the HVAC from a gas supply line to the incubators, bypassing
system was on air quality. Although room air qual- the air pump that is normally used for room air. Air
ity is important, even more important is the qual- pressure delivered to the incubators must be 5–15
ity of the air in the incubators. This is true because psi, depending on the brand of incubator. This
more than 97% of an egg/embryo’s time in the lab- design requires the security of having a backup
oratory is spent in the incubator, which places compressor to ensure there is no breach in the deliv-
enormous importance on the source of air. ery of air to the incubators should one compressor
There are at least three ways to supply air to the fail. This point is critical because in contrast to a
incubators. This discussion focuses on the delivery compressor for medical air, CO2 is most commonly
of air to the incubators where the mixture of gases supplied to incubators via compressed air tanks and
in the incubators is 95% air and 5% CO2. Reduc- would not be influenced by a compressor failure.
ing the oxygen tension in the incubators is an alter- This situation would then result in a rapid increase
native approach, which presents its own set of chal- in the CO2 concentration in the incubator if no
lenges (not discussed here). backup compressor is in place.
Most commercial incubators are designed to An alternative to room air and compressor air is
obtain air from the room via a pump and CO2 from medical grade air supplied in compressed air tanks.
a gas cylinder. In nearly all cases the gas line going The advantage of this approach is primarily short-
into the incubator is fitted with a 0.2 m pore size term cost compared to a duplex compressor system
filter for sterilization purposes. This system relies equipped with adequate filtration. Other advantages
on the HVAC system to purify the air and provide include the fact that it requires less space than a
enough air exchanges to remove contaminants that duplex compressor, is not prone to failure, and
build up in the room over time. This system is at does not require adding more components to the
the mercy of the function of the HVAC system, HVAC system (which in most cases requires a large
which in turn is influenced greatly by the quality amount of space). The major disadvantage to this
of outside or return air. If gas phase filtration is not system is that the quality of the air within the tanks
used, this setup is particularly vulnerable to the is controlled by the individuals and the systems pro-
wide fluctuations of air quality in urban environ- viding the air from the tanks, for which there are
ments where vehicular exhaust is a major pollutant. no guarantees of consistency. Although by defini-
However, given an appropriately designed HVAC tion medical grade air must meet the guidelines set
system with adequate filtration and verification pro- forth by the NFPA, it is possible that tank-to-tank
cedures, room air can be a good source for incu- variation can occur and that an individual tank can
bator air. contain contaminants. For this reason, it is a good
An alternative to room air is the use of air lines idea to install line-filters of charcoal and potassium
that deliver air from a medical air compressor permanganate to remove any gaseous contami-
directly to the location of the incubators in the lab- nants. The same can be said for medical grade CO2.
oratory. A medical air compressor is designed to However, because CO2 comprises only 5% of the
exclude oil from the air stream and compression air in the incubator it is not as much a factor if the
chamber and does not add any toxic or flammable remaining air is supplied from the room or from a
contaminants to the compressed air. According to generator. Finally, the other major drawback to
the National Fire Protection Association (NFPA) using compressed air tanks for the incubators is the
“Standard for Healthcare Facilities,” 1999 Edition, labor-intensive nature of switching tanks to keep
medical air must comply with the following: Liq- the supply current.
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 74

74 D.E. Morbeck

The best supply of air for incubators is from a The grade of water to use for media preparation
duplex compressor with gas phase filtration. Most is the National College for Clinical Laboratory
hospitals have a system of this type and can deliver Standards (NCCLS) type I water. In addition to
this air directly to the laboratory. Because this can using the highest purity standards of the water
be both cost and space prohibitive in the private set- grades, the water should be used immediately after
ting, the next best system is the use of room air production to avoid its inevitable degradation to a
with gas phase filtration on the HVAC and at least lower type of water. Because pure water leaches
15 air exchanges per hour. In the event that none components out of storage vessels (e.g., lead from
of the aforementioned options is possible, there are glass), it should not be stored. Once it is used to
commercially available in-room purifiers that can prepare media, its osmolarity precludes these
remove gas contaminants via activated charcoal changes in quality due to storage. This is not to say
filtration. that all purchased water is bad. On the contrary,
The final type of gas plumbing that is useful in there are several good sources of water for IVF;
an IVF laboratory is supply of tri-gas (95% air with and because the water is stored in a relatively inert
5% CO2) directly to the benchtop for gassing cul- plastic or glass bottle the water maintains its qual-
ture dishes during procedures. Most laboratories ity. The main problem with buying water is unless
use this type of gas, although many keep the tank you have an established program you have no way
in the room near the point of use. Providing a sep- of testing the water against proven high quality
arate room for CO2 and 95/5 tank storage and hav- media. So even if the water passes all quality con-
ing pipes deliver the gas to the locations needed trol standards, there are no guarantees that it will
avoids the problems associated with storing and perform well in IVF.
exchanging dirty tanks in the laboratory proper. If a water purification system is used, it should
One final note is needed on the CO2 supply (and be located by the sink where dishwashing is done
medical grade air from cylinders, if used). The pre- and close to the media preparation area. Most sys-
ferred configuration for maintaining a constant sup- tems include pretreatment of water using reverse
ply of CO2 is use of a dual manifold. The manifold osmosis (or deionization) followed by ultrafiltra-
keeps two separate supplies of gas: a current one tion. The first phase of treatment, reverse osmosis,
and a reserve supply. Once the pressure from the is a broad-based purification technique that re-
current supply side drops below a certain level, the moves more than 93% of inorganic ions, more than
manifold switches to the other tanks so the supply 99% of dissolved organics over 300 MW, more than
is automatically continued. Once this switch 99% of particles, and more than 99% of micro-
occurs, an alarm is set that notifies the laboratory organisms. The ultrafiltration process removes the
the tanks have switched. The empty tanks can then remaining microorganisms and results in two- to
be replaced. four-log reduction of pyrogens. The final product
of these two purification steps is 18 megohm-cm
Vacuum resistivity water that is ideal for IVF.

A vacuum line system is desirable if the laboratory

director prefers to make media in-house. The vac- Electrical System and
uum is used for filtering media. Because many lab-
oratories now use premade media, this may not be Device Monitoring
necessary; however, most facilities require a vac-
uum system for patient care. Thus running addi- Much of the equipment in the IVF laboratory is
tional lines to strategic locations in the laboratory electronically controlled and therefore should have
could prove useful in the future. protection against power surges, fluctuations in
power quality, and power outages. A system that
rapidly notifies someone if there is a device mal-
Water Purification function is critical for IVF laboratories.
High purity water is required in the IVF laboratory
for media preparation. Pure water should also be Power Reliability, Quality, and Backup
used to wash glassware and to fill waterbaths and
humidity pans from the incubators. Because it is Any equipment that contains a computer is subject
possible to purchase high quality water and pre- to abrupt, periodic loss of function as a result of
made media, a water purification system is needed changes in electrical current. Although it is now
only if the laboratory director wants one. commonplace to have all personal computers on
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 75

7. Basics of Laboratory Setup in the Office 75

some sort of surge protector or even an uninter- as well as controlling temperature and humidity. A
ruptible power supply (UPS), it is probably even short power outage would have a minimal effect on
more important to protect laboratory equipment these factors, as would a long outage during non-
that has microprocessors and performs essential working hours. Given that the incubators are on
functions. backup power, they continue to function and func-
The two types of equipment that may be the most tion normally if they have a good air source. If the
critical to protect are controlled-rate freezers and incubators obtain their air from the room, however,
infrared-CO2 sensor incubators. If there is a power the quality of the air is critical, especially during a
surge or a variation in current during a programmed prolonged power outage. The final decision about
embryo freeze, the rate of freezing is altered, which putting the HVAC system on backup power should
may affect the viability of the embryos. This can be made when considering the history of power
be prevented with a UPS. A similar situation exists reliability to the area and the likelihood of a major
with infrared sensor incubators. This type of incu- outage.
bator gives more reliable and rapid adjustment of
CO2 concentrations than incubators that use timed
injections of CO2. However, it is prone to failure Instrument Monitoring
owing to power fluctuations that would not affect A state-of-the-art monitoring system provides some
other incubators. A failure in the CO2 sensor results peace of mind for the laboratory director. There are
in rapid loss of the proper CO2 concentration and two main functions the system can perform: a
incapacitates the incubator until the sensor board is switch for out-of-normal-limit detection and ana-
replaced, at a substantial cost. If a facility has sev- logue values for continuous monitoring of actual
eral incubators, failure of this type would be man- levels. In both cases the system notifies someone
ageable unless it occurred at night, at which point if a value is beyond its set-point. The equipment
it would provide a major inconvenience. This loss that should be monitored and the degree of moni-
of function can be prevented in most cases with a toring are listed in Table 7–4.
UPS. The importance of monitoring these devices and
Complete power outages due to a variety of being notified immediately, by phone or beeper,
causes are not uncommon and thus require alter- goes without saying. The utility of analogue meas-
native power supplies. In most cases a propane- or urements in the incubator is the ability to determine
natural gas-operated generator is used to supply recovery times and the effects of varying amounts
backup power. The challenge in a private setting is of use (i.e., door opening frequency). If this level
determining which outlets and systems should be of monitoring is not desired, a switch on incubator
powered by the generator to allow continued func- temperature and CO2 can be used instead.
tion of vital systems and equipment yet minimiz-
ing the size and cost of the generator.
In general, all outlets and lights in the IVF lab- Security Systems
oratory and procedure rooms should be on backup Several security systems are available. A security
power. If an ICSI case or a retrieval is being per- system should be in place for the entire building,
formed at the time a power outage occurs, rapid including window break detectors, motion detec-
restoration of power is essential. Likewise, if a tors, and door opening sensors. This establishes the
power outage occurs that lasts a few hours in the general security that is essential for not only the
middle of the night, it is critical that the incubators
are able to maintain temperature and CO2 content.
It should be noted, however, that generator power TABLE 7–4. Laboratory Systems Monitored by a
backup is not immediate and thus can influence Simple Out-of-Range Switch or Analogue Detectors
some systems, such as a programmable freezer. Switch
This is one more reason to use a UPS with certain Room temperature
equipment to prevent power fluctuations. Room humidity
Given the size of the HVAC system, determin- Refrigerator and freezer temperatures
Liquid nitrogen levels in tanks
ing if it should be on backup power is not easy due CO2 line pressure
to the amount of energy it uses. In general, if an Medical air line pressure (if used)
HVAC system is included in the emergency power Analogue detector
setup, the size of the generator is twice that if it is Incubator temperature
Incubator CO2 concentration
not included. The job of the HVAC system is fil- Incubator humidity
tering, ventilating, and pressurizing the laboratory
3051_Seifer_07_p63-76 11/5/01 9:46 AM Page 76

76 D.E. Morbeck

laboratory but the entire building. Entrance into the proves useful for discussing progress during an egg
building should require a key and a code to disarm retrieval. Although such a system can be added at
the security system. any time, it is best to plan ahead and have it in place
The most important area in terms of security is during the construction of the building.
the IVF laboratory and the location of the liquid
nitrogen tanks. Separate locks with access limited
to key personnel are important to maintain the secu- Conclusions
rity of incubating and stored embryos. This gives
one additional layer of defense should a break-in This chapter describes most of the critical compo-
occur, plus it should prevent someone with general nents of laboratory design and construction, includ-
access to the building from entering the laboratory ing specifications that at this time are neither stan-
(i.e., cleaning personnel). dard nor regulated for IVF laboratories. Knowledge
of these factors is essential for the reproductive
endocrinologist or laboratory director planning a
Computer Capabilities new facility or redesigning an existing one.
Without question, the single most important
No new facility should be built without the latest component of a new or redesigned facility is the
technologies of computer interconnectivity and indoor air quality for the IVF laboratory and the
wiring. Every room should have telephone and data incubators. Indoor air quality is influenced by
jacks for computers. Even if a practice does not nearly all major design components of the labora-
have a large computer network or even plans to tory, including the HVAC system, engineering of
install one, being prepared is worth the minimal the system for proper pressurization, temperature
expense involved. and humidity control, physical layout and con-
Several IVF computer programs are on the mar- struction quality of the laboratory to maintain pres-
ket that are networkable and allow data entry from surization, and choice of building materials to min-
many terminals. This is important for IVF given the imize off-gassing of noxious fumes.
need to report data to the Centers for Disease Con- Although many of the important design decisions
trol (CDC). Placing laptops or desktop computers can be arrived at intuitively, fundamental knowl-
in the laboratory allows convenient entry of data edge of the workings of an HVAC system and
that otherwise would have to wait until a more suit- related variables offers a measure of security. This
able time. In addition to the ability to access the security translates into the ability to make an edu-
database, much of the equipment in laboratories cated assessment of the validity of the construction
now has the ability to export directly to a personal and design plans, or if nothing else, the ability to
computer or be monitored by one. Thus the issue recognize when a second opinion is in order.
of wiring is an important one.
Suggested Reading
Audiovisual System American Society of Heating and Refrigerating and Air
Conditioning Engineering. Clean spaces. In: 1995
The ability to project images from the laboratory
Applications Handbook. Atlanta: ASHRACE, 1995.
and procedure rooms to other parts of the building American Society of Heating and Refrigerating and Air
is useful for educational purposes and patient Conditioning Engineering. Health care facilities. In:
involvement. A cable system in the building makes 1995 Applications Handbook. Atlanta: ASHRACE,
this possible. Thus ultrasonographic images from 1995.
eggs or embryos can be broadcast. We typically do Cohen J, Gilligan A, Esposito W, Schimmel T, Dale B.
this during egg retrievals and embryo transfers; for Ambient air and its potential effects on conception in
the latter, patients can view their embryos being vitro. Hum Reprod 1997;12:1742–1749.
loaded into the catheter. A video film of the Cooper EC. Laboratory Design Handbook. Boca Raton:
embryos can also be prepared to show patients CRC Press, 1994.
Lieberman A. Contamination Control and Cleanrooms.
more detail than the printed pictures, and they pro-
Problems, Engineering Solutions, and Applications.
vide a more complete picture of the embryos for New York: Van Nostrand Reinhold, 1992.
future reference. May JV, Hanshew K. Organization of the in vitro fertil-
The audio portion of the system includes a stan- ization and embryo transfer laboratory. In: Keel BA,
dard sound system for music in every room with Webster BW (eds) CRC Handbook of the Laboratory
volume controls. In addition, a wireless micro- Diagnosis and Treatment of Infertility. Boca Raton:
phone setup for the physician and laboratory staff CRC Press, 1990:291–327.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 77

8
Anesthesia in the Office
Angeline N. Beltsos

The advent of outpatient surgery revolutionized the guided follicle aspiration can be performed easily
medical world during the last century and added in the outpatient setting.
new dimensions to both surgery and anesthesia.
Ancient Greeks and Egyptians routinely practiced
outpatient anesthesia; they used alcohol and opi-
oids for pain relief in the home. In 1842 Crawford
Types of Anesthesia
Long made a major contribution to surgery by uti- General Anesthesia
lizing ether for the first clinical general anesthesia
case, which interestingly occurred in the outpatient General anesthesia involves hypnosis, amnesia,
setting. Most surgeries were then performed in the analgesia, and possibly muscle relaxation. Induction
inpatient hospital. By the early 1900s the first out- should be pleasant and rapid (one arm–brain circu-
patient centers opened, and over the next 60–70 lation time). Sedative, hypnotic, or opioid drugs
years ambulatory surgicenters, separate from the given beforehand may help relax the anxious patient
hospital operating room, began to appear. Out- but may also prolong recovery from the general
patient surgery initially was performed on healthy anesthesia. In the ART setting, some choose not
patients and expected to be uncomplicated and to give anything preoperatively so as to minimize
brief. As experience has expanded it now includes oocyte exposure and allow speedier recovery. In-
less healthy patients and longer, more difficult pro- duction of anesthesia is usually accomplished with
cedures. The consequential development of ambu- rapid-acting intravenous (IV) anesthesia such as
latory surgery has provided a major tool to do more barbiturates (thiopental, thiamylal, methohexital),
with less for many surgical specialties including ketamine, propofol, or etomidate. The opioids fen-
infertility. Furthermore, with the explosion of re- tanyl, sufentanyl, and alfentanil can induce anes-
sources and technologies for the treatment of infer- thesia, but when used at higher doses to induce
tility, most of these procedures can be performed unconsciousness they may cause complications
in the outpatient setting. (chest wall rigidity, delayed recovery, postoperative
Advanced reproductive technology (ART) cen- respiratory depression, nausea). For patients under-
ters provide treatment for infertility that may in- going a tubal transfer procedure [gamete or zygote
clude in vitro fertilization (IVF), encompassing intrafallopian tube transfer (GIFT, ZIFT) Tubal
care for both male and female infertility. Oocyte Embryo Transfer (TET)], decreasing the incidence
retrieval using transvaginal ultrasonography is fre- of emesis is important so as not to disturb the trans-
quently performed allowing visualization of folli- ferred products.
cle borders without blind entry into follicular Maintenance of anesthesia can be done by con-
spaces as occurs with a laparoscopic approach. In tinuing the intravenous medicine with intermittent
addition, less anesthesia can be given, which may boluses or continuous drip or by adding inhaled
decrease oocyte exposure to anesthetics. The in- anesthetics. Inhaled agents include nitrous oxide,
creased success of IVF and its decreased invasive- isoflurane, desflurane, or sevoflurane. Analgesics
ness (usually no laparoscopy required) have made for pain relief include opioids such as fentanyl,
this the more popular ART. Moreover, ultrasound- sufentanil, or alfentanil, which can be given for bal-

77
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 78

78 A.N. Beltsos

anced anesthesia (balance of different medications). TABLE 8–1. Necessary Points for Administering
Muscle relaxants, if used in outpatient setting, must Anesthesia
have a rapid onset and short duration of action. Suc- Person administering anesthesia must:
cinylcholine is ultra-short-acting and frequently 1. Be cardiac pulmonary resuscitation (CPR) certified
used. Newer agents popular in the outpatient setting 2. Be Advanced Cardiac Life Support (ACLS) certified
include mevacurium and cisatracurium (nondepo- 3. Understand the anesthetic agents being administered
4. Know the antidotes and have them available (see Appen-
larizing). dix C. Antidotes)
5. Be prepared to handle general anesthesia/intubation
6. Have crash cart available and know how to use it
Regional Anesthesia: Epidural or Spinal 7. Have other team members available for help if needed
Regional anesthesia includes epidural or spinal
anesthesia. Advantages of regional anesthesia in-
clude postoperative pain relief, maintenance of the oxygen when indicated, and (3) intravenous admin-
patient’s own airway, and decreased incidence of istration of sedatives, anxiolytics, antiemetics, and
nausea and vomiting. The expertise of the anesthe- other medicines. Levels of sedation vary from anal-
sia personnel is an important determining factor gesia (pain relief), local anesthesia (pain relief to
when choosing regional anesthesia in the outpatient one part of body), conscious sedation (depressed
setting. At L2-3, L3-4, or L4-5 of the lumbar spine, level of consciousness but responsive), and deep
a small-gauge needle is placed in the epidural space sedation or hypnosis (unconscious and unrespon-
for epidural anesthesia (19-gauge needle) or into the sive). Sedation (drug-induced tranquility) and anx-
subarachnoid space for spinal anesthesia (26- or 27- iolysis (relaxation) provide relief during procedures.
gauge needle). The epidural space lies between the Benzodiazepines, propofol, opioids (fentanyl, alfen-
spinal meninges (maters) and the vertebral canal, tanyl), and inhalation agents are used.
which is a series of discontinuous compartments Anesthesia personnel include an anesthesiologist
that become continuous with the injection of air or or certified registered nurse anesthetist (CRNA)
fluid. The subarachnoid space is defined as the area from the department of anesthesia. In some settings
under the dura mater and arachnoid mater. Epidural (e.g., procedures by dentists, radiologists, gastro-
anesthesia may involve use of lidocaine, 2-chloro- enterologists) conscious sedation is frequently ad-
procaine, or mepivacaine. Lidocaine, marcaine, or ministered by the attendant nurse or doctor who is
tetracaine may be utilized for spinal blockade. Other properly qualified. In all cases, a physician is
advantages of spinal anesthesia in the ART setting always available. Nonetheless, whoever is admin-
is the faster onset of anesthesia and the need for less istering the anesthetic must meet the criteria in
equipment. Frequently, the patient is premedicated Table 8–1. Other members of the team must know
with a sedative such as midazolam (Versed). Dur- how to respond to emergencies and have emergency
ing regional anesthesia, oxygen may be given on an phone numbers close at hand (e.g., 911).
as-needed basis or routinely depending on the facil- In the ART setting, MAC usually involves con-
ity’s protocols or preference of anesthesia. scious sedation with anesthesia personnel adminis-
tering intravenous medicine and monitoring the
patient. Some centers use a member of the ART
Monitored Anesthesia Care team to administer the anesthesia. In a review of
The American Society of Anesthesiologists (ASA) anesthesia practices in the United States, Ditkoff et
stated that monitored anesthesia care (MAC) in- al. found that 95% of IVF centers use conscious
cludes (1) the usual noninvasive cardiocirculatory sedation and 56–68% use anesthesia personnel for
and respiratory monitoring, (2) administration of MAC (Table 8–2).

TABLE 8–2. Common ART/IVF Anesthesia Scenarios

Parameter Anesthesia personnel IVF team personnel p
Who administers anesthesia (MAC) Academic program 56% 36%
Private program 68%
Cost $391  $15 $157  $11 0.05
Usual medicines used Midazolam (Versed) and/or Meperidine (Demerol) and
diprivan (Propofol) with midazolam (Versed)
fentanyl

Source: Ditkoff et al., 1997.

ART, assisted reproductive technology; IVF, in vitro fertilization; MAC, monitored anesthesia care.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 79

8. Anesthesia in the Office 79

Local Anesthesia Anesthetic options in ART programs have also

been evaluated in regard to human pregnancy out-
Local anesthetics act by interfering with the exci- come. Pierce et al. compared thiopental sodium to
tation-conduction process in the nerve membrane propofol given for induction of anesthesia during
causing conduction blockade (see Appendix A). 282 GIFT cycles. Pregnancy rates of 24.6% and
They can be used as infiltration for a peripheral 25.8% for the thiopental and propofol groups,
nerve block or for a regional block (including spinal respectively, were not significantly different. Palot
or epidural anesthesia). et al. found that the use of nitrous oxide with and
These substances cause a reversible blockade of without halothane caused a decrease in cleavage
nerve function and fall into two major categories: rates when used for general anesthesia during
amino esters and amino amides. The discovery of oocyte retrievals.
cocaine as a benzoic ester led to the synthesis Regional anesthesia has also been evaluated and
of amino esters derived from benzoic acid ester, has the potential advantages of lower serum drug
which include benzocaine, procaine, tetracaine, levels and a lower incidence of nausea and vomit-
and chloropaine. Lidocaine was developed in 1943 ing. Lefebre et al. found that transvaginal retrieval
as the first amino amide and differed because it under epidural anesthesia had a higher cleavage rate
was essentially free of allergic reactions. Prilo- than did laparoscopic retrieval with general anes-
caine, mepivacaine, and bupivacaine are other thesia. Confounding variables color the interpreta-
types from this category. Paracervical block is an tion of these results. Another study, by Botta et al.,
option for anesthesia during ART procedures to compared epidural anesthesia to propofol/nitrous
decrease the discomfort of needle penetrance into oxide (mask-assisted ventilation) and found no dif-
the vagina but is infrequently used. Manipulation ference in fertilization, cleavage, or pregnancy rates
of the ovaries and entrance into the peritoneal cav- between the two groups. In a study from Beltsos et
ity may require further intravenous sedation. al., oocytes recovered early, compared to those
recovered later, did not differ in rates of fertiliza-
tion, cleavage, or pregnancy. Imoedemhe et al. also
Studies on Anesthesia studied propofol and found no difference in oocytes
and ART/IVF retrieved from the beginning versus the end of a
case when followed through pregnancy occurrence.
Anesthetic agents have been found to accumulate This is in contrast to the earlier reports of Boyers
quickly in follicular fluid after an intravenous et al. and Hayes et al., who found that fertilization
bolus. For this reason, oocytes have been tested in and cleavage were decreased with anesthesia expo-
an animal model to determine if increasing expo- sure, but the latter studies used general anesthesia
sure of anesthetic agents affects oocyte quality and and laparoscopic retrieval.
the ability to create a pregnancy. The mouse oocyte/ What remains unclear is which anesthetic med-
embryo is a frequently utilized model to examine icines are best for optimizing ART pregnancy out-
the potential deleterious effects of toxins and for comes. It appears that decreasing exposure to gen-
laboratory quality assurance. eral anesthesia may be helpful. To study the effects
Depypere et al. found that exposing the mouse of anesthesia, the murine model or the ART setting
oocyte to increasing doses of propofol decreased can be used. Whether parallels can be drawn be-
fertilization rates from 84.7% in controls to 22.7% tween phylogenetically similar models or less sim-
in the highest concentration (10.0 g/ml) and that ilar mammalian systems such as the murine and
increasing the time of propofol exposure decreased human models is a constant issue in science. The
the fertilization rates from 92.0% in controls to ART arena is limited because it would be difficult
46.9% in oocytes exposed to propofol 1 g/ml to have a pure negative control, as some level of
for 40 minutes. Blastocyst development was not sedation is required. Certainly continued efforts to
affected by either parameter. More recently, Jans- evaluate this subject in a prospective form will be
senswillen et al. found that increasing concentra- welcomed to maintain ART success while provid-
tions of propofol affected the ability of the oocyte ing the optimum in anesthesia care.
to fertilize and the blastocyst to develop. Further-
more, in this study increasing the dose and duration
of exposure to propofol appeared to activate the
oocytes parthenogenetically. Parthenogenesis can Indications and Purpose
be elicited in oocytes by exposing them to a variety
of agents including ethanol, heat-cold shock, and Institutional, local, or regional regulations and poli-
anesthetics; it also occurs in vivo, as in teratomas. cies may govern the preoperative evaluation.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 80

80 A.N. Beltsos

TABLE 8–3. Preoperative Laboratory Tests for Women Based on Age

Test recommended by age
40 40–49 50–59 60–69 70
Laboratory test years years years years years
CBC/hemoglobin ✓ ✓ ✓ ✓ ✓
Electrolyte panel (✓) (✓) ✓ ✓
hCG (positive after hCG injection for ART) — — — — —
Chest radiography ✓
Electrocardiogram ✓ ✓ ✓

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

Preoperative Screening Premedication

A careful history and physical examination by the Anxiolytics
physician and anesthesia team must be performed.
Anxiolytics provide relaxation and amnesia. The
As an initial screen in the office the patient is offered
most commonly used anxiolytic is midazolam
tests for human immunodeficiency virus (HIV) and
(Versed); others are diazepam (Valium) and triazo-
hepatitis B surface antigen, a rubella titer, and rapid
lam (Halcion). Considerations include careful dos-
plasma reagin/Veneral Disease Research Laboratory
ing to prevent hypotension, a changing heart rate,
(RPR/VDRL) testing. Consider screening for ethnic-
and respiratory depression. There is concern that
related diseases (e.g., thalassemia, sickle cell dis-
there may be deleterious effects on the oocyte with
ease, Tay-Sachs disease). Table 8–3 indicates min-
potential effects on fertilization. In light of this,
imum preoperative screening considerations based
preoperative anxiolytics should be administered as
on age and assuming a healthy woman. Appendix
close to the time of the procedure as possible to
D is the American Society of Anesthesiologists’
decrease oocyte exposure; they should not be used
(ASA) statement on routine preoperative laboratory
if the patient is not anxious.
and diagnostic screening. If the patient has medical
problems, further testing should be focused on their Protection Against Aspiration
disease. If significant disease exists, consider med-
ical clearance not only for the surgery but also for It has been noted that 25 ml of solutions of pH 
preconception counseling. Suggestions for tests 2.5 if aspirated may lead to aspiration pneumoni-
based on disease are provided in Table 8–4. tis. This condition is defined as gastric contents

TABLE 8–4. Testing Recommendations for Various Diseases

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

ECG, electrocardiography; BUN, blood urea nitrogen; NPO, nothing by mouth; OR, oper-
ating room; WBC, white blood cell; IVPB, intravenous piggyback.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 81

8. Anesthesia in the Office 81

entering the pulmonary tract via emesis or reflux, Prophylaxis Against Postoperative
causing a life-threatening lung condition. Preoper- Nausea and Vomiting
atively, sodium citrate, metoclopramide (Reglan),
or an H2-receptor antagonist can be given for Patients who had significant nausea and vomiting
women who are at risk for aspiration, such as those with previous anesthesia or who have problems
with a hiatal hernia or who are obese. Patients dif- with motion sickness may require attention.
ficult to intubate or who will be masked are also Droperidol (before anesthesia), transdermal scopo-
candidates for prophylaxis (the mask can also lamine (given the night before surgery), or
insufflate the stomach, increasing the likelihood of ondansetron HCl (Zofran) may be considered in
reflux). this situation.
The length of the fast should be at least 4–6
hours. Preoperative instructions should be in writ- Prophylactic Antibiotics
ten form, signed by the patient, and a copy kept in
Pelvic Inflammatory Disease
her chart (see Appendix G and Appendix H). If the
ART patient is not compliant and presents with a The ART protocol frequently include oral antibiot-
recent ingestion, she must be carefully counseled ics (doxycycline for possible Chlamydia tra-
regarding the risk of aspiration pneumonitis. chomatis coverage) before the cycle begins. The
Recent liquid intake is less significant than food. American College of Obstetrics and Gynecology
Obesity and the history of a hiatal hernia increase (ACOG) considers antibiotic prophylaxis to reduce
the patient’s risk. Because the ART procedure is the incidence of surgical site infection by contam-
timed by human chorionic gonadotropin (hCG) ination with lower genital tract flora. It is frequently
injection, a delay may result in ovulation, which used in women having a hysterectomy or cesarean
would make the ART procedure impossible. The section. In regard to ART with needle penetrance
window of time is evaluated from the hCG injec- from the vagina into the peritoneal cavity to the
tion and last meal for considering if there is poten- ovary, the possibility of infection exists. For the
tial for delaying the case. Some might cancel the routine patient without a history of pelvic infec-
procedure to avoid potential medical and legal ram- tions, a single dose of a cephalosporin may be used.
ifications. Others advocate that this procedure is The choice of agent is based on the institution’s
“necessary enough” (time, resources, money spent) microbiology reports and hospital formulary.
to proceed. Proceeding at the scheduled time should Arguments against treating the routine patient
involve written consent and assumption of respon- include the increasing number of resistant organ-
sibility by the patient for her error. Anesthetic isms, increased cost with unknown benefit, and
choices include spinal anesthesia (because the oocyte exposure. If there is a history of PID,
patient can maintain her own airway) or general hydrosalpinx, or abscess, prophylactic intravenous
anesthesia, securing the airway with gastric suc- antibiotics (cefotetan 1–2 g IVPB and doxycycline
tioning. H2-receptor antagonists, sodium citrate, 100 mg IVPB) are an appropriate consideration.
and metoclopramide should also be considered. Oral antibiotics before and after the procedure com-
MAC/conscious sedation is an alternative, but the prise another option for this type of patient.
medicine used should induce the least amount of
nausea and vomiting and allow the patient to pro- Subacute Bacterial Endocarditis
tect her own airway.
For subacute bacterial endocarditis (SBE) prophy-
Upper Respiratory Infection at laxis, the American Heart Association 1997 rec-
ommendations depended on the severity of the dis-
the Time of the Procedure
ease: high risk, moderate risk, negligible risk. High
If the patient has a bacterial upper respiratory infec- risk patients includes those with prosthetic valves,
tion (URI), consider antibiotic treatment as soon as previous bacterial endocarditis, complex congeni-
the infection is recognized to improve her condi- tal heart disease, or surgically corrected systemic
tion prior to surgery. Fever, congestion auscultated pulmonary shunts or conduits. The moderate risk
(wheezes, rales, rhonchi) by stethoscope, or signif- group includes those with mitral valve prolapse
icant malaise or lethargy at the time of surgery are with regurgitation.
factors that must be considered when cancelling a Prophylaxis is optional and is used only in the
case. Some, nonetheless, would proceed with the high risk patients undergoing vaginal hysterectomy
procedure because it is considered “urgent” though or vaginal delivery. Dilation and curettage, sterili-
not emergent. zation procedures, and intrauterine device (IUD)
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 82

82 A.N. Beltsos

placements or removals do not require prophylaxis. (Demerol) to keep the patient in conscious sedation
Extrapolating these recommendations to the ART and comfortable. Other specialty operations are
patient with possible peritoneal contamination from performed by the physician, who also supervises or
the vagina, SBE prophylaxis might be indicated but directly gives the anesthetic such as for percuta-
only in high risk patients. SBE prophylaxis would neous radiologic and dental procedures. This is
include, at 30 minutes before the procedure, giving becoming a more popular option with ART proce-
ampicillin 2 g IVPB and gentamicin 80 mg IVPB. dures in the current health care environment of cost
At 6 hours after the procedure amoxicillin 1.5 g PO consciousness. Care must be taken not to have a
is given. For penicillin allergy, give vancomycin surgeon who is concentrating on a procedure or an
1 g over 1 hour with gentamicin 80 mg IVPB. SBE unqualified person be the responsible party for
prophylaxis does not appear to be indicated for monitoring the patient under intravenous sedation.
embryo transfers.
Additional Local Anesthesia
SBE and PID
Topical application of local anesthetics such as
For both SBE and PID antibiotic prophylaxis, con- plain lidocaine or bupivacaine is a consideration at
sider a combination of ampicillin 2 g IVPB, gen- the site of the needle insertion site. It is usually not
tamicin 80 mg IVPB, and doxycycline 100 mg used, however, as the intravenous sedation is ade-
IVPB 30 minutes prior to the procedure and amox- quate, and the application requires an additional
icillin 1.5 g PO 6 hours later. needlestick. If used, be sure to aspirate prior to
injection to avoid intravascular injection, which can
produce significant complications.
Anesthesia Options Based Regional Anesthesia
on the ART Procedure
If spinal or epidural is used, the USFA can be done
Ultrasound-Guided Follicle Aspiration with less intravenous anesthesia but is usually too
involved for this simple procedure. It is a consid-
MAC With Anesthesia Personnel Present eration for the patient who has had a recent inges-
The advent of ultrasound-guided follicle aspiration tion. It is more frequently used with microlaparo-
(USFA) has allowed retrievals to be done with scopic GIFT.
MAC using intravenous or conscious sedation. As
mentioned above, many programs use an anesthe- Fallopian Tube Transfer Procedures
siologist or CRNA to administer the medicine and Via Laparoscopy
monitor the patient (see Types of Anesthesia,
above). In this setting it is common to use intra- MAC/General Anesthesia
venous midazolam (Versed), diprivan (Propofol),
Oocytes are still retrieved via USFA under con-
and/or fentanyl. Opioid anesthesia must be used at
scious sedation; general anesthesia can then be
the point of distribution (where it has been deliv-
given for the laparoscopic transfer. Aside from the
ered) because of its classification, so traveling anes-
technical advantage and ease of USFA, another
thesia personnel who come to one’s office may not
advantage of this setup is that in the event there are
have this form available for use. Anesthesia per-
no eggs the patient has not undergone an unneces-
sonnel must be prepared for possible general anes-
sary general anesthetic. The laparoscopic retrieval
thesia and have all necessary equipment with them
may be performed when the ovary is transvaginally
(see Anesthesia Equipment, below).
inaccessible, and this requires either regional or
general anesthesia. Local injection of port sites with
MAC Without Anesthesia Personnel Present
0.25–0.50% bupivacaine (Marcaine) prior to the
Some programs have taken on the responsibility of incision has been found to decrease postoperative
MAC themselves and have an IVF team member pain. The need to intubate the patient for laparos-
administering the anesthetics. Usually a registered copy depends on her size, the ability to establish
nurse (RN) or a physician administers midazolam an airway without difficulty, and the experience and
(Versed) or fentanyl via intravenous infusion speed of the surgeon. Asthmatics and singers are
with intravenous fluids running. Others merely examples of patients in whom avoidance of intu-
place a heplock and administer enough meperidine bation is advantageous. Mask anesthesia during
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 83

8. Anesthesia in the Office 83

laparoscopy with abdominal insufflation in steep trained and able to handle. Do not overextend your-
Trendelenburg position can be arduous. Gastric dis- self to cover areas where you and your staff are not
tension resulting from a partially obstructed airway capable of providing the full standard of care.
can increase to the point that the trocard is inserted
into the stomach. Also, gastric distension increases
reflux and possible aspiration. Special Preparation
Regional Anesthesia Patient
With regional anesthesia, both the USFA and the If the patient has a serious medical condition, pre-
laparoscopic transfer is done with an epidural or operative and preconception counseling should be
spinal block. Microlaparoscopy, where the instru- undertaken. Other steps include informed consent
ments are as small as 2 mm, can easily be done (see Appendix I); ovulation induction (or can be
under regional block. spontaneous cycle); and NPO after midnight prior
to the procedure with written instructions that are
signed, with the office keeping a copy (see Appen-
Percutaneous or Open Testicular dix G or H).
Biopsy for Sperm Collection
Local anesthetic with or without intravenous seda- Nurse
tion can be used for a percutaneous sperm aspira- The nurse counsels the patient regarding the ex-
tion or an open testicular biopsy. It can be done pected procedure and what will occur; completes the
with the anesthesia personnel present or in the preoperative checklist (see Appendix F); assists in
office with the physician administering the local coordinating the surgeon, anesthesia, laboratory, and
agent, with staff assistance to administer some family; and assists in the discharge of the patient.
intravenous conscious sedation.
Doctor
Contraindications to Anesthesia The physician obtains the patient’s history and per-
forms a physical examination; reviews the preop-
in the Office erative laboratory results and any preoperative con-
sults; reviews the accessibility of the ovaries prior
In-office anesthesia is not an option for every
to the day of the surgery by transvaginal ultra-
patient. The patient with significant medical con-
sonography; obtains informed consent after it is
ditions or a history of anesthesia-related complica-
explained to the patient and possibly the significant
tions may be better off in an inpatient setting. An
other (see Appendix I); and writes preoperative
unstable/uncontrolled medical problem requiring
instructions and an explanation of the USFA pro-
inpatient treatment or a patient with ASA physical
cedure and anesthesia given to patient (see Appen-
status III or IV should be treated in a full operat-
dix G or H).
ing suite. Pulmonary or cardiac conditions that
require invasive monitoring with a Swan-Ganz
catheter (e.g., pulmonary hypertension) must not be Anesthesia Equipment
treated in the office. Patients who may require pro-
longed intravenous treatment (increased nausea/ It is recommended that, no matter what type of
emesis or antibiotic prophylaxis overnight) should anesthesia is given, the team be prepared for gen-
be in a facility prepared for overnight care. Patients eral anesthesia including intubation and the possi-
susceptible to malignant hyperthermia (acetyl- ble use of crash cart. Table 8–5 indicates what is
cholinesterase deficiency) also must be in an in- necessary for patient care during anesthesia. The
patient setting. Recent exposure to diet pills or anesthesia personnel may already be part of an
monoamine oxidase (MAO) inhibitors can result in operating room staff in an outpatient surgery cen-
a complicated anesthetic reaction, so anesthesia ter or in a hospital where the procedures are per-
should be administered cautiously and in an inpa- formed. Some centers perform ART in their office
tient facility (see Special Considerations, Diet Pills, procedure room, and anesthesia personnel (fre-
below). quently a CRNA supervised by an off-site anes-
The salient message is that one should provide thesiologist) come to the office with portable equip-
care in a setting for which health care providers are ment (Fig. 8–1). This is usually a private company
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 84

84 A.N. Beltsos

TABLE 8–5. Necessary Anesthesia Equipment

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

A B

C D
FIGURE 8–1. Portable anesthesia equipment commonly used in the office setting. (A) Equipment stored and carried
in wheeled luggage. (B) Full crash cart equipment. (C) Mandatory equipment for monitored anesthesia care: blood
pressure cuff, pulse oximeter, electrocardiography leads for cardiac tracing. (D) Intubation equipment and ambubag
must also be at hand.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 85

8. Anesthesia in the Office 85

certified and staffed for this particular type of work. billing must be well educated and continually
Other centers, in an effort to decrease expenses, updated on this ever-changing topic. Errors in
have their own anesthesia equipment and adminis- billing can have legal consequences.
ter anesthesia themselves as mentioned.

Outline of Steps
Special Considerations
Procedure
Latex Allergy 1. Preoperative counseling forms and written
As many as 20% of health care workers have devel- instructions (see Appendix G or H) are signed,
oped allergies to latex, which can involve an ana- with a copy given to the patient; the original
phylactic reaction. If a patient has latex allergy, care goes in the chart.
must be taken to protect the patient against expo- 2. Informed consent is signed by patient and sur-
sure to latex products (transvaginal probe, sur- geon (see Appendix I). The surgeon should
geon’s gloves). This problem must also take into always obtain the consent from the patient.
account the nonlatex products that have been found Include the possibility of bleeding with poten-
to be oocyte- and embryo-toxic. tial need for blood transfusion; infection; injury
to internal organs (female organs, intestines,
bladder, major blood vessels); thromboembolic
Diet Pills phenomenon; anesthetic complications; possi-
If the patient has been exposed to diet pills such as ble laparoscopy/laparotomy; and death.
Fen-Phen (fenfluramine-phenteramine), a thorough 3. Patient changes into a gown, and valuables are
cardiac physical examination and an echocardio- left with the family, in the car, or at home.
gram should be performed to ensure that no cardiac Clothing is placed in a secured locker.
defects occurred as a result of these medicines. Fur- 4. An identification bracelet is placed on the
thermore, recent exposure to these medicines can patient.
have catecholamine-depleting effects, and therefore 5. Baseline vital signs including height, weight,
anesthesia must be administered with extreme cau- blood pressure, pulse, respiratory rate, and tem-
tion. These patients are best treated in the inpatient perature are recorded.
setting where instant resuscitative measures are 6. Surgeon and anesthesia specialist perform the
available. history and physical examination. Chart is
checked for current medications, allergies,
medical/surgical history, previous anesthesia
Billing and complications, and medical clearance if
requested. The anesthesia specialist should also
In the current health care milieu, careful attention examine the patient’s airway and conduct a car-
to current procedural terminology (CPT) and Inter- diac and pulmonary examination.
national Classification of Diseases, 9th Revision 7. Patient is taken to the procedure room, and an
(ICD-9) coding is imperative. Because these spe- intravenous infusion is started.
cific items continue to change every day, refer to 8. Blood pressure cuff, pulse oximeter, and car-
the most current publications regarding the anes- diac monitor are placed.
thesia and procedure performed. Some carriers do 9. Proceed to the anesthesia of choice.
not want the anesthesia code but the surgical code. 10. Go through the postoperative checklist (see Ap-
The time spent on anesthesia is usually needed on pendix J).
the claim and may be requested in either minutes
or units (units are calculated in 15-minute inter- Discharge
vals). Other carriers, particularly Medicare and
Prior to discharge the patient must be observed after
Medicaid, want to know if the anesthesia was
anesthesia and the procedure. Recommendations
personally performed by an anesthesiologist or a
for the anesthesia specialist includes a minimal
CRNA. If CRNAs are being utilized, the number
duration of observation of the following.
of CRNAs per supervising anesthesiologist may be
requested information. If a nonanesthesiologist MAC: 1 hour
physician is providing the anesthesia, a different General: 2 hours
code is submitted. The staff responsible for the Regional: until sensation returns
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 86

86 A.N. Beltsos

The patient should also meet the requirements With heavy sedation or an involved procedure,
below. this should not be the person performing the
procedure. Avoid fixed drug combinations;
1. No vomiting.
rather, incrementally dose the patient to the
2. Tolerates oral fluids or intake (not absolutely
point of sedation. Be aware that the patient
necessary).
could go from conscious sedation to deep or
3. Voiding; if unable, catheter should be in place
general sedation quickly, and antidotes should
or patient should be instructed on self-catheter-
be on hand (see Appendix C)
ization (see Potential Complications, below).
7. Arrhythmia/cardiac arrest.
4. State of hydration normal.
8. Hemorrhage: Large-bore intravenous access
5. Medical condition stable.
should be initiated immediately if significant
6. Distance between home and ambulatory facil-
bleeding occurs. Surgeon must be able to per-
ity is not far or there is a nearby hospital.
form a laparoscopy or laparotomy if needed.
7. Available responsible adult.
Blood must be immediately accessible for
8. Anticipation of whether the patient is likely to
transfusion as needed. Disseminated intravas-
suffer any complications if little or no intake
cular coagulation (DIC) is another complica-
(e.g., diabetes).
tion if significant bleeding has occurred.
9. Postoperative pain relief may include acet-
9. Allergic reaction.
aminophen for USFA or at most a mild anal-
10. Urinary retention (especially with spinal anes-
gesic such as acetaminophen with codeine.
thesia). Catheterize the patient and allow an
For laparoscopy, acetaminophen (Tylenol) with
attempt to void. If unsuccessful, teach self-
codeine or an equivalent should suffice. If more
catheterization for 1–2 days or leave a Foley
than this is needed, further evaluation is indi-
catheter in place for 1–2 days with bladder
cated to ensure that there is no significant
training to be initiated afterward.
intraperitoneal injury.
11. Postdural headache (1–10%). Needle and tech-
10. Review postoperative instructions (see Appen-
nique selection are important. Treat with an
dix K or L). Once signed, a copy is given to
epidural blood patch.
the patient; original goes in the chart.
12. Hypoxic events.
11. Consider calling the patient the day after sur-
13. Thromboembolic phenomena.
gery to make sure she is recovering well.
14. Malignant hyperthermia: Treatment is dantro-
lene sodium.
Potential Complications 15. Death: Incidence of anesthetic deaths is 0.7–3.7
per 10,000 inpatients receiving anesthetics. In
1. Nausea and vomiting. the ambulatory care setting this may be 0.012–
2. Pain: Immediately after operation, particularly 0.15 deaths per 10,000.
after laparoscopy, pain relief is important. After 16. Unanticipated hospital admissions: Overall
USFA, pain should be manageable with minimal incidence of hospital admission ranges from
medicine. If the pain is significant, further eval- 0.68% to 4.10%.
uation for possible complications is required.
3. Postoperative hypertension: commonly a pre-
existing condition. Patient should take their Conclusions
medications before surgery with sips of water.
4. Hypotension and syncope: Causes include Outpatient anesthesia has developed into a sophis-
hypovolemia, position changes, anesthetics, ticated arena where high-tech care can be delivered
and a full bladder. Other possibilities include in one’s office. Precautions must be taken to pro-
pulmonary embolus and myocardial infarction. tect the patient when administering potent agents
5. Aspiration pneumonitis. in settings away from a hospital, and only formally
6. Respiratory arrest/apnea: ASA recommends the trained personnel should be responsible for this
same standards for basic intraoperative MAC care. The least amount of anesthesia necessary to
as for regional or general anesthesia. The anes- maintain patient comfort should be administered.
thesia team, physicians, or nurses administer- Oocyte exposure to anesthetic agents is a recent
ing the anesthesia should follow the same stan- concern, as it is found in the follicular fluid and
dards. Personnel should always be in charge of may affect oocyte fertilization and ultimately preg-
observing the patient for untoward reactions. nancy rates.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 87

8. Anesthesia in the Office 87

Suggested Reading thetic agent propofol (‘Diprivan’) on the outcome of

human in vitro fertilization. J Assist Reprod Genet
Accreditation Manual for Hospitals. Joint Commission 1992;9:488–491.
on Accreditation of Healthcare Organizations, 1988. Janssenswillen C, Christaens F, Camu F, Van Steirtegham
American College of Obstetricians and Gynecologists. A. The effect of propofol on parthogeneic activation,
Antibiotics and Gynecologic Infections. Educational in vitro fertilization and early development of mouse
Bulletin 237. Washington, DC: ACOG, 1997. oocytes. Fertil Steril 1997;67:769–774.
American Society of Anesthesiologists. Standards, Guide- Keenan RL. Anesthetic Disasters: Causes, Incidence,
lines and Statements, Park Ridge, IL: ASA, 1997. Preventability. Refresher Course Lectures, American
Barash PG, Cullen BF, Spoetling RK. Clinical Anesthe- Society of Anesthesiologists 242. Philadelphia: Lipin-
sia, 3rd ed. Philadelphia: Lippincott-Raven, 1997. cott, 1988.
Baylor-Pridham DD, Reshef E, Drury K, et al. Follicu- Lefebre G, Vauthier D, Seebacher J, et al. In vitro fertil-
lar fluid lidocaine levels during transvaginal oocyte ization: a comparative study of cleavage rates under
retrieval. Fertil Steril 1990;53:171–173. epidural and general anesthesia-interest for gamete
Beltsos A, Oldham L, Mahendra S, Basuray R, Williams intrafallopian tube transfer. J In Vitro Fertil Embryo
D. Propofol exposure in ART cycles. In: Abstracts of Transfer 1988;5:305.
the Pacific Coast Fertility Society, 1996. Palot M, Visseaux H, Harika G, Carre-Pigeon F, Rendo-
Botta G, D’angelo A, D’ari G, et al. Epidural anesthesia ing J. Effects of nitrous oxide and/or halothane on
in an in vitro fertilization and embryo transfer pro- cleavage rate during general anesthesia for oocyte
gram. J Assist Reprod Genet 1995;12:187–190. retrieval. Anesthesiology 1990;73:A930.
Boyers SP, Lavy G, Russell JB, DeCherney AH. A paired Pierce RD, Syrope CH, Van Voorhis BJ, et al. An evalu-
analysis of in vitro fertilization and cleavage rates of ation of the effect of anesthetic technique on repro-
first- versus last-recovered preovulatory human oocytes ductive success after laparoscopic pronuclear stage
exposed to varying intervals of 100% CO2 pneumo- transfer. Anesthesiology 1995;83:352–358.
peritoneum and general anesthesia. Fertil Steril 1987; Positions on Monitored Anesthesia Care. Park Ridge, IL:
48:969. American Society of Anesthesiologists, 1986.
Chetkowski RJ, Nass TE. Isoflurane inhibits early mouse Shapira SC, Chrubasik S, Hoffmann A, et al. Use of
embryo development in vitro. Fertil Steril 1988;49: alfentanil of in vitro fertilization oocyte retrieval. J
171. Clin Anesth 1996;8:282–285.
Coetsier T, Dhont M, De Sutter P, et al. Propofol anes- Teaubeaut JR. Aspiration of gastric contents: an experi-
thesia for ultrasound guided oocyte retrieval: accumu- mental study. Am J Pathol 1952;28:51.
lation of the anesthetic agent in follicular fluid. Hum Warren RJ, Shaw B, Stainkampf MP. Effects of nitrous
Reprod 1992;10:1422–1424. oxide on preimplantation mouse embryo cleavage and
Coombs DW. Aspiration pneumonia prophylaxis. Anesth development. Biol Reprod 1990;43:158.
Analg 1983;62:1055. White P. Outpatient Anesthesia. New York: Churchill
Dajani AS, Taubert KA, Wilson W, et al. Prevention of Livingstone, 1990.
bacterial endocarditis: recommendations by the Amer-
ican Heart Association. JAMA 1997;277:1794–1801.
Degueldre M, Puissant F, Camus M, et al. Effects of car- Additional Readings
bon dioxide insufflation at laparoscopy on the gas
phase in oocyte recovery fluids. J In Vitro Fertil Kim WO, Kil HK, Koh SO, Kim JI. Effects of general
Embryo Transfer 1984;1:106. and locoregional anesthesia on reproductive outcome
Depypere HT, Dhont M, De Sutter P, Vanderkerckhove for in vitro fertilization: a meta-analysis. J Korean
D. The influence of propofol on in vitro fertilization Med Sci. 2000 Feb;15(1):68–72.
in mice [abstract]. Hum Reprod 1991;127(suppl): Casati A, Valentini G, Zangrillo A, Senatore R, Mello A,
151. Airaghi B, Torri G. Anaesthesia for ultrasound guided
De Sutter P, Dhont M, Merchiers E, et al. Effect of oocyte retrieval: midazolam/remifentanil versus propofol/
sequence of oocyte retrieval on oocyte fertilizability fentanyl regimens. Eur J Anaesthesiol. 1999 Nov;
[abstract P483]. Hum Reprod 1991;127(suppl 1): 16(11):773–8.
340. Stener-Victorin E, Waldenstrom U, Nilsson L, Wikland
Ditkoff EC, Plumb J, Selick A, Sauer MV. Anesthesia M, Janson PO. A prospective randomized study of
practices in the United States common to in vitro fer- electro-acupuncture versus alfentanil as anaesthesia
tilization (IVF) centers. J Assist Reprod Genet 1997; during oocyte aspiration in in-vitro fertilization. Hum
14:145–147. Reprod. 1999 Oct;14(10):2480–4.
Hayes MF, Sacco AG, Savoy-Moore RT, et al. Effect of Bokhari A, Pollard BJ. Anaesthesia for assisted concep-
general anesthesia of fertilization and cleavage of tion: a survey of UK practice. Eur J Anaesthesiol. 1999
human oocytes in vitro. Fertil Steril 1987;48:975. Apr;16(4):225–30.
Imoedemhe DAG, Sigue AB, Ghani IA, Aboezeid MA, Martin R, Tsen LC, Tzeng G, Hornstein MD, Datta S.
Halim MSA. An evaluation of the effect of the anes- Anesthesia for in vitro fertilization: the addition of
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 88

88 A.N. Beltsos

fentanyl to 1.5% lidocaine. Anesth Analg. 1999 Mar; epididymal sperm aspiration and testicular sperm aspi-
88(3):523–6. ration. Hum Reprod. 1998 Mar;13(3):646–50.
Bokhari A, Pollard BJ. Anaesthesia for assisted concep- Christiaens F, Janssenswillen C, Van Steirteghem AC,
tion. Eur J Anaesthesiol. 1998 Jul;15(4):391–6. Devroey P, Verborgh C, Camu F. Comparison of
Trout SW, Vallerand AH, Kemmann E. Conscious seda- assisted reproductive technology performance after
tion for in vitro fertilization. Fertil Steril. 1998 May; oocyte retrieval under general anesthesia (propofol)
69(5):799–808. versus paracervical local anaesthetic block: a case-
Gorgy A, Meniru GI, Naumann N, Beski S, Bates S, Craft controlled study. Hum Reprod 1998 Sep;13(9):
IL. The efficacy of local anaesthesia for percutaneous 2456–60.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 89

8. Anesthesia in the Office 89

Appendix A: Types of Local Anesthetic Agents

Agent Duration Use
Procaine Short Infiltration/peripheral block
Tetracaine Short Topical mucous membrane/spinal
Chloroprocaine Short Infiltration/peripheral block/epidural
Lidocaine Moderate Infiltration/peripheral block/spinal/epidural
Mepivicaine Moderate Not for topical use
Prilocaine Moderate Intravenous regional
Bupivacaine Long Infiltration/peripheral block MAC

Appendix B: Commonly Used Medicines

Trade name Generic name Mechanism of action
Alfentanyl Alfenta Opioid analgesic
Ancef Cefazolin Cephalosporin antibiotic
Anectine Succinylcholine Depolarizing muscle relaxant
Atracurarium Tracrium Nondepolarizing muscle relaxant
Atropine Anticholinergic
Brevital Methohexital General anesthetic
Demerol Meperidine Analgesic
Diazepam Benzodiazepine Sedative
D-TC d-Tubocararine Muscle relaxant
Edrophonium Acetylcholinesterase agent inhibitor Neuromuscular reversal
Fentanyl Opioid analgesic
Inapsine Droperidol Neuroleptic agent
Ketamine Sedative-hypnotic
Labetalol Antihypertensive
Norcuron Vecuronium Nondepolarizing agent
Pavulon Pancuronium Neuromuscular blocade
Pentathol Thiopental IV Anesthetic
Propofol Diprivan IV Anesthetic
Reglan Metoclopramide Dopamine antagonist/GI motility
Robinol Glycopyrrolate Anticholinergic
Romazicon Flumazenil Receptor antagonist/reversal agent
Toradol Ketoralac NSAID
Valium Diazepam Sedative
Versed Midazolam Analgesic, amnesic
Xylocaine Lidocaine Local anesthetic
Zofran Ondansetron HCl Antiemetic

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

Appendix C: Antidotes for Most Commonly

Used IV Sedation Medications
Drug name Antidote
Narcotic analgesic: fentanyl, meperidine (Demerol) Naloxone HCl (Narcan)
Diprivan (Propofol) None
Midazolam (Versed) Flumazenil (Romazicon)
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 90

90 A.N. Beltsos

Appendix D: American Society of Anesthesiologists Statement

on Routine Preoperative Laboratory and Diagnostic Screening
(Approved by House of Delegates on October 14, 1987 and
Last Amended on October 13, 1993)
Preanesthetic laboratory and diagnostic testing is ment of the anesthesia and surgery. Legal require-
often essential; however, no routine* laboratory or ments for laboratory testing where they exist should
diagnostic screening† test is necessary for the pre- be observed. The results of tests relevant to anes-
anesthetic evaluation of patients. Appropriate indi- thetic management should be reviewed prior to ini-
cations for ordering tests include the identification tiation of the anesthetic. Relevant abnormalities
of specific clinical indicators or risk factors (e.g., should be noted and action taken, if appropriate.
age, preexisting disease, magnitude of the surgical
procedure). Anesthesiologists, anesthesiology de-
partments, or health care facilities should develop *Routine refers to a policy of performing a test or tests
appropriate guidelines for preanesthetic screening without regard to clinical indications in an individual
tests in selected populations after considering the patient.
probable contribution of each test to patient out- †Screening means efforts to detect disease in unselected
come. Individual anesthesiologists should order populations of asymptomatic patients.
test(s) when, in their judgment, the results may Source: ASA, 520 N. Northwest Highway, Park Ridge,
influence decisions regarding risks and manage- IL 60068-2573. Reprinted with permission.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 91

8. Anesthesia in the Office 91

Appendix E: American Society of Anesthesiologists

Guidelines for Nonoperating Room Anesthetizing Locations
(Approved by House of Delegates on October 19, 1994)
ASA endorses and supports the concept of Ambu- which assumes responsibility for credentials
latory Surgery and Anesthesia and encourages the review, delineation of privileges, quality
anesthesiologist to play a role of leadership in both assurance, and peer review.
the hospital and freestanding setting. VII. Personnel and equipment shall be on hand to
manage emergencies. The facility must have
I. An ambulatory surgical facility may be hos- an established policy and procedure concern-
pital-affiliated or freestanding. The facility is ing unanticipated patient transfer to an acute
established, equipped, and operated primarily care hospital.
for the purpose of performing outpatient sur- VIII. Minimal patient care shall include:
gical procedures. A. Preoperative instructions and preparation.
II. ASA Standards, Guidelines, and Policies B. An appropriate history and physical exam
should be adhered to in all areas except where by a physician prior to anesthesia and
they are not applicable to outpatient care. surgery.
III. A licensed physician, preferably an anesthesi- C. Preoperative studies as medically indicated.
ologist, must be in attendance in the facility D. Anesthesia shall be administered by anes-
at all times during patient treatment, recovery, thesiologists, other qualified physicians,
and until medically discharged. or medically directed nonphysician anes-
IV. The facility must be established, equipped, thetists.
constructed, and operated in accordance with E. Discharge of the patient is a physician re-
applicable local, state, and federal laws. sponsibility.
V. Staff shall be adequate to meet patient and F. Patients who receive other than unsupple-
facility needs and consist of: mented local anesthesia must be dis-
A. Professional Staff charged to the company of a responsible
1. Physicians and other practitioners who adult.
are duly licensed and qualified. G. Written postoperative and follow-up care
2. Nurses who are duly licensed and qual- instructions.
ified. H. Accurate, confidential, and current med-
B. Administration Staff ical records.
C. Housekeeping and Maintenance Staff
VI. Physicians providing medical care in the facil- Source: ASA, 520 N. Northwest Highway, Park Ridge,
ity should be organized into a Medical Staff IL 60068-2573. Reprinted with permission.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 92

92 A.N. Beltsos

Appendix F: Preoperative Checklist

 Patient notified of time and location of procedure.
 Notified of procedure:
 Operating room  Office  Surgeon  Nurses
 Lab  Anesthesia  Sonographer
 Patient given Preop Instruction sheet, signed and a copy retained for chart [see Appendix G or H].
 Patient signed surgical consent [see Appendix I].
 Physician history and physical completed.
 Anesthesia history and physical completed.
 OR equipment checked and in stock.
 Preop. lab results  reviewed and  on chart.
 Address any medical problems.
 Review current medicines.

 Allergies:

 Order antibiotics if indicated for PID and/or SBE prophylaxis.

 Consents also signed for  ART,  micromanipulation/ICSI,  embryo freezing.
 ID band on patient.
 Hospital gown given and clothes in locker.
 Prosthesis removed and secured.
Teeth
Glasses
Contact lens
Artificial limb
Other
 Time of last meal: ___________
 Have patient void.
 Preop vitals: Temp ______ Pulse ______ RR ______
BP ______ Height ______ Weight ______
 Preop meds given.
Medicine __________________ Method ______ Time ________ By whom ___________
Medicine __________________ Method ______ Time ________ By whom ___________
Medicine __________________ Method ______ Time ________ By whom ___________

Signature of RN ________________________________
Date ________________
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 93

8. Anesthesia in the Office 93

Appendix G: Preoperative Instructions for

Ultrasound-Guided Follicle Aspiration
This surgery involves transvaginal ultrasonography similar to what you have undergone already to mea-
sure the follicles. A needle is attached to the probe, which goes from the vagina to the ovary and aspi-
rates (sucks out) the eggs. You will be made comfortable for this procedure with anesthesia, which will
allow you to essentially sleep through it. Afterward you will be allowed to go hom, where you must rest.

1. The evening before surgery you may have a regular dinner.

2. After midnight, you cannot eat or drink anything. You may brush your teeth and rinse your mouth.
No candy or gum is allowed.
3. Take a shower or bath the morning of surgery.
4. Come to the place where the laparoscopy/oocyte retrieval will be performed. Please arrive at the
______________________. Attached is a map and phone number.
Date __________ Time __________
5. Do not take aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen (Advil,
Motrin) or naproxen (Alleve) starting 10 to 14 days before the procedure.
6. If you are taking a blood thinner such as heparin, please discuss this with the doctor prior to
surgery.
7. If you have any medical conditions or problems and are taking medicine every day (example: insulin
or antihypertensive), on the day of surgery you should:

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

Signed __________________________________ Date ___________________

Witness _________________________________ Date ___________________

3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 94

94 A.N. Beltsos

Appendix H: Preoperative Instructions for a Laparoscopic Procedure

This surgery involves transvaginal ultrasonography similar to what you underwent already to measure
the follicles. A needle is attached to a probe, which goes from the vagina to the ovary and aspirates (sucks
out) the eggs. Once the eggs are retrieved, a laparoscopy is performed, which involves small incisions
made at your bellybutton, pubic bone, and side. Through these small incisions, small instruments are
used to place the eggs and sperm into the tube.

1. The evening before surgery you may have a regular dinner.

2. After midnight, you cannot eat or drink anything. You may brush your teeth and rinse your mouth.
No candy or gum is allowed.
3. Take a shower or bath the morning of surgery.
4. Come to the place where the laparoscopy/oocyte retrieval will be performed. Please arrive at the
______________________. Attached is a map and phone number.
Date __________ Time __________
5. Do not take aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen (Advil,
Motrin) or naproxen (Alleve) starting 10 to 14 days prior to the surgery.
6. If you are taking a blood thinner such as heparin please discuss this with the doctor prior to surgery.
7. If you have any medical conditions or problems and are taking medicine every day (example: insulin
or antihypertensive), on the day of surgery you should:

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

Signed __________________________________ Date ___________________

Witness _________________________________ Date ___________________

3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 95

8. Anesthesia in the Office 95

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

Consent for Procedure/Anesthesia: Ultrasound-Guided Follicle Aspiration

PATIENT ________________________________________
AGE ______________
DATE _____________ TIME _________ PLACE ____________

I hereby authorize (doctor) _________________________________, M.D. and whomever he/she may

designate as the assistants to administer such treatment as may be necessary for and/or to perform upon
myself the following procedure:

ULTRASOUND-GUIDED FOLLICLE ASPIRATION [Transvaginal ultrasonography is performed with a

needle attached to aspirate (“suck out”) the eggs.]

If any unforeseen condition arises during the course of the procedure, calling, in his or her judgment,
for procedures in addition to, or different from those contemplated, I further request and authorize (a)
the administration of blood during and immediately after the operation as deemed necessary by the sur-
geon and/or anesthesiologist; (b) disposal of any tissue removed from my body in a manner customary
to the facility; and (c) taking photographs as deemed desirable by the attending physician and/or anes-
thesiologists.

The nature and the purpose of the procedure includes retrieving the eggs as described above. Usually,
fertility medicine has been utilized to make many follicles (cysts that contain the eggs), which can also
make the ovaries swollen. This can be uncomfortable and is called ovarian hyperstimulation syndrome
(OHSS). OHSS can make a woman feel bloated, can cause weight gain, and can lead to fluid collecting
in the abdomen or lungs, which may require hospitalization for close monitoring. OHSS can also make
the blood “thicker” so that it clots too easily (hypercoagulability).

Possible alternatives include obtaining the eggs through a laparoscopic approach, which requires more
anesthesia. Risks include infection; bleeding; injury to internal organs including the female organs, blad-
der, intestines, and major blood vessels; thromboembolic phenomenon (blood clots); complications from
anesthesia; need for further surgery such as laparoscopy or laparotomy; and death. I acknowledge that
no guarantee or assurance has been made as to the results that may be obtained. Sometimes an estimate
of the number of eggs expected is given, but it can be more or less than that number, including zero.

I consent to the administration of an anesthetic to be given by or under the direction of the anesthesiol-
ogy department or company, or the surgeon, or whomsoever he/she may designate, using anesthetics as
may be deemed desirable with the exception of __________________________ [if none, state]. The
anesthesia may be intravenous medicine to make me sleepy; general anesthesia; or epidural or spinal
anesthesia.

I CERTIFY THAT I HAVE READ AND FULLY UNDERSTAND THE ABOVE CONSENT TO TREAT-
MENT AND/OR OPERATION AND/OR PROCEDURE, THAT THE EXPLANATIONS THEREIN
REFERRED TO WERE MADE, THAT ALL BLANKS OR STATEMENTS REQUIRING INSERTION
OR COMPLETION WERE FILLED IN, AND THAT INAPPLICABLE PARAGRAPHS, IF ANY, WERE
STRICKEN AND INITIALIZED BY ME BEFORE I SIGNED.

SIGNATURE ____________________________________ DATE ________________

WITNESS ______________________________________ DATE ________________

3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 96

96 A.N. Beltsos

Consent for Procedure/Anesthesia: Ultrasound-Guided Follicle Aspiration

with Laparoscopic Surgery with Tubal Transfer
PATIENT __________________________________
AGE _________
DATE _______________ TIME ____________ PLACE ______________

I hereby authorize (doctor) _________________________________, M.D. and whomever he/she may

designate as the assistants to administer such treatment as may be necessary for and/or to perform upon
myself the following procedure:

ULTRASOUND-GUIDED FOLLICLE ASPIRATION WITH LAPAROSCOPIC SURGERY WITH TUBAL

TRANSFER [Transvaginal ultrasonography is performed with a needle attached to aspirate (“suck out”)
the eggs. Then laparoscopy is performed to place the egg and sperm in the tube.]

If any unforeseen condition arises during the course of the procedure, calling, in his or her judgment,
for procedures in addition to, or different from those contemplated, I further request and authorize (a)
the administration of blood during and immediately after the operation as deemed necessary by the sur-
geon and/or anesthesiologist; (b) disposal of any tissue removed from my body in a manner customary
to the facility; and (c) taking photographs as deemed desirable by the attending physician and/or anes-
thesiologists.

The nature and the purpose of the procedure includes retrieving the eggs as described above. Usually,
fertility medicine has been utilized to make many follicles (cysts that contain the eggs), which can also
make the ovaries swollen. This can be uncomfortable and is called ovarian hyperstimulation syndrome
(OHSS). OHSS can make a woman feel bloated, can cause weight gain, and can lead to fluid collecting
in the abdomen or lungs, which may require hospitalization for close monitoring. OHSS can also make
the blood “thicker” so that it clots too easily (hypercoagulability).

Possible alternatives include obtaining the eggs through a laparoscopic approach, which requires more
anesthesia. Risks include infection; bleeding; injury to internal organs including the female organs, blad-
der, intestines, and major blood vessels; thromboembolic phenomenon (blood clots); complications from
anesthesia; need for further surgery such as laparoscopy or laparotomy; and death. I acknowledge that
no guarantee or assurance has been made as to the results that may be obtained. Sometimes an estimate
of the number of eggs expected is given, but it can be more or less than that number including zero.

I consent to the administration of an anesthetic to be given by or under the direction of the anesthesiol-
ogy department or company, or the surgeon, or whomsoever he/she may designate, using anesthetics as
may be deemed desirable with the exception of __________________________ (if none, state). The
anesthesia may be intravenous medicine to make me sleepy; general anesthesia; or epidural or spinal
anesthesia.

I CERTIFY THAT I HAVE READ AND FULLY UNDERSTAND THE ABOVE CONSENT TO TREAT-
MENT AND/OR OPERATION AND/OR PROCEDURE, THAT THE EXPLANATIONS THEREIN
REFERRED TO WERE MADE, THAT ALL BLANKS OR STATEMENTS REQUIRING INSERTION
OR COMPLETION WERE FILLED IN, AND THAT INAPPLICABLE PARAGRAPHS, IF ANY, WERE
STRICKEN AND INITIALIZED BY ME BEFORE I SIGNED.

SIGNATURE ____________________________________ DATE ________________

WITNESS ______________________________________ DATE ________________

3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 97

8. Anesthesia in the Office 97

Appendix J: Postoperative Checklist

Check off list as indicated or completed.

 Patient recovered in recovery room for appropriate time. Recommendations for the anesthesia
includes minimal durations of observation of:
MAC: 1 hour
GENERAL: 2 hours
REGIONAL: until sensation returns
 Received necessary antibiotics.
 When time has ended and if no nausea or emesis, attempt oral intake.
 When tolerating oral intake and/or no nausea or vomiting is present, discontinue IVF.
 Voiding without difficulty.
 Count from sponge, instruments, needles was correct at end of case.
 Operative complications: No: _____ Yes: _____
 If yes: ______________________________________________________
 Anesthesia complications: No: _____ Yes: _____
 If yes: ______________________________________________________
 If any complications, what (if any) follow-up is necessary?
________________________________________________________________________________
 Waiting husband or significant other notified that surgery is complete.
 Operative report signed by surgeon as indicated.
 Anesthesia report is signed by anesthesia specialist as indicated.
 If laparoscopy, prescription for pain medicine given.
 If SBE prophylaxis, prescription for postoperative antibiotic given.
 Discharge instructions reviewed with patient and significant other is signed; copy given to patient
and original put in chart.
 Any other medical condition addressed as needed.
 Patient given instructions for progesterone post-ART procedure as indicated.
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 98

98 A.N. Beltsos

Appendix K: Discharge Instructions for

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

Signature ________________________________________
Date _______________________
Witness ______________________________________________
Date _______________________
3051_Seifer_08_p77-99 11/5/01 9:47 AM Page 99

8. Anesthesia in the Office 99

Appendix L: Discharge Instructions for a Laparoscopic Procedure

1. No driving for 24 hours; therefore someone must drive you home.
2. A responsible adult should be with you when you go home today.
3. No tampons, intercourse, or douching for 2 weeks or when allowed by physician.
4. Rest at home the first few days following surgery.
5. You may increase your activity as tolerated the day after surgery and return to work if you desire.
Stairs are okay if you are able. This does not include exercise.
6. You may shower or bathe the day of surgery with assistance. Do not bathe or shower if you are
groggy from anesthesia.
7. Exercise may be attempted 2–4 weeks after surgery if you feel up to it and if it is okay with your
doctor. If your ovaries are swollen from the fertility medicines (“ovarian hyperstimulation syn-
drome”), you should not exercise until given the okay from the doctor.
8. You may return to work within 2–3 days if you feel up to it and it is not physically challenging. No
heavy lifting for 2–4 weeks.
9. You may eat or drink as you feel up to it. Avoid alcohol until your doctor says it is okay.
10. If you do not have a bowel movement within 2 days after the surgery, try a laxative or an enema.
11. For pain, you may take the pain medicine from the prescription or acetaminophen (Tylenol). If this
does not help, call your doctor.
12. You may have a sore throat from the surgery and anesthesia. Gargle with warm salt water and drink
hot tea with real lemon.
13. You may have shoulder pain from the surgery (“referred pain”). Hot tea with lemon can be helpful.
Also curl up with a pillow, face down, with knees curled up under you. It may alleviate some of the
discomfort.
14. If you have:
Heavy vaginal bleeding
Fever over 100.5°F, 6 hours apart or over 101.0°F at any time
Persistent nausea or vomiting
Significant abdominal pain
Inability to urinate
Swelling or pain of your leg(s)
Difficulty breathing
Chest pain
Persistent drainage of fluid or blood from your incisions
Any urgent questions or problems
Call the office immediately at phone number _____________________________
15. The day of surgery you should take progesterone as instructed by the ART nurse.
Day of surgery: ______________________________________
Starting the day after surgery (date __________), take _____________________________.
16. You may be asked to have tests done following surgery.
Date: ______________________
Test: ___________________________________________
Date: ______________________
Test: ___________________________________________
Date: ______________________
Test: ___________________________________________
Signature ________________________________________
Date _______________________
Witness ______________________________________________
Date _______________________
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 100

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

Ovulation induction with human pituitary gonado- Physiology

tropins (hPG) was first achieved in 1958. Subse-
quently, urinary menopausal gonadotropins (hMG) Gonadotropins, whether derived from pituitary
were successful in the treatment of anovulatory glands, extracted from postmenopausal urine, or
infertile women. Clomiphene citrate was first re- developed using recombinant technology, have
ported in 1961 to be successful in ovulation in- similar receptor binding characteristics and stimu-
duction and conception. Since then, ovulation in- latory effects in the ovary yielding similar results.
duction using exogenous gonadotropins has been Preparations contain varying quantities and ratios
successful in amenorrheic women with functional of follicle-stimulating hormone (FSH) and luteiniz-
ovarian tissue, and fecundity rates of 15–30% are ing hormone (LH) or no LH. Current dogma sug-
now expected. Women with chronic anovulation gests that both FSH and LH are required to stimu-
and women who fail to ovulate with clomiphene late folliculogenesis and result in ultimate ovulation
citrate may also be candidates for treatment with (Table 9–1). The amount of LH required appears to
exogenous gonadotropins. be low, as evidenced by successful ovulation in
Initially, functional disorders of the pituitary patients using pure FSH products. According to the
gland causing amenorrhea were successfully treated two-cell theory, FSH is necessary for recruitment
with exogenous gonadotropins. Now indications for of the follicles and stimulation of the granulosa
treatment include other chronic anovulatory disor- cells, and it is most likely responsible for selecting
ders, luteal phase dysfunction, cervical factor, and the dominant follicle. LH stimulates the thecal cells
idiopathic (unexplained) infertility. Exogenous go- to produce androgens, which are subsequently aro-
nadotropins have also been given to normal ovula- matized to estrogens by granulosa cells under the
tory women to improve follicular stimulation and influence of FSH stimulation. This synergistic ac-
oocyte harvesting during assisted reproductive tech- tion of FSH and LH results in rising estrogen lev-
nologies. els in the follicular fluid. These estrogens in turn
In this chapter we review the indications for influence the rate of follicular growth and the dif-
treatment with exogenous gonadotropins and pa- ferentiation of follicular cells through the stimula-
tient selection. Methods to monitor patient response tion of gonadotropin receptor synthesis. Ovulation
to improve efficacy and ultimately avoid compli- results when appropriate physiologic FSH/LH
cations are discussed. Complications of therapy are ratios are secreted from the pituitary gland. The
mentioned and addressed in greater detail in Chap- pituitary gland is dependent on the pulsatile deliv-
ter 19. We review expected outcomes of treatment ery of gonadotropin-releasing hormone (GnRH)
and introduce the recombinant products currently from the hypothalamus. Significant alterations of
available. In the latter section, we review the indi- either pulsatile GnRH secretion or pituitary gonad-
cations and rationale for controlled ovarian hyper- otropin secretion patterns result in anovulation.
stimulation in conjunction with intrauterine insem- Abnormal gonadotropin pulsatility can cause ex-
ination (COH/IUI) in apparently ovulatory women cessive circulating LH, which leads to elevated
with unexplained infertility. androgens and creation of an androgenic milieu.

100
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 101

9. Ovulation Induction and Intrauterine Insemination 101

TABLE 9–1. Mechanisms of Action of FSH and LH or hCG support; and without the luteotropic effects
Follicle-stimulating hormone (FSH) of hCG or LH, a truncation of menstrual cycle
Granulosa cell membrane binding length is observed. Short luteal phase lengths, pre-
Activation of adenylate cyclase system mature menstruation, and early pregnancy wastage
Synthesis of cytochrome P450 aromatase occurs without the provision of continued luteo-
Induction of luteinizing hormone (LH) receptors
Enzyme activation for P synthesis tropic support. This co-dependence led to the now
Luteinizing hormone widely used combination of gonadotropins and
Provides androgen substrate for FSH-induced aromatase hCG or LH for ovulation induction.
Resumption of oocyte meiosis
Cumulus oöphorus maturation
Follicular rupture
Corpus luteum formation and support Drugs
Pharmaceutical preparations of gonadotropins play
an important role in the treatment of infertility.
This androgenic environment promotes follicular They are used to stimulate follicular development
atresia, which is not conducive to normal follicu- in anovulatory women and for stimulating multiple
logenesis. This condition is most commonly seen follicular developments in women undergoing
in conjunction with polycystic ovarian disease assisted reproductive techniques (ARTs). In men,
(PCO). FSH is utilized to initiate and maintain spermato-
The administration of gonadotropins can override genesis in those with hypogonadotropic hypogo-
normal ovulatory mechanisms for ovarian follicu- nadism. It is usually administered in combination
logenesis, as evidenced by the use of these agents with LH.
in normogonadotropic women undergoing in vitro Gemzell first used human FSH in women in 1960
fertilization (IVF) treatments. The timing of the to treat anovulatory infertility, and pregnancies
administration of gonadotropins is critical. Signifi- were reported. This human FSH was derived from
cantly more follicles are recruited and selected if human pituitaries. Subsequently, gonadotropins
hMG is administered early in the follicular phase. were extracted from postmenopausal urine (hMG);
Therefore the number of follicles recruited and hMG contains a mixture of FSH and LH. They were
selected are dependent on both the timing of gonad- quite effective, and for the next 30 years they
otropin administration and the FSH content of the became the standard for therapy. Since then, there
gonadotropin preparation. have been many efforts to develop more purified
Luteinizing hormone continues to determine the urinary products. These products were subject to
steroidogenic pattern and the final maturation of the LH antibody treatment to remove the LH content
dominant follicle. Subsequent ovulation is induced from the final product (Table 9–2). Up to now, hCG
by a surge of spontaneous LH activity (after ade- has been derived from the urine of pregnant women.
quate exposure of the pituitary gland to estrogens) Until recently gonadotropins were of urinary ori-
or by the administration of an LH-like material such gin. This source implies a number of disadvantages
as human chorionic gonadotropin (hCG). Because and concerns. One concern is the small risk of
the occurrence of a spontaneous endogenous LH transmitting infectious agents such as viruses, as
surge is infrequent during gonadotropin therapy, reported in some pituitary-derived growth hormone
LH or hCG is necessary for ovulation to occur after products. This has not been reported with the use
gonadotropin-induced follicular growth and, more of the urinary products. The disadvantages include
importantly, for maintenance of the corpus luteum. low purity, no absolute source control, cumbersome
The corpus luteum is dependent on continued LH collection of urine, some LH contamination even

TABLE 9–2. Preparation of Human Gonadotropins

FSH activity LH activity
Preparation Source (IU) (IU)
hMG Urine 75 75
uFSH Urine 75 0.7
uFSH-HP Urine 75–150 0.001
rFSH CHO cells 75–150 None

hMG, human menopausal gonadotropin; u, urinary; HP, highly purified; CHO, Chinese hamster ovary; rFSH, recombinant FSH.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 102

102 R.L. Collins

in pure FSH products, and low specific activity. The and ruled out. Evaluations should exclude other
recently developed recombinant products are nearly causes of amenorrhea and anovulation treatable by
100% pure, devoid of contamination, and demon- other direct means, such as hyperprolactinemia.
strate batch-to-batch consistency. Patients with hyperprolactinemia, either idiopathic
Through the application of recombinant DNA or secondary to small pituitary microadenomas,
technology, it is now possible to produce human can be considered candidates for gonadotropin
gonadotropins (hFSH, hLH, hCG) for medical use therapy if they were unresponsive or intolerant to
without having to extract them from human fluids. primary therapy, such as dopamine agonists (i.e.,
These recombinant products are produced in vitro bromocriptine).
by genetically engineered mammalian cells [Chi- All patients should undergo a basic infertility
nese hamster ovary (CHO) cells]. The technical investigation to rule out other causes. Pretreatment
description of the development of the products is studies should include a semen analysis to verify
beyond the scope of this chapter. The production that the man does not have severe oligospermia,
of these products by recombinant (r) technology azoospermia, or another gross abnormality. The
results in the formulation high specific activity, uterine and tubal factors should be investigated by
consistent batch to batch products suitable for clin- hysterosalpingography, saline infusion sonography
ical use. Several studies have demonstrated similar (SIS), or office flexible hysteroscopy. Diagnostic
pharmacokinetic characteristics between the re- laparoscopy with chromopertubation should be
combinant FSH (rFSH) and urinary FSH (uFSH) considered prior to initiation of treatment to assess
preparations. The bioavailability is approximately completely and possibly treat tubal or peritoneal
60% and is comparable after both subcutaneous and factors. These pretreatment procedures ensure that
intramuscular administration. After subcutaneous there are no contraindications to therapy.
administration the apparent half-life is FSH is ap- Extensive counseling of the couple regarding
proximately 37 hours. For clinicians, this means side effects, risks, expenses, logistics of treatment,
that rFSH can be administered using doses and and prognosis should be done before therapy. The
schedules previously utilized in their urinary impact of pregnancy on their health or any under-
gonadotropin protocols. lying medical condition should be considered.
Many studies have assessed the clinical useful- Risks such as ovarian hyperstimulation, multifetal
ness and overall safety of these recombinant prod- pregnancies, and treatment cycle cancellation due
ucts. Routes of administration—subcutaneous, in- to hyperstimulation should be discussed with the
travenous, intramuscular—have been compared, patient. Because high order pregnancies can result,
and no differences have been found. The usefulness selective fetal reduction procedures, although con-
of rFSH in patients with LH excess, such as those troversial and highly sensitive, should be given spe-
with PCO and those almost devoid of endogenous cial attention. Counseling should be based on sci-
LH) has been demonstrated. Comparisons have entific and factual data. The duration of treatment
been made between rFSH and uFSH in (OI) pro- should be discussed beforehand. The couple should
tocols as well as in ART, with or without agonists be advised that the chance of conceiving during any
or antagonists. It is clear that FSH-induced one course is approximately 25%, and the average
steroidogenesis was not jeopardized after GnRH number of treatment courses needed to achieve a
agonists induced pituitary suppression. In one study pregnancy is three. Overall, 60% of couples con-
that summarized several papers, involving more ceive within 4 months.
than a 1000 ART treatment cycles, comparisons All anovulatory patients may be classified as
were made between uFSH and rFSH products. It having (1) hypogonadotropic hypogonadism, (2)
indicated that after rFSH treatment significantly euestrogenic normogonadotropic euprolactinemic
more oocytes were retrieved, more embryos were ovulatory dysfunction, or (3) hypergonadotropic
obtained, and more pregnancies resulted. hypogonadism. The categories correspond with
World Health Organization (WHO) classes 1, 2,
and 3, respectively. Patients with hypogonadotropic
Patient Selection hypogonadism have signs and symptoms of estro-
gen deficiency including amenorrhea and failure to
Ovulatory dysfunction is usually a symptom of an respond to progestin withdrawal, low concentra-
underlying disease process. Patients should be tions of gonadotropins, and low serum estrogen
evaluated to include an assessment of the overall levels. Women in this group include those with
health. Thyroid dysfunction, hyperprolactinemia, stress- or exercise-induced amenorrhea, low-
and other endocrinopathies should be considered weight-related amenorrhea, pituitary adenomas,
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 103

9. Ovulation Induction and Intrauterine Insemination 103

isolated gonadotropin deficiency, and hypothalamic There are rare instances where exogenous gonado-
amenorrhea. tropins are reported to have induced ovulation in
The next classification group is called euestro- hypergonadotropic hypogonadal patients with sus-
genic normogonadotropic ovulatory dysfunction. pected premature ovarian failure or resistant ovary
Women in this diagnostic category have serum con- syndrome (Savage syndrome).
centrations of gonadotropins in the normal range Patients who are clomiphene failures (both con-
and in some cases slightly elevated LH. Included ception and ovulatory failures) may also be candi-
in this group of disorders are polycystic ovary syn- dates for gonadotropin therapy. The use of gonad-
drome and luteal phase defect. otropin in women with cervical factor infertility
Women with hypergonadotropic hypogonadism after failed conventional therapy has been success-
have elevated serum concentrations of FSH and LH ful. Despite the fact that gonadotropins can also be
and abnormally low concentrations of estrogen. associated with induction of a luteal phase defect,
This group includes women with premature ovar- gonadotropin stimulation protocols have also been
ian failure, which may be idiopathic or induced by used to correct a preexisting luteal phase defect.
autoimmunity, surgery, chemotherapy, or irradia- Unexplained (idiopathic) infertility is another indi-
tion. These disorders are characterized by endoge- cation for gonadotropins.
nous gonadotropin elevation, and these patients do
not benefit from additional exogenous gonadotro-
pins. Clinical Monitoring
Ideal candidates for ovulation induction with
gonadotropins have functional ovarian tissue and Proper monitoring of the patient’s ovarian response
low endogenous gonadotropin secretion patterns is mandatory to determine dosage of drugs, opti-
that are amenorrheic or anovulatory (Table 9–3). mize therapeutic benefits, time hCG administra-
These patients (i.e., normoprolactinemic eugonado- tion, and minimize risks. Without proper monitor-
tropic anovulation, or hypogonadotropic hypogo- ing gonadotropins may cause severe adverse
nadism) may also be candidates for pulsatile GnRH reactions including superovulation, multiple preg-
treatment. nancies, and the ovarian hyperstimulation syn-
Prior to treatment it is necessary to document the drome (OHSS). Early experiences with induction
presence of functional ovarian follicles. Women of ovulation with human gonadotropins demon-
responsive to a progesterone challenge, who pre- strated the dual risk of OHSS and the occurrence
sent clinically with severe oligomenorrhea or of multiple gestations. Monitoring should involve
amenorrhea, are presumed to have endogenous serial serum estradiol determinations and ultrasonic
estrogen secretion and therefore have functioning follicular measurements. Clinical monitoring is less
follicles. Women with primary or secondary amen- precise and insensitive for achieving the above
orrhea who do not have uterine bleeding after pro- goals.
gesterone administration are presumed to be estro- The clinical assessment of early investigators uti-
gen-deficient, and these patients should undergo lized careful assessment of cervical mucus pro-
further evaluation. Measurement of the serum FSH duction and monitoring of preovulatory ovarian
level is indicated. Elevated FSH concentration size by pelvic examination. However, it became
(hypergonadotropic hypogonadism) is consistent apparent that there were significant variations in the
with ovarian failure, and these women are usually responsive cervical mucus production among the
not candidates for treatment with ovulatory drugs. individuals. A major source of this difficulty lay in
the fact that the cervical mucus response was insen-
sitive to subtle estrogen changes and maximum at
TABLE 9–3. Clinical Indications for Gonadotropin the estrogen concentrations that optimized the preg-
Therapy nancy rate. There was no room for an increased
response to signal ovarian hyperstimulation.
Hypothalamic amenorrhea
Hypogonadotropic hypogonadism
Previously, the detection of preovulatory ovarian
Chronic anovulation (clomiphene citrate failure) enlargement by pelvic examination was the only
Luteal phase dysfunction other parameter available to signal hyperstimula-
Cervical factor tion. The impreciseness of the bimanual examina-
Timing artificial insemination tion limited its ability to predict accurately the
Unexplained infertility
Follicular development during ART development of OHSS. Also, the lack of ovarian
enlargement did not exclude the hyperstimulation
ART, assisted reproductive technologies. syndrome. Because of the limitations of the clini-
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 104

104 R.L. Collins

cal parameters experienced by earlier investiga- Transvaginal ovarian ultrasonography (TVUS) is

tions, their use alone today for the purpose of mon- performed serially to determine the number of fol-
itoring ovarian response is inappropriate. licles being stimulated and to monitor follicular
Taymor reported data indicating the successful sizes to time hCG administration (Fig. 9–1). The
use of 24-hour serial urinary estrogen determina- addition of follicular ultrasonographic scanning to
tions for monitoring ovulation induction. Urinary the clinical monitoring protocol has allowed the use
determinations of estradiol, estrone, estriol, and of gonadotropins in a safer environment. Difficult
pregnanediol have all been used to monitor the patients can be pushed harder, and extremely brit-
ovarian response. Determination of a specific estro- tle patients with rapid estradiol rises can be moni-
gen was not found to be superior to determination tored more accurately with ultrasonography. Im-
of the total urinary estrogen secretion. An optimal provements in ultrasound equipment and the
excretion rate of total urinary estrogen was deter- development of vaginal probes with superior imag-
mined to be 50–60 g per day, with the upper safe ing qualities have provided exquisite details of fol-
limits of total urinary estrogens being variably licular development.
established as 100–150 g per day. The above Ultrasonography has been used to observe fol-
estrogen ranges are consistent with maximum con- licular growth during normal menstrual cycles and
ception rates, and the incidence of hyperstimula- during gonadotropin treatments. Follicular growth
tion and multiple births is reduced. There is no sig- was noted to be linear during the ultrasonic exam-
nificant effect of injection time on the urinary ination, and there appeared to be strong correlations
estrogen result so along as the injections are given between follicular growth and estradiol measure-
once daily. ments. Furthermore, it became possible to observe
The difficulty of collecting complete 24-hour the development of multiple follicles and to assess
samples and the availability of a rapid radioim- the risk of multiple gestations or the occurrence of
munoassay for plasma estradiol led investigators to OHSS. Sonographic visualization may also be used
abandon urinary estrogen determinations. Because to discriminate between single and multiple follic-
plasma estradiol was determined on a single sam- ular growth, and it may therefore aid in clarifying
ple of blood, the timing of the sampling relative to the source of estradiol. Because the prevailing evi-
the previous injection of gonadotropin became a dence suggests that follicles with diameters of
critical variable. A study of the plasma estradiol 16–22 mm will ovulate, sonography may be a more
concentrations over the 24-hour period following precise predictor of the subsequent development of
injection of the gonadotropin demonstrated that OHSS and may become a more precise indicator
although the 24-hour plasma estradiol value corre- for determining the time of hCG administration to
lated with the level of ovarian stimulation, plasma cause ovum release. Ultrasonic monitoring of fol-
estradiol concentrations were maximum during the licular growth during ovulation induction is dis-
8- to 10-hour postinjection interval. At midcycle in cussed in greater detail in Chapter 4.
normal ovulatory women, the serum estradiol con- Ultrasonography has also been used to document
centration varies between 200 and 400 pg/ml. and observe morphologic changes in the cervix
Higher levels of estradiol are necessary to increase
the probability of conception, and Tredway con-
cluded that raising the estradiol level from 500 to
1000 pg/ml could increase the rate of ovulation.
Associated with these higher plasma estradiol lev-
els were increased rates of ovulation, pregnancy,
and OHSS. Despite later experiments, no unifor-
mity has been established, and there has been a ten-
dency to allow higher levels of estrogen prior to
hCG. This can be accomplished when ultrasonog-
raphy is used to follow follicular development.
Consequently, the estrogen level above which hCG
is withheld to minimize the development of OHSS
has varied greatly (from more than 500 pg/ml to
more than 2000 pg/ml). It is important to use
threshold estradiol values that correspond to your
laboratory and to individualize patient management FIGURE 9–1. Multiple follicles in polycystic ovarian
in cases that exceed this threshold. disease.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 105

9. Ovulation Induction and Intrauterine Insemination 105

endometrial thickness was 9 mm or 13 mm dur-

ing IVF treatment cycles. This relation was not
seen following ovulation induction during non-IVF
treatment cycles. Yet there may be a minimal endo-
metrial thickness that is associated with conception;
in fact, this concept of a minimal endometrial thick-
ness is becoming widely accepted. The minimal
endometrial thickness varies between 5 and 8 mm
when measured during the late proliferative to early
luteal phase.
It must be emphasized that ultrasonography
should not replace serum estradiol determinations.
The results of ultrasound scanning of follicular
growth are complementary to the estradiol data.
Serum estradiol levels coupled with ultrasonic find-
FIGURE 9–2. Multilayered endometrial pattern. ings provide the most information on each indi-
vidual’s ovarian response and subsequent risks for
OHSS and multifetal pregnancies (Fig. 9–3).
and endometrial cavity and canal during ovulation
induction. TVUS endometrial assessment has been
used as a noninvasive marker of endometrial recep- Typical Treatment Cycle
tivity. Two parameters were suggested to evaluate
the endometrium: endometrial thickness and endo- A physician trained and experienced in the tech-
metrial pattern. Several patterns have been de- nique should supervise ovulation induction. Such
scribed in the literature, but they have been reduced physicians should be skilled in the methods of mon-
to two grades: nonmultilayered or multilayered. A itoring and interpreting ovarian and endometrial
triple-line multilayered pattern may be the sono- ultrasound scans. The availability of rapid estradiol
graphic parameter that most reflects endometrial and progesterone assays is critical. The ability to
receptivity (Fig. 9–2). Endometrial thickness mea- interpret the assays is essential for safe and suc-
surement has been used as a clinical tool to predict cessful management of these high risk medications.
implantation following ovulation induction in both The physician should also be experienced in the
IVF and non-IVF treatment cycles. In many reports management of OHSS, which clinically varies from
conception cycles had a significantly higher mean mild bloating and weight gain to hospitalization
endometrial thickness than did the nonconception secondary to hemoconcentration, electrolyte imbal-
cycles. An ideal range for endometrial thickness ance, ascites, coagulation defects, and oliguria.
has not been established, although Dickey et al. Each patient responds uniquely and individually
observed more biochemical pregnancies when the to gonadotropins. Although multiple gonadotropin
dosages and treatment schedules have been advo-
cated, only the individualized regimen can be con-
sidered the most commonly used dosage schedule
(Table 9–4). The amount of medication and the
duration of therapy vary not only among patients
but also from one treatment cycle to another in the

TABLE 9–4. Gonadotropin Dosage Schedules

Level
Gradual increase
Intermittent therapy
Initial step-up, then step-down
Sequential estrogen-gonadotropins
Individualized based on response
Sequential clomiphene-gonadotropins
Sequential GnRH agonist-gonadotropins (down-regulation)
Simultaneous GnRH agonist-gonadotropin (flare)

FIGURE 9–3. Ovarian hyperstimulation syndrome. GnRH, gonadotropin-releasing hormone.

3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 106

106 R.L. Collins

same patient. Therefore it is imperative to monitor If intrauterine insemination (IUI) is not planned,
the patient carefully each cycle to determine when the patient is instructed to have intercourse on the
a mature follicle is present, to time hCG adminis- night of the hCG injection and again on the fol-
tration, and to assess the risk of OHSS. lowing two nights (minimally). If IUI is planned,
The patient is usually begun on two ampules of the couple is advised to have relations on the night
gonadotropins (75 IU of both FSH and LH per of hCG administration and then to abstain until the
ampule) daily early in the follicular phase or after IUI specimen is obtained. After hCG she is in-
a progestin-induced menstrual period. A prepara- structed to record her weight every other day, and
tion containing FSH only may be preferred in any total weight gain of 10 lb or more or 3 lb in
patients with PCO or who manifest other types of 24 hours is to be reported.
ovulatory dysfunction. A systematic flow sheet or A serum pregnancy test is obtained approxi-
a plot of the logarithm of the plasma estradiol ver- mately 14–20 days after the initial hCG injection
sus linear days is useful for following the ovula- if no menstrual bleeding has occurred. If the
tory response to gonadotropins and for predicting patient’s hCG is positive, ultrasonography should
the day of hCG injection. Slow or no rise in the be undertaken 2 weeks later (4 weeks following the
serum estradiol level indicates that the gonadotro- hCG injection) to determine the number and loca-
pin dose should be increased in increments, and tion of fetuses present. This timely ultrasound scan
these incremental rises should be maintained a min- allows early recognition of multiple fetuses and
imum of 72 hours prior to further increases. Ide- gives time to plan for the special care necessary for
ally, one should aim for a follicular length of ap- these high risk pregnancies or to plan for other pos-
proximately 9–12 days. Pregnancy rates are low in sible options such as selective reduction.
patients given hCG before day 6. Ectopic pregnancies can also be diagnosed early
Follicular development should be monitored by ultrasound scans before tubal rupture and dam-
with frequent ultrasound studies. Ultrasonography age. Early recognition of ectopic gestations allows
plays a critical role in assessing the response to outpatient laparoscopic or medical management
gonadotropins and timing the hCG administration. and enhances the opportunity for conservative sur-
A baseline ultrasound scan is suggested during the gical procedures to preserve the functional capac-
early follicular phase to determine the presence or ity of the fallopian tube. A typical treatment cycle
absence of persistent cysts. A blood estradiol level is summarized in Table 9–5.
is determined at baseline. If the estradiol is less than
80 pg/ml and no ovarian cysts are present, therapy
is begun. When the estradiol level significantly Clinical Results
increases, ultrasound imaging should be repeated
every 2–3 days. Scanning becomes more frequent The results of a survey of several large series of
when the follicle reaches 14 mm or more. When patients given gonadotropin therapy from several
follicles 16–18 mm or more are identified, gonad- institutions over the past 30 years indicate that
otropins are discontinued and hCG is given 24 gonadotropin therapy is successful and has become
hours after the last gonadotropin dosage to cause widely accepted. Success rates up to 30% per cycle
ovum release approximately 36 hours later. Usu- have been reported. One survey included approxi-
ally 5000–10,000 IU of hCG is given to trigger ovu- mately 12,619 treatment cycles given to approxi-
lation. To maintain corpus luteum function, a sup- mately 5000 patients resulting in more than 2100
plemental dose of 5000 IU of hCG is given
approximately 5 days after the initial ovum release TABLE 9–5. Typical Gonadotropin Treatment Protocol
injection. Some prefer multiple small injections of
hCG (1500 IU every 3 days) or progesterone sup- Baseline estradiol and transvaginal ovarian ultrasonography
Initiate therapy by cycle day 3
positories for luteotropic support. If there are signs Individualized/graduated dosage starting at 2 ampules per day
of ovarian enlargement, the estradiol level exceeds Initial estradiol and scan by day 4–5, then every 2–3 days
1000 pg/ml, or pelvic/abdominal tenderness is More frequent estradiol and ultrasonography when leading
present, the supplemental dosage of hCG (5000 IU) follicle  14 mm
Postcoital test when appropriate
is withheld. Progesterone suppositories may be Continue scans until leading follicle  16–18 mm
substituted for luteotropic support without addi- Give 10,000 units hCG 24 hours after last gonadotropin
tional stimulation from supplemental hCG. If mul- dosage
tiple (more than six) mature follicles more than Supplemental 5000 hCG 5 days later
16–18 mm are present or estradiol is excessive, Intrauterine insemination 36 hours after hCG (if necessary)
Serum hCG in 14 days after hCG
hCG is withheld and intercourse is discouraged. Ultrasonic scan 4 weeks after ovulation if pregnant
Complications such as OHSS are thus avoided.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 107

9. Ovulation Induction and Intrauterine Insemination 107

pregnancies. Patients were stratified into two tional hypophysectomy to reduce circulating LH
groups: hypothalamic pituitary failure (group I) or and to mimic the group I pituitary failure patient.
hypothalamic pituitary dysfunction (group II). By abolishing the endogenous source of gonado-
Group I patients were hypoestrogenic, character- tropin pulsatility, the investigators hopefully would
ized by low or absent endogenous GnRH pulsatil- achieve a more uniform patient response, reduce
ity. Group II patients had some endogenous GnRH individual variability, and consequently reduce the
pulsatility, albeit aberrant or dysfunctional. They risk of ovarian hyperstimulation.
were also estrogenized and progestin-responsive.
Patients with clomiphene failure were more likely
to be among the group II patients. Complications
The results of these series, summarized by
Blankstein et al., showed higher ovulatory and Complications include OHSS, multifetal preg-
pregnancy rates in the group I subjects. Of the nancy, pregnancy wastage, and an increased inci-
279 patients in group I, an 82% conception rate dence of heterotopic pregnancies. A major compli-
occurred in patients receiving gonadotropin treat- cation associated with the use of gonadotropins
ments. The cumulative pregnancy rates for the is the occurrence of OHSS. All complications of
group I patients was 91.2% after six cycles of treat- gonadotropin therapy are essentially related to the
ment, which is approximately 30% higher than the degree of ovarian stimulation during ovulation
cumulative pregnancy rate in the normal nulli- induction. Fortunately, with careful clinical, ultra-
parous population. In contrast, of the 117 patients sonographic, and biochemical monitoring, the
with hypothalamic pituitary dysfunction who failed degree of severity and the frequency of complica-
to conceive following clomiphene citrate (group II), tions can be reduced significantly. Theoretically, by
the pregnancy rate following gonadotropins was controlling the degree of ovarian stimulation, the
only 21.4% and the ovulation rate significantly less other complications of multiple pregnancy and
at 42.0%. Consequently, the success rates were pregnancy wastage can likewise be reduced. There
60.6% in group I versus 11.5% in group II in terms are no reported ovulation induction stimulation pro-
of the percentage of people who took home at least tocols that reduce the risk of ovarian hyperstimu-
one living child. The mean number of ampules of lation to zero.
gonadotropins likewise differed between groups:
40.0 for group I versus 18.2 ampules in group II.
Among the patients who conceived, 94% did so
Ovarian Hyperstimulation
within five cycles of treatment. The clinical presentation of OHSS is variable. The
These findings suggest that among the patients syndrome is characterized by ovarian enlargement,
with endogenous gonadotropin pulsatility (group ascites, hydrothorax, electrolyte imbalance, hypov-
II) there is greater patient variability and they tend olemia, and oliguria. In the severe forms hemocon-
to be more difficult to manage. This group also had centration, increased viscosity of blood, throm-
a higher risk of ovarian hyperstimulation and treat- boembolic phenomena, and hypovolemic shock may
ment cancellation. The poorer performance of occur and death may ensue. The incidence of OHSS
patients in group II who have hypothalamic pitu- is 3–23% for the mild form and 0.4–4.0% for the
itary dysfunction led investigators to consider the severe and potentially lethal form (Table 9–6). OHSS
use of GnRH agonists to create a temporary, func- is discussed thoroughly in Chapter 19.

TABLE 9–6. Incidence of OHSS After Gonadotropin Therapy

Treatment cycles Mild OHSS Severe
Study (no.) (%) OHSS (%)
Brown 222 3.2 ?
Caspi 343 6.0 1.20
Ellis 322 5.0 0.60
Spadoni 225 4.4 1.80
Thompson 2,798 a 1.30
Lunenfeld 3,646 3.1 0.25

Total 11,343 3.4 0.84

Source: Modified from Blankstein et al., 1986.

OHSS, ovarian hyperstimulation syndrome.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 108

108 R.L. Collins

One study investigated risk factors and prognos- initial pregnancy cycle following gonadotropin
tic variables in the development of OHSS. Signif- treatment, the abortion rate was 28%. In contrast,
icantly higher levels of estradiol and prolactin were during a subsequent pregnancy cycle the abortion
seen during the follicular phase in the treatment rate was only 12%, which is comparable to the
group when compared to controls. Also, there was abortion rate in the normal population. The factors
a tendency for more follicular recruitment with sig- operative in the increased abortion rate observed in
nificantly smaller follicles (12–14 mm) present on those patients were not identified, but ovarian
day 0 for all grades of OHSS. Among 22 variables hyperstimulation was suspected because approxi-
identified, an increased risk is seen only in the mately 50% of the patients with hyperstimulation
young, lean patient. Using a mathematic model for ultimately aborted.
predicting ovarian hyperstimulation, the authors in
the above study suggested that three parameters
(age, estradiol level on day 0, basal prolactin lev- Multiple Births
els) had a combined predictive value that could not The incidence of multiple births increases after
be improved with additional parameters. A pro- gonadotropin therapy. In an early report by
posed clinical profile of the patient at greatest risk Gemzell, prior to the prospective use of estrogen
for the development of the syndrome is young and data, the rate of multiple gestations was equal to
lean, receives few ampules of gonadotropins but the rate of single gestations. By controlling the
has rapidly increasing estradiol levels, and subse- degree of ovarian stimulation using plasma estro-
quently develops multiple small follicles. gen determinations coupled with frequent monitor-
Therapy for moderate to severe hyperstimulation ing by ultrasonography, the incidence of multiple
requires hospitalization and active management. births has decreased. The reported incidence of
Patients should be on bed rest with avoidance of multiple birth ranges from 11% to 44%, with most
pelvic examinations until the size of the ovaries of the multiple gestations being twins. Multiple
decreases. Baseline and serial blood chemistry pro- gestations are to be avoided because of the obstet-
files and coagulation studies should be performed. ric complications. Apart from the increased inci-
Treatment is directed at maintaining vital signs, dence of spontaneous abortions and the increased
correcting electrolyte imbalances, and maintaining obstetric risks associated with multiple gestations,
adequate hydration. Patients who become severely the outcome of pregnancies following ovulation
oliguric or anuric require renal hemodialysis. An induction using gonadotropins appears normal. In
intake–output balance should be carefully main- summary, careful monitoring has reduced the inci-
tained to prevent overhydration. Only fluid lost dence of hyperstimulation, but the incidence of
should be replaced. twins and triplets has not been significantly reduced
because they occur spontaneously in the popula-
Pregnancy Wastage tion. The frequency of births of more than triplets
appears to be reduced but not totally eliminated
Other complications of gonadotropin-induced ovu- by carefully monitoring the patient’s ovulatory
lation include an increased spontaneous abortion response to exogenous gonadotropins (Table 9–8).
rate, which has been reported to range from 12%
to 31%. In the series of patients reported by
Blankstein et al., the overall abortion rate was Gender Ratios
25.2% with no significant differences between pa- The incidence of male children in single pregnan-
tients belonging to group I or group II. However, a cies following gonadotropins therapy was 51.8%.
significant difference in abortion rate was observed The incidence of twins was 53.8% and triplets
in consecutive pregnancies (Table 9–7). During the 66.7%. The expected ratio is 1.06. The increased

TABLE 9–7. Pregnancy Wastage After Gonadotropins TABLE 9–8. Multiple Gestations (n  162)
Condition Wastage (%) Pregnancies Total no.
First conception 28 Singleton 113 (69.8%)
Second conception 12 Twins 41 (25.3%)
No treatment after gonadotropins 13 Triplets 5 (3.1%)
Hyperstimulation 50 Quadruplets 3 (1.8%)

Source: Modified from Blankstein et al., 1986. Source: Bettendorf et al., 1981.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 109

9. Ovulation Induction and Intrauterine Insemination 109

incidence of male births in Bettendorf et al.’s series induced ovulation induction are at any greater
is probably due to the small numbers involved in risk of malformations than the general population
the study. In reviewing the literature, the expected (Table 9–9).
gender ratio is approximated when several series
are combined. There is no increased tendency in
either direction. In a large series of patients reported Controlled Ovarian
by Ben-Rafael et al., 256 children were born in 195 Hyperstimulation and
births to 176 women; the secondary gender ratio
was 50% male and 50% female. The same trend Intrauterine Insemination
was observed for singletons and twin gestations.
Mechanism of Action
Spontaneous Conception After Controlled ovarian hyperstimulation (COH) is
Gonadotropin Therapy the intentional induction of multiple ovulation to
increase the number of eggs ovulated in an other-
Few studies have reported on spontaneous pregnancy wise normally ovulating woman. COH is often car-
rates after gonadotropin-induced pregnancies. Go- ried out with intrauterine insemination (IUI) with
nadotropin treatment does not cure the patient per- washed sperm. Sperm washing allows selection of
manently of her ovulatory disorder. A larger series sperm with the most normal morphology and motil-
reported by Ben-Rafael et al. showed that among 141 ity and with the absence of antibodies, white blood
women who had previously conceived using gonad- cells, and infectious organisms. IUI avoids cervical
otropin therapy the cumulative spontaneous preg- problems such as poor mucus, cervical antibodies,
nancy rate was 30.4% after 5 years. The miscarriage and infection.
rate was 29.0% in gonadotropin-induced pregnancy, The rationale for COH/IUI is that the IVF preg-
whereas the subsequent pregnancy enjoyed a mis- nancy rate varies as the number of embryos trans-
carriage rate of 8.8%. The cumulative pregnancy rate ferred are increased, and the IVF fertilization rate
of 30.4% was much lower than that in a group of varies with the number of sperm present; therefore
normal parous women. Another study, by Lam et al., increasing the number of eggs and the number of
indicated a much lower spontaneous conception rate sperm creates a possible improvement in the num-
of 66.4% at 115 months when compared to the ber of sperm at the fertilization site and sperm
88.6% at 23 months during the first course of gonad- capacitation. Follicular endocrine function and
otropin therapy. They concluded that women receiv- oocyte release may be affected; and tubal oocyte
ing gonadotropin therapy have an 11-fold better capture, secretory function, and transport may be
chance of conceiving in a given cycle. The baseline improved. Endometrial receptivity may also be
estrogen and FSH levels, diagnosis, previous result improved because of increased estrogen and pro-
of gonadotropin therapy, age, and menstrual pattern gesterone levels. Placing a large number of sperm
did not affect their fertility potential. This contrasted close to a large number of eggs empirically results
with Ben-Rafael et al.’s study, which found a lower in higher pregnancy rates.
cumulative spontaneous pregnancy rate in patients
with low baseline gonadotropin and estrogen levels.
Indications and Contraindications
The COH/IUI option is indicated in women with
Congenital Anomalies unexplained infertility, prolonged subinfertility,
The clinical data available in the literature do not in- cervical factor infertility, or stage I or II endome-
dicate that babies born as a result of gonadotropin- triosis and in women with two ovaries and one

TABLE 9–9. Congenital Anomalies After Gonadotropin-Induced Conceptions

Study Infants (no.) Anomalies (no.)
Thomspon et al. 358 5 (1.4%)
Schwartz et al. 211 2 (0.9%)
Hack et al. 115 4 (3.1%)
Spadoni et al. 36 2 (5.5%)
March 63 1 (1.6%)
Total 783 14 (1.8%)

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

3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 110

110 R.L. Collins

TABLE 9–10. Candidates for Controlled Ovarian The density gradient technique employs solu-
Hyperstimulation/Intrauterine Insemination tions of high molecular weight, inert compounds
Unexplained infertility that establish a density gradient through which the
Minimal endometriosis semen contents are centrifuged. The gradient is
Immunologic infertility constructed in a way that allows most of the mor-
Luteal phase defects phologically normal sperm to sediment to the bot-
Oligoasthenospermia
Cervical factor infertility tom of the tube, whereas the abnormal forms, non-
sperm cells, and cellular debris float in the upper
parts of the gradient. Sperm recovery is usually
much better with this technique. (Figure 9–4).
fallopian tube (Table 9–10). Contraindications for Another, less desirable technique is direct sperm
COH/IUI include ovarian failure, significant pres- washing (SW). SW is a common method used in
ence of male factor, significant tubal adhesions or many physicians’ offices, as it is simple and can be
tubal dysfunction, or significant uterine abnormal- performed in a minimum amount of time; however,
ities. it offers no improvement of sample motility and
Intrauterine insemination is not necessary for permits contamination of the uterus with extracel-
insemination of normal women with normal semen, lular material and nonsperm cells. Sperm washing
but it has been shown to be definitely effective for should be used only when the semen sample is rel-
insemination of normal women with cryopreserved atively clear of debris, bacteria, and round cells or
semen. It is probably effective for cervical factor where there are so few motile cells that any other
infertility, men with semen anti-sperm antibodies separation technique would harm the sample. See
or retrograde ejaculation, and as an adjunct to Appendix A for a complete description of each
superovulation. It is probably not effective for male technique.
factor infertility.
Frozen Sperm
Administration The use of frozen semen for IUI is relatively com-
mon for a variety of infertility diagnoses. It is
Patients may be treated with gonadotropins, as highly successful in initiating pregnancy among the
described. Ovarian stimulation to induce super- normal female population, and inseminations are
ovulation is carried out in a fashion similar to that commonly performed one of two ways: intracervi-
in women with ovulatory dysfunction. IUI is per- cal (ICI) or intrauterine (IUI). Frozen sperm is pur-
formed 36 hours after hCG is given. chased by the patient from any of the approved cry-
obanks. Thawing procedures are recommended by
Sperm Preparation the supplier and must be followed to not jeopard-
ize any warranties provided in the purchase.
Fresh Semen
The method for sperm selection and separation for
the placement of sperm directly into the uterus is
left to the discretion of the clinician or andrologist.
The preparation yielding the largest population of
highly motile cells free of other cellular and chem-
ical components of the seminal plasma is preferred.
The choice of technique is based on the initial qual-
ity of the sample. The most commonly used meth-
ods are the standard swim-up and density gradient
preparations.
The swim-up (SU) procedure separates the
motile sperm from other components of the ejacu-
late by allowing the sperm to swim up and out of
the ejaculate. Recovery of motile sperm is usually
poor with the SU method, and therefore only sam-
ples of low viscosity and with a high concentration/
large percentage of motile sperm should be used FIGURE 9–4. Sperm prep for IUI by density gradient cen-
(Appendix A). trifugation.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 111

9. Ovulation Induction and Intrauterine Insemination 111

Intracervical inseminations with frozen sperm non-IUI cycles. Concerns have also been raised
are the simplest and in most cases do not require about the possible production of anti-sperm anti-
extensive laboratory preparation other than thaw- bodies, although data do not conclusively demon-
ing. Refer to the procedure by the respective sup- strate any clinically significant problems with this
plier. The IUI procedure involves more detailed procedure.
processing aimed chiefly at creating a clean sam-
ple free from any proteins or seminal fluids. IUIs Ongoing Management
require the sperm to be deposited directly into the
uterine cavity, eliminating cell selection by cervi- Generally, three or four cycles of COH/IUI are
cal mucus. The procedure requires use of a clean clinically appropriate. A maximum number is four
sample. Many cryoprotectants and seminal fluid cycles of hMG/IUI in selected patients. Some con-
components create severe cramping when put into troversy exists as to the optimal number of insem-
the uterus and are extremely painful to the woman. inations per cycle. Data generally support one well
Some suppliers provide samples prepared and la- timed IUI when adequate numbers of sperm are
beled for direct IUI use. Further processing is not present. In addition, at least 3 million total motile
necessary and would void any guarantee. Androlo- sperm should be available for IUI. Any number
gists must identify the sperm supplier and use the lower than this results in lower pregnancy rates.
recommended thawing protocol. Pregnancy rates increase slightly with 5 million
The protocol described in Appendix B is to be total motile sperm per inseminate and increase only
used as additional processing to prepare an intra- minimally with more than 5 million total motile
vaginal or intracervical frozen specimen for IUI use. sperm per inseminate.
Pregnancy rates that approach the fecundity of
normal women and that equal or exceed the preg-
Results nancy rates reported for IVF and GIFT have been
There is a wide range of success reported: cycle reported. If the rationale for GIFT is delivery of
fecundity after clomiphene citrate/IUI, increasing increased numbers of gametes at the site of fertil-
from 25% to 100% and after gonadotropins increas- ization in normal fallopian tubes, the combination
ing from 50% to 300%. Cycle fecundity may range of gonadotropin/hCG superovulation and IUI can
from 4% per cycle with male factor infertility to accomplish that goal without the expense and risk
25–30% per cycle for minimal endometriosis in of operative intervention. Cycle fecundities of 0.17
women less than 30 years of age. Multiple preg- for endometriosis, 0.29 for cervical factor, and 0.19
nancies with approximately 25% twins, 5% triplets, for idiopathic infertility have been reported and
and 2% quadruplets occur, which is similar to the seem to justify the expense and risks of COH/IUI.
results of ovulation induction without IUI. Ectopic The major criticism of that study was that it was
pregnancy occurs in up to 5–10% of patients. Most an uncontrolled, retrospective analysis. Prospec-
of the pregnancies occur within two to four cycles tive, controlled comparisons of IVF, GIFT, and
of treatment. Birth defects are the same as those in superovulation with IUI are still lacking. Nonethe-
the general population. less, the data suggest that the provision of multiple
Recently, a trial of controlled superovulation gametes and correction of subtle ovulatory dys-
with gonadotropins/hCG in combination with IUI function may be the mechanism(s) of the improved
has been advocated for couples with unexplained fertilization and pregnancy rates.
infertility. Pregnancy rates comparable to gamete
intrafollicular transfer (GIFT) have been reported. Suggested Reading
We have used a similar protocol for couples who
completed the evaluation and have a diagnosis of Ben-Rafael Z, Dor J, Mashiach S, et al. Abortion rate in
unexplained infertility. We attempt controlled pregnancies following ovulation induced by human
superovulation combined with IUI therapy prior to menopausal gonadotropin/human chorionic gonado-
in vitro fertilization (IVF) and in couples previously tropin. Fertil Steril 1983;39:157–161.
demonstrating successful fertilization during IVF Ben-Rafael Z, Mashiach S, Oelsner G, et al. Spontaneous
pregnancy and its outcome after human menopausal
therapies who did not become pregnant. gonadotropin/human chorionic gonadotropin-induced
pregnancy. Fertil Steril 1981;36:560–564.
Side Effects and Complications Ben-Rafael Z, Matalon A, Blankstein J, et al. Male to
female ratio after gonadotropin-induced ovulation.
Side effects and complications of COH/IUI are the Fertil Steril 1986;45:36–40.
same as those seen with gonadotropin therapy in Bettendorf G, Braendle W, Sprotte C, et al. Overall
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 112

112 R.L. Collins

results of gonadotropin therapy. In: Insler V, Betten- Insler V, Melmed H, Mashiach S, et al. A functional clas-
dorf G (eds) Advances and Diagnosis in Treatment of sification of patients selected for gonadotropic ther-
Infertility. New York: Elsevier North-Holland, 1981: apy. Obstet Gynecol 1968;32:620–626.
21–34. Jones KP, Ravnikar VA, Schiff I. Results of human meno-
Blankstein J, Mashiach S, Lunenfeld B. Induction of ovula- pausal gonadotropin therapy at the Boston Hospital for
tion with gonadotropins. In: Ovulation Induction and In Women (1979–1981). Int J Fertil 1987;32:131–134.
Vitro Fertilization. Chicago: Year Book, 1986:131–154. Kurachi K, Aono T, Suzuki M. Results of gonadotropins-
Blankstein J, Shalev J, Saadon T, et al. Ovarian hyper- hCG therapy in 1096 treatment cycles of 2166 Japan-
stimulation syndrome: prediction by number and size ese women with anovulatory infertility. Eur J Obstet
of preovulatory ovarian follicles. Fertil Steril 1987;47: Gynecol Reprod Biol 1985;19:43–52.
597–602. Lam SY, Baker G, Pepperell R, et al. Treatment-inde-
Corsan GH, Kemmann E. The role of superovulation with pendent pregnancies after cessation of gonadotropin
menotropins in ovulatory infertility: a review. Fertil ovulation induction in women with oligomenorrhea
Steril 1991;55:468–477. and anovulatory menses. Fertil Steril 1988;50:26–
Couzinet B, Lestrat N, Brailly S, et al. Stimulation of 30.
ovarian follicular maturation with pure follicle-stimu- Lunenfeld B, Insler V. Gonadotropins. In: Diagnosis and
lating hormone in women with gonadotropin defi- treatment of functional infertility. Berlin: Grosse Ver-
ciency. J Clin Endocrinol Metab 1988;66:552–556. lag, 1978:76–89.
Dickey RP, Olar TT, Taylor SN, et al. Relationship of March CM, Davajan V, Mishell DR Jr. Ovulation induc-
biochemical pregnancy to preovulatory endometrial tion in amenorrheic women. Obstet Gynecol 1979;53:
thickness and pattern in patients undergoing ovulation 8–11.
induction. Hum Reprod 1993;7:418–421. Out HJ, Mannaerts BM, Driessen SG, et al. Recombinant
Dodson WC, Haney AF. Controlled ovarian hyperstimu- follicle stimulating hormone (rFSH; Puregon) in
lation and intrauterine insemination for treatment of assisted reproduction: more oocytes, more pregnancies;
infertility. Fertil Steril 1991;55:457–467. results from five comparative studies. Hum Reprod
Fleischer AC, Pittaway DE, Beard LA, et al. Sonographic 1996;2:162–171.
depiction of endometrial changes occurring with ovu- Seibel MM, McArdle CR, Thompson IF, et al. The role
lation induction. J Ultrasound Med 1984;3:341–346. of ultrasound in ovulation induction: a critical ap-
Friedler S, Schenker JG, Herman A, et al. The role of praisal. Fertil Steril 1981;36:573–577.
ultrasonography in the evaluation of endometrial re- Shoham Z, Insler V. Recombinant technique and gonad-
ceptivity following assisted reproductive treatments: a otropins production: new era in reproductive medicine.
critical review. Hum Reprod Update 1996;2:323–335. Fertil Steril 1996;66:187–201.
Gemzell C. Induction of ovulation with human gonado- Silverberg KM. Ovulation induction in the ovulatory
tropins. Recent Prog Horm Res 1965;21:179–197. woman. Semin Repro Endocrinol 1996;14:339–344.
Gemzell CA, Diczfalusy E, Tillinger KG. Clinical effect Tricomi V, Ferrd M, Solish G. The ratio of male and
of human pituitary follicle stimulating hormone female embryo as determined by the sex chromosome.
(FSH). J Clin Endocrinol Metab 1958;18:1333–1348. Am J Obstet Gynecol 1960;75:504–509.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 113

9. Ovulation Induction and Intrauterine Insemination 113

Appendix A: Techniques
Modified Swim-Up Technique
The swim-up procedure is used to separate motile 5. Place in a 37°C incubator and incubate 45–60
sperm from nonmotile sperm and extracellular minutes.
debris. It is particularly useful and the preferred 6. Remove as much of the supernatant as possi-
method for separating samples that have large ble while leaving the semen–media interface
amounts of gelatinous material or debris and oth- intact.
erwise normal parameters. 7. Pool the supernatants into one or two 5-ml ster-
The swim-up procedure is performed for one of ile test tubes.
two purposes. The first, for diagnostic reasons, is 8. Centrifuge at 600g for 5 minutes.
to evaluate the recovery of a motile population from 9. Resuspend the pellet to 0.3–0.5 ml with MHTF.
a given sample. It is important to have an estimate 10. Record the concentration, motility, progressive
of the expected yield from a sample for intrauter- motility, and incubation time used. Compute
ine insemination (IUI) purposes. The second pur- and record the concentration of motile sperm
pose is to harvest a population of highly motile cells and total number of motile sperm.
for use in a therapeutic IUI. When a separation is 11. Transport sperm and data to the clinician for
performed for immediate patient use the sample the IUI.
must be aseptically prepared.
There are many acceptable methods used to Density Gradient
perform a swim-up in the andrology community;
all yield comparable results. The sample can be
Centrifugation Technique
processed on the benchtop at room temperature or Density gradient preparation of sperm for IUI takes
in a 37°C incubator. Other variations include use advantage of the natural buoyant density properties
of a sodium bicarbonate-buffered medium and of sperm. The gradient described below is designed
incubation at 37°C in a 5% CO2 atmosphere. to allow the morphologically normal sperm to
migrate to the bottom of the tube, and the abnor-
Materials mal forms and nonsperm cells “float” in the upper
parts of the gradients. The major advantage of this
1. Sterile 5 ml round bottom tubes: Falcon No.
type of preparation is that it yields a high concen-
2001.
tration of morphologically normal, motile sperm
2. Sterile disposable transfer pipettes (Coning Sci-
for the insemination.
entific Corporation, 1050 Arroyo Avenue, San
Fernando, CA 91340-1822; distributed by Bax-
Materials
ter Scientific, cat. no. 222-105).
3. Pipettors. 1. PureSperm (manufactured by NidaCon Interna-
4. Disposable pipette tips. tional AB, Gothenburg, Sweden; distributed by
5. Sterile pasteur pipettes and clean bulbs. genX International 170 Fort Path Road,
6. Makler chamber. Madison, CT 06433, cat no. PS0250).
7. Sperm washing medium (manufactured and dis- 2. Sperm washing medium (manufactured and dis-
tributed by Irvine Scientific, Santa Ana, CA, tributed by Irvine Scientific, Santa Ana, CA,
92705, cat. no. 9983). 92705, cat. no. 9983).
3. Conical centrifuge tubes (Falcon no. 352099).
Procedure 4. Sterile disposable transfer pipettes (manufactured
by Coning Scientific Corporation, 1050 Arroyo
1. Perform a semen analysis. Record the volume,
Avenue, San Fernando, CA 91340-1822, distrib-
concentration, motility, progressive motility,
uted by Baxter Scientific, cat. no. 222-105).
normal morphology, viscosity, liquefaction,
5. Sterile 5 ml round-bottom tubes (Falcon no.
and debris.
2001).
2. “Wet” the bottom and sides of several sterile 5
ml round-bottom tubes.
Equipment
3. Add 0.25–0.50 ml of the liquefied semen to
each of the tubes. 1. Clinical centrifuge capable of spinning samples
4. Layer 1.0–1.5 ml of modified human tubal fluid at 600–700g.
(MHTF) on top of the semen. Tightly cap the 2. Makler chamber.
tubes. 3. Phase-contrast microscope.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 114

114 R.L. Collins

Solutions 12. Determine cell count, motility, and progression.

Record the results.
PureSperm Gradient: gradient dilutions can be 13. Take the sperm suspension and all appropriate
stored up to 2 weeks at 4°C. documentation to the clinician for the IUI.
1. Label three sterile tubes with today’s date and
95% PureSperm, 70% PureSperm, and 40%
PureSperm, respectively. Sperm Wash
2. To tube labeled 95%, add 9.5 ml of stock Pure- Materials
Sperm and 0.5 ml of sperm wash medium.
3. To tube labeled 70%, add 7.0 ml of stock Pure- 1. Sterile 5 ml round-bottom tubes (Falcon no.
Sperm and 3.0 ml of sperm wash medium. 2001).
4. To tube labeled 40%, add 4.0 ml of stock Pure- 2. Sterile disposable transfer pipettes (manufac-
Sperm and 6.0 ml of sperm wash medium. tured by Coning Scientific Corporation, 1050
5. Label two sterile conical centrifuge tubes with Arroyo Avenue, San Fernando, CA 91340-1822;
the patient’s name. Rinse the tubes with 2–3 ml distributed by Baxter Scientific, cat. no. 222-
of sperm wash medium. Gently add 0.5 ml of 105).
95% PureSperm to the bottom of the tube. Next 3. Pipettors.
gently layer 0.5 ml of 70% PureSperm on top of 4. Disposable pipette tips.
the 95% layer. Follow with layering 0.5 ml of 5. Sterile pasteur pipettes and clean bulbs.
the 40% PureSperm. 6. Makler chamber.
7. Sperm washing medium (manufactured and dis-
Procedure tributed by Irvine Scientific, Santa Ana, CA,
92705, cat. no. 9983).
1. Perform semen analysis as per the standard pro-
tocol. Record the results.
2. Layer up to 2–3 ml of liquefied semen to each
Procedure
of the gradient tubes. (Split the ejaculate as 1. Perform the semen analysis as per the standard
evenly as possible so you can use the tubes as procedure. Record volume, concentration, motil-
each other’s counterbalance.) ity, progressive motility, abnormal morphology,
3. Centrifuge the tubes at 600–700g for 20–25 viscosity, liquefaction, and debris.
minutes. 2. Aliquot 2.5 ml of ejaculate into a clean 5.0 ml
4. Using a sterile Pasteur pipette or other narrow tube. Repeat as necessary until the entire ejacu-
sterile pipette (i.e., 1 ml serologic), remove the late is aliquotted.
pellet and transfer to a labeled sterile 5 ml 3. Aliquot 2.5 ml of medium into each tube and
round-bottom tube. mix thoroughly.
5. Dilute the pellet with 3 ml of sperm wash 4. Centrifuge at 200g for a minimum of 5 minutes.
medium and thoroughly suspend. 5. Aspirate supernatant and resuspend pellet in
7. Centrifuge at 600g for 5 minutes. 0.5 ml medium.
8. Carefully remove the supernatants and resus- 6. Pool all resuspended pellets into a single tube
pend the pellet in 3 ml of sperm wash medium. and make up the volume to 4.5 ml with clean
9. Centrifuge at 600g for 5 minutes. medium.
10. Carefully remove the supernatant and resus- 7. Repeat steps 4 and 5.
pend the pellet in 0.3–0.5 ml of sperm wash 8. Perform a cell count. Record concentration,
medium. motility, progressive motility, and final volume.
11. Aseptically remove 0.005 ml of sperm suspen- 9. Transport sperm and data to the clinician for the
sion and place it on a Makler chamber. IUI.
3051_Seifer_09_p100-115 11/5/01 9:48 AM Page 115

9. Ovulation Induction and Intrauterine Insemination 115

Appendix B: Preparation of Intravaginal or Intracervical

Frozen Specimen for IUI
Materials 4. Perform a semen analysis. Record volume, con-
centration, motility, progression, and abnormal
1. Frozen semen.
morphology. Record viscosity, liquefaction,
2. Sterile 5 ml round-bottom tubes (Falcon no.
and debris as “NA.”
2001).
5. Maintain sterile technique for the duration of
3. Sterile disposable transfer pipettes (manufac-
the IUI preparation. Gently pipette the thawed
tured by Coning Scientific Corporation, 1050
sample from the cryo-vial into a 5 ml test tube
Arroyo Avenue, San Fernando, CA 91340-1822;
labeled with the sperm and patient’s identity.
distributed by Baxter Scientific, cat. no. 222-
6. Using the same pipette, add medium one drop
105).
at a time, shaking between additions to slowly
4. Pipettors.
change the osmolality of the sperm solution.
5. Disposable pipette tips.
Adding medium too quickly results in lysis of
6. Sterile Pasteur pipettes and clean bulbs.
the sperm cells.
7. Makler chamber.
7. Continue adding medium dropwise until the
8. Sperm washing medium (manufactured and dis-
volume has tripled.
tributed by Irvine Scientific, Santa Ana, CA
8. Cap the tube tightly and centrifuge at 300g
92705, cat. no. 9983).
(half-speed) for 5 minutes.
9. Aspirate supernatant and discard. Resuspend
Procedure pellet in 4.0 ml of clean medium and repeat
1. Begin thawing approximately 1.5–1.0 hour step 8.
before the sample is needed for use. 10. Aspirate supernatant and discard. Resuspend
2. Check the inventory books and tank to verify pellet in 0.5 ml of clean medium.
the correct sample and the storage location. 11. Perform a final count. Report volume, concen-
Note the total number of samples remaining for tration, motility, and progressive motility. Com-
this patient. pute and record concentration of motile sperm
3. Thaw the sample as directed by the appropri- and number of motile sperm.
ate supplier. 12. Load the insemination catheter.
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 116

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

The clinical presentation of gynecologic patients Traditionally, hysteroscopy has been a hospital
often mandates evaluation of the uterine cavity. or outpatient surgery center procedure, usually
Symptoms requiring evaluation include menorrha- necessitating a major anesthetic (general anesthe-
gia, intermenstrual bleeding, postmenopausal sia or regional block). With the advent of better
bleeding, and infertility, particularly those prepar- optics smaller instrumentation became available,
ing for in vitro fertilization (IVF). Techniques for reducing the need for major anesthesia; office-
uterine evaluation include endometrial biopsy, based hysteroscopy became a reality. Publications
vaginal ultrasonography, sonohysterography, hys- have confirmed the safety, efficacy, and utility of
terosalpingography, and hysteroscopy. Dating back office-based hysteroscopy.7,8
to its introduction by Bazzini during the early This chapter focuses on the use of in-office hys-
1800s, hysteroscopic evaluation has added to the teroscopy for diagnostic and therapeutic purposes
elucidation of uterine factors for infertility, which in the management of infertility patients. Indications
may account for 10–15% of cases.1,2 for office hysteroscopy are reviewed, as are tech-
Infertility is defined as 1 year of unprotected niques for performing this procedure. We review
intercourse without conception. It is estimated that also some emerging technology that will provide
10–15% of couples at reproductive age are infer- new options for the clinician in his or her office.
tile (Table 10–1).3 Uterine factors, which include Lastly, economic considerations for the clinician
structural and developmental defects (müllerian regarding the cost of equipment (capitalization) ver-
anomalies) account for 10% of infertility cases sus potential economic benefit are explored.
(Table 10–2).4,5
Hysterosalpingography (HSG) has been the
time-honored modality for uterine evaluation. The
procedure has diagnostic limitations, however, and
Indications
is not useful as a treatment modality. Nonetheless,
The indications for hysteroscopy are listed in Table
HSG remains a useful tool with relatively high sen-
10–3. Endometrial curettage has been the standard
sitivity and specificity. Indeed, recent publications
procedure for evaluating the endometrial cavity
have confirmed the continuing value of HSG. Sono-
hysterography (sonoHG, sometimes termed hys-
terosonography) has been developed and may play
a significant role in the evaluation of the uterine TABLE 10–1. Causes of Infertility
cavity.6 Hysteroscopy does not necessarily replace Cause of Infertility %
HSG or sonoHG but, rather, augments these modal-
Male 40–45
ities. The major advantage of hysteroscopy is direct Female 40–50
visualization of the uterine cavity. Most impor- Ovulatory dysfunction 40–45
tantly, hysteroscopy—and with advances in equip- Tubal 40–45
ment, office hysteroscopy—can be utilized to diag- Uterine 10–20
Cervical 1–2
nose and treat intrauterine lesions at a single Unexplained 5–10
session.

116
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 117

10. Diagnostic and Therapeutic Hysteroscopy in the Office 117

TABLE 10–2. Uterine Factors as a Cause of Infertility The occurrence of carcinoma in seemingly benign
Study % polyps is reported to be less than 0.5%.13 Even
though some polyps can be removed with blind
Rock 5
DeCherney 7 curettage, many are missed during the process
Diamond 4 because of their mobility. Polyps are often mor-
phologically described as broad-based and sessile,
Source: Li and Cook4 and Rock and Murphy.5 pedunculated, or attached to endometrium by a slen-
der stalk. Clinical implications lie with categoriza-
tion of polyps into one of three broad areas: hyper-
(specifically, endometrial histology) for many plastic, atrophic, or functional.
years. Several studies have demonstrated the inad- Hyperplastic polyps often populate the endome-
equacies of dilatation and curettage (D&C), includ- trial cavity diffusely. Malignant tumors are more
ing inadequate sampling, missed lesions (including likely to develop from these polyps secondary to
large polyps), and, most concerning, missed diag- their source (the baseline), which is much less
nosis of endometrial carcinoma.9,10 Hysteroscopy responsive to progesterone than estrogen. Atrophic
offers the distinct advantage of direct visualization polyps are found in postmenopausal patients and
and directed sampling (biopsy). Loeffer has dem- may represent the process of regressive changes in
onstrated the value of negative hysteroscopic a hyperplastic or functional polyp. Functional
results in women with abnormal bleeding. With a polyps resemble the surrounding endometrium in
normal hysteroscopic evaluation, he (and others) that they respond to hormonal changes during the
have shown that histologic evaluation is abnormal menstrual cycle. Virtually any size polyp can be
in fewer than 3% of patients.10,11 removed in the office.14 Scissors or cautery are uti-
lized to incise the attachment of the polyp from the
uterine wall. Large broad-based sessile polyps may
Intrauterine Masses require follow-up treatment in the operating room
Endometrial polyps are occasionally suspected on with the resectoscope. The polyps are excised under
sonography and can usually be confirmed by HSG direct visualization. Functional polyps are identi-
or sonoHG. The diagnosis can be confirmed and a fied as those with a lining identical to the sur-
definitive diagnosis established with hysteroscopy. rounding endometrium. Nonfunctional polyps are
(This is just one example of the complementary noted to be white protuberances that are covered
nature of HSG or sonoHG and hysteroscopy.) Patho- with branching surface vessels. All removed polyps
physiologic characteristics of these polyps include should be sent to the pathology laboratory for his-
their origination as a focal hyperplastic process of tologic evaluation. Approximately 20% of uteri
the basalis, which develops into a benign over- removed for endometrial carcinoma have additional
growth of endometrial tissue containing glands, pathology, including benign polyps.14
stroma, and vasculature. The estimated prevalence Leiomyomas of the uterus are the most common
of endometrial polyps in the general population is uterine neoplasms. In hysterectomy specimens,
2–4%.12 For some patients polyps are a source of 75% of uteri have histologic evidence of leiomy-
infertility, presumably acting as an intrauterine oma.15 They are more common in black women
device (IUD). Many of these patients present with than white women. Myomas arise often during the
abnormal uterine bleeding in addition to infertility. third and fourth decade, thus affecting reproductive
performance. Myomas arise from the myometrium
and are thought to be a clonal tumor. Indeed,
approximately 60% of uterine fibroids are kary-
TABLE 10–3. Indications for Hysteroscopy otypically abnormal.16,17 These tumors shrink with
Abnormal uterine bleeding gonadotropin-releasing hormone (GnRH) analogue
Menorrhagia treatment but generally return to their pretreatment
Intracycle bleeding size within 3 months of discontinuing the therapy.18
Postmenopausal bleeding
Intrauterine mass(es)
Submucous fibroids tend to cause problems with
Asherman syndrome abnormal bleeding or early pregnancy loss(es);
“Lost” intrauterine device (IUD) large myomas may cause pressure symptoms or
Foreign object obstruction of labor, or they may inhibit palpation
Abnormal hysterosalpingography (HSG) or of adnexal structures.19 Myomas are classified by
sonohysterography (sonoHG)
Before artificial reproductive therapy (pre-ART) their location: subserosal, intramural, submucosal,
or pedunculated (into the uterine or peritoneal cav-
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 118

118 D.A. Grainger, B.L. Tjaden, and A. Shah

ities). Treatment for leiomyomas is indicated if they ting, often with laparoscopic visualization to estab-
are symptomatic, interfere with fertility, enlarge lish the diagnosis (septate uterus versus bicornuate
rapidly, or pose diagnostic problems. uterus). Using imaging techniques such as mag-
The definitive diagnosis of submucosal leiomy- netic resonance imaging, laparoscopy may not be
oma is made by hysteroscopy and excisional required to confirm the diagnosis. Furthermore,
biopsy. They appear as white spherical masses many hysteroscopic surgeons are comfortable treat-
covered with a fragile, thin-walled vasculature. ing the known uterine septum without laparoscopic
Myomas can be sessile or pedunculated. Hystero- visualization. Thus the procedure is amenable to
scopic resection of myomas is often relatively sim- use in an office setting with proper instrumentation.
ple when the tumor diameter is less than 2 cm.14 Pregnancy outcomes appear to be quite good for
For larger submucous fibroids, pretreatment with patients with recurrent pregnancy loss secondary to
GnRH analogues should be considered. Maximal a uterine septum after metroplasty (85% pregnant
shrinkage occurs after 3 months of therapy.18 This with a 75% delivery rate). It is less clear what rela-
therapy results in a decrease in size and may also tion a uterine septum may have with infertility.23
decrease the bleeding by reducing the vasculature Treatment with estrogens after resection of the
of the tumor. septum may help with reepithelialization of the raw
surfaces of the endometrial cavity. Additionally, an
intrauterine balloon or IUD may be left in the uter-
Müllerian Anomalies ine cavity to help reduce the chance of intrauterine
Congenital abnormalities of the uterus are uncom- adhesions. The transcervical approach, whether in
mon and appear to be transmitted by a polygenic or the operating room or the office, is less invasive
multifactorial pattern of inheritance. Based on ret- and avoids the risk of pelvic adhesions associated
rospective studies, the incidence of these abnor- with abdominal procedures.
malities appears to be 2–3%. Uterine anomalies are
found in 4% of infertile women and in 10–15% of Asherman Syndrome
women with recurrent abortion.20 Spontaneous
abortion and obstetric complications such as pre- Intrauterine synechiae (Asherman syndrome) most
mature labor and abnormal fetal presentation are the commonly develop after curettage is performed
most common reproductive symptoms in patients during the postpartum or postabortal period. The
with uterine anomalies.21 Uterine defects are not a concurrent presence of an intrauterine infection
proven primary cause of infertility, and most authors raises the probability of synechia formation. The
agree that müllerian anomalies are more commonly clinical presentation may consist of hypomenorrhea
associated with pregnancy wastage (Table 10–4). or amenorrhea and infertility. The diagnosis is
The septate uterus is the most common uterine made by HSG or hysteroscopy. Hysteroscopic
abnormality (30%) associated with recurrent early examination reveals bands of fibrous tissue or
spontaneous abortion.22 The septum is a product of smooth muscle, without significant inflammation,
the persistence of the fused müllerian ducts with that traverse the endometrial cavity. The treatment
failure of resorption of the intervening wall. lies in identifying the adhesions and dividing them
Hysteroscopic metroplasty has been the main- with scissors or cautery. The office setting often is
stay of therapy for the uterine septum. Though orig- utilized for dividing central synechiae, which do
inally described as a procedure necessitating lapa- not need to be excised, just divided.14 Lateral and
rotomy, metroplasty is now most commonly done diffuse adhesions are probably best lysed in the
via hysteroscopy. Hysteroscopic metroplasty has operating room with concomitant laparoscopic
traditionally been performed in a minor surgery set- guidance. Upon restoration of normal intrauterine
anatomy, or IUD or a pediatric Foley catheter is
generally placed in the uterine cavity. The catheter
is removed in 7–10 days; the IUD may be left in
for 1–3 months. Patients are placed on conjugated
TABLE 10–4. Müllerian Anomalies Associated with estrogen (1.25 mg per day) for 1 month. Hys-
Poor Reproductive Performance terography or office hysteroscopy can be done for
Septate uterus follow-up within 1–3 months of surgery. Repro-
Unicoruate uterus ductive outcomes are related to the extent of pre-
Bicornuate uterus
Uterine didelphys
operative endometrial damage and are summarized
in Table 10–5.24–29
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 119

10. Diagnostic and Therapeutic Hysteroscopy in the Office 119

TABLE 10–5. Reproductive Outcomes Following Treatment of

Intrauterine Adhesions
No. of pregnancies/study population
Study Pretreatment Posttreatment
March24 14/84 33/38
Valle25 8/266 85/95
Lancet26 189/484 77/113
Caspi27 40/122 28/33
Oelsner28 9/57 14/20
Total 260/1013 (25.7%) 237/299 (79.3%)

Other Indications patients were studied, all having had normal HSGs
prior to enrollment. Twelve patients (43%) had
Retrieval of an IUD often can be attempted using abnormal hysteroscopic findings, including small
the office hysteroscope prior to obtaining radio- uterine septa, small submucous fibroids, uterine
graphic imaging. Transvaginal ultrasonography can hypoplasia, and cervical ridges. Significant differ-
be utilized to identify the location of the device in ences in the clinical pregnancy rates were found in
the endometrial cavity that is not readily found on patients with abnormal and normal findings by hys-
palpation with a uterine sound. If the IUD has par- teroscopy (8.3% vs. 37.5%).
tially perforated the abdominal cavity, hystero- The above indications for office hysteroscopy
scopic removal with concurrent laparoscopy may deal with correcting abnormalities of the cavity in
provide the safest means.30 Postpartum or postabor- an attempt to improve pregnancy outcomes. Indi-
tal bleeding may be a result of retained products of cations for office hysteroscopy for patients attempt-
conception. Such persistent bleeding can be evalu- ing conception who have a normal cavity include
ated and treated by hysteroscopy-guided removal transcervical transfer of gametes or embryos. One
of the retained products. After completion of the review summarized the experience with hystero-
procedure, antibiotic therapy is generally recom- scopic replacement of gametes and embryos.31
mended. Overall, the pregnancy rates from these procedures
do not appear to offer any advantage to ultrasound-
guided transfers and are comparable to the preg-
Hysteroscopy Prior to nancy rates after transcervical intrauterine embryo
In Vitro Fertilization transfer (see Table 10–6).

Detectable uterine abnormalities have been noted

in up to 45% of the patients undergoing IVF.31
Contraindications
These abnormalities include endometrial polyps, In concordance with the relative safety and ease of
submucous leiomyomas, uterine malformations, office hysteroscopy, absolute contraindications are
and cervical stenosis. Shamma et al. studied pa- cervical carcinoma, acute pelvic infection, and
tients who underwent office hysteroscopy under pregnancy. If pelvic infection occurs with an unre-
paracervical block prior to IVF.32 Twenty-eight trievable IUD, office hysteroscopy may be per-

TABLE 10–6. Outcome of Transcervical GIFT Using Hysteroscopy or Ultrasonography

Outcome
Procedure Cycles (no.) Pregnancy Ectopic
Ultrasound-guided 173 36 (20.1%) 2 (6%)
Hysteroscopy 131 25 (19%) NR
SART; IVF in 1994 31,000 21% 4%

GIFT, gamete intrafollopian transfer; SART, Society for Assisted Reproductive Technology; IVF,
in vitro fertilization.
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 120

120 D.A. Grainger, B.L. Tjaden, and A. Shah

formed to remove the device. The patient would exceed 500 ml as there is significant risk of pul-
then undergo an antibiotic regimen to complete the monary edema. Furthermore, rare adverse reactions
treatment for pelvic infection. including anaphylaxis and disseminated intravas-
Relative contraindications include extensive cular coagulation have been reported. Overall, this
intrauterine adhesions, leiomyomas larger than 2 medium is unlikely to find a useful place in office
cm, severe medical disorders (diabetes, asthma, hysteroscopy.
blood dyscrasias), and excessive uterine bleeding Low viscosity fluids are easier to use in an office
(restricting the hysteroscopic view).14 Gestations setting. They include ionic fluids (electrolyte-
with an IUD in place can be managed by hystero- containing, such as normal saline or lactated Ringer’s)
scopic removal of the device. and non-ionic fluids (such as sorbitol, mannitol, or
glycine). The electrolyte-containing solutions are
advantageous in that their absorption, even in rel-
Equipment atively large amounts, poses little risk to the patient.
The uterine cavity is a potential space and must be However, they cannot be used with traditional
distended to allow complete visualization for ade- monopolar electrosurgery. The non-ionic solutions
quate diagnosis and treatment. Optical systems may be used with monopolar electrosurgery but
must provide adequate light and resolution, and carry the risk of water intoxication if absorbed in
there must be a means of delivering energy to the large amounts. Therefore, it is critical that accurate
areas requiring therapy (mechanical energy, ther- measurements of fluid absorption be maintained
mal energy, laser energy). We discuss each of these throughout the procedure. In the office setting, this
three areas separately as they apply to office hys- is less likely to pose significant problems, as the
teroscopy. more difficult and extensive hysteroscopic proce-
dures should be performed in an ambulatory sur-
Distension of the Cavity gery center or in the hospital. Visualization of the
endometrial cavity is best accomplished using con-
Carbon dioxide gas has been used most commonly tinuous flow of distension medium. Office hys-
to distend the uterine cavity in an office setting. The teroscopes with dual channels for inflow and out-
insufflators are relatively inexpensive, use low rates flow are readily available and are preferred for both
of flow, and are easy to maintain. Visualization diagnostic and therapeutic use.
using CO2 is excellent and for strictly diagnostic
purposes provides an adequate means of distend-
ing the cavity. CO2 is rapidly absorbed into the Light and Optics: Flexible, Micro,
bloodstream and cleared by the lungs. There are or Rigid Hysteroscopes?
several disadvantages. The CO2 often leaks around
the hysteroscope, making distension of the cavity Although advances in fiberoptics, light sources, and
difficult. Furthermore, it is inadequate for operative delivery systems have occurred, it is the authors’
procedures as it tends to form bubbles when mixed opinion that the visual clarity of rigid hysteroscopic
with blood. Care must be taken to use only in- systems remains superior at the present time. Addi-
sufflators specifically designed for hysteroscopy tionally, rigid systems are more adaptable to ther-
for CO2 delivery. Laparoscopic insufflators are apeutic usage. We profile some of the more com-
designed for high flow rates, and deaths have been mon systems, including one flexible hysteroscope
reported using laparoscopic insufflators for hys- (Olympus), one microhysteroscope (Imagyn), and
teroscopy (high flow, leading to CO2 embolism). one rigid system (Wolf). Many other products are
Fluid distension media include high-molecular- available and are adequate or perhaps superior, but
weight dextran (Hyskon), electrolyte solutions, and these systems give the reader an idea of what is
non-ionic solutions (sorbitol, mannitol, glycine). available currently.
Hyskon is used relatively infrequently for several
reasons. It is messy, with a consistency of syrup, Flexible Hysteroscopy
and if not cleaned from instruments quickly results
in immobilization of moving parts. It provides The advantages of a flexible hysterocope is its small
excellent visualization, particularly if there is any size, resulting in improved tolerance by the patient.
bleeding present. We have found the easiest deliv- Most patients do not require anesthesia or cervical
ery system to be a 50 cc syringe, intravenous exten- dilation. The Olympus hysterofiberscope (Fig.
sion tubing, and a strong nurse or medical student. 10–1) provides an ergonomic design and single-
Generally, the amount of Hyskon used should not handed control. Minor surgical procedures may be
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 121

10. Diagnostic and Therapeutic Hysteroscopy in the Office 121

Rigid Hysteroscopy
Rigid hysteroscopes range from 3 to 5 mm outside
diameter and can be configured for continuous flow
and operative procedures (Fig. 10–3). The optical
resolution with these systems is excellent and
approaches or exceeds that of the large resecto-
scopes utilized in the operating room. The hys-
teroscopes are generally inserted with no dilation
of the cervix; if dilation is required, a paracervical
block is used. Operating channels allow introduc-
tion of semirigid instruments or bipolar electrodes
(Versapoint). The resolution obtained with these
FIGURE 10–1. Microhysteroscope. instruments, combined with the increased “fire-
power” obtained by using bipolar technology in
physiologic distension media, should add greatly to
the therapeutic benefits of office hysteroscopy.
performed through this hysteroscope, including
directed biopsy or excisional biopsy of small polyps.
Energy Sources
Microhysteroscopy
Mechanical Energy
Imagyn Medical (Laguna Niguel, CA) has intro-
duced the MicoSpan hysteroscopy system (Fig. Mechanical energy in the form of biopsy instru-
10–2), which has as an integral component a 1.6 ments is the most common application of “energy”
mm offset microhysteroscope with enhanced in the office. These instruments are small (2 mm)
microoptics. The outside diameter, when used with
the sheath, is approximately the size of a Pipelle,
yet the fused image fiber and the microoptics pro-
vides 150% of the illumination and up to three
times the resolution of similar-size hysteroscopes.
This system is used in combination with the
MicroSpan Sheath, which has an expandable work-
ing channel that accepts 2 mm semirigid instru-
ments for biopsy or excision. The sheath also
allows continuous flow or distension medium, with
controls for inflow and outflow optimizing visual-
ization of the cavity.

FIGURE 10–2. Flexible hysteroscope appropriate for per- B

forming minor surgical procedures including directed
biopsy or excisional biopsy of small polyps. FIGURE 10–3. A, B. Rigid hysteroscope.
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 122

122 D.A. Grainger, B.L. Tjaden, and A. Shah

and semirigid, allowing them to pass down the

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

Unipolar Energy
Generators producing unipolar energy use the
patient as a conductor, with the source of energy
being the active electrode, and the ground plate
being the receiver of the electrons. Thus conduc-
tive distension solutions may not be used, as the
energy is dissipated in the medium, extinguishing
any meaningful tissue interaction. These forms of FIGURE 10–4. Bipolar electrosurgery system (Versa-
energy are commonly conducted via electrodes point). (Courtesy of Gynecare)
designed to be used for endometrial ablation, resec-
tion of large fibroids or polyps, or metroplasty.
Non-ionic solutions are used (glycine, sorbitol, one of the emerging thermal therapies such as
mannitol); it is incumbent on the surgeon to main- ThermaChoice, shown in Figure 10–5 (Gynecare).
tain accurate measurements of fluid absorption
(infused minus recovered). Several devices have Procedure
been designed to aid in the accurate measurement
of fluid absorption. The experienced hysteroscopist Timing the Examination
recognizes situations in which fluid absorption is
likely (bleeding from ablation or resection of Especially for the novice, hysteroscopy is best per-
fibroids). However, one must always be alert to the formed during the early to mid-proliferative phase
problem of excessive fluid absorption, even with of the cycle. Bleeding has stopped, but the endo-
seemingly benign cases, as fluid overload with metrium has not grown to the point that it obscures
these solutions can have serious sequelae. the view. With insertion of the hysteroscope, strips
of late proliferative or secretory endometrium can
be elevated and easily confused with polyps. If ther-
Bipolar Energy apeutic procedures such as ablations are performed
in the office, endometrial preparation with either
A new hysteroscopic energy delivery system has danazol (Danocrine) or GnRH analogues can pro-
been introduced. Traditionally, unipolar energy is vide thinning of the endometrium, allowing excel-
utilized through loops, bars, or other types of abla-
tive electrode, which requires the use of non-ionic
solutions with the attendant risks of water intoxi-
cation and hyponatremia. Versapoint (Gynecare,
Menlo Park, CA) is a bipolar electrosurgery sys-
tem that employs at least three distinct advantages:
(1) normal saline may be used as a distension
medium; (2) the electrodes are small and pass eas-
ily through a 5 mm hysteroscope; and (3) instanta-
neous tissue vaporization eliminates resection chips
(Fig. 10–4).
The generator delivers energy to the active elec-
trode, creating a “vapor pocket,” which causes
instantaneous cellular rupture upon contact with
tissue. This bipolar energy source also provides
excellent hemostasis and is useful for treating sub-
mucus leiomyoma or endometrial polyps. Versa-
point may also be used as an adjunct to endome- FIGURE 10–5. ThermaChoice system. (Courtesy of
trial ablation, either traditional rollerball or using Gynecare)
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 123

10. Diagnostic and Therapeutic Hysteroscopy in the Office 123

lent visualization and perhaps more efficacious perception scores by the patients.33 This study eval-
treatment. uated 177 women undergoing outpatient hys-
teroscopy. Paracervical block consisted of 10 cc of
Medications 1% mepivacaine hydrochloride solution (87 pa-
The patient should be given nonsteroidal antiin- tients) or no block (90 patients). The pain scores
flammatory drugs (NSAIDs) approximately 30–60 for the treated group were 4.2  2.0 and for the
minutes prior to the procedure. Some of these med- untreated group 5.2  2.1, which were not signif-
ications are available as rectal suppositories and are icantly different. It is probably more important to
effective within 15–30 minutes of administration. pretreat patients with nonsteroidal medications
The procedure is generally well tolerated with no 30–60 minutes prior to the procedure. Occasional
further medications being given. The occasional patients do not tolerate office hysteroscopy (e.g.,
patient benefits from a mild sedative or tranquilizer those who do poorly with an endometrial biopsy
(e.g., the patient who does not tolerate an endo- may tolerate diagnostic hysteroscopy but probably
metrial biopsy). These medications should also be not do well with therapeutic procedures). Several
administered 30–60 minutes prior to the procedure. techniques may be used for a paracervical or intra-
Most of these procedures are performed without cervical block. We prefer to inject 0.25% bupivi-
intravenous access; therefore, if any narcotic med- caine into the cervix through a 20-gauge spinal nee-
ications are required, they are usually administered dle, using 5 cc at the 4 and 8 o’clock positions.
intramuscularly. This situation arises only in rare Bupivicaine has a little longer onset of action but
patients in our experience. provides longer relief after the procedure.
Insertion of the Hysteroscope
Patient Position
The hysteroscope is gently inserted through the
The patient is placed in the dorsal lithotomy posi-
external cervical os, and the endocervical canal is
tion, and a bimanual examination is performed to
inspected. Insufflation medium (CO2 or liquid) is
make certain no adnexal tenderness is present and
injected, allowing visualization of the cavity, which
to determine uterine size and position. Ideally, an
appears as a dark spot (the location of this “dark
adjustable electric bed with leg rests is available for
spot” depends on the angle of scope and the posi-
patient comfort. As the examinations are brief, it
tion of the uterus). The hysteroscope is directed
has been our experience that the procedure is well
toward this dark spot until the cavity is entered. The
tolerated even with a normal examination table. If
flow of medium is adjusted so the cavity is ade-
video equipment is available, the patient is posi-
quately distended. Systematic inspection of the
tioned such that she can view the screen. Involve-
cavity is performed and should include examina-
ment of the patient with the ongoing procedure is
tion of the fundus, anterior and posterior walls, lat-
beneficial for both educational purposes and patient
eral walls, both tubal ostia, and the lower uterine
comfort (distraction).
segment. The findings should be recorded on hard
Cervical Preparation copy, which is kept with the patient’s record.

After placing a bivalved speculum, the cervix is

cleansed with povidone-iodine solution. The bi-
Complications
valved speculum allows for its easy removal after Inadequate Visualization
the uterine cavity has been entered with the hys-
teroscope. Removing the speculum allows more Inadequate visualization is the most common
range of motion with the hysteroscope and thus “complication” of hysteroscopy, and the most com-
more complete inspection of the cavity. mon cause of inadequate visualization is lack of
flow of the distension medium. Increasing the flow
Paracervical Block rate by raising the bag of medium, increasing pres-
sure on the syringe, or increasing the flow rate on
The use of a paracervical block is controversial. In the CO2 insufflator may resolve the problem. If the
general, with small hysteroscopes (3.5–5.0 mm) no cervical canal is narrow, it may be gently dilated
cervical dilation is necessary to introduce the prior to inserting the hysteroscope. Blood in the
instrument. A prospective randomized comparison cavity, obscuring the view, generally responds to
of paracervical blocks with anesthetic versus no increasing flow rate. If blood continues to obscure
injection revealed no significant difference in pain the field, high-molecular-weight dextran may be
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 124

124 D.A. Grainger, B.L. Tjaden, and A. Shah

used. This medium is immiscible with blood but the procedure. The discussion in this chapter has
has the potential complications listed above. If CO2 focused on an office-based system. One should rec-
is used and leakage is occurring at the external cer- ognize that a state of the art system is expensive
vical os, the tenaculum may be adjusted to narrow ($15,000–$20,000) as it includes light sources, hys-
the canal. Downward traction on the tenaculum is teroscopes, video equipment, and hysteroscopic
often useful for the anteverted or retroverted uterus. instruments. Additional costs may include bipolar
instrumentation, the modality that allows true ther-
Perforation of the Uterus apeutic efficacy in the office. It becomes clear that
so long as physician reimbursement is unaffected
If the hysteroscope advances easily, and the cavity by the site of the procedure (i.e., a traditional fee-
is not visualized, uterine perforation should be sus- for-service system), there is no incentive for the
pected and the procedure terminated. Likewise, capitalization costs. However, in a managed care
insufflation of large amounts of distension medium environment (capitated or global fee), the hospital
with little return indicates perforation. These per- portion of the expense falls to the physician. This
forations are generally midline and require no fur- may run $1000–$2000 per procedure. It therefore
ther therapy. Exceptions include perforation of the requires few procedures to justify the expenditure
uterus with a monopolar or bipolar device, or if for the equipment. This, combined with the over-
there is any suspicion of bowel injury. These all patient satisfaction and improvements in tech-
patients should undergo a laparoscopic evaluation nology, may result in more of these procedures
of the pelvis, with possible laparotomy if indicated. being performed in-office.
Infection
Infection following hysteroscopy is rare. Careful Summary
selection of patients by bimanual examination and
careful inspection of the cervical discharge prior Assessing the endometrial cavity is an integral part
to the procedure prevents infectious sequelae. Pro- of the infertility evaluation. Traditionally, it was
phylactic antibiotics should be administered to accomplished using HSG. Although HSG contin-
patients with mitral valve prolapse per recommen- ues to be utilized, along with sonoHG, it appears
dations of the American Heart Association. that hysteroscopy is the most sensitive method for
examining the endometrial cavity. Whether the
Bleeding small lesions identified at hysteroscopy that are
Bleeding following office hysteroscopy is rare. As missed with other evaluations are clinically signif-
more therapeutic procedures are performed in an icant is not known.
office setting, the risk of bleeding increases. Bleed- The advances in optics has allowed much smaller
ing can occur from the cervix (laceration from hysteroscopes to be utilized; and combined with
the tenaculum). The cervix should be carefully in- advances in energy delivery this has made other
spected at the end of the procedure, and if a lacer- diagnostic and therapeutic hysteroscopy feasible.
ation is present it should be repaired using a The cost of the equipment (and reimbursement con-
figure-of-eight suture. Intracavitary bleeding due to straints) remains a barrier to more widespread use
resection of polyps or fibroids, the septum, or after of this effective therapy. Furthermore, many clini-
ablation may be controlled by placing a Foley cath- cians are easily frustrated when beginning to use
eter with a 30 cc balloon in the uterus and inflat- hysteroscopy and abandon the procedure, to the
ing with 10–30 cc of saline. The catheter acts as detriment of their patients. Educational efforts
both a tamponade and a drain and is left in place directed at both clinicians and third-party payers
for 24 hours. Antibiotic prophylaxis should be pro- may increase utilization of this extremely benefi-
vided for patients in whom a catheter is left in the cial, cost-effective procedure.
uterus.

Options for the Next Step in

Economic Considerations the Treatment Algorithm
After recognizing the benefits of hysteroscopy from Evaluation of the uterine cavity is an important step
both a diagnostic and therapeutic viewpoint, the cli- in the evaluation of the infertile couple. Office hys-
nician must then decide in which setting to perform teroscopy is a valuable technique that is probably
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 125

10. Diagnostic and Therapeutic Hysteroscopy in the Office 125

more sensitive than HSG or sonoHG in detecting 19. Buttram VC Jr, Reiter RC. Uterine leiomyomata: eti-
small lesions (for some of which the clinical sig- ology, symptomatology and management. Fertil
nificance is not well established). The next steps Steril 1981;36:433–445.
include evaluation of tubal patency and function 20. Valle RF. Hysteroscopy in the evaluation of female
infertility. Am J Obstet Gynecol 1980;137:425–431.
(HSG or falloposcopy).
21. Rock JA, Schlaff WD. The obstetrical consequences
of utero-vaginal anomalies. Fertil Steril 1985;43:
References 681–692.
22. Heinonen PK, Saarikoski S, Pystynen P. Reproduc-
1. Russell JR. History and development of hyster-
tive performance of women with uterine anomalies.
oscopy. Obstet Gynecol Clin North Am 1988;15:
Acta Obstet Gynecol Scand 1982;61:157–162.
1–11.
23. Hassiakos DK, Zourlas PA. Transcervical division of
2. Pellicer A. Hysteroscopy in the infertile women.
uterine septa. Obstet Gynecol Surv 1990;45:165–
Obstet Gynecol Clin North Am 1988;15:99–105.
173.
3. Mosher WB, Pratt WF. Fecundity and infertility in
24. March CM, Israel R. Gestational outcome following
the United States: incidence and trends. Fertil Steril
hysteroscopic lysis of adhesions. Fertil Steril 1981;
1991;56:192–193.
36:455–459.
4. Li TC, Cooke ID. Uterine factors in infertility. Curr
25. Valle RF, Sciarra JJ. Intrauterine adhesions: classifi-
Opin Obstet Gynecol 1992;4:212–219.
cation, treatment and reproductive outcome. Am J
5. Rock JA, Murphy AA. Anatomic abnormalities. Clin
Obstet Gynecol 1988;158:1459–1470.
Obstet Gynecol 1986;29:886–911.
26. Lancet M, Kessler I. A review of Ashermans syn-
6. Parsons AK, Lense JJ. Sonohysterography for endo-
drome, and results of modern treatment. Int J Fertil
metrial abnormalities: preliminary results. J Clin
1988;33:14–24.
Ultrasound 1993;21:87–95.
27. Caspi E, Peripinal S. Reproductive performance after
7. Valle RF. Future growth and development of hys-
treatment of intrauterine adhesions. Int J Fertil 1975;
teroscopy. Obstet Gynecol Clin North Am 1988;15:
20:249–252.
111––126.
28. Oelsner G, David A, Insler V, et al. Outcome of preg-
8. Chambers JT, Chambers SK. Endometrial sampling:
nancy after treatment of intrauterine adhesions.
When? Where? Why? With What? Clin Obstet
Obstet Gynecol 1974;44:341–344.
Gynecol 1992;35:28–39.
29. Schlaff WD, Hurst BS. Preoperative sonographic
9. Gimpelson RJ, Rappold HO. A comparative study
measurement of endometrial pattern predicts out-
between panoramic hysteroscopy with directed biop-
come of surgical repair in patients with severe Ash-
sies and dilatation and curettage: a review of 276
erman’s syndrome. Fertil Steril 1995;63:410–413.
cases. Am J Obstet Gynecol 1988;158:489–492.
30. Thompson JD, Rock JA. Te Linde’s Operative Gyne-
10. Loeffer FD. Hysteroscopy with selective endometrial
cology. Philadelphia: Lippincott, 1992, pp 385–409.
sampling compared with D & C for abnormal uter-
31. Balmaceda JP, Ciuffardi I. Hysteroscopy and assisted
ine bleeding: the value of a negative hysteroscopic
reproductive technology. Obstet Gynecol Clin North
view. Obstet Gynecol 1989;73:16–20.
Am 1995;22:507–518.
11. Fraser IS. Hysteroscopy and laparoscopy in women
32. Shamma FN, et al. The role of office hysteroscope
with menorrhagia. Am J Obstet Gynecol 1990;162:
in in vitro fertilization. Fertil Steril 1992;58:1237–
1264–1269.
1239.
12. Van Bogaert LJ. Clinicopathologic findings in endo-
33. Vercillini P, Colombo A, Mauro A, et al. Paracervi-
metrial polyps. Obstet Gynecol 1988;71:771–773.
cal anesthesia for outpatient hysteroscopy. Fertil
13. Pettersson B, Adami HO, Lindgren A. Endometrial
Steril 1994;62:1083–1085.
polyps and hyperplasia as risk factors for endome-
trial carcinoma. Acta Obstet Gynecol Scand 1985;
64:653–659. Suggested Readings
14. Gimpleson RJ. Office hysteroscopy. Clin Obstet
Gynecol 1992;35:270–281. Lindheim SR, Kavic S, Shulman SV, et al. Operative hys-
15. Cramer SF, Patel D. The frequency of uterine leiomy- teroscopy in the office setting. J Am Assoc Gynecol
omas. Am J Clin Pathol 1990;94:435–438. Laparosc 2000;7:65–69.
16. Fletcher AJ, Morton CC, Pavelka K, Lage JM. Chro- Zullo F, Pellicano M, Stigliano CM, DiCarlo C, Fabrizio
mosome aberrations in uterine smooth muscle A, Nappi C. Topical anesthesia for office hysteroscopy.
tumors: potential diagnostic relevance of cytogenetic A prospective randomized study comparing two
instability. Cancer Res 1990;50:4092–4097. modalities. J Reprod Med 1999;6:331–6.
17. Meloni AM, Surti U, Contento AM, Davare J. Uter- Pal L, Lapensee L, Toth TL, Isaacson KB. Comparison
ine leiomyomas: cytogenetic and histologic profile. of office hysteroscopy, transvaginal ultrasonography,
Obstet Gynecol 1992;80:209–217. and endometrial biopsy in evaluation of abnormal uter-
18. Stewart EA, Friedman AJ. Steroidal treatment of ine bleeding. J Soc Laparaoendosc Surg 1997;1:125–
myomas: preoperative and long-term medical ther- 30.
apy. Semin Reprod Endocrinol 1992;10:344–350. Valli E, Zupi E, Marconi D, Solima E, Nagar G,
3051_Seifer_10_p116-126 11/5/01 9:48 AM Page 126

126 D.A. Grainger, B.L. Tjaden, and A. Shah

Romanini C. Outpatient diagnostic hysteroscopy. J Am Ross JW. Numerous indications for office flexible mini-
Assoc Gynecol Laparosc 1998;5:397–402. hysteroscopy. J Am Assoc Gynecol Laparosc 2000;7:
Saidi MH, Sadler RK, Theis VD, Akright BD, Farhart 221–226.
SA, Villanueva GR. Comparison of sonography, sono- Marrello F, Bettochi S, Greco P, Ceci O, Vimercati A, Di
hysterography, and hysteroscopy for evaluation of Venere R, Loverro G. Hysteroscopic evaluation of meno-
abnormal uterine bleeding. J Ultrasound Med 1997; pausal patients with sonographically atrophic endome-
16:587–591. trium. J Am Assoc Gynecol Laparosc 2000;7:197–200.
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 127

11
Endoscopic Evaluation
of the Fallopian Tube
Eric S. Surrey

The human fallopian tube plays a vital role in the occlusion or in more subtle dysfunction in the pres-
reproductive process. Its functions include sperm ence of patent fallopian tubes.
transport, ovum pickup, and embryo transport. The Thus it is clear that the fallopian tube plays a
tube is the site for sperm capacitation, oocyte fer- much greater role in the reproductive process than
tilization, and early embryo development and main- that of a passive conduit between ovary and uterus.
tenance. Tubal ovum and embryo transport are The primary means of assessing the fallopian tube
dependent on a rich interplay between the endo- have traditionally included hysterosalpingography
crine milieu, cilial function, muscular contractions, (HSG) and laparoscopy.
and adrenergic innervation. The accuracy of HSG findings when compared
Vascular perfusion studies have demonstrated the to laparoscopic findings has been debated. Investi-
presence of fluid in the tubal lumen with high con- gators from a multicenter World Health Organiza-
centrations of metabolic substrates. Substances tion (WHO) trial reported that only 55% of 125
secreted in the tube include trypsin inhibitors, pros- women undergoing both laparoscopy and HSG had
taglandins, immunoglobulins (particularly IgA), similar findings. In an investigation in which HSG
bicarbonate, and such cytokines as transforming was performed the day prior to laparoscopy, the
growth factor- (TGF). These substances may sensitivity of HSG was noted to be only 0.54. In
play a role in zona pellucida dispersion and pro- contrast, Opsahl and colleagues reported that HSGs
vide sustenance to the oocyte and early embryo. that were interpreted as “normal,” as would be the
Studies suggest compromise of implantation and case in women with unexplained infertility, were
pregnancy rates after attempted in vitro fertilization confirmed at surgery in 96.6% of cases, but in only
(IVF) in women with hyrosalpinges. This suggests 63.1% of patients with HSGs were they interpreted
that inflammatory tubal fluid may have a direct as “suspicious.” Swart and colleagues performed a
deleterious effect on the uterine environment as meta-analysis of 20 previously published papers
well. comparing the accuracy of the diagnosis of tubal
Investigators have reported that in a population patency or peritubal adhesions by HSG in compar-
of infertile patients 11–16% present with various ison to laparoscopy. Point estimates for tubal
tubal factors. Significant prognostic factors include patency of 0.65 and 0.83 (sensitivity and specificity,
a history of pelvic infection, sexually transmitted respectively) were calculated. This means that
diseases, tubal or ovarian surgery, endometriosis, although tubal disease is highly likely in the pres-
or use of various intrauterine devices. Distal tubal ence of an abnormal HSG, tubal patency on HSG
disease most commonly stems from prior infection does not rule out pathology. In addition, the diag-
or as a response to inflammatory insults (e.g., prior nosis of peritubal adhesions by HSG was com-
pelvic surgery, endometriosis). Proximal disease pletely unreliable based on the findings of this
may result from inflammation or infection as well study. Neither HSG nor laparoscopy allow the cli-
but may also stem from salpingitis isthmica nodosa, nician to differentiate between true proximal occlu-
spasm, amorphous casts, or extrinsic compression sion and spasm at the uterocornual ostium or the
due to adenomyosis, endometriosis, or leiomy- presence of occlusive mucous plugs.
omas. These disorders may result in total tubal Selective salpingography, a procedure involving

127
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 128

128 E.S. Surrey

transcervical catheterization of the fallopian tube not be visualized, although secondary factors such
under fluoroscopic guidance with subsequent imag- as endometriosis or leiomyomas can be assessed.
ing and canalization, has been proposed as a sec- A patent tube with normal-appearing fimbriae may
ondary measure when proximal tubal occlusion is still harbor unrecognized luminal defects that may
initially appreciated at HSG. Hydrostatic pressure impair fertility.
due to dye infusion or direct placement of the cath- As a result, various investigators have attempted
eter in the case of selective salpingography may to assess more accurately the nature of the fallo-
dislodge debris and mucous plugs or lyse intralu- pian tubal lumen by direct visualization. Advances
minal adhesions. Letterie and Sakas reported that in fiberoptic technology have made this possible.
93% of resected tubal segments demonstrated true “Salpingoscopy” is defined as endoscopic visuali-
pathology, such as fibrosis or salpingitis isthmica zation of the tubal lumen from the ampullary–
nodosa, if obstruction persisted after selective sal- isthmic junction to the fimbria employing trans-
pingography. fimbrial access. “Falloposcopy” represents endo-
More recently, transvaginal sonography has been scopic evaluation of the fallopian tube from the
employed to assess tubal patency. Saline, air, and uterotubal ostium to the fimbria employing trans-
echo enhancing agents have been injected into fal- cervical access.
lopian tubes transcervically as transvaginal sonog-
raphy is performed. The patency of each tube is
assessed by the escape of air bubbles, color Doppler Indications and Contraindications
flow patterns, or the progressive collection of fluid
in the cul-de-sac. Concordance with laparoscopic The primary indication for performance of fallo-
findings is variable, and this technique requires fur- poscopy is assessment of the infertile woman with
ther development before it can be generally ac- suspected proximal tubal disease after HSG or in
cepted as part of the routine evaluation of the fal- whom HSG is contraindicated (Table 11–1). The
lopian tube. poor correlation between findings at HSG and sur-
Unfortunately, none of these imaging studies gery particularly with regard to proximal tubal
provides a truly accurate assessment of tubal anat- occlusion has been reported. Prior to subjecting a
omy. A patent tube is not necessarily a normal tube. patient to microsurgical anastomosis at laparotomy
A radiologic or sonographic finding of tubal occlu- or tubal bypass employing assisted reproductive
sion or other luminal defect does not confirm the technologies (ART), a thorough assessment of the
presence of a true disease state or define the nature tubal lumen may reveal such findings as spasm of
of the lesion, only its location. Evaluation of the the uterotubal ostium, intraluminal polyps, or
endothelial lining or nonobstructive defects cannot mucous plugs, which may lend themselves to less
be performed. Thus more direct visualization would invasive therapy. Similarly, the finding of an
be ideal. irreparably damaged tubal lumen may allow the
patient to avoid laparoscopy altogether and be
referred directly for in vitro fertilization-embryo
Endoscopic Techniques transfer (IVF-ET).
The patient with hydrosalpinges diagnosed radi-
Laparoscopy has traditionally served as the gold ologically may benefit from falloposcopy or sal-
standard for diagnosing tubal and peritubal pathol-
ogy. Tubal obstruction can be assessed by chro-
mopertubation: transcervical infusion of diluted TABLE 11–1. Indications and Contraindications for
indigo carmine or methylene blue dye. The extent Tubal Endoscopy
of peritubal adhesions can be assessed along with Indications
the remainder of the pelvic cavity. Various findings Suspected proximal tubal occlusion
at laparoscopy have been employed to predict tubal Suspected distal tubal occlusion
function in cases of suspected distal disease: wall Unexplained infertility
thickness, ampullary dilation, extent of peritubal Contraindication to hysterosalpingography (contrast dye
allergy)
adhesions, and fimbrial mucosal appearance. How- Gamete and/or zygote transfer?
ever, laparoscopy provides little information re- Contraindications
garding the tubal lumen itself in that access can be Active pelvic infection
achieved only to the most distal aspect. Laparos- Active uterine bleeding
Allergic reaction to local anesthetic agents
copy is even less helpful for assessing a presumed Extensive uterine synechiae or submucous myomas
proximal occlusion, as a true causative factor can-
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 129

11. Endoscopic Evaluation of the Fallopian Tube 129

pingoscopy. Salpingoscopy, which is performed

during concomitant laparoscopy, provides informa-
tion regarding both the tubal lumen and the per-
itubal environment. Although falloposcopy pro-
vides no information regarding peritubal disease,
should the endothelial lining prove to be damaged
beyond repair, further surgical investigation would
be unwarranted. In contrast, a patient with a less
severely damaged endothelial lining noted at fallo-
poscopy would require a concomitant or subse-
quent laparoscopic procedure to assess the extent
of peritubal disease with the potential need to
undergo endoscopic tubal reconstruction.
A third indication is the patient with otherwise
unexplained infertility after a standard evaluation.
Patients with normal findings at HSG and laparos- FIGURE 11–1. Flexible salpingoscope with irrigating
copy have been noted to have intraluminal adhe- channel. (Courtesy of Olympus, Lake Success, NY)
sions and abnormal endothelial vascular patterns
during tubal microendoscopy. In addition, the use
of falloposcopic visualization of the tubal lumen to neosalpingostomy incision is made with microscis-
confirm appropriate catheter placement prior to sors or laser to allow tubal cannulation. This inci-
transcervical gamete transfer on an outpatient basis sion serves as the start of a potential full distal
has been reported. neosalpingostomy procedure should the tube be
Contraindications to tubal endoscopy are dis- deemed repairable. If necessary, this site can also
played in Table 11–1. This procedure should not be be subsequently sealed.
performed in the presence of active pelvic infec- Visualization is performed in a retrograde fash-
tion or uterine bleeding or in patients unable to tol- ion as the tubal lumen is distended with Ringer’s
erate local anesthetic agents if the procedure is to lactate solution to which heparin 5000 U/L has been
be undertaken in an office setting. Patients with added. Although this procedure must be performed
such endometrial pathology as synechiae or a during laparoscopy, a general anesthetic may not
submucous myoma, preventing visualization and be necessary when salpingoscopy is combined with
access to the uterotubal ostium, are poor candidates microlaparoscopy employing outpatient conscious
for falloposcopy as well. sedation techniques. Dripping 1% lidocaine on the
tubal serosa makes the procedure more easily tol-
erated in this setting.
Although this procedure was initially designed
Salpingoscopy: Equipment to assess the potential for successful repair of the
and Technique distally occluded fallopian tube, several investiga-
tive teams have assessed the role of salpingoscopy
Transfimbrial salpingoscopy, performed during in the patient with patent tubes. Surrey and Surrey
laparoscopy, is a means of visualizing the tubal noted a strong correlation between laparoscopic
lumen from the ampullary–isthmic junction to the and salpingoscopic findings in 40 tubes believed to
fimbria. Flexible fiberoptic or rigid salpingoscopes have moderate to severe disease at laparoscopy. In
with camera attachments and outer diameters rang- marked contrast, no correlation was noted between
ing from 1.8 to 2.8 mm (Olympus, Lake Success, findings derived from these two techniques in 51
NY; Karl Storz, Culver City, CA) are introduced tubes noted to be normal or to have minimal dis-
into the peritoneal cavity through an accessory ease at laparoscopy. In the latter group, 35.7% were
5 mm trochar with a 3 mm reducer (Fig. 11–1). The shown to have moderate to severe luminal abnor-
fallopian tube to be evaluated is stabilized by plac- malities at salpingoscopy. Marconi and colleagues
ing an atraumatic grasping forceps on the antimes- reported that 37% of patients described as having
enteric serosal border just proximal to the fimbria. normal tubes at laparoscopy had endothelial ab-
The fimbrial ostium is cannulated by the salpingo- normalities appreciated only by salpingoscopy.
scope until a point of resistance is met or until the Shapiro et al. reported a 23.5% discordance in find-
ampullary–isthmic junction is reached (Fig. 11–2). ings between the two procedures. Of 151 normal-
In the event of total distal occlusion, a small appearing tubes at laparoscopy, Antony and co-
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 130

130 E.S. Surrey

FIGURE 11–2. Cannulation of

the fallopian tube with a
flexible salpingoscope. The
distal serosal edge is stabi-
lized by atraumatic grasping
forceps.

workers reported that 39 (25.8%) had no mucosal Falloposcopy: Equipment

lesions appreciated at salpingoscopy. Discrepancies
between salpingoscopic and HSP findings have also and Technique
been reported. Numerical salpingoscopy scores
have been shown to be highly predictive of preg- One of the disadvantages of transfimbrial salpin-
nancy by several investigative teams (Fig. 11–3). goscopy is the need for concomitant laparoscopy
The ability to visualize mucosal abnormalities and the inability to access regions of the fallopian
directly may therefore provide valuable informa- tube proximal to the ampullary–isthmic junction.
tion that would not otherwise be obtained by Kerin and colleagues initially reported successful
employing more traditional techniques. transcervical microendoscopy of the entire tubal
lumen from the uterotubal ostium to the fimbria, a
procedure termed “falloposcopy.” A variety of fal-
loposcopes have been developed as modifications
of fiberoptic angioscopes. These flexible instru-
ments measure approximately 1.5 m in length and
0.45–0.5 mm in outer diameter (Conceptus, San
Carlos, CA; Medical Dynamics, Englewood, CO;
Intramed, San Diego, CA; Olympus) (Fig. 11–4).
Two basic techniques for performing fallo-
poscopy have been described: a coaxial approach
and a linear everting catheter approach. With the
coaxial approach, the uterotubal ostium (UTO) is
first visualized by introducing a flexible hystero-
scope into the endometrial cavity under video mon-
itoring to achieve a long axis view within 1–2 mm
FIGURE 11–3. Estimated cumulative spontaneous intra- of the tubal ostia. Cervical dilation is rarely re-
uterine pregnancy rates from the time of surgery based quired and is avoided if possible to prevent leak-
on mean salpingoscopy scores based on results of life-
age. A variety of hysteroscopes with 1.5–2.0 mm
table analysis. Circles, patients (n  18) with mean
scores 12 (mean  SEM) (follow-up 11.7  2.3 o.d. and a single operating channel have been
months). Squares, patients (n  24) with mean scores employed (Olympus; Intramed; Mitsubishi Cable
12 (mean  SEM) (follow-up 14.6  1.9 months). Industries, Itami, Japan). Lactated Ringer’s solu-
†p  0.038 vs. patients with scores 12. (From Surrey tion is infused as a distension medium through
and Surrey, 1996, with permission.) extension tubing connected to one arm of an
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 131

11. Endoscopic Evaluation of the Fallopian Tube 131

FIGURE 11–4. Coaxial falloposcope with 0.45 mm OD

and camera attachments. (Courtesy of Conceptus, San
Carlos, CA) FIGURE 11–5. Coaxial falloposcopy. Falloposcope has
been placed through the straight arm of a Y-connector
into a Teflon over-the-wire catheter.

attached Tuohy-Borst type Y-connector (Cook tain the falloposcope flush with the distal opening
Ob/Gyn, Spencer, IN). A flexible platinum-tipped of the catheter. A white-out occurs if the lens
tapered guidewire of 0.3–0.8 mm o.d. (Target Ther- directly touches the tubal endothelial lining. Dual
apeutics, San Jose, CA; Conceptus; Cook Ob/Gyn; video monitoring of hysteroscopy and falloposcopy
Glidewire Medi-Tech, Watertown, NH) is then is helpful. This approach allows simultaneous diag-
introduced into the UTO through the second arm nosis and potential therapy of visualized lesions
of the Y-connector and advanced until either a point with the subsequent use of stiffer wires or balloon
of resistance, increased patient discomfort, or a dis- catheters. This technique is summarized in Table
tance of 15 cm is reached. Care should be taken to 11–2.
avoid passage of the wire through the UTO during The linear everting catheter system (Imagyn,
a period of ostial spasm. It should be noted that Laguna Niguel, CA) represents an alternative ap-
although the intramural segment of the fallopian proach for transcervical cannulation and visualiza-
tube is fairly straight over its 1.5–2.5 cm length it tion of the fallopian tube lumen. The linear evert-
may form an acute angle with the cavity. A gentle ing catheter (LEC) consists of an outer and an inner
torque motion may facilitate guidewire passage catheter body that is joined distally by a balloon
through this region. (Fig. 11–6). This balloon everts by pressurization
Once the wire has been introduced, a Teflon- of a joining membrane, which slowly unrolls the
coated catheter with 1.2–1.3 mm o.d. (Target Ther- catheter tip as the inner body is advanced.
apeutics; Conceptus; Cook Ob/Gyn) is introduced The UTO is visualized by introducing the fallo-
over the wire for a similar distance. The guidewire poscope through the distal lumen of the catheter,
is then withdrawn. obviating the need for use of a separate hystero-
A second Tuohy-Borst Y-connector is then scope. The balloon is pressurized and the catheter
attached to the proximal end of the catheter. The slowly everted. This catheter system allows the bal-
falloposcope is introduced through the straight arm loon to conform to the tortuous path of the fallo-
of the second Y-connector. This allows protection
for the atraumatic leading end of the highly flexi-
ble falloposcope, which measures 120–130 cm in TABLE 11–2. Coaxial Falloposcopy:
length and 0.3–0.5 mm o.d. (Olympus; Mitsubishi; Summary of Technique
Intramed; Medical Dynamics, Englewood, CO).
Visualization of uterotubal ostium (UTO) with flexible
The coaxial system is displayed in Figure 11–5. hysteroscope
Lactated Ringer’s solution is infused through the Guidewire cannulation of UTO
angled arm of this second Y-connector. A xenon Over-the-wire catheter placement
light source, a camera chip, and a high resolution Removal of guidewire
Introduction of falloposcope through catheter
video monitor are required. The tubal lumen is visu- Retrograde visualization
alized in a retrograde fashion taking care to main-
3051_Seifer_11_p127-136 11/5/01 9:49 AM Page 132

132 E.S. Surrey

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

pian tube more accurately while eliminating lateral Normal Anatomy and
shear forces. Once the tube has been completely Pathologic Findings
catheterized to the point at which resistance is met
or until the catheter is advanced for a distance of The endothelial lining of the intramural portion of
15 cm, the 0.5 mm o.d. falloposcope is subse- the fallopian tube is 0.8–1.0 mm in diameter and is
quently introduced through the everted catheter. marked by several flattened folds. The isthmic
Falloposcopy is performed in a retrograde fashion. region extends for 2–3 cm with a 1–2 mm diame-
Office-based falloposcopy has been described ter, and it is marked by four to six longitudinal folds
with use of the LEC system in only several pub- with a more delicate vascular pattern (Fig. 11–7).
lished series to date. Scudamore and coworkers The ampulla rapidly increases in diameter from
were able to perform bilateral tubal endoscopic 1.5–4.0 mm proximally to 8–10 mm distally. Its
visualization successfully in 18 of 19 patients with variable length is 5–10 cm. As one progresses dis-
a mean operating time of 35 minutes (range 25–50 tally, a radial pattern of primary folds 4 mm in
minutes). Epithelial characteristics were appreci- height, which increase in number, are visualized
ated in 34 of 37 tubes visualized. No complications (Fig. 11–8). Delicate secondary folds that incorpo-
were reported. Bauer and colleagues performed rate a fine vascular pattern are appreciated as one
outpatient falloposcopy in eight tubes in seven reaches the more distal aspects of the ampullary
patients prior to intratubal insemination. No irriga- region.
tion was employed in the tube, and falloposcopy A variety of pathologic findings in the tubal
was performed solely to confirm catheter location lumen have been effectively visualized with the aid
in the tube. Catheterization was successfully per- of tubal endoscopy. Distally, one is able to assess
formed in all patients without complications. Dun- the extent of inflammatory vascular patterns,
phy and colleagues reported that in-office fallo- mucosal atrophy, and loss of primary endothelial
poscopy induced significantly less intense pain than folds characteristic of hydrosalpinges (Fig. 11–9).
HSG. Rapid eversion, cannulation, and flushing More proximal lesions that can be appreciated
near the UTO were associated with the most severe include varying degrees of stenoses, nonocclusive
discomfort in this series. intraluminal adhesions, tubal polyps, mucous
3051_Seifer_11_p127-136 11/5/01 9:50 AM Page 133

11. Endoscopic Evaluation of the Fallopian Tube 133

FIGURE 11–7. Falloposcopic image of the normal tubal FIGURE 11–9. Hydrosalpinx visualized with a linear
isthmus obtained with the linear everting catheter. (From everting catheter system. Note the flattened fibrotic endo-
Pearlstone et al., 1992, with permission) thelial lining. (From Pearlstone et al., 1992, with per-
mission)

plugs, and the endothelial diverticula associated

with salpingitis isthmica nodosa. imal tubal occlusion based on laparoscopic or radi-
Kerin and coworkers developed a classification ologic findings, no abnormalities were noted in
system to standardize and quantify findings at fal- 46%. Venezia and colleagues noted that HSG and
loposcopy. Point scores are attributed for patency, LEC falloposcopy findings failed to correlate in
dilation, vascular patterns, epithelial quality, and 40% of tubes visualized. Another small series
intraluminal adhesions. As has been shown with reported that 9 of 12 tubes described as proximally
salpingoscopy, findings at falloposcopy correlate occluded as seen by HSG were normal at fallo-
poorly with findings at HSG. In a large series of poscopy. We have reported that 40% of visualized
falloposcopies performed on 112 tubes in 75 tubes in patients with otherwise unexplained infer-
women who had a presumptive diagnosis of prox- tility and normal HSG had abnormalities appreci-
ated only at falloposcopy. The likelihood of HSG
or chromo per tubation depicting normal tubes
when abnormalities were detected at falloposcopy
was 22.7% in this study. Management changes were
made in 52.4% of patients in this series as a result
of falloposcopic findings. A clear correlation
between falloposcopic findings and conception has
been described.

Complications
The primary risk of falloposcopy is that of tubal
perforation, the incidence of which is extremely
low. Exaggerated acute angles formed by the junc-
tion of the intramural portion of the tube with the
uterotubal ostium, peritubal adhesions limiting
tubal flexibility, and narrowing of the lumen due to
fibrotic obstruction predispose to perforation. No
perforations that occurred during procedures we
FIGURE 11–8. Image of the normal tubal ampulla obtained performed have been associated with significant
with a flexible salpingoscope. sequelae. Gentle manipulation and a keen aware-
3051_Seifer_11_p127-136 11/5/01 9:50 AM Page 134

134 E.S. Surrey

TABLE 11–3. Fallopian Tube Evaluation Techniques

Selective Laparoscopy/
Parameter HSG salpingography chromoperturbation Salpingoscopy Falloposcopy
Tubal access Cervical Cervical Cervical/fimbrial Fimbrial Cervical
Patency confirmed     
Access entire tube     
Confirm obstruction site /  /  
Visualize lumen   Extreme distal only  
Overcome UTO spasm   /  
OR setting/conscious sedation     /
Visualize nonobstructive lesions     
Assess peritubal disease     

HSG, hysterosalpingography; OR, operating room.

ness of tubal anatomy represents a crucial means concomitant laparoscopy may prove to be limiting
of avoiding this complication. A low incidence of factors. Patients with dense fibrotic obstruction
guidewire dissection between the endothelium, require tubal bypass with IVF or resection and
without sequelae, has also been reported. Aside microsurgical anastomosis as appropriate.
from the standard risks of laparoscopy, no compli-
cations attributed to salpingoscopy per se have been
reported. Distal Disease
Evaluation of the fallopian tube in the infertile The patient with suspected hydrosalpinges is man-
woman by standard HSG or laparoscopy may not aged in a different fashion. If a grossly dilated tube
represent a completely accurate means of ruling out with no functional endothelial lining or extensive
underlying pathology. Advances in fiberoptic cath- intraluminal adhesions is noted at falloposcopy, fur-
eter technology allow the investigator to visualize ther surgical intervention may prove unnecessary,
the tubal lumen directly. The relative merits of the or salpingectomy may be performed if appropriate.
techniques employed to assess the fallopian tube The patient should be referred directly for IVF. If
are summarized in Table 11–3. Whether tubal the lining appears only minimally compromised,
endoscopy after selective salpingography should laparoscopic assessment of peritubal disease with
represent a standard part of the infertility evalua- the potential for neosalpingostomy should be per-
tion shall come from the results of larger ongoing formed. IVF would be appropriate in the presence
clinical trials. of extensive peritubal disease or more advanced
maternal age. This management paradigm is sum-
marized in Table 11–4.
Management Decisions
Proximal Disease TABLE 11–4. Management Based on Findings at
Patients with intraluminal mucous plugs or debris Falloscopy/Salpingoscopy
may best be managed with aquadissection tech- Normal lumen: treat as unexplained infertility; perform
niques. Intraluminal endometriosis and endosal- laparoscopy if indicated
Suspected proximal occlusion
pingiosis may perhaps best be treated medically Mucous plugs, debris: aquadissection
with a trial of gonadotropin-releasing hormone Endometriosis, endosalpingiosis: medical suppression
(GnRH) agonist or danazol therapy, although min- Nonobstructive adhesions: guidewire dissection
imal intraluminal adhesions may be more appro- Moderate adhesions, stenosis: guidewire dissection or
directed balloon tuboplasty
priately approached with gentle guidewire dissec- Dense obstruction: IVF/ET vs. resection and microsurgical
tion. Denser adhesions or mild stenoses may also anastomosis
be approached employing balloon dilation tech- Suspected distal occlusion
niques. These procedures may someday be per- Severe disease: IVF/ET, possible salpingectomy
formed in an office setting, once sufficient data Mild to moderate disease: IVF/ET vs. laparoscopy, possible
neosalpingostomy depending on patient’s age and extent
addressing safety and patient tolerance have been of peritubal disease
reported. Increased analgesic requirements and the
inability to avoid tubal perforation by performing IVF/ET, in vitro fertilization–embryo transfer.
3051_Seifer_11_p127-136 11/5/01 9:50 AM Page 135

11. Endoscopic Evaluation of the Fallopian Tube 135

Falloposcopy and salpingoscopy represent excit- Dunphy B, Tawzer P, Bultz B, et al. A comparison of
ing new and evolving technologies that allow visu- pain experienced during hysterosalpingography and
alization of the tubal lumen in a minimally inva- in-office falloposcopy. Fertil Steril 1994;62:62–70.
sive fashion. This procedure clearly lends itself to Dunphy BC. Office falloposcopy assessment in proximal
performance in an office setting with minimal anes- tubal disease. Fertil Steril 1994;61:168–170.
Gordts S, Campo R, Romhauts L, Brosens I. Transvagi-
thesia. As a result, management decisions can now nal hydrolaparoscopy as an outpatient procedure for
be made based on visualization of the pathologic infertility investigation. Hum Reprod 1998;13:99–103.
findings. As experience and technology progress, Grow DR, Coddington CC, Flood JF. Proximal tubal
tubal endoscopy may become a standard part of the occlusion by hysterosalpingogram: a role for fallo-
outpatient evaluation of the infertile patient with poscopy. Fertil Steril 1993;60:170–174.
suspected tubal disease. Guerriero S, Ajoosa S, Mais V, Paoletti AM, Melis GB.
The screening of tubal abnormalities in the infertile
Acknowledgments. Special thanks to John F. Kerin, couple. J Assist Reprod Genet 1996;13:407–412.
M.D., Ph.D. and Mark W. Surrey, M.D. for their Henry-Suchet J, Loffredo V, Tesuier L, Pez J. Endoscopy
vision and guidance. of the tube ( tuboscopy): its prognostic value for
tuboplasties. Acta Eur Fertil 1985;16:139–145.
Heylen SM, Brosens IA, Puttemans P. Clinical value and
Suggested Reading cumulative pregnancy rates following rigid salpin-
Andersen A, Yue Z, Meng F, Patersen K. Low implanta- goscopy during laparoscopy for infertility. Hum
tion rate after in vitro fertilization in patients with Reprod 1995;11:2913–2916.
hydrosalpinges diagnosed by ultrasonography. Hum Katz E, Akman MA, Damewood MD, Garcia JE. Dele-
Reprod 1994;9:1935–1938. terious effect of the presence of hydrosalpinx on
Antony A, Slanger T, van Herendael BJ. Salpingoscopy implantation and pregnancy rates with in vitro fertil-
is an important part of the infertility work-up. J Am ization. Fertil Steril 1996;66:122–125.
Assoc Gynecol Laparosc 1996;3:369–374. Kerin J, Daykhovsky L, Grundfest W, Surrey E. Fallo-
Bauer O, Diedrich K, Bacich S, et al. Transcervical poscopy: a microendoscopic transvaginal technique
access and intra-lumenal imaging of the fallopian tube for diagnosing and treating endotubal disease incor-
in the non-anesthetized patient: preliminary results porating guide wire cannulation and direct balloon
using a new technique for fallopian access. Hum tuboplasty. J Reprod Med 1990;35:606–612.
Reprod 1992;7(suppl):7–11. Kerin J, Daykhovsky L, Segalowitz J, et al: Fallo-
Boer-Meisel M, te Velde E, Habbema J, Kardaun J. Pre- poscopy: a microendoscopic technique for visual
dicting the pregnancy outcome in patients treated for exploration of the human fallopian tube from the utero-
hydrosalpinx: a prospective study. Fertil Steril 1986; tubal ostium to the fimbria using a transvaginal
45:23–29. approach. Fertil Steril 1990;54:390–400.
Brosens I, Boackx W, Delattin P, Puttemans P, Vasquez Kerin J, Williams D, San Roman G, et al. Falloposcopic
G. Salpingoscopy: a new preoperative diagnostic tool classification and treatment of fallopian tube lumen
in tubal infertility. Br J Obstet Gynaecol 1987;94: disease. Fertil Steril 1992;57:731–741.
768–773. Kerin JF, Pearlstone AJ, Surrey ES. Tubal microen-
Cummings DC, Taylor PJ. Historical predictability of doscopy: salpingoscopy and falloposcopy. In: Keye
abnormal laparoscopic findings in the infertile woman. WR Jr, Chang RJ, Rebar RW, Soules MR (eds) Infer-
J Reprod Med 1979;23:295–298. tility: Evaluation and Treatment. Philadelphia: Saun-
De Bruyne F, Hucke J, Willers R. The prognostic value ders, 1995:372–386.
of salpingoscopy. Hum Reprod 1997;12:266–271. Letterie GS, Sakas EL. Histology of proximal tubal
Dechaud H, Daures JP, Hedon B. Prospective evaluation obstruction. Fertil Steril 1991;56:831–835.
of falloposcopy. Hum Reprod 1998;13:1815–1818. Mage G, Pouly J-L, de Joliniere J, et al. A preoperative
Dickens CJ, Maguiness SD, Conur MT, et al. Human classification to predict the intrauterine and ectopic
tubal fluid: formation and composition during vascu- pregnancy rates after distal tubal microsurgery. Fertil
lar perfusion of the fallopian tube. Hum Reprod 1995; Steril 1986;46:807–810.
10:505–508. Marana R, Catalano GF, Muzii L, et al. The prognostic
Dor J, Homburg R, Rabau E. An evaluation of etiologic role of salpingoscopy in laparoscopic tubal surgery.
factors and therapy in 665 infertile couples. Fertil Hum Reprod 1999;14:2991–2995.
Steril 1977;28:718–722. Marana R, Rizzi M. The role of salpingoscopy and fal-
Dubuisson J, Chapion C, Morice P, et al. Laparoscopic loposcopy in infertility. Curr Opin Obstet Gynecol
salpingostomy: fertility results according to the tubal 1996;8:257–260.
mucosal appearance. Hum Reprod 1994;9:334–339. Marana R, Rizzi M, Muzii L, et al. Correlations between
Dunphy B, Greene C. Falloposcopic cannulation, oviduc- the American Fertility Society classifications of
tal appearances and prediction of treatment indepen- adnexal adhesions and distal tubal occlusion, salpin-
dent intrauterine pregnancy. Hum Reprod 1995;10: goscopy, and reproductive outcome in tubal surgery.
3313–3316. Fertil Steril 1995;64:924–929.
3051_Seifer_11_p127-136 11/5/01 9:50 AM Page 136

136 E.S. Surrey

Marconi G, Auge L, Sojo E, Young E, Quintana R. Sal- Surrey ES. Microendoscopy of the human fallopian tube.
pingoscopy: systematic use in diagnostic laparoscopy. J Am Assoc Gynecol Laparosc 1999;6:383–389.
Fertil Steril 1992;57:742–746. Surrey ES, Surrey MW. Correlation between salpingo-
Opsahl MS, Miller B, Klein TA. The predictive value of scopic and laparoscopic staging in the assessment of
hysterosalpingography for tubal and peritoneal infer- the distal fallopian tube. Fertil Steril 1996;65:267–
tility factors. Fertil Steril 1993;6:444–448. 271.
Pearlstone AC, Surrey ES, Kerin JF. The linear everting Surrey ES, Adamson GD, Surrey MW, et al. Introduc-
catheter: a nonhysteroscopic transvaginal technique tion of a new coaxial falloscopy system: a multicen-
for access and microendoscopy of the fallopian tube. ter feasibility study. J Am Assoc Gynecol Laparosc
Fertil Steril 1992;58:854–857. 1997;4:473–78.
Puttemans P, Brosens I, DeLattis P, Vasquez G, Boeckx Surrey ES, Surrey MW, Kerin JF. Salpingoscopy and fal-
W. Salpingoscopy versus hysterosalpingography in loposcopy. In: Adamson GD, Martin DC (eds) Endo-
hydrosalpinges. Hum Reprod 1987;2:535–540. scopic Management of Gynecologic Disease. Phila-
Puttemans PJ, De Bruyne F, Heylen SM. A decade of delphia: Lippincott-Raven, 1996:345–358.
salpingoscopy. Eur J Obstet Gynecol Reprod Biol Swart P, Mol BWJ, Van der Veen F, et al. The accuracy
1998;81:197–206. of hysterosalpingography in the diagnosis of tubal
Savada T, Tsukada K, Satoh M, Kawakami S. Correla- pathology: a meta-analysis. Fertil Steril 1995;64:486–
tion between salpingoscopic score and subsequent 491.
pregnancy outcome in patients with tubal infertility. J Swolin K, Rosencrantz M. Laparoscopy vs. hysterosal-
Assist Reprod Genet 1997;14:562–565. pingography in sterility investigations, a comparative
Scudamore IW, Dunphy BC, Cooke ID. Outpatient fal- study. Fertil Steril 1972;23:270–273.
loposcopy: intralumenal imaging of the fallopian tube Thurmond AS, Novy M, Uhcida BT, Rösch J: Fallopian
by trans-uterine fiberoptic endoscopy as an outpatient tube obstruction: selective salpingography and re-
procedure. Br J Obstet Gynaecol 1992;99:829–835. canalization. Radiology 1987;163:511–514.
Shapiro B, Diamond M, de Cherney A. Salpingoscopy: Venezia R, Zangara C, Knight C, Cittadini E. Initial expe-
an adjunctive technique for evaluation of the fallopian rience of a new linear everting falloposcopy system in
tube. Fertil Steril 1988;49:1076–1079. comparison with hysterosalpingography. Fertil Steril
Sulak P, Letterie G, Coddington C, et al. Histology of 1993;60:771–725.
proximal tubal obstruction. Fertil Steril 1991;56: World Health Organization. Comparative trial of tubal
831–835. insufflation, hysterosalpingography, and laparoscopy
Surrey ES. Falloposcopy. Obstet Gynecol Clin North Am with dye hydrotubation for assessment of tubal
1999;26:53–62, vi. patency. Fertil Steril 1980;46:1101–1107.
3051_Seifer_12_p137-140 11/27/01 3:44 PM Page 137

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

Bilateral or unilateral proximal tubal obstruction microsurgically resected segments, justifying more
(PTO) is a common finding on a hysterosalpin- invasive management.
gogram (HSG) obtained as a part of the infertility The etiology of PTO varies widely. Intraluminal
workup. The traditional management of this radio- factors such as muscular spasm, amorphous debris,
logic finding is laparoscopic assessment of the and mucous plugs are the most common reasons
oviducts. If no spill of transcervically injected con- for obstruction and can be easily removed by tubal
trast is noted from the fimbriated end of the fal- cannulation. Other conditions such as obliterative
lopian tube, microsurgical resection of the obliter- fibrosis (most likely secondary to inflammatory
ated segment of the oviduct and anastomosis is changes), chronic salpingitis, and salpingitis isth-
performed. HSG alone has a nearly 40% false- mica nodosa do not easily respond to cannulation.
positive rate, and PTO is often overdiagnosed. Lap- Rare etiologies of PTO have also been reported,
aroscopic evaluation of PTO does not eliminate the including parasitic infection, tuberculosis, and
false-positive rate. Serious pathology is found in hyalinized ectopic pregnancy. If PTO develops after
only 40% of the microsurgically resected tubal a surgical tubal anastomosis, tubal cannulation is
segments, and amorphous casts, calcifications, or a rarely successful, and tubal wall perforation or fis-
patent lumen are the findings in the remaining 60% tula may occur.
of the excised oviducts. Therefore the need for The success of TCTC is measured not only by
major abdominal surgery can be questioned in such passing a catheter along the oviduct but also by
cases. The need for accurate diagnosis of PTO has maintaining the patency and achieving an intrauter-
led to the development of several diagnostic modal- ine pregnancy. The reproductive success following
ities: (1) selective fluoroscopically guided salpin- an effective tubal cannulation depends on multiple
gography; (2) transcervical tubal cannulation; and factors: the etiology of the obstruction, functioning
(3) transfimbrial or transcervical salpingoscopy. of the tubal muscularis and the mucosa, status of
The advent of assisted reproductive techniques the distal portion of the oviduct, the presence of
(ARTs) contributed another treatment option to the peritubal adhesions, age, and the presence of other
management of PTO-related infertility. Both micro- independent infertility factors (male and female).
surgical anastomosis and ART are invasive, labori- Overall, 82% of all catheterized tubes become
ous, and costly. Transcervical tubal cannulation patent, and 68% of them remain open; 24% patients
(TCTC), which provides a diagnostic and thera- achieve an intrauterine pregnancy, and the ectopic
peutic modality, has become an attractive approach pregnancy rate is 6%.
to the management of PTO. TCTC offers less
expensive, less invasive restoration of tubal patency
and can be performed as an outpatient office pro- Indications/Purpose
cedure under minimal anesthesia. The success of
recanalization of the affected oviduct depends on The TCTC procedure is performed to reestablish
the etiology of the obstruction and the extent of the tubal patency of a proximally obstructed oviduct(s)
blocked segment. When TCTC fails to recanalize in women who desire a pregnancy. Assessment of
the oviduct, serious pathology is found in 93% of tubal status is an essential part of the infertility

137
3051_Seifer_12_p137-140 11/27/01 3:44 PM Page 138

138 J.W. Graczykowski and D.B. Seifer

workup. If PTO is suspected during the initial HSG (which can be performed at the same time), a preg-
procedure, selective salpingography should be per- nancy test, and a semen analysis. A Chlamydia tra-
formed to confirm the diagnosis. A TCTC setup chomatis antibody [immunoglobulin G and M (IgG,
may be available at the same time; and if selective IgM)] titer and Chlamydia and gonorrhea cervical
salpingography fails to image a patent oviduct, cultures are also recommended. Prophylactic anti-
careful cannulation can be attempted. biotics (doxycycline 100 mg PO bid  6 days) may
Not all women who have evidence of PTO on be started 2 days prior to the procedure.
prior HSG may benefit from TCTC. The selection Counseling before the procedure should be indi-
of candidates for TCTC and selection of the method vidualized, based on the results of the workup, and
of cannulation should be undertaken carefully. should include an explanation of the technique, its
Women under the age of 40 with minimal risk of effectiveness and anticipated pregnancy chance,
distal tubal disease according to their history, no possible complications, and finally other manage-
filling defects in the uterine cavity on HSG, and an ment options. Patient should sign an informed con-
absence of severe male factor are excellent candi- sent prior to the procedure.
dates for office fluoroscopically guided selective
salpingography combined with TCTC. If distal
tubal damage is strongly suspected (history of sal- Equipment
pingitis, high seropositive titer for Chlamydia tra-
chomatis), selective salpingography and TCTC There are several TCTC systems available. If the
could be performed at the time of a diagnostic lap- procedure is performed in the physician’s office or
aroscopy, which allows simultaneous assessment at the time of HSG, the oviducts can be cannulated
of the distal segment of the oviduct. Women with under fluoroscopic guidance. The hysteroscopic
intrauterine radiographic filling defects may be
served better by a hysteroscopically guided TCTC,
which allows concomitant assessment of the endo-
metrial cavity. An algorithm for PTO is summa-
rized in Fig. 12–1.

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

Special Preparation
The TCTC is best performed during the early fol-
licular phase of the menstrual cycle when the endo-
metrium is thin and the patient is unlikely to be
pregnant. Heavy menstrual bleeding may interfere
with accurate assessment of the uterine cavity and FIGURE 12–1. Algorithm for proximal tubal obstruction
the oviducts. (PTO) management. HSG, hysterosalpingography; ART,
The workup prior to TCTC should include HSG assisted reproductive technology.
3051_Seifer_12_p137-140 11/27/01 3:44 PM Page 139

12. Transcervical Tubal Cannulation 139

approach using a distension medium and cervical ing radiopaque catheter is advanced via the cervi-
dilatation requires an operating room. The best cal cannula and positioned under fluoroscopic
results are obtained when a coaxial catheter system guidance in the uterine cornu with the blocked
is used, and the oviduct is penetrated by a thin plat- oviduct. A syringe with radiographic contrast is
inum wire and a 3 French (3F) Teflon catheter attached to the end of the cervical catheter, and
advanced over the wire. A double-lumen plastic small amounts of contrast can be injected period-
catheter (7.5F to 12.0F; Cook Ob/Gyn, Spencer, IN) ically to improve visualization of the endometrial
with a balloon is placed in the endometrial cavity cavity. If the oviduct fails to fill after direct injec-
via the cervical canal, and the balloon is inflated. tion of the contrast during selective salpingogra-
One lumen of the catheter allows injection of the phy, a T-J wire can be introduced via the 5.5F guid-
radiographic contrast, and the larger port is used to ing cannula and placed into the tubal ostium to
pass other catheters. A 5.5F radiopaque curved cath- open it up. Then the T-J wire can be replaced with
eter (40 cm long, Cook Ob/Gyn) can be used for the inner catheter (3F) containing a guidewire
selective salpingography and as an introducer a ended with a platinum tip; it is threaded via the
curved T-J wire (0.89 mm diameter, 90 cm long, outer guiding catheter (5.5F), and the wire tip is
ended with a 1.5 mm Safe-T-J tip, Cook Ob/Gyn) then advanced into the tubal ostium. Once this is
or a 3F catheter (65 cm long, Cook Ob/Gyn) con- accomplished, the inner 3F catheter is gently intro-
taining a steel wire ended with a platinum tip (0.38 duced into the isthmus over the guidewire.
mm diameter, 90 cm long, Cook Ob/Gyn). The exact Advancement of the catheter can be monitored by
choice equipment depends on the surgeon’s prefer- fluoroscopy. Successful cannulation is signified by
ence. TCTC with a wire alone yields less effective the distal oviduct filling with contrast. The proce-
results followed by lower pregnancy rates. Catheters dure is then repeated on the contralateral side when
ended with inflatable balloons for tubal dilatation indicated.
have also been described. The TCTC catheter sys-
tem described below is the most practical and
widely used in an outpatient setting. It consists of a
coaxial catheter system, which is placed in the Complications
oviduct under direct fluoroscopy guidance.
Complications with TCTC are relatively rare. The
most serious is pelvic infection and salpingitis,
which may lead to sepsis. Infection is most likely
Steps a flare of a subclinical inflammatory process that
was not detected prior to the procedure. Aggressive
1. Perform HSG. infectious workup of any febrile episode following
2. Perform selective salpingography under fluo- TCTC, hospitalization, and administration of ther-
roscopy. apeutic intravenous doses of broad-spectrum anti-
3. Introduce the coaxial catheter system into the biotics may contain the spread and severity of the
uterine cavity under fluoroscopic guidance. infectious process. The use of prophylactic antibi-
4. Cannulate radiographically the nonfilling ovi- otics may reduce the risk of this complication.
duct(s) under fluoroscopic guidance. Perforation of the oviduct with the guidewire has
5. Assess the radiographic image of the distal por- also been described. The surgeon should pay close
tion of the oviduct. attention to the direction of the wire while advanc-
ing it along the blocked area of the oviduct. Any
outpouching of the radiographic contrast may be
consistent with an oviduct wall perforation, a false
Detailed Description track, or a fistula. Although this complication is rel-
of the Procedure atively rare, it has been observed during laparos-
copy performed by a second team during tubal can-
The initial HSG is performed in the usual fashion. nulation. The sequelae of tubal perforation during
Local anesthesia is administered (paracervical the cannulation procedure are difficult to assess.
block using 1% solution of lidocaine). Additional Excessive exposure to radiation should be
intravenous conscious sedation with midazolam avoided. The surgeon should keep track of the total
HCl and fentanyl citrate is recommended. If a time of x-ray exposure during fluoroscopy and
double-lumen balloon cannula was used to per- should not extend beyond a total of 10 minutes of
form HSG, a 5.5F (40–65 cm long) curved guid- exposure.
3051_Seifer_12_p137-140 11/27/01 3:44 PM Page 140

140 J.W. Graczykowski and D.B. Seifer

TABLE 12–1. Three Methods for Proximal Tubal Obstruction Management.

Parameter Microsurgical anastomosis IVF TCTC
Cost Expensive Expensive Inexpensive
Hospitalization Inpatient Outpatient Outpatient
Technical difficulty Technically difficult and Technically difficult and Technically not difficult
requires hi-tech requires hi-tech
equipment equipment
Distal oviduct and pelvis Gives opportunity to No need to correct distal Unable to evaluate and
evaluation evaluate and correct oviduct correct distal oviduct
distal oviduct and pelvis and pelvis
Evaluation of tubal lumen Unable to evaluate the No need to evaluate tubal Provides information on
status of tubal lumen status status of tubal lumen
Subsequent fertility Restores long-term fertility Fertility “on-demand” only Restores long-term fertility
Long-term retained tubal 70% Not applicable 70%
patency
Subsequent cumulative 60% 80% 25–40%
intrauterine pregnancy
rate
Risk of ectopic pregnancy 15% 8% 6–10%
Possible complications Adhesion formation, Hyperstimulation Oviduct perforation
surgical risks, syndrome, multiple infection
anesthesia risks pregnancies

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

Conclusion obstructed postoperative fallopian tubes. Eur Radiol

1998;8:461–465.
Letterie GS, Sakas EL. Histology of proximal tubal
The TCTC procedure is an easy, practical diagnos-
obstruction in cases of unsuccessful tubal canalization.
tic and therapeutic procedure for management of Fertil Steril 1991;56:831–835.
PTO. The technical simplicity, low cost, high effec- Novy MJ, Thurmond AS, Patton P, Uchida BT, Rosch J.
tiveness, and low rate of complications make TCTC Diagnosis of cornual obstruction by transcervical fal-
an attractive alternative to more invasive and expen- lopian tube cannulation. Fertil Steril 1988;50:434–
sive laparoscopy or microsurgery (Table 12–1). 440.
Each infertility patient with a suspicion of PTO Osada H, Kiyoshi Fujii T, Tsunoda I. Outpatient evalu-
should be offered selective salpingography com- ation and treatment of tubal obstruction with selective
bined with TCTC as the first-line approach. This salpingography and balloon tuboplasty. Fertil Steril
approach may eliminate the need for more invasive 2000;73:1032–1036.
Risquez F, Confino E. Transcervical tubal cannulation,
and costly procedures in many women. The future past, present, and future. Fertil Steril 1993;60:211–
developments of new instrumentation (e.g., trans- 226.
cervical salpingoscopy, sometimes called fallo- Thurmond AS, Rosch J. Nonsurgical fallopian tube
poscopy; everted catheters; transcervical balloon recanalization for treatment of infertility. Radiology
tuboplasty) may expand and improve the results 1990;174:371–374.
obtained with TCTC. Thurmond AS. Pregnancies after selective salpingogra-
phy and tubal recanalization [editorial]. Radiology
1994;190:11–13.
Suggested Reading Woolcott R. Proximal tubal occlusion: a practical ap-
proach. Hum Reprod 1996;11:1831–1833.
American Fertility Society [presently American Society Woolcott R, Petchpud A, O’Donnell P, Stanger J. Dif-
for Reproductive Medicine]. Guideline for Practice. ferential impact on pregnancy rate of selective salpin-
Tubal Disease. Birmingham, AL: AFS, February 15, gography, tubal catheterization and wire-guided re-
1993. canalization in the treatment of proximal fallopian tube
Lang EK. The efficacy of transcervical recanalization of obstruction. Hum Reprod 1995;10:1423–1426.
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 141

13
Microlaparoscopy for
Infertility in the Office
Steven F. Palter

Infertility remains a problem of significant magni- pressures of quality versus cost in an era of man-
tude today. In that a major life function, the ability aged care. It is likely that this technique will soon
to biologically reproduce, is compromised, this dis- become a major part of the practicing general gyne-
ease represents a major disability to those affected. cologist’s diagnostic and operative armamentarium.
Moreover, significant secondary psychological Office microlaparoscopy under local anesthesia is
trauma often results. Current surveys estimate that especially well suited to the evaluation of patients
approximately 10% of the U.S. population suffer with infertility. Laparoscopy is the preferred diag-
from infertility.1 One of the major etiologic factors nostic and therapeutic tool utilized by gynecolo-
in infertility is a pelvic abnormality resulting in gists to evaluate peritoneal and tubal factor infer-
tubal blockage. Tubal factor infertility is estimated tility. This approach allows visualization of the
to be present in 30–40% of women with infertil- entire abdominal cavity with far less morbidity and
ity.2,3 Salpingitis, endometriosis, and postoperative risk of adhesion formation than laparotomy.18,19
adhesions remain the primary causes.3 Common findings in patients with infertility at lap-
For decades gynecologists have searched for aroscopy are endometriosis, adhesions, and evi-
accurate, well tolerated, inexpensive methods to dence of acute or chronic pelvic inflammatory
determine tubal patency in the office setting. His- disease.
torically, the first method widely used was the Unfortunately, the basic evaluation of the female
Rubin test, initially described in 1920.4 Here CO2 pelvis has changed little over the last decade. Cur-
gas is insufflated through the cervix and uterus and rently, evaluation of the status of the fallopian tubes
ultimately the fallopian tubes if patent. Patency was is a standard component of the infertility investiga-
determined via measurements of gas pressure or tion, and laparoscopy remains the gold standard
documentation of subdiaphragmatic gas on radio- against which all methods are judged. A survey of
graphs. Unfortunately, the test is significantly pain- practice patterns of nearly 400 board-certified repro-
ful and provides information only on the patency ductive endocrinologists in the United States con-
of the tube. This test was later replaced by hystero- firmed the high prevalence of evaluating tubo-
salpingography (HSG), also initially described by peritoneal factors during the infertility evaluation.20
Rubin.5 Microlaparoscopy in the office under local About 96% of practitioners indicated that they
anesthesia is the most recent technique available for always, or almost always, ordered HSG during the
tubal assessment and represents the intersection of infertility workup for new couples seeking fertility
two technologies. The first, microlaparoscopy, is treatment. Similarly, the same group of respondents
the use of sub-5-mm laparoscopes and accessory always or almost always performed laparoscopy
instrumentation. The second is a technique to per- more than 89% of the time. This represented the third
form laparoscopy under local anesthesia, often in and fourth most commonly performed procedures
nontraditional (i.e., nonoperating room) settings, for evaluating new couples seeking fertility treat-
such as the hospital procedure room or a physi- ment, following only semen analysis and assessment
cian’s office.6–17 of ovulation. Also indicated by this sample was the
The technique of office laparoscopy under local almost universal performance of both HSG and lap-
anesthesia is especially suited to meet the current aroscopy for any given couple. Recently, attention

141
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 142

142 S.F. Palter

has focused on the cost-effectiveness of each aspect the NNT allows economic calculations to be made
of the evaluation and treatment of the couple with with regard to the cost of achieving a pregnancy
infertility. As such, there has been a general trend to when laparoscopy is performed for unexplained
delay or exclude the one test of greatest expense and infertility. It has been estimated that the cost per
invasiveness—laparoscopy. pregnancy is approximately $10,000 for clomi-
As early as 1980 Hulka et al. wrote on the stan- phene administration and intrauterine insemina-
dardization of the infertility workup to “balance the tions, $17,000 for gonadotropin therapy with intra-
cost-effectiveness of certain empiric treatment tri- uterine inseminations, and $40,000–$50,000 for
als with the need for the physician to know the assisted reproductive technologies.6 When evaluat-
nature of the underlying disease.”21 They recom- ing the cost of any given therapy the total cost of
mend, among other tests, HSG during initial eval- treatment must be calculated. This includes the
uation of the patient. If any tubal pathology is dis- physician professional component, anesthesia- and
covered, laparoscopy was indicated. Otherwise, anesthesiologist-related charges, and hospital oper-
laparoscopy was delayed until after at least four ating room time and supply charges. Currently,
cycles of successfully induced ovulation. Hulka et anesthesia and hospital room charges are billed in
al. emphasized that “laparoscopy is indicated at the time intervals. In fact, charges of $10–$20 per
end of the routine of infertility survey.”21 Again, minute for hospital room charges alone are not
laparoscopy was to be performed at least 6 months uncommon. Total global charges for diagnostic
after HSG. They similarly stated that the low inci- infertility laparoscopies routinely range from
dence of positive findings on routine endoscopy $6,000 to $10,000. At $8000, the total cost per preg-
should relegate laparoscopy to the end of the infer- nancy would rise to $24,000–$80,000. If office lap-
tility evaluation.21 They concluded, however, that aroscopy under local anesthesia is performed for a
the low cost, minimal invasiveness, and high toler- total global fee of $3000, the cost per pregnancy
ance of the Rubin test made it preferable to lapa- drops to $9,000–$30,000.22 Even at a cost per pro-
roscopy. Today, these same benefits may be real- cedure of $5000 (more than double our current
ized by office laparoscopy without compromising cost), the cost per pregnancy is $9,000–$30,000.
diagnostic accuracy and maintaining some correc- When compared to the $15,000–$50,000 for other
tive potential. interventions, office laparoscopy is a cost-effective
The primary motivating factor justifying a delay technique.
in performing laparoscopy is the belief that what is Currently, HSG remains the most frequent ini-
perceived to be a small yield may not justify the tial screening test used to evaluate tuboperitoneal
relatively large cost of the procedure or the risks factors. Unfortunately, there is a large body of lit-
(primarily anesthesia-related). Others believe that erature demonstrating the limited sensitivity and
alternative, nearly equivalent information can be specificity of this test. A study of 433 patients with
obtained by less expensive and less invasive tests. primary infertility was performed in which all
Finally, it has been suggested that the era of surgi- patients underwent HSG and laparoscopy.23 Almost
cal repair of structurally damaged fallopian tubes 50% of the population showed some abnormality
is over, replaced by assisted reproductive tech- by either one or both diagnostic methods. Thirty
nologies of presumably higher (at least monthly) percent of the time the findings on HSG and lapa-
fecundity rates. Therefore any evaluation of the role roscopy were discordant. The single most frequent
of laparoscopy in the evaluation and treatment of discrepancy (19%) was an abnormality found on
couples with infertility must address the following laparoscopy that was missed on HSG. A meta-anal-
points: (1) What is the prevalence of tuboperitoneal ysis by Swart et al. of 20 retrospective comparisons
disease diagnosed by laparoscopy? (2) What is the of HSG and laparoscopy determined point esti-
effectiveness of laparoscopy in treating such dis- mates of 0.65 sensitivity and 0.83 for specificity for
ease? (3) What alternative methods of diagnosis are the evaluation of tubal patency by HSG.24 Swolin
available? (4) What is the comparative sensitivity and Rosencrantz simultaneously performed lapa-
and specificity of these methods? (5) What is the roscopy and HSG and determined a sensitivity of
cost-effectiveness of the decision to include or 0.54 and a specificity of 0.83.25 Opsahl et al. how-
exclude laparoscopy in the evaluation? ever, demonstrated that even in the normal HSG
Office microlaparoscopy under local anesthesia group a high likelihood (16%) of moderate to
shifts the cost-benefit balance in favor of the early severe pelvic disease was found.26
performance of laparoscopy versus late or no lap- The two most common causes of tuboperitoneal
aroscopy, as demonstrated by an analysis of the disease are prior pelvic surgery and prior pelvic
“number needed to treat” (NNT).22 Calculation of inflammatory disease (PID). Unfortunately, the his-
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 143

13. Microlaparoscopy for Infertility in the Office 143

tory and physical examination alone have been the safety, feasibility, and advantages of laparos-
shown to be poor predictors of who has such dis- copy under local anesthesia.10,11,33
ease. A retrospective study by Rosenfeld et al. of Laparoscopy was largely developed as a proce-
more than 650 laparoscopies for infertility found a dure under local, not general, anesthesia. Perhaps
poor predictive value of historical risk factors or the greatest wealth of literature related to laparos-
the physical examination.27 Only 25% of patients copy under local anesthesia was published during
with laparoscopically documented chronic PID rec- the 1970s in conjunction with the development of
ollected a prior episode of acute PID. Similarly, the laparoscopic methods of female sterilization. Most
physical examination was equally poor in predict- early American endoscopists learned the technique
ing PID-related adhesive disease. In fact, clinical of laparoscopy while performing tubal sterilization
examination is poorly able to diagnose even acute procedures. Virtually all of the currently employed
PID accurately. Studies have demonstrated that methods of tubal sterilization were developed as
nearly one-third of patients with a clinical diagno- procedures under local anesthesia. More than 80%
sis of acute PID had another diagnosis or no dis- of the initial procedures using monopolar cautery,
ease at all.28–30 bipolar cautery, Silastic bands, and mechanical clips
were performed under local anesthesia.12,14,34–36
More dramatic is a combined series of more than
History of Laparoscopy Under 250,000 women who were sterilized in rural camps
Local Anesthesia in India under local anesthesia.6 Despite an average
operating time of 6 minutes per patient, sterilization
The first reported case of laparoscopy in a human of equipment with boiling water, and make-shift
patient was by Jacobaeus of Sweden in 1910 using accommodations (often auditoriums or tents), com-
a Nitze cystoscope.31 The endoscopy took place plication and failure rates rival that of standard
after establishing a pneumoperitoneum using room Western techniques during the same period.
air. The first American laparoscopy followed Many common procedures have increasingly
shortly thereafter in 1920, by Orndoff, using a mod- become outpatient and office-based. Laparoscopy
ified thoracoscope passed through a customized also has been performed in office-based settings
trocar. It was a remarkable publication by Short in under local anesthesia and has been shown to be
the British Medical Journal in 1925 that was the safe and well tolerated; moreover, it offers many
first described laparoscopy under local anesthesia advantages over traditional hospital-based proce-
outside a traditional medical setting.32 That report dures.12,17 Similarly, office laparoscopy using tra-
described a technique whereby the disadvantages ditionally sized instrumentation under local anes-
and dangers of laparotomy are avoided by inspect- thesia was reported to be associated with a re-
ing the abdominal viscera through a cystoscope. duction in cost, time, and patient discomfort.12
The scope is inserted through an infraumbilical Refinements in fiberoptic technology have allowed
incision under strict local anesthesia. It is uncanny creation of a new generation of microlaparoscopes
how accurately present-day advantages of office with diameters less than 5 mm that maintain the
laparoscopy under local anesthesia were predicted optical quality and diagnostic abilities of traditional
in that early publication. As Short described32: laparoscopes.37
Faber and Coddington performed a direct com-
In a certain number of cases, not many perhaps, there is parative study of the diagnostic accuracy of a 1.98
a far less formidable alternative [to laparotomy]: this is mm fiberoptic laparoscope versus a traditional 10
to distend the abdomen with air, which can be done with- mm rod-lens scope for diagnostic laparoscopy under
out serious discomfort under a local anaesthetic through general anesthesia.38 Here, diagnostic laparoscopy
a tiny incision, and to inspect the viscera with a cysto- was performed using the microlaparoscope, and all
scope. . . . The advantages of coelioscopy over ex- operative findings were reported. The surgical team
ploratory laparotomy are: (1) it can be done without dis-
comfort under novocaine; (2) the incision is so small that
was then changed, and subsequent traditional 10
it is only necessary to keep the patient in bed for a day mm diagnostic laparoscopy was performed. Opera-
or two; (3) no special instruments are needed; (4) it can tive findings reported by each surgeon using the
be done at the patient’s own house; (5) it is available microlaparoscopic equipment correlated with the
when it would be dangerous to perform laparotomy. operative findings reported using the traditionally
sized equipment. Scores for both endometriosis and
Contrary to common beliefs, this report of lapa- adhesions did not differ in any statistically signifi-
roscopy under local anesthesia is not an isolated cant way. Direct comparative studies under local
anomaly, and there is a long history in support of anesthesia remain to be performed.
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 144

144 S.F. Palter

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

Parameter ALL CPP INF p
Age (years) 35.33 36.45 34.56 NS
Gravidity 0.96 1.55 0.56 0.05
Operating time (min) 20.85 23.91 18.75 NS
Recovery time (min) 51.65 51.64 51.67 NS
Fentanyl (g) 81.48 90.91 75.00 0.05
Versed (mg) 3.20 4.00 2.66 0.05
Pain Scale Score (0–10) 5.87 7.00 5.04 0.05
30-Minutes postop pain (0–10) 1.48 3.17 0.53 0.005
Time to normal activity (days) 1.88 1.73 2.01 NS
Time to return to work (days) 1.70 2.23 1.29 0.05
Time to resume intercourse (days) 4.61 5.42 4.21 NS
Postop. meds. usage (tablets ibuprofen) 4.88 9.45 1.53 0.005

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

Office Microlaparoscopy Here, office microlaparoscopy under local anes-

thesia is performed with one or two secondary 2-
for Infertility or 3-mm punctures. The pelvis and abdomen are
inspected in the same fashion as for traditional lap-
Infertility is especially suited for the application of aroscopy. A dilute solution of indigo carmine dye
office microlaparoscopy in that it has a relatively is then injected via the uterine manipulator. Care
high incidence of negative or minimal findings. In must be taken to inject the dye slowly to avoid the
1980 it was noted that “by far the largest segment risk of tubal spasm and false-positive findings. This
of an unscreened group will reveal either local or potential is being investigated on ongoing trials,
absent findings on routine endoscopy.”21 In fact, a although initial experience suggests that the occur-
physician’s own personal rate of pathology encoun- rence of tubal spasm and false-positive dye perfu-
tered at laparoscopy must be assessed when decid- sion studies is similar to that seen with HSG. This
ing on the setting in which to perform laparoscopy would be expected for laparoscopy under local
under local anesthesia. In our center, approximately anesthesia, as the muscle-relaxing effects of gen-
20% of patients undergoing laparoscopy have eral anesthesia are not available. All of these
pathology of significant enough magnitude to war- patients reported that they were highly satisfied
rant repeat surgical intervention. It is not uncom- with the procedure; 96% would repeat the proce-
mon for a general practice to have negative or min- dure in the office under local anesthesia, and 93%
imal pathology rates of 10–40%. Selected specialty preferred the office laparoscopy to a previous tra-
referral practices, however, may have rates of only ditional operating room-based laparoscopy. There
10%. Obviously, this must be taken into consider- were no procedures that could not be performed
ation when counseling patients. In this regard, some owing to patient or equipment failure, and no pro-
practitioners choose to perform diagnostic micro- cedures required general anesthesia. All aspects of
laparoscopy under local anesthesia in the operating the infertility investigation could be successfully
room as a preoperative adjunct to traditional oper- performed including chromopertubation, biopsy of
ative laparoscopy. Diagnostic microlaparoscopy is endometriosis, and inspection of all areas of the
then performed under local anesthesia in the oper- pelvis and abdomen. The average procedure dura-
ating room. If no pathology is visualized, the pro- tion was 18 minutes (range 8–50 minutes). Fur-
cedure is completed under local anesthesia. If thermore, patients were stable enough for discharge
pathology is visualized, however, the patient can within less than 50 minutes. The average patient
then be put under general anesthesia and a formal required minimal to no postoperative medication
operative laparoscopy performed. and fully returned to her usual activities within 24
We performed a cohort study on all patients hours. Analysis of costs demonstrated an approxi-
requiring diagnostic laparoscopy as part of their mately 75% reduction in charges compared with
general infertility evaluation (n  27) to determine traditional laparoscopy. These results suggest that
whether a complete laparoscopic infertility evalua- the use of office microlaparoscopy might allow
tion (including chromopertubation) could be per- diagnostic laparoscopy to be considered earlier in
formed under local anesthesia in an office setting.16 the infertility investigation. For those who perform
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 145

13. Microlaparoscopy for Infertility in the Office 145

laparoscopy-guided assisted reproduction technol- 14. Fishburne J, Omran K, Hulka J, Mercer J, Edelman
ogy (ART) procedures such as [gamete or zygote D. Laparoscopic tubal clip sterilization under local
intrafallopian transfer (GIFT, ZIFT) or (TET)], anesthesia. Fertil Steril 1974;25:762–766.
office laparoscopy under local anesthesia can sig- 15. Fishburne JJ. Office laparoscopic sterilization with
local anesthesia. J Reprod Med 1977;18:233–234.
nificantly improve the scheduling difficulties and
16. Palter S, Olive D. Office laparoscopy under local
reduce the cost of these procedures. anesthesia for infertility: utility, acceptance, and cost-
Our experience has indicated that diagnostic benefit/outcome analysis. Fertil Steril 1995;64:S8.
laparoscopies performed for the evaluation of infer- 17. Palter S, Olive D. Office laparoscopy under local
tility are the most well tolerated office laparoscopic anesthesia for chronic pelvic pain. J Am Assoc
procedures.17 This is independent of the presence Gynecol Laparosc 1996;3:359–364.
of associated pathology such as endometriosis or 18. Lundberg W, Wall J, Mathers J. Laparoscopy in eval-
adhesions. uation of pelvic pain. Obstet Gynecol 1973;42:872–
876.
19. Diamond M, Daniell J, Johns D, et al. Postoperative
References adhesion development after operative laparoscopy:
evaluation at early second look procedures. Fertil
1. Sauer MV. Investigation of the female pelvis. J Steril 1991;55:700–704.
Reprod Med 1993;38:269–276. 20. Glatstein IZ, Harlow BL, Hornstein MD. Practice
2. Witt B. Pelvic factors and infertility. Infertil Reprod patterns among reproductive endocrinologists: the
Clin North Am 1991;2:371. infertility evaluation. Fertil Steril 1997;67:443–451.
3. Trimbos-Kemper T, Trimbos B, van Hall E. Etiolog- 21. Hulka J, Israel R, Hoffman J. During the infertility
ical factors in tubal infertility. Fertil Steril 1982;37: survey, at which period do you feel endoscopy is indi-
384–388. cated? Open forum. Int J Fertil 1980;25:1–6.
4. Rubin I. Nonoperative determination of patency of 22. Taylor HS OD. Unexplained infertility: the role of
fallopian tubes in sterility: intrauterine insufflation laparoscopy. 1997.
with oxygen and production of subphrenic pneumo- 23. Portuondo JA, Pena Irala J, Ibanez E, Echanojauregui
peritoneum: preliminary report. JAMA 1920;75:661. AD. Clinical selection of infertile patients for lapa-
5. Rubin I. Roentgendiagnostik der uterus tumorens mit roscopy. Int J Fertil 1984;29:234–238.
hilfe von intrauterine Collargol injecktionen: Vor- 24. Swart P, Mol BW, van der Veen F, et al. The accu-
laeufige Mitteilung. Zentralbl Gynaekol 1914;38: racy of hysterosalpingography in the diagnosis of
658. tubal pathology: a meta-analysis. Fertil Steril 1995;
6. Metha P. A total of 250,136 laparoscopic steriliza- 64:486–491.
tions by single operator. Br J Obstet Gynaecol 1989; 25. Swolin K, Rosencrantz RM. Laparoscopy vs. hys-
96:1024–1034. teroscopy in sterility investigations, a comparative
7. Childers J, Hatch K, Surwit E. Office laparoscopy study. Fertil Steril 1972;23:270–273.
and biopsy for evaluation of patients with intraperi- 26. Opsahl MS, Miller B, Klein TA. The predictive value
toneal carcinomatosis using a new optical catheter. of hysterosalpingography for tubal and peritoneal
Gynecol Oncol 1992;47:337–342. infertility factors. Fertil Steril 1993;60:444–448.
8. Steege J. Repeated clinic laparoscopy for the treatment 27. Rosenfeld DL, Seidman SM, Bronson RA, Scholl
of pelvic adhesions: a pilot study. Obstet Gynecol GM. Unsuspected chronic pelvic inflammatory dis-
1994;83:276–279. ease in the infertile female. Fertil Steril 1983;39:44–
9. Snabes M, Poindexter A III. Laparoscopic tubal ster- 48.
ilization under local anesthesia in women with cya- 28. Jacobson L. Differential diagnosis of acute pelvic
notic heart disease. Obstet Gynecol 1991;78:437– inflammatory disease. Am J Obstet Gynecol 1980;
440. 138:1006.
10. Peterson H, Hulka J, Spielman F, Lee S, Marchbanks 29. Jacobson L, Westrom L. Objectivized diagnosis of
P. Local vs. general anesthesia for laparoscopic ster- acute pelvic inflammatory disease. Am J Obstet
ilization: randomized study. Obstet Gynecol 1987; Gynecol 1969;105:1088.
70:903–908. 30. Bartsich E, Dillon T. Acute pelvic inflammatory dis-
11. Brown D, Fishburne J, Roberson V, Hulka J. Venti- ease: laparoscopic assessment. NY State J Med 1981;
latory and blood gas changes during laparoscopy 81:25.
with local anesthesia. Am J Obstet Gynecol 1976; 31. Gunning J. The history of laparoscopy. J Reprod Med
124:741–745. 1974;12:222–226.
12. Wheeless C Jr. Outpatient laparoscopic sterilization 32. Short A. The use of celioscopy. BMJ 1925;2:254.
under local anesthesia. Obstet Gynecol 1972;39:767– 33. Rothfusz E, Kitz D, Andrews R, et al. O2sat HR,
770. MAP among patients receiving local anesthesia.
13. Alexander G, Goldrath M, Brown E, Smiler B. Out- Anesth Analg 1988;67:S189.
patient laparoscopic sterilization under local anes- 34. Penfield A. Laparoscopic sterilization under local
thesia. Am J Obstet Gynecol 1973;116:1065–1068. anesthesia. Obstet Gynecol 1974;12:251.
3051_Seifer_13_p141-146 11/5/01 9:54 AM Page 146

146 S.F. Palter

35. Yoon I, King T. A preliminary and intermediate Palter SF. Microlaparoscopy under local anesthesia and
report on a new laparoscopic tubal ring procedure. J conscious pain mapping for the diagnosis and man-
Reprod Med 1975;15:54–56. agement of pelvic pain. Curr Opin Obstet Gynecol
36. Hulka J, Omran K, Phillips JJ, et al. Sterilization by 1999;11:387–393.
spring clip: a report of 1000 cases with a 6-month Palter SF. Office microlaparoscopy under local anesthesia.
follow-up. Fertil Steril 1975;26:1122–1131. Obstet Gynecol Clin North Am 1999;26:109–120, vii.
37. Molloy D. The diagnostic accuracy of a microla- Palter S. Office laparoscopy under local anesthesia. In:
paroscope. J Am Assoc Gynecol Laparosc 1995;2: Azziz R, Murphy A (eds). New York: Springer, 1997.
203–206. Perez R-D. Second-look laparoscopy adhesiolysis: the
38. Faber BM, Coddington CC III. Microlaparoscopy: a procedure of choice for preventing adhesion recur-
comparative study of diagnostic accuracy. Fertil rance. J Reprod Med 1991;36:700–702.
Steril 1997;67:952–954. Raj S, Hulka J. Second-look laparoscopy in infertility
surgery: therapeutic and prognostic value. Fertil Steril
1982;38:325–329.
Rosser J, Olive D, Zreik T, et al. Decreased performance
Suggested Reading of skilled laparoscopic surgeons at microlaparoscopy
versus traditional laparoscopy. J Am Assoc Gynecol
Group OLS. Postoperative adhesion development after Laparosc 1996;3:S44.
operative laparoscopy: evaluation at early second-look Rosser JC Jr, Palter SF, Rodas EB, et al. Minilaparoscopy
procedures. Fertil Steril 1991;55:700–704. without general anesthesia for the diagnosis of acute
Jansen R. Early laparoscopy after pelvic operations to appendicitis. J Soc Laparoendosc Surg 1998;2:79–82.
prevent adhesions: safety and efficacy. Fertil Steril Steege J, Stout A. Resolution of chronic pelvic pain after
1988;49:26–31. laparoscopic lysis of adhesions. Am J Obstet Gynecol
Marcoux S, Maheux R, Berube S. Laparoscopic surgery 1991;165:278–283.
in infertile women with minimal or mild endometri- Tulandi T, Murray C, Guralnick M. Adhesion formation and
osis. Canadian Collaborative Group on Endometriosis. reproductive outcome after myomectomy and second-
N Engl J Med 1997;337:217–222. look laparoscopy. Obstet Gynecol 1993;82:213–215.
3051_Seifer_14_p147-149 11/5/01 9:54 AM Page 147

14
Treatment of Cervical Stenosis
Gary N. Frishman

Cervical stenosis is a condition in which the cervix Purpose

becomes narrowed and constricted. Although there
is no one accepted diagnosis in the literature, the The purpose of treating the stenotic cervix is usu-
inability to pass a fine probe, endocervical brush, ally to reverse the preexisting condition. However,
or cotton-tipped applicator and the retention of dye prophylactic treatment has been described as well,
in the uterus following hysterosalpingography via placing a temporary cervical stent following a
(HSG) are acceptable diagnostic tests. cone biopsy.3
Cervical stenosis may follow a cone biopsy or
laser surgery for dysplastic changes in the cervix,
with reported rates ranging from 1% to 29%.1,2
Higher incidences of stenosis may reflect more
aggressive treatment required because of larger,
Indications for Treatment
deeper lesions or an earlier learning curve with any of Cervical Stenosis
given surgical technique. In addition, treatment of
intraepithelial neoplasia in a patient with diethyl- Indications for treatment include non-fertility-
stilbestrol or in a menopausal woman may be more related issues such as amenorrhea and dysmenor-
likely to result in cervical stenosis. Inherited con- rhea. The inability to view or sample the endocervix
ditions and müllerian anomalies may also be etio- (in conjunction with colposcopy) or the endome-
logic agents. trium (in conjunction with an endometrial biopsy
Cervical stenosis is associated with many gyne- or dilatation and curettage) are additional indica-
cologic conditions, including dysmenorrhea related tions. From the perspective of fertility, the inabil-
to the increased uterine pressure necessary to ity to evaluate the uterus (i.e., to perform HSG) or
achieve menstrual flow. The stenosis may also pre- to transfer gametes or embryos mandate consider-
dispose the patient to endometriosis secondary to ation for treatment of any cervical stenosis.
retrograde menstruation. The stenotic cervix can
have a negative impact on fertility. It may com-
promise the mucus-producing glands and adversely
affect the survival of sperm as reflected in a post- Contraindications
coital test. If the transfer of gametes or embryos
through the cervix is indicated, the stenosis may Contraindications for treatment of cervical steno-
lead to an inability to perform these procedures. sis include active cervical or lower genital tract
Finally, poor visualization of the endocervix may infection, the presence of a desired preterm preg-
lead to inadequate colposcopy, necessitating a cone nancy, or concern about the upper reproductive tract
biopsy, which in and of itself may further potenti- anatomy (i.e., possible previous supracervical hys-
ate this condition. terectomy or a müllerian anomaly).

147
3051_Seifer_14_p147-149 11/5/01 9:54 AM Page 148

148 G.N. Frishman

Equipment probe. Treatment is continued along the probe to a

depth below which the stenosis is no longer pres-
The following equipment is needed for cervical ent. Topical estrogen supplementation may be con-
dilatation. sidered in menopausal women.
Alternative techniques for the stenotic cervix
Tenaculum depend on the specific goal. For visualizing the
Anesthetic (Xylocaine) uterus as part of an infertility evaluation, consider-
Spinal needle ation may be given to HSG using a modified tech-
Syringe 10 cc nique. A 3.5 French (3.5F) Tom Cat catheter (Sher-
Small set of dilators wood Medical, St. Louis, MO) is passed through
Open-sided speculum the usual acorn tip, permitting installation of dye
To maintain cervical patency, a stem pessary can through this more narrow aperture.6 Alternatively,
be considered.4 Although stem pessaries are no the acorn tip may be shaved down with a tenacu-
longer made, many hospitals (or older gynecolo- lum placed on either side of the cervix to allow a
gists) may have some available. The Word Cathe- good approximation and seal, following which the
ter (Vioteque, Langhorn, PA) serves as a useful dye usually finds its way up into the uterus.
alternative. If the goal is to perform adequate cervical sam-
A suturing tray and 2-0 monofilament permanent pling, consideration may be given to using a moist
suture (Prolene, Nylon) are required for fixation of urethral swab. This swab is on a stiff wire stem and
the stent. is supplied with some chlamydial culture sets
(VIDAS Chlamydia Collection Kit; Medical Pack-
aging Corporation, Camarillo, CA). The urethral
Procedure swab’s small size often permits entry into the
cervix. It may also be used as a malleable probe,
For initial entry into the uterus for dilation, con- as the wire can be bent.
sideration may be given to concomitant ultra- If colposcopy is necessary when there is an inabil-
sonography should the cervical canal be obliter- ity to visualize the endocervical canal (despite use
ated.5 During any procedure to dilate the stenotic of an endocervical speculum), consideration may be
cervix, it may be easier to locate the cervical os if given to placing an extra thin laminaria.7,8 When
the patient comes in during her menstrual period. using a Laminaria japonica, moistening it before
A paracervical block along with a nonsteroidal insertion speeds the dilation process. Regardless of
medication may help reduce any discomfort. Once the type of laminaria used, it should be able to be
the cervix is dilated, the stem pessary may be removed 30 minutes to several hours following
placed. When the pessary is to be sutured into the placement with adequate dilatation achieved for
cervix, it may be easier to first place the sutures visualizing the endocervix.
through the pessary, then suture the cervix at the Cervical stenosis may also present during meno-
desired location, and finally pass the pessary down pause as an endometrial fluid collection. If this
along the sutures (similar to a gondola) into the cer- accumulation results from a stenotic cervix, the
vical canal. This technique is easier than attempt- fluid is likely to be a benign condition if the endo-
ing to pass a needle in the confined space of the metrial stripe is less than 3 mm.9
vaginal fornix through the pessary when it is
already in place in the cervix. The stem pessary
should be left in for approximately 6 weeks. The Complications
patient is placed on prophylactic antibiotics (doxy-
cycline 100 mg PO bid) during this time. If the Complications principally relate to perforation of
patient is actively trying to conceive she can be the uterus during dilation. If this occurs, the patient
counseled that, although not the standard of care, should be followed for bleeding and infection.
it is probably acceptable to become pregnant dur- Some patients experience a vasovagal reaction to
ing this time. cervical manipulation.
If the cervix cannot be cannulated, a laser should Although failure to complete the procedure is not
be considered to evert the cervix. A CO2 laser with generally considered a complication, the patient
a small fixed spot size at a power density setting of should be counseled about the possibility of an
20 watts/cm2 is used to remove a 1 cm cylinder unsuccessful procedure. Should the cervix not be
along the site of the obliterated os. It may be facil- able to be dilated adequately as a single procedure
itated by passage of a extremely fine sound or in the office, options include serial progressively
3051_Seifer_14_p147-149 11/5/01 9:54 AM Page 149

14. Treatment of Cervical Stenosis 149

aggressive dilations with or without an extra thin 4. Frishman GN. The use of the stem pessary to facilitate
laminaria or taking the patient to the operating transcervical embryo transfer in women with cervical
room. stenosis. J Assoc Reprod Genet 1994;11:225–228.
Although reocclusion of the os is also not a com- 5. Hornstein MD, Osathanondh R, Birnholz JC, et al.
Ultrasound guidance for selected dilatation and evac-
plication, the patient should be followed up 4–6
uation procedures. J Reprod Med 1986;31:947–950.
weeks following removal of the stent or after any 6. Rosenwaks Z, Sultan KM, Davis OK. A novel tech-
dilatation to make sure the cervix is still patent. Se- nique for cervical cannulation during hysterosalpin-
rial cervical dilations can subsequently be per- gography. Fertil Steril 1993;59:1329–1330.
formed in the office if there is a concern about 7. Stern JL. Preventing cervical conization by achieving
restenosis. satisfactory colposcopy with hygroscopic cervical
dilators. Am J Obstet Gynecol 1990;163:176–177.
8. Johnson N, Crompton AC, Wyatt J, et al. Using Lam-
Conclusions icel to expose high cervical lesions during colposcopic
examinations. Br J Obstet Gynaecol 1990;97:46–52.
The stem pessary or Word Catheter is useful for 9. Goldstein SR. Postmenopausal endometrial fluid col-
treating cervical stenosis. Following completion of lections revisited: look at the doughnut rather than the
this procedure and confirmation of the maintenance hole. Obstet Gynecol 1994;83:738–740.
of cervical patency, the patient may undergo intra-
uterine insemination or embryo transfer as indi- Suggested Reading
cated. Some techniques exist to assist in the per-
formance of HSG. Dysmenorrhea, if resulting from Baldauf JJ, Dreyfus M, Ritter J. Risk of cervical steno-
cervical stenosis, should be relieved. sis after large loop excision or laser conization. Obstet
Adequate cervical sampling and colposcopy can Gynecol 1996;88:933–938.
often be performed in women with cervical steno- Barbier RL. Stenosis of the external cervical os: an asso-
ciation with endometriosis in women with chronic
sis. If so, it avoids a cone biopsy and the likelihood pelvic pain. Fertil Steril 1998;70:571–573.
of progression of this condition. Glatstein IZ, Pang SC, McShane PM. Successful preg-
nancies with the use of laminaria tents before embryo
References transfer for refractory cervical stenosis. Fertil Steril
1997;67:1172–1174.
1. Baggish MS, Dorsey JH, Adelson M. A ten year expe- Groutz A, Lessing JB, Wolf Y, et al. Cervical dilatation
rience treating cervical intraepithelial neoplasia with during ovum pick-up in patients with cervical stenosis:
the CO2 laser. Am J Obstet Gynecol 1989;161:60–68. effect on pregnancy outcome in an in vitro fertilization-
2. Byrne GD. Cone biopsy: a survey of 100 cases. Aust embryo transfer program. Fertil Steril 1997;67:909–
NZ J Obstet Gynaecol 1966;6:266–270. 911.
3. Luesley DM, Redman CWE, Buxton EJ, et al. Pre- Noyes H. Hysteroscopic cervical canal shaving: a new
vention of post-cone biopsy cervical stenosis using a therapy for cervical stenosis before embryo transfer in
temporary cervical stent. Br J Obstet Gynaecol 1990; patients undergoing in vitro fertilization. Fertil Steril
97:334–337. 1999;71:965–966.
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 150

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

Increased awareness of fertility issues and techno- thral anatomy. Small testes with a soft consistency
logic advances in the field of infertility have are typically indicative of compromised spermato-
resulted in a major increase in the number of cou- genesis. Inability to palpate the vasa is the hallmark
ples seeking treatment. Proper assessment and cor- of congenital bilateral absence of the vas deferens
rection of male factors contributing to infertility is (CBAVD.) Subtle findings center around delicate
required as part of the complete evaluation for the palpation of the epididymis to describe its length
infertile couple. A male factor can be identified in and degree of fullness. An indurated or engorged
almost 50% of infertile couples. This chapter vas deferens or epididymis may be indicative of a
reviews some of the foundations of diagnosis and distal obstructive process. Varicocele refers to
treatment for male factor infertility. Procedures that dilated veins of the pampiniform plexus and is seen
are more optimally performed in the operating in approximately 40% of infertile men. Varicoceles
room with anesthesia monitoring are briefly dis- may affect the quantity and quality of spermatoge-
cussed. Treatment modalities that can be performed nesis and are left-sided in 80% of patients (18% are
efficiently in the office setting are reviewed in more bilateral).
detail.

Laboratory Evaluation
History
The semen analysis provides valuable clues during
A thorough history helps elucidate the etiology of assessment of the infertile man. Low semen volume
reproductive dysfunction before initiating a treat- (1 ml) in an azoospermic patient typically points
ment regimen. Surgical and nonsurgical causes of to ejaculatory duct obstruction (EDO) or vasal
infertility should be assessed (Table 15–1). In pa- aplasia/anomaly. Examples of the latter include
tients with oligospermia or oligoasthenospermia CBAVD, in which mesonephric duct developmen-
(decreased sperm count and motility) various risk tal pathology also affects seminal vesicle formation
factors should be considered and the offending and hence seminal volume. EDO may be secondary
agents eliminated if possible. See Chapter 3 for a to congenital causes such as midline prostatic cysts
more complete discussion. of müllerian origin or acquired causes such as pre-
vious prostatic inflammatory/infectious processes.
Normal semen volume azoospermia usually implies
Physical Examination abnormal spermatogenesis or an obstructive process
blocking the flow of sperm. Etiologies of ductal
A careful physical examination is crucial for deter- occlusion include prior vasectomy, postinflamma-
mining diagnosis and directing therapy. Obvious tory tubular stenosis, and Young syndrome. Nonob-
findings include the number, location, size, texture, structive azoospermia is typically accompanied by
and consistency of the testes; the presence or elevated follicle-stimulating hormone (FSH) values
absence of vasa deferentia; the presence or absence and has a variety of causes, both genetic (e.g., Kline-
and the grade of varicoceles; and the penile/ure- felter syndrome, XX male syndrome, deletion of the

150
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 151

15. Treatment of Male Reproductive Dysfunction in the Office 151

TABLE 15–1. Risk Factors for Male Reproductive at its distal end (the ampulla) before joining the
Dysfunction duct of the seminal vesicle to form the ejaculatory
Cryptorchidism duct. The ejaculatory duct pierces the prostatic cap-
Testicular trauma, torsion, cancer sule and finally opens up at the verumontanum.
Sexually transmitted diseases
Epididymitis
Adult-onset mumps Ejaculatory Neurophysiology
Alcohol, drug, or tobacco abuse
Spinal cord injury Emission, bladder neck closure, and antegrade
Scrotal irradiation propulsion constitute the three phases of ejacula-
Pediatric hernia repair
Chemotherapy tion. Emission consists of seminal fluid deposition
Prostatitis into the posterior urethra and is under sympathetic
Urinary tract anomalies control (T12–L2). Bladder neck closure is the sec-
Medications ond phase of ejaculation and prevents reflux of the
Environmental toxin exposure
Retroperitoneal surgery
ejaculate into the bladder. It is also dependent on
Systemic medical illness sympathetic innervation. The final phase of ejacu-
lation, antegrade propulsion, which involves ure-
thral expulsion of the ejaculate by contraction of
the periurethral musculature, is mediated by
DAZ gene cluster on the Y chromosome) and somatic efferents from S2–4. These processes and
acquired (e.g., chemotherapy, viral orchitis, radio- inputs from higher cerebral locations and various
therapy). sensory stimuli are integrated at the ejaculatory
reflex center (T12–L2). This controls the temporal
sequence of neuronal firing during the ejaculatory
Basic Review of Male event.
Reproductive Physiology
Spermatogenesis Treatment Strategies for Male
The production of mature spermatozoa from sper- Reproductive Dysfunction
matogonia in the seminiferous tubule is termed
spermatogenesis. Two meiotic reduction divisions Nonmedical treatment of the infertile male patient
take spermatogonia through the primary and sec- may be subdivided into those procedures that can
ondary spermatocyte stages to the haploid sper- be performed in the office setting and those that are
matid. Spermiogenesis is a morphologic alteration generally done in the operating room. Although
of the spermatid to form the mature spermatozoan. most surgical procedures for male infertility can be
Nuclear elongation and flattening, acrosome for- accomplished with local anesthesia, the use of mild
mation, and shedding of residual cytoplasm are intravenous sedation and monitoring in the operat-
some of the events that comprise spermiogenesis. ing room is recommended for certain procedures,
as follows.
Ductal System Sperm Transport
Varicocelectomy
Once sperm are produced in the seminiferous
tubules in the parenchyma of the testis, continuous Operative approaches for varicocelectomy include
fluid flow moves the newly released sperm into the standard inguinal, subinguinal, retroperitoneal
intratesticular rete testis. Arising from the rete (high ligation), and laparoscopic approaches.
testis, six to eight efferent ducts emerge from the Regional or general anesthesia is typically required
testicular capsule to form the caput epididymis. The for the laparoscopic, high ligation, and standard
individual efferent ducts coalesce into a single, inguinal approaches. The subinguinal incision may
highly coiled epididymal tubule that forms the cor- be easily performed with local anesthesia and a
pus and cauda epididymis. The tubule acquires a small amount of intravenous sedation. Patient com-
thicker muscularis and becomes the convoluted vas fort is clearly enhanced when the latter is employed.
deferens, which gradually straightens out to form We recommend use of the operating microscope to
the vas deferens proper. The vas travels up and out minimize the chances of testicular artery or lym-
of the scrotum and turns back at the internal phatic injury. Clips or ties may be used to occlude
inguinal ring to enter the pelvis. The vas corkscrews the dilated venous segments. It should be men-
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 152

152 H. Sadeghi-Nejad and R. Oates

tioned that varicoceles may also be treated with eral, this sperm is of poor quality, and even its use
percutaneous venous embolization performed by in conjunction with intracytoplasmic sperm injec-
an interventional radiologist. Vein occlusion is tion (ICSI) results in few pregnancies. When
achieved by means of coils or detachable balloons. TURED is not an appropriate option, microsurgi-
cal sperm aspiration from the proximal ductal sys-
tem with cryopreservation is the most direct treat-
Microsurgical Reconstruction ment strategy to consider to obtain viable sperm.
Microsurgical reconstruction with local anesthesia
and intravenous sedation is performed in previously
vasectomized patients and those with congenital or
postinflammatory epididymal obstruction. The suc- Office Procedures
cess of vasectomy reversal depends on the sur-
geon’s skill and the number of years elapsed since Penile Vibratory Stimulation
the vasectomy. Patency rates are superior to preg- Penile vibratory stimulation (PVS) is the first-line
nancy rates because the latter may be adversely treatment modality in spinal cord injury patients
affected by female factors and sperm quality. suffering from anejaculation. It is used to provide
Although some surgeons insist on observing viable a semen specimen via stimulation of the ejacula-
spermatozoa at the anastomotic site (hence moving tory reflex center (Fig. 15–1).
proximal to the epididymis in some cases for vaso-
epididymostomy), others perform vasovasostomy
even if no fluid/sperm is observed in the proximal Indications
vasal limb. For congenitally obstructed patients, Spinal cord injury patients whose lesion is above
microsurgical reconstruction usually entails vasoe- or at T10 and who have active lower extremities
pididymostomy because the level of occlusion to are candidates for penile vibratory stimulation.
sperm flow is typically found in the epididymis. These patients usually have intact sympathetic out-
Although it is possible to use local anesthesia flow and thus normally innervated vasal ampullae,
alone, the patient is required to be perfectly still for prostate, seminal vesicles, and bladder neck. Be-
prolonged periods of time. In addition, the operat- cause of the high level of injury, the ejaculatory
ing microscope is not an item that most surgeons integration center at T12–L1 and its associated
have in an office setting, dictating that this proce- tracts are typically not affected, nor are the sensory
dure be carried out in an operating room environ- afferent or efferent nerves entering and exiting the
ment. cord at S2–4. Inactivity of the lower cord, demon-
strated by an atonic bladder or flaccid lower
Transurethral Resection for EDO extremities, is correlated with low PVS success
rates. PVS success/failure rates are illustrated in
Transurethral resection for EDO (TURED) in- Figure 15–2.
volves TUR of the dilated intraprostatic ejaculatory
ducts or of midline cystic structures. It must be per- Contraindications
formed in the operating room under general or
regional anesthesia after the obstructing anatomy Severely dysreflexic patients who are unable to be
has been carefully defined with transrectal ultra- easily controlled pharmacologically should not
sonography (TRUS). Whereas complete EDO pre- have PVS. Autonomic dysreflexia stimulated by
sents as low-volume azoospermia, severe oligoas- ejaculation is seen in patients with lesions above
thenospermia may be seen in partial forms of EDO. the T6 neurologic level. Dysreflexia occurs when
Cyst unroofing at the level of the verumontanum sympathetic nervous system activation induced
allows decompression of the cyst and relieves duc- as part of the ejaculatory event is poorly regulated
tal obstruction. Ejaculatory duct incision is carried and incompletely controlled. Hypertension, pound-
out in cases where no cyst is identified. If TRUS ing headache, diaphoresis, and a vagal counterre-
demonstrates fibrosed, nondilated ducts, TUR is sponse bradycardia are clinical signs of significant
not likely to be helpful. Transrectal-guided aspira- autonomic dysreflexia. Head elevation and cessa-
tion of the seminal vesicles (into which sperm has tion of the vibratory stimulus usually ends the dys-
collected secondary to downstream blockage of the reflexic episode. Pretreatment with calcium chan-
ejaculatory duct) or the vasal ampullae has been nel blockers prior to PVS is needed in certain
reported as a treatment for these situations. In gen- circumstances.
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 153

15. Treatment of Male Reproductive Dysfunction in the Office 153

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

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

Procedure
The bladder must be catheterized and emptied
before stimulation. A small volume of medium
appropriate for sperm survival may be left in the
bladder, although most stimulations result in ante-
FIGURE 15–2. Penile vibratory stimulation (PVS) suc- grade ejaculate flow. The vibrator tip is gently
cess/failure rates with regard to the level of injury. pressed against the frenular area on the undersur-
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 154

154 H. Sadeghi-Nejad and R. Oates

of the vasal ampullae and seminal vesicles. The

sample may then be processed for IUI, in vitro fer-
tilization (IVF), or ICSI.

Indications
The RPE procedure provides the means for semen
retrieval in spinal cord-injured patients in whom
FIGURE 15–3. Hand-held vibrating massage unit with a PVS has failed, regardless of the level of their
conical tip for penile vibratory stimulation.
lesion, above or below T10. It is also employed in
patients with testicular cancer who have undergone
retroperitoneal lymph node dissection and are an-
face of the glans penis and moved slowly from side ejaculate due to disruption of the periaortic sym-
to side. Abdominal muscle spasticity or a sudden pathetic chain, which innervates the vasal ampul-
increase in the tumescence and rigidity of the reflex lae and seminal vesicles. Other candidates include
erectile response indicates that the vibrator is cor- patients with transverse myelitis, multiple sclero-
rectly placed and heralds impending ejaculation. sis, diabetes mellitus, or myelodysplasia who also
The antegrade seminal fluid discharged is collected suffer from an inability to initiate emission. The
into a sterile container for analysis and possible only patients who are appropriate candidates for
processing. Once deemed successful and safe, the office RPE are those spinal cord-injured men who
couple is instructed about how to perform the tech- are insensate in the rectal area and who do not dem-
nique so all subsequent specimen collections do not onstrate uncontrollable autonomic dysreflexia upon
require the assistance of the original practitioner. stimulation.
If the couple is using the semen for home self-
insemination, PVS is carried out by the couple Contraindications
themselves during the ovulatory window. If intra-
uterine insemination (IUI) or in vitro technologies The RPE procedure is strictly contraindicated in
are being employed, the man simply collects the men with ongoing anorectal pathology that is
seminal fluid and presents it to the reproductive lab- potentially exacerbated by electrical stimulation or
oratory at the appropriate time. that precludes easy insertion of the rectal probe.
Diabetic men with calcification of the distal vasa
Comments and ejaculatory ducts usually do not respond to
external electrical stimuli with a contraction as the
Complications include autonomic dysreflexia, as smooth muscle in the walls of the target structures
described above. In summary, PVS is a simple, is nonfunctional. RPE should not be performed in
inexpensive, safe modality for treating anejacula- the office setting in patients who have sensation in
tion in spinal cord-injured patients with lesions the rectal area or who have uncontrollable auto-
above T10. It is less effective in those with lower nomic dysreflexia and require intravenous pharma-
cord lesions as various limbs of the reflex arc are cotherapy.
disrupted. The best aspect is that the patient and his
partner can be taught how to collect the samples
themselves, divorcing them from the requirement Equipment
of medical intervention. An RPE unit developed by Seager and associates
For the anejaculatory patient in whom PVS has (National Rehabilitation Hospital) is typically em-
failed, rectal probe electroejaculation (EEJ) and ployed (Fig. 15–4). A similar computerized version
direct sperm harvesting should be considered. In has been developed by others to deliver electrical
patients who are insensate in the rectal area, EEJ pulses rhythmically to the target area. The Seager
may be done in the office setting without anesthe- model consists of a rectal probe attached to a power
sia. It is the next logical treatment modality. unit with a transformer that allows changes in the
current and voltage output. Three electrodes deliver
and pick up the current. A thermometer embedded
Rectal Probe Electroejaculation into the rectal probe helps monitor the rectal tem-
Rectal probe electroejaculation (RPE) is used to perature to avoid thermal injury. The delivered cur-
provide a semen specimen by induction of electri- rent is displayed on the power unit and can be mod-
cally mediated contractions of the smooth muscle ified accordingly with the power knobs by the
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 155

15. Treatment of Male Reproductive Dysfunction in the Office 155

Comments
Complications include autonomic dysreflexia, as
described above. Preprocedure treatment with cal-
cium channel blockers can prevent the onset of
autonomic dysreflexia or blunt its severity in those
prone to its development. However, aborting the
procedure and removing the rectal probe is still the
best way to resolve an acute situation most expe-
ditiously. Other complications include minor
anorectal burns and lacerations, urinary retention,
and rectal perforation, all of which are potential
problems but in actuality are seen only rarely.
The RPE procedure is a safe, highly effective
FIGURE 15–4. Rectal probe electroejaculator unit devel- treatment for anejaculation secondary to upper
oped by Seager and associates, National Rehabilitation motor neuron and lower motor neuron dysfunction.
Hospital.
The result of stimulation is an electrically induced
contraction of the vasal ampullae and seminal vesi-
cles. In this way, semen can be harvested for use
operator. The safety profile of this series of units is with a variety of adjunctive reproductive techniques.
excellent when used with proper instruction. Direct epididymal sperm aspiration is the next
appropriate therapeutic maneuver in patients who
Procedure have failed RPE. Table 15–2 lists pregnancy rates
With the patient in the dorsal lithotomy or lateral and adjunctive reproductive techniques employed
decubitus position, the bladder is catheterized and in couples in whom the male partner is spinal cord-
emptied. Further washing is done with 20–25 ml injured.
of buffered solution; another 25 ml aliquot is left
indwelling in the bladder for later sperm retrieval,
if necessary. The lubricated 1.25 inch rectal probe
is gently inserted into the anorectum such that the
electrodes are facing anteriorly toward the prostate
and the seminal vesicles (Fig. 15–5). Smaller
probes may be employed if the rectum is contracted
and defunctionalized. Some authors recommend
anoproctoscopy to examine the rectal mucosa prior
to probe insertion. Gradually increasing pulsatile
stimulations to a maximum voltage of 20 V and a
maximum current density of 400 mA are delivered
while monitoring the rectal temperature. The latter
should not rise above 39°C. A sterile container is
used to collect the antegrade seminal fluid, which
usually simply drips from the meatus. There is no
periurethral muscular contraction, only electrically
induced emission. The bladder neck is probably
stimulated as well to coapt and prevent retrograde
flow. More semen is occasionally obtained by
catheterizing the bladder at the end of the proce-
dure and collecting any retrograde fraction. This
necessarily occurs if the patient has had a prior
transurethral resection of the bladder neck. The
specimens are then used for IUI, IVF, or ICSI. The
choice of which adjunctive technique to employ FIGURE 15–5. Patient positioning and insertion of the rec-
depends not only on the semen parameters but also tal probe electroejaculator. (From Goldstein, 1995, with
on any concomitant female and financial issues. permission)
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 156

156 H. Sadeghi-Nejad and R. Oates

TABLE 15–2. Pregnancy Rates and Adjunctive Reproductive Techniques Employed in Couples in whom
the Male Partner is Spinal Cord-Injured: PVS and RPE
Total no. Successful Pregnancy
Technique of cycles couples/total (no.) rate/cycle (%)
Self-insemination — 5/8 —
Intrauterine insemination
Natural cycle 11 0/6 0
Clomiphene citrate 6 1/4 17
Human menopausal gonadotropin 19 4/8 21
Gamete intrafallopian transfer 9 5/6 56
In vitro fertilization 5 2/7 29

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

Analysis and Processing bladder neck in an open position. Transurethral

of Retrograde Ejaculates resection of the prostate or the bladder neck and
prior Y-V-plasty of the bladder neck are some of
The purpose of analyzing retrograde ejaculates is the anatomic causes of retrograde ejaculation, but
to diagnose retrograde ejaculation and treat it by it should be noted that most of these patients are
means of sperm retrieval from the postejaculate able to void on their own and there is no need for
urine. catheterization to obtain the postejaculate urine. It
is only when alkalinization through oral bicarbon-
Indications ate therapy or postejaculatory voiding into an
Patients with retrograde ejaculation who have failed appropriate buffer solution does not successfully
pharmacologic induction of bladder neck coapta- provide an optimal sperm specimen that the need
tion can have their retrograde specimens optimized arises for instillation of buffer/medium into the
for use with any one of a number of adjunctive bladder prior to ejaculation to establish the best
reproductive techniques. Table 15–3 lists various possible mileu that can be achieved.
anatomic and neuropathic etiologies of retrograde
ejaculation. In all of these circumstances emission Contraindications
is intact, so vasal and seminal vesicle contraction Patients with acute bacterial prostatitis should not
occurs and seminal fluid is deposited into the pro- be catheterized, as the infection may become sys-
static urethra. During the rhythmic periurethral temic and more severe. Although severe meatal
muscular contraction, however, the circular muscle anomalies or urethral stricture may preclude suc-
fibers of the bladder neck do not coapt to prevent cessful catheterization, these conditions are not
retrograde flow of the seminal fluid. strict contraindications for bladder catheterization.
Anatomic causes of retrograde ejaculation
include those surgical procedures that, as a direct
consequence of their intent, permanently fix the Equipment
The equipment required includes a Foley catheter
and sperm medium.
TABLE 15–3. Etiology of Retrograde Ejaculation
Neurologic causes Procedure
Spinal cord injury
S/P retroperitoneal lymph node dissection Retrograde ejaculation is diagnosed by microscop-
Diabetes mellitus ically evaluating the postejaculate urine specimen.
Transverse myelitis The patient should void to completion, ejaculate,
Multiple sclerosis
Pharmacologic (-sympatholytic medications) and void again as soon as possible after ejacula-
Idiopathic tion. In this way only a small amount of urine
Anatomic causes comes into contact with the seminal fluid when it
Prior Y-V-plasty of the bladder neck travels in a retrograde fashion. In addition, pro-
Transurethral resection of the prostate
Transurethral resection of the bladder neck
cessing of the specimen is made easier because of
the reduced volume. It should be spun down and
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 157

15. Treatment of Male Reproductive Dysfunction in the Office 157

the pellets joined and resuspended to 1 ml final vol- In an obviously obstructed circumstance, the pre-
ume. Sperm density and motility are then deter- liminary testis biopsy is not required prior to under-
mined. taking definitive reconstructive microsurgery. In the
To optimize the milieu of the sperm when they clearly nonobstructive azoospermic man, a prelim-
are used for IUI or other assisted reproductive tech- inary biopsy serves only to prove that spermatogen-
nology, it is necessary to alkalinize the urine com- esis is deficient; it does not prove that sperm will
ponent by having the patient ingest bicarbonate or will not be found at the time of testicular sperm
(650 mg tablets  4) approximately 1 hour prior to extraction (TESE). Therefore testis biopsy is rarely
the anticipated ejaculation. This often maximizes indicated as a sole, separate procedure.
the motility by reducing the harmful effects of urine For the purposes of this chapter, the focus is on
acidity. If the pH is in the normal range of 7.0–8.5 performance of a testis biopsy in the office setting
and the motility is still poor, it may be worthwhile when testis tissue is being harvested for analysis,
to instill 30 ml of an approved sperm-processing processing, and possible cryopreservation or simul-
medium into the bladder via catheter prior to ejac- taneous use as the sperm source for ICSI. It can be
ulation. Addition of an albumin source can further performed in nonobstructed and obstructed pa-
stabilize the sperm membrane and may add to tients. Of importance is the concept that when
improved sperm vitality. If the patient is able to ini- reconstructive microsurgery is a possibility for the
tiate voiding on his own, the urine/medium/semen obstructed patient, it should always be viewed as
mixture is processed as soon as it is available from the first option, as it gives the couple many more
the patient, usually within 10–15 minutes follow- choices and affords them the opportunity to achieve
ing ejaculation. pregnancy through natural means. There are both
open and percutaneous approaches.
Complications
This is a minimally invasive procedure where the Indications
only possible complications are those associated In the obstructed patient, if testicular tissue must
with bladder catheterization. be harvested, it is retrieved at the time of recon-
struction. In the patient with spermatogenic failure
Comments as the etiology of azoospermia, testis biopsy (for
histologic analysis) can be performed at the same
Urine processing for retrieval of postejaculate time as testicular tissue extraction for the purpose
sperm in patients with retrograde ejaculation in of identifying individual whole spermatozoa for use
whom -sympathomimetic medication does not with ICSI. Although a small amount of intravenous
restore antegrade sperm flow is safe and minimally sedation nicely supplements local anesthesia, this
invasive. Many such patients are able to achieve procedure may be carried out in the office setting
pregnancies in conjunction with adjunctive repro- where only local anesthesia is available.
ductive techniques. To optimize the condition of the Certain patients are not appropriate candidates
sperm, rare patients benefit from instillation of for this approach (see below). If tissue is being har-
sperm-processing medium with albumin directly vested for use with ICSI that day or for analysis
into the bladder prior to ejaculation, which requires and cryopreservation (if sperm are found) for use
catheterization. with ICSI at a later date, coordination with the
embryology laboratory is of the utmost importance.
Testicular Biopsy/Testicular Tissue If there has been no prior documentation that the
Extraction for Azoospermia patient with nonobstructive azoospermia actually
has whole spermatozoa in his spermatogenic
A biopsy of the testis has long been the traditional epithelium, it is not wise to schedule a simultane-
mode of evaluating spermatogenic potential in the ous ICSI procedure. In the event no sperm are
azoospermic patient. The histologic pattern seen found, the physical and fiscal investment the cou-
upon pathologic review allows one to differentiate ple has made to get to that point is all for naught.
between obstructive and nonobstructive causes of It is best to extract the tissue prior to an ICSI
azoospermia. However, many clinical clues allow cycle and cryopreserve it. If sperm are found in suf-
the same assessment to be made without the need ficient quantity, the frozen–thawed sample can
for an invasive biopsy, including the physical char- serve as the sperm source for a subsequent ICSI.
acteristics of the testes, vasa, and epididymides and Alternatively, a fresh sample can be obtained on the
the hormonal values, most specifically FSH. day of oocyte harvest, secure in the knowledge that
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 158

158 H. Sadeghi-Nejad and R. Oates

there have been sperm found at an earlier date and Procedure

that there is tissue available to supply that sperm
should no sperm be found that day. Open ap- For an open biopsy, if it is combined with TESE,
proaches are favored in patients with nonobstruc- the procedure must be coordinated with the embry-
tive azoospermia because the volume of tissue ology laboratory for tissue processing. Local anes-
obtained is much greater, an important considera- thesia is obtained by instilling bupivacaine 0.25%
tion when spermatogenesis is so limited. (7–10 cc) into the spermatic cord near the pubic
tubercle. Approximately 5 cc of the anesthetic is
injected subcutaneously along the intended incision
Contraindications line. Standard skin preparation and draping are per-
Although not strictly a contraindication, in the pa- formed, followed by a small (approximately 1.5
tient with exceedingly small testes or a small soli- cm) transverse skin incision while the assistant
tary testis, care must be taken to preserve enough holds the testicle taut against the overlying skin
testicular tissue to support adequate testosterone (Fig. 15–6). The tunica vaginalis is similarly
production by the Leydig cells located in the inter- incised; the skin, dartos layer, and tunica vaginalis
stititum between the seminiferous tubules. It would edges are held apart with an eyelid retractor. A no.
be a drastic outcome if the patient were left hypo- 11 blade is used to make a 0.5 cm transverse inci-
androgenic and required life-long testosterone sion into the tunica albuginea on the anterior sur-
replacement. face of the testis. Gentle compression of the testis
Certain patients are not good candidates for helps extrude and expose an adequate tissue sam-
office-based scrotal procedures. They tend to pull ple, which is subsequently grasped with jewelers
up on their testes and are extremely uncomfortable. forceps and excised using iris scissors. A drop of
With testicular compression, a vagal response may sperm medium is placed on a glass slide, and the
be elicited resulting in severe bradycardia. Each excised tissue is blotted on its surface for “wet
case must be individualized in terms of the man’s
ability to have his operation in a setting away from
monitored anesthesia care.

Equipment
The equipment requirements differ depending on
whether an open or percutaneous approach is
selected.

Open approach: bupivacaine 0.25% (7 cc); 25-

gauge needle; sterile preparation kit; scalpels (11
and 15 blades); eyelid retractor; jewelers’ forceps;
small, sharp tissue scissors; glass microscope
slides; cytofixative; phase contrast microscope
with 400 magnification; Bouin’s solution
(picric acid, acetic acid, formaldehyde); test yolk
buffer (TYB; Irvine Scientific, Santa Ana, CA);
12 ml conical tubes; cauterizing instrument;
catgut suture (4-0)
Percutaneous approach: bupivacaine 0.25% (7 cc);
25-gauge needle; sterile preparation kit; glass
microscope slides; cytofixative; phase contrast
microscope with 400 magnification; Bouin’s
solution (picric acid, acetic acid, formaldehyde);
test yolk buffer (TYB; Irvine Scientific); 12 ml
conical tubes; Vim Silverman needle, Tru-Cut
needle, Biopty gun (Bard Urological), or other
self-designed instruments for tissue extraction/ FIGURE 15–6. Testicular positioning and incision for open
aspiration. biopsy. (From Goldstein, 1995, with permission)
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 159

15. Treatment of Male Reproductive Dysfunction in the Office 159

prep” analysis. If no sperm are seen, a second spec- Indications

imen may be similarly excised from a different
location on the ipsilateral testicle. Lack of sperm The PESA procedure is used in the treatment of
in this sample mandates contralateral TESE be- obstructive azoospermia. It should be emphasized
cause there is no guarantee that the embryology that sperm aspiration, with an open or a percuta-
laboratory will be more successful in finding tes- neous approach, is not the first option if recon-
ticular sperm despite a more extensive and inten- struction is possible. Extraction of epididymal
sive search. For therapeutic purposes, the tissue is spermatozoa from patients with conditions not
minced into small segments and placed in a coni- amenable to repair is best performed as an open
cal tube containing 1 ml of TYB for laboratory approach, as sufficient quantities of fluid and sperm
analysis and possible cryopreservation. A 0.3 mm are routinely collected to ensure adequate supplies
piece is placed in Bouin’s solution for formal his- for cryopreservation into numerous vials, each of
tologic analysis. which can serve as the sperm source for an ICSI
The percutaneous biopsy is performed by inject- cycle at a later date. Percutaneous extraction does
ing 2–3 cc of local anesthetic into the scrotal skin not require use of an operating microscope but may
in the intended biopsy area. The scrotal skin may compromise the ability of the couple to achieve
be incised for a tiny distance prior to the actual fir- pregnancy if no sperm are easily obtained.
ing of the biopsy device to prevent inclusion of skin
in the final specimen. It is important to consider the Contraindications
trajectory of the needle device (lateral to medial) Bleeding diatheses may lead to intrascrotal hema-
such that the epididymis is not accidentally injured. toma formation. If the testis is small and the epi-
Tissue is processed as above for the wet prepara- didymis is soft, there may be little intraepididymal
tion, formal histologic analysis, and therapeutic fluid, making percutaneous aspiration difficult.
uses. The biopsy site is compressed for 5–10 min-
utes for hemostasis. Equipment
The equipment required includes a 21-gauge but-
Comments terfly needle, 3 cc syringe, sterile conical tube,
Incisional or biopsy site bleeding/hematoma may buffered culture medium, and local anesthetic.
be encountered. Temporarily decreased sperm den-
sity has been reported but has not been clinically Procedure
significant. Blood contamination of the specimen After initiating a local spermatic cord block and
is a potential problem and makes processing and infiltrating the skin where the puncture will be
sperm extraction more difficult in cases where ICSI made, a 21-gauge needle is directed toward the epi-
is planned. didymal corpus or head while the assistant immo-
Testicular biopsy is a safe, well tolerated proce- bilizes the testis. Gentle traction on the aspirating
dure that may be performed in the office setting and syringe connected to the needle results in the
may be combined with therapeutic TESE. Because appearance of epididymal fluid in the connector
of the larger specimen size for histologic analysis tubing between the butterfly needle and the syringe.
and use with ICSI, the open technique is superior The needle is then gradually withdrawn, and the
to a blind percutaneous biopsy in most instances. tubing is occluded to prevent spillage. Compres-
If no sperm are retrieved from the testicular tis- sion is applied to the scrotum.
sue, donor insemination or adoption may be con-
sidered. Comments
Bleeding may occur at the aspiration site, and blood
Percutaneous Epididymal contamination of the specimen hampers processing
for ICSI. In cases where no epididymal fluid is
Sperm Aspiration obtained or if no sperm are noted in the aspirated
The purpose of percutaneous epididymal sperm epididymal fluid, the blind nature of the procedure
aspiration (PESA) is to recover spermatozoa from may seriously jeopardize the success of open
the epididymis using a percutaneous technique for microscopic epididymal sperm aspiration by injur-
use with advanced reproductive techniques such as ing the epididymal tubules.
ICSI. The PESA procedure is safe and may be per-
3051_Seifer_15_p150-160 11/5/01 9:55 AM Page 160

160 H. Sadeghi-Nejad and R. Oates

formed in the office setting using a percutaneous Mulhall JP, Burgess CM, Cunningham D, et al. Presence
approach. Despite its advantages of a shorter oper- of mature sperm in testicular parenchyma of men with
ating time and minimal patient discomfort, it typi- nonobstructive azoospermia: prevalence and predictive
cally yields less epididymal fluid and less usable factors. Urology 1997;49:91–96.
Oates RD, Lobel SM, Harris DH, et al. Efficacy of intra-
sperm than microscopic epididymal sperm aspira-
cytoplasmic sperm injection using intentionally cryo-
tion (MESA). The success of MESA may be preserved epididymal spermatozoa. Hum Reprod
adversely affected by tubular damage during PESA. 1996;11:133–138.
Failure to obtain sperm using PESA entails mov- Phillipson GT, Petrucco GM, Matthews CD. Congenital
ing on to an open procedure for microscopic epi- bilateral absence of the vas deferens, cystic fibrosis
didymal sperm retrieval (MESA). mutation analysis and intracytoplasmic sperm injec-
tion. Hum Reprod 2000;15:431–435.
Rosenlund B, Westlander G, Wood M, et al. Sperm
Suggested Reading retrieval and fertilization in repeated percutaneous
epididymal sperm aspiration. Hum Reprod 1998;13:
Brackett NL. Semen retrieval by penile vibratory stimu- 2805–2807.
lation in men with spinal cord injury. Hum Reprod Schlegel PN. Testicular sperm extraction: microdissec-
Update 1999;5(3):216–222. tion improves sperm yield with minimal tissue exci-
Craft I, Tsirigotis M, Bennet V, et al. Percutaneous epi- sion. Hum Reprod 1999;14(1):131–135.
didymal sperm aspiration and intracytoplasmic sperm Seftel AD, Oates RD, Krane RJ. Disturbed sexual func-
injection in the management of infertility due to tion in patients with spinal cord disease. Neurol Clin
obstructive azoospermia. Fertil Steril 1995;63:1038– 1991;9:757–778.
1042. Sheynki YR, Ye Z, Menendez S, et al. Controlled com-
Devroey P, Liu J, Goossens A, et al. Pregnancies after parison of percutaneous and microsurgical sperm
testicular sperm extraction and intracytoplasmic sperm retrieval in men with obstructive azoospermia. Hum
injection in nonobstructive azoospermia. Hum Reprod Reprod 1998;13:3086–3089.
1995;10:1457–1460. Silber SJ. Microsurgical TESE and the distribution of
Dohle GR, Ramos L, Pieters MH, et al. Surgical sperm spermatogenesis in non-obstructive azoospermia.
retrieval and intracytoplasmic sperm injection as Hum Reprod 2000;15(11):2278–2284.
treatment of obstructive azoospermia. Hum Reprod Silber SJ. New concepts in operative andrology: a review.
1998;13:620–623. Int J Androl 2000;23(suppl):66–76.
Goldstein M. Surgery of Male Infertility, 1st ed. Phila- Silber SJ, Nagy Z, Devroey P. The effect of female age
delphia: Saunders, 1995. and ovarian reserve on pregnancy rate in male infer-
Kamischke A, Nieschlag E. Treatment of retrograde ejac- tility: treatment of azoospermia with sperm retrieval
ulation and anejaculation. Hum Reprod Update 1999; and intracytoplasmic sperm injection. Hum Reprod
5(5):448–474. 1997;12:2693–2700.
Levine LA, Lisek EW. Successful sperm retrieval by per- Silber SJ, Nagy Z, Liu J, et al. The use of epididymal
cutaneous epididymal and testicular sperm aspiration. and testicular spermatozoa for intracytoplasmic sperm
J Urol 1998;159:437–440. injection: the genetic implications for male infertility.
Lipshultz L, Howards S. Infertility in the Male, 3rd ed. Hum Reprod 1995;10:2031–2043.
New York: Mosby, 1997. Takihara H. The treatment of obstructive azoospermia in
Mercan R, Urman B, Alata C, Aksoy S, Nuhoglu A, Isik- male infertility: past, present, and future. Urology
lar A, Balaban B. Oucome of testicular sperm retrieval 1998;51(suppl 5A):150–155.
procedures in non-obstructive azoospermia: percuta- Tournaye H. Surgical sperm recovery for intracytoplas-
neous aspiration versus open biopsy. Hum Reprod mic sperm injection: which method is to be preferred?
2000;15(7):1548–1551. Hum Reprod 1999;14 Suppl 1:71–81.
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 161

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

Since the birth of the first child conceived using the ally involve IVF. Although there is still a role for
process of in vitro fertilization (IVF) in 1978, many alternative forms of ART, such as GIFT, IVF has
thousands of children have been born worldwide many advantages, including a transvaginal ap-
through this fascinating procedure. In the early days proach to follicle aspiration permitting minimal (if
of IVF, only a few highly specialized centers around any) anesthesia, confirmation of fertilization, and
the world were prepared to perform the dramatic control of the number of embryos being delivered
surgical procedure involving the recovery of to the uterus. For these reasons, hundreds of cen-
oocytes. At the same time, behind the scenes a ters worldwide offer highly successful and mini-
highly skilled team of biologists waited patiently to mally invasive IVF procedures performed in the
receive and prepare the oocytes for in vitro insem- office setting.
ination. Although the emotional intensity involved
with each IVF procedure performed remains con-
stant, over time the process itself has been greatly
simplified. In fact, over the past 20 years, IVF has Purpose
become increasingly successful, all the while be-
coming less expensive and less invasive. The desire to have a child is one of the most pow-
A comparison of statistics reported by the Soci- erful, innate drives of most men and women.
ety for Assisted Reproductive Technology (SART) Despite this desire, approximately 15% of couples
supports the use of IVF over alternative forms of actively trying to conceive for 1 year remain infer-
assisted reproduction. For instance, in 1989 SART tile. These couples do demonstrate subfertility. Yet
reported statistics based on the national registry for when expectantly managed, nearly one-half of the
assisted reproductive technologies (ART) per- remaining couples conceive over the next year. At
formed in the United States during the 1987 cal- the end of 2 years a couple’s fecundity is reduced.
endar year. IVF accounted for approximately 80% At some point in time along the way, many cou-
of ART procedures, with the remaining 20% being ples seek assistance.
gamete intrafallopian transfer (GIFT). The success A variety of factors adversely affect fertility
rate for IVF was 16%, whereas the success rate for rates. For example, advancing maternal age has a
GIFT was 25%. The main advantage of IVF over profound negative impact on fertility rates; and
GIFT is that it does not require laparoscopy and with women delaying childbearing for a number of
therefore is less invasive and less expensive, but socioeconomic reasons, the percentage of couples
one could not ignore the difference in success rates presenting for evaluation of infertility is increasing.
of the two procedures during that period. Over the As more couples seek evaluation and treatment of
past decade, embryo culture techniques and embryo infertility, IVF is being used more frequently. For
transfer techniques have improved dramatically and many of these couples, IVF is a minimally inva-
so have IVF success rates. As a result, today IVF sive, cost-effective means to increase their statisti-
and GIFT success rates are similar and approxi- cal chance of achieving a pregnancy. Ultimately,
mately 95% of ART procedures performed annu- this is the true purpose of IVF.

161
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 162

162 B.L. Bopp and G.K. Adaniya

Indications junction with ICSI. Another equally important con-

traindication rests with religious beliefs. Some reli-
As couples undergo evaluation and treatment of gious doctrine does not permit fertilization outside
infertility, IVF is the first line of therapy in certain the human body and therefore does not allow IVF
situations. For instance, in women with tubal occlu- as a treatment option. All of these factors must be
sion, IVF may be the only option available for the considered with each couple preparing for IVF.
couple. On the other hand, for couples with unex-
plained infertility IVF may represent one of the Special Preparation Needed
final therapeutic options available. In both situa-
tions, IVF ultimately increases the couple’s chance by Patient and Physician
of achieving a pregnancy. The causes of infertility
justifying the use of IVF as a therapeutic option Once a couple has been thoroughly evaluated and
include tubal disease, tubal occlusion, unexplained in some instances failed more conservative treat-
infertility, endometriosis, ovulatory dysfunction, ment, IVF may be appropriate. IVF abounds with
cervical factor, pelvic adhesions, a combination of ethical dilemmas for many couples, and these must
factors, and sperm abnormalities. The latter in- be addressed before proceeding. First, the couple
cludes even severe sperm abnormalities now that must be fully educated as to the techniques involved
intracytoplasmic sperm injection (ICSI) is avail- in manipulating their gametes. Issues such as fer-
able. tilization occurring outside the body may ultimately
All of the aforementioned factors involve either preclude some couples from proceeding. In addi-
an unfavorable environment for egg–sperm inter- tion, whether a couple elects to cryopreserve em-
action or an inability of a given egg and sperm to bryos is of great significance. Likewise, the num-
unite and fertilize. The principal advantage of IVF ber of embryos a couple elects to have transferred
is that in certain couples it allows the rescue of eggs may create an uncomfortable situation if all the
and sperm from unfavorable conditions, provides a embryos implant and result in a multiple gestation.
more favorable environment for egg–sperm inter- These issues should be discussed and documented
action, confirms fertilization, and ensures delivery using consent forms that conform to local, state,
of the embryo to the uterus. Today IVF is carried and federal legal precedence. Our consent forms
out routinely in the office setting at hundreds of contain several pages of discussion regarding the
facilities worldwide. Yet we must not forget that, medication risks, procedural risks, pregnancy risks,
although minimally invasive and cost-effective, multiple pregnancy risks, failure possibilities,
facilities offering IVF must ensure staffing by financial responsibilities, and more. We require that
appropriately trained physicians and laboratory all consent forms are either notarized or are wit-
personnel. nessed by appropriate members of our office staff
prior to initiating a cycle.
When preparing couples for IVF, a thorough his-
Contraindications tory and physical examination should be performed
and a normal Papanicolaou smear confirmed. A
Although IVF provides an excellent option for normal endometrial cavity should be confirmed
many couples seeking treatment for impaired fer- with either a hysterosalpingogram or a sonohys-
tility, it is not indicated for some couples. For terogram. In addition, we frequently perform a trial
instance, women with significantly diminished embryo transfer during the follicular phase of the
ovarian reserve or ovarian failure do not benefit cycle preceding stimulation to document catheter
from IVF. Additionally, some couples do not ben- placement and ease of the transfer. We identify
efit from IVF for physiologic reasons that compli- blood types and screen for infectious diseases
cate the procedure. For example, some women have including human immunodeficiency virus (HIV),
cervical abnormalities that preclude embryo trans- hepatitis B and C, syphilis (rapid plasma reagin,
fer. Other women have undergone ovarian trans- RPR), Chlamydia trachomatis, and rubella. A re-
fixation, thereby making a transvaginal approach to cently obtained semen analysis should be docu-
follicle aspiration difficult if not impossible. For mented. In women over 38 years of age, we often
these women, an alternative technique involving a assess ovarian reserve with a clomiphene citrate
laparoscopic approach such as GIFT or zygote challenge test (CCCT), and in women over 40 years
intrafallopian transfer (ZIFT) may be more appro- of age a normal mammogram should be docu-
priate. In couples with severe sperm abnormalities, mented. If clinically indicated, we have a low
IVF may be ineffective unless performed in con- threshold for additional testing such as a chest radi-
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 163

16. In Vitro Fertilization in the Office Setting 163

ography or electrocardiography. Because IVF is an Large cotton swabs

elective process, ensuring maternal well-being is Powder-free gloves
essential prior to initiating therapy. Ring forceps
Tenaculum
Wallace catheter, 23 cm (Cooper Surgical, Shelton,
Equipment CN)

Clinical Preparation Laboratory Preparation

Follicle Aspiration
The following is a comprehensive list of the equip-
The following list contains the basic instrumenta- ment needed in an assisted reproductive laboratory
tion needed for follicle aspiration. The disposable to perform IVF procedures. The number of items
equipment, including the gloves, is tested for required, such as incubators, depend on the num-
embryo toxicity. The nondisposable equipment is ber of cycles performed.
prepared as a kit and sterilized.
37°C Incubator
12-Well heating block in a dry bath incubator Alarm timers
Round-bottom test tubes, 17  100 mm Alarms for incubators and liquid nitrogen storage
Dulbecco’s phosphate-buffered saline (DPBS) tank
(Life Technologies, Baltimore, MD), 20 ml Camera for inverted microscope
Modified human tubal fluid (mHTF) with 500 units CO2 incubators
heparin sodium, 50 ml (Irvine Scientific, Santa Compound microscope
Ana, CA) Dial-out equipment for alarm system
Bivalved speculum Dry bath heater with 12-well heating block
Datascope Environmental chamber for inverted microscope
Echotip Norfolk XS ovum aspiration needle, 16- Heating stage for inverted microscope
gauge, 30 cm (Cook IVF, Spencer, IN) Inverted phase contrast microscope
Flexible tubing Isolette
Sterile gown Laminar flow hood
Needle guide designed specifically for the trans- Liquid nitrogen storage tank
vaginal probe Pipettors
Packet of sterile sponges Programmable embryo freezer with computer
Pioneer Pro Pump suction apparatus with a foot Refrigerator
pedal control (Pioneer Medical, Madison, CT) Slide warmer
Powder-free gloves Sperm counter
Ring forceps Stereo dissecting microscope
Sterile aquasonic 100 ultrasound transmission gel Swinging bucket centrifuge
(Parker Laboratories, Fairfield, NJ) Thermometers
Sterile endocavity ultrasound cover kit (CIVCO
In addition, the following items are required if
Medical Instruments, Kalona, IA)
the laboratory intends to perform intracytoplasmic
Ultrasound machine with a transvaginal probe
sperm injection (ICSI).
Embryo Transfer Antivibration table
Coarse and fine micromanipulators
Minimal equipment is required for the embryo Holding pipettes
transfer. The disposable equipment is tested for ICSI injection needles
embryo toxicity prior to use. The nondisposable Microinjectors
instruments are sterilized and stored in an incuba-
tor maintained at 37°C. Disposable items include the following.
Syringe, 1 cc Syringe filters, 0.2 m
Syringe, 10 cc Syringes, 1 cc, 3 cc, and 10 cc
Preimplantation stage one (P1) culture medium, 20 Plastic pipettes, 1 ml, 5 ml, 10 ml, and 25 ml
ml (Irvine Scientific, Santa Ana, CA) Plastic round-bottom test tubes, 12  75 mm and
Bivalved speculum 17  100 mm
Sterile gown Conical plastic test tubes, 15 ml and 50 ml
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 164

164 B.L. Bopp and G.K. Adaniya

Tissue culture flasks, 50 ml and 250 ml Procedures

Tissue culture dishes, 60 mm and 100 mm
Aluminum canes for cryopreservation The justification for each of the procedures de-
Borosilicate glass Pasteur pipettes scribed below are beyond the scope of this chap-
Cardboard sleeves for canes ter. They reflect a carefully selected combination
Cryovials of protocols based on a review of the literature that,
Gloves in our hands, result in success rates well above that
Microcells (Conception Technologies, San Diego, of the national average reported by SART. Please
CA) refer to the Suggested Reading list for some of the
Organ culture dishes references. We conform to SART reporting guide-
Pipette tips lines, and our results are based on an average of
Tuberculin syringes 2.9 embryos transferred to a patient population sim-
Wallace catheter ilar to that of an average IVF facility. Factors that
The media/solutions needed are as follows: influence the number of embryos we transfer
include patient age, embryo quality, previous his-
1,2-Propanediol (PrOH) (Sigma, St. Louis, MO) tory, and diagnosis. Only in the most unusual cir-
Blastocyst medium (Irvine Scientific, Santa Ana, cumstances do we transfer more than three em-
CA) bryos. Fortunately, as we increase the frequency of
Dulbecco’s phosphate-buffered saline (DPBS) use of blastocyst transfers, the number of embryos
Glycerol (Sigma) we transfer on average continue to decrease toward
Hyaluronidase (Sigma) 2.0, thereby eliminating the triplet risk for most
Isolate (Irvine Scientific) couples undergoing IVF.
Mineral oil (Sigma)
Modified human tubal fluid (mHTF)
P1 medium Clinical Procedures
Polyvinylpyrrolidone (PVP) (Irvine Scientific)
Preparation
Serum substitute supplement (SSS) (Irvine Scientific)
From the start of the GnRHa down-regulation,
about 5 weeks pass before a couple finds out the
Brief Outline of Steps result of their pregnancy test. We typically begin
GnRHa on menstrual cycle day 21 or the equiva-
Clinical Steps lent luteal phase day. In anovulatory women, oral
Initial history, physical examination, testing, con- contraceptive pills or a progestational agent may be
sent used in combination with the GnRHa. Menses typ-
Ovarian suppression using luteal phase gonadotropin- ically begin as normally expected and on cycle day
releasing hormone agonist (GnRHa) or antagonist 1, 2, or 3 a baseline ultrasound scan is performed
Ovulation induction using follicle-stimulating to assess the ovaries for cysts or pathology. In addi-
hormone (FSH), either recombinant or urinary tion, a blood sample is drawn to measure the serum
products estradiol, which indicates the efficacy of GnRHa
Human chorionic gonadotropin (hCG) administra- ovarian suppression. If appropriately suppressed,
tion and scheduling follicle aspiration we reduce the GnRHa dose by one-half and initi-
Transvaginal oocyte aspiration ate controlled ovarian stimulation using gonado-
Luteal phase progesterone support and possibly tropins in an a.m. and p.m. divided dosing interval.
hCG boosters We adjust our dosing according to age, menstrual
Embryo transfer characteristics, and if available response to previ-
Pregnancy test 15 days after follicle aspiration ous gonadotropin stimulation. After 5 days of com-
pleted gonadotropin therapy, the ovarian response
is monitored with sequential ultrasound scans and
Laboratory Steps serum estradiol levels. Typically, when two lead
Identification and grading of oocytes follicles reach 18–20 mm in size, hCG is adminis-
Sperm preparation tered. Factors such as follicle quantity, follicle size,
Oocyte insemination/ICSI and serum estradiol levels vary widely in every
Fertilization assessment individual, so a precise guideline is difficult to rec-
Embryo culture ommend. For “poor” responders and “high” re-
Embryo transfer sponders we use modified protocols. When a cohort
Embryo cryopreservation of follicles demonstrate adequate quantity, size, and
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 165

16. In Vitro Fertilization in the Office Setting 165

serum estradiol production, hCG is administered to vital signs with continuous pulse oximetry, elec-
induce oocyte maturation. At 36 hours after hCG trocardiography, and blood pressure assessment.
administration, we schedule the follicle aspiration.
Follicle Aspiration
Anesthesia
The IVF suite is adjacent to the laboratory, and a
The type of anesthetic a patient chooses determines small pass-through window connects the two rooms
the location where we perform the follicle aspira- (Fig. 16–1). The pass-through window can be seen
tion. Women opting for no anesthetic, oral narcotic in the background. The 12-well heating block in
medication, or intramuscular narcotic medication the dry bath incubator sits in the window. The
undergo their procedure in our transfer suite, instrument tray is positioned along the back wall,
thereby avoiding operating room and anesthesiol- and a procedure light is mounted to the back wall.
ogy charges. A Datascope is used during the pro- Proceeding from left to right in the foreground is
cedure to monitor pulse and oxygen saturation and the ultrasound machine, the Pioneer Pro Pump suc-
the blood pressure. The procedure room should be tion apparatus, the Datascope, and the procedure
equipped with a resuscitation cart, and the staff table. The laboratory is located on the other side of
must be appropriately trained to respond to an the pass-through window (Fig. 16–2). Proceeding
emergency. To conform to local standards of care, from left to right in Figure 16–2 is the laminar flow
we follow the same postoperative guidelines used hood, isolette, incubators, liquid nitrogen storage
for our ambulatory surgery patients. Oxygen satu- tank, and inverted microscope.
ration and pulse are continuously monitored using Once adequate sedation has been administered,
a Datascope for 1 hour after follicle aspiration the patient’s legs are positioned in stirrups, and she
while assessing blood pressure every 15 minutes. is draped in a sterile fashion. The sterile instru-
Most women in our practice opt for intravenous mentation used for the follicle aspiration is shown
sedation, and we provide an anesthesiologist. Prior in Figure 16–3. Proceeding from left to right is the
to the procedure, the anesthesiologist reviews the Echotip Norfolk Needle, bivalved speculum, ring
history and performs a physical examination. Anes- forceps, needle guide, an endocavity ultrasound
thetic consent forms are signed. The anesthesiolo- cover kit, aquasonic ultrasound gel, two rubber
gist then administers an intravenous combination bands, round-bottom test tubes, rubber tubing, and
of propofol, midazolam, and fentanyl. Oxygen is sponges. A bivalved speculum is inserted in the
provided via nasal cannula. The anesthesiologist vagina to expose the cervix. The vagina and cervix
maintains the patient’s airway, and monitors her are prepared using 20 ml of DPBS soaked on ster-

FIGURE 16–1. In vitro

fertilization suite contain-
ing the ultrasonography
machine, equipment
table, Pioneer Pro Pump
aspiration device, Data-
scope, and procedure
table. In the background
is the pass-through win-
dow containing the dry
well incubator.
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 166

166 B.L. Bopp and G.K. Adaniya

FIGURE 16–2. Assisted

reproductive technology
laboratory with the pass-
through window located
in the background. In the
foreground, proceeding
from left to right, is the
laminar flow hood, Iso-
lette, incubators, liquid
nitrogen storage tank,
and inverted microscope.

ile sponges. The instruments are removed. Using a from a round-bottom test tube. The suction pres-
sterile draped vaginal probe, real-time ultrasonog- sure should be adjusted to 100 mmHg. Suction
raphy is performed. The ovaries are visualized, and pressures over 100 mmHg may be associated with
the endometrium is characterized. An Echotip Nor- an increased risk of oocyte trauma, such as a frac-
folk XS ovum aspiration needle should be tested tured zona pellucida.
using the foot pedal to activate the Pioneer Pro The needle is then inserted in the vaginal probe
Pump suction apparatus and aspirate modified HTF, guide, the vaginal apex is punctured, and the first

FIGURE 16–3. Follicle

aspiration tray. Proceed-
ing from left to right, the
Echotip Norfolk Needle,
bivalved speculum, ring
forceps, needle guide,
Endocavity Ultrasound
Cover, Aquasonic Ultra-
sonic Gel, two rubber
bands, round-bottom test
tubes, rubber tubing, and
sponges.
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 167

16. In Vitro Fertilization in the Office Setting 167

ovarian follicle is entered. Using the foot pedal, 100 uled for day 3 and day 5 transfers. In most instances
mmHg suction pressure is then applied to tubing luteal phase progesterone support is initiated on the
equipped with a test tube trap mechanism, and the evening before the follicle aspiration or on the
first follicle begins to decompress. The fluid is aspi- evening of the follicle aspiration. The precise tim-
rated into a round-bottom test tube containing ap- ing of initiating luteal phase progesterone and the
proximately 1 ml of modified HTF. As the follicle best delivery system to be used remains to be deter-
approaches total collapse, the needle is spun around mined. Regardless, on the third or fifth day after
its long axis until all of the fluid has been drained. follicle aspiration, the couple returns for embryo
Next, an adjacent follicle is directly entered, and all transfer. We prescribe Valium and indomethacin 1
of the follicles are aspirated sequentially in a simi- hour prior to the transfer. The decision concerning
lar fashion. Continuous pressure should be main- the number of embryos to transfer either has been
tained. After aspirating the last follicle, the pressure predetermined or will be modified at the time of
is released and the needle removed from the ovary transfer depending on the embryo quality.
and vagina. The needle is flushed with modified Upon entering the transfer suite, the patient’s
HTF. Repeat the process on the contralateral ovary. identity is confirmed by the reproductive biologist,
With each follicle aspirated, the volume remain- and the patient is then positioned on an examina-
ing in the test tube is evaluated prior to decom- tion table in close proximity to the laboratory win-
pressing the next follicle. Avoid aspirating a folli- dow. This minimizes the manipulation of the
cle that requires interrupting the pressure during embryos prior to the transfer. The sterile instrument
decompression to change test tubes. As each test pack consists of a bivalved speculum, ring forceps,
tube fills with fluid a new test tube is connected, tenaculum, large cotton swabs, sponges, and a
and the full test tube is capped and immediately towel sterilized and stored in an incubator at 37°C.
taken to the window opening into the laboratory. The pack is opened at the time of the transfer. The
The test tube is placed in a 12-well heating block physician reviews the trial transfer notes or past
located in a dry bath incubator maintained at a tem- transfer notes and confirms the number of embryos
perature of 37°C. The reproductive biologists then to be transferred.
scan the fluid for oocytes. When both ovaries have Minimal instruments are needed for the embryo
been decompressed, the ultrasound probe is re- transfer (Fig. 16–4). Proceeding from left to right,
moved and the vaginal wall puncture sites visually there is a bivalved speculum, tenaculum, ring for-
inspected for hemostasis. If needed, pressure is ceps, large cotton swabs, 10 cc syringe, 1 cc sy-
applied or a suture placed at the bleeding site. In ringe, Wallace catheter, and sponges. The physician
some women, it is appropriate to aspirate the free scrubs and uses embryo-tested, powder-free gloves.
fluid from the cul-de-sac as oocytes may be recov- The speculum is placed in the vagina, and the cervix
ered from the fluid obtained. is centered. The vagina is prepared using P1
In situations where low oocyte recovery is antic- medium, and the exocervix is wiped with medium-
ipated, a double-lumen needle (Follicle Aspiration soaked swabs. P1 medium (10 ml) is then connected
Set; Swemed Lab, Billdal, Sweden) may be used to a Wallace catheter outer sheath, and the outer
to flush the follicles immediately after aspiration. sheath tip is inserted in the cervical os to approxi-
In this instance, a 10 ml syringe containing modi- mately 1 cm. The endocervix is gently irrigated to
fied HTF is connected to the tubing provided with flush the cervical mucus from the canal. Often a
the double-lumen needle. The follicle is decom- bubble of mucus protrudes from the canal and can
pressed in the usual fashion; and upon completion, be easily wiped away from the cervix. A tuberculin
1–3 ml of fluid is injected into the follicle to force syringe is then inserted in the external os, and suc-
reexpansion, thereby causing turbulence in the fol- tion is applied to aspirate additional mucus. A trial
licle and potentially dislodging an oocyte for aspi- transfer is performed using a sterile Wallace cathe-
ration. Oocyte recovery rates are similar for both ter inserting either the inner catheter or the sheath
single-lumen and double-lumen aspiration, but alone to just beyond the internal cervical os.
physician anxiety may be reduced and multiple The embryos are loaded into a sterile Wallace
attempts can be made to find an oocyte from each catheter and handed to the physician through the
follicle with the double-lumen tube. pass-through window. The Wallace catheter is then
inserted into the cervix and advanced to a point on
Embryo Transfer the catheter corresponding to 6.5–7.0 cm. The
embryos are expelled, and after approximately 30
Now that blastocyst transfer has gained increasing seconds the catheter is rotated and slowly with-
popularity and success, many patients are sched- drawn. The catheter is passed back to the repro-
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 168

168 B.L. Bopp and G.K. Adaniya

FIGURE 16–4. Embryo

transfer tray. Proceeding
from left to right, a
bivalved speculum,
tenaculum, ring forceps,
large cotton swabs, a 10
cc syringe, 1 cc syringe,
Wallace catheter, and
sponges.

ductive biologist, who flushes the catheter and the transfer catheters, gloves, and media. Toxicity test-
sheath with equilibrated P1 medium. If the flush is ing is usually done with a bioassay such as the
clear, the transfer is complete. If one is retained, mouse one-cell assay, the mouse two-cell assay, the
the embryo is reloaded into a sterile Wallace cath- hamster sperm survival test, or the human sperm
eter and the transfer is repeated. survival test. The use of cryopreserved one-cell or
With increasing frequency ART facilities are two-cell mouse embryos (Conception Technolo-
using ultrasound guidance to perform embryo gies, San Diego, CA) eliminates the need for main-
transfer. It provides visual confirmation of embryo taining a mouse colony.
placement and may lead to enhanced success rates. If the semen analysis and preparation of the
The patient is taken to a holding area and asked to semen sample are done in the ART laboratory, the
recline for 1 hour prior to discharge. Over the next laboratory is considered to be performing high
2 weeks hCG boosters may be administered along complexity testing and is subject to the Clinical
with progesterone support. The pregnancy test is Laboratory Improvement Amendments of 1988
scheduled for 15 days after follicle aspiration. (CLIA ‘88) guidelines. The guidelines are exten-
sive and cover such areas as proficiency testing,
Laboratory Procedures patient test management, quality control, quality
assurance, personnel, and the inspection process.
Quality Control The laboratory must undergo the inspection pro-
cess and receive a CLIA certificate to be in com-
It is critically important that a strict, comprehen-
pliance. The reader is encouraged to examine the
sive quality control program be followed in the
guidelines, which may be found in the Suggested
ART laboratory to ensure success. Daily tempera-
Reading list.
ture checks of incubators, refrigerators, slide warm-
ers, heated microscope stages, Isolettes, heating Media
blocks, and dry incubators are performed and re-
corded. In addition, daily monitoring of incubator A wide variety of media have been used for ART
and Isolette CO2 levels must be performed. procedures during the past 20 years. Some exam-
All laboratory disposable items that come into ples are Ham’s F10, Ham’s F12, human tubal fluid
contact with the embryos or spermatozoa must be (HTF), and Eagle’s medium. Historically, the me-
tested for toxicity, including such items as petri dium was prepared in the ART laboratory, allow-
dishes, flasks, test tubes, pipettes, pipette tips, ing each laboratory to have control over media
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 169

16. In Vitro Fertilization in the Office Setting 169

preparation. Today, there are many choices of com- sound-guided vaginal retrieval. Finally, prepare 50
mercially available media that may be utilized by ml of modified HTF by adding 500 units of hep-
ART laboratories. We conducted studies compar- arin and place in the 37°C incubator overnight.
ing a commercial medium (P1) with the P1 medium
produced by our ART laboratory and found that the Oocyte Retrieval
two media produced similar fertilization rates and Preparation of the Isolette is the first step in prepar-
embryo development. ing for oocyte retrieval. Place the culture and rinse
The advantages of purchasing media are con- dishes into the Isolette just prior to the start of the
venience and decreased utilization of technician retrieval. In addition, label an appropriate number
time. An additional advantage is that the medium of 100 mm petri dishes and place them in the Iso-
arrives with embryo bioassay and endotoxin results. lette. Finally, place a sterile glass Pasteur pipette
The end user has the option of using those results with an aspiration bulb attached in a sterile test tube
as their quality control testing, which would save sitting in a test tube rack located in the Isolette.
both time and money. However, because there is Follicular aspirates are suctioned into round-bot-
uncertainty regarding the conditions to which the tom test tubes and passed through the access win-
medium was exposed between the time it was tested dow into the ART laboratory. These tubes are then
at the medium production facility and the time it placed in a rack located in the Isolette, which has
arrives in the laboratory, testing it at the ART lab- been calibrated to 37°C and 5% CO2. Aspirates are
oratory is recommended. poured into the large petri dishes, and the test tubes
One of the developments in culture media is the are discarded. Using the dissecting microscope
new sequential medium, which takes into account located in the Isolette, locate the oocyte-cumulus
the various metabolic requirements of the develop- complex (OCC). Aspirate the OCCs with the Pas-
ing embryo. These media have allowed ART labo- teur pipette, rinse them thoroughly in the rinse
ratories to grow embryos to the blastocyst stage dishes to remove excess red blood cells, and place
without the use of co-culture before performing the them in the culture dishes. Repeat with the remain-
embryo transfer. ART programs are thus able to der of the aspirates until all the OCCs have been
decrease the number of transferred embryos owing collected. Place all the culture dishes in the culture
to the higher implantation potential of blastocysts. incubator.
This has led to a dramatic decrease in the number
of higher-order multiple gestations. Semen Preparation
A wide variety of sperm preparation techniques are
IVF Procedure currently available. The goal of any preparation
method should be to remove both the immotile and
Day Prior to Oocyte Retrieval
morphologically abnormal spermatozoa, to remove
Culture dishes are prepared the day before oocyte any bacteria and cellular debris, and to retain as
retrieval and placed in a CO2 incubator overnight to many of the motile spermatozoa as possible. Some
equilibrate. Make a 10% serum substitute supple- sperm preparation techniques are sperm washing,
ment (SSS) with P1 medium, and filter it using a migration methods such as the swim-up and swim-
syringe filter. Label the appropriate number of 60 down techniques, adherence methods such as glass
mm petri dishes (depending on the number of fol- wool filtration, and density gradient centrifugation.
licles) with the patient’s name. Pipette five 35 l The density gradient centrifugation technique is
drops into the petri dishes and overlay with 5 ml of performed as follows. Remove an aliquot from the
mineral oil. Prepare dishes to rinse the oocyte cumu- liquefied sample, load it onto a Microcell, and per-
lus complexes by pipetting 5 ml of the P1 medium form an initial semen analysis. Place the semen on
into petri dishes labeled with the patient’s name. top of a density gradient column consisting of 1 ml
Finally, prepare the sperm-washing medium by of 45% Isolate over 1 ml of 90% Isolate in a 15 ml
making 20 ml of P1 with 10% SSS in a tissue cul- conical test tube. Centrifuge at 200g for 15 min-
ture flask. Place the culture dishes, rinse dishes, and utes and then aspirate all the fluid above the sperm
sperm-washing medium (making sure the cap is pellet. Resuspend the pellet in 5 ml of sperm wash-
loose) into an incubator at 37°C and 5% CO2 in air. ing medium and centrifuge at 200g for 5 minutes.
Additionally, pour 20 ml of Dulbecco’s phos- Remove the supernatant and resuspend the pellet;
phate-buffered saline into a tissue culture flask and wash again for 5 minutes. Finally, remove the
let it sit at room temperature overnight. This is used supernatant and resuspend in the minimum appro-
for preparation of the vagina prior to the ultra- priate volume. Take an aliquot and determine the
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 170

170 B.L. Bopp and G.K. Adaniya

concentration and motility. Calculate the volume of tilization during a previous cycle. It is beyond the
the sample required to inseminate the oocytes at a scope of this chapter to describe the ICSI procedure
concentration of 100,000 motile spermatozoa/ml, in detail, so the reader is encouraged to review the
then place the sample in the incubator at 37°C and suggested readings on ICSI. Briefly, use two 1 cc
5% CO2 until the time of insemination. syringes with needles to mechanically strip away
most of the cumulus cells surrounding the oocytes.
Insemination Place the oocytes in a hyaluronidase solution 80
IU/ml to help dislodge the remainder of the cumu-
Approximately 4–6 hours after oocyte retrieval, lus and corona cells. Use a finely drawn sterile glass
place the sperm sample and the oocytes in the Iso- Pasteur pipette to help remove the cells by carefully
lette. Verify the identity of the gametes and record aspirating the oocyte in and out of the pipette. Once
on the patient’s verification form. Have a second the cells are removed, rinse the oocytes in equili-
biologist verify the gametes prior to insemination brated P1  10% SSS. Observe the oocyte using the
to ensure proper identification. Resuspend the sper- inverted microscope to check for the presence of a
matozoa, as some settling occurs while sitting in polar body, the indicator of oocyte maturity.
the incubator. Add the predetermined amount of Set up the holding and injection pipettes on the
spermatozoa to each oocyte and observe the cul- ICSI microscope and aspirate a 10% polyvinyl-
ture drops microscopically to confirm the approx- pyrrolidone (PVP) solution into the injection
imate number of spermatozoa per oocyte. Return pipette to aid in control of the spermatozoa. Pre-
the oocytes to the incubator until the fertilization pare an oocyte injection dish by placing four 5 l
check. drops of modified HTF  10% SSS around a cen-
Intracytoplasmic Sperm Injection tral 5 l drop of PVP. Cover the drops with min-
eral oil. Add approximately 1 l of the processed
Extra equipment is needed in laboratories perform- sperm sample to the PVP drop. The volume of
ing ICSI (Fig. 16–5). As shown, the equipment sperm added may need to be adjusted according to
includes an inverted microscope positioned on an the sperm concentration. Add the mature oocytes
antivibration table, course and fine micromanipula- to the modified HTF drops and bring the dish to
tors, and microinjectors. ICSI has become the stan- the ICSI microscope.
dard insemination method for couples with male Immobilize a motile spermatozoon with the
factor infertility and couples with poor or failed fer- injection pipette and then aspirate it into the pipette

FIGURE 16–5. Intracyto-

plasmic sperm injection
setup. Equipment
includes the inverted
microscope positioned
on an antivibration table,
coarse and fine micro-
manipulators, and
microinjectors.
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 171

16. In Vitro Fertilization in the Office Setting 171

tail first. Secure the oocyte with the holding pipette, Preparation for Embryo Transfer
positioning the oocyte so injection does not take
place into the area of polar granularity, which usu- On the day prior to the embryo transfer prepare a
ally means orienting the polar body at either the 12 50% transfer dish by pipetting 2 ml of a 50% SSS
or 6 o’clock position. With the spermatozoon at the in P1 solution into the inner well of a 3037 organ
tip of the injection pipette, insert the pipette into culture dish. Add 4 ml of P1 to the outer well and
the oocyte at the 3 o’clock position. Aspirate the incubate overnight at 37°C and 5% CO2. In addi-
spermatozoon and the cytoplasmic organelles into tion, add approximately 20 ml of P1 to a test tube
the injection pipette, break the oolemma, and inject and equilibrate overnight. This will be used to help
the spermatozoon and organelles slowly back into remove any cervical mucus while performing the
the cytoplasm. Withdraw the needle and repeat for embryo transfer.
the remainder of the mature oocytes. Return the On the day of the transfer, separate the embryos
injected oocytes back to the incubator until fertil- to be transferred from those that are of suitable
ization assessment the following day. quality for cryopreservation. Move the embryos to
be transferred into the 50% transfer dish within 1
Fertilization Assessment hour of the scheduled transfer time and move the
50% dish and the cervix rinse into the Isolette.
The oocytes are checked for the presence of pro- When the patient is properly prepared for the trans-
nuclei, which are the indicators of fertilization, fer, aspirate the embryos into the transfer catheter
approximately 14–18 hours after insemination. in no more than a 30 l volume. Pass the catheter
This is accomplished with the aid of a finely drawn through the access door to the physician. Once the
sterile glass Pasteur pipette attached to a small transfer is complete, the catheter is passed back to
pipette bulb. The oocyte is usually located among the ART laboratory, and the catheter is rinsed thor-
the dispersed cumulus cells on the bottom of the oughly with P1/SSS to check for the presence of
petri dish. Gently aspirate the oocyte in an out of residual embryos. If none is present, the transfer is
the glass pipette to dislodge the attached cells. This complete. Otherwise, reload the retained embryos
is done to aid in visualizing the pronuclear struc- into a new transfer catheter and repeat the transfer
tures. Sometimes the surrounding cells have formed procedure.
a tight clump of cells, and the oocyte must be gen-
tly removed from the clump by careful dissection Embryo Cryopreservation
with the aid of two 1 cc syringes with 27-gauge
needles. Observe the oocyte microscopically for the The addition of embryo cryopreservation has greatly
presence of two pronuclei, and place the fertilized enhanced the overall pregnancy rates per fresh cycle
oocytes into fresh equilibrated P1. If more than two for patients who have frozen embryos. Cryopreser-
pronuclei are observed, the polypronuclear em- vation has allowed multiple attempts to achieve
bryos should be discarded immediately, as they are pregnancy from only one stimulated cycle. Many
capable of apparently normal-looking cell division. embryo cryopreservation protocols are available,
Once the fertilization assessment is completed, such as those utilizing the cryoprotectant glycerol,
return the fertilized and unfertilized oocytes to the dimethylsulfoxide (DMSO), or 1,2-propanediol
incubator. Check the unfertilized oocytes again in (PrOH). We currently use a combination of PrOH
the afternoon for signs of late fertilization. and sucrose to freeze/thaw pronuclear and cleavage-
stage embryos and a protocol utilizing glycerol for
Embryo Culture freezing and thawing blastocysts. Only the PrOH
protocol is presented here. The reader is encouraged
The embryos of patients undergoing a day 3 trans- to examine the Suggested Reading list for more
fer remain in the P1 until the day of transfer. For detail on both cleavage-stage embryo freezing and
patients scheduled for a blastocyst transfer, move blastocyst freezing.
the embryos from P1 to equilibrated blastocyst Briefly, prepare the following solutions.
medium  10% SSS on day 3 and return the
0.5 M PrOH in Dulbecco’s phosphate buffered
embryos to the incubator until the day 5 transfer.
saline (DPBS)
On the day prior to the scheduled blastocyst trans-
1.0 M PrOH in DPBS
fer, prepare new culture dishes with blastocyst
1.5 M PrOH in DPBS
medium  10% SSS and equilibrate overnight.
1.5 M PrOH  0.2 M sucrose in DPBS
Transfer new embryos that require extended cul-
ture past day 5 to the fresh blastocyst medium  Place the embryos in 0.5 M PrOH for 5 minutes,
10% SSS. followed by 5 minutes in 1.0 M PrOH and then 10
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 172

172 B.L. Bopp and G.K. Adaniya

minutes in 1.5 M PrOH. Finally, place the embryos tations. Complications can be categorized by those
in the 1.5 M PrOH  0.2 M sucrose solution for 5 related to the stimulation, the procedure, and the
minutes and then into a labeled cryovial contain- outcome of the cycle.
ing 1 ml of 1.5 M PrOH  0.2 M sucrose. Complications related to the stimulation itself
Load the embryos into an embryo freezer, such include reactions to medications and ovarian hyper-
as the Planer Kryosave (T.S. Scientific, Perkasie, stimulation. Severe ovarian hyperstimulation syn-
PA) and initiate the freezing program. drome complicates about 1–2% of cycles, and man-
agement strategies should be clearly understood
1. Ramp from room temperature to 7.0°C at
when this complex, potentially lethal complication
2.0°C/min.
is encountered.
2. Hold for 5 minutes, then manually seed the vial
Procedure-related complications include anes-
to induce ice formation.
thesia reactions, traumatic organ injury, and post-
3. Continue to hold at 7.0°C for 15 minutes.
procedure complications. Anesthesia-related com-
4. Ramp from 7.0°C to 35.0°C at 0.3°C.
plications include nausea, vomiting, adverse drug
5. At the end of the cryopreservation program,
reactions, malignant hyperthermia, airway obstruc-
quickly place the vials on a labeled freezing
tion, airway injury, and aspiration pneumonia.
cane, place a labeled cardboard sleeve over the
Traumatic injury includes bowel perforation, blood
cane, and plunge the cane into a small Dewar
vessel laceration, and ovarian hemorrhage. Post-
filled with liquid nitrogen. Transfer the cane into
procedure complications include ovarian abscess,
a liquid nitrogen storage tank.
pyosalpinges, endomyometritis, ovarian torsion,
hydrosalpinges, and pelvic hematoma.
Embryo Thawing
Outcome-related complications are most com-
The embryos should be thawed quickly to avoid the monly related to multiple gestations. Complications
generation of ice damage in the embryo. Briefly, due to multiple gestations include both fetal and
prepare the following solutions and bring them to maternal adverse outcomes. Multiple gestations
room temperature. account for 30–35% of the pregnancies achieved
through IVF, and up to 10% are triplets or more.
1.0 M PrOH  0.2 M sucrose in DPBS
Spontaneous abortion, premature labor, preeclamp-
0.5 M PrOH  0.2 M sucrose in DPBS
sia, and cesarean delivery are only a few of the
0.2 M sucrose in DPBS
potential complications associated with multiple
Fill a large beaker of water with water and bring gestations. Potential neonatal complications are
the temperature to 37°C. Remove the cryovial from numerous and are typically related to prematurity.
the cane and plunge it into the 37°C water. After Equally important to the issue of multiple ges-
the vial is thawed, pipette the contents into a 3037 tation is that of ectopic gestation. Despite the use
petri dish and locate the embryos. Move the of IVF, in which the fallopian tubes are bypassed,
embryos into 1.0 M PrOH  0.2 M sucrose for ectopic pregnancies occur with an incidence of
5 minutes. Transfer the embryos to the 0.5 M approximately 3%. Additionally, heterotopic preg-
PrOH  0.2 M sucrose solution for 5 minutes. nancies also occur, with a reported incidence of
Finally, move the embryos into DPBS  0.2 M 0.1–0.3%. Early pregnancies resulting from IVF
sucrose for 5 minutes before placing the embryos must be intensely monitored, and gestation location
in a culture dish containing microdrops of P1 must be confirmed as early as possible. Sound judg-
medium. Observe the embryos microscopically for ment and careful monitoring of patients minimize
evidence of ice damage. The embryo is judged to the incidence of all of the mentioned complications.
be viable if fewer than 50% of the blastomeres
exhibit ice damage. Place the embryos in the incu-
bator and transfer on the appropriate day. Conclusions
The evolution of IVF has been rapid and signifi-
Complications cant. Once available to only a few couples around
the world, IVF is now a viable therapeutic option
Complications occur with any intervention; but for thousands of couples. No longer considered
when related to elective procedures, they seem experimental, IVF has become a routine part of
more significant. Fortunately, IVF is a safe proce- infertility treatment protocols. Success rates con-
dure, and significant complications are uncommon. tinue to improve, and costs continue to decrease.
An exception is, arguably, high-order multiple ges- As advances in technology continue to simplify
3051_Seifer_16_p161-173 11/5/01 9:56 AM Page 173

16. In Vitro Fertilization in the Office Setting 173

IVF procedures, IVF is rapidly becoming a routine ductive Medicine. San Diego, CA: American Society
part of infertility treatment in the office. for Reproductive Medicine, 2000:S30.
Hammitt D, Barud K, Galanits T, et al. Post-ICSI culture
of oocytes in G1.2 versus HTF-SSS—fertilization,
Suggested Reading embryo quality and pregnancy outcomes [abstract no.
P-025]. In: 2000 Annual Meeting Program Supplement
Adashi E, Rock J, Rosenwaks Z (eds). Reproductive of the 56th Annual Meeting of the American Society
Endocrinology, Surgery, and Technology. Philadel- for Reproductive Medicine. San Diego, CA: American
phia: Lippincott-Raven, 1996. Society for Reproductive Medicine, 2000:S103.
Behr B, Pool T, Milki A, et al. Preliminary clinical expe- Keel BA, May JV, DeJonge CJ. Handbook of the Assisted
rience with human blastocyst development in vitro Reproduction Laboratory. Boca Raton: CRC Press, 2000.
without co-culture. Hum Reprod 1999;14:454–457. May J, Hanshew K. Organization of the in vitro fertil-
Centers for Disease Control and Prevention, American ization/embryo transfer laboratory. In: Keel B, Web-
Society for Reproductive Medicine, Society for ster B (eds) CRC Handbook of the Laboratory Diag-
Assisted Reproductive Technology, RESOLVE. The nosis and Treatment of Infertility. Boca Raton: CRC
National Fertility Association. 1997 Assisted Repro- Press, 1990:291–327.
ductive Technology Success Rates. Atlanta: CDC, Medical Research International, The American Fertility
1999:41. Society Special Interest Group. In Vitro Fertilization.
CLIA ‘88 Final Rules: A Summary of Major Provisions Embryo Transfer in the United States: 1987 Results
of the Final Rules Implementing the Clinical Labora- from the National IVF-ET Registry. Fertil Steril
tory Improvement Amendments of 1988. Northfield, 1989;51:13–20.
IL: College of American Pathologists, February 1992. Menezo Y, Nicollet B, Herbaut N, et al. Freezing cocul-
Clinical Laboratory Improvement Amendments of 1988; tured human blastocysts. Fertil Steril 1992;58:977–
Final Rule. Federal Register 1992;57:7002–7298. 980.
Coroleu B, Carreras O, Veiga A, et al. Embryo transfer Palermo G, Cohen J, Alikani M, et al. Intracytoplasmic
under ultrasound guidance improves pregnancy rates sperm injection: a novel treatment for all forms of male
after in-vitro fertilization. Hum Reprod 2000;15:616– factor infertility. Fertil Steril 1995;63:1231–1240.
620. Sallam H, Farrag A, Ezzeldin F, et al. Vigorous flushing
Edwards R, Brody S. Principles and Practice of Assisted of the cervical canal prior to embryo transfer—A
Reproduction. Philadelphia: Saunders, 1995. prospective randomized study [abstract no. P-345]. In:
Fluker M, Copeland J, Yuzpe A. An ounce of prevention: 2000 Annual Meeting Program Supplement of the 56th
outpatient management of the ovarian hyperstimula- Annual Meeting of the American Society for Repro-
tion syndrome. Fertil Steril 2000;73:821–824. ductive Medicine. San Diego, CA: American Society
Gardner D. Development of serum-free media for the cul- for Reproductive Medicine, 2000:S203.
ture and transfer of human blastocysts. Hum Reprod Surrey E, Schoolcraft W. Evaluating strategies for
1998;13:218–225. improving ovarian response of the poor responder
Gardner D, Schoolcraft W, Wagley L, et al. A prospec- undergoing assisted reproductive technologies. Fertil
tive randomized trial of blastocyst culture and trans- Steril 2000;73:667–676.
fer in in-vitro fertilization. Hum Reprod 1998;13: Veeck LZ (eds) Cryopreservation of embryos/eggs. In:
3434–3440. Adashi E, Rock J, Rosenwaks Z (eds) Reproductive
Glass K, Green C, Fluker M, et al. Multicenter random- Endocrinology, Surgery, and Technology, vol 2. Phil-
ized controlled trial of cervical irrigation at the time adelphia: Lippincott-Raven, 1996:2353–2365.
of embryo transfer [abstract no. O-085]. In: 2000 Wood E, Batzer F, Go K, et al. Ultrasound-guided soft
Annual Meeting Program Supplement of the 56th catheter embryo transfers will improve pregnancy rates
Annual Meeting of the American Society for Repro- in in-vitro fertilization. Hum Reprod 2000;15:107–112.
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 174

17
Unstimulated In Vitro Fertilization
and In Vitro Oocyte Maturation
Phillip E. Patton and Don P. Wolf

Unstimulated or natural cycle in vitro fertilization more, oocyte retrieval required operative laparos-
(IVF), and in vitro maturation (IVM-IVF) of imma- copy, often at inconvenient times during the night.
ture oocytes are two new and potentially important In the initial 79 cases of unstimulated IVF reported
adjuncts to conventional IVF involving ovarian in 1980, preovulatory oocytes were recovered in 45
stimulation. Both procedures offer significant ad- of 68 cycles. The probability of a live birth per pro-
vantages over conventional IVF, but because the cedure was only 0.029.
pregnancy rates with these procedures remain low The disappointing low fecundity rate with un-
few centers have introduced unstimulated IVF or stimulated IVF provoked a reexamination of pro-
IVM-IVF into routine clinical practice. The appli- tocols using ovarian stimulants. Initially, protocols
cation of the novel techniques and approaches using clomiphene citrate and ultimately protocols
involved in IVF without gonadotropins will likely employing menotropins exclusively or a combina-
have a major impact on practitioners of the assisted tion of menotropins and gonadotropin-releasing
reproductive technologies and on the laboratory hormone (GnRH) agonists largely replaced unstim-
during the next few years. The purpose of this ulated IVF when pregnancy rates were proved
review is to focus, for the practicing clinician, on superior. During the late 1980s practitioners of the
the fundamental principles of unstimulated IVF and assisted reproductive technologies observed the
IVM-IVF of oocytes. reemergence of unstimulated IVF. In part, this reju-
venation occurred secondary to two well recog-
nized technologic advances. The development of
Unstimulated In Vitro Fertilization transvaginal ultrasound-guided follicle aspiration
was a key component, as oocyte retrieval was taken
On July 25, 1978, a baby girl was born as a result out of the operating room and into the outpatient
of IVF performed during an unstimulated menstrual setting. Because the technique could be performed
cycle. Use of an unstimulated cycle was not based in an outpatient setting, a significant cost savings
on concerns of cost, the complexity of ovarian stim- was also realized. Transvaginal oocyte retrieval
ulation protocols, or problems in endometrial proved superior in women with well recognized
receptivity induced by gonadotropins; rather, it was risk factors for laparoscopic surgery. Moreover, the
used because protocols using exogenous gonado- fear of failed oocyte retrieval secondary to ovarian
tropins were largely disappointing, resulting in no scaring or premature ovulation was largely avoided
live births in the initial series of 77 women. with transvaginal techniques.
Steptoe and Edwards provided the first evidence Along with the advances in oocyte retrieval sys-
that unstimulated IVF was a legitimate, effective tems, the industry observed the advent of reliable,
option to protocols using ovarian stimulation. With sensitive kits to measure urinary luteinizing hor-
experience, the initial enthusiasm of unstimulated mone (LH) and less costly immunoassay methods
IVF was dampened for several reasons. Monitor- for measuring serum estradiol. As a result of these
ing follicular development was complex and labor- improvements, unstimulated IVF reemerged as
intensive. At the time, multiple blood and urine an attractive alternative to IVF with ovarian stim-
samples were required on a daily basis. Further- ulation.

174
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 175

17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation 175

Patient Selection culating LH. Monitoring serial blood and urine

samples for initiation of the LH surge was at times
Initially, unstimulated IVF was used in ovulatory cumbersome, costly, and unreliable. Because the
women of all ages and with disparate diagnoses. onset of the LH surge can occur at variable times
With experience, however, it became apparent that throughout the day, some oocyte retrievals were
women in specific diagnostic categories did poorly. scheduled during the night to avoid problems asso-
Examples include couples with male factor infer- ciated with monitoring the LH surge. Modern pro-
tility, in whom pregnancy rates are extremely low tocols for unstimulated IVF use injectable human
in the presence of oligozoospermia or astheno- chorionic gonadotropin (hCG) to mimic the effects
zoospermia. It is also likely that men with high of LH on follicle development. Administration of
titers of sperm antibodies do poorly and should con- hCG has several important advantages over a spon-
sider other reproductive options. A second group taneous LH surge. First, hCG can serve as a surro-
that has done poorly is women over age 40. In most gate to LH by allowing the ovarian oocyte to com-
reported series of unstimulated IVF, women over plete the first maturation division and become
40 years of age have been excluded from analysis. fertilizable. Second, night-time administration of
The true fecundity rate from a single IVF cycle for hCG allows predictable morning oocyte retrieval.
this subgroup is still ill-defined; Nevertheless, the Accurate timing of the hCG injection is a criti-
limited reported results in women over age 40 have cal component for unstimulated IVF. To best deter-
been discouraging. mine the timing of hCG, three important aspects of
Women who respond poorly to gonadotropins the menstrual cycle must be monitored.
may be candidates for unstimulated IVF. This
group can be identified by tests of ovarian reserve. 1. Follicular maturity using pelvic ultrasonogra-
Serum follicle-stimulating hormone (FSH) testing phy. During the unstimulated cycle, pelvic ultra-
performed on the third day of the menstrual cycle sonography can be used to track the develop-
is one such test of ovarian reserve (a decreased ment of the preovulatory follicle initiated at least
reserve in young women is associated with poor 3–4 days before the predicted LH surge. Follic-
egg quality and low pregnancy rates). Low serum ular growth rates average 2.0–2.5 mm per day,
FSH (10 IU/ml) correlate with successful IVF. A and mature oocytes may be obtained in follicles
cycle day 3 FSH value may in fact predict outcome as small as 15 mm (mean diameter). However,
better than age. Nevertheless, a single blood test follicle size must be correlated with serum
during a single menstrual cycle may miss detect- estradiol testing because of the significant inter-
ing women with diminished ovarian reserve. As a patient variability. Generally, two or three ultra-
result of this concern, the clomiphene citrate chal- sound scans are required to track the rate of
lenge test (CCCT) was developed, and has been growth of the preovulatory follicle adequately.
examined in a variety of infertility populations. 2. Serum estradiol. The mature preovulatory folli-
With the CCCT, baseline FSH (day 3) and stim- cle cannot be identified by ultrasonographic
ulated FSH (day 10) values are obtained following parameters alone. The second component in
administration of clomiphene citrate. FSH testing determining oocyte maturity involves serum
before and after clomiphene citrate may be a supe- estradiol testing with one of a variety of com-
rior screening tool when compared to baseline FSH mercially available immunoassay kits. Because
testing alone. Based on extensive but preliminary of between-kit variations in measured estradiol
studies, the CCCT appears to be predictive of out- levels, determination of a threshold value that
come in both the general infertility population and predicts follicular maturity is difficult. Programs
with assisted reproductive technologies. Women that are contemplating unstimulated IVF should
with elevated day 3 FSH levels or stimulated (day establish their own correlations between estra-
10) FSH levels may be poor candidates for unstim- diol levels and follicular dimensions by moni-
ulated IVF. toring a control group of fertile women with
serial ultrasound scans and estradiol levels.
Paulson and coauthors have established approx-
Cycle Monitoring imate guidelines for defining follicular maturity
on the basis of both follicle size and serum estra-
In the initial unstimulated IVF series, Steptoe and diol (Table 17–1). It should be noted that these
Edwards carefully monitored the LH surge because guidelines represent maximal diameters as mea-
fertilization rates were known to be dependent on sured with a General Electric 5 MHz vaginal
a critical length of exposure of the follicle to cir- transducer and not mean measurements of fol-
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 176

176 P.E. Patton and D.P. Wolf

TABLE 17–1. Follicle Maturity Criteria as Indication for Follicle Aspiration

hCG Administration During Unstimulated IVF Cycles
The techniques of follicle aspiration for unstimu-
Follicle size (mm) Serum estradiol (pg/ml)a
lated IVF are similar to those used for conventional
 20  200 IVF. Prior to oocyte retrieval, prophylactic antibi-
 18  250
 15  300
otics (doxycycline 100 mg twice daily and contin-
ued for 2–5 days) are frequently recommended.
Source: Adapted from Paulson et al., 1990, with permission. Approximately 34–36 hours after hCG injection,
hCG, human chorionic gonadotropin; IVF, in vitro fertiliza- transvaginal sonography is performed to identify
tion. the preovulatory follicle and to confirm that pre-
aPantex extraction kit.
mature rupture has not occurred. After the follicle
is identified, the patient can be given analgesics,
but we have found that most patients require only
licle size. When serum estradiol levels measured minimal sedation and analgesia. Special care must
in a morning blood sample meet criteria that cor- be exercised when directing the aspiration needle
respond to follicle dimensions, hCG (10,000 IU) toward the single preovulatory follicle. It is proba-
is administered during the evening of that day. bly best to first puncture the peritoneum before
Routinely, oocyte aspiration is performed ap- puncturing the follicle in a two-step process be-
proximately 34–36 hours following the hCG cause any unanticipated motion from the patient
injection. could compromise successful aspiration. Following
3. Luteinizing hormone testing. The onset of the peritoneal puncture, the needle is directed slowly
LH surge is abrupt and occurs usually within the toward the single preovulatory follicle, usually
same 24 hour interval as the peak preovulatory toward the largest dimensions of the follicle. When
estrogen level. In most cases the LH surge can the follicle is entered from an acute angle or from
be detected in serial urine specimens collected the side, the chances of a successful aspiration are
during the periovulatory period. It is advisable reduced. Both single-lumen and double-lumen
to collect a minimum of three urine samples aspiration needles can be used for unstimulated
daily, assaying for LH using commercially avail- IVF. Secondary follicles can also be aspirated and
able immunoassays (e.g., OvuQUICK; Mono- may improve the outcome, if additional oocytes are
clonal Antibodies, Sunnyvale, CA). The last recovered, because of the ability to transfer multi-
specimen should be collected immediately ple embryos.
before hCG injection.
The LH surge most commonly occurs during the
early morning (3–7 a.m.); urine samples test posi- Culture and Embryo Transfer
tive several hours later as determined by semi- The culture conditions for unstimulated IVF are
quantitative assay. When both mid-day and evening similar to those for conventional IVF. Cleaving
urine samples are tested, the LH surge is detected embryos (day 2 or 3) can be transferred to the uter-
95% of the time. The occurrence of a surge before ine fundus using techniques identical to those
hCG administration is not uncommon even when described for conventional IVF.
relatively conservative criteria for follicular matu-
rity are met. In our series, LH surges were detected
during 25% of the cycles prior to hCG injection. Pros and Cons of Unstimulated IVF
Previous studies have shown that the best results
occur during surge cycles when oocytes are col- Unstimulated IVF offers several advantages over
lected at a time near spontaneous ovulation IVF with ovarian stimulation (Table 17–2). Ethical,
(roughly 36 hours from the serum LH surge onset moral, and legal difficulties associated with embryo
or 28 hours after urinary detection). Reasonably cryopreservation are largely avoided; and because
good outcomes can be achieved during retrieval ovarian stimulants are not required, the cost of
cycles in which a premature LH surge has occurred. unstimulated IVF is significantly less. Furthermore,
Nevertheless, the results are unpredictable, and the the morbidity secondary to ovarian stimulation or
work is labor-intensive because of the possible need multiple pregnancy is essentially nonexistent. De-
for evening retrievals. Therefore cycle cancellation spite the absence of conclusive data, women are
is often recommended when an LH surge is de- worried about the potential link between repeated
tected by standard urinary assays. exposure to ovarian stimulation and ovarian cancer.
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 177

17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation 177

TABLE 17–2. Advantages and Disadvantages of GnRH analogues are used. The cost of a passed
Unstimulated IVF and IVF with Ovarian Stimulation cycle ($500–$600) for single-egg IVF is not in-
Stimulated IVF significant, particularly when cycles are canceled
Advantages because of an LH surge. Failed oocyte retrieval or
Embryos for cryopreservation failed fertilization probably occurs more frequently
Infrequent failed oocyte retrieval with unstimulated IVF. Finally, the laboratory costs
Low cycle cancellation rate
Multiple embryo transfer with unstimulated IVF are similar to those with
Disadvantages conventional IVF. Although only a single oocyte is
Altered endometrial receptivity manipulated by laboratory personnel, the time re-
Frequent monitoring quired for preparation, processing the oocyte at the
High cost
Labor intensive
time of retrieval, and culture and transfer is only
Multiple pregnancy slightly less than for conventional IVF.
Ovarian hyperstimulation
? Ovarian cancer
Unstimulated IVF Success Rates with Unstimulated IVF
Advantages
Easy monitoring The reported success rates with unstimulated IVF
Low cost are highly variable. Some of the major reported
No multiple pregnancy series are summarized in Table 17–3. As with many
No ovarian hyperstimulation innovative technologies, early success was met with
No ovarian stimulants required
Disadvantages enthusiasm. However, in the past two reported
Monovular cycles series from the In Vitro Fertilization Registry the
Possible LH surge cycles success rates with unstimulated IVF have been dis-
High cancellation rate appointing. In 1993 an overall clinical pregnancy
Rigid patient selection criteria
rate of 4.9% per retrieval was reported for 481
cycles. Nearly one-third of the cycles were can-
celed, and only one pregnancy during 122 initiated
cycles was reported in women over age 40. As a
Unstimulated IVF represents a legitimate option to group women under age 40 did the best, with a 7%
women with a strong family history of ovarian can- clinical pregnancy rate per retrieval (6.3% deliver-
cer or women who are fearful of the risks of exoge- ies/retrieval). The 1994 data were similar, with an
nous gonadotropin exposure. In many cases, overall clinical pregnancy rate per retrieval of 10%,
unstimulated IVF is less labor-intensive. The time but no women over age 40 delivered a viable preg-
used by office personnel for teaching sessions and nancy. Women under 40 years of age had a 15.0%
office procedures is reduced compared to conven- clinical pregnancy rate per retrieval and a 10.2%
tional IVF. live birth rate per retrieval. A staggering 50% of
There are several well recognized limitations cycles were canceled.
with unstimulated IVF. Because GnRH analogues The discrepancies in reported pregnancy rates
are not used, the timing of oocyte retrieval is unpre- between the early series and those that are more
dictable. The vagaries of the menstrual cycle make recent are perplexing. In part, some of the differ-
it difficult to predict the timing of office procedures ences could be due to the careful selection and
and laboratory use. Detection of an LH surge dur- screening of patients and the intense monitoring
ing a monitored cycle is common and generally that is inevitably associated with new clinical pro-
leads to cycle cancellation. In contrast, LH surge tocols. Nevertheless, the results of more recent data
activity is rarely seen with stimulated IVF when suggest that the widespread application of unstim-

TABLE 17–3. Success Rates with Unstimulated IVF

Cycles Clinical pregnancy rate
Study initiated Cancellation rate per embryo transfer
Foulot et al., 1989 71 3/71 (4%) 17/53 (32%)
Paulson et al., 1989 36 11/36 (30%) 5/25 (20%)
Patton et al., 1989 27 15/27 (55%) 2/8 (25%)
IVF Registry, 1993 481 155/481 (32%) 16/203 (8%)
IVF Registry, 1994 460 206/410 (50%) 22/157 (14%)
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 178

178 P.E. Patton and D.P. Wolf

ulated IVF is ill-advised, and clinicians should potential candidates from the pool of couples con-
carefully select candidates for this procedure in an sidering assisted reproductive technology.
effort to maximize pregnancy rates.

Maximizing Pregnancy Rates In Vitro Maturation

with Unstimulated IVF In contrast to unstimulated IVF, which may be
Unfortunately, there are no scientifically tested cri- appropriate for only a small percentage of infertil-
teria developed for selecting candidates for unstim- ity couples, in vitro maturation (IVM), or the pro-
ulated IVF. Based on the collected published data, cess of maturing oocytes harvested from an unstim-
we recommend the following guidelines for patient ulated ovary, has the potential to serve a large
selection. Unstimulated IVF would best serve population of patients. Advantages include elimi-
women under age 40 with regular, predictable men- nation of gonadotropin use for ovarian stimulation
strual cycles and without any evidence of a male and the small but theoretic risk of ovarian cancer
factor. Women who are poor responders to con- or ovarian hyperstimulation syndrome. There is
ventional ovarian hyperstimulation protocols but also significant cost reduction when compared to
who have normal tests of ovarian reserve are also conventional IVF. With IVM, overall costs may be
potential candidates. Prior to any procedure, we decreased by at least 50% by eliminating exposure
recommend ultrasonography and endocrine testing to gonadotropins, reducing monitoring costs, and
during the menstrual cycle to exclude the possibil- decreasing costs of IVF personnel.
ity of aberrant folliculogenesis or luteal dysfunc- In vitro maturation of mammalian oocytes is
tion. A mock cycle that indirectly assesses follicu- based on the recognition that oocytes released from
lar dynamics and luteal function in women antral follicles resume meiosis spontaneously under
contemplating unstimulated IVF may be helpful. appropriate culture conditions in vitro. In most
Women with menstrual cycles exhibiting low serum mammals, meiosis is initiated during fetal devel-
estradiol levels at the time of follicular maturity opment but is arrested at prophase of the first mei-
(Table 17–1) are not ideal candidates. Luteal prob- otic division by the time of birth [termed the ger-
lems identified by serial luteal phase progesterone minal vesicle (GV) stage] (Fig. 17–1). Meiotic
values or endometrial biopsies can also be used as arrest, in nearly all of the several million oocytes
exclusion criteria. present in the infant human ovary, is maintained
Women with recurrent pregnancy loss or endo- in the primordial or preantral follicle throughout
crinopathies are not good candidates for unstimu- reproductive life. Thus only a few oocytes escape
lated IVF. Previous laboratory testing that provided arrest and are destined for release at ovulation each
evidence of endocrine dysfunction during the men- month during the menstrual cycle, with the remain-
strual cycle must be carefully reviewed. If con- der perhaps never completing meiosis but, rather,
vincing, an alternate option for fertility is recom- undergoing degeneration secondary to follicular
mended. In all, this leaves a small subset of atresia. Completion of the first meiotic division

FIGURE 17–1. Immature, germinal vesicle (GV)-intact, rhesus monkey oocyte (left) and mature, metaphase II oocyte
(right).
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 179

17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation 179

occurs only after the oocyte and the ovarian folli- GV-intact oocytes mature to MII. As long ago as
cle that encompasses it have undergone extensive 1935, in classic experiments conducted by Pincus
growth and exposure to LH. During a normal men- and Enzmann, it was recognized that oocytes iso-
strual or stimulated cycle, the resumption of meio- lated from graafian follicles and placed in culture
sis is triggered in oocytes contained in mature, would resume meiosis spontaneously. In 1984
antral follicles by the preovulatory surge of LH or Schroeder and Eppig demonstrated that the devel-
hCG injection, respectively. GV breakdown and opmental capacity of in vitro matured mouse
chromatin condensation occurs with completion of oocytes was normal. Systems are now established
the first meiotic division followed in several hours for the recovery of oocytes from preantral follicles
by a second meiotic arrest (MII, Fig. 17–1), this that are capable of completing growth and matura-
time at metaphase of the second meiotic division. tion in vitro and subsequently undergoing fertil-
Meiosis is completed only after sperm penetration ization and development to term following transfer
triggers oocyte activation. to a surrogate. Remarkably, this capability has also
Control of meiosis during the oocyte’s tenure in been demonstrated for oocytes isolated from pri-
the ovary is complex, involving communication mordial follicles.
between the oocyte and the surrounding cumu- A major effort has also focused on IVM in
lus/granulosa cell mass. Cell processes from sup- domesticated species such as the bovine species,
porting cells extend through the zona pellucida and where a trip to the local abattoir can provide hun-
establish intimate contacts in the form of gap junc- dreds of ovaries with the potential to conduct exper-
tions with oocyte surface microvilli. Cycle 3,5- iments involving thousands of oocytes. Although
adenosine monophosphate has been implicated in the overall efficiency of producing calves follow-
the maintenance of meiotic arrest as oocytes re- ing IVM-IVF is low, improvements in individual
leased from the follicular environment can be held components or steps in IVM protocols will un-
in the GV-intact state by agents that promote high doubtedly be forthcoming.
intracellular levels of this second messenger. The
effect of the gonadotropin surge on meiosis may be
exerted through disruption of the cumulus–oocyte
Nonhuman Primate Studies
communication system. Nonhuman primate studies of IVM are of theoretic
The aspect of oocyte maturation just discussed interest to the clinical arena because of similarities
focuses on nuclear progression. Another compo- to human reproductive processes. Follicular devel-
nent of oocyte maturation concerns cytoplasmic opment, hormone secretion, and luteal function are
events. Indeed, cytoplasmic changes may well con- similar to those in humans, supporting the nonhu-
trol nuclear events. Changes in cytoplasmic levels man primate as a model for investigating regula-
of metaphase-promoting factor (MPF) are thought tion of the menstrual cycle. An advantage of the
to control meiosis. MPF is a complex between model is the ability to conduct invasive experi-
cyclin B and a 34 kDa protein, homologous to the mentation without the ethical limitations attendant
product of the cdc2 gene in fission yeast and there- to clinical research. Although the model is not
fore referred to as p34cdc2. This protein is a ser- robust enough to support systematic or extensive
ine/threonine kinase whose state of phosphoryla- molecular level approaches, conditions for the har-
tion and association with cyclin B determines MPF vest of ovarian oocytes and their subsequent mat-
activity. High levels of MPF are associated with uration in culture have been defined in the rhesus
maturation arrest, whereas low or decreasing lev- monkey.
els are correlated with release of the meiotic block. In studies from Alak and Wolf, IVM was con-
Once MPF levels fall, phosphorylation–dephos- ducted in TALP, a simple medium composed of bal-
phorylation cascades are activated that culminate in anced salts, lactate, and pyruvate, supplemented in
additional cytoplasmic events prerequisite to fertil- this case with 20% fetal calf serum and human
ization and the activation of development, such as gonadotropins. The highest yield and quality of
chromosome condensation and nuclear laminin oocytes was associated with ovaries excised during
breakdown. the early follicular phase from unstimulated ani-
mals. Most (55%) of the oocytes surrounded by two
Animal Studies or more layers of cumulus and at least 100 m in
diameter underwent germinal vesicle breakdown
The mouse has served as a convenient and useful (GVBD) with 40% maturing to MII. The presence
model for IVM based on access to large numbers of exogenous human FSH and LH improved GVBD
of oocytes and the efficiency and speed in which and MII levels in a way that was dependent on the
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 180

180 P.E. Patton and D.P. Wolf

stage of the menstrual cycle. The fertilization rate context of an oocyte donation program, ovarian tis-
for in vitro matured oocytes was 32% (16/50). The sue was obtained from biopsied or whole excised
authors concluded that IVM in the rhesus monkey ovaries, and oocytes were aspirated with a 21-gauge
can be enhanced by more rigorous selection of mei- needle from 2- to 5-mm follicles. IVM was con-
otically competent oocytes isolated from ovarian ducted in modified Hams’ F10 medium with 20%
oocyte pools using follicular size, oocyte size, and fetal calf serum (FCS) or 50% follicular fluid (FF)
the appearance of the OCC as selection criteria. In for up to 48 hours of culture. Of the 270 oocytes
a follow-up study, Alak and coworkers demon- recovered (11.7 per ovary), 76.7% appeared
strated that the regulatory peptides inhibin and healthy, 56% matured to MII in the presence of fol-
activin or their combination could significantly licular fluid, and 36% did so in medium supple-
improve the success rate of IVM in the rhesus mon- mented with FCS. The authors examined the results
key. Such findings may ultimately play a major role as a function of stage of the menstrual cycle and
in directing the development of clinical protocols. concluded that the percentage of healthy oocytes
was unrelated to cycle phase. The number of col-
lected oocytes did, however, decline significantly
Evolution of Clinical IVM Technology with increasing age of the donor. The only recipi-
Studies on the maturation of human ovarian oocytes ent in whom embryos were transferred, conceived,
(Table 17–4) date back to the 1960s with the pio- and delivered. The oocytes were recovered from a
neering work of Edwards and coworkers in Cam- 28-year-old patient 13 days from her last menstrual
bridge. Edwards noted that maturation can occur period from a single ovary yielding 11 healthy
upon follicular release in several animal species and oocytes. Among the seven resulting embryos, five
humans. The application of this knowledge within were transferred on day 18 of steroid replacement
the context of ongoing conventional IVF and the to a 33-year-old woman with premature ovarian
production of viable pregnancies, however, did not failure. A triplet pregnancy ensued.
occur for decades, with a report from the Jones The first robust experience showing promise of
Clinic in Norfolk. In this case, oocytes were recov- widespread clinical utility was reported in 1994.
ered and matured from patients undergoing ovar- Although only one pregnancy was reported follow-
ian stimulation, presumably from the inadvertent ing IVM-IVF, an efficient recovery method was de-
aspiration of small antral follicles, a relatively in- scribed whereby erythrocytes were first removed
frequent and unpredictable event. It probably occurs from aspirates by ultrafiltration facilitating oocyte
more commonly than at first appreciated because identification and recovery. Oocyte maturation, fer-
GV-intact oocytes may not be surrounded by a large tilization, and development rates for patients with
cumulus mass and hence are difficult to find. More- and without polycystic ovarian syndrome (PCOS)
over, those that are recovered in cumulus may not were compared. A larger number of oocytes were
be examined closely until long after collection, such obtained from PCOS patients. Two culture methods
that their status at pickup would be unknown. A sec- and maturation time intervals were also examined.
ond, more recent report confirmed the clinical use- A more aggressive approach to handling IVM
fulness of immature oocytes collected from patients oocytes was introduced in a follow-up report by this
during ovarian stimulation and matured over a time group. Intracytoplasmic sperm injection (ICSI) was
course of 30 hours. employed rather than conventional insemination,
The first pregnancy success following IVM of and the resultant embryos were cultured to blasto-
oocytes collected from a nonstimulated patient was cyst stage and hatched before transfer. This approach
reported by Cha and coworkers in 1991. In the produced one pregnancy, with the birth of a girl.

TABLE 17–4. Development of Clinical IVM-IVF

Study Development
Edwards, 1965 Human oocytes mature spontaneously in vitro
Veeck et al., 1983 IVM in stimulated cycle results in pregnancy
Cha et al., 1991 IVM-IVF in unstimulated cycle results in pregnancy
Trounson et al., 1994 Improved collection techniques for IVM
Barnes et al., 1995 ICSI and assisted hatching with IVM-IVF

IVM-IVF, in vitro oocyte maturation–in vitro fertilization; ICSI, intracytoplasmic

sperm injection.
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 181

17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation 181

The relatively poor pregnancy success rate for quality oocyte is fully grown (100 m), enclosed
IVM-IVF led Barnes and coworkers to evaluate the by more than two layers of cumulus cells, and has
influence of ovulatory function (regular, anovula- a homogeneous, evenly colored ooplasm. Atretic
tory, or irregular PCOS patients) on IVM outcome oocytes are dark or discolored and may contain vac-
and embryo quality. Oocytes from regularly cycling uoles. Successful maturation is usually measured
patients gave optimum results: 82% maturation rate by cumulus expansion, GVBD or disappearance of
in 48 hours in TCM199 medium supplemented with the germinal vesicle, and the appearance of a first
10% FCS, recombinant hFSH, hCG, pyruvate, peni- polar body. Maturation to PB1 should occur within
cillin, and streptomycin. When compared to in vivo 48 hours of recovery for oocytes obtained from
matured oocytes, IVM-IVF-produced embryos nonstimulated patients and within 30 hours for pa-
showed a higher arrest rate during cleavage and a tients subjected to ovarian stimulation with gonado-
slower cleavage rate. IVM-IVF embryos from reg- tropins. The medium employed for IVM varies
ularly cycling patients also performed better than from simple TCM199 or HTF to the relatively com-
did those from anovulatory or irregular PCOS plex solutions such as Ham’s F10 or Menezo’s B2.
patients. These findings suggest that clinical out- Typically these media are supplemented with a pro-
come may well depend on patient selection, which tein source, such as serum, follicular fluid or a com-
reflects the quality of the primary oocyte recovered mercially available serum derivative (SSS or Plas-
and placed in culture for IVM. manate), hormones or growth factors (FSH, hMG,
hCG, -estradiol, activin), pyruvate, antibiotics,
Steps in IVM-IVF and bicarbonate to provide buffering in 5% CO2 in
air. Experience to date indicates that most (approx-
Follicular Monitoring imately 55%) primary oocytes mature to MII within
Pelvic ultrasonography is initiated within the first 48 hours.
2–3 days of the unstimulated cycle to assess the
number of oocytes available for harvest. Many pro- IVM-IVF
tocols use the information from a second ultrasound In vitro fertilization following maturation initially
scan (cycle days 5–7) to schedule oocyte retrieval involved conventional insemination, with highly
(cycle days 7–14). Determination of peripheral ste- variable fertilization levels (around 30–40%).
roid concentration is not required. Exogenous oral More recent reports have incorporated intracyto-
or intramuscular estrogen has been used to promote plasmic sperm injection (ICSI) into the protocol
endometrial development in IVM protocols. Theo- with fertilization levels in the 60–70% range. This
retically, supplemental estrogen may be necessary difference, if significant, may result because
to stimulate endometrial growth suitable for im- adverse alterations in the zona pellucida can occur
plantation. Preliminary results using estrogen hold during prolonged culture, which in turn may
promise; but the optimal dose, timing, and method reflect precocious release of the oocyte’s cortical
of administration require further testing. granules.
Oocyte Collection Embryo Culture
Collection occurs during the mid- to late-follicular
phase by transvaginal ultrasound-guided aspiration For the culture of embryos produced by conven-
of 0.4- to 2.0-cm (diameter) follicles using a 30 cm tional IVF and presumably those from IVM-IVF, a
needle (17 gauge with a short bevel). Removal of number of media and culture durations have been
erythrocytes and follicular cells from the aspirates employed successfully. Usually for short-term cul-
can be accomplished by ultrafiltration. The flush ture (up to 3 days) a simple medium supplemented
medium employed is probably not critical to suc- with a serum product is adequate (e.g., HTF with
cess and may involve heparinized human tubal fluid 10% serum or serum substitute). For longer culture
(HTF) or phosphate-buffered saline (PBS). The (4 days or more) a complex medium such as Gard-
number of oocytes collected from PCOS patients ners G1 or G2 with a serum product would be
averaged approximately 15 and from non-PCOS favored or perhaps co-culture on Vero cells.
patients 3.
Embryo Transfer
Oocyte Maturation Embryo transfer mimics conventional IVF. Assisted
Maturation is undoubtedly related to oocyte qual- hatching may be appropriate depending on the ex-
ity, which should be assessed at recovery. A high perience of the ART program providing the service.
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 182

182 P.E. Patton and D.P. Wolf

Conclusions Eppig JJ, O’Brien MJ. Development in vitro of mouse

oocytes from primordial follicles. Biol Reprod 1996;
54:197.
The development of IVM-IVF technology, which
Foulot H, Ranoux C, Dubuisson J-B, et al. In vitro fer-
at first glance may seem slow, is gaining momen- tilization without ovarian stimulation: a simplified pro-
tum and in our opinion will soon be an integral part tocol applied in 80 cycles. Fertil Steril 1989;52:617.
of every ART program. Concomitant with the appli- Kasper KC, Rodrick-Highberg G, Lankford JC. Ovu-
cation of this technology will be increased reliance STICK Kit for Semiquantitative Analysis of Human
on a quality laboratory. Prolonged culture times, Luteinizing Hormone in Urine. Technical Report No.
increased reliance on ICSI, and assisted hatching 6. Sunnyvale, CA: Monoclonal Antibodies, 1986.
require an added time commitment from laboratory Loumaye E, Billion JM, Mine JM, et al. Prediction of
personnel. On a research and development level, it individual response to controlled ovarian hyperstimu-
is possible that the technology could benefit from lation by means of a clomiphene citrate challenge test.
Fertil Steril 1990;53:295.
improvements in the initial selection of oocytes and Patton PE, Burry KA, Wolf DP et al. The use of oral con-
their quality evaluation, with attention focused on traceptives to regulate oocyte retrieval. Fertil Steril
cytoplasmic and nuclear maturation. These are 1988;49:716.
areas where model animal studies may ultimately Paulson RI, Sauer MV, Francis MM, et al. In vitro fer-
provide useful guidance. When IVM-IVF does tilization in unstimulated cycles: a clinical trial using
become a part of our armamentarium of technolo- hCG for timing of follicle aspiration. Obstet Gynecol
gies, the storage of follicular oocytes at low tem- 1990;76:788.
peratures may represent an alternative to frozen Scott RT, Leonardi MR, Hofmann GE, et al. A prospec-
embryo storage, as it avoids the ethical objections tive evaluation of clomiphene citrate challenge test
of the latter. screening in the general fertility population. Obstet
Gynecol 1993;82:539.
Scott RT, Toner JF, Muasher SJ, et al. Follicle stimulat-
Suggested Reading ing hormone levels on cycle day 3 are predictive of in
Alak BM, Coskun S, Friedman CI, et al. Activin A stim- vitro fertilization outcome. Fertil Steril 1989;51:651.
ulates meiotic maturation of human oocytes and mod- Smitz J, Cortvrindt R. Oocyte in-vitro maturation and fol-
ulates granulosa cell steroidogenesis in vitro. Fertil licle culture: current clinical achievements and future
Steril 1998;70:1126–1130. directions. Hum Reprod 1999;14(suppl 2):145–161.
Alak BM, Smith GD, Woodruff TK, et al. Enhancement Tanbo T, Dale PO, Lunde O, et al. Prediction of response
of primate oocyte maturation and fertilization in vitro to controlled ovarian hyperstimulation: a comparison
by inhibin A and activin A. Fertil Steril 1996;66:646. of basal and clomiphene citrate-stimulated follicle-
Alak BM, Wolf DP. Rhesus monkey oocyte maturation stimulating hormone levels. Fertil Steril 1992;57:819.
and fertilization in vitro: roles of the menstrual cycle Thornton MH, Francis MM, Paulson RJ. Immature oocyte
and of exogenous gonadotropins. Biol Reprod 1994; retrieval: lessons from unstimulated IVF cycles. Fertil
51:879. Steril 1998;70:647–650.
Barnes FL, Crombie A, Gardner DK, et al. Blastocyst Toner JP, Philput CB, Jones GS, et al. Basal follicle stim-
development and birth after in vitro maturation of ulating hormone level is a better predictor of in vitro
human primary oocytes, intracytoplasmic sperm injec- fertilization performance than age. Fertil Steril 1991;
tion and assisted hatching [case report]. Hum Reprod 55:784.
1995;10:3243. Trounson A, Wood C, Hausche A. In vitro maturation
Barnes FL, Kausche A, Tiglias J, et al. Production of and the fertilization and developmental competence of
embryos from in vitro matured primary human oocytes recovered from untreated polycystic ovarian
oocytes. Fertil Steril 1996;65:1151. patients. Fertil Steril 1994;62:353.
Burry KA, Hickok LR, Patton PE, et al. Preliminary expe- Veeck LL, Wortham JW Jr, Witmyer J, et al.: Maturation
rience with natural cycle in vitro fertilization [abstract and fertilization of morphologically immature human
0-001]. In 39th Annual Meeting of the Pacific Coast oocytes in a program of in vitro fertilization. Fertil
Fertility Society, April 10–14, 1991, Indian Wells, CA. Steril 1983;39:594–602.
Cha KY, Koo JJ, Ko JJ, et al. Pregnancy after in vitro Whitacre KS, Seifer DB, Friedman CI, et al. Effects of
fertilization of human follicular oocytes collected from ovarian source, patient age, and menstrual cycle phase
nonstimulated cycles, their culture in vitro and their on in vitro maturation of immature human oocytes.
transfer in a donor oocyte program. Fertil Steril 1991; Fertil Steril 1998;70:1015–1021.
55:109.
Edwards RG. Maturation in vitro of mouse, sheep, cow, Additional Reading
pig, rhesus monkey and human ovarian oocytes.
Nature 1965;208:349. Beckers NG, Pieters MH, Ramos L, et al. Retrieval, mat-
Edwards RG, Steptoe PC, Purdy JM. Establishing full- uration, and fertilization of immature oocytes obtained
term human pregnancies using cleaving embryos from unstimulated patients with polycystic ovary syn-
grown in vitro. Br J Obstet Gynaecol 1980;87:737. drome. J Assist Reprod Genet 1999;16:81–6.
3051_Seifer_17_p174-183 11/5/01 9:57 AM Page 183

17. Unstimulated In Vitro Fertilization and In Vitro Oocyte Maturation 183

Cahill DJ, Wardle PG, Harlow CR, et al. Expected con- Chung HM, Hong SW, Lim JM, et al. In vitro blastocyst
tribution to serum oestradiol from individual ovarian formation of human oocytes obtained from unstimu-
follicles in unstimulated cycles. Hum Reprod 2000; lated and stimulated cycles after vitrification at vari-
15:1909–12. ous maturational stages. Fertil Steril 2000;73:545–
Cha KY, Han SY, Chung HM, et al. Pregnancies and 51.
deliveries after in vitro maturation culture followed by Cobo AC, Requena A, Neuspiller F, et al. Maturation in
in vitro fertilization and embryo transfer without stim- vitro of human oocytes from unstimulated cycles:
ulation in women with polycystic ovary syndrome. selection of the optimal day for ovum retrieval based
Fertil Steril 2000;73:978–83. on follicle size. Hum Reprod 1999;14:1864–8.
Chian RC, Buckett WM, Too LL, et al. Pregnancies Mikkelsen AL, Smith S, Lindenberg S. Impact of oestra-
resulting from in vitro matured oocytes retrieved from diol and inhibin A concentrations on pregnancy rate in
patients with polycystic ovary syndrome after priming in vitro oocyte maturation. Hum Reprod 2000;15:
with human chorionic gonadotropin. Fertil Steril 1999; 1685–90.
72:639–42. Nogueira D, Staessen C, Van de Velde H, et al. Nuclear
Chian RC, Buckett WM, Tulandi T, et al. Prospective ran- status and cytogenetics of embryos derived from in
domized study of human chorionic gonadotrophin vitro-matured oocytes. Fertil Steril 2000;74:295–8.
priming before immature oocyte retrieval from un- Thornton MH, Francis MM, Paulson RJ. Immature oocyte
stimulated women with polycystic ovarian syndrome. retrieval: lessons from unstimulated IVF cycles. Fertil
Hum Reprod 2000;15:165–70. Steril 1998;70:647–50.
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 184

18
Intratubal Gamete Transfer
Kristin Sinnock Friel and Alan S. Penzias

In 1978 the birth of the first human conceived in steady since 1991, with a reported rate of 28.4% in
vitro and delivered to her mother’s uterus through 1994. Rather, it seems that the rising success of IVF
the cervix astounded the world and electrified fer- (Fig. 18–3), coupled with its less invasive approach,
tility specialists. Old assumptions, paradigms, and has increased the frequency with which IVF is cho-
treatment algorithms were shaken; and a new era sen over GIFT. In 1987 approximately 80% of all
in the management of infertility emerged. In vitro ART procedures were IVF with 20% GIFT. In 1994
fertilization (IVF), the first of the assisted repro- the proportion was nearly 90% IVF with 10%
ductive technologies (ART), burst onto the world GIFT. Despite the decline, GIFT remains a viable,
stage and the race was on to match the feat. With important therapeutic option for select couples with
progress there is doubt; nonetheless, IVF centers primary or secondary infertility.
proliferated, each attempting to duplicate and im-
prove on the technique. Just 2 years later, gamete
intrafallopian transfer (GIFT) was introduced when Purpose of GIFT
the technique was successfully carried out in pri-
mates. Since the late 1980s the technical steps used in the
The first human GIFT procedures were per- GIFT procedure have evolved, but the theory
formed by Asch et al. in 1984, and the study was behind its application has not changed. The pur-
reported in 1986. In their cohort of 10 couples, four pose of GIFT is to transfer mature, preovulatory
patients achieved a clinical pregnancy and two of oocytes and concentrated, motile, washed sperm
those took home viable infants. The American Fer- into one or both fallopian tubes to place gametes
tility Society formed the Society for Assisted at their “natural site of fertilization.” The mecha-
Reproductive Technology (SART), which in turn nism of the enhanced pregnancy rate per treatment
developed a national ART registry. The first reg- cycle in women with normal pelvic anatomy is the
istry report summarized the data for 1987. That year increase in the number of sperm and oocytes that
the number of ART procedures performed in the have the opportunity to interact in the ampulla of
United States topped 10,000 (Fig. 18–1). The sum- the fallopian tube.
mary success rate for IVF was 16% per initiated It is generally believed that couples in the gen-
cycle in contrast to a 25% rate for GIFT. The appar- eral population conceive at a rate of 20–25% per
ent discrepancy in the success rates spurred further month. If a couple has not succeeded in achieving
interest in the GIFT procedure; and like IVF, GIFT pregnancy after 1 year despite adequate frequency
grew in popularity. In 1987 a total of 1968 GIFT of unprotected intercourse, it is presumed that their
procedures were performed. This number nearly cycle fecundity is lower than that of the general
tripled in just 5 years when in 1992 there were 5767 population. There is some debate as to the actual
GIFT cases. It is worthy to note that 1992 was the fecundability of these couples but it is clearly less
year in which GIFT peaked in popularity (Fig. than that of the fertile population. After a compre-
18–2). The reasons for the decline in the popular- hensive evaluation, some couples are found to have
ity of GIFT have little to do with its rate of suc- a discernible, treatable cause of their infertility.
cess. The pregnancy rates have held relatively These couples are directed to specific therapies

184
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 185

18. Intratubal Gamete Transfer 185

FIGURE 18–3. Total number of IVF procedures reported

to the SART registry along with the crude delivery rate
by year.
FIGURE 18–1. Total number of ART procedures reported
to the Society of Assisted Reproductive Technologies
(SART) registry, by year.
or for the early development of an embryo that
leads to pregnancy, each factor secreted by the fal-
meant to address their particular problem. However, lopian tube may have intrinsic properties important
experience has demonstrated that relative to their to the ultimate success of fertilization. Presumably,
native chances for conception without treatment the the ampulla of the fallopian tube is an ideal envi-
GIFT procedure does increase the cycle fecundity ronment for human conception, and to this end
among couples who have been completely evalu- many of the culture media used in the assisted
ated for primary or secondary infertility. reproductive technologies have attempted to reca-
pitulate the tubal environment by mimicking the
concentrations of certain elements and substances
Why Is GIFT Better? in the tube.
In addition, some evidence suggests that the
It is known that fallopian tubes actively secrete a proximity of the tube and ovary may allow intravas-
host of substances, including growth factors, pros- cular or intercellular communication between these
taglandins, and glycoproteins, which serve a vari- two organs. Such substances, though yet to be
ety of tubal functions. Although IVF has shown us specifically defined, may also contribute to the suc-
that the fallopian tube itself is not absolutely nec- cess of fertilization. Anecdotally, placement of the
essary for successful fertilization of a human oocyte gametes in the tube proximal to the ovary with the
greatest number of corpora lutea improves the
chances for success. This as yet unsubstantiated
impression suggests that local exchange of sub-
stances in the vascular arcade between the ovary
and fallopian tube somehow exerts a positive influ-
ence over the events leading to fertilization and,
ultimately, tubal transport of early embryos into the
uterus. Therefore by placing gametes directly into
the fallopian tube the ovarian-tubal communication
may be preserved.

Indications for GIFT

FIGURE 18–2. Total number of GIFT (Gamete Intrafal- One infertility problem that GIFT corrects is a
lopian Transfer) procedures reported to the SART (Soci- mechanical defect in ovum pickup. In highly fer-
ety of Assisted Reproductive Technology) registry along with tile women each tube has only about a 63% effi-
the crude delivery rate by year. ciency rate at picking up an ovum released by a
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 186

186 K. Sinnock Friel and A.S. Penzias

TABLE 18–1. Indications for GIFT caused by infectious processes stand a greater risk
Pelvic adhesions unrelated to pelvic inflammatory disease for ectopic pregnancy and should be steered toward
Endometriosis IVF.
Cervical factor infertility Infertility patients with a history of minimal and
Oligoanovulatory infertility mild endometriosis are good candidates for GIFT.
Idiopathic infertility
Religious principles Evidence of improved cycle fecundity with the lap-
aroscopic treatment of stage I and II endometriosis
GIFT, gamete intrafallopian transfer. suggests that this condition in some way inhibits
the process of sperm–egg interaction and transport.
Placing the gametes directly into the fallopian tube
removes them from the peritoneal milieu influ-
given ovary. A number of other species are much enced by the endometriosis.
more efficient at the process of ovum capture. In Cervical factor infertility is difficult to define in
these species the ovary is surrounded by a bursa absolute terms. Previously, this diagnosis was lim-
connected to the fallopian tube. This bursa limits ited to patients with “hostile” cervical mucus. The
the migration of the extruded oocyte to within a inhospitable mucus is thought to act as a barrier to
few millimeters of the fimbria thereby ensuring sperm entry, which decreases cycle fecundity. With
nearly 100% efficiency in the capture of ovulated the advent of IVF, cervical factor infertility takes
oocytes. The anatomic relation between the human on a new dimension. Atraumatic transfer of
fallopian tube and ovary is highly susceptible to the embryos to the endometrium is crucial to the suc-
intrusive effects of mechanical distortion. Table cess of IVF. In many patients, embryo transfer can
18–1 lists the conditions that make a patient a can- be done with ease owing to the current generation
didate for GIFT. of embryo transfer catheters. Some patients, how-
Because the GIFT procedure can overcome inef- ever, have cervical anatomy that is challenging. In
ficiencies of ovum pickup, candidates for GIFT these patients, ultrasound-guided embryo transfer
include women with a history of pelvic adhesions has been proposed to observe the path of the cath-
unrelated to pelvic inflammatory disease. These eter and assist in guiding it atraumatically into the
individuals lack the ability to capture efficiently the endometrium. Although this is useful in some cir-
oocytes released from the ovary spontaneously. cumstances, particularly where there is sharp ante-
Clearly, there is the need for surgical judgment in flexion or retroflexion of the uterus, it does not cor-
these cases. Adhesions that severely distort the rect the anatomy when odd configurations are
pelvic anatomy make the process of oocyte retrieval encountered. In these women, difficulty transfer-
at laparoscopy difficult. Because the ovaries have ring embryos atraumatically may pose the greatest
been stimulated by gonadotropins to raise multiple challenge to inducing pregnancy. Although distor-
follicles, they are particularly sensitive to excess tion of the normal cervical anatomy should not pose
manipulation. Bleeding can be induced with greater a barrier to sperm transport to the uterus following
ease than when manipulating unstimulated ovaries. intercourse, those couples who remain infertile
Furthermore, at the time of laparoscopy it is ex- despite less aggressive conventional therapies
pected that all preovulatory oocytes will be aspi- sometimes progress to the assisted reproductive
rated. Mechanical limitations that prevent complete technologies. GIFT may be an ideal alternative for
aspiration of all preovulatory follicles can therefore these individuals with normal tubal anatomy. The
place the patient at greater risk for the ovarian transfer of gametes to the fallopian tube may prove
hyperstimulation syndrome. Limiting GIFT to pa- a better route for giving embryos across to the
tients with mild pelvic adhesive disease may be pru- uterus than further attempts at transcervical embryo
dent, but another caveat is the absence of intratubal transfer.
damage. Patients with adhesions and a history of Women with a history of oligoanovulation may
upper genital tract infections should not undergo also be candidates for GIFT. If conception has not
the GIFT procedure. These patients are at signifi- occurred with the use of less aggressive treatments,
cantly greater risk for ectopic pregnancy, as the including ovulation induction with intrauterine
microvillous ovum transport system in the fallopian insemination, GIFT may be used. Likewise, pa-
tube may be compromised. In summary, patients tients with idiopathic infertility may become preg-
with adhesions resulting from endometriosis or past nant with GIFT. Following a comprehensive eval-
abdominal surgery are candidates for GIFT in select uation and lacking success with more conservative
circumstances. Those whose pelvic adhesions were methods in the treatment algorithm, GIFT may be
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 187

18. Intratubal Gamete Transfer 187

an effective next step. There is some debate about these patients before proceeding. Studies including
the place of diagnostic laparoscopy in the evalua- hysterosalpingography and diagnostic laparoscopy
tion of idiopathic infertility. Some practitioners should be carried out prior to choosing GIFT. In
believe that in the absence of a history suggesting such cases, even perfectly normal-appearing pelvic
pelvic adhesive disease or endometriosis, combined anatomy does not guarantee normal function.
with a normal hysterosalpingogram, ovulation Patients who have undergone tubal anastomosis fol-
induction may be prescribed without performing lowing reversal of tubal sterilization make poor
diagnostic laparoscopy. Others believe that a com- GIFT candidates. These individuals have a signifi-
bination procedure, the diagnostic GIFT, should be cantly increased risk for ectopic pregnancy and
performed. This can benefit the patient with unex- should be steered towards IVF.
plained infertility, as the normal findings on lapa- For GIFT to succeed, the sperm must be capa-
roscopy can be treated at that time by placing ble of fertilizing an oocyte. Unlike IVF, there is no
gametes into the fallopian tubes. If laparoscopy direct proof that fertilization takes place following
reveals distorted pelvic anatomy not amenable to gamete placement. Some indirect evidence can be
laparoscopic ovum capture or intratubal gamete gleaned. When supernumerary oocytes are obtained
transfer, the procedure can be converted. The con- they can be placed in culture with sperm and the
version would include transvaginal oocyte retrieval resulting embryos frozen for the patient’s later use.
followed by traditional IVF and transcervical If the fertilization rate among these excess oocytes
embryo transfer. is good, many assume that the transferred gametes
The GIFT procedure enables fertilization to would likely have shared the same fate. If preg-
occur in the patient’s body. At least one major reli- nancy occurs, the suspicion is confirmed. When it
gion that prohibits IVF (partly on the basis of con- does not, the question remains open. Therefore
ception occurring outside a woman’s body) permits when selecting patients for GIFT one must be rea-
GIFT. Therefore some couples may choose GIFT sonably certain that fertilization could occur. Nor-
when presented with the option of assisted repro- mal semen parameters including normal sperm con-
ductive technology. centrations, motility, and morphology are a good
start Should there be a question about the ability of
sperm to penetrate the eggs, or should there be no
fertilization among the supernumerary eggs of an
Contraindications to GIFT unsuccessful GIFT cycle, consideration should be
given to alternate methods. Finally, any patient with
If the fallopian tubes are compromised, GIFT is not a contraindication to laparoscopy should be ruled
an appropriate therapeutic choice. Table 18–2 is out for the GIFT procedure. As techniques for lap-
a list of contraindications to GIFT. During the ini- aroscopy under local anesthesia and gasless lapa-
tial investigation of the infertile couple, attention roscopy emerge, the number of patients for whom
should be paid to the fallopian tubes in more detail laparoscopy is contraindicated may decline.
than simply noting whether the structure is patent. Zygote intrafallopian transfer (ZIFT) is an alter-
The tubes should be examined carefully for the nate methodology whereby fertilization is first
presence of salpingitis isthmica nodosum. This observed in vitro, after which the zygotes are trans-
finding, indicative of intrafallopian damage, miti- ferred laparoscopically to the fallopian tubes. Much
gates against performing the GIFT procedure. Like- like GIFT in concept, ZIFT differs in that oocytes
wise, a history of documented pelvic inflammatory are retrieved vaginally and then fertilized in vitro.
disease (PID) should be used to guide patients away In cases where a male factor may reduce the like-
from this therapeutic option. Undocumented cases lihood of fertilization, intracytoplasmic sperm
of PID pose a significant dilemma. It is important injection (ICSI) can be performed and the resultant
to obtain maximum anatomic information about embryos returned to the patient the next day, fol-
lowing confirmation of fertilization. ZIFT, as an
analogue to GIFT, extends the range of intrafal-
lopian transfer to patients with male factor infertil-
TABLE 18–2. Contraindications to GIFT ity. One drawback to this approach is the need for
History of pelvic inflammatory disease two surgical procedures: the first wherein the
Known tubal abnormalities oocytes are retrieved and the second at which the
Severe male factor infertility
Any known contraindication to laparoscopy
zygotes are returned to the fallopian tubes laparo-
scopically.
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 188

188 K. Sinnock Friel and A.S. Penzias

Equipment
The equipment required to perform GIFT consists
of laparoscopic instruments and laboratory equip-
ment. In our setting we perform the GIFT proce-
dure under general endotracheal anesthesia. There-
fore our equipment and procedures reflect this
practice preference. Table 18–3 is an itemized
checklist used to prepare for the GIFT procedure.
The laparoscopic equipment includes a video sys-
tem, a CO2 insufflator, a fiberoptic light source and
fiberoptic cable, and a pedal-activated Rocket suc-
tion pump. These items are all stored on a mobile
vertical cart that can be rolled into position for the
procedure (Fig. 18–4). In the background the prox-
imity of the laboratory to the operating room is
apparent. In addition to a window through which
tubes of follicular aspirates can be passed, there is
an access door into the operating room. The embry-
ologist uses this door to enter the operating room
with the loaded GIFT catheter at the appropriate
time. The laboratory, contiguous to the operating
room, is equipped with a Nikon inverted 10 dis-
secting microscope with heated stage. A warming
tray containing two 12-well heating blocks sits
adjacent to the laboratory to maintain the temper-
ature of the conical tubes containing the follicle
aspirates while they await evaluation by the embry-
ologist. FIGURE 18–4. Video system, insufflator, and suction
apparatus mounted on a portable cart in the operating
room. Note the proximity of the laboratory to the oper-
ating room immediately behind the portable cart.
TABLE 18–3. Itemized Checklist Used to Prepare for
the GIFT Procedure
Laparotomy pack
One 4-0 Vicryl suture
Power-free (PF) gloves for physician Procedure
PF gloves for scrub nurse
One steri-drape The steps for performing GIFT are similar to those
Light handle of standard IVF protocols. Initially, the ovaries are
One camera drape
10 Raytech sponges
stimulated by intramuscular or subcutaneous ad-
Rocket needle ministration of gonadotropins most often in com-
Glass syringe, 30 cc bination with gonadotropin-releasing hormone
Modified HTF medium, 100 cc (GnRH) agonist. The ovaries are then monitored
Conical Falcon tubes, 15 ml for follicular growth with transvaginal ultrasonog-
Drape sheet
Gowns (3) raphy and serum estradiol levels. Human chorionic
PF gloves for embryologist gonadotropin (hCG) is administered when three or
One no. 11 blade more follicles exceed 16 mm in greatest diameter.
One sterile plastic bowl The precise combination of follicle quantity, folli-
One set of 0.5-inch Steri-strips
One 7 mm laparoscope
cle size, and estradiol level is difficult to render, but
Suprapubic trochar, 5 m an adequate responder should produce at least six
GIFT aspiration needle mature follicles in response to stimulation.
Fenestrated aspirator, 5 mm When the follicle quantity and size in combina-
Pyrex beaker, 250 ml tion with the serum estradiol level is adequate, hCG
Polypropylene tubing, 18 g
is administered. A laparoscopic oocyte retrieval is
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 189

18. Intratubal Gamete Transfer 189

scheduled to occur 36 hours after the intramuscu- oocytes obtained in excess of those transferred. Ver-
lar hCG administration. Upon arrival at the ART balization of the previously agreed-on fate of the
center, the patient is identified and interviewed by supernumerary oocytes is particularly useful to
a staff anesthesiologist, and anesthesia consent is ensure that the patient understands exactly what
obtained. The physician performing the GIFT pro- will happen to each of her eggs. In our program we
cedure then interviews the patient and reviews her commonly offer the patient “mini-IVF” for spare
cycle flow sheet. The flow sheet contains vital oocytes. This procedure is IVF of the excess
information about her history, including the status oocytes with cryopreservation of those that meet
of her fallopian tubes and any comments regarding predetermined quality criteria. Those couples who,
the GIFT procedure the patient’s personal physi- for religious or personal reasons, choose not to have
cian may have written. The flow sheet also reflects “mini-IVF” performed can choose to have the eggs
the number of oocytes to be placed in one or both discarded. We do not permit concurrent egg dona-
fallopian tubes. The quantity of oocytes to transfer tion with spare oocytes.
is agreed upon in advance of the procedure by the The patient is brought to the operating room
couple and their personal physician. There has been where the embryologist who will perform the
some controversy in the literature regarding the gamete manipulation greets her and confirms her
number of oocytes to transfer at the time of GIFT. identity. General endotracheal anesthesia is ap-
This has become an increasingly important issue as plied, and the patient is prepared in the supine posi-
efforts are under way to limit the incidence of mul- tion. An instrument table is laid out (Fig. 18–5) con-
tiple pregnancy. At the same time, there is increased taining the necessary equipment for the procedure.
economic pressure to limit the expense of the pro- With the patient in position, heating blocks and
cedure and improve the ratio of dollars spent per a 250 ml beaker containing modified human tubal
pregnancy. In addition, religious reasons for select- fluid (HTF) are placed on a Mayo stand. The con-
ing GIFT aside, excess oocytes obtained at GIFT ical Falcon tubes are filled with 1 cc of heparinized
can be inseminated and the resulting embryos modified HTF and placed in sterilized heating
frozen for a patient’s later use. If subsequent trans- blocks (Fig. 18–6). A Veress needle is used to insuf-
fer of these embryos is done transvaginally to the flate the abdomen with CO2, and the gas pressure
uterus, the savings relative to another stimulated is limited to 15 mmHg. The laparoscope is placed
cycle are high. infraumbilically, and a 5 mm port is placed supra-
We looked at the success rates of GIFT as a func- pubically in midline. The Rocket needle is placed
tion of the number of oocytes transferred. We found midway between the two ports for manipulation of
that women who received four or more oocytes the GIFT retrieval needle followed by the transfer
were three times more likely to achieve clinical catheter (Fig. 18–7). Follicle aspiration is carried
pregnancy compared to those who received three out under direct laparoscopic vision, and all visi-
or less. There was a marginal advantage to receiv- ble follicles are aspirated. The follicles are aspi-
ing five versus four oocytes, but any more than six rated into 15 ml conical Falcon tubes that contain
showed no statistically significant difference with 1 cc of heparinized modified HTF medium. The
respect to clinical pregnancy rates. It seems, there- GIFT needle is flushed with medium at the con-
fore, that there is a limit to the success of GIFT that clusion of the retrieval portion of the case and
may not simply be overcome by increasing the passed off the field. The glass syringe is used to
number of eggs transferred. Our routine transfer wash the pelvis with modified HTF medium. The
recommendations are listed in Table 18–4. The physician then chooses a fallopian tube for trans-
physician performing the procedure reviews the fer and grasps the fimbriated portion. A practice
previously signed and witnessed consent forms and catheter is passed into the distal end of the fallo-
verbalizes the previously agreed-on fate of any pian tube, and once entry is confirmed it is
removed.
A question that arises with GIFT is whether to
TABLE 18–4. Recommended Number of transfer the gametes to one tube or two. In 1991
Oocytes to Transfer at GIFT we evaluated 399 GIFT cycles. In 133 of these
cycles, gametes were transferred to one fallopian
Age (years) Oocytes (no.)
tube, and the rest had bilateral transfer. The clini-
30 3 cal pregnancy rate for the unilateral group was
31–34 4 25.6% and for the bilateral transfer group it was
35–39 5
40 6 23.3%. The lack of a significant difference in preg-
nancy rates enabled us to conclude that there was
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 190

190 K. Sinnock Friel and A.S. Penzias

FIGURE 18–5. From left to

right: scalpel, Veress needle,
7 mm reusable laparoscopic
trocar, a 35 cm 18 gauge
GIFT needle with polypropy-
lene tubing and rubber stop-
per, a Rocket needle, a
reusable 5 mm laparoscopic
trocar, a blunt probe, a trial
transfer catheter, and a glass
syringe attached to a hollow
suction wand.

no advantage to bilateral tubal transfer. We were tilization, embryo transport, and ultimately success.
able to reduce the total operating time by perform- The countercurrent mechanism has demonstrated
ing the transfer in a single tube. When choosing the that the ovarian vein, which contains ovarian secre-
tube for transfer, we considered the dominance of tions, can transfer these substances to the ovarian
the ipsilateral ovary and the general appearance of artery, suggesting that a fraction of the products of
the tube. Tubal patency, absence of adhesions, and the ovary are returned to the ovary in a short loop
easy manipulation may be more important factors feedback system. In addition, the distal portion of
than simply the state of the ipsilateral ovary. the fallopian tube is supplied by the ovarian artery.
It is thought that the tubes themselves have an Thus ovarian secretions directly influence the
intrinsic role in the success of fertilization. In addi- ampulla of the fallopian tube proximal to it through
tion, there is a countercurrent blood flow exchange a short feedback loop. Because the tube is influ-
mechanism between the tube and the ovary. This enced hormonally by the proximal ovary through
countercurrent flow exchange mechanism may the short loop feedback mechanism, initially it
facilitate the flow of substances that influence fer- was thought to be most advantageous to transfer

FIGURE 18–6. Adjusting the

suction pressure by aspirating
medium from the 250 ml
beaker just prior to commenc-
ing the procedure.
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 191

18. Intratubal Gamete Transfer 191

FIGURE 18–7. Abdominal

placement of instruments. The
laparoscope is at left and the
5 mm blunt probe at right. In
the center is the Rocket nee-
dle containing the GIFT aspi-
ration needle.

gametes into the tube next to the ovary with the Each fallopian tube was sounded, and the transfer
most follicles to simulate the natural, physiologic catheter was marked at distances of 2, 3, and 4 cm
state. from the distal end. Both tubes received gametes,
In 1994 Ransom et al. in retrospectively analyzed but a maximum of four eggs were transferred. The
the effect of gamete transfer to the tube next to the overall pregnancy rate in this group was 35.4%,
ovary with the greater number of follicles. A total with a clinical pregnancy rate of 30.9%. In general,
of 144 GIFT cycles were examined, and indeed a the pregnancy rate increased with the number of
higher pregnancy rate was reported for those trans- eggs transferred and with the depth of the distal
fers to the ipsilateral rather than the contralateral tubal lumen. For tubal transfer of less than 3 cm,
tube of the ovary with the greater number of dom- the rate was 16.7%; for transfers at 3–4 cm the rate
inant follicles. was 28.1%; and for those at more than 4 cm the
The embryologist examines all follicular aspi- pregnancy rate was 36.4%.
rates and places the oocytes identified in Irvine P1 After depositing the gametes the catheter is re-
medium. During the interval between the aspiration turned to the laboratory to confirm that it is indeed
and the transfer, the oocytes in the tissue culture empty. The instruments and CO2 are removed from
plate are incubated at 37°C in 5% CO2 in air. At the patient’s body, and the incisions are closed. The
the conclusion of the aspiration procedure the patient then spends 30–60 minutes in the supine
embryologist selects the predetermined number of position in our two-bed recovery room followed by
oocytes for transfer. The scientist then scrubs and 30 minutes in a reclining chair in our two-chair
puts on a gown. Upon returning to the laboratory, step-down unit.
the embryologist, with the aid of another scientist,
draws up a small pocket of fluid containing oocytes Anesthesia
surrounded on either side by a small pocket of fluid,
each with 50,000–100,000 sperm. The embryolo- During the early work on GIFT, egg retrievals and
gist then delivers the gametes to the surgeon for transfers were performed under general anesthesia
tubal cannulation. The tip of the catheter is then via a minilaparotomy or laparoscopy. General anes-
placed at approximately 4 cm depth in the ampulla thesia itself comes with a series of risk factors: aspi-
of the fallopian tube. ration pneumonia, airway trauma, reactive airway
The issue of how far into the tube the gametes disease, malignant hyperthermia, nausea, vomiting,
should be placed was answered in 1989. Yee et al. and a significant time for recovery. The potential
followed 246 consecutive GIFT cycles over an 18- embryotoxic effect from general anesthesia is an
month period. A standard ovarian stimulation pro- additional theoretic risk. In 1995 Silva et al. re-
tocol was used. Likewise, a standard method of ported on the technique of spinal anesthesia for
oocyte retrieval and gamete transfer were used. GIFT. Spinal anesthesia was administered at a level
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 192

192 K. Sinnock Friel and A.S. Penzias

between L3 and S1 at the time of laparoscopy. via the transvaginal technique there were four preg-
Intravenous midazolam and fentanyl were used as nancies. Among 60 matched controls who under-
adjuncts, and intraoperative monitoring included went laparoscopic transfer there were 21 pregnan-
electrocardiography (ECG), end-tidal CO2, blood cies. In this report, pregnancy rates for transvaginal
pressure, and pulse oximetry. Of the 68 GIFT transfers were no more than-two thirds of those
cycles in which spinal anesthesia was used, clini- with laparoscopic GIFT.
cal pregnancy rates overall were 49/%, with a de- Woolcott and Stanger in 1994 reported 83 pa-
livery rate of 37%. There was only one observed tients who underwent transvaginal GIFT. The clin-
anesthesia-related complication. One patient suf- ical pregnancy rate in this cohort was 27.7%. This
fered from a mild spinal headache, which resolved group emphasized that the physics behind trans-
on its own without requiring a blood patch or fur- ferring gametes vaginally was inherently different
ther medical intervention. from those governing laparoscopic transfer. There
In 1996 Padilla et al. proposed the use of local is concern that transperitoneal migration is a risk
anesthesia plus intravenous sedation for GIFT pro- with vaginal transfer. The fluid dynamics of retro-
cedures. Intravenous sedatives included midazolam, grade tubal gamete deposition may play a role such
fentanyl, inapsine, and propofol. Oocyte retrieval that low volumes and slow rates of injection may
was performed using transvaginal ultrasonography be important factors for preventing transperitoneal
aspiration. Just prior to laparoscopy 0.5% bupiva- migration. There is also concern that the currently
caine was infiltrated at the laparoscopic incision available techniques for transvaginal gamete trans-
sites. A 5 mm endoscope was used, and the intraab- fer may damage the endometrium in the process.
dominal pressure was held at 8–12 mmHg. Cathe- At the present time, there is active research into
ter transfer of gametes was then carried out in the designing better systems for transvaginal gamete
usual fashion. Patients were monitored for up to 2 transfer.
hours in the recovery room. The average operating
room time was 64  12 minutes and the recovery
time 92  30 minutes. The clinical pregnancy rate Complications
per transfer was 39% with an ongoing pregnancy
rate of 32%. There were no intraoperative or post- Anesthetic complications during GIFT have been
operative complications. Only two patients reported reported but are fortunately rare. Like all proce-
nausea, and only one required additional intra- dures where general anesthesia is applied, adequate
venous narcotic sedation. safety measures must be taken. Critical to this is
General anesthesia by endotracheal tube is used having trained personnel administer the anesthesia
in our practice. The patients receive an intravenous in a setting equipped with instruments essential to
combination of fentanyl and propofol. The gases monitoring vital functions. Backup procedures, in-
administered include O2 and N2O. The patient’s cluding mechanisms for treating malignant hyper-
vital signs are monitored intraoperatively with con- thermia, should be in place.
tinuous ECG, end-tidal CO2 quantitation, blood Intraoperative complications reported during the
pressure determination, and pulse oximetry. GIFT procedure include bowel injury, blood vessel
damage, and ovarian hemorrhage. Ordinary tech-
Laparoscopic Versus niques used to avoid these complications in other
laparoscopic procedures are applied in GIFT as
Transvaginal Transfer well. In the outpatient setting, however, it is nec-
The question of anesthesia type is also a factor in essary to develop protocols to handle such unan-
the decision whether to proceed with gamete trans- ticipated events. Personnel should be trained to
fer laparoscopically or transvaginally. Early trans- react to these rare events and immediate operative
fer technique relied solely on laparoscopy and repair begun or appropriate transfer to a local inpa-
minilaparotomy for gamete transfer for which gen- tient hospital setting enacted.
eral anesthesia was required. The push to enable To further limit the risks of both anesthetic and
assisted reproductive technologies to be carried intraoperative complications, we require a preop-
out in the outpatient ambulatory setting prompted erative anesthesia consultation for women with a
investigation of less invasive techniques or retrieval history of an anesthetic complication or a body
and transfer. In 1993 Jansen et al. developed and mass index (BMI) above 28. In our outpatient set-
reported on the use of a catheter system for can- ting we limit the performance of GIFT to women
nulating the fallopian tubes through the vagina. In with a BMI below 28. The risk of ovarian injury
an early series of 20 patients who underwent GIFT can be minimized by gentle handling of the gonad
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 193

18. Intratubal Gamete Transfer 193

during the procedure. We favor use of a blunt probe many patients who could have undergone this
to elevate and fix the ovary against the side wall somewhat less invasive procedure. Still, GIFT is an
above the level of the ovarian blood supply. Direct excellent option for many infertile couples. Future
visualization of the ovary and path of the retrieval developments may see the resurgence of GIFT,
needle is critical. Keeping the needle still during especially in the area of transcervical fallopian
aspiration is important because excessive pulling or transfer. The ability to make this technique nonlap-
tension can cause rents in the ovarian cortex. When aroscopic with the reliable, atraumatic transfer of
picking up the fallopian tube for gamete transfer gametes to the fallopian tubes will certainly enable
we take care to limit the tension placed so as to more patients to take advantage of the technique
avoid inadvertent avulsion of fimbria. Whole blood and will allow more centers to offer the procedure.
in an inhibitor of sperm–egg interaction, so it is
also important to avoid repeated cannulation of the
fallopian tube prior to transfer. Suggested Reading
Postoperative complications include ovarian hy- Abramovici H, Dirnfeld M, Bornstein J, Lissak A, Gonen
perstimulation syndrome (OHSS). There is func- Y. Gamete intrafallopian transfer: an overview. J
tionally no difference between the reported rates of Reprod Med 1993;38:698–702.
OHSS with GIFT and IVF. Bear in mind that fol- Asch RH, Balmaceda JP, Ellsworth LR, Wong PC. Pre-
licle aspiration reduces the risk of OHSS relative liminary experiences with gamete intrafallopian trans-
to the same number of follicles and estradiol level fer (GIFT). Fertil Steril 1986;45:366–371.
Assisted reproductive technology in the United States
during routine ovulation induction cycles where and Canada: 1991 results from the Society for Assisted
intrauterine insemination will occur. Therefore it is Reproductive Technology generated from the Ameri-
important to empty all follicles even in couples who can Fertility Society Registry. Fertil Steril 1993;59:
do not plan to generate embryos for cryopreserva- 956–962.
tion with supernumerary oocytes. Assisted reproductive technology in the United States
Like all patients with stimulated ovaries, there is and Canada: 1992 results generated from the Ameri-
an increased risk of ovarian torsion. Postoperative can Fertility Society/Society for Assisted Reproduc-
instructions should include advice to avoid strenu- tive Technology Registry. Fertil Steril 1994;62:1121–
ous physical activity and to enumerate the warning 1128.
symptoms of ovarian torsion. These warnings signs Assisted reproductive technology in the United States
and Canada: 1993 results generated from the Ameri-
include sharp intermittent or unrelenting pain ac- can Society for Reproductive Medicine/Society for
companied by nausea or vomiting (or both). Infec- Assisted Reproductive Technology Registry. Fertil
tion following GIFT is rare but possible. Patients Steril 1995;64:13–21.
with multiple corpora lutea who are using supple- Assisted reproductive technology in the United States
mental progesterone may have a somewhat elevated and Canada: 1994 results generated from the Ameri-
temperature; fever above 100°F should be reported. can Society for Reproductive Medicine/Society for
Outcome-related complications are primarily re- Assisted Reproductive Technology Registry. Fertil
lated to pregnancy. The risk of ectopic pregnancy Steril 1996;66:697–705.
has been reported to range from 5% to 8%. There Bauer O, Diedrich K. Transcervical tubal transfer of
is also an increased risk of heterotopic pregnancy: gametes and embryos. Curr Opin Obstet Gynecol
1994;6:178–183.
from one in 30,000 spontaneous conceptions to as Beilin Y, Bodian CA, Mukherjee T, Andres LA, Vincent
many as one in 1000 GIFT pregnancies. Patients RD Jr, Hock DL, Sparks AE, Munson AK, Minnich
with significant risk factors for ectopic pregnancy ME, Steinkampf MP, Christman GM, McKay RS,
are not ideal GIFT candidates, but it should be Eisenkraft JB. The use of propofol, nitrous oxide, or
noted that IVF does not preclude the development isoflurane does not affect the reproductive success rate
of an ectopic pregnancy. following gamete intrafallopian transfer (GIFT): a
multicenter pilot trial/survey. Anesthesiology 1999;90:
36–41.
Conclusions Bendz A. The anatomical basis for a possible counter
current exchange mechanism in the human adnexa.
Prostaglandins 1977;13:355–362.
Development of the GIFT procedure represented a
Cramer DW, Liberman RF, Powers D, Hornstein MD,
major advancement in the assisted reproductive McShane P, Barbieri RL. Recent trends in assisted
technologies. The popularity of GIFT grew over reproductive techniques and associated outcomes.
time owing to its exceptional success rates. The Obstet Gynecol 2000;95:61–6.
improvements in IVF technology, which have Dawood MY. In vitro fertilization, gamete intrafallopian
increased its success, has taken back from GIFT transfer, and superovulation with intrauterine insemi-
3051_Seifer_18_p184-194 11/5/01 9:58 AM Page 194

194 K. Sinnock Friel and A.S. Penzias

nation: efficacy and potential health hazards on babies Penzias AS, Alper MM, Oskowitz SP, Berger MJ,
delivered. Am J Obstet Gynecol 1996;174:1208–1217. Thompson IB. Gamete intrafallopian transfer: assess-
Driscoll GL, Tyler JP, Clark L, Bernstein J. Transfer of ment of the optimal number of oocytes to transfer. Fer-
gametes into the fallopian tubes—is choice of side til Steril 1991;55:311–313.
important? Hum Reprod 1996;11:1881–1883. Penzias AS, Thompson IB, Alper MM, Oskowitz SP,
Guirgis RR, al Shawaf T, Craft I. Ovarian torsion: a com- Berger MJ. Successful use of gamete intrafallopian
plication of GIFT: a report on two cases and literature transfer does not reverse the decline in fertility in
review. Hum Reprod 1992;7:967–969. women over 40 years of age. Obstet Gynecol 1991;
In vitro fertilization/embryo transfer in the United States: 77:37–39.
1987 results from the National IVF-BT Registry. Fer- Penzias AS, Alper MM, Oskowitz SP, Berger MJ,
til Steril 1989;51:13–19. Thompson LB. Comparison of unilateral and bilateral
In vitro fertilization-embryo transfer in the United States: tubal transfer in gamete intrafallopian transfer (GIFT).
1988 results from the IVF-ET Registry. Medical J In Vitro Fert Embryo Transfer 1991;8:276–278.
Research International, Society for Assisted Repro- Ransom MX, Corsan GH, Garcia AJ, Doherty KA, Kem-
ductive Technology, American Fertility Society. Fertil mann B. Tubal selection for gamete intrafallopian
Steril 1990;53:13–20. transfer. Fertil Steril 1994;61:386–389.
In vitro fertilization-embryo transfer (IVF-ET) in the Schenker JG, Ezra Y. Complications of assisted repro-
United States: 1989 results from the IVF-ET Registry. ductive techniques. Fertil Steril 1994;61:411–422.
Medical Research International, Society for Assisted Silva PD, Kang SB, Sloane KA. Gamete intrafallopian
Reproductive Technology, The American Fertility transfer with spinal anesthesia. Fertil Steril 1993;
Society. Fertil Steril 1991;55:14–22; discussion 22– 59:841.
23. Silva PD, Meisch AL, Meisch JK, Kang SB, Rooney B.
In vitro fertilization-embryo transfer (IVF-BT) in the Factors associated with improving success rates with
United States: 1990 results from the IVF-BT Registry, gamete intrafallopian transfer under thin-needle spinal
Medical Research International, Society for Assisted anesthesia. J Assist Reprod Genet 1995;12:569–573.
Reproductive Technology (SART), The American Fer- Silva PD, Olson KL, Meisch JK, Silva DE. Gamete
tility Society. Fertil Steril 1992;57:15–24. intrafallopian transfer. A cost-effective alternative to
Jansen RP, Anderson JC. Transvaginal versus laparo- donor oocyte in vitro fertilization in women aged
scopic gamete intrafallopian transfer: a case-controlled 40–42 years. J Reprod Med 1998;43:1019–22.
retrospective comparison. Fertil Steril 1993;59:836– Swisher ED, Wobster R, Armstrong A. Age-related preg-
840. nancy rates in GIFT patients. Mil Med 1998;163:
Kenny DT. The impact of maternal age on clinical preg- 449–50.
nancy and spontaneous abortion in women undergoing Woolcott R, Stanger J. The fluid dynamics of injection:
in vitro fertilization and gamete intra-fallopian trans- variables as they relate to transvaginal gamete intrafal-
fer. Aust NZ J Obstet Gynaecol 1994;34:443–448. lopian transfer and tubal embryo transfer. Hum Reprod
Kenny DT. In vitro fertilisation and gamete intrafallopian 1994;9:1670–1672.
transfer: an integrative analysis of research, 1987– Woolcott R, Stanger J, Cohen R, Silber S. Refinements
1992. Br J Obstet Gynaecol 1995;102:317–325. in the methodology of injection for transvaginal
Mastroyannis C. Gamete intrafallopian transfer: ethical gamete intrafallopian transfer. Hum Reprod 1994;9:
considerations, historical development of the proce- 1466–1468.
dure, and comparison with other advanced reproduc- Yee B, Barnes RB, Vargyas JM, Marrs RP. Correlation
tive technologies. Fertil Steril 1993;60:389–402. of transabdominal and transvaginal ultrasound mea-
Milki AA, Tazuke SI. Comparison of carbon dioxide and surements of follicle size and number with laparo-
air pneumoperitoneum for gamete intrafallopian trans- scopic findings for in vitro fertilization. Fertil Steril
fer under conscious sedation and local anesthesia. Fer- 1987;47:828–832.
til Steril 1998;69:552–4. Yee B, Rosen GF, Chacon RR, Soubra S, Stone SC.
Padilla SL, Dugan K, Maruschak V, Smith RD, Zinder Gamete intrafallopian transfer: the effect of the num-
H. Laparoscopically assisted gamete intrafallopian ber of eggs used and the depth of gamete placement
transfer with local anesthesia and intravenous seda- on pregnancy initiation. Fertil Steril 1989;52:639–
tion. Fertil Steril 1996;66:404–407. 644.
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 195

19
Complications of Ovulation Induction
Janee A. Fonslick and David B. Seifer

Over 2 million women age 15–44 years are esti- developed the other form, which suggests two dis-
mated to have taken fertility drugs in the United tinct mechanisms of OHSS.
States. This number will continue to increase as
more women seek treatment for infertility, and many
undergo treatment with ovulation induction agents. Early OHSS
Thus it is important to be aware of the possible com- The early form of OHSS is believed to be due to
plications associated with superovulation so we can the acute effect of exogenous hCG administration,
adequately counsel, diagnose, and treat our patients usually administered 35 hours before egg retrieval.
appropriately. We discuss here several iatrogenic As implied, it presents earlier than the late form,
complications associated with the use of ovulation and it can occur in patients who do not become
induction agents, including ovarian hyperstimula- pregnant. The increased number of oocytes and ele-
tion syndrome, multifetal gestations, preterm deliv- vated estradiol concentration on the day hCG is
ery, heterotopic/ectopic pregnancy, spontaneous given are predictors of early OHSS.
abortion, and the theoretic risk of a possible increase
in the incidence of ovarian cancer.
Late OHSS
The late form of OHSS is thought to be induced by
Ovarian Hyperstimulation endogenous hCG and is seen in women who
Syndrome become pregnant with one or more gestational sacs.
The number of gestational sacs, serum hCG, and
As the number of women undergoing in vitro fer- serum progesterone and estradiol levels 11–13 days
tilization (IVF) techniques increases, it is antici- after hCG are predictive of late OHSS.
pated that the number of cases of ovarian hyper-
stimulation syndrome (OHSS) will increase. When
human menopausal gonadotropin (hMG) is used for Pathogenesis of OHSS
ovarian hyperstimulation, even with close monitor- The exact etiology of OHSS is unknown, but it is
ing of estradiol levels and the use of ultrasonogra- hypothesized to result from a substance produced
phy the incidence of OHSS is 4%, including the by the ovary. It is possible that this substance is
moderate and severe types. stimulated by hCG. OHSS can exist in a mild or
Lyons et al. in 1994 identified two distinct pre- severe form. The signs and symptoms of severe
sentations of OHSS: early and late. This study was OHSS are listed below.
a retrospective analysis of 592 IVF cycles during
1988–1993. Six (1%) of the cohort had moderate Marked ovarian enlargement
or severe OHSS presenting 3–7 days after human Ascites
chorionic gonadotropin (hCG) administration Pleural effusion
(early OHSS), whereas four (0.7%) had severe Nausea and vomiting
OHSS presenting 12–17 days after hCG. None of Acute respiratory distress syndrome (ARDS)
the patients who developed early or late OHSS Thromboembolic phenomena

195
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 196

196 J.A. Fonslick and D.B. Seifer

Hematocrit 45% Patients at Risk

White blood cell (WBC) count 15,000/mm3 with
left shift The OHSS is more frequent in young patients and
Elevated liver function tests patients with polycystic ovaries, conception cycles
Creatinine 1.5 mg/dl (particularly related to either endogenous or exoge-
Increased plasma renin and aldosterone nous hCG), high estradiol levels, and multiple
Sodium retention and oliguria second-degree follicles. When a gonadotropin-
releasing hormone (GnRH) analogue is used in com-
Potentially lethal aspects of OHSS include bination with hMG administration, patients exhibit
hypotension, renal failure, thromboembolic phe- higher estradiol levels without the interference of
nomena, and ARDS. This increased vascular per- endogenous luteinization; therefore high estradiol
meability, mainly of the ovarian vessels, results in levels in this type of protocol put patients into a sig-
leakage of large amounts of fluid into the peritoneal nificantly higher risk group, according to Ron et al.
space with resultant acute reduction of the intravas- Also, luteal phase supplementation with hCG leads
cular volume. The clinical picture is similar to that to a higher incidence of OHSS.
of a large surface area burn or a patient with severe
pancreatitis where a large amount of third spacing
of intravascular fluid occurs. This leads to severe Treatment
hypotension, decreased preload, and tachycardia.
The decreased preload may also be due in part to Treatment is empiric. The initial decision is whether
tense ascites compressing the inferior vena cava. to hospitalize the patient. If the hematocrit is less
The increased permeability is mediated through than 45% and signs and symptoms are restricted to
prostaglandins and histamine by the ovaries and an a swollen abdomen, nausea, and mild dyspnea,
activated follicular renin-angiotensin system. Acti- treatment is mainly bed rest with increased fluid
vation of renin and angiotensin leads to increased intake to maintain urine output. If the patient goes
antidiuretic hormone (ADH) from the kidney, even- home, it is important that she fulfills the following
tually leading to hemoconcentration and oliguria. requirements.
Vascular permeability factor (VPF) has been impli-
cated in playing a role in this mechanism. 1. Remains well hydrated: drink 12 oz every 2
hours during waking hours
2. Weighs herself daily with the same scale (needs
Vascular Permeability Factor to inform physician if she gains 3–5 lb/day)
The VPF causes vascular leakage and is present in 3. Performs daily abdominal girth measurements
the corpus luteum. Investigators have compared the in the same manner
concentrations of VPF in serum, peritoneal fluid, 4. Avoids exercise, intercourse
and follicular fluid in women who developed OHSS 5. Incurs no pelvic examinations by other health
to that in women who did not. They found a 100- care workers
fold increase in follicular fluid compared to serum 6. Consumes a diet low in potassium with high
and peritoneal fluid, suggesting that the ovary is a protein
significant source of VPF. Serum concentrations of
VPF on day 14 after hCG revealed that patients If the hematocrit is 45% or symptoms include
who developed severe OHSS had significantly ascites and patient discomfort, tachypnea, vomiting,
higher serum VPF concentrations (15.2 vs. 0.7 pg/ or diarrhea, treatment requires hospital admission,
ml) than those who did not develop the syndrome. with close monitoring of plasma electrolytes, and
Interestingly, age, serum estradiol, and the number renal and liver function. Intravenous crystalloids,
of follicles 13 mm on the day of hCG adminis- usually 5% dextrose in normal saline (D5NS), are
tration were not statistically different between the administered just enough to perfuse the kidneys
two groups. Three of four patients who developed (sometimes only 500 ml per day) with close moni-
severe OHSS had positive serum hCG values 14 toring of body weight, fluid balance, abdominal
days after administration, whereas the patients who girth, respiratory rate, hematocrit, and electrolytes.
did not develop severe OHSS had negative hCG It is important to avoid hypotonic solutions, espe-
values. Krasnow et al. postulated that “the hCG that cially lactated Ringer’s (LR), which contains potas-
rescues the corpus luteum results in an increase in sium. Dextran, fresh frozen plasma, and albumin
ovarian VPF secretion, which in turn causes an encourage third spacing and further formation of
exacerbation of OHSS.” ascites with increased abdominal pressure, de-
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 197

19. Complications of Ovulation Induction 197

creased venous return, decreased cardiac output, and Incidence with Assisted
oliguria with a resultant increase in creatinine. Para- Reproductive Technology
centesis performed in a slow gravitational manner
can result in immediate improvement marked by The incidence of multifetal gestations among preg-
diuresis. nancies achieved with assisted reproductive tech-
nology (ART) depends on the number of embryos
transferred. Series in which up to six embryos were
transferred yielded multiple pregnancy rates of
Prevention about 38%, with four embryos 18%, and with three
Multiple steps that can be taken toward preventing embryos 12%. Similarly, with gamete intrafallo-
OHSS. It may be as simple as using a reduced dos- pian transfer (GIFT), multifetal gestations occurred
age of gonadotropins. Withholding hCG adminis- at a rate of 43% with nine or ten oocytes trans-
tration should be considered when the estradiol ferred, 39% with seven or eight oocytes, and 15%
level exceeds 2000 pg/ml in the presence of many with four oocytes. Age also affects the multiple ges-
second degree follicles and during induction of tation rate in ART pregnancies. One series reported
ovulation or a non-IVF cycle. GnRH analogues a 28.5% rate in women age 35–39 and 16.4% in
may be used for triggering ovulation if they have women over age 40. A reported series on zygote
not been used for initial down-regulation. It is also intrafallopian transfer (ZIFT) reported a multifetal
important to avoid hCG supplementation of the gestation rate of 17.6% when three zygotes were
luteal phase if the cycle is thought to be high risk transferred.
for development of OHSS; progesterone supple-
mentation can be used alternatively. Other alterna-
tives for avoiding OHSS during an IVF cycle Prevention
include cryopreserving all embryos for later trans- Steps for prevention of multifetal gestations include
fer during an unstimulated cycle. Some have de- the following. Withholding hCG when the estradiol
scribed preventing OHSS in high risk cases by level is higher than 4000 pg/ml or when there are
administering 50 g of intravenous albumin during four or more follicles at 15 mm diameter or greater.
oocyte recovery and immediately afterward. Also, it is imperative to be conservative with poly-
cystic ovary syndrome (PCOS) patients starting
with low doses of hMG. Because with in vitro fer-
tilization (IVF) multiple gestations are controlled
Multifetal Gestations by the number of transferred embryos (discussed
above), it is recommended that three or fewer
The incidence of multiple pregnancies during embryos be placed if the patient is less than 35
cycles induced with hMG is 10–20%. The hCG in years old, whereas four-embryo placement is
doses less than 5000 IU resulted in fewer multiple acceptable for patients more than age 35. Although
pregnancies compared with doses of more than the clinical impact of these guidelines for reducing
6000 IU. Thompson and Hansen reported that their multiple gestations remains to be demonstrated,
multiple pregnancy rate was 25% when hCG over- recent modification of embryo cultures are allow-
lapped hMG therapy during the last few days, ing programs to transfer two blastocysts on day 5
whereas when given 1–3 days after the last injec- after oocyte retrieval while maintaining pregnancy
tion the rate was 19%. The number of preovulatory rates and meaningfully reducing the birth of three
follicles are probably a better parameter than the or more babies. Treatment of higher-order multiple
estradiol level, as the latter is also a reflection of gestations (i.e., three or more) can be accomplished
the number of second degree follicles (14 mm in by selective reduction, with up to 90% success rates
diameter), and these follicles are probably not reported in experienced hands.
involved in conception.
Combined clomiphene citrate–hMG reduces the
incidence of multiple pregnancies to 7.7–10.0% Selective Reduction: Transcervical,
probably because the selection phase is over once
hMG is introduced; the exogenous gonadotropins
Transvaginal, Transabdominal
propel the follicles to the preovulatory size. The The transcervical method of selective reduction
cohort of follicles is believed to be smaller than involves gradual dilatation of the cervix and aspi-
with hMG alone yet significantly higher than with rating the lowest sac(s) or crushing the embryo with
clomiphene citrate alone. a biopsy forceps. Typically, it is done up to week
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 198

198 J.A. Fonslick and D.B. Seifer

9 of the pregnancy. The transvaginal method uses or uterine anomalies. Preterm delivery was defined
a 25 cm long 16-gauge needle inserted into the sac as delivery before 37 weeks estimated gestational
closest to the vaginal wall. Aspiration is done up to age for singletons and 34 weeks for multiple ges-
week 7 of the gestation; alternatively, potassium tations. The study group consisted of 114 patients:
chloride can be injected into the fetal thorax. 76 singletons, 31 multiple gestations including
The transabdominal approach is most commonly three triplets, and 7 vanishing fetuses. The preg-
used. An 18-gauge needle is inserted transabdom- nancies were divided into good and bad outcomes.
inally into the fetal thorax, and demise is achieved Good outcomes were defined as uneventful births,
by trauma or an injection of saline or potassium and poor outcomes were births with either preterm
chloride. This is usually done during weeks 9–11. labor or cervical incompetence requiring cerclage.
The transabdominal approach is believed to be Hyperrelaxinemia was defined as mean values
safer, with fewer infections and fewer abortions. more than 3 SD above the normal mean. Overall,
there were 74 patients with hyperrelaxinemia and
40 with normal relaxin. The patients in the hyper-
Preterm Delivery relaxinemic group had a significantly higher pre-
maturity risk or preterm delivery than the group
There is evidence that pregnancies conceived by with normal relaxin (31.0% vs. 7.5%). When this
ART are more likely to result in preterm delivery. group was divided into multiple gestations and sin-
Many studies have focused on the role of relaxin gletons, the differences observed in the multiple
in this phenomenon. gestation group retained statistical significance
The major biologic action of relaxin in mammals only with hyperrelaxinemia remaining associated
is allowing accommodation of pregnancy and with increased prematurity risk or preterm delivery.
remodeling of connective tissues. In vitro, relaxin Logistic regression analysis of the singleton data
affects collagen synthesis. Studies have shown that demonstrated this trend as well. The authors con-
administration of relaxin intravaginally or intracer- cluded that “in women who became pregnant after
vically can effect cervical softening, effacement, ovarian stimulation, first trimester hyperrelaxine-
and dilatation and can decrease the time to deliv- mia identifies a group of high risk women who can
ery. Relaxin is not necessary for delivery of preg- be monitored more closely to detect and potentially
nant patients who conceive with donor oocytes treat early cervical dilation of premature labor, per-
without producing relaxin, as the corpus luteum is haps with cervical cerclage.”
absent. Relaxin is normally produced by the cor-
pus luteum, and concentrations are highest during
the first trimester. After 12 weeks of pregnancy, lev-
els remain fairly stable in a given individual, as Heterotopic/Ectopic Pregnancies
there is no diurnal secretion pattern, pulsatility, or
Spontaneous heterotopic pregnancy incidence is
minute-to-minute variation.
estimated between 1:4000 and 1:10,000 compared
It has been shown that multiple gestations and
with an incidence of ectopic pregnancy of 1% in
ovarian stimulation cause increased relaxin con-
the general population. With the use of gonadotro-
centrations. Studies have been performed to deter-
pins, the incidence of heterotopic pregnancy
mine whether high peripheral relaxin concentra-
increases to 1%, and the incidence of ectopic preg-
tions contribute to preterm delivery. A study by
nancy is 3%. Because tubal disease and pelvic sur-
Weiss et al. demonstrated that elevated first tri-
gery are more common among patients treated with
mester serum relaxin concentrations in pregnant
IVF-embryo transfer (IVF-ET) the incidence of
women following ovarian stimulation were predic-
ectopic pregnancies is expected to be higher; it is
tive of increased prematurity. This study involved
estimated to be 4.5%. The incidence of heterotopic
comparisons between two groups of women; those
pregnancies among IVF-ET gestations is similar
who became pregnant with ovarian stimulation
to that for gonadotropin-induced pregnancies
(hMG and hCG with and without GnRH agonists,
(about 1%).
clomiphene citrate with and without hCG, IVF, and
clomiphene citrate with hMG and hCG) and those
who became pregnant without the use of fertility Signs and Symptoms
drugs. Excluded from this study were those at risk
for preterm labor, including patients with a history Symptoms include abdominal pain (present in
of diethylstilbestrol (DES) exposure, a history of 80%) and hypovolemic shock with abdominal ten-
more than one major operative cervical procedure, derness (in 10%). It is important to remember that
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 199

19. Complications of Ovulation Induction 199

signs and symptoms of ovarian hyperstimulation and hence an increased prevalence of chromosomal
may present with a similar picture, but tenderness aberrations such as trisomies. In addition, the
is usually unilateral with an ectopic pregnancy and higher rate of multiple pregnancies can result in
bilateral with ovarian hyperstimulation. Vaginal increased pregnancy loss. Finally, there is earlier
bleeding may or may not be present (found in up recognition of these pregnancies as abortions as
to 50% of cases), creating possible confusion with they are often followed from the time of concep-
threatened abortion. tion with close surveillance.
About 40% can be diagnosed by ultrasonogra- Bohrer and Kemman performed a retrospective
phy with the remaining 60% by laparotomy or lap- analysis comparing women treated with gonado-
aroscopy. Approximately 70% are diagnosed at 5–8 tropins resulting in spontaneous abortion and
weeks’ gestation and approximately 10% after 11 women treated with gonadotropins who delivered
weeks. Treatment options included salpingectomy, a viable infant to determine if there were factors
salpingostomy, KCl injection, or expectant man- predictive of women likely to miscarry. Factors they
agement. Systemic methotrexate is a less than ideal examined included age, history of past miscar-
treatment, as it aborts both the tubal and the intra- riages, duration of infertility, diagnostic category,
uterine pregnancy. weight, body surface area, duration and weight-cor-
rected dose of gonadotropin administration, maxi-
mum estradiol level, estradiol pattern, hCG dose,
Pregnancy Outcome presence or absence of hCG support during the
Two-thirds of intrauterine pregnancies are delivered luteal phase, results of postcoital testing, methods
alive. One-third abort early during the first tri- of insemination, and results of the husband’s semen
mester. analysis. The only significant difference between
the two study groups was weight and advanced age.
Theories The increased risk of miscarriage with advancing
age is consistent with the general experience of
Sex steroids have been suggested to alter the con- increased miscarriage rates in older women. The
tractility of the tube musculature or effect endo- increased rate seen with obesity is independent of
salpingeal proliferation, thereby controlling embryo age and estradiol level at ovulation and increases
transport through the tube. Joupilla et al. showed with increasing weight. It is unclear whether obese
significantly lower estradiol E2 and progesterone women in the general population have higher mis-
levels in ectopic than intrauterine pregnancies. With carriage rates.
ovulation induction or ART the preovulatory estra- The observed association between weight and
diol is supraphysiologic and remains high during miscarriage may be partly the result of an increase
the luteal phase because of multiple corpora lutea. in peripheral conversion to estrone and an increased
Molling et al. and McBain found a correlation estrone/estradiol ratio, which may affect endoge-
between ectopic pregnancies and high late follicu- nous gonadotropins. Also, baseline androgen lev-
lar phase estradiol levels after treatment with els are relatively increased in obese women; andro-
menotropins. Luteal phase progesterone levels after gen levels are further augmented with hMG therapy
ovulation induction and ART are higher than dur- secondary to thecal cell stimulation by hMG.
ing normal cycles because of multiple corpora lutea Therefore, the altered steroid milieu could alter the
and early progesterone supplementation. Proges- endometrium or developing ovum or conceptus. A
terone has a slowing effect on tubal contractility higher miscarriage rate in hMG-treated was shown
and ciliary beat, which may contribute to ectopic in women who had endogenous gonadotropin activ-
pregnancies by affecting tubal transport. ity than in those who were hypogonadotropic. It is
not clear if these women were obese. The authors
concluded that “obese women weighing more than
Spontaneous Abortion 81.8 kg should make every effort to lose weight
before beginning gonadotropin therapy.”
In contrast to earlier reports no increase in the spon-
taneous abortion rate in clomiphene citrate (CC)-
treated patients. In contrast, hMG-treated patients Ovarian Cancer
continue to be associated with a higher rate of spon-
taneous abortion (25%) than the general popula- Several case reports of ovarian carcinoma and
tion. This high incidence is attributed partly to tumors of low malignant potential in women under-
the increased age of patients using this medication going treatment for infertility generated concern
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 200

200 J.A. Fonslick and D.B. Seifer

over the possible relation between ovulation- pared to only 11 controls. Among nulligravidas, the
inducing medication and ovarian tumors. During OR was 27 and the 95% CI 2.3–316 based on only
1992–1993 a series of publications gave wide- 12 exposed infertile cancer cases and 1 infertile
spread attention to the possibility of this associa- control. In a separate analysis of borderline ovar-
tion. This discussion reviews the theories of the ian cancer, the adjusted OR among all women
development of ovarian cancer based on risk fac- regardless of gravidity was 4.0 (95% CI 1.1–13.9).
tors. It also reviews the epidemiologic studies con- A study by Ron et al. suggested an association
sidering this association. between infertility and ovarian cancer. Kaufman et
An undisputed risk factor for the development of al. recalculated these data using infertile women as
ovarian cancer is low parity, whereas high parity is the reference group. This reduced the crude OR for
protective. It has been theorized that protection is the nulligravid women from 17 to 12, still demon-
due to suppression of ovulation, so it follows that strating an increased OR.
this may be the mechanism by which oral contra- Limitations of the Ron et al. study include the
ceptives are protective against ovarian cancer. relatively small number of women who had been
Therefore infertility and incessant ovulation are exposed to fertility drugs and the wide 95% CIs,
risk factors. It has been further speculated that ovar- with lower limits as low as 1.3. In addition, there
ian hyperstimulation produced by fertility drugs was a lack of information on the etiology of the
can increase this risk. In 1971 Fathalla suggested infertility, ovarian cancer histology, and family his-
that “with each ovulation the ovarian surface tory of cancer. Moreover, the specific drug therapy
(epithelium) incurs minor trauma, and the cumula- used was unknown for 16 of 20 exposed cases and
tive effect of repetitive surface injury contributes to 8 of 11 exposed controls, and there was no infor-
the development of ovarian neoplasms.” mation regarding recall bias confounding this study
Five case-control studies and two retrospective such as dosage, duration, and concomitant use of
cohort studies examined this issue as well as one multiple agents. Cancer patients may have remem-
pooled reanalysis of three of these case-control bered their exposure history more thoroughly than
studies. A large study by Venn et al. (discussed did the controls, thereby exaggerating the observed
later), did not find evidence that ovulation induc- ORs.
tion contributed to ovarian cancer risk, whereas More recently the results of a retrospective case-
studies by Cramer, Nasca, Hartge et al., and Ross- cohort study were reported by Rossing et al. Instead
ing et al. did find evidence supporting the role of of identifying ovarian cancer cases and comparing
ovulation induction in ovarian cancer risk. The Col- their fertility drug exposure history to a set of con-
laborative Ovarian Cancer Group (COCG) pooled trols, they identified a cohort of infertile women,
data from the Cramer, Nasca, and Hartge et al. stud- determined which of them subsequently developed
ies because studies were determined to be the only ovarian cancer, and compared their fertility drug
ones of ovarian cancer during 1956–1986 for which usage to a subcohort of 135 women chosen at ran-
fertility drug exposure were available and met other dom from a larger group of 3837 women. Cancer
criteria (i.e., defining cases as women newly diag- cases were obtained from the Seattle tumor registry.
nosed with invasive epithelial ovarian cancer at Infertility records were obtained for specific infor-
a U.S. hospital). (COCG) investigators excluded mation on infertility type, reproductive history, and
women who never married, those who may have specific drug exposures. Eleven ovarian cancers
undergone bilateral oophorectomy, data provided were found: four invasive epithelial, five border-
by surrogates, women with borderline tumors, and line, and two granulosa cell tumors. All were diag-
nonwhites (due to insufficient data among non- nosed in women ages 24–43. The subgroup of clo-
whites). miphene users for at least 12 cycles had a risk ratio
Data on infertility and fertility drug exposure of 11.1. Duration of use less than 1 year was not
were available for 622 women and their 1101 con- associated with increased risk. This risk was seen
trols. Among these women, 96 cases and 135 con- regardless of gravidity.
trols were infertile (15% and 12%, respectively). The limitations of this study included the lack of
After adjusting for age, parity, breast feeding, and consideration of oophorectomy rates, incomplete
oral contraceptive use, women who had used fer- information regarding drug exposure before enroll-
tility drugs had nearly three times the risk of inva- ment, the small number of cancer cases, and the
sive epithelial ovarian cancer as women lacking a fact that the group largely used clomiphene whereas
history of infertility [odds ratio (OR) 2.8; 95% con- only 4% of the subcohort was exposed to Pergonal.
fidence interval (CI) 1.3–6.1]. This results from the The strengths of the Rossing et al. study included
20 cancer cases who had used fertility drugs com- the mean time (7 years) from enrollment to diag-
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 201

19. Complications of Ovulation Induction 201

nosis (unlikely for the risk elevation to be due to by women with a family history of ovarian cancer
preexisting tumors that led to infertility and subse- reduced their risk to below that of never-users
quent fertility drug exposure). Moreover, 9 of 11 whose family history was negative for ovarian can-
cases were diagnosed after the patient had stopped cer. Furthermore, oral contraceptive use appears to
being cared for by fertility specialists; therefore protect against the development of ovarian cancer
detection was probably not due to a surveillance with an average risk reduction of up to 80% for
bias related to infertility workups. The authors had users compared to nonusers (RR  0.2). Protection
access to extensive information on infertility sub- from ovarian cancer increases with increasing dura-
type, fertility drug class, and number of induction tion of use and persists for up to 20 years follow-
cycles. Recall bias was reduced because exposure ing discontinuation.
data were collected before the tumor was diag- The speculation that ovulation-inducing agents
nosed. cause ovarian cancer is based on the incessant ovu-
Venn et al. examined the incidence of ovarian, lation theory that repeated trauma to the ovarian
breast, and uterine cancer in a cohort of 10,358 epithelium promotes cell division in the context of
women in Australia referred for IVF between 1978 elevated gonadotropin levels noted in postmeno-
and 1992. The exposed group consisted of 5564 pausal women. Two studies, however, refute these
patients. The agents used depended on the period theories. Schildkraut et al. found that patients with
of treatment; until 1987 CC  hMG followed by PCOS (who are oligoovulatory) have an increased
hCG was used; in 1987 GnRH agonists (leuprolide, risk (2.5-fold) of ovarian cancer. Helzlsouer et al.
buserelin) replaced CC to prevent an untimely surge found that mean FSH levels were lower among
of LH; and finally during 1990–1992 GnRH patients with ovarian cancer than in controls and
agonist was used in combination with hMG or that increasing levels were associated with signifi-
follicle-stimulating hormone (FSH) followed by cantly lower risk.
hCG. The unexposed group of 4794 were registered The possibility that fertility drugs increase the
for IVF but did not receive ovarian stimulation and risk of ovarian cancer requires additional investi-
had “natural cycle” IVF only. gation. Physicians should consider informing
There was no apparent increase in the risk asso- women about what is and what is not known regard-
ciated with the level of exposure to stimulated treat- ing this possible association. Currently studies
ment cycles. The median number of cycles was two; funded by the National Institutes of Health and the
77.0% of women had three or fewer cycles; and National Cancer Institute are under way to answer
1.9% of women had ten or more cycles. Seventy- these questions.
four percent of cancers occurred in women having
only one or two stimulated cycles. There was also
no association between infertility type and breast Conclusions
cancer or exposure to IVF. In the charts of none of
the women with ovarian cancer was an ovarian dis- There are numerous possible complications associ-
order recorded as the cause of infertility. ated with the use of ovulation induction agents. As
For both ovarian and uterine cancer an unex- more and more women are undergoing superovu-
pectedly large number of women had unexplained lation, it is important to be well informed of these
infertility recorded; the standardized incidence risks so we may adequately counsel our patients,
ratio of ovarian cancer was 6.9, and the standard- take steps to minimize these risks, and know how
ized incidence ratio of uterine cancer was 8.3. Can- to manage such complications when they occur.
cers of the ovary, breast, and uterus and all cancers
combined were not associated with exposure to Suggested Reading
stimulated IVF cycles.
A study by Gross et al. in 1994 examined the Antsaklis AJ, Drakakis P, Vlazakis GP, et al. Reduction
incidence of ovarian cancer among oral contracep- of multifetal pregnancies to twins does not increase
tive users and nonusers considering combined data obstetric or perinatal risks. Hum Reprod 1999;14:
1338–1340.
from the Cancer and Steroid Hormone (CASH)
ASRM Practice Committee Report. Guidelines on Num-
study; the Surveillance, Epidemiology, and End ber of Embryos Transferred, November 1999.
Results (SEER) network; and published reports of ASRM Practice Committee Report. Multiple Pregnancy
epidemiologic studies. They demonstrated that Associated with Infertility Therapy, November 2000.
increasing duration of oral contraceptive use de- Bohrer M, Kemmann E. Risk factors for spontaneous
creased the incidence of ovarian cancer in all abortion in menotropin-treated women. Fertil Steril
groups. In fact, 10-year use of oral contraceptives 1987;48:571–575.
3051_Seifer_19_p195-202 11/27/01 3:41 PM Page 202

202 J.A. Fonslick and D.B. Seifer

Bristow RE, Karlan BY. Ovulation induction, infertility, McElhinney B, McClure N. Ovarian hyperstimulation
and ovarian cancer risk. Fertil Steril 1996;66:499–507. syndrome. Baillieres Best Pract Res Clin Obstet
Bristow RE, Karlan BY. The risk of ovarian cancer after Gynaecol 2000;14:103–122.
treatment for infertility. Curr Opin Obstet Gynecol Ron EL, Lunenfeld B, Menczer J, et al. Cancer incidence
1996;8:32–37. in a cohort of infertile women. Am J Epidemiol 1987;
Fisch JD, Milki AA, Behr B. Sibling embryo blastocyst 125:780–790.
development correlates with the in vitro fertilization Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors
day 3 embryo transfer pregnancy rate in patients under in a cohort of infertile women. N Engl J Med 1994;
age 40. Fertil Steril 1999;71:750–752. 331:771–776.
Fluker MR, Copeland JE, Yuzpe AA. An ounce of pre- Schenker, et al. Complications of assisted reproductive
vention: outpatient management of the ovarian hyper- techniques. Fertil Steril 1994;61:411–422.
stimulation syndrome. Fertil Steril 2000;73:821– Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A,
824. Hughes C. Epithelial ovarian cancer risk among women
Gross TP, Schlesselman JJ. The estimated effect of oral with polycystic ovary syndrome. Obstet Gynecol 1996;
contraceptive use on the cumulative risk of epithelial 88:554–559.
ovarian cancer. Obstet Gynecol vol. 83 p. 619–626, Sherwood OD. Relaxin. In: Knobil E, Neill (eds) The
1996. Physiology of Reproduction. New York: Raven, 1988:
Haning RV Jr, Canick JA, Goldsmith LT, et al. The effect 585–673.
of ovulation induction on the concentration of mater- Shu XO, Brinton LA, et al. Population-based case-con-
nal serum relaxin in twin pregnancies. Am J Obstet trol study of ovarian cancer in Shanghai. Cancer Res
Gynecol 1996;174:227–232. 1989;49:3670–3674.
Hartge P, Schiffman MH, Hoover R, et al. A case con- Spirtas R, Kaufman SC, Alexander NJ. Fertility drugs
trol study of epithelial ovarian cancer. Am J Obstet and ovarian cancer: red alert or red herring? Fertil
Gynecol 1989;161:10–16. Steril 1993;59:291–293.
Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum Strandell A, Thorburn J, Hamberger L. Risk factors for
gonadotropins and steroid hormones and the develop- ectopic pregnancy in assisted reproduction. Fertil
ment of ovarian cancer. JAMA 1995;274:1926–1930. Steril 1999;71:282–286.
Hock DL, Seifer DB. Ovarian hyperstimulation syn- Tal J, Haddad S, Gordon N, Timor-Tritsch I. Heterotopic
drome. Infertil Reprod Med Clin North Am 2000; pregnancy after ovulation induction and assisted repro-
11:399. ductive technologies: a literature review from 1971 to
Houmard BS, Seifer DB. Infertility treatment and 1993. Fertil Steril 1996;66:1–12.
informed consent: current practices of reproductive Venn A, Watson L, Lumley J, et al. Breast and ovarian
endocrinologists. Obstet Gynecol 1999;93:252–257. cancer incidence after infertility and in vitro fertiliza-
Krasnow JS, Berga SL, Guzick DS, Zeleznik AJ, Yeo tion. Lancet 1995;346:995–1000.
K-T. Vascular permeability factor and vascular endo- Weiss G, Goldsmith LT, Sachdev R, et al. Elevated first-
thelial growth factor in ovarian hyperstimulation syn- trimester serum relaxin concentrations in pregnant
drome: a preliminary report. Fertil Steril 1996;65: women following ovarian stimulation predict prema-
552–555. turity and preterm delivery. Obstet Gynecol 1993;82:
Lyons CA, Wheeler CA, Frishman GN, et al. Early and 821–828.
late presentation of the ovarian hyperstimulation syn- Whelan J III, Vlahos N. The ovarian hyperstimulation
drome: two distinct entities with different risk factors. syndrome. Fertil Steril 2000;73:883.
Hum Reprod 1994;9:792–799. Whittemore AS, Harris R, Itnyre J, et al. Characteristics
Mathur RS, Akande AV, Keay SD, et al. Distinction relating to ovarian cancer risk: collaborative analysis
between early and late ovarian hyperstimulation syn- of 12 US case-control studies. Part II. Am J Epidemiol
drome. Fertil Steril 2000;73:901–907. 1992;136:1184–1203.
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 203

Index

Abnormalities, Müllerian findings from falloposcopy, 132–33

detecting with ultrasound, 40 Andrology, laboratory design features, 72
spontaneous abortion associated with, 118 Anejaculation, treating, 2–21
Abortion, spontaneous Anesthesia
and age, 24 for gamete intrafallopian transfer, 191–92
and gonadotropin-induced ovulation, 108 in the office, 77–99
in ovarian induction, 199 reaction to, as a complication of in vitro fertilization,
Adhesions, intrauterine, outcomes of treatment of, 172
118–19 for in vitro fertilization, 165
Age Aneuploidy, and diminished ovarian reserve, 35
and fertility, 24–38 Antibiotics, prophylactic, prior to surgery, 81–82
and multifetal gestations, with assisted reproductive Antibodies
technology, 197 anti-sperm, 13–14
and prediction of pregnancy, and the clomiphene therapy for, 19–20
citrate challenge test, 29–30 on sperm, 2
and reproduction, 7–8, 161 Antidotes, for sedation medications, 89
Air compressor, medical, 73 Antral follicles, relationship of count of with assisted
Air delivery system reproductive therapy outcomes, 31
for an in vitro fertilization laboratory, 63–72 Anxiolytics, preoperative administration of, 80
outside air delivery, 64–66 Asherman syndrome, development of, after curettage,
Airflow, directing, in the laboratory, 67 118
Air quality, in the laboratory, 76 Aspiration, protecting against, with premedication,
Air volume, 67–68 8–81
American Board of Obstetrics and Gynecology, 61 Assay, variability of, immunoassays of luteinizing and
American Registry of Diagnostic Medical follicle-stimulating hormones, 31–35
Sonographers, 61 Assisted hatching, 35
American Society of Anesthesiologists (ASA) Assisted reproductive technology (ART), 20, 77, 145
guidelines for nonoperating room anesthetizing effects of inhibin levels on success of, 26
locations, 91 gamete technologies, 6
on monitored anesthesia care, 78 gonadotropins used in, 101–2
on routine preoperative laboratory and diagnostic for male factor infertility, 22
screening, 90 for managing proximal tubal obstruction, 137
American Society of Heating, Refrigeration and Air multifetal gestations in, 197–98
Conditioning Engineers (ASHRAF), ultrasound guidance for embryo transfer at, 168
specification for operating rooms, 63 Audiovisual system, educational, for the laboratory, 76
Amoxicillin, prophylactic administration of, after Azoospermia, testicular biopsy for evaluating, 157–59
surgery, 82
Ampicillin, prophylactic administration of, before Basal body temperature (BBT) chart, 3
surgery, 82 Basal follicle-stimulating hormone ratio to luteinizing
Analysis, of retrograde ejaculates, 156–57 hormone, 27–28
Anatomy Bates Consulting Company, model for infertility
defects leading to infertility, 3–5 treatment, 58–59

203
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 204

204 Index

Benzocaine, 79 of treatment for cervical stenosis, 148–49

Billing, descriptive terminology used in, 85 of in vitro fertilization, 172
Biopsy, of the testis, 17–18 Comprehensive History of Infertility, The (Burns and
Bleeding, after hysteroscopy, 124 Greenfeld), 54–55
Body mass index, and gamete intrafallopian transfer in Computers, capability of, 76
an office setting, 192–93 Conception, spontaneous, after gonadotropin-induced
British Medical Journal, early description of pregnancies, 109
laparoscopy in, 143 Confirmation, of infertility, 1
Bromocriptine, for treating pituitary tumors, 19 Congenital anomalies
Bupivacaine (Marcaine), administration during adrenal hyperplasia
fallopian tube transfer, 82 androgen excess in, 15
androgen excess in, treating, 19
Capitated payment, in fertility treatment, 58 after gonadotropin therapy, studies, 109
Carbon dioxide, for uterine cavity distension, 120 See also Genetic abnormalities
Cefotetan, prophylactic administration of, before Congenital bilateral absence of the vas deferens
surgery, 81 (CBAVD), 150
Centers for Disease Control (CDC), reporting data to Consent forms, for ultrasound-guided follicle
with computers, 76 aspiration, 94–95
Centrifugation, density gradient, for sperm preparation, Contraindications
113–14 to anesthesia in the office, 83
Cervical mucus, interaction with sperm, 14 to controlled ovarian hyperstimulation, 109–10
Cervical stenosis, treatment of, 147–49 to falloposcopy, 128–29
Checklist to gamete intrafallopian transfer, 187
for in-office surgery with anesthesia, 85–86 to hysteroscopy in the office, 119–20
postoperative, 97 to penile ejaculatory stimulation, 152
preoperative, for in-office surgery with anesthesia, to percutaneous epididymal sperm aspiration, 159
92 to rectal probe electroejaculation, 154
Chocolate cyst, in endometriosis, 42 to retrograde ejaculate processing, 156
Chromosomal anomalies to testicular biopsy, 158
Down syndrome, 7 to transcervical tubal cannulation, 138
male reproductive dysfunction accompanying, 15–51 to treating cervical stenosis, 147
risk for, as a function of age, 7 to in vitro fertilization, 162
Cisatracurium, 78 Contrast agents, in sonography, 42–43
Clean rooms, specifications for, 64 Controlled ovarian hyperstimulation, 43
Clinical results, of ovulation induction, 106–7 and intrauterine insemination, 10–115
Clomiphene citrate (Clomid) See also Ovarian hyperstimulation syndrome
gonadotropins for treating anovulation, 100 Coping, with infertility, psychosocial issues, 49–57
for treating anovulation, 7 Costs
for treating oligospermia, 19 of hysteroscopy, justifying in managed care, 124
Clomiphene citrate challenge test (CCCT), 28–31 of microlaparoscopy
Coaxial falloposcopy, 13–31 justifying in managed care, 141–42
Color power angiography (CPA), 45–46 versus other procedures, 142
Complications versus traditional laparoscopy, 144
of falloposcopy, 133–34 of transcervical tubal cannulation, versus
of gamete intrafallopian transfer, 192–93 microsurgical anastomosis and ART, 137
of hysteroscopy, 123–24 of unstimulated in vitro fertilization, 176–77
of ovulation induction, 100, 195–202 of in vitro maturation, 178
with gonadotropin therapy, 107, 111 Counseling, about ovulation induction, 102–3
of penile vibratory stimulation, 154 Couples therapy, in infertility, 55
postoperative, in gamete intrafallopian transfer, 193 Credentialing, of professionals, 6–61
of pregnancy, and age, 59 Cryopreservation, of embryos, 171–72
of processing of retrograde ejaculates, 157 Cryptorchidism, effect on the germinal epithelium, 10
of rectal probe electroejaculation, 155 Culture, of embryos, for in vitro maturation, 181
of transcervical tubal cannulation, 139–40 Cumulative probability of pregnancy, 7
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 205

Index 205

Current procedural terminology (CPT), 85 Endometrium

Cystic fibrosis, family history of, and male infertility, 11 biopsy of, in the secretory phase, 3
ultrasonography for evaluating, 4–41, 105
Database analysis, 60 in stimulated cycles, 44
Design, of a laboratory, 72 Endoscopy
Diabetes, effect on potency and ejaculatory function, for evaluating the fallopian tube, 127–36
11 for evaluating the pelvic anatomy, 5
Diagnosis Energy, for humidification, 70
of infertility by transabdominal and transvaginal Energy sources, for hysteroscopy, 121–22
ultrasonography, 4–46 Epidural anesthesia, advantages of, 78
studies of male infertility, 16–18 studies, 79
Diazepam (Valium), premedication with, in surgery, 80 Equipment
Diet pills, allergy to, special considerations in surgery, for anesthesia, in an office setting, 83–85
85 for cervical dilatation, 148
Discharge instructions energy sources for hysteroscopy, 121–22
for a laparoscopic procedure, 99 for gamete intrafallopian transfer, 188
for ultrasound-guided follicle aspiration, 98 hysteroscopes, structure variations, 12–21
Disease for an office laboratory, 71–72
accompanying ovulatory dysfunction, evaluating, for penile vibratory stimulation, 153
102–3 for percutaneous epididymal sperm aspiration, 159
screening for, prior to surgery, 80 for rectal probe electroejaculation, 154–55
Distension, of the uterine cavity, for hysteroscopy, 120 for retrograde ejaculate processing, 156
Doppler ultrasound, 45–46 for testicular biopsy, 158–59
Down syndrome (trisomy 21), risk of, as a function of for transcervical tubal cannulation, 138–39
age, 7 for in vitro fertilization, 163–64
Doxycycline Estradiol, levels of
prophylactic administration of, before surgery, 81 and basal follicle-stimulating hormone levels, 27–28,
for treating distal tubal occlusion, 4 106
for treating pyospermia, 20 and ovarian stimulation, 104
Droperidol, for reducing nausea and vomiting, 81 and timing for oocyte aspiration, 175–76
Drugs, preparations of gonadotropins, 101–2. See also Estrogen, urinary determination of, for monitoring
Medications ovulation induction, 104
Ductal system, sperm transport in, 151 Etiology
Duration, of therapy, initial counseling about, 102–3 of cervical stenosis, 147
of ejaculatory duct obstruction, 15–51
Ectopic gestation, 198–99 Euestrogenic normogonadotropic ovulatory
management of, 106, 172 dysfunction, 103
rate of, in gamete intrafallopian transfer, 193 Evaluation
Ejaculatory duct obstruction (EDO), 15–51 of the female for infertility, 1–9
Ejaculatory function laboratory, for male infertility, 12–18, 15–51
effect on potency and ejaculatory function, 11 of the male factor in infertility, 1–2, 1–23
neurophysiology of, 151 results, 18
Electrical system, for the laboratory, 74–76 uterine, hysteroscopic, 116
Embryos
culture of, 171 Fallopian tube
number of, for in vitro fertilization/embryo transfer, endoscopic evaluation of, 127–36
34 ultrasonography of, 42
thawing of, 172 Fallopian tube transfer, anesthesia during, 82–83
Embryo transfer Falloposcopy, equipment and technique, 13–34
equipment for, 163 Fecundity
preparation for, 171 and age, 59
procedure for, 167–68, 181 defined, 7
Empiric therapy, for male infertility, 19 Fentanyl, administration in surgery, without anesthesia
Endometriosis, 41–42 personnel present, 82
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 206

206 Index

Fertility rate, in the United States, 1 Gentamicin, prophylactic administration of, before
Fertilization assessment, for in vitro fertilization, 171 surgery, 82
Fever, effect on testicular function, 11 Glucocorticoids, for treating congenital adrenal
Fiberoptic technology, microlaparoscopy using, 143 hyperplasia, 19
Fibroids, submucous, hysteroscopic diagnosis of, 42 Gonadotoxins, list of, 11
Filtration, of air, 65–66 Gonadotropin-releasing hormone, agonists to, down-
Follicle aspiration regulation with, and ovarian responsiveness,
equipment for, 163 32–33
procedures, 165–67, 176 Gonadotropins
ultrasound-guided administration of, in gamete intrafallopian transfer,
anesthesia during, 82 188–89
preoperative instruction, 93 dosage of, in treating diminished ovarian reserve,
Follicles 32
functional ovarian, documenting the presence of, exogenous, indications for treatment with, 10–115
103 See also Human chorionic gonadotropin (hCG);
maturity of, evaluating, 175 Human menopausal gonadotropin (hMG);
monitoring, for in vitro maturation/in vitro Human pituitary gonadotropin (hPG)
fertilization, 181 Gonadotropin therapy, outcomes of, 106–7
puncture of, in vitro fertilization, 44–45 Group therapy, in infertility, 55
Follicle-stimulating hormone (FSH) Growth hormone, role in follicular development, 34
administration in ovulation induction, 10–101 Guidelines for nonoperating room anesthetizing
and age, 24–28 locations, American Society of
assay of, to evaluate male infertility, 15–16 Anesthesiologists, 91
basal levels of, intercycle and intracycle variability Guilt, as a response to infertility, 50
of, 26–27
to initiate and maintain spermatogenesis, 101 Heating, ventilating and air conditioning (HVAC)
Follicular fluid, a1ccumulation of anesthetic agents in, system, design of, 64–66
79 Heterotopic pregnancies, 198–99
Freezers, for the in vitro laboratory, 75 Histerelin, response of the pituitary to, 33
Frozen semen, for intrauterine insemination, 11–11 History
Fructose, seminal, for evaluating ejaculatory duct medical
obstruction, 13 risk factors for aspiration after anesthesia, 81
Future, of treating age-related infertility, 35 of the infertile male, 1–11, 150
of outpatient surgery
Gamete intrafallopian transfer (GIFT), 184–94 laparoscopy under local anesthesia, 143–44
anesthesia for, 77 modern, 77
comparison with controlled superovulation, 111 tests for tubal patency, 141
multifetal gestations with, 197 of in vitro fertilization, 161–73
success rate of, comparison with in vitro Hood, placement of, in planning a laboratory, 72
fertilization, 161 Hormones
Gametes, donor, pregnancy following treatment with, medical therapy for male infertility related to, 18–19
53–54 screening for, in male evaluation, 15–16
Gamete technologies. See Assisted reproductive Human chorionic gonadotropin (hCG)
technology (ART) early ovarian hyperstimulation syndrome and, 195
Gaseous pollutants, from construction materials, 7–71 timing of administration, and patient preparation, 81
Gas supply, in a laboratory, 73–74 Human menopausal gonadotropin (hMG)
Gender, and response to infertility, 51–52 ovulation induction with, 100
Gender ratios, after gonadotropin therapy, 108–9 rate of ovarian hyperstimulation syndrome and, 195
General anesthesia, 77–78 spontaneous abortion rate with use of, 199
Genetic abnormalities for treating hypogonadotrophic hypogonadism, 7
screening for, and recommendation for Human pituitary gonadotropin (hPG), ovulation
preconception counseling, 80 induction with, 100
testing for, in male evaluation, 16 Humidity, control of, in a laboratory, 69–70
See also Chromosomal anomalies; Congenital Hydrogen receptor antagonist, preoperative
anomalies administration of, to prevent aspiration, 81
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 207

Index 207

Hypergonadotropic hypogonadism, symptoms of, 103 Intrauterine masses, identifying with hysteroscopy,
Hyperprolactinemia 117–18
symptoms of, 15 Intravasation syndrome, following oil-based contrast
treating, 18–19 material use in hysterosalpingography, 4
Hypogonadism, sources of androgen excess inducing, Intubation, during laparoscopy, contraindications to,
15–16 82–83
Hypogonadotropic hypogonadism In vitro fertilization (IVF), 43–44, 161–73
medical treatment of, 18–19 hysteroscopy prior to, 119–22
symptoms of, 102–3 laboratory for, 63–76
Hypothalamic pituitary dysfunction outcomes of, and intercycle variability in follicle-
outcomes of gonadotropin therapy in, 107 stimulating hormone levels, 27
Hypothalamic pituitary failure, outcomes of sperm-bound antibodies as a contraindication to, 20
gonadotropin therapy in, 107 unstimulated, 174–83
Hyskon, for uterine distension, advantages and risks of In Vitro Fertilization Registry, 177
using, 120 In vitro maturation (IVM), 178–79
Hysterosalpingo-contrast sonography, 43
Hysterosalpingography (HSG), 4 Jacobaeus of Sweden, historic laparoscopy by, 143
for fallopian tube evaluation, 127 Kallmann syndrome
for tubal patency evaluation, 141–42 medical treatment for, with human chorionic
for uterine evaluation, 116 gonadotropic, 18–19
Hysteroscopy, diagnostic and therapeutic, 116–26 symptoms of, 15

Identity shift, on achieving pregnancy, 53 Laboratory in the office

Immunobead test, for anti-sperm antibodies, 14 evaluation for male infertility, 12–18
Incubators, air supply to, 73 preparation for in vitro fertilization, 163–64, 168–69
Indications setup basics, 63–76
for controlled ovarian hyperstimulation, 109–10 tests for evaluation of male infertility, 15–51
for falloposcopy, 128–29 tests recommended for women, based on age, 80
for gamete intrafallopian transfer, 185–87 Laparoscopic procedure, discharge instructions, 99
for gonadotropin therapy, 103 Laparoscopic transfer versus transvaginal transfer, 192
for hysteroscopy, 116–19 Laparoscopy
for penile ejaculatory stimulation, 152 for diagnosing tubal and peritubal pathology, 128
for percutaneous epididymal sperm aspiration, 159 diagnostic, in idiopathic infertility, 187
for processing retrograde ejaculates, 156–57 for fallopian tube evaluation, 127
for rectal probe electroejaculation, 154 preoperative instructions, 94
for testicular biopsy, 157–58 Latex, allergy to, special considerations in surgery, 85
for transcervical tubal cannulation, 137–38 Layout, model laboratory, in a reproductive center, 68
for treating cervical stenosis, 147 Leiomyomas, identification and treatment of, 117–18
for in vitro fertilization, 162 Leukocytes, in semen, 13
Individual therapy, in infertility, 55 Leuprolide acetate, ovarian responsiveness and
Indomethacin, administration prior to embryo transfer, pregnancy rate after administration of, 34
167 Lewin VHI, algorithm for fertility treatment, 59
Infection, after hysteroscopy, 124 Lidocaine, 79
Infertility, defined, 116 Lighting, effect on in vitro cell cultures, 71
Inguinal surgery, reproductive effects of, 11 Linear everting catheter falloposcopy, 131–32
Inhibin, changes in levels of with age, 25–26 Line filters, for commercial compressed air tanks, 73
Insemination, for male factor treatment, outcomes of, 6 Local anesthesia, 79
Instruments, monitoring system for the laboratory, 75 for gamete intrafallopian transfer, 192
International Classification of Diseases, 85 for laparoscopy, history of, 143
Intracytoplasmic sperm injection (ICSI), 17–18 list of agents for, 89
procedure for, 17–71 for microlaparoscopy, 141
Intratubal gamete transfer, 184–94 with ultrasound-guided follicle aspiration, 82
Intrauterine insemination Loss
and controlled ovarian hyperstimulation, 10–115 associated with infertility, 5–51
technique, 115 of pregnancy, 53
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 208

208 Index

Luteinizing hormone (LH) Metroplasty, hysteroscopic, for treating uterine septum,

administration of, in ovulation induction, 10–101 118
assay of Mevacurium, 78
to evaluate male infertility, 15–16 Microlaparoscopy, 141
in unstimulated in vitro fertilization, 174, 176 Microsurgical epididymal sperm aspiration (MESA),
22, 160
Male Microtubular obstructive disease, surgical treatment of,
response to infertility, 52 22
treating reproductive dysfunction of, 15–60 Midazolam (Versed)
Managed care, effect on office-based infertility administration in surgery, without anesthesia
practice, 58–62, 141 personnel present, 82
Management premedication with, in surgery, 78, 80
of fallopian tube problems, 134–35 Miscarriage rate, after in vitro fertilization, and age, 34
ongoing, in controlled ovarian hyperstimulation, Monitored anesthesia care (MAC), 78
111 in ultrasound-guided follicle aspiration, 82
of proximal tubal obstruction, table, 140 Monitoring
Mechanism of controlled ovarian clinical, of ovarian response, 103–5
hyperstimulation/intrauterine insemination, cycle, in unstimulated in vitro fertilization, 175
109–11 Morphologic tests, of ovarian responsiveness, 31
Media, for assisted reproductive technology, 168–69 Müllerian abnormalities
Medical therapy, for male infertility, 18–21 detecting with ultrasound, 40
Medications spontaneous abortion associated with, 118
amoxicillin, 82 Multifetal gestations
ampicillin, 82 in assisted reproduction, complications of, 172
benzocaine, 79 in ovulation induction, 197–98
bromocriptine, 19 risk of
bupivacaine (Marcaine), 82 with human chorionic gonadotropin
cefotetan, 81 administration, 103, 108
cisatracurium, 78 in assisted reproduction, 53
clomiphene citrate (Clomid), 7, 19, 100 Mumps, postpubertal, 11
doxycycline, 4, 20, 81 Muscle relaxants, for outpatient use, 78
droperidol, 81 Myomas, ultrasound for detecting, 40, 42
fentanyl, 82
gentamicin, 82 National College for Clinical Laboratory Standards
histerelin, 33 (NCCLS), 74
before hysteroscopy, 123 National Fire Protection Association (NFPA), 73
indomethacin, 167 Networks, social and legal issues in, for reproductive
leuprolide acetate, 34 endocrinologists, 61
lidocaine, 79 Nonsteroidal antiinflammatory drugs (NSAIDs)
meperidine (Demerol), 82 before hysteroscopy, 123
metoclopramide (Reglan), 81 for treating pyospermia, 20
mevacurium, 78 Number needed to treat (NNT), evaluative tool for
midazolam (Versed), 78, 80, 82 economic calculations, 142
ondansetron (Zofran), 81 Nurse, preparation for anesthesia and surgery in the
triazolam (Halcion), 80 office, 83
valium, 167
vancomycin, 82 Obstruction, ejaculatory duct, treating, 21–22
Medicines, names and mechanism of action, 89 Ondansetron (Zofran), for reducing nausea and
Meiosis, control of, 178–79 vomiting, 81
Mental health professional, role in infertility treatment, Oocyte-cumulus complex (OCC), harvesting, 169
54–55 Oocytes
Meperidine (Demerol), administration in surgery, collection of, for in vitro maturation/in vitro
without anesthesia personnel present, 82 fertilization, 181
Metoclopramide (Reglan), preoperative administration maturation of, 178–79
of, to prevent aspiration, 81 for in vitro maturation/in vitro fertilization, 181
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 209

Index 209

minimizing exposure to anesthesia, 77–78 selection of

minimizing exposure to medication, 80 for gamete intrafallopian transfer, 186
preparation for retrieval for in vitro fertilization, 169 for ovulation induction, 102–3
Open biopsy, testicular, 158–59 for unstimulated in vitro fertilization, 178
Operating rooms, specifications for, air delivery for in vitro fertilization, 175
systems, 63 for in vitro maturation, 181
Opioid anesthetics, 77–78 Payment, insurance for infertility services, 60
Oral contraceptives, pretreatment with, 34 Pelvic inflammatory disease (PID)
Outcomes considerations in prophylactic administration of
of assisted reproductive technology, effects of antibiotics before surgery, 81
inhibin levels on, 25 ultrasonographic identification of, 42
of controlled ovarian hyperstimulation, 111 Penile vibratory stimulation (PVS), to obtain a semen
database for analysis of, 60 specimen, 152
of pregnancies, with ovarian induction, 198–99 Percutaneous biopsy, testicular, 158–59
of unstimulated in vitro fertilization, success rates, Percutaneous epididymal sperm aspiration, 159–60
177–78 Personnel, for anesthesia administration, 78
of in vitro fertilization, 27 traveling, 82
complications involving, 172 Physical examination
Ovarian cancer, risk of, in ovulation induction, of the male, 11–12
199–201 in treating male reproductive dysfunction, 150
Ovarian hyperstimulation syndrome (OHSS), 195–96 Physicians
as a complication to gamete intrafallopian transfer, preparation for anesthesia and surgery in the office,
193 83
as a complication to in vitro fertilization, 172 recommendations for, in managing psychosocial
risk of, with human chorionic gonadotropin issues, 56
administration, 103 Physiology
risks accompanying, 105–9 of ovulation induction, 10–101
therapy for, 108 reproductive, of the male, 151
See also Controlled ovarian hyperstimulation Pituitary tumor, excluding, in hyperprolactinemia,
Ovarian reserve 18–19
diminished Plumbing, for a laboratory, 73
as a contraindication to in vitro fertilization, 162 Polycystic ovary disease (PCO), 41
and reproduction, 24, 28–29 Polyps, endometrial
evaluating during patient selection for unstimulated association with infertility, 117
in vitro fertilization, 175 ultrasonography for evaluating, 4–42
Ovarian torsion, risk of, with stimulated ovaries, 193 Power, reliability of, for the laboratory, 74–75
Ovaries Pregnancy
basal follicle-stimulating hormone screening with early, ultrasound images in, 44
one only, 27 after infertility, special considerations in, 52–53
sonography for evaluating, 41–42 rate of, and basal follicle-stimulating hormone
Ovulation levels, 25–26
assessment of, 2–3 wastage in gonadotropin-induced ovulation, 108
defects in, 6 See also Multifetal gestations
induction of, 43, 10–115 Preparation
complications of, 195–202 for clinical procedures, in vitro fertilization, 164–65
verifying the occurrence of, 3 for office surgery, 83
for transcervical tubal cannulation, 138
Parthenogenesis, induction by propofol, 79 for in vitro fertilization, 162–63
Pathogenesis, of ovarian hyperstimulation syndrome, Pressurization, in the air delivery system, 67
195–96 Preterm delivery, as a complication of assisted
Pathology, of the tubal lumen, 132–33 reproductive technology, 198
Patient Prevention
preparation for anesthesia and surgery in the office, of multifetal gestations, 197
83 of ovarian hyperstimulation syndrome, 197
preparation for hysteroscopy, 123 Primary care, evaluation of women with infertility in, 1
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 210

210 Index

Primate studies, of in vitro maturation, 179–80 preoperative, 80

Procedure routine, American Society of Anesthesiologists
in cervical dilatation, 148 (ASA) on, 90
in gamete intrafallopian transfer, 188–91 See also Patient, selection of
in hysteroscopy, 122–23 Security systems, for the laboratory, 75–76
in penile vibratory stimulation, 153–54 Selective fetal reduction, 53
in percutaneous epididymal sperm aspiration, 159 counseling about, 102
in processing retrograde ejaculates, 156–57 in multifetal gestations, 197–98
in rectal probe electroejaculation, 155 Semen
in transcervical tubal cannulation, 139 adjunctive studies of, 13–14
in vitro fertilization, 164–72 analysis of, 2, 12–13
Progesterone, luteal phase serum levels of, 3 preparing for in vitro fertilization, 169–70
and pregnancy rate in women over forty, 34–35 Septate uterus, and pregnancy wastage, 118
Prophylaxis, against postoperative nausea and Sex hormone-binding globulin (SHBG), effect of, on
vomiting, 81 measurement of unbound testosterone, 15
Propofol, experimental administration to mice, effect Side effects, in controlled ovarian hyperstimulation,
on fertilization rate, 79 111
Proximal tubal obstruction (PTO), evaluation and Smoking, and age at menopause, 30
management of, 137 Society for Assisted Reproductive Technology (SART),
Psychological evaluation, 54–55 statistics on advantages of in vitro fertilization,
Psychosocial issues, in coping with infertility, 49–57, 161
141 Sodium citrate, preoperative administration of, to
Pyospermia, treatment of, 20 prevent aspiration, 81
Sonography, for detecting uterine structural lesions, 5
Quality control, in the laboratory, for in vitro Sperm, preparation of, for controlled ovarian
fertilization, 168 hyperstimulation, 11–11
Spermatogenesis, physiology of, 151
Recombinant DNA technology, production of Sperm capacitation index (SCI), 14
gonadotropins using, 102 Sperm function
Recommendations, for ovarian reserve screening, penetration assay, 14–15
31–32 tests of, 14–15
Reconstruction, microsurgical, in epididymal Sperm washing (SW), 110
obstruction, 152 technique, 114
Rectal probe electroejaculation, 154–56 Spinal anesthesia, advantages of, 78
Regional anesthesia, 78 Spinal cord injury, adjunctive techniques in, and
with ultrasound-guided follicle aspiration, 82–83 pregnancy rates, 155–56
Relaxin, levels of, and risk of preterm delivery, 198 Strategy
Retrograde ejaculation, treatment of, 20 for coping, and response to a failed treatment cycle,
Risk factors 50
for development of sperm-bound antibodies, 14 for infertility testing, 1
for ovarian hyperstimulation syndrome, 108, 196–97 female evaluation, 5
Room construction, for a laboratory, 7–72 Subacute bacterial endocarditis (SBE), risk evaluation
Rubin test, for tubal patency, 141 and prophylactic antibiotic administration,
81–82
Saline infusion sonohysterography (SIS), 42–43 Succinylcholine, 78
Salpingoscopy, equipment and technique, 129–30 Superovulation, risk of, with human chorionic
Scopolamine, transdermal, for reducing nausea and gonadotropin administration, 103
vomiting, 81 Support, psychological, 55
Screening Surgery, retroperitoneal lymph node dissection, 1–11
with the clomiphene citrate challenge test, 29 Surgical therapy, for male infertility, 21–22
for disease, prior to surgery, 80 Swim-up (SU) procedure, for sperm preparation, 110,
for genetic diseases, 80 113
ovarian reserve Symptoms
recommendations for, 31–32 of ectopic pregnancy, 198–99
threshold values, 3–35 of ovarian hyperstimulation syndrome, 197
3051_Seifer_index_p203-212 11/5/01 10:00 AM Page 211

Index 211

Technology Ultrasonography
fiberoptic, microlaparoscopy using, 143 for monitoring changes in the cervix and
of in vitro maturation, 18–81 endometrial cavity, 104–5
Temperature, control of, in a laboratory, 69–70 for following ovulation induction, 106
Testicle, undescended, 1–11 role in infertility evaluation, 39–48
Testicular biopsy scrotal, 16
for evaluating azoospermia, 157–59 transrectal, for evaluating male infertility, 16
sedation during, 83 Ultrasound-guided follicle aspiration, discharge
Testicular sperm extraction (TESE), 157–59 instructions for, 98
Testosterone, serum levels of, 15 Upper respiratory infection, factors affecting decisions
Three dimensional scan, transvaginal ultrasound, 46 about surgery in the presence of, 81
Timing Urinalysis, postejaculate, 17
of human chorionic gonadotropic injection, 175–76 Urinary tract infections, and male infertility, 13
of hysteroscopy, 122–23 U.S. HealthCare, infertility treatment model of, 58
Transcervical microendoscopy, of the tubal lumen, Uterus, perforation of, as a complication of
13–34 hysteroscopy, 124
Transcervical tubal cannulation, 137–40
Transfimbrial salpingoscopy, 129–30
Transrectal ultrasonography (TRUS), for detecting Vacuum line, for the laboratory, 74
ejaculatory duct obstruction, 13, 16–17 Valium, administration prior to embryo transfer, 167
Transurethral resection, for ejaculatory duct Vancomycin, substitution for penicillin in patients with
obstruction, 152 allergy, 82
Transvaginal transfer versus laparoscopic transfer, 192 Varicocele
Transvaginal ultrasonography (TVUS), 39–48 gonadal function in the presence of, 12
advantage of, for oocyte retrieval, 77 surgery for, 21
for assessing tubal patency, 128 Varicocelectomy, 151–52
in follicle aspiration, and unstimulated in vitro Vasal aplasia, 15–51
fertilization, 174 Vascular permeability factor (VPF), in ovarian
to monitor follicular size, before human chorionic hyperstimulation syndrome, 196
gonadotropin administration, 104 Vas deferens, congenital absence of, 12, 150
Treatment surgical treatment in, 22
cycle of, typical, 105–6 Vasectomy, reversal of, 152
of diminished ovarian reserve, 32–35 VIVA program, prospective payment plan in, 60
ending, decisions about, 52
of infertility, emotional impact of, 51 Water, purification of, for the laboratory, 74
of male factor infertility, 6, 18–22 Women, response to infertility, 51
monitoring, 43–44 World Health Organization (WHO),
strategy for, 5–6 hysterosalpingography versus laparoscopy
in male reproductive dysfunction, 151–52 study, 127
Triazolam (Halcion), premedication with, in surgery,
80
Tubal disease, treatment and outcomes, 6 Zygote intrafallopian transfer (ZIFT), 187
Tubal Embryo Transfer (TET), anesthetics selected for anesthesia for, 77–78
use in, 77–78 multifetal gestation rate in, 197