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Human

Embryo Transfer

Gautam N. Allahbadia
Claudio F. Chillik
Editors

123
Human Embryo Transfer
Gautam N. Allahbadia
Claudio F. Chillik
Editors

Human Embryo Transfer


Editors
Gautam N. Allahbadia Claudio F. Chillik
Medical Director Director of Matercell
Rotunda - The Center for Human Department of Reproductive Medicine
Reproduction, Center for Studies in Genetics
Rotunda - Blue Fertility Clinic & and Reproduction
Buenos Aires
Keyhole Surgery Center Argentina
Mumbai
India

ISBN 978-81-322-1114-3 ISBN 978-81-322-1115-0 (eBook)


DOI 10.1007/978-81-322-1115-0

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Springer New Delhi Heidelberg New York Dordrecht London


© Springer India 2015
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Don’t get hung up on the hard times, the challenges. Tell your
story by highlighting the victories. Because it’s your victories
that will inspire, motivate, encourage other people to live their
stories in grander ways.
~Iyanla Vanzant

We have seen amazing progress against cancer thanks to the


dedicated work of researchers around the world. Their efforts
have led to new and better ways to prevent, detect, diagnose,
and treat cancer. As a result, more people are living longer,
fuller lives after their cancer diagnosis. We are on the brink
of even more life-saving breakthroughs in prevention and
treatment. This book is dedicated to these cancer researchers
and doctors, who gave us the possibility of living beyond
cancer.
Gautam N. Allahbadia and Claudio F. Chillik
Foreword

This monograph, entitled Human Embryo Transfer, edited by Dr. Gautam N.


Allahbadia and Dr. Claudio F. Chillik, includes in-depth, important, new and
useful information about this seemingly simple procedure, the culmination of an
in vitro fertilization cycle, and which may determine its final outcome.
Transferring the embryos into the uterine cavity is definitely the last and most
critical step in IVF. In this monograph, Dr. Allahbadia and Dr. Chillik present
their personal and vast experience, together with the work of some of the fore-
most authorities in the field, in order to summarize the knowledge regarding the
queries that revolve around the embryo transfer (ET) procedure.
Many women undergoing in vitro fertilization cycles fail to conceive. Not
all the causes can be explained and treated. Failure at the stage of embryo
transfer, due to improper preparation or the transfer technique itself, should
not be permissible. It has been demonstrated that about 15 % of the trans-
ferred embryos are expelled after embryo transfer. Most of these cases are
caused due to poor experience of the provider or a faulty embryo transfer
technique. In a recent study, it was demonstrated that when embryo transfer
was performed by a senior (attending) physician, the pregnancy rate was
29.9 % and only 19.1 % for a resident physician (p < 0.05). The importance
of a proper embryo transfer method for successful IVF cannot be overstated.
Numerous methods including the use of abdominal ultrasound for proper
location of the catheter in the uterine cavity, proper application of the specu-
lum on the uterine cervix, correct loading of the ET catheter with culture
medium and air bubbles, dealing with a difficult cervical canal caused fre-
quently by an acute anteversion or anteflexion of the uterus, anatomical
alteration, or using a mock transfer prior to the real one, have been proposed
as a means of improving the technique of ET. All these topics have been
elegantly discussed here, with the respective chapters providing up-to-date
evidence and suggestions.
Proper assessment of the uterine cavity before commencing an IVF cycle
is important. This evaluation is accurately described in the first chapter of the
monograph. Uterine contractions, as a result of the ET process, is one of the
main causes for embryo expulsion, a problem that can be, at least partially,
avoided. This issue as well as the interesting and most debatable facts and
myths of embryo transfer have nicely been detailed in specific chapters in the
book.

vii
viii Foreword

In conclusion, the editors have presented new and very practical data on
ET, highlighting not just a “simple and routine” process of this last and criti-
cal stage of the assisted reproductive technology procedure but one that
deserves more care and attention to detail. This valuable and instructive
monograph will be a useful tool not only for the learning resident but also for
senior physicians, who may experience difficult situations in their daily prac-
tice of embryo transfer.

Adrian Ellenbogen, MD
Clinical Assistant Professor in Obstetrics and Gynecology at the
Rappaport School of Medicine, Technion- Israel Institute of Technology,
Haifa, Israel
Director of In Vitro Fertilization Unit at Hillel Yaffe Medical Center,
Hadera, Israel
Director of the Postgraduate Course in Infertility for Residents in
Obstetrics and Gynecology, Rappaport School of Medicine,
Technion- Israel Institute of Technology, Haifa, Israel
Member of many international (ASRM, ESHRE, ISMAAR, ISIVF,
ISGE) and national (Israeli Fertility Association, Israeli Society of
Obstetrics and Gynecology) societies
Editorial Board Member of the Journal of Reproduction
System and Sexual Disorders
Reviewer: Fertility and Sterility; The Journal of Reproduction System
and Sexual Disorders, Harefuah, IVF Lite
Dr. Ellenbogen has a special interest in in vitro maturation of oocytes,
poor responders, PCOS, IVF outcome, has pioneered IVF treatment
with minimal stimulation and egg donation law in Israel,
and is researching and publishing in these fields.
Received 2012, 2013, and 2014 Star Award of the American Society
of Reproductive Medicine.
Preface

In this book, we have assembled the leaders in their respective fields to update
our concepts about the rate-limiting step in assisted reproduction: the embryo
transfer. The embryo transfer procedure starts by placing a speculum in the
vagina to visualize the cervix, which is cleansed with saline solution or cul-
ture medium. A soft transfer catheter is loaded with the embryos and handed
to the clinician after confirmation of the patient’s identity. The catheter is
inserted through the cervical canal and advanced into the uterine cavity. After
insertion of the catheter, the contents are expelled and the embryos deposited.
Limited evidence suggests avoiding negative pressure from the catheter after
expulsion. After withdrawal, the catheter is handed to the embryologist, who
inspects it for retained embryos. There is good and consistent evidence of the
benefit of ultrasound guidance to ensure correct placement, which is 1–2 cm
from the uterine fundus. There is evidence of a significant increase in clinical
pregnancy using ultrasound guidance compared with using only “clinical
touch.” Having embryos retained in the catheter after embryo transfer is a
relatively uncommon and frustrating event. The reported incidence of retained
embryos varies between 1 % and 8 %. It can be difficult to explain this
unwanted event to patients. Luckily, having to retransfer embryos retained in
the transfer catheter does not have any significant effect on clinical pregnancy
rates during in vitro fertilization (IVF) treatment cycles.
But, there are still many unanswered questions about a procedure that was
first done in 1978 and is still experiencing fine-tuning. In women undergoing
IVF and intracytoplasmic sperm injection (ICSI), embryos transferred into
the uterine cavity can be expelled due to many factors including uterine peri-
stalsis and contractions, low site of deposition, and negative pressure gener-
ated when removing the transfer catheter. Techniques to reduce the risk of
embryo loss following embryo transfer (ET) have been discussed in this
monograph. There is insufficient evidence to support any specific length of
time for women to remain recumbent, if at all, following embryo transfer, nor
is there sufficient evidence to recommend the use of fibrin sealants added to
the embryo transfer fluid. There is very limited evidence to support the use of
mechanical pressure to close the cervical canal following embryo transfer.
Improvements in vitrification now make frozen embryo transfers (FETs) a
viable alternative to fresh embryo transfer, with reports from observational
studies and randomized controlled trials suggesting that (1) the endometrium
in stimulated cycles is not optimally prepared for implantation, (2) pregnancy
rates are increased following FET, and (3) perinatal outcomes are less affected

ix
x Preface

after FET. Laboratory-based studies demonstrate morphological and molecu-


lar changes to the endometrium and reduced responsiveness of the endome-
trium to hCG, resulting from controlled ovarian stimulation. The literature
demonstrates reduced endometrial receptivity in controlled ovarian stimula-
tion cycles and supports the clinical observations that FET reduces the risk of
ovarian hyperstimulation syndrome and improves outcomes for both the
mother and the baby.
Uterine contractile activity plays an important role in the reproduction of
mammals, influencing sperm transport in the genital tract and positioning of
the implanting embryo within the uterine cavity. In humans, apart from the
time of menses, the activity of a nonpregnant uterus is usually not perceived,
and it is also not a subject of any routine clinical testing. Major contractile
factors in nongravid uteri are oxytocin and prostaglandins, locally produced
within the endometrium. Oxytocin synthesis and expression of its receptors
gradually increase in the follicular phase, following an increase in estrogen
levels, and reach their peaks in the periovulatory period. In stimulated cycles,
where supraphysiological estradiol concentrations are present, uterine con-
tractile activity can be elevated. Exaggerated uterine contractions before
embryo transfer are observed in one-third of women undergoing controlled
ovarian stimulation.
Detection of such patients could enable their qualification for pharmaco-
logical treatment. Evaluation of uterine contractions in such cases should be
done noninvasively in order to avoid any endometrial trauma. Ultrasound
evaluation of the movements of the endometrial interface can be applied, and
an entire chapter in this monograph has been devoted to this topic.
Pharmacological treatment of elevated uterine contractility before embryo
transfer could improve the success rates of fertility treatments. So far, appli-
cation of beta mimetics or nonsteroid anti-inflammatory drugs has not been
associated with any progress. The oxytocin receptor system in the myome-
trium and the endometrium is a potential target for a new class of medications
aiming to improve implantation rates.
We hope that this monograph will help not only the beginners in the field
but also the well-established practitioners to update current knowledge and
research in the technique and procedure of embryo transfer.

Gautam N. Allahbadia, MD, DNB, FNAMS


Medical Director
Department of Assisted Reproduction
New Hope IVF, Sharjah, UAE
Rotunda-Center for Human Reproduction,
Rotunda-Blue Fertility Clinic & Keyhole Surgery Center, Mumbai, India

Claudio F. Chillik, MD
Director of Matercell
Center for Studies in Genetics
and Reproduction
Buenos Aires
Argentina
Contents

1 Evaluation of the Uterus Prior to Embryo Transfer. . . . . . . . . 1


Demian Glujovsky and Claudio F. Chillik
2 Trial Embryo Transfer (Mock Transfer) . . . . . . . . . . . . . . . . . . 7
Carlos E. Sueldo, Carolina Borghi, and Adan Nabel
3 Does the Experience of the Provider Affect
Pregnancy Rates After Embryo Transfer? . . . . . . . . . . . . . . . . 11
Grace Younes, Ron Auslander, and Martha Dirnfeld
4 Ultrasound-Guided ETs or Clinical Touch ETs? . . . . . . . . . . . 17
Gautam N. Allahbadia, Rubina Merchant, Goral Gandhi,
and Akanksha Allahbadia
5 Variables That Affect a Successful Embryo Transfer. . . . . . . . 27
Hassan N. Sallam and Nooman H. Sallam
6 Management of Difficult Embryo Transfers . . . . . . . . . . . . . . . 37
Brian A. Levine and Isaac Kligman
7 Facts and Myths of Embryo Transfer . . . . . . . . . . . . . . . . . . . . 51
Claudio F. Chillik, Ivan E. Chillik, and Carolina Borghi
8 Uterine Contractility and Embryo Transfer . . . . . . . . . . . . . . . 61
Sarah Sebag-Peyrelevade and Renato Fanchin
9 Embryo Transfer Media and Catheters. . . . . . . . . . . . . . . . . . . 69
Ayse Seyhan, Mete Işıkoğlu, and Baris Ata
10 Is There A Role for Tubal Transfers? . . . . . . . . . . . . . . . . . . . . 79
Monika Chawla, Michael H. Fakih, Amal Al-Shunnar,
and Jayaprakash Divakaran
11 Loading and Expulsion of Embryos . . . . . . . . . . . . . . . . . . . . . . 87
Gautam N. Allahbadia, Rubina Merchant, Goral Gandhi,
and Akanksha Allahbadia

xi
Contributors

Gautam N. Allahbadia, MD, DNB, FNAMS Medical Director,


Department of Assisted Reproduction, New Hope IVF, Sharjah, UAE
Rotunda-The Center for Human Reproduction, Mumbai, India
Rotunda-Blue Fertility Clinic & Keyhole Surgery Center, Mumbai, India
Akanksha Allahbadia, MBBS Department of Assisted Reproduction,
Rotunda – The Center for Human Reproduction, Mumbai, India
Amal Al-Shunnar, LRCP and SI, MB, BCh, BAO (NUI) Al-Shunnar
Polyclinic, Fakih IVF Fertility Center, Dubai, UAE
Baris Ata, MD, MCT Department of Obstetrics and Gynecology,
Koc University School of Medicine, Istanbul, Turkey
Ron Auslander, MD Obstetrics and Gynecology Department,
Carmel Medical Center, Haifa, Israel
Carolina Borghi, MD Department of Reproductive Medicine,
Center for Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina
Monika Chawla, MD, MRCOG Reproductive Endocrinologist and
Infertility Specialist, Fakih IVF Fertility Center,
Abu Dhabi and Dubai, UAE
Claudio F. Chillik, MD Director of Matercell, Department of Reproductive
Medicine, Center for Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina
Ivan E. Chillik, MD Buenos Aires Cardiovascular Institute,
Buenos Aires, Argentina
Martha Dirnfeld, MD Professor and Head, Division Reproductive
Endocrinology - IVF, Ruth & Bruce Faculty of Medicine, Technion,
Carmel Medical Center, Haifa, Israel

xiii
xiv Contributors

Jayaprakash Divakaran, MSc, PhD Fakih IVF Fertility Center,


Abu Dhabi and Dubai, UAE
Michael H. Fakih, MD Fakih IVF Fertility Center,
Abu Dhabi and Dubai, UAE
IVF Michigan Fertility Center, Michigan, MI, USA
Renato Fanchin, PU-PH Department of Gynecology and Obstetrics,
Unit of Reproductive Medicine, Hospital Antoine Béclère, Clamart, France
Goral Gandhi, MSc Department of Assisted Reproduction,
Rotunda – The Center for Human Reproduction, Mumbai, India
Demian Glujovsky, MD, MSc Department of Reproductive Medicine,
Center for Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina
Mete Işıkoğlu, MD Department of IVF, Obstetrics and Gynecology,
GELECEK: The Center for Human Reproduction, Antalya, Turkey
Isaac Kligman, MD Associate Professor of Obstetrics, Obstetrics,
Gynecology and Reproductive Medicine, The Ronald O. Perelman and
Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical
College/New York Presbyterian Hospital, New York, NY, USA
Brian Allan Levine, MD, MS The Ronald O. Perelman and Claudia
Cohen, Weill Cornell Medical College/New York Presbyterian Hospital,
Center for Reproductive Medicine, New York, NY, USA
Rubina Merchant, PhD Department of Assisted Reproduction,
Rotunda – The Center for Human Reproduction, Mumbai, India
Adan Nabel, MD Department of Assisted Reproduction, Center for Studies in
Genetics and Reproduction (CEGYR), Buenos Aires, Argentina
Hassan N. Sallam, MD, FRCOG, PhD Professor, Department of
Obstetrics and Gynecology, Alexandria University, Alexandria, Egypt
Nooman H. Sallam, MB, BCh Assisted Reproduction Unit,
Alexandria Fertility Center, Alexandria, Egypt
Sarah Sebag-Peyrelevade, MD Department of Gynecology
and Obstetrics, Hospital Antoine Béclère, Clamart, France
Ayse Seyhan, MD Department of Obstetrics and Gynecology, American
Hospital of Istanbul, Women’s Health and Assisted Reproduction Center,
Istanbul, Turkey
Carlos E. Sueldo, MD Department of Obstetrics and Gynecology,
University of California, San Francisco-Fresno, Fresno, CA, USA
Grace Younes, MD Department of Infertility, IVF Division,
Carmel Medical Center, Haifa, Israel
Evaluation of the Uterus Prior
to Embryo Transfer 1
Demian Glujovsky and Claudio F. Chillik

Abstract
Although not very common, uterine abnormalities are one of the causes of
infertility and should be evaluated before starting any treatment. Polyps,
myomas and synechiae are the most frequent pathologies. Direct visual-
ization with hysteroscopy or indirect methods using intracavity fluid, such
as hysterosalpingography or sonohysterography, are the more accurate
methods to evaluate the uterine cavity. However, an initial screening with
a transvaginal ultrasound is usually recommended. Molecular evaluations
of the endometrium are not ready to be used in clinical practice yet.

Keywords
Cavity assessment • Uterine abnormalities • Sonohysterography •
Hysterosalpingography • Hysteroscopy • Ultrasonography • In vitro fertil-
ization • Reproductive Medicine

Introduction believed that it represents 2–3 % of infertility;


intrauterine lesions are much more common in
Implantation failure is usually due to issues related infertile women, and therefore, abnormalities of
to gametes. However, the endometrium plays an uterine anatomy or function should be excluded.
important role in reproduction. Although it is not Some of the main concerns that arise from the
one of the most common causes of infertility, it is above sentence are the following: are all the endo-
metrial abnormalities real causes of infertility?
Can all of them be referred to as ‘abnormalities’?
D. Glujovsky, MD, MSc (*)
Department of Reproductive Medicine, Center for When we say that several women with infertil-
Studies in Genetics and Reproduction (CEGYR), ity have uterine abnormalities but that these are a
Buenos Aires, Argentina very uncommon cause of infertility, it is not dif-
e-mail: glujovsky@cegyr.com
ficult to arrive at the conclusion that a large pro-
C.F. Chillik, MD portion of those ‘abnormalities’ do not impact on
Department of Reproductive Medicine, Center for
the fertility rates and, if they were considered
Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina pathological, the tests would have a high false-
e-mail: cchillik@yahoo.com positive rate. Therefore, the most important

© Springer India 2015 1


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_1
2 D. Glujovsky and C.F. Chillik

considerations to take into account are: Which distort the uterine cavity and those that are large
types of uterine abnormalities should be consid- could have some impact on the fertility outcomes,
ered as responsible for infertility? All of them? and (c) myomectomy should be considered after
Only those that are large? Which size and loca- a thorough evaluation is completed [7].
tion of these abnormalities are related with lower
success rates?
Synechiae

Cavity Abnormalities Synechiae are fibrous tissue strings in the uterine


wall that could impact embryo implantation or
Major uterine cavity abnormalities can be found development. They are commonly caused by
approximately in one of every eight women seek- inflammation (sometimes, after a D&C proce-
ing treatment for subfertility, and the most com- dure) and are present in 0.3–14 % of subfertile
mon pathology is an endometrial polyp (which is women [8].
present in 1–41 %, depending on the test used for
diagnosis, the size to be considered as abnormal
and the population that is evaluated) [1, 2]. Congenital Uterine Abnormalities

The origin of most of the abnormalities in the


Polyps uterus result from a defect in the development of
the Mullerian ducts, usually due to polygenic
Polyps could impact on fertility rates by distorting mechanisms.
the endometrial cavity, having a detrimental effect Septate uterus is the most common structural
on endometrial receptivity and increasing the risk anomaly, present in 1–3.6 % of women with oth-
of implantation failure [3]. Some authors conclude erwise unexplained subfertility [9, 10]. Although
that the impact of the polyp depends mainly on the it can be seen using hysterosalpingography, it is
number of polyps, their size and location [4, 5]. not easy to distinguish from a bicornuate uterus.
Therefore, the accurate diagnosis is better
obtained using ultrasonography and magnetic
Myomas resonance imaging (MRI). Septate uterus is asso-
ciated with recurrent miscarriage and with high
Regarding the fibroids, only those that are sub- rates of infertility, mainly as a result of poor
mucosal or those intramural that distort the endo- blood supply at the septum, which is not good
metrial cavity are considered to interfere with enough for the implanting embryo.
fertility by deforming the uterine cavity. Although Partial failures in development or fusion of the
this is a widely accepted theory, there are some Mullerian ducts result in unicornuate and bicor-
authors who do not agree. A systematic review nuate uterus. The first of these two abnormalities,
about observational studies showed that the pres- although less common, is associated with a
ence of non-cavity-distorting intramural fibroids higher incidence of urinary tract anomalies and
could be associated with adverse pregnancy out- with poor reproductive outcomes. The second
comes in women undergoing IVF treatment [6]. one is the most common uterine anomaly and is
In order to avoid confusion, we should confirm usually present in women with recurrent miscar-
this data with better designed studies. In other riages. However, most women with bicornuate
words, nowadays, only those fibroids that impact abnormalities have no reproductive problems.
on the endometrium are suggested to be resected. Uterus didelphys is the abnormality that
The American Society for Reproductive Medicine results from a complete failure of fusion of the
(ASRM) states that (a) effects of fibroids on Mullerian ducts. These patients have a duplica-
infertility are not well established, (b) those that tion of the uterus. Although women with uterus
1 Evaluation of the Uterus Prior to Embryo Transfer 3

didelphys have higher incidence of miscarriage some tests that most scientific societies and
and preterm deliveries, they usually have good expert authors agree should be performed before
prognosis in terms of difficulty to achieve a preg- an embryo transfer is done. Methods for evalua-
nancy. Nowadays, surgery is not usually indi- tion of the uterus include the following:
cated in these cases.

Hysterosalpingography
Chronic Endometritis
Hysterosalpingography (HSG) is a test that uses
No good-quality studies have evaluated the asso- X-rays to define the shape and size of the uterine
ciation between subclinical chronic endometritis cavity, revealing developmental anomalies (uni-
and infertility. Although bacterial vaginosis is cornuate, septate, bicornuate uteri) or other
associated with histological endometritis and acquired abnormalities (endometrial polyps, sub-
some studies observed that bacterial vaginosis is mucous myomas, synechiae) which could have
more prevalent among patients undergoing IVF potential reproductive consequences. This test
and, especially, in those with unexplained infer- has been used for a long time. However, its diag-
tility, there is no good-quality data supporting the nostic profile is not always considered by health
evaluation of endometritis and its treatment [11, providers, and therefore, diagnosis may some-
12]. Nowadays, there are no scarce data focused times be inaccurate. At the same time, we should
on the evaluation and treatment of chronic endo- also say that it is not so easy to perform a serious,
metritis and IVF outcomes. non-biased research on diagnostic tools in the
infertility field. Although in the case of the HSG,
the most obvious reference test could be the hys-
Uterine Fluid teroscopy and/or laparoscopy (depending on if
we are evaluating the uterine cavity or tubes), in
The incidence of the presence of endometrial an ideal research world, we would like to assess
cavity fluid on the day of oocyte retrieval in an the HSG in a work-up model, where live birth
IVF cycle is around 2–3 % [13]. The presence of rate (or at least pregnancy rate) is the outcome
fluid has a negative impact on the cycle out- that says what is a true positive and what is a true
come, as it is published in several studies. One negative. Real world that shows that such kinds
study showed that the presence of fluid higher of studies are not easy and, therefore, they are not
than 3.5 mm is associated with lower pregnancy available. Then, what do we have to evaluate the
rates [13]. Another study showed that the pres- performance of HSG?
ence of fluid is associated with a lower implan- A retrospective study, published in 2011, that
tation rate and suggested cancelling the embryo evaluated 359 patients, showed that HSG, when
transfer. Nowadays, as vitrification has shown compared with hysteroscopy, had a sensitivity of
excellent results, postponing the embryo trans- 21.56 %, a specificity of 83.76 %, a positive pre-
fer seems to be a good option, when fluid is dictive value of 55.26 %, and negative predictive
present in the endometrial cavity [14]. value of 70.75 %. Overall, agreement between
the two procedures was 68.9 %, and the risk of
abnormal hysteroscopy increased with advanced
Cavity Assessment patient age and duration of infertility [15].
HSG is a test with a long history and is widely
Nowadays, unfortunately, research on the role of used all around the world. Its use is mainly sup-
the endometrium in the implantation process ported to screen for tubal occlusion. According to
seems to be a couple of steps behind, and the the above-mentioned false-positive and false-
focus of research seems to be gametes and negative results, interpretations of the endome-
embryo interactions. Nevertheless, there are trial cavity pathology should be done with care.
4 D. Glujovsky and C.F. Chillik

In summary, as HSG gives reliable information Sonohysterography


about the Fallopian tubes, its use is usually rec-
ommended. Although it could also be helpful in Sonohysterography is a procedure that includes
evaluating the endometrial cavity, care should be the introduction of sterile saline into the uterine
taken because of the relatively high false-positive cavity while doing a transvaginal ultrasonogra-
and false-negative rates. phy in real time. This liquid enables the ultra-
sound to acquire better images, identifying
endometrial polyps, submucous myomas and
Virtual Hysterosalpingography synechiae with a higher definition and, according
to some published studies, with higher sensitivity
Virtual hysterosalpingography (VHSG) is a new and specificity.
technology combining the old HSG with the However, as it is said at the beginning of this
multi-detector computed tomography (CT). chapter, the fact of diagnosing more polyps or
There are few papers about VHSG, and only one even smaller ones does not mean that its resolu-
group has published most of them. This technol- tion improves the prognosis before an assisted
ogy allows the reconstruction of two-dimensional, reproductive treatment cycle. Although there is a
three-dimensional, and virtual endoscopic views consensus regarding the excision of the intracav-
and is proposed as an alternative instead of the ity pathology, there is no strong evidence show-
regular HSG. Another advantage is that it is a ing which of the ‘abnormalities’ are pathological
quicker test that avoids the use of forceps, result- and, therefore, reduce the success rate and which
ing in a less painful procedure. In the published ones are not clinically relevant. Therefore, when
studies, it showed a good accuracy for a variety that information is not clearly available, parame-
of uterine abnormalities and a less discomfort ters such as sensitivity, specificity, false positives
index among the patients. More studies are and false negatives are not easily obtained.
needed to evaluate the role of this technology in A study published in 2011 evaluated 346
the workup of infertility patients [16–18]. patients with a hysteroscopy, following a trans-
vaginal ultrasound and a hysterosonography [19].
This study showed that hysterosonography had
Ultrasonography more accuracy (sensitivity and positive predictive
value over 95 %) for uterine pathologies than a
Transvaginal ultrasonography is a well-tolerated transvaginal ultrasound when using the hysteros-
diagnostic tool that is routinely used in every IVF copy as a reference test.
program. It is useful to diagnose most uterine However, another study published in the same
pathologies, including endometrial polyps, myo- year showed that hysterosonography is not useful
mas, synechiae, congenital uterine abnormalities after a normal tranvaginal ultrasound [20]. In this
and intracavity fluid. Besides, it can be used to study, 124 women with normal ultrasounds and
evaluate some other organs such as the ovaries, 170 women with an abnormal scan were evalu-
the presence of hydrosalpinx and to monitor an ated with sonohysterography. None of the ultra-
ovarian stimulation cycle. It should be noted that sound group with normal ultrasound and
even when it is a reliable tool, it is operator- abnormal sonohysterography had pathology in
dependent, and therefore, the operator should be the latter confirmatory hysteroscopy. On the other
trained in an infertility facility. hand, of those with an abnormal scan, only
Although ultrasonography is usually the 36.4 % showed an abnormal sonohysterography,
first test to be done, sometimes, especially for with a confirmation of pathology in 67 % of the
intracavity pathologies, a complementary test cases. Sonohysterography helped in those cases
is needed: HSG, sonohysterography or with abnormal scan but did not in those with a
hysteroscopy. normal scan.
1 Evaluation of the Uterus Prior to Embryo Transfer 5

In summary, sonohysterography is a useful Endometrial Biopsy Prior to IVF


tool to evaluate the endometrial cavity, mainly
when a suspected lesion is present, and is usually Performing an endometrial biopsy could be use-
less expensive and invasive than the hysteros- ful, not only in terms of diagnosis but also it
copy. Although it seems to have a better diagnos- could be therapeutical. There is some evidence
tic performance than the HSG to evaluate the suggesting that a mild endometrial injury in the
uterine cavity, it is not useful to evaluate the cycle prior to IVF is associated with higher preg-
Fallopian tubes. nancy rates. It has been suggested especially for
those couples with repetitive implantation fail-
ure. The hypothesis is that the injury increases
Hysteroscopy some inflammatory molecules, increasing the
expression of those that are involved in the
Hysteroscopy is a minimally invasive method for embryo implantation. Two systematic reviews
direct visualization of the endometrial cavity, were published in 2012. One of them pooled 7
which allows not only the diagnosis but also the studies (4 were randomized), including 2,062
treatment of intrauterine pathology. A systematic patients with repetitive implantation failure, and
review published in 2012 by the Cochrane showed an increase in clinical pregnancy rates in
Collaboration found only two randomized con- those women that had an endometrial injury (RR
trolled trials that met their inclusion criteria. The 2.32, 95 % CI 1.72–3.13) [23]. The other one
authors showed that polyp resection prior to an gathered 8 studies (2 were randomized) and
intrauterine insemination had a statistically sig- showed an increase in pregnancy rates, both in
nificant increment in the odds of getting a clinical the randomized (RR, 2.63, 95 % CI 1.39–4.96)
pregnancy (OR 4.4, 95 % CI 2.5–8.0) [21]. In the and in the non-randomized studies [24]. Although
same review, it is shown that a hysteroscopic it is not offered as a routine procedure yet, it
myomectomy resulted in higher, although not could be an option for those women with repeti-
statistically significant, pregnancy rates when it tive failures.
was compared to regular fertility-oriented inter-
course in women with submucous fibroids and Conclusions
unexplained subfertility (OR 2.4, 95 % CI 0.97– Uterine abnormalities are common in infertile
6.2, P = 0.06). women. Although polyps and myomas are
In cases of uterine malformations, hysteros- very frequent and it is suggested to remove
copy could be useful. This procedure is the elec- them, large good-quality studies are still lack-
tive choice for a septate uterus. Hysteroscopic ing to confirm the efficacy of this therapeutic
metroplasty is usually performed in these cases, approach. On the other hand, most congenital
and some surgeons perform a laparoscopy at the abnormalities are usually not treated, and
same time in order to avoid uterine perforations. most women can get pregnant with those
In cases of recurrent miscarriage with the pres- conditions.
ence of a septum, this surgery had good results, As a normal uterine cavity is necessary to
improving the pregnancy outcomes [22]. achieve a pregnancy, its evaluation during the
There is no strong evidence supporting the use infertile couple work-up is a routine. Usual
of hysteroscopy as a routine [10]. Therefore, as the standard tests at the initial evaluation are a
effectiveness of this procedure in improving preg- transvaginal ultrasound and a hysterosalpin-
nancy rates has not been established, women are gography (as it is also useful to evaluate the
not generally offered it unless clinically indicated. Fallopian tubes). The rest of the mentioned
In summary, hysteroscopy is usually indicated fol- techniques are used in order to confirm a sus-
lowing repeated implantation failure or, mainly, pected abnormality, diagnosed with these tests
when there is a suspicion of intracavity pathology. or in cases with repeated implantation failure.
6 D. Glujovsky and C.F. Chillik

In the future, new techniques evaluating 12. Wilson JD, Ralph SG, Rutherford AJ. Rates of bacte-
rial vaginosis in women undergoing in vitro fertilisa-
molecular characteristics of the endometrium
tion for different types of infertility. BJOG.
will probably help to better understand why, 2002;109(6):714–7.
even when the endometrial cavity seems to be 13. He RH, Gao HJ, Li YQ, Zhu XM. The associated fac-
normal, some women still fail to get pregnant. tors to endometrial cavity fluid and the relevant impact
on the IVF-ET outcome. Reprod Biol Endocrinol.
2010;8:46.
14. Herrero L, Martinez M, Garcia-Velasco JA. Current
status of human oocyte and embryo cryopreservation.
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15. Taskin EA, Berker B, Ozmen B, Sonmezer M,
Atabekoglu C. Comparison of hysterosalpingogra-
1. Wallach EE. The uterine factor in infertility. Fertil
phy and hysteroscopy in the evaluation of the uter-
Steril. 1972;23(2):138–58.
ine cavity in patients undergoing assisted
2. Silberstein T, Saphier O, van Voorhis BJ, Plosker
reproductive techniques. Fertil Steril. 2011;96(2):
SM. Endometrial polyps in reproductive-age fertile
349–52 e342.
and infertile women. Isr Med Assoc J. 2006;8(3):
16. Carrascosa PM, Capunay C, Vallejos J, Martin Lopez
192–5.
EB, Baronio M, Carrascosa JM. Virtual hysterosal-
3. Rackow BW, Jorgensen E, Taylor HS. Endometrial
pingography: a new multidetector CT technique for
polyps affect uterine receptivity. Fertil Steril.
evaluating the female reproductive system.
2011;95(8):2690–2.
Radiographics. 2010;30(3):643–61.
4. Yanaihara A, Yorimitsu T, Motoyama H, Iwasaki S,
17. Carrascosa P, Baronio M, Capunay C, et al.
Kawamura T. Location of endometrial polyp and
Multidetector computed tomography virtual hystero-
pregnancy rate in infertility patients. Fertil Steril.
salpingography in the investigation of the uterus and
2008;90(1):180–2.
fallopian tubes. Eur J Radiol. 2008;67(3):531–5.
5. Stamatellos I, Apostolides A, Stamatopoulos P, Bontis
18. Carrascosa P, Capunay C, Vallejos J, Baronio M,
J. Pregnancy rates after hysteroscopic polypectomy
Carrascosa J. Virtual hysterosalpingography: experi-
depending on the size or number of the polyps. Arch
ence with over 1000 consecutive patients. Abdom
Gynecol Obstet. 2008;277(5):395–9.
Imaging. 2011;36(1):1–14.
6. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y,
19. Bingol B, Gunenc Z, Gedikbasi A, Guner H, Tasdemir
Coomarasamy A. The effect of intramural fibroids
S, Tiras B. Comparison of diagnostic accuracy of
without uterine cavity involvement on the outcome of
saline infusion sonohysterography, transvaginal
IVF treatment: a systematic review and meta-analysis.
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Hum Reprod. 2010;25(2):418–29.
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7. Practice Committee of American Society for
20. Almog B, Shalom-Paz E, Shehata F, et al. Saline
Reproductive Medicine in collaboration with Society
instillation sonohysterography test after normal base-
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21. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol
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BW, D’Hooghe TM. Hysteroscopy for treating sub-
fertilization. Hum Reprod. 2010;25(8):1959–65.
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9. Saravelos SH, Cocksedge KA, Li TC. Prevalence and
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10. The American Fertility Society classifications of
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23. Potdar N, Gelbaya T, Nardo LG. Endometrial injury
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Jenkins JM, Hull MG. The influence of bacterial vagi-
injury and IVF outcome: a systematic review and
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345–54.
Reprod. 1999;14(9):2411–5.
Trial Embryo Transfer (Mock
Transfer) 2
Carlos E. Sueldo, Carolina Borghi, and Adan Nabel

Abstract
Mock transfer is an important part of the in vitro fertilization (IVF) proce-
dure; it can be easily done during the cycle before the procedure and will
collect valuable information for when the actual embryo transfer takes
place. Knowing the length of the uterine cavity, its orientation and, above
all, how easy it is to pass the endocervical canal should help in doing an
easy transfer when the time comes. Avoiding the use of a tenaculum, lami-
naria or cervical dilators should optimize the success of assisted reproduc-
tive technology (ART) procedures, as the incidence of uterine contractions
and blood in the catheter is significantly decreased.

Keywords
Mock transfer • Laminaria • Tenaculum • Stylet

Introduction ity, with over five million births worldwide. Since


the pioneering years of IVF, many changes have
In vitro fertilization (IVF) has become the most been introduced, all geared towards improving
effective tool for the treatment of human infertil- the pregnancy rates that we can offer our patients.
The impact of these changes has been significant,
C.E. Sueldo, MD (*) especially in the so-called good prognosis IVF
Department of Obstetrics and Gynecology, University
patients, in which clinical pregnancy rates over
of California, San Francisco-Fresno, Fresno, CA, USA
e-mail: drsueldo@hotmail.com 50 % are not unusual today. It is worth mention-
ing that today, the IVF laboratory is functioning
C. Borghi, MD
Department of Reproductive Medicine, Center for with great predictability, systematically culturing
Studies in Genetics and Reproduction (CEGYR), and making available high-quality blastocysts
Buenos Aires, Argentina that carry a high rate of implantation.
e-mail: cborghi@cegyr.com
Transferring embryos transcervically was tra-
A. Nabel, MD ditionally considered a simple technical proce-
Department of Assisted Reproduction, Center for
dure, and no major changes have taken place
Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina since it was first introduced three decades ago by
e-mail: nabeladan@cegyr.com Edwards et al. [1]. Yet, it is fair to say that

© Springer India 2015 7


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_2
8 C.E. Sueldo et al.

complicated or difficult embryo transfers (ETs) ing diagnostic hysteroscopies after mock trans-
are not uncommon and can ruin many days of fers with different catheter types. However, there
hard work in the IVF laboratory, compromising a are multiple other reasons for a difficult ET,
couple’s chance of achieving pregnancy. among which, the dexterity and experience of the
Clinicians typically describe the embryo operator is felt to be an important factor, with
transfer procedures as easy or difficult, reflecting reports showing that a minimum number of trans-
the technical problems that one may encounter in fers are needed before a clinician shows compe-
trying to pass the embryo transfer catheter tency in performing ETs [5].
through the cervical canal and into the uterine There is no universal agreement that perform-
cavity, where the embryo or embryos are going to ing mock transfers is useful [6], with the main
be placed. Englert et al. [2] reported a 33.3 % criticism being that the position of the uterus may
clinical pregnancy rate with embryo transfers change at the time of actual ET, possibly due to
rated as excellent, while in difficult cases, the the enlarged ovaries resulting from controlled
pregnancy rate was only 10.5 %. ovarian hyperstimulation (COH). Henne and
There are many factors that may be associated Milki [6] compared the uterine position at actual
with a difficult embryo transfer. Sometimes, the ET with that at the mock ET in 996 cycles, and
challenges are anatomical in nature, reflecting the these authors concluded that a retroverted uterus
presence of ridges or folds in the cervical canal, at mock ET was more likely to change at the time
while at other times, they may be due to variations of actual ET; while if the uterus was anteverted, it
in the cervical-uterine body axis and/or uterine was more likely to stay in the same position. As
position. Whatever the existing problem might be, ultrasound-guided transfers are becoming the
there is consensus that a complicated embryo trans- standard of care, the full bladder needed for the
fer typically, is associated with a lower pregnancy procedure may decrease the rate of position
rate, in comparison to the pregnancy rate expected, change from retroverted to anteverted [6].
based on the patient’s age, embryo quality, etc. The uterine measurement during mock trans-
fer has also been criticized, arguing that during
the actual ET the clinician may sometimes find a
When and How to Do It ‘larger’ uterus by 1 cm or more. It has been shown
that in order to optimize the pregnancy rates, the
The trial embryo transfer, or mock transfer, is a embryos should be placed 1.5–2 cm from the
procedure typically performed in the month before uterine fundus [7], and therefore, a ‘blind’ trans-
the actual IVF cycle, with the objective of evaluat- fer, only based on the mock transfer measure-
ing the passage of a transfer catheter into the uterus, ment, may be a less than optimal site for final
as well as to establish the length of the cavity, from placement of the embryos.
the external cervical os to the uterine fundus. It As mentioned earlier in the chapter, the most
documents the position of the uterus (anteverted, common time to perform an ET is during cycle
retroverted, etc.) and is later used as a reference preparation, and before COH is started. The type
during the actual embryo transfer, with the objec- of catheter used, the need for a tenaculum, the
tive of avoiding any possible complications that use of stylets in order to successfully pass the
may hinder a patient’s chance for success. internal os as well as the direction of the uterus
The goal of a successful ET is to deliver the can all be recorded for future reference. These
embryos atraumatically to a location in the uterus findings may lead the clinician to take additional
where implantation is maximized [3]. Potential precautions before the actual ET.
reasons for failing to accomplish that may be due When the ET trial was unsuccessful during
to a disruption of the endometrium by the transfer cycle preparation, especially if it was associated
catheter itself, as demonstrated by our group [4]. with patient discomfort, some clinicians may try
We clearly showed that soft catheters are less to perform a mock transfer after completing the
traumatic to the endometrial tissue, by perform- oocyte aspiration, while others may prefer to
2 Trial Embryo Transfer (Mock Transfer) 9

perform the trial ET right before the actual trans- need for cervical dilation as a result of the infor-
fer but with great caution, so as not to touch the mation obtained at the ET trial, we recommend
uterine fundus, as this has been shown to elicit using osmotic dilators (Laminaria tents), which
uterine contractions, which may decrease the can be placed and removed before COH and, as
success of the embryo transfer or increase the shown, will facilitate the actual transfer proce-
tubal pregnancy rate. Disruption of the endome- dure [10, 11].
trium at any of these points by the transfer cath- Mansour et al. [12] reported a significant ben-
eter, the catheter sheath or the stylet if passed efit by performing trial ETs, showing in one of
beyond the internal os may theoretically cause a the few randomized clinical trials performed on
deleterious effect on the pregnancy outcome. 335 IVF patients that implantation and pregnancy
There are few comparisons in the literature rates were improved in the group that had trial
among different times for ET trials and preg- ETs.
nancy rates, yet a report by Katariya et al. [8]
showed in a retrospective study of 289 patients Conclusions
that the timing of the trial transfer, either during There is a wide spectrum amongst clinicians
oocyte retrieval or before COH, did not signifi- regarding the performance of trial ETs or
cantly impact pregnancy rates (48.4 % vs. 47.6 % mock transfers; this spectrum varies from sys-
respectively). tematically doing the procedure in all IVF
At our Centre, when the ET trials are per- patients to never using the technique and in
formed just before the actual ET, we prefer to do these cases, always guiding the placement of
it under ultrasound guidance, passing the catheter the embryos by ultrasound at the time of the
just above the internal os but without going fur- actual embryo transfer.
ther into the fundal area. As we routinely use soft We recommend doing trial ETs, as it can
catheters for our embryo transfers, either Wallace identify those problematic patients that
catheters (Smiths Medical, UK) or Cook cathe- will end up having traumatic transfers,
ters (Cook Ob-Gyn, USA), if the first 5 cm of the with the proven consequences of poor
catheter (which is the length of the soft portion pregnancy rates.
outside the sheath) does not pass the internal os In our clinical practice, we perform trial
easily, we then attempt to advance the sheath of ETs just before COH, to gain preliminary
the catheter to the internal os and then ‘feed’ the information about the uterine anatomy, and
catheter, to avoid placing the sheath itself inside then repeat the trial under ultrasound guid-
the endometrial cavity and possibly injuring the ance just before the actual transfer, but only
endometrium and/or triggering uterine contrac- passing the soft catheter above the internal
tions. Only in cases where everything else has cervical os. In addition, if the trial ET is easy
been unsuccessful, we will push the sheath above and satisfactory, we will use the same cathe-
the internal os, in order to secure that the catheter ter for the actual embryo transfer.
loaded with embryos (after-loading technique) In summary, although the data available in
will go safely into the upper cavity, for ideal the literature about the value of routinely per-
placement under ultrasound guidance. forming trial ETs does not universally support
The use of firm stylets and tenaculum is to be its use, we believe that mock transfers are
avoided, as these would make the transfer trau- important in identifying those IVF patients
matic and possibly trigger uterine contractions, likely to have complicated and difficult
as shown by Franchin et al. [9]. If there is a need embryo transfers, allowing the clinicians to be
for traction on the cervix to facilitate the ET pro- prepared and institute measures that will facil-
cedure, placing a cervical stitch during the folli- itate this important step in the optimization of
cle aspiration and leaving a long suture for IVF pregnancy results, ultimately providing
traction may be a better option, especially when a the couple with the highest chance of success
difficult ET is likely to occur. Also, if there is a of their treatment cycle.
10 C.E. Sueldo et al.

References 7. Coroleu B, Carreras O, Veiga A, et al. Embryo trans-


fer under ultrasound guidance improves pregnancy
rates after in-vitro fertilization. Hum Reprod.
1. Edwards RG, Fishel SB, Cohen J, Fehilly CB, Purdy
2000;15:616–20.
JM, Slater JM, Steptoe PC, Webster JM. Factors influ-
8. Katariya K, Bates GW, Robinson RD, Arthur NJ,
encing the success of in vitro fertilization for alleviat-
Propst AM. Does the timing of mock embryo transfer
ing human infertility. J In Vitro Fert Embryo Transf.
affect in vitro fertilization implantation and preg-
1984;1:3–23.
nancy rates? Fertil Steril. 2007;88(5):1462–4.
2. Englert Y, Puissant F, Camus M, Van Hoeck J, Leroy
9. Fanchin R, Righini C, Olivennes F. Uterine contrac-
F. Clinical study on embryo transfer after human
tions at the time of embryo transfer alter pregnancy
in vitro fertilization. J In Vitro Fert Embryo Transf.
rates after in vitro fertilization. Hum Reprod.
1986;3:243–6.
1998;13:1968–74.
3. Mains L, Van Voorhis BJ. Optimizing the technique
10. Glatstein IZ, Pang SC, McShane PM. Successful
of embryo transfer. Fertil Steril. 2010;94(3):785–95.
pregnancies with the use of laminaria tents before
4. Marconi G, Vilela M, Belló J, Diradourián M,
embryo transfer for refractory cervical stenosis. Fertil
Quintana R, Sueldo C. Endometrial lesions caused by
Steril. 1997;67(6):1172–4.
catheters used for embryo transfers: a preliminary
11. Schoolcraft WB, Surrey ES, Gardner DK. Embryo
report. Fertil Steril. 2003;80(2):363–7.
transfer: techniques and variables affecting success.
5. Shah DK, Missmer SA, Correia K, Racowsky MC,
Fertil Steril. 2001;76:863–70.
Ginsburg E. Efficacy of intrauterine inseminations as
12. Mansour R, Aboulghar M, Serour G. Dummy embryo
a training modality for performing embryo transfer in
transfer: a technique that minimizes the problems of
reproductive endocrinology and infertility fellowship
embryo transfer and improves the pregnancy rate in
programs. Fertil Steril. 2013;100(2):386–91.
human in vitro fertilization. Fertil Steril.
6. Henne MB, Milki AA. Uterine position at real embryo
1990;54:678–81.
transfer compared with mock embryo transfer. Hum
Reprod. 2004;19(3):570–2.
Does the Experience
of the Provider Affect Pregnancy 3
Rates After Embryo Transfer?

Grace Younes, Ron Auslander,


and Martha Dirnfeld

Abstract
Embryo transfer is one of the most critical procedures in assisted repro-
duction. The influence of the individual physician performing the embryo
transfer on pregnancy outcome is unclear, and published reports on this
issue have shown conflicting results. While some research found that the
pregnancy rate varied greatly among individual physicians within the
same IVF, others have not found such a difference. A difference in implan-
tation and pregnancy rates between clinicians, if found, could be related to
the experience of the provider and the technical method of embryo trans-
fer. It seems that this difference between physicians could be overcome
with a learning curve and practice, and by standardizing the method of
transfer.

Keywords
Embryo transfer • Physician • Provider • Pregnancy rate • Learning curve

Introduction
G. Younes, MD (*) Embryo transfer is one of the most critical
Department of Infertility, IVF Division,
procedures in assisted reproduction. Despite
Carmel Medical Center, Haifa, Israel
e-mail: graceyo@clalit.org.il progress in the assisted reproduction field during
the past years, little impact has been seen on the
R. Auslander, MD
Obstetrics and Gynecology Department, pregnancy rate of replaced embryos. The esti-
Carmel Medical Center, Haifa, Israel mated clinical pregnancy rate for in vitro fertil-
e-mail: ronmd@clalit.org.il ization (IVF) is 28.9 % per aspiration and 32.9 %
M. Dirnfeld, MD per transfer [1], for intracytoplasmic sperm injec-
Division of Reproductive Endocrinology - IVF, tion (ICSI) 28.7 % per aspiration and 32 % per
Ruth and Bruce Faculty of Medicine,
transfer, and for frozen embryo replacement the
Technion,Carmel Medical Center, Haifa, Israel
e-mail: Dirnfeld_martha@clalit.org.il, pregnancy rate is around 20.9 % per thawing and
dirnfeld@clalit.org.il 42.3 % per transfer [1]. The delivery rates per

© Springer India 2015 11


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_3
12 G. Younes et al.

aspiration and per transfer are 20.6–33.6 % and The most likely factors explaining conflicting
23–36.6 % for IVF and 19.3–33.9 % and 21.5– results from different studies on the experience of
36.6 % for ICSI and frozen embryo transfer, the provider are related to the method or tech-
respectively [1]. So far, the delivery rates in nique of embryo transfer, which varies among
Europe remain lower than in the USA [1]. physicians, prior experience of the physicians
The conservative and optimal estimates of performing the transfers, different methods of
cumulative live birth rates at the third cycle are loading the catheter used by embryologists and
around 42.7 % and 65.3 %, respectively for trans- the number of transfers performed per physician,
fer of cleavage stage embryos and 52.4 % and which varied widely among the studies, claiming
80.7 % for transfer of blastocyst embryos [2]. differences among performers [9–13].
Variable factors affecting pregnancy rates In addition, the existence of other confound-
have been proposed including patient’s age, the ing factors and the criteria used to limit those fac-
cause and length of infertility, endometrial tors, such as the cause of infertility, stimulation
thickness, embryo quality, number of embryos protocols, embryo quality and proper placement
transferred, genetic abnormalities of embryos, of embryos in the uterine cavity, may also affect
uterine receptivity and the embryo transfer tech- analysis and results.
nique [3, 4]. The pregnancy rate varied among the physi-
Several factors related to the transfer tech- cians in different studies from 13 % to 54 %, and
nique have been reported to be associated with the implantation rate varied from 4.4 % to 14 %
unsuccessful implantation including blood or [9–13].
mucus on or in the catheter, type of catheter used, Hearns-Stokes and colleagues [11] found that
uterine contractions, retained embryos, expulsion after addressing confounding factors, such as
of embryos, site of embryo deposition in the embryo quality, choice of stimulation protocol
uterus, bacterial contamination of the catheter and type of catheter used, the individual provider
and difficult transfer [5–8]. strongly influences pregnancy rates after embryo
Until recently, little attention had been focused transfer 17 % vs. 54.3 % (p < 0.05), and consis-
on the role of the individual performing the tent with this finding, a difference was also
embryo transfer. observed in implantation rates.
One possible explanation for the difference in
pregnancy rates among providers is the experi-
Are the Extent of the Physician’s ence of the provider as proposed by Hearns-
Experience and Level of Skill Critical Stokes and colleagues [11]. They showed that
Factors Affecting the Potential some but not all providers have a learning curve
Success Rate of IVF Procedures? with the embryo transfer procedure and the preg-
nancy rate may thus, increase accordingly.
The influence of the individual physician on Karande and colleagues [12] showed that
pregnancy outcome at embryo transfer is unclear, even in homogeneously managed IVF-embryo
and published reports on this issue have shown transfer programs, outcomes remain to a large
conflicting results. Despite the relative homoge- degree physician-dependent and therefore, vari-
nous patients’ characteristics, similar stimulation able. The pregnancy rate varied among the phy-
protocols, similar number and quality of embryos sicians from 13.2 % to 37.4 %, and the
transferred, it is still unclear, and the data reported implantation rate varied from 4.4 % to 14 %.
are few and conflicting. Some publications Different physicians had varying success rates
reported that pregnancy rate did not differ signifi- despite the fact that they used the same embryol-
cantly between physicians performing embryo ogy laboratory and similar stimulation protocols
transfer [9, 10]. Others suggested that pregnancy [12]. Interestingly, a significant improvement in
rate varied greatly among individual physicians pregnancy rates and implantation rates had been
within the same IVF centre [11–13]. shown after improved physician supervision
3 Does the Experience of the Provider Affect Pregnancy Rates After Embryo Transfer? 13

[12]. Variables that seem to have resulted in A cross-sectional survey was performed among
some of this improvement were more gentle han- all American Board of Obstetrics and Gynecology-
dling of the Wallace catheter, slow injection of approved Reproductive Endocrinology and
the embryos and holding the catheter in place for Infertility Fellowships [14]. Surveys were distrib-
a minute before withdrawing it. uted in 2005 to fellows graduating within the previ-
Angelini and colleagues [13] examined the ous two years. The response rate was 51 % (62/122
difference in pregnancy rates between two pro- fellows). Eighty-nine percent of the fellows who
viders. Some 1,285 embryos were transferred to answered the questionnaires indicated that training
486 women, 253 patients to provider A and 233 in embryo transfer techniques was either extremely
patients to provider B. There was no significant important or important. Fifty-six percent of all fel-
difference between the two groups regarding the lows received experience in embryo transfer during
patients’ distribution and characteristics, or per- their fellowship; most performed embryo transfers
centage of difficult transfers. The method of in their first or second years (67 %, 24 % respec-
loading embryos into the embryo transfer cathe- tively). Out of the respondents, 44 % did not per-
ter and the number and quality of embryos trans- form embryo transfers during their fellowship
ferred did not differ between the two groups. training; the most common reasons for this were
Clinical pregnancy rate (p ≤ 0.01) as well as the that only attending physicians were allowed to
implantation rate (p ≤ 0.001) varied significantly transfer embryos or that patients were unwilling to
between the two providers, being significantly let fellows perform the transfers [14].
higher for the provider A: 36.1 % and 18.3 % in In 2012 a similar 12-question survey was con-
group A and 20.6 % and 9.4 % in group B, ducted of all fellows who graduated from a single
respectively [13]. One observation made was the ART programme from 1985 to 2009. Thirty out
incidence of blood and mucus on the tip of the of forty fellows responded to the survey, and
catheter that was significantly higher in provider 41 % reported performing embryo transfer dur-
B compared to A. ing their fellowship, while 59 % did not acquire
Indeed, blood and excessive mucus on the cath- any experience in embryo transfer. Obviously,
eter is a finding that is often associated with a dif- those who did not acquire experience in embryo
ficult transfer and has been reported to negatively transfer during their fellowship needed more
affect the embryo transfer outcome [7, 8, 13]. training by their colleagues during the first year
The reason for the substantial influence of the after graduation from their fellowship [15].
provider on the pregnancy rate and differences There is continuous striving to find an optimal
among providers remains to be investigated. training programme to acquire the needed skills
Differences in training, skill acquisition and without reducing pregnancy rates, while main-
learning curve, manual dexterity or patience are taining patient’s satisfaction.
possible explanations. Papageorgiou and colleagues [16] examined
Several studies reported that there could be a the pregnancy rates of five fellows at the begin-
learning curve for some but not all providers, ning of their training and showed a learning
with improving pregnancy rates after appropriate curve, with lower pregnancy rates in the first 25
practice and supervision. In addition, standard- cycles as compared to the following 25. They
ization of techniques could lower the differences concluded that after 50 transfers, the results of
among providers. fellows in training are statistically indistinguish-
Studies have also demonstrated the impor- able from those of experienced staff. These
tance of the provider’s practice and supervision results suggest that the performers’ experience
during embryo transfer on the pregnancy rates. with a minimum of 25 embryo transfer might be
This could be of critical value in training new an important variable to improve results. It may
practitioners and fellows. In that context, it is also suggest that it is reasonable to closely super-
important to examine what is the best appropriate vise a new fellow for minimum of 25 embryo
method of training. transfers and define a minimum number of
14 G. Younes et al.

supervised transfers requested until a learning years of IVF practice than physician B. Embryo
curve is reached. transfer in assisted reproduction treatments has
Close surveillance of embryo transfers with traditionally been performed exclusively by gyn-
continuous feedback on pregnancy rates will help aecologists at most IVF units globally. During
identify practitioners who may benefit from addi- the past years more units have adopted the idea
tional assistance in the technique. Karande et al. that embryo transfer be performed by midwives
[12] have succeeded in showing substantial and nurses and they have proven that with ade-
improvement in implantation and pregnancy quate practice, the pregnancy rates when nurses
rates with consistent supervision of the transfer perform embryo transfer could be comparable to
technique for those physicians whose pregnancy those achieved by doctors [19–21].
rates were initially observed to be inadequate. Few studies have compared pregnancy and
In another recent study, Shah et al. [17] exam- implantation rates when embryo transfer was
ined the efficacy of intrauterine insemination (IUI) performed by nurses or midwives after adequate
as a training modality for performing embryo training compared to doctors. In an IVF centre at
transfer in Reproductive Endocrinology and Oxford, the clinical pregnancy rate after transfer
Infertility fellowship programmes. The pregnancy by a nurse was 36.2 %, and the pregnancy rate
rate for the first 100 embryo transfers, performed after transfer by a doctor was 29.4 % [19].
by fellows, was unchanged after implementing IUI Another study in Birmingham reported clini-
training, though a learning curve was noted and cal pregnancy rate of 29.4 % when embryo trans-
the pregnancy rates improved as fellows pro- fer was performed by nurses and 31.8 % when
gressed from the first 20–100 embryo transfers. performed by doctors [20]. A third study in
Although IUI might not be the answer for a Sweden confirmed the same results with a 31 %
training programme for embryo transfer, IUI as a pregnancy rate when embryo transfer was per-
method of training is currently used in many formed by midwives compared to 29 % when
institutions [15]. performed by gynaecologists [21].
Other approaches used are mock transfers, There was no statistically significant difference
performed by trainees immediately before the in clinical pregnancy rate or the implantation rate
staff or trainee performs the live embryo transfer. between the two groups of performers in all the
Mock transfers have been shown to reduce the above studies, which indicates that with appropri-
incidence of difficult transfers during embryo ate training and medical backup, nurses or mid-
transfers and to improve pregnancy and implan- wives can also perform embryo transfers without
tation rate. Patients are likely to find this accept- compromising clinical pregnancy outcomes.
able as it will not reduce the pregnancy rate. In contrast to the above-mentioned studies on
Another approach is the afterload method; a the effect of the providers and experience on the
mock transfer is performed, and if the catheter is outcome of ET, Van Weering and colleagues [10]
easily passed into the uterus, the embryos are have shown that the probability of success in IVF
loaded into a second inner catheter transferred is not dependent on the provider if the transfer
into the uterine cavity while leaving the first cath- procedure is standardized, and they concluded
eter in place. With this method, there is no addi- that the differences between the pregnancy rates
tional step of catheter removal and replacement achieved by the physicians are within the limits
[18]. Further studies to evaluate these methods, of random variation.
as a training programme, need to be performed. It has been shown that when all physicians
It has also been noted that the substantial varia- used the fixed distance method, expelling the
tion noted among individual fellows decreased as embryos at a fixed distance (6 cm) from the
more embryo transfers were completed, indicating external cervical ostium and with that decreasing
that heterogeneity in the inherent skills of individ- the variation between physicians, the pregnancy
ual learners may be overcome with practice. rates increased from 33.6 % to 40.4 % [10]. This
In the study of Angelini et al. [13], physician suggests that standardizing the embryo transfer
A with the higher pregnancy rate had two more procedure might reduce the effect of the physi-
3 Does the Experience of the Provider Affect Pregnancy Rates After Embryo Transfer? 15

Table 3.1 Experience of the performer and parameters influencing a successful embryo transfer
Affected by Not affected by
Parameters experience experience Increase No effect Decrease
Mock embryo transfer v V
Cleaning/aspirating cervical v V
mucous
Us guidance v V
Distance from fundus v V
Touch technique v v
Leaving the catheter inside v V
the uterine cavity for 30–60′
Full bladder v V
Tenaculum usage v V
Blood on catheter v v
Soft catheter v v

cian factor on the probability of successful IVF By applying a technique in which the embryos are
treatment. expelled at a fixed distance from the external os
Van de Pas and colleagues [22] have investi- (6 cm), a remarkable decrease was observed in the
gated the effects of a change in embryo transfer variability in the success rates among physicians:
technique on the variability in success rates most physicians could reach the success rates of the
among physicians. They compared the ‘clinical best-performing physician.
touch’ method versus ‘the fixed distance’ tech- Using ultrasound-guided embryo transfer
nique and found that with the ‘clinical touch’ may assist the deposition of embryos at a fixed
method, pregnancy rates differed greatly among distance without touching the fundal endome-
providers (depending on the degree of trauma trium and allow a less traumatic embryo transfer
caused to the endometrium), whereas after the [22, 24–26].
introduction of the fixed distance technique these Based on available data, although limited,
differences disappeared. In addition, the overall from reviews and Cochrane analyses [27], the
clinical pregnancy rate increased with ‘the fixed parameters influencing a successful embryo
distance’ method from 33.6 % to 40.4 % per transfer are summarized in Table 3.1.
transfer [22]. This could be attributable to the
less traumatic effect of the fixed distance Conclusions
technique. Embryo transfer is the final and most vulner-
The ‘clinical touch’ method was first described able step in IVF treatment. There is still an
by Steptoe and Edwards in 1976 [23] and was a enigma around many factors influencing suc-
well-known and accepted technique for embryo cess rates including the performers’ experi-
transfer. With this method, the catheter is gently ence. Although the influence of the individual
inserted into the cavity until it touches the fundal physician on pregnancy outcome at embryo
endometrium; then it is withdrawn out for 0.5 cm, transfer is still uncertain, according to some
after which the embryos are expelled. Differences reports, there seems to be a difference in
in pregnancy rates between physicians have been implantation and pregnancy rates among clini-
noted when using the clinical touch methods, cians. The difference could be related to the
depending on the degree of trauma caused to the experience of the provider and the technical
endometrium. method of embryo transfer. The differences in
Recently, with ultrasound-guided ET widely skills among physicians could be overcome
implemented, many studies showed that the sites of with a learning curve and practice, using ultra-
deposition of the embryos within the uterine cavity sound-guided embryo transfer and by stan-
have significant effects on success rates [24, 25]. dardizing the method of transfer.
16 G. Younes et al.

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2006;23(7–8):329–32.
Ultrasound-Guided ETs or Clinical
Touch ETs? 4
Gautam N. Allahbadia, Rubina Merchant,
Goral Gandhi, and Akanksha Allahbadia

Abstract
Embryo transfer (ET) is the final rate-limiting step that concludes an
assisted reproductive technology (ART) cycle and determines its clinical
outcome. Hence, an absolute knowledge of the factors that positively
influence the outcome, utmost skill and experience with the technique of
ET is paramount to the desired success. Several factors, such as a routine
uterine evaluation, prior knowledge about the uterine position, cavity
depth, utero-cervical angle and abnormalities, if any, a mock ET to assess
transfer difficulty, the use of ultrasound guidance to monitor ET, soft cath-
eters, avoidance of uterine contractions or blood or mucus on the catheter,
depositing embryos in the mid-portion of the endometrial cavity and, most
importantly, the experience of the provider in performing ET, have been
documented to positively impact the ET outcome. Though the use of ultra-
sound guidance versus clinical touch ET has been a much debated issue,
clinical practice has now largely settled in favour of ultrasound-guided ET,
owing to the numerous advantages provided by the technology,
significantly, the possibility of executing an accurate and atraumatic
embryo transfer under visual guidance.

Keywords
Embryo transfer • Ultrasound guidance • Clinical touch • Embryo transfer
catheter • Uterine cavity • Ultrasound-guided ET • Atraumatic • Clinical
outcome

G.N. Allahbadia, MD, DNB, FNAMS (*)


Department of Assisted Reproduction,
New Hope IVF, Sharjah, UAE
R. Merchant, PhD • G. Gandhi, MSc
Rotunda-The Center for Human Reproduction,
A. Allahbadia, MBBS
Mumbai, India
Department of Assisted Reproduction,
Rotunda-Blue Fertility Clinic & Keyhole Surgery Rotunda – The Center for Human Reproduction,
Center, Mumbai, India Mumbai, India
e-mail: gautam@rotundaivf.com, e-mail: rubinamm@gmail.com; goralgandhi@gmail.com;
gautam@newhopeivf.com, drallah@gmail.com Akanksha.03@gmail.com

© Springer India 2015 17


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_4
18 G.N. Allahbadia et al.

Introduction implantation in a clinical setting [37] to this


effect. However, the documented improvement in
Embryo transfer (ET), the deposition of embryos pregnancy and live birth rates and decreased mul-
into the uterine cavity with the help of an ET cath- tiple pregnancy rates [38–40] has evidently been
eter, is a crucial final step of an assisted reproduc- possible with an optimal ET technique, further
tive technology (ART) cycle, where accuracy and emphasizing the significance of the embryo qual-
skill in performing an atraumatic technique will ity and a carefully performed ET, especially
finally dictate the success with the technique. where an SET policy is mandatory.
Failure at the embryo transfer stage may be due to
lack of good-quality embryos, lack of uterine
receptivity or the transfer technique itself [1]. Clinical Discussion: Ultrasound-
Factors documented to play an instrumental Guided ET Versus Clinical Touch ET
role in influencing the outcome of an ET include
embryo quality, ultrasound guidance [2–7], the use Ultrasound-guided ET involves the transfer of
of soft [8] and echogenic catheters [9–11], the embryos into the uterine cavity at a fixed distance
depth of transfer in the uterine cavity [12–14], the from the fundus under ultrasonographic vision,
experience of the clinician performing ET [15– while ‘clinical touch’ ET involves the transfer of
17], trial transfer, removal of cervical mucus, a embryos into the uterine cavity on the basis of
well-timed ET [18], straightening the utero- clinical perception of the depth of transfer.
cervical angle [19], an embryo after-loading tech- Advances in ultrasound technology and the
nique [20], absence of bacterial contamination use of ultrasound guidance for ET has given the
[21] and slow injection speed [22], in that order of ART practitioner the ability to visually track the
importance. Factors that are known to negatively ET procedure to ensure an accurate and atrau-
impact the ET outcome include a difficult transfer matic delivery of embryos to the site of implanta-
[23–25], presence of blood on the catheter [26– tion. While a standard evidence-based protocol is
29], leaving the embryos inside it for more than still lacking, both transabdominal [2–5] and trans-
120 s [30], contamination of the catheter tip with vaginal [6] ultrasound-guided embryo transfer
cervical bacteria and stimulation of uterine con- have been documented to significantly increase
tractions during ET [31, 32] The use of antibiotics the chances of clinical pregnancy, embryo implan-
prior to treatment [33, 34], immediate catheter tation, ongoing pregnancy and a live birth com-
withdrawal, air in the catheter [35], performing pared to clinical touch alone [2–6]. A systemic
two transfers in the same cycle, prolonged bed rest review and meta-analysis of prospective random-
and sexual intercourse after ET do not influence ized trials comparing ultrasound guidance with
the outcome. However, in this chapter, we will clinical touch ET has demonstrated significantly
focus on the use of ultrasound guidance versus the increased chances of live birth (odds ratio
clinical touch method of performing ET. [OR] = 1.78, 95 % confidence interval [CI] = 1.19–
2.67), ongoing pregnancy (OR = 1.51, 95 %
CI = 1.31–1.74), clinical pregnancy (OR = 1.50,
Rationale 95 % CI = 1.34–1.67), embryo implantation
(OR = 1.35, 95 % CI = 1.22–1.50) and easy trans-
Increasing emphasis on reducing the complica- fer rates with ultrasound-guided ET compared
tions associated with ART, such as multiple ges- with the clinical touch method in 5,968 ET cycles
tation, have led to an increase in the acceptance with no difference in multiple pregnancy, ectopic
and practice of single embryo transfer (SET), pregnancy or miscarriage rates [41]. Brown et al.
with concomitant advances in embryo culture [42] also reported significantly higher ongoing
systems and improved methods to screen and pregnancies with ultrasound-guided ET per
select embryos with good developmental poten- woman randomized compared to clinical touch
tial [36], determine the exact timing of embryo (P < 0.0003) but no evidence of a significant dif-
cleavage and, possibly, estimate the time of ference in the live birth rates. However, owing to
4 Ultrasound-Guided ETs or Clinical Touch ETs? 19

high heterogeneity (64 %), they concluded that mock embryo transfer, 26 % converted to AV at
their results should be interpreted with caution real embryo transfer (P < 0.0001). In frozen-
and primary outcome measures of future studies thawed embryo transfer cycles, 12 % of AV uteri
should be live births per woman randomized [42]. at mock embryo transfer became RV, while 33 %
Ultrasound guidance for ET is an indispens- of RV uteri became AV (P = 0.01). Hence, an RV
able tool that is useful before, during and after ET. uterus at mock embryo transfer will often change
position at real embryo transfer. Since a signifi-
cant number of RV uteri will convert to an AV
Before Embryo Transfer position, they suggested patients with an RV
uterus at mock embryo transfer should still pres-
Routine Uterine Cavity Evaluation ent with a full bladder for embryo transfer [44].
A routine uterine cavity evaluation prior to the
ET procedure enables the clinician to explore Utero-cervical Angle
cavitary abnormalities that may interfere with An ultrasound-guided trial transfer (UTT) prior
embryo implantation and an opportunity to cor- to the actual embryo transfer enables the clini-
rect these prior to proceeding with the transfer. cian to estimate the utero-cervical angle, thus
Studies have reported a 22.9 % incidence of cavi- allowing direction of the catheter along the con-
tary abnormalities following outpatient hysteros- tour of the endometrial cavity, and thereby, avoid-
copy in patients with previous in vitro ing disruption of the endometrium, plugging of
fertilization-embryo transfer (IVF-ET) cycle fail- the catheter tip with the endometrium and insti-
ure and a benefit for resection of submucosal gation of bleeding [7]. Misdirecting the embryo
leiomyomas, adhesions and, at least, a subset of transfer catheter can be avoided by accurate
polyps. A three-dimensional saline sonohys- knowledge of the uterine position at the time of
terography may be particularly useful in the eval- embryo transfer, which can be more accurately
uation. However, prospective randomized trials assessed by routine ultrasound guidance [44]. It
that clearly demonstrate that surgical removal of also enables the clinician to estimate the transfer
all abnormalities improves IVF-ET outcome and difficulty to ensure an accurate and atraumatic
the value of performing this procedure before an ET procedure. Sallam et al. [45] observed that
initial cycle in patients without previous implan- moulding the embryo transfer catheter according
tation failure are mandatory before definitive rec- to the uterocervical angle, measured by ultra-
ommendation can be made [43]. sound, increases clinical pregnancy and implan-
tation rates and diminishes the incidence of
Uterine Position difficult and bloody transfers compared with the
An adequate knowledge about the uterine posi- ‘clinical feel’ method. Patients with large angles
tion, anteverted (AV) or retroverted (RV), prior to (>60°) had significantly lower pregnancy rates
proceeding with the actual ET is essential to pre- compared with those with no angle [OR = 0.36,
vent misdirecting the ET catheter along the cervi- 95 % CI (0.16–0.52)] [45]. Figure 4.1 demon-
cal canal into the endometrial cavity. The value strates negotiation of the ET catheter according
of a mock transfer a few days before the actual to the utero-cervical angle, respectively.
procedure has been challenged as the position of Moreover, the full bladder required to perform
the uterus may change [30]. According to Henne transabdominal ultrasonographic guidance is
and Milki [44], the uterine position may not be itself helpful in straightening the cervical uterine
consistent between a mock transfer performed a access and improving pregnancy rates [7].
month prior to the actual ET and the real ET. They
demonstrated that among 585 patients undergo- Estimation of Cavity Depth
ing 996 consecutive embryo transfer cycles, of The cavity depth, estimated by ultrasound (US),
74 % patients with an AV uterus at mock embryo is clinically useful to determine the depth beyond
transfer, only 2 % became RV at the real ET, which catheter insertion should not occur. The
while of 55 % patients with an RV uterus on clinical pregnancy rate (PR) is reported to be
20 G.N. Allahbadia et al.

infertile couples conducted by Tiras et al. [47] also


reported higher pregnancy and ongoing PRs when
embryos were replaced at a distance >10 mm from
the fundal endometrial surface suggesting that a
distance 10–20 mm seems to be the best site for
embryo transfer to achieve higher PRs [47].
Hence, the depth of embryo transfer is an impor-
tant variable in the embryo transfer technique that
positively influences the implantation rates.
Demonstrating significantly reduced live birth
delivery rates (LBDR) with external guidance as
compared to an atraumatic ET (26.0 % vs. 32.5 %,
respectively), Spitzer et al. [25] concluded that
Fig. 4.1 Negotiating the ET catheter according to the besides embryo culture and patient history, the
utero-cervical angle (Used with permission from quality of an ET might also have an important
Allahbadia et al. [61])
impact on pregnancy outcome. Techniques to
ensure an atraumatic ET, such as mechanical
significantly influenced by the transfer distance uterine cavity length measurements, before start-
from the fundus (difference between the cavity ing treatment might help identify patients at risk
depth and depth of catheter insertion) after con- for a difficult ET and lead to modified treatments,
trolling for potential confounders unlike that esti- such as the primary use of a stylet [25].
mated in a mock transfer 1 month before
treatment. Pope et al. [12] observed that the cav- Endometrial Evaluation
ity depth by US differed from cavity depth by Three-dimensional US facilitates non-invasive
mock by at least 10 mm in >30 % of cases and the evaluation of the human endometrium and identi-
odds of clinical pregnancy increased by 11 % for fies some organic problems that can negatively
every additional millimeter that embryos are influence the implantation process [48, 49].
deposited away from the fundus [12].
Several authors have attested the benefit of
depositing embryos at a distance of >10 mm from During Embryo Transfer
the fundus [13, 46, 47]. Coroleu et al. [13]
reported a significantly higher (P < 0.05) implan- Ultrasound guidance offers several advantages
tation rate when the transfer distance from the during embryo transfer compared to the clinical
uterine fundus at the moment of the embryo touch method such as
deposition in the uterus was 15 ± 1.5 mm (31.3 %)
or 20 ± 1.5 mm (33.3 %) compared to when it was • Facilitates placement of soft catheters and
10 ± 1.5 mm (20.6 %) [13]. There was no differ- increases the ease of transfer performance [7].
ence in the IVF or demographic characteristics An atraumatic ET is crucial to the success
among the groups. Keeping the technique of rates of an ART procedure, and transfer diffi-
embryo loading and the number and quality of culty and endometrial damage may compro-
embryos transferred constant, Pacchiarotti et al. mise the outcome. US-guided ET significantly
[46] also observed significantly higher clinical increases the ease of transfer performance
pregnancy rates when the distance between the compared to the clinical touch method, and
tip of the catheter and the uterine fundus at trans- clinicians recommend that embryo transfer
fer was 10–15 mm compared to ≤10 mm (27.7 % should be performed under US guidance in
vs. 4 %, respectively; p < 0.05) [46]. combination with the use of a soft catheter to
A large recent study that included 5,055 optimize embryo transfer results [6, 50].
ultrasound-guided embryo transfers in 3,930 A decrease in cervical and uterine trauma can
4 Ultrasound-Guided ETs or Clinical Touch ETs? 21

play a role in increasing the pregnancy rates tant to emphasize the significance of using soft
associated with US-guided transfer [6]. catheters, such as the Wallace catheters, here,
A significant concordance has been along with ultrasound guidance to maximize
observed between the perceived difficulty of the clinical outcome. Significantly higher preg-
transfer, presence of blood on the catheter and nancy (P < 0.0005) and implantation rates
degree of endometrial damage (P < 0.05) fol- (P < 0.01) [26] and significantly less frequently
lowing hysteroscopic assessment of endocer- observed severe endometrial lesions [8] have
vical and endometrial damage inflicted by the been reported with the use of soft catheters
embryo transfer trial. Cevrioglu et al. [24] compared to rigid catheters.
reported significantly higher minor and mod- • Avoids touching the fundus.
erate endocervical lesions (19 % and 3 %, • Confirms that the catheter is beyond the inter-
respectively; P > 0.05), a higher incidence of nal os in cases of an elongated cervical canal.
endometrial damage (42 % minor, 29 % mod- • May facilitate an uncomplicated access
erate and 29 % no damage) in the difficult ET through the cervix to the uterine cavity, thus
group compared to the easy transfer group overcoming cervical stenosis [7].
(32 % minor, 3 % moderate and 65 % no dam- • Catheter identification: Ultrasound guidance
age) and a significantly higher incidence of enables the easy visualization and catheter
blood on the catheter (71 %) in the difficult tracking of echogenic catheters, such as the
transfer group compared to the easy and mod- Sure View® catheter (Smiths Medical, UK)
erate groups (25 % and 56 %, respectively) [9], the echogenic WallaceTM catheter (Smiths
[24]. A significantly lower (P < 0.05) implan- Medical, UK) [10] and the Cook® Echo-Tip®
tation (13.8 % vs. 19.4 %), clinical pregnancy catheter (Cook Medical, USA) [11], owing to
(31.1 % vs. 41.9 %) and live birth rate (27.4 % their ultrasonic contrast properties. This, in
vs. 37.3 %) has been reported following the turn, minimizes the need for catheter move-
use of the stylet when the soft inner catheter ment to identify the tip and results in a signifi-
could not negotiate the internal os during ultra- cantly shorter duration of embryo transfer
sound-guided ET compared to easy ETs where procedure since the loaded catheter is handed
the stylet was not required [23]. Despite a to the physician and up to embryo discharge,
higher but statistically insignificant difference thus simplifying USG-guided ET [9–11].
in pregnancy outcomes between the ultrasound Figure 4.2 illustrates the identification of the
and clinical touch groups, Mirkin et al. [50]
observed that the frequency of negative factors
typically associated with difficult transfers,
such as the requirement of a tenaculum, and
presence of blood or mucus on the catheter tip
were significantly lower in the ultrasound-
guided group in comparison with the clinical
touch group [50]. Hence, US-guided ET seems
essential to reduce the transfer difficulty.
A hysteroscopic assessment of the effects of
embryo transfer catheters on the endometrial
surface with ultrasound guidance by Ressler
et al. [51] concluded that despite ultrasound
guidance, endometrial disruption and catheter
displacement occurs with difficult embryo
transfer catheter placement, which may sug-
gest an explanation for lower pregnancy rates Fig. 4.2 Identification of the Sure View® catheter (Smiths
in these difficult cases [51]. It would be impor- Medical, UK) with air bubble
22 G.N. Allahbadia et al.

Fig. 4.4 Placement of air bubble


Fig. 4.3 Cross-section of the Sure View® catheter (Smiths
Medical, UK) (Used with permission from Allahbadia
et al. [61])
patients [53]. There was a significant decrease
Sure View® catheter with air bubble on ultra- (P < 0.05) in the clinical pregnancy and
sound while Fig. 4.3 illustrates the cross sec- implantation rates with a disparity of 10 mm
tion of the Sure View® catheter on or greater in transfer distance from the fundus
ultrasound. (TDF) between 2D and 3D images [54, 55].
• Ultrasound-guided ET may be especially ben-
eficial in patients with previously failed IVF
cycles or in patients with previous cycles
when embryos were transferred by the clinical After Embryo Transfer
touch method [6].
With regard to the technique, both trans- Facilitates Tracking of the Site
vaginal ultrasound-guided ET (with empty of Embryo Deposition [7]
bladder, using the Kitazato Long ET catheter, The air bubble location following ET is the pre-
Japan) and TA ultrasound-guided procedure sumable placement spot of embryos [25].
(with full bladder, using the echogenic Sure Figure 4.4 illustrates the placement of air bubble
View® WallaceTM catheter, Smiths Medical, with the Sure View® catheter. The correlation
UK) yield similar clinical pregnancy and between the observation of the relative position of
implantation rates, with no difference in the the air bubbles in the fundal half of the endome-
transfer difficulty and uterine cramping rates. trial plate following US-guided ET and pregnancy
However, the total duration of transfer rates is controversial, with some studies reporting
(154 ± 119 versus 85 ± 76 s) was statistically a positive correlation [14], while recent, large
significantly higher in the TV ultrasound studies [56, 57] failing to support a relation.
group, but the TV ultrasound-guided proce- Similar live birth rates were observed in patients
dure was associated with increased patient with air bubbles moving towards the uterine fun-
comfort due to the absence of bladder disten- dus with ejection compared with those where air
sion [52]. bubbles remained stable after transfer [57].
• Studies have demonstrated that 3D sonogra- According to Confino et al. [56], bubble migration
phy offers a higher precision in catheter place- analysis supported a rather random movement of
ment in the endometrial cavity [53–55], noting the bubbles and possibly the embryos, even with
catheter tip placement in a different and less- the patient in the horizontal position following
than-ideal area when studied with three- ET, suggestive of active uterine contractions, that
dimensional ultrasound in one-fifth of the horizontal rest post ET may not be necessary, that
4 Ultrasound-Guided ETs or Clinical Touch ETs? 23

gravity-related bubble motion was uncommon rate and atraumatic manner possible com-
and that, a very accurate ultrasound-guided pared to the blind clinical touch method and a
embryo placement may not be mandatory [56]. significant step in favour of a positive clinical
outcome.

Experience of the Provider

According to Kably et al. [1], apart from the


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Variables That Affect a Successful
Embryo Transfer 5
Hassan N. Sallam and Nooman H. Sallam

Abstract
Despite its apparent simplicity, embryo transfer is affected by many vari-
ables. Randomized controlled trials have shown that some of these vari-
ables are associated with significantly higher clinical pregnancy rates.
These include ultrasound guidance during transfer, mid-fundal deposition
of the embryos, performing the transfer with a full bladder and using a soft
catheter rather than a rigid one (unless ultrasound guidance is used).
Difficult transfers and cervical infection diminish the clinical pregnancy
rate significantly, while bed rest, sexual intercourse, presence of air in the
catheter, use of a fibrin sealant, performing the transfer under the effect of
acupuncture or in the lithotomy (rather than the knee-chest) position and
the routine use of antibiotics have no affect on the outcome.

Keywords
Embryo transfer • Embryo replacement • IVF • ICSI • Assisted reproduc-
tion • ART • Outcome of IVF

Introduction (ICSI). Nevertheless, and despite numerous


developments in the field of assisted concep-
Embryo transfer (ET) is the last and arguably tion, the implantation rate of replaced embryos
the most important step in in vitro fertilization remains low. It has been estimated that up to
(IVF) and intracytoplasmic sperm injection 85 % of the replaced embryos fail to implant
[1]. The exact cause of this low implantation
rate is unknown but may reside in the tech-
H.N. Sallam, MD, FRCOG, PhD (*) nique of ET, endometrial receptivity or the
Department of Obstetrics and Gynecology, ability of the embryo to invade the endome-
Alexandria University, Alexandria, Egypt
e-mail: hnsallam@link.net
trium properly. This review will concentrate
on the variables affecting ET in patients under-
N.H. Sallam, MB, BCh
Assisted Reproduction Unit,
going assisted reproductive technology (ART),
Alexandria Fertility Center, Alexandria, Egypt and these will now be discussed in the light of
e-mail: Nooman_sallam@hotmail.com evidence. They include:

© Springer India 2015 27


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_5
28 H.N. Sallam and N.H. Sallam

Position of the Patient During ET Performing a Dummy (Trial) ET

In 1986, Englert et al. [2] conducted a random- In order to prevent a difficult ET, many authors
ized controlled trial (RCT) on 100 patients under- have advocated the performance of dummy (or
going ET. They found no significant difference in trial) ET to determine the position of the uterus
the clinical pregnancy rate between patients who before the actual ET, with varying claims of suc-
had their ET in the knee-chest position compared cess [18, 19]. In the RCT conducted by Mansour
to those who had it in the lithotomy position. et al. [18], the authors found that a trial ET, per-
They therefore advocated the lithotomy position formed in the cycle preceding the actual cycle
as the most convenient for both, the patient and improved the clinical pregnancy rate significantly
the provider [2]. from 13.1 % to 22.8 % (P < 0.05). However,
these studies were challenged by a subsequent
study by Henne and Milki [20], who found that
Acupuncture for ET 55 % of the uteri which were retroverted during
the trial ET reverted to an anteversion position at
Various studies have been published on per- the time of the actual ET while 2 % of those who
forming ET under the effect of acupuncture with were anteverted during the trial ET were retro-
conflicting results [3–5]. In 2008, El-Toukhy verted at the time of the actual ET [20].
et al. [6] conducted a meta-analysis of random-
ized trials and found no significant difference
between patients who had acupuncture versus The Impact of a Full Bladder
those who did not regarding both, the clinical During ET
pregnancy rate (OR = 1.23; 95 % CI = 0.96–1.5)
and the live birth rate (OR = 1.34; 95 % It has been suggested that a full bladder can
CI = 0.85–2.11) [6]. straighten the uterus during ET and obliterate the
utero-cervical angle, therefore facilitating the
introduction of the ET catheter into the uterine
Gentle and Atraumatic Technique cavity. In 2007, Abou-Setta et al. [21] conducted
a meta-analysis of randomized trials and found
The importance of a gentle technique during that a full bladder was associated with a signifi-
embryo transfer has been emphasized by cantly higher ongoing pregnancy (OR = 1.44;
numerous authors who studied the difficulty in 95 % CI = 1.04–2.04) and clinical pregnancy
introducing and/or positioning the ET catheter (OR = 1.55; 95 % CI = 1.16–2.08) rates [21].
inside the uterine cavity, the presence of blood
during ET (coming from the internal os, pres-
ent at the tip of the catheter after ET or just Removing the Cervical Mucus Prior
soiling the outer sheath of the catheter), the to ET
necessity of changing the catheter, the neces-
sity of holding the cervix with a vulsellum It has also been suggested that removing the cer-
(tenaculum), or even the impossibility of reach- vical mucus prior to ET can improve the outcome
ing the uterine cavity altogether [7–16]. In of IVF and ICSI. In 1994, Mansour et al. [22]
2004, we conducted a meta-analysis of the used methylene blue in lieu of the culture medium
published studies and found that a difficult ET droplets containing embryos to investigate the
technique was associated with a significantly matter. They found that when mucus was aspi-
lower clinical pregnancy rate compared to a rated before this dummy ET, the dye was extruded
gentle and atraumatic technique (OR = 0.73; from the uterine cavity in 23 % of instances
95 % CI = 0.63–0.85) [17]. compared to 57 % when it was not [22]. Similarly,
5 Variables That Affect a Successful Embryo Transfer 29

in a real clinical trial, Nabi et al. found that the detrimental remains to be seen by conducting a
embryos were retained in the ET catheter in controlled study with the pregnancy or live birth
17.8 % of instances when the mucus was aspirated rate as the primary outcome.
prior to ET compared to 3.3 % when it was not
[9]. An RCT is needed with clinical pregnancy
rate (or better live birth rate) as the primary out- Sexual Intercourse After ET
come in order to properly evaluate this technique.
Patients undergoing IVF or ICSI usually refrain
from having sexual relationships around the time
Flushing the Cervical Canal of ET for the fear of preventing implantation of
with Culture Medium Prior to ET the embryos. This matter was investigated in an
RCT conducted by Tremellen et al. [27] They
Vigorous flushing of the cervical canal with cul- found no significant difference in clinical preg-
ture medium prior to embryo transfer has been nancy rate in women who had sexual intercourse
suggested as a method to prevent the embryos (23.6 %) compared to those who did not (21.2 %).
from being trapped in the cervical mucus and Moreover, the implantation rate was significantly
hence, improve implantation. In 1999, MacNamee higher in patients who had sexual intercourse
[23] reported that vigorous flushing of the cervi- (11.01 % versus 7.69 %; P = 0.036) [27].
cal canal and the use of a soft catheter improved Consequently, we do not ask our patients to refrain
the pregnancy rates (from 25.3 % to 36.2 %) and from sexual intercourse around the time of ET.
implantation rates (from 8.7 % to 17.7 %) [23].
However, these observations were based on a ret-
rospective analysis, and the authors did not study Performing ET Under Ultrasound
each factor separately (i.e. flushing the cervical Guidance
canal or using a soft catheter) [23]. In a prospec-
tive randomized controlled study of 110 embryo Performing embryo transfer under trans-abdominal
transfers, we have found no statistically signifi- ultrasound guidance improves the pregnancy and
cant difference with and without flushing in preg- implantation rates. The technique was first sug-
nancy rates (25.5 % and 34.5 %, P = 0.4053) or gested by Strickler et al. [28], who compared 16
implantation rates (15.38 % and 17.46 %, abdominal ultrasound-guided transfers with 12
P = 0.7687) [24]. transfers guided by ‘clinical feel’. They found that
ultrasound-guided transfers were easier and there
was less catheter distortion. They concluded that
Avoiding the Use of a Tenaculum with ultrasound guidance (1) transfers can be done
(Vulsellum) During ET with the patient supine in the lithotomy position,
(2) the catheter tip can be accurately positioned in
In 1998, Fanchin et al. [25] described a method the fundus of the uterine cavity, (3) the ejection of
for using ultrasound to study the uterine junc- the transfer bubble into the uterus can be docu-
tional zone contractions [25]. The technique was mented and (4) the observation of the bubble was
used by Lesney et al. [26] to study the effect of comforting to the patient [28].
holding the cervix with a tenaculum (vulsellum) This early study was followed by a plethora of
in 20 subjects. They found that this resulted in a publications, some claiming that ultrasound-
significant increase in the number of uterine con- guided ET was beneficial [29–33], while others
tractions. These contractions included cervico- failed to confirm these results [34–38]. In order
fundal contractions, fundo-cervical contractions, to clarify the issue, we conducted a meta-analy-
random contractions and opposing contractions sis of RCTs and found that ultrasound-guided ET
[26]. Whether these contractions are beneficial or was associated with significantly higher clinical
30 H.N. Sallam and N.H. Sallam

(OR = 1.42, 95 % CI = 1.17–1.73) and ongoing two arms of their study and these results cannot
pregnancy rates (1.49, 95 % CI = 1.22–1.82) therefore, be substantiated [43].
compared to the clinical touch method [39]. Our Most infertility specialists use ultrasound-
findings were confirmed in another meta-analy- guided ET to confirm that the embryos have been
sis, published in the same issue of the journal deposited in the intended site and to ensure that
[40]. In 2007, a Cochrane review included more the embryo did not move after catheter with-
RCTs and concluded that ultrasound-guided ET drawal. However, we believe that the biggest
was associated with significantly higher clinical advantage of ultrasound-guided ET is to measure
pregnancy (OR = (1.42, 95 % CI = 1.17–1.73) the utero-cervical angle prior to ET. We subse-
and live birth (OR = (1.40, 95 % CI = 1.18–1.66) quently bend the tip of the catheter according to
rates [41]. However, in 2008, Drakeley et al. [42] the width of the angle to guarantee a smooth
published an RCT on ultrasound-guided ET passage of the catheter through this point of max-
involving 2,295 patients and found that ultra- imum resistance [44]. We have found that at the
sound-guided ET was not associated with a time of ET, 10 % of patients have a mild angle
higher clinical pregnancy rate and asked to (<30°), 37.2 % have a moderate angle (30° to
update the Cochrane review [42]. Unfortunately, < 45°) and 40.6 % have a large angle (>45°),
detailed information showed that these workers while 10 % of the patients have no angle or a ret-
were using different ET catheters in each of the roverted uterus (Fig. 5.1) [44]. In this randomized

a b

c d

Fig. 5.1 Measuring the utero-cervical angle by transabdominal ultrasonography (a) no angle, (b) small angle (<30°),
(c) moderate angle (30°–60°), (d) large angle (>60°) (Used with permission from Sallam et al. [44])
5 Variables That Affect a Successful Embryo Transfer 31

study, we found that bending the tip of the cathe- pregnancy rate (31.3 %, 33.3 %) compared to
ter at the time of ET improved our clinical preg- depositing it 1 cm below the fundus (20.6 %)
nancy rate significantly, and this is indeed, our [51]. These findings were later confirmed by
current practice [44]. Trans-vaginal [45] and Pope et al., who performed a regression analysis
3D/4D ultrasound-guided ET [46] were also study and showed that for every additional milli-
described but do not seem to offer any advantage meter embryos are deposited away from the fun-
over trans-abdominal ultrasound-guided ET. dus, the odds of clinical pregnancy increased by
11 % [52].

Soft Catheters Versus Rigid


Catheters Time Between Loading
and Discharging the Embryos
It has been suggested that soft ET catheters
should be associated with a better outcome when The time between loading the embryos in the ET
compared to firm catheters, and two meta- catheter and discharging them into the uterine
analyses of RCTs confirmed that soft catheters cavity is critical as the embryos may be affected
were indeed associated with a higher clinical by being outside the CO2 incubator. In an obser-
pregnancy rate (OR = 1.34, 95 % CI = 1.17–1.53) vational study, Matorras et al. [53] found that the
[47, 48]. However, when soft and firm catheters clinical pregnancy rate started decreasing signifi-
were compared in patients undergoing ultrasound- cantly when the loading-to-discharging time
guided ET, a meta-analysis found no difference lapse exceeded 120 s [53].
in clinical and ongoing pregnancy rates between
them [49]. This confirms the fact that a prior
knowledge of the uterine configuration (includ- Waiting 30 s After Embryo
ing the utero-cervical angle) may help the clini- Deposition
cian in conducting a smoother ET, even if he is
using a firm catheter. Many clinicians prefer to wait for 30 s after
embryo deposition before withdrawing the ET
catheter from the uterine cavity. This practice
Presence of Air in the Transfer was studied by Martinez et al. [54], who found no
Catheter significant difference in clinical pregnancy rate
when the catheter was withdrawn immediately
The presence of two small air bubbles after embryo deposition or after 30 s. They con-
surrounding the embryo-containing droplet in cluded that either waiting was not necessary or
the ET catheter does not seem to affect the that waiting a longer time may improve the out-
outcome of IVF or ICSI. Moreno et al. [50] come, but this latter point has not so far been
conducted an RCT on 102 patients and found clarified [54].
no difference in the clinical pregnancy rate
between the presence and the absence of these
air bubbles [50]. The Use of a Fibrin Sealant

Different substances have been added to the


Site of Embryo Deposition embryo-containing droplet in order to increase its
capacity to adhere to the endometrium with vari-
The best site for embryo deposition has been a ous claims of success. Bar-Hava et al. [55] used a
matter of debate. In 2002, Coroleu et al. con- fibrin sealant for this purpose and found that this
ducted an RCT and found that depositing the practice increased the clinical pregnancy rate sig-
embryo 1.5–2 cm away from the uterine fundus nificantly [55]. However, an RCT did not confirm
was associated with a significantly higher clinical these findings [56]. Similarly, Valojerdi et al. [57]
32 H.N. Sallam and N.H. Sallam

conducted a quazi-randomized study using They found no significant difference in the


embryo glue but could not find any significant implantation rate between both groups [68].
difference in the clinical pregnancy rate [57]. Similar conclusions were reported by Brook et al.
However, a Cochrane review of RCTs found that [69], who conducted a similar RCT in 2006 [69].
this practice was associated with a significantly
higher clinical pregnancy rate (OR = 1.41; 95 %
CI = 1.22–1.63) but the live birth rate remained Experience of the Clinician
unchanged [58].
The experience of the clinician seems to play an
important role in determining the outcome of
Bed Rest After ET ET. Hearns-Stokes [70] analyzed the results of
two clinicians performing ET in the same unit
Various studies have been conducted to investi- with embryos provided by the same embryologist
gate whether bed rest after ET would improve the and found a significant difference in the clinical
outcome of IVF and ICSI, with most of them pregnancy rate between both clinicians (17 %
showing no advantage of keeping the patient in versus 54.7 %; P < 0.05). They concluded that
bed after ET [59–61]. A Cochrane systematic training of clinicians is essential before allowing
review on the subject concluded that bed rest them to perform ET on their own [70].
after ET had no effect on the clinical pregnancy Furthermore, well-trained nurses have been found
(OR = 1.33; 95 % CI = 0.77–1.67) or live birth to perform as good if not better than clinicians in
(OR = 1.00; 95 % CI = 0.54–1.85) rates [62]. two studies, and many units are now allowing
their trained nurses to perform ET [71, 72].
Papageorgiou et al. [73] found that the learning
Routine Use of Antibiotics curve requires at least 50 ETs. These should be
done under supervision before the clinician or
Various studies have shown that infection in the nurse is allowed to perform ET on his own [73].
cervical mucus has a detrimental effect on the
outcome of IVF and ICSI [63–65]. Infection Conclusions
can be confirmed by culturing a swab taken Despite its apparent simplicity, ET is affected
from the cervical mucus or from the tip of the by many variables. RCTs have shown that
catheter after ET. We have conducted a meta- ultrasound guidance, mid-fundal deposition of
analysis of these studies and found that cervical the embryos, performing ET with a full blad-
infection was indeed associated with a lower der and using a soft catheter rather than a rigid
clinical pregnancy rate (OR = 0.42; 95 % one (if no ultrasound guidance is used) are
CI = 0.29–0.60) [66]. associated with significantly higher clinical
Administering antibiotics to women undergo- pregnancy rates. They have also shown that
ing ET was also a matter of controversy. Egbase difficult transfers and cervical infection
et al. [67] cultured the tip of the catheter after ET decrease the clinical pregnancy rate signifi-
and prescribed prophylactic antibiotics to patients cantly. On the contrary, RCTs have shown that
with positive cultures. They found that the clini- bed rest after ET, waiting 30 s after ET, sexual
cal pregnancy rate increased significantly from intercourse after ET, the presence of air in the
18.7 % to 41.3 % (P < 0.01) after the use of anti- ET catheter, the use of a fibrin sealant, per-
biotics [67]. However, administering prophylac- forming the ET under the effect of acupunc-
tic antibiotics to all patients undergoing IVF or ture, performing ET in the lithotomy rather
ICSI did not affect the outcome of ET. Peikrishvili than the knee-chest position and the routine
et al. [68] conducted an RCT and prescribed use of antibiotics do not affect the outcome of
amoxicillin and clavulanic acid to half of their the procedure. Finally, performing a dummy
patients, while the other half served as controls. ET, removing the cervical mucus before ET,
5 Variables That Affect a Successful Embryo Transfer 33

flushing the cervical canal before ET and 13. Burke LM, Davenport AT, Russell GB, Deaton
avoiding the use of a tenaculum require fur- JL. Predictors of success after embryo transfer: expe-
rience from a single provider. Am J Obstet Gynecol.
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Martikainen H. The degree of difficulty of embryo
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Management of Difficult Embryo
Transfers 6
Brian A. Levine and Isaac Kligman

Abstract
Difficult embryo transfers are associated with reduced pregnancy and live
birth rates in IVF cycles. Numerous factors including physiological and
anatomical variations can influence the ease of an embryo transfer. In this
chapter, we review how to perform a uterine evaluation, the variables that
influence an embryo transfer, and how to address obstacles to a successful
transfer.

Keywords
Difficult embryo transfer • Cervical stenosis • Cervico-uterine angulation

Introduction transfer medium, and the catheter is placed


intracervically to a uterine depth, approximately
Embryo transfer begins with the placement of 1–2 cm from the fundus. The syringe is
the patient in the dorsal lithotomy position. A depressed, expelling the embryos and medium,
sterile speculum is then inserted into the vagina and the catheter is withdrawn [1].
and the cervix cleaned with culture medium to Although embryo transfer (ET) is relatively
remove excess cervical mucus and vaginal secre- straightforward compared to controlled ovarian
tions. The embryologist loads the embryo(s) into hyperstimulation (COH), oocyte retrieval or
a sterile transfer catheter with a small volume of embryo manipulation, it is critical to a successful
in vitro fertilization (IVF) outcome.
Previous studies have suggested that numer-
B.A. Levine, MD, MS (*)
ous variables can influence IVF success rates
The Ronald O. Perelman and Claudia Cohen Center for
Reproductive Medicine, Weill Cornell Medical College/ with respect to ET-derived outcomes [2–4]. Some
New York Presbyterian Hospital, New York, NY, USA of those variables are the use of ultrasound guid-
e-mail: Bal9016@med.cornell.edu ance, presence of blood or mucus on the catheter
I. Kligman, MD tip at the completion of the procedure, pretransfer
Obstetrics, Gynecology and Reproductive Medicine, cervical dilation, multiple embryo transfer
The Ronald O. Perelman and Claudia Cohen Center for
attempts, the use of anesthesia, uterine contrac-
Reproductive Medicine, Weill Cornell Medical College/
New York Presbyterian Hospital, New York, NY, USA tions, or simply the perceived difficulty of the
e-mail: ikligman@med.cornell.edu embryo transfer procedure [5–9]. In a recent

© Springer India 2015 37


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_6
Table 6.1 Characteristics of the included studies in systematic review and meta-analysis by Phillips et al. [7]
38

Study type, location Inclusion and Markers of difficult


Study and size Intervention exclusion Embryo transfer transfer Outcomes NOS
Bodri (2008) Spain, single-centre Trans-abdominal Fresh IVF Day 2 or 3 transfer Longer, more difficult, Clinical pregnancy 7
RCT, n = 330 ultrasound versus donor cycles with soft catheter, full repeat transfer or use of rate, ongoing
trans-vaginal bladder for TA, dilator. Any amount of pregnancy rate,
unclear for TV blood miscarriages
Drakeley (2008)a UK-based, single- Ultrasound-guided All IVF and Variety of soft Use of outer sheath, Clinical pregnancy 7
centre RCT, n = 2,276 versus clinical touch ICSI cycles catheters, stylet or tenaculum rate
using fresh and ‘comfortably full’
frozen embryos bladder. Day of
transfer unclear
Eskander (2008) Saudi Arabia, Ultrasound-guided Fresh IVF Day 3 transfer with Blood and mucus on Clinical pregnancy 7
single-centre RCT, versus clinical touch cycles with Sydney catheter and catheter tip rate
n = 373 good-quality full bladder
embryos
Karande (2002) USA, single-centre, Cook Echotip™ Not stated. Day 3 transfer with Blood on catheter tip Clinical pregnancy 7
quasi-RCT, n = 251 versus Wallace Fresh, frozen soft catheter, full rate
catheter and donor bladder and
embryo IVF ultrasound guidance
cycles
Mansour (1990) Egypt, single-centre, Mock transfer prior Not stated. Day 2 transfer with Required Clinical pregnancy 7
quasi-RCT, n = 168 to IVF cycle Fresh IVF Wallace, Craft or ‘manipulations and rate
cycles metal catheter. No strong push’ or use of
ultrasound the metal catheter
Rhodes (2007) USA, single-centre Cook™ versus Fresh IVF and Day 3 transfer with ‘Tinge’, moderate, or Clinical pregnancy 7
RCT, n = 99 Wallace™ catheter ICSI cycles. mock transfer at time extensive blood on or in rate
Less than 40 of transfer. the catheter
years old, BMI Moderately full
20–35, first bladder/use of
cycle of IVF ultrasound not clear
B.A. Levine and I. Kligman
Study type, location Inclusion and Markers of difficult
Study and size Intervention exclusion Embryo transfer transfer Outcomes NOS 6
Rhodes (2005) USA, single-centre, To determine factors Fresh IVF and Day 3 transfer with ‘Tinge’, moderate, or Clinical pregnancy 7
prospective cohort instrumental in ART ICSI cycles. soft catheter and extensive blood on or in rate
study, n = 205 outcome Less than 40 mock transfer at time the catheter
years old, BMI of transfer.
20–35, first Moderately full
cycle of IVF bladder, ultrasound
used in some
transfers
Shaker (1993)b UK-based, single- To assess ease of None stated. Unclear Anything other than a Clinical pregnancy 7
centre retrospective transfer and All cycles smooth and direct rate
cohort study, n = 398 pregnancy rate included insertion
Shaker (1993)b UK-based, single- Sublingual GTN First cycle of Transfer with Wallace Use of outer sheath, Clinical pregnancy 7
centre RCT, n = 120 3 min prior to IVF catheter and empty tenaculum or uterine rate
transfer versus bladder sound, or a need to fill
placebo the bladder
Management of Difficult Embryo Transfers

Spandorfer (2003) USA, single-centre To identify which IVF cycles Day 3 transfer with Required manipulation, Clinical pregnancy 7
retrospective cohort factors influence with fresh Wallace catheter and multiple attempts, force, rate
study, n = 2,263 pregnancy outcome embryos mock transfer. dilatation or resulted in
Ultrasound was not trauma
used
Used with permission from Phillips et al. [7]
NOS Newcastle Ottawa Scale
a
Data from ‘first attempts only’ was used rather than from all cycles during the study period
b
This study reported both retrospective data and a prospective RCT using definitions of difficult transfer which were analyzed independently
39
40 B.A. Levine and I. Kligman

systematic review and meta-analysis, 3,066 septum from a bicornuate uterus without further
papers were identified that discussed difficult evaluation.
embryo transfers, 194 were reviewed, and 9 were It is important to note that an HSG is not a
included in the study (Table 6.1) [7]. Although perfect test. Operator errors, such as the presence
live birth outcomes were not reported in any of of air bubbles in the radio-opaque dye, can sug-
the included studies, pooled analysis of five stud- gest the presence of an intracavitary lesion, tubal
ies demonstrated lower clinical pregnancy rates spasm can demonstrate false occlusion of the
subsequent to “non-easy” embryo transfers; this Fallopian tubes, and tubal fistula or extravasation
included three studies that demonstrated that sub- of the dye into the uterine tissues can suggest
jective difficult transfers resulted in reduced false patency [12]. Therefore, this examination
pregnancy rates and that the need for “additional cannot be used as the sole evaluation of uterine
maneuvers” also resulted in lower clinical preg- pathology and should be used in concert with
nancy rates. The authors concluded that despite sonographic imaging. In our practice, we find it
low-quality evidence, the literature suggests that useful for the reproductive endocrinologist to
a difficult embryo transfer reduces the chance of perform the hysterosalpingogram because it
achieving a clinical pregnancy [7]. allows the physician to evaluate the difficulty in
In this chapter, we will review how to perform cannulating the cervix, which is suggestive of the
a uterine evaluation, the role of specific physio- difficulty that may be experienced in the perfor-
logical and anatomical variations on the ease of mance of other transcervical procedures, includ-
embryo transfer, and how to address the difficult ing the embryo transfer [10]. Abnormalities
embryo transfer. found on HSG usually require further imaging or
surgical evaluation (i.e., hysteroscopy or laparos-
copy) and, if necessary, surgical correction.
How to Perform a Uterine Saline infusion sonohysterography (SIS) is
Evaluation the optimal imaging modality for the evaluation
of suspected endometrial polyps and submucosal
As part of the initial infertility evaluation, ana- fibroids. However, in the diagnosis of intrauterine
tomical causes of infertility should be addressed adhesions, it has limited accuracy, similar to that
with a comprehensive physical exam. Vaginal obtained by HSG. Both suffer from a high false-
and/or cervical inspection may reveal structural positive diagnosis rate [13]. Of note, three-
abnormalities that may suggest the presence of a dimensional SIS may surpass the technical
Müllerian anomaly or cervical stenosis. Bimanual limitations of conventional two-dimensional SIS,
exam may reveal uterine enlargement; an irregu- allowing for an evaluation of the uterine cavity
lar shape, acute cervico-uterine angulation or the that is similar to that of a direct hysteroscopic
lack of uterine mobility may be representative of evaluation [14].
adhesive disease or the presence of a peritoneal- If the patient has demonstrable pathology on
uterine adhesion [10]. any of the aforementioned tests or if the study is
Mid-cycle transvaginal sonography can be inconclusive, surgical evaluation may be war-
used to assess the length of the cervix, the con- ranted. Hysteroscopy is the definitive method for
tour of the endometrial stripe, the length of the evaluation of abnormalities of the endometrial
uterine cavity, the presence of Nabothian cysts, cavity and also, can be used to treat intrauterine
or overt pathology such as a Müllerian anomaly, (i.e., adhesions, fibroids, polyps) or intracervical
uterine myoma, or endometrial polyps [11]. (i.e., stenosis) pathology. Laparoscopy allows for
A hysterosalpingogram (HSG) allows the the evaluation of peritoneal structures and for the
assessment of tubal patency and elucidation of possible treatment of peritoneal/uterine adhesions,
submucosal fibroids, uterine polyps, uterine which may be causing overt uterine pathology and
adhesions, and uterine anomalies such as a affecting the contour of the endometrial cavity.
T-shaped cavity secondary to diethylstilbestrol In our program, every patient undergoes a trial
(DES) exposure or possible Müllerian anomaly, transfer, also known as a “uterine sounding” or
although it is difficult to distinguish a uterine “uterine mapping”, prior to starting or during
6 Management of Difficult Embryo Transfers 41

Fig. 6.1 Selection of uterine


catheters. (a) InsemiTM-Cath
(Cook Medical, Spencer, IN,
USA). (b) Wallace® Trial
a
Transfer Catheter (Smiths
Medical International Ltd.,
Hythe, Kent, UK). (c) Wallace®
Malleable Stylet (Smiths
b
Medical International Ltd.,
Hythe, Kent, UK)

Fig. 6.2 Cornell trial transfer


record

Date: Anteverted

Last Menstrual Period: Retroverted


Axial
Catheter Type (Cook, Wallace, Stylet):
Up then Down
Depth:
Down then Up
Comments (i.e., ultrasound guided):
To Patient’s Right
To Patient’s Left
Anterior Ridge
Posterior Ridge

controlled ovarian hyperstimulation or at the garnered regarding the type/size of the speculum
time of oocyte retrieval. The trial transfer is done required, the direction and curve of the catheter,
using an InsemiTM-Cath (Cook Medical, Spencer, the length of the cavity, the perceived difficulty
IN, USA) that is attached to a 0.5 cc tuberculin of the procedure and the need for ultrasound
syringe (Fig. 6.1a). The catheter is advanced to guidance is recorded (Fig. 6.2). Of note, not
the uterine fundus to measure the full length of every transfer in our program is performed under
the uterine cavity and cervical canal. Information ultrasound guidance. This information is also
42 B.A. Levine and I. Kligman

available to the physician performing the embryo into the uterine cavity along with the catheter and
transfer. In the event that the patient has an inter- this may affect implantation. In the same regard,
val pregnancy or uterine surgery, the trial transfer if the embryos adhere to the cervical mucus, they
procedure is repeated either prior to starting or may be dragged out of the uterus upon removal of
during COH or at the time of oocyte retrieval. All the ET catheter. In fact, the presence of mucus on
patients undergoing donor oocyte recipient the catheter tip has been associated with a signifi-
cycles have a trial transfer performed prior to cantly higher incidence of retained embryos [15,
starting their recipient synchronization cycle. 16]. Along the same lines, blood found outside,
In all IVF cases, physicians at our center addi- but not inside, the transfer catheter after ET is
tionally perform a mock embryo transfer imme- associated with lower rates of embryo implanta-
diately before transferring the embryos. The tion and clinical pregnancy although this is likely
patient is positioned and prepared as described not related to the same mechanism as cervical
above and a blunt-ended Wallace® Trial Transfer mucus and instead, is related to a traumatic ET
Catheter (Smiths Medical International Ltd., [17].
Hythe, Kent, UK) advanced to just past the inter- In a prospective study by Mansour et al. [18],
nal os so as not to disturb the endometrium methylene blue dye was used as a surrogate for
(Fig. 6.1b). Using the information gained from culture media in a mock embryo transfer model.
the trial transfer, the physician does a mock As part of their study, the patients underwent
embryo transfer as a means of assessing any mock ET twice, before and after aspiration of the
potential challenges with the procedure and to cervical mucus. Their results demonstrated that
also familiarize him- or herself with the patient’s the dye was extruded at the external os in 57 % of
specific uterine alignment and visualize the opti- the cases when the cervical mucus was not aspi-
mal path of the embryo transfer. rated compared to 23 % when the mucus was
aspirated, a statistically significant difference
[18].
Physiological and Anatomical In a retrospective analysis of patients under-
Variations going a day 3 ET by a single provider, it was
found that by using an embryo afterloading tech-
Cervical Mucus nique, the researchers had a higher clinical preg-
nancy rate as compared to standard direct ET
As part of the initial infertility physical exam, (52.4 % vs. 34.9 % respectively) [19]. In the
cervical aberrations may be noted. Cervical fac- embryo afterloading technique, an empty embryo
tors that may affect a successful embryo transfer transfer catheter was passed into the lower uter-
may include copious cervical mucus, cervical ine segment under ultrasound guidance, the inner
stenosis, acute cervico-uterine angulation, or sheath was slowly removed, and a second inner
anatomical distortion of the cervix to a hard-to- sheath with the embryos was threaded into the
visualize position, such as the anterior vaginal inner sheath into the catheter. The authors postu-
surface. Regardless of the anomaly, passage late that the embryo afterloading technique may
through the cervix is required for successful tran- result in higher pregnancy rates by preventing
scervical embryo transfer. mucus contamination/plugging, since there were
It is likely that the easiest cervical challenge to significantly more transfer catheters with mucus
tackle, cervical mucus, if not addressed, has the contamination in the direct transfer group
ability to plug the tip of the ET catheter, thereby (25.58 % vs. 5.95 %) [19].
making it difficult to gently transfer the embryos Furthermore, cervical mucus has been found
to the endometrial cavity, especially since they to be a possible source of bacterial contamination
are transferred in a small volume of culture of the endometrial cavity and the embryos [20–
media. Beyond plugging the ET catheter, it is 22]. In a prospective study of patients undergoing
possible that cervical mucus may be introduced transcervical embryo transfer, microbiological
6 Management of Difficult Embryo Transfers 43

cultures were performed on endocervical swabs years [25]. This is compared to an approximate
and embryo transfer catheter tips. The authors 10 % risk after a cold knife conization or 4–19 %
found positive microbial growths from endocer- incidence after a loop electrocautery excision
vical swabs in 70.9 % of patients and from procedure (LEEP) [26–28]. Due to the newly
catheter tips in 49.1 %. The clinical pregnancy updated American Congress of Obstetricians
rates were 57.1 % in the group of patients without and Gynecologists cervical cancer screening
growth and 29.6 % in the group with positive guidelines and vaccination against HPV, fewer
microbial growth from catheter tips [20]. In women are having destructive cervical proce-
another study, it was found that the clinical and dures, and as a result, iatrogenic cervical steno-
ongoing pregnancy rates as well as implantation sis frequency should diminish. However, since
rates were significantly lower in those who had the IVF patient population is an older popula-
positive versus negative cultures from the tips of tion, it is possible that many of these women
the mock embryo transfer catheters immediately underwent a cervical procedure prior to the
prior to embryo transfer (24 % vs. 37 %, 17 % vs. changes in the guidelines [29].
28 %, and 9 % vs. 16 %, respectively) [21]. The Although the cervix may appear stenotic, it is
authors reported that the positive cultures were possible that the uterine sound may be able to tra-
predominantly Escherichia coli (64 %) and verse the os; therefore, it is our program’s policy
Streptococcus species (8 %). Selman et al. [22] that the trial transfer be attempted on all visually
conducted a study where separate samples were abnormal cervices in those patients undergoing a
collected for microbial examination from the fol- future ET. In the event that either the catheter
lowing sites: the fundus of the vagina, the cervix, cannot pass through the stenotic external cervical
the embryo culture medium prior and post os or the os cannot be clearly identified, the
embryo transfer, the tip of the catheter, and the patient should return to the office at the time of
external sheet. All the samples were separately menses since the origin of the menstrual blood
cultured to identify any bacteria or yeast present. may help identify the cervical os. In some cases,
They found that the pregnancy rates were signifi- the patient may warrant surgical intervention
cantly lower in only patients testing positive for either prior to initiation of COH/recipient syn-
Entrobacteriaceae and Staphylococcus species chronization or, if absolutely necessary, at the
[22]. Taken together, the literature supports aspi- time of oocyte retrieval.
ration and removal of all visible cervical mucus. While some authors have advocated for dila-
tion of the cervix at the time of oocyte retrieval
given that the patient is already under anesthesia
Cervical Stenosis and does not have to come to an additional proce-
dural visit, both Visser et al. [15] and Groutz
Upon initial inspection of the cervix, it may be et al. [30] found that a short interval between
noted that the cervical os is either punctate or dilation and embryo transfer has resulted in poor
even difficult to visualize. Cervical stenosis may pregnancy outcomes [15, 30]. This may be due to
be congenital, iatrogenic, or secondary to infec- the fact that the endometrium does not have suf-
tion, cervical trauma, endometriosis, or post- ficient time to recover from any trauma, inflam-
menopausal atrophy. The classic description of mation, or bacterial contamination caused by the
cervical stenosis is a narrowing of the cervical dilation [4]. However, Abusheikha et al. [31]
canal to less than 2.5 mm; stenosis of the visible evaluated the effects of cervical dilation, per-
external cervical os has been described as an formed approximately 2 weeks before embryo
external os diameter less than 4.5 mm or roughly transfer and found that of those women who
the size of a cotton-tipped applicator [23, 24]. In failed to conceive after a prior embryo transfer,
patients who have had a laser cone biopsy, there nearly 37 % achieved a pregnancy [31]. Therefore,
has been a reported incidence of postprocedural it is advisable to perform cervical dilation prior to
cervical stenosis in 17 % of patients within 3–5 initiation of COH/recipient synchronization.
44 B.A. Levine and I. Kligman

Typically, we manage cervical stenosis with Previous authors have described hysteroscopic
mechanical dilation under monitored anesthesia endocervical resection or cervical shaving as
care (MAC) or “conscious” sedation. As has been means of creating a distinct and compatible cer-
previously described, the patient is brought to the vical canal. Wortman and Daggett [38] described
operating room with a full bladder, she is placed a method whereby hysteroscopic endocervical
in dorsal lithotomy position, a speculum is resection was used to create a portal of entry to
placed, the upper lip of the cervix is grasped with the endometrial canal for women undergoing a
a single-toothed tenaculum, and the cervix is hysteroscopic myomectomy [38]. In their model,
mechanically dilated under transabdominal ultra- they reconfigured the contours of the surgical
sound guidance starting with a lacrimal duct electrode of a standard hysteroscope. Of the 33
probe to ensure that a false passage is not created patients that were treated, entry into the endome-
[32–34]. In the event that the cervix is indistinct trial cavity was achieved in all cases without any
or flush against the vagina, a sponge stick can be demonstrable complications [38].
used to manipulate the uterus with sonographic With respect to cervical shaving, a modified
confirmation. At this point, a tenaculum can be surgical electrode of a standard hysteroscope was
used to grab any remnant of cervical tissue, or as used to create a smooth cervical tract by shaving
described by Valle et al. [35], the vaginal apex away approximately 0.5 mm of cervical scar tis-
and the cervix can then be probed with a lacrimal sue starting at the level of the internal cervical os
dilator; again, transabdominal ultrasound should and extending at least halfway down the cervical
be used to confirm entry into the endometrial canal toward the external cervical os [39]. The
cavity before sequential dilation [35]. authors report that of the 8 patients with a history
Some authors advocate for preoperative pros- of an extremely difficult cervical passage who
taglandin (misoprostol) or antiprogestogen underwent surgical correction, there were a total
(mifepristone) administration in those patients of 12 postoperative IVF-ETs resulting in 8 clini-
who are anticipated to have a challenging cervi- cal pregnancies [39]. In our program, we do not
cal dilation. Misoprostol can be administered perform any cervical shaving or destructive pro-
orally or vaginally in doses ranging from 200 to cedures because of the concern about future cer-
400 mcg. In a systematic review of the literature, vical incompetence.
Polyzos et al. [36] found that premenopausal Other investigators have described a
women treated with misoprostol had a signifi- fluoroscopy-guided dilation procedure performed
cantly lower risk for further cervical dilation in on 15 patients. The cervix was cannulated with a
the diagnostic setting and a significantly lower guide wire and the endocervical canal dilated
risk for cervical laceration in the operative setting with either an angioplasty balloon or with serial
when compared with placebo [36]. In addition, dilators [40, 41]. Using this method, the cervix
the mean cervical width prior to hysteroscopy could be easily cannulated up to 7 months after
was significantly higher in premenopausal dilation. There was ultimately one resultant preg-
women treated with misoprostol compared with nancy from IVF-ET, one from intrauterine insem-
placebo [36]. In contrast, Cooper et al. [37] also ination (IUI), and two spontaneous pregnancies
conducted a systematic review of the literature in this patient group [40].
and found that prostaglandin administration con- Irrespective of the mechanical dilation modal-
ferred no benefit with respect to the pain experi- ity, most authors advocate for either placing a
enced during cervical dilation and there was only pediatric rubber catheter transcervically into the
some evidence that misoprostol reduced the uterine cavity at the completion of the procedure
amount of force and requirement for dilation of in conjunction with oral antibiotics or for postop-
the cervix beyond 5 mm [37]. The authors go on erative estrogen supplementation with progester-
to state that preoperative mifepristone did not one overlap or a combination of both [24, 35, 38,
have any significant effect on the pain experi- 39]. In a study of 36 women with a distinct his-
enced during the procedure or dilation of the cer- tory of cervical stenosis and difficult entry into
vix [37]. the uterine cavity, the patients underwent
6 Management of Difficult Embryo Transfers 45

mechanical cervical dilation with sequential dila- the time of embryo transfer [4, 9, 46]. In a sys-
tors, hysteroscopy, and had a Malecot catheter tematic review of patients, who underwent fresh
placed for an average of 10 days; embryo transfer embryo transfers or frozen-thawed embryo trans-
was performed 3 weeks to 3 months after the pro- fers, it was found that quite often, the uteri that
cedure [42]. Of the 36 patients that were treated, were presumed to be retroverted at a previous
32 had an “easy entry” into the uterine cavity at visit proved to be anteverted on the day of trans-
the time of embryo transfer, which resulted in 15 fer [45]. The authors suggest that the growth of
pregnancies and 12 term deliveries [42]. the ovaries and their position in relation to the
Another alternative to surgical intervention is uterus may be contributing factors in the altered
the placement of cervical laminaria tents or uterine position. At our institution, a mock
osmotic dilators in the days preceding embryo embryo transfer is always performed immedi-
transfer. Laminaria are derived from compressed ately before the embryo transfer to confirm uter-
seaweed and expand in diameter as a result of the ine position and to make any necessary
fluid they extract from the cervical stroma. In a modifications to the catheter to improve the ease
case report of two patients, Glatstein et al. [43] of transfer.
report that laminaria can be used to successfully In those patients where the cervico-uterine
dilate the cervix prior to embryo transfer [43]. In angle is a significant challenge to an easy trans-
this article, the authors state that in the first case fer, it may be advisable to have the patient pas-
the patient underwent cervical dilation at the time sively fill their bladder. In a study of approximately
of oocyte retrieval with subsequent laminaria 800 patients, Lewin et al. [46] randomized
placement and in the second case, the laminaria patients to ET with either an empty bladder or a
tents were placed the day before a frozen embryo full bladder; the authors found a statistically
transfer. Both of the patients were treated with higher pregnancy rate in those who had a pas-
prophylactic antibiotics and the embryo transfer sively distended bladder [46]. In multiple studies
was subsequently found to be technically less dif- reviewing the utility of transabdominal ultra-
ficult, with both resulting in successful pregnan- sound at the time of embryo transfer, it has been
cies [43]. It should be noted that a short interval postulated that one of the ways that ultrasound
between dilation and embryo transfer has resulted may improve the quality of ETs is by the require-
in poor pregnancy outcomes, therefore, we can- ment of a full bladder for a sonographic window
not advocate for the safety or efficacy of lami- to the uterus or possibly, the pressure exerted
naria immediately before ET [15, 30]. upon the bladder, which may assist in straighten-
ing the uterus [4, 6, 44, 47–49].
If bladder distention and transabdominal pres-
Acute Cervico-uterine Angulation sure do not correct the cervico-uterine angle, it
may be necessary to modify the angle with direct
Beyond overt cervical stenosis, an embryo trans- traction on the cervix. In a prospective study of
fer may be technically difficult due to acute 24 women undergoing a diagnostic curettage, a
cervico-uterine angulation. This anatomical chal- radio-opaque guide wire was inserted through the
lenge may be due to scarring from previous sur- cervical canal into the uterine cavity and a lateral
gery, the presence of a fibroid, a congenital pelvic X-ray taken before and after cervical trac-
anomaly, or a variant of normal anatomy [44]. In tion with a spring balance attached to a tenacu-
a retrospective analysis of mock embryo transfer lum [50]. The authors reported that with a caudal
results, approximately 75 % of the patients were force of 2 N, they were able to reduce the median
noted to have an anteverted uterus while 25 % uterocervical angle from 75° to 10°, thereby
were noted to have a retroverted uterus [45]. facilitating passage into the uterine cavity [50].
Given that the angulation occurs at the cervico- In a study of patients at the time of mock
uterine junction, an acutely anteverted or retro- embryo transfer, Lesney et al. [51] found that
verted uterus can present a significant obstacle at when a tenaculum was applied, the number of
46 B.A. Levine and I. Kligman

contractions of all types (cervico-fundal, random, may be technically difficult due to the topogra-
and opposing) as well as the number of total con- phy of the cervical and/or uterine canal. The
tractions, all increased significantly [51]. In a presence of “ridges” or irregular contours of the
prospective study of women undergoing an canal may make it challenging to easily pass a
embryo transfer, serial blood samples were col- soft catheter transcervically. In a review by
lected in 20-s time intervals; the authors found Mansour et al. [44], the authors describe a sce-
that when a tenaculum was placed, four out of nario where a soft catheter has kinked or coiled in
five patients had a demonstrable elevation in their the cervical canal instead of passing smoothly
serum oxytocin level, which remained elevated into the uterine cavity. In an attempt to ensure
until the end of ET procedure [52]. The authors proper placement of the catheter, the authors
state that in the absence of a tenaculum, none of describe a simple test where the practitioner
the procedures associated with ET led to an rotates the catheter 360°; if the catheter recoils, it
increase in serum oxytocin concentration [52]. It means that it is in the cervical canal [44].
has also been found that when tissue forceps If the catheter continues to curve in the cervi-
were applied to the upper lip of the cervix, after cal and/or uterine canal or the cervico-uterine
one movement mimicking correction of the uter- angulation proves to be a challenge for a soft
ine position, they also noted a significant increase catheter, a rigid but malleable embryo transfer
in uterine activity [51]. Therefore, any movement catheter can be used. This catheter can be bent to
or manipulation of the cervix can and likely will align the catheter to the uterine axis to facilitate
be associated with increased uterine activity. easy passage; however, this enlarged catheter
It is important to note that uterine contractions should be used minimally, as extra dilation and
have been noted throughout the IVF process with manipulation may lead to the release of prosta-
the strongest uterine activity occurring on the day glandins [48]. In our practice, we use the Wallace®
of oocyte retrieval [51, 53]. On days 2, 3, and 4 Malleable Stylet (Smiths Medical International
after oocyte retrieval, regular wave-like contrac- Ltd., Hythe, Kent, UK), which has a soft outer
tility has been found to gradually decrease with sheath and a firm malleable inner stylet
only single random movements seen on day 4 (Fig. 6.1c). Upon tactile or sonographic confir-
after oocyte retrieval [53]. The authors postulate mation that the catheter has navigated the con-
that the uterine quiescence that is noted 4 days tours of the cervical and uterine canals, the rigid
after oocyte retrieval may be partly responsible inner stylet is carefully removed, and the embry-
for the higher pregnancy rates that are noted with ologist assists with threading a soft inner catheter
blastocyst ETs [54]. into the lumen of the uterine catheter using the
In an attempt to minimize cervical trauma, Wallace® Embryo Replacement Catheter (Smiths
and thereby, reduce the potential for inducing Medical International Ltd., Hythe, Kent, UK). As
uterine contractions, a suture can be placed at the with a standard embryo transfer, the inner cathe-
apex of cervix at the time of oocyte retrieval [48]. ter is introduced into the cavity to a depth that is
This suture should be cut to approximately approximately 1–2 cm shorter than the length
3–4 cm and can be used for relatively atraumatic that was measured during the sounding
traction at the time of ET before removal after the procedure.
embryo transfer. In our practice, it is quite rare
that we require cervical traction. We suggest
using a cervical stitch over all other instruments/ Ultrasound-Guided Embryo
modalities for the reasons outlined above. Transfer

Numerous studies have been published advocat-


Irregular Cervical and Uterine Contours ing for a spectrum of ultrasound usage, from
stringent recommendations of ultrasound guid-
Despite correction of cervical stenosis and/or ance for every embryo transfer to reserving ultra-
acute cervico-uterine angulation, embryo transfer sound guidance for only those technically
6 Management of Difficult Embryo Transfers 47

challenging cases at the time of the trial transfer study done in our center, it was found that
to reserving ultrasound guidance for those with a approximately 19 % of the patients enrolled in
history of challenging embryo transfer to only the study had a variation of 1.5 cm or more when
using “clinical touch” [4, 6, 48, 49, 55, 56]. In a comparing the sounded measured distance with
meta-analysis of ultrasound-guided versus clini- clinical touch (length of the catheter from the
cal touch embryo transfer, ultrasound-guided external os to the catheter tip) versus ultrasound-
embryo transfer was found to significantly derived measurement at the time of embryo
increase the chance of a clinical pregnancy and transfer [56]. With that said, sonographic mea-
significantly increase the embryo implantation surement of the length of the uterus may not be as
rate [57]. However, the authors do state that the helpful as real-time ultrasound guidance since
main disadvantages of ultrasound-guided embryo the measured length may not be accurate [59].
transfer are the time, space, equipment, and the
requirement for extra trained personnel [57]. In a
follow-up Cochrane review, Brown et al. [49] Alternative Embryo Transfer
state that the studies on this question are limited Modalities
by evidence quality, with only two studies report-
ing details about randomization and allocation In the event that a transcervical embryo transfer
concealment. The authors state that the results is impossible either due to troublesome cervical
“appear to improve the chances of live/ongoing anatomy or due to a challenging anatomic varia-
and clinical pregnancies” but that future studies tion, a successful pregnancy is still possible.
are necessary to make a definitive statement Through the use of a transvaginal-guided needle
about the role of ultrasound guidance [49]. or laparoscope, it is possible to transfer gametes,
In a review of the literature on ultrasound- zygotes, and embryos into the Fallopian tubes
guided embryo transfer, Flisser et al. [6] list the and have successful pregnancy outcomes [60–
benefits of ultrasound guidance. Ultrasound 65]. In fact, a recent report describes the intrafal-
allows the physician to detect malpositioned lopian transfer of blastocyst-stage embryos and a
transfer catheters and avoids placing embryos at successful ongoing pregnancy [65].
inappropriate sites or those that may decrease the If access to an operating room and laparo-
chance of implantation [6]. In a review of 121 scopic equipment is not available, or tubal trans-
transvaginal ultrasound-guided embryo transfers, fer is not advisable, some authors have advocated
Woolcott and Stanger [58] found that the outer attempting a transmyometrial embryo transfer. In
guiding catheter inadvertently abutted the fundal the original study published by Kato et al. [66],
endometrium in 17.4 % transfers, while it the authors used the Towako method of
indented the endometrium in 24.8 % transfers, transvaginal-transmyometrial embryo transfer,
and that, the transfer catheter embedded in the where a needle is inserted transmyometrially
endometrium in 33.1 % transfers [58]. Taken with transvaginal ultrasound guidance and the tip
together, this research demonstrates that inadver- of the needle is placed into the outer layer of the
tent catheter placement is not uncommon. endometrium at endometrial–myometrial junc-
However, it is important to also recognize that in tion. The authors report that the procedure was
a large academic practice like ours, where ultra- used in 100 patients with a clinical pregnancy
sound guidance is reserved for only a subset of rate of approximately 36.5 % [66]. In another
patients, our clinical pregnancy rates demonstrate study by Groutz et al. [67], it was found that in
that inadvertent catheter placement is likely not those patients where the embryo transfer could
as prominent as reported by Woolcott and be performed, and there was no discrete limita-
Stanger. tion to accessing the endometrial cavity, there
Another justification for the use of ultrasound was no benefit to electing transmyometrial ET in
guidance is the concern about the change in the preference to transcervical ET in patients who
size and shape of the uterine cavity from the time had failed to conceive in previous cycles [67]. In
it was initially assessed to the day of transfer. In a a small study of 10 patients with a previously dif-
48 B.A. Levine and I. Kligman

ficult embryo transfer or mock embryo transfer, References


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Facts and Myths of Embryo
Transfer 7
Claudio F. Chillik, Ivan E. Chillik,
and Carolina Borghi

Abstract
Embryo transfer is one of the most critical steps in determining the success
of an in vitro fertilization (IVF) cycle. Despite all the advances in the IVF
process, the overall success rate still remains less than 50 %. This is what
led to the exploration of alternative medicine and the empirical use of
certain drugs such as corticoids, aspirin, antibiotics, glucocorticoids, and
heparin.

Keywords
Embryo transfer • Aspirin • Heparin • Glucocorticoids • Antibiotics •
Acupuncture • Bed rest

Introduction area [1]. These advances have occurred in almost


every aspect of the IVF process. Current ovarian
Since the first successful birth resulting from stimulation regimens now include the use of
in vitro fertilization-embryo transfer (IVF-ET) in gonadotropin-releasing hormone agonists as well
1978, there have been numerous advances in this as antagonists, which prevent premature hormone
surges and unexpected ovulation. There have also
C.F. Chillik, MD (*) been changes in the medications used for ovarian
Department of Reproductive Medicine, Center for
stimulation from urinary-derived products to
Studies in Genetics and Reproduction (CEGYR),
Buenos Aires, Argentina highly purified recombinant derived products [2].
e-mail: cchillik@yahoo.com The in vitro culture environment has been modi-
I.E. Chillik, MD fied from media originally obtained from the
Department of Cardiovascular Studies, Buenos Aires growth of somatic cells to the current media that
Cardiovascular Institute, Buenos Aires, Argentina contains nutritional requirements specific for the
e-mail: Ivan.chillik@gmail.com
growing human embryo [3]. In 1991, the intro-
C. Borghi, MD duction of intracytoplasmic sperm injection
Department of Reproductive Medicine,
(ICSI) revolutionized the treatment of male factor
Center for Studies in Genetics and Reproduction
(CEGYR), Buenos Aires, Argentina infertility [4]. These important changes have been
e-mail: cborghi@cegyr.com critical to the steady increase in the “take-home

© Springer India 2015 51


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_7
52 C.F. Chillik et al.

baby rate” from IVF-ET. Despite these advances, potential role in increasing the IVF success rate
the overall success rate for IVF-ET still remains through improving either ovarian blood flow,
less than 50 %. folliculogenesis, and ovarian responsiveness or
Embryo implantation is one of the most criti- uterine vascularity and receptiveness or both. If
cal steps in determining the success of an IVF aspirin is effective, it would be a simple and
cycle. Implantation is a complex process, which affordable medication to improve IVF outcome
depends on many variables including embryonic, [6].
endometrial, anatomical, immunological, and The dose of aspirin varies from 75 to 100 mg
endocrinological factors. Most of these factors (low-dose) from the day of the embryo transfer
have not been adequately defined [5]. Implantation until the pregnancy test [7] or from the luteal
failure in couples undergoing assisted reproduc- phase of the previous menstrual cycle until
tion is common despite the transfer of good- embryo transfer [8]. The objective of this treat-
quality embryos. Up to 50 % of women under the ment is to improve clinical pregnancy and live
age of 35 years, who receive a blastocyst transfer, birth rate. Lorenz et al. [9] demonstrated that all
do not achieve a pregnancy. This would suggest doses of aspirin suppressed thromboxane A2
that endometrial receptivity and factors at the excretion by more than 80 % and the suppression
endometrial level play a significant role in estab- of prostacyclin (PG I2) excretion was more pro-
lishing successful implantation. nounced with the 324 mg dose. Low doses of
One important aspect that has been neglected aspirin seem to be more platelet selective than
is the utilization of complimentary alternative high doses [9].
medical therapies to enhance IVF-ET success One of the mechanisms proposed for the treat-
[5]. This is what led to the exploration of alterna- ment with low-dose aspirin is that the vascular-
tive medicine and the empirical use of other med- ization of the follicles may play a role in their
ications such as heparin, aspirin, progesterone, maturation from the early follicular phase.
corticoids, etc. In this chapter, we propose to Aspirin seems to increase vascularization by the
bring together the different scientific evidence vasodilatation effect that could result in preferen-
and conclude if these techniques are really effec- tial action of gonadotropic hormones or other
tive or not. growth factors or substrates required for steroido-
genesis, thus improving folliculogenesis [8]. On
the other hand, aspirin increases blood flow in the
Aspirin (Acetylsalicylic Acid) ovaries, which may improve folliculogenesis and
increase the number of oocytes retrieved. Due to
Over the years, low-dose aspirin has been used in the fact that implantation requires dilatation of
the prevention and treatment of cardiovascular endometrial blood vessels, it has been proven that
disease. In obstetrics, aspirin is used to increase the uterine blood flow velocity increases after
the weight of newborns when they have fetal administration of aspirin. This may improve
growth retardation and to improve placental and implantation, but reports showed that uterine
fetal blood flow in women with pre-eclampsia. artery Doppler indices do not correlate signifi-
Another use is in the antiphospholipid syndrome, cantly with the outcome of IVF cycles as they
with or without heparin. may reflect enhanced blood flow to the uterus but
Aspirin (acetylsalicylic acid) is a widely used not necessarily the endometrium.
vasoactive substance that exerts its effects by At present, trials conducted to evaluate the
inhibiting the enzyme cyclo-oxygenase in plate- effects of aspirin in IVF have yielded inconclu-
lets. In low doses, it inhibits synthesis of throm- sive or conflicting results, and there is still no
boxane A2 (a vasoconstrictor and promoter of consensus on the value of using aspirin to
platelet aggregation) more than that of prostacy- enhance IVF outcome. Khairy et al. [10] con-
clin (vasodilator). Due to these antithrombotic ducted a systematic review and meta-analysis
and vasodilator effects, aspirin has been one of from seven different trials [8, 11–17] in order to
the agents studied in several trials to evaluate its generate more precise estimates of effects and
7 Facts and Myths of Embryo Transfer 53

attempt to explore the reasons for the inconsis- trophoblast invasion as well as the early stages of
tencies in the studies. They took into account par- embryo development. Heparin is also thought to
ticipants, period of treatment, intervention, and exert a beneficial effect on embryo implantation
outcomes. They concluded that the studies did through interactions with adhesion molecules,
not show a significant benefit of aspirin therapy growth factors, cytokines, and enzymes like
in improving clinical pregnancy rate (7 studies; matrix metalloproteineases. Heparin also modu-
RR: 1.11; CI 95 % 0.95, 1.31) or live birth rate (2 lates the decidualization of human endometrial
studies, RR: 0.94; CI 95 % 0.64, 1.39). The stromal cells through the production of insulin-
results for both live birth and clinical pregnancy like growth factor 1 and prolactin.
were not statistically different (P = 0.31, P = 0.07, The value of heparin as an adjunct to IVF
respectively). There was no difference in miscar- treatment has been assessed in a number of stud-
riage rate (RR 1.06, CI 95 % 0.52, 2.11) or ecto- ies, which have reported conflicting results [18–
pic pregnancy rate (RR 2.24 CI 95 % 0.70, 7.24). 20]. While some studies [18, 19, 21] have
There was an improvement in the uterine artery suggested a beneficial effect of heparin in recur-
pulsatility index in patients taking low-dose aspi- rent implantation failure, others have found no
rin. This review showed that there is insufficient evidence of benefit [20, 22, 23].
evidence to support the routine use of low-dose Seshadri et al. [18] published a systematic
aspirin to improve clinical pregnancy and live review in which they evaluated the literature on the
birth rates. use of heparin as an adjunct to improve IVF out-
Regarding aspirin safety, based on trials come. They demonstrated that the role of adjuvant
reported until now, none provided evidence of heparin therapy during IVF has not been ade-
teratogenicity or long-term adverse effect of aspi- quately evaluated by current literature. On the
rin use. Despite this, aspirin therapy should not be basis of published literature, the group of patients
recommended for routine clinical use [11–17]. who could benefit from heparin therapy could not
be identified with certainty. Specifically, the role
of heparin in subfertile women with known throm-
Heparin bophilia and those with unexplained recurrent IVF
implantation failure needs further evaluation with
Coagulation defects, both congenital and acquired, adequately powered randomized studies.
have been found to be more prevalent in patients
with recurrent implantation failure. Antiphospholipid
antibodies (APAs) have been implicated in implan- Antibiotics
tation failure, recurrent miscarriages, pregnancy-
induced hypertension, and intrauterine growth Pelvic infection is an uncommon complication of
retardation [18]. Consequently, several researches IVF despite the invasive nature of oocyte retrieval
have evaluated the role of a number of therapeutic and embryo transfer [24]. However, subclinical
interventions including heparin, corticosteroids, infection of the endometrium from or before the
and aspirin among other approaches to assess their transfer procedure has been implicated as a possi-
effect on modulating endometrial receptivity and ble cause for failure of implantation. Positive cul-
improving the IVF outcome. tures from the cervix or catheter have been
It is known that heparin causes modulation of associated with diminished IVF outcomes [25].
basic physiological processes required for blasto- Egbase et al. [26] showed in a trial of 110 women
cyst adherence, implantation, and trophoblast that 71 % of the cultures from cervical mucus and
invasion, which has the potential to improve 49 % of the catheter tips were positive. These
pregnancy outcomes. The heparinoids have been patients had a clinical pregnancy rate of 29.6 %
shown to have a regulatory effect on heparin- compared with 57.1 % in patients with negative
binding epidermal growth factor and insulin-like cultures. Cleaning the cervix and vagina with
growth factors, both of which were reported to saline may reduce bacterial contamination to some
have a modulatory role on implantation and extent. Vaginal antiseptics are not recommended
54 C.F. Chillik et al.

at embryo transfer due to the potential toxicity to concept of eastern energy fields (qi) found in the
the embryos [26]. Use of antibiotics before body through invisible meridians. The needles
embryo transfer has been suggested but has not are inserted into specific points, blocking the pain
been shown to increase pregnancy rates [25, 27]. or energy to stimulate the body to function prop-
Due to the lack of proven benefit as well as the erly. Some of the acupuncture points used in fer-
potential to disrupt normal cervical flora and result tility are Baihui DU20, REN3 Zhongji, E29
in an inflammatory response, antibiotics are cur- Guilai, Xuehai B10, B6 Sanyinjiao, E36 Zusanli
rently not recommended for embryo transfer. and Hegu IG4, located in the head, lumbar area,
thighs, and legs (Fig. 7.1). These points were
chosen considering the increase in blood perfu-
Corticoids sion in the uterus, relaxing the patient, and
improving endometrial receptivity for embryo
The use of glucocorticoids has been proposed implantation [29]. In most publications, needles
after embryo transfer on IVF cycles in order to were applied deep in tissue layers, bilaterally,
improve the implantation rate. Glucocorticoids 30 min before and after embryo transfer.
may improve the intrauterine environment by There is a growing body of research evaluat-
acting as immunomodulators, reducing the uter- ing the effect of acupuncture administered during
ine natural killer (NK) cell count, and normaliz- IVF, and specifically, on the day of embryo trans-
ing the cytokine expression profile in the fer [30, 31]. The first systematic review was pub-
endometrium and by suppression of endometrial lished in 2008 by Manheimer et al. [31]. They
inflammation. found that acupuncture, as an adjunct to embryo
In a Cochrane Database Systematic Review transfer, was associated with a statistically and
[28], there was no clear evidence that administra- clinically significant increases in the pregnancy,
tion of glucocorticoids in IVF significantly ongoing pregnancy, and live birth rates [31].
improves the clinical outcome. The use of gluco- Although these findings were encouraging, they
corticoids in a subgroup of women undergoing were preliminary, and they need further placebo-
IVF was associated with an improvement in controlled trials.
pregnancy rates of borderline statistical signifi- One of the possible pathophysiological mech-
cance and should be carefully interpreted. These anisms of acupuncture is the anesthesia-like
findings were limited to the routine use of gluco- effects. Acupuncture needles stimulate muscle
corticoids and cannot be extrapolated to women afferents innervating ergoreceptors, which leads
with autoantibodies, unexplained infertility, or to increased β-endorphin concentration in the
recurrent implantation failure. Further well- cerebrospinal fluid [32, 33]. The hypothalamic
designed randomized studies are required to elu- β-endorphinergic system has inhibitory effects
cidate the possible role of this therapy in on the vasomotor center, thereby reducing sym-
well-defined patient groups. pathetic activity. In addition to central sympa-
thetic inhibition by the endorphin system,
acupuncture stimulation of the sensory nerve
Acupuncture fibers may inhibit the sympathetic outflow at the
spinal level. By changing the concentration of
Acupuncture (from Lat. Acus: needle, and pung- central opioids, acupuncture may also regulate
ere: puncture) is a traditional Chinese medicine the function of the hypothalamic-pituitary-
technique that involves the insertion and manipu- ovarian axis via the central sympathetic system
lation of needles in the body with the aim of [3]. Although in most clinical studies this mecha-
restoring health and well-being of the patient nism is responsible for a higher pregnancy rate, it
through the stimulation of the nervous system. It is still considered speculative.
is believed that acupuncture stimulates hormones, Recently, several randomized controlled studies
reduces stress, and improves blood supply to have shown a beneficial effect of acupuncture at the
specific organs. This technique focuses on the time of embryo transfer [30, 32, 34, 35]. Moreover,
7 Facts and Myths of Embryo Transfer 55

Fig. 7.1 These are some of Baihui DU20


the acupuncture points used
in fertility. They are located
in the head, lumbar area,
thighs, and legs: Baihui
DU20, REN3 Zhongji, E29
Guilai, Xuehai B10, B6
Sanyinjiao, E36 Zusanli,
Hegu IG4

REN3 Zhongji

E29 Guilai

Hegu IG4

Xuehai B10

E36 Zusanli

B6 Sanyinjiao

in a review from the Cochrane Collaboration [35], Transfer Position


the pooled results of 6 trials including a total of
1,022 patients showed a significantly higher clini- In the first years of IVF, the position of the uterus
cal pregnancy rate favoring the use of acupuncture dictated the position of the patient during transfer
on the day of embryo transfer. Several trials were to bring the uterine fundus into a dependent level.
heterogeneous and the results inconsistent. There The knee-chest position was used for an ante-
are several possible explanations for the heteroge- verted uterus and the dorsal lithotomy position
neity, the most common being the type of patients for the retroverted uterus. At present, we place all
submitted in the trials and the different treatment patients in the dorsal lithotomy position regard-
protocols. Most of the reviews submitted women less of the uterine position, as this does not appear
under 42 years old (mean = 32 ± 4) who were under- to affect the pregnancy rate [38].
going assisted reproductive technology (IVF/
ICSI). They were blinded and divided into two
groups, the control group and the other group that Bed Rest
received acupuncture. The type of stimulation,
number of transferred embryos, and diagnosis were Patients undergoing IVF were given a general
similar [8, 29–37]. recommendation for bed rest immediately after
There still remains insufficient evidence to the embryo transfer. The rationale behind this
determine if acupuncture can enhance live birth recommendation came from the belief that
rates when used as an adjunct to IVF treatment. decreased physical activity would encourage
56 C.F. Chillik et al.

embryo retention within the uterine cavity after ficulties are exacerbated by anxiety and the loss of
placement [39]. Mechanical expulsion of the privacy associated with infertility treatment and
transferred embryos is a possible cause for may be compounded by the fear that intercourse
implantation failure and probably is the reason will dislodge the early implanting embryo [42].
why most patients are asked to stay in bed for The possible mechanisms that intercourse
several hours following ET. However, the exact may affect embryo implantation could be ovarian
cause is not clearly understood [5]. torsion, infections, and uterine contraction.
Implantation in humans is not yet fully under-
stood but is generally accepted to occur 4–7 days
following fertilization. Bed rest for a few hours Before Embryo Transfer
following ET is unlikely to affect implantation
that will occur a few days later. During the IVF process many women may expe-
This approach, however, is not grounded on rience tenderness and pain as the ovaries will
evidence-based trials. Sharif et al. [5] performed a become physically larger while they are being
retrospective study comparing 1,091 IVF cycles stimulated. There is a risk of ovarian torsion dur-
in patients who did and did not undergo bed rest ing this period. Ovarian torsion occurs when an
and found no difference in the pregnancy rates [5]. ovary is twisted in such a way that the ovarian
Just a few studies were submitted until now, vein is distressed, resulting in severe abdominal
and no one demonstrated that bed rest has any pain, and is usually resolved through surgery. For
influence on the IVF outcome. In those studies in this reason all torso-twisting activities and other
which the patients chose not to have bed rest, abdominal exercises are not advised during this
they may have felt more confident and less period.
stressed than those who chose bed rest after After egg retrieval, it is advised to abstain
embryo transfer, and these positive feelings could from intercourse due to the risk of ovarian torsion
have contributed to their chances of conceiving and of infection. The wall of the cervix and uterus
[40]. Patients’ own behavior can affect the treat- are more at risk from the retrieval procedure to
ment results and may lead to unnecessary con- upper reproductive tract infections, and the cervi-
cern and stress that lasts for weeks after the cal mucus barrier to ascending infection is dis-
embryo transfer, as well as guilt feelings if preg- rupted by the passage of the embryo transfer
nancy does not occur [40]. catheter [42].
Practitioners should minimize the relevance of
bed rest and focus on other ways of improving
embryo transfer quality. The volume of air and After Embryo Transfer
media, as well as the density of media, have been
shown to be important predictors of movement of There are different recommendations regarding
the embryos within the uterine cavity and are not intercourse during this period. Most practitioners
related to bed rest [41]. recommend no sexual intercourse between trans-
It is important that clinicians carefully explain fer and first beta human chorionic gonadotropin
these findings to their patients after ET and advise (hCG) test. This is due to the belief that uterine
them to return to normal routine daily activities. myometrial activity is increased during inter-
course, especially in the event of female orgasm.
These contractions may interfere with implanta-
Intercourse tion of the early embryo.
Until now, there is no scientific evidence which
The conventional relationship between sexuality demonstrates that having sexual intercourse dur-
and conception is altered by infertility, with many ing this period affects the implantation rate.
couples reporting diminished sexual activity once Despite these events, there are a few clinical
they have been diagnosed as infertile. These dif- trials which indicate that intercourse may assist
7 Facts and Myths of Embryo Transfer 57

implantation. There have been animal studies in pregnancy rates in IVF/ET patients led to contra-
mice, which reveal that exposure to seminal dictory conclusions, indicating that there is prob-
plasma is particularly important for achieving ably no simple direct relationship [4, 48–52].
normal embryo development and implantation. Nevertheless, psychological factors may be
One of the mechanisms proposed for this is the improved by intervention; with these in mind, we
immune-active compounds such as transforming can be more aware of what kind of patients we
growth factor beta (TGFβ) and prostaglandin E, are working with and we can recommend differ-
both present in high concentrations in human ent types of counseling.
semen. They may be responsible for the benefi-
cial effect, but the mechanism is still unknown.
Prayer

Stress and Emotional Factors The use of alternative or complementary medi-


cine has been increasing in popularity; these
Fertility problems consist of both medical and approaches include the use of healing touch and
emotional aspects. While the physical impact of prayer, with several reports suggesting a potential
the medical treatment is considerable, couples therapeutic benefit in a variety of disorders [53,
consider emotional aspects more stressful. For 54]. In the last years, the use of intercessory
most couples, an unsuccessful IVF result means prayer (IP) has been studied, and while prelimi-
the end of further medical treatment possibilities. nary experiments have been interpreted as sug-
The main stress factor in infertility comprises gesting a possible improvement in patients with
various elements: the threat of treatment and pos- heart disease and AIDS [55–57], a recent review
sible childlessness, uncertainty and lack of con- of the literature does not indicate any conclusive
trol of the treatment outcome, and the loss of benefit overall.
hopes of pregnancy and creating a family. Petitionary or intercessory prayer (IP) is when
Differentiating between anxiety and depression the prayer participants request God’s intervention
is important because they both require different or assistance for the benefit of another individual,
psychosocial interventions [3, 43]. and directed IP is praying for a specific outcome
The role of psychological intervention in IVF for an individual or individuals (i.e., prayers for
results is very controversial. Zaig et al. [44] have conception).
recently demonstrated that transitory moods, In relation with in vitro fertilization, there has
such as anxiety and depression, have no predic- been only one study with the intention of proving
tive value on the outcome of IVF. Nevertheless, application of IP to the treatment of infertility.
the incorporation of psychological interventions Kwang et al. [58] made a prospective, random-
and even spirituality seems to improve the well- ized, double-blind study in which the efficacy of
being of women during IVF cycles [45]. IP was assessed in patients undergoing IVF-ET
Domar et al. [46], in 1990, described a Mind/ treatment. They included a total of 169 cases
Body Program for Infertility. It is a 10-week whose characteristics as age, duration of infertil-
group stress management program whose focus ity, and number of prior attempts and IVF-ET
is on cognitive behavior therapy, relaxation train- were similar.
ing, negative health behavior modification, and The study found that, during the treatment,
social support components. Infertility patients both groups (those who received IP vs. no IP) had
with varied diagnoses and at different stages of similar numbers of oocytes retrieved, numbers of
treatment who participated in the Mind/Body oocytes fertilized, and pre-embryos transferred.
Program for Infertility experienced significantly The IP group, however, had a significantly higher
higher pregnancy rates than control subjects [47]. pregnancy rate as compared to the controls (50 %
Attempts to comprehend whether psychologi- vs. 26 %; P = 0.0013); these rates were not modi-
cal interventions have any beneficial effects over fied when they were adjusted by the variables,
58 C.F. Chillik et al.

except in women undergoing ICSI and women 7. Young JH. American health quackery. Princeton:
Princeton University Press; 1992. p. 59–63.
under 30 years, in whom IP did not show any
8. www.cbs.nl/statline.
benefit. The adjusted OR for pregnancy rates (IP 9. Lorenz RL, Boehking B, Vedelhoven WM, Weber PC.
vs. no IP) was 3.3 (95 % CL, 1.6–6.6). Also, the Superior antiplatelet action of alternative day pulsed
implantation rate was significantly higher in the dosing versus split dose administration of aspirin. Am
J Cardiol. 1989;325-1137-41.
IP group (16.3 % vs. 8 %, P = 0.0005). The higher
10. Khairy M, Banerjee K, El-Touskhy T, Coomarasamy
rate of pregnancies in the IP group was indepen- A, Khalaf Y. Aspirin in women undergoing in vitro
dent of the type of infertility [58]. fertilization treatment: a systematic review and meta-
These data suggest a benefit of IP on analysis. Fertil Steril. 2007;88:822–30.
11. Urman B, Mercan Cengiz Alatas R, Balaban B, Isiklar
IVF-ET. However, it must be considered as pre-
A, Nuhoglu A. Low-dose aspirin does not increase
liminary because of the multiple biological fac- implantation rates in patients undergoing intracyto-
tors and unknown variables inherent in the plasmic sperm injection: a prospective randomized
treatment process of IVF-ET. study. J Assist Reprod Genet. 2000;17(10):586–90.
12. Check JH, Dietterich C, Lurie D, Nazari A, Chuong
J. A matched study to determine whether low-dose
Conclusions aspirin without heparin improves pregnancy rates fol-
Since the first successful birth from in vitro lowing frozen embryo transfer and/or affects endome-
fertilization-embryo transfer in 1978, there trial sonographic parameters. J Assist Reprod Genet.
1998;15(10):579–82.
have been numerous advances in IVF-ET. These
13. Weckstein LN, Jacobson A, Galen D, et al. Low-dose
advances have occurred in almost every aspect aspirin for oocyte donation recipients with a thin
of the IVF process, but we still do not know endometrium: prospective, randomized study. Fertil
why more than half of the patients do not get Steril. 1997;68:927–30.
14. Lok IH, Yip S, Cheung LP. Adjuvant low-dose aspirin
pregnant in each attempt. This opens the use of
therapy in poor responders undergoing in vitro fertil-
different medications, alternative medicines, ization: a prospective, randomized, double-blind,
spiritual and religious support, excessive bed placebo-controlled trial. Fertil Steril. 2004;81:556–61.
rest, or lack of sexual activity that after 35 15. Van Dooren IM, Schoot BC, Dargel E. Low-dose
aspirin demonstrates no positive effect on clinical
years have not yet been proven but, neverthe-
results in the first in vitro fertilization (IVF) cycle.
less, are widely used. Fertil Steril. 2004;82 Suppl 1:S18.
16. Pakkila M, Rasanen J, Heinonen S, Tinkanen H,
Tuomivaara L, Makikallio K, Hippelainen M,
Tapanainen JS, Martikainen H. Low-dose aspirin does
not improve ovarian responsiveness or pregnancy rate in
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Uterine Contractility and Embryo
Transfer 8
Sarah Sebag-Peyrelevade and Renato Fanchin

Abstract
Uterine contractility of the non-pregnant uterus is likely to play an impor-
tant role in human reproduction, in particular, in the embryo implantation
process. After ovulation, contractility is characterized by a relative quies-
cence in response to the level of progesterone produced. The development
of high-resolution ultrasound probes has enabled the visualization of the
myometrial activity in a non-invasive way. It can also provide additional
characteristics such as amplitude and direction. The nearly quiescent con-
tractility reached at hCG+ 7 days may favour embryo permanence in the
endometrial cavity, and therefore, assist implantation. Studying and under-
standing contractility of the non-pregnant uterus can improve embryo
transfers and implantation rates.

Keywords
Contractility • Embryo transfer • Progesterone • High-resolution ultrasound

Introduction acterization and consequences of contractions of


the non-pregnant uterus have been much less
Whereas a plethora of clinical publications investigated. Yet, all indicate that the constant,
devoted to the study of uterine contractility during rhythmic contractions of the non-pregnant uterus
pregnancy is available in the literature, both char- are likely to play an important role in human
reproduction, in particular, in the fertilization and
embryo implantation processes. During the fol-
S. Sebag-Peyrelevade, MD (*) licular phase of the menstrual cycle, the progres-
Department of Gynecology and Obstetrics, Hospital sive increase in uterine contraction frequency
Antoine Béclère, Clamart, France probably exerts a facilitating role on the sperm
e-mail: sarahpeyrelevade@gmail.com ascension toward the distal end of the Fallopian
R. Fanchin, PU-PH tubes where fertilization takes place [1–3]. After
Department of Gynecology and Obstetrics, Unit of ovulation, the uterus undergoes progressive relax-
Reproductive Medicine, Hospital Antoine Béclère,
Clamart, France ation that culminates at the mid-luteal phase and
e-mail: Renato.fanchin@abc.aphp.fr that may assist proper embryo positioning [4, 5] in

© Springer India 2015 61


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_8
62 S. Sebag-Peyrelevade and R. Fanchin

the middle section of the uterine cavity and facili- With both methods (IUP and EMG), invasiveness
tate embryo implantation. has greatly limited the possibility of conducting
The possibility of visualizing uterine contrac- clinical studies, notably in natural and assisted
tions directly and non-invasively at ultrasound reproduction. Another inconvenience of both IUP
scans [6, 7] has opened new horizons in the study and EMG is the possible inherent influence of
of the possible relation between uterine contrac- devices used on the characteristics of uterine con-
tility and human reproduction. The present chap- tractions that may alter the reliability of results.
ter aims at discussing how uterine contractility More recently, an alternative method for
can play a key role in embryo transfer while facil- assessing uterine contractions in non-pregnant
itating embryo implantation, the advantages and women has emerged from studying the uterus on
limitations of the ultrasonographic approach for ultrasounds [6]. The development of high-
assessing uterine contractions and the available resolution vaginal ultrasound probes has enabled
data on the possible influence of uterine contrac- the direct visualization of the myometrial con-
tility on natural and assisted fertilization and tractile activity that can be recorded and studied
embryo implantation. in real-time motion [7, 19, 20]. The validity of
the ultrasound approach for assessing the fre-
quency of uterine contractions has been con-
Assessment of Uterine Contractility firmed by demonstrating the concordance of
findings made simultaneously on ultrasound and
Throughout the last century, uterine contractility IUP recordings [21]. It is also possible that the
in non-pregnant women has been assessed using a ultrasound approach can provide information on
wide range of methods [8–12]. Schematically, the additional characteristics of uterine contrac-
they may be sorted into two main groups: intra- tions as their amplitude and direction. Yet, the
uterine pressure measurement (IUP) [8, 10, 11, reliability of ultrasound for studying these latter
13–17] and electromyography (EMG) [12, 18]. features of uterine contractions remains to be
The IUP method measures pressure increase validated.
resulting from the shortening of uterine muscle Today, ultrasonography has been proven to
fibers during contraction and provides information offer reliable information on uterine contraction
on its amplitude, duration, and frequency. Besides frequency and benefits from being non-invasive.
its invasiveness, a remarkable disadvantage of the To facilitate both, the identification and quantifi-
IUP approach is the difficulty in quantifying mus- cation of uterine contractions, ultrasound scans
cular activity that does not lead to noticeable pres- commonly are stored in VHS tapes or digitized
sure modification, such as the sliding friction sequences that are analyzed in fast motion.
between uterine walls. It is conceivable that these However, the analysis of ultrasonographic
milder uterine contractions may influence sperm recordings remains subjective. In an attempt to
transport and embryo positioning. improve the reliability of uterine contraction
Another reference method used for assessing measurements on ultrasound scans, we devel-
contractility of the non-pregnant uterus is the oped an original approach based on using a three-
measurement of the electromechanical activity of dimensional (3-D) reconstruction software
the uterus by EMG [12, 18]. This approach [22–24].
requires the placement of multiple electrodes in In the 3-D derived approach, at first, ultra-
the uterine cavity to detect changes in pacesetter sound images are digitized online using a two
(slow waves) and action potentials (rapid spikes) image/second rate with a computer-assisted
of the uterus [18]. Hence, EMG provides infor- image analysis system (IôTEC 3.1.2, IôDP, Paris,
mation on the contractile activity of the uterus France). Uterine contraction frequency is then
because electrical activity, in particular, action assessed on time-mode graphs generated elec-
potentials of the uterus has been shown to take tronically using three-dimensional reconstruction
part in the triggering of uterine contractions. software (IôTEC 3.1.2, IôDP, Paris, France). For
8 Uterine Contractility and Embryo Transfer 63

this, instead of swapping the ultrasound probe as infrequent and long-lasting contractions as
done for volume acquisition and three- detected by IUP [13, 14, 27, 29, 30] and ultra-
dimensional reconstruction, the probe is kept sound [19, 20] recordings. Further, a predomi-
steady and two-dimensional (2-D) images are nance of converging contractions (from the
acquired over time for 2 min. In the electronic fundus to the cervix and from the cervix to the
matrix, the “z” axis, instead of being the third fundus, concomitantly) has been also identified
dimension of volume, becomes time. In the time- during the first 5 days after ovulation [25].
mode graphs, the uterine contraction frequency is Moreover, both the exciting role of estrogens and
identifiable by the number of vertical displace- relaxing role of progesterone on the mechanical
ments of the myometrial-endometrial interface activity of the myometrium have been further
and of the uterine cavity line over time. Yet, in a confirmed by the monitoring of electromechani-
further study, our team compared the 3-D derived cal activities in isolated human uteri, recorded
approach with the conventional ultrasound using bipolar silver-silver electrodes, endolumi-
method and concluded that analyzing uterine nal pressure catheters, and a dedicated acquisi-
contraction frequency on accelerated image tion, storage, and analytical system [31].
sequences is as effective as our more complex Based on the possible physiological roles of
approach based on identifying contractions on uterine contractility, i.e., assistance for sperm
time-mode graphs, electronically reconstructed transport through the genital tract at mid-cycle
using 3D software. and support of the embryo implantation process
during the mid-luteal phase, some therapeutic
measures may be contemplated, such as the
Hormonal Drive of Uterine administration of E2 to improve fertilization by
Contractility stimulating sperm ascension (enhancement of
uterine contractility) or progesterone to improve
The contractility of the non-pregnant human embryo implantation rates by fostering the per-
uterus undergoes periodic variations according to manence of embryos in the uterine cavity (reduc-
the phase of the menstrual cycle. The follicular tion of uterine contractility), in spontaneous or
phase is characterized by a progressive increase controlled ovarian hyperstimulation (COH)
in the uterine contractile activity, which culmi- cycles.
nates at the preovulatory period at 3–5 contrac- This led us to conduct an ultrasonographic
tions/min, as detected by either traditional investigation in order to elucidate the possible
methods [10, 11, 13–18] or transvaginal ultra- role of plasma E2 and progesterone levels on the
sound measurements [7, 19, 20, 25]. These pro- uterine contractility during COH cycles [23]. In
gressive changes in uterine contractile patterns 59 in vitro fertilization-embryo transfer (IVF-ET)
throughout the proliferative phase of the cycle candidates, on days of human chorionic gonado-
probably are a response to estrogen stimulation. tropin (hCG) administration and ET, plasma E2
In support of this, early reports have indicated and progesterone were measured, and 5-min
that administration of estrogens to women ultrasound scans of the uterus were digitized and
deprived of ovarian function, as a result of surgi- analyzed with the 3-D derived system to assist
cal menopause [26] or primary amenorrhea [10, uterine contraction frequency measurement.
27], induces a normal proliferative pattern of Cycles were sorted according to whether proges-
uterine contractions. After ovulation, uterine terone levels on the day of ET were ≤100 (n = 34)
contractility is characterized by a relative quies- or >100 (n = 25) ng/mL. On the day of hCG
cence with small, slow, and superimposed uterine administration, uterine contraction frequency
contractions, presumably as a response to the was similar in both groups at 4.5 ± 0.2 and
production of progesterone by the corpus luteum 4.6 ± 0.3 contractions/min (mean ± SE), respec-
[28]. Indeed, a reorganization of uterine contrac- tively. On the day of ET, uterine contraction fre-
tions is observed during the luteal phase with quency remained steady in the low progesterone
64 S. Sebag-Peyrelevade and R. Fanchin

group, whereas it decreased (3.5 ± 0.2 contrac- in natural or medically assisted conditions, is
tions/min) in the high progesterone group (P < likely to provide valuable information on possi-
0.001), and correlated negatively with progester- ble uterine dyskinesia that could hamper sperm
one levels (r = −0.56; P < 0.001). No influence of transport and reduce the probability of fertiliza-
supraphysiological estradiol (E2) levels on uter- tion. In line with this, Brown et al. [33] investi-
ine contraction frequency was noticed [23]. gated the impact of administering vaginally
These results led us to conclude that uterine 400 μg of misoprostol at the time of intrauterine
contraction characteristics are influenced by insemination. An overall improvement in preg-
plasma progesterone levels on the day of ET and nancy rates following this technique was observed
are refractory to E2 levels on the day of hCG and attributed at least in part to the prostaglandin-
administration and ET. Moreover, on the day of induced increase in uterine contractions [34].
ET, as compared to the day of hCG administra-
tion, only patients displaying high progesterone
levels (>100 ng/mL) had a reduction in uterine Uterine Contractility
contraction frequency. This suggests that impor- and Implantation
tant tissue concentrations of progesterone are
needed to alter uterine contractility during the In animals, uterine contractions have been shown
early luteal phase of COH. to partake in the proper embryo positioning in the
uterine cavity [4, 5]. In humans, indirect data
suggests that the contractile activity of the myo-
Uterine Contractions and Sperm metrium partakes in the establishing of the suffi-
Transport cient conditions to embryo implantation [35, 36].
Consistently with this, uterine contractility
The remarkably fast sperm ascent through the decreases during the luteal phase of the menstrual
genital tract to the Fallopian tubes in a few min- cycle. The introduction and improvement of
utes [2, 3, 32] may not be exclusively attributed in vitro fertilization and embryo transfer
to the inherent sperm motility. Sperm motility per (IVF-ET) techniques has permitted to perfect the
se would lead to a much longer ascension time. understanding of some mechanisms related to
Hence, it is likely that external factors, in particu- embryo implantation. Indeed, the timed transfer
lar uterine contractions, assist sperm transport. of embryos into the uterine cavity facilitates the
This hypothesis is consistent with increased study of the relationship between the embryos
myometrial contractility during the late follicular and the uterus.
phase of the menstrual cycle. To further elucidate Hence, we decided to assess the potential role
this issue, Kunz et al. [3] have introduced of uterine contractions on human embryo implan-
technetium-labeled, sperm-sized spheres into the tation by combining both, the non-invasiveness of
cervix at different moments of the follicular vaginal ultrasound scans and controlled model of
phase. Using hysterosalpingoscitigraphic con- IVF-ET. In this study [22], we looked at the uter-
trol, the authors observed a progressive increase ine contraction frequency at the time of ET and its
in the ascension of spheres toward the Fallopian possible detrimental effect on IVF-ET outcome.
tubes from the early to the late follicular phase of We studied 209 women undergoing 220 IVF-ET
the menstrual cycle [3]. This suggests that the cycles with controlled ovarian hyperstimulation.
progressive increase in uterine contraction fre- To limit the interference of confounding variables
quency that occurs during this phase of the men- affecting embryo quality and/or uterine receptiv-
strual cycle is likely to foster passive sperm ity, we only selected patients who were under 39
transport to the fertilization site. years of age, whose uteri were normal, and who
Inherently impossible in actual cycles, the had at least three good-quality embryos available
ultrasonographic monitoring of uterine contrac- for transfer. For uterine contraction assessment,
tions during sperm ascension through the uterus, just before ET, all patients underwent transvaginal
8 Uterine Contractility and Embryo Transfer 65

ultrasound scans and measurement of uterine con- or whether the hormonal changes induced a resis-
traction frequency with the 3-D derived system. tance to the relaxing effects of progesterone. As
The 220 ETs studied were sorted arbitrarily into already mentioned, another study by our team
four groups according to uterine contraction fre- [23] observed that, despite the very high estradiol
quency: ≤3.0 contractions/min (n = 53), 3.1–4.0 levels achieved at the end of COH, the overall
contractions/min (n = 50), 4.1–5.0 contractions/ uterine contraction frequency remained at the
min (n = 43), and >5.0 contractions/min (n = 74). menstrual cycle level (4.6 uterine contractions/
All frequency groups were similar with regard min) on the day of hCG administration. Hence,
to the age of patients, indications for IVF-ET, the supraphysiological levels of estradiol charac-
ovarian reserve assessment [baseline FSH and E2 teristic of IVF-ET do not further stimulate uterine
levels on cycle day 3, performed during the 2 or 3 contraction frequency beyond menstrual cycle
months prior to COH], number of human meno- values. However, uterine contraction frequency
pausal gonadotropin (hMG) ampules adminis- remained nearly unchanged on the day of ET, not
tered, duration of COH, plasma E2 and P levels on showing the prompt decrease seen in the men-
the day of hCG administration, number of mature strual cycle after ovulation. Prompted by these
oocytes retrieved, and number of available and results, we formulated the hypothesis that further
transferred embryos. Contrasting with the similar- increasing the exposure of the uterus to progester-
ity in individual and COH data among groups, we one will overcome the resistance and bring the
observed a marked stepwise decrease in clinical needed utero-relaxation. Hence, we investigated
and ongoing pregnancy as well as in implantation the effects of vaginal progesterone administration
rates from the lowest to the highest contraction fre- to relax the uterus at the time of ET.
quency group (53 %, 36 %, 21 %; 46 %, 32 %, It has now been amply documented that vagi-
20 %; 23 %, 19 %, 10 %; and 14 %, 11 %, 4 %, nal progesterone administration provides a direct
respectively, in the ≤3.0, 3.1–4.0, 4.1–5.0 and access of progesterone to the uterus, which leads
>5.0 UC/min groups; P < 0.001). These results to high uterine tissue concentration of progester-
may be explained by the possible mechanical one [37–40]. Therefore, vaginal progesterone
expulsion of embryos from the uterine cavity as a administration, started before ET, could be effec-
result of uterine contractions. tive for restoring uterorelaxation at the time of
Another important observation from this study ET and improve embryo implantation. To address
[22] was that the overall mean uterine contraction this issue, we studied 84 IVF-ET candidates
frequency, observed during the early luteal phase undergoing 84 controlled ovarian hyperstimula-
of COH (4.3 contractions/min on the day of ET), tion cycles [41]. On the day of oocyte retrieval,
appeared higher than that measured during the women were randomly attributed to either early
corresponding phase of the menstrual cycle (2.5– (group A, n = 43) or “conventional” (group B,
3.0 contractions/min) [19, 20]. This increased n = 41) onset luteal support. In group A, women
uterine contraction frequency during the early started daily applications of a vaginal progester-
luteal phase in COH cycles was corroborated in a one gel immediately after the oocyte retrieval. In
later study [23]. group B, the vaginal progesterone gel was started
on the evening of the ET. In both groups, luteal
support was continued until pregnancy was ruled
Effects of Vaginal Progesterone out by a negative serum hCG measurement.
Administration on Uterine Uterine contractility was studied on the day of
Contractility hCG administration and just before ET using the
ultrasound 3-D derived system. Serum estradiol
Based on these results [22, 23], we questioned and progesterone levels were also measured.
whether IVF-ET patients might have an overall Similar patient characteristics were observed in
increase in uterine contraction frequency as a women who started progesterone supplementa-
result of the high estradiol levels brought by COH tion on the day of oocyte retrieval or ET with
66 S. Sebag-Peyrelevade and R. Fanchin

regard to age, indication for IVF-ET, and ovarian administration in COH for IVF-ET [42]. This
reserve data. Data on controlled ovarian hyper- could provide an additional explanation for the
stimulation and embryology were also similar high implantation rates reported with blastocysts
between both groups. As expected, serum estra- [43–46]. For this, we studied 43 infertile women
diol levels fell from the day of hCG to ET in both undergoing 43 GnRH-a and FSH/hCG cycles for
groups. After hCG, progesterone levels increased IVF-ET. On the day of hCG administration, on
progressively in both groups but reached levels the day of non-cavitating ET (hCG+ 4), and on
slightly higher in women who started progester- the day of blastocyst transfers (hCG+ 7), 2-min
one supplementation on the day of oocyte sagittal uterine scans were obtained with a
retrieval. Uterine contraction (UC) frequency, 7.5 MHz vaginal ultrasound probe, and uterine
which was similar on the day of hCG administra- contraction frequency was assessed according to
tion in groups A and B (4.6 ± 0.3 to 4.5 ± 0.3 con- the similar methodology as previously described
tractions/min), declined significantly at the time [22, 23]. The results of that investigation showed
of ET in the group receiving luteal support with a slight yet significant decrease in UC frequency
vaginal progesterone early, starting on the day of from the day of hCG (4.4 ± 0.2 contractions/min)
oocyte retrieval (2.8 ± 0.2 contractions/min, to hCG+ 4 (3.5 ± 0.2 contractions/min). A remark-
P < 0.001). On the contrary, uterine contraction able additional decrease occurred on hCG+ 7
frequency remained practically unchanged in the (1.5 ± 0.2 contractions/min). Concurring with the
untreated group who only started luteal support putative embryo selection through extended cul-
only after the ET (4.1 ± 0.3 contractions/min). ture, the nearly quiescent contractility status
Supporting our prior observation on the negative reached by the uterus on the day of blastocyst
effect of uterine contractility on IVF outcome, transfers may favour embryo permanence in the
we observed a trend for higher pregnancy and endometrial cavity and, therefore, assist implan-
implantation rates in women who started luteal tation. Therefore, these data offer an additional
support with vaginal progesterone early. Clinical explanation of the high implantation rates
pregnancy rates (defined as presence of intrauter- reported after blastocyst transfers [43–46].
ine gestational sac with cardiac activity) were Further, based on these results, extending culture
42 % and 29 %, ongoing pregnancy rates and transferring blastocysts instead of 2–8 cell
(≥12 weeks of amenorrhea) were 35 % and 22 %, embryos may be opportune in case of high uter-
and implantation rates (number of intrauterine ine contraction frequency (>4 UC/min) on the
gestational sacs/transferred embryos × 100) were day of non-cavitating ETs.
18 % and 12 %, in groups A and B, respectively.
This study concluded that vaginal progesterone
administration starting 2 days before ET induces a Promising Approaches to Inhibit
significant reduction in uterine contraction fre- Uterine Contractility Before ET
quency at the time of ET [41]. This uterorelaxation
may propitiate embryo permanence in the endo- Besides hormonal treatment, other approaches
metrial cavity and, therefore, assist implantation. may be helpful to reduce the myometrial contrac-
Yet, the favourable effects of this approach on tile activity just before ET to provide more ade-
IVF-ET outcome deserve additional investigation. quate uterine conditions to embryo implantation.
They include a large array of drugs, endowed
with different properties, that include cyclooxy-
Uterine Contractility on the Day genase inhibitors, ß2-adrenoreceptor agonists,
of Blastocyst Transfers calcium-channel blockers, phosphodiesterase
inhibitors, and oxytocin antagonists. In a recent
Another issue remaining to be investigated was pilot trial, Pierzynski et al. [46] observed a
the possible reduction in uterine contractility on noticeable decrease in uterine contractility after
the day of blastocyst transfers, 7 days after hCG 1-h infusion of a potent oxytocin antagonist
8 Uterine Contractility and Embryo Transfer 67

before ET in an infertile woman. The patient who 5. Pusey J, Kelly WA, Bradshaw JMC, Porter
DG. Myometrial activity and the distribution of blas-
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Embryo Transfer Media
and Catheters 9
Ayse Seyhan, Mete Işıkoğlu, and Baris Ata

Abstract
An embryo transfer catheter is a special equipment that’s designed and manu-
factured to ensure safe deposition of human embryos generated in the embry-
ology laboratory to the endometrial cavity. As such, they undergo several tests
of embryo toxicity before being marketed. The vast majority of currently
available embryo transfer sets consist of two parts: an outer sheath and the
inner catheter proper. While the first is used to negotiate the cervical canal, the
embryos are loaded into the inner catheter, which is then introduced to the
endometrial cavity through the lumen of the former. Embryo transfer catheters
are defined by several features. These include material, malleability and shape
of the outer sheath, stiffness and echogenicity of the inner catheter. Several
randomized controlled trials have demonstrated that a soft catheter yields bet-
ter clinical results compared to a stiff embryo transfer catheter. More recent
models with a pre-curved outer sheath and a bulb tip seem to facilitate the
negotiation of the cervical canal without compromising the clinical outcome.
While catheters with increased echogenicity are better visualized during the
transfer procedure, the clinical outcome is not improved. According to the
available data, hyaluronan- enriched transfer medium can improve the clinical
outcome, especially in patients with poor prognostic features.

Keywords
Embryo transfer • In vitro fertilization • Assisted reproduction • Catheter

A. Seyhan, MD (*)
Department of Obstetrics and Gynecology,
American Hospital of Istanbul, Women’s Health and
Assisted Reproduction Center, Istanbul, Turkey
e-mail: ayseseyhan@amerikanhastanesi.org
M. Işıkoğlu, MD
Department of IVF, Obstetrics and Gynecology,
GELECEK: The Center for Human Reproduction,
Antalya, Turkey
e-mail: misikoglu@hotmail.com
B. Ata, MD, MCT
Department of Obstetrics and Gynecology,
Koc University School of Medicine, Istanbul, Turkey
e-mail: barisata@ku.edu.tr; barisata@hotmail.com

© Springer India 2015 69


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_9
70 A. Seyhan et al.

Introduction ET catheters are made of non-embryo toxic


plastic such as polyurethane or polyethylene.
The final step of an assisted reproductive technol- The outer sheath is made of polycarbonates or
ogy (ART) cycle is the placement of embryo(s) metal, albeit, the latter is rarely used. Some
generated in the laboratory in the endometrial manufacturers also use polytetrafluorethylene
cavity through the cervical canal. Although the for outer sheaths. ET catheters should not con-
majority of patients undergoing ART reach tain the natural rubber latex as it can trigger
embryo transfer (ET), implantation rates are still allergic reactions. The Mouse Embryo Assay
relatively low at around 35 % even for women (MEA) is used to test for embryo toxicity. MEA
younger than 35 years of age [1]. The likelihood involves culturing one- or two-cell mouse
of implantation depends on the competency of embryos in the material for a predetermined
the embryo itself, endometrial receptivity and a time for exposure. Following exposure the
successful ET procedure. Undoubtedly, a sub- embryos are cultured in a defined culture media
stantial proportion of implantation failures are for 3–4 days and evaluated for blastocyst devel-
due to chromosomal aneuploidies or other abnor- opment. At least 80 % of the tested embryos
malities of the embryos, yet, some are due to an should reach blastocyst stage for the material to
inefficient ET. be considered non-toxic. ET catheters should
The aim of ET is to gently deliver embryos to also be tested for the presence of gram-negative
the endometrial cavity in an atraumatic fashion. bacterial endotoxin, which can be harmful or
During the early days of ART, ET was regarded a lethal for embryos. Limulus amebocyte lysate
simple procedure and did not attract much interest (LAL) test is commonly used for this purpose.
from researchers. However, it was soon realized Although there is no gold standard for the
that ET was not that simple and various compo- acceptable lower limit of endotoxin levels for
nents of the procedure, such as cleaning the cervi- IVF equipment, generally a level less than
cal mucus, having a full bladder at the time of ET, 0.5 Eu/mL is sought for. ET catheters in the
use of ultrasound guidance, type of embryo trans- market are sterilized with either ethylene oxide
fer media, and the choice of transfer catheter, or gamma irradiation. Toxicity testing and ster-
were considered to affect the success rate. Indeed, ilization information should be clearly docu-
as early as 1999 and 2001, two surveys conducted mented on the labels and packages.
in Australia and the U.K. showed that the “type of
catheter” was ranked the third and the fourth,
respectively, important factors thought to affect Types of Embryo Transfer Catheters
the success of the ET procedure [2, 3]. In this
chapter, we will review embryo transfer catheters Unlike the intrauterine insemination (IUI)
and adherence media that are being currently used catheters, most ET sets are composed of an
worldwide while other aspects of ET are scruti- inner catheter and an outer sheath. There are
nized in the other chapters. few one-piece ET catheters such as the Semtrac
C (Gynetics, Lommel, Belgium) in the market.
ET catheters vary in material, length, caliber,
General Requirements for Embryo degree of stiffness, and echogenicity of the
Transfer Catheters inner catheter as well as malleability and
design of the outer sheath, i.e., curved or
An ideal ET catheter should be safe for embryos, straight, with or without a bulb tip. Table 9.1
easy to handle by embryologists and physicians, represents some of the more commonly used
easily visible under ultrasound guidance, capable ET catheters in the market. Although an ET
of gently negotiating the cervical canal and the catheter is defined by several of these features
internal ostium, and finally, atraumatic to the simultaneously, we will scrutinize each of
endometrial lining. them separately.
9 Embryo Transfer Media and Catheters 71

Table 9.1 Commonly used embryo transfer catheters in the market


Malleability Precurved Bulb tip Echogenicity
Wallace® Yes No No Regular
Classic
Wallace® SureView® Yes No No Entire inner catheter
Wallace SurePro® Noa Yes No Surepro Ultra model combines surepro and sureview
features
Cook Sydney IVF Noa Yes Yes Echogenic ring at the tip
Labotect No Yes Yes Regular
Kitazato Noa Yes Yes Echogenic ring at the tip
a
Malleable stylets are available

Soft Versus Firm Embryo Transfer While some physicians prefer to use a firm
Catheters catheter routinely, most would reserve them for
technically difficult transfers, e.g., in the pres-
Trauma to the cervical canal during ET can cause ence of a convoluted or stenotic cervical canal.
bleeding and can stain the embryos, possibly There are numerous retrospective studies and
decreasing their contact and interaction with the prospective trials comparing various soft and
endometrium. Stimulation of the internal ostium firm ET catheters. According to two systematic
by the pressure applied by the catheter is thought reviews and meta-analyses, the use of soft ET
to trigger uterine contractions, which can lead to catheters is associated with significantly higher
expulsion of the embryos from the endometrial clinical pregnancy rates [4, 5]. Abou-Setta et al.
cavity. Obviously, endometrial trauma can cause [4] pooled randomized controlled trials (RCTs)
the same problems and decrease the chances of comparing soft versus firm ET catheters [4]. The
successful implantation. Therefore, the ideal ET “soft” catheters used in the original studies were
catheter should be atraumatic to the endocervix Wallace, Frydman, Cook (Sydney IVF and K-soft
and endometrium. models), and Gynetics Delphin. The comparators
“Soft” ET catheters, such as various models of included TDT, Gynetics Emtrac A, Tom Cat,
Wallace® (Smiths Medical, St. Paul, MN, USA), Rocket, or Erlangen as the “firm catheters” [6–
Frydman (Laboratoire CCD, Paris, France), and 15]. The odds of achieving a clinical pregnancy
Cook (Cook Ob/Gyn Inc., Bloomington, IN, was 1.39-fold higher (95 % confidence interval
USA), are usually preferred over “stiff” or “hard” (CI) = 1.08–1.79, p = 0.01) with the soft ET cath-
catheters such as the Tight Difficult Transfer eters. One can question whether these results are
(TDT) catheter (Laboratoire CCD), Rocket still valid because nowadays, the Erlangen and
(Rocket Medical, Watford, England) and TomCat catheters are used rarely, if at all. When
Emtrac-A (Gynetics). Despite the use of similar the three trials comparing Erlangen or TomCat
material, the latter models have firmer inner cath- with Cook and Wallace catheters were excluded
eters than those of the former models, and there- from the analysis, the difference was still signifi-
fore, are considered as “firm” ET catheters. In the cantly in favor of soft catheters (Fig. 9.1).
past, the Erlangen® ET catheter with a metallic Although it is unclear how soft catheters yield
outer sheath and the TomCat® (Sherwood higher pregnancy rates than firm catheters, a logi-
Medical, St. Louis, MO, USA) catheter, which cal assumption is that the former inflict less
was originally designed to drain the bladder of trauma to the endometrium. This was indeed
male cats, were also used for human ET. Today, shown in a small study where women underwent
to the best of our knowledge, there are only two a diagnostic hysteroscopy immediately following
brands, which carry metallic outer sheaths: a mock embryo transfer during the postovulatory
IVF-ET Flex by Dr. Peter Steiner and the period [16]. When the outer sheath was not
Gyneflex by Gynetics. Both are rarely used. pushed beyond the internal cervical os, the soft
72 A. Seyhan et al.

Soft catheter Firm catheter Odds ratio Odds ratio


Study or subgroup Events Total Events Total Weight M–H, Random, 95 % Cl M–H, Random, 95 % Cl
Amorocho (1999) 45 113 27 101 10.7 % 1.81 [1.02, 3.24]
Curfts (2001) 113 240 100 240 20.4 % 1.25 [0.87, 1.79]
Foutouh (2003) 32 114 13 91 7.6 % 2.34 [1.15, 4.79]
Grunert (1998) 35 99 20 51 7.9 % 0.85 [0.42, 1.70]
Lavery (2001) 37 160 34 148 12.2 % 1.01 [0.59, 1.71]
Van Weering (2002) 173 639 135 657 28.3 % 1.44 [1.11, 1.86]
Wisanto (1989) 50 200 28 200 12.9 % 2.05 [1.23, 3.42]

Total (95 % Cl) 1,565 1,488 100.0 % 1.43 [1.15, 1.77]


Total events 485 357
2 = 0.03; c 2 = 8.74, df = 6 (P = 0.19); I 2 = 31 %
Heterogeneity: t
Test for overall effect: Z = 3.24 (P = 0.001) 0.01 0.1 1 10 100
Favours experimental Favours control

Fig. 9.1 Comparison of clinical pregnancy rates with soft and stiff embryo transfer catheters

Wallace catheter did not cause any trauma to the ing the inner catheter loaded with embryos into
endometrial lining, while tunnel-like, groove- the endometrial cavity. Whether such a strategy
like, and ulcer-like lesions were frequently converts a “soft” catheter to a “firm” catheter
observed following mock ET with Frydman or and eliminates the advantage of the former was
TomCat catheters [16]. However, one needs to investigated in a retrospective study [20]. In
ensure that the outer sheath of a soft catheter is that study, 18 (45 %) of the 40 women who
not introduced into the endometrial cavity. underwent ET with this alternative technique
Despite providing a higher overall chance of achieved a clinical pregnancy as compared to
clinical pregnancy, the risk of failure to negoti- 51 (50 %) of 102 women who underwent an
ate the cervical canal is higher with soft cathe- “inner catheter first” ET with the same cathe-
ters, although the absolute difference was short ters, despite a similar number of embryos trans-
of statistical significance in the meta-analysis ferred. The difference was short of statistical
by Abou-Setta et al. [4] (OR = 7.51, 95 % significance (OR = 0.82, 95 % CI = 0.39–1.7,
CI = 0.94–60.11, p = 0.06) [4]. Difficulty in p = 0.59). Although one retrospective study is
negotiating the cervical canal with a soft cathe- inadequate to provide solid evidence, soft cath-
ter led to the use of a tenaculum or stylet or eters may be able to maintain their pregnancy
sounding the uterus more often than firm cathe- rates when used in an “outer sheath first” fash-
ters (OR = 5.4, 95 % CI = 1.28–222.8, P < 0.0001) ion for difficult cases.
[4]. According to two randomized controlled Indeed, catheters, which are specifically
trials and a retrospective study, changing the designed to be used in the “outer sheath first”
catheter or the use of a stylet was necessary in fashion, are marketed more recently. These
more than 25 % of ETs when the transfer was include the Labotect (M) (Goettingen, Germany)
first attempted with a soft Wallace catheter, ET catheter, all models of Kitazato (Shizuoka,
which is considered to be the benchmark of soft Japan), and the Cook Sydney IVF and Guardia
ET catheters [17–19]. The use of a stylet, either Access ET models. These ET catheters have a
by the effect of the stylet per se or the difficulty slightly curved outer sheath to fit the natural
of ET, which led to the requirement for a stylet, curve of the cervical canal, and there is a small
seems to be associated with a decreased chance bulb at the tip to facilitate negotiating cervical
of implantation (OR = 0.67, 95 % CI = 0.50– crypts and the internal ostium. Based on three
0.90, p = 0.01) and clinical pregnancy randomized controlled trials comparing the
(OR = 0.63, 95 % CI = 0.42–0.92, p = 0.02) [18]. Sydney IVF or Labotect catheters with the
An alternative method of negotiating the cer- Wallace catheter, similar clinical pregnancy rates
vical canal and internal ostium is to first pro- are achieved with the new “outer sheath first”
ceed with the plastic outer sheath slightly catheters and the soft Wallace catheter (Fig. 9.2)
beyond the internal ostium, followed by push- [17, 21, 22].
9 Embryo Transfer Media and Catheters 73

Bulb tip Wallace Odds ratio Odds ratio


Study or subgroup Events Total Events Total Weight M–H, Fixed, 95 % Cl M–H, Fixed, 95 % Cl
Ata (2008) 45 130 58 130 37.3 % 0.66 [0.40, 1.08]
Mcllveen (2005) 23 75 22 75 15.0 % 1.07 [0.53, 2.14]
Saldeen (2008) 81 202 80 198 47.6 % 0.99 [0.66, 1.47]

Total (95 % Cl) 407 403 100.0 % 0.88 [0.66, 1.16]


Total events 149 160
Heterogeneity: c 2 = 1.91, df = 2 (P = 0.38); I 2 = 0 %
Test for overall effect: Z = 0.91 (P = 0.36) 0.01 0.1 1 10 100
Favours Wallace Favours Bulb tip

Fig. 9.2 Comparison of clinical pregnancy rates with new curved, bulb-tipped catheters and the Wallace® catheter
(Smiths Medical)

Catheters with Enhanced There are two RCTs comparing the SureView
Echogenicity catheter with the regular Wallace catheter [25,
26]. In addition to implantation and clinical preg-
Two meta-analyses reported that clinical preg- nancy rates, visualization of the catheter and ease
nancy and embryo implantation rates were sig- of transfer were assessed in both trials.
nificantly improved with ET under ultrasound Descriptions used to categorize the ease of ET
guidance compared to ET with the “clinical procedures and catheter visualization were the
touch” method [23, 24]. This has led to the pro- same in the two trials. ET was categorized as very
duction of ET catheters with increased echo- easy when the catheter passed smoothly through
genicity. Two different techniques are used to the cervix. If the outer Teflon sheath was used to
increase echogenicity of ET catheters. The more negotiate the cervical canal, ET was defined as
commonly used technique involves integration of easy, and if a tenaculum was required, ET was
a metal ring close to the tip of the inner catheter. defined as difficult. A single experienced physi-
Examples include Kitazato catheters, Cook cian conducted all ETs in both the trials. They
Echotip, and Rocket EchoCat series. The metal both aimed to dislodge the embryos at 15 mm
ring is <2 mm and only provides increased echo- from the fundal endometrium.
genicity toward the tip. On the other hand, the Although both the trials reported improved
SureView® series by Smiths Medical is unique in visualization of the catheter, the incidence of
providing increased echogenicity through the easy transfers was not significantly different
entire length of the inner catheter. This is achieved between SureView and regular Wallace, despite
by mixing air bubbles into the material. a trend in favour of the former. However, the dif-
Some physicians are hesitant to use ET cathe- ference was short of statistical significance even
ters with echogenic rings due to concerns about when data from the two trials were pooled for a
endometrial trauma, which can be inflicted by the meta-analysis (pooled odds ratio (OR): 1.11,
metallic ring. This concern does not seem to be 95 % Confidence interval (CI): 0.91–1.34).
justified, because Karande et al. [19] compared Neither trial reported significantly increased
the Cook Echo-Tip with the regular Wallace cath- clinical pregnancy rates with SureView. When
eter in an RCT. Some 251 women were random- the results from the two trials were combined,
ized, and implantation (30 % vs. 35 %), clinical SureView and regular soft Wallace catheter
pregnancy (57 % vs. 55 %), and ongoing preg- again yielded similar clinical pregnancy rates
nancy rates (49 % vs. 47 %) were similar between (Fig. 9.3). It should be noted that embryo implan-
the two catheters. However, it is also possible to tation rates were higher in the SureView arms of
interpret these results as a failure of the echo tip both trials; however, the difference was signifi-
catheter to improve clinical outcome [19]. cant in only one [25].
74 A. Seyhan et al.

SureView Regular Wallace Risk ratio Risk ratio


Study or Subgroup Events Total Events Total Weight M- H, Fixed, 95 % Cl Year M- H, Fixed, 95 % Cl
Coroleu (2006) 53 98 39 95 51.4 % 1.32 [0.97, 1.78] 2006
Allahbadia (2010) 34 78 42 97 48.6 % 1.01 [0.72, 1.41] 2010

Total (95 % Cl) 176 192 100.0 % 1.17 [0.93, 1.46]


Total events 87 81
2
Heterogeneity: c = 1.34, df = 1 (P = 0.25); I = 26 %
2

Test for overall effect: Z = 1.34 (P = 0.18) 0.2 0.5 1 2 5


Favours regular Wallace Favours Surview

Fig. 9.3 Comparison of clinical pregnancy rates with Wallace® SureView® (Smiths Medical) and the regular Wallace®
catheter (Smiths Medical)

Overall, according to the best available evi- neither of the two techniques provided better
dence, the echogenic SureView catheter does not pregnancy rates and that uterine position, parity,
seem to increase clinical pregnancy rates. These and physician’s preference should dictate the
results should be interpreted with caution for sev- choice between the two approaches [28]. The
eral reasons. Both, the number of RCTs and the second RCT included 330 donor oocyte recipi-
sample sizes of each RCT are limited. A single ents undergoing ET with TVS or TAS guidance
experienced physician conducted all ETs in both and found similar pregnancy (50.9 % vs. 49.4 %)
trials. Any additional advantage of echogenic and embryo implantation rates (34.5 % vs.
catheter can be more important for less experi- 31.4 %) with both the techniques. However,
enced physicians. Selected participants of the 63 % of the patients in the TAS-guided ET
two RCTs could have obscured an additional reported discomfort related to bladder disten-
advantage of echogenic catheters. While tion, which was avoided by the TVS-guided ET
Allahbadia et al. [26] did not report the partici- [29]. Although TVS-guided ET can be done with
pants’ body mass index (BMI), the vast majority any ET catheter, in the latter trial, the Kitazato
(>95 %) of the participants in the trial by Coroleu Long catheter was used (order number 233340).
et al. [25] had a BMI < 30 kg/m2. Echogenic cath- This model consists of a 20 cm long, curved
eters can be more advantageous in a selected external sheath with a bulb tip and a 40 cm long
group of patients, e.g., obese women or women 3 Fr thick inner catheter. The longer external
with a retroverted uterus. sheath and inner catheter is designed to facilitate
handling the catheter by the physician who
simultaneously holds the TVS probe.
Catheters for Transvaginal
Ultrasound-Guided ET
Towako ET Catheter
It is not possible to acquire a proper view of the for Transmyometrial Embryo Transfer
cervical canal, uterocervical angle, the endome-
trial stripe, and the catheter tip in about 10 % of Accomplishment of transcervical ET in an atrau-
women undergoing ET under transabdominal matic fashion is impossible in some women with
ultrasound (TAS) guidance [27]. Transvaginal a tortuous cervical canal or an extremely stenotic
ultrasound (TVS)–guided ET was proposed as cervical os. Sometimes, it also proves difficult to
an alternative to TAS-guided ET. The first ran- insert the ET catheter into the uterine cavity fol-
domized clinical trial that directly compared lowing trachelectomy as a fertility-preserving
TVS-guided versus TAS-guided ET involved a treatment for cervical cancer. A transcervical
total of 186 women with similar implantation transfer is also impossible for women with iso-
(33.1 % vs. 31.1 %), clinical pregnancy (48 % lated cervical agenesis. Transmyometrial ET is
vs. 45 %), and live birth rates (30 % vs. 39 %) in an alternative under these circumstances. The
the two groups. The investigators concluded that Towako ET set (Cook) is specifically designed
9 Embryo Transfer Media and Catheters 75

for transmyometrial ET. The set consists of a HA. Overall, despite a consistent trend toward
stainless steel needle with an echotip, a stainless increased live birth rate with increased HA in
steel stylet, and the transfer catheter proper. The transfer medium, the difference was short of sta-
ET technique resembles oocyte collection proce- tistical significance (Odds ratio (OR): 1.17, 95 %
dure, i.e., the needle is inserted into the endome- Confidence interval (CI): 0.81–1.70). However,
trium or endometrial cavity under TVS guidance analysis of the clinical pregnancy rate, which
using the needle guide attached to the vaginal included a much higher number of participants
ultrasound probe. Following removal of the sty- and therefore, had more power, showed a statisti-
let, the 2 Fr catheter is inserted into the endome- cally significant increase with HA as compared
trial cavity through the needle lumen. When the with both transfer medium devoid of HA (OR:
catheter hub is fitted into the Luer lock on the 1.97, 95 % CI: 1.46–2.67) and transfer medium
needle, the catheter tip is 1 mm beyond the nee- with a lower dose of HA (OR: 1.27, 95 % CI:
dle bevel. Following the expulsion of the 1.08–1.50). It remains to be determined whether
embryos into endometrial cavity the whole set is the observed beneficial effect of HA on live birth
removed. rates will also reach statistical significance as the
Compared to transcervical ET, there is limited number of studies increases in time. The benefi-
data regarding the success rates with transmyo- cial effect of HA on clinical pregnancy rates was
metrial ET. In the largest series so far, Kato and more pronounced in women with poor prognostic
colleagues [30] reported an impressive 26.7 % features, such as multiple failed IVF cycles or
pregnancy rate after 1,298 transmyometrial ET advanced age, and when multiple embryos were
procedures with the Towako method [30]. transferred simultaneously.
A more recent RCT included 314 women
with a history of multiple implantation failures
Adherence Compounds in Embryo [36]. Results were analyzed in three strata: fresh
Transfer Media embryo transfers, frozen embryo transfers in a
natural cycle (FET – N), and frozen embryo
The most commonly used implantation- transfers in a hormone replacement cycle (FET –
enhancing molecule that has been introduced into H). Pregnancy rates were statistically signifi-
transfer media is hyaluronic acid (HA). It is a cantly increased with HA-enriched medium in
glycosaminoglycan molecule with a strong nega- all three strata (37.5 % vs. 10.9 %, 31.4 % vs.
tive charge; thus, it attracts a large volume of 10 %, and 41.2 % vs. 15.7 %, for fresh ET, FET-
water. This hydration produces a viscous solu- N, and FET-H, respectively, p < 0.05 for all
tion, which might facilitate embryo transfer and comparisons).
prohibit expulsion of the embryo [31, 32]. There is only one study in the literature with
However, the beneficial effect of HA on implan- fibrin sealant in the ET media as the implantation-
tation can not only be explained by its viscosity, enhancing compound, published in 1995 [37].
as other highly viscous solutions have failed to Ben-Rafael et al. reported no evidence of treat-
improve implantation rates. An alternative expla- ment effect of the compound (OR 0.98, 95 % CI
nation involves interaction of HA with CD44 0.54–1.78; P = 0.95) [37].
molecules, expressed on human embryos and on
the endometrial stroma [33, 34]. HA can act as Conclusion
the hub connecting the two. There are various embryo transfer catheters in
A recent Cochrane review evaluated the effect the market. Despite small differences between
of HA as an adherence compound to transfer stiffness of the inner catheters, it would not be
medium on reproductive outcomes [35]. Transfer wrong to say that all currently available models
medium enriched with HA was compared to have soft inner catheters as compared to cathe-
both, transfer medium devoid of HA and transfer ters used in the early days of IVF. The more
medium which contained lower doses of recent precurved catheters with bulb tip seem to
76 A. Seyhan et al.

better negotiate the cervical canal without com- 12. McDonald JA, Norman RJ. A randomized controlled
promising clinical outcome. Models with trial of a soft double lumen embryo transfer catheter
versus a firm single lumen catheter: significant
increased echogenicity do not seem to improve improvements in pregnancy rates. Hum Reprod.
clinical results despite better visualization dur- 2002;17(6):1502–6.
ing the procedure. However, like any equip- 13. Mortimer D, Fluker M, Yuzpe A. Effect of embryo
ment, the physician should choose the catheter transfer catheter on implantation rates. Fertil Steril.
2002;78(3):S17–8.
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32. Gardner DK, Rodriegez-Martinez H, Lane M. Fetal ant in in vitro fertilization and embryo transfer. Int J
development after transfer is increased by replacing Fertil Menopausal Stud. 1995;40(6):303–6.
Is There A Role for Tubal
Transfers? 10
Monika Chawla, Jayaprakash Divakaran,
Michael H. Fakih and Amal Al-Shunnar

Abstract
Tubal transfers were a forgotten entity due to development of culture media,
laboratory conditions and other advances in laboratory techniques includ-
ing the advent of intracytoplasmic sperm injection (ICSI). There is resur-
gence of interest in this modality as a means to bypass technical and
mechanical difficulties during uterine embryo transfers and in dealing with
the uterine embryo transfers facing high-order recurrent failures. In the last
and most common indication, the tubal transfer of embryos or zygote intra-
fallopian transfer may enhance the implantation rates and pregnancy rates
by providing a more conducive physiologic environment, emphasizing the
role of Fallopian tube in embryogenesis and its development, by improving
the synchrony of the endometrium and embryo development, bypassing the
junctional contractions, which are inevitable, even in the most atraumatic
uterine embryo transfers and playing a role in embryo expulsion. The logis-
tics, cost, risks of laparoscopy and slightly increased risk of ectopic preg-
nancy may hinder its frequent application but may be a saving grace for
high-order recurrent failures where extensive investigations reveal nothing.
It has been performed most often for cleavage-stage embryos (day 1–3),
both fresh and cryopreserved embryos, though blastocyst intra-fallopian
transfer has also successfully achieved intrauterine pregnancy.

M. Chawla, MD, MRCOG (*) IVF Michigan Fertility Center,


Reproductive Endocrinologist and Infertility Specialist, Michigan, MI, USA
Fakih IVF Fertility Center, Abu Dhabi and Dubai, UAE e-mail: mfakih@fakihivf.com
e-mail: monikachawla@hotmail.com
A. Al-Shunnar, LRCP and SI, MB, BCh, BAO (NUI)
J. Divakaran, MSc, PhD Al-Shunnar Polyclinic, Fakih IVF Fertility Center,
Fakih IVF Fertility Center, Abu Dhabi and Dubai, UAE Dubai, UAE
e-mail: j.prakash@fakihivf.com e-mail: Amal.shunnar@gmail.com
M.H. Fakih, MD
Fakih IVF Fertility Center,
Abu Dhabi and Dubai, UAE

© Springer India 2015 79


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_10
80 M. Chawla et al.

Keywords
Tubal transfer • Recurrent implantation failure • Gamete intra-fallopian trans-
fer • Zygote intra-fallopian transfer • Laparoscopic transfer • Embryo transfer

Introduction ZIFT was a much popular technique in the


early days of IVF, and subsequently, with the
The ability of tubal transfer of an embryo to pro- major advances in culture media, laboratory con-
duce pregnancy and live birth was first demon- ditions and development of ICSI, its use has
strated in a non-human primate model in 1984 declined due to physical burden, logistics and
[1]. Two years later the first successful micro- costs involved [8]. The understanding of the
laparoscopic intra-fallopian transfer in humans mechanism of superiority of ZIFT over standard
was demonstrated [2]. UET is fragmentary and incomplete.
Clinical experience with the transcervical uter- The conduit that the Fallopian tube is anatom-
ine embryo transfer (UET) shows that it is a rela- ically thought to be is much more than a passive
tively simple technique and has been the most passage for gametes and embryos. It is an active
common route of transfer. It does not entail risk of channel, which participates in several significant
anaesthesia and laparoscopy [3], and its cost- functions which are dynamic, like muscular con-
effectiveness has been proven time and again. It tractions and metabolism, as well as chemokine
allows the selection of the best embryo after 2–5 production [9]. It is a major contributor to the
days of culture and is a widely practised procedure process of fertilization and early embryogenesis.
requiring training with a short learning curve. The use of in vitro fertilization (IVF) enables
Transcervical embryo transfer is far from per- the bypassing of tubes but fails to create the same
fect though. Experimental studies with mock ET tubal microenvironment for the initial stages of
have shown expulsion of methylene blue in 57 % embryo development in the laboratory. It may be
of transfers [4] and movement of roentgenogram argued that tubal transfer of zygotes and early
contrast medium towards the Fallopian tubes, embryos is more physiological and creates an envi-
cervix and/or vagina in 38.2 %, 8.8 % and 11.8 % ronment more conducive for this and hence, results
transfers, respectively [5]. in higher implantation and pregnancy rates [2]. The
Embryos have been found in the vagina after transfer of zygotes to the Fallopian tubes allows for
embryo transfer [6, 7]. If the mock ET had been the early cleavage and development in the natural
the actual ET, 32 % (optimum ET position) and and physiological environment of the Fallopian
52 % (no optimum ET position) of all patients tube with the presence of natural cytokines and
would have lost their opportunity for pregnancy growth factors, which may enhance implantation.
as a result of the ET procedure [5]. The tubal environment will be potentially superior
to the artificial culture media and incubators [10].
Avoidance of poor in vitro culture media is
Back to Nature with Tubal Embryo unlikely to be the major mechanism involved in the
Transfers (TET) or Zygote Intra- successful outcome of ZIFT. It may be more likely
fallopian Transfer (ZIFT) related to mechanical aspects of the procedure.
A better synchronization between embryonic
The resurgence of interest in tubal embryo transfers development and endometrial development is
has been due to recurrent failures with uterine highly apparent with this transfer, with the advan-
embryo transfer or technical difficulties encountered tage of avoidance of potential traumatic insertion
in it. The first pregnancy from ZIFT was reported in of catheters. It is well known that functional con-
1986 as a modification of gamete intra-fallopian tractions on the day of transfer are associated
transfer (GIFT). It was meant to treat patients with with a reduced pregnancy rate [11].
male factor infertility or failed GIFT procedure but Routine procedures and, more often, difficult
was extended to cover other aetiologies [2]. cervical transfers produce strong junctional
10 Is There A Role for Tubal Transfers? 81

waves and contractions in the fundal area which them are technically tedious, and some do not
may then migrate to the cervix, affect the reten- have evidence from randomized trials of being
tion of the embryos in the favourable endometrial statistically significant to success. Cruz et al. [23],
environment and promote expulsion. Easy trans- in a retrospective study on RIF patients, reported
fers will not affect the pattern of contractions to enhanced success with blastocyst transfer, with a
that extent. Hence, mechanical factors due to the increase in implantation and pregnancy rates as
catheter stimulation may play a significant role in compared to conventional day 3 transfers.
the implantation process. However, in a prospective study comparing
Moreover, inoculation of the uterine cavity the blastocyst transfer versus ZIFT in patients
with cervical micro-organisms during uterine with recurrent implantation failure, highly
embryo transfer can also play a role in decreasing favourable clinical pregnancy and live birth rates,
implantation rates [12, 13]. all in the range of 40 %, emphasized the role of
ZIFT as a powerful clinical tool for these patients.
The extended culture and transfer at the blasto-
Indications for ZIFT cyst stage failed to increase the implantation or
improve prognosis for patients with RIF [24].
Most retrospective studies show increased preg- A retrospective cohort study was performed at
nancy rates with ZIFT [14, 15]. Many non- a tertiary referral university hospital in Israel,
randomized studies have also reported higher where a group of patients with approximately 8.1
pregnancy rates for tubal transfer of embryos previous cycles underwent 280 ZIFT procedures.
(ZIFT) than for intrauterine embryo transfer (ET) The live birth rate of patients was 39.8 %, which
[16, 17]. In contrast, other studies show compara- is remarkable considering the poor prognosis
ble rates between the two procedures [18, 19]. The associated with RIF. They concluded that ZIFT
largest uncontrolled study, the SART registry, has remains an important modality in the manage-
consistently shown higher pregnancy rates with ment of high-order RIF and is possible with at
tubal transfers than uterine transfers in the past least one unobstructed tube in such patients [25].
decade. The clinical pregnancy rate per retrieval Aslan et al. [26] analyzed 141 ZIFT cycles
(37.5 % versus 31.1 %) and per transfer (40.1 % among 132 patients with RIF and compared them
versus 33.3 %) remains higher for ZIFT in this with 145 UET cycles amongst 97 RIF patients. The
non-randomized database [20]. In the following implantation rates, clinical pregnancy rates and live
sections, we will discuss each of the indications. birth rates were comparable in both groups. The
clinical pregnancy rate was found to be 22.7 % [26].
The authors’ experience with ZIFT is a series
Recurrent Implantation Failure (RIF) of 32 cases from January 2011 to April 2013,
which resulted in a clinical pregnancy rate of
Recurrent implantation failure presents a major 37.5 %. The most common indication was recur-
challenge for the medical team [21, 22]. The rent implantation failure. There were three cases
pathophysiology of RIF should be intensely with cervical stenosis and scarring due to previ-
investigated to allow the application of therapeu- ous cervical surgeries (cone biopsy and large loop
tic or modifying measures during the course of excision of the transformation zone). The number
initiation of treatment of the next cycle. The preg- of previous failures was 4.6 ± 2.5, and no ectopic
nancy rates do not change over the first four pregnancy was found in this series so far [27].
attempts but drop by 40 % in subsequent cycles in
IVF failures [9]. There are multiple therapeutic
approaches, which have been tried in these Tubal Factor Infertility
patients like laser-assisted hatching, embryo co-
culture, blastocyst transfer, aneuploidy screening Farhi et al. [28] performed zygote intra-fallopian
by preimplantation diagnosis and salpingectomy transfers in patients for the first time with mild
for hydrosalpinges [8]. None of them have been tubal factor infertility without hydrosalpinges.
found to be consistent and promising. Some of Patients with tubal factor but at least one patent
82 M. Chawla et al.

tube proven on HSG or laparoscopy, with at least clinical pregnancy rate per retrieval was 12 %
four previous implantation failures after IVF-ET per ZIFT and 26.5 % for UET though the treat-
in which at least three embryos were replaced per ment protocol was not comparable for all
transfer, were included. Four to six zygotes were patients [31].
transferred by laparoscopy 24–48 h after retrieval. A critical meta-analysis of six published ran-
In the 112 cycles, the pregnancy rates and implan- domized trials of outcomes of ZIFT and UET for
tation rates were 35.1 % and 11.1 % respectively. in vitro fertilization cycles was done. It did not
Similar rates were present in both tubal and non- demonstrate any statistically significant difference
tubal factor patients. There was an ectopic preg- in clinical pregnancy rate per transfer and implan-
nancy rate of 2.5 %. The pregnancy and tation rate between ZIFT and UET (36.5 %, 15 %
implantation rates in IVF-transcervical ET were in ZIFT versus 31.4 %, 12 % in UET) although
6.9 % and 2.5 %, which was significantly lower. there was a tendency towards a higher pregnancy
The ZIFT procedure was performed only in rate with ZIFT [9]. None of these studies included
patients who had a fertilization rate of >60 %, who patients of RIF. There was considerable heteroge-
produced four or more zygotes in the ZIFT cycle neity in the sub-groups of patients that included
and who had an endometrial thickness of ≥7 mm patients with cryopreserved embryos, male factor
on the day of human chorionic administration infertility, oocyte donation and the general IVF
(hCG) administration. If hydrosalpinges are pres- population. No conclusions could be drawn from
ent, salpingectomy is the best way forward [28]. this analysis. In contrast, the SART database from
A comparative study between combined 1991 to 1996 shows a statistically significant
GIFT/IVF and ZIFT /IVF was performed for increased pregnancy rate per transfer and per
unexplained infertility, anovulation and male fac- retrieval (p < 0.005) favouring ZIFT, with an
tor facing recurrent IVF failures. Both resulted in increase in ectopic pregnancy rate (p < 0.005)
similar pregnancy, delivery, implantation and which may reflect biases in reporting [20].
multiple gestation rates [29]. In another study of ZIFT with tubal transfer of
cryopreserved embryos, tubal transfer improved
the pregnancy rates. They reported a clinical preg-
Non-tubal Factor Infertility nancy rate of 68 % and ongoing pregnancy rate of
58 % per transfer with ZIFT compared with 24 %
A prospective randomized study from Iran ran- and 19 % with UET. It was proposed to mimic the
domized patients with normal hysterosalpingo- natural conception cycle in terms of early embryo
grams and/or normal laparoscopy and those who development and implantation [32].
had easy mock transfers to be randomized for
ZIFT and UET. The patients with RIF with contra-
indications to laparoscopy, azoospermia and diffi- Difficult or Non-feasible Trans-
cult mock ETs were excluded. The study showed a cervical Uterine Embryo Transfers
clinical pregnancy rate per transfer of 42.1 % fol- Due to Cervical Factors
lowing ZIFT and 21 % following UET. The ongo-
ing pregnancy rates were 35.3 % following ZIFT Congenital cervical atresia and hypoplasia are rare
versus 20 % following UET [3]. abnormalities that generally require reconstructive
The reported pregnancy rate per transfer was or extirpative procedures to relieve outflow tract
47.7 % for IVF and 37.9 % for ZIFT in a study by obstruction. Infertility is a common sequel, and
Tanbo et al. [30] which included couples with only four previous pregnancies have been reported.
unexplained infertility, peritoneal endometriosis In selected cases, zygote intra-fallopian transfer
or reduced semen quality [30]. (ZIFT) or other assisted reproductive techniques
A Canadian study failed to show any benefit may offer alternatives for conception [31].
of tubal transfer compared to uterine transfer in Murray et al. [33] reported the management of
59 couples who underwent oocyte retrieval a woman who presented with secondary infertil-
with transfer of four cleaving embryos. The ity and amenorrhoea after two large loop excision
10 Is There A Role for Tubal Transfers? 83

of the transformation zone (LLETZ) procedures and through a 5-mm mid-line supra-pubic incision,
and a cone biopsy and who had cervical stenosis, all peritoneal fluid and blood was aspirated. In
a foreshortened cervix and haematometra. In this patients without tubal factor, the Fallopian tube
case an intra-fallopian blastocyst transfer was chosen for the transfer was the one with the more
performed successfully [33]. healthy-looking appearance. In patients with tubal
As discussed before, junctional contractions factor, transfer was performed to the tube with
during ET play an important role in the rate of proven patency according to data from laparoscopy
implantation of embryos. Manipulation of the cer- or hysterosalpingography (HSG), done during the
vix, such as instrumentation to correct persistent infertility investigation. Four to six pronuclear-
angulation, dilatation for severe cervical stenosis stage zygotes were loaded into the catheter (deliv-
at the time of embryo transfer or use of a stylet to ery catheter, 35 cm; Cook) and transferred through
negotiate the passage may increase contractility a third para-umbilical puncture deep into the
and chances of expulsion. If these problems recur Fallopian tube to the ampular region [28].
after required corrective steps, such as after hys- Siam [35] used the new advanced micro-
teroscopic dilatation/adhesiolysis, the success of laparoscopic set with the fibre-optic technology
this rate-limiting step needs to be addressed, and in an office procedure without general anaesthe-
alternatives have to be considered. sia for the transfer of zygotes, selected according
In cases of cervical aplasia, severe dysplasia, to single observation of pronuclear morphology
treated with cone biopsy or repeated LLETZ versus day 3 embryos. This technique takes
causing scarring with non-negotiable cervical 7–15 min, and the images produced from the
passage, ZIFT serves as a good alternative with micro-laparoscopic system were nearly similar to
success similar or better than UET. those from the traditional 10 mm system. The
couples included in the study had previous failed
ICSI and uterine embryo transfer due to failed
Advanced Maternal Age (AMA) implantation [35].

Recurrent failures and spontaneous abortions are


more commonly prevalent in advanced maternal Trans-myometrial versus Tubal Transfer
age due to increase in gamete and embryonic
aneuploidy. In vitro culture may contribute to The other alternative route of difficult embryo
abnormal human embryo development leading to transfers due to cervical factors is the trans-
implantation failure. ZIFT may improve implan- myometrial route. The drawback with it is the
tation rates by improving early embryonic devel- significantly increased risk of junctional zone
opment by providing a better intra-fallopian contractions, which becomes an important reason
environment for development. ZIFT was found to for failure. This was recorded in a study with
be a viable treatment option for women of transvaginal scanning for 5 min. The tubal or
AMA. Despite a higher mean age and a higher zygote intra-fallopian transfer seems to bypass
number of previously failed cycles, ZIFT patients this effect [36].
had pregnancy outcomes and implantation rates
similar to patients undergoing IVF-ET [34].
Risks

Technique Zygote intra-fallopian transfer is a surgical pro-


cedure and is not free from risks and complica-
Zygote intra-fallopian transfer is performed with tions [25]. These are as follows:
the use of a three-puncture laparoscopy method.
After introducing the umbilical trocar and optical 1. Risks of laparoscopies are inherent to this
equipment, after surveying the abdominal cavity procedure. In a report, summarizing 29,966
84 M. Chawla et al.

laparoscopies for gynaecological surgery, the the zygotes by detailed morphological evaluation
mortality rate was 3.33 % per 100,000 proce- can, however, change this practice. Criteria of
dures, and the overall complication rate was zygote scoring have been described to provide
4.64 per 1,000 laparoscopies [9]. better selection on day 1 prior to transfer [40, 41].
2. Ectopic pregnancy. Increased risk of ectopic
pregnancy was demonstrated with this proce-
dure despite the presence of healthy tubes. When to Offer ZIFT?
Habana et al. [9] found an incidence of 3 %
compared to the intrauterine transfer group A thorough investigation of any case is manda-
(1.5 %) [9]. This incidence was higher than the tory before ZIFT is offered. In cases of recurrent
0.2 % reported in the SART registry after ZIFT implantation failure, where tubal transfers have
and 0.4 % after intrauterine transfers [20]. This been used most often, a detailed analysis of pre-
aspect needs counselling before the procedure. vious protocols and laboratory parameters, hys-
Falloposcopic or salpingoscopic scoring before teroscopy, karyotyping of the couple, performance
tubal transfer may help select patients with of myomectomy, if necessary, and treatment of
healthy endotubal features though this may not hydrosalpinges is necessary before ZIFT is
translate into better success rates [37]. offered. Other modalities, such as PGS (pre-
3. Cost and complexity implantation genetic screening), assisted hatch-
ing, endometrial irritation or blastocyst transfer,
could be offered prior to ZIFT [25].
The presence of at least one normal-appearing
Timing of Intra-fallopian Transfer tube is necessary to proceed with ZIFT. This
evaluation would be on the basis of HSG or lapa-
There is no consensus regarding the optimal stage roscopy to prove the patency.
of the zygotes/embryos to be transferred. In a retro- Zygote intra-fallopian transfer has been
spective analysis, 176 patients who failed in applied to mild forms of tubal pathology in a
7.65 +/− 3.7 previous IVF cycles underwent 200 study [28], but moderate to severe tubal damage
ZIFT and 73 embryo intra-fallopian transfer (EIFT) or the presence of hydrosalpinges has to be
procedures. Implantation and live birth rates were addressed differently. The incidence of ectopic
compared for both groups. Patients in both groups pregnancy was not seen to be increased in this
were found comparable for demographic and clini- data compared to the general risk of extrauterine
cal parameters. Similar numbers of oocytes were pregnancies in the IVF population.
retrieved and fertilized in both groups, and 5.2 +/− If used with good selection criteria after a thor-
1.2 zygotes/embryos were transferred. Implantation ough work-up to rule out any correctable factors,
and live birth rates (10.5 and 26.5 % versus 10.9 zygote intra-fallopian transfers could offer a unique
and 24.7 % for ZIFT and EIFT respectively) were modality to achieve reasonable success rates in
comparable. It is concluded that tubal transfer of patients who failed conception from all other
zygotes and day 2 cleavage-stage embryos are modalities. Prior adequate counselling for associ-
equally effective [38]. ated risks and chances of success is mandatory.
A successful transfer of two vitrified/warmed
blastocysts was carried out in one of the tubes
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Steril. 2009;91(3, supplement):15–6. C, Cohen-Bacrie P, Dumont-Hassan M. Embryos with
35. Siam EM. Office microlaparoscopic intrafallopian high implantation potential after intracytoplasmic
transfer of day one zygote versus day three embryo sperm injection can be recognized by a simple, non-
transfer after previous failed ICSI trials. Afr J Reprod invasive examination of pronuclear morphology. Hum
Health. 2011;15(2):153–61. Reprod. 2000;15(6):1396–9.
Loading and Expulsion of Embryos
11
Gautam N. Allahbadia Rubina Merchant,
Goral Gandhi, and Akanksha Allahbadia

Abstract
The catheter-loading technique and the velocity with which the catheter
load is transferred into the uterine cavity strongly influence the efficiency
of embryo transfer and the implantation outcome. Embryo-containing
medium may be loaded into the embryo transfer catheter, either bracketed
by air columns on either sides to avoid accidental spillage or without the
use of air. Air bubble formation that may result from intentional (air buf-
fers) or unintentional (within the embryo-containing medium) aspiration
of air into the catheter may have detrimental effects, such as embryo
entrapment, production of reactive oxygen species, and suboptimal supply
of culture medium. Several variables, such as the transfer volume, type of
syringe, experience of the personnel, position of the patient, and transfer
speed, may influence the formation of air bubbles in the uterus, hence the
potential for embryo implantation. Very high transfer volumes (>60 μL)
are associated with drawbacks such as reflux of embryos and ectopic preg-
nancies; hence, transfer volumes ≤30 μL have been recommended by
most authors. The velocity of embryo expulsion may in turn be influenced
by the property of the syringe, the volume of the transfer medium, and
presence of air in the catheter. Gentle release of the catheter load at an
optimal position into the uterine cavity may avoid the theoretical possibil-
ity of embryo retention within the catheter due to low-velocity expulsion
or reflux of embryos, ectopic pregnancies, and uterine contractions due to

Rotunda-Blue Fertility Clinic & Keyhole Surgery


Center, Mumbai, India
e-mail: gautam@rotundaivf.com;
gautam@newhopeivf.com; drallah@gmail.com
R. Merchant, PhD • G. Gandhi, MSc • A. Allahbadia,
G.N. Allahbadia, MD, DNB, FNAMS (*)
MBBS
Department of Assisted Reproduction,
Department of Assisted Reproduction, Rotunda – The
New Hope IVF, Sharjah, UAE
Center for Human Reproduction, Mumbai, India
Rotunda-The Center for Human Reproduction, e-mail: rubinamm@gmail.com; goralgandhi@gmail.
Mumbai, India com; Akanksha.03@gmail.com

© Springer India 2015 87


G.N. Allahbadia, C.F. Chillik (eds.), Human Embryo Transfer, DOI 10.1007/978-81-322-1115-0_11
88 G.N. Allahbadia et al.

high-velocity expulsion. Dosing devices have proved useful in standard-


izing the aspiration and expulsion process.

Keywords
Catheter loading • Techniques • Embryo loading • Embryo expulsion •
Transfer volume • Catheter load • Velocity of expulsion

Introduction endometrium, trigger uterine contractions, or


increase the exposure of embryos to the ambient
Despite the high fertilization rates in the labora- conditions [2].
tory (>90 %), the overall success of assisted Though most of the above-mentioned param-
reproductive technology (ART), i.e., the take- eters controlling the outcome of ET have been
home baby, is still very low (<25 %) and assumed detailed by most studies, there exists a paucity of
to be mainly due to implantation failure [1]. The randomized controlled trials on catheter-loading
predictors for a successful ART cycle include techniques and the velocity of expulsion of
female age, ovarian reserve, embryo quality, embryos into the uterine cavity, which could, if
endometrial receptivity, and the embryo transfer not heeded to, jeopardize the outcome. According
(ET) technique [2]. Embryo transfer is the final to Montag et al. [6], loading embryos into the
and crucial step in an ART cycle that involves the transfer catheter is of utmost importance, espe-
atraumatic transfer of embryos in the uterine cav- cially in view of variances in the results among
ity with the main aim of increasing the proximity different operators, particularly with low vol-
between the embryo and endometrium to facili- umes of medium [6].
tate implantation. Parameters that may influence An ideal catheter-loading technique involves
the outcome of ET include (i) anatomy and phys- the aspiration of embryo-containing medium and
iology (geometry of uterus and cervix, uterine air (when employed) in the desired volumes and
position and contractions, uterine fluid viscosity), delivery of the catheter load into the uterine cav-
(ii) technical procedure (catheter insertion, place- ity at a desired velocity, both of which involve
ment and withdrawal, injection pattern, synchro- efficiency on the part of the embryologist and the
nization with contractions, ultrasound guidance), clinician, respectively, and may constitute a sig-
(iii) catheter (type, diameter, tip shape), (iv) nificant step in achieving successful implantation,
transferred matter (volume, air/liquid, liquid vis- as will be discussed in the following sections.
cosity), and (v) embryo selection (quality, num-
ber of cells) [3]. Besides these and other operating
parameters such as the delivery speed of the cath- Clinical Discussion
eter load [4, 5], the outcome of ET depends on
the catheter-loading technique, removal of the Embryo-Loading Techniques
cervical mucus prior to ET, performance of a
mock transfer, the ease of transfer and primarily, Embryos within a liquid medium may be loaded
the knowledge, dexterity, and co-ordinated efforts in an ET catheter for transfer into the uterine cav-
of the clinician and embryologist. ity, using different loading schemes that may
Despite the lack of consensus regarding the vary between clinics. Catheter-loading tech-
optimal ET technique, it is generally recom- niques may be essentially of two types: (i) the
mended that ET be performed as atraumatically air–fluid model in which the embryo-containing
as possible, placing the embryos at an optimal medium in the syringe–catheter complex is
position in the fundal region of the uterine cavity, bracketed with varying volumes of air spaces on
while avoiding difficult transfers that disrupt the either sides, thus preventing the embryos from
11 Loading and Expulsion of Embryos 89

accidental spillage, and (ii) the fluid-only model However, Ebner et al. [11] concluded that fac-
in which the catheter is entirely filled with the tors related to the technical equipment (syringe,
embryo-containing transfer medium to benefit catheter, transfer medium) did not significantly
from the hydraulic properties of a whole-liquid affect the rising of air bubbles, though a trend
phase [7]. Some authors use a “three-drop” pro- towards certain types of transfer catheters
cedure in which the embryos in transfer medium (Edwards-Wallace catheter, Smiths Industries,
are separated by a bubble of air from a preceding Lancing, UK) and transfer medium (UTM
and a following drop of medium [8]. In a novel Medium, MediCult, Copenhagen, Denmark)
modification of the standard air–fluid loading could be observed [11].
technique, we used only one air bubble at the tip
of the embryo transfer catheter instead of two air
bubbles to bracket the embryo-containing Factors that Affect Dispersion
medium [9], therefore introducing a lesser of the Catheter Load
amount of air into the uterine cavity. A retrospec-
tive evaluation using the results of a web-based Simulation experiments in a uterine laboratory
survey (IVF Worldwide (www.IVF-worldwide. model at different inclinations with various
com) from 265 centers in 71 countries showed sequences of liquid and air, various transfer
that the most commonly reported methods of speeds of the catheter load, and placement of the
embryo loading were medium-air-embryo-air- catheter tip near and remote from the fundus
medium (42 %), medium in catheter with embryo demonstrated dispersion of the transferred mat-
at end (20 %), and medium-air-embryo (15 %) ter, hence, the potential for embryo implantation
[10]. depended on the position of sagittal cross section
of the uterine cavity with respect to the horizon or
the fundal level of the uterine cavity, location of
Factors that Affect Catheter Loading the catheter tip, and transfer speed. They recom-
mended that when ET is performed with a cathe-
Several factors, such as the type of syringe and ter loaded with air in addition to the transferred
transfer catheter, the choice of medium, or the liquid, the patient should be positioned such that
individual performing the loading, may cause a the fundus will be at the highest point in the sagit-
deviation from a presumed optimal aspiration tal cross section above the horizon, especially in
technique, leading to an ineffective loading pro- subjects with retroverted uteri, the catheter tip be
cess [11]. To observe the dynamics of embryo placed at mid-cavity, about 2.0 cm from the fun-
release, Correa-Pérez et al. [12] used seven ways dal end, and the catheter load be delivered gently
of loading the catheters (air–fluid or fluid-only over a period of 10 s. These measures could max-
combinations), three different syringes (flat, con- imize the potential of the embryo to be present
ical, piston-like plunger), and three embryo posi- near the fundal endometrium during the window
tions (proximal, middle, distal) with respect to of implantation and with the assistance of normal
the catheter tip. They showed chaotic dispersion uterine peristalsis toward the fundus, possibly
patterns of the embryos released from the cathe- improving the embryo implantation rate [3].
ters and embryo entrapment within the catheter Intrauterine embryo transport after ET is
when air was introduced in the catheter, an effect determined by the pattern of mixing between the
enhanced by certain syringes. On the basis of transferred media and the uterine fluid, which
their findings, they recommended the use of have different viscosities, uterine fluid having a
syringes with a flat plunger rather than conical relatively higher viscosity compared to the trans-
and piston-like plungers, no air in the catheter, ferred liquid [9]. Using mock embryo transfers
and positioning of the embryos within the proxi- into an artificial uterus filled with glycerine that
mal or towards the middle of the fluid column mimicked the viscous uterine fluid, Eytan et al.
with reference to the tip of the catheter [12]. [13] showed that the distribution of the transferred
90 G.N. Allahbadia et al.

matter within the uterine cavity was determined uterus inclined above the horizontal plane, the
by the composition of the liquid-air sequence and resulting air bubbles within the uterus were car-
the viscosity ratio between the transferred liquid ried upward toward the fundus by buoyant forces,
and the uterine fluid, and backward spillage of thereby dragging behind them the embryo-
embryos toward the cervix could be avoided by containing transfer medium that could substan-
adjusting the viscosity of the so-called embryo- tially increase the probability of embryos to be
containing fluid to the uterine milieu [13]. present near the fundal wall during the window of
implantation. Their results demonstrated, for the
first time, the importance of having a gas phase in
Significance of Air in the Transfer the catheter load [20]. A low injection speed gen-
Catheter erated several air bubbles, which led to more of
the transferred liquid being carried towards the
Air can enter the uterine milieu either intention- fundal end, thus possibly enhancing the potential
ally (protective air buffers) or unintended, during for implantation [20]. As air exits the catheter tip,
aspiration of the liquid transfer volume [7]. it is subjected to surface tensions at the interface
Traditionally, in the early phases of IVF-ET treat- with intrauterine liquid, compression stresses
ment, the use of various volumes of air to bracket from the surrounding intrauterine liquid, gravity
the embryo-containing medium in the transfer forces because of its weight, and buoyancy forces
catheter was a standard practice [14]. because of the uterine liquid it displaces. The
dynamic interaction between these forces, which
Advantages of Air in the Transfer is largely dependent on the angle of inclination of
Catheter the uterine cavity and the speed of injection, dic-
The use of air columns in the transfer catheter tates the number of generated bubbles, as well as
has been supported by some clinicians to iden- the speed of their upward movement [3].
tify the positioning of embryos in the catheter
and uterus on ultrasound [15, 16], to prevent Disadvantages of Air in the Transfer
transport of the embryos within the catheter [13], Catheter
to protect the embryos from the cervical mucus Some clinicians have suggested that the presence
and from accidental discharge before entering of air could be a non-physiological factor with a
the endometrial cavity [17], or for a psychologi- deleterious effect on the embryos and implanta-
cal benefit for both, the clinician and patient, tion. It could increase the likelihood of embryo
ensuring embryo release only after proper place- entrapment, increase reactive oxygen species, the
ment in the uterus [18]. The embryo-containing occurrence of retained embryos within the cath-
droplet can easily be visualized on ultrasound eter, or chaotic dispersion patterns of the embryos
through the detection of the two air bubbles sur- released from the catheter [12, 15]. While air
rounding the media [9]. Clinical pregnancy rates bubbles are formed during injection of liquid
appeared higher in cases where the air bubbles with air into the uterus, inhibiting the dispersion
were closer to the fundus, the optimal position of the transferred liquid phase toward the fundus
being <10 mm from the fundal endometrial sur- [13], smaller bubbles may arise accidently within
face; however, though the final position of the air the embryo-containing medium, forming a single
bubble, used as identifier of the position of the large air bubble, which can spread the transferred
embryo at ET, can be determinative for PR, it liquid backward, heading to the presumed cervix,
cannot be predicted [19]. a situation which in real embryo transfer could
Tracking the dispersion of the transferred liq- cause spillage out of the uterus [7].
uid in their in vitro experimental setup, Eytan Embryos could be harmed directly due to a
et al. [20] demonstrated that when ET was per- suboptimal supply of culture medium, as a result
formed with the subject in the supine position, the of surface tension or related phenomena [11] or
sagittal cross section of the normal anteverted indirectly, if a larger air bubble blocks the expul-
11 Loading and Expulsion of Embryos 91

sion of the concepti. Hence, there is a close cor- presence of two 5 μL air bubbles on both sides of
relation between the amount of air used for 15 μL of transferred liquid did not induce the
transfer and the capacity of the embryos to freely expulsion of the transferred matter through the
migrate into the uterus, suggesting that the actual cervix as long as the total volume did not exceed
volume of air entering the uterus should be kept 15–20 μL [21]. Montag et al. [6] demonstrated
to a minimum in order to avoid embryonic wast- that ET with a high fluid volume (40 μL) com-
age [7], and to enhance the embryos’ chances of pared to a low fluid volume (15–20 μL) yielded
reaching the site of implantation [13]. However, significantly higher pregnancy (40 % versus
Mansour et al. [21] reported that the presence of 23 % respectively; P = 0.0124) and embryo
air bubbles did not affect the rate of expulsion of implantation rates (24.4 % versus 14.7 % respec-
the dye [21]. tively; P = 0.0109) and enabled easier catheter
loading, a higher reproducibility among techni-
Solutions cians, and easier control of transfer, thus facili-
Bearing in mind that the total volume of air tating and improving the technique of ET. They
(intended and unintended aspiration) may inter- indicated that the occurrence of an ectopic preg-
fere with adequate intrauterine dispersal of the nancy as well as a probable reflux after the trans-
concepti, efforts should be made to keep this fer are more likely related to the positioning of
gaseous volume to a minimum [8]. Air is a limit- the catheter and uterine contractions (e.g., due to
ing factor, and several measures may be taken to touching the fundus) than to a high fluid volume,
minimize the accidental entry of air into the at least as long as the volume does not exceed
catheter such as (i) increasing the amount of cul- 40 μL [6].
ture medium in the four-well dish prepared for The presence of air bubbles and/or the use of a
transfer up to 750 μL, thus avoiding air contact smaller volume of embryo transfer medium
due to incomplete immersion of the transfer (<10 μL) is reported to have a negative impact on
catheter tip in the culture medium [11], (ii) omit- the implantation and clinical pregnancy rates.
ting the proximal air buffer as the amount of Significantly higher implantation (19.1 % vs.
medium entering the uterus may also be limited 14.1 % respectively) and clinical pregnancy
by carefully pressing the piston to a certain mark (46.5 % vs. 26.0 % respectively) rates were
of the syringe’s graduation during injection [7], observed when the volume of embryo transfer
and (iii) minimizing the volume of the distal air medium was >10 μL compared a smaller volume
buffer to 5–10 μL to prevent the embryos from (<10 μL). In addition, avoidance of air bubbles
spillage [7]. led to a significant increase in implantation rate
(20.5 % vs. 9.3 % respectively) and pregnancy
rate (44.7 % vs. 15.9 % respectively) [11]. The
Significance of the Transfer Volume authors concluded that of all the technical details
(syringe, catheters, transfer medium) analyzed,
Replacing the air within the transferred matter the volume of transfer medium strongly corre-
with a similar volume of liquid is reported to lated with the presence of air bubbles (p < 0.001),
increase the rates of implantation and pregnancy thus possibly limiting the embryo’s capacity to
[22]. The volume of transfer medium may have a implant. Smaller volumes of the embryo-
significant impact on the potential of embryos to containing medium (10 μL) could result in addi-
implant. High transfer volumes (>60 μL) have tional air bubble formation, which may impair
been reported to result in expulsion of the forward dispersal of the embryos or cause insuf-
embryos through the cervix into the vagina [23] ficient culture medium supply due to surface ten-
or a high risk of ectopic pregnancies [24, 25]. sion or related phenomena [11]. However, in our
Hence, transfer volumes of ≤30 μL have been laboratory, we have been able to restrict the vol-
recommended for use to avoid these problems ume of embryo transfer medium to <10 μL, with
[21, 24, 25]. Mansour et al. [21] showed that the satisfactory results.
92 G.N. Allahbadia et al.

Fig. 11.1 Catheter-loading technique employed at Rotunda-The Center for Human Reproduction

Embryo-Loading Technique at catheter can cause retained embryos due to


Rotunda the Center for Human negative pressure.)
Reproduction (Fig. 11.1) • The catheter is slowly withdrawn after inject-
ing the embryos. (Caution: Rapid withdrawal
After scoring and selecting the best embryos for may create a negative pressure and result in
transfer, prior to catheter loading, the identity of the withdrawal of the embryos following the
the patient is reconfirmed by the embryologist. catheter.)
The culture dish with the respective embryos is
removed from the incubator and embryos loaded
into the ET catheter as follows: Inspection of Retained Embryos
After the embryos have been transferred, the cath-
• A 1 mL syringe is filled with 0.5 mL culture eter is handed back to the embryologist. The cath-
medium. (Caution: Ensure that the syringe eter is flushed by in-and-out suction in media on
does not contain any air bubbles.) the sterile dish cover. The catheter tip is gently
• The nozzle of the filled syringe is firmly fixed rolled on the lid and inspected for retained embryos,
to the inner soft catheter. (Caution: Ensure blood, and mucus under the microscope.
that the fitting is tight otherwise the assembly
may detach at the critical point of embryo
transfer.) Air-Fluid Versus Fluid-Only Method
• The entire medium is dispelled out rinsing the
lining of the inner catheter. This results in the When the formation of air bubbles within the
entire inner catheter being filled with media, small volume containing the embryos was care-
without the existence of any dead space. fully avoided, no differences in implantation and
• The catheter is loaded with about 20 mm col- pregnancy rates were reported in a prospective,
umn of air. (Tip: This will ensure enough air to randomized study that compared two catheter-
push out the embryos.) loading techniques: (i) Group 1 (n = 52), 200 μL
• The catheter tip is brought near the embryos of air in the syringe, 100–125 μL of air in the
and the catheter loaded with the embryos in a proximal part of the catheter, 20–25 μL of medium
continuous column of medium (~5–8 μL). The containing the embryos to be transferred, and
medium segment containing the embryos 10 μL of air at the tip of the catheter; (ii) Group 2
should be no more than 10 μL. This is fol- (n = 50), the syringe and the entire catheter filled
lowed by small column of air (~3 mm) and with medium and the embryo-containing medium
then ~2.5 μL of culture medium. (Caution: (20–25 μL) without being bracketed by air spaces.
The position of the embryos within the cathe- The authors concluded that the air loaded into the
ter plays a very important role in retained transfer catheter to bracket the embryo-containing
embryos.) medium has no negative effect on ET success
• During embryo transfer, once the syringe [26]. These results are in agreement with the study
plunger is pushed, it is kept pressed until with- by Krampl et al. [15].
drawal of the catheter. (Caution: Releasing the A meta-analysis of randomized trials that com-
pressure before complete withdrawal of the pared air bubbles to bracket the embryo-containing
11 Loading and Expulsion of Embryos 93

medium during embryo transfer versus fluid-only group conducted a prospective, randomized study
methods also showed no significant differences in a private academically affiliated infertility cen-
between the two methods with regard to live birth ter, using a new embryo transfer catheter-loading
(OR = 1.34; 95 % CI = 0.59–3.07), ongoing preg- technique to test whether the embryos actually
nancy (OR = 1.34; 95 % CI = 0.59–3.07), and clin- retain their position of deposition in the upper
ical pregnancy (OR = 1.13; 95 % CI = 0.70–1.83) uterine cavity and do not migrate. Fifty-six
rates or rates of implantation, miscarriage, multi- patients undergoing donor egg IVF underwent
ple and ectopic pregnancies, and retained ultrasound-guided ET by a single physician with
embryos. The authors concluded insufficient evi- a standardized technique, randomly using one of
dence to suggest the superiority of fluid-only the two loading techniques: (i) the standard tech-
method over the use of air brackets during embryo nique in which the syringe was filled with
loading and suggested a need for well-designed medium right up to the proximal part of the ET
and powered randomized trials to determine any catheter, which was followed by 2.5 μL air, fol-
possible benefit to either method [27]. lowed by 7.5 μL of embryo-containing medium,
Marek et al. [18] reported significantly higher followed by 2.5 μL air, and eventually by 2.5 μL
implantation and clinical pregnancy rates in the of culture medium at the tip of the catheter
air-column (n = 278) group compared to the (Group A), and (ii) that in which the syringe and
group in which a full column of medium (n = 264) the entire catheter were filled with medium fol-
was used to expel the embryos despite no signifi- lowed by 12.5 μL of embryo-containing culture
cant difference in the incidence of retained medium followed by 2.5 μL of air at the tip
embryos (1.1 % in both groups) [18]. They (Study Group B). The 2.5-μL volume of air at the
opined that if an increase in reactive oxygen spe- catheter tip, in the study group, was used to
cies occurs with the presence of air in the cathe- prevent spillage of the medium containing the
ter, this does not translate into lower implantation embryos. The 2.5 μL gap of air between the
and pregnancy rates [15, 18, 26]. embryo-containing medium and the next bolus of
Hence, the use of small air spaces to bracket medium in the control group was used to prevent
the embryo-containing medium in the catheter the transport of the embryos within the catheter
does not adversely affect the implantation and [14]. The liquid that does not contain the embryos
pregnancy rates provided that the total volume of and extends into the fluid column in the syringe
transfer is small, <10 μL of air at the tip of the was used to push the catheter load during transfer
catheter is injected, and air bubbles within the to avoid embryos from sticking to the catheter
volume of transfer media containing the embryos wall [14]. The visualization of the ET-associated
are avoided [9], both of which were observed in air bubble was better in Group A, but the air bub-
Moreno et al.’s [26] study. Results of early, ble movement was eliminated using the new
uncontrolled studies, [22, 23] suggesting an loading technique in Group B. Though the
improvement in pregnancy rates by the removal implantation (22.5 % vs. 17.7 %) and clinical
of air from the transfer catheter can be explained pregnancy rates (47.2 % vs. 45 %) were similar in
by a reduction in the total transfer volume both the groups, the observations led us to con-
(including both transfer medium and air) and clude that the new loading technique enables
other refinements in the IVF program rather than embryos to retain their place of deposition and
by a specific deleterious effect of the air [9]. In we could consistently deposit embryos at the
our study, the total volume of transfer was small desired site in the uterine cavity [14].
and included only the 10–12.5 μL of medium
containing the embryos and the 2.5–5.0 μL of air
that almost unavoidably exists within the catheter Velocity of Embryo Expulsion
when a full column of medium is not used [14].
A transient motion of the ET-associated air The embryo transport pattern within the uterine
bubbles has been observed using our standard fluid is controlled by the uterine peristalsis fac-
embryo transfer loading technique. Hence, our tors, such as amplitude and frequency of the uter-
94 G.N. Allahbadia et al.

ine wall’s motility, as well as the synchronization Variables that may influence the velocity of
between the onset of catheter discharge and uter- embryo expulsion include (i) the property of the
ine peristalsis [4]. syringe, (ii) the volume of the transfer medium,
A gentle and atraumatic ET technique that and (iii) the presence of air in the catheter [6].
avoids uterine contractions and placement of the Though a 1 mL tuberculin syringe is normally
embryo(s) at 1.5–2 cm below the top of the uter- used for ET, it may be necessary to get acquainted
ine cavity have been rated as among the most with the force necessary to aspirate the medium
important parameters that may secure the highest in a controlled manner by squeezing in a trial
chance of implantation. However, prospective, fashion to avoid embryos from being damaged or
randomized studies on the velocity with which thrust into the Fallopian tube. Unintentional
the embryos should be expelled into the uterine reaspiration of embryos on release of the piston,
cavity have rarely been addressed in literature on owing to a certain degree of recoil, associated
ET techniques [6]. with some syringes, may be reduced by ensuring
Theoretically, low-velocity embryo expulsion that the syringe and catheter are attached in an
into the uterine cavity may increase the risk of the airtight way [28].
embryos being retained in the catheter, adhering The variables affecting catheter loading have
to the tip of the catheter, thus resulting in embryo been investigated as a one-variable-at-a-time
deposition in the cervical canal on retraction of approach rather than as a unit, which consists of
the catheter. Hence, wrong placement of the a plastic cannula attached to a syringe. The
embryos will not be discovered when the catheter syringe is used to create negative or positive
is checked under the microscope by the embry- pressure inside the catheter for the aspiration or
ologist after ET. While it would seem that these release of the embryos. Comparing different
hazards could be diminished or avoided by deliv- syringes (flat, conical, and piston-like plungers),
ering embryos with high velocity, this could different catheters, embryo positions in the fluid
thrust the embryos into the Fallopian tubes or by column with respect to the catheter tip, and dif-
a forced retrograde flow, down into the cervical ferent loading schemes, Correa-Pérez et al. [12]
canal, decreasing the chance of implantation and demonstrated that the type of syringe and the
increasing the risk of an ectopic pregnancy. In positioning of embryos within the fluid column
addition, expulsion of embryos with high veloc- in the catheter may have a significant effect on
ity may provoke uterine contractions, which the speed of embryo release, whereas the type of
would tend to adversely affect the chances of catheter used does not influence these events
intrauterine implantation [6]. It has been demon- [12]. Syringes with a conical or piston-like
strated that placement of the catheter tip near the plunger provide less control for the release of
fundus appeared to transfer the embryos into the embryos, resulting in the abrupt propelling of
tube when transfer was performed at fast speeds, embryos, which could result in damage caused
possibly leading to ectopic pregnancies [3]. by a ricochet–compression effect [12].
Using a computational model to simulate ET While a large transfer volume >60 μL may
within the uterine cavity with a fluid-filled cath- result in expulsion of the embryos through the
eter inserted into a two-dimensional channel with cervix into the vagina or cause adherence to the
oscillating walls, Yaniv et al. [1] demonstrated outside of the catheter, irrespective of the veloc-
that the speed at which the embryos are injected ity of expulsion [27], transfer volumes <10 μL, as
from the catheter dominates the procedure and well as the presence of air bubbles, are known to
controls the velocity of their transport within the have a negative effect on the implantation rate
uterine cavity. ET at excessively high injection [11]. Though it would seem beneficial to increase
speeds may lead to ectopic pregnancies, while the velocity of expulsion when small volumes
uterine peristalsis affects transverse dispersion (<20 μL) are used, this remains unclear, as no
only during injection at low injection speeds. The investigations have addressed the question [6],
presence of the catheter within the uterus does and transfer volumes 20–30 μL are commonly
not affect flow patterns downstream of its tip [1]. used [29].
11 Loading and Expulsion of Embryos 95

Though there are some indications in the lit- for right- and left-handed users that can be easily
erature suggesting that expulsion of embryos handled even by a single person, its low weight
with high velocity should be considered when the (less than 150 g), and a built-in xenon lamp help
catheter has been loaded according to the “three- to optimize the embryo transfer technique [7].
drop” (air-embryo-containing droplet-air) proce-
dure, randomized, prospective studies of ample Conclusion
size comparing the implantation rates with the From the available evidence, a good catheter-
use of high- or low-velocity embryo expulsion loading technique would involve the use of opti-
with use of the “three-drop” procedure for ET are mal volumes of air (ideally <10 μL) and medium,
needed to prove this point. Until scientific evi- loaded in the right sequence with the right tech-
dence in favor of one of the two options is not nical equipment, avoiding methodological
available, the velocity of expulsion of embryos is errors, thus minimizing the detrimental effects of
entirely left up to theoretical considerations and air bubble formation and very high/low transfer
the clinician’s decision [5]. volumes. Most authors recommend the use of
transfer volumes ≤30 μL but not <10 μL to avoid
the risk of air bubble formation. However, we
Standardized Loading Techniques have obtained consistently good results with
transfer volumes <10 μL. Gently delivering the
Owing to interindividual differences in loading embryos into the uterine cavity would minimize
the embryos into the replacement catheter that the detrimental effects of low/high embryo
may be attributed to sex, size of hands, or trem- expulsion velocity. The use of standardized dos-
bling, it has proved useful to standardize the aspi- ing devices could help to carefully and reliably
ration and expulsion process. Devices such as control embryo loading and discharge without
conventional microinjectors (e.g., Narishige the risk of air bubble formation. Optimizing the
IM-6, Tokyo, Japan) have specifications fixed to catheter-loading technique and velocity of
the syringe that allow precise control of aspiration embryo expulsion would help to maximize the
and injection, making it extremely reliable. As implantation potential. However, more robust
one full rotation of the knob aspirates approxi- evidence from large-scale randomized con-
mately 10 μL of volume, a definite sequence of trolled trials on loading and expulsion of
embryo-containing medium and protective air embryos is mandatory.
buffer can be used. In addition, the slow velocity
of the aspiration process reduces air bubble for-
mation to a minimum or avoids it at all. However,
the main disadvantage of this equipment is its References
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