Monitoring In Vitro Fertilization Outcome ppt

However, several positive practice devel-opments are underway now, including a genuine effort underpinned by legis-lation to reduce the risk of higher-order births still the main risk to

Monitoring In Vitro Fertilization Outcome

Alastair G Sutcliffe Department of Community Child Health, Royal Free and University College Medical School, and

University College London, London, U.K

INTRODUCTION

In this chapter, I will provide insights into the following areas of in vitro fer-tilization outcome First, why we monitor in vitro ferfer-tilization (IVF) outcome Second, why monitoring IVF outcome is not well done Third,

a brief overview of the known IVF literature Fourth, how to do monitoring

in an ideal world, and what outstanding questions have not been addressed which are of concern to families, fertility practitioners, the broader scientific community, and general public

WHY MONITOR IVF OUTCOME?

The first generation of assisted reproductive technology (ART)-conceived children are now growing up and ART practice has changed much during this period The initial method of IVF has been supplemented by embryo cryopreservation and more recently by intracytoplasmic sperm injection (ICSI) Following on from these procedures, trans epididimal sperm aspiration (TESA) and testicular biopsy have resulted in a less naturally selective form of reproduction These developments and also such things

as extended culture, blastocyst transfers, etc., are often used without explicit

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consideration of the risks for the child However, several positive practice devel-opments are underway now, including a genuine effort (underpinned by legis-lation) to reduce the risk of higher-order births (still the main risk to children born after ART), and efforts to consider the well-being of the child more for-mally from the start of new therapies For example, I have been involved recently

as an advisor on a (confidential) trial which investigates the efficacy of a treat-ment to enhance embryo implantation The study designers, from the outset, asked advice on how to assess the health of any children born after successful pregnancies, both at birth and one year, with possibly longer-term plans Subfertile parents who conceived by IVF in its various forms are per se

a skewed population of individuals whose offspring may well be at risk of problems via their parents’ genetic natures, rather than the procedural-based aspects of their treatment for subfertility This is not to trivialize the treat-ment-related aspects that are a topic of some concern, particularly at the present time when animal experiments seem to be backed up by recent human-related literature that suggests, e.g., imprinting disorders are some-times a higher risk for children conceived after assisted reproductive therapies (see below) Families who are going to have assisted conception in its various forms, will often ask what the risks are to potential offspring as well as regarding the more immediate risk to themselves as patients undergoing what are often invasive and unpleasant procedures in order to conceive

Crude epidemiological data have shown some striking phenomena as a result of ART, the most obvious of those is the birth of higher-order birth children such as triplets or quadruplets These children themselves are at risk

of problems as a direct consequence of having to share the fetal environment with their siblings and being born early

Whenever a new form of ART is introduced (it seems that we are constantly, with the innovative nature of the development of fertility treat-ments, using seemingly more and more invasive methods of helping couples

to conceive), there should be monitoring in place to look at the consequences for any births and pregnancies Systematic follow-up is always better and if the processes are not in place to do that from the beginning, then attempting

to ‘‘pick up the pieces’’ often leads to erroneous interpretation A good example of monitoring resulting in changing a practice in the literature was the first child or groups of children born after round spermatid conception (1) Fortunately, these cases were reported, and as they had congenital anomalies, the procedure was suddenly banned by the Human Fertilization and Embry-ology Authority Another example concerns the work of Eppig and O’Brien (2) in the United States, whose laboratory managed to persuade the primordial follicle of a mouse to be progressed through developmental stages to a mature follicle that then was inseminated, and subsequently the mouse which he called Eggbert was born This mouse had an allegedly happy life but unfortunately developed a midlife crisis and dropped dead from obes-ity, diabetes, and sarcoma Had this mouse’s growth not been monitored,

it would have been unhelpful to the scientific community to not be aware that this mouse developed problems (albeit as an adult)

The message from this anecdote/case report is clear: the monitoring of children born after assisted conception must continue until they grow up This is a sensitive and personal matter for the parents who must be con-sidered in the conflict of interest of necessity versus privacy Parents who are approached to participate in studies do not have to participate, but they must be made to see that it is useful to them as well as to the broader scien-tific and public communities My assessments performed with these families have always given added value to those couples, families, and children WHAT ARE THE PROBLEMS KNOWN TO HAVE OCCURRED

WITH OUTCOME STUDIES?

The first-choice approach in doing outcome studies concerning IVF is not to

do them This is the usual approach by most clinics throughout the world

I am only aware of two systematic follow-up clinics arranged specifically to monitor the outcome of ART: one is based in Sydney and is a local small affair, the other is with my collaborators in Belgium and arises from a very large clinic set up by former pediatrician Andre van Steirteghem It is to his credit that he could see the necessity/appropriateness for such work Other projects have been piecemeal or ad hoc Common criticisms of the designs of studies looking at pediatric outcome include the following:

1 Poor matching criteria (3)

2 No controls (4)

3 Inappropriate tools of assessment (5)

4 Comparing two groups who superficially seem similar but are actually quite distinct (6)

5 Underpowered studies involving small numbers of children (4)

6 Mixing up groups of children, e.g., twins versus singletons versus triplets (7)

7 Poor response rates to follow-up (8)

8 Using multiple observers (9)

9 No blinding to conception status (10)

The ideal study has yet to be done and none of these cited studies were

so, however, all contributed significantly to the understanding of ART out-come at the time of their publication

WHY MONITOR: WHAT CAN GO WRONG IF THE DATA

ARE MISUNDERSTOOD OR MISINTERPRETED?

An anecdote from my own clinical institution illustrates this well A single woman was expecting a baby conceived with donor sperm and with the use of ICSI The obstetrician had read that there was a higher risk of sex

chromosomal aneuploidy after ICSI and suggested that an amniocentesis for fetal karyotyping be performed The literature underpinning this advice

is weak and far from sufficient to give this advice to a pregnant woman She refused the amniocentesis, but then became concerned After birth, she requested a karyotype on her child and this was done The karyotype was XYY Subsequently, this nice little boy (who is now 8 years) is living with this ‘‘label,’’ with the majority of the literature on this topic suggesting most children with this ‘‘variant’’ are normal and indeed grow up to be healthy adults It could be argued that this bad advice and indeed the subsequent testing contravened the well-established guidelines concerning the clinical testing of children for genetic conditions These guidelines should be rigidly applied and clearly state that where a condition has no health implications during childhood or an intervention cannot ameliorate the condition, there

is no ethically justifiable reason for the child to be tested Indeed, this child may well have refused such a test when grown up I am sure the reader does not need to be convinced that the whole scenario would not have arisen if the child was not ART-conceived, and the Bonduelle et al (11) work on the subject of aneuploidy after ICSI had been carefully checked

WHAT IS KNOWN FROM THE CURRENT LITERATURE

AS AN ALTERNATIVE?

Perinatal and Congenital Anomaly Studies of Children

Conceived After ART

Herein lies the largest short-term risk for children born after ART, largely but not entirely due to the risk of higher-order births, well described after all types of ART In developed nations, the rate of twinning has doubled

in the past 25 years This is thought to be 90% due to ART and 10% due

to rising maternal age at first pregnancy Fifty percent of twins are born at less than 2500 gms and 50% are born at less than 38 weeks gestation Yet the risk of higher-order births (multiple pregnancies) after ART is 20% to 30% There is one clinic in the United States where the service is no

preg-nancy—no fee, but that fee is alleged to be $20,000 The clinic replaces large

numbers of embryos, despite the evidence that beyond two embryos, the only risk of three-embryo replacement is a triplet birth, not a higher overall preg-nancy rate To a pediatrician, this is grossly irresponsible However, recently published guidelines in the United States (12), which are consistent with those in other countries, may well impact on such a practice

What is the overall message from the literature concerning the risk of congenital anomalies and ART? Although one major study suggested a higher risk (doubling) of anomalies after ICSI generally, other large studies suggest that while there is a broadly increased risk of anomalies post-ART, that risk is modest A large prospective study is needed and such

a study has not been performed Such studies are very expensive and all

studies to date can be criticized due to the inescapable fact that there may be experimental bias

It is unsurprising that such a small increased risk of anomalies exists in view of the nature of the ART couple Genetic factors come to bear in all types of infertility With the advent of ICSI couples where there is predom-inantly male factor subfertility being able to reproduce, some clearly have known genetic defects resulting in the non-obstructive oligozoospermia that underlies the need for ICSI Then there are other possible factors that may increase the risks from ART, such as culture media which may be relevant especially to the recently described increased risk of genomically imprintable disorders after ART, such as Beckwith Weidemann syndrome

A summary of the three most major studies of congenital anomalies after different types of ART is provided in Table 1 Also, further commen-tary allows consideration of studies in different categories

EVALUATION OF THE MAJOR PUBLISHED STUDIES

IVF Compared to the General Population

Different studies based on registry data have yielded contradictory results After allowance for confounders, the difference in studies as authored by Westergaard et al disappeared, but those by Hansen et al., even after adjust-ing for confounders such as maternal age, parity, and sex, still showed an increased risk of odds ratio (OR) of two However, the Hansen et al (6) study did not control for a number of variables, which could have been dif-ferent in the two populations and could have led to difdif-ferent results ICSI Compared to the General Population

Retrospective Studies

In the Australian study (Hansen et al.) concerning congenital malformations

at the age of a year, the OR remained two after adjustments However, there was no allowance for years of infertility or socio-demographic factors, such

as ethnic background, which may have been different in the two popula-tions Two Swedish analyses showed an increase in congenital malforma-tions in ICSI and IVF; however, the adjustments for maternal age and other adjustments resulted in the differences disappearing

Prospective Studies

There is only one prospective study, which was an excellent one, by a

major malformations in ICSI and the naturally conceived (NC) population base Here the risk, as stated in my summary above, was slightly above the natural population, at 1.24

Table

population-based control

Table

ICSI compared to the IVF

Bonduelle et al.’s excellent series of papers (8,14–16,19) gives valid com-ments on this topic and no difference in malformation rates has been found between ICSI and IVF children, the largest cohort being 2995 IVF versus

2899 ICSI

Malformations in Different Organ Systems

None of the studies is sufficiently substantive to comment on this; however, there is emerging evidence from Bonduelle et al.’s work, and others suggest that urogenital malformations in ICSI are more common (17) This is surely unsurprising in view of the parental genetic background and the increased risk of male subfertility, when there are genitourinary defects in the father Various sub-analyses have been performed to look at whether sperm quality and sperm source are relevant, but no clear message is available for this because of the limited number of children in sub-groups

Developmental Outcome Studies of IVF and ICSI Children

Refer to Table 2 for an overview of some earlier IVF studies Table 3 focuses

on ICSI children International collaborative study of ICSI–Child and family outcomes (ICSI–CFO), an international collaborative study of ICSI-child and family outcomes, is by far the largest (and most recent) study of IVF/ICSI children It was performed in five European countries Approxi-mately 500 singleton ICSI, 500 IVF, and 500 NC children aged five years were each assessed with observer blinding to conception status Confoun-ders were avoided by ensuring that all children were more than 32 weeks gestation, singleton, matched for sex, social class, and Caucasian These children were comprehensively assessed This study showed no effect what-soever of conception status on neurodevelopment (18), and although there was greater use of health service resources by ICSI and IVF children in relation to NC children, when examined in a comprehensive manner ‘‘top

to toe,’’ these children were not found to be physically different from NC children with the exception of congenital anomalies

Developmental differences in an ICSI-conceived group of children when compared to conventional IVF and NC controls were reported in 1998 (19) The study found an increase in mild developmental delay using the Bayley scales of infant development to derive a mean developmental index (MDI) However, the study used comparison groups of IVF and NC children who were already enrolled in a separate study and had differing demographics

to the ICSI group There was also no blinding of the assessors and the number

of participants in the study was small, with 89 ICSI-conceived children Bonduelle et al have published several papers investigating congenital malformation rates and physical development of ICSI children (8,9,16,19–21)

prematurity, birth

non-IVF 110.6

non-IVF 104.4

prematurity because