Monitoring In Vitro Fertilization Outcome ppt

21 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 fertilization (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 465 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 s tudy d esigners, 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 qua druplets. 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, 466 Sutcliffe 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 AR T: 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 followin g: 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 Monitoring In Vitro Fertilization Outcome 467 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 amnioc entesis, 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-establis hed guidelines concerning the clinical testing of childr en 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 consis tent with those in other countries, may well impact on such a practice. What is the overall message from the literature co ncerning 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 468 Sutcliffe 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 ha ve 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 different 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 ag e and other adjustments resulted in the differences disappearing. Prospective Studies There is only one prospective study, which was an excellent one, by a German group, Katalinic et al. (13). ICSI children (n ¼ 3372) were com- pared to a select control group (n ¼ 8016). This prospective study compared 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. Monitoring In Vitro Fertilization Outcome 469 Table 1 Major Malformation Studies Few of Their Conclusion. Authors Study group Study type Outcome Comments Bonduelle The follow-up study included agreement to genetic counseling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 mo, after 1 yr, and after 2 yrs; 2840 ICSI children (1991–1999) and 2955 IVF children (1983–1999) were live born after replacement of fresh embryos; ICSI was carried out using ejaculated, epididymal, or testicular sperm Ongoing retrospective cohort study Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI live born children and in 3.8% of the IVF children (P ¼ 0.538); malformation rate in ICSI was not related to sperm origin or sperm quality; the number of stillbirths (born !20 wks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group; total malformation rate taking into account major malformations in stillborns, in terminations, and in live borns was 4.2% in ICSI and 4.6% in IVF (P ¼ 0.482) A superb series of papers on this cohort hindered only by the comparison group being IVF and not ICSI 470 Sutcliffe Katalinic Three thousand three hundred and seventy-two children and fetuses and 8016 children and fetuses after the 16th wk of gestation in pregnancies after ICSI and natural conception, respectively Prospective controlled study The major malformation rate was 8.7% (295 of 3372) for the ICSI cohort and 6.1% (488 of 8016) for the population-based control cohort [relative risk, 1.44 (1.25–1.65)]; after adjustment for risk factors, the risk declined [adjusted odds ratio (OR), 1.24 (95% CI, 1.02–1.50)]; regarding singletons, there was a significant difference for birth weight and gestational age, with a higher number of preterm and low birth weight children in pregnancies achieved after ICSI substantially by the IVF centers in Germany themselves In my view, the best study so far due to its prospective nature Bergh The medical records were retrieved for 1139 infants, 736 singletons, 200 sets of twins, and one set of triplets; the Retrospective case– control study in which a smaller number of infants was compared For ICSI children, the odd ratio (OR) for having any major or minor malformation was 1.75 Good-quality retrospective data compared to an acknowledged high- (Continued) Monitoring In Vitro Fertilization Outcome 471 Table 1 Major Malformation Studies Few of Their Conclusion. (Continued ) Authors Study group Study type Outcome Comments total number of infants with an identified anomaly was 87 (7.6%), 40 of which were minor; the incidence of malformations in children born after ICSI was also compared with all births in Sweden using data from the Swedish Medical Birth Registry and the Registry of Congenital Malformations with the Swedish Medical Birth Registry [95% confidence interval (CI) 1.19–2.58] after stratification for delivery hospital, year of birth, and maternal age; if stratification for singletons/twins was also done, the OR was reduced to 1.19 (95% CI 0.79–1.81); the increased rate of congenital malformations is thus mainly a result of a high rate of multiple births; the only specific malformation which was found to occur in excess in children born after ICSI was hypospadias (relative risk 3.0, exact 95% CI 1. 09–6.50) which may be related to paternal subfertility quality national registry; disadvantage could be experimental bias in the index cases Abbreviations: IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection. 472 Sutcliffe 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 perfor med 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). Monitoring In Vitro Fertilization Outcome 473 Table 2 Developmental Outcome Studies for Conventional In Vitro Fertilization Children Authors Study group Study type Outcome Key results Comments D’Souza et al. (1997) 278 IVF and 278 NC UK children; IVF singletons mean 25.5 mo (SD 7.9); IVF multiple births mean 24.8 mo (SD 5.1) Prospective case– control study; matched for sex and social class Results of Griffiths scales of development Mean DQ: IVF singletons 116.9 (SD 12.6); IVF multiple births 106.9 (SD 10.9); not stated for controls; developmental delay (DQ < 70 ) noted in two multiple birth IVF children only 46% IVF children from multiple births; all controls were singleton; no matching for prematurity, birth weight or gestation Cederblad et al. (1996) 99 Swedish IVF children (age 33–85 mo) Single cohort compared to Swedish and American norms Results of Griffiths scales of development DQ above Swedish norm No matched control group; high numbers of multiple births and prematurity Brandes et al. (1992) 116 Israeli (Hebrew speaking) IVF children and 116 matched non-IVF children (age 12–45 mo) Case–control study; matched for birth weight, gestational age, birth order, order in multiple births, mode of delivery, sex, age, maternal age, and education Bayley scales for infants up to 30 mo; Stanford– Binet scales for children >30 mo; scales mean 100 Æ 16 MDI Bayley scores: IVF 106 Æ 19.6; non-IVF 110.6 Æ 19.3; composite index for Stanford–Binet IVF 106.2 Æ 8; non-IVF 104.4 Æ 10.2 No correction for prematurity because children all >12 mo 474 Sutcliffe [...]... methylation in humans is uncertain, but two hypotheses have the most credence (39) Based on animal studies, it has been suggested in vitro embryo culture might predispose to KvDMR1 or SNRPN DMR LOM Alternatively, there may be an increased Monitoring In Vitro Fertilization Outcome 481 risk of an imprinting disorder following ART because of an association with infertility per se rather than with in vitro embryo... finding needs verification but is somewhat alarming, as so far nobody has accurately Monitoring In Vitro Fertilization Outcome 479 charted growth of ART children, and so far larger children may have been ‘‘buried’’ in the effects of prematurity and higher-order births Retinopathy of Prematurity The increase in multiple births and premature births related to assisted conception has led to an increase in. .. of decreasing risk of cerebral palsy with increasing gestation, particularly in those infants born after 30 weeks (37) Also in a commentary by Sutcliffe, it was noted that the study used proxy measures for disability and that it was unexplained why the rate of problems seemed higher in the singleton group, than the IVF group, in contradiction to the entire twin literature! GENOMIC IMPRINTING—THE ARTID... gestational age Higher scores for singletons Matching not discussed in this letter Single observer 60% follow-up Monitoring In Vitro Fertilization Outcome 477 478 Sutcliffe Several of these papers allude to the fact that developmental milestones were assessed, and formal assessments of these children, undertaken between 1995 and 1998, were published in a research letter to the Lancet in 1998 (18) This article... DM Medical and developmental outcome at 1 year for children conceived by intracytoplasmic sperm injection Lancet 1998; 351(9115):1529–1534 4 Mushin DN, Barreda-Hanson MC, Spensley JC In vitro fertilization children: early psychosocial development J In Vitro Fert Embryo Transf 1986; 3(4):247–252 5 Strom CM, Levin R, Strom S, Masciangelo C, Kuliev A, Verlinsky Y Neonatal outcome of preimplantation genetic... MP, Camus M, Devroey P, et al Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999) Hum Reprod 2002; 17(3):671–694 Monitoring In Vitro Fertilization Outcome 483 10 Sutcliffe AG, Taylor B, Li J, Thornton S, Grudzinskas JG, Lieberman BA Children born after intracytoplasmic sperm injection: population control study BMJ 1999; 318(7185):704–705... study Fertil Steril In press 14 Bonduelle M, Desmyttere S, Buysse A, et al Prospective follow-up study of 55 children born after subzonal insemination and intracytoplasmic sperm injection Hum Reprod 1994; 9(9):1765–1769 15 Bonduelle M, Legein J, Derde MP, et al Comparative follow-up study of 130 children born after intracytoplasmic sperm injection and 130 children born after in vitro fertilization Hum... genetic diagnosis by polar body removal: the first 109 infants Pediatrics 2000; 106(4):650–653 6 Hansen M, Kurinczuk JJ, Bower C, Webb S The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization N Engl J Med 2002; 346(10):725–730 7 Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B Outcome in children from cryopreserved embryos Arch Dis Child... used a record-linkage cohort design to link assisted reproduction births to a population-based cancer registry in Australia (30) This study included 5249 births and found no increase in the incidence of cancers in the assisted reproduction groups However, these groups were relatively small and underpowered for the outcomes measured The mean length of follow up was only three years nine months, although... physical outcomes weight, head circumference, and malformation rates were no different between groups (24) The IVF group had a greater mean length percentile and the twins in each group had poorer physical outcomes, with an increase in prematurity and lower birth weights, and reduced height and weight at age two when compared to singletons in each group Here the ICSI–CFO study concurs in showing that . 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 fertilization (IVF) outcome. Second, why monitoring. 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. (8,9,16,19–21). Monitoring In Vitro Fertilization Outcome 473 Table 2 Developmental Outcome Studies for Conventional In Vitro Fertilization Children Authors Study group Study type Outcome Key results