Department of Epidemiology and Public Health, University of Leicester, 2228 Princess Road West, Leicester LE1 6TP, UK. e-mail: jjk6{at}le.ac.uk
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Abstract |
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Key words: cerebral palsy/IVF and ICSI/male infertility/multiple pregnancy/Y-chromosome microdeletions
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Introduction |
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From the outset the invasive nature of ICSI led to concerns about its safety and the potential risks for the health and future fertility of offspring (Cummins and Jequier, 1994; Patrizio, 1995
; de Kretser, 1995
). In the absence of data, these concerns were largely theoretical. They included the risks of using sperm that potentially carry genetic abnormalities or structural defects; of mechanical or biochemical damage; of introducing foreign material into the oocyte and of circumventing natural selection processes. Ten years on from the first ICSI pregnancies, we can now consider just how theoretical these concerns are in the light of what we now know about the health of children conceived following ICSI. There are two broad areas to consider: firstly, the risks of adverse health outcomes for the offspring directly related to ICSI and with clear cause; and secondly, the risks of adverse health outcomes that are associated with ICSI conception but without obvious cause.
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Adverse health outcomes directly related to ICSI |
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Congenital bilateral absence or atrophy of the vas deferens (CBAVD) accounts for about 2% of all cases of infertility and can occur in the absence of cystic fibrosis (Patrizio et al., 1993 Lissens et al., 1996
). Mutations in the CF gene responsible for causing cystic fibrosis are associated with CBAVD (Patrizio et al., 1993
; Persson et al., 1996
). Because of the high carrier frequency of about 1 in 25 for the CF gene mutation in the general population, when CBAVD is present and a couple are considering microsurgical epididymal sperm extraction with ICSI (MESAICSI), it is recommended that both partners are screened for CF mutations prior to treatment (Dodge, 1995
; Forti and Krausz, 1998
). If the female partner is a CF carrier, MESAICSI is offered in some instances with treatment including pre-implantation genetic diagnosis (PGD) or prenatal diagnosis with the option of termination.
The presence and effects of microdeletions on the long arm of the Y chromosome have been investigated intensively over the last 10 years. Three independent spermatogenesis loci (AZF a, b, and c) have been mapped to the Y chromosome. These loci are large and cover candidate genes implicated in male germ cell development and maintenance (McElreavey and Krausz, 1999; Foresta et al., 2001a;
b; Quintana-Murci et al., 2001
). Microdeletions in these regions are associated with male infertility and credible estimates suggest that
1015% of azoospermic and severely oligozoospermic men have microdeletions, primarily in the AZFc and AZFb regions (McElreavey and Krausz, 1999
). Successful ICSI procedures have been carried out using ejaculated and extracted sperm from men with an AZFc deletion, producing male offspring with the deletion (Silber et al., 1998
; Kamischke et al., 1999
; Page et al., 1999
; Cram et al., 2000a;
b). Genetic anticipation in the form of more severe deletions in successive generations is a possibility that requires investigation.
With the capacity of ICSI to enable the inheritance of Y microdeletions it has been repeatedly recommended that, prior to ICSI, all men with azoospermia or severe oligozoospermia should be carefully examined, counselled, karyotyped and systematically screened for Y microdeletions (de Kretser, 1995; Krausz and McElreavey, 1999
; Krausz et al., 1999; 2001
; Foresta et al., 2001a
). Systematic screening is essential since microdeletions may be present when the Y chromosome is apparently intact and the deletions cannot be detected using conventional cytogenetic techniques (Siffroi et al., 2000
). When Y microdeletions are found, the options include proceeding with ICSI, in the certain knowledge that any male offspring will inherit the microdeletion and by definition will be infertile. Sex selection by PGD and replacement of only female embryos is also an option.
To date ICSI has been carried out in the presence of Y microdeletions on the basis that these deletions are not associated with any risks other than spermatogenesis failure in male progeny. However, a recent study of 14 infertile men with apparently normal Y chromosomes in their 46,XY line, when analysed using standard cytogenetic techniques, has raised questions about this assumption. A high percentage of 45,XO cells was found in both their peripheral lymphocytes and germ cells, which suggests a novel mechanism for the formation of 45,XO Turners syndrome (Siffroi et al., 2000). The results also raise the possibility of phenotypic anomalies found in association with sex chromosome mosaicism, including ambiguous genitalia. It remains to be seen whether these potential risks translate into real cases following ICSI. In the meantime Siffroi et al. (2000) recommend that ICSI candidates carrying a Y microdeletion are screened for the presence of gonosomal mosaicism prior to treatment.
Concerns are beginning to emerge about the effects of ICSI on imprinted genes. These are genes that are specifically labelled by methylation so that, depending upon their specific function, the expression of the maternally or paternally inherited copy is consistently repressed. Many imprinted genes are involved in fetal growth and development. Imprinting appears particularly vulnerable to physical and chemical stress (Young et al., 2001) and the concern is that the stressful process of ICSI may lead to disruption of these genes. Loss of function of imprinted genes can have devastating consequences as illustrated by the BeckwithWiedemann, PraderWilli and Angelman syndromes, which result from disruption of imprinted genes on chromosomes 11, 15 and 15 respectively (Surani, 2002
). Two case reports of Angelman Syndrome associated with imprinting defects in children born following ICSI prompted the authors to conclude "...that ICSI might interfere with the establishment of the maternal imprint in the oocyte or pre-embryo and increase the risk of imprinting defects" (Cox et al, 2002
). Cox et al. suggested that a long-term follow-up study of a large cohort of children is required to establish if this is the case. Two recent reports in relation to BeckwithWiedemann syndrome have further added to the concerns about the effects of ART on imprinted genes (DeBaun et al., 2002
; Maher et al., 2002
).
In a study of 92 ICSI offspring, Manning et al. (2000) found no evidence of an imprinting error on chromosome 15 for any of the children. They concluded "...the results of this study do not indicate a higher risk of DNA-methylation defects in children born after ICSI " (Manning et al., 2000
). However, for such an extremely rare condition this is quite a misleading conclusion to reach on the basis of such a small study. Imprinting related Angelman syndrome affects about 1 in 300 000 newborns. If the true incidence of Angelman syndrome in ICSI offspring was in fact 1 in 30 000 (ie. a ten-fold increased risk for ICSI offspring), there is a 99.6% chance that a study of 92 children would find no cases. Even if there was a 500-fold increase, there is still more than an 85% chance that a study of this size would reveal no cases. The difficulty we face is that in order to find, for example, a five-fold increased risk of an imprinting disorder, if in reality this increased risk actually exists, for a condition as rare as Angelman syndrome, 400 000 ICSI children would require systematic follow-up. The only realistic prospect of achieving this size of prospective cohort study would be by linking sufficiently large high quality population-based disease registers to population-based registers of ICSI offspring. An alternative approach would be to carry out a casecontrol comparison similar to that of Maher et al. (2002
) and DeBaun et al. (2002
) whose recent results suggest there maybe a three-to six-fold increased risk of BeckwithWiedemann syndrome following ART treatment.
Other concerns about the capacity of ICSI to lead to the inheritance of conditions associated with defective spermatogenesis include the possibility of a relationship between expanded trinucleotide (CAG) repeat length in the androgen-receptor gene and the risk of infertility due to defective spermatogenesis. It has been suggested that further elongation of the repeat length in future generations could result in spino-bulbar muscular atrophy (Dowsing et al., 1999; Vogt, 1999
; Loy and Yong, 2001
), although other results have provided some reassurance (Cram et al., 2000a
;b; Dadze et al., 2000
). At an even earlier stage of consideration are those, as yet unknown, gene defects that could potentially cause both infertility and other serious health problems. For example, there are mouse models for genes involved in DNA replication error repair with human homologs (MLH-1, MSH2) that have devastating consequences such as hereditary non-polyposis colon cancer (HNPCC) (Fishel et al., 1993
; Bronner et al., 1994
). Of concern is the increase in sperm aneuploidy found in men affected by HNPCC with the hMSH2 mutation suggesting that the hMSH2 mutation may affect meiosis in humans (Martin et al., 2000
). Questions have also been raised about the possibility of an increased risk of childhood cancer (Doyle et al., 1998
; Bergh et al., 1999
; Bruinsma et al., 2000
; Lerner-Geva et al., 2000
; Klip et al., 2001
). However again, as with the imprinting disorders, the rarity of these conditions make it difficult to reach conclusions from the relatively small studies reported so far (Doyle et al., 1998
).
The effects of treatment success
In terms of our current understanding, given the certainty of the outcome and the magnitude of the effect, the single most important impact of ICSI, and indeed all forms of ART, on offspring health remains the multiple pregnancy rate. The inherent maternal and fetal health risks associated with multi-fetal gestation are of concern following all forms of ART including ICSI. These risks are clearly very high in relation to triplets and higher order multiples. However, the extent of morbidity and mortality associated with twinning must not be ignored simply because the risks are even higher for triplets and higher order multiples. This is especially so since, depending upon the embryo replacement policy, of the order of a fifth to a third of all ART pregnancies are twins, and twins outnumber ART triplets and higher order multiples by a factor of between four and ten (Hurst et al., 1997; Schieve et al., 2002
).
Multi-fetal gestations face greater problems than singletons at every stage of pregnancy, labour and in the neonatal period. Fifty years ago McKeown and Record (1952) demonstrated that each additional fetus leads to curtailment of both fetal growth and the duration of gestation, two of the most important predictors of fetal and neonatal well-being. Complications specific to multiples, including the death of a co-multiple, compound the risks of sharing one uterus (Petterson et al., 1993
; Stanley et al., 2000
).
The majority of twins who survive do well and, having overcome the perinatal and neonatal consequences of intra-uterine growth restriction and preterm delivery, the majority are disability free and have an IQ in the normal range. However, we should not forget that twins are at an increased risk of cerebral palsy, development delay, learning disability, sensory impairment, language delay, and attention and behavioural problems (Allen, 1995). For example, with a risk of cerebral palsy of 13.2 per 1000 confinements twin pregnancies produce at least one child with cerebral palsy eight times more often than singleton pregnancies (Petterson et al., 1993
). The cerebral palsy rate for triplets is 75.9 per 1000 confinements, which is 47 times that of singletons. Overall, 1 in 10 women pregnant with twins and 1 in 5 women carrying triplets, regardless of mode of conception, who reach 20 weeks gestation will experience at least one of the following: a stillbirth, an infant death or a child with cerebral palsy (Petterson et al., 1993
).
The emotional, physical and social challenges for the parents of a child with cerebral palsy are profound, and both professionals and prospective parents underestimate the challenges associated with coping with twins (Bryan, 1995). However, the challenge of coping with twins or triplets where one (or more) has cerebral palsy is impossible to truly quantify, but is illustrated in part by the increase in marital breakdown in families with a child with cerebral palsy (Joesch and Smith, 1997
). A further illustration is the multi-million pound costs that courts award for the future care of children with cerebral palsy when cases are found to be due to medical negligence.
Prior to ART treatment, couples often regard multiple pregnancy as a bonus outcome of the treatment (Hecht, 1995). A lack of appreciation of the risks inherently associated with multiple pregnancy may be a result of inadequate counselling, denial born of the desperation of infertility and the hope for success, or a desire to avoid repeating the treatment experience. The risk of conception of a multiple pregnancy is directly related to the number of embryos replaced. This in turn is the result of a balance between achieving a pregnancy rate that is acceptable and achieving an acceptable multiple pregnancy rate. Clearly the balance of this benefit versus risk equation is difficult to convey to desperately hopeful people. Yet this balance leads to one of the most important consequences in terms of offspring health faced by couples whose treatment is successful. It is sobering to realise that a reduction of ART multiple pregnancies by limiting embryo replacement to one embryo per treatment cycle is the single most important and achievable means of preventing cerebral palsy currently available.
Multifetal pregnancy reduction following multiple embryo transfer is a mainstay of infertility therapy in the United States, allowing more aggressive treatment of patients resistant to more conservative therapy (Evans et al., 1998). Once a triplet or higher order multiple pregnancy has been conceived, it is clear that early mutifetal reduction offers benefits in terms of perinatal outcome (Evans et al., 1998
). However, treatment by pregnancy reduction must not be seen as an alternative to the prevention of iatrogenic multiples, since at present we simply have insufficient information about the long-term impact of the death of a co-multiple early in pregnancy on the wellbeing of the survivor(s). What we do know, however, is that in pregnancies
20 weeks gestation, the death of a co-twin is associated with an eight-fold increase in the risk of cerebral palsy for the surviving twin compared with the risk for twins when both survive (Petterson et al., 1993
). Furthermore, for premature infants, exposure to multifetal pregnancy reduction is associated with an eight-fold increased risk of periventricular leukomalacia (Geva et al., 1998
), a strong predictor of cerebral palsy in preterm infants.
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Adverse health outcomes associated with ICSI |
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A recent series of studies have reported rather less reassuring results. Schieve et al., (2002) found that, compared with full-term singletons in the general population, IVF full-term singletons are at a two-fold increased risk of low birth weight. While the results for ICSI were not reported separately, male factor infertility was associated with nearly a three-fold excess risk. The underlying mechanisms are not known, but the authors postulate a role for gondadotrophins, other endometrial proteins, placental abnormalities and maternal complications such as pregnancy-induced hypertension.
Strömberg et al. (2002) found over a two-fold increased risk of cerebral palsy and developmental delay in IVF singletons that was in part, but not completely, explained by preterm delivery and low birthweight. Again there is no obvious explanation for this. In one of our studies (Hansen et al, 2002
) we found a two-fold increased risk of major birth defects for both ICSI and IVF singletons, in all births and in term births having adjusted for maternal age, parity, infant sex and risk correlation between siblings. We found a disparate range of birth defects in both the ICSI and IVF offspring with no obvious explanation, a somewhat surprising result given that human teratogens tend to cause single defects not groups of defects (Mitchell, 2002
).
One of the main difficulties in determining the health outcomes of ART offspring compared with their spontaneously conceived counterparts is the heterogeneous nature of both the causes of infertility and the wide range of possible effects on offspring health. In studies of all types of infertility even relatively large risks will be difficult to detect if they are associated only with a small proportion of the many different causes of infertility. To detect such differences will require infertility specific stratification within very large studies or studies of specific diagnostic groups that will potentially be difficult to define, identify and recruit. As illustrated earlier by the imprinting example, even when large relative risks affect the risk of rare diseases then these effects will be extremely difficult to detect and will require prohibitively large studies to do so. In some instances we may simply have to accept that we may not know for many years if there is an increased risk of a particular outcome, or group of outcomes, associated with ICSI. In these situations, until the molecular biology is completely understood, if indeed it ever is, it would be prudent to acknowledge the possibility that based on theoretical evidence there maybe an increased risk and counsel prospective patients accordingly. However, to put some of these potential risks into perspective they also need to be made aware that given the rarity of conditions such as the imprinting disorders, that even if the relative risk associated with ART was extremely large the chance of occurrence for their child is still very small.
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Conclusions |
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While imprinting disorders and other rare conditions are important, even if they occur more commonly following ICSI, they will nevertheless remain rare conditions and the absolute risk of occurrence will be very small. This is in contrast to the risk of cerebral palsy associated with multiple pregnancy and possibly with multi-fetal pregnancy reduction. It is also important to realise that the universal practice of single embryo transfer, except in exceptional circumstances, would have a significant impact on the overall population rate of cerebral palsy. Once this is achieved the inheritance of the genetic problems following ICSI, such as Y microdeletions, will assume greater importance.
We now also have a body of evidence that suggests children born following ART, including ICSI, are at an increased risk of a diverse range of other adverse health outcomes. Some of these findings are controversial and would benefit from replication. However, until these results are available, if indeed they ever are, we should not sweep unpalatable findings under the carpet and assume all is well just because P > 0.05. To do so would be to deny potential parents the right to make a fully informed decision about possible health effects that may be faced by their potential future child and to assume a degree of paternalism no longer compatible with the practice of modern medicine.
Pregnancy is something of a lottery for all couples. However, compared with couples who conceive spontaneously, for those who require IVF or ICSI the lottery is weighted more heavily against a successful outcome at every stage of the process, not just conception. This is the reality alongside the hope that must be conveyed at counselling to all couples contemplating treatment. Indeed this counselling must be sufficiently detailed to ensure that, whilst the ICSI procedure itself is regarded as a routine procedure in most IVF clinics, prospective recipients do not equate routine with being completely safe and completely risk-free for their offspring.
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Acknowledgements |
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