Does assisted reproductive treatment increase the risk of birth defects in the offspring?

In a recent paper published in the New England Journal of Medicine based on an Australian cohort of 6163 in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) children (1407 after ICSI), Davies et al. (1) conclude that “the risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded”. This has raised a lot of media attention and concerns among couples treated or pregnant after IVF treatment. Davies et al. presented an elegant study based on a cohort of assisted reproductive technologies (ART) infants born from 1986 to 2002. However, the study did not refer to a recent Swedish population-based study on 15 570 ART infants (9372 conceived after ICSI) born between 2001 and 2007 (2). In the Australian study an overall increased adjusted risk of birth defects was demonstrated for ART vs. the general population with an adjusted odds ratio (aOR 1.28; 95%CI 1.16–1.41). Among singleton newborns from fresh-embryo IVF compared with the general population, the adjusted risk was 1.06 (95%CI 0.87–1.30), thus showing no increased overall risk for birth defects after IVF. Among singleton newborns after ICSI based on fresh embryo transfer, the study demonstrated a raised adjusted risk (aOR1.55; 95%CI 1.24–1.94). On the other hand, the Swedish study demonstrated that the adjusted risk of birth defects for the ICSI vs. IVF cohort (2001–2007) had an OR of 0.90 (95%CI 0.78–1.04). Thus there did not seem to be any apparent risk difference associated with the IVF method. The aOR for malformations among IVF/ICSI infants compared with the general population was 1.15 (95%CI 1.07–1.24) and the adjusted risks decreased in the younger cohort of women undergoing ART (2001–2007) compared with the older ART cohort (children born in 1982–2000) published earlier (3). Moreover, the risk of hypospadiasis, which had previously been associated with ICSI, was no longer significantly different from the risk in the general population. A recent meta-analysis looking at ICSI vs. IVF reaches the same conclusion as the Swedish study, i.e. there is no additional risk connected to ICSI (4). Some differences between the Australian and the Swedish study may explain the different findings regarding ICSI. The follow-up period was five years for all children in the Australian study, but shorter for some of the children in the Swedish study. The Australian study included medical termination of pregnancies due to malformations after week 20, whereas the Swedish only included births after week 20. However, the distribution of birth defects in the medical terminations after IVF and ICSI treatments is not available either in the article itself or in its supplementary files. Furthermore, the Australian study also included those cases of cerebral palsy (CP) that were not acquired after the perinatal period. As CP is closely related to preterm birth, one can question whether it is appropriate to define cerebral palsy as a birth defect. It would have been intriguing to see the distribution of CP between IVF and ICSI children and the total risk of birth defects excluding CP in the Australian study. The largest article so far on malformations among ART children and the differences between the studies ought to have been discussed by Davies et al. The reassuring finding that the younger or more recent ART populations may have a lower risk of malformations should have been mentioned. This finding may be due to changes in the subfertile parent populations; the IVF parent populations are healthier in a reproductive sense than a decade ago, i.e. ICSI is performed on broader indications than just very severe male infertility. The improved perinatal outcomes may also be due to improvements in the ART stimulation regimens and laboratory techniques. Moreover, the Australian study included a little more than half the number of pregnancies that were in the Swedish study. By enlarging the cohorts, the “effect” of a higher birth defect incidence observed after ICSI may simply vanish – the known effect related to a larger sample size which is less liable to be confounded by various methodological aspects, such as inclusion or exclusion criteria. Earlier studies have demonstrated that ICSI children carry a higher risk of chromosomal aberrations related to the severity of the male infertility (5); however, Davies et al. do not disentangle data to determine whether this was the case in the Australian figures.