In this large observational study using detailed Australian databases with information on several potential confounders, we confirmed previous findings of an increased risk of birth defects among births conceived with assisted reproductive technology as compared with births from spontaneous conception.4,5,10,15,19 After multivariate adjustment, the association between IVF and the risk of any birth defect was no longer significant, whereas the increased risk of any birth defect associated with ICSI remained significant.

These findings are consistent with the results of previous studies.19,20 The strengths of the present study include the use of a single population registry with ascertainment of birth defects from pregnancy to a child's fifth birthday and information on multiple treatment methods. The possibility of treatment effects that are specific to ICSI is biologically plausible,20,21 although differences in male infertility factors that lead to the use of ICSI may also underlie the association.7 Information on paternal age was not available for the present study, although this variable is unlikely to be a major confounder, because the association between paternal age and birth defects is generally weak22 and adjustment for maternal age may reduce the potential influence of paternal age, with which it correlates.

In contrast to clinically managed induction of ovulation with the use of any of several drugs (e.g., clomiphene citrate, follicle-stimulating hormone, and human chorionic gonadotropin), the use of clomiphene citrate as a single agent at home was associated with an increased risk of birth defects. This finding is consistent with the results of previous case–control studies.23-25 However, because we cannot rule out residual confounding or chance as an explanation for the increased risk observed and given the small number of patients treated in this way, caution is warranted in interpreting this result.

The risks of birth defects associated with other forms of minimal treatment (e.g., timed intercourse, semen tests, or low-dose hormonal stimulation) were not significantly different from the risk with spontaneous conception. However, the numbers for these analyses were also relatively small, and the confidence intervals do not reliably exclude risks on the order of those associated with other treatments.

When we looked separately at births resulting from fresh-embryo cycles versus frozen-embryo cycles of IVF or ICSI as compared with births to fertile women, we found a significant increase in the risk of birth defects associated with fresh-embryo cycles but not with frozen-embryo cycles. The risk of birth defects in fresh-embryo cycles of IVF was also significantly lower than that in fresh-embryo cycles of ICSI. This is a more robust result than the finding in previous studies of a nonsignificant tendency for frozen-embryo cycles to be at lower risk than fresh-embryo cycles,26,27 although in those studies, as in the current study, the numbers for frozen-embryo cycles were smaller, and thus the power for these analyses lower, than for fresh-embryo cycles. Possible explanations for a reduced risk of birth defects with cryopreservation include a reduced likelihood that developmentally compromised embryos will survive the thawing process and the temporal separation of the developing embryo from exposure to hormonal stimulation drugs used early in treatment with assisted reproductive technology.26-28

The risk of a birth defect was increased among women with a history of infertility but no accompanying history of treatment with assisted reproductive technology, an observation that is consistent with the findings in a large Danish registry8 and that implicates patient factors in this increased risk. Similarly, we found that “spontaneous” conception among women receiving treatment with assisted reproductive technology was also associated with an increased risk of birth defects. However, we cannot rule out the possibility that a proportion of the women with infertility received clomiphene citrate outside the infertility clinics licensed to manipulate gametes from medical practitioners treating anovulatory infertility, because we have previously reported that the use of clomiphene citrate as a sole therapy is common in this circumstance.29 Treatment received by these patients would not be included in the registry of patients using assisted reproductive technology, and information on this practice was unavailable.

Significant associations between assisted conception and birth defects were evident for singleton births but not multiple births, a finding that is consistent with the results of other studies.1,30 There was not a significant difference in risk between singletons and twins from assisted conception; however, the confidence intervals around risk estimates were wide for multiple births. As noted previously, combining estimates of risk among singleton and multiple births may modify estimates of risk relative to births not resulting from assisted conception.30,31 The absence of a significantly increased risk of birth defects for multiple births conceived by assisted reproductive technology may be explained, in part, by the fact that twins conceived by assisted reproductive technology are much more likely to be dizygotic (owing to transfer of more than one embryo) than twins conceived spontaneously; dizygotic twins are at lower risk for birth defects than are monozygotic twins.31,32

As reported in previous studies,4,7,10,15,33 we observed associations of assisted conception with birth defects in analyses of single and multiple birth defects and in analyses that included or excluded cerebral palsy. Treatment with assisted reproductive technology was associated with increased risks of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects and cerebral palsy. The absence of an observed association with syndromes in our study is consistent with a review34 of large studies but may also reflect the low frequency of these outcomes in South Australia. The increased risk of cerebral palsy that we observed in association with assisted conception is consistent with a report by Strömberg et al., who observed an increase in risk by a factor of 3.7 among children conceived by IVF and by a factor of 2.8 among singletons conceived by IVF.33

Although the large majority of births resulting from assisted conception were free of birth defects, treatment with assisted reproductive technology was associated with an increased risk of birth defects, including cerebral palsy, as compared with spontaneous conception. In the case of ICSI, but not IVF, the increased risk of birth defects persisted after adjustment for maternal age and several other risk factors. Although we cannot rule out the possibility that other patient factors contribute to or explain the observed associations, our findings can help provide guidance in counseling patients who are considering treatment for infertility.