The impact of specific fertility treatments on cognitive development in childhood and adolescence: a systematic review

STUDY QUESTION: Does fertility treatment influence cognitive ability in school aged children, and does the impact vary with the type of treatment? SUMMARY ANSWER: The available high-quality evidence indicates that specific treatments may give rise to different effects on cognitive development, with certain treatments, including ICSI, associated with cognitive impairment. WHAT IS KNOWN ALREADY: Previous reviews of the literature concerning cognitive outcomes among children conceived with medical assistance have concluded that study findings are generally 'reassuring', but limited attention has been paid to the quality of this research. In addition, no review has separately assessed the range of treatment modalities available, which vary in invasiveness, and thus, potentially, in their effects on developmental outcomes. STUDY DESIGN, SIZE, DURATION: A systematic review was undertaken. We searched PubMed, PsycINFO and the Educational Resources Information Centre database to identify English-language studies published up until 21 November 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two authors independently reviewed identified articles, extracted data and assessed study quality. Studies were eligible if they assessed cognitive development from age 4 years or more, among children conceived with fertility treatment compared with either children conceived naturally or children born from a different type of fertility treatment. Where available, data were extracted and reported separately according to the various components of treatment (e.g. mode of fertilization, embryo freezing, etc.). Risk of bias was assessed using the Newcastle-Ottawa Scale, with a score ≥7/9 indicative of high quality. MAIN RESULTS AND THE ROLE OF CHANCE: The search identified 861 articles, of which 35 were included. Of these, seven were rated high quality. Most studies (n = 22) were subject to selection bias, due to the exclusion of children at increased risk of cognitive impairment. Among high-quality studies, there was no difference in cognitive outcomes among children conceived with conventional IVF and those conceived naturally. Findings among high-quality studies of children conceived with ICSI were inconsistent: when compared with children conceived naturally, one study reported lower intelligence quotient (IQ; 5-7 points, on average) among ICSI children whereas the remaining two high-quality studies reported no difference between groups. Furthermore, among the three high-quality studies comparing children conceived with ICSI compared with conventional IVF, one reported a significant increase in the risk of mental retardation, one reported a small difference in IQ (3 points lower, on average) and one no difference at all. There were scant studies examining exposure to embryo freezing, or less invasive treatments such as ovulation induction without IVF/ICSI. LIMITATION, REASONS FOR CAUTION: Most existing studies had methodological limitations including selection bias and/or failure to address confounding by family background. In addition, a meta-analysis could not be performed due to heterogeneity in the assessment of cognitive outcomes. These factors impeded our ability to synthesize the evidence and draw reliable conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The conflicting findings among studies of children conceived with ICSI require clarification, in light of the increasing use of this technique for reasons other than male-factor infertility. Further population-based studies are needed that utilize contemporary data to examine specific aspects of treatment and combinations of techniques (e.g. ICSI with frozen embryo cycles). Importantly, studies should include the complete group of children exposed to treatment. STUDY FUNDING/COMPETING INTEREST(S): A.R.R. is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia. L.J.M. is funded by a fellowship from the Heart Foundation of Australia. The authors declare there are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

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