Cognitive outcomes in children conceived with infertility treatments: a systematic review.

Background: The study of long-term developmental outcomes following infertility treatment is now possible and timely. Objective: To examine the impacts of specific fertility treatment on cognitive ability in school age children. Materials and Methods: We performed an update of our previous review by searching PubMed and a range of other databases for studies published up to 24 June 2024. We included original studies reporting associations between fertility treatment(s) and the outcomes IQ and cognitive scales, intellectual disability (IQ < 70), school performance and developmental delay, among children ≥ 4 years, using spontaneous conceptions (SC) among the general population or sub fertile couples or conception via a different fertility treatment as the referent. Study quality was assessed using established tools. Only studies rated as high quality were included in the main synthesis. Where possible, meta-analyses were performed. The meta-analysis combined adjusted point estimates and 95% confidence intervals of outcome measures (RR, OR, MD) reported by studies with no cohort overlapping participants (Stata, Random Effects Model). Results: We identified 31 new studies, resulting in 66 included in total. Of these, 22 (33%) were rated high quality. Variation in the methods of outcome assessment precluded meta-analysis of IQ and other cognitive scales. Among high quality studies, there was no clear difference in IQ scores in children conceived with conventional IVF without ICSI compared with spontaneous conceptions in the general population or conceptions to sub-fertile couples. However, meta-analysis was possible for the outcome of intellectual disability. We identified that unlike IVF alone, IVF when used with ICSI and frozen embryo transfer combined was associated with a two-fold higher risk of intellectual disability when compared with spontaneous conceptions in the general population (RR 2.14, 95% CI: 1.32 to 2.97). Stratification by multiplicity increased imprecision, which reflects variability between studies. For instance, there was no significant effect among singletons (RR 1.83, 95% CI: 0.35 -3.31) despite a moderate RR. Conclusions: Further research examining the long-term outcomes of children conceived with ICSI stratified by treatment modalities, particularly frozen embryo transfer, is warranted. Support: National Health and Medical Research Council Project Grant.