Does the risk of neurodevelopment disorders in children differ with different ART treatments? A systematic review and meta-analysis

ABSTRACT Objective: This meta-analysis aimed to investigate the risk of neurodevelopmental disorders in children conceived through assisted reproductive technology (ART), focusing on comparisons of neurodevelopment outcomes in children conceived using intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF), as well as using frozen and fresh embryo transfers. Methods: A systematic literature search of PubMed, Web of Science, Scopus and Embase databases was done for studies focusing on singleton pregnancies, published in the last two decades (from year 2004 onwards to 31st May 2024) and reporting confounder-adjusted effect sizes. Pooled effect sizes were expressed as relative risk (RR) with 95% confidence intervals (CIs). Egger’s test and funnel plots were used to assess publication bias. The certainty of the pooled evidence was assessed using the GRADE approach. Results: Analysis of the 13 included studies showed that ICSI correlated with a higher incidence of autism spectrum disorder (ASD) in offspring compared to IVF ART (RR 1.36, 95% CI: 1.05, 1.75). However, the risks of attention-deficit/hyperactivity disorder (ADHD), intellectual disability, cerebral palsy and “any” developmental disorder were similar between the groups. There was no significant difference in neurodevelopmental outcomes, such as ASD, intellectual disability and cerebral palsy, in children conceived after frozen or fresh embryo transfer. The overall quality of evidence for these outcomes was judged to be “Low” according to the GRADE assessment criteria. Conclusion: Based on the low-quality evidence, children conceived through ICSI may be at higher risk of ASD compared to children conceived through IVF, while risks of other neurodevelopmental disorders appear similar. Frozen embryo transfer does not seem to increase the risk of neurodevelopmental disorders in offspring compared to fresh transfer. Registration: PROSPERO: CRD42024557480).