Neurodevelopmental Outcomes in Children Born After Fresh Versus Frozen Embryo Transfer

Objective Evidence on the long-term neurodevelopmental outcomes of children born after frozen embryo transfer (ET) versus fresh embryo transfer (ET) remains limited and inconclusive. This study aimed to compare the risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), and intellectual disability (ID) in children conceived via frozen ET, fresh ET, and natural conception (NC).Method This nationwide population-based cohort study linked four Taiwanese national databases to identify a cohort of singleton births between 2004 and 2016, with follow-up until the end of 2022. The study included 4,604 children from frozen ET, 16,877 from fresh ET, and 85,924 matched controls from NC. Adjusted hazard ratios (aHRs) for neurodevelopmental disorders were estimated using Cox proportional hazards models, adjusting for demographic, perinatal, and parental psychiatric factors.Results Among singletons, no significant difference in the risk of ADHD, ASD, CP, or ID was observed between the frozen ET and fresh ET groups. Similarly, intracytoplasmic sperm injection (ICSI) conferred no additional risk compared to conventional IVF. However, compared to children born from NC, ART demonstrated slightly higher incidence rates for ADHD (7.7 vs. 6.3 per 1,000 person-years) and ASD (2.5 vs. 1.9 per 1,000 person-years). In multivariable analyses, both frozen ET and fresh ET were associated with a modestly increased risk of ADHD frozen ET: aHR 1.27 95% CI 1.12-1.44, ; fresh ET: aHR 1.23, 95%CI 1.14-1.31,) and ASD (frozen ET: aHR 1.47, 95% CI 1.21-1.8 ; fresh ET: aHR1.33, 95%CI 1.19-1.5) (all P Conclusion Our findings provide reassurance regarding the long-term neurodevelopmental safety of frozen ET and ICSI compared to fresh ET and conventional IVF, respectively. The modestly increased risks of ADHD and ASD observed in all assisted reproductive technology (ART)-conceived children warrant further investigation to disentangle the effects of the ART procedures themselves from the underlying parental subfertility. Nevertheless, the minimal absolute risk increase is clinically small and remains reassuring for patients and providers considering ART.