Cognitive function in offspring born after frozen embryo transfer following hormone replacement therapy cycles versus natural cycles: a retrospective cohort study

Most previous studies have focused on the obstetric and perinatal outcomes of different endometrial preparation protocols for frozen embryo transfer (FET) and have shown that hormone replacement therapy (HRT) is associated with a higher risk of large for gestational age (LGA) and macrosomia. However, the associations between endometrial preparation protocols and cognitive function in children are poorly understood. This study aimed to evaluate whether the cognitive function of children born after HRT-FET differs from that of children born after natural cycle-frozen embryo transfer (NC-FET). This retrospective cohort study enrolled singletons born to women with a regular menstrual cycle by FET from 2004 to 2017 who completed the follow-up assessment at a university-affiliated reproductive center between 2010 and 2022 when they were 3- to 6-year-old. The participants were categorized into two groups: children born after HRT-FET and children born after NC-FET. The groups were compared in terms of the verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), full-scale intelligence quotient (FIQ) and incidence of intellectual disability (FIQ < 80). Subgroup analysis was performed by stratifying offspring based on sex or fertilization method. A total of 790 children were included in the study. After adjusting for potential confounders, no statistically significant differences were found between the endometrial preparation protocols in children’s VIQ (coefficient − 1.91, 95% CI: -4.08 to 0.27, P = 0.085), PIQ (coefficient − 1.71, 95% CI: -3.70 to 0.28, P = 0.092), and FIQ (coefficient − 1.96, 95% CI: -3.98 to 0.06, P = 0.057). No significant differences were observed in the rate of intellectual disability (adjusted odds ratio (aOR) 0.75, 95% CI: 0.29 to 1.94, P = 0.553) between the two groups. When the patients were stratified by sex or fertilization method (IVF and ICSI), no differences were found between the endometrial preparation protocols regarding intelligence development. The cognitive function of 3- to 6-year-old singletons following HRT-FET was comparable with that following NC-FET. When children were stratified by sex or fertilization method, the findings demonstrated consistency with the general population. This study was retrospectively registered on May 14, 2025 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ). Registration number: ChiCTR2500102406.