Trigger-day hCG effects on DNA methylation and neurodevelopment in ART offspring

Assisted reproductive technology influences the epigenetic landscape of offspring, but whether trigger-day pharmacotherapy affects epigenetics and neurodevelopment remains unclear. In a prospective birth cohort of 365 families, higher trigger-day human chorionic gonadotropin dose associates with reduced global DNA methylation in peripheral blood from offspring conceived assisted reproduction compared with naturally conceived children. In a cohort of 1333 singleton offspring, higher maternal human chorionic gonadotropin dose associates with increased risk of suboptimal neurodevelopment. In mice, transient human chorionic gonadotropin exposure impairs offspring neurocognitive behaviours, reduces hippocampal dorsal dentate gyrus neurogenesis, and downregulates euchromatic histone methyltransferase 1 expression with reduced methylation observed in oocytes. Microinjection of euchromatic histone lysine methyltransferase 1 mRNA into exposed zygotes restores neurogenesis and improves behavioural outcomes in offspring. These findings suggest potential epigenetic and neurodevelopmental risks of higher-dose human chorionic gonadotropin exposure and support optimized trigger protocols in assisted reproductive technology that balance treatment efficacy with long-term offspring health.