Abstract
The potential effect of artificial oocyte activation (AOA) following intracytoplasmic sperm injection (ICSI) on neurodevelopment remains uncertain. Since AOA does not fully replicate the physiological Ca²⁺ oscillations essential for fertilization, concerns persist regarding its safety. This study evaluates neurodevelopmental outcomes in children conceived via ICSI-AOA compared to conventional ICSI. A multicentre, cross-sectional study was conducted at Keio University Hospital and eight affiliated institutions, assessing 158 children (ICSI: n = 81, ICSI-AOA: n = 77) aged 12-60 months using the Japanese Ages and Stages Questionnaire, 3rd Edition (J-ASQ-3), covering communication, gross motor, fine motor, problem-solving, and personal-social skills. No significant differences were found in J-ASQ-3 subdomain scores across age groups, and fully adjusted models showed no significant differences in children scoring below the monitoring zone. Subgroup analyses compared differences between AOA protocols (A23187: n = 59; ionomycin: n = 15). AOA protocols were not significantly associated with score variations. Neurodevelopmental outcomes in children conceived via ICSI-AOA were comparable to those conceived via conventional ICSI, suggesting that AOA does not adversely affect early childhood neurodevelopment. These findings support the safety of AOA in assisted reproduction, though further longitudinal research is needed to assess long-term outcomes.