Metformin Exposure in Pregnancy and Childhood Developmental Outcomes

Importance Metformin is an oral hypoglycemic agent increasingly prescribed during pregnancy. In animal models, metformin influences embryonic cortical development, and it is uncertain whether this translates to clinical implications for humans. Objective To examine whether metformin prescription in pregnancy is associated with a risk of developmental vulnerability among offspring at school entry. Design, Setting, and Participants This cohort study used population-level pregnancy and birth data from January 1, 2009, to December 31, 2020, linked with the Australian Early Development Census (AEDC), a standardized national assessment of childhood development completed every 3 years during the first year of full-time school (age 4-6 years). The data analysis was performed between March 14, 2025, and January 30, 2026. Exposure Metformin prescription dispensation during pregnancy. Main Outcome and Measures The association of developmental vulnerability, defined as scoring below the 10th percentile in at least 2 of the 5 assessed domains of the AEDC (physical health and well-being, social competence, emotional maturity, school-based language and cognitive skills, and communication skills and general knowledge), was estimated using inverse probability of treatment weighting combined with regression adjustment. Results From 871 627 singleton births in Victoria between 2009 and 2020, 177 409 children with linked developmental outcome data were identified, of whom 1095 (0.6%) were exposed to metformin antenatally (43 [3.9%] aged ≤5 years 0 months, 860 [78.5%] aged 5 years 1 month to 6 years 0 months, and 192 [17.5%] aged ≥6 years 1 month at assessment; 557 male [50.9%]). Developmental vulnerability was observed in 199 children (18.2%) exposed to metformin compared with 24 379 children (13.9%) not exposed. After adjustment for confounders, metformin was not associated with developmental vulnerability among children exposed to metformin (adjusted relative risk, 0.97 [95% CI, 0.74-1.29]) or across any of the individual developmental domains. Conclusions and Relevance This cohort study found that metformin use in pregnancy was not associated with an altered risk of developmental vulnerability among children aged 4 to 6 years and may provide reassurance to clinicians and women considering metformin use during pregnancy.