Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis

Objective To examine the impact of maternal metformin use in pregnancy on offspring neurodevelopmental outcomes. Data sources MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. Study eligibility criteria Studies of women receiving treatment with metformin at any stage of pregnancy for any indication, with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomised controlled trials, case-control, cohort and cross-sectional studies were included in the review. Study appraisal and synthesis methods Studies were screened for inclusion, and data extracted independently by two reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for non-randomised studies, and the Risk of Bias 2 tool for randomised trials. Results Seven studies met inclusion criteria, including a combined 14,042 children, with 7,641 exposed children up to 14 years of age. Metformin use in pregnancy was not associated with neurodevelopmental delay in infancy (relative risk [RR] 1.09 (95% confidence interval (CI) 0.54–2.17; 3 studies; 9,668 children) or at ages 3-5 (RR 0.90 (95%CI 0.56–1.45); 2 studies; 6,118 children). When compared with unexposed peers, metformin use in pregnancy was not associated with altered motor scores (mean difference 0.30 (95%CI -1.15–1.74); 3 studies; 714 children), or cognitive scores (mean difference -0.45 (95%CI -1.45–0.56); 4 studies; 734 children). Studies included were of high quality and deemed to be of low risk of bias. Conclusions In-utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.