Metformin in High Metabolic Risk Pregnancies — A Patient-Level Meta-Analysis

BACKGROUND: The goal of this study was to determine whether metformin prevents gestational diabetes (GDM) and adverse pregnancy outcomes. METHODS: We searched Medline/Medline In-Process, Embase, and Evidence-Based Medicine Reviews databases through May 9, 2025, to identify double-blind randomized placebo-controlled trials using metformin in pregnancies without diabetes. Predefined primary maternal outcomes were GDM and glycemic indices from oral glucose tolerance tests (OGTTs). Primary neonatal outcomes were gestational age at delivery and neonatal anthropometry. One-stage mixed-effects models using individual participant data (IPD) were adjusted for maternal age, body mass index, gestational age at commencement, and baseline blood glucose level. RESULTS: Ten trials (N=2695) met inclusion criteria and seven provided IPD (n=2485; 92.2% of available IPD). After data harmonization, 2297 pregnancies (1159 participants randomly assigned to metformin and 1138 participants to placebo) were included. Metformin was not associated with reduced GDM in adjusted or unadjusted analyses, including by World Health Organization 1999 criteria (odds ratio, 1.04; 95% CI 0.80 to 1.36; adjusted odds ratio, 1.00; 95% CI 0.71 to 1.41) or by National Institute of Health and Care Excellence 2015 criteria (odds ratio 0.98; 95% CI, 0.76 to 1.27; adjusted odds ratio, 1.00; 95% CI 0.71 to 1.41), except on adjusted analysis using International Association of Diabetes and Pregnancy Study Groups thresholds (odds ratio 0.83; 95% CI, 0.65 to 1.06; adjusted odds ratio 0.71; 95% CI 0.52 to 0.98). Metformin was associated with marginally lower fasting blood glucose level (mean difference [MD], -0.06 mmol/l; 95% CI, -0.10 to -0.01), with no apparent difference in 2-hour postload blood glucose level. Metformin was also associated with longer gestation (MD, 0.30 weeks' gestation; 95% CI, 0.06 to 0.54), lower odds of preterm birth (adjusted odds ratio, 0.64; 95% CI, 0.47 to 0.89), and larger neonatal head circumference (MD, 2.43 percentile; 95% CI, 0.13 to 4.72). Gastrointestinal side effects were more commonly reported with metformin. CONCLUSIONS: In this IPD meta-analysis, metformin was not associated with a reduction in GDM, but was associated with an increase in gestational age at delivery.