Reassessing Metformin Safety in Pregnancy: Robust Disproportionality Mining of FAERS Uncovers De-novo Teratogenic Signals Across Multiple Fetal Organ Systems

Background: While metformin is increasingly prescribed for gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) during pregnancy, its fetal safety profile remains incompletely characterized. This pharmacovigilance study systematically evaluates potential teratogenic risks and adverse perinatal outcomes associated with prenatal metformin exposure. Methods: We conducted a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database (2004-2025), employing four complementary signal detection methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Pregnancy-related cases were identified through standardized MedDRA queries, with rigorous sensitivity analyses restricted to metformin monotherapy and transplacental exposure to control for confounding. Results: Among 2,882 pregnancy-related metformin exposures, we identified statistically significant safety signals across multiple organ systems. The most robust associations included lactic acidosis ( IC025 = 2.90), hypoglycaemia (IC025 = 2.86, ), foetal macrosomia (IC025 = 2.67). Sensitivity analyses confirmed persistent signals for specific anomalies including tracheo-oesophageal fistula (IC025 = 2.48), oesophageal atresia (IC025 = 2.31), and urethral valves (IC025 = 2.13). The median time-to-onset for adverse events (AEs) was 252 days (IQR 67-337), with 45.97% occurring in late gestation (181-360 days). Subgroup analysis demonstrated generally consistent reporting patterns between healthcare professionals and consumers. Conclusions: This large-scale pharmacovigilance study identifies significant safety signals for metformin use in pregnancy, spanning congenital, metabolic, and perinatal outcomes. While confounding by maternal conditions cannot be completely excluded, these findings underscore the need for enhanced fetal monitoring and long-term follow-up of exposed offspring.