Metformin Exposure in Pregnancy and Fetal Programming: A Focused Review of Contemporary Evidence

Background: Fetal programming, conceptualized within the Developmental Origins of Health and Disease framework, describes how intrauterine exposures may shape long-term offspring physiology and disease susceptibility. Metformin is increasingly used during pregnancy for gestational diabetes mellitus, type 2 diabetes mellitus, and selected cases of polycystic ovary syndrome. Its developmental interpretation is complex because the drug improves the maternal metabolic environment but also crosses the placenta and directly exposes the fetus. Methods: This focused narrative review used iterative, targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify pharmacological, placental, mechanistic, clinical, guideline-based, and offspring follow-up evidence. The literature search covered publications available through 31 May 2026. The manuscript was subsequently revised during the editorial submission and peer-review process, and the evidence synthesis was re-evaluated against this final literature cut-off date. Earlier landmark studies were retained where necessary for historical, pharmacological, or methodological context. Results: Metformin reduces hepatic glucose production and maternal insulin resistance and may limit gestational weight gain, insulin requirements, neonatal hypoglycemia, and excessive fetal growth in selected pregnancies. Placental transfer creates biological plausibility for direct effects on AMPK, mitochondrial, mTOR, nutrient-sensing, and epigenetic pathways. Long-term studies are broadly reassuring regarding neurodevelopment and major metabolic disease, but findings on growth trajectory, adiposity, and small-for-gestational-age risk remain heterogeneous and indication-dependent. Conclusions: Metformin should be interpreted neither as uniformly beneficial nor as developmentally neutral. Its use should be individualized according to maternal phenotype, indication, glycemic benefit, placental function, fetal growth, dose, timing, and the limitations of long-term offspring evidence.