Impact of metformin use during pregnancy on fetal congenital malformations across 11 organ systems: a meta-analysis and drug-target Mendelian randomization study.

AIMS: Metformin is a cost-effective alternative to insulin for gestational diabetes mellitus (GDM), yet concerns regarding potential teratogenicity persist. This study aimed to evaluate the association between prenatal metformin exposure and multisystem congenital malformations (CMs), and to explore biologically relevant pathways.

METHODS

This study first conducted a meta-analysis of RCTs and cohort studies assessing maternal metformin use and fetal CMs. Subsequently, drug-target Mendelian randomization (DTMR) examined genetically proxied associations between metformin pharmacodynamic targets (eQTLs) and 64 CMs (FinnGen), reflecting lifelong target perturbation, adjusting for maternal confounders and validating with placental eQTL data.

RESULTS

Meta-analysis showed a protective effect of metformin versus insulin on overall CMs (RR = 0.83, 95% CI 0.71-0.99). In DTMR, following Bonferroni correction and covariate adjustment, seven of 92 target genes (e.g., NDUFS5, NDUFA2) showed significant associations, primarily exhibiting protective effects against circulatory and musculoskeletal system. Validation in placental eQTLs corroborated the direction of effects for 17 gene-outcome pairs, reinforcing the robustness of key safety signals.

CONCLUSION

By integrating clinical and genetic evidence, this study is consistent with the overall clinical safety of metformin use during pregnancy with respect to congenital malformations and provides hypothesis-generating insights into relevant biological pathways.