Maternal diabetes has been linked to increases in autism spectrum disorder attention-deficit hyperactivity disorder in offspring. Yet, no interventions are available to improve the fetal neurodevelopmental effects of maternal diabetes. Metformin has been used in pregnancies complicated by type 2 diabetes mellitus (T2DM) and gestational diabetes (GDM). Compared with insulin treatment, it has a lower cost and is easier to administer. Metformin also has demonstrated neuroprotective effects in preclinical models. However, because metformin readily crosses the placenta, there are concerns that it may have long-term effects on a fetus. The aim of this study was to examine whether metformin treatment in pregnancies with T2DM or GDM is associated with beneficial changes in biomarkers of fetal brain health. This was a nested case-control study of the Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy (MOMPOD) trial. The MOMPOD trial involved pregnancies with pre-existing T2DM or GD before 23 weeks of gestation. These pregnancies were randomized 1:1 to compare metformin plus insulin (MET/INS) with insulin (INS) alone on a composite of neonatal complications. No differences between the MET/INS and INS groups were observed in the MOMPOD trial. This nested study used the maternal serum samples collected from participants between 24 and 30 weeks of gestation. In addition, there was an additional substudy among patients who elected termination of pregnancy that sampled fetal brain tissue. Fetal neuronally derived extracellular vesicles were isolated from maternal blood to assess the independent effect of metformin on the fetal brain. Three biomarkers associated with oxidative stress (Sirtuin-1 [SIRT-1]), neuroinflammation (tumor necrosis factor-alpha [TNF-α]), and apoptosis (Bcl-2-associated X protein [BAX]) were used to assess the protective effects. Correlations between extracellular vesicle biomarkers and matched fetal brain tissue concentrations were also evaluated. A total of 80 participants were included in this study—with 40 in the MET/INS group and 40 in the INS group. Those in the MET/INS group saw a 39.2% increase in fetal neuronal extracellular vesicle SIRT-1 concentrations versus INS alone ( b =0.331; 95% CI: 0.023-0.640; P =0.039). No significant differences were observed for TNF-α or BAX. A significant correlation was observed in SIRT-1 concentrations in fetal neuronally derived extracellular vesicles and corresponding fetal brain tissue concentrations ( P =0.513; 95% CI: 0.211-0.720; P =0.003). Male fetuses showed an 86.5% increase in SIRT-1 concentrations over female fetuses ( b =0.623; 95% CI: 0.345-0.900; P <0.001). In conclusion, maternal metformin treatment in pregnancies complicated by T2DM or GD was associated with increased fetal brain SIRT-1, a biomarker that has been associated with protection against oxidative stress. (Summarized from Ibarra C, Fekry B, Ugartemendia L, et al. Can maternal metformin protect the developing fetal brain? Am J Obstet Gynecol . 2026 Mar;234(3):741-751. doi: 10.1016/j.ajog.2025.10.025)
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