Can maternal metformin protect the developing fetal brain?

Abstract

Background: Maternal diabetes is associated with an increased risk of autism spectrum disorder and attention-deficit hyperactivity disorder. Metformin has an emerging role as a neuroprotective agent, both in perinatal preclinical models and in nonobstetric clinical trials. Metformin crosses the placenta and fetal exposure has potential risks and benefits. New techniques allow for isolation of extracellular vesicles that originate from fetal neurons and cross the placenta into maternal blood, providing a window into ongoing neurodevelopment.

Objective: To determine if maternal treatment with metformin for maternal diabetes had beneficial effects on biomarkers of fetal brain health.

Study design: A nested case-control study was performed on maternal samples from a randomized controlled trial of metformin (1000 mg twice daily) + insulin vs insulin only for perinatal type 2 diabetes mellitus (n=40 in each group) or gestational diabetes mellitus. Fetal neuronally derived extracellular vesicles were purified from maternal serum collected at 24 to 30 weeks. Sirtuin-1, tumor necrosis factor-alpha and Bcl-2-associated X protein were quantified. Correlation between vesicle and fetal brain concentrations of biomarkers was validated in a second set of individuals undergoing voluntary pregnancy termination. Generalized linear modeling was performed to evaluate the effect of metformin treatment on fetal neuronal markers.

Results: In-utero exposure to metformin was associated with a 39% increase in Sirtuin-1 (b=0·331; 95% confidence interval, 0.023, 0.640; P=.039) in fetal neuronally derived extracellular vesicles. No significant differences were observed in other biomarkers. Sirtuin-1 in vesicles and matched fetal brain tissue were highly correlated (ρ=0·513; 95% confidence interval=0.211, 0.720; P=.003) supporting the use of vesicle biomarkers as a valid proxy measure.

Conclusion: Maternal metformin treatment increases fetal brain Sirtuin-1, a change that is beneficial for the developing fetal brain through support of neuronal differentiation and prevention of mitochondrial loss. Lower Sirtuin-1 may contribute to cognitive impairments and reduced brain plasticity. Clinicians can add this new information to the risk benefit analysis of metformin use in pregnant women. Further research is needed to better understand the potential neuroprotective role of metformin.