Foetal Metformin Exposure, Childhood Adiposity and Future Cardiovascular Risk: Can We Connect the Dots?

The prevalence of gestational diabetes (GD) and pre-existing diabetes during pregnancy has been increasing. Insulin is the accepted pharmacological treatment for hyperglycaemia in pregnancy. Metformin has emerged as a promising alternative or adjunct due to its ease of use, lower cost and reduced risk of hypoglycaemia. Beyond GD, metformin also shows potential utility in early GD and polycystic ovary syndrome. Current evidence suggests that using metformin in these settings does not raise short-term safety concerns. Some studies show that metformin reduces maternal weight gain and lowers the incidence of large-for-gestational-age (LGA) infants. Despite these benefits, the broader adoption of metformin is limited by concerns about its ability to cross the placenta, resulting in foetal concentrations comparable to maternal levels. <i>In utero</i> exposure to metformin has been shown to induce mitochondrial and epigenetic alterations in animal and <i>ex vitro</i> studies. These changes have been linked to childhood obesity, altered adiposity markers and future cardiovascular disease (CVD) risk. Both LGA and small-for-gestational-age (SGA) neonates have an increased risk of future CVD. Metformin may offer protection by reducing the incidence of LGA births; however, an increase in SGA rates, reported in some studies, could offset this potential benefit. SGA infants who experience rapid catch-up growth are particularly vulnerable. It remains unclear whether the altered growth trajectory in offsprings of metformin-treated mothers increases future CVD risk. The final risk likely reflects a multifactorial interaction involving maternal metabolic status, degree of glycaemic control, placental function, the mitigating effect of metformin on LGA, and a predisposition to SGA and childhood adiposity. Longitudinal prospective studies are essential to understand the long-term cardiovascular implications of foetal metformin exposure. Applying precision medicine to identify women likely to benefit from metformin, offers a rational strategy to optimize pregnancy outcomes.