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

Year: 2025

Type: article

Abstract: T he 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.In utero exposure to metformin has been shown to induce mitochondrial and epigenetic alterations in animal and ex vitro 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.Gestational diabetes (GD) is a heterogeneous disorder that arises when pancreatic insulin secretion fails to compensate for the insulin resistance of pregnancy.A disbalance in either component, insufficient secretion or excessive resistance, can lead to GD and reflects its variable pathophysiological spectrum.1 Additionally, hyperglycaemia in pregnancy could be because of pre-existing type 1 diabetes or type 2 diabetes (T2D).Besides, overt diabetes can be identified during first-trimester screening.Overt diabetes is diagnosed during pregnancy when a woman meets non-pregnant diagnostic criteria for diabetes.2,3 The prevalence of both GD and pre-existing diabetes in pregnancy has increased in recent years, mainly due to the global obesity epidemic.4,5 Increasing maternal age, sedentary lifestyles and dietary shifts towards high-calorie, processed foods have further contributed to this trend.6 According to the International Diabetes Federation estimates for 2024, 19.7% of pregnancies were affected by some form of hyperglycaemia, impacting around 23 million live births globally.GD (79.2%) accounted for the majority of these, followed by pre-existing diabetes (11%) and overt diabetes identified first during pregnancy (9.9%).7 Furthermore, early gestational diabetes (eGD), or early abnormal glucose metabolism (EAGM), has been recognized as another spectrum of hyperglycaemia in pregnancy.2,8 Hyperglycaemia that is diagnosed in early pregnancy, typically before 24 weeks of gestation, but does not meet the criteria for overt diabetes has been labelled as eGD.8,9 The prevalence of eGD varies from 9.2% to 43.4%, depending on the criteria and the

Source: touchREVIEWS in Endocrinology

DOI: 10.17925/ee.2025.21.2.4

Authors: Simran Thakkar, Saptarshi Bhattacharya, Lakshmi Nagendra, Nitin Kapoor, Deep Dutta, Sanjay Kalra