Long-term effects of metformin on offspring health: A review of current evidence and future directions

Abstract

Metformin is widely prescribed for the management of type 2 diabetes mellitus, polycystic ovary syndrome, and gestational diabetes mellitus in pregnancy. Its use is driven by factors including oral administration, lower patient and health system burden and cost, and benefits including lower risk of excess gestational weight gain and hypoglycemia compared with insulin. Metformin use appears safe in pregnancy; however, there remain concerns regarding long-term effects of intrauterine metformin exposure on offspring health. Randomized controlled trial follow-up studies suggest that metformin-exposed offspring may have altered postnatal growth trajectories and increased adiposity in childhood, although data are limited. Whether this is a transient adaptation or a precursor to long-term metabolic dysfunction is unclear, as data on cardiometabolic and neurodevelopmental parameters, including glucose homeostasis, lipid metabolism, and cognitive function, are sparse and inconsistent. Methodological challenges include heterogeneous study designs, high attrition rates, and inadequate control for confounding variables. Given these uncertainties, further well-powered, long-term prospective studies and individual patient data meta-analyses, harmonizing data and adjusting for confounders, are needed to clarify risks and benefits of metformin use in pregnancy. Until such data are available, clinicians must weigh the benefits and advantages of metformin use in pregnancy against the unknowns regarding potential long-term impact on offspring health. PLAIN LANGUAGE SUMMARY: Metformin is a medicine often used during pregnancy to help manage conditions such as type 2 diabetes, gestational diabetes, and polycystic ovary syndrome (PCOS). It is commonly chosen because it is taken as a tablet rather than by injection, has a lower risk of causing low blood sugar, and is generally easier and less expensive to use than insulin. Research has shown that metformin is safe for use during pregnancy in the short term. However, there are still questions about whether it has any lasting effects on children who were exposed to it before birth. This review explores this topic in detail. Some studies have found that children exposed to metformin during pregnancy may have slightly different growth patterns, such as having more body fat or being heavier in early childhood. However, these results are inconsistent and most studies show no clear differences in overall health outcomes, including in heart health, metabolism, or brain development. The results are mixed, and many studies are small or have design limitations, which makes it difficult to draw strong conclusions. At this stage, there is no clear evidence that metformin causes harm to children in the long term. However, because some studies suggest there may be effects on childhood growth and development, researchers emphasize the need for further long-term research. These future studies should follow children into adolescence and adulthood to better understand any lasting impacts. Until more is known, doctors and patients will need to carefully consider the known benefits of metformin in pregnancy alongside the current uncertainties about long-term effects on child health.

Keywords: infant; long‐term outcomes; metformin; offspring; pregnancy; review; safety.