Controversies in metformin use in pregnancy and the role of triglycerides in fetal overgrowth

Abstract

Preemptive, early-life strategies beginning in utero that reduce risk for childhood obesity are imperative to arrest the intergenerational cycle of diabetes and metabolic disease including childhood obesity and non-alcoholic fatty liver disease (NAFLD).  Metabolic factors as well as drugs that cross the placenta can create an intrauterine environment with profound effects on prenatal development and enhanced susceptibility to later chronic disease. 

In the first part of this talk we take a close look at metformin, widely used to treat GDM but an agent in which fetal concentrations are higher than maternal and concentrated 1000-fold in fetal and placental mitochondria due to organic cation transporters.  We review metformin’s multitude of intracellular effects including its anticancer effects, growth inhibitory properties, and suppression of mitochondrial respiration.  We also review data from the Metformin in Gestation (MiG) and PCOS RCTs which randomized pregnant women to metformin, and which found an increased risk of childhood overweight at 5-10 years^1,2.  We will discuss how the growth inhibiting properties of metformin appear to increase the risk for small-for-gestational-age (SGA) infants, also a risk factor for subsequent childhood obesity, demonstrated recently in the MiTY RCT in which metformin was added to insulin for Type 2 diabetes.