Over 100,000 pregnant women with overt type 2 diabetes (T2DM) give birth in the United States every year. Strict maternal glycemic control is the key to optimizing infant outcomes. Medical treatment of overt T2DM in pregnancy is generally restricted to insulin as data on the safety and efficacy of oral hypoglycemic agents for overt T2DM is limited. However, over one-third infants born to women with overt T2DM experience an adverse outcome such as premature delivery, large-for-gestational age (LGA), hypoglycemia, hyperbilirubinemia, or birth trauma, suggesting that current treatment regimens fall short of optimizing outcomes. We believe that further research is needed to identify better strategies to reduce neonatal complications of overt T2DM in pregnancy. Metformin is the pharmacologic treatment of choice for overt T2DM outside of pregnancy. Metformin is favored over insulin because it results in less weight gain, fewer hypoglycemic episodes, and is oral rather than injectable. Metformin?s mechanism of action directly counteracts the insulin resistance characteristic of T2DM. Metformin is not recommended for treatment of T2DM complicating pregnancy, mainly because there are no large clinical studies examining its use in this context. Research is needed to address this knowledge gap. Our long-range goal is to optimize maternal and infant outcomes in overt T2DM complicating pregnancy. The objective of this proposal is to study the efficacy and safety of adjuvant metformin for treatment of T2DM among pregnant women receiving insulin therapy. Our central hypothesis is that compared to insulin alone, insulin plus metformin will result in improved neonatal outcomes. We will test this hypothesis byprospectively randomizing 1334 pregnant women with overt T2DM to insulin plus placebo therapy versus insulin plus metformin to accomplish the following specific aims: 1: To measure the effect of insulin/metformin on composite adverse neonatal outcome (perinatal mortality-miscarriage; stillbirth or neonatal death; preterm delivery, neonatal hypoglycemia, hyperbilirubinemia, and/or birth trauma); infant birth weight and fat mass, among pregnant women with T2DM.; 2: To measure safety of insulin/metformin use among pregnant women with overt T2DM; and 3: To quantify gestational weight gain (GWG) and satisfaction with therapy among women treated with metformin. Successful completion of this proposal will result in high quality contemporary evidence for management of overt T2DM complicating pregnancy to improve neonatal outcomes.
Changing clinical practice to optimize outcomes in pregnancies complicated by T2DM requires that data be generalizable to the majority of pregnant women with T2DM. This trial will be conducted at 10 centers with a wide geographic reach and patient diversity to optimize generalizability. Considering the current prevalence of T2DM and the expected increase over the next decade, even a modest reduction in composite neonatal morbidity would result in significantly fewer medically compromised infants as a result of overt T2DM complicating pregnancy.