10-Year Follow-Up of the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes (MOMPOD FU) Study - In the U.S., more than 1 in 5 children have obesity, and 1 in 5 adolescents have prediabetes, with rapidly rising rates of youth-onset type 2 diabetes (T2D) and significant impacts on long-term health and mortality. One of the key risk factors for development of childhood obesity and diabetes is exposure to maternal T2D in pregnancy. The effectiveness of metformin in treating T2D in pregnancy and reducing neonatal morbidity was recently tested in the “Medical Optimization and Management of Pregnancies with Overt T2D” (MOMPOD) randomized, double-blind, placebo-controlled trial. Compared with placebo, addition of metformin to insulin therapy failed to reduce the incidence of composite neonatal morbidity. Although metformin reduced the rate of large-for-gestational-age (LGA) neonates and birthweight, it did so at the expense of fat free (lean muscle) mass, questioning whether the reduction in birthweight was actually beneficial. Critical knowledge gaps remain concerning long-term effects of metformin on childhood outcomes. Small follow-up studies of 5-10 year-old children exposed to metformin in utero for treatment of other maternal conditions (GDM and PCOS) have shown paradoxically higher rates of childhood obesity and abnormal cardiometabolic health. Given that metformin readily crosses the placenta and continues to be used in >1 in 4 pregnant women with T2D, it is crucial to define the long-term impact on childhood outcomes. MOMPOD, the largest T2D treatment trial in pregnancy, provides a unique opportunity to address this critical knowledge gap, and thereby improve lifelong health of children born to women with T2D in pregnancy. We plan to enroll 462 (~65% of all eligible) children born to MOMPOD participants and conduct a single in-person visit at 9-11 years of age to address: Aim 1: To evaluate the association between in utero metformin exposure and childhood obesity at age 10 (9-11) years. Hypothesis 1a: Among children born to pregnant women with insulin-treated T2D, metformin exposure is associated with higher prevalence of obesity (BMI >95th percentile for age/sex), compared to placebo. 1b: Metformin exposure is also associated with greater central adiposity and fat mass, measured by skinfold thicknesses, waist circumference and DXA imaging, compared to placebo. Aim 2: To quantify the association between in utero metformin exposure and childhood cardiometabolic health at age 10 (9-11) years. Hypothesis 2a: Compared to placebo, in utero metformin exposure is associated with poorer cardiometabolic health measured with an NHANES-validated continuous metabolic syndrome risk score calculated using BMI Z-score, systolic blood pressure, glucose, triglycerides, and HDL cholesterol, which is predictive of adult metabolic syndrome from 5 years old. 2b: Metformin exposure is also associated with lower time in tight range on continuous glucose monitoring, increased insulin resistance and decreased β-cell function calculated using fasting and oral glucose tolerance test results. Successful completion of this study will generate high-quality, practice-changing results to inform treatment of diabetes in pregnancy and break this vicious cycle of intergenerational transmission of obesity and diabetes.
