Vanderbilt Integrated Center of Excellence in Maternal and Pediatric Precision Therapeutics (VICE-MPRINT)

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PROJECT SUMMARY In the United States (US), there is a crisis in maternal mortality, which has increased over recent years. The increasing incidence of severe morbidity and mortality tracks with a rising prevalence of chronic health problems such as pre-pregnancy obesity (PPO), which itself is a causal driver of adverse pregnancy outcomes4. Furthermore, observational studies reveal that maternal PPO predicts an offspring’s risks for obesity, coronary heart disease, stroke, type 2 diabetes mellitus (T2D) and asthma. Obesity also increases the risk for obstetric complications, including maternal diabetes, preeclampsia, cesarean delivery, and induced preterm delivery, as well as infant congenital anomalies and macrosomia. In addition, PPO contributes to the “developmental origins of health and disease” (DOHaD), shaping the future health of offspring during childhood and later adult life. Thus, maternal obesity is now a serious maternal and pediatric health crisis. Diabetes is one of the most common comorbidities of PPO, with 1 to 2% of women having type 1 or T2D during pregnancy and another one in five obese women going on to develop gestational diabetes mellitus (GDM). Metformin (an orally used biguanide) to treat diabetes has been shown to have more favorable pregnancy outcomes compared to a controlled diet, however, there is significant debate on its use because metformin crosses the placental barrier and thus may transport into fetal blood. Many medical professionals have preferred insulin or a combination of insulin and oral medications for diabetes treatment during pregnancy due to concerns about the impacts on oral medications on fetal health. Major research gaps we address in this study is include understanding the impact of PPO on placenta gene expression, as well how pharmacologic treatments for comorbidities like diabetes, specifically metformin, further alter expression. This proposal’s premise is rooted in knowledge that mother-to-child transmission of risk for obesity is multifactorial and begins with conception in utero, but understanding the causal mechanisms of risk transmission at play during gestation requires close attention to the maternal-fetal interface. We hypothesize that maternal obesity and metformin used to treat diabetes influence gene transcription in the human placenta in both maternal and fetal tissues. With these Aims we will also establish the Placental Biobank for Genomics and Outcomes (PB-GO), which we propose as a new MPRINT Scientific Core. Our specific aims are: Aim 1. Evaluate associations between placental gene expression, pre-pregnancy BMI. Aim 2. Determine the impact of metformin on placental gene expression. Aim 3. Conduct a phenome-wide association study (PheWAS) in a large clinical population to identify diseases associated with placental gene expression from fetal derived placental tissue. These data will be the basis of a future R01 to deeply assess the impact of maternal health and pharmacologic treatments on placental biology. Furthermore, these data will also be made available via the MPRINT Hub, catalyzing additional studies.