UC San Diego Center for Stillbirth Prevention: Maternal and Placental Determinants of Fetal Growth Restriction

Project Summary/Abstract Stillbirth, defined as intrauterine fetal demise (IUFD) at or above 20 weeks gestational age, is a devastating pregnancy outcome, with rates that have remained steady over the last decade and are higher in under-resourced communities. Fetal growth restriction (FGR) is a significant risk factor for stillbirth, and is defined as a fetus that fails to reach its growth potential. However, “true” (pathologic) FGR is difficult to distinguish from a constitutionally-small fetus, and is hard to diagnose, particularly in the antenatal period. A major underlying cause of FGR is placental dysfunction, where the placenta fails to meet the energy demands of a growing fetus. However, placental dysfunction is not a uniform condition, and is difficult to diagnose in an ongoing pregnancy. Post delivery, placental dysfunction can be identified following a complete pathologic evaluation, categorized as either vascular (maternal vascular malperfusion/MVM or fetal vascular malperfusion/FVM), and/or inflammatory (villitis of unknown etiology/VUE or acute chorioamnionitis/ACA) patterns of injury. At the UC San Diego Center for Perinatal Discovery (CPD), our group specializes in placenta-based diseases of pregnancy, including preeclampsia, preterm birth, FGR, and stillbirth. Over the past five years, through study of pregnant patients within our ongoing CPD cohort, all of whom have detailed clinical and pathologic annotation, we have identified molecular pathways underlying multiple placental patterns of injury, which are associated with placental dysfunction and FGR. Most recently, through limited proteomic profiling, we have identified maternal serum biomarkers associated with MVM. We now propose to develop a maternal serum-based test for antepartum identification of placental dysfunction and FGR, and hence those at risk for stillbirth (Project 1). In addition to validation of this test using retrospectively- collected biosamples, we propose a prospective cohort, which can be replicated across all Stillbirth Research Centers, in which we will follow pregnant patients suspected of having FGR in the third trimester. We will collect detailed information on this cohort, including data and biological measurements of psychosocial determinants of health, in addition to maternal biosamples and placental pathology. Using these data, we propose to construct a high-dimensional bio-psycho-social prediction model for FGR and stillbirth (Project 2). As in the past, we will engage the local community, especially those who have experienced stillbirth, throughout development of the prediction model and dissemination plan as we seek to make the greatest impact on stillbirth prevention. Successful completion of this proposal will establish a prediction model, through integration of maternal serum biomarkers and bio-psycho-social determinants, for placental dysfunction and FGR, and enable identification of pregnant patients at high risk of stillbirth.