PROJECT SUMMARY Preeclampsia (PE) is a serious complication that affects up to 8% of pregnant individuals and remains a leading cause of maternal morbidity and mortality in the US, Canada, and worldwide. In developing countries, it accounts for more than 50% of all maternal mortality or more than 70 thousand maternal deaths annually. In the United States specifically, a report from the Centers for Disease Control and Prevention found a preeclampsia case-fatality rate of 6.4 per 10,000 cases at delivery, with more recent data suggesting that preeclampsia contributes to almost 20% of maternal death and to racial and ethnic disparities, with Black individuals 2-3 times more likely to die from preeclampsia compared with White individuals. During the last decade, a better understanding of the pathogenesis of preeclampsia has emerged. A family of proteins that regulate placental angiogenesis, including placental growth factor (PlGF) and serum-associated plasma protein-A (PAPP-A), have been identified as non-invasive biomarkers that accurately reflect placental health. In Europe, diagnostic tests that assess biomarkers such as PlGF and PAPP-A, as well as imaging biomarkers (uterine arterial flow abnormalities on ultrasound), have been established and are now routinely used in clinical care for prediction and prognostication of preeclampsia. Currently, these biomarker tests are not FDA-approved, limiting their use in the United States. The goal of this project is to develop a large, adequately powered, racially and ethnically diverse, North American cohort (U.S. and Canada) that may be used to qualify blood based biomarkers for the prediction of early-onset preeclampsia that will be generalizable to the population. We are proposing a retrospective analysis of data and samples from a large North American cohort of more than 25,000 pregnant individuals with biological samples (serum/plasma) that were prospectively collected between 10-14 weeks gestation across five studies with adjudicated pregnancy outcomes. The aims of the project are: Aim 1: To measure serum biomarkers PlGF and PAPP-A in a representative, racially diverse cohort of pregnant North American individuals in early pregnancy (10-14 weeks) who subsequently develop or do not develop early-onset preeclampsia (<34 weeks) using existing biospecimens and datasets. Aim 2: Develop an algorithm/model combining biomarkers PlGF and PAPP-A and maternal risk factors and to compare whether the addition of biomarkers improves the detection rate as compared to maternal risk factors alone to predict early-onset preeclampsia (<34 weeks). Exploratory Aim: Develop algorithm/models for additional outcomes including preeclampsia (all gestational ages), preterm preeclampsia < 37 weeks, fetal growth restriction < 10th percentile, fetal growth restriction < 3rd percentile, and preeclampsia related fetal death / stillbirth.