M15.1 Low first trimester PAPP-A and PlGF are independently predictive of early onset severe pre-eclampsia

Abstract

The pathogenic origin of preeclampsia is defective placental development (placentation) during early pregnancy. Owing to the lack of reliable early detection biomarkers, preeclampsia is not diagnosed until later in pregnancy and delivery remains the sole effective therapy. HtrA3 is a recently cloned gene with high expression during placentation in the mouse, rhesus monkey and human. We established that in women, placental HtrA3 protein was maximally produced in the 1st trimester, then dramatically down-regulated, especially in the syncytiotrophoblasts. HtrA3 was secreted into the maternal circulation with a serum profile reflecting placental production. Oxygen tension, which is dynamic during placentation, regulated HtrA3; hypoxia enhanced, while hypoxia-normoxia transition decreased, HtrA3 protein production and secretion specifically in syncytiotrophoblast, reflecting placental HtrA3 production. Importantly, maternal serum HtrA3 levels around the time of placental oxygen switch (∼13-14 weeks) significantly differed between women who subsequently experienced normal or preeclamptic pregnancies, being much higher in women destined to develop preeclampsia. This delay in HtrA3 down-regulation, likely reflects prolonged placental hypoxic exposure due to abnormalities in vessel remodeling (the root cause of preeclampsia). We thus provide experimental evidence and a molecular rationale suggesting abnormal maternal serum HtrA3 levels during early pregnancy are associated with development of preeclampsia.