Oxytocin sensitivity and postpartum hemorrhage: testing genetic and epigenetic biomarkers for improving maternal morbidity

Project Summary Postpartum hemorrhage is a complication of childbirth that affects 3-8% of births in the United States, each year this represents a minimum of 120,000 births. Postpartum hemorrhage is also a primary cause of maternal mortality worldwide. Rates of severe postpartum hemorrhage and hemorrhage requiring invasive treatments or blood transfusions are on the rise, particularly for labors that are induced. Severe hemorrhage is also more common among women of color, contributing to disparities in maternal health. Oxytocin is a naturally occurring hormone as well as a medication used to stimulate labor, prevent or treat postpartum hemorrhage. Oxytocin binds available oxytocin receptors in uterine muscle, stimulating contraction. While oxytocin is the first-line hemorrhage treatment, people who have been given oxytocin to stimulate contractions during labor are more likely to have a less effective uterine contraction response to oxytocin administered postpartum, leading to more bleeding and the need for other medical treatments or procedures. Currently, 4 of 10 people who hemorrhaged, did so despite not having been identified as high risk by current clinical prediction tools. This inaccuracy and the rising rates of hemorrhage indicate that more research is needed to help identify possible risks for this potentially life-threatening complication. Because people with ineffective labor contractions or a personal/family history (of hemorrhage) are more likely to have postpartum hemorrhage, the role of innate oxytocin function/ sensitivity is the primary focus of this investigation. As such, our lab has been researching biomarkers that can help identify people at risk for hemorrhage by testing how genetic and epigenetic variation of the oxytocin receptor gene is associated with oxytocin response and hemorrhage. In this proposal, we use a biosocial framework to test the central hypothesis that maternal variation in the oxytocin receptor gene can be useful for predicting pharmacologic oxytocin needs and hemorrhage. First, we will examine DNA methylation (epigenetic differences) from blood samples using banked data as well as prospectively collected non-invasive salivary samples in association with oxytocin needs in labor and postpartum hemorrhage. Social determinants of health will be examined in association with DNA methylation differences; evaluating the role of adverse environments in shaping the oxytocin receptor epigenotype. Furthermore, we will test how DNA methylation affects gene expression and the oxytocin receptor availability in uterine tissues. Second, we will examine genetic variants of the oxytocin receptor gene in association with the clinical endpoints with the aforementioned specimens and test pharmacologic response by measuring contractility of uterine muscle specimens. Given that clinicians have no method of predicting how well oxytocin will work in the emergency of postpartum hemorrhage, we aim to develop a clinically useful biomarker measuring intrinsic oxytocin sensitivity before labor or birth occurs. The long-range goal of this project is to use biomarker data to improve clinical decision- making, test personalized interventions and lower maternal morbidity.