OPTIMUM OB-TXA: Optimal TIMing, route and dose of tranexamic acid prior to UMbilical cord clamp for postpartum hemorrhage prevention

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Project Summary The primary goal of this proposal is to fill critical gaps related to timing, route and dose of tranexamic acid (TXA) in prevention of postpartum hemorrhage (PPH) to maximize maternal benefit while minimizing fetal-neonatal and maternal risks. With my clinical background in Maternal-Fetal Medicine, research experiences in epidemiologic and translational coagulation methods, and prior preliminary data, I have the expertise and strong scientific premise to successfully complete these aims. The proposed innovative study focuses on three unique subpopulations (vaginal delivery, cesarean delivery, morbid obesity) and has three routes of TXA administration (intravenous over 2 minutes, intravenous over 10 minutes and intramuscular) immediately prior to childbirth. Neonatal exposure will be assessed through TXA concentrations in umbilical cord blood and breast milk, as well as clinical outcomes at delivery, 2 weeks and 6 weeks postpartum. The specific aims are as follows: 1a) Determine the optimal timing, route and dose of prophylactic TXA for prevention of PPH 1b) Determine neonatal exposure to TXA through transplacental transfer and breast milk when TXA is administered pre-cord clamp, and 2) Characterize prothrombotic and fibrinolytic biomarkers in maternal circulation following TXA. The innovative nature of this grant is multifold: a) repurposing an inexpensive generic drug to address disparities in obstetric hemorrhage; b) exploring rapid administration via IM and 2min infusion to improve access in low resource settings; c) pre-cord clamp TXA administration as a novel approach not yet considered in large obstetric clinical trials; d) refinement of dosing in unique subpopulations (morbidly obese, vaginal delivery); e) biomarker safety including a no drug group and f) a robust team of multidisciplinary experts with regional and international expertise. Specifically, team members have expertise in clinical pharmacology, neonatal medicine, lab medicine, thrombosis and hemostasis, clinical trials in pregnant women and newborns, pharmacometrics and epidemiology/biostatistics. I have an ideal working environment, rooted in the Clinical and Translational Science Institute partnering GW and Children’s National Hospital but also extended through supplemental sites at University of Maryland Center for Translational Medicine and University of North Carolina Coagulation Lab. In summary, this proposal sets forth aims that are significant, innovative, feasible, and will help the obstetric community better understand how peripartum hemostasis can be optimized using TXA while being sure to minimize fetal/neonatal risks. Ultimately, our work will answer important questions that are part of the solution for how to prevent maternal morbidity and mortality for the 140 million women worldwide that give birth each year.