To assess the cost and quality of life implications of alternative strategies incorporating tranexamic acid (TXA) into postpartum hemorrhage prevention programs in the United States. We developed a Markov decision-analytic model evaluating 16 alternative prophylactic TXA strategies from the health system and societal perspectives: the status quo (no TXA), 3 cesarean delivery strategies, 3 vaginal delivery strategies, and 9 mixed strategies. We modeled a risk-stratified cohort of 3.8-million pregnant women and employed a lifetime time horizon to capture fertility implications. Outcomes of interest included adverse maternal outcomes averted, cost savings, and quality-adjusted life-years. Deterministic and probabilistic sensitivity analyses were conducted to evaluate a range of plausible outcomes stemming from parameter uncertainty. All 15 TXA strategies were dominant relative to the status quo, with superior quality of life and decreased cost in >99.9% of Monte Carlo simulations. Uniform prophylaxis was determined to be the most desirable strategy despite its high upfront costs ($142 million), yielding cost savings of $673 million and an estimated 149,000 postpartum hemorrhage cases, 2920 hysterectomies, and 57 maternal deaths averted per annual cohort. While mode-specific prophylaxis produced the least desirable results among TXA strategies, cesarean delivery strategies were generally more desirable than their vaginal delivery counterparts. Additional threshold analyses found that TXA is likely to be cost-saving below a threshold of $262 per gram. We have shown that a policy of routine prophylaxis with tranexamic acid in vaginal and cesarean deliveries is likely to result in greater benefit to society than either the status quo or mode-specific strategies. While more data is necessary before a recommendation for routine prophylaxis can be made, our results support advancing trials to evaluate the efficacy of TXA in the prevention of postpartum hemorrhage.View Large Image Figure ViewerDownload Hi-res image Download (PPT)