PROJECT SUMMARY/ABSTRACT Preterm birth is well established as the leading cause of perinatal mortality and a significant contributor to both chronic medical conditions and learning/societal challenges amongst those born too soon. Though complex in its origins, preterm birth is predominantly the result of spontaneous preterm birth and ischemic placental diseases (preeclampsia, fetal growth restriction and abruption). Beginning in the 1980's low dose aspirin (LDA) was trialed as a therapy for the prevention of preeclampsia. Subsequent meta-analyses of randomized controlled trials of LDA have demonstrated its efficacy in preventing both preterm birth and other components of ischemic placental diseases. Limited data suggest that the effect of LDA in preventing both preterm birth and preeclampsia may be greater if therapy is begun before 16 weeks and utilizing doses >100 mg. Recently the ASPIRIN trial randomized 11,976 nulliparous women with a singleton gestation in low-middle income countries to either aspirin 81 mg orally or an identical appearing placebo between 60/7 weeks and 136/7 weeks. This trial demonstrated a 11% decrease in preterm birth, 25% decrease in early preterm birth <34 weeks, 11% decrease in hypertensive disorders of pregnancy and 62% decrease in preterm delivery at <34 weeks with hypertension. Though promising, Aspirin has yet to be fully accepted as a preventive strategy for preterm birth, whether aspirin portends efficacy in a dose-response fashion remains unexplored, and mechanistic studies of the pathways by which LDA prevents both preterm birth and ischemic placental disease are lacking. The proposed project is designed to overcome these limitations. The goal is to enroll 1,300 women with a prior preterm birth due to either spontaneous birth or indicated preterm birth and a current singleton pregnancy between 100/7 weeks to 166/7 to a randomized clinical trial of Aspirin 81 mg orally daily and a sham (n = 650) or 162 mg orally daily (n = 650). We will test three overarching hypotheses: (i) Women with a prior preterm birth randomized to 162 mg of Aspirin daily compared to 81 mg of Aspirin daily will have lower rates of preterm birth; (ii) Women with a prior preterm birth randomized to 162 mg of aspirin daily compared to 81 mg of Aspirin daily will have lower rates of ischemic placental diseases; and (iii) Biochemical markers (Thromboxane B2, Specialized pro-resolving mediators, etc.) will correlate with clinical outcomes. Our research group will draw upon the collective experience and leadership of the Perinatal Research Consortium (10 academic centers), an experienced data management and statistical analysis core and a strong biospecimen analytic core. This innovative project by combining a rigorously conducted RCT with appropriate biospecimen analysis will both address a pressing question about one of the few therapies shown to improve the obstetrical outcomes of preterm birth and ischemic placental diseases and provide insig...