Project Summary Aspirin is currently recommended during pregnancy to help prevent preeclampsia, and also shows promise for protecting against pregnancy loss. Preeclampsia is a dangerous complication of pregnancy that puts both the pregnant person and their baby at risk of serious morbidity and death, and pregnancy loss is the most common complication of pregnancy estimated to affect 20-30% of all conceptions. Current clinical guidelines from the U.S. Preventive Services Task Force (USPSTF) recommend the use of daily “baby” aspirin (81 mg), begun at 12 weeks' gestation, to prevent preeclampsia. However, data suggest that even earlier initiation of aspirin and at higher doses may result in greater protection. Furthermore, initiating aspirin immediately upon pregnancy recognition may maximize effects on preeclampsia while also providing the added opportunity to prevent pregnancy loss. Therefore, we propose to conduct a randomized trial to investigate whether daily “double low- dose” aspirin therapy (162 mg per day) initiated at the time of first positive pregnancy test (up to 6 weeks' gestation) may help prevent both outcomes. Clinical recruitment of participants through the follow-up of all initial pregnancy tests throughout the Penn Medicine system will ensure feasibility for early detection of pregnancy, enabling pregnancy loss monitoring and initiation of the trial intervention. The findings from this study will provide essential, high-quality evidence in a diverse sample of U.S. pregnant people to inform potential changes to clinical guidelines for aspirin use in pregnancy. We will (Aim 1) determine the effect of aspirin treatment (dose 162 mg) initiated upon positive pregnancy test (up to 6 weeks' gestation) compared to standard of care (dose 81 mg initiated at 12 weeks' gestation) on preeclampsia in a diverse population; (Aim 2) determine the effect of aspirin treatment (dose 162 mg) initiated upon positive pregnancy test (up to 6 weeks' gestation) compared to standard of care (dose 81 mg initiated at 12 weeks' gestation) on pregnancy loss in a diverse population; and (Aim 3) identify phenotypes who may benefit most from “double low-dose” aspirin (162 mg) begun soon after conception, using machine learning, to inform more targeted therapy for optimal overall pregnancy outcomes. As a safe, affordable intervention, these findings will have immediate translational value to improve reproductive outcomes in pregnant patients, including minorities such as Black women vastly underrepresented in current data.