PROJECT SUMMARY/ABSTRACT Malaria in pregnancy (MiP) carries substantial - but largely preventable - risks for both the pregnant woman and unborn child. Despite rigorous evidence supporting the efficacy of current interventions, such as long-lasting insecticidal nets (LLIN) and intermittent preventive treatment of malaria in pregnancy (IPTp), MiP is estimated to occur in more than 40% of livebirths in endemic areas of sub-Saharan Africa. Therefore, additional interventions that would complement existing strategies are urgently needed One intriguing, but largely unexplored strategy for preventing MiP would be to reduce the risk of malaria transmission in the home environment, essentially creating a “safe zone” around the pregnant woman. This strategy has many potential advantages, including (i) leveraging the spatiotemporal clustering of malaria risk, (ii) bridging gaps in the existing package of interventions (i.e., imperfect LLIN use and missed IPTp doses), and (iii) the established safety and effectiveness of mass drug administration (MDA) programs. Therefore, the scientific objective of this Exploratory/Developmental Grant (R21) application is to demonstrate the feasibility, acceptability, and preliminary effectiveness of a focal mass drug administration (fMDA) program for household members of pregnant women to protect against MiP. Our hypothesis is that eliminating the parasite reservoir within the household will provide a complementary layer of protection against MiP especially when access to care is limited and visits may be delayed or missed. To achieve this, we will conduct a pilot randomized controlled trial to: Aim 1: Determine the feasibility and acceptability of a fMDA program with dihydroartemisinin- piperaquine (DP) as a novel component of the MiP prevention package. We will conduct an open-label, randomized pilot study at a primary health center in rural western Uganda. Women presenting to their first antenatal clinic visit will be randomized 1:1:1: to (i) monthly fMDA, (ii) one-time fMDA, or (iii) usual care. Using an established implementation framework, we will assess process measures such as the proportion of household members reached, adherence to the course of treatment, and frequency of adverse events. Aim 2: Estimate the efficacy of fMDA to create a “safe zone” in the immediate home environment and ultimately prevent MiP. Using the study design outlined in Aim 1, we will follow participating pregnant women and associated households through delivery, including longitudinal assessments of P. falciparum infection. As a pilot study, the trial is deliberately not powered for statistical tests of significance, but we will measure the incidence of (i) clinical malaria, defined as the presence of typical symptoms (e.g., fever, lethargy) and a positive malaria rapid diagnostic test (RDT), (ii) asymptomatic P. falciparum parasitemia and placental malaria by PCR throughout pregnancy and (iii) the incidence of adverse birth outcomes (...