Improving Neonatal health Through Rapid malaria testing in Early Pregnancy with high-sensitivity Diagnostics (INTREPiD)

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Project Summary/Abstract Newborn health has improved globally but there remains a critical need in resource-limited settings to reduce neonatal mortality. Nearly all infant deaths in sub-Saharan Africa occur in babies that are small or low birthweight, which often result from antenatal infections with Plasmodium falciparum. These malaria effects can be partially mitigated by pregnancy-specific measures including the administration of monthly antenatal doses of sulfadoxine-pyrimethamine as intermittent preventive therapy during pregnancy (IPTp-SP), but these are not typically implemented until the 2nd trimester, and so do not mitigate the risks of infection in the 1st trimester. It is now feasible to include 1st trimester screening for malaria parasites owing to: i) updated WHO guidelines that recommend an expended schedule of 8 ANC contacts, with the first prior to 12 weeks gestation, ii) the availability of high-sensitivity malaria rapid diagnostic tests (HS-RDT) with enhanced detection of low-density infections, and iii) accumulated safety data that enable the use of Artemether-Lumefantrine (AL) for malaria treatment in the 1st trimester. We hypothesize that, compared to women who enter ANC and receive usual care, women who are screened in the 1st trimester with an HS-RDT will have a lower prevalence of a poor pregnancy outcome, and we will test this through the Improving Neonatal health Through Rapid malaria testing in Early Pregnancy with high-sensitivity Diagnostics (INTREPiD) study in Western Kenya and the Democratic Republic of the Congo (DRC). In Aim 1, the INTREPiD study will enroll women in the 1st trimester and randomize them 1:1 to usual care or to screening with an HS-RDT followed by treatment of positives with AL, and then follow them through delivery. Following the 1st trimester intervention, all women will receive usual ANC, including IPTp-SP. The primary outcome will be the composite outcome of low birthweight, small-for- gestational age, preterm birth, fetal loss, or neonatal death. In Aim 2, we will measure the therapeutic efficacy and pharmacokinetics of AL administration in the 1st trimester through a population PK study following standard AL dosing and compare PK parameters with historical controls. In Aim 3, we will use trial data to model the potential incremental benefits of enhanced-sensitivity diagnostics and alternate treatment regimens on the risk of an adverse pregnancy outcome in order to maximize the impact of our trial data. Collectively these data will guide the development and implementation of fresh approaches to intercept parasites early in pregnancy and thereby enhance pregnancy outcomes and newborn health.