Worldwide, an estimated 85.3 million pregnant women are exposed to Plasmodium falciparum malaria annually, resulting in increased risks of maternal anemia, spontaneous abortions, and low birthweight (LBW) babies due to prematurity and intrauterine growth restriction. The sequestration of infected erythrocytes at the maternal-fetal interface (placental malaria) induces placental inflammation. Placental inflammation and its sequelae, including decreased placental and fetal growth and impaired micronutrient transport, have all been associated with impaired child neurodevelopment (ND), but no study to date has assessed the effect of malaria prevention in pregnancy on subsequent child ND. Studies on malaria prevention in children suggest that it may improve ND, but the extent to which it adds to the effects of malaria prevention in the mother is unknown. The PROMOTE-II randomized clinical trial in Tororo, Uganda, led by investigators from Makerere University and the University of California-San Francisco, provides an ideal setting to assess the effects of malaria prevention in pregnant women and their children on childhood ND. In PROMOTE-II Project 1, 300 pregnant HIV- uninfected women will be randomized at 12-20 weeks of gestation to malaria prophylaxis with 3 does of sulfadoxine-pyrimethamin, 3 doses of dihydroartemisinin-piperaquine (DP), or DP monthly. Their children will be randomized to receive DP prophylaxis monthly or every 3 months, from age 2 to 24 months. Children will be followed for malaria episodes from birth to age 36 months. Our proposed study, Prophylaxis against malaria To Enhance Child developmenT (PROTECT), will be nested within the PROMOTE-II cohort. The study has two primary aims.
In Aim 1, we will determine the effect of malaria prevention in pregnant women and children on child ND. We hypothesize that long-term child ND improves with more effective chemoprevention in pregnant women and in their children, and that the effect of malaria prevention on child ND persists through 36 months of age. Neurodevelopment will be assessed with a testing battery validated in our previous studies of Ugandan children.
In Aim 2, we will identify the major mechanisms by which malaria prevention in pregnant women and children affects child ND. We hypothesize that a) malaria prevention in pregnant women affects child ND through prevention of placental sequestration and inflammation, and b) malaria prevention in pregnant women and children affects child ND through reduction, in the mother and child, of systemic inflammation, endothelial activation, micronutrient deficiency and anemia. This study will provide the first data on the effects of maternal and child malaria prevention on child ND, and form the basis for interventions to improve child ND in the millions of children born to mothers in malaria endemic areas.
Establishing whether prevention of malaria in pregnancy or childhood leads to improved child neurodevelopment, and identifying the factors induced by malaria in pregnancy or childhood that lead to worsened neurodevelopment, could lead to effective prevention of neurodevelopmental impairment in hundreds of thousands of children in sub-Saharan Africa.