Millions of infants are born to women who experience infection with Plasmodium falciparum malaria during pregnancy. Although repeated malaria infections during childhood promote the acquisition of immunity to malaria, exposure to malaria antigens in utero might have the opposite effect. Observational studies suggest that malaria detected at delivery either from the maternal blood or the placenta is associated with increased risk of malaria in the infant. Conclusions from previous observational studies are limited because they cannot control for potential confounders, such as risk factors common to mother and infant such as environment and genetic factors that may impact the risk of malaria infection and severity of disease. Alteration in infant susceptibility to malaria is attributed to the development of fetal immune tolerance in response to in utero exposure to malaria proteins and characterized by increased frequency of T regulatory cells and a Th2-skewed cytokine milieu. This tolerant phenotype could have important health implications for infants by increasing susceptibility to malaria infection and interfering with infants' ability to respond to a malaria vaccine. We will study the infants born to mothers who participate in a clinical trial comparing sulfadoxine-pyrimethamine, a drug compromised by widespread resistance, to dihydroartemisinin-piperaquine, a highly effective, long acting therapy, for the prevention of malaria during pregnancy. The former treatment arm is likely to allow women to develop malaria infection during pregnancy and the latter is expected to prevent all infections. Thus, the in utero exposure of the infants to malaria differ randomly. By examining cord blood responses and the subsequent risk of malaria during infancy, we will determine if prenatal exposure to malaria is responsible for increased susceptibility to malaria during infancy and if the perturbation of the neonatal immune response is the mechanism underlying this phenomenon. The results will be timely. Alternatives to the currently recommended regimen for preventing malaria during pregnancy of sulfadoxine-pyrimethamine are currently being evaluated and the impact existing or new interventions have on infant health and survival may be important factors to consider. In addition, understanding the maternal conditions that prime the fetal immune system to develop a tolerant response may improve our ability to develop vaccines to protect against malaria and other infectious diseases for children in malaria-endemic countries.