| Malaria in pregnancy is associated with considerable maternal, fetal, and infant morbidity and mortality. In an effort to prevent poor outcomes, the World Health Organization recommends using the combination antimalarial sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment (IPTp) during pregnancy. Where parasite resistance levels are low, SP-IPTp reduces the incidence of placental malaria (PM), maternal anemia, and low birth weight (LBW). However, resistance to SP has spread rapidly world-wide. The present dissertation examines the unintended consequences of SP-IPTp in a delivery cohort from Muheza, Tanzania, an area of widespread resistance. Among PM+ women, SP-IPTp selected for placental infections of increased drug resistance, decreased diversity, increased parasitemia, and increased inflammation. These data suggest exacerbation of disease, which may have been a result of competitive facilitation of drug resistant parasites. Further, when evaluating delivery and infancy outcomes, SP-IPTp was not associated with a reduction in risk of maternal anemia or LBW but, perversely, was associated with an increased risk of fetal anemia at delivery and an increased risk of severe malaria across infancy. In addition, PM status strongly modified the short and long-term effects of SP-IPTp. Among PM-women, who may have cleared infections, SP-IPTp was associated with decreased risk of LBW, but also decreased fetal hemoglobin at delivery and a trend toward increased risk of severe malaria and hyperparasitemia across infancy. By contrast among PM+ women, who may have failed to clear infections, SP-IPTp was associated with decreased mean birth weight and cord hemoglobin at delivery, decreased time to first parasitemia, and increased risk of severe malaria across infancy. In addition, there was an independent association between the dhps codon 581 resistance allele and decreased fetal hemoglobin, suggesting that SP-IPTp may select for parasites of increased resistance and virulence. Finally, preliminary data from an in vitro model of parasite competitive facilitation are presented. Together these data argue that in the community of Muheza, Tanzania, IPTp is failing and may be causing harm and that the underlying mechanism for these observations is alteration of parasite population dynamics. |
