Malaria during pregnancy: Physiological and evolutionary perspectives on poor birth outcomes.

Abstract

Malaria infection during pregnancy is associated with poor outcomes, including low birth weight, preterm delivery, and anemia. Although the mechanisms are not fully elucidated, malaria-induced proinflammatory cytokine production and placental monocyte infiltration may play a role. In three studies in Blantyre, Malawi, malaria-related birth outcomes were investigated in light of proximate physiological mechanisms affecting outcome and evolutionary conflicts and compromises ultimately affecting fitness. Chapter 3 was the first study to identify MCP-1 and MIP-1beta as the chemokines, or chemoattractant cytokines, that draw monocytes into malaria-infected placentas. In placental tissue, MIP-1beta was localized to hemozoin-laden maternal macrophages and MCP-1 to fetal stromal cells and maternal macrophages. Fetal production of MCP-1 is important in establishing fetal contribution to the very immune responses associated with poor birth outcomes. Chapter 4 determined that HIV infection, infrequent antenatal clinic attendance, low maternal weight, not taking iron/folate tablets, and chorioamnionitis, but not malaria, were the main risk factors for preterm delivery (PTD) in the study population. As chorioamnionitis triggers PTD via proinflammatory cytokines, malaria-induced cytokines were hypothesized to act similarly. There was no overlap between the cytokines affected by malaria and those associated with PTD, suggesting that chorioamnionitis, but not malaria, causes PTD via its effect on proinflammatory cytokines. Chapter 5 investigated the relationship between maternal and neonatal hematological status in malaria-infected and uninfected women, yielding three main findings. First, neonates of malaria-infected mothers, contrary to previous reports, did not have atypically low hemoglobin levels. Second, increased maternal parasitemia was associated with increased cord ferritin, an acute shock protein, suggesting that the fetus was immunologically primed by maternal malaria. Third, elevated cord ferritin was associated with lower birth weight and shorter gestation following malaria-infected pregnancies, and may mediate poor birth outcomes. Together, these studies illustrate the physiological pathways by which malaria during pregnancy results in poor birth outcomes, and demonstrate that the fetus participates in inflammatory responses to malaria despite the ill effects on growth, perhaps to prevent congenital malaria. From an evolutionary perspective, these adaptations reflect the strong selective pressure of malaria.