Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities

Malaria infection during pregnancy is associated with adverse birth outcomes but underlying mechanisms are poorly understood. Here, we discuss the impact of malaria in pregnancy on three pathways that are important regulators of healthy pregnancy outcomes: L-arginine-nitric oxide biogenesis, complement activation, and the heme axis. These pathways are not mutually exclusive, and they collectively create a proinflammatory, antiangiogenic milieu at the maternal–fetal interface that interferes with placental function and development. We hypothesize that targeting these host-response pathways would mitigate the burden of adverse birth outcomes attributable to malaria in pregnancy. Impaired L-arginine-nitric oxide biogenesis, complement activation, and heme axis dysregulation are associated with adverse birth outcomes in the context of malaria in pregnancy.Altered levels of bioavailable L-arginine and nitric oxide are associated with dysregulation of angiogenic and inflammatory pathways, increased placental vascular resistance and microvascular dysfunction, resulting in pathological pregnancy outcomes.Malaria-in-pregnancy-induced activation of the complement signaling pathways negatively impacts fetal growth by enhancing inflammation and driving an imbalance of angiogenic factors critical for endothelial cell function and placental vasculature development.Dysregulation of the heme axis is linked to angiogenic dysfunction, vaso-occlusion, and inflammation, processes that are detrimental to a healthy and successful pregnancy.