Placental pathogenesis of fetal growth restriction during Plasmodium falciparum infection in human pregnancy

© 2010 Dr. Alexandra UmbersIn endemic areas malaria infection during pregnancy is a leading cause of low birth weight and major risk factor for maternal and neonatal mortality. Most low birth weight deliveries are a consequence of placental malaria-associated inflammation, which causes fetal growth restriction (FGR). Placental insufficiency has been hypothesized to underlie the pathogenesis of FGR, but specific studies on placental function are lacking. To determine the mechanisms involved, the relationship between malaria infection and placental development and function were examined using in vitro models and in Plasmodium falciparum infected and non-infected pregnancies from two endemic regions in sub-Saharan Africa and south east Asia. In women with infection during early pregnancy, soluble factors in maternal blood significantly reduced trophoblast invasion in vitro. Evidence from this model of placental development implies that maternal infection may impair placental development, and consequently placental sufficiency later in pregnancy. At delivery, placental malaria infection in Malawian women caused significant changes in syncytiotrophoblast (SCT) cortisol metabolic function that were related to FGR and maternal anemia. This suggests that excess prenatal cortisol exposure may contribute to restricted fetal growth. Likewise, analysis of growth regulating hormones in a cohort of Papua New Guinean pregnancies revealed concordant disturbances in the maternal and fetal compartments of the insulin like growth (IGF) factors axis with placental malaria-associated inflammation. Reduced IGF hormones, and the down stream effectors of nutrient partitioning, may play a central role in the development of FGR in malaria infected pregnancies. Use of an in vitro model of placental malaria indicated that synthesis of key hormonal mediators of fetal growth within the SCT were unaffected by malaria infection, at least in the absence of inflammation. This study provides evidence to support the hypothesis that malaria during pregnancy causes fetal growth restriction by multiple pathogenic mechanisms that affect placental sufficiency and hormones that regulate fetal growth. Such findings suggest intervention strategies that specifically target prevention of infection early in pregnancy and placental malaria throughout pregnancy may decrease the burden of FGR associated with malaria in pregnancy