The World Health Organization (WHO) estimates that nearly half of pregnant women worldwide suffer from anemia, with 52% residing in lesser-developed countries (LDCs). Despite the enormous global burden of disease due to anemia, there is a paucity of data addressing specific causes of anemia during pregnancy, and how these influence both maternal and newborn outcomes. In fact, there is little data to support the efficacy of pre-natal iron supplementation to improve pregnancy outcomes. In malaria-endemic areas, an iron replete state may actually increase risk to pregnant women and newborns. The design of cost-effective interventions to modify this enormous burden of disease depends on examining and quantifying the role of specific causes of maternal anemia. This study will begin to fill these lacunae by clearly defining the two most common causes of anemia in LDCs, iron deficiency and anemia of inflammation (AI), and relating these to pregnancy outcomes. Recent studies have demonstrated the important role of AI in the pathogenesis of anemia in pregnancy in LDCs, where a host of infectious diseases lead to ongoing inflammation. Inflammation, in turn, leads to alterations in iron absorption and distribution, ultimately limiting iron delivery t host tissues. This study will address the novel hypothesis that AI will decrease delivery of iron t the developing fetus 1) by limiting iron delivery to the placenta and 2) through fetal hepcidin elaboration which will decrease ferroportin expression and limit iron uptake. This proposal will utilize samples from an ongoing NIH funded randomized controlled trial of S. japonicum treatment in pregnancy to address the role of iron deficiency anemia and AI in mediating adverse pregnancy outcomes. AI is the primary cause of anemia in the context of S. japonicum. This study, therefore, provides the unique opportunity to examine how amelioration of AI influences pregnancy outcomes. This proposal will leverage the extensive data being collected to quantify the role of AI in adverse pregnancy outcomes and investigate potential mechanisms. The specific goals of this study are to: 1) carefully define the etiology of anemia and relate thi to maternal and newborn outcomes, 2) examine the sensitivity and specificity of novel iron and inflammatory bio-markers with respect to their ability to capture newborn risk of anemia and iron insufficiency, 3) examine how these two causes of maternal anemia affect iron delivery to placental tissues using confocal microscopy, Laser Capture Microdissection, Western blot, and qPCR techniques to quantify placental iron transport proteins, 4) understand how amelioration of maternal and fetal AI improves maternal and newborn outcomes. Given iron deficiency anemia and AI are the two leading causes of anemia in pregnancy, and interventions to address these are vastly different, understanding how each etiology affects pregnancy outcomes and developing diagnostic tools to differentiate them are of paramount importance.
The global burden of disease attributable to anemia in pregnancy is enormous, yet little is known about which specific causes of anemia lead to adverse pregnancy outcomes. Further, little is known about how maternal infections influence signals from the fetus that also control iron transfer. This study will address the extent to which the two most common causes of anemia in pregnancy, iron deficiency and anemia of inflammation, lead to adverse outcomes for pregnant women and their newborns, which is significant as treatment approaches differ greatly.