Hormonal Regulation of Iron Partitioning During Pregnancy

Abstract

Iron deficiency is the most prevalent nutrient deficiency worldwide. Pregnant women are at an increased risk of iron deficiency, and this condition has been associated with adverse maternal and neonatal outcomes. Despite the magnitude and known consequences of iron deficiency during pregnancy and at birth, much is left to learn about iron homeostasis during these life stages. It is increasingly appreciated that iron homeostasis is under hormonal control, namely erythropoietin, erythroferrone and hepcidin, however normative concentrations at birth and changes in these hormones during pregnancy and are not fully understood. The overall goal of this research was to characterize maternal iron regulatory hormones across pregnancy, within the placenta, and at birth, highlight challenges with interpretating iron status biomarkers, quantify iron transfer to the fetus from different maternal sources and explore determinants of iron partitioning between the maternal and neonatal compartment. A main novel focus of this dissertation is on the recently identified hormone, erythroferrone. Concentrations of this hormone were characterized for the first time across gestation, in placental tissue obtained at delivery and within the neonatal compartment using umbilical cord blood collected at birth. The study utilized two pregnancy cohorts, one comprised of women carrying multiple fetuses (n = 83) and the other comprised of pregnant adolescents (n = 255). Maternal and neonatal erythroferrone was associated with hemoglobin and erythropoietin in the respective compartments, however differences in erythroferrone’s relationship with hepcidin were evident between pregnant women and their neonates. Erythroferrone was not a strong predictor of maternal or neonatal iron status or anemia, however erythropoietin and the ratio between hepcidin/erythropoietin appeared to perform superior. All placentae collected from these women and adolescents expressed all three hormones, including those delivered as early as 25 weeks of gestation. Only placental erythroferrone and erythropoietin appeared to be associated with maternal, placental or neonatal iron status, and different relationships between these placental transcripts and maternal/neonatal iron status existed between the two cohorts. In an additional cohort of 15 women, stable iron isotopes (57Fe and 58Fe) were used, one to label the maternal RBC pool early in pregnancy and one to label dietary iron in the third trimester to assess relative transfer of iron from these sources to the fetus. Iron absorption increased as pregnancy progressed and was strongly related to maternal iron status, as was transfer of both iron sources to the neonatal compartment. This study also demonstrated that the lifespan of the red blood cell during human pregnancy appears to be shorter than adult men and non-pregnant women. Women with increased iron demand demonstrated greater iron absorption, shorter red blood cell lifespan and transfer of more iron from red blood cell catabolism to their developing fetus. Future research should be focused on understanding the utility of erythropoietin in identifying women with increased iron need and differential partitioning of iron between pregnant adult women and adolescents.