Adequate iron availability during pregnancy is essential for fetal development and maternal health. Iron deficiency and its most common manifestation, anemia, are highly prevalent during pregnancy and can have adverse effects on the mother and the fetus. Recognition of detrimental effects of iron deficiency has led to the policy of universal iron supplementation in many countries including the US. However, in developed countries, more pregnant women are iron-replete than iron-deficient. Indiscriminate iron supplementation in this setting may be not only unnecessary, but may even have harmful effects related to increased oxidative stress or potential adverse interaction with inflammation. Despite its importance, little is known about the basic physiology of iron regulation during pregnancy, or how it is altered in complicated pregnancies.
Specific Aim 1. We will define the role of maternal and fetal hepcidin in regulating iron homeostasis during pregnancy. Our preliminary data in mouse models indicate that maternal iron-regulatory hormone hepcidin must be suppressed during pregnancy to ensure sufficient iron availability for placental transfer, and that trophoblast is an important source of the hepcidin-suppressive activity. We will identify the mechanism(s) by which maternal hepcidin is suppressed in healthy pregnancy; and determine whether maternal hepcidin levels are inappropriately increased in human inflamed pregnancies to promote maternal iron restriction.
Specific Aim 2. Our preliminary data show that during maternal iron deficiency or excess, placental iron transporters are regulated to ensure the maintenance of placental iron homeostasis. In response to maternal iron deficiency in both mice and humans, this mechanism sequesters iron in the placenta at the expense of providing adequate iron to the fetus, a phenomenon we termed the ?selfish placenta?. This has important implications for understanding the pathogenesis of fetal iron deficiency. We will define the regulatory circuitries and biological relevance of the selfish placental response in pregnancy.
Specific Aim 3. Our preliminary data in mouse models demonstrate a dramatic adverse interaction between maternal iron excess and maternal inflammation during pregnancy, targeting placental endothelium, and resulting in fetal malformations and embryonic lethality. We will define the underlying mechanisms by focusing on maternal inflammation and pregnancy hormones, as well as placental and fetal inflammation, oxidative stress, and cell death pathways. Our proposal will answer fundamental questions about the pathophysiology of maternal and fetal iron regulation during pregnancy. Long-term, it has the potential to change our approaches to managing iron disorders during pregnancy.
Adequate iron supply during pregnancy is essential for fetal development and maternal health. How iron transfer from the mother to the fetus is regulated in healthy or complicated pregnancies is poorly understood. We propose to define endocrine regulation of iron homeostasis in pregnancy, determine how maternal iron status controls placental iron transport, and elucidate how maternal iron excess potentiates adverse effects of inflammation during pregnancy.
