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The physiology and pathology of iron in pregnancy

  • Author(s): Fisher, Allison Lynn
  • Advisor(s): Nemeth, Elizabeta
  • et al.
Abstract

Iron is an essential nutrient required for vital metabolic and cellular processes. Despite its importance, it is poorly understood how maternal and fetal iron homeostasis is regulated during pregnancy, including the contribution of the maternal, placental, and fetal signals during healthy pregnancy or in conditions of iron deficiency and excess. Maternal iron insufficiency causes anemia, which is a global health problem linked to adverse outcomes. Iron availability in maternal circulation is ensured by the physiological suppression of the hormone hepcidin. We showed that suppression of maternal hepcidin during pregnancy is essential for embryo health, as high maternal hepcidin activity induced by administering a hepcidin mimetic to pregnant mice caused severe iron restriction and anemia in dams and embryos, low birthweight, and embryo mortality. Using mouse models, we showed that during maternal iron deficiency, maternal hepcidin is further suppressed, but this is not sufficient to maintain plasma iron levels and embryo iron endowment. With severe iron deficiency, the placenta altered iron transporters to preserve its own iron and metabolic function at the expense of the fetus, ultimately protecting the fetus from the consequences of placental dysfunction.

We further showed that embryo hepcidin does not regulate placental iron transfer under physiological conditions. However, in mouse, rhesus macaques and human pregnancies complicated by inflammation, we found that fetal hepcidin was increased and associated with fetal hypoferremia. The fetus’s ability to respond to inflammatory signals represents a conserved mechanism thought to be important in fetal host defense.

We discovered in mouse models an adverse interaction between maternal iron excess and inflammation that led to embryotoxicity which was not observed with either condition alone. Embryotoxicity was observed not only in a mouse model of systemic acute inflammation induced by bacterial lipopolysaccharide, but also with chronic inflammation caused by diet-induced obesity. We found that maternal iron excess increased oxidative stress in the placenta and embryo endothelium, which sensitized the placental and embryo endothelium to inflammation-induced lethal apoptotic damage. The interaction between iron excess and inflammation is dependent on TNFα-signaling and can be reversed by maternal anti-TNFα and antioxidant therapy. These findings raise important questions about the safety of indiscriminate iron supplementation in pregnant women with underlying inflammation.

We analyzed the interaction between iron, inflammation, and the endothelium in cultured endothelial cells. Iron loading induced cholesterol biosynthesis, promoted novel TNFR1 proteolytic processing, and sensitized cells to TNFα-mediated apoptosis. We determined that during iron excess, the contribution of altered cholesterol homeostasis is the driving pathogenic mediator of apoptosis. Altered cholesterol metabolism by iron excess in endothelial cells may contribute to iron-mediated toxicity in human iron overload disorders.

We further described that iron deficiency in pregnant mice also adversely interacts with inflammation caused by acute and chronic inflammation, triggered respectively by lipopolysaccharide and diet-induced obesity. Only the combination of maternal iron deficiency and inflammation caused embryo malformations and demise. Iron deficiency potentiated placental inflammation in complicated pregnancies, and in normal pregnancies iron deficiency induced TNFα-receptor 1 expression in mouse and human placentas, representing possible mechanisms for how iron deficiency worsens outcomes in inflamed pregnancies.

We defined the pathophysiology of iron regulation in pregnancy and articulated several novel concepts: placental adaptation to limited iron availability, the roles of maternal and fetal hepcidin, and adverse synergy between iron and inflammation. The discovery of the interaction between iron and inflammation highlights the utility of iron status as a modifying factor to ameliorate severity of injury in inflamed pregnancy and in a variety of inflammatory conditions outside of pregnancy. These concepts have translational impact and may eventually inform the clinical management of pregnant women worldwide.

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