Iron Homeostasis During Pregnancy: Maternal, Placental, and Fetal Regulatory Mechanisms

Abstract

Pregnancy entails a large negative balance of iron, an essential micronutrient. During pregnancy, iron requirements increase substantially to support both maternal red blood cell expansion and the development of the placenta and fetus. As insufficient iron has long been linked to adverse pregnancy outcomes, universal iron supplementation is common practice before and during pregnancy. However, in high-resource countries with iron fortification of staple foods and increased red meat consumption, the effects of too much iron supplementation during pregnancy have become a concern because iron excess has also been linked to adverse pregnancy outcomes. In this review, we address physiologic iron homeostasis of the mother, placenta, and fetus and discuss perturbations in iron homeostasis that result in pathological pregnancy. As many mechanistic regulatory systems have been deduced from animal models, we also discuss the principles learned from these models and how these may apply to human pregnancy.

Keywords: hepcidin; inflammation; iron; iron deficiency; placenta; pregnancy.

Figure 1

Iron flows in (a) normal nonpregnant females, (b) normal pregnancy, (c) iron-deficient pregnancy, and (d) inflamed pregnancy. Iron flows are shown in shades of blue and different arrow sizes, where darker thick arrows indicate increased iron flows and lighter dashed arrows indicate decreased or absent iron flows compared with normal flow. Hepcidin effects are shown in red. The asterisk indicates intra-amniotic infection. Abbreviations: Fe, iron; RBC, red blood cell; Tf, transferrin.

Figure 2

Iron trafficking across the syncytiotrophoblast. (a) Human placenta, with a single layer of syncytiotrophoblast. (b) Mouse placenta, with two syncytiotrophoblast layers (SynT-I and SynT-II). In both humans and mice, transferrin-bound iron (holo-Tf) from the maternal circulation binds to transferrin receptor TFR1, expressed on the apical membrane of the placental syncytiotrophoblast (SynT-I in mice). The iron-transferrin-receptor complex is internalized via clathrin-mediated endocytosis, and ferric iron (Fe³⁺) is released from transferrin (Tf) in acidified endosomes. The apo-Tf/TFR1 complex is recycled back to the cell surface. Fe³⁺ in the endosome is thought to be reduced to ferrous iron (Fe²⁺) by a ferrireductase and exported into the cytoplasm through an endosomal iron transporter. Cytoplasmic Fe may be chaperoned, possibly by PCBP1 or PCBP2, either to ferritin for storage or to ferroportin (FPN) on the basal membrane (SynT-II in mice) for export toward the fetal circulation. In the mouse placenta (b), it is unknown how Fe is transported from SynT-I to SynT-II, but it likely occurs through gap junctions. The fate of iron following export through ferroportin is unclear; it may enter the fetal circulation as nontransferrin bound iron (NTBI) or be oxidized to Fe³⁺ by ferroxidases and loaded onto transferrin prior to reaching the fetal circulation. Figure adapted with permission from Reference .