Advances in understanding the crosstalk between mother and fetus on iron utilization

A full-term pregnancy comes with significant demand for iron. Not meeting this demand has adverse effects on maternal health and on the intrauterine and postnatal development of the infant. In the infant, some of these adverse effects cannot be reversed by postnatal iron supplementation, highlighting the need to tackle iron deficiency in utero. Achieving this requires sound understanding of the pathways that govern iron transfer at the fetomaternal interface. Two pathways are emerging as key players in this context; the hepcidin/ferroportin axis pathway and the iron regulatory protein (IRPs) pathway. In late gestation, suppression of maternal hepcidin, by as yet unknown factors, is required for increasing iron availability to the growing fetus. In the placenta, the rate of iron uptake by transferrin receptor TfR1 at the apical/maternal side and of iron release by ferroportin FPN at the basal/fetal side is controlled by IRP1. In fetal hepatocytes, build up of fetal iron stores requires post-translational inhibition of FPN by the cell-autonomous action of hepcidin. In the fetal liver, FPN is also subject to additional control at the transcriptional level, possibly by the action of hypoxia-inducible factor HIF2α. The rates of apical iron uptake and basal iron release in the placenta are modulated according to iron availability in the maternal blood and the placenta's own needs. This placental modulation ensures that the amount of iron delivered to the fetal circulation is maintained within a normal range, even in the face of mild maternal iron deficiency or overload. However, when maternal iron deficiency or overload are extreme, placental modulation is not sufficient to maintain normal iron supply to the fetus, resulting in fetal iron deficiency and overload respectively. Thus, the rate of iron transfer at the fetomaternal interface is subject to several regulatory signals operating simultaneously in the maternal liver, the placenta and the fetal liver. These regulatory signals act in concert to maintain normal iron supply to the fetus within a wide range of maternal iron states, but fail to do so when maternal iron deficiency or overload are extreme. The limitations of existing experimental models must be overcome if we are to gain better understanding of the role of these regulatory signals in normal and complicated pregnancy. Ultimately, that understanding could help identify better markers of fetal iron demand and underpin novel iron replacement strategies to treat maternal and fetal iron deficiency.