Maternal Hepcidin Suppression Is Essential for Healthy Pregnancy

Iron is essential for maternal and fetal health during pregnancy, and iron requirements increase substantially in the second half of gestation¹. However, the molecular mechanisms ensuring increased iron availability during pregnancy are not well understood. Hepcidin is the key iron-regulatory hormone and functions by occluding and degrading the iron exporter ferroportin (FPN) to inhibit dietary iron absorption and mobilization of iron from stores. In healthy human and rodent pregnancies, maternal hepcidin decreases starting in the second trimester and is nearly undetectable by late pregnancy^2,3 (Figure A). We explored the role of maternal and embryo hepcidin in regulating embryo iron endowment using mouse models.

By generating combinations of dams and embryos lacking hepcidin or not, we showed that in normal mouse pregnancy, only maternal but not embryo or placental hepcidin determines embryo iron endowment⁴. Maternal hepcidin was inversely related to embryo iron stores, and embryos from hepcidin-deficient dams had significantly higher hepatic iron stores regardless of their own hepcidin genotype. When maternal hepcidin was elevated during the second half of pregnancy in mice by administering a hepcidin mimetic, this led to dose-dependent embryo iron deficiency, anemia, and in severe cases, embryo death⁴. Embryos were particularly sensitive to maternal iron restriction as they developed iron deficiency in the liver and the brain even when maternal hematological parameters were unaffected. These data highlight the critical role of maternal hepcidin suppression for heathy pregnancy. Yet, the physiological mechanism of maternal hepcidin suppression remains unknown.

We showed in mice that maternal hepcidin decreases prior to a significant decrease in liver iron and without any changes in serum iron, suggesting that maternal hepcidin suppression is not driven solely by iron deficiency. Using an in vitro model, we determined that the placenta secretes a hepcidin-suppressing factor. Exposure of primary mouse hepatocytes to supernatants from cultured human placenta cells, but not control media, suppressed hepcidin mRNA more than 10-fold (Figure B) and for up to 48hrs. The suppressive factor in the supernatant was >100kDa in size and not associated with exosomes. Studies to identify the placenta-derived hepcidin suppressor are ongoing.

In summary, suppression of maternal hepcidin is essential to ensure adequate iron supply for transfer to the fetus and for the increase in maternal red blood cell mass², and a placenta-derived hepcidin suppressor likely plays an important role in this adaptation.

¹Fisher AL and Nemeth E, Am J Clin Nutr, 2017

²Sangkhae V et al, JCI, 2020

³van Santen S et al, Clin Chem Lab Med, 2013

⁴Sangkhae V et al, Blood, 2020