Fetal factors disrupt placental and maternal iron homeostasis in murine β-thalassemia

• Hyperferremia in thalassemic dams caused iron loading of Th3/+ and WT fetuses, potentiating intrauterine (fetal) growth restriction.

• Hepatic Hamp was transactivated in iron-loaded fetuses; fetal hepcidin likely repressed placental ferroportin, thus mitigating iron loading.

Pregnancy rates in β-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. Hbb^Th3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively affect their unborn offspring. The experimental design included these groups: wild-type (WT) dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, nonpregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all 3 groups of experimental dams. Intestinal ⁵⁹Fe absorption was lower in Th3/+ dams (as compared with WT1/2 dams) but splenic ⁵⁹Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction, and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when mothers with thalassemia have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress likely contributed to fetal growth impairment; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental ferroportin expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.