Adverse pregnancy outcomes in thalassemic (Th3/+) mice, such as placenta enlargement and growth restriction, could be related to iron overload in a way not previously appreciated, according to research published in Blood.
Though the findings need further exploration, they point to the need for better management of iron in women with thalassemia who are pregnant or are planning to become pregnant, said the researchers.
James Collins, PhD, professor of human nutrition at the University of Florida in Gainesville and the study’s senior author, said iron likely plays a role in adverse pregnancy outcomes in addition to other factors such as problems with red blood cell production and hypoxia.
“What we’re positing is that some of those known pathologies could be exacerbated by iron accumulation, which I don’t think has been recognized in this particular disorder,” he said.
Researchers bred female mice with males to have wild-type dams pregnant with only wild-type fetuses; wild-type dams pregnant with both wild-type fetuses and Th3/+ fetuses; and Th3/+ dams pregnant with TH3/+ fetuses and wild-type fetuses.
They found that the placental weight in the thalassemic pregnant mice was higher than those of wild-type mice carrying only wild-type fetuses. This placental enlargement was found for both wild-type and thalassemic fetuses.
Researchers also found that the weights of both wild-type and thalassemic fetuses that were carried by thalassemic mice were lower than those of wild-type mice carrying only wild-type fetuses, showing growth restriction.
Levels of non-heme iron in the placenta were elevated for both wild-type and thalassemic fetuses that were carried by the thalassemic dams, as they were for the thalassemic fetuses carried by wild-type dams.
The correlation of elevated iron levels shows that iron seems to be an important factor in the adverse conditions in the pregnancies of the thalassemic dams, Dr. Collins said.
“That’s our working hypothesis, that the iron loading contributes in some way to these and potentially other pathological outcomes in the fetuses — and maybe in the newborns, which we haven’t studied yet,” he said. “It might be worth doing iron studies in thalassemic pregnancy to see if the same phenomenon occurs in humans, where the fetus or the placenta become iron loaded.”
The issue of iron overload during pregnancy can be tricky because women with thalassemia might require blood transfusions, which adds iron to the body. However, iron chelation therapy, which reduces excess iron, is contraindicated in pregnancy because of concerns about effects on fetal development.
“This is fairly delicate because we don’t have a lot of data on the management of iron during thalassemic pregnancy,” said study author Michael Garrick, PhD, who is a professor of biochemistry at SUNY Buffalo. “If we’re dealing with a planned pregnancy, certainly the management of iron should be fairly vigorous prior to her getting pregnant. But you then want to be much more cautious during the pregnancy.”
Options that are being studied include hepcidin replacement therapy — to restore normal levels of the hormone that regulates iron homeostasis — and nanoparticle-mediated delivery of inhibitory RNAs that can block activity of the main iron importer in the intestine, Dr. Collins said.
“Either approach would blunt absorption of dietary iron,” he said. “And if that was done to a successful magnitude, you might mitigate some of the excess iron accumulation.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Yu Y, Woloshun RR, Lee JK, et al. Fetal factors disrupt placental and maternal iron homeostasis in murine β-thalassemia. Blood. 2023;142(2):185-196.