Maternal iron deficiency perturbs embryonic cardiovascular development
Kalisch-Smith J., Ved N., Szumska D., Munro J., Troup M., Harris S., Jacquemot A., Miller J., Stuart E., Wolna M., Hardman E., Prin F., Lana-Elola E., Aoidi R., Fisher E., Tybulewicz V., Mohun T., Lakhal-Littleton S., Giannoulatou E., Sparrow D.
Congenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births 1 . Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases 2 . Many of the remaining cases of CHD are caused by in utero exposure to environmental factors 3 . Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic 4 , and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.