Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Allison L Fisher,Elizabeta Nemeth,Nicolaos J Palaskas,Veena Sangkhae,Tomas Ganz,Kamila Balušíková

doi:10.1038/s41467-021-24333-z

Allison L Fisher, Elizabeta Nemeth + Show 4 more

Open Access

https://doi.org/10.1038/s41467-021-24333-z

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Abstract

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection. In this study, we use mouse models to determine whether maternal iron loading, inflammation, or their interaction cause poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, causes embryo malformations and demise. Maternal iron excess potentiates embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction depends on TNFα signaling, causes apoptosis of placental and embryo endothelium, and is prevented by anti-TNFα or antioxidant treatment. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.

Highlights

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status
We examined the contribution of tumor necrosis factor α (TNFα) in mediating embryo demise in vivo by treating pregnant iron-loaded hepcidin KO dams with TNFα-neutralizing antibody or control IgG antibody targeting trinitrophenol, prior to E15.5 LPS treatment (Fig. 3a)
Most women have sufficient iron stores, but women are still advised to take 30–60 mg elemental iron daily starting at the first prenatal visit[3], even without screening for iron deficiency

Summary

Introduction

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. Iron requirements increase substantially over the course of pregnancy to support growth of the fetus and placenta and for maternal erythropoietic expansion[1] To meet these demands, both dietary iron absorption and mobilization of iron from stores increase, and this is mediated by a decrease in maternal hepcidin, the iron regulatory peptide hormone produced in the liver[2]. Large epidemiological studies show a U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse outcomes such as low birthweight, stillbirth, preterm birth (

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