The roles of free iron, heme, haemoglobin, and the scavenger proteins haemopexin and alpha‐1‐microglobulin in preeclampsia and fetal growth restriction

Abstract

Background Preeclampsia (PE) is a complex pregnancy syndrome characterised by maternal hypertension and organ damage after 20 weeks of gestation and is associated with an increased risk of cardiovascular disease later in life. Extracellular haemoglobin (Hb) and its metabolites heme and iron are highly toxic molecules and several defence mechanisms have evolved to protect the tissue. Objectives We will discuss the roles of free iron, heme, Hb, and the scavenger proteins haemopexin and alpha‐1‐microglobulin in pregnancies complicated by PE and fetal growth restriction (FGR). Conclusion In PE, oxidative stress causes syncytiotrophoblast (STB) stress and increased shedding of placental STB‐derived extracellular vesicles (STBEV). The level in maternal circulation correlates with the severity of hypertension and supports the involvement of STBEVs in causing maternal symptoms in PE. In PE and FGR, iron homeostasis is changed, and iron levels significantly correlate with the severity of the disease. The normal increase in plasma volume taking place during pregnancy is less for PE and FGR and therefore have a different impact on, for example, iron concentration, compared to normal pregnancy. Excess iron promotes ferroptosis is suggested to play a role in trophoblast stress and lipotoxicity. Non‐erythroid α‐globin regulates vasodilation through the endothelial nitric oxide synthase pathway, and hypoxia‐induced α‐globin expression in STBs in PE placentas is suggested to contribute to hypertension in PE. Underlying placental pathology in PE with and without FGR might be amplified by iron and heme overload causing oxidative stress and ferroptosis. As the placenta becomes stressed, the release of STBEVs increases and affects the maternal vasculature.

Effects of gestational diseases on the distribution of trace elements in the maternal-fetal system

“…Since free-form sub Fe ions (Fe 2+ ) can cause the production of FR or reactive oxygen species (ROS), which can lead to peroxidation and FR chain reactions and nally to molecular damage [11]. A high Fe content will increase the risk of HDCP (e.g., PE) [10,13]. The results of this study showed that there was a signi cant difference in Fe content in maternal blood, placenta and umbilical cord blood in the normal group (Figure . 2.…”

Ferroptosis and Its Emerging Role in Pre-Eclampsia

“…It has also been shown that, in 18% of PE patients, the transferrin saturation levels are high, which is related to iron overload [ 114 ]. During normal pregnancy, the maternal plasma blood volume increases at the first trimester and can increase by 30–50% at the third trimester [ 115 ]. This hypervolemia has little effect on pregnancy complications, while increased plasma volume can cause changes in iron concentration and other factors, which have different effects on normal pregnancy and PE pregnancy [ 116 ].…”

A Review of Nanotechnology for Treating Dysfunctional Placenta

“…Failure to transform the branches of the placental spiral artery restricts the flow of maternal blood to the villus space, and continuous ischemic and perfusion damages the developing placental villi. Compared with normal pregnancy, the volume and surface area of the fetal FGR placenta decreases significantly, placental thickness increases, the blood vessels in the villi decrease or disappear, the lumen narrows or even becomes occluded, and the percentage of villi, capillaries, and surface area of the villi are all reduced ( Erlandsson et al, 2021 ). Through experiments in guinea pigs, Canas et al found that FGR is associated with a heterogeneous pro-constrictive vascular remodeling that sets in during pathologic pregnancy to sustain fetal blood redistribution ( Cañas et al, 2017 ).…”