Iron Homeostasis Disruption and Oxidative Stress in Preterm Newborns

Genny Raffaeli, Francesca Manzoni, Valeria Cortesi, Giacomo Cavallaro, Fabio Mosca, Stefano Ghirardello, Genny Raffaeli, Francesca Manzoni, Valeria Cortesi, Giacomo Cavallaro, Fabio Mosca, Stefano Ghirardello

Abstract

Iron is an essential micronutrient for early development, being involved in several cellular processes and playing a significant role in neurodevelopment. Prematurity may impact on iron homeostasis in different ways. On the one hand, more than half of preterm infants develop iron deficiency (ID)/ID anemia (IDA), due to the shorter duration of pregnancy, early postnatal growth, insufficient erythropoiesis, and phlebotomy losses. On the other hand, the sickest patients are exposed to erythrocytes transfusions, increasing the risk of iron overload under conditions of impaired antioxidant capacity. Prevention of iron shortage through placental transfusion, blood-sparing practices for laboratory assessments, and iron supplementation is the first frontier in the management of anemia in preterm infants. The American Academy of Pediatrics recommends the administration of 2 mg/kg/day of oral elemental iron to human milk-fed preterm infants from one month of age to prevent ID. To date, there is no consensus on the type of iron preparations, dosages, or starting time of administration to meet optimal cost-efficacy and safety measures. We will identify the main determinants of iron homeostasis in premature infants, elaborate on iron-mediated redox unbalance, and highlight areas for further research to tailor the management of iron metabolism.

Keywords: anemia; blood-sparing; iron; prematurity; redox unbalance; transfusion.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Presumptive molecular pathways of ferroptosis following brain injury in the developing brain. Excess free iron in the brain may be the result of Hb degradation by HO-1 after intracerebral hemorrhage. Similarly, a hypoxic-ischemic insult enhances iron liberation from its binding proteins. Fe2+, the reactive form of iron, promotes ROS production via the Fenton reaction leading to lipid peroxidation and membrane damage while the damaged brain releases glutamate. High extracellular glutamate concentrations inhibit the cystine/glutamate antiporter system xc- thus reducing cellular cystine levels, necessary for GSH synthesis. Reduced intracellular cystine concentration indirectly inactivates GPX4, the enzyme responsible for lipid hydroperoxide reduction and GSH consumption. The accumulation of lipid hydroperoxides in an enriched Fe2+ environment leads to significant lipid ROS formation that induces membrane permeabilization and ferroptosis [6,47]. Fe2+: ferrous cation; GPX4: glutathione peroxidase 4; GSSG: oxidized GSH; GSH: reduced glutathione; Hb: hemoglobin; HO-1: heme oxygenase 1; LOOH: lipid hydroperoxides; LOH: lipid alcohols; ROS: reactive oxygen species; TF: transferrin; TfR1: transferrin receptor 1. Adapted from Wang et al. [6].
Figure 2
Figure 2
Iron homeostasis in preterm newborns: risk factors, prevention strategies and treatment.

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Source: PubMed

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