Abstract
Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite for optimal child development, yet nutritional iron deficiency and inflammation-related iron restriction are widespread amongst young children in low- and middle-income countries (LMICs), meaning iron demands are frequently not met. Consequently, therapeutic iron interventions are commonly recommended. However, iron also influences infection pathogenesis: iron deficiency reduces the risk of malaria, while therapeutic iron may increase susceptibility to malaria, respiratory and gastrointestinal infections, besides reshaping the intestinal microbiome. This means caution should be employed in administering iron interventions to young children in LMIC settings with high infection burdens. In this narrative review, we first examine demand and supply of iron during early childhood, in relation to the molecular understanding of systemic iron control. We then evaluate the importance of iron for distinct aspects of physiology and development, particularly focusing on young LMIC children. We finally discuss the implications and potential for interventions aimed at improving iron status whilst minimising infection-related risks in such settings. Optimal iron intervention strategies will likely need to be individually or setting-specifically adapted according to iron deficiency, inflammation status and infection risk, while maximising iron bioavailability and considering the trade-offs between benefits and risks for different aspects of physiology. The effectiveness of alternative approaches not centred around nutritional iron interventions for children should also be thoroughly evaluated: these include direct targeting of common causes of infection/inflammation, and maternal iron administration during pregnancy.
Highlights
Young children growing up in low- and middle-income countries (LMICs) are frequently exposed to concurrent physiological challenges and environmental hazards that may influence both their current health and future development
The erythroid compartment contributes to systemic iron homeostasis by returning iron to circulation: hepcidin-sensitive ferroportin is expressed by erythroblasts and is found on mature erythrocyte membranes [38,39]; erythroid-specific ferroportin knockout mice display mild serum iron deficiency, consistent with a proportion of circulating iron being derived from the erythron [40]
After iron deprivation, decreased brain iron that preceded anaemia was reported in phlebotomized lambs [133], in human infants born from diabetic mothers [134], and in sheep affected by intrauterine hypoxemia [135]
Summary
Young children growing up in low- and middle-income countries (LMICs) are frequently exposed to concurrent physiological challenges and environmental hazards that may influence both their current health and future development. In such settings, a high infection risk often co-exists with nutritional deficiencies, amongst which iron deficiency (ID) is of major importance. The clinical and developmental impacts of iron deficiency go beyond anaemia [3] In this narrative review, we discuss the biology of iron in early childhood, with a particular focus on children living in settings with high burdens of infection, nutritional deficiency and anaemia. The final section summarises factors that should be accounted for when planning interventions aimed at adjusting iron status in such populations
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