Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study

Abstract

Abstract. Hepcidin, the master regulator of bioavailable iron, is a key mediator of anemia and also plays a central role in host defense against infection. We hypothesized that measuring hepcidin levels in cord blood could provide an early indication of interindividual differences in iron regulation with quantifiable implications for anemia, malaria, and mortality-related risk. Hepcidin concentrations were measured in cord plasma from a birth cohort (N = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002Tanzania ( -2006. At the time of delivery, cord hepcidin levels were correlated with inflammatory mediators, iron markers, and maternal health conditions. Hepcidin levels were 30% (95% confidence interval [CI]: 12%, 44%) lower in children born to anemic mothers and 48% (95% CI: 11%, 97%) higher in placental malaria-exposed children. Relative to children in the lowest third, children in the highest third of cord hepcidin had on average 2.5 g/L (95% CI: 0.1, 4.8) lower hemoglobin levels over the duration of follow-up, increased risk of anemia and severe anemia (adjusted hazard ratio [HR]

Iron Status and Associated Malaria Risk Among African Children

“…Since the parasite requires iron for growth, it has been suggested that withholding iron from hepatocytes inhibits the development of malaria [16]. Furthermore, high cord blood hepcidin has been associated with decreased risk of clinical malaria, although not parasitemia or severe malaria, in Tanzanian infants [18]. However, in agreement with our study in an independent cohort of Kenyan children [17], we found no association between hepcidin concentrations and clinical malaria episodes.…”

“…Little is known about whether other indicators of iron status (including hepcidin, hemoglobin, soluble transferrin receptors [sTfR], and transferrin saturation [TSAT]) influence malaria risk in humans. In mouse models, hepcidin has been shown to play a role in preventing superinfection by depriving the Plasmodium liver stage of iron [16], but studies in children have reported mixed findings [17, 18]. Two previous studies have reported that hemoglobin concentrations do not influence malaria risk [19, 20], while in vitro culture indicates otherwise [21].…”

Iron, Inflammation, and Malaria in the Pregnant Woman and Her Child: Saving Lives, Saving Brains

“…The study by Brickley and others 1 shows that placental malaria is associated with increased cord blood hepcidin concentrations in neonates, which are in turn associated with a lower risk of malaria and death in early childhood. Yet, we know placental malaria is not good for the fetus: it is associated with prematurity and intrauterine growth restriction, 9 and placental inflammation in other conditions is associated with impaired child neurodevelopment.…”

“…The battle for iron between host and pathogen in children living in malaria-endemic areas is fierce, and new evidence presented by Brickley and others 1 in this month's issue suggests it may well begin before birth. In previous work, this group showed that iron deficiency in children living in a malaria-endemic area of Tanzania was associated with a decreased risk of malaria and death.…”

“…Hepatic production of hepcidin is known to have multiple drivers, including dietary iron sufficiency, inflammation, and slowed erythropoietic rate. 3 – 5 The study by Brickley and others 1 shows that in malaria-endemic areas, inflammation inparticular has an outsize influence on cord blood hepcidin concentrations, as conditions associated with inflammation (placental malaria, high malaria transmission season) and markers of inflammation (higher placental, maternal, and cord blood concentrations of inflammatory cytokines and C-reactive protein [CRP]) together predicted the greatest portion of variability in cord blood hepcidin concentrations. The study findings also suggest that in malaria-exposed pregnant mothers, limited maternal systemic iron availability—and perhaps consequent limited iron transfer to the fetus—may be protective for their children in terms of later malarial morbidity.…”