Volume 95, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



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 ( = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002–2006). 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] [95% CI]: 1.18 [1.03, 1.36] and 1.34 [1.08, 1.66], respectively), and decreased risk of malaria and all-cause mortality (adjusted HR [95% CI]: 0.78 [0.67, 0.91] and 0.34 [0.14, 0.84], respectively). Although longitudinal measurements of hepcidin and iron stores are required to strengthen causal inference, these results suggest that hepcidin may have utility as a biomarker indicating children's susceptibility to anemia and infection in early life.


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  1. Grantham-McGregor S, Ani C, , 2001. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 131: 649S666S; discussion 666S–668S. [Google Scholar]
  2. Burke RM, Leon JS, Suchdev PS, , 2014. Identification, prevention and treatment of iron deficiency during the first 1,000 days. Nutrients 6: 40934114.[Crossref] [Google Scholar]
  3. Roca-Feltrer A, Carneiro I, Smith L, Schellenberg JR, Greenwood B, Schellenberg D, , 2010. The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings. Malar J 9: 282.[Crossref] [Google Scholar]
  4. Murphy SC, Breman JG, , 2001. Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg 64: 5767. [Google Scholar]
  5. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T, , 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113: 12711276.[Crossref] [Google Scholar]
  6. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J, , 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 20902093.[Crossref] [Google Scholar]
  7. Rodriguez R, Jung CL, Gabayan V, Deng JC, Ganz T, Nemeth E, Bulut Y, , 2014. Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun 82: 745752.[Crossref] [Google Scholar]
  8. Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D, , 2005. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106: 18641866.[Crossref] [Google Scholar]
  9. Doherty CP, Cox SE, Fulford AJ, Austin S, Hilmers DC, Abrams SA, Prentice AM, , 2008. Iron incorporation and post-malaria anaemia. PLoS One 3: e2133.[Crossref] [Google Scholar]
  10. Cercamondi CI, Egli IM, Ahouandjinou E, Dossa R, Zeder C, Salami L, Tjalsma H, Wiegerinck E, Tanno T, Hurrell RF, Hounhouigan J, Zimmermann MB, , 2010. Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization: a double stable-isotope study in young Beninese women. Am J Clin Nutr 92: 13851392.[Crossref] [Google Scholar]
  11. Mabeza GF, Loyevsky M, Gordeuk VR, Weiss G, , 1999. Iron chelation therapy for malaria: a review. Pharmacol Ther 81: 5375.[Crossref] [Google Scholar]
  12. Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel J, Fisher N, Taylor SM, Kasthuri RS, Cerami C, , 2014. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum . Nat Commun 5: 4446.[Crossref] [Google Scholar]
  13. Portugal S, Carret C, Recker M, Armitage AE, Goncalves LA, Epiphanio S, Sullivan D, Roy C, Newbold CI, Drakesmith H, Mota MM, , 2011. Host-mediated regulation of superinfection in malaria. Nat Med 17: 732737.[Crossref] [Google Scholar]
  14. Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Back R, Kortok M, Chemtai AK, Marsh K, Williams TN, , 2004. Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis 190: 439447.[Crossref] [Google Scholar]
  15. Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy PE, , 2008. Decreased susceptibility to Plasmodium falciparum infection in pregnant women with iron deficiency. J Infect Dis 198: 163166.[Crossref] [Google Scholar]
  16. Senga EL, Harper G, Koshy G, Kazembe PN, Brabin BJ, , 2011. Reduced risk for placental malaria in iron deficient women. Malar J 10: 47.[Crossref] [Google Scholar]
  17. Gwamaka M, Kurtis JD, Sorensen BE, Holte S, Morrison R, Mutabingwa TK, Fried M, Duffy PE, , 2012. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin Infect Dis 54: 11371144.[Crossref] [Google Scholar]
  18. Sangare L, van Eijk AM, Ter Kuile FO, Walson J, Stergachis A, , 2014. The association between malaria and iron status or supplementation in pregnancy: a systematic review and meta-analysis. PLoS One 9: e87743.[Crossref] [Google Scholar]
  19. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM, , 2006. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367: 133143.[Crossref] [Google Scholar]
  20. Veenemans J, Milligan P, Prentice AM, Schouten LR, Inja N, van der Heijden AC, de Boer LC, Jansen EJ, Koopmans AE, Enthoven WT, Kraaijenhagen RJ, Demir AY, Uges DR, Mbugi EV, Savelkoul HF, Verhoef H, , 2011. Effect of supplementation with zinc and other micronutrients on malaria in Tanzanian children: a randomised trial. PLoS Med 8: e1001125.[Crossref] [Google Scholar]
  21. Drakesmith H, Prentice AM, , 2012. Hepcidin and the iron-infection axis. Science 338: 768772.[Crossref] [Google Scholar]
  22. Kabyemela E, Goncalves BP, Prevots DR, Morrison R, Harrington W, Gwamaka M, Kurtis JD, Fried M, Duffy PE, , 2013. Cytokine profiles at birth predict malaria severity during infancy. PLoS One 8: e77214.[Crossref] [Google Scholar]
  23. World Health Organization, Department of Nutrition for Health and Development, 2001. Iron Deficiency Anaemia: Assessment, Prevention and Control: A Guide for Programme Managers. Geneva, Switzerland: World Health Organization. [Google Scholar]
  24. Prentice AM, Doherty CP, Abrams SA, Cox SE, Atkinson SH, Verhoef H, Armitage AE, Drakesmith H, , 2012. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood 119: 19221928.[Crossref] [Google Scholar]
  25. Coutinho HM, McGarvey ST, Acosta LP, Manalo DL, Langdon GC, Leenstra T, Kanzaria HK, Solomon J, Wu H, Olveda RM, Kurtis JD, Friedman JF, , 2005. Nutritional status and serum cytokine profiles in children, adolescents, and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines. J Infect Dis 192: 528536.[Crossref] [Google Scholar]
  26. Chong SS, Boehm CD, Higgs DR, Cutting GR, , 2000. Single-tube multiplex-PCR screen for common deletional determinants of α-thalassemia. Blood 95: 360362. [Google Scholar]
  27. Fibrinogen Studies Collaboration Kaptoge S, White IR, Thompson SG, Wood AM, Lewington S, Lowe GD, Danesh J, , , 2007. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the Fibrinogen Studies Collaboration. Am J Epidemiol 166: 867879.[Crossref] [Google Scholar]
  28. Easton DF, Peto J, Babiker AG, , 1991. Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 10: 10251035.[Crossref] [Google Scholar]
  29. Nweneka CV, Doherty CP, Cox S, Prentice A, , 2010. Iron delocalisation in the pathogenesis of malarial anaemia. Trans R Soc Trop Med Hyg 104: 175184.[Crossref] [Google Scholar]
  30. de Mast Q, Nadjm B, Reyburn H, Kemna EH, Amos B, Laarakkers CM, Silalye S, Verhoef H, Sauerwein RW, Swinkels DW, van der Ven AJ, , 2009. Assessment of urinary concentrations of hepcidin provides novel insight into disturbances in iron homeostasis during malarial infection. J Infect Dis 199: 253262.[Crossref] [Google Scholar]
  31. de Mast Q, Syafruddin D, Keijmel S, Riekerink TO, Deky O, Asih PB, Swinkels DW, van der Ven AJ, , 2010. Increased serum hepcidin and alterations in blood iron parameters associated with asymptomatic P. falciparum and P. vivax malaria. Haematologica 95: 10681074.[Crossref] [Google Scholar]
  32. Howard CT, McKakpo US, Quakyi IA, Bosompem KM, Addison EA, Sun K, Sullivan D, Semba RD, , 2007. Relationship of hepcidin with parasitemia and anemia among patients with uncomplicated Plasmodium falciparum malaria in Ghana. Am J Trop Med Hyg 77: 623626. [Google Scholar]
  33. Casals-Pascual C, Huang H, Lakhal-Littleton S, Thezenas ML, Kai O, Newton CR, Roberts DJ, , 2012. Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria. Haematologica 97: 16951698.[Crossref] [Google Scholar]
  34. Burte F, Brown BJ, Orimadegun AE, Ajetunmobi WA, Afolabi NK, Akinkunmi F, Kowobari O, Omokhodion S, Osinusi K, Akinbami FO, Shokunbi WA, Sodeinde O, Fernandez-Reyes D, , 2013. Circulatory hepcidin is associated with the anti-inflammatory response but not with iron or anemic status in childhood malaria. Blood 121: 30163022.[Crossref] [Google Scholar]
  35. Atkinson SH, Uyoga SM, Armitage AE, Khandwala S, Mugyenyi CK, Bejon P, Marsh K, Beeson JG, Prentice AM, Drakesmith H, Williams TN, , 2015. Malaria and age variably but critically control hepcidin throughout childhood in Kenya. EBioMedicine 2: 14781486.[Crossref] [Google Scholar]
  36. Muehlenbachs A, Fried M, Lachowitzer J, Mutabingwa TK, Duffy PE, , 2007. Genome-wide expression analysis of placental malaria reveals features of lymphoid neogenesis during chronic infection. J Immunol 179: 557565.[Crossref] [Google Scholar]
  37. Van Santen S, de Mast Q, Luty AJ, Wiegerinck ET, Van der Ven AJ, Swinkels DW, , 2011. Iron homeostasis in mother and child during placental malaria infection. Am J Trop Med Hyg 84: 148151.[Crossref] [Google Scholar]
  38. Marchini G, Berggren V, Djilali-Merzoug R, Hansson LO, , 2000. The birth process initiates an acute phase reaction in the fetus-newborn infant. Acta Paediatr 89: 10821086.[Crossref] [Google Scholar]
  39. Basu S, Kumar N, Srivastava R, Kumar A, , 2016. Maternal and cord blood hepcidin concentrations in severe iron deficiency anemia. Pediatr Neonatol doi: 10.1016/j.pedneo.2015.09.012. [Google Scholar]
  40. Rehu M, Punnonen K, Ostland V, Heinonen S, Westerman M, Pulkki K, Sankilampi U, , 2010. Maternal serum hepcidin is low at term and independent of cord blood iron status. Eur J Haematol 85: 345352.[Crossref] [Google Scholar]
  41. Lorenz L, Herbst J, Engel C, Peter A, Abele H, Poets CF, Westerman M, Franz AR, , 2014. Gestational age-specific reference ranges of hepcidin in cord blood. Neonatology 106: 133139.[Crossref] [Google Scholar]
  42. Martin ME, Nicolas G, Hetet G, Vaulont S, Grandchamp B, Beaumont C, , 2004. Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos. FEBS Lett 574: 187191.[Crossref] [Google Scholar]
  43. Gambling L, Danzeisen R, Gair S, Lea RG, Charania Z, Solanky N, Joory KD, Srai SK, McArdle HJ, , 2001. Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro. Biochem J 356: 883889.[Crossref] [Google Scholar]
  44. Wang HZ, He YX, Yang CJ, Zhou W, Zou CG, , 2011. Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection. J Immunol 187: 64106416.[Crossref] [Google Scholar]
  45. Goyal J, McCleskey B, Adamski J, , 2013. Peering into the future: hepcidin testing. Am J Hematol 88: 976978.[Crossref] [Google Scholar]
  46. Cangemi G, Pistorio A, Miano M, Gattorno M, Acquila M, Bicocchi MP, Gastaldi R, Riccardi F, Gatti C, Fioredda F, Calvillo M, Melioli G, Martini A, Dufour C, , 2013. Diagnostic potential of hepcidin testing in pediatrics. Eur J Haematol 90: 323330.[Crossref] [Google Scholar]
  47. Pasricha SR, Atkinson SH, Armitage AE, Khandwala S, Veenemans J, Cox SE, Eddowes LA, Hayes T, Doherty CP, Demir AY, Tijhaar E, Verhoef H, Prentice AM, Drakesmith H, , 2014. Expression of the iron hormone hepcidin distinguishes different types of anemia in African children. Sci Transl Med 6: 235re3.[Crossref] [Google Scholar]
  48. Arezes J, Jung G, Gabayan V, Valore E, Ruchala P, Gulig PA, Ganz T, Nemeth E, Bulut Y, , 2015. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus . Cell Host Microbe 17: 4757.[Crossref] [Google Scholar]
  49. Ganz T, , 2003. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102: 783788.[Crossref] [Google Scholar]

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  • Received : 17 Mar 2016
  • Accepted : 06 May 2016
  • Published online : 05 Oct 2016

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