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

Elizabeth B. Brickley Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

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Natasha Spottiswoode Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York.

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Edward Kabyemela Muheza Designated District Hospital, Muheza, Tanzania.

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Robert Morrison Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.

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Jonathan D. Kurtis Rhode Island Hospital, Department of Pathology and Laboratory Medicine, Brown University Medical School, Providence, Rhode Island.

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Angela M. Wood Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

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Hal Drakesmith Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

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Michal Fried Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.

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Patrick E. Duffy Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.

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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 (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.

Author Notes

* Address correspondence to Patrick E. Duffy, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook I, Room 1111, 5640 Fishers Lane, Rockville, MD 20852. E-mail: patrick.duffy@nih.gov
† These authors contributed equally to this work.

Financial support: This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (http://www.niaid.nih.gov/), the Bill & Melinda Gates Foundation (grant number 29202, http://www.gatesfoundation.org/), the Grand Challenges in Global Health Initiative (grant number 1364, http://grandchallenges.org/), the National Institutes of Health Fogarty International Center (grant number D43 TW005509, http://www.fic.nih.gov/), and the National Institutes of Health (grant number R01A152059 to Patrick E. Duffy). During the duration of study, Elizabeth B. Brickley and Natasha Spottiswoode were supported by the National Institutes of Health Oxford Cambridge Scholars Program (http://oxcam.gpp.nih.gov/). Hal Drakesmith is supported by the Medical Research Council, United Kingdom (http://www.mrc.ac.uk/).

Authors' addresses: Elizabeth B. Brickley, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, and Department of Epidemiology, Dartmouth College Geisel School of Medicine, Lebanon, NH, E-mail: elizabeth.b.brickley@dartmouth.edu. Natasha Spottiswoode, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom, and Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, E-mail: nns2115@cumc.columbia.edu. Edward Kabyemela, Mother-Offspring Malaria Studies Project, Muheza Designated District Hospital, Muheza, Tanzania, E-mail: earkabyemela@yahoo.com. Robert Morrison, Michal Fried, and Patrick E. Duffy, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, E-mails: bob.morrison@cidresearch.org, michal.fried@nih.gov, and patrick.duffy@nih.gov. Jonathan D. Kurtis, Center for International Health Research, Rhode Island Hospital, Providence, RI, E-mail: jonathan_kurtis@brown.edu. Angela M. Wood, Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, E-mail: amw79@medschl.cam.ac.uk. Hal Drakesmith, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom, E-mail: alexander.drakesmith@ndm.ox.ac.uk.

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