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A.E. Armitage et al.
tive investigations of cohorts that had been enrolled for other purposes, certain desirable variables were unavail- able: for example, hemoglobin data were not collected in VPM, and for both cohorts, we cannot exclude the possi- bility that participants took iron-containing supplements, breast-milk substitutes or fortified complementary diets during the study period since this information was not systematically collected. Furthermore, given the known impact of season on iron status in this region,21 it would have been desirable for enrollment to span at least one full year in each cohort. This was not the case in VPM, mean- ing the majority of VPM 12-month samples were taken in the dry season (Online Supplementary Table S2A), possibly explaining in part the apparent higher prevalence of ID in VPM at 12 months (Online Supplementary Table S3). Nevertheless, we believe our models are still of great value in characterizing predictors of hepcidin and ferritin decline in infancy.
Other limitations should also be considered. Self-report- ing of infectious episodes may have poor sensitivity and specificity for actual infection. Plasma biomarkers of inflammation may only capture current or recent inflam- matory insults; since previous inflammation may con- tribute to reduced iron status through chronically raised hepcidin, higher resolution tracking of inflammatory events between key time points would be desirable. Finally, whether the effects we describe are maintained in distinct LMIC infant populations, most notably regions with a high malarial burden, should be further investigat- ed.
Universal iron interventions for LMIC infants have proven to be relatively ineffective in reducing the burden of anemia, partly because only a proportion of anemia is
thought to be iron responsive.48 Iron absorption is facili- tated in the presence of low hepcidin concentrations, but inhibited when hepcidin is raised (such as during infec- tion/inflammation), potentially explaining why many infants respond poorly to iron interventions.20,49,50 Growth rate has previously been linked to reduced ferritin and iron deficiency,51-54 and has been shown to be predictive of hemoglobin response to iron supplementation;55 hepcidin suppression during rapid growth likely explains the latter effect. Since rapid growth predicts greater hepcidin sup- pression, our data suggest that simple weight monitoring could enable identification of rapidly growing infants to whom oral iron might be advantageously targeted.
Acknowledgments
The authors would like to thank the study participants and their families, the field teams and laboratory staff. We thank Rita Wegmüller for overseeing laboratory analyses at the MRC Keneba field station and for helpful discussions. The original VA study was funded by the UK Medical Research Council (MRC) (see below).
Funding
The original VPM study was funded by the Bill & Melinda Gates Foundation (BMGF). The current analyses were support- ed by BMGF (OPP 1055865) awarded to the MRC International Nutrition Group which is core-funded by MCA760-5QX00 from the MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement. AEA and HD receive core-funding through the MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford (MC_UU_12010/3).
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