Abstract
BackgroundIron deficiency prevalence rates frequently exceed 50 % in young children in low-income countries. The World Health Organization (WHO) recommended universal supplementation of young children where anaemia rates are >40 %. However, large randomized trials have revealed that provision of iron to young children caused serious adverse effects because iron powerfully promotes microbial growth. Hepcidin – the master regulator of iron metabolism that integrates signals of infection and iron deficiency – offers the possibility of new solutions to diagnose and combat global iron deficiency. We aim to evaluate a hepcidin-screening-based iron supplementation intervention using hepcidin cut-offs designed to indicate that an individual requires iron, is safe to receive it and will absorb it.MethodsThe study is a proof-of-concept, three-arm, double blind, randomised controlled, prospective, parallel-group non-inferiority trial. Children will be randomised to receive, for a duration of 12 weeks, one of three multiple micronutrient powders (MNP) containing: A) 12 mg iron daily; B) 12 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not; C) 6 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not. The inclusion criteria are age 6-23 months, haemoglobin (Hb) concentration between 7 and 11 g/dL, z-scores for Height-for-Age, Weight-for-Age and Weight-for-Height > -3 SD and free of malaria. Hb concentration at 12 weeks will be used to test whether the screen-and-treat approaches are non-inferior to universal supplementation. Safety will be assessed using caregiver reports of infections, in vitro bacterial and P. falciparum growth assays and by determining the changes in the gut microbiota during the study period.DiscussionA screen-and-treat approach using hepcidin has the potential to make iron administration safer in areas with widespread infections. If this proof-of-concept study shows promising results the development of a point-of-care diagnostic test will be the next step.Trial registrationISRCTN07210906, 07/16/2014
Highlights
Iron deficiency prevalence rates frequently exceed 50 % in young children in low-income countries
Low cost iron supplements are efficacious in combatting Iron deficiency anaemia (IDA); in countries with anaemia rates of >40 %, World Health Organization (WHO) recommended universal supplementation of pregnant women and young children
In 2006, the Pemba Trial was prematurely terminated due to significant increases in the number of serious adverse outcomes and deaths in young children receiving iron-folic acid supplements [3]. This result was attributed to a malign interaction between iron, folic acid and malaria, and WHO revised its policy guidance for iron supplementation to a more cautionary approach in areas with endemic malaria [4]
Summary
Iron deficiency prevalence rates frequently exceed 50 % in young children in low-income countries. In 2006, the Pemba Trial was prematurely terminated due to significant increases in the number of serious adverse outcomes and deaths in young children receiving iron-folic acid supplements [3]. This result was attributed to a malign interaction between iron, folic acid and malaria (since a parallel trial in a non-malarious area of Nepal revealed no increase in adverse outcomes), and WHO revised its policy guidance for iron supplementation to a more cautionary approach in areas with endemic malaria [4]. There is an urgent need: a) to understand the pathways by which provision of iron favours pathogen virulence; and b) to use this knowledge to design safer modes for preventative and therapeutic provision of iron to infants and young children living in infectious environments in order to reduce infections and to allow maximal brain development
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