Abstract
BackgroundWe aimed to show the non-inferiority of home fortification with a daily dose of 3 mg iron in the form of iron as ferric sodium ethylenediaminetetraacetate (NaFeEDTA) compared with 12.5 mg iron as encapsulated ferrous fumarate in Kenyan children aged 12–36 months. In addition, we updated a recent meta-analysis to assess the efficacy of home fortification with iron-containing powders, with a view to examining diversity in trial results.MethodsWe gave chemoprevention by dihydroartemisinin-piperaquine, albendazole and praziquantel to 338 afebrile children with haemoglobin concentration ≥70 g/L. We randomly allocated them to daily home fortification for 30 days with either placebo, 3 mg iron as NaFeEDTA or 12.5 mg iron as encapsulated ferrous fumarate. We assessed haemoglobin concentration (primary outcome), plasma iron markers, plasma inflammation markers and Plasmodium infection in samples collected at baseline and after 30 days of intervention. We conducted a meta-analysis of randomised controlled trials in pre-school children to assess the effect of home fortification with iron-containing powders on anaemia and haemoglobin concentration at end of intervention.ResultsA total of 315 children completed the 30-day intervention period. At baseline, 66.9% of children had inflammation (plasma C-reactive protein concentration >5 mg/L or plasma α1-acid glycoprotein concentration >1.0 g/L); in those without inflammation, 42.5% were iron deficient. There was no evidence, either in per protocol analysis or intention-to-treat analysis, that home fortification with either of the iron interventions improved haemoglobin concentration, plasma ferritin concentration, plasma transferrin receptor concentration or erythrocyte zinc protoporphyrin-haem ratio. We also found no evidence of effect modification by iron status, anaemia status and inflammation status at baseline. In the meta-analysis, the effect on haemoglobin concentration was highly heterogeneous between trials (I2: 84.1%; p value for test of heterogeneity: <0.0001).ConclusionsIn this population, home fortification with either 3 mg iron as NaFeEDTA or 12.5 mg iron as encapsulated ferrous fumarate was insufficiently efficacious to assess non-inferiority of 3 mg iron as NaFeEDTA compared to 12.5 mg iron as encapsulated ferrous fumarate. Our finding of heterogeneity between trial results should stimulate subgroup analysis or meta-regression to identify population-specific factors that determine efficacy.Trial RegistrationThe trial was registered with ClinicalTrials.gov (NCT02073149) on 25 February 2014.
Highlights
We aimed to show the non-inferiority of home fortification with a daily dose of 3 mg iron in the form of iron as ferric sodium ethylenediaminetetraacetate (NaFeEDTA) compared with 12.5 mg iron as encapsulated ferrous fumarate in Kenyan children aged 12–36 months
We aimed to show non-inferiority of home fortification with 3 mg iron as NaFeEDTA compared with 12.5 mg iron as encapsulated ferrous fumarate in children aged 12–36 months under cover of chemoprevention against malaria
Subgroup analysis Because iron absorption is known to depend on iron status, we considered iron markers at baseline as potential modifiers for intervention effects on haemoglobin concentration and plasma ferritin concentration at the end of the 30-day intervention period
Summary
We aimed to show the non-inferiority of home fortification with a daily dose of 3 mg iron in the form of iron as ferric sodium ethylenediaminetetraacetate (NaFeEDTA) compared with 12.5 mg iron as encapsulated ferrous fumarate in Kenyan children aged 12–36 months. In 2011, the World Health Organisation (WHO) recommended daily home fortification with iron (12.5 mg as a ferrous salt) in populations where the prevalence of anaemia in children younger than 5 years of age is ≥20% [1], which covers most developing countries [2]. This recommendation was based on a meta-analysis of randomised controlled trials showing moderate quality evidence for an effect on anaemia and haemoglobin concentration [3]. The frequency and severity of such effects depend on dose and dosage schedule [10, 11], may be due to oxidative stress [12] and appear to be reduced when iron is taken with food
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