Daily home fortification with iron as ferrous fumarate versus NaFeEDTA: a randomised, placebo-controlled, non-inferiority trial in Kenyan children

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 α 1-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 (I 2: 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0839-z) contains supplementary material, which is available to authorized users.

Micronutrient powders to combat anaemia in young children: do they work?

“…Our meta-analysis suggested a small gain in haemoglobin concentration in most trials, indicating that point-of-use fortification with iron-containing micronutrient powders provides some benefit across different settings [ 2 ]. On average, in an arbitrarily selected setting, and with an adherence as obtained under trial conditions, one may expect an increase in haemoglobin concentration by only 3.9 g/L, with the upper limit of the 95% CI virtually excluding an effect beyond 5.5 g/L; the attenuated effect that is likely to be achieved under real-world conditions is even lower.…”

“…In a recent placebo-controlled trial among Kenyan children aged 12–36 months, we found no evidence that daily point-of-use fortification with either 3 mg iron as NaFeEDTA or 12.5 mg iron as ferrous fumarate was efficacious in improving haemoglobin concentration or plasma iron markers [ 2 ]. As discussed in a commentary [ 3 ], the decline in anaemia prevalence over time that we observed in all intervention groups may have been due to premedication with anti-malarial and anti-helminth medication at baseline, or due to the vitamin A or zinc content in the fortification powders.…”

Anaemia, vitamin-A deficiency, anthropometric nutritional status and associated factors among young school children in Kodzobi, Ghana, a peri-urban community

“…Although nutritional deficiencies (like VAD), hookworm infection, and haemoglobinopathies [17,18] may predispose children to the development of anaemia, evidence suggests that, malaria is one of the most important factors [16]. Other predisposing factors include increased pathogenic profile in the gut, inflammations, inhibitory food compounds and infections [19,20]. Ghanaian school children are confronted with adverse effect of anaemia: low physical activity and low attention span, which can lead to poor academic achievement.…”

Adherence to home fortification with micronutrient powders in Kenyan pre-school children: self-reporting and sachet counts compared to an electronic monitoring device

“…The basis of this recommendation was a meta-analysis of randomised controlled trials showing moderate quality evidence for an effect on anaemia and haemoglobin concentration [ 2 ]. In a recent placebo-controlled trial, however, we failed to find effects of home fortification with iron-containing micronutrient powders on either anaemia or haemoglobin concentration [ 3 ]. In addition, in an updated meta-analysis, we showed that the magnitude of the effect on haemoglobin concentration varied between trials [ 3 ].…”

“…In a recent placebo-controlled trial, however, we failed to find effects of home fortification with iron-containing micronutrient powders on either anaemia or haemoglobin concentration [ 3 ]. In addition, in an updated meta-analysis, we showed that the magnitude of the effect on haemoglobin concentration varied between trials [ 3 ]. Such variability in trial results may be due in part to population differences in adherence to home fortification.…”