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

Abstract

Background: 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 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.

Methods: We 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.

Results: A 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).

Conclusions: In 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 registration: The trial was registered with ClinicalTrials.gov ( NCT02073149 ) on 25 February 2014.

Keywords: Anaemia; Child; Ferric sodium EDTA; Home fortification; Iron; Meta-analysis; Non-inferiority; Pre-school.

Fig. 1

Participant flow through the trial. *Sample sizes below number indicated are due to missing values, which varied by outcome. In the intention-to-treat analysis, missing values were replaced by multiple imputation

Fig. 2

EDTA intake at daily home fortification levels of 3 mg iron as NaFeEDTA, at baseline (a) and at 30 days after start of intervention (b). The acceptable daily intake (ADI) for EDTA is <1.9 mg/kg body weight

Fig. 3

Effect of interventions on haemoglobin concentration (g/L) at 30 days after start of intervention, by subgroups of iron status and haemoglobin concentration class at baseline. Inflammation was defined to be absent when plasma C-reactive protein (CRP) concentration was ≤5 mg/L and plasma α ₁-acid glycoprotein concentration was ≤1.0 g/L, and present when either plasma CRP concentration was >5 mg/L or plasma α ₁-acid glycoprotein concentration was >1.0 g/L. Group means were obtained by one-way ANOVA. Intervention effects were adjusted for stratified block design as well as plasma concentrations of ferritin and soluble transferrin receptor at baseline (both continuous variables). The p values indicate the two-sided probability that group effects are as different as observed or more extreme when assuming that they are identical

Fig. 4

Effect of interventions on plasma ferritin concentration (μg/L) at 30 days after start of intervention, by subgroups of iron status and haemoglobin concentration class at baseline. Inflammation was defined to be absent when plasma CRP concentration was ≤5 mg/L and plasma α ₁-acid glycoprotein concentration was ≤1.0 g/L, and present when either plasma CRP concentration was >5 mg/L or plasma α ₁-acid glycoprotein concentration was >1.0 g/L. Group geometric means were obtained by exponentiation of results of one-way ANOVA. Intervention effects were adjusted for stratified block design as well as plasma concentrations of ferritin and soluble transferrin receptor at baseline (both log-transformed continuous variables). Exponentiation of group differences with log-transformed outcomes resulted in associations being expressed as relative differences. GSD geometric standard deviation. The p values indicate the two-sided probability that group effects are as different as observed or more extreme when assuming that they are identical