Daily home fortification with iron as ferrous fumarate versus NaFeEDTA

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%.This recommendation was based on a meta-analysis of randomised controlled trials showing moderate quality evidence for an effect on anaemia and haemoglobin concentration.However, several trials have shown, that supplementation or food fortification with iron at 12.5 mg can increase rates of hospital admissions as well as diarrheal and respiratory diseases.

A team of researchers in Kenya, with input from staff from MRC Unit The Gambia, conducted a randomised controlled trial in pre-school children to assess the effect of home fortification with iron-containing powders on anaemia and haemoglobin concentration at the end of the intervention.

Child taking fortified

Child taking fortified uji

The study aimed to show the non-inferiority of home fortification with a much smaller 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. The study was supported by Sight and Life, through a research grant and a personal grant to Emily Teshome Program Development Advisor (Nutrition, Food security, and Community health).

Surprisingly the findings showed 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. The investigators also found no evidence of effect modification by iron status, anaemia status and inflammation status at baseline.

Emily Teshome, Program Development Advisor (Nutrition, Food security and Community health)

Emily Teshome, Program Development Advisor (Nutrition, Food security, and Community health)

The researchers concluded that 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. The findings of heterogeneity between trial results should stimulate subgroup analysis or meta-regression to identify population-specific factors that determine efficacy.

When asked to comment on the findings, Prof Andrew Prentice, Nutrition Theme Leader said, “These disappointing results once again emphasise the huge challenges of correcting population iron deficiency. Based on recent data in The Gambia we strongly suspect that low-grade inflammation is blocking iron absorption through the actions of hepcidin”.

Speaking on the outcome of the results, Emily Teshome, said, “The cut-off points for inflammation markers used in our study have been used in previous studies but not validated in children, therefore, and as pointed out by Andrew, it is possible that a substantial blockage of iron absorption by elevated hepcidin concentration at lower inflammatory markers due to chronic infections occurred. This together with consumption of high amounts of iron-inhibiting factors in the food vehicles used for home fortification, and suboptimal adherence to daily Home-fortification with iron may explain the lack of efficacy in both iron interventions. These findings do necessitate a follow-up study to address anaemia in malaria endemic area”.

Read more about the findings on the BioMed Central website on https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0839-z

Acknowledgments

We thank the parents, children, staff and volunteers. In addition, we thank René Hampsink, Abbott Diagnostics, Hoofddorp, The Netherlands and Annet de Bats, Meander Medical Centre, Laboratory for Clinical Chemistry, Amersfoort, The Netherlands, for support in the biochemical analyses and Stephen Senn for statistical advice.

Authors

Emily M. Teshome, Pauline E. A. Andang’o, Victor Osoti, Sofie R. Terwel, Walter Otieno, Ayşe Y. Demir, Andrew M. Prentice and Hans Verhoef