Effectiveness of intermittent iron and high-dose vitamin A supplementation on cognitive development of school children in southern Ethiopia: a randomized placebo-controlled trial

Background: Iron is an essential mineral whose deficiency results in cognitive alteration, impaired emotional behaviors, and altered myelination and neurotransmission. In animal models, it has been shown that vitamin A (VA) could affect cognition. Objectives: The study aimed to evaluate the effectiveness of intermittent iron and VA supplementation on cognitive development of schoolchildren, and to assess the interaction between these supplementations. Methods: Considering a 2 x 2 factorial design, 504 children were randomly assigned to 1 of the 4 arms: placebo VA and placebo iron supplement; highdose vitamin VA and placebo iron supplement; iron supplement and placebo VA; and iron and high -dose vitamin VA supplements. Cognitive development was assessed using Raven's Coloured Progressive Matrices, digit span, Tower of London, and visual search tasks. Results: The mean [+/- standard deviation (SD)] age of the enrolled children was 9.6 (+/- 1.6) y. One -fifth of the children had iron deficiency or anemia, whereas 2.9%, 3.9%, and 12.1% of children had low iron stores, iron deficiency anemia, and VA deficiency, respectively. Intermittent iron supplementation did not result in any significant improvement of children's cognitive development and had a negative effect on the performance index of the visual search task compared with placebo (-0.17 SD, 95% confidence interval: -0.32, -0.02). Effects were evident among children with stunting, thinness, or children coming from understimulating home environments. High -dose VA supplementation resulted in a significant improvement of digit span z -score with a mean difference of 0.30 SD (95% confidence interval: 0.14, 0.46) compared with placebo VA. VA had a more beneficial impact for girls, children infected with helminths, and those from food secure households. Conclusion: In a population where the prevalence of iron deficiency is low, intermittent iron supplementation did not have any or negative effect on the child's cognitive development outcomes. Conversely, VA supplementation improved the child's working memory. Trial registration number: The study is registered at clinicaltrials.gov as NCT04137354 (https://clinicaltrials.gov/study/NCT04137354).