Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial

Community-based, cluster-randomized, placebo-controlled trial in the southern plains of Nepal. Preschool children aged 1 to 36 months in Sarlahi District were randomized to iron plus folic acid, iron plus folic acid plus zinc, or placebo and followed for mortality and morbidity outcomes.

Children were assigned to daily oral dispersible tablets containing iron 12.5 mg and folic acid 50 g, given either without zinc or with added zinc, and supplementation continued until age 36 months. Children aged 1 to 11 months received half a tablet; tablets were administered by study staff in blister packs, with younger children instructed to dissolve the tablet in clean water or breastmilk.

Daily iron plus folic acid, with or without zinc, did not reduce all-cause mortality versus placebo. All-cause mortality was similar across groups: HR 1.03 (95% CI 0.78 to 1.37) for iron plus folic acid and HR 1.00 (95% CI 0.74 to 1.34) for iron plus folic acid plus zinc. Neither regimen significantly reduced diarrhoea, dysentery, or acute lower respiratory infection, although effect estimates were generally in a protective direction. Iron status improved: haemoglobin increased by 0.71 g/L with iron plus folic acid and 0.59 g/L with iron plus folic acid plus zinc, and iron-deficiency anaemia was less common than in placebo, with relative prevalence 0.16 and 0.47, respectively.

Clinical event counts were modest for several outcomes, and morbidity analyses were based on subsamples rather than the full cohort. The trial stopped the iron-containing groups early, follow-up duration differed across arms, and some safety signals were based on very small numbers, limiting precision. The intervention also showed biomarker benefit without a corresponding mortality benefit, which limits clinical interpretation.