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-randomised, double-masked, placebo-controlled, 2×2 factorial trial in southern Nepal (NNIPS-4). Participants were children aged 1–36 months living in the NNIPS catchment area; four treatment groups: iron+folic acid; zinc alone; iron+folic acid+zinc; placebo; randomised by sector; double-masked.

Daily oral dispersible tablet given to children up to 36 months; half-dose for ages 1–11 months. Four regimens: (i) iron 12.5 mg + folic acid 50 µg; (ii) zinc alone 10 mg; (iii) iron 12.5 mg + folic acid 50 µg + zinc 10 mg; (iv) placebo. For 1–11 months, half-dose (iron 6.25 mg + 25 µg; zinc 5 mg in regimens including zinc). Tablets packaged in blister packs of seven; older children swallow the tablet; younger children dissolve the tablet in clean water or breastmilk. Administered by field staff during home visits. Duration: from enrollment until age 36 months; iron and folic acid–containing groups stopped early in November 2003.

Primary outcome: all-cause mortality showed no difference across groups (iron+folic acid vs placebo HR 1.03, 95% CI 0.78–1.37; iron+folic acid+zinc vs placebo HR 1.00, 95% CI 0.74–1.34). There were no significant differences in diarrhoea, dysentery, or acute respiratory infections between groups; most relative risks favored the active regimens but were not statistically significant. Iron and folic acid supplementation improved iron status after ~12 months ( haemoglobin higher; serum ferritin higher; severe anaemia reduced from ~6% in placebo to ~1% with iron+folic acid and ~3% with iron+folic acid+zinc; iron-deficiency anaemia reduced by ~84% with iron+folic acid and ~53% with iron+folic acid+zinc vs placebo). Adding zinc to iron+folic acid did not confer mortality benefit and may reduce iron absorption. No strong interactions by sex or ethnicity. Routine iron+folic acid supplementation did not reduce mortality in this setting, but potential developmental benefits may warrant consideration in contexts with different disease patterns (e.g., Zanzibar showed adverse effects).

Low overall mortality reduced statistical power to detect mortality differences; iron+folic acid groups were stopped early in 2003, limiting follow-up; cause-specific mortality analyses had small event numbers; morbidity outcomes relied on maternal reports and were based on two subsamples; some participant loss to follow-up and taste-related refusals may affect adherence estimates; generalizability is limited to similar populations.