Comparative efficacy of biweekly preventive supplementation, with multiple micronutrients and iron folic acid or iron folic acid alone, on hemoglobin concentrations and anemia prevalence in children aged 6–59 months: a randomized controlled trial in rural India

Background: Anemia affects more than two-thirds of children aged <5 y in India, despite biweekly iron folic acid (IFA) supplementation under the Anemia Mukt Bharat national program. Multiple micronutrient (MMN) deficiencies may also contribute to the presence of anemia, but the incremental benefit of MMN supplementation in addition to IFA remains unclear. Objectives: We aimed to compare the efficacy of biweekly preventive supplementation with MMNs plus IFA compared with IFA alone on hemoglobin concentrations and prevalence of anemia in children aged 6–59 mo. Methods: In this individually randomized, open-label trial, eligible children received biweekly supplementation with either MMN plus IFA (intervention) or IFA alone (control) for 100 doses over 50 wk. Primary outcomes were mean hemoglobin concentration and anemia prevalence. Secondary outcomes included serum ferritin, soluble transferrin receptor, vitamin B12, folate, and zinc. Results: Among 1300 children enrolled (648 intervention and 652 control), supplementation compliance exceeded 75%. At the endline, the mean hemoglobin was slightly higher in the intervention group [adjusted mean difference, 0.12 g/dL; 95% confidence interval (CI): 0.00, 0.25]. The prevalence of anemia was 17.6% in the intervention group and 24.0% in the control group (adjusted relative risk, 0.72; 95% CI: 0.58, 0.90). No significant differences were observed in serum biomarkers of iron status or other micronutrients. Conclusions: Biweekly supplementation with MMN plus IFA resulted in a modest increase in hemoglobin concentrations and a relative reduction in anemia prevalence compared with IFA alone, particularly in older children. Lack of improvement in biochemical markers and a small rise in hemoglobin concentrations suggest that a reduction in the prevalence of anemia may be driven by shifts near diagnostic thresholds, rather than meaningful physiological benefits. MMN adds minimal value where IFA adherence is already high.The study was registered at Clinical Trial Registry of India as #CTRI/2020/10/028299 (https://ctri.nic.in/Clinicaltrials/login.php).