Comparative Efficacy of Biweekly Preventive Supplementation, with Multiple Micronutrients and Iron Folic Acid (IFA) or IFA Alone, on Hemoglobin Concentrations and Anemia Prevalence in Children Aged 6 to 59 Months: A Randomized Controlled Trial in Rural India

Background: Anemia remains a significant public health challenge in India, affecting over two-thirds of children under five, despite longstanding national programs. Biweekly iron and folic acid (IFA) supplementation is recommended under the Anemia Mukt Bharat national program, but improvements in prevalence rates have been limited. Evidence suggests that multiple micronutrient (MMN) deficiencies may also contribute to the presence of anemia. However, the incremental benefit of MMN supplementation in addition to IFA remains unclear. Methods: In this individually randomized, open-label trial conducted in rural Haryana, India, children aged 6–59 months were randomized (1:1) to receive biweekly supplementation with either MMN plus IFA (intervention), or IFA alone (control) for 100 doses over 50 weeks. Primary outcomes assessed were mean hemoglobin concentration and anemia prevalence, defined as Hb <10·5 g/dL for children <24 months, and <11 g/dL for those ≥24 months. Secondary outcomes assessed included serum concentrations of ferritin, soluble transferrin receptor, vitamin B12, folate, and zinc. Analyses followed the intention-to-treat principle. The trial was registered with the Clinical Trial Registry of India (#CTRI/2020/10/028299). Findings: Among 1,300 children randomized (648 intervention, 652 control), adherence to protocol exceeded 75% in both groups. At the endline, the mean hemoglobin was slightly higher in the intervention group (adjusted mean difference, MD 0·12 g/dL; 95% CI: 0·00 to 0·25). The prevalence of anemia was lower in the intervention group (17·6%) than in the control group (24·0%), with an adjusted relative risk of 0·72 (95% CI: 0·58 to 0·90). No significant differences were observed in serum biomarkers of iron status, or other micronutrients between the 2 groups. Interpretation: Biweekly supplementation with MMN plus IFA resulted in a modest increase in hemoglobin levels, and a relative reduction in anemia prevalence compared to IFA alone, particularly in older children. However, the lack of improvement in biochemical markers, and the small magnitude of change seen in hemoglobin concentrations suggest that the observed reduction in prevalence of anemia may be driven by shifts near diagnostic thresholds, rather than meaningful physiological benefits. In settings where adherence to IFA supplementation is high, addition of MMN may not offer substantial added value.