Hemoglobin outcomes associated with supervised therapeutic iron or preventive multiple micronutrient powder supplementation in high-altitude Peruvian infants: A real-world natural experiment

BACKGROUND: In Peru, legally mandated universal micronutrient supplementation policies preclude randomized trials. OBJECTIVE: To evaluate hemoglobin (Hb) outcomes associated with enhanced follow-up of therapeutic iron or preventive multiple micronutrient powder (MNP) supplementation among high-altitude infants within a real-world natural experiment. METHODS: This observational study leveraged a policy-driven natural experiment to analyze two population-based cohorts of 317 infants aged 6-12 months from Puno, Peru (3,832 m), evaluated before and after implementation of strict follow-up. According to national guidelines, infants with anemia received therapeutic iron syrup (ferrous sulfate or iron polymaltose), while non-anemic infants received preventive MNP. Supplements were provided monthly for six months. Hemoglobin was measured at baseline and follow-up and adjusted for altitude using the WHO 2024 criteria. Adequate Hb response was defined as an increase ≥1 g/dL. Multivariable regression models assessed factors associated with hemoglobin response. RESULTS: Overall, 14.8% of infants achieved an Hb increase ≥1 g/dL (18.7% vs. 11.8% in the strict and non-strict follow-up groups, respectively). Among non-anemic infants at baseline, adequate Hb response was more frequent under strict follow-up (8.3% vs. 2.7%). In the prespecified primary adjusted model, strict follow-up was associated with higher odds of achieving an adequate Hb response (aOR 3.53; 95% CI 1.40-8.84), compared with the crude estimate (OR 2.45; 95% CI 1.30-4.63). In sensitivity analyses incorporating additional socioeconomic, nutritional, and program-related covariates, the association was attenuated (aOR 2.18; 95% CI 0.53-8.99). When evaluated as a continuous outcome, strict follow-up was associated with greater hemoglobin increases (adjusted mean difference 0.74 g/dL; 95% CI 0.23-1.25). At six months, altitude-adjusted anemia prevalence was lower in the strict follow-up group than in the non-strict group (25.2% vs. 38.2%, p = 0.019). Baseline anemia and older age were independently associated with larger hemoglobin gains. CONCLUSIONS: Strict follow-up was associated with greater increases in hemoglobin concentration and lower altitude-adjusted anemia prevalence at follow-up. Although anemia prevalence was lower among infants receiving strict follow-up, residual anemia remained common after six months of supplementation. These findings suggest that enhanced programmatic follow-up may improve hematologic outcomes under routine public health conditions, while additional factors contributing to anemia persistence warrant further investigation.