Objective: To assess long-term developmental outcome in children who received iron-fortified or low-iron formula.
Design: Follow-up at 10 years of a randomized controlled trial (1991-1994) of 2 levels of formula iron. Examiners were masked to group assignment.
Setting: Urban areas around Santiago, Chile.
Participants: The original study enrolled healthy, full-term infants in community clinics; 835 completed the trial. At 10 years, 473 were assessed (56.6%).
Intervention: Iron-fortified (mean, 12.7 mg/L) or low-iron (mean, 2.3 mg/L) formula from 6 to 12 months.
Main outcome measures: We measured IQ, spatial memory, arithmetic achievement, visual-motor integration, visual perception, and motor functioning. We used covaried regression to compare iron-fortified and low-iron groups and considered hemoglobin level before randomization and sensitivity analyses to identify 6-month hemoglobin levels at which groups diverged in outcome.
Results: Compared with the low-iron group, the iron-fortified group scored lower on every 10-year outcome (significant for spatial memory and visual-motor integration; suggestive for IQ, arithmetic achievement, visual perception, and motor coordination; 1.4-4.6 points lower; effect sizes, 0.13-0.21). Children with high 6-month hemoglobin levels (> 12.8 g/dL [to convert to grams per liter, multiply by 10]) showed poorer outcome on these measures if they received iron-fortified formula (10.7-19.3 points lower; large effect sizes, 0.85-1.36); those with low hemoglobin levels (< 10.5 g/dL) showed better outcome (2.6-4.5 points higher; small but significant effects, 0.22-0.36). High hemoglobin levels represented 5.5% of the sample (n = 26) and low hemoglobin levels represented 18.4% (n = 87).
Conclusion: Long-term development may be adversely affected in infants with high hemoglobin levels who receive 12.7 mg/L of iron-fortified formula. Optimal amounts of iron in infant formula warrant further study.
Trial registration: ClinicalTrials.gov NCT01166451.