Infants with high hemoglobin concentration who received iron-fortified formula have poorer long-term developmental outcomes

"The high prevalence of iron deficiency in infancy has led to routine iron fortification of infant formula and foods in many countries," the authors write as background information in the study. "These interventions help reduce iron-deficiency anemia and iron deficiency without anemia. However, the optimal amount of iron in such products, especially infant formula, is debated."

To assess long-term developmental outcomes in children who received iron-fortified formula, Betsy Lozoff, M.D., of the University of Michigan, Ann Arbor, and colleagues conducted a 10-year follow-up of children originally enrolled in a randomized controlled trial who were receiving either iron-fortified formula or a low-iron formula. The original study enrolled 835 healthy, full-term infants at community clinics in urban areas around Santiago, Chile, who were randomized at six months of age to receive formula with or without iron. The 10-year assessment conducted in this study included 473 (56.5 percent) children and measured IQ, spatial memory, arithmetic achievement, visual-motor integration (VMI), visual perception and motor functioning.

At the 10-year follow-up, 244 (56.7 percent) children in the iron-fortified group and 229 (56.5 percent) children in the low-iron group were reassessed. No statistically significant differences were found in iron status at 10 years, and only one child had iron-deficiency anemia. Nine infants (4.1 percent) and 17 (6.9 percent) in the iron-fortified group met criteria for iron deficiency. Compared to the low-iron group, the iron-fortified group scored lower on every 10-year outcome measured. Of the seven tests administered at the 10-year follow-up, two (spatial memory and VMI) showed statistically significant lower scores in the iron-fortified group compared to the low-iron group, and four (IQ, visual perception, motor coordination and arithmetic achievement) showed suggestive trends that did not reach statistical significance.

The authors also found that children with the highest hemoglobin levels at 6-months of age had lower 10-year scores if they had received the iron-fortified formula, but those with the lowest 6-month hemoglobin levels had higher scores.

"In conclusion, this study indicates poorer long-term developmental outcome in infants with high hemoglobin concentrations who received formula fortified with iron at levels currently used in the United States," the authors write. "Optimal amounts of iron in infant formula warrant further study."

Editorial: Iron in Infancy and Long-term Development

In an accompanying editorial, Parul Christian, Dr.P.H., M.Sc., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, writes that the importance of the study by Lozoff et al, "lies in its evaluation of the long-term developmental outcomes of an early-infancy iron intervention."

"The relationship between iron deficiency and iron deficiency anemia and developmental outcomes in children has been controversial, and clear causal evidence for a link found lacking when existing trials have been carefully evaluated," notes Dr. Christian. "Lozoff et al have made significant contributions to establishing this link and demonstrated in longitudinal observational studies that iron deficiency in early life can result in cognitive and motor impairments that may be irreversible."

Dr. Christian also notes, however, that, "Caution is needed in generalizing the results of the follow-up study by Lozoff et al, which stands, as yet, alone in showing small-sized negative consequences on developmental outcomes among iron-sufficient children exposed to iron-fortified vs low-iron formula during infancy."

"Whether iron deficiency in infancy, manifest largely due to deficiency in utero, can be overcome with supplementation during infancy for improving central nervous system development and function needs to be further examined in rigorous studies of short and long duration," she concludes.