"Children who entered the trial with high hemoglobin levels, suggesting iron sufficiency, showed poorer outcome if they received iron-fortified formula.... There was an 11-point difference in IQ scores [between the low-iron and high-iron groups]," Dr. Lozoff told Medscape Pediatrics. "This was a significant difference."

"The randomized trial design suggests a causal relation between the 12 mg/L iron-fortified formula and poorer developmental outcome at 10 years," she noted. "The results raise the possibility that long-term development is adversely affected in iron-sufficient infants who receive formula fortified with iron at the level commonly used in the United States."

Dr. Lozoff emphasized that the findings were for infants with adequate nutrition at baseline. For poor infants, who may receive primarily cow's milk, "a notoriously poor source of iron...the outcomes may be different and likely favor iron-fortified formula," she stressed.

"I think it is important to understand the definition of 'low-iron' and 'iron-fortified' formulas. These are FDA definitions," cautioned Michael K. Georgieff, MD, professor of pediatrics and child development and director of the Center for Neurobehavioral Development at the University of Minnesota School of Medicine, Minneapolis, in an interview with Medscape Pediatrics after Dr. Lozoff's presentation.

"Any formula with a content less than 6.7 mg/L of iron is considered 'low iron.' Originally, many of the unfortified formulas had as little as 1.5 mg iron/L, and this caused extremely high rates of iron-deficiency anemia and its attendant cognitive sequelae. In...the 1960s...an all-time low for breastfeeding rates, infants were fed predominantly formula and were converted to whole milk at 6 months, which put them into an even more negative iron balance," Dr. Georgieff commented.

"When the formula industry started to make iron-fortified formula, they added enough to not only keep the infant sufficient from 0 to 6 months (which can be achieved with 4 – 7 mg/L) but enough to 'tide the child over' to 12 months, until they were eating more of a meat-based diet rich in iron. When [Dr. Lozoff] did her study in Chile in the early 1990s, these 2 types of formulas were still prevalent down there," he continued.

"Given that the [American Academy of Pediatrics] and other organizations now advocate breast-feeding for 12 months, and using formula instead of whole milk after 6 months for those that are not breast-feeding, the supplementation strategy of the 1960s seems archaic," Dr. Georgieff said.

"[Dr. Lozoff's] study...is striking because it has a lot of children in it. Moreover, the important finding is that the highly supplemented formula was associated with poorer outcome only in the children who were the most iron-sufficient to start with. Those with more normal iron status had no adverse effect and those with low iron status benefited from the high-iron formula.

"Most of us in the iron field would be comfortable with formulas having less iron in them, more in the range of 4 to 7 mg/L, and that there may be potential toxicity in certain groups consuming a high-iron formula," Dr. Georgieff said.

"We were quite surprised by our findings," Dr. Lozoff noted. "I have worked all of my life on the opposite hypothesis — that iron supplementation leads to better infant health. Iron supplementation is a concern on a global scale, but not in our country," she said.

Dr. Lozoff and Dr. Georgieff have disclosed no relevant financial relationships.

PAS 2008: Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting: Poster 5340.2. Presented May 8, 2008.

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