Iron-Fortified Formula Associated With Poorer Developmental Outcomes

Infants with high hemoglobin levels who received iron-fortified infant formula had poorer long-term developmental outcomes than those who got a low-iron formula, based on 10-year follow-up data published online Nov. 7 in Archives of Pediatrics & Adolescent Medicine.

Manufacturers routinely fortify infant formula and foods with iron (4-7 mg/L in Europe and 12-13 mg/L in the United States) to reduce the prevalence of iron-deficiency anemia and iron deficiency without anemia. But the optimal amount of iron in such products, especially infant formula, is not known. And the question of whether providing iron to infants whose levels are already sufficient leads to poorer growth, increased morbidity, and effects on the developing brain is also unresolved.

To assess long-term developmental outcomes in children who received iron-fortified formula, Dr. Betsy Lozoff of the University of Michigan, Ann Arbor, and her colleagues conducted a 10-year follow-up of children who participated in a randomized controlled trial in which they received iron-fortified formula or low-iron formula (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.197]).

Sarah L.G. Breeden/Elsevier Global Medical News

In the original study (1991-1994), researchers randomized 1,120 healthy, term infants in urban areas around Santiago, Chile, to receive low-iron or iron-fortified formula (2.3 mg/L and 12.7 mg/L) between ages 6 and 12 months; 835 completed the study. At the 10-year follow-up, Dr. Lozoff’s team reassessed 473 children (57% of the original sample). Of these children, 244 had received iron-fortified formula and 229 had received low-iron formula.

The researchers determined that 9 infants (4.1% percent) who received low-iron formula and 17 (6.9%) who got the iron-fortified formula were iron deficient (two or more abnormal iron measures). At 10 years, however, there were no statistically significant differences in iron status between the two groups, and only one child had iron-deficiency anemia.

Dr. Lozoff’s team also measured IQ, spatial memory, arithmetic achievement, visual-motor integration (VMI), visual perception and motor functioning. Scores were similar between both groups at the end of the original randomized controlled trial, but in this study, children who received the higher level of iron-fortified formula scored 1.4-4.6 points lower on every outcome measured. This was statistically significant on the spatial memory and VMI tests.

Another finding: Children who had the highest hemoglobin levels (more than 12.8 g/dL) at age 6 months and received iron-fortified formula scored 10.7-19.3 points lower on these measures than did those with low hemoglobin levels (less than 10.5 g/dL), indicating a poorer long-term developmental outcome. Those with low hemoglobin levels scored 2.6-4.5 points higher.

These findings may be due to the adverse effects of supplemental iron on neurodevelopmental outcome. "This explanation presumes children in our study with high hemoglobin levels in infancy were iron sufficient," Dr. Lozoff and her colleagues said. "However, high hemoglobin levels can be due to other factors, such as chronic hypoxia. Without a panel of iron measures for all infants before randomization, the iron status of those with high hemoglobin levels in our study is uncertain."

"The recommendations of universal iron supplementation might need reconsideration."

Other factors might also be at work, the investigators said. For example, this sample included more female infants and more maternal smoking among infants with high hemoglobin levels. Maternal smoking, in particular, has been associated with poorer developmental outcomes, and hemoglobin levels can be elevated because of chronic mild hypoxia.

Possible limitations to this study include the small number of children (11-13 per formula group, or 5% of the sample) with extremely high hemoglobin levels; high attrition (25% between 6 and 12 months of age and 43% between 12 months and 10 years of age); use of hemoglobin level as the only iron measure for all infants before randomization; and the fact that randomization was not stratified by iron status. In addition, there was a lack of data on maternal smoking at 10 years or smoking habits of other household members at any point; exposure could affect long-term outcome.

More studies are needed, Dr. Lozoff and her colleagues said. Meanwhile, there are several potential implications of these results.

"Hemoglobin levels (and/or other measures of iron status) might need to be tested in early infancy before iron supplementation," the researchers said. "The recommendations of universal iron supplementation might need reconsideration. In any case, the optimal level of iron in infant formula warrants further study to avoid giving more iron than infants need."

Dr. Lozoff and her colleagues said they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.

Infants with high hemoglobin levels who received iron-fortified infant formula had poorer long-term developmental outcomes than those who got a low-iron formula, based on 10-year follow-up data published online Nov. 7 in Archives of Pediatrics & Adolescent Medicine.

Manufacturers routinely fortify infant formula and foods with iron (4-7 mg/L in Europe and 12-13 mg/L in the United States) to reduce the prevalence of iron-deficiency anemia and iron deficiency without anemia. But the optimal amount of iron in such products, especially infant formula, is not known. And the question of whether providing iron to infants whose levels are already sufficient leads to poorer growth, increased morbidity, and effects on the developing brain is also unresolved.

To assess long-term developmental outcomes in children who received iron-fortified formula, Dr. Betsy Lozoff of the University of Michigan, Ann Arbor, and her colleagues conducted a 10-year follow-up of children who participated in a randomized controlled trial in which they received iron-fortified formula or low-iron formula (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.197]).

Sarah L.G. Breeden/Elsevier Global Medical News

In the original study (1991-1994), researchers randomized 1,120 healthy, term infants in urban areas around Santiago, Chile, to receive low-iron or iron-fortified formula (2.3 mg/L and 12.7 mg/L) between ages 6 and 12 months; 835 completed the study. At the 10-year follow-up, Dr. Lozoff’s team reassessed 473 children (57% of the original sample). Of these children, 244 had received iron-fortified formula and 229 had received low-iron formula.

The researchers determined that 9 infants (4.1% percent) who received low-iron formula and 17 (6.9%) who got the iron-fortified formula were iron deficient (two or more abnormal iron measures). At 10 years, however, there were no statistically significant differences in iron status between the two groups, and only one child had iron-deficiency anemia.

Dr. Lozoff’s team also measured IQ, spatial memory, arithmetic achievement, visual-motor integration (VMI), visual perception and motor functioning. Scores were similar between both groups at the end of the original randomized controlled trial, but in this study, children who received the higher level of iron-fortified formula scored 1.4-4.6 points lower on every outcome measured. This was statistically significant on the spatial memory and VMI tests.

Another finding: Children who had the highest hemoglobin levels (more than 12.8 g/dL) at age 6 months and received iron-fortified formula scored 10.7-19.3 points lower on these measures than did those with low hemoglobin levels (less than 10.5 g/dL), indicating a poorer long-term developmental outcome. Those with low hemoglobin levels scored 2.6-4.5 points higher.

These findings may be due to the adverse effects of supplemental iron on neurodevelopmental outcome. "This explanation presumes children in our study with high hemoglobin levels in infancy were iron sufficient," Dr. Lozoff and her colleagues said. "However, high hemoglobin levels can be due to other factors, such as chronic hypoxia. Without a panel of iron measures for all infants before randomization, the iron status of those with high hemoglobin levels in our study is uncertain."

"The recommendations of universal iron supplementation might need reconsideration."

Other factors might also be at work, the investigators said. For example, this sample included more female infants and more maternal smoking among infants with high hemoglobin levels. Maternal smoking, in particular, has been associated with poorer developmental outcomes, and hemoglobin levels can be elevated because of chronic mild hypoxia.

Possible limitations to this study include the small number of children (11-13 per formula group, or 5% of the sample) with extremely high hemoglobin levels; high attrition (25% between 6 and 12 months of age and 43% between 12 months and 10 years of age); use of hemoglobin level as the only iron measure for all infants before randomization; and the fact that randomization was not stratified by iron status. In addition, there was a lack of data on maternal smoking at 10 years or smoking habits of other household members at any point; exposure could affect long-term outcome.

More studies are needed, Dr. Lozoff and her colleagues said. Meanwhile, there are several potential implications of these results.

"Hemoglobin levels (and/or other measures of iron status) might need to be tested in early infancy before iron supplementation," the researchers said. "The recommendations of universal iron supplementation might need reconsideration. In any case, the optimal level of iron in infant formula warrants further study to avoid giving more iron than infants need."

Dr. Lozoff and her colleagues said they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.

Infants with high hemoglobin levels who received iron-fortified infant formula had poorer long-term developmental outcomes than those who got a low-iron formula, based on 10-year follow-up data published online Nov. 7 in Archives of Pediatrics & Adolescent Medicine.

Manufacturers routinely fortify infant formula and foods with iron (4-7 mg/L in Europe and 12-13 mg/L in the United States) to reduce the prevalence of iron-deficiency anemia and iron deficiency without anemia. But the optimal amount of iron in such products, especially infant formula, is not known. And the question of whether providing iron to infants whose levels are already sufficient leads to poorer growth, increased morbidity, and effects on the developing brain is also unresolved.

To assess long-term developmental outcomes in children who received iron-fortified formula, Dr. Betsy Lozoff of the University of Michigan, Ann Arbor, and her colleagues conducted a 10-year follow-up of children who participated in a randomized controlled trial in which they received iron-fortified formula or low-iron formula (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.197]).

Sarah L.G. Breeden/Elsevier Global Medical News

In the original study (1991-1994), researchers randomized 1,120 healthy, term infants in urban areas around Santiago, Chile, to receive low-iron or iron-fortified formula (2.3 mg/L and 12.7 mg/L) between ages 6 and 12 months; 835 completed the study. At the 10-year follow-up, Dr. Lozoff’s team reassessed 473 children (57% of the original sample). Of these children, 244 had received iron-fortified formula and 229 had received low-iron formula.

The researchers determined that 9 infants (4.1% percent) who received low-iron formula and 17 (6.9%) who got the iron-fortified formula were iron deficient (two or more abnormal iron measures). At 10 years, however, there were no statistically significant differences in iron status between the two groups, and only one child had iron-deficiency anemia.

Dr. Lozoff’s team also measured IQ, spatial memory, arithmetic achievement, visual-motor integration (VMI), visual perception and motor functioning. Scores were similar between both groups at the end of the original randomized controlled trial, but in this study, children who received the higher level of iron-fortified formula scored 1.4-4.6 points lower on every outcome measured. This was statistically significant on the spatial memory and VMI tests.

Another finding: Children who had the highest hemoglobin levels (more than 12.8 g/dL) at age 6 months and received iron-fortified formula scored 10.7-19.3 points lower on these measures than did those with low hemoglobin levels (less than 10.5 g/dL), indicating a poorer long-term developmental outcome. Those with low hemoglobin levels scored 2.6-4.5 points higher.

These findings may be due to the adverse effects of supplemental iron on neurodevelopmental outcome. "This explanation presumes children in our study with high hemoglobin levels in infancy were iron sufficient," Dr. Lozoff and her colleagues said. "However, high hemoglobin levels can be due to other factors, such as chronic hypoxia. Without a panel of iron measures for all infants before randomization, the iron status of those with high hemoglobin levels in our study is uncertain."

"The recommendations of universal iron supplementation might need reconsideration."

Other factors might also be at work, the investigators said. For example, this sample included more female infants and more maternal smoking among infants with high hemoglobin levels. Maternal smoking, in particular, has been associated with poorer developmental outcomes, and hemoglobin levels can be elevated because of chronic mild hypoxia.

Possible limitations to this study include the small number of children (11-13 per formula group, or 5% of the sample) with extremely high hemoglobin levels; high attrition (25% between 6 and 12 months of age and 43% between 12 months and 10 years of age); use of hemoglobin level as the only iron measure for all infants before randomization; and the fact that randomization was not stratified by iron status. In addition, there was a lack of data on maternal smoking at 10 years or smoking habits of other household members at any point; exposure could affect long-term outcome.

More studies are needed, Dr. Lozoff and her colleagues said. Meanwhile, there are several potential implications of these results.

"Hemoglobin levels (and/or other measures of iron status) might need to be tested in early infancy before iron supplementation," the researchers said. "The recommendations of universal iron supplementation might need reconsideration. In any case, the optimal level of iron in infant formula warrants further study to avoid giving more iron than infants need."

Dr. Lozoff and her colleagues said they had no relevant financial disclosures. The study was supported by grants from the National Institutes of Health.