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Do breast-fed babies benefit from iron before 6 months?

2003; Elsevier BV; Volume: 143; Issue: 5 Linguagem: Inglês

10.1067/s0022-3476(03)00530-4

1097-6833

Betsy Lozoff,

Infant Nutrition and Health

In this issue of the Journal, Friel et al1.Friel J.K. Aziz K. Andrews W.L. Harding S.V. Courage M.L. Adams R. A double-masked, randomized controlled trial of iron supplementation in early infancy in healthy full-term infants.J Pediatr. 2003; 143: 582-586Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar report a randomized placebo-controlled trial of supplementing breast-fed infants with iron. Babies who received iron between 1 and 6 months of age had better visual acuity and higher motor test scores at 12 months. Although the sample is small, the study makes several important contributions to the accumulating evidence of iron's role in infant behavior and development. By assessing visual acuity—a measure other than a global test of development, the study helps understand specific central nervous system (CNS) processes that depend on iron. By determining iron status repeatedly, the study helps shed light on the issue of differential timing effects of iron supplementation and/or iron deficiency in infancy. And by focusing on developmental effects of early iron supplementation in well-nourished breast-fed infants, the study stands alone. The results challenge current recommendations that breast-fed infants do not need other sources of iron for the first 6 months of life.Better visual acuity in the infants who received iron seems to fit with current understanding of iron's role in CNS development, especially myelination. Visual acuity improves dramatically in early infancy, due in large part to myelination of the visual system.2.Dobson V. Teller D.Y. Visual acuity in human infant.Vision Res. 1987; 18: 1467-1483Google Scholar, 3.Van Hof-van Duin J. Mohn G. Vision in the preterm infant.in: Prechtel H.F.R. Continuity of neural function from prenatal to postnatal life. Blackwell, Oxford1984: 93-114Google Scholar Iron is required for the normal functioning of oligodendrocytes, which produce the fatty myelin sheath around axons.4.Connor J.R. Menzies S.L. Relationship of iron to oligodendrocytes and myelination.GLIA. 1996; 17: 83-93Crossref PubMed Scopus (550) Google Scholar Despite this compelling rationale, previous studies have not assessed visual acuity in the context of iron deficiency or iron supplementation, and thus the study breaks new ground. Although the results need to be replicated, they are congruent with other recent studies. For instance, in a new study of preventing iron-deficiency anemia in infancy, infants who received supplemental iron showed evidence of faster processing of visual information,5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar a finding that could relate to a difference in visual acuity. The findings are also consistent with recent observations of slower transmission in both the auditory and visual systems. Using auditory-evoked potentials, 6-month-old infants with iron-deficiency anemia tended to have slower conduction in the auditory pathway, with differences that increased after 1 year despite iron therapy.6.Roncagliolo M. Garrido M. Walter T. Peirano P. Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses.Am J Clin Nutr. 1998; 68: 683-690PubMed Google Scholar Children treated for iron-deficiency anemia in infancy still had slower transmission in both the auditory and visual systems at age 4 years.7.Algarin C. Peirano P. Garrido M. Pizarro F. Lozoff B. Iron deficiency anemia: long-lasting effects on auditory and visual systems functioning.Pediatr Res. 2003; 53: 217-223Crossref PubMed Scopus (263) Google ScholarImpaired myelination could contribute to differences in broader behavioral systems reported in other studies of iron deficiency in infancy (reviewed in 8.Grantham-McGregor S. Ani C. A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-668SPubMed Google Scholar). Differences in motor development, like those observed by Friel et al, are certainly relevant in this context, because the role of myelination in early motor development is well established. As noted by the authors, several studies have found lower motor test scores in iron-deficient anemic infants. Of the few preventive trials of the behavioral and developmental effects of iron supplementation,5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 10.Jahari A.B. Saco-Pollitt C. Husaini M. Pollitt E. Effects of energy and micronutrient supplementation on motor development and motor activity in undernourished children in Indonesia.Eur J Clin Nutr. 2000; 54: S60-S68Crossref PubMed Scopus (37) Google Scholar, 11.Morley R. Abbott R. Fairweather-Tait S. MacFayden U. Sterman M.B. Iron-fortified follow on formula from 9 to 18 months improves iron status but not development or growth: a randomised trial.Arch Dis Child. 1999; 81: 247-252Crossref PubMed Scopus (90) Google Scholar, 12.Williams J. Wolff A. Daly A. MacDonald A. Aukett A. Booth I.W. Iron supplemented formula milk related to reduction in psychomotor decline in infants for inner city areas: randomised study.BMJ. 1999; 318: 693-698Crossref PubMed Google Scholar three reported motor effects.5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 10.Jahari A.B. Saco-Pollitt C. Husaini M. Pollitt E. Effects of energy and micronutrient supplementation on motor development and motor activity in undernourished children in Indonesia.Eur J Clin Nutr. 2000; 54: S60-S68Crossref PubMed Scopus (37) Google Scholar Other studies observed that children who had been treated for chronic, severe iron deficiency in infancy showed marked differences in visual-motor integration, perceptual speed, tachistoscopic threshold, and/or motor proficiency years later, up to ten years after treatment.13.Lozoff B. Jimenez E. Wolf A.W. Long-term developmental outcome of infants with iron deficiency.N Engl J Med. 1991; 325: 687-694Crossref PubMed Scopus (756) Google Scholar, 14.De Andraca I. Walter T. Castillo M. Pino P. Rivera P. Cobo C. Iron-deficiency anemia and its effects upon psychological development at preschool age: a longitudinal study. Nestle Foundation Nutrition Annual Report 1990. Nestec Ltd, Vevey (Switzerland)1991Google Scholar, 15.Lozoff B. Jimenez E. Hagen J. Mollen E. Wolf A.W. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy.Pediatrics. 2000; e51: 1-11Google Scholar Thus, the study by Friel et al adds support for the hypothesis that iron is required for the normal function of systems whose development depends on myelination. However, iron is required for many other processes, including neurotransmitter functioning and neuronal metabolism.16.Beard J. Iron deficiency alters brain development and functioning.J Nutr. 2003; 133: 1468S-1472SPubMed Google Scholar, 17.DeUngria M. Rao R. Wobken J.D. Luciana M. Nelson C.A. Georgieff M.K. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.Pediatr Res. 2000; 48: 169-176Crossref PubMed Scopus (223) Google Scholar Thus, it is unlikely that poorer outcome is the result of disruption in a single process.The study provides further suggestions about timing and differential effects. It is plausible that the impact of iron supplementation or iron deficiency will differ depending on developmental stage. One of the challenges in understanding the timing question, however, is that timing, duration, and severity are intimately intertwined in early iron deficiency. The design of the Friel study goes a long way to disentangle timing from duration and severity, because iron supplementation or placebo were randomly assigned shortly after birth in groups that were similar in iron status. With repeated measures, the study showed that iron-supplemented babies had better iron status at 3 and 6 months but not at 12 months. These findings suggest that better visual acuity and higher motor scores were because of better iron status in the first 6 months of life. The results of this study, in combination with other studies where iron deficiency or supplementation occurred in the first six months of life,6.Roncagliolo M. Garrido M. Walter T. Peirano P. Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses.Am J Clin Nutr. 1998; 68: 683-690PubMed Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 18.Nelson C.A. Wewerka S. Thomas K.M. Tribby-Walbridge S. deRegnier R.-A. Georgieff M. Neurocognitive sequelae of infants of diabetic mothers.Behav Neurosci. 2000; 114: 950-956Crossref PubMed Scopus (125) Google Scholar, 19.Tamura T. Goldenberg R.L. Hou J. Johnston K.E. Cliver S.P. Ramey S.L. et al.Cord serum ferritin concentrations and mental and psychomotor development of chidren at five year of age.J Pediatr. 2002; 140: 165-170Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar might thus lead to the conclusions that early infancy is particularly vulnerable to the effects of iron and that some domains, such as motor or visual development, are most affected. However, the absence of a difference in mental test scores in the Friel study does not mean that there were no cognitive effects of iron supplementation. Overall tests of development in the first year of life lack specificity and do not predict later development. Furthermore, social/emotional behavior was not reported. Yet a number of studies have pointed to the effects of iron deficiency/iron supplementation in cognitive and social/emotional domains5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar (also see reference 8 for a review). There is an obvious need to determine what functions are more or less affected by early iron deficiency or iron supplementation.Nor should it be concluded that early infancy is the age most vulnerable to lack of iron. Plasticity and recovery might also be more possible earlier on, and no human study has systematically altered timing. This experimental design may best be done in animal models. Functions in a more rapid phase of development later in infancy might be affected by iron deficiency at those times, and research involving adolescents and adults shows effects of iron deficiency and/or iron treatment at much older ages.16.Beard J. Iron deficiency alters brain development and functioning.J Nutr. 2003; 133: 1468S-1472SPubMed Google ScholarThe focus on the healthy breast-fed infant is a very special contribution of this study. The results add to concerns about the iron status of breast-fed babies. Although some studies find little iron deficiency in breast-fed infants, others in Chile, Canada, and elsewhere have found that iron-deficiency anemia occurs in 15% to 28% of well-nourished breast-fed babies at 9 months.20.Pizarro F. Yip R. Dallman P.R. Olivares M. Hertrampf E. Walter T. Iron status with different infant feeding regimens: relevance to screening and prevention of iron deficiency.J Pediatr. 1991; 118: 687-692Abstract Full Text PDF PubMed Scopus (137) Google Scholar, 21.Calvo E.B. Galindo A.C. Aspres N.B. Iron status in exclusively breast-fed infants.Pediatrics. 1992; 90: 375-379PubMed Google Scholar, 22.Innis S.M. Nelson C.M. Wadsworth L.D. MacLaren I.A. Lwanga D. Incidence of iron-deficiency anaemia and depleted iron stores among nine-month-old infants in Vancouver, Canada.Can J Public Health. 1997; 88: 80-84PubMed Google Scholar In the Friel study, iron supplementation between 1 and 6 months of age and complementary feeding with iron-fortified formula did not prevent iron deficiency at 12 months; 35% to 37% of infants had iron-deficiency anemia and/or a low ferritin level, regardless of iron supplementation. Why the breast-fed baby, despite all the benefits of breast-feeding, might still be vulnerable to iron deficiency, is an interesting and important puzzle. In an evolutionary sense, something that confers a strong adaptive advantage need not be perfect. Other factors may also be relevant. The authors point out some (eg, the bioavailability of iron in breast milk may be lower than previously thought). Another possibility is that whatever solid food, milk, or formula the infants received interfered with the absorption of breast-milk iron. It may also be that the rapid growth of infants in industrialized societies exceeds the capacity of breast milk to meet iron needs for some infants. Even though breast-fed babies grow more slowly than bottle-fed babies,23.Garza C. De Onis M. A new international growth reference for young children.Am J Clin Nutr. 1999; 70: 169S-172SGoogle Scholar birth weights and growth rates are higher now than they are likely to have been through much of human history. The infants in the study by Friel et al were large, with average birth weights of 3.6 to 3.7 kg and doubling by 4 months or so.Despite the important contributions of this study, the sample was very small. This makes it impossible to use the study to inform any discussion about potential ill effects of early iron supplementation for breast-fed babies. The sample size is also too small to address the issue of lowering the cut-off for defining anemia in the first year of life. In fact, the study's findings conflict with the authors' use of 95 g/L as a cut-off. The 5th percentile for hemoglobin levels (−1.65 SD) in the iron-supplemented group was 109.0 g/L and 110.1 g/L at 6 and 12 months, respectively.This study points to the urgent need for the findings to be replicated in a larger sample and the issues of safety to be resolved. Unfortunately, the authors' suggestion that a more immediate solution is to find a better screening approach does not look promising. No simple accurate way of identifying breast-fed infants at 1 or 2 months who will later become iron-deficient is available now or in the foreseeable future. Thus, at this time, individual clinicians and parents of breast-fed infants have to make decisions on their own. The low levels of iron supplementation used in this study seem an excellent approach to reduce any concerns about potential risks. The results indicate that even minimal amounts of added iron early on for the breast-fed infant may be sufficient to benefit the developing brain. In this issue of the Journal, Friel et al1.Friel J.K. Aziz K. Andrews W.L. Harding S.V. Courage M.L. Adams R. A double-masked, randomized controlled trial of iron supplementation in early infancy in healthy full-term infants.J Pediatr. 2003; 143: 582-586Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar report a randomized placebo-controlled trial of supplementing breast-fed infants with iron. Babies who received iron between 1 and 6 months of age had better visual acuity and higher motor test scores at 12 months. Although the sample is small, the study makes several important contributions to the accumulating evidence of iron's role in infant behavior and development. By assessing visual acuity—a measure other than a global test of development, the study helps understand specific central nervous system (CNS) processes that depend on iron. By determining iron status repeatedly, the study helps shed light on the issue of differential timing effects of iron supplementation and/or iron deficiency in infancy. And by focusing on developmental effects of early iron supplementation in well-nourished breast-fed infants, the study stands alone. The results challenge current recommendations that breast-fed infants do not need other sources of iron for the first 6 months of life. Better visual acuity in the infants who received iron seems to fit with current understanding of iron's role in CNS development, especially myelination. Visual acuity improves dramatically in early infancy, due in large part to myelination of the visual system.2.Dobson V. Teller D.Y. Visual acuity in human infant.Vision Res. 1987; 18: 1467-1483Google Scholar, 3.Van Hof-van Duin J. Mohn G. Vision in the preterm infant.in: Prechtel H.F.R. Continuity of neural function from prenatal to postnatal life. Blackwell, Oxford1984: 93-114Google Scholar Iron is required for the normal functioning of oligodendrocytes, which produce the fatty myelin sheath around axons.4.Connor J.R. Menzies S.L. Relationship of iron to oligodendrocytes and myelination.GLIA. 1996; 17: 83-93Crossref PubMed Scopus (550) Google Scholar Despite this compelling rationale, previous studies have not assessed visual acuity in the context of iron deficiency or iron supplementation, and thus the study breaks new ground. Although the results need to be replicated, they are congruent with other recent studies. For instance, in a new study of preventing iron-deficiency anemia in infancy, infants who received supplemental iron showed evidence of faster processing of visual information,5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar a finding that could relate to a difference in visual acuity. The findings are also consistent with recent observations of slower transmission in both the auditory and visual systems. Using auditory-evoked potentials, 6-month-old infants with iron-deficiency anemia tended to have slower conduction in the auditory pathway, with differences that increased after 1 year despite iron therapy.6.Roncagliolo M. Garrido M. Walter T. Peirano P. Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses.Am J Clin Nutr. 1998; 68: 683-690PubMed Google Scholar Children treated for iron-deficiency anemia in infancy still had slower transmission in both the auditory and visual systems at age 4 years.7.Algarin C. Peirano P. Garrido M. Pizarro F. Lozoff B. Iron deficiency anemia: long-lasting effects on auditory and visual systems functioning.Pediatr Res. 2003; 53: 217-223Crossref PubMed Scopus (263) Google Scholar Impaired myelination could contribute to differences in broader behavioral systems reported in other studies of iron deficiency in infancy (reviewed in 8.Grantham-McGregor S. Ani C. A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-668SPubMed Google Scholar). Differences in motor development, like those observed by Friel et al, are certainly relevant in this context, because the role of myelination in early motor development is well established. As noted by the authors, several studies have found lower motor test scores in iron-deficient anemic infants. Of the few preventive trials of the behavioral and developmental effects of iron supplementation,5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 10.Jahari A.B. Saco-Pollitt C. Husaini M. Pollitt E. Effects of energy and micronutrient supplementation on motor development and motor activity in undernourished children in Indonesia.Eur J Clin Nutr. 2000; 54: S60-S68Crossref PubMed Scopus (37) Google Scholar, 11.Morley R. Abbott R. Fairweather-Tait S. MacFayden U. Sterman M.B. Iron-fortified follow on formula from 9 to 18 months improves iron status but not development or growth: a randomised trial.Arch Dis Child. 1999; 81: 247-252Crossref PubMed Scopus (90) Google Scholar, 12.Williams J. Wolff A. Daly A. MacDonald A. Aukett A. Booth I.W. Iron supplemented formula milk related to reduction in psychomotor decline in infants for inner city areas: randomised study.BMJ. 1999; 318: 693-698Crossref PubMed Google Scholar three reported motor effects.5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 10.Jahari A.B. Saco-Pollitt C. Husaini M. Pollitt E. Effects of energy and micronutrient supplementation on motor development and motor activity in undernourished children in Indonesia.Eur J Clin Nutr. 2000; 54: S60-S68Crossref PubMed Scopus (37) Google Scholar Other studies observed that children who had been treated for chronic, severe iron deficiency in infancy showed marked differences in visual-motor integration, perceptual speed, tachistoscopic threshold, and/or motor proficiency years later, up to ten years after treatment.13.Lozoff B. Jimenez E. Wolf A.W. Long-term developmental outcome of infants with iron deficiency.N Engl J Med. 1991; 325: 687-694Crossref PubMed Scopus (756) Google Scholar, 14.De Andraca I. Walter T. Castillo M. Pino P. Rivera P. Cobo C. Iron-deficiency anemia and its effects upon psychological development at preschool age: a longitudinal study. Nestle Foundation Nutrition Annual Report 1990. Nestec Ltd, Vevey (Switzerland)1991Google Scholar, 15.Lozoff B. Jimenez E. Hagen J. Mollen E. Wolf A.W. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy.Pediatrics. 2000; e51: 1-11Google Scholar Thus, the study by Friel et al adds support for the hypothesis that iron is required for the normal function of systems whose development depends on myelination. However, iron is required for many other processes, including neurotransmitter functioning and neuronal metabolism.16.Beard J. Iron deficiency alters brain development and functioning.J Nutr. 2003; 133: 1468S-1472SPubMed Google Scholar, 17.DeUngria M. Rao R. Wobken J.D. Luciana M. Nelson C.A. Georgieff M.K. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.Pediatr Res. 2000; 48: 169-176Crossref PubMed Scopus (223) Google Scholar Thus, it is unlikely that poorer outcome is the result of disruption in a single process. The study provides further suggestions about timing and differential effects. It is plausible that the impact of iron supplementation or iron deficiency will differ depending on developmental stage. One of the challenges in understanding the timing question, however, is that timing, duration, and severity are intimately intertwined in early iron deficiency. The design of the Friel study goes a long way to disentangle timing from duration and severity, because iron supplementation or placebo were randomly assigned shortly after birth in groups that were similar in iron status. With repeated measures, the study showed that iron-supplemented babies had better iron status at 3 and 6 months but not at 12 months. These findings suggest that better visual acuity and higher motor scores were because of better iron status in the first 6 months of life. The results of this study, in combination with other studies where iron deficiency or supplementation occurred in the first six months of life,6.Roncagliolo M. Garrido M. Walter T. Peirano P. Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses.Am J Clin Nutr. 1998; 68: 683-690PubMed Google Scholar, 9.Moffatt M.E.K. Longstaffe S. Besant J. Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through iron-fortified infant formula: a randomized clinical trial.J Pediatr. 1994; 125: 527-534Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 18.Nelson C.A. Wewerka S. Thomas K.M. Tribby-Walbridge S. deRegnier R.-A. Georgieff M. Neurocognitive sequelae of infants of diabetic mothers.Behav Neurosci. 2000; 114: 950-956Crossref PubMed Scopus (125) Google Scholar, 19.Tamura T. Goldenberg R.L. Hou J. Johnston K.E. Cliver S.P. Ramey S.L. et al.Cord serum ferritin concentrations and mental and psychomotor development of chidren at five year of age.J Pediatr. 2002; 140: 165-170Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar might thus lead to the conclusions that early infancy is particularly vulnerable to the effects of iron and that some domains, such as motor or visual development, are most affected. However, the absence of a difference in mental test scores in the Friel study does not mean that there were no cognitive effects of iron supplementation. Overall tests of development in the first year of life lack specificity and do not predict later development. Furthermore, social/emotional behavior was not reported. Yet a number of studies have pointed to the effects of iron deficiency/iron supplementation in cognitive and social/emotional domains5.Lozoff B. De Andraca I. Castillo M. Smith J. Walter T. Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants.Pediatrics. 2003; 112: 1-9Crossref PubMed Scopus (328) Google Scholar (also see reference 8 for a review). There is an obvious need to determine what functions are more or less affected by early iron deficiency or iron supplementation. Nor should it be concluded that early infancy is the age most vulnerable to lack of iron. Plasticity and recovery might also be more possible earlier on, and no human study has systematically altered timing. This experimental design may best be done in animal models. Functions in a more rapid phase of development later in infancy might be affected by iron deficiency at those times, and research involving adolescents and adults shows effects of iron deficiency and/or iron treatment at much older ages.16.Beard J. Iron deficiency alters brain development and functioning.J Nutr. 2003; 133: 1468S-1472SPubMed Google Scholar The focus on the healthy breast-fed infant is a very special contribution of this study. The results add to concerns about the iron status of breast-fed babies. Although some studies find little iron deficiency in breast-fed infants, others in Chile, Canada, and elsewhere have found that iron-deficiency anemia occurs in 15% to 28% of well-nourished breast-fed babies at 9 months.20.Pizarro F. Yip R. Dallman P.R. Olivares M. Hertrampf E. Walter T. Iron status with different infant feeding regimens: relevance to screening and prevention of iron deficiency.J Pediatr. 1991; 118: 687-692Abstract Full Text PDF PubMed Scopus (137) Google Scholar, 21.Calvo E.B. Galindo A.C. Aspres N.B. Iron status in exclusively breast-fed infants.Pediatrics. 1992; 90: 375-379PubMed Google Scholar, 22.Innis S.M. Nelson C.M. Wadsworth L.D. MacLaren I.A. Lwanga D. Incidence of iron-deficiency anaemia and depleted iron stores among nine-month-old infants in Vancouver, Canada.Can J Public Health. 1997; 88: 80-84PubMed Google Scholar In the Friel study, iron supplementation between 1 and 6 months of age and complementary feeding with iron-fortified formula did not prevent iron deficiency at 12 months; 35% to 37% of infants had iron-deficiency anemia and/or a low ferritin level, regardless of iron supplementation. Why the breast-fed baby, despite all the benefits of breast-feeding, might still be vulnerable to iron deficiency, is an interesting and important puzzle. In an evolutionary sense, something that confers a strong adaptive advantage need not be perfect. Other factors may also be relevant. The authors point out some (eg, the bioavailability of iron in breast milk may be lower than previously thought). Another possibility is that whatever solid food, milk, or formula the infants received interfered with the absorption of breast-milk iron. It may also be that the rapid growth of infants in industrialized societies exceeds the capacity of breast milk to meet iron needs for some infants. Even though breast-fed babies grow more slowly than bottle-fed babies,23.Garza C. De Onis M. A new international growth reference for young children.Am J Clin Nutr. 1999; 70: 169S-172SGoogle Scholar birth weights and growth rates are higher now than they are likely to have been through much of human history. The infants in the study by Friel et al were large, with average birth weights of 3.6 to 3.7 kg and doubling by 4 months or so. Despite the important contributions of this study, the sample was very small. This makes it impossible to use the study to inform any discussion about potential ill effects of early iron supplementation for breast-fed babies. The sample size is also too small to address the issue of lowering the cut-off for defining anemia in the first year of life. In fact, the study's findings conflict with the authors' use of 95 g/L as a cut-off. The 5th percentile for hemoglobin levels (−1.65 SD) in the iron-supplemented group was 109.0 g/L and 110.1 g/L at 6 and 12 months, respectively. This study points to the urgent need for the findings to be replicated in a larger sample and the issues of safety to be resolved. Unfortunately, the authors' suggestion that a more immediate solution is to find a better screening approach does not look promising. No simple accurate way of identifying breast-fed infants at 1 or 2 months who will later become iron-deficient is available now or in the foreseeable future. Thus, at this time, individual clinicians and parents of breast-fed infants have to make decisions on their own. The low levels of iron supplementation used in this study seem an excellent approach to reduce any concerns about potential risks. The results indicate that even minimal amounts of added iron early on for the breast-fed infant may be sufficient to benefit the developing brain.