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• W2158959013 abstract "For the last 25 years, the American Academy of Pediatrics (AAP) has endorsed the use of iron-fortified infant formulas, noting “no role for the use of low-iron formulas.” The rationale for these policies was the recognition that the increase in the use of iron-fortified formulas, accounting for 80% of all formula sold in 1985, was responsible for the declining prevalence of iron-deficiency anemia in US infants.1American Academy of Pediatrics Committee on NutritionIron-fortified infant formulas.Pediatrics. 1989; 84: 1114-1115PubMed Google Scholar These recommendations were also based on the absence of evidence of discernible adverse effects. Controlled trials had reported no differences in gastrointestinal symptoms, such as colic, constipation, diarrhea, regurgitation, and fussiness, among infants receiving low-iron vs iron-fortified formulas.2Oski F.A. Bennett R. Campbell J. Charles W. Cirincione F.J. Corwin R. et al.Iron-fortified formulas and gastrointestinal symptoms in infants: a controlled study.Pediatrics. 1980; 66: 168-170PubMed Google Scholar, 3Nelson S.E. Ziegler E.E. Copeland A.M. Edwards B.B. Fomon S.J. Lack of adverse reactions to iron-fortified formula.Pediatrics. 1988; 81: 360-364PubMed Google Scholar Likewise, evidence was lacking to support another theoretical concern of clinically significant interactions with other micronutrients, specifically zinc and copper. In 1999, the AAP took an even stronger stand and recommended that low iron formulas be removed from the market entirely,4American Academy of Pediatrics Committee on NutritionIron fortification of infant formulas.Pediatrics. 1999; 104: 119-123Crossref PubMed Scopus (152) Google Scholar for reasons similar to those of the 1989 policy. Further, it was recommended that the minimum iron content for all term infant formulas be at least 4 mg/L.4American Academy of Pediatrics Committee on NutritionIron fortification of infant formulas.Pediatrics. 1999; 104: 119-123Crossref PubMed Scopus (152) Google Scholar Currently, standard, term infant formulas on the market are all iron-fortified and contain 4-12 mg/L of iron, even though there are some regional differences. In the US, the AAP recommends that infant formulas have an iron content of 10-12 mg/L5Baker R.D. Greer F.R. American Academy of Pediatrics Committee on NutritionDiagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age).Pediatrics. 2010; 126: 1040-1050Crossref PubMed Scopus (661) Google Scholar; in Europe, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends 4-8 mg/L.6Domellöf M. Braegger C. Campoy C. Colomb V. Decsi T. Fewtrell M. et al.Iron requirements of infants and toddlers.J Pediatr Gastroenterol Nutr. 2014; 58: 119-129Crossref PubMed Scopus (265) Google Scholar In the recommendations, the contrast in the iron exposure of formula-fed infants vs breastfed infants has primarily focused on the better bioavailability of the iron in breast milk. Although an absorption efficiency of approximately 50% is often quoted, some studies have actually reported absorption in the range of 12%-16%,7Davidsson L. Kastenmayer P. Yuen M. Lönnerdal B. Hurrell R.F. Influence of lactoferrin on iron absorption from human milk in infants.Pediatr Res. 1994; 35: 117-124Crossref PubMed Scopus (111) Google Scholar, 8Domellöf M. Lönnerdal B. Abrams S.A. Hernell O. Iron absorption in breast-fed infants: effects of age, iron status, iron supplements, and complementary foods.Am J Clin Nutr. 2002; 76: 198-204PubMed Google Scholar making that bioavailability distinction much less potent. This also suggests that absorption of substantial amounts of dietary iron simply is not critical during the early months of life in healthy infants of normal birth weight. Among all the compositional differences between human milk and formula, the differences in iron content are the most extreme. Virtually all mammalian milks are low in iron, with the exception of rodents, in which postnatal growth is extremely rapid. It seems implausible that this conserved biological pattern is without purpose. It is also clear that iron deficiency occurs in breastfed infants only after the very early months of life. The practical challenge is to identify when the birth iron endowment is exhausted, at which point the infant needs a source of iron from the diet. This article will discuss the potential advantages of a low iron intake for the infant and the potential adverse effects of drastically altering this, especially in the first 6 months of life. From the outset, two realities must be acknowledged. First, iron deficiency (especially without anemia) in infants remains common, particularly in high-risk groups, including older normal breastfed infants and premature and/or in low birth weight infants. Whether this mild iron deficiency has adverse effects on development is not known. Second, research on potential adverse effects of early and excessive iron exposure is limited, and the evidence base for caution is suggestive but not yet demonstrated by rigorously designed trials. Thus, this represents an emerging area of consideration, and, given the advances in understanding of iron metabolism, the interaction between iron and inflammation, and the importance of early influences on the immature gut and immune system, it is an area that warrants much stronger scientific investigation. The iron concentration in early human milk is ∼0.5 mg/L and declines slightly to ∼0.2-0.4 mg/L in mature milk.9Domellöf M. Lönnerdal B. Dewey K.G. Cohen R.J. Hernell O. Iron, zinc, and copper concentrations in breast milk are independent of maternal mineral status.Am J Clin Nutr. 2004; 79: 111-115PubMed Scopus (156) Google Scholar Thus, even with a relatively low level of fortification in infant formula (eg, 4 mg/L), the amount is ∼10-fold higher. For the high end of fortification levels (eg, 12 mg/L), the difference is up to 60-fold greater. Thus, typical intakes from formula by the young infant represent a distinctly unnatural exposure. Another distortion of the balance of micronutrients resulting from fortification of formula is the ratio of zinc to iron. In contrast to iron, zinc is very high in early human milk (2-3 mg/L) and remains >1 mg/L until ∼6 months postpartum.10Krebs N.F. Reidinger C.J. Hartley S. Robertson A.D. Hambidge K.M. Zinc supplementation during lactation: effects on maternal status and milk zinc concentrations.Am J Clin Nutr. 1995; 61: 1030-1036Crossref PubMed Scopus (117) Google Scholar Therefore, during the 0- to 6-month period, the Zn:Fe in human milk is ∼3-8, depending on the stage postpartum (or Fe:Zn ∼0.25). In contrast, current levels of iron and zinc fortification in formulas are the opposite; the iron concentration is typically about twice that of zinc, which is at least 5-7 mg/L, resulting in Zn:Fe of only 0.5. The effects of this difference are unknown but may be relevant to the effects discussed below. Iron is recognized as a reactive element; its easy redox cycling properties contribute to its utility as a biocatalyst in proteins and as an electron carrier in energy metabolism. It is, however, a potent pro-oxidant. Under anoxic or anaerobic conditions, free iron can be toxic by the formation of reactive oxygen species, including superoxide and other free radicals. Thus, given the “double-edged sword” features of iron—its essentiality as a nutrient and its potential toxicity—very little free iron is present in the circulation under normal circumstances. The majority of iron is bound as part of the heme molecule in hemoglobin; the other major pool is storage iron in the form of ferritin. During transport in the circulation, iron is tightly bound to transferrin. Additional iron given to iron-replete infants has been suggested to impair growth. This has been shown in several randomized, controlled studies where iron supplementation was given to infants after 4 months of age.11Idjradinata P. Watkins W.E. Pollitt E. Adverse effect of iron supplementation on weight gain of iron-replete young children.Lancet. 1994; 343: 1252-1254Abstract PubMed Scopus (132) Google Scholar, 12Lind T. Seswandhana R. Persson L.A. Lönnerdal B. Iron supplementation of iron-replete Indonesian infants is associated with reduced weight-for-age.Acta Paediatr. 2008; 97: 770-775Crossref PubMed Scopus (55) Google Scholar, 13Majumdar I. Paul P. Talib V.H. Ranga S. The effect of iron therapy on the growth of iron-replete and iron-deplete children.J Trop Pediatr. 2003; 49: 84-88Crossref PubMed Scopus (79) Google Scholar, 14Dewey K.G. Domellöf M. Cohen R.J. Landa Rivera L. Hernell O. Lönnerdal B. Iron supplementation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras.J Nutr. 2002; 132: 3249-3255PubMed Scopus (222) Google Scholar However, this possible adverse effect has not been confirmed in meta-analyses.15Ramakrishnan U. Nguyen P. Martorell R. Effects of micronutrients on growth of children under 5 years of age: meta-analyses of single and multiple nutrient interventions.Am J Clin Nutr. 2009; 89: 191-203Crossref PubMed Scopus (136) Google Scholar Only a few studies have compared growth of infants <4 months of age receiving formulas with different levels of iron fortification. One small study compared 2 vs 4 mg/L and found no difference in growth between the 2 iron levels or any difference between the formula-fed and breastfed infants from 1-6 months of age.16Hernell O. Lönnerdal B. Iron status of infants fed low-iron formula: no effect of added bovine lactoferrin or nucleotides.Am J Clin Nutr. 2002; 76: 858-864PubMed Google Scholar An earlier randomized trial compared two relatively high iron concentrations (7.4 vs 12.7 mg/L formula) from 1-6 months and found no difference between the two groups, but both groups were longer and heavier than a concurrent group of breastfed infants.17Bradley C.K. Hillman L. Sherman A.R. Leedy D. Cordano A. Evaluation of two iron-fortified, milk-based formulas during infancy.Pediatrics. 1993; 91: 908-914PubMed Google Scholar Potential interactions among trace minerals were noted in the 1989 AAP policy statement and are often raised as a concern for adverse effects of iron fortification and supplementation.18Iannotti L.L. Tielsch J.M. Black M.M. Black R.E. Iron supplementation in early childhood: health benefits and risks.Am J Clin Nutr. 2006; 84: 1261-1276PubMed Google Scholar, 19Lind T. Lönnerdal B. Stenlund H. Ismail D. Seswandhana R. Ekström E.C. et al.A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc.Am J Clin Nutr. 2003; 77: 883-890PubMed Google Scholar, 20Berger J. Ninh N.X. Khan N.C. Nhien N.V. Lien D.K. Trung N.Q. et al.Efficacy of combined iron and zinc supplementation on micronutrient status and growth in Vietnamese infants.Eur J Clin Nutr. 2006; 60: 443-454Crossref PubMed Scopus (56) Google Scholar Several investigations have been undertaken to evaluate this, and, overall, the evidence does not support a potent adverse effect of iron fortification on either zinc or copper absorption.21Domellöf M. Hernell O. Abrams S.A. Chen Z. Lönnerdal B. Iron supplementation does not affect copper and zinc absorption in breastfed infants.Am J Clin Nutr. 2009; 89: 185-190Crossref PubMed Scopus (21) Google Scholar, 22Haschke F. Ziegler E.E. Edwards B.B. Fomon S.J. Effect of iron fortification of infant formula on trace mineral absorption.J Pediatr Gastroenterol Nutr. 1986; 5: 768-773Crossref PubMed Scopus (90) Google Scholar, 23Esamai F. Liechty E. Ikemeri J. Westcott J. Kemp J. Culbertson D. et al.Zinc absorption from micronutrient powder is low but is not affected by iron in Kenyan infants.Nutrients. 2014; 6: 5636-5651Crossref PubMed Scopus (23) Google Scholar Several investigators have shown that iron supplements decrease serum or plasma zinc concentrations.19Lind T. Lönnerdal B. Stenlund H. Ismail D. Seswandhana R. Ekström E.C. et al.A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc.Am J Clin Nutr. 2003; 77: 883-890PubMed Google Scholar, 20Berger J. Ninh N.X. Khan N.C. Nhien N.V. Lien D.K. Trung N.Q. et al.Efficacy of combined iron and zinc supplementation on micronutrient status and growth in Vietnamese infants.Eur J Clin Nutr. 2006; 60: 443-454Crossref PubMed Scopus (56) Google Scholar, 24Whittaker P. Iron and zinc interactions in humans.Am J Clin Nutr. 1998; 68: 442S-446SPubMed Google Scholar, 25Friel J.K. Andrews W.L. Aziz K. Kwa P.G. Lepage G. L'Abbe M.R. A randomized trial of two levels of iron supplementation and developmental outcome in low birth weight infants.J Pediatr. 2001; 139: 254-260Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar However, plasma zinc, as an index of zinc status, has low sensitivity, is susceptible to many confounding factors including inflammation, and is not a direct reflection of absorption. Data on the effects of different levels of iron fortification in formula have been somewhat conflicting, with very high iron fortification (∼14-19 mg/L vs 1.4-2.4 mg/L) having a depressing effect on plasma zinc concentrations in 3- to 4-month-old infants.26Craig W.J. Balbach L. Harris S. Vyhmeister N. Plasma zinc and copper levels of infants fed different milk formulas.J Am Coll Nutr. 1984; 3: 183-186Crossref PubMed Scopus (17) Google Scholar A frequently cited systematic review of oral iron supplementation trials reported a modest but statistically significant increase in the risk of developing diarrhea with oral iron administration, but this review was not specific for or limited to fortification of formula nor to young infants.27Gera T. Sachdev H.P. Effect of iron supplementation on incidence of infectious illness in children: systematic review.BMJ. 2002; 325: 1142Crossref PubMed Google Scholar Recent trials in Pakistan, Ghana, and Kenya28Soofi S. Cousens S. Iqbal S.P. Akhund T. Khan J. Ahmed I. et al.Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial.Lancet. 2013; 382: 29-40Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 29Zlotkin S. Newton S. Aimone A.M. Azindow I. Amenga-Etego S. Tchum K. et al.Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial.JAMA. 2013; 310: 938-947Crossref PubMed Scopus (124) Google Scholar, 30Jaeggi T. Kortman G.A. Moretti D. Chassard C. Holding P. Dostal A. et al.Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants.Gut. 2015; 64: 731-742Crossref PubMed Scopus (387) Google Scholar relating iron-containing micronutrient powders to increased diarrhea, including severe and bloody diarrhea, also are not within the scope of this chapter, which concerns infants in resource-rich countries. As noted above, the early recommendations for the safety of iron-fortified formulas, including from birth, were based on trials undertaken with different levels of fortification.2Oski F.A. Bennett R. Campbell J. Charles W. Cirincione F.J. Corwin R. et al.Iron-fortified formulas and gastrointestinal symptoms in infants: a controlled study.Pediatrics. 1980; 66: 168-170PubMed Google Scholar, 3Nelson S.E. Ziegler E.E. Copeland A.M. Edwards B.B. Fomon S.J. Lack of adverse reactions to iron-fortified formula.Pediatrics. 1988; 81: 360-364PubMed Google Scholar Gastrointestinal complaints such as constipation, spitting-up, vomiting, fussiness, or cramping were not different among infants randomized at birth and continued on fortified (12 mg/L) or unfortified (1.5 mg/L) formulas for approximately 6-12 weeks.2Oski F.A. Bennett R. Campbell J. Charles W. Cirincione F.J. Corwin R. et al.Iron-fortified formulas and gastrointestinal symptoms in infants: a controlled study.Pediatrics. 1980; 66: 168-170PubMed Google Scholar, 3Nelson S.E. Ziegler E.E. Copeland A.M. Edwards B.B. Fomon S.J. Lack of adverse reactions to iron-fortified formula.Pediatrics. 1988; 81: 360-364PubMed Google Scholar Both studies concluded that, in the absence of gastrointestinal signs or symptoms, “there are few indications for feeding commercially prepared formulas that are not fortified with iron.”2Oski F.A. Bennett R. Campbell J. Charles W. Cirincione F.J. Corwin R. et al.Iron-fortified formulas and gastrointestinal symptoms in infants: a controlled study.Pediatrics. 1980; 66: 168-170PubMed Google Scholar Relevant to the topic of this article, the gastrointestinal tract of the young infant is particularly vulnerable to any imbalances that can alter the mucosal barrier function, the maturation of the intraepithelial tight junctions and intestinal permeability, and the development of the innate immune system and a favorable intestinal microbial community. In recent years, there has been a growing appreciation of the critical interrelationships of the enteric microbiome with the host immune system and metabolism and of the influence of diet on both the compositional and functional features. In particular, early postnatal life is a time for intestinal maturation and colonization by the commensal microbiota and the establishment of immunologic and metabolic programming that may have long-term consequences. Differences in the enteric microbiome between breastfed and formula-fed infants have been clearly documented.31Harmsen H.J. Wildeboer-Veloo A.C. Raangs G.C. Wagendorp A.A. Klijn N. Bindels J.G. et al.Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods.J Pediatr Gastroenterol Nutr. 2000; 30: 61-67Crossref PubMed Scopus (1075) Google Scholar, 32Fallani M. Young D. Scott J. Norin E. Amarri S. Adam R. et al.Intestinal microbiota of 6-week-old infants across Europe: geographic influence beyond delivery mode, breast-feeding, and antibiotics.J Pediatr Gastroenterol Nutr. 2010; 51: 77-84Crossref PubMed Scopus (399) Google Scholar, 33Schwartz S. Friedberg I. Ivanov I.V. Davidson L.A. Goldsby J.S. Dahl D.B. et al.A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response.Genome Biol. 2012; 13: r32Crossref PubMed Scopus (171) Google Scholar Generally recognized patterns include breastfed infants as having higher counts of Bifidobacteria and Lactobacillus and lower counts of Bacteroides, Clostridium coccoides group, Staphylococcus, and Enterobacteriaceae than formula-fed infants.34Matamoros S. Gras-Leguen C. Le Vacon F. Potel G. de La Cochetiere M.F. Development of intestinal microbiota in infants and its impact on health.Trends Microbiol. 2013; 21: 167-173Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar Breast milk is an important source of the specific colonization pattern of the infant that resembles closely the maternal genotypes. Prebiotics, especially human milk oligosaccharides, are thought to favorably shape the commensal bacteria of the newborn's intestinal tract. In addition to feeding type, mode of delivery, antibiotic exposure, and environmental factors have been found to influence the enteric microbiome.34Matamoros S. Gras-Leguen C. Le Vacon F. Potel G. de La Cochetiere M.F. Development of intestinal microbiota in infants and its impact on health.Trends Microbiol. 2013; 21: 167-173Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar However, primary determinants of its composition within different nutritional sources are not yet clear. The potential impact of iron exposure on young infants' microbiota has not been investigated in controlled interventional studies. Interest is emerging specifically on the influence of iron exposure on the gut (specifically colonic) microbiota, and this raises particular theoretical concern for the potential impact for the young infant when colonization is rapidly established after virtual “sterility” at birth. A low iron environment, such as that resulting from exclusive feeding of human milk, influences intestinal bacterial growth (ie, fosters growth of Lactobacillus), which is distinctly not dependent on iron. The initial colonization pattern following vaginal delivery shows a predominance of facultative anaerobes E coli and Enterobacteriaceae, changing in the low oxygen environment in the gut to a predominance of strict anaerobes, especially Bifidobacterium, Clostridium, and Bacteroides. In contrast, a high intraluminal iron enhances both bacterial replication and the production of virulence factors in pathogenic bacteria.35Kortman G.A. Raffatellu M. Swinkels D.W. Tjalsma H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective.FEMS Microbiol Rev. 2014; 38: 1202-1234Crossref PubMed Scopus (150) Google Scholar The iron in formula that is not absorbed may, in effect, interfere with the typical progression of colonization. The low iron content of human milk fosters a “simple” microbiota and the predominance of commensal bacteria. Illustrative of this, in a study reported nearly 3 decades ago, newborn nonbreastfed infants were randomized to receive cow milk based preparations with (5 mg/L) and without (0.5 mg/L) iron fortification, and both groups were compared with exclusively breastfed infants. Using culture techniques, the gut flora of the breastfed infants at 3 months of age comprised predominantly Bifidobacteria, low counts of E coli, and virtually no other bacteria. Similar patterns were reported for the unfortified cow milk preparation, except for a greater frequency of E coli. In contrast, infants receiving the iron-fortified cow milk preparation had low counts of Bifidobacteriaceae, high counts of Bacteroides spp and E coli, and frequent counts of other bacteria.36Mevissen-Verhage E.A. Marcelis J.H. Harmsen-Van Amerongen W.C. de Vos N.M. Verhoef J. Effect of iron on neonatal gut flora during the first three months of life.Eur J Clin Microbiol. 1985; 4: 273-278Crossref PubMed Scopus (49) Google Scholar Notably, results of cultures were significantly different among the 3 groups as early as 1 week of age.37Mevissen-Verhage E.A. Marcelis J.H. Harmsen-van Amerongen W.C. de Vos N.M. Berkel J. Verhoef J. Effect of iron on neonatal gut flora during the first week of life.Eur J Clin Microbiol. 1985; 4: 14-18Crossref PubMed Scopus (22) Google Scholar As noted above, human milk contains several prebiotic factors, including a range of oligosaccharides. Lactoferrin, which binds and facilitates the uptake of iron by the enterocyte,38Lönnerdal B. Georgieff K.M. Hernell O. Developmental physiology of iron absorption, homeostasis, and metabolism in the healthy term infant.J Pediatr. 2015; 167: S8-S14Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar is also a prebiotic with important functional characteristics that foster a healthy intestinal microbiome. Lactoferrin binds iron avidly and contributes to the low iron environment in the gut lumen of breastfed infants. It is also resistant to proteolysis and present in the stool of breastfed infants, thus, potentially offering a colonic “mechanism” to deprive pathogenic microbes of iron and facilitate growth of commensals. Lactoferrin also has immunomodulatory activity by means of induction of T-helper cells that protect the young infant against infection.39Sherman M.P. Lactoferrin and necrotizing enterocolitis.Clin Perinatol. 2013; 40: 79-91Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Thus, in addition to the striking difference in iron content of standard infant formulas compared with human milk, the absence of lactoferrin and its iron binding effects is another potential risk factor for gastrointestinal effects, especially in the young healthy term infant for whom iron status is likely to be adequate and the drive for absorption of dietary iron is minimal. Compared with iron, even less is known about the effects of other micronutrients on the developing microbiome, including the role of zinc. In contrast to the low iron content of human milk and the iron binding capacity of lactoferrin, the young exclusively breastfed infant is naturally exposed to a very high zinc intake, of which only about 50% is absorbed. Besides its effects on intestinal maturation,40Krebs N.F. Miller L.V. Hambidge K.M. Zinc deficiency in infants and children: a review of its complex and synergistic interactions.Paediatr Int Child Health. 2014; 34: 279-288Crossref PubMed Scopus (104) Google Scholar the high ratio of zinc to iron may be another factor that promotes development of a healthy microbial profile for the young infant and/or protects against invasion by pathogenic organisms. Inhibition of several virulence factors of enteropathogens has been associated with high intraluminal zinc content, as would be expected in the young breastfed infant.41Crane J.K. Byrd I.W. Boedeker E.C. Virulence inhibition by zinc in shiga-toxigenic Escherichia coli.Infect Immun. 2011; 79: 1696-1705Crossref PubMed Scopus (46) Google Scholar This poses a potential adverse effect of the reversal of the balance of zinc to iron described above resulting from the use of iron-fortified formula for young infants. One retrospective case control analysis examined the relationship between feeding mode from birth to 4 months and the development of type 1 diabetes mellitus (T1DM) by 1-6 years of age.42Ashraf A.P. Eason N.B. Kabagambe E.K. Haritha J. Meleth S. McCormick K.L. Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study.Diabetol Metab Syndr. 2010; 2: 58Crossref PubMed Scopus (8) Google Scholar Children who developed T1DM had significantly higher total iron intake, reflecting consumption of high iron fortified formula. For each SD of increase in iron intake, the OR for T1DM was 2.0 among all children and 2.26 when affected children were compared with a sibling control. Several limitations of this study were noted, including use of retrospective self-reported dietary intake data and potential bias for feeding choice (breast milk vs low- and high-iron formula). However, the findings raise important questions that merit prospective large-scale studies to investigate the potential causal relationship between early iron exposure and T1DM, as well as other autoimmune-based conditions. The long-term developmental effects of iron exposure during infancy were assessed in a 10-year follow-up report of infants randomized at 6 months of age to either a high iron (12.7 mg/L) or low iron (2.3 mg/L) infant formula.43Lozoff B. Castillo M. Clark K.M. Smith J.B. Iron-fortified vs low-iron infant formula: developmental outcome at 10 years.Arch Pediatr Adolesc Med. 2012; 166: 208-215Crossref PubMed Scopus (103) Google Scholar Infants assigned to the high iron formula scored lower on all developmental outcomes tested.44Zlotkin H.S. Davidsson L. Lozoff B. Balancing the benefits and risks of iron fortification in resource-constrained settings.J Pediatr. 2015; 167: S26-S30Abstract Full Text Full Text PDF Scopus (3) Google Scholar The findings illustrate the potential adverse effects of unduly high iron exposure, especially to those who seemed to be iron replete as would be the case for the majority of healthy term infants in the first few postnatal months. This discussion concerns iron needs primarily of very low birth weight infants during their hospital stay.45Domellöf M. Georgieff M.K. Postdischarge iron requirements of the preterm infant.J Pediatr. 2015; 167: S31-S35Abstract Full Text Full Text PDF Scopus (21) Google Scholar The dilemma is that the iron needs of the preterm infant, which are high, need to be met while at the same time avoiding unduly high intakes of iron that could potentially overwhelm the diminished antioxidant defenses of the premature infant.46Buonocore G. Perrone S. Longini M. Vezzosi P. Marzocchi B. Paffetti P. et al.Oxidative stress in preterm neonates at birth and on the seventh day of life.Pediatr Res. 2002; 52: 46-49Crossref PubMed Scopus (177) Google Scholar Preterm infants are born with lower iron stores than term infants. In the neonatal period, premature infants typically incur substantial losses of hemoglobin iron because of phlebotomy but also often receive red blood cell transfusions that provide substantial intakes of iron. For these reasons, the amount of storage iron available to the infant at any given time is not known. Determination of serum ferritin could provide this information.47Hernell O. Fewtrell M.S. Georgieff M.K. Krebs N.F. Lönnerdal B. Summary of current recommendations on iron provision and monitoring of iron status for breastfed and formula-fed infants in resource-rich and resource-constrained countries.J Pediatr. 2015; 167: S40-S47Abstract Full Text Full Text PDF Scopus (24) Google Scholar The amount of iron needed for growth can be estimated by the factorial method. At birth, the total body iron of the premature infant is assumed to be 75 mg/kg body weight, the same as that of the term infant. The physiologic increase in body iron of the growing premature infant was estimated by Griffin and Cooke48Griffin I. Cooke R.J. Iron retention in preterm infants fed low iron intakes: a metabolic balance study.Early Hum Dev. 2010; 86: 49-53Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar to be approximately 0.29 mg/kg/d at around 32 weeks, rising to 0.37 mg/kg/d close to term, and declining gradually after term. These estimates serve as basis for estimating necessary intakes of iron. Absorption of iron determined by isotope balance in premature infants averaged 31.5%,49Gorten M.K. Hepner R. Workman J.B. Iron metabolism in premature infants. I. Absorption and utilization of iro" @default.
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• W2158959013 date "2015-10-01" @default.
• W2158959013 modified "2023-09-25" @default.
• W2158959013 title "Balancing Benefits and Risks of Iron Fortification in Resource-Rich Countries" @default.
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