Recommendations on Iron Questioned

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I recognize that a great deal of hard work and thought has gone into these current recommendations and that the authors used the best available in-formation well considered by experts. However, I believe it would be prefera-ble to do the best study possiprefera-ble and then make a recommendation on the basis of that evidence.

Lydia M. Furman, MD

Department of Pediatrics Rainbow Babies & Children’s Hospital Cleveland, OH 44106

REFERENCES

1. Baker RD, Greer FR; American Academy of Pediat-rics, Committee on Nutrition. Diagnosis and pre-vention of iron deﬁciency and iron-deﬁciency ane-mia in infants and young children (0–3 years of age).Pediatrics. 2010;126(5):1040–1050 2. Friel JK, Aziz A, Andrews WL, Harding SV,

Cour-age ML, Adams RJ. A double-masked, random-ized control trial of iron supplementation in early infancy in healthy term breast-fed infants. J Pediatr. 2003;143(5):582–586

3. Ziegler EE, Nelson SE, Jeter JM. Iron supple-mentation of breastfed infants from an early age.Am J Clin Nutr. 2009;89(2):525–532 4. Domellöf M, Cohen RJ, Dewey KG, Hernell O, Rivera

LL, Lönnerdal B. Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age.J Pediatr. 2001;138(5):679–687 5. Dewey KG, Domellöf M, Cohen RJ, Landa

Ri-vera L, Hernell O, Lönnerdal B. Iron supple-mentation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras.J Nutr. 2002; 132(11):3249 –3255

6. McCann JC, Ames BN. An overview of evi-dence for a causal relation between iron de-ﬁciency during development and deﬁcits in cognitive or behavioral function.Am J Clin Nutr. 2007;85(4):931–945

doi:10.1542/peds.2011-0201

Recommendations on Iron

Questioned

We read with interest the recently pub-lished clinical report by Baker, Greer, and the American Academy of Pediat-rics Committee on Nutrition1_{but were}

astonished to ﬁnd that the authors rec-ommended changing the recommen-dation on provision of iron, now to

in-clude all breastfed infants, on the basis of 1 clinical study while ignoring clinical studies that have suggested adverse effects of this practice. This is especially surprising because they, in their introduction, emphasized the need for larger studies and systematic reviews for evaluating the potential correlation between iron-deﬁciency anemia (IDA) and iron deﬁciency (ID) and neurodevelopment; they con-cluded that “an unequivocal relation-ship between IDA and ID and neurode-velopmental outcomes has yet to be established.”

In a study by Friel et al,2 _{which is the}

basis for the new recommendations, term breastfed infants were randomly selected to receive either 7.5 mg/day of elemental iron as ferrous sulfate or placebo from 1 month (study entry) to 6 months of age, and anthropometry and hematologic indexes were evalu-ated at entry and at 31_⁄₂_{, 6, and 12}

months of age. In addition, Mental and Psychomotor Developmental Indexes were assessed by using the Bayley scales, and visual acuity was assessed by Teller cards at 12 to 18 months of age.

One problem, which the authors ac-knowledged, is that the study was un-derpowered, partially because of the low initial breastfeeding rate in the population studied and partially be-cause of the high drop-out rate. In fact, the authors’ power calculation led them to conclude that 100 infants would be needed in each group to de-tect a 5% difference in the Mental and Psychomotor Developmental Indexes, but at 12 months of age only 26 and 20 infants, respectively, were available for intention-to-treat analyses, and only 24 and 17 had received iron for

⬎30 days (of the intended 150 days). There was a trend toward improved vi-sual acuity with iron supplementation, which became signiﬁcant only when excluding noncompliers. It is

question-able whether an effect on visual acuity as measured by Teller cards can be based on 17 and 23 infants at a mean age of 13 months (range: 12–18 months).3,4_{Power calculations for}

an-thropometry and hematologic indexes were not reported, but it is generally agreed that for anthropometry, con-siderably larger sample sizes are needed. From what we have learned during the last decades on the associ-ation of the intakes of docosa-hexaenoic acid (DHA) and neurodevel-opment, interpretations of the effect of single nutrients based on underpow-ered studies warrant caution.3–5_Friel

et al2_{found a difference of 7 points in}

the Psychomotor Developmental Index, and mean values for both groups were within the normal range.

The new recommendation is to give iron supplements, 1 mg/kg per day, to all breastfed infants (if breast milk constitutes more than half of the daily feedings) from 4 months of age until appropriate iron-containing comple-mentary foods are introduced into the diet. This recommendation is based on the observation by Friel et al2_that

in-fants in the intervention group had signiﬁcantly higher hemoglobin con-centrations and mean corpuscular volume values than the infants in the placebo group at 6 months of age, based on data from 28 and 21 infants, respectively.2 _{Iron supplements}

pre-vented the decrease in hemoglobin concentration seen in breastfed in-fants not given supplementary iron and reduced the decrease in serum ferritin level.

In our studies comparing various lev-els of iron content in infant formulas, we found no difference in hemoglobin concentration reﬂecting the difference in iron intake, and more iron in the for-mula did not prevent the decrease in hemoglobin concentration between 1 and 6 months of age.6,7_{In our study on}

the effects of giving exclusively breast-LETTERS TO THE EDITOR

PEDIATRICS Volume 127, Number 4, April 2011 e1099

at Viet Nam:AAP Sponsored on August 29, 2020

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fed infants iron supplements as iron drops, we found that giving supple-ments between 4 and 6 months in-creased hemoglobin levels.8 _{Thus, it}

seems that giving iron as a supple-ment affects hemoglobin levels differ-ently than giving more iron as fortiﬁca-tion in formulas.9_{Our interpretation is}

that an increased hemoglobin concen-tration does not necessarily reﬂect previous ID or IDA, but the effect may rather reﬂect immature metabolism of surplus iron. When we compared Hon-duran infants (with initially lower iron status) with Swedish infants (with sat-isfactory iron status), the change in hemoglobin levels between 4 and 6 months was similar (⫹5 g/L in both groups), which emphasizes that hemo-globin increases with iron supplemen-tation regardless of initial iron status. Thus, the suggestion by the authors to use hemoglobin response to iron sup-plementation as a diagnostic tool for IDA1_{is, in our view, highly questionable}

for that age group.

It should be noted that in the study by Friel et al,2 _{there was a slower}

de-crease in serum ferritin level in the in-tervention group, but the values con-tinued to decrease until 12 months of age and there was no difference be-tween the groups at that age, which also indicates that supplemental iron between 1 and 6 months did not affect iron stores at 12 months and supports our observation that supplemental iron, in contrast to fortiﬁcation iron, is not incorporated into ferritin during the ﬁrst half of infancy.9 _{These shifts}

in associations between dietary iron intake and hemoglobin and serum ferritin, respectively, may be a result of developmental changes in the channeling of dietary iron to erythro-poiesis relative to storage in the ab-sence of IDA.10_{We ﬁnd it notable that}

the authors did not clearly discrimi-nate between iron fortiﬁcation (ie, iron content in infant formulas)

and iron supplementation (ie, medic-inal iron given as iron drops) when discussing potential adverse effects of high iron intakes.

We have shown that iron supplements to iron-replete Swedish breastfed in-fants at the same level as now recom-mended in the clinical report had a sig-niﬁcant negative effect on linear growth. In contrast, there was no obvi-ous effect on growth in the Honduran cohort of the same study. However, when the latter infants were catego-rized as iron-deﬁcient or iron-replete infants, a negative effect was seen in the iron-replete subgroup.11 _This

re-sult most likely explains why this ad-verse effect has not been noted in more studies, because most popula-tions studied have included a signiﬁ-cant proportion of iron-deﬁcient in-fants and/or children and, thus, obscured a negative effect on iron-replete infants. In fact, when initial in-fant iron status has been measured and groups have been studied sepa-rately with regard to outcome, an ad-verse effect was noticed in several studies.12–14 _{Although these studies}

were performed in developing coun-tries, it is interesting that in a recent study by Ziegler et al,15 _{in which the}

effect of medicinal iron and iron-fortified cereals between 4 and 9 months of age was evaluated (ie, a de-sign similar to ours), a de-significant re-duction in length gain and a trend to-ward reduced weight gain was noted. Our suggestion that iron in fortified foods is handled differently from me-dicinal iron and that this needs to be taken into account when recommen-dations are given9_{is in agreement with}

results of the study by Ziegler et al,15

who observed the adverse effect in the infants given medicinal iron but not in the group given fortiﬁed cereals. Although we agree with the authors that few adverse effects have been noted for “high” iron-fortiﬁed infant

formulas (12 mg/L), we still believe that this level is unnecessarily high and that some caution is warranted. This is also the position taken by the European Society for Paediatric Gas-troenterology, Hepatology and Nutri-tion (ESPGHAN) coordinated interna-tional expert group on a global standard for the composition of infant formulas.16_{Although iron may be}

bet-ter absorbed from breast milk than from infant formula, it seems unrea-sonable that infant formula should contain⬃4000% more iron than the average concentration in breast milk. Several studies have shown similar iron status in infants who received in-fant formulas that contained 4 or 7 to 8 mg of iron per L, and in fact, we have shown similar iron status in infants fed formula that contained 1.8 mg of iron per L up to 6 months of age.7_Iron

is a known pro-oxidant, and having a high luminal concentration of iron may not be beneﬁcial, although the adverse consequences may not be immediately apparent. Infant formula that contains a high level of iron has been shown to be less protective against oxidative stress than breast milk in vitro,17_but

clinical studies on this subject have been scarce. Although we believe that the risk of adverse effects is lower with iron fortiﬁcation than with medicinal iron, the results of a recent study by Lozoff et al suggest a long-term nega-tive effect of high-iron formula on neurodevelopment.18

We also ﬁnd it surprising that Baker, Greer, and the Committee on Nutrition did not discuss the problem of diag-nosing ID and IDA during infancy when iron metabolism obviously is in dy-namic change (ie, if the same cutoffs for hemoglobin and serum ferritin should be used to deﬁne ID and IDA throughout infancy). We have sug-gested that this may not be the case.19

They also did not discuss particular groups at risk for ID among the

popu-e1100 LETTERS TO THE EDITOR

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lation of term breastfed infants (eg, those with a birth weight between 2500 and 3000 g).20

Friel et al concluded from their study that “[a] larger study that focuses on the long-term developmental out-comes is needed before recommenda-tions can be considered regarding the whole population of breast-fed in-fants.”2 _{We are surprised that Baker,}

Greer, and the Committee on Nutrition1

reached a different conclusion. We also do not believe that recommending iron supplements to the population of breastfed infants at large is appropri-ate or that an iron-fortiﬁcation level of infant formulas as high as 12 mg/L is necessary. In both cases we ﬁnd the lack of an evidenced-based approach remarkable, particularly because these recommendations will be used for US infants in general.

Olle Hernell, MD, PhD

Department of Clinical Sciences/Pediatrics Umeå University SE-901 85 Umeå, Sweden

Bo Lönnerdal, PhD

Department of Nutrition University of California Davis, CA 95616-5270

REFERENCES

1. Baker RD, Greer FR; American Academy of Pediatrics, Committee on Nutrition. Diagno-sis and prevention of iron deﬁciency and iron-deﬁciency anemia in infants and young children (0 –3 years of age). Pediatrics. 2010;126(5):1040 –1050

2. Friel JK, Aziz A, Andrews WL, Harding SV, Courage ML, Adams RJ. A double-masked, randomized control trial of iron supple-mentation in early infancy in healthy term breast-fed infants.J Pediatr. 2003;143(5): 582–586

3. SanGiovannia JP, Catherine S, Berkey CS, Dwyer JT, Colditz GA. Dietary essential fatty acids, long-chain polyunsaturated fatty ac-ids, and visual resolution acuity in healthy fullterm infants: a systematic review.Early Hum Dev. 2000;57(3):165–188

4. Simmer K, Patole SK, Rao SC. Longchain polyunsaturated fatty acid supplementa-tion in infants born at term.Cochrane Data-base Syst Rev. 2008;(1):CD000376

5. Beyerlein A, Hadders-Algra M, Kennedy K, et

al. Infant formula supplementation with long-chain polyunsaturated fatty acids has no effect on Bayley developmental scores at 18 months of age: IPD meta-analysis of 4 large clinical trials.J Pediatr Gastroenterol Nutr. 2010;50(1):79 – 84

6. Lönnerdal B, Hernell O. Iron, zinc, copper and selenium status of breast-fed infants and infants fed trace element fortiﬁed milk-based infant formula.Acta Paediatr. 1994; 83(4):367–373

7. Hernell O, Lönnerdal B. Iron status of infants fed low-iron formula: no effect of added bo-vine lactoferrin or nucleotides.Am J Clin Nutr. 2002;76(4):858 – 864

8. Domellöf M, Cohen RJ, Dewey KG, Hernell O, Rivera LL, Lönnerdal B. Iron supplementa-tion of breast-fed Honduran and Swedish infants from 4 to 9 months of age.J Pediatr. 2001;138(5):679 – 687

9. Domellöf M, Lind T, Lönnerdal B, Persson LA, Dewey KG, Hernell O. Effects of mode of oral iron administration on serum ferritin and haemoglobin in infants. Acta Paediatr. 2008;97(8):1055–1060

10. Lind T, Hernell O, Lönnerdal B, Stenlund H, Domellöf M, Persson LA. Dietary iron intake is positively associated with hemoglobin concentration during infancy but not during the second year of life.J Nutr. 2004;134(5): 1064 –1070

11. Dewey KG, Domellöf M, Cohen RJ, Landa Ri-vera L, Hernell O, Lönnerdal B. Iron supple-mentation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras.J Nutr. 2002; 132(11):3249 –3255

12. Idjradinata P, Watkins WE, Pollitt E. Adverse effect of iron supplementation on weight gain of iron-replete young children.Lancet. 1994;343(8908):1252–1254

13. Majumdar I, Paul P, Talib VH, Ranga S. The effect of iron therapy on the growth of iron-replete and iron-deplete children.J Trop Pe-diatr. 2003;49(2):84 – 88

14. Lind T, Seswandhana R, Persson LA, Lönner-dal B. Iron supplementation of iron-replete Indonesian infants is associated with re-duced weight-for-age.Acta Paediatr. 2008; 97(6):770 –775

15. Ziegler EE, Nelson SE, Jeter JM. Iron status of breastfed infants is improved equally by medicinal iron and iron-fortiﬁed cereal.Am J Clin Nutr. 2009;90(1):76 – 87

16. Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group.J Pediatr Gastroenterol Nutr. 2005;41(5): 584 –599

17. Friel JK, Martin SM, Langdon M, Herzberg GR, Buettner GR. Milk from mothers of both premature and full-term infants provides better antioxidant protection than does in-fant formula. Pediatr Res. 2002;51(5): 612– 618

18. Lozoff B, Castillo M, Smith JB. Poorer devel-opmental outcome with 12 mg/L iron-fortiﬁed formula in infancy [Abstr 2225]. Presented at: Pediatric Academic Societies annual meeting; May 2– 8, 2008; Honolulu, HI. EPASS2008:635340.2

19. Domellöf M, Dewey KG, Lönnerdal B, Cohen RJ, Hernell O. The diagnostic criteria for iron deﬁciency in infants should be reeval-uated.J Nutr. 2002;132(12):3680 –3686 20. Yang Z, Lönnerdal B, Adu-Afarwuah S, et al.

Prevalence and predictors of iron deﬁ-ciency in fully breastfed infants at 6 mo of age: comparison of data from 6 studies.Am J Clin Nutr. 2009;89(5):1433–1440

doi:10.1542/peds.2011-0201C

In Reply

Iron nutriture has always been a difﬁ-cult and controversial, but important, topic in pediatrics. It is not surprising that the American Academy of Pediat-rics’ clinical report on iron has gener-ated a number of letters. We thank Drs Schanler et al, Dr Furman, and Drs Her-nell and Lönnerdal for their comments on our report on iron.

The comments focus on the recom-mendation that term exclusively breastfed infants receive iron supple-mentation starting at 4 months of age and continue until a complementary dietary source of iron is established. In making this recommendation, we weighed the potential harm of not sup-plementing these infants with the po-tential harm of providing supplemen-tal iron. We readily admit that the evidence on either side of this equa-tion is not yet certain; however, we concluded that there was substantial and growing evidence of behavioral and developmental harm from iron de-ﬁciency and scant and yet-to-be-established evidence of deleterious ef-fects from iron supplementation. We also concluded that exclusively breast-LETTERS TO THE EDITOR

PEDIATRICS Volume 127, Number 4, April 2011 e1101

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DOI: 10.1542/peds.2011-0201C

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Pediatrics

Olle Hernell and Bo Lönnerdal

Recommendations on Iron Questioned

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Pediatrics

Olle Hernell and Bo Lönnerdal

Recommendations on Iron Questioned

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