DOI: 10.1542/peds.2011-0201C 2011;127;e1099Pediatrics

Olle Hernell and Bo LönnerdalRecommendations on Iron Questioned

  

  http://pediatrics.aappublications.org/content/127/4/e1099.full.html

located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from

I recognize that a great deal of hardwork and thought has gone into thesecurrent recommendations and thatthe authors used the best available in-formation well considered by experts.However, I believe it would be prefera-ble to do the best study possible andthen make a recommendation on thebasis of that evidence.

Lydia M. Furman, MD

Department of PediatricsRainbow Babies & Children’s Hospital

Cleveland, OH 44106

REFERENCES1. Baker RD, Greer FR; American Academyof Pediat-rics, Committee on Nutrition. Diagnosis and pre-ventionof irondeficiencyand iron-deficiencyane-mia in infants and young children (0–3 years ofage). 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 inearly infancy in healthy termbreast-fed infants.J Pediatr. 2003;143(5):582–586

3. Ziegler EE, Nelson SE, Jeter JM. Iron supple-mentation of breastfed infants from an earlyage. Am J Clin Nutr. 2009;89(2):525–532

4. DomellöfM,CohenRJ,DeweyKG,HernellO,RiveraLL, Lönnerdal B. Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9months 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 ofbreast-fed infants: results of a randomizedtrial 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 incognitive or behavioral function. Am J ClinNutr. 2007;85(4):931–945

doi:10.1542/peds.2011-0201

Recommendations on IronQuestionedWe read with interest the recently pub-lished clinical report by Baker, Greer,and the American Academy of Pediat-rics Committee on Nutrition1 but wereastonished to find that the authors rec-ommended changing the recommen-dation on provision of iron, now to in-

clude all breastfed infants, on thebasis of 1 clinical study while ignoringclinical studies that have suggestedadverse effects of this practice. This isespecially surprising because they, intheir introduction, emphasized theneed for larger studies and systematicreviews for evaluating the potentialcorrelation between iron-deficiencyanemia (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 beestablished.”

In a study by Friel et al,2 which is thebasis for the new recommendations,term breastfed infants were randomlyselected to receive either 7.5 mg/dayof elemental iron as ferrous sulfate orplacebo from 1 month (study entry) to6 months of age, and anthropometryand hematologic indexes were evalu-ated at entry and at 31⁄2, 6, and 12months of age. In addition, Mental andPsychomotor Developmental Indexeswere assessed by using the Bayleyscales, and visual acuity was assessedby Teller cards at 12 to 18 months ofage.

One problem, which the authors ac-knowledged, is that the study was un-derpowered, partially because of thelow initial breastfeeding rate in thepopulation studied and partially be-cause of the high drop-out rate. In fact,the authors’ power calculation ledthem to conclude that 100 infantswould be needed in each group to de-tect a 5% difference in the Mental andPsychomotor Developmental Indexes,but at 12 months of age only 26 and 20infants, respectively, were availablefor intention-to-treat analyses, andonly 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 whenexcluding noncompliers. It is question-

able whether an effect on visual acuityas measured by Teller cards can bebased on 17 and 23 infants at a meanage of 13 months (range: 12–18months).3,4 Power calculations for an-thropometry and hematologic indexeswere not reported, but it is generallyagreed that for anthropometry, con-siderably larger sample sizes areneeded. From what we have learnedduring the last decades on the associ-ation of the intakes of docosa-hexaenoic acid (DHA) and neurodevel-opment, interpretations of the effect ofsingle nutrients based on underpow-ered studies warrant caution.3–5 Frielet al2 found a difference of 7 points inthe Psychomotor Developmental Index,and mean values for both groups werewithin the normal range.

The new recommendation is to giveiron supplements, 1 mg/kg per day, toall breastfed infants (if breast milkconstitutes more than half of the dailyfeedings) from 4 months of age untilappropriate iron-containing comple-mentary foods are introduced into thediet. This recommendation is based onthe observation by Friel et al2 that in-fants in the intervention group hadsignificantly higher hemoglobin con-centrations and mean corpuscularvolume values than the infants in theplacebo group at 6 months of age,based on data from 28 and 21 infants,respectively.2 Iron supplements pre-vented the decrease in hemoglobinconcentration seen in breastfed in-fants not given supplementary ironand reduced the decrease in serumferritin level.

In our studies comparing various lev-els of iron content in infant formulas,we found no difference in hemoglobinconcentration reflecting the differencein iron intake, andmore iron in the for-mula did not prevent the decrease inhemoglobin concentration between 1and 6 months of age.6,7 In our study onthe effects of giving exclusively breast-

LETTERS TO THE EDITOR

PEDIATRICS Volume 127, Number 4, April 2011 e1099 at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from

fed infants iron supplements as irondrops, we found that giving supple-ments between 4 and 6 months in-creased hemoglobin levels.8 Thus, itseems that giving iron as a supple-ment affects hemoglobin levels differ-ently than givingmore iron as fortifica-tion in formulas.9 Our interpretation isthat an increased hemoglobin concen-tration does not necessarily reflectprevious ID or IDA, but the effect mayrather reflect immaturemetabolism ofsurplus iron. When we compared Hon-duran infants (with initially lower ironstatus) with Swedish infants (with sat-isfactory iron status), the change inhemoglobin levels between 4 and 6months was similar (�5 g/L in bothgroups), which emphasizes that hemo-globin increases with iron supplemen-tation regardless of initial iron status.Thus, the suggestion by the authors touse hemoglobin response to iron sup-plementation as a diagnostic tool forIDA1 is, in our view, highly questionablefor that age group.

It should be noted that in the study byFriel 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 ofage and there was no difference be-tween the groups at that age, whichalso indicates that supplemental ironbetween 1 and 6 months did not affectiron stores at 12 months and supportsour observation that supplementaliron, in contrast to fortification iron, isnot incorporated into ferritin duringthe first half of infancy.9 These shiftsin associations between dietary iron

intake and hemoglobin and serumferritin, respectively, may be a resultof developmental changes in thechanneling of dietary iron to erythro-poiesis relative to storage in the ab-sence of IDA.10 We find it notable thatthe 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) whendiscussing potential adverse effectsof high iron intakes.

We have shown that iron supplementsto 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 lineargrowth. In contrast, there was no obvi-ous effect on growth in the Hondurancohort of the same study. However,when the latter infants were catego-rized as iron-deficient or iron-repleteinfants, a negative effect was seen inthe iron-replete subgroup.11 This re-sult most likely explains why this ad-verse effect has not been noted inmore 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 measuredand groups have been studied sepa-rately with regard to outcome, an ad-verse effect was noticed in severalstudies.12–14 Although these studieswere performed in developing coun-tries, it is interesting that in a recentstudy by Ziegler et al,15 in which theeffect of medicinal iron and iron-fortified cereals between 4 and 9months of age was evaluated (ie, a de-sign similar to ours), a significant re-duction in length gain and a trend to-ward reduced weight gain was noted.Our suggestion that iron in fortifiedfoods is handled differently from me-dicinal iron and that this needs to betaken into account when recommen-dations are given9 is in agreement withresults of the study by Ziegler et al,15

who observed the adverse effect in theinfants given medicinal iron but not inthe group given fortified cereals.

Although we agree with the authorsthat few adverse effects have beennoted for “high” iron-fortified infant

formulas (12 mg/L), we still believethat this level is unnecessarily highand that some caution is warranted.This is also the position taken by theEuropean Society for Paediatric Gas-troenterology, Hepatology and Nutri-tion (ESPGHAN) coordinated interna-tional expert group on a globalstandard for the composition of infantformulas.16 Although iron may be bet-ter absorbed from breast milk thanfrom infant formula, it seems unrea-sonable that infant formula shouldcontain �4000% more iron than theaverage concentration in breast milk.Several studies have shown similariron status in infants who received in-fant formulas that contained 4 or 7 to 8mg of iron per L, and in fact, we haveshown similar iron status in infantsfed formula that contained 1.8 mg ofiron per L up to 6 months of age.7 Ironis a known pro-oxidant, and having ahigh luminal concentration of ironmaynot be beneficial, although the adverseconsequences may not be immediatelyapparent. Infant formula that containsa high level of iron has been shown tobe less protective against oxidativestress than breast milk in vitro,17 butclinical studies on this subject havebeen scarce. Although we believe thatthe risk of adverse effects is lowerwithiron fortification than with medicinaliron, the results of a recent study byLozoff et al suggest a long-term nega-tive effect of high-iron formula onneurodevelopment.18

We also find it surprising that Baker,Greer, and the Committee on Nutritiondid not discuss the problem of diag-nosing ID and IDA during infancy wheniron metabolism obviously is in dy-namic change (ie, if the same cutoffsfor hemoglobin and serum ferritinshould be used to define ID and IDAthroughout infancy). We have sug-gested that this may not be the case.19

They also did not discuss particulargroups at risk for ID among the popu-

e1100 LETTERS TO THE EDITOR at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from

lation of term breastfed infants (eg,thosewith a birthweight between 2500and 3000 g).20

Friel et al concluded from their studythat “[a] larger study that focuses onthe long-term developmental out-comes is needed before recommenda-tions can be considered regarding thewhole population of breast-fed in-fants.”2 We are surprised that Baker,Greer, and the Committee on Nutrition1

reached a different conclusion. Wealso do not believe that recommendingiron supplements to the population ofbreastfed infants at large is appropri-ate or that an iron-fortification level ofinfant formulas as high as 12 mg/L isnecessary. In both cases we find thelack of an evidenced-based approachremarkable, particularly becausethese recommendations will be usedfor US infants in general.

Olle Hernell, MD, PhD

Department of Clinical Sciences/PediatricsUmeå University

SE-901 85 Umeå, Sweden

Bo Lönnerdal, PhD

Department of NutritionUniversity of CaliforniaDavis, CA 95616-5270

REFERENCES1. Baker RD, Greer FR; American Academy ofPediatrics, Committee on Nutrition. Diagno-sis and prevention of iron deficiency andiron-deficiency anemia in infants and youngchildren (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 termbreast-fed infants. J Pediatr. 2003;143(5):582–586

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

4. Simmer K, Patole SK, Rao SC. Longchainpolyunsaturated 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 withlong-chain polyunsaturated fatty acids hasno effect on Bayley developmental scores at18 months of age: IPD meta-analysis of 4large clinical trials. J Pediatr GastroenterolNutr. 2010;50(1):79–84

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

7. Hernell O, Lönnerdal B. Iron status of infantsfed low-iron formula: no effect of added bo-vine lactoferrin or nucleotides. Am J ClinNutr. 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 Swedishinfants 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 oraliron administration on serum ferritin andhaemoglobin in infants. Acta Paediatr.2008;97(8):1055–1060

10. Lind T, Hernell O, Lönnerdal B, Stenlund H,Domellöf M, Persson LA. Dietary iron intakeis positively associated with hemoglobinconcentration during infancy but not duringthe 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 ofbreast-fed infants: results of a randomizedtrial in Sweden and Honduras. J Nutr. 2002;132(11):3249–3255

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

13. Majumdar I, Paul P, Talib VH, Ranga S. Theeffect 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-repleteIndonesian infants is associated with re-duced weight-for-age. Acta Paediatr. 2008;97(6):770–775

15. Ziegler EE, Nelson SE, Jeter JM. Iron statusof breastfed infants is improved equally bymedicinal iron and iron-fortified cereal. AmJ Clin Nutr. 2009;90(1):76–87

16. Koletzko B, Baker S, Cleghorn G, et al. Globalstandard for the composition of infantformula: recommendations of an ESPGHANcoordinated international expert group. JPediatr Gastroenterol Nutr. 2005;41(5):584–599

17. Friel JK, Martin SM, Langdon M, HerzbergGR, Buettner GR. Milk from mothers of bothpremature and full-term infants providesbetter 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 Societiesannual meeting; May 2–8, 2008; Honolulu,HI. EPASS2008:635340.2

19. Domellöf M, Dewey KG, Lönnerdal B, CohenRJ, Hernell O. The diagnostic criteria foriron 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 ofage: comparison of data from 6 studies. AmJ Clin Nutr. 2009;89(5):1433–1440

doi:10.1542/peds.2011-0201C

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

The comments focus on the recom-mendation that term exclusivelybreastfed infants receive iron supple-mentation starting at 4 months of ageand continue until a complementarydietary source of iron is established. Inmaking this recommendation, weweighed the potential harm of not sup-plementing these infants with the po-tential harm of providing supplemen-tal iron. We readily admit that theevidence on either side of this equa-tion is not yet certain; however, weconcluded that there was substantialand growing evidence of behavioraland developmental harm from iron de-ficiency and scant and yet-to-be-established evidence of deleterious ef-fects from iron supplementation. Wealso concluded that exclusively breast-

LETTERS TO THE EDITOR

PEDIATRICS Volume 127, Number 4, April 2011 e1101 at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from

DOI: 10.1542/peds.2011-0201C 2011;127;e1099Pediatrics

Olle Hernell and Bo LönnerdalRecommendations on Iron Questioned

  

ServicesUpdated Information &

htmlhttp://pediatrics.aappublications.org/content/127/4/e1099.full.including high resolution figures, can be found at:

References

html#ref-list-1http://pediatrics.aappublications.org/content/127/4/e1099.full.at:This article cites 18 articles, 8 of which can be accessed free

Citations

html#related-urlshttp://pediatrics.aappublications.org/content/127/4/e1099.full.This article has been cited by 1 HighWire-hosted articles:

Subspecialty Collections

y:oncology_subhttp://pediatrics.aappublications.org/cgi/collection/hematologHematology/Oncologythe following collection(s):This article, along with others on similar topics, appears in

Permissions & Licensing

mlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhttables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,

Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Suny Health Sciences on October 7, 2014pediatrics.aappublications.orgDownloaded from