Screening and RoutineSupplementation for Iron DeficiencyAnemia: A Systematic ReviewMarian S. McDonagh, PharmD, Ian Blazina, MPH, Tracy Dana, MLS, Amy Cantor, MD, MPH, Christina Bougatsos, MPH

abstractBACKGROUND AND OBJECTIVES: Supplementation and screening for iron-deficiency anemia (IDA) inyoung children may improve growth and development outcomes. The goal of this study was toreview the evidence regarding the benefits and harms of screening and routinesupplementation for IDA for the US Preventive Services Task Force.

METHODS: We searched Medline and Cochrane databases (1996–August 2014), as well asreference lists of relevant systematic reviews. We included trials and controlled observationalstudies regarding the effectiveness and harms of routine iron supplementation andscreening in children ages 6 to 24 months conducted in developed countries. One authorextracted data, which were checked for accuracy by a second author. Dual quality assessmentwas performed.

RESULTS: No studies of iron supplementation in young children reported on the diagnosisof neurodevelopmental delay. Five of 6 trials sparsely reporting various growth outcomesfound no clear benefit of supplementation. After 3 to 12 months, Bayley Scales of InfantDevelopment scores were not significantly different in 2 trials. Ten trials assessing ironsupplementation in children reported inconsistent findings for hematologic measures.Evidence regarding the harms of supplementation was limited but did not indicatesignificant differences. No studies assessed the benefits or harms of screening orthe association between improvement in impaired iron status and clinical outcomes.Studies may have been underpowered, and control factors varied and could haveconfounded results.

CONCLUSIONS: Although some evidence on supplementation for IDA in young children indicatesimprovements in hematologic values, evidence on clinical outcomes is lacking. No randomizedcontrolled screening studies are available.

Department of Medical Informatics & Clinical Epidemiology, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Portland, Oregon

Dr McDonagh conceptualized and designed the review, conducted analyses, and edited the draft and final versions of the manuscript; Mr Blazina and Ms Danaconceptualized and designed the review, conducted analyses, and reviewed and revised the manuscript; Dr Cantor conceptualized and designed the review; MsBougatsos conceptualized and designed the review, and edited the draft and final versions of the manuscript; and all authors approved the draft and final versions ofthe manuscript.

The investigators are solely responsible for the content and the decision to submit it for publication. The findings and conclusions in this document are those of theauthors, who are responsible for its content, and do not necessarily represent the views of the Agency for Healthcare Research and Quality. No statement in this reportshould be construed as an official position of the Agency for Healthcare Research and Quality or of the US Department of Health and Human Services.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-3979

DOI: 10.1542/peds.2014-3979

Accepted for publication Jan 13, 2015

Address correspondence to Marian McDonagh, PharmD, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code: BICC, Portland, OR 97239. E-mail:mcdonagh@ohsu.edu

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Iron-deficiency anemia (IDA), definedas iron deficiency (serum ferritin,12 µg/L) with hemoglobin levels,110 g/L,1,2 can present a significantburden of disease in infancy andchildhood. Iron is required in theproduction of hemoglobin, anessential protein found in red bloodcells, and is stored in the body for usein hemoglobin production. Irondeficiency occurs when the level ofstored iron becomes depleted. IDAoccurs when iron levels aresufficiently depleted to produceanemia, characterized byhypochromic microcytic red bloodcells.3 Although infants in the UnitedStates with iron deficiency are usuallyasymptomatic, IDA has beenassociated in some observationalstudies with cognitive and behavioraldelays in children. However, thesestudies had methodologic flaws4; forexample, the outcomes examinedwere varied and not clearly clinicallyimportant. The effect of IDA ininfancy and childhood has beenreported in few well-designed, long-term controlled studies.

Iron deficiency among infants andtoddlers in the United States hasa prevalence of ∼8% in the generalpopulation5–7; however, only aboutone-third of children who are irondeficient have associated anemia.5,8,9

The prevalence of IDA in childrenbetween the ages of 1 and 5 years isestimated to be ∼1% to 2% in theUnited States.8,10 The prevalence inchildren from low-income families isestimated to be slightly higher (ie, ∼3%for boys and 4% for girls based on1 study of 432 one- to three-year-oldchildren residing in California).7

Current evidence regarding theprevalence of IDA in infants ,1 yearold in the United States is lacking,although estimates for low-risk infantsin other developed countries rangefrom 2% to 4%.11,12 Screening youngchildren for IDA may lead to earlieridentification and therefore earliertreatment, which has the potential toprevent negative health outcomes.However, the advent of iron fortification

in the United States in many children’sfood products may influence ourcurrent understanding of IDA.

In 2006, the US Preventive ServicesTask Force (USPSTF) concluded thatthe evidence was insufficient torecommend for or against routinescreening for IDA or routine ironsupplementation for asymptomaticchildren aged 6 to 12 months who areat average risk for IDA(I Recommendations).13 Theserecommendations were based ona lack of evidence that screeningresulted in improved healthoutcomes, as well as poor andconflicting evidence regarding thebenefit of iron supplementation inchildren who are not at increased riskof IDA. At that time, the USPSTFrecommended routine ironsupplementation for asymptomaticchildren aged 6 to 12 months who areat increased risk for IDA (BRecommendation), based on evidencethat iron supplementation mayimprove neurodevelopmentaloutcomes in children who are atincreased risk of IDA, whichoutweighs any potential harms.

The present review wascommissioned by the USPSTF toupdate the previousrecommendations.13 The scope of thisreview includes evidence regardingthe benefits and harms of routine ironsupplementation, screening for IDAin children ages 6 to 24 months, andthe association between a change iniron status and improvement in childhealth outcomes in populationsrelevant to the United States.

METHODS

Detailed methods and data for thisreview (including search strategies,inclusion criteria, abstraction andquality rating tables, information onrisk factors and risk assessment tools,and results related to biochemical andcomposite intermediate outcomes) areprovided in the full report.14 Theprotocol was developed by usinga standardized process15 with input

from experts and the public. Inconsultation with the USPSTF, analyticframeworks and Key Questions weredeveloped for routine supplementation(Supplemental Appendix Figure 2) andfor screening for IDA (SupplementalAppendix Figure 3) to show thelinkages between Key Questions andbodies of evidence.

A research librarian searched theCochrane Central Register ofControlled Trials, the CochraneDatabase of Systematic Reviews(through the second quarter, 2014),and Medline (1996–August 2014) forrelevant studies to update theprevious USPSTF reviews.16,17

Because the previous researchfocused on systematic reviews andkey studies of treatments for IDA, wealso searched the reference lists ofsystematic reviews18–20 to identifyany additional, relevant studiespublished before 1996.

Studies were selected on the basis ofinclusion and exclusion criteriadeveloped for each Key Question.Articles were selected for full reviewif they were related to IDA in childrenwho received an intervention(supplementation or screening andrelated treatment) between the agesof 6 and 24 months. We restrictedinclusion to English-language articlesand excluded studies published onlyas abstracts. For all Key Questions,the focus was on studies that involvediron supplementation and treatmentregimens commonly used in clinicalpractice in the United States. Weexcluded studies conducted inresource-poor populations, includingnutritionally deficient populationsin developing countries and populationsin areas expected to have a highprevalence of hemoparasites, byselecting studies conducted incountries listed as having “high” or“very high” human developmentbased on the international UnitedNations Human DevelopmentIndex.21 At least 2 reviewersindependently evaluated each studyto determine eligibility.

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Clinical outcomes of study weremorbidity (including growth;cognitive, psychomotor, andneurodevelopmental outcomes; anddiagnosis of developmental delay),mortality, and quality of life. Harmoutcomes included accidentaloverdose, study discontinuations,and other harms related toscreening, supplementation, ortreatment. Included intermediateoutcomes were incidence of IDA,iron deficiency, and anemia, as wellas hematologic indices such asferritin levels. Randomizedcontrolled trials, nonrandomizedcontrolled clinical trials,and controlled cohort studies wereincluded for all Key Questions.

Details about the study design,patient population, setting, screeningmethod, interventions, analysis,follow-up, and results wereabstracted. A second investigatorreviewed the data abstraction foraccuracy. Two investigatorsindependently applied criteriadeveloped by the USPSTF15 to ratethe internal validity (quality) of eachstudy as good, fair, or poor.Discrepancies were resolved througha consensus process. When otherwisenot reported and where possible,relative risks (RRs) and 95%confidence intervals (CIs) or P valueswere calculated.

The aggregate quality of the body ofevidence for each Key Question (ie,good, fair, poor) was assessed byusing methods developed by theUSPSTF; these assessments werebased on the number, quality and sizeof studies; consistency of resultsbetween studies; and directness ofevidence.15 Meta-analysis was notattempted due to the limited numberof studies for each Key Question anddifferences among studies in design,population, and outcomes.

RESULTS

Figure 1 shows the results of theliterature search and selectionprocess.

Routine Iron Supplementation

Benefits of Routine IronSupplementation in Children Ages 6 to24 Months

A 1996 review conducted for theUSPSTF17 found adequate evidencethat iron prophylaxis resulted inreductions in the incidence of irondeficiency and IDA, but few datafocusing on clinical outcomes werereported. The 2006 update16 did notassess the effect of supplementationon intermediate outcomes, and itfound mixed evidence regarding thebenefit of iron supplementation onneurodevelopmental test scores.

Overall, 10 trials of ironsupplementation were included in thisupdate.22–34 One study was rated asgood quality,29 7 as fair quality,22–28,32

and 2 as poor quality.30,31 In general,children were enrolled between 6 and9 months of age. Iron supplementationwas administered for durationsranging from 3 to 18 months.Supplementation was provided as oraliron drops, iron-fortified formula, andas iron-fortified milk, foods, or meat.Controls used in the studies varied,and included a non-iron-containingformula or supplement, a specific diet,cow’s milk, or nothing. Race orethnicity was poorly reported.Enrolled sample sizes ranged from 24to 493, except for 1 larger study of1798 children; many studies analyzedfewer numbers due to loss to follow-up or refusal to undergo venipuncture.Only 1 study analyzed children on anintention-to-treat basis29; theproportion of the sample available foranalysis at the end of the other studiesranged from 53% to 92%. Moststudies excluded children bornprematurely and those with conditionslikely to affect iron absorption, growth,or development, thus ruling outsome children at higher than averagerisk for IDA but not specificallytargeting those at average risk.

Methodologic shortcomings includedunclear methods of randomizationand allocation concealment,25–27,30–32

lack of or unclear methods of

blinding,22,23,25,27,30,31 and high ordifferential loss to follow-up.24,27,28,30,31 In addition, studiesmay be underpowered; although7 studies reported some power orsample size calculations, they werelimited to certain outcomes andvarying differences in effectsizes.24,26–29,31,32 For example,2 studies were reported to bepowered for developmental outcomes,with 1 sufficient to detect a 5-pointdifference on the Bayley Scales ofInfant Development28 and 1 sufficientto detect a 2.5-point difference in“developmental scores” (scale notmentioned).26 We did not pool theresults because of the heterogeneity ofthe studies in terms ofsupplementation method, dose,duration, timing of initiation andfollow-up, and methodologiclimitations. In addition, risk factorswere largely not reported, and nostudies stratified results according torisk groups.

Six fair-quality placebo-controlledtrials of routine iron supplementationin young children sparsely reportedvarious growth outcomes; 5 trialsfound no clear effect ofsupplementation on weight, length,or head circumference after 3 to12 months of follow-up(Table 1).22,25,26,28–30 As notedearlier, studies may have beenunderpowered to detect growthoutcomes. Most sample sizes variedfrom 70 to 428, with 1 studyincluding 1657 children. The onlystudy reporting statisticallysignificant differences in growthparameters found lesser growthvalues in the iron-supplementedgroup, possibly due to baselinedifferences in these growthoutcomes.26 The group that receivediron began the study with lesservalues (weight: 7.98 vs 8.09 kg;length: 66.6 vs 66.9 cm [bothP, .01]). Although this study was thelargest, it was conducted in Chile, hada high incidence of IDA in the controlgroup (22.6%), and suffered frommethodologic flaws. Children were

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initially randomized to receive low-or high-iron supplementation, but thelow-iron intervention was replacedwith a no-iron intervention partiallythrough the study, partly because theinterim analysis suggested that thelow-iron condition was sufficient toprevent IDA. For analysis, all childrenwho received any ironsupplementation were combined andcompared with children who did notreceive supplementation, breakingrandomization and leading tobaseline differences between thegroups. Because randomization wasbroken, we viewed the results asa fair-quality, comparativeobservational study. The authorsfound the following significant resultsfor the iron-supplemented versus

no-iron groups, respectively, after12 months: weight, 10.0 vs 10.1 kg(P , .05); length, 74.7 vs 75.1 cm(P , .001); length for age (z score),–0.27 vs –0.15 (P , .01); and headcircumference, 46.7 vs 47.0 cm(P, .001); the changes were significantpossibly because the iron-supplemented group had lowervalues at baseline. Other clinicaloutcomes, such as diagnosis ofpsychomotor or neurodevelopmentaldelay or quality of life, were notreported in any trial.

Although not clearly clinical outcomes,developmental test scores after follow-up periods of 3 to 12 months werereported in 3 fair-quality trials.23,26,28

Two trials (N = 428 and 1657,respectively), including the Chilean

study with methodologic flawsmentioned earlier, found nostatistically significant differencebetween groups on the Bayley Scalesof Infant Development (Table 2).Differences between groups weresmall and ranged from 0.6 to 0.7 onmental development and 0.2 to 0.7 forpsychomotor development.26,28 Onetrial of children potentially at higherrisk for IDA used the Griffiths scale tomeasure psychomotor development.23

Although scores in both groupsdeclined and were within normallimits at 24 months, they declined lessin the iron-supplemented group(general quotient score at 24 months:–9.3 vs –14.7; P = .04).

Ten trials of iron supplementation inchildren reported inconsistent

FIGURE 1Literature flow diagram. aCochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of SystematicReviews. bOther sources include previous reports, reference lists of relevant articles, and systematic reviews. cSome studies are included for .1 KeyQuestion (KQ). dIncludes 2 poor-quality studies.

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TABLE1

Good-QualityandFair-QualityTrialsof

Iron

Supplementationin

ChildrenAges

6to

24Monthson

HematologicandGrow

thOutcom

es

Study,Year,Country,N,

Duration;Quality

Risk

FactorsReported

Interventions

and

Comparator

Outcom

es:S

upplem

entationVersus

ControlGroups

IDA(Hb,110g/Land

Iron

Deficiency

a )Anem

ia(Hb,110g/L)

Iron

Deficiency

aHb

Serum

Ferritin

Grow

th

Domellöfet

al,2001,32

Sweden,N

=70,

3mo;fair

Race:N

otreported;

Preterm

andlow

birthweightinfants

excluded

A.Placebofrom

4to

6moandiron

supplementfrom

6to

9moof

age

(n=34)

Noeffect

(num

bers

notreported)

——

117.1vs

114.4g/L;

P=NS

47.3vs

22.9mg/L;

P,

.001

Weightat

9mo:8.9vs

8.9kg

(P=NS)

B.Placebofrom

4to

9mo(n

=36)

Geltm

anet

al,2004,24

UnitedStates,N

=284,3mo;fair

Race:55%

vs48%

black;Preterm

and

lowbirthweight

infantsexcluded

A.Oral

multivitamin

drops,10

mgof

iron/d

8%(11/138)

vs8%

(11/144)

anem

icandhad2other

abnorm

alhematologicvalues;

RR:1.04(95%

CI:

0.47–2.33)

22%

(31/138)

vs19%

(27/144);R

R:1.20

(95%

CI:0.76–1.90)

78%

(108/138)vs

84%

(121/144)had1

abnorm

alhematologicvalue

indicativeof

iron

deficiency;R

R:0.93

(95%

CI:0.83–1.04)

117vs

117g/L;P=NS

32.0vs

29.2mg/L;

P=NS

—

B.Multivitamin

dropswithout

iron

Gillet

al,1997,25

UnitedKingdom

andIreland,

N=

302,11

mo;fair

Race:not

reported;

Preterm

andlow

birthweightinfants

excluded

A.Iron-fortified

form

ula

—11%

vs13%

vs33%b

6%vs

22%

vs43%b

121.5vs

117.7vs

111.4

g/L;P=.006

c25.1vs

15.3vs

11.0

mg/L;P,

.001

Weight:11.1vs

11.1vs

11.3kg

(P=NS);

Length:78.9vs

79.1

vs80.3cm

(P=NS)

B.Noniron-fortified

form

ula

C.Cow’smilk

Lozoffet

al,2003,26

Chile,N

=1657,

6–12

mo;fair

Race:not

reported;

Preterm

andlow

birthweightinfants

excluded

A.Multiple

interventions

with

varyingiron

concentrations

3.1%

(34/1114)vs

22.6%

(116/514);

RR:0.14(95%

CI:

0.09–0.20)

4.3%

(48/1123)vs

25.8%

(138/534);

RR:0.17(95%

CI:

0.12–0.23)

26.5%

(286/1081)

vs51.3%

(273/532);

RR:0.52(95%

CI:

0.45–0.59)

123.6vs

115.6g/L;

P,

.001

14.0vs

8.7mg/L;

P,

.001

Weight:10.0vs

10.1kg

(P,

.05);W

eight

forage(z

score):

0.05

vs0.13

(P=NS)

B.No

iron

supplementation

Length:74.7vs

75.1

cm(P

,.001);

Length

forage

(zscore):–

0.27

vs–0.15

(P,

.01)

Head

circum

ference:

46.7vs

47.0cm

(P,

.001)

Makridesetal,1998,27

Australia,N

=62,

6mo;fair

Race:not

reported;

Preterm

andlow

birthweightinfants

excluded

A.High-iron

weaning

diet

0vs

00vs

19.2%

(5/26);

RR:0.07(95%

CI:

0.00–1.15)

3.9%

(5/36)

vs7.7%

(2/26);R

R:1.81

(95%

CI:0.38–8.60)

120vs

115g/L;P=NS

26vs

35mg/L;P=NS

—

B.Controlweaning

diet

Morleyet

al,1999,28

UnitedKingdom,

N=428,9mo;fair

Race:not

reported;

Preterm

andlow

birthweightinfants

excluded

A.Iron-fortified

form

ula,1.2mg

iron/L

——

—126vs

120vs

119g/L;

P,

.01forA

versus

C,P,

.05

forAversus

B

21.7vs

13.1vs

14.3

mg/L;P,

.0001for

Aversus

BandA

versus

C

Weight:11.4vs

11.3vs

11.4kg

(P=NS);

Length:82.3vs

82.3

vs82.6cm

(P=NS)

B.Unfortified

form

ula,0.9mg

iron/L

C.Cow’smilk

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findings for incidence of IDA, irondeficiency, and anemia, as well aschanges in hemoglobin and serumferritin (Table 1 [poor-quality studieswere omitted from tables]).22,24–32

Iron supplementation was not found toinfluence the incidence of IDA in4 good- or fair-quality studies(N values ranged from 62 to284).24,26,27,29,32 One study, theaforementioned larger Chilean study(N = 1657) with a high incidence ofIDA in the control group (22.6%) andmethodologic flaws regardingrandomization, reported a significantbenefit (RR: 0.14 [95% CI:0.09–0.20]).26 Overall, the studiesreported ranges of IDA from 0% to 8%for those in the supplementation groupand 0% to 22.6% in the placebo group.

For incidence of iron deficiency,2 fair-quality studies with highincidences in the control groupssuggest a significant benefit ofsupplementation. These findingsincluded 1 study (N = 302) thatcompared iron-fortified formula withnoniron-fortified formula and cow’smilk (6% vs 22% vs 43%)24 and thelarge (N = 1657) Chilean study(26.5% vs 51.3%; RR: 0.52 [95% CI:0.45–0.59]).26 Three other studiesfound no difference in rates of irondeficiency,24,27,30 including the onlystudy conducted in the United States(RR: 0.94 [95% CI: 0.74–1.20]).24

Overall, the studies reported rates ofiron deficiency ranging from 3.9% to78% for those in the supplementationgroup and from 7.7% to 84% in theplacebo group.

Six trials (5 fair-quality and 1 poor-quality; N values ranged from 62 to1657) reported the effect ofsupplementation on the rate ofanemia (variably defined ashemoglobin ,100–110 g/L,sometimes in combination with otherabnormal iron measures).22–27,30

Two of these studies (from the UnitedStates and the United Kingdom)found no clear benefit fromsupplementation.24,25 The remainder,including the large Chilean study,TA

BLE1

Continued

Study,Year,Country,N,

Duration;Quality

Risk

FactorsReported

Interventions

and

Comparator

Outcom

es:S

upplem

entationVersus

ControlGroups

IDA(Hb,110g/Land

Iron

Deficiency

a )Anem

ia(Hb,110g/L)

Iron

Deficiency

aHb

Serum

Ferritin

Grow

th

Szym

lek-Gayet

al,

2009,29New

Zealand,

N=225,5

mo;good

Race:84%

vs78%

vs76%

white

A.$2portions

ofredmeat,1.3mg

ofiron

per

portion

Nodifferencebetween

groups

(dataonly

reported

inafigure)

——

118.6vs

121.5vs

120.2

g/L;P=NS

32.8vs

43.5vs

29.9

mg/L;effect

size

infortified

milk

group

1.68

(95%

CI:

1.27–2.24)

Noeffect

ongrow

th

B.Iron-fortified

milk,

1.5mgiron/100

gC.

Cow’smilk

Williamset

al,1999,23

otherpublication:

Dalyet

al,1996,22

UnitedKingdom,

N=92,10–12

mo;

fair

Race:74%

white,24%

black,2%

Asian;

Receivingincome

support:59%;

Preterm

andlow

birthweightinfants

excluded

A.Iron-

supplemented

form

ula,1.2mg

iron/100

mL

—At

18moof

age:2%

(1/46)

vs33%

(15/

46);RR

:0.07(95%

CI:0.01to

0.48)

——

30.5vs

15.9mg/L;

P=.001

Noeffect

ongrow

th(datanotshow

n)

B.Cow’smilk

Twotrialswereom

itted

from

thetabledueto

poor-qualityrating(Yalçinet

al,20003

0andYeungandZlotkin,

2000

31).Hb,hem

oglobin;

NS,not

significant.

aIron

deficiency

was

definedvariablyas

serum

ferritin,10

mg/L,25,27,30,15

mg/L,24or

,12

mg/Lin

additionto

1of

2otherhematologicindicators.26

bRR

notcalculable

basedon

data

reported.

cGroups

differedsignificantlyat

baseline.

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reported significant benefits, withRRs ranging from 0.07 (95% CI:0.01–0.48)26 to 0.14 (95% CI:0.09–0.20).23 However, variability inthe definitions of anemia, theunknown mix of baseline risk ofchildren enrolled, and the variation incontrol group rates across thesestudies (from 13% to 33%) limit theinterpretability of the findings for USpopulations. Overall, the studiesreported rates of anemia rangingfrom 0% to 22% for those in thesupplementation group and from13% to 33% in the placebo group.

In addition, hemoglobin results werereported in 8 studies,24–30,32 withsmall differences between groups; 3were significant.25,26,28 Nine studiesreported ferritin concentrations, withconflicting results.22–30,32

Harms of Routine Iron Supplementationin Children Ages 6 to 24 Months

None of the studies of ironsupplementation reported seriousharms, including accidental overdoseor withdrawals due to adverse events.Five studies reported on adherence tothe assigned regimen and found noimpact based on iron content. In somecases, however, the control group waspreferred (eg, cow’s milk over fortifiedor unfortified formula).24,28–31

In 1 fair-quality trial, no clinicallysignificant adverse events thought tobe related to study interventionswere reported.25 No differences inrate of gastrointestinal adverseevents in toddlers consuming iron-fortified milk and those consumingunfortified milk were found in

a good-quality trial (2% vs 2%; RR:1.0 [95% CI: 0.9–11]).29 No otherstudies reported the incidence ofgastrointestinal adverse events.

Screening for IDA

Benefits and Harms of ScreeningAsymptomatic Children Ages 6 to24 Months for IDA

As in previous reviews,16,17 nostudies evaluating the benefits orharms of screening programs forasymptomatic children ages 6 to24 months for IDA were found.

Benefits and Harms of Treatment of IDAin Children Ages 6 to 24 Months

No new studies of oral iron treatmentof IDA in infants and children 6 to24 months of age were found. Of thestudies included in the previousreviews, only 1 study (N = 110) metour current criteria.35 This study wasrated as poor quality due to baselinedifferences in age and unclearreporting of methods. Improvedgrowth velocity and hemoglobin andferritin levels were found, but nodifferences were reported in DenverDevelopmental Screening Testpsychomotor development outcomescompared with control subjects.

No newly published studiesreporting harms of iron treatment inchildren ages 6 to 24 months werefound. One older randomizedcontrolled trial (N = 334), publishedin 199136 and not included in theprevious reviews, reported nodifferences between childrenreceiving iron treatment and thosereceiving placebo in overall

incidence or incidence of specificadverse events, includinggastrointestinal events.

Association Between a Change in IronStatus and Improvement in Child HealthOutcomes in Populations Relevant to theUnited States

No studies met the establishedcriteria to evaluate an associationbetween improvement in impairediron status and child health outcomesin populations relevant to the UnitedStates.

One poor-quality and 2 fair-qualitysupplementation studies providedevidence regarding changes in ironstatus and measures of growth ordevelopment scale scores in childrenwith normal iron status atbaseline.22,25,30 Two fair-qualitystudies (Table 3) found statisticallysignificant changes in iron statusmeasures but no differences betweengroups in measures of weight orheight after 9 and 18 months.22,25 Apoor-quality trial found largenumerical (but nonsignificant)differences in hemoglobin and serumferritin levels and a significantdifference in transferrin saturation,but no differences in weight, height,or head circumference outcomes or inneurodevelopmental outcomes basedon the Bayley Scales of InfantDevelopment.30

DISCUSSION

As in the previous USPSTFreviews,16,17 we found no evidenceregarding the effects of routine ironsupplementation in young children on

TABLE 2 Bayley Scales of Infant Development Outcomes in Iron Supplementation Studies

Study, Year, Country,N; Quality

Duration Risk FactorsReported

Interventions andComparator

Mental DevelopmentIndex

PsychomotorDevelopment Index

Lozoff et al, 2003,26

Chile, N = 1657;fair

6 mo Race: Not reported; Pretermand low birth weight infantsexcluded

A. Multiple interventions withvarying iron concentrations

103.9 vs 104.6; P = NS 96.7 vs 97.5; P = NS

B. No iron supplementationMorley et al, 1999,28

United Kingdom,N = 428; fair

9 mo Race: Not reported; Pretermand low birth weight infantsexcluded

A. Iron-fortified formula,1.2 mg of iron/L

93.9 vs 94.5 vs 96.2;P = NS

94.8 vs 94.6 vs 93.6;P = NS

B. Unfortified formula,0.9 mg of iron/L

C. Cow’s milk

One trial omitted from table due to poor-quality rating (Yalçin et al, 200030). NS, not significant.

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diagnosis of psychomotor orneurodevelopmental delay or quality oflife, and the evidence regardingdevelopmental test scores after 3- to12-month follow-up periods (althoughnot clearly clinical outcomes) does notindicate important differences.23,26,28,30

We found no evidence of important orclear benefit in growth outcomes,which is consistent with the findings ofa recent meta-analysis of 21randomized controlled trials thatincluded studies from any country.18

Although the study findings are notconsistent, the evidence from10 trials of iron supplementation inchildren indicates no benefit in termsof incidence of IDA, anemia, orhemoglobin; the findings wereinconsistent regarding incidence ofiron deficiency and serum ferritinconcentrations.22–32

Some of the variation in findings mayhave been due to inadequate samplesizes for specific outcomes. Thissituation is often ideal for poolingstudies to gain statistical power; inthis case, however, we found bothclinical and methodologic

heterogeneity and did not combinethe studies. For example, there wasimportant variability in thedefinitions of IDA, anemia, and irondeficiency (mostly unknown baselinerisk of children enrolled) and widevariation in control group ratesacross these studies. Although theprevalence rates of iron deficiency inthe United States are currentlyestimated at 8%5–7, control grouprates in these studies ranged from13% to 33%, such thatgeneralizability of these findings tothe US population is unclear. Studiesthat did find a benefit generally hadhigher rates of iron deficiency in thecontrol groups compared with studieswhich found no benefit, suggestingthat baseline risk is important indetermining who will benefit fromsupplementation, in terms ofpreventing iron deficiency. Anadditional factor potentiallycontributing to variability was the useof cow’s milk as a control in severalstudies; use of cow’s milk isconsidered a risk factor for IDA and isadvised against before 12 months ofage by the American Academy of

Pediatrics, and the Centers forDisease Control and Prevention.2,37,38

In addition, 1 of the largest studiesincluded in the review thatconsistently found statisticallysignificant results supportingsupplementation for mosthematologic values was conducted inChile and had a high incidence ofhematologic values in the controlgroups. This study, which initiallyrandomized children to receive low-or high-iron supplementation, brokerandomization, leading to baselinedifferences between the groups.26

Harms of routine iron supplementationin children were rarely reported, andsupplementation did not result inhigher rates in studies reportingharms. Although an older meta-analysis of 28 studies (randomizedcontrolled trials and cohort studies)found a slightly increased risk ofdiarrhea with iron supplementation(RR: 1.1 [95% CI: 1.0–1.2]),39 themajority of studies were conducted indeveloping countries, and the age ofthe populations ranged from 2 days to14 years.

TABLE 3 Association Between Change in Iron Status and Health Outcomes

Study, Year,Country,N; Quality

Duration InterventionGroups

Baseline IronStatus

Follow-up IronStatus

Mean Change inIron Status

Health Outcomes

Daly et al, 1996,22

United Kingdom,N = 100; fair

18 mo A. Iron-fortifiedformula (n = 41)

A vs B A vs B A vs B A vs BHemoglobin: 119 vs120 g/L

Hemoglobin: 124 vs118 g/L

Hemoglobin: 5.0 vs–2.0 g/L (P , .0001)

No difference betweengroups in weight forage, weight for height,or height for age (datanot shown)

B. Cow’s milk (n =43)

Serum ferritin: 33.2 vs34.6 mg/L

Serum ferritin: 32.4 vs14.9 mg/L

Serum ferritin: 0.8 vs–19.7 mg/L (P , .0001)

Gill et al, 1997,25

N = 406; UnitedKingdom andIreland; fair

9 mo A. Iron-fortifiedformula (n =264)

A vs B vs C A vs B vs C A vs B vs C A vs B vs CHemoglobin: 118.9 vs116.6 vs 114.4 mg/L

Hemoglobin: 121.5 vs117.7 vs 111.4 mg/L

Hemoglobin: 2.6 vs 1.1vs –3.0 mg/L (A versusB and C, P , .01)

Weight, mean changefrom baseline: 11.1(3.2) kg vs 11.1 (3.1) kgvs 11.3 (3.0) kg (P = NSfor all comparisons)

B. Formula withoutiron fortification(n = 85)

Serum ferritin: 41.6 vs42.3 vs 31.9 mg/L

Serum ferritin: 25.1 vs15.3 vs 11.0 mg/L

Serum ferritin: –16.5 vs–27.0 vs –20.9 mg/L(A vs B and C, P , .001)

Length, mean changefrom baseline: 79.1(11.3) cm vs 78.9 (11.5)cm vs 80.3 (12.2) cm(P = NS for allcomparisons)

Serum iron: 14.9 vs13.9 vs 12.5 mmol/L

Serum iron: 14.4 vs12.9 vs 10.0 mmol/L

Serum iron: –0.5 vs –1.0vs –2.5 mmol/L (A vs Band C, P = .04)

C. Cow’s milk (n =57)

Total iron-bindingcapacity: 61.1 vs 59.0vs 64.9 mmol/L

Total iron-bindingcapacity: 63.0 vs 70.3vs 73.2 mmol/L

Total iron bindingcapacity: 1.9 vs 11.3 vs8.3 mmol/L (A vs B andC, P = .05)

One poor-quality trial was omitted from the table (Yalçin et al, 200030). NS, not significant.

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As in the previous reports, evidenceregarding the benefits and harms ofscreening for IDA in children ages 6 to24 months is absent. Similarly, we foundonly very limited evidence regarding thebenefits and harms of IDA treatmentthat is generalizable to children ages 6to 24 months in the United States.Based on this evidence, benefits wereshown only for some iron statusmeasures in the short term. PreviousUSPSTF reports concluded that therewas no evidence regarding the relativeharms of treatment. This updateidentified only 1 additional study, whichindicated no differences betweenchildren receiving iron supplementationand placebo in the incidence of overallor specific adverse events, includinggastrointestinal events.36

The potential for long-term benefit ofpreventing IDA in young childrenpresumes that improvement in ironstatus is associated with good long-term clinical outcomes, such asnormal growth andneurodevelopment. Evidence capableof showing this specific associationwas extremely limited and did notsupport a clear association betweenchange in iron status and differencesin growth or neurodevelopment.

Limitations of our report includerestricting inclusion of studies

published in English and studiesconducted in developed countries orstudies in developing countries wherethe population enrolled was similar tothe population of the United States,particularly in terms of rates ofmalnutrition, hemoparasite burden,and general socioeconomic status. Anumber of studies of ironsupplementation and treatment thatwere conducted in developingcountries were excluded.40–46

Malnourishment, very lowsocioeconomic status, and/or presenceof parasitic endemic diseases werecommon in the included populationsin these studies. Also excluded werestudies of iron supplementation thatenrolled children aged ,6months47–50; this population wasoutside the scope of the review.

Good-quality, randomized controlledtrials of routine supplementation,screening programs, and treatment ofIDA in children 6 to 24 months of age,with adequate sample sizes for keyiron status and clinical healthoutcomes, are needed. Such trialsshould clearly report prognosticbaseline characteristics of enrolledchildren, details of interventions,longer term benefits (particularlydevelopmental outcomes usingappropriate neurodevelopmental

tests), and harms, and the studiesshould use appropriate controls (ie, notcow’s milk). In addition, these studiesshould report neurodevelopmentaldiagnoses rather than test scores.

CONCLUSIONS

Expanded and better research isneeded to assess the benefits andharms of routine ironsupplementation and screening toprevent IDA in young children indeveloped countries. At present, thelimited evidence indicates no benefitsin growth and neurodevelopmentaltest scores with supplementation, andhematologic outcomes are variablyaffected. The benefits and harms oftreatment are largely unclear, as is theassociation between improvement inIDA or iron deficiency and clinicaloutcomes.

ACKNOWLEDGMENTS

The authors thank the Agency forHealthcare Research and QualityMedical officers: Tina Fan, MD, MPH,and Iris Mabry-Hernandez, MD, MPH.They also thank the USPSTF leads:David Grossman, MD, MPH, GlennFlores, MD, Francisco Garcia, MD,MPH, Alex Kemper, MD, MPH, MS, andVirginia Moyer, MD, MPH.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Funded by the Agency for Healthcare Research and Quality (AHRQ) under Contract No. HHSA290201200015i, Task Order No. 2. This research was funded by

the AHRQ under a contract to support the work of the US Preventive Services Task Force. Investigators worked with US Preventive Services Task Force members and

AHRQ staff to develop the scope, analytic framework, and Key Questions. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided

project oversight, reviewed the report to assure that the analysis met methodologic standards, and distributed the draft for peer review, including representatives

of professional societies and federal agencies.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Marian S. McDonagh, Ian Blazina, Tracy Dana, Amy Cantor and Christina BougatsosSystematic Review

Screening and Routine Supplementation for Iron Deficiency Anemia: A

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