Review Articles

Iron supplementation in early childhood: health benefits and risks1–3

Lora L Iannotti, James M Tielsch, Maureen M Black, and Robert E Black

ABSTRACTThe prevalence of iron deficiency among infants and young childrenliving in developing countries is high. Because of its chemical prop-erties—namely, its oxidative potential—iron functions in severalbiological systems that are crucial to human health. Iron, which is noteasily eliminated from the body, can also cause harm through oxi-dative stress, interference with the absorption or metabolism of othernutrients, and suppression of critical enzymatic activities. We re-viewed 26 randomized controlled trials of preventive, oral iron sup-plementation in young children (aged 0–59 mo) living in developingcountries to ascertain the associated health benefits and risks. Theoutcomes investigated were anemia, development, growth, morbid-ity, and mortality. Initial hemoglobin concentrations and iron statuswere considered as effect modifiers, although few studies includedsuch subgroup analyses. Among iron-deficient or anemic children,hemoglobin concentrations were improved with iron supplementa-tion. Reductions in cognitive and motor development deficits wereobserved in iron-deficient or anemic children, particularly withlonger-duration, lower-dose regimens. With iron supplementation,weight gains were adversely affected in iron-replete children; theeffects on height were inconclusive. Most studies found no effect onmorbidity, although few had sample sizes or study designs that wereadequate for drawing conclusions. In a malaria-endemic populationof Zanzibar, significant increases in serious adverse events were asso-ciated with iron supplementation, whereas, in Nepal, no effects onmortality in young children were found. More research is needed inpopulations affected by HIV and tuberculosis. Iron supplementation inpreventive programs may need to be targeted through identification ofiron-deficient children. Am J Clin Nutr 2006;84:1261–76.

KEY WORDS Iron, supplementation, children, development,growth, infection

INTRODUCTION

Iron deficiency has been considered an important risk factorfor ill health (1) and is estimated to affect 2 billion people world-wide (2). Concerns have been raised about the effects of irondeficiency in children on their health and development, whichhave led to recommendations for supplementation of all childrenof certain ages in populations with a high prevalence of anemia(2). This recommendation for a preventive iron intervention willreach both children in need of additional iron and children with-out that need. This nondiscrimination may be acceptable if no

harm is done by the iron supplementation, especially in thosechildren who receive no benefit. Although some studies suggestrisks with iron supplementation, it is important to determinewhether these risks are generally supported by available evi-dence and whether they can be mitigated with altered recom-mendations regarding iron supplementation. The focus of thisreview was to examine the evidence for the health benefits andrisks of preventive iron supplementation in children aged �5 y indeveloping countries.

Iron is essential for all tissues in a young child’s developingbody. Iron is present in the brain from very early in life, when itparticipates in the neural myelination processes. Other roles thatwould affect growth and immune function have been postulated(3). Iron, which is essential to both the host and invading patho-gens, must be carefully regulated to promote optimal conditionsthat preserve the health of young children. Furthermore, iron caninterfere with the absorption of other nutrients and, in excess, cangenerate free radicals that impair cellular functions and suppressenzymatic activity (4, 5).

Iron supplementation for children �5 y old is recommendedon the basis of anemia prevalence (Table 1). Low-birth-weightinfants are at high risk of iron deficiency, and the current recom-mendation is that they receive supplementation from 2 mothrough 2 y of age. Anemia prevalence, determined by hemo-globin status, is used as a practical indicator because of therelative difficulty in collecting additional markers of iron defi-ciency. The consumption of iron-poor complementary diets(lacking iron-fortified foods or heme iron) is also used to justifysupplementation in infants and preschool-aged children. Com-plementary foods, even with continued breastfeeding, must con-tribute nearly 100% of dietary iron for young children becausebreast milk contains little iron (6). Other prevention and controlapproaches for iron deficiency—such as food fortification,

1 From the Department of International Health, Bloomberg School ofPublic Health, Johns Hopkins University, Baltimore, MD (LLI, JMT, andREB), and the Department of Pediatrics, University of Maryland School ofMedicine, Baltimore, MD (MMB).

2 Supported by the Global Research Activity Cooperative Agreement be-tween USAID and the Johns Hopkins Bloomberg School of Public Health.

3 Address reprint requests to RE Black, Department of InternationalHealth, Johns Hopkins Bloomberg School of Public Health, 615 North WolfeStreet, Room E8527, Baltimore, MD 21205. E-mail: rblack@jhsph.edu.

Received March 23, 2006.Accepted for publication July 18, 2006.

1261Am J Clin Nutr 2006;84:1261–76. Printed in USA. © 2006 American Society for Nutrition

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dietary improvements, and treatment of hookworm and otherhelminth infections—were not considered in this review.

The objective of this review was to evaluate the health benefitsand risks of iron supplementation as a strategy to prevent irondeficiency in children 0–4 y old. Evidence (primarily) fromrandomized placebo-controlled trials (RCTs) provided the basisfor this assessment because these designs allow causal inferencethat is not possible with cross-sectional or quasi-experimentaldesigns.

We conducted a literature review in PubMed (National Li-brary of Medicine, Bethesda, MD) to identify studies meetingseveral criteria. The review was limited to RCTs published after1980 and targeting young children 0–59 mo of age who wereliving in developing countries. Oral iron supplementation, asprevention and not therapy, was the intervention examined incomparison with placebo and, in a few studies, in comparisonwith other micronutrients. Trials of iron fortification or paren-teral iron were excluded. In certain circumstances when datawere scarce, as in the case of iron supplementation and HIVinfection or tuberculosis, some observational studies were re-viewed to suggest possible relations that should be further inves-tigated with RCTs.

Twenty-six RCTs were identified for this review. If recentmeta-analyses of RCTs have been performed, results are given,even though selection criteria such as the age of the children mayhave differed slightly. The outcomes examined in these ironsupplementation trials were grouped into the following catego-ries: anemia and iron status, development (including cognition,motor skills, and language), growth, morbidity, and mortality. Tohighlight particular findings, these outcome categories were thenplaced within the sections of the review as either benefits or risks.However, findings were not consistent across many of these out-comes, and this variability deserves careful consideration when pol-icy is made for programs in countries throughout the world.

BENEFITS OF IRON SUPPLEMENTATION IN EARLYCHILDHOOD

Possible beneficial effects of iron supplementation in youngchildren are primarily in the realms of anemia prevention andimprovements in developmental outcomes.

Anemia

Anemia may be due to iron deficiency (inadequate iron intake,poor iron absorption, or excess iron losses), insufficient hema-topoiesis (eg, from vitamin B-12 deficiency), loss of blood (hem-orrhagic anemia), premature red blood cell plasma membrane

rupture (hemolytic anemia), deficient or abnormal synthesis ofhemoglobin (eg, thalassemia), or destruction of bone marrow(aplastic anemia) (7). In developing countries, the prevalence ofanemia among preschool-aged children is 42%, and the regionsmost affected regions are Southeast Asia, Central and East Af-rica, and the Eastern Mediterranean (8). Hemoglobin concentra-tions are most often used for anemia screening. In children 6–59mo old, anemia is defined as hemoglobin �110 g/L or hematocrit�6.83 mmol/L or 0.33 L/L (9).

Evidence of the effect of iron supplementation on anemiaoutcomes is widely available. Studies usually incorporate ironstatus indicators, such as serum ferritin or transferrin saturation.One meta-analysis of 21 data sets from iron supplementationRCTs in children ranging in age from 0 to 12 y found a significantdifference in the mean change in hemoglobin concentrationsbetween treatment and control groups of 7.8 g/L, or an effect sizeof 1.49 (95% CI: 0.46, 2.51) (10).

Of the studies we examined for development, growth, andinfectious disease outcomes (Tables 2, 3, and 4), 13 reportedsignificantly increased hemoglobin concentrations and reducedanemia prevalence associated with iron supplementation ofyoung children (11–15, 19, 23, 30, 31). Eleven studies showedimprovements in other iron status indicators: serum iron, serumferritin, transferrin saturation, and free erythrocyte protoporphy-rin (11, 13, 15, 16, 19, 20, 23, 24, 30–32). Of the 5 studiesreporting no significant effect on hemoglobin concentrations inthe entire sample or particular strata (11, 16, 17, 24, 32), 4 showedimprovements in iron status markers (11, 16, 24, 32). This in-consistent effect on hemoglobin concentrations may be indica-tive of the varied causes of anemia in these study populations.Sustained significant (P � 0.022) improvements in hemoglobinconcentrations 7 mo after a 3-mo treatment period were found inone study (21), whereas another study found that only serumferritin concentrations remained significantly higher in the treat-ment group 6 mo after cessation of supplementation (31). He-moglobin improvements appeared to be related to baseline status(11, 17) and to exposure to anemia risk factors in addition to irondeficiency (ie, residence in malarial endemic regions) (16, 32).

Development

Iron supplementation has been hypothesized to have benefitsin children that prevent possible detrimental effects of iron de-ficiency during development. The pace of neurologic develop-ment in young children aged 0–4 y is rapid, including criticalperiods of neural circuit formation and myelination occurring inthe brain. Iron’s role in the brain is likely to be multifaceted and

TABLE 1Dosage schedule for iron supplementation1

Age group Indications for supplementation Dosage schedule2 Duration

Low-birthweight infants(2–23 mo old)

Universal supplementation 2 mg · kg body wt�1 · d�1 From age 2 mo to 23 mo

Children 6–23 mo old Diet does not include foods fortified withiron; anemia prevalence �40%

2 mg · kg body wt�1 · d�1 From age 6 mo to 23 mo

Children 24–59 mo old Anemia prevalence �40% 2 mg · kg body wt�1 · d�1

(up to 30 mg)3 mo

1 Adapted from reference 2.2 Recommended forms for children: liquid, powder, or crushable tablet. Recommended iron compounds: ferrous fumarate; ferrous gluconate; ferrous

sulfate (7H2O); ferrous sulfate, anhydrous; ferrous sulfate, exsiccated (1 H2O).

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BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION 1263

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n�

12�

g/L

,TS

�16

%,f

ree

eryt

hroc

yte

prot

opor

phyr

in�

1.77

�m

mol

/LR

BC

sIr

on-r

eple

tegr

oup:

hem

oglo

bin

�11

0g/

Lpl

us2

ofth

efo

llow

ing:

ferr

itin

�12

�g/

L,T

S�

16%

,fre

eer

ythr

ocyt

epr

otop

orph

yrin

�1.

77�

mm

ol/L

RB

Cs

Dis

crim

inat

ion

lear

ning

;th

ree

oddi

tyle

arni

ngta

sks;

PPV

T

IDA

asso

ciat

edw

ithvi

sual

atte

ntio

nan

dco

ncep

tacq

uisi

tion,

corr

ecte

dby

iron

trea

tmen

tN

oef

fect

inir

on-r

eple

tech

ildre

n

Stol

tzfu

set

al,

Zan

ziba

r(1

6)6–

59m

ool

dT

otal

:614

Hou

seho

lds

stra

tifie

dby

age

stra

taan

dra

ndom

lyas

sign

edto

rece

ive

iron

orpl

aceb

o;ch

ildre

nth

enst

ratif

ied

byir

onal

loca

tion

and

rand

omly

assi

gned

tore

ceiv

em

eben

dazo

leIr

ongr

oup:

307

Plac

ebo

grou

p:30

7M

eban

dazo

legr

oup:

306

Plac

ebo

grou

p:30

8

Ferr

ous

sulf

ate

(10

mg/

d)M

eban

dazo

le(5

00m

g)12

-mo

dura

tion

Res

iden

tof

Ken

geja

villa

geon

Pem

ba;a

geel

igib

ility

for

lang

uage

deve

lopm

ents

cale

was

12–4

8m

oan

dth

atfo

rm

otor

deve

lopm

ents

cale

was

12–3

6m

o

97%

wer

ean

emic

(hem

oglo

bin

�11

0g/

L);

18%

wer

ese

vere

lyan

emic

(hem

oglo

bin

�70

g/L

)

Lan

guag

e;m

otor

scor

eL

angu

age

deve

lopm

enti

mpr

oved

0.8

poin

ts(r

ange

:0.2

–1.4

)on

20-p

oint

scal

eM

otor

deve

lopm

enti

mpr

oved

inch

ildre

nw

ithhe

mog

lobi

n�

90g/

LIn

tera

ctio

nw

ithba

selin

ehe

mog

lobi

n(P

�0.

015)

(Con

tinu

ed)

1264 IANNOTTI ET AL

at GlaxoS

mithK

line on July 28, 2011w

ww

.ajcn.orgD

ownloaded from

TA

BL

E2

(Con

tinu

ed)

Stud

yan

dlo

catio

nA

gegr

oup

Sam

ple

size

bysu

pple

men

tD

osag

ean

ddu

ratio

nE

ligib

ility

and

excl

usio

ncr

iteri

aB

asel

ine

stat

usO

utco

me

mea

sure

sR

esul

ts

Wal

ter

etal

,C

hile

(14)

12m

ool

dT

otal

:196

Iron

grou

p:10

2Pl

aceb

ogr

oup:

94

Iron

(45

mg/

d)10

-ddu

ratio

nR

esid

ents

ofw

ell-

defi

ned

geog

raph

ical

area

Ane

mic

grou

p:he

mog

lobi

n10

0�

9g/

L;M

CV

62�

5gL

;iro

nan

dir

on-

bind

ing

capa

city

6.8

�2.

9%;s

erum

ferr

itin

5.4

�g/

L;f

ree

eryt

hroc

yte

prot

opor

phyr

in19

5�

103.

1�

g/dL

pack

edR

BC

sN

on-a

nem

icir

on-d

efic

ient

grou

p:he

mog

lobi

n12

1�

7g/

L;M

CV

70�

4gL

;iro

nan

dir

on-

bind

ing

capa

city

12.2

�0.

7%;s

erum

ferr

itin

11.9

�g/

L;f

ree

eryt

hroc

yte

prot

opor

phyr

in10

8�

33�

g/dL

pack

edR

BC

sC

ontr

olgr

oup:

hem

oglo

bin

127

�8

g/L

;MC

V76

�3

gL;i

ron

and

iron

-bi

ndin

gca

paci

ty16

.7�

6.3%

;ser

umfe

rriti

n19

.8�

g/L

;fre

eer

ythr

ocyt

epr

otop

orph

yrin

78�

13�

g/dL

pack

edR

BC

s

Bay

ley

MD

I;B

ayle

yPD

IN

otr

eatm

ente

ffec

twas

obse

rved

for

men

tala

ndps

ycho

mot

orde

velo

pmen

taft

er10

dor

3m

oN

odi

ffer

ence

sby

base

line

stat

usA

fter

3m

oof

iron

trea

tmen

t,an

emia

was

corr

ecte

d

1M

UA

C,m

idup

pera

rmci

rcum

fere

nce;

BSI

D,B

ayle

ySc

ales

ofIn

fant

Dev

elop

men

t;H

OM

E,H

ome

Obs

erva

tion

Mea

sure

men

tofE

nvir

onm

ent;

PDI,

Psyc

hom

otor

Dev

elop

men

tInd

ex;I

DA

,iro

n-de

fici

ency

anem

ia;M

DI,

Bay

ley

Men

talD

evel

opm

entI

ndex

;TS,

tran

sfer

rin

satu

ratio

n;R

BC

,red

bloo

dce

ll;PP

VT

,Pea

body

Pict

ure

Voc

abul

ary

Tes

t;M

CV

,mea

nco

rpus

cula

rvo

lum

e.

BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION 1265

at GlaxoS

mithK

line on July 28, 2011w

ww

.ajcn.orgD

ownloaded from

TA

BL

E3

Gro

wth

and

iron

supp

lem

enta

tion1

Stud

yan

dlo

catio

nA

gegr

oup

Sam

ple

size

Dos

age

and

dura

tion

Elig

ibili

tyan

dex

clus

ion

crite

ria

Bas

elin

est

atus

Out

com

em

easu

res

Res

ults

n

Ang

eles

etal

,In

done

sia

(19)

2–5

yol

dT

otal

:76

Iron

:39

Plac

ebo:

37

Ferr

ous

sulf

ate

(30

mg/

d)2-

mo

dura

tion

WA

Zbe

twee

n�

2an

d�

3SD

sH

emog

lobi

n�

80to

�11

0g/

LFe

rriti

n�

120

�g/

L

Iron

grou

p:he

mog

lobi

n10

2�

9g/

LPl

aceb

ogr

oup:

hem

oglo

bin

103

�8

g/L

WA

Z�

2.53

HA

Z�

2.33

WH

Z�

1.48

Wei

ght,

heig

ht,d

ieta

ryin

take

,hem

oglo

bin,

seru

mfe

rriti

n;fe

ver

(tem

pera

ture

�37

°C);

diar

rhea

(�4

wat

ery

stoo

ls/d

);R

TI

Incr

ease

sin

heig

htan

dH

AZ

intr

eatm

entg

roup

wer

ela

rger

than

thos

ein

cont

rolg

roup

(P�

0.01

);he

mog

lobi

n,se

rum

ferr

itin,

and

MC

Vim

prov

edsi

gnif

ican

tlyFr

eque

ncy

offe

ver,

resp

irat

ory

infe

ctio

ns,a

nddi

arrh

eaw

assi

gnif

ican

tlyle

ssin

trea

tmen

tgr

oup

Stud

yw

asad

just

edfo

rfo

odin

take

effe

cton

grow

th;d

ecre

ased

mor

bidi

tyin

supp

lem

enta

tion

grou

pis

sugg

este

dto

have

med

iate

dth

egr

owth

incr

ease

Dew

eyet

al,

Swed

enan

dH

ondu

ras

(26)

Dom

ello

fet

al,

Swed

enan

dH

ondu

ras

(23)

4–9

mo

old

Tot

al:1

31Fe

rrou

ssu

lfat

e(1

mg

·kg

�1

·d�

1)

from

4to

6m

oof

age

Plac

ebo

from

4to

6m

oof

age

and

then

ferr

ous

sulf

ate

(1m

g·k

g�1

·d�

1)

from

7to

9m

oof

age

Plac

ebo

from

4to

9m

oof

age

Ges

tatio

nala

ge�

37w

k;bi

rth

wei

ght�

2500

g;no

chro

nic

illne

ss;m

ater

nal

age

�16

y;in

fant

excl

usiv

ely

brea

stfe

dat

4m

o(r

ecei

ved

�90

mL

infa

ntfo

rmul

a/d

sinc

ebi

rth)

;mot

her

inte

nded

toco

ntin

uebr

east

feed

ing

until

infa

ntag

e9

mo

Hem

oglo

bin

90g/

LB

lood

sam

ples

at4,

6,an

d9

mo

(hem

oglo

bin,

ferr

itin,

eryt

hroc

yte

zinc

prot

opor

phyr

in,

MC

V,p

lasm

atr

ansf

erri

nre

cept

or);

C-r

eact

ive

prot

ein;

birt

hw

eigh

t;w

eigh

t,le

ngth

,an

dhe

adci

rcum

fere

nce

bym

onth

;nut

rien

tint

ake

inco

mpl

emen

tary

food

s;m

orbi

dity

bym

ater

nal

reco

rds

onca

lend

ar(s

tool

freq

uenc

y,co

nsis

tenc

y,co

ugh,

feve

r,na

salc

onge

stio

nor

disc

harg

e,di

arrh

ea,

vom

iting

,ors

kin

rash

);m

orbi

dity

bype

diat

rici

andi

agno

sis

Red

uced

gain

sin

leng

thin

child

ren

4–6

mo

old

and

hem

oglo

bin

�11

0g/

Lin

iron

grou

pW

eigh

tgai

nlo

wer

inth

ein

fant

sre

ceiv

ing

iron

for

6–9

mo

than

inth

ose

rece

ivin

gpl

aceb

ow

ithin

low

erfe

rriti

nsu

bgro

upN

osi

gnif

ican

teff

ecto

nm

orbi

dity

,bu

tdia

rrhe

aw

asle

ssco

mm

onat

4m

oin

infa

nts

inbo

thH

ondu

ras

and

Swed

enw

hoha

dba

selin

ehe

mog

lobi

n�

110

g/L

;in

fant

sw

ithhe

mog

lobi

n�

110

g/L

atba

selin

eha

dm

ore

diar

rhea

From

age

4to

6m

o,he

mog

lobi

nan

dfe

rriti

nim

prov

ed;f

rom

age

6to

9m

o,ir

onst

atus

indi

cato

rsim

prov

edbu

tnot

hem

oglo

bin;

IDA

was

sign

ific

antly

redu

ced

at9

mo

Dijk

huiz

enet

al,

Indo

nesi

a(2

0)

4m

ool

dT

otal

:478

Iron

(10

mg/

d)Ir

on(1

0m

g/d)

�zi

nc(1

0m

g/d)

6-m

odu

ratio

n

Age

;res

iden

tof

any

of6

adja

cent

villa

ges

inW

est

Java

;exc

lusi

onba

sed

onch

roni

cor

seve

reill

ness

,se

vere

clin

ical

mal

nutr

ition

,or

cong

enita

lan

omal

ies

Hem

oglo

bin

and

plas

ma

ferr

itin

notr

epor

ted

atba

selin

eIr

on-s

uppl

emen

ted

grou

pba

selin

est

atus

:W

AZ

�0.

06H

AZ

�0.

89W

HZ

0.77

—N

oef

fect

ongr

owth

;hem

oglo

bin

and

plas

ma

ferr

itin

conc

entr

atio

nssi

gnif

ican

tlyhi

gher

inir

on-t

reat

edgr

oup

Dos

saet

al,

Ben

in(2

1)3–

5y

old

Tot

al:1

40Ir

on(6

0m

g/d)

Iron

(60

mg/

d)�

albe

ndaz

ole

3-m

odu

ratio

n

Age

3–5

y;re

side

ntof

sem

i-ru

rala

rea

ofso

uthe

rnB

enin

;exc

lusi

on:n

oac

ute

dise

ase

Hem

oglo

bin

10.1

g/L

;76%

wer

ean

emic

(hem

oglo

bin

�11

0g/

L)

WA

Z�

1.59

HA

Z�

2.03

WH

Z�

0.53

Ant

hrop

omet

ric

mea

sure

s;he

mog

lobi

n;eg

gs/g

fece

s

No

effe

cton

grow

thin

stud

ygr

oups

orst

ratif

ied

grou

psby

nutr

ition

alan

dhe

mog

lobi

nst

atus

(Con

tinu

ed)

1266 IANNOTTI ET AL

at GlaxoS

mithK

line on July 28, 2011w

ww

.ajcn.orgD

ownloaded from

TA

BL

E3

(Con

tinu

ed)

Stud

yan

dlo

catio

nA

gegr

oup

Sam

ple

size

Dos

age

and

dura

tion

Elig

ibili

tyan

dex

clus

ion

crite

ria

Bas

elin

est

atus

Out

com

em

easu

res

Res

ults

Idjr

adin

ata

etal

,In

done

sia

(27)

12–1

8m

ool

dT

otal

:47

Ferr

ous

sulf

ate

(3m

g·

kg�

1·d

�1)

4-m

odu

ratio

n

Bir

thw

eigh

t�25

00g;

sing

leto

npr

egna

ncy;

nom

ajor

cong

enita

lan

omal

ies

orpe

rina

tal

com

plic

atio

ns;n

oja

undi

cetr

eate

dw

ithph

otot

hera

py;n

oho

spita

ladm

issi

onor

supp

lem

enta

tion

with

mic

ronu

trie

nts

duri

ngth

e6

mo

befo

reen

rollm

ent;

noch

roni

cill

ness

orfo

licac

idde

fici

ency

;he

mog

lobi

n�

80g/

L;n

osi

gns

ofab

norm

alhe

mog

lobi

nor

thal

asse

mia

;wei

ght,

leng

th,a

ndhe

adci

rcum

fere

nce

2SD

sof

refe

renc

est

anda

rds

Iron

-rep

lete

(hem

oglo

bin

�12

0g/

L;T

S�

10%

;se

rum

ferr

itin

�12

�g/

L)

Wei

ght,

leng

th,a

ndar

mci

rcum

fere

nce

(bi-

wee

kly)

;mor

bidi

ty(p

edia

tric

ian

diag

nosi

s);i

llnes

sin

cide

nce

(gas

troi

ntes

tinal

,upp

eror

low

erre

spir

ator

ytr

acti

nfec

tion)

for

2w

k

Red

uced

rate

ofw

eigh

tgai

nin

iron

grou

p(x

�SE

:0.1

06�

0.01

1ve

rsus

0.07

0�

0.01

1kg

/2w

k,P

�0.

02)

No

sign

ific

antd

iffe

renc

esin

leng

than

dar

mci

rcum

fere

nce

No

sign

ific

antd

iffe

renc

ein

resp

irat

ory

orga

stro

inte

stin

alin

fect

ions

(Oth

erco

nfou

ndin

gfa

ctor

sno

tco

rrec

ted

for)

Lin

det

al,

Indo

nesi

a(1

8)

6-m

ool

dT

otal

:666

Iron

grou

p:16

6Ir

on�

zinc

grou

p:16

4Z

inc

grou

p:16

7Pl

aceb

ogr

oup:

169

Iron

(10

mg/

d)Z

inc

(10

mg/

d)Ir

on(1

0m

g)�

zinc

(10

mg)

6-m

odu

ratio

n

Res

iden

tin

Purw

orej

o,C

entr

alJa

va;s

ingl

eton

infa

nts

�6

mo

old;

excl

usio

ns:m

etab

olic

orne

urol

ogic

diso

rder

s;ha

ndic

aps

affe

ctin

gde

velo

pmen

t,fe

edin

g,or

activ

ity;s

ever

eor

prot

ract

edill

ness

;hem

oglo

bin

�90

g/L

Hem

oglo

bin

114

g/L

(hem

oglo

bin

�11

0g/

Lob

serv

edin

41%

;he

mog

lobi

n�

110

and

ferr

itin

�12

�g/

Lob

serv

edin

8%)

WA

Z�

0.42

HA

Z�

0.57

WH

Z�

0.02

Ant

hrop

omet

ric

inde

xes;

deve

lopm

enta

lind

exes

(BSI

D);

mor

bidi

ty

No

effe

ctof

iron

alon

eon

grow

thbu

tiro

n�

zinc

sign

ific

antly

impr

oved

knee

-hee

llen

gth

asco

mpa

red

with

plac

ebo;

iron

sign

ific

antly

impr

oved

BSI

Dps

ycho

mot

orde

velo

pmen

tin

dex

asco

mpa

red

with

plac

ebo;

noef

fect

onm

orbi

dity

Maj

umda

ret

al,I

ndia

(25)

6–24

mo

old

Tot

al:1

50Ir

on-r

eple

tegr

oup:

Iron

:50

Plac

ebo:

50Ir

on-d

efic

ient

grou

p:50

Iron

-rep

lete

grou

p:ir

on(2

mg

·kg�

1·d

�1)

Iron

-def

icie

ntgr

oup:

iron

(6m

g·k

g�1

·d�

1)

4-m

odu

ratio

n

Bir

thw

eigh

t�25

00g;

sing

leto

npr

egna

ncy;

wei

ght,

leng

th,a

ndhe

adci

rcum

fere

nce

with

in2

SDs

ofN

CH

Sre

fere

nce;

diet

ofad

equa

tepr

otei

n,ca

lori

es,a

ndm

icro

nutr

ient

s;ex

clus

ions

:m

ajor

cong

enita

lano

mal

yor

pren

atal

com

plic

atio

ns,

hosp

itala

dmis

sion

orir

onsu

pple

men

tatio

ndu

ring

the

mon

ths

befo

reen

rollm

ent,

chro

nic

illne

ss,a

nem

iabe

yond

iron

defi

cien

cy,o

rre

cent

bloo

dtr

ansf

usio

n

Hem

oglo

bin

139

g/L

Iron

-rep

lete

grou

p:he

mog

lobi

n�

110

g/L

,se

rum

ferr

itin

�12

�g/

L,T

S�

10%

Iron

-def

icie

ntgr

oup:

hem

oglo

bin

50–1

10g/

L,

seru

mfe

rriti

n�

12�

g/L

,TS

�10

%

Ant

hrop

omet

ric

inde

xes

(wei

ght,

leng

th,h

ead

circ

umfe

renc

e)

Inir

on-d

efic

ient

child

ren,

sign

ific

antly

grea

ter

mea

nm

onth

lyw

eigh

tgai

n(P

�0.

001)

and

linea

rgr

owth

(P�

0.00

1)In

iron

-rep

lete

child

ren,

sign

ific

antly

less

wei

ghtg

ain

(P�

0.00

1)an

dlin

ear

grow

th(P

�0.

001)

Palu

piet

al,

Indo

nesi

a(2

2)

2–5

yol

dT

otal

:194

Iron

:96

Plac

ebo:

98

Ferr

ous

sulf

ate

(15

mg/

wk)

2-m

odu

ratio

n

Reg

iste

red

atvi

llage

heal

thce

nter

Hem

oglo

bin

113

g/L

WA

Z�

1.84

HA

Z�

1.92

WH

Z�

0.85

Wor

min

fest

atio

n(a

sin

dica

ted

byst

ool

mic

rosc

opy)

No

effe

cton

chan

ges

inhe

ight

orw

eigh

t(SD

was

larg

efo

rin

crea

sein

hem

oglo

bin

conc

entr

atio

nin

both

iron

and

plac

ebo

grou

ps;n

oho

okw

orm

prev

alen

cean

dno

addi

tiona

lef

fect

ofan

thel

min

thtr

eatm

ent)

Rah

man

etal

,B

angl

ades

h(2

8)

0.5–

6y

old

Tot

al:3

17Fe

rrou

sgl

ucon

ate

(15

mg/

d)�

vita

min

sA

,D

,and

C1-

ydu

ratio

n

Res

iden

tin

poor

peri

urba

nco

mm

unity

ofD

haka

;ex

clus

ions

:con

geni

tal

abno

rmal

ity,m

etab

olic

diso

rder

,or

any

clin

ical

sign

ofan

emia

WA

Z�

2.4

HA

Z�

2.3

WH

Z�

1.3

No

hem

oglo

bin

repo

rted

No

diff

eren

ces

inw

eigh

tor

heig

htin

crem

ents

betw

een

inte

rven

tion

and

cont

rolg

roup

sN

odi

ffer

ence

sw

hen

stra

tifie

dby

age

ornu

triti

onal

cate

gori

esR

osad

oet

al,

Mex

ico

(24)

1.5–

3y

old

Tot

al:2

19Ir

on:1

09Pl

aceb

o:11

0

Ferr

ous

sulf

ate

(20

mg/

d)Fe

rrou

ssu

lfat

e�

zinc

met

hion

ine

12-m

odu

ratio

n

Res

iden

tin

1of

5ru

ral

com

mun

ities

Hem

oglo

bin

108

g/L

WA

Z�

1.6

HA

Z�

1.6

WH

Z�

0.7

Seru

mfe

rriti

ngr

oup:

Plac

ebo:

20.1

�44

.6Ir

on:2

1.2

�38

.1Z

inc:

18.9

�15

.8Z

inc

�ir

on:1

4.7

�15

.6

RT

I(r

unny

nose

,com

mon

cold

,sor

eth

roat

,co

ugh)

;dia

rrhe

a(m

ater

nalr

epor

ting)

;fe

ver

(mat

erna

lre

port

ing)

No

effe

cton

grow

thve

loci

tyor

body

com

posi

tion

Zin

can

dzi

nc�

iron

sign

ific

antly

decr

ease

ddi

arrh

ea(P

�0.

01)

and

dise

ase

epis

odes

(P�

0.03

)(N

oef

fect

with

iron

alon

e)

1W

AZ

,wei

ght-

for-

age

zsc

ore;

HA

Z,h

eigh

t-fo

r-ag

ez

scor

e;M

CV

,mea

nco

rpus

cula

rvol

ume;

WH

Z,w

eigh

t-fo

r-he

ight

zsc

ore;

RT

I,re

spir

ator

ytr

acti

nfec

tion;

IDA

,iro

nde

fici

ency

anem

ia;T

S,tr

ansf

erri

nsa

tura

tion;

BSI

D,B

ayle

ySc

ales

ofIn

fant

Dev

elop

men

t;N

CH

S,N

atio

nalC

ente

rfo

rH

ealth

Stat

istic

s.

BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION 1267

at GlaxoS

mithK

line on July 28, 2011w

ww

.ajcn.orgD

ownloaded from

TA

BL

E4

Mor

bidi

tyan

dir

onsu

pple

men

tatio

n1

Stud

yan

dlo

catio

nA

gegr

oup

Sam

ple

size

Dos

age

and

dura

tion

Elig

ibili

tyan

dex

clus

ion

crite

ria

Bas

elin

est

atus

Out

com

em

easu

res

Res

ults

n

Ang

eles

etal

,In

done

sia

(19)

2–5

yol

dT

otal

:76

Iron

:39

Plac

ebo:

37

Ferr

ous

sulf

ate

(30

mg/

d)2-

mo

dura

tion

WA

Zbe

twee

n�

2an

d�

3SD

Hem

oglo

bin

�80

to�

110

g/L

Ferr

itin

�12

0�

g/L

Iron

grou

p:he

mog

lobi

n10

2�

9g/

LPl

aceb

ogr

oup:

hem

oglo

bin

103

�8

g/L

WA

Z�

2.53

HA

Z�

2.33

WH

Z�

1.48

Wei

ght,

heig

ht,d

ieta

ryin

take

;he

mog

lobi

n;se

rum

ferr

itin;

feve

r(t

empe

ratu

re�

37°C

);di

arrh

ea(�

4w

ater

yst

ools

/d);

resp

irat

ory

trac

tinf

ectio

n

Freq

uenc

yof

feve

r,re

spir

ator

yin

fect

ions

,and

diar

rhea

sign

ific

antly

less

intr

eatm

entg

roup

Incr

ease

sin

heig

htan

dH

AZ

intr

eatm

entg

roup

wer

ela

rger

than

inco

ntro

lgro

up(P

�0.

01)

Hem

oglo

bin,

seru

mfe

rriti

n,an

dM

CV

sign

ific

antly

impr

oved

(Stu

dyad

just

edfo

ref

fect

offo

odin

take

ongr

owth

;stu

dysu

gges

ted

that

the

low

erm

orbi

dity

inth

esu

pple

men

tatio

ngr

oup

med

iate

da

grow

thin

crea

se)

Ber

ger

etal

,T

ogo

(31)

6–36

mo

old

Tot

al:1

97Ir

on:1

00Pl

aceb

o:97

Iron

beta

inat

e(2

–3m

g·k

g�1

·d�

1)

3-m

odu

ratio

n9-

mo

follo

w-u

p

Res

iden

tin

sele

cted

villa

ge;a

ged

6–36

mo;

hem

oglo

bin

�80

g/L

Iron

grou

p:he

mog

lobi

n98

.9�

11.6

g/L

,TS

18.3

�10

.1%

,se

rum

ferr

itin

109.

2�

110.

6�

g/L

,fre

eer

ythr

ocyt

epr

otop

orph

yrin

105

�63

�g/

dLpa

cked

RB

Cs

Plac

ebo

grou

p:he

mog

lobi

n10

0.4

�10

.6g/

L,T

S17

.0�

7.78

%,s

erum

ferr

itin

109.

7�

138.

6�

g/L

,fre

eer

ythr

ocyt

epr

otop

orph

yrin

101

�62

�g/

dLpa

cked

RB

Cs

Upp

erR

TI;

low

erR

TI;

mal

aria

:pa

rasi

tede

nsity

mea

sure

dsm

ear;

diar

rhea

;cut

aneo

usin

fect

ion;

feve

r;w

orm

s

No

effe

cton

inci

denc

eof

infe

ctio

nsor

mal

aria

Aft

erad

just

men

tfor

base

line

stat

us,

hem

oglo

bin

TS,

and

ferr

itin

at3

mo

wer

esi

gnif

ican

tlyim

prov

ed;a

t9m

o,on

lyfe

rriti

nre

mai

ned

sign

ific

antly

high

erin

trea

tmen

tgro

up(T

reat

men

tand

plac

ebo

grou

psw

ere

also

give

nm

alar

iapr

ophy

laxi

san

dde

wor

min

g)

Chi

ppau

xet

al,

Tog

o(3

3)6–

36m

ool

dT

otal

:190

Iron

:95

Plac

ebo:

95

Iron

beta

inat

e(2

.5m

g·k

g�1

·d�

1)

3-m

odu

ratio

n9-

mo

follo

w-u

p

Hem

oglo

bin

�80

g/L

NA

Mal

aria

(sm

ear

posi

tive)

;ant

ibod

ytit

ers

No

effe

cton

infa

ntsu

scep

tibili

tyto

mal

aria

orim

mun

ere

spon

seH

igh

para

sita

nem

iafr

eque

ncy

inal

lgr

oups

duri

ngra

iny

seas

onN

ova

riat

ion

inan

tibod

ytie

rs

Dew

eyet

al,

Hon

dura

san

dSe

wed

en(2

6)D

omel

lof

etal

,H

ondu

ras

and

Swed

en(2

3)

4–9

mo

old

Tot

al:1

31Fe

rrou

ssu

lfat

e(1

mg

·kg

�1

·d�

1)

Iron

(4–9

mo)

Plac

ebo

(4–6

mo)

�ir

on(6

–9m

o)Pl

aceb

o(4

–9m

o)

Ges

tatio

nala

ge�

37w

k;bi

rth

wei

ght

�25

00g;

noch

roni

cill

ness

;m

ater

nala

ge�

16y;

infa

ntex

clus

ivel

ybr

east

fed

at4

mo

(rec

eive

d�

90m

Lin

fant

form

ula/

dsi

nce

birt

h);m

othe

rin

tend

edto

cont

inue

brea

stfe

edin

gun

til9

mo

ofag

e

Hem

oglo

bin

�90

g/L

Blo

odsa

mpl

esat

4,6,

and

9m

o(h

emog

lobi

n,fe

rriti

n,er

ythr

ocyt

ezi

ncpr

otop

orph

yrin

,mea

nco

rpus

cula

rvo

lum

e,pl

asm

atr

ansf

erri

nre

cept

or);

C-r

eact

ive

prot

ein;

birt

hw

eigh

t;w

eigh

t,le

ngth

,and

head

circ

umfe

renc

eby

mon

th;n

utri

enti

ntak

ein

com

plem

enta

ryfo

ods;

mor

bidi

tyby

mat

erna

lrec

ord

ona

cale

ndar

(sto

olfr

eque

ncy;

stoo

lco

nsis

tenc

y;co

ugh,

feve

r,na

sal

cong

estio

nor

disc

harg

e;di

arrh

ea,

vom

iting

,or

skin

rash

)M

orbi

dity

bype

diat

rici

andi

agno

sis

No

sign

ific

ante

ffec

ton

mor

bidi

tyin

the

data

from

Hon

dura

sbu

tin

the

com

bine

dda

tafr

omH

ondu

ras

and

Swed

en,d

iarr

hea

was

less

com

mon

at4

mo

insu

pple

men

ted

infa

nts

with

base

line

hem

oglo

bin

�11

0g/

L;

infa

nts

with

hem

oglo

bin

�11

0g/

Lat

base

line

had

mor

edi

arrh

eaR

educ

edga

ins

inle

ngth

inch

ildre

n4–

6m

ool

dan

dw

ithhe

mog

lobi

n�

110

g/L

inth

eir

ongr

oup

Wei

ghtg

ain

low

erin

the

grou

pre

ceiv

ing

iron

for

6–9

mo

than

inth

epl

aceb

ogr

oup

with

inth

elo

wer

ferr

itin

subg

roup

Idjr

adin

ata

etal

,In

done

sia

(27)

12–1

8m

ool

dT

otal

:47

Iron

:24

Plac

ebo:

23

Ferr

ous

sulf

ate

(3m

g·

kg�

1·d

�1)

4-m

odu

ratio

n

Bir

thw

eigh

t�25

00g;

sing

leto

npr

egna

ncy;

nom

ajor

cong

enita

lan

omal

ies

orpe

rina

tal

com

plic

atio

ns;n

oja

undi

cetr

eate

dw

ithph

otot

hera

py;n

oho

spita

lad

mis

sion

orsu

pple

men

tatio

nw

ithm

icro

nutr

ient

sdu

ring

the

6m

obe

fore

enro

llmen

t;no

chro

nic

illne

ssor

folic

acid

defi

cien

cy;h

emog

lobi

n�

80g/

L;n

osi

gns

ofab

norm

alhe

mog

lobi

nor

thal

asse

mia

;wei

ght,

leng

th,a

ndhe

adci

rcum

fere

nce

2SD

sof

refe

renc

est

anda

rds

Iron

-rep

lete

hem

oglo

bin

grou

p:�

120

g/L

;TS

�10

%;s

erum

ferr

itin

�12

�g/

L

Wei

ght,

leng

than

dar

mci

rcum

fere

nce

(biw

eekl

y);

mor

bidi

ty(p

edia

tric

ian

diag

nosi

s);

illne

ssin

cide

nce

(gas

troi

ntes

tinal

orup

per

orlo

wer

resp

irat

ory

trac

tin

fect

ion

for

2w

k

No

sign

ific

antd

iffe

renc

ein

resp

irat

ory

orga

stro

inte

stin

alin

fect

ions

Red

uced

rate

ofw

eigh

tgai

nin

iron

grou

p(x�

�SE

:0.1

06�

0.01

0ve

rsus

0.07

0�

0.01

1;kg

/2w

k,P

�0.

02)

No

sign

ific

antd

iffe

renc

esin

leng

than

dar

mci

rcum

fere

nce

(Oth

erco

nfou

ndin

gfa

ctor

sw

ere

not

corr

ecte

dfo

r)

(Con

tinu

ed)

1268 IANNOTTI ET AL

at GlaxoS

mithK

line on July 28, 2011w

ww

.ajcn.orgD

ownloaded from

TA

BL

E4

(Con

tinu

ed)

Stud

yan

dlo

catio

nA

gegr

oup

Sam

ple

size

Dos

age

and

dura

tion

Elig

ibili

tyan

dex

clus

ion

crite

ria

Bas

elin

est

atus

Out

com

em

easu

res

Res

ults

Lin

det

al,

Indo

nesi

a(1

8)6

mo

old

Tot

al:6

66Ir

on:1

66Ir

on�

zinc

:16

4Z

inc:

167

Plac

ebo:

169

Iron

(10

mg/

d)Z

inc

(10

mg/

d)Ir

on(1

0m

g)�

zinc

(10

mg)

6-m

odu

ratio

n

Res

iden

tin

Purw

orej

o,C

entr

alJa

va;

sing

leto

nin

fant

s;�

6m

ool

d;ex

clus

ions

:met

abol

icor

neur

olog

icdi

sord

ers;

hand

icap

saf

fect

ing

deve

lopm

ent,

feed

ing,

orac

tivity

;sev

ere

orpr

otra

cted

illne

ss;h

emog

lobi

n�

90g/

L

Hem

oglo

bin

114

g/L

(hem

oglo

bin

�11

0g/

Lob

serv

edin

41%

;hem

oglo

bin

�11

0an

dfe

rriti

n�

12�

g/L

obse

rved

in8%

)W

AZ

�0.

42H

AZ

�0.

57W

HZ

�0.

02

Ant

hrop

omet

ric

inde

xes;

deve

lopm

enti

ndex

es(B

SID

);m

orbi

dity

No

effe

cton

mor

bidi

tyN

oef

fect

ofir

onal

one

ongr

owth

but

iron

�zi

ncsi

gnif

ican

tlyim

prov

edkn

ee-h

eell

engt

has

com

pare

dw

ithpl

aceb

oIr

onsi

gnif

ican

tlyim

prov

edB

SID

psyc

hom

otor

deve

lopm

enti

ndex

com

pare

dw

ithpl

aceb

o

Meb

raht

uet

al,

Tan

zani

a(3

2)6–

59m

ool

dT

otal

:614

Hou

seho

lds

stra

tifie

dby

age

and

rand

omly

assi

gned

tore

ceiv

eir

onor

plac

ebo,

and

then

child

ren

stra

tifie

dby

iron

allo

catio

nan

dra

ndom

lyas

sign

edto

meb

enda

zole

Iron

:307

Plac

ebo:

307

Meb

anda

zole

:30

6Pl

aceb

o:30

8

Ferr

ous

sulf

ate

(10

mg/

d)M

eban

dazo

le(5

00m

g)12

-mo

dura

tion

Res

iden

tof

Ken

geja

villa

geon

Pem

ba94

.4%

wer

ean

emic

(hem

oglo

bin

�11

0g/

L)

17%

wer

ese

vere

lyan

emic

(hem

oglo

bin

�70

g/L

)80

%w

ere

infe

cted

with

Pla

smam

odiu

mfa

lcip

arum

48.1

%ha

dH

AZ

��

2

Blo

odfi

lms

wer

eas

sess

edm

onth

lyfo

rpr

eval

ence

and

dens

ityof

infe

ctio

n

No

sign

ific

ante

ffec

tson

mal

ario

met

ric

mea

sure

sor

afte

rad

just

men

tfor

age

and

seas

on

Men

ende

zet

al,

Tan

zani

a(2

7)2

mo

old

Tot

al:8

32Fe

rrou

sgl

ycin

esu

lfat

e(2

mg

·kg�

1·d

�1)

Del

tapr

imm

alar

iapr

ophy

laxi

s4-

mo

dura

tion

10-m

ofo

llow

-up

Bir

thw

eigh

t�15

00g;

PCV

�25

%at

8w

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BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION 1269

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1270 IANNOTTI ET AL

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ownloaded from

has not been fully elucidated. Iron in oligodendrocytes is re-quired for proper myelination of the neurons used in sensorysystems (visual, auditory) and learning and interacting behaviors(38). Dopaminergic neurotransmitter systems related to behav-ioral development (eg, inhibition, affect, attention processing,and extraneous motor movements) are sensitive to changes iniron status. Iron is also a cofactor for enzymes that synthesizeneurotransmitters such as tryptophan hydroxylase (serotonin)and tyrosine hydroxylase (norepinephrine, dopamine) (39). Irondeficiency has been linked to changes in neuronal metabolism inthe hippocampus and prefrontal projections where memory pro-cessing occurs (40).

Lead and other neurotoxic metals that impair early childhooddevelopment have been shown to be absorbed during iron defi-ciency (41). Iron is recognized as sharing the divalent metaltransporter 1 (DMT1) with both lead and cadmium (42). Nostudies investigating reduced lead absorption as an outcome ofiron supplementation met the criteria for this review. One RCT inMexican school-age children, 51% of whom had blood leadconcentrations �10 �g/dL, found no effect of a 6-mo regimen ofiron supplementation on cognitive performance (43) or parent orteacher ratings of behavior (44).

A meta-analysis of RCTs examining iron in relation to devel-opment in children included trials of oral iron supplementation,fortified milks and cereals, and parenteral iron. Significant ben-eficial effects on mental development for children who wereanemic or iron deficient at baseline and for all children �7 y oldwere reported (45) The standardized mean difference (SMD) forthe mental development score, a composite of different testsassessing the same aspect of mental development, was 0.30 (95%CI: 0.15, 0.46; P � 0.001). This is a modest effect, equivalent to1.5 to 2 Intelligence Quotient points. In younger children (aged�27 mo), no effect of iron supplementation on mental develop-ment was detected. Motor development was not found to beimproved through iron supplementation (SMD: 0.09; 95% CI:�0.08, 0.26, P � 0.28) (35).

Of the 8 RCTs identified for this review that addressed devel-opmental outcomes, 5 found some possible benefits of iron sup-plementation (11, 13, 16–18), but the importance of many ofthese effects on later academic performance is unknown (Table2). One study in Bangladesh found that a weekly dose of 20 mgferrous sulfate over 6 mo significantly reduced developmentallosses in orientation engagement (exploration), whereas placebodid not affect the losses with age (17). A study in Indonesia foundthat iron supplementation for 4 mo resulted in higher motor andmental development scores on the Bayley Scales for Infant De-velopment II (BSID) in children with iron deficiency anemia, butnot in children who were iron deficient without anemia or whowere iron replete (11). In contrast, a trial in Guatemala thatprovided supplementation for only 1 wk found no benefit of ironsupplements when testing with the BSID was used (12). In Chile,another trial of short-term (10 d) iron supplementation also foundno benefit when testing by BSID was used (14). The third studythat found no developmental effects of iron treatment was con-ducted in Costa Rica and was of longer duration but had a smallersample than the other 2 studies had (15). Two Indonesian studieswith longer supplementation periods (6 and 2 mo, respectively)indicated positive development outcomes: one related to motordevelopment as assessed by BSID in all children (18), and theother related to visual attention and concept acquisition only inchildren with iron deficiency anemia (13). A Zanzibar study

found that iron supplementation given for 12 mo was associatedwith more rapid achievement of language milestones in all chil-dren and motor milestones in the more anemic children (16).

The BSID is probably the most well standardized, widely usedassessment of infant development in the world, and it has beensensitive to deviations in early development associated with ironstatus. However, the BSID is a global assessment that may ob-scure subtle differences in neurobehavioral development. Evi-dence for developmental continuity in cognitive functioning sug-gests the importance of variability in early processing skills, suchas those associated with iron deficiency, and of the modifyingeffects of the home environment and the family’s socioeconomicstatus (46). Thus, estimates of the effects of iron status duringinfancy on school-age measures of academic performance maybe enhanced by the combination of a well-standardized assess-ment of development such as the BSID, measures of specificneurobehavioral processes thought to be sensitive to iron defi-ciency, and consideration of the home and family environment.

RISKS OF IRON SUPPLEMENTATION IN EARLYCHILDHOOD

Because iron is not easily eliminated from the body, attentionhas been paid to circumstances in which excess iron may beabsorbed or used inappropriately. An overabundance of ironmay catalyze the generation of hydroxyl radicals through theFenton reaction (47). Chronic iron overload has been studiedin the context of hemochromatosis (48), and these studies mayprovide insight into the mechanisms and clinical manifesta-tions of excess iron. Tissue injury, in particular that to theliver, may result from the generation of free radicals, butevidence also exists of intracellular damage. Extensive stud-ies and reviews have looked at oxidative damage to DNA,proteins, and lipids (49, 50).

Excess iron may be detrimental to cognitive, motor, and be-havioral development, although this detrimental effect is likelylimited to cases of genetically susceptible children. Childrenwith mutations in the gene encoding pantothenate kinase 2(PANK2) have neuronal brain iron accumulation that is manifestin dystonia, dysarthria, rigidity, and early death (51). Animalmodels have shown potential neurologic dysfunctions associatedwith dietary iron overload early in life (53); evidence for theseeffects in humans is less clear.

From the murine model, it is known that iron supplementationcan result in the generation of free radicals (49) and will increaseintestinal susceptibility to peroxidative damage in an iron-deficient state (53). Known defense systems in the body protectagainst free radical damage. In young children, lactoferrin frombreast milk may be used for iron chelation, although this processis largely thought to produce mostly antiinfective properties.Antioxidants such as selenium or glutathione also are known toprotect against free radical damage. Malnourished children withkwashiorkor or marasmus may be deficient in antioxidants,which leaves them susceptible to potential harm due to excessiron (54, 55). Other mechanisms besides the generation of freeradicals have been postulated for the observed negative effects ofiron supplementation, including potential interference with ab-sorption of other essential nutrients (5, 56), the growth and pro-liferation of invading pathogens, and the suppression of enzymeactivity in host defense (3).

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Growth

In the early months and years of life, infants and young chil-dren pass through a crucial period of growth that may not beregained later in life. Results from trials of iron supplementationoverall have not found significant growth effects, even in anemicchildren, though some studies have shown an adverse effect,especially in iron-replete children. Dietary iron may inhibit theabsorption of other essential growth-promoting nutrients such aszinc, although a recent review of trials found no conclusiveevidence of this association (56). Iron supplementation may lead toincreased morbidity and, consequently, to reduced dietary intakes,poor nutrient absorption, and negative energy balance (57).

A meta-analysis of RCTs examining vitamin A, iron, andmultimicronutrient interventions in children aged �18 y foundthat, in the 21 iron-supplementation RCTs identified, no signif-icant effect on growth was reported (10). The overall effect sizewas 0.09 (95% CI: �0.07, 0.24) for height and 0.13 (95% CI:�0.05, 0.30) for weight, and negligible differences in height gain(0.007 cm) and weight gain (0.012 kg) were found between treat-ment and controls. When the studies were stratified for baselinehemoglobin status, the lack of significant differences remained,although the effect size for height gain was greater in subjects whowere anemic at baseline (0.21; 95% CI: �0.14, 0.56) than in thosewho were not anemic (0.02; 95% CI: �0.14, 0.18) (10).

The International Research on Infant Supplementation (IRIS)analysis is a recent pooled-data analysis that compared the find-ings from RCTs of supplementation in infants aged 6–12 mo inIndonesia, Peru, South Africa, and Vietnam. The 4 supplemen-tation groups were daily iron supplementation, daily multiplemicronutrients, weekly multiple micronutrients, and placebo. Ascomparedwithplacebo, iron treatmenthadnosignificantlydifferenteffect on weight or height gains over the course of the 6-mo trials.Changes in hemoglobin and plasma ferritin concentrations weresignificantly larger in the iron group than in the placebo group (58).

In the current review, the 10 identified studies had variedresults (Table 3). In 2 studies, iron supplementation had a sig-nificant positive effect on height or length gains and height-for-age z score (19, 25), and low baseline hemoglobin and irondeficiency appeared to be associated with this effect in bothstudies. The study in Indonesia adjusted for dietary intake in theassessment of the effect on growth and concluded that a decreasein morbidity in the supplementation group may have mediatedthe growth effect (19). In India, iron supplements were random-ized within iron-replete and iron-deficient strata of children.Monthly weight gain and linear growth increased significantly(both: P � 0.001) in iron-deficient children but not in iron-repletechildren (25). This study was the only 1 of the 10 to find im-provements in weight gain associated with iron supplementation.

Three of the 10 studies, including one described above thatfound improvements in iron-deficient children (25), reportedsignificant reductions in weight gains in the iron treatmentgroups (25–27); 2 of these studies also found reductions in lineargrowth in those groups (25, 26). The study in Honduras foundthat, in infants aged 4–6 mo with baseline hemoglobin �110g/L, length gains were less than those in infants who receivedplacebo (26). This study also examined iron treatment effects ina population of breastfed infants in Sweden and found lowergains in length and head circumference in supplemented infantsaged 4–9 mo. Infection did not appear to influence growth out-comes. Similarly, the study in India found an adverse effect of

iron supplementation on weight gain and linear growth in iron-replete children aged 6–24 mo (25). In Indonesia, the negativeeffect was seen only on weight, and no effect was found on lengthor arm circumference (27). In the remaining 6 reviewed studies,no effect of iron supplementation was reported for either weightor height (18, 20–22, 24, 28).

From the available literature, it appears that iron supplemen-tation may be of limited or no benefit for growth; the few studiesthat showed a benefit found it primarily in the children with irondeficiency at baseline. Evidence suggests that iron supplemen-tation in young children without iron deficiency may jeopardizeoptimal height and weight gains.

Morbidity due to infectious disease

Growing concern about the effect of iron supplementation onincreased susceptibility to infection has prompted several studiesto examine this relation. The physiologic process most com-monly implicated is that of the enhanced growth of pathogensfrom available iron in tissues. Iron is an important nutrient bothfor host requirements and for the metabolism of invading patho-gens. Nutritional immunity involves iron-withholding defensesystems that include hypoferremia, a condition in which theamount of iron available for parasites and other organisms isreduced by the activity of iron-binding proteins (59). Anotherpathway proposed in defense against parasitic infection in par-ticular is one in which iron inhibits the expression of induciblenitric oxide synthase (iNOS), which subsequently down-regulates the formation of nitric oxide in macrophages. Nitricoxide appears to be critical to macrophage defense against Plas-modium falciparum (60).

The influence of iron supplementation on infection may bedifferentiated by such variables as increased incidence, duration,or severity of infection. One meta-analysis of 28 RCTs examin-ing iron (oral, parenteral, and fortified foods or beverages) foundthat the pooled estimate of the incidence rate ratio for all infec-tious illnesses, including respiratory tract infection, diarrhea,malaria, and other infections, was not elevated in iron-supplemented children (61). A higher risk of diarrhea (incidencerate ratio: 1.11; 95% CI: 1.01, 1.23; P � 0.04) was found, how-ever, in those given iron than in those given placebo. A nonsig-nificant increase in malaria was also observed in the iron-supplemented group (incidence rate ratio: 1.06; 95% CI: 0.94,1.24). Interpretation of these findings should consider that sev-eral of the studies screened for and included only anemic chil-dren. Moreover, the trials used forms of iron administration otherthan supplements, including parenteral iron (3 studies) and for-tified beverages or foods (5 studies). The age of the study par-ticipants also varied from 2 d to 14 y, and the inclusion andexclusion criteria were heterogeneous.

Our review identified 16 RCTs of oral iron supplementationfor infants and young children in developing countries with in-fectious disease outcomes (Table 4) (16, 18, 19, 22, 24, 26, 27,29–37). The methods applied to measure morbidity variedgreatly across studies. Five studies used clinical measures, 4 studiesused blood or stool samples for assessment, and the remaining 7combined these approaches. Of the 4 studies finding an associationbetween iron supplementation and infection, 3 used the combinedapproach, with both blood and clinical measures of morbidity.

Four studies in our review reported adverse outcomes relatedto iron supplementation. In Bangladesh, in children aged �12mo, iron supplementation resulted in a 49% increase (P � 0.03)

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in the number of episodes of dysentery (34). An earlier study inthe Gambia that included only children who were anemic atbaseline (hemoglobin �3rd percentile of reference population)found that iron treatment was associated with an increase infever-associated severe malaria (37). Although 2 small studies inTanzania found no infection-related adverse effects with ironsupplements (29, 32), a third study from Tanazania found, inchildren with severe anemia (hemoglobin � 5.0 g/L), a signifi-cant increase in morbidity from infectious causes and a signifi-cantly higher incidence of pneumonia in the iron group (both:P � 0.004) (35).

A large trial conducted in Zanzibar, Tanzania (n � 24 076)found a 12% (95% CI: 2%, 23%) greater risk of severe illnessleading to hospitalization or death and a 16% (95% CI: 2%, 32%)greater risk of adverse events due to malaria associated with ironand folic acid supplementation (36). To further examine theeffects of supplementation on hematologic and zinc status andmorbidity, a substudy in Zanzibar (n � 2413) was also carriedout. In this analysis, supplement effect was assessed by iron andanemia status. Children with iron-deficiency anemia who werebeing treated for malaria and other infections had a significantly(P � 0.006) lower risk of adverse events (eg, hospitalization ordeath) (RR: 0.51; 95% CI: 0.31, 0.83) associated with concom-itant treatment with iron and folic acid than did those givenplacebo. Those who were iron replete (with or without anemia)showed a trend toward a greater risk of adverse events when theywere iron supplemented, but the substudy sample size lackedsufficient power to detect statistically significant differences. Inaddition, any apparent adverse effects of iron supplementation inthe iron-replete groups may have been mitigated by the moreextensive diagnosis and treatment services provided by the sub-study than by the routine government services in the larger study.

Only one study in Indonesia (n � 76) found a positive effectfor reduced frequency of fever, respiratory infection, and diar-rhea associated with iron supplementation in children aged 2–5y (19). In infants with hemoglobin �110 g/L at baseline inHonduras, a trend toward a lower risk of diarrhea was seen in theiron-supplemented group (OR: 0.11; 95% CI: 0.01, 1.08; P �0.06), but no similar reverse trend was seen in infants with he-moglobin �110 g/L (26). In the current study, however, thecombined analysis, which included Swedish infants randomlyassigned to iron supplementation and placebo, found a signifi-cant protective effect against diarrhea with iron supplementationin infants with hemoglobin �110 g/L (OR: 0.21; 95% CI: 0.04,0.95; P � 0.04) and an adverse effect among those with hemo-globin �110 g/L (OR: 2.4; 95% CI: 1.0, 5.8; P � 0.05). Theremaining 10 studies of the review found no effect on morbidityassociated with iron supplementation of young children.

Malaria

Malarial infection contributes to the development and severityof anemia through the destruction of parasitized red blood cells,through immune mechanisms including the destruction of un-parasitized red cells, and through dyserthropoiesis (7). Its rela-tion to iron status is less well characterized. Other studies havefound that additional risks may be associated with malarial in-fection and iron supplementation in children, which has in-creased the attention the public is directing toward this associa-tion. Of the 7 studies identified in our review, 5 (29, 31–33, 35)showed no significantly greater risk in the iron supplementationgroups and 2 (36, 37) indicated a greater risk of adverse events

due to malaria. Only 3 of these studies did not use anemia as anenrollment criteria (24, 30, 36); one of these studies, the trial inZanzibar, was the only study of malarial outcomes with adequatepower to detect serious adverse events or mortality (36). Thatstudy found a 16% (95% CI: 2%, 32%; P � 0.02) greater risk ofserious adverse events due to clinical malaria in the treatmentgroups that received iron (iron � folic acid and iron � folic acid� zinc groups) than in the placebo groups. More specifically, thisgroup had an elevated risk of illnesses with clinical signs ofcerebral malaria and a malaria-positive blood film (RR: 1.22;95% CI: 1.02, 1.46; P � 0.03). Cerebral malaria as a cause ofdeath was increased by 70% (RR: 1.70; 95% CI: 1.08, 2.68; P �0.02) in the iron � folic acid treatment group.

HIV

The risks and benefits of iron supplementation in HIV-positivechildren have not been extensively studied. No RCTs were iden-tified in this age category. Globally, 2.2 million children aged�15 y are living with HIV/AIDS; most of them live in sub-Saharan Africa and South and Southeast Asia (36). Numerousrisk factors for compromised health, that may be either dimin-ished or exacerbated by iron supplementation are present in chil-dren born to HIV-positive mothers. Evidence from a review ofobservational studies suggests that infants born to HIV-positivemothers are at greater risk of low birth weight (63); low-birth-weight infants are currently recommended to receive iron sup-plementation from 2 to 23 mo of age. Moreover, infants born toHIV-positive mothers may have compromised iron nutriture (64)and, conversely, may be susceptible to iron overload throughantioxidant deficiencies (65).

Before highly active antiretroviral therapy (HAART), whichremains largely unavailable in developing countries, iron loadingwas observed in various tissues of HIV-positive adults, includingbone marrow, brain, muscle, liver, and spleen (66). Evidencefrom a study of HIV-positive, iron-deficient pregnant women inAfrica found no relation between the severity of HIV disease andiron status indicators (ie, hemoglobin, ferritin, transferrin recep-tor, HIV load, and CD4� lymphocyte count) (67). One RCT in asmall group of HIV-infected adults (n � 45) in Kenya found nodifferences in viral load between the placebo and the iron-supplemented groups after 4 mo of follow-up (68). Further researchis needed in developing countries, especially in young children (in-fected or noninfected) and those born to HIV-positive mothers.

Tuberculosis

Approximately one-third of the world’s population is infectedwith Mycobacterium tuberculosis, the pathogen that causes tu-berculosis. The incidence of tuberculosis has increased dramat-ically with the HIV/AIDS epidemic (69). Whereas we found noRCTs examining the effect of iron supplementation on tubercu-losis in young children, this research may be necessary. Iron hasbeen shown to enhance the growth of M. tuberculosis growth inmice (70). The loading of iron in macrophages where this bac-terium grows may both facilitate its acquisition of iron and inhibitcellular defense systems (71). However, in a study of anemia inadult males with pulmonary tuberculosis, no differences werefound in the recovery rates between iron-supplemented and pla-cebo groups (72). Another study examined retrospective expo-sure to dietary iron and found a significant increase in the odds oftuberculosis with high iron, after adjustment for HIV status and

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liver function (71). These studies highlight the need for moreinvestigation, particularly in young children.

Overall mortality

Two additional RCTs that investigated infection outcomesexamined the risk of mortality related to oral iron supplementa-tion. As stated above, the study in Tanzania found a trend towarda greater risk of mortality in the iron � folic acid treatmentgroups, which is consistent with the increase in hospitalizationfor severe infectious diseases (36). Serious adverse events weremainly attributed to malaria. In Nepal, no effect was found fortotal mortality (30). In “other infections” (including sepsis, hep-atitis, meningitis, and gastrointestinal infections) category ofcause-specific mortality, a significant increase was seen in therelative risk in the iron � folic acid treatment group comparedwith placebo group. Cautious interpretation of these findings iswarranted given the limited reliability of cause of death data. A70% reduction in severe anemia was seen with iron supplemen-tation, but it did not lead to a reduction in mortality.

CONCLUSIONS: BALANCE OF BENEFITS AND RISKS

Twenty-six studies were assessed in this review; they reportedvarious effects associated with preventive iron supplementationin children aged 0–4 y. The outcomes of anemia, development,growth, infectious disease morbidity, and mortality were con-sidered, and the following conclusions were drawn.

For anemia, hemoglobin concentrations were consistently in-creased in iron-supplemented children who were anemic or hadiron-deficient anemia at baseline. Improvements or increases iniron status indicators were also associated with iron supplemen-tation in both iron-deficient and iron-replete children at baseline,although the response was less in the latter group. Iron supple-mentation may have had some positive effects on a number ofdevelopmental outcomes, primarily through reducing preexist-ing deficits or preventing losses over time in cognitive and motorskill development among preschool-aged children who were irondeficient or anemic before supplementation. Treatment at lowerdoses for 2–12 mo appeared to be more beneficial than very shortcourses of supplementation. The variations in developmentalresponses to iron supplementation, combined with the poor orunknown correlations of the measured outcomes with longer-term cognition, make interpretation or quantification of the pos-sible benefits difficult.

In terms of growth, we found evidence from trials of varioussizes for significant adverse effects on weight gains in iron-replete subgroups of young children. For height or linear growth,results varied. Two studies found a positive effect of iron sup-plementation on height increases in iron-deficient children, but 2found a negative effect and 2 found no effect on height or lengthin iron-replete children.

With respect to infectious disease morbidity and mortalityoutcomes, our review found mixed evidence for increased inci-dence, duration, or severity of all infections in association withiron supplementation. Nearly all of the studies to date have beentoo small to enable examination of severe disease events ordeaths. The only trials of sufficient size for these outcomes arethose in Nepal and Zanzibar. In Nepal, no benefit or adverseeffect of iron � folic acid supplements on mortality was found inyoung children. In Zanzibar, clear evidence shows that iron �folic acid supplementation, in a population of children with highrates of malaria and other infectious diseases and with limitedaccess to disease-control programs, results in a significant in-crease in serious adverse events, including deaths. Additionalevidence from this setting suggests that the degree of infectious-disease treatment and the child’s baseline iron status are criticaldeterminants of who benefits and who is harmed in terms ofserious infectious-disease outcomes when the population isprovided low-dose oral iron supplements. Insufficient data areavailable on iron supplementation in relation to HIV or tuber-culosis outcomes for conclusions to be drawn about possiblebenefits or risks.

One general conclusion that may be drawn from this analysisis that baseline hemoglobin and iron status indicators appear to beimportant determinants of these outcomes (Table 5). Our reviewfound this through results from 12 trials screening for and in-cluding children according to hemoglobin or iron status at base-line (11–15, 19, 25, 29, 32, 33, 35, 37) and 8 trials that laterstratified or adjusted for hemoglobin and iron status parametersin analyses associating supplementation with various outcomes(16–18, 21, 22, 26, 28, 36). In the first case of screening orrestriction design, the ability to generalize to the larger popula-tion may be absent, although several studies showed effects withscreening in all outcome categories. Larger, well-designed RCTswere among those finding differential effects of baseline hemo-globin and iron status markers on development, growth, andmorbidity outcomes that support this conclusion. Only 2 studiesreported an interaction between iron supplementation and initial

TABLE 5Effects determined by baseline hemoglobin, iron status, or both

Study Design

Screening or restriction Stratification or adjustment

Outcomes Effect No effect Outcomes Differential effect No differential effect

Development Idjradinata et al (11) Lozoff et al (12) Development Stoltzfus et al (16) Black et al (17)Lozoff et al (15) Walter et al (14) Lind et al (18)Soewondo et al (13) Growth Dewey et al (26) Dossa et al (21)

Growth Majumdar et al (25) Angeles et al (19) Lind et al (18)Morbidity Smith et al (37) Angeles et al (19) Palupi et al (22)

van den Hombergh Chippaux et al (33) Rahman et al (28)et al (35) Mebrahtu et al (32) Morbidity Sazawal et al (36) Lind et al (18)

Menendez et al (27) Palupi et al (22)

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hemoglobin concentration: significant findings for developmentoutcomes were reported from Zanzibar (16), and marginal sig-nificance for morbidity outcomes was found in Honduras (26).Studies from industrialized countries may also suggest the po-tential for interaction. A trial in Greek preschoolers aged 3–4 y(n � 49) found a significant interaction with cognitive perfor-mance (choice reaction time) for baseline iron status and treat-ment group (73). Additional analyses of the interaction of anemiaand iron status at baseline for iron supplementation are needed.

In the substudy of the Zanzibar trial in which substantial ma-laria treatment was provided, in contrast with the larger trial,children with iron deficiency anemia had a reduction in adverseevents. However, an elevated rate of adverse events was ob-served in those without iron deficiency. Detection and treatmentof iron deficiency anemia at an individual level may be requiredto provide the best overall balance of health benefits and risks.Particular caution is advised in areas with high rates of malariaand other serious infections. Futhermore, there may be irregu-larities in both iron absorption and metabolism when particulargenetic polymorphisms—ie, those that may also be associatedwith infection variables—are present. A study in Zimbabwefound a significant interaction effect with ferroportin Q248Hmutation and elevated C-reactive protein (CRP) for higher fer-ritin concentrations (74). More research is needed in this area. Ul-timately, in the consideration of supplementation of young childrenwith low doses of oral iron, an assessment of the balance of risks andbenefits should be integral to the decision-making process.

We recognize that the realities of nutrition and disease-controlprograms may be vastly different from those of the controlledenvironment of these trials. The availability of resources, bothfinancial and staffing, may be a problem if screening for irondeficiency and targeting treatment regimens are necessary toavoid causing harm to some children in the population. At theindividual level, problems of compliance have often been citedwith respect to implementing effective iron-supplementationprograms. Alternative prevention and control strategies such asdiet-based approaches may be preferred, if vulnerable populationgroups have access to foods, because those groups may be able toavoid the adverse effects associated with supplementation.

The need to address the problem of iron deficiency and therelated consequences affecting millions worldwide is undis-puted. Finding the appropriate response, however, particularlyfor young children living in developing countries, is a moredifficult endeavor. This review presents the available evidencefrom carefully designed trials and offers context and individual-specific results with respect to a variety of outcomes. Further re-search is warranted, especially with respect to populations affectedby malaria, HIV, and tuberculosis. In the short term, these findingssuggest that the current recommendations regarding preventive ironsupplementation should be reexamined.

REB and JMT were responsible for the concept of the study; LLI con-ducted the literature research and wrote the draft of the manuscript; and REB,JMT, LLI, and MMB revised and edited the manuscript. None of the authorshad a personal or financial conflict of interest.

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