Iron supplementation in early childhood: health benefits and risks

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

ABSTRACT harm is done by the iron supplementation, especially in those
The prevalence of iron deficiency among infants and young children children who receive no benefit. Although some studies suggest
living in developing countries is high. Because of its chemical prop- risks with iron supplementation, it is important to determine
erties—namely, its oxidative potential—iron functions in several whether these risks are generally supported by available evi-
biological systems that are crucial to human health. Iron, which is not dence and whether they can be mitigated with altered recom-

Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
easily eliminated from the body, can also cause harm through oxi- mendations regarding iron supplementation. The focus of this
dative stress, interference with the absorption or metabolism of other review was to examine the evidence for the health benefits and
nutrients, and suppression of critical enzymatic activities. We re- risks of preventive iron supplementation in children aged 5 y in
viewed 26 randomized controlled trials of preventive, oral iron sup- developing countries.
plementation in young children (aged 0 –59 mo) living in developing Iron is essential for all tissues in a young child’s developing
countries to ascertain the associated health benefits and risks. The body. Iron is present in the brain from very early in life, when it
outcomes investigated were anemia, development, growth, morbid- participates in the neural myelination processes. Other roles that
ity, and mortality. Initial hemoglobin concentrations and iron status would affect growth and immune function have been postulated
were considered as effect modifiers, although few studies included (3). Iron, which is essential to both the host and invading patho-
such subgroup analyses. Among iron-deficient or anemic children,
gens, must be carefully regulated to promote optimal conditions
hemoglobin concentrations were improved with iron supplementa-
that preserve the health of young children. Furthermore, iron can
tion. Reductions in cognitive and motor development deficits were
interfere with the absorption of other nutrients and, in excess, can
observed in iron-deficient or anemic children, particularly with
generate free radicals that impair cellular functions and suppress
longer-duration, lower-dose regimens. With iron supplementation,
enzymatic activity (4, 5).
weight gains were adversely affected in iron-replete children; the
Iron supplementation for children 5 y old is recommended
effects on height were inconclusive. Most studies found no effect on
morbidity, although few had sample sizes or study designs that were
on the basis of anemia prevalence (Table 1). Low-birth-weight
adequate for drawing conclusions. In a malaria-endemic population infants are at high risk of iron deficiency, and the current recom-
of Zanzibar, significant increases in serious adverse events were asso- mendation is that they receive supplementation from 2 mo
ciated with iron supplementation, whereas, in Nepal, no effects on through 2 y of age. Anemia prevalence, determined by hemo-
mortality in young children were found. More research is needed in globin status, is used as a practical indicator because of the
populations affected by HIV and tuberculosis. Iron supplementation in relative difficulty in collecting additional markers of iron defi-
preventive programs may need to be targeted through identification of ciency. The consumption of iron-poor complementary diets
iron-deficient children. Am J Clin Nutr 2006;84:1261–76. (lacking iron-fortified foods or heme iron) is also used to justify
supplementation in infants and preschool-aged children. Com-
KEY WORDS Iron, supplementation, children, development, plementary foods, even with continued breastfeeding, must con-
growth, infection tribute nearly 100% of dietary iron for young children because
breast milk contains little iron (6). Other prevention and control
approaches for iron deficiency—such as food fortification,
INTRODUCTION 1
From the Department of International Health, Bloomberg School of
Iron deficiency has been considered an important risk factor Public Health, Johns Hopkins University, Baltimore, MD (LLI, JMT, and
for ill health (1) and is estimated to affect 2 billion people world- REB), and the Department of Pediatrics, University of Maryland School of
wide (2). Concerns have been raised about the effects of iron Medicine, Baltimore, MD (MMB).
2
deficiency in children on their health and development, which Supported by the Global Research Activity Cooperative Agreement be-
tween USAID and the Johns Hopkins Bloomberg School of Public Health.
have led to recommendations for supplementation of all children 3
Address reprint requests to RE Black, Department of International
of certain ages in populations with a high prevalence of anemia
Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe
(2). This recommendation for a preventive iron intervention will Street, Room E8527, Baltimore, MD 21205. E-mail: rblack@jhsph.edu.
reach both children in need of additional iron and children with- Received March 23, 2006.
out that need. This nondiscrimination may be acceptable if no Accepted for publication July 18, 2006.

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

1262 IANNOTTI ET AL

TABLE 1
Dosage schedule for iron supplementation1

Age group Indications for supplementation Dosage schedule2 Duration
1 1
Low-birthweight infants Universal supplementation 2 mg · kg body wt ·d From age 2 mo to 23 mo
(2–23 mo old)
1 1
Children 6–23 mo old Diet does not include foods fortified with 2 mg · kg body wt ·d From age 6 mo to 23 mo
iron; anemia prevalence Œ40%
Children 24–59 mo old Anemia prevalence Œ40% 2 mg · kg body wt 1
·d 1
3 mo
(up to 30 mg)
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).

dietary improvements, and treatment of hookworm and other rupture (hemolytic anemia), deficient or abnormal synthesis of
helminth infections—were not considered in this review. hemoglobin (eg, thalassemia), or destruction of bone marrow
The objective of this review was to evaluate the health benefits (aplastic anemia) (7). In developing countries, the prevalence of
and risks of iron supplementation as a strategy to prevent iron anemia among preschool-aged children is 42%, and the regions
deficiency in children 0 – 4 y old. Evidence (primarily) from most affected regions are Southeast Asia, Central and East Af-
randomized placebo-controlled trials (RCTs) provided the basis rica, and the Eastern Mediterranean (8). Hemoglobin concentra-

for this assessment because these designs allow causal inference tions are most often used for anemia screening. In children 6 –59
that is not possible with cross-sectional or quasi-experimental mo old, anemia is defined as hemoglobin 110 g/L or hematocrit
designs. 6.83 mmol/L or 0.33 L/L (9).
We conducted a literature review in PubMed (National Li- Evidence of the effect of iron supplementation on anemia
brary of Medicine, Bethesda, MD) to identify studies meeting outcomes is widely available. Studies usually incorporate iron
several criteria. The review was limited to RCTs published after status indicators, such as serum ferritin or transferrin saturation.
1980 and targeting young children 0 –59 mo of age who were One meta-analysis of 21 data sets from iron supplementation
living in developing countries. Oral iron supplementation, as RCTs in children ranging in age from 0 to 12 y found a significant
prevention and not therapy, was the intervention examined in difference in the mean change in hemoglobin concentrations
comparison with placebo and, in a few studies, in comparison between treatment and control groups of 7.8 g/L, or an effect size
with other micronutrients. Trials of iron fortification or paren- of 1.49 (95% CI: 0.46, 2.51) (10).
teral iron were excluded. In certain circumstances when data Of the studies we examined for development, growth, and
were scarce, as in the case of iron supplementation and HIV infectious disease outcomes (Tables 2, 3, and 4), 13 reported
infection or tuberculosis, some observational studies were re- significantly increased hemoglobin concentrations and reduced
viewed to suggest possible relations that should be further inves- anemia prevalence associated with iron supplementation of
tigated with RCTs. young children (11–15, 19, 23, 30, 31). Eleven studies showed
Twenty-six RCTs were identified for this review. If recent improvements in other iron status indicators: serum iron, serum
meta-analyses of RCTs have been performed, results are given, ferritin, transferrin saturation, and free erythrocyte protoporphy-
even though selection criteria such as the age of the children may rin (11, 13, 15, 16, 19, 20, 23, 24, 30 –32). Of the 5 studies
have differed slightly. The outcomes examined in these iron reporting no significant effect on hemoglobin concentrations in
supplementation trials were grouped into the following catego- the entire sample or particular strata (11, 16, 17, 24, 32), 4 showed
ries: anemia and iron status, development (including cognition, improvements in iron status markers (11, 16, 24, 32). This in-
motor skills, and language), growth, morbidity, and mortality. To consistent effect on hemoglobin concentrations may be indica-
highlight particular findings, these outcome categories were then tive of the varied causes of anemia in these study populations.
placed within the sections of the review as either benefits or risks. Sustained significant (P 0.022) improvements in hemoglobin
However, findings were not consistent across many of these out- concentrations 7 mo after a 3-mo treatment period were found in
comes, and this variability deserves careful consideration when pol- one study (21), whereas another study found that only serum
icy is made for programs in countries throughout the world. ferritin 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
BENEFITS OF IRON SUPPLEMENTATION IN EARLY
(11, 17) and to exposure to anemia risk factors in addition to iron
CHILDHOOD
deficiency (ie, residence in malarial endemic regions) (16, 32).
Possible beneficial effects of iron supplementation in young
children are primarily in the realms of anemia prevention and
improvements in developmental outcomes. Development
Iron supplementation has been hypothesized to have benefits
Anemia in children that prevent possible detrimental effects of iron de-
Anemia may be due to iron deficiency (inadequate iron intake, ficiency during development. The pace of neurologic develop-
poor iron absorption, or excess iron losses), insufficient hema- ment in young children aged 0 – 4 y is rapid, including critical
topoiesis (eg, from vitamin B-12 deficiency), loss of blood (hem- periods of neural circuit formation and myelination occurring in
orrhagic anemia), premature red blood cell plasma membrane the brain. Iron’s role in the brain is likely to be multifaceted and

TABLE 2
Development and iron supplementation1

Study and Sample size by Eligibility and exclusion Outcome
location Age group supplement Dosage and duration criteria Baseline status measures Results
n
Black et al, 6–12 mo old Total: 221 Ferrous sulfate (20 mg) Age 6 mo; not receiving Iron: 10.3 0.8 BSID II; HOME Significantly smaller decrease in
Bangladesh Iron group: 49 riboflavin (1 mg) formula; MUAC 110 mm; Zinc: 10.5 1.0 scale orientation engagement
(17) Zinc group: 49 Zinc acetate (20 mg) hemoglobin 90 g/L; no Iron zinc: 10.5 1.0 (exploration) scores in iron and
Iron zinc group: riboflavin (1 mg) obvious neurologic disorders, Multivitamin: 10.5 0.8 iron zinc groups than in
43 Iron (20 mg) zinc physical disabilities, or Riboflavin: 10.8 1.4 placebo group (P 0.05); PDI
Multivitamin (20 mg) riboflavin chronic illness scores from 6 mo to 12 mo of
group: 35 (1 mg) age decreased less for iron
Riboflavin group: Multivitamins (with iron zinc and multivitamins (P
45 and zinc) 0.05); hemoglobin at baseline
Riboflavin and change in hemoglobin not
Weekly dose associated with development
6-mo duration outcomes
Idjradinata and 12–18 mo old Total: 126 IDA group: ferrous Attending clinic at Padjadjaran IDA group: hemoglobin MDI; PDI Significant changes in mean mental
Pollitt, IDA group: 50 sulfate (3 mg · kg 1 · University; birth weight 105 g/L, TS 10%, development and psychomotor
Indonesia Iron-deficient, d 1) or placebo Œ2500 g; singleton; no major serum ferritin 12 g/L scores of IDA infants, but not in
(11) nonanemic Iron-deficient, congenital anomalies or Iron-deficient, nonanemic other groups; developmental
group: 29 nonanemic group: perinatal complications; no group: hemoglobin delay reversed after 4 mo of
Iron-sufficient ferrous sulfate (3 mg · jaundice treated with 120 g/L, TS 10%, treatment
group: 47 kg 1 · d 1) or placebo phototherapy; no hospital serum ferritin 12 g/L
4-mo duration admission or supplementation Iron-sufficient group:
with micronutrients during hemoglobin 120 g/L,
the 6 mo before enrollment; TS Œ 10%, serum
no clinically identified ferritin Œ12 g/L
neuromotor delay; no chronic
illness or folic acid
deficiency; hemoglobin Œ80
g/L; no abnormal hemoglobin
or thalassemia; weight,
length, and head
circumference within 2 SD of
reference standards
Lind et al, 6 mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Hemoglobin 114 g/L Anthropometric Iron improved BSID psychomotor
Indonesia Iron group: 166 Zinc (10 mg/d) Java; singleton infants; age (hemoglobin 110 g/L indexes; development index significantly
(18) Iron zinc group: Iron (10 mg) zinc (10 6 mo observed in 41%, developmental more than did placebo; no effect
164 mg) Exclusions: metabolic or hemoglobin 110 g/L indexes on morbidity; no effect of iron
Zinc group: 167 Placebo neurologic disorders; and ferritin 12 g/L (BSID); alone on growth, but iron zinc
Placebo group: 169 6-mo duration handicaps affecting in 8%) morbidity significantly improved knee-heel
development, feeding, or Weight-for-age z score length compared with placebo;
activity; severe or protracted 0.42; height-for-age z no confounding or interaction
illness: hemoglobin 90 g/L score 0.57; weight- found according to initial iron
for-height z score status
0.02
Lozoff et al, 12–23 mo old Total: 86 Oral iron (3 mg/kg twice Resident of periurban area Anemic group: hemo- Bayley MDI; No significant differences in mental
BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION

Costa Rica IDA iron- a day) Desamparados; birth weight globin 94 6 g/L; free Bayley PDI or motor test scores; mental test
(15) supplemented 6-mo duration 2500 g; singleton birth; free erythrocyte scores in both IDA and
group: 32 of acute or chronic medical protoporphyrin 335.3 nonanemic groups declined over
Nonanemic iron- conditions 173.6 g/dL; packed 6 mo, with significantly lower
supplemented IDA group: hemoglobin 100 RBC ferritin 4.4 4.7 scores in the IDA group at study
group: 27 g/L plus 2 of 3 iron measures g/L; TS 8.4 2.6% entry and 3 mo
Nonanemic group: indicating deficiency: serum Nonanemic group: IDA group: hemoglobin increased
27 ferritin 12 mg/L, hemoglobin 132 5 by 34 g/L at 3 mo and 35 g/L at 6
erythrocyte protoporphyrin g/L; free erythrocyte mo; anemia corrected for all by 6
Œ100 mg/dL, or transferrin protoporphyrin 59.6 mo
saturation 10% 24.1 g/dL; packed Nonanemic iron-supplemented
Nonanemic group: hemoglobin RBC ferritin 13.0 group: iron status improved
125 g/L 17.1 g/L; TS 16.8
1.9%
1263

(Continued)


1264

TABLE 2 (Continued)
Lozoff et al, 6–24 mo Total: 64 Ferrous ascorbate (5 mg · Residents of Guatemala City; Anemic group: hemoglobin Bayley MDI; Deficits at baseline in psychomotor
Guatemala Iron group: 31 kg 1 · d 1) or placebo hemoglobin 105 or Œ120 95 9 g/L; serum iron Bayley PDI development and mental
(12) Placebo group: 33 1-wk duration g/L; no birth complications, 34.5 9.3 g/dL; TS development indexes were not
acute or chronic illness, 7.9 3.1%; serum reversed in 6–8 d of treatment
neonatal distress, congenital ferritin 4.0 5.0 g/ L;
anomalies, developmental free erythrocyte
retardation, generalized protoporphyrin 166.6
malnutrition, or iron therapy 100.1 g/dL packed
during the previous mo; RBCs
mature infants Nonanemic group:
hemoglobin 126 5
g/L; serum iron 60.7
22.3 g/dL; TS 16.9
6.4%; serum ferritin
14.4 19.3 g/L; free
erythrocyte
protoporphyrin 67.9
28.5 g/dL packed
RBCs
Soewondo et al, 5 y Total: 127 Iron (50 mg/d) or placebo Female head of household IDA group: hemoglobin Discrimination IDA associated with visual attention
Indonesia Iron group: 51 2-mo duration works as tea picker; husband Œ110 g/L plus 2 of the learning; and concept acquisition,
(13) Placebo group: 76 present in household; one following: ferritin 12 three oddity corrected by iron treatment
preschool-age child present; g/L, TS 16%, free learning No effect in iron-replete children
family lives on a farm erythrocyte tasks; PPVT
protoporphyrin Œ1.77
mmol/L RBCs
Iron-depleted group:
hemoglobin 110 g/L
plus 2 of the following:
ferritin 12 g/L, TS
IANNOTTI ET AL

16%, free erythrocyte
protoporphyrin Œ1.77
mmol/L RBCs
Iron-replete group:
hemoglobin 110 g/L
plus 2 of the following:
ferritin 12 g/L, TS
16%, free erythrocyte
protoporphyrin 1.77
mmol/L RBCs
Stoltzfus et al, 6–59 mo old Total: 614 Ferrous sulfate (10 mg/d) Resident of Kengeja village on 97% were anemic Language; Language development improved
Zanzibar (16) Households stratified Mebandazole (500 mg) Pemba; age eligibility for (hemoglobin 110 g/ motor score 0.8 points (range: 0.2–1.4) on
by age strata and 12-mo duration language development scale L); 18% were severely 20-point scale
randomly assigned was 12–48 mo and that for anemic (hemoglobin Motor development improved in
to receive iron or motor development scale was 70 g/L) children with hemoglobin 90
placebo; children 12–36 mo g/L
then stratified by Interaction with baseline
iron allocation and hemoglobin (P 0.015)
randomly assigned
to receive
mebendazole
Iron group: 307
Placebo group: 307
Mebandazole group:
306
Placebo group: 308

(Continued)


TABLE 2 (Continued)

Walter et al, 12 mo old Total: 196 Iron (45 mg/d) Residents of well-defined Anemic group: hemoglobin Bayley MDI; No treatment effect was observed
Chile (14) Iron group: 102 10-d duration geographical area 100 9 g/L; MCV 62 Bayley PDI for mental and psychomotor
Placebo group: 94 5 gL; iron and iron- development after 10 d or 3 mo
binding capacity 6.8 No differences by baseline status
2.9%; serum ferritin 5.4 After 3 mo of iron treatment,
g/L; free erythrocyte anemia was corrected
protoporphyrin 195
103.1 g/dL packed
RBCs
Non-anemic iron-deficient
group: hemoglobin 121
7 g/L; MCV 70 4
gL; iron and iron-
binding capacity 12.2
11.9 g/L; free
erythrocyte
protoporphyrin 108
33 g/dL packed RBCs
Control group: hemoglobin
127 8 g/L; MCV 76
3 gL; iron and iron-
binding capacity 16.7
19.8 g/L; free
erythrocyte
protoporphyrin 78 13
g/dL packed RBCs
1
MUAC, midupper arm circumference; BSID, Bayley Scales of Infant Development; HOME, Home Observation Measurement of Environment; PDI, Psychomotor Development Index; IDA, iron-deficiency
anemia; MDI, Bayley Mental Development Index; TS, transferrin saturation; RBC, red blood cell; PPVT, Peabody Picture Vocabulary Test; MCV, mean corpuscular volume.
1265


1266

TABLE 3
Growth and iron supplementation1

Study and Dosage and Eligibility and exclusion Baseline Outcome
location Age group Sample size duration criteria status measures Results
n
Angeles et al, 2–5 y old Total: 76 Ferrous sulfate (30 mg/d) WAZ between 2 and 3 Iron group: hemoglobin Weight, height, dietary Increases in height and HAZ in
Indonesia Iron: 39 2-mo duration SDs 102 9 g/L intake, hemoglobin, treatment group were larger
(19) Placebo: 37 Hemoglobin Œ 80 to 110 Placebo group: hemoglobin serum ferritin; fever than those in control group (P
g/L 103 8 g/L (temperature Œ 37°C); 0.01); hemoglobin, serum
Ferritin 120 g/L WAZ 2.53 diarrhea (Œ4 watery ferritin, and MCV improved
HAZ 2.33 stools/d); RTI significantly
WHZ 1.48 Frequency of fever, respiratory
infections, and diarrhea was
significantly less in treatment
group
Study was adjusted for food intake
effect on growth; decreased
morbidity in supplementation
group is suggested to have
mediated the growth increase
Dewey et al, 4–9 mo old Total: 131 Ferrous sulfate (1 mg · Gestational age 37 wk; Hemoglobin 90 g/L Blood samples at 4, 6, and Reduced gains in length in
Sweden and kg 1 · d 1) from 4 to birth weight Œ2500 g; no 9 mo (hemoglobin, children 4–6 mo old and
Honduras 6 mo of age chronic illness; maternal ferritin, erythrocyte hemoglobin 110 g/L in iron
(26) Placebo from 4 to 6 mo age 16 y; infant zinc protoporphyrin, group
Domellof et al, of age and then ferrous exclusively breastfed at 4 MCV, plasma Weight gain lower in the infants
Sweden and sulfate (1 mg · kg 1 · mo (received 90 mL transferrin receptor); receiving iron for 6–9 mo than
Honduras d 1) from 7 to 9 mo of infant formula/d since C-reactive protein; birth in those receiving placebo
(23) age birth); mother intended to weight; weight, length, within lower ferritin subgroup
Placebo from 4 to 9 mo continue breastfeeding and head circumference No significant effect on morbidity,
of age until infant age 9 mo by month; nutrient intake but diarrhea was less common
in complementary foods; at 4 mo in infants in both
morbidity by maternal Honduras and Sweden who had
IANNOTTI ET AL

records on calendar baseline hemoglobin 110 g/L;
(stool frequency, infants with hemoglobin 110
consistency, cough, g/L at baseline had more
fever, nasal congestion diarrhea
or discharge, diarrhea, From age 4 to 6 mo, hemoglobin
vomiting, or skin rash); and ferritin improved; from age
morbidity by 6 to 9 mo, iron status indicators
pediatrician diagnosis improved but not hemoglobin;
IDA was significantly reduced
at 9 mo
Dijkhuizen et 4 mo old Total: 478 Iron (10 mg/d) Age; resident of any of 6 Hemoglobin and plasma — No effect on growth; hemoglobin
al, Iron (10 mg/d) zinc adjacent villages in West ferritin not reported at and plasma ferritin
Indonesia (10 mg/d) Java; exclusion based on baseline concentrations significantly
(20) 6-mo duration chronic or severe illness, Iron-supplemented group higher in iron-treated group
severe clinical baseline status:
malnutrition, or congenital WAZ 0.06
anomalies HAZ 0.89
WHZ 0.77
Dossa et al, 3–5 y old Total: 140 Iron (60 mg/d) Age 3–5 y; resident of semi- Hemoglobin 10.1 g/L; 76% Anthropometric measures; No effect on growth in study
Benin (21) Iron (60 mg/d) rural area of southern were anemic hemoglobin; eggs/g groups or stratified groups by
albendazole Benin; exclusion: no acute (hemoglobin 110 g/L) feces nutritional and hemoglobin
3-mo duration disease WAZ 1.59 status
HAZ 2.03
WHZ 0.53

(Continued)


TABLE 3 (Continued)

Study and Dosage and Eligibility and exclusion Baseline Outcome
location Age group Sample size duration criteria status measures Results
Idjradinata et 12–18 mo Total: 47 Ferrous sulfate (3 mg · Birth weight Œ2500 g; singleton Iron-replete (hemoglobin Weight, length, and arm Reduced rate of weight gain in
al, old kg 1 · d 1) pregnancy; no major congenital Œ 120 g/L; TS Œ10%; circumference iron group (x SE: 0.106
Indonesia 4-mo duration anomalies or perinatal serum ferritin Œ12 g/ (bi-weekly); morbidity 0.011 versus 0.070 0.011
(27) complications; no jaundice L) (pediatrician kg/2 wk, P 0.02)
treated with phototherapy; no diagnosis); illness No significant differences in
hospital admission or incidence length and arm circumference
supplementation with (gastrointestinal, upper No significant difference in
micronutrients during the 6 mo or lower respiratory respiratory or gastrointestinal
before enrollment; no chronic tract infection) for 2 wk infections
illness or folic acid deficiency; (Other confounding factors not
hemoglobin Œ80 g/L; no signs corrected for)
of abnormal hemoglobin or
thalassemia; weight, length, and
head circumference 2 SDs of
reference standards
Lind et al, 6-mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Hemoglobin 114 g/L Anthropometric indexes; No effect of iron alone on growth
Indonesia Iron group: 166 Zinc (10 mg/d) Java; singleton infants 6 mo (hemoglobin 110 g/L developmental indexes but iron zinc significantly
(18) Iron zinc Iron (10 mg) zinc (10 old; exclusions: metabolic or observed in 41%; (BSID); morbidity improved knee-heel length as
group: 164 mg) neurologic disorders; handicaps hemoglobin 110 and compared with placebo; iron
Zinc group: 167 6-mo duration affecting development, feeding, ferritin 12 g/L significantly improved BSID
Placebo group: or activity; severe or protracted observed in 8%) psychomotor development
169 illness; hemoglobin 90 g/L WAZ 0.42 index as compared with
HAZ 0.57 placebo; no effect on morbidity
WHZ 0.02
Majumdar et 6–24 mo Total: 150 Iron-replete group: iron Birth weight Œ2500 g; singleton Hemoglobin 139 g/L Anthropometric indexes In iron-deficient children,
al, India old Iron-replete (2 mg · kg 1 · d 1) pregnancy; weight, length, and Iron-replete group: (weight, length, head significantly greater mean
(25) group: Iron-deficient group: iron head circumference within 2 hemoglobin Œ110 g/L, circumference) monthly weight gain (P
Iron: 50 (6 mg · kg 1 · d 1) SDs of NCHS reference; diet of serum ferritin Œ12 g/ 0.001) and linear growth (P
Placebo: 50 4-mo duration adequate protein, calories, and L, TS Œ 10% 0.001)
Iron-deficient micronutrients; exclusions: Iron-deficient group: In iron-replete children,
group: 50 major congenital anomaly or hemoglobin 50–110 g/L, significantly less weight gain
prenatal complications, serum ferritin 12 g/ (P 0.001) and linear growth
hospital admission or iron L, TS 10% (P 0.001)
supplementation during the
months before enrollment,
chronic illness, anemia beyond
iron deficiency, or recent blood
transfusion
Palupi et al, 2–5 y old Total: 194 Ferrous sulfate (15 Registered at village health center Hemoglobin 113 g/L Worm infestation (as No effect on changes in height or
Indonesia Iron: 96 mg/wk) WAZ 1.84 indicated by stool weight (SD was large for
(22) Placebo: 98 2-mo duration HAZ 1.92 microscopy) increase in hemoglobin
WHZ 0.85 concentration in both iron and
placebo groups; no hookworm
prevalence and no additional
effect of anthelminth treatment)
Rahman et al, 0.5–6 y old Total: 317 Ferrous gluconate (15 Resident in poor periurban WAZ 2.4 No differences in weight or height
Bangladesh mg/d) vitamins A, community of Dhaka; HAZ 2.3 increments between

(28) D, and C exclusions: congenital WHZ 1.3 intervention and control groups
1-y duration abnormality, metabolic disorder, No hemoglobin reported No differences when stratified by
or any clinical sign of anemia age or nutritional categories
Rosado et al, 1.5–3 y old Total: 219 Ferrous sulfate (20 mg/d) Resident in 1 of 5 rural Hemoglobin 108 g/L RTI (runny nose, common No effect on growth velocity or
Mexico (24) Iron: 109 Ferrous sulfate zinc communities WAZ 1.6 cold, sore throat, body composition
Placebo: 110 methionine HAZ 1.6 cough); diarrhea Zinc and zinc iron significantly
12-mo duration WHZ 0.7 (maternal reporting); decreased diarrhea (P 0.01)
Serum ferritin group: fever (maternal and disease episodes (P
Placebo: 20.1 44.6 reporting) 0.03)
Iron: 21.2 38.1 (No effect with iron alone)
Zinc: 18.9 15.8
Zinc iron: 14.7 15.6
1
WAZ, weight-for-age z score; HAZ, height-for-age z score; MCV, mean corpuscular volume; WHZ, weight-for-height z score; RTI, respiratory tract infection; IDA, iron deficiency anemia; TS, transferrin
1267

saturation; BSID, Bayley Scales of Infant Development; NCHS, National Center for Health Statistics.


TABLE 4
Morbidity and iron supplementation1
1268

Study and Dosage and Eligibility and exclusion Outcome
location Age group Sample size duration criteria Baseline status measures Results
n
Angeles et al, 2–5 y old Total: 76 Ferrous sulfate (30 WAZ between 2 and 3 SD Iron group: hemoglobin 102 Weight, height, dietary intake; Frequency of fever, respiratory
Indonesia (19) Iron: 39 mg/d) Hemoglobin Œ80 to 110 g/L 9 g/L hemoglobin; serum ferritin; fever infections, and diarrhea significantly
Placebo: 37 2-mo duration Ferritin 120 g/L Placebo group: hemoglobin 103 (temperature Œ 37°C); diarrhea less in treatment group
8 g/L (Œ4 watery stools/d); respiratory Increases in height and HAZ in
WAZ 2.53 tract infection treatment group were larger than in
HAZ 2.33 control group (P 0.01)
WHZ 1.48 Hemoglobin, serum ferritin, and MCV
significantly improved
(Study adjusted for effect of food intake
on growth; study suggested that the
lower morbidity in the
supplementation group mediated a
growth increase)
Berger et al, 6–36 mo Total: 197 Iron betainate (2–3 mg Resident in selected village; aged 6–36 Iron group: hemoglobin 98.9 Upper RTI; lower RTI; malaria: No effect on incidence of infections or
Togo (31) old Iron: 100 · kg 1 · d 1) mo; hemoglobin 80 g/L 11.6 g/L, TS 18.3 10.1%, parasite density measured smear; malaria
Placebo: 97 3-mo duration serum ferritin 109.2 110.6 diarrhea; cutaneous infecti on; After adjustment for baseline status,
9-mo follow-up g/L, free erythrocyte fever; worms hemoglobin TS, and ferritin at 3 mo
protoporphyrin 105 63 were significantly improved; at 9 mo,
g/dL packed RBCs only ferritin remained significantly
Placebo group: hemoglobin higher in treatment group
100.4 10.6 g/L, TS 17.0 (Treatment and placebo groups were
7.78%, serum ferritin 109.7 also given malaria prophylaxis and
138.6 g/L, free deworming)
erythrocyte protoporphyrin
101 62 g/dL packed
RBCs
Chippaux et al, 6–36 mo Total: 190 Iron betainate (2.5 mg Hemoglobin 80 g/L NA Malaria (smear positive); antibody No effect on infant susceptibility to
Togo (33) old Iron: 95 · kg 1 · d 1) titers malaria or immune response
Placebo: 95 3-mo duration High parasitanemia frequency in all
9-mo follow-up groups during rainy season
IANNOTTI ET AL

No variation in antibody tiers
Dewey et al, 4–9 mo old Total: 131 Ferrous sulfate (1 mg · Gestational age 37 wk; birth weight Hemoglobin Œ90 g/L Blood samples at 4, 6, and 9 mo No significant effect on morbidity in the
Honduras and kg 1 · d 1) Œ2500 g; no chronic illness; (hemoglobin, ferritin, erythrocyte data from Honduras but in the
Seweden (26) Iron (4–9 mo) maternal age 16 y; infant zinc protoporphyrin, mean combined data from Honduras and
Domellof Placebo (4–6 mo) exclusively breastfed at 4 mo corpuscular volume, plasma Sweden, diarrhea was less common
et al, iron (6–9 mo) (received 90 mL infant formula/d transferrin receptor); C-reactive at 4 mo in supplemented infants with
Honduras and Placebo (4–9 mo) since birth); mother intended to protein; birth weight; weight, baseline hemoglobin 110 g/L;
Sweden (23) continue breastfeeding until 9 mo of length, and head circumference by infants with hemoglobin 110 g/L at
age month; nutrient intake in baseline had more diarrhea
complementary foods; morbidity Reduced gains in length in children 4–6
by maternal record on a calendar mo old and with hemoglobin 110
(stool frequency; stool g/L in the iron group
consistency; cough, fever, nasal Weight gain lower in the group
congestion or discharge; diarrhea, receiving iron for 6–9 mo than in the
vomiting, or skin rash) placebo group within the lower
Morbidity by pediatrician diagnosis ferritin subgroup
Idjradinata et al, 12–18 mo Total: 47 Ferrous sulfate (3 mg · Birth weight Œ2500 g; singleton Iron-replete hemoglobin group: Weight, length and arm No significant difference in respiratory
Indonesia (27) old Iron: 24 kg 1 · d 1) pregnancy; no major congenital Œ120 g/L; TS Œ10%; serum circumference (biweekly); or gastrointestinal infections
Placebo: 23 4-mo duration anomalies or perinatal ferritin Œ12 g/L morbidity (pediatrician diagnosis); Reduced rate of weight gain in iron
complications; no jaundice treated illness incidence (gastrointestinal group (x SE: 0.106 0.010 versus
with phototherapy; no hospital or upper or lower respiratory tract 0.070 0.011; kg/2 wk, P 0.02)
admission or supplementation with infection for 2 wk No significant differences in length and
micronutrients during the 6 mo arm circumference
before enrollment; no chronic illness (Other confounding factors were not
or folic acid deficiency; hemoglobin corrected for)
Œ80 g/L; no signs of abnormal
hemoglobin or thalassemia; weight,
length, and head circumference 2
SDs of reference standards

(Continued)

TABLE 4 (Continued)

Lind et al, 6 mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Java; Hemoglobin 114 g/L Anthropometric indexes; No effect on morbidity
Indonesia (18) Iron: 166 Zinc (10 mg/d) singleton infants; 6 mo old; (hemoglobin 110 g/L development indexes (BSID); No effect of iron alone on growth but
Iron zinc: Iron (10 mg) zinc exclusions: metabolic or neurologic observed in 41%; hemoglobin morbidity iron zinc significantly improved
164 (10 mg) disorders; handicaps affecting 110 and ferritin 12 g/L knee-heel length as compared with
Zinc: 167 6-mo duration development, feeding, observed in 8%) placebo
Placebo: 169 or activity; severe or protracted WAZ 0.42 Iron significantly improved BSID
illness; hemoglobin 90 g/L HAZ 0.57 psychomotor development index
WHZ 0.02 compared with placebo
Mebrahtu et al, 6–59 mo Total: 614 Ferrous sulfate (10 Resident of Kengeja village on Pemba 94.4% were anemic Blood films were assessed monthly No significant effects on malariometric
Tanzania (32) old Households mg/d) (hemoglobin 110 g/L) for prevalence and density of measures or after adjustment for age
stratified Mebandazole (500 17% were severely anemic infection and season
by age and mg) (hemoglobin 70 g/L)
randomly 12-mo duration 80% were infected with
assigned to Plasmamodium falciparum
receive 48.1% had HAZ 2
iron or
placebo,
and then
children
stratified
by iron
allocation
and
randomly
assigned to
mebendazole
Iron: 307
Placebo: 307
Mebandazole:
306
Placebo: 308
Menendez et al, 2 mo old Total: 832 Ferrous glycine sulfate Birth weight Œ1500 g; PCV Œ 25% at P P group: PCV 33.3 5.6 Malaria (axillary temperature No effect on frequency of malaria;
Tanzania (27) (2 mg · kg 1 · d 1) 8 wk; exclusions: congenital I P group: PCV 33.4 5.0 Œ35.5°C with asexual P. 12.8% protective efficac y ( 12.8–
Deltaprim malaria malformation, congenital or neonatal D P group: PCV 33.4 6.4 falciparum parasitemia of any 32.5%)
prophylaxis infection P I group: PCV 33.0 5.3 density)
4-mo duration
10-mo follow-up
Mitra et al, 2–48 mo Total: 349 Ferrous gluconate (15 Exclusions: critically ill, congenital Diarrhea ( 3 liquid stools/d and No effect on number of episodes, mean
Bangladesh old Iron: 172 mg/d) malformations, metabolic disorders maternal report for breastfed duration of each episode, total days
(34) Placebo: 177 Vitamins infants): dysentery (blood, mucus, of illness due to diarrhea, dysentery,
3-mo duration or both in stools) and acute respiratory infection
Acute respiratory infection Œ50 49% of children 12 mo old had an
breaths/min in child 1 y old, increase in the number of episodes of
40 breaths/min in child 1–5 y old dysentery in supplementation group
Palupi et al, 2–5 y old Total: 194 Ferrous sulfate (15 Registered at village health center 10 g/L Worm infestation (as indicated by No effect on hookworm prevalence

Hemoglobin 112
Indonesia Iron: 96 mg/wk) stool microscopy)
(122) Placebo: 98 2-mo duration
Rosado et al, 1.5–3 y old Total: 219 Ferrous sulfate (20 Resident in 1 of 5 rural communities; Hemoglobin 108 g/L RTI (runny nose, common cold, sore No effect on morbidity with iron
Mexico (24) Iron: 109 mg/d) age as stated WAZ 1.6 throat, cough); diarrhea (maternal treatment alone
Placebo: 110 Ferrous sulfate zinc HAZ 1.6 reporting); fever (maternal No effect on growth velocity or body
methionine WHZ 0.7 reporting) composition
12-mo duration and Serum ferritin group:
follow-up Placebo: 20.1 44.6
Iron: 21.2 38.1
Zinc: 18.9 15.8
Zinc iron: 14.7 15.6

(Continued)
1269


1270

TABLE 4 (Continued)
Sazawal et al, 1–35 mo Total: 24 076 Ferrous sulfate (12.5 Age; resident on island of Pemba; no Serious adverse events; all-cause 12% greater risk of mortality or severe
Tanzania (36) old Iron folic mg) severe malnutrition; substudy mortality; cause-specific mortality; illness leading to hospitalization with
acid: 7950 Folic acid (50 g) exclusion: hemoglobin 70 g/L hospitalizations; malaria (parasite iron and folic acid (2–23%; P
Iron folic Zinc (10 mg) count and fever), meningitis, 0.02)
acid Tablet daily for diarrhea, dysentery, pneumonia 16% greater risk of adverse events due
zinc: 8120 children Œ 12 mo to malaria (2–32%; P 0.03)
Placebo: old; half-tablet for No effect with cumulative dose
8006 children 12 mo Substudy findings: in iron-deficient
Substudy: old anemic children, iron and folic acid
2413 12-mo duration treatment significantly reduced the
risk of adverse events (RR: 0.51;
95% CI: 0.31, 0.83; P 0.006)
In iron-replete children, the trend was
toward greater risk of adverse events:
with anemia (RR: 2.00; 95% CI:
0.46, 8.75; P 0.36); without
anemia (RR: 1.51; 95% CI: 0.54,
3.98; P 0.41)
[Children with malaria (parasite count
Œ5000 and axillary temperature
Œ37.5 °C) were given a dose of
sufadoxine/pyrimethamine]
Smith et al, 6 mo–5 y Total: 213 Ferrous sulfate in Hemoglobin and MCV 3% of Hemoglobin and MCV 3rd Malaria (axillary temperature Significantly increased fever-associated
Gambia (37) old Iron: 106 orange juice reference population percentile of reference Œ37.5°C with P. falciparum severe malaria in iron-treated group
Placebo: 107 (3–6 mg · kg 1 · Exclusion: infants with hemoglobin population positivity) than in placebo group
d 1) 50 g/L
3-mo duration
IANNOTTI ET AL

Tielsch et al, 1–35 mo Total: 25 490 Placebo, iron and folic 1–35 mo living in study area All cause mortality; secondary: No effect on mortality: iron and folic
Nepal (30) old acid, zinc, iron and cause-specific mortality; incidence acid (HR 1.03, 95% CI: 0.78, 1.37)
folic acid zinc: or severity of diarrhea; dysentery; or iron and folic acid zinc (HR
Ferrous sulfate ARI, clinic utilization 1.00, 95% CI: 0.74, 1.34)
(12.5 mg) No significant differences in attack rates
Folic acid (50 g) for diarrhea, dysentery, or respiratory
Zinc (10 mg) infections
Tablet daily for children Greater risk of “other infections” and
aged 12 mo; deaths in iron and folic acid group
half-tablet for
children aged
12 mo
12-mo duration
van den 30 mo Total: 100 Ferrous sulfate Hemoglobin 50 g/L; positive smear Hemoglobin 41 8 g/L Malaria (smear positive); pneumonia; No effect on rate of parasitemia or
Hombergh et old Iron: 50 (200 mg/d) for malaria parasites; exclusions: other infections parasite density
al, Tanzania Placebo: 50 Folic acid cerebral malaria, nonfalciparum Increase in morbidity from other causes
(35) 3-mo duration and malaria, sickle cell anemia, other in iron group (P 0.004)
follow-up significant illness Significant difference in pneumonia
incidence; higher in iron group (P
0.004)
1
WAZ, weight-for age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score; MCV, mean corpuscular volume; TS, transferrin saturation; RTI, respiratory tract infection; RBC, red blood cell;
NA, not applicable; BSID, Bayley Scales of Infant Development; P P, placebo placebo; I P, iron placebo; D P, Deltaprim malaria syrup placebo; D I, Deltaprim malaria syrup iron; PCV, packed
cell volume; ARI, acute respiratory infection: bpm, beats/min; RR, risk ratio; HR, hazard ratio.


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