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Effects of micronutrients on growth of children under 5 y of age: meta-

analyses of single and multiple nutrient interventions1-3

Article  in  American Journal of Clinical Nutrition · January 2009

DOI: 10.3945/ajcn.2008.26862 · Source: PubMed

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Effects of micronutrients on growth of children under 5 y of age:
meta-analyses of single and multiple nutrient interventions1–3
Usha Ramakrishnan, Phuong Nguyen, and Reynaldo Martorell
ABSTRACT
Background: Micronutrient interventions have received much atten-
tion as a cost-effective and promising strategy to improve child health,
but their roles in improving child growth remain unclear.
Objective: Meta-analyses of randomized controlled trials were con-
ducted to evaluate the effect of micronutrient interventions on the
growth of children aged ,5 y old.
Design: Eligible studies were identified by PubMed database
searches and other methods. Weighted mean effect sizes and 95%
CIs were calculated for changes in height, weight, and weight-
for-height z scores (WHZ) by using random-effect models. Tests
for publication bias were done by using funnel plots, heterogeneity,
and stratified analyses by predefined characteristics.
Results: Interventions including iron (n ¼ 27) or vitamin A (n ¼ 17)
only had no significant effects on growth. Interventions including zinc
only (n ¼ 43) had a small positive effect (effect size ¼ 0.06; 95% CI:
0.006, 0.11) on change in WHZ but no significant effect on height or
weight gain. Multiple micronutrient interventions (n ¼ 20) improved
linear growth (0.09; 95% CI: 0.008, 0.17).
Conclusions: Our findings confirm earlier results of no benefits for
interventions including iron and vitamin A only but differ from the
earlier meta-analysis that found improvements in linear growth for
zinc only interventions. This may be due to the improved nutritional
status of children in the more recent studies. Multiple micronutrient
interventions improve linear growth, but the benefits are small.
Other strategies are needed to prevent stunting. Am J Clin Nutr
2009;89:191–203.
INTRODUCTION
Recent estimates indicate that 20% of young children are un-
derweight, 32% are stunted, and 10% are wasted, which places
these children at an increased risk of dying as well as at risk for
a range of adverse consequences over the life cycle and hinders
them from meeting their full potential (1, 2). Although significant
progress has been made over the past few decades in reducing the
prevalence of malnutrition, recent data show that the prevalence of
underweight and stunting has more than doubled in Sub-Saharan
Africa, and South Asia continues to be home to nearly half of the
world’s undernourished children (2).
Adequate access to food, health, and care are well recognized as
necessary to ensure optimal growth and development during the
early years, but interventions that address these underlying causes
have not always been successful in large-scale programs. Ap-
parently, simple strategies such as ensuring adequate frequency of
Am J Clin Nutr 2009;89:191–203. Printed in USA. Ó 2009 American Society for Nutrition
feeding, ie, at least 5 times/d for young children, provision of high-
quality complementary foods that are rich in both macro- and
micronutrients, and promotion of exclusive breastfeeding, require
behavior change that is often difficult to accomplish (2, 3). It is in
this context that the potential of micronutrient interventions as
cost-effective measures to prevent child undernutrition has re-
cently received considerable attention (3–5).
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Several studies have been conducted to explore the link be-
tween micronutrient deficiencies and growth failure, but there
is considerable variability in the nature of the interventions,
choice of control groups, age group, study setting, and other key
explanatory variables that make it difficult to provide unques-
tionable evidence-based advice to policy makers and program
implementers. Although several reviews have been published, to
date few meta-analyses have been published on this topic (6–9).
The earlier and widely known meta-analysis is the one by Brown
et al (6) that evaluated studies of zinc supplementation and child
growth. This analysis included children of all age groups (,18 y)
and found evidence of a small-to-medium effect of zinc supple-
mentation in improving height among children, especially among
those who were younger and stunted at baseline. Another meta-
analysis concluded that whereas iron and vitamin A interventions
do not improve child growth, there was a suggestion of benefit for
multiple micronutrient (MM) interventions (8). Since these meta-
analyses, several more trials have been conducted, including the
large multi-country International Research on Infant Supple-
mentation Initiative (IRIS) trials that evaluated the effect of a MM
intervention in very young children (10–13). The purpose of this
review was to identify well-designed randomized controlled trials
(published and unpublished) that have been conducted to date in
young children ,5 y old with selected micronutrients, both single
and combined interventions, and conduct meta-analyses to eval-
uate the effect of these interventions in improving child growth,
measured as changes in height, weight, and weight-for-height z
scores (WHZ).
1
From the Nutrition and Health Sciences Program and Hubert Department
of Global Health, Rollins School of Public Health, Emory University, At-
lanta, GA.
2
Supported by the Micronutrient Initiative, Ottawa, Canada.
3
Reprints not available. Address correspondence to U Ramakrishnan,
Hubert Department of Global Health, Rollins School of Public Health,
Emory University, 1518 Clifton Road, Atlanta, GA 30322. E-mail: uramakr@
sph.emory.edu.
Received August 21, 2008. Accepted for publication October 15, 2008.
First published online December 3, 2008; doi: 10.3945/ajcn.2008.26862.
191
192 RAMAKRISHNAN ET AL
METHODS
Identification of studies
The studies considered for possible inclusion in the current meta-
analyseswereidentifiedbycombiningtheresultsof2separatesearch
strategies that were completed by April 15, 2008, with the PubMed
(National Library of Medicine, Bethesda, MD) database (1966 to
present). The first search for each intervention included the word
vitamin A or iron or zinc or multi-micronutrients in the title and the
words growth, infant, or child or children in any field. The second
search contained all articles that had the word supplement or sup-
plemental in the title and the words growth or weight or length or
height in any field. The results of these 2 searches were then merged
and examined for inclusion and exclusion as described below. Us-
ing similar specifications, we repeated the search using EMBASE
(Elsevier, Amsterdam. Netherlands) and the Cochrane review for
randomized controlled trials (Wiley InterScience, Hoboken, NJ).
Additional studies that were identified through the bibliographies of
review articles were also included.
Exclusion criteria
Exclusion criteria were as follows: 1) animal studies; 2) studies
not in English; 3) review articles, commentary, editorial, or letter;
4) non-intervention studies; 5) inappropriate age (children .5 y
old, adults, pregnant women); 6) micronutrients not unique fac-
tors in treatment; 7) studies that had subjects with chronic diseases
such as sickle cell diseases, cystic fibrosis, and other conditions
such as severe energy-protein malnutrition, Down syndrome, and
beta-thalassemia that might independently affect growth; 8) du-
ration of follow-up ,8 wk; 9) lack of control groups; and 10) lack
of sufficient data on growth to calculate effect size.
Inclusion criteria
Inclusion criteria were as follows: 1) randomized, placebo-
controlled intervention trial; 2) children had to be 5 y old; and 3)
intervention provided to treatment and control children differed
only in the inclusion of the micronutrients of interest (vitamin A,
iron, zinc, or multiple micronutrients). Initially, the first 3 exclu-
sion criteria were applied by using the appropriate search terms in
the electronic databases, after which complete citations (title and
abstract) were reviewed to identify the studies that were most
likely to meet the inclusion criteria. The complete publications
of this subsample of studies were then read to ensure that they met
the inclusion criteria. Most of the information was obtained from
the published articles. In a few cases (n ¼ 3), we also contacted the
authors directly.
Statistical analyses
The primary outcomes were change in height (expressed in cm/y
or height-for-age z score; HAZ), change in weight (measured in
kg/y or weight-for-age z score; WAZ), and change in WHZ. We
used change in HAZ or WAZ for studies that did not report changes
in absolute height or weight in light of the high correlation between
height and HAZ or weight and WAZ (r ¼ 0.8–0.9). For studies that
had different sample sizes at the beginning and end of the in-
tervention, the lower value was assumed to be the sample size for
the change. If the studies did not report the mean change, we cal-
culated it as the difference of mean post- and pre-intervention
measurements. If the study reported only SE or 95% CI, the SD was
calculated from SE or 95% CI. If studies did not report the SD of the
anthropometric changes, we calculated the SD for change, as-
suming that the correlation between the pre- and post-test variances
was equal to the average correlation found in available studies.
To make sure our assumptions did not bias the results, we per-
formed the sensitivity analysis noted by Sachdev et al (9) using the
following different assumptions for the correlation between the pre-
and post-test variances: 1) using the average correlation in data sets
from available studies, 2) assuming a correlation ¼ 0.5 (14), 3)
assuming no correlation (14), 4) using postintervention values to
calculate the effect size, and 5) calculated effect size only for the
subsample of studies that reported the changes and SD of change.
Effect sizes were calculated for individual studies by dividing the
difference between the mean change in treatment and control groups
by the pooled SD. This value is known as Cohen’s effect size or
Cohen’s d, and it is useful in meta-analyses because it eliminates the
problems of units of measurement and duration, which may vary
across studies (15). The overall mean effect size and 95% CI across
studies was then estimated by assuming a random effects model that
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used the weighted mean effect size for each study where the weight
was the inverse of the intrastudy variance.
Weighted mean effect sizes were calculated with and without
outliers. We tested for heterogeneity of effect sizes by using the chi-
square test of homogeneity as described by Hedges and Pigott (16).
On evidence of significant heterogeneity (P , 0.05), we assessed
the role of several potential predefined effect modifiers: mean initial
age of children (age ,24 or 24 mo), duration of intervention
(duration ,24 or 24 wk), baseline nutritional status (defined as
HAZ,22 or 22, WAZ ,22 or 22, WHZ ,0 or 0) and
baseline hemoglobin (hemoglobin ,110 or 110 g/L only for
iron intervention trials). For studies that did not provide baseline
z scores, we calculated the z scores from baseline height and
weight by using the World Health Organization/National Center
for Health Statistics growth standards (17) to be comparable to
the studies that reported z scores. In the case of MM interventions,
we also stratified by mode of administration (supplementation or
fortification) and combinations of MM (the ones that have similar
combination as IRIS and those with fewer micronutrients).
Weighted mean effect sizes were calculated in each subgroup that
contained at least 2 studies.
The presence of publication bias was evaluated by the funnel
plot, which is a plot of a measure of study size (usually SE or
precision) on the vertical axis as a function of effect size on the
horizontal axis (18). Egger’s test of the intercept and the Begg and
Mazumdar rank correlation test were used for statistical testing of
funnel plot asymmetry (19).
All statistical tests were 2-sided, and significance was reported
for P values ,0.05. All statistical analyses were done by using
SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS
The flow of the number of studies that were included in the
various meta-analyses is shown in Table 1.
Single micronutrients
Vitamin A
The characteristics of the 19 data sets from the 17 studies (20–
36) included in the vitamin A meta-analysis are summarized in
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH 193
TABLE 1 Table 2; for ease of presentation, studies are identified by the last
Studies excluded and included in the meta-analyses of the effects of name of the first author. The publication by Kirkwood et al (32)
micronutrients on growth in children aged ,5 y old1 included the results of 2 distinct studies referred to by the authors
Vitamin A Iron Zinc MM as ‘‘Health’’ and ‘‘Survival’’; these are referred to as Kirkwood/
Health and Kirkwood/Survival in Table 2. The study by Rahman
Potential studies
PubMed search 214 563 602 378 et al (25) compared vitamin A with placebo and vitamin A 1 zinc
Other sources 2 6 3 8 with zinc alone, also resulting in 2 data sets. The total number of
Total potential studies 216 569 605 386 subjects for the 17 studies was 69,320 with a wide range across
Excluded studies studies (51–21,250). The duration of the studies ranged from 12 to
Animal study2 36 78 64 208 104 wk, and vitamin A was provided as a high-dose supplement
Studies not in English2 9 45 35 6 (60 mg) every 4–6 mo in most of the studies. Eleven studies were
Review paper, editorial, letter2 27 74 80 27 conducted in Asia, 4 in Africa, and 2 in Latin America and the
Meta-analysis2 2 3 2 2
Caribbean. The initial ages of the children ranged between 5 and
Nonintervention study3 99 259 293 64
Inappropriate age3 10 37 42 37 48 mo.
Intervention trials in children 33 73 89 42 Although 11 out of 17 data sets had positive effect sizes for
aged ,5 y change in height in favor of vitamin A (Figure 1), the overall
Ineligible studies in children weighted mean effect size was small and was not statistically
aged , 5 y4 significant (0.08; 95% CI: 20.18, 0.34). Two (22, 27) of the 7
Micronutrients not unique 2 20 7 9 studies (22, 26–30, 35) with significant effect sizes were extreme
factors in treatment

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outliers (their effect sizes were 3–5 times larger than the next
Underlying diseases or 5 12 31 1
largest effect size) and therefore are not shown in Figure 1. Ex-
severe malnutrition
Duration of follow-up ,8 wk — 1 2 — clusion of these 2 outlier studies did not greatly affect the sum-
Lack of control group 2 5 — 3 mary estimate. There was evidence of heterogeneity for change in
Lack of data on growth 7 8 6 9 height (P , 0.05), but stratified analyses did not find any differ-
Eligible studies 17 27 43 20 ences by age, duration, or baseline nutritional status.
Number of data sets in eligible studies 19 36 56 27 The overall weighted mean effect size (20.03; 95%: CI 20.23,
1
MM, multiple micronutrients. 0.18) for weight gain also indicated no benefits of vitamin A
2
Search limitation terms. supplementation. There was evidence of heterogeneity (P , 0.01).
3
Title or abstract reviews. The results did not vary by age or duration of follow-up but
4
Complete article reviews.

TABLE 2
Characteristics of 19 data sets from 17 intervention studies included in the meta-analyses of vitamin A and child growth of children aged ,5 y old1
Mean Mean Mean Mean Mean
Mean initial initial initial initial initial
Authors Year Country Subjects initial age Dose Doses Duration height weight WAZ HAZ WHZ
n mo mg n wk cm kg
Fahmida2 (20) 2007 Indonesia 378 5 30 1 24 — — 20.48 21.02 0.40
Alarcon2 (21) 2004 Peru 229 17 60 1 18 76.8 10.4 20.18 20.82 0.47
Pangaribuan (22) 2003 Indonesia 400 36.5 60 1 16 89.2 12.1 21.52 21.48 20.72
Villamor (23) 2002 Tanzania 687 18.7 60 4 52 76.1 9.4 21.62 22.1 20.67
Yang3 (24) 2002 China 63 48 0.2 260 52 95.15 13.78 21.31 21.55 20.29
Rahman (I) (25) 2002 Bangladesh 317 23.7 60 1 24 — — 22.38 22.31 21.24
Rahman (II)4 (25) 2002 Bangladesh 336 23.7 60 1 24 — — 22.46 22.51 21.22
Hadi (26) 2000 Indonesia 1407 27 60 6 16 — — — — —
Smith (27) 1999 Central 51 44 3 24 24 92 13.9 21.04 21.94 0.23
America
Donnen (28) 1998 Zaire 235 36 60 2 52 — — — — —
West (29) 1997 Nepal 3497 36 60 4 64 84.3 10.83 22.23 22.46 21.01
Fawzi (30) 1997 Sudan 21,251 39 60 3 72 88.8 11.79 21.92 21.99 20.91
Bahl (31) 1997 India 900 26.3 60 1 12 77.9 9.04 22.87 22.83 21.38
Kirkwood/Health5 (32) 1996 Ghana 1500 30 60 3 52 — — 21.78 22.04 20.59
Kirkwood/Survival5 (32) 1996 Ghana 15,000 30.6 60 3 104 — — 21.82 — —
Ramakrishnan (33) 1995 India 592 17.7 60 2 52 — — 21.79 21.34 21.22
Lie (34) 1993 China 172 21 60 2 52 — — — — —
Rahmathullah (35) 1991 India 15,419 33 2.5 52 52 — — — — —
West (36) 1988 Indonesia 2766 36 60 2 52 — — — — —
1
WAZ, weight-for-age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score.
2
Intervention group received vitamin A 1 iron 1 zinc; control group received iron 1 zinc.
3
Intervention group received vitamin A 1 calcium 1 zinc; control group received calcium 1 zinc.
4
Intervention group received vitamin A 1 zinc; control group received zinc.
5
Two data sets (‘‘Health’’ and ‘‘Survival’’) from one publication.
194 RAMAKRISHNAN ET AL
FIGURE 1. Effect sizes for height gain in vitamin A intervention trials
among children aged ,5 y old. Data are presented as means with 95% CIs.
All (I) is a calculation with inclusion of outliers [Pangaribuan et al (22) and
Smith et al (27)]; All (II) is a calculation without outliers.
suggested weight loss (effect size ¼ 20.34; 95% CI: 20.66,
20.01) among those who received vitamin A compared with
placebo in the subsample of studies conducted in underweight
children (baseline WAZ , 22; n ¼ 3) compared with no effect
(effect size 0.00; 95% CI: 20.17, 0.17) among the studies where
baseline WAZ 22 (n ¼ 10). There was no overall effect on
change on WHZ (weighted mean effect size was 0.01; 95% CI:
20.06, 0.09), but data were available for only 5 studies.
Iron
Sufficient information was available from the 36 data sets from
27 studies (10–13, 20, 37–58) for calculating the effect of iron
supplementation on child growth (Table 3). Most of the studies
were conducted in developing countries since the 1990s with more
than half (n ¼ 17) in Asia, followed by Africa (n ¼ 3) and Latin
America and the Caribbean (n ¼ 3). Two studies were conducted
in North America and 3 in Europe. Most studies delivered iron in
the form of a tablet or syrup taken daily, and the most common
dosage was 10 mg/d; higher doses (20–60 mg/d) were used in
some of the studies with children older than 15 mo. Aweekly dose
was used in 2 studies (40, 51). Seven studies (20, 37–40, 46, 50)
also used different combinations of iron and zinc and therefore
yielded 2 data sets each, namely, comparisons of iron only to
placebo and iron 1 zinc to zinc only. Three studies used fortifica-
tion-based strategies, namely, comparisons of iron-fortified formula
with non-fortified formula (48, 52, 56); the one by Adish et al (49)
compared cooking in an iron pot with cooking in an aluminum pot.
x 6 SD: 24.3 6
The duration of intervention varied from 8 to 52 wk (
10.4 wk). The initial ages of the children ranged from 1 to 48 mo.
Effect sizes for change in height were calculated for 34 data sets
(Figure 2) and ranged from 25.00 to 0.99. The weighted mean
effect size for height was 20.01 (95% CI: 20.17, 0.15) and in-
creased to 0.01 (95% CI: 20.08, 0.10) after excluding the study by
Majumdar et al (41) that was considered an outlier because its
effect size (25.00; 95% CI: 25.80, 24.20) was more than 5 times
smaller than the next smallest effect size.
Effect sizes for weight gain ranged from 28.14 to 2.18 and,
similar to height, the study by Majumdar et al (41) was defined an
outlier because of its extreme value. The overall weighted mean
effect size with and without the outlier was 0.07 (95% CI: 20.17,
0.30) and 0.08 (95% CI: 20.11, 0.27), respectively. Fourteen
studies had sufficient data to calculate effect sizes for WHZ; the
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effect sizes ranged from 20.56 to 1.21 and the weighted mean
effect size was 20.02 (95% CI: 20.15, 0.12).
For all outcomes, therewas significant heterogeneity (P , 0.001),
but the stratified analysis did not find any predictors that could
explain the variation in effect sizes. Sensitivity analysis using
different assumptions did not alter the overall conclusions; how-
ever, when we restricted the analysis to the subset of 18 studies that
reported only change in weight gain, we found a significant
negative effect on weight (effect size ¼ 20.11; 95% CI:
20.20, 20.02).
Zinc
Of the 602 potential studies identified from the database search
and 3 studies from bibliographies of review articles, only 89 were
zinc intervention trials among young children; an additional 46
studies were excluded because of zinc not being a unique factor in
treatment (n ¼ 7), underlying diseases or severe malnutrition (n ¼
31), lack of growth data (n ¼ 6), or short duration of intervention
and follow up (n ¼ 2), resulting in a final sample of 43 studies (20,
21, 24, 27, 37–40, 46, 50, 59–91) with 56 data sets for inclusion in
the zinc meta-analysis (Table 1). Selected characteristics of the
studies included in this meta-analysis are described in Table 4. All
studies were published between 1976 and 2008, of which 15 were
conducted in Asia, 13 in Latin America and the Caribbean, 8 in
North America and Europe, and 7 in Africa. Mean initial age
ranged from 0 to 48 mo with most of the studies being conducted in
younger children (initial age , 24 mo). Eight studies were con-
ducted in newborns that were either term or small-for-gestational
age infants. The intervention was provided daily as a liquid sup-
plement (syrup mixed into a beverage); the dosage, however,
varied from as low as 20 mg/wk to 20 mg/d. A few studies also
provided zinc in fortified formula (24, 68, 91) or as a fortified
cereal porridge (60).
Similar to iron, several studies had more than one intervention
resulting in 2 or 3 data sets each. For example, Wuehler et al (59)
compared 3 different doses (3, 7, and 10 mg) of zinc with placebo,
and Brown et al (60) compared 2 modes of interventions allowing
us to compare zinc fortification in iron-fortified cereal porridge
plus MM versus MM alone, and zinc supplementation added in
MM versus MM alone. Similarly, several studies used different
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH 195
TABLE 3
Characteristics of the 36 data sets from 27 intervention studies included in the meta-analysis of iron and child growth of children aged ,5 y old1
Mean Mean Mean Mean Mean Mean Mean
initial initial initial initial initial initial initial
Authors Year Country Subjects age Dose2 Duration height weight WAZ HAZ WHZ Hb
n mo mg wk cm kg g/L
Fahmida3 (20) 2007 Indonesia 378 5 10 24 — — 0.05 20.97 0.40 96.6
Wasantwisut (I) (37) 2006 Thailand 306 4.5 10 24 62.40 6.60 20.11 20.66 0.47 117.4
Wasantwisut (II)3 (37) 2006 Thailand 303 4.5 10 24 61.95 6.45 20.20 20.69 0.40 113.8
Berger (I) (38) 2006 Vietnam 399 5.9 10 24 63.85 6.90 20.58 21.02 0.27 109.7
Berger (II)3 (38) 2006 Vietnam 385 5.9 10 24 63.80 6.90 20.57 21.05 0.31 109.1
Uronto (11) 2005 Indonesia 134 9.2 10 23 — — 20.95 20.73 20.49 109.1
Smuts (10) 2005 South A 99 8.4 10 24 68.70 9.10 0.48 20.73 1.30 112.3
Lopez de Romana (13) 2005 Peru 146 9 10 24 — — 20.27 20.99 0.62 106.0
Hople (12) 2005 Vietnam 148 8 10 24 — — 20.91 20.93 20.27 99.85
Lind (I) (39) 2004 Indonesia 327 6 10 24 — — 20.41 20.35 20.07 —
Lind (II)3 (39) 2004 Indonesia 323 6 10 24 — — 20.37 20.35 20.01 —
Black (I) (40) 2004 Bangladesh 43 6.5 20 (/wk) 24 — — 21.05 21.20 0.10 105.5
Black (II)3 (40) 2004 Bangladesh 53 6.5 20 (/wk) 24 — — 21.00 21.20 0.10 105.0
Majumdar (41) 2003 India 100 15 2 (/kg/d) 16 — — — — — 139.0
Friel (42) 2003 Canada 77 1 7.5 20 53.50 4.75 1.05 20.23 1.36 125.0

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Dewey (I)4 (43) 2002 Honduras 131 4 1 (/kg/d) 20 — — 0.22 20.52 — —
Dewey (II)4 (43) 2002 Sweeden 101 4 1 (/kg/d) 20 — — 0.56 0.57 — —
Geltman (44) 2001 USA 310 6 10 12 — — — — — —
Dossa (I)5 (45) 2001 Benin 68 46 60 12 92.10 12.95 21.74 22.26 20.60 101.0
Dossa (II)5 (45) 2001 Benin 72 46 60 12 91.25 12.65 21.84 22.21 20.64 99.5
Dijkhuzen (I) (46) 2001 Indonesia 239 4 10 24 60.90 6.35 20.10 20.89 0.72 —
Dijkhuzen (II)3 (46) 2001 Indonesia 239 4 10 24 61.30 6.55 20.06 20.81 0.76 —
Rahman (47) 1999 Bangladesh 250 34 15 52 — — 22.25 22.20 21.20 —
Morley (48) 1999 UK 327 9 1.2 (/L) 36 71.75 9.15 20.16 20.47 0.29 97.5
Adish (49) 1999 Ethiopia 407 31 — 31 87.60 11.75 21.21 20.86 20.72 106.0
Rosado (I) (50) 1997 Mexico 108 28 20 52 82.95 10.95 21.50 21.70 20.55 108.0
Rosado (II)3 (50) 1997 Mexico 109 28 20 52 83.55 11.25 21.30 21.55 20.35 108.0
Palupi (51) 1997 Indonesia 289 42 30 (/wk) 9 90.50 12.35 21.77 21.82 20.83 112.7
Gill (52) 1997 UK & Ireland 349 6 12.3 (/L) 36 67.60 7.95 0.46 0.28 0.21 117.8
Idjradinata (53) 1994 Indonesia 44 14 27 16 76.05 9.27 20.99 20.61 20.78 —
Bhatia (I)6 (54) 1993 India 117 48 40 24 93.25 12.25 22.26 22.18 21.32 93.0
Bhatia (II)6 (54) 1993 India 53 48 40 24 97.80 13.45 21.60 21.08 21.17 115.5
Angeles (55) 1993 Indonesia 76 37 30 8 86.40 10.60 22.54 22.26 21.52 102.5
Javaid (56) 1991 Pakistan 86 4 7.5 (/100 mg) 34 — — — — — —
Pereira (57) 1978 India 27 42 20 14 92.50 12.69 21.60 21.52 20.84 99.5
Migasena (58) 1972 Thailand 48 40 10 16 — — — — — 101.5
1
WAZ, weight-for-age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score; Hb, hemoglobin. The study by Morley et al and Gill et al
used iron-fortified formula; therefore, the dose is reported as mg Fe/L. The study by Javaid et al used iron-fortified cereal; therefore, the dose is reported as mg
Fe/100 mg.
2
Intervention was daily in all studies except Palupi and Black (weekly).
3
Intervention group received iron and zinc; control received zinc alone.
4
Data set I study conducted in Honduras; data set II study conducted in Sweden.
5
Data set I compared iron and placebo; data set II compared iron 1 deworming with deworming alone.
6
Data set I participants were anemic; data set II participants were not anemic.

combinations of zinc and iron (20, 37–40, 46, 50) that yielded 2
data sets each, namely, comparisons of zinc only to placebo and
zinc 1 iron to iron only. The duration of intervention varied from 8
to 64 wk with a median of 24 wk.
Effect sizes for change in height were calculated for 53 data sets
(n ¼ 40 studies) and ranged from 20.80 to 1.12 (Figure 3). Thirty
(56.6%) studies had a positive effect size and 11 were statistically
significant; however, the overall weighted mean effect (0.07; 95%
CI: 20.03, 0.17) was small and not statistically significant. Sen-
sitivity analyses using different assumptions did not alter the ob-
served effect sizes and conclusions (results not shown). There was
significant heterogeneity (P , 0.001), but the stratified analysis
did not identify any predictors that could explain the variation in
effect sizes.
Effect sizes for zinc intervention on weight gain were calcu-
lated for 54 data sets (n ¼ 41 studies) and ranged from 20.78 to
3.89. Approximately 61% of the data sets (n ¼ 33) had positive
effect sizes, and 10 were statistically significant. The study by
Shrivastava et al (86) was considered an outlier because of the
large effect size (3.89; 95% CI: 2.95, 4.83) that was at least 2 times
larger than the next largest effect size. The overall weighted mean
effect sizes were 0.09 (95% CI: 20.11, 0.25) and 0.06 (95% CI:
20.10, 0.23) with and without the outlier, respectively, indicating
no statistically significant effect of zinc on weight gain. Sensitivity
196 RAMAKRISHNAN ET AL
FIGURE 2. Effect sizes for height gain in iron intervention trials among
children aged ,5 y old. Data are presented as means with 95% CIs. All (I) is
a calculation with inclusion of outliers [Majumdar et al (41)]; All (II) is
a calculation without outliers.
analysis revealed a larger effect size when we used only post-
intervention results (0.11; 95% CI: 0.04, 0.19) or restricted the
sample to studies (n ¼ 34) that reported only change (0.13; 95%
CI: 0.03, 0.24). Similar to height, there was significant heteroge-
neity (P , 0.001), but no significant results were seen in the
stratified analysis.
Twenty-two studies had sufficient data (33 data sets) to estimate
changes in WHZ in response to zinc intervention, and effect sizes
ranged from 20.35 to 0.34; the overall weighted mean effect size
was 0.06 (95% CI: 0.006, 0.11). Sensitivity analysis showed that the
findings were no longer significant if we assumed independence or
restricted the analysis to studies that reported only change in WHZ
(resultsnotshown).Therewasnoevidenceofheterogeneity(P¼ 0.29).
Two-way combinations
Few studies provided sufficient information to calculate the
effect size of iron and zinc (20, 37–40, 46, 50), vitamin A and zinc
(21, 25, 27), and iron and folic acid (20, 62, 92) on growth. The
results (Figure 4) indicate that these combinations do not sig-
nificantly improve child linear growth compared with a placebo.
The overall weighted mean effect sizes for the combination of iron
and zinc were 0.0004 (95% CI: 20.21, 0.21) for height, 0.05 (95%
CI: 20.10, 0.21) for weight, and 0.07 (95% CI: 20.05, 0.18) for
WHZ. The overall weighted mean effect sizes for the combination
of vitamin A and zinc were 0.10 (95% CI: 20.41, 0.61) for height,
0.11 (95% CI: 20.58, 0.80) for weight, and 0.05 (95% CI: 20.12,
0.22) for WHZ. The overall weighted mean effect sizes for the
combination of iron and folic acid were 0.16 (95% CI: 20.05,
0.38) for height and 0.79 (95% CI: 20.35, 1.94) for weight.
Multiple micronutrients (3 micronutrients or more)
We identified 33 intervention trials that were conducted in young
children and allowed us to isolate the effects of multiple micro-
nutrients, of which 20 had growth data. A description of the 27 data
sets from the 20 studies (10–13, 20, 24, 40, 62, 67, 92–102) in-
cluded in the meta-analysis is shown in Table 5. All the studies
were published between 1993 and 2008 and were conducted pri-
marily in developing countries: 8 in Asia, 7 in Africa, and 5 in
Latin America and the Caribbean. The initial ages of the children
ranged from 3 to 50 mo. The study by Begin (93) compared MM 1
bovine serum concentrate versus bovine serum concentrate and
Downloaded from www.ajcn.org at Emory Univ on February 27, 2009
MM1 whey protein concentrate versus whey protein concentrate,
resulting in 2 data sets. The studies by Hople et al (12), Lopez de
Romana et al (13), Smuts et al (10), Uronto et al (11), and Thu et al
(100) compared both daily and weekly MM supplementation with
placebo; thus, each yielded 2 data sets. The study by Ramakrishnan
et al (102) also yielded 2 data sets because the intervention was
nested within a prenatal intervention trial in which the mothers
received either multiple micronutrients or iron only during
pregnancy.
MM interventions were administered either as daily or weekly
supplements or as fortified foods. The supplements were given
in several forms such as a foodlets (10–13), syrup (20, 40, 67,
98, 100, 102), or tablets (24, 62). MM fortificants were delivered in
the form of sprinkles that were added to food (92), fortified
complementary food (96, 99), or a fortified maize-meal or spread
food (10, 93, 95, 97, 101). The intervention was given 5 d/wk in
all studies. In addition, the interventions were also given weekly in
the IRIS trials (10–13) and by Thu et al (100). All interventions
contained at least 3 micronutrients, and 80% of them contained
vitamin A, iron, and zinc. Some interventions also contained io-
dine (40, 73), selenium (10, 40, 67, 73), and copper (67, 73). In
most cases, the daily supplements provided 1–2 times the Rec-
ommended Dietary Allowance for the various micronutrients.
Details of the micronutrient composition of the supplements and
fortified products will be provided on request.
The effect sizes for change in height ranged from 20.64 to
0.63 (Figure 5). Using the random effects model, the overall
weighted mean effect size was 0.09 (95% CI: 0.008, 0.17). The
mean effect size was similar (0.11; 95% CI: 0.02, 0.18) when we
restricted the analysis to studies that provided at least vitamin A,
iron, and zinc.
The effect sizes for change in weight ranged from 20.28 to 1.52,
and the overall weighted mean effect size was small (0.04; 95%
CI: 20.05, 0.12). Restricting the analyses to studies in which the
MM intervention contained at least vitamin A, iron, and zinc
showed a similar mean effect size of 0.03 (95% CI: 20.04, 0.10).
Effect sizes for change in WHZ were calculated for 19 data sets and
ranged from 20.70 to 0.29. The overall mean weighted effect size
of MM interventions on change in WHZ was 20.001 (95% CI:
20.07, 0.07; P ¼ 0.98). Restricting the analyses to the subsample
of studies in which the MM intervention contained at least vitamin
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH 197
TABLE 4
Selected characteristics of 56 data sets from 43 intervention studies included in the meta-analyses of zinc on growth of children aged ,5 y old1
Mean Mean Mean Mean Mean Mean Mean
initial initial initial initial initial initial initial
Authors Year Country Subjects age Dose Duration height weight WAZ HAZ WHZ zinc

n mo mg/d wk cm kg lmol/L
Wuehler (I)2 (59) 2008 Ecuador 251 21 3 24 77.45 9.75 21.25 22.30 20.15 —
Wuehler (II) (59) 2008 Ecuador 253 21 7 24 77.40 9.70 21.25 22.30 20.15 —
Wuehler (III) (59) 2008 Ecuador 253 21 10 24 77.40 9.70 21.25 22.25 20.20 —
Brown (I)3 (60) 2007 Peru 302 7.5 3 24 65.2 7.6 20.65 21.19 0.60 11.96
Brown (II) (60) 2007 Peru 302 7.5 3 24 65.4 7.6 20.75 21.19 0.46 11.87
Fahmida (20) 2007 Indonesia 399 5 10 24 — 0.0 20.06 20.99 0.28 15.30
Berger (I) (38) 2006 Vietnam 393 5.9 10 24 63.9 6.9 20.57 21.01 0.26 14.50
Berger (II)4 (38) 2006 Vietnam 391 5.9 10 24 63.8 6.9 20.58 21.07 0.31 14.18
Heinig (61) 2006 USA 85 4 5 24 64.1 7.0 0.74 0.49 0.30 —
Olney (I)5 (62) 2006 Zanzibar 433 8.8 10 52 — 0.0 21.25 21.45 20.15 —
Olney (II) (62) 2006 Zanzibar 443 8.8 10 52 — 0.0 21.15 21.45 20.06 —
Silva (63) 2006 Brazil 58 23.5 10 16 — 0.0 0.00 21.95 21.20 8.61
Wasantwisut (I) (37) 2006 Thailand 304 4.5 10 24 62.3 6.6 20.18 20.70 0.42 11.30
Wasantwisut (II)4 (37) 2006 Thailand 305 4.5 10 24 62.1 6.5 20.13 20.66 0.45 10.85
Brooks (64) 2005 Bangladesh 1665 5.3 70 (/wk) 52 62.7 6.4 20.80 21.10 0.04 9.80
Gardner (65) 2005 Jamaica 114 19 10 24 77.1 8.6 20.87 21.43 21.65 —
Alarcon (21) 2004 Peru 213 17 3 18 76.8 10.5 20.26 21.04 0.52 —

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Black (66) 2004 India 200 1 5 32 47.5 2.4 21.90 21.20 — —
Black (I) (40) 2004 Bangladesh 94 6.5 20 24 — — 21.00 21.20 0.15 —
Black (II)4 (40) 2004 Bangladesh 92 6.5 20 24 — — 21.05 21.20 0.05 —
Lind (I) (39) 2004 Indonesia 340 6 10 24 — — 20.39 20.37 20.02 —
Lind (II)4 (39) 2004 Indonesia 340 6 10 24 — — 20.39 20.32 20.06 —
Penny (67) 2004 Peru 246 19 10 24 76.4 9.8 21.13 21.56 20.16 10.76
Diaz-Gomez (68) 2003 Spain 36 1 5 24 — 2.3 22.15 — — 11.25
Muller (69) 2003 Germany 709 18.5 12.5 24 75.7 8.7 22.00 21.55 21.25 —
Sur (70) 2003 India 100 0 5 52 46.4 2.3 22.14 21.70 — —
Zlotkin (71) 2003 Ghana 231 10.3 10 8 — — 21.75 21.76 20.63 14.20
Osendarp (72) 2002 Bangladesh 301 0.9 5 20 51.2 3.5 0.00 0.00 0.00 11.80
Yang (I) (24) 2002 China 61 48 3.5 52 96.4 14.3 21.12 21.41 20.26 —
Yang (II)6 (24) 2002 China 55 48 3.5 52 95.4 13.8 21.40 21.66 20.46 —
Castillo-Duran (73) 2001 Chile 150 0 5 52 50.3 3.4 0.24 20.06 0.28 —
Dijkhuizen (I) (46) 2001 Indonesia 238 4.2 10 24 61.2 6.5 20.10 20.79 0.70 —
Dijkhuizen (II)4 (46) 2001 Indonesia 240 4.2 10 24 61.0 6.5 20.06 20.90 0.79 —
Umeta (I)7 (74) 2000 Ethiopia 100 9.6 10 24 69.9 7.5 21.40 20.64 21.14 —
Umeta (II) (74) 2000 Ethiopia 100 9.3 10 24 64.5 6.5 22.58 22.81 20.59 —
Hershkovitz (75) 1999 Israel 25 6.3 6 12 — — 21.91 21.61 21.01 —
Smith (27) 1999 Central America 51 44 70 24 — — — — — —
Meeks Gardner (76) 1998 Jamaica 61 14 10 12 68.7 7.0 0.00 22.85 21.30 —
Kikafunda (77) 1998 Uganda 155 55.8 10 24 103.3 16.7 20.42 20.70 0.00 —
Lira (I)8 (78) 1998 Brazil 137 0 1 8 — — — — — —
Lira (II) (78) 1998 Brazil 134 0 5 8 — — — — — —
Rivera (79) 1998 Guatemala 89 7.5 10 28 63.7 7.2 21.18 22.16 0.69 —
Rosado (I) (50) 1997 Mexico 109 28 20 52 83.2 11.1 21.40 21.70 20.40 13.70
Rosado (II)3 (50) 1997 Mexico 108 28 20 52 83.4 11.1 21.40 21.55 20.50 15.85
Ruz (80) 1997 Chile 102 39.8 10 56 95.6 15.6 0.13 20.52 0.66 17.45
Ninh (81) 1996 Vietnam 146 17.5 10 20 71.3 7.9 22.61 22.91 21.07 —
Sempertegui (82) 1996 Ecuador 50 42.3 10 9 — — 21.40 22.00 — —
Castillo-Duran (83) 1995 Chile 68 0 3 24 47.2 2.3 22.06 21.36 — —
Dirren (84) 1994 Ecuador 96 32 10 64 81.6 11.2 21.75 22.89 20.07 —
Bates (85) 1993 Gambia 110 18 70 (/2 wk) 64 76.8 8.9 21.89 21.57 21.41 —
Shrivastava (86) 1993 India 60 16 5.625 12 — 13.0 1.97 — — 13.67
Hong (87) 1992 China 102 0 5 24 50.0 3.3 0.13 20.08 20.15 13.15
Walravens (88) 1992 France 57 5.7 5 12 66.5 8.1 0.78 0.12 0.81 —
Walravens (89) 1989 USA 50 15 5.7 24 74.6 8.2 22.04 21.35 21.73 —
Walravens (90) 1983 USA 40 50 10 52 — — 21.76 22.07 20.65 —
Walravens (91) 1976 USA 68 0 4 24 49.62 3.2 20.12 20.26 20.26 —
1
WAZ, weight-for-age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score.
2
In data set I, the intervention group received 3 mg Zn/d. In data set II, the intervention group received 7 mg Zn/d. In data set III, the intervention group
received 10 mg Zn/d.
3
In data set I, the intervention group received multiple micronutrients (MM) 1 zinc as fortification; the control group received MM without zinc. In data
set II, the intervention group received MM 1 zinc as supplementation; the control group received MM without zinc.
4
The intervention group received zinc and iron; the control group received iron alone.
5
The intervention group received zinc 1 iron and folic acid; the control group received iron and folic acid.
6
The intervention group received zinc 1 calcium and vitamin A; the control group received calcium and vitamin A.
7
Data set I for nonstunted children; data set II for stunted children.
8
In data set I, the intervention group received 1 mg Zn/d. In data set II, the intervention group received 5 mg Zn/d.
198 RAMAKRISHNAN ET AL
FIGURE 3. Effect sizes for height gain in zinc intervention trials among
children aged ,5 y old. Data are presented as means with 95% CIs.
A, iron, and zinc showed a similar mean effect size of 20.002
(95% CI: 20.08, 0.07).
For all 3 outcomes, there was no evidence of heterogeneity
(P ¼ 0.08 for height and weight and P ¼ 0.51 for WHZ).
Sensitivity analyses using different assumptions confirmed the
overall findings.
Publication bias
Except for the studies of effects of zinc on WHZ, the funnel plot
in each meta-analysis was relatively symmetrical, thus indicating
the absence of publication bias (data not shown). The Egger’s
weighted regression method and Begg’s rank correlation method
further confirmed the symmetrical observation of the funnel plot
with P values . 0.05. For the effect of zinc on WHZ, the funnel plot
was quite asymmetrical, indicating evidence of publication bias (P
of Egger’s method ¼ 0.01 and P of Begg’s method ¼ 0.02). The
effects of zinc on WHZ were reported in only 22 studies (32 data
sets); many studies that reported effects of zinc on height and
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FIGURE 4. Effect sizes for height gain in intervention trials with 2-way
micronutrient combinations among children aged ,5 y old. Data are
presented as means with 95% CIs.
weight change did not report WHZ, which may explain some of
the observed publication bias.
DISCUSSION
The key findings of this review are summarized in Table 6.
Interventions containing iron only, vitamin A only, and combi-
nations of iron and zinc, iron and vitamin A, and zinc and vitamin
A do not improve growth in height, weight, or WHZ in children
aged ,5 y. Interventions containing zinc only have a small posi-
tive effect (0.06; 95% CI: 0.006, 0.11) on change in WHZ but do
not improve height or weight gain in young children. Finally, MM
interventions have a small effect only on growth in height (0.09;
95% CI: 0.008, 0.17).
A major strength of the current review is the sample size for the
various meta-analyses, except for the 2-way combinations. This is
especially true for MM interventions, because several studies were
completed since the previous review that had only 5 studies, of
which only 3 were conducted in young children (98, 99, 101). The
present review included 20 studies that contributed 27 data sets,
and many of them were conducted in infants. Although most
of these studies (19 data sets) provided the intervention as ‘‘sup-
plements,’’ some used food-based approaches and the findings did
not differ by mode of delivery (results not shown).
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH 199
TABLE 5
Selected characteristics of 27 data sets from 20 intervention studies included in the meta-analyses of multiple micronutrients on growth of children aged
,5 y old1
Mean Mean Mean Mean Mean Mean Mean
initial initial initial initial initial initial initial
Authors Year Country Subjects age Duration height weight WAZ HAZ WHZ Hb
n mo wk cm kg g/L
Begin (I)2 (93) 2008 Guatemala 69 6.8 32 64.0 6.89 21.07 21.52 0.18 115.5
Begin (II) (93) 2008 Guatemala 63 6.8 32 64.1 6.94 21.05 21.54 0.22 115.5
Fahmida (20) 2007 Indonesian 386 5 24 — — 20.59 21.04 0.28 95.6
Giovannini (92) 2006 Cambodia 127 6 52 — — 20.87 20.79 20.38 101.2
Olney (62) 2006 Zanzibar 114 8.8 52 — — 21.25 21.50 . 93.9
Faber (94) 2005 South Africa 288 9 24 68.8 9.05 0.33 20.86 1.23 111.0
Hop Le (I)3 (12) 2005 Vietnam 149 8 24 — — 20.94 20.92 20.31 99.4
Hop Le (II) (12) 2005 Vietnam 150 8 24 — — 20.93 20.89 20.31 98.7
Lopez de Romana (I)3 (13) 2005 Peru 135 9 24 — — 20.16 20.79 0.59 106.0
Lopez de Romana (II) (13) 2005 Peru 137 9 24 — — 20.20 20.91 0.65 105.0
Nesamvuni (95) 2005 South Africa 36 24 52 76.15 10.2 21.63 22.78 0.09 111.5
Smuts (I)3 (10) 2005 South Africa 99 8.4 24 68.1 8.7 0.21 20.82 1.08 111.2
Smuts (II) (10) 2005 South Africa 96 8.4 24 68.25 8.9 0.39 20.77 1.24 112.4
Uronto (I)3 (11) 2005 Indonesian 132 9.2 23 — — 20.88 20.69 20.44 108.7

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Uronto (II) (11) 2005 Indonesian 124 9.2 23 — — 20.91 20.69 20.47 109.1
Black (40) 2004 Bangladesh 80 6.5 24 — — 21.10 21.20 0.10 106.5
Penny (67) 2004 Peru 153 19 24 77.05 10.05 20.97 21.37 20.11 101.5
Oelofse (96) 2003 South Africa 30 6 24 64.5 7.7 0.59 20.63 1.35 —
Lopriore (97) 2002 Algeria 209 50 24 90.95 12.5 22.22 22.85 20.73 90.0
Yang (24) 2002 China 53 48 52 95.94 14.18 21.19 21.53 20.26 —
Rivera (98) 2001 Mexico 319 12 52 72.43 8.15 21.47 21.45 20.56 —
Lartey (99) 1999 Ghana 104 6 24 66.15 7.32 20.21 20.27 20.09 104.5
Thu (I)3 (100) 1999 Vietnam 109 15 12 71.7 8.3 21.54 21.63 20.67 110.4
Thu (II) (100) 1999 Vietnam 108 15 12 72.1 8.3 21.72 21.84 20.74 111.1
Liu (101) 1993 China 164 9.7 12 70.7 8.77 20.37 20.61 0.15 —
Ramakrishnan (I)4 (102) 2004 Mexico 221 3 21 59.82 6.10 0.34 20.17 0.42 —
Ramakrishnan (II) (102) 2004 Mexico 218 3 21 59.67 6.08 0.3 20.22 0.43 —
1
WAZ, weight-for-age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score; Hb, hemoglobin.
2
In data set I, the intervention group received multiple micronutrients (MM) 1 bovine serum concentrate; the control group received bovine serum
concentrate. In data set II, the intervention group received MM 1 whey protein concentrate; the control group received whey protein concentrate.
3
In data set I, the intervention group received daily MM supplementation. In data set II, the intervention group received weekly MM supplementation.
4
In data set I, the intervention children and their mothers received MM. In data set II, the intervention children received MM but their mothers received
placebo.

Overall, our findings confirm the results of the earlier meta-
analyses conducted by Ramakrishnan et al (8) but contradict the
findings presented by Brown et al (6) regarding the benefits of zinc
supplementation. The findings for vitamin A are not surprising;
we added 2 new studies (20, 21) and only one study (103) in the
earlier review was not eligible because it was conducted in older
children (9–12 y). In the case of iron, although the results are
similar, the current meta-analyses included 13 new studies (10–
13, 20, 37, 38, 40, 42, 44, 52, 54, 56), and 7 studies (103–109)
included in the earlier review were ineligible for the current meta-
analyses because they were conducted among older children. Our
findings are also consistent with the conclusions by Sachdev et al
(9), who conducted a meta-analysis of iron supplementation trials
on physical growth and found no positive effect. That study in-
cluded 25 studies, of which 15 were conducted among children
,5 y old, in contrast to the 27 studies that contributed 36 data sets
in the current meta-analysis. Many of these were the recently
completed IRIS trials that were not included in the earlier meta-
analyses. It is important to note that there were no significant
differences when we stratified by baseline hemoglobin level for
the various study populations (results not shown).
The most surprising result of the current review is the one for
zinc interventions. We did not find the significant positive
effects that were seen both in height and weight gain in the
earlier meta-analyses by Brown et al (6). Our findings are
timely and important in light of the fact that the Lancet series
on Maternal and Child Undernutrition recommended zinc
supplementation as an effective intervention to reduce mor-
bidity and prevent stunting (3). The Lancet series estimated
that universal coverage with zinc supplementation in the 36
countries with the highest burden of undernutrition would re-
duce the prevalence of stunting by 9.1% at 12 mo, by 15.5% at
24 mo, and by 17% at 36 mo (3). The recommendation of zinc
supplementation as an effective intervention to reduce mor-
bidity rates was based on a new meta-analysis that showed very
large preventive effects, namely, reductions of 14% and 20% in
episodes of diarrhea and lower respiratory infections, re-
spectively (3). In the case of zinc supplementation as an in-
tervention to prevent stunting, no new analyses were carried
out; instead, the Lancet series accepted the results of the meta-
analysis by Brown et al (6), which reported an effect of zinc
supplementation on growth rates in height of 0.35 (95% CI:
200 RAMAKRISHNAN ET AL
FIGURE 5. Effect sizes for height gain in multiple micronutrient
intervention trials among children aged ,5 y old. Data are presented as
means with 95% CIs.
0.19, 0.51). Our meta-analysis indicates that zinc supplemen-
tation would not prevent stunting.
What explains the differences between our meta-analysis
and that of Brown et al (6)? Comparison of the studies included in
the 2 meta-analyses reveals that the results from studies that
were published after the study by Brown et al (6) account for
the differences. Specifically, we find significant effects of zinc
supplementation on both height (0.26; 95% CI: 0.08, 0.43) and
weight gain (0.33, 95% CI: 0.04, 0.62) if we restrict our analysis to
the 21 data sets included in both our analysis and that of Brown
et al (6). On the other hand, restricting our analysis to recent
studies, that is, to those 32 data sets included in our meta-analysis
but not in the earlier analysis by Brown et al (6), indicates no
effect on growth in height (0.02; 95% CI: 20.07, 0.11) or weight
(20.003; 95% CI: 20.15, 0.14). Note that we also excluded a few
TABLE 6
Summary estimates of mean effect sizes (95% CI) for all growth outcomes by type of micronutrient intervention1
Outcomes Vitamin A Iron
Height gain (cm/y) 0.08 (20.18, 0.34) 0.008 (20.08, 0.10)
Weight gain (kg/y) 20.03 (20.23, 0.18) 0.08 (20.11, 0.27)
Changes in WHZ (/y) 0.01 (20.06, 0.09) 20.02 (20.15, 0.12)
1
MM, multiple micronutrients; WHZ, weight-for-height z score.
studies that were in the earlier review: the studies by Hong et al
(110, 111), which were in Chinese, and the one by Matsuda et al
(112) that provided zinc 1 copper and did not allow us to isolate
the specific of zinc; however, including or excluding these studies
did not account for the observed differences between the 2 meta-
analyses. Another difference between the older and more recent
studies is that the latter have a lower prevalence of stunting,
reflecting secular improvements in many parts of the world.
Although Fischer-Walker and Black (113) recently confirmed the
results reported by Brown et al (6), their meta-analysis was not
restricted to children ,5 y of age and did not include any studies
published after 2005. It may be that the response to zinc supple-
mentation in the more recent trials was attenuated by improve-
ments in baseline nutritional status. However, we do not find
evidence in our analysis that effects sizes were modified by
baseline anthropometric characteristics (results not shown).
Whether it has been easier to publish null results over time as the
result of efforts to combat publication bias remains a possibility. In
short, we do not have an explanation for the contrasting results
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between older and newer studies of zinc supplementation. What is
important is that the combined weight of evidence indicates no
effect of zinc supplementation on growth of children ,5 y of age.
Another contribution of the present review was the inclusion of
studies that provided combinations of 2 micronutrients. We
identified very few studies for iron-folic acid and vitamin A-zinc
combinations. In contrast, we did identify 7 studies for iron-zinc
combinations and found no improvements in child growth. Most
of these studies were done among infants and these interventions
improved micronutrient status, namely, hemoglobin and zinc
status (results not shown), and may result in other benefits such as
reduced morbidity and mortality (3).
The main limitations relate to the nature of the studies that were
available for inclusion in these meta-analyses. The limited vari-
ability in the dosage used and lack of data on baseline nutrient
status, especially zinc, make it difficult to identify the conditions
under which these interventions might be beneficial (113). Other
limitations include the dearth of well-designed trials that evaluate
the benefits of micronutrients in the context of food-based ap-
proaches or examine the long-term effects of these interventions.
In conclusion, this review demonstrates that micronutrient
interventions, whether single or multi-nutrient, can do little to
prevent stunting, a problem with major, adverse, long-term con-
sequences for cognition, education, and income (114). Although
there is no doubt that micronutrient interventions such as sup-
plementation with vitamin A, iron, and zinc have important
benefits for child survival and health that amply justify their im-
plementation, more comprehensive approaches that improve the
diets of small children are needed to promote child growth
and development. The Lancet series on maternal and child
undernutrition underscored the importance of exclusive
Zinc Iron 1 zinc MM
0.07 (20.03, 0.17) 0.0004 (20.21, 0.21) 0.09 (0.008, 0.17)
0.06 (20.10, 0.23) 0.05 (20.10, 0.21) 0.04 (20.05, 0.12)
0.06 (0.006, 0.11) 0.07 (20.05, 0.18) 20.001 (20.07, 0.07)
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH
breastfeeding for survival and reduced morbidity but at the same
time noted that breastfeeding promotion interventions do not
improve growth. Of the nutrition interventions that we have at our
disposal, only direct efforts to improve complementary feeding
have been shown to improve growth. On the basis of a limited
number of studies, it is known that education and counseling of
caretakers in food-secure populations can improve growth in
height (0.25; 95% CI: 0.01, 0.49) and providing complementary
food, with or without education and counseling, can improve
height in food-insecure populations (0.41; 95% CI: 0.05, 0.76) (3).
What we do not know is whether education and counseling alone
can be effective in food-insecure populations. Thus, while we
move forward to correct micronutrient deficiencies to improve
child survival and health, we must, at the same time, focus on
interventions to improve complementary feeding.
The authors’ responsibilities were as follows—UR: contributed to the study
design, including the development of the analytical approach, reviewing the
studies, interpretation of findings, and writing the article; PN: conducted the
literature searches to identify the studies, extracted data from identified studies,
conducteddata analysis, and assisted in the interpretation offindings and writing
the article; RM: secured funding and contributed to study design, interpretation
of findings, and writing and reviewing of the article. None of the authors had any
conflicts of interest.
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UNICEF, 2006.
3. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for
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