Community and International Nutrition

Multimicronutrient Interventions but Not Vitamin A or Iron Interventions

Alone Improve Child Growth: Results of 3 Meta-Analyses1
Usha Ramakrishnan,*†2 Nancy Aburto,† George McCabe,** and Reynaldo Martorell*†
*Department of International Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322;
†
Program in Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Emory
University, Atlanta GA 30322; and **Department of Statistics, Purdue University, West Lafayette, IN 47907

ABSTRACT Meta-analyses of randomized controlled intervention trials were conducted to assess the effects of
vitamin A, iron, and multimicronutrient interventions on the growth of children ⬍ 18 y old. A PubMed database
search and other methods identified 14 vitamin A, 21 iron, and 5 multimicronutrient intervention studies that met
the design criteria. Weighted mean effect sizes and CI were calculated using a random effects model for changes
in height and weight. Tests for homogeneity and stratified analyses by predefined characteristics were conducted.
Vitamin A interventions had no significant effect on growth; effect sizes were 0.08 (95% CI: ⫺0.20, 0.36) for height
and ⫺0.01 (95% CI: ⫺0.24, 0.22) for weight. Iron interventions also had no significant effect on child growth. Overall
effect sizes were 0.09 (95% CI: ⫺0.07, 0.24) for height and 0.13 (95% CI: ⫺0.05, 0.30) for weight. The results were
similar across categories of age, duration of intervention, mode and dosage of intervention, and baseline anthro-
pometric status. Iron interventions did result in a significant increase in hemoglobin (Hb) concentrations with an
effect size of 1.49 (95% CI: 0.46, 2.51). Multimicronutrient interventions had a positive effect on child growth; the
effect sizes were 0.28 (95% CI: 0.16, 0.41) for height and 0.28 (95% CI: ⫺0.07, 0.63) for weight. Interventions
limited to only vitamin A or iron did not improve child growth. Multimicronutrient interventions, on the other hand,
improved linear and possibly ponderal growth in children. J. Nutr. 134: 2592–2602, 2004.

KEY WORDS: ● vitamin A ● iron ● multimicronutrient ● meta-analysis ● growth

Child undernutrition, as indicated by linear growth failure
and wasting, remains a major public health concern worldwide
because of its significance for child morbidity and mortality
and long-term consequences, such as reduced adult muscle
mass and increased obstetric risk (1,2). Although substantial
progress was made over the past few decades, stunting still
affects about a third of preschool age children in developing
nations, whereas wasting affects ⬃3, 7, and 10% of preschool
children in Latin America, Africa, and Asia, respectively
(3–5). Growth retardation usually begins in utero in many of
these settings and continues during the first 2–3 y of life as a
result of inadequate food intake and infections such as diarrhea
(6). Research on the causes of growth failure over the last half
century focused initially on protein and then energy intake;
recently, more attention has been paid to micronutrients.
Several randomized controlled trials (RCTs)3 were conducted
in developing countries to examine the effects of many of
these nutrients either alone or in combinations of 2 or more on
1
Funding provided by World Bank, National Institutes of Health grant HD-
34531– 05, and the Woodruff Health Sciences, Emory University, Atlanta, GA.
2
To whom correspondence should be addressed.
E-mail: uramakr@sph.emory.edu.
3
Abbreviations used: BW, body weight; HAZ, height-for-age Z-score; Hb;
hemoglobin; RCT, randomized controlled trials; WAZ, weight-for-age Z-score;
WHZ, weight-for-height Z-score.
a range of maternal and child health outcomes including early
childhood growth and development (7–14).
The most conclusive evidence to date linking the intake of
a specific micronutrient to child growth is for zinc. Brown et al.
(15) concluded that zinc supplementation has a significant
positive effect on both linear and ponderal growth of prepu-
bertal children based on a meta-analysis of ⬎ 30 RCTs. A
pooled analysis of RCTs also showed that zinc supplementa-
tion significantly reduced the incidence of diarrhea and pneu-
monia in preschool children (16), which are associated with
poor growth. In contrast, the evidence is less clear for the role
of vitamin A and iron on child growth. Although observa-
tional studies reported significant correlations between vita-
min A status and stunting (17–19) and wasting (17,20), the
results from RCTs are contradictory. In a recent review,
Bhandari et al. (21) concluded that vitamin A supplementa-
tion had little effect on linear growth of young children, but
the evidence was not evaluated using a meta-analysis and
included nonrandomized studies. Although several observa-
tional studies showed a positive correlation between stunting
and iron deficiency (22–24), the evidence that iron supple-
mentation improves child growth is also contradictory, with
some studies showing significant improvement, and others
reporting null findings or even suggesting harmful effects. No
systematic review of the findings of these studies has been
conducted to date, making it very difficult to draw any overall

0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.

Manuscript received 16 March 2004. Initial review completed 16 May 2004. Revision accepted 3 August 2004.

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 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH
conclusions from the current research on iron supplementa-
tion as it relates to child growth.
The main objective of this paper was therefore to compile
the results of multiple studies and assess, through a formal
meta-analysis, the overall effect of vitamin A and iron on the
growth of children. Also, we assessed whether effects varied by
baseline nutritional status, age, duration, dosage, and mode of
intervention. In addition to these 2 nutrients, we also evalu-
ated the effect of multimicronutrient interventions on child
growth.
MATERIALS AND METHODS
Identification of studies
Potential studies for inclusion into the meta-analysis were iden-
tified through 2 searches on PubMed database 1966-present on Sep-
tember 11, 2003 for vitamin A, on August 24, 2003 for iron, and on
October 21, 2003 for multimicronutrients. The first search for each
intervention included the word “vitamin A” or “iron” or “micronu-
trient” in the title and the words “growth, infant or child or children”
in any field and the second search included the word “supplement or
supplemental” in the title and the words “growth or weight or length
or height” in any field. Additional studies were identified through the
bibliographies of review articles.
Exclusion criteria. Animal studies, review articles, cell or tissue
studies and nonintervention studies were rejected. Additional exclu-
sion criteria included studies in which 1) the treatment and control
groups differed in more than simply their inclusion of vitamin A, or
iron, or multimicronutrients; 2) participants were ⬎18 y old; 3) there
was no control group; 4) there were doubts about randomization; 5)
there was a lack of sufficient data on growth to calculate an effect size;
and 6) the duration of follow-up was ⬍8 wk. The selection process
resulted in a final set of published studies that were randomized,
controlled intervention studies in children ⬍ 18 y old in which the
intervention provided to treatment and control participants differed
only in the inclusion of the micronutrient(s) of interest (vitamin A,
or iron, or multimicronutrients).
Statistical analyses
The primary outcomes of interest were changes in height (cm)
and weight (kg). Changes in serum retinol or hemoglobin (Hb)
concentration were also examined for vitamin A and iron, respec-
tively. 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 is useful in meta-analyses because it eliminates the
problems of units of measurement and duration, which may vary
among studies (25). The overall mean effect size and 95% CI across
studies was then estimated assuming the random effects model that
used the weighted mean effect size for each study in which the weight
was the inverse of the intrastudy variance.
We tested for heterogeneity by using the ␹2 test of homogeneity as
described by Hedges (26) to test the hypothesis that the population
effect sizes across studies were equivalent and by visual examination
in which effect sizes calculated for each study were compared with the
overall pattern of effect sizes. Outliers were defined as any study
which differed markedly from the overall pattern. Overall weighted
mean effect sizes were calculated with and without outliers. Several
potential effect modifiers were also considered in the analyses. Studies
were stratified according to age of participants, mode of administra-
tion, dosage, duration of intervention, and initial Hb (iron only) and
Z-scores. Weighted mean effect sizes were calculated in each stratified
subgroup that contained at least 2 studies. Regression analyses were
also performed to determine whether study duration, baseline weight-
for-age Z-score (WAZ), height-for-age Z-score (HAZ), weight-for-
height Z-score (WHZ), and Hb or serum retinol levels predicted
effect sizes.
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RESULTS
Vitamin A
Study attributes. Of the 170 potential vitamin A studies
identified, 156 were rejected and of the 39 intervention trials
in children, 14 studies that yielded 17 datasets with growth
outcomes were included in the meta-analysis and are described
in Table 1. Because the publication by Kirkwood et al. (27)
included the results of 2 distinct studies referred to by the
authors as “Health” and “Survival,” we included the results in
2 data sets which we called KirkwoodHealth and Kirkwood-
Survival. Mwanri et al. (28) compared vitamin A with a
placebo and compared vitamin A ⫹ iron with iron alone,
resulting in 2 data sets. The study by Rahman et al. (29)
compared vitamin A with placebo and vitamin A ⫹ zinc with
zinc alone, also resulting in the 2 data sets. Vitamin A was
provided as a high-dose supplement (liquid or capsule) in most
of the studies (27,29 –38), except for the following: 1) Mwanri
et al. (28) in which a vitamin A–fortified corn gruel was
compared with a nonfortified corn gruel; 2) Rahmathullah et
al. (39) in which a weekly dose was used; and 3) Yang et al.
(40) in which a supplement (vitamin A ⫹ calcium ⫹ zinc vs.
calcium ⫹ zinc) was provided 5 d/wk either mixed with milk
powder or in tablet form. The duration of the studies ranged
from 3 to 24 mo and most had a follow-up period of 4 – 6 mo
post-vitamin A dosage. The studies using high-dose vitamin A
supplements provided 1– 6 doses with 4 – 6 mo between doses.
The studies by Mwanri et al. (28) and Bahl et al. (32) had a
follow-up period of 3 mo, whereas those of Rahmathullah et al.
(39) and Yang et al. (40) reported changes in anthropometric
measures after 52 wk of weekly or daily supplementation. The
initial mean age of the participants ranged from 9 mo to 10.5 y
as follows: ⬍2 y (3 studies), 2–5 y (10 studies), and ⬎5 y (1
study).
Height/Weight. Sufficient information for the calculation
of effect size on change in absolute height was obtained in 15
data sets (Fig. 1) totaling 44,492 participants, and was avail-
able in 17 data sets with a total of 68,678 participants for
weight change (Fig. 2). The study by Hadi et al. (31) was
considered an extreme outlier because the effect size of 3.90
(95% CI: 3.72, 4.08) for height was at least 4 times larger than
the next largest effect size and therefore not shown in Figure
1; comparison of summary estimates, with and without it,
indicate that the exclusion of this study did not greatly affect
the summary estimate but did reduce the overall 95% CI. The
overall weighted mean effect size was 0.08 (95% CI: ⫺0.20,
0.36) for height and ⫺0.01 (95% CI: ⫺0.24, 0.22) for weight.
Stratification and regression analysis. Stratifying studies
by baseline characteristics, i.e., age, dosage, and duration did
not result in any significant effect sizes or evidence of effect
modification. Due to limited data, effect modification by base-
line vitamin A status was not examined. However, there was
a suggestion of effect modification for linear growth by baseline
nutritional status using anthropometry. Although not signifi-
cant (P ⬎ 0.05), the effect sizes were much larger if the initial
HAZ or WAZ was less than ⫺2 (0.46, 0.52) vs. more than ⫺2
(0.03, 0.03) or if the initial WHZ was less than ⫺1 (0.47) vs.
more than ⫺1 (0.03). Although there was evidence of heter-
ogeneity, regression analysis confirmed that no baseline char-
acteristics were significant predictors of the effect size.
Iron
Study attributes. Of the 413 potential studies identified
for the iron meta-analysis, 392 were rejected, and of the 59
 2594 RAMAKRISHNAN ET AL.

TABLE 1
Characteristics of 17 data sets from 14 intervention studies included in the meta-analyses of vitamin A and child growth

Initial Initial Initial

Author Year Country Age Dosage Doses Duration Subjects WAZ HAZ WHZ

y mg n1 wk n

West (36) 1988 Indonesia 1–5 60 2 52 2012 — — —

Rahmathullah (39) 1991 India 0.5–5 2.5 52 52 15419 — — —
Lie (35) 1993 China 0.5–3 60 2 52 172 — — —
Ramakrishnan (34) 1995 India 0.5–3 60 3 52 592 ⫺1.79 ⫺1.34 ⫺1.22
KirkwoodHealth2 (27) 1996 Ghana 0.5–5 60 3 52 1300 ⫺1.79 ⫺2.03 ⫺0.60
KirkwoodSurvival2 (27) 1996 Ghana 0.5–5 60 6 104 21906 ⫺1.83 — —
Bahl (32) 1997 India 1–5 60 1 12 900 ⫺2.87 ⫺2.83 ⫺1.38
Fawzi (33) 1997 Sudan 1–6 60 3 72 21251 — — —
West (38) 1997 Nepal 1–5 60 4 64 3497 ⫺2.24 ⫺2.45 ⫺1.03
Donnen (37) 1998 Zaire 0–6 60 2 52 235 — — —
Hadi (31) 1999 Indonesia 0.5–4 60 6 104 1437 — — —
Mwanri(I) (28) 2000 Tanzania 9–12 1.5 36 12 68 ⫺1.59 ⫺2.13 ⫺0.15
Mwanri(II)3 (28) 2000 Tanzania 9–12 1.5 36 12 68 ⫺1.32 ⫺1.39 ⫺0.45
Rahman(I) (29) 2002 Bangladesh 1–3 60 1 24 317 ⫺2.38 ⫺2.31 ⫺1.24
Rahman(II)4 (29) 2002 Bangladesh 1–3 60 1 24 336 ⫺2.41 ⫺2.48 ⫺1.19
Villamor (30) 2002 Tanzania 0.5–5 60 4 52 687 ⫺1.62 ⫺2.1 ⫺0.67
Yang5 (40) 2002 China 3–5 0.2 260 52 63 ⫺1.20 ⫺1.50 ⫺0.30

1 Intervention was a megadose in all studies except Rahmathullah (weekly syrup); Mwanri (fortified vs. nonfortified corn gruel given 3 d/wk), and
Yang (supplement added to milk powder or given as a tablet 5 d/wk).
2 Two distinct studies called “Health” and “Survival” in the same publication (27).
3 Intervention group received vitamin A and iron; control received iron alone.
4 Intervention group received vitamin A and zinc; control received zinc alone.
5 Intervention group received vitamin A, Ca, and zinc; control received Ca and zinc.

intervention trials among children, 21 studies resulting in 28
data sets that had data on growth were included in the iron
meta-analysis (Table 2). The study by Chwang et al. (41)
separated the participants according to Hb status before ran-
domization and reported the results for anemic and nonanemic
participants each with a treatment and control group. In this
case, each data set was included in the analysis separately.
Similarly, in the study by Dewey et al. (42) there were 2 test
sites, Honduras and Sweden, which yielded 2 data sets for the
meta-analysis. Many studies included a deworming regimen. If
groups differed by deworming treatment, only data comparing
the iron and placebo with the same deworming status were
compared (43– 45). In the paper by Dossa et al. (43), there
were 2 treatments and 2 controls (iron ⫹ albendazole vs.
placebo ⫹ albendazole and iron ⫹ placebo vs. placebo ⫹ pla-
cebo); therefore 2 data sets were generated from this study.
The study by Mwanri et al. (28) compared iron with a placebo
and compared iron ⫹ vitamin A to a vitamin A only group
also resulting in 2 data sets. Similarly, 3 studies (46 – 48) that
used different combinations of iron and zinc also yielded 2
datasets each, i.e., comparisons of iron only to placebo and
iron ⫹ zinc to zinc only.
Most studies delivered iron in the form of a tablet or syrup
taken either daily,(41– 44,46 –56) or weekly (45,46,57,58).
However, the study by Mwanri et al. (28) compared an iron-
fortified corn gruel with a nonfortified corn gruel, the one by
Morley et al. (59) compared an iron-fortified with a nonforti-
fied infant formula, and the one by Adish et al. (60) compared
cooking in an iron pot with cooking in an aluminum pot. The
duration of intervention (wk) varied from 8 to 52 with a
median of 16 wk. The mean initial Hb concentration was
⬍110 g/L, the recommended cutoff for anemia, in 12 of 22
data sets. Ten studies provided at least 2 mg/kg body weight
(BW) of iron, the therapeutic dose of iron recommended by
UNICEF/WHO for rehabilitation of anemia (61). Dose infor-
mation was not available for 2 studies (57,58), whereas the rest
(n ⫽ 16) provided ⬍ 2 mg/kg BW. The initial age of the
participants was ⬍2 y (6 studies), 2–5 y (8 studies), and ⬎5 y
(7 studies).
Height/Weight. Sufficient information for the calculation
of effect size on change in absolute height was available in 19
studies, which yielded 26 data sets (Fig. 3) with 3444 partic-
ipants. There were 21 studies for a total of 28 data sets and
3610 participants with sufficient data to calculate effect sizes
for iron intervention on weight gain (Fig. 4). The effect sizes
for the study by Majumdar et al. (56) were ⬎ 5 times greater
than the next largest effect size [height ⫺5.00 (95% CI:
⫺5.80, ⫺4.20), weight ⫺8.14 (95% CI: ⫺9.34, ⫺6.94)] and
therefore not included in Figures 3 and 4; comparison of
summary estimates, with and without them, indicated that
their removal did not significantly affect the summary estimate
but did reduce the 95% CI. The overall weighted mean effect
size after excluding the outlier was 0.09 (95% CI: ⫺0.07, 0.24)
for height and 0.13 (95% CI: ⫺0.05, 0.30) for weight.
Stratification and regression analysis. Stratifying studies
based on baseline characteristics such as age, type of interven-
tion, and dose did not result in any significant weighted mean
effect sizes nor did it reveal any significant effect modifiers.
There were also no significant differences by baseline Hb
status, although effect sizes were greater among anemic sub-
jects for height gain. The mean effect sizes were 0.21 (95% CI:
⫺0.14, 0.56) and 0.15 (95% CI: ⫺0.11, 0.41) for height and
weight gain, respectively, in the studies in which Hb was ⬍110
g/L, compared with 0.02 (95% CI: ⫺0.14, 0.18) and 0.16
(95% CI: ⫺0.24, 0.57), respectively, in studies in which base-
line Hb was ⬎110 g/L. Similarly, there was a suggestion that
baseline nutritional status using anthropometric indicators

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 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH
modified the response to iron intervention. Although not
significant (P ⬎ 0.05), effect sizes were larger in studies with
participants with an initial HAZ or WAZ of less than ⫺1 or
WHZ ⬍ 0 compared with those with participants with an
initial HAZ, WAZ greater than ⫺1 or WHZ ⬎ 0 for both
height (0.15 vs. ⫺0.05, 0.14 vs. ⫺0.03, 0.12 vs. ⫺0.02) and
weight gain (0.14 vs. 0.07, 0.20 vs. 0.02, 0.16 vs. ⫺0.02).
Although there was evidence of heterogeneity, regression
analysis showed that no characteristics were significant pre-
dictors of effect sizes.
Hemoglobin. There were 16 studies with a total of 21 data
sets and 2542 participants with sufficient information to cal-
culate effect sizes of iron intervention on Hb concentrations.
The effect sizes ranged from 0.00 to 14.53. The largest effect
size, 14.53 (95% CI 12.17, 16.88), occurred among severely
anemic children in the study by Chwang et al. (41) that was
defined as an outlier. The overall weighted mean effect size
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2595
FIGURE 1 Effect size for height
gain in vitamin A intervention trials
among children. Data are presented as
means with 95% CI.
without the above study was a significant value of 1.49 (95%
CI: 0.46, 2.51).
Multiple micronutrients
Study attributes. The database searches on multimicro-
nutrient intervention trials resulted in 225 potential studies.
Six more studies were identified through other sources for a
total of 231 potential studies, of which 226 were rejected.
Almost a third (n ⫽ 74) were review papers/commentaries/
editorials; a number of food supplementation trials were also
excluded because they did not permit isolation of the effects of
micronutrients. Of 18 potential trials conducted in children,
only 5 RCTs in which the treatment and control differed only
in the inclusion of multimicronutrients were included in the
meta-analysis (Table 3).
The intervention was given ⱖ5 d/wk either as a syrup (62),
 2596 RAMAKRISHNAN ET AL.
FIGURE 2 Effect size for weight
gain in vitamin A intervention trials
among children. Data are presented as
means with 95% CI.
fortified beverage (63,64), or a fortified food (65,66) and
contained vitamin A, iron, Zn, B vitamins, and folic acid in all
studies. Some interventions also contained iodine (62,64),
vitamin C (63,66), vitamin E (63,64), calcium (63,65,66),
potassium (63,66), copper (62,66), and other trace vitamins
and minerals (62). Three studies had participants ⬍ 24 mo old
(62,65,66), whereas 2 had participants ⬎ 5 y old (63,64).
Height/Weight. Sufficient information for the calculation
of effect size on change in absolute height was obtained in 4
studies totaling 1330 participants and for change in weight
gain in 5 studies totaling 1604 participants (Table 4). The
overall weighted mean effect size was 0.28 (95% CI: 0.16,
0.41) for height and 0.28 (95% CI: ⫺0.07, 0.63) for weight,
respectively. There was no evidence of heterogeneity in the
case of linear growth.
Stratification and regression analysis. There was an in-
sufficient number of studies to perform formal stratified anal-
yses. Analysis was done, however, with the 4 studies with
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participants ⬍ 5 y old; the weighted mean effect size on height
was 0.19 (95% CI 0.03, 0.35) and on weight was ⫺0.07(95%
CI ⫺0.23, 0.09). There was only 1 study with information on
height change in children ⬎ 5 y old; the mean initial age was
8.5 y and the effect size was 0.35 (95% CI 0.21, 0.50). Two
studies with participants ⬎ 5 y old had information on weight
change; both studies had significant positive values for effect
size with a weighted mean effect size of 0.48 (95% CI 0.39,
0.61). No significant correlations were found between effect
sizes of height or weight and baseline HAZ, WAZ, WHZ, and
Hb, or study duration.
DISCUSSION
Our findings indicate that neither vitamin A nor iron
interventions improve linear or ponderal growth in children.
Further, there was no evidence of effect modification by base-
line characteristics such as age, nutritional status, or factors
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH 2597

TABLE 2
Characteristics of the 28 data sets from 21 intervention studies included in the meta-analysis of iron and child growth

Initial Initial Initial Initial

Author Year Country Age Dosage Duration Subjects Hb WAZ HAZ WHZ

mg/kg
y BW wk n g/L

Migasena (55) 1972 Thailand 0.5–6 10 16 31 102 — — —

Pereira (44) 1978 India 2–5 1.5 14 54 100 ⫺1.62 ⫺1.59 ⫺0.81
Chwang(I)2 (41) 1988 Indonesia 8–13.5 2 12 78 97 ⫺1.39 ⫺1.66 —
Chwang(II)2 (41) 1988 Indonesia 8–13.5 2 12 41 133 ⫺1.34 ⫺1.56 —
Latham (50) 1990 Kenya 8–10 4 32 55 115 ⫺1.38 ⫺0.87 ⫺1.16
Angeles (51) 1993 Indonesia 2–5 2.7 8 76 103 ⫺2.53 ⫺2.33 ⫺1.48
Idjradinata (49) 1994 Indonesia 1–1.5 3 16 47 — ⫺0.96 ⫺0.72 ⫺0.67
Lawless (52) 1994 Kenya 6–11 1.3 14 87 111 ⫺1.3 ⫺1.2 ⫺0.74
Palupi (45) 1997 Indonesia 2–5 2.5 9 289 113 ⫺1.84 ⫺1.92 ⫺0.85
Rosado(I) (47) 1997 Mexico 1.5–3 1.8 52 108 108 ⫺1.6 ⫺1.6 ⫺0.7
Rosado(II)3 (47) 1997 Mexico 1.5–3 1.8 52 109 108 ⫺1.3 ⫺1.6 ⫺0.4
Adish (60) 1999 Ethiopia 2–5 — 52 407 106 ⫺1.36 ⫺1.05 ⫺0.78
Morley (59) 1999 UK 0.66 — 36 493 97 ⫺0.11 ⫺0.41 0.3
Rahman (54) 1999 Bangladesh 0.5–6 1.4 52 317 — ⫺2.4 ⫺2.3 ⫺1.3
Aguayo (57) 2000 Bolivia 6–12 3 18 73 157 ⫺0.96 ⫺1.38 0.37
Beasley (58) 2000 Tanzania 12–18 2.2 16 234 116 ⫺1.57 — —
Mwanri(I) (28) 2000 Tanzania 9–12 1.5 12 68 105 ⫺1.56 ⫺1.71 —
Mwanri(II)4 (28) 2000 Tanzania 9–12 1.5 12 68 105.4 ⫺1.34 ⫺1.61 ⫺0.29
Dijkhuzen(I) (48) 2001 Indonesia 0.33 1.6 24 239 — ⫺0.06 ⫺0.89 0.77
Dijkhuzen(II)3 (48) 2001 Indonesia 0.33 1.6 24 239 — ⫺0.01 ⫺0.81 0.76
Dossa(I)5 (43) 2001 Benin 3–5 4.7 12 68 101 ⫺1.59 ⫺2.03 ⫺0.53
Dossa(II)5 (43) 2001 Benin 3–5 4.7 12 72 100 ⫺1.88 ⫺2.16 ⫺0.72
Dewey(I)6 (42) 2002 Honduras 0.33 1 20 142 — 0.27 ⫺0.43 —
Dewey(II)6 (42) 2002 Sweden 0.33 1 20 121 — 0.62 0.67 —
Sungthong (53) 2002 Thailand 6–13 2.5 16 397 121 ⫺1.3 ⫺1.55 0.09
Lind(I) (46) 2003 Indonesia 0.5 1.4 24 279 114 ⫺0.42 ⫺0.57 ⫺0.02
Lind(II)3 (46) 2003 Indonesia 0.5 1.4 24 270 113 ⫺0.32 ⫺0.61 0.15
Majumdar (56) 2003 India 0.5–2 2 16 189 139 — — —

1 Intervention was daily in all studies except Palupi, Aguayo, and Beasley (weekly); Adish (iron pot vs. aluminum pot); Morley (fortified vs.
nonfortified follow on formula); and Mwanri (fortified vs. nonfortified corn gruel).
2 At baseline, data set I participants were anemic; data set II participants were not anemic.
3 Intervention group received iron and zinc; control received zinc alone.
4 Intervention group received iron and vitamin A; control received vitamin A alone.
5 Data set I did not include a deworming regime for any participants; data set II included a deworming regime for treatment and control groups.
6 Data set I study conducted in Honduras; data set II study conducted in Sweden.

related to the delivery of the intervention, i.e., duration,
mode, and dosage of intervention. In contrast to the lack of
effect of these single nutrient interventions, multimicronu-
trient interventions did improve linear growth and possibly
ponderal growth in children, which may be due to beneficial
interactions among nutrients and/or the direct effect of
nutrients such as zinc, which was shown to benefit child
growth (15).
The lack of effect of vitamin A on growth is indeed con-
trary to the dramatic reductions seen in young child mortality
and the severity of infections such as measles and diarrhea,
which are known predictors of child growth. Many of the
studies that examined child growth were done in settings
similar to those that examined child morbidity and mortality.
Although 3 studies reported significant effects of vitamin A
supplementation on either linear growth or weight gain, the
overall weighted mean effect size for vitamin A for both these
outcomes was indeed small (⬍0.1) and not significant. Fur-
ther, the overall conclusions did not differ with our without
the inclusion of outliers. In terms of adverse effects, only 1
study (37) reported a significant negative effect size (⫺0.70)
for height, but the same study had a significant positive effect
on weight gain (1.15).
One limitation was the use of sample averages to classify
studies for the stratified analysis especially when there was
considerable variation within a study. For example, the initial
age of participants in 2 studies ranged from 6 mo to 6 y
(33,37), resulting in the study being classified in the age
category of 2– 4.9 y, even though there were 3 distinct cate-
gories, i.e., infants, toddlers, and older preschool-age children,
who differ in their growth patterns and perhaps response to the
intervention. The use of averages may also have limited the
effectiveness of the regression analysis, which found no signif-
icant correlations between initial characteristics of partici-
pants and effect size. Nevertheless the findings of some studies
that conducted post-hoc analyses for some of these character-
istics are consistent with our conclusions. For example, West
et al. (36) reported improved growth after vitamin A supple-
mentation in boys aged 4 –5 y but not in younger boys, whereas
5 other studies (29,30,32,35,39) did not find any differences in
growth based on age. Similarly, no differences were seen by
initial Z-scores of participants (29). An interesting finding,
however, was the effect of season on the response to vitamin
A. Supplementation of vitamin A during the summer months
in India resulted in a significant weight gain in participants age
1–5 y, whereas supplementation during any other season dur-

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 2598 RAMAKRISHNAN ET AL.
FIGURE 3 Effect size for height
gain in iron intervention trials among
children. Data are presented as means
with 95% CI.
ing the year resulted in no changes in weight or height
increment compared with controls (32). Significant seasonal
variation in dietary intake of vitamin A is common, especially
in settings in which the main sources of this vitamin are fruits
and vegetables (67–70), and it is reasonable to expect vitamin
A interventions to benefit children more during the time of
year when they are at greatest risk of vitamin A deficiency
(38). Although only the study by Bahl et al. (32) examined
the role of season, it should be noted that many studies had at
least 1 y of follow-up, which could have diluted any positive
effect of vitamin A supplementation received during any one
season of the year. Finally, another possible reason for the lack
of effect is that most studies excluded children with clinical
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symptoms of vitamin A deficiency; although the effect on
growth may be limited to this subgroup (29,30,32–34,36,71),
reductions in mortality were demonstrated in children with
mild-to-moderate vitamin A deficiency (8). The lack of data
on baseline serum retinol limited our ability to examine the
role of this factor.
The results of the meta-analysis of iron intervention trials
were similar to those seen for vitamin A. In contrast to the
lack of effect on growth, there was an overall effect on Hb,
confirming the efficacy of iron interventions in reducing ane-
mia. As with the vitamin A studies, the possible reason that
the overall weighted mean effect sizes were not significant for
the effect of iron on growth could be due to the heterogeneity
 MICRONUTRIENT INTERVENTIONS AND CHILD GROWTH
of studies. Although we did not find any effects even after
stratifying studies according to baseline characteristics and
mode of intervention, there were considerable interstudy dif-
ferences within the strata. The findings of the few studies that
conducted post-hoc analysis, however, indicated that that
there were no differences in the effect of iron supplementation
after stratifying subjects based on initial HAZ (43,47,54), Hb
status (43), or age (54). Only one study used a multiple
regression approach to determine any effect modifiers and
found that the positive effect of iron on growth was decreased
with increasing age over the age range of 7–9 y (50).
There has been recent concern that widespread iron sup-
plementation could actually have a detrimental effect on
growth in iron-replete children and/or young infants (21).
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2599
FIGURE 4 Effect size for weight
gain in iron intervention trials among
children. Data are presented as means
with 95% CI.
None of the studies that enrolled iron-replete participants
with a mean initial Hb value ⬎ 110 g/L reported a significant
negative effect of iron on growth, whereas 3 data sets had
significantly positive effect sizes for height (52) and weight
(50,52,58). Additionally, regression analysis found no signifi-
cant negative correlation between effect size for either height
or weight and initial Hb. A major contribution of this meta-
analysis is that although there is no overall effect of iron
interventions on growth, the findings suggest that there are no
adverse effects in iron-replete children, thereby indicating that
targeting all children for iron supplementation in the effort to
eliminate iron deficiency and anemia is safe. However, we are
limited by lack of adequate data on the safety of iron supple-
ments for young infants (⬍6 mo of age).
 2600 RAMAKRISHNAN ET AL.

TABLE 3
Characteristics of 5 intervention studies included in the meta-analysis of multiple micronutrients and child growth1

Author Year Country Age Duration Subjects Initial Hb Initial WAZ Initial HAZ Initial WHZ

y wk n g/L

Liu (65) 1993 China 0.5–1.1 12 226 126 ⫺0.4 ⫺0.6 0.1
Lartey (66) 1999 Ghana 0.5 24 216 105 ⫺0.2 ⫺0.2 ⫺0.1
Abrams (63) 2003 Botswana 6–11 8 311 129 ⫺0.8 — ⫺0.5
Ash (64) 2003 Tanzania 6–11 24 841 119 ⫺1.4 ⫺2.0 0.2
Rivera (62) 2003 Mexico 0.66–1.2 52 337 — ⫺1.4 ⫺1.4 ⫺0.5

1 All interventions contained at least vitamin A, iron, zinc, B vitamins, and folic acid.
2 Intervention was ⱖ5 d/wk in all studies.

In contrast to the lack of effect on growth of vitamin A or
iron interventions when administered as single nutrients, our
findings suggest that correcting multiple nutrient deficiencies
simultaneously is efficacious. In many settings, growth faltering
has been associated with overall poor dietary quality, which
includes inadequate intakes of animal foods that are sources of
highly bioavailable forms of several micronutrients, and high
intakes of inhibitors such as phytates (72–75). We found that
multimicronutrient interventions that provided the recom-
mended daily allowance of iron, zinc, vitamin A, folic acid,
and B vitamins had a positive effect on height and weight gain
in children. Although there were a limited number of studies,
the results were reported from Latin America, Africa, and
Asia, had durations of 8 –52 wk, and participants ranging in
age from 6 mo to 11 y.
The increased effectiveness of multimicronutrient inter-
ventions compared with vitamin A or iron alone may be
explained by the high prevalence of concurrent micronutrient
deficiencies (68,74,76 –79) and/or the positive synergistic ef-
fects between some of these nutrients at the level of both
absorption and metabolism (for example, vitamin A and iron,
vitamin A and zinc, iron and vitamin C) (74). Another
plausible explanation is the role of zinc. A comparison of our
results with the effect sizes reported for height (0.350, 95% CI:
0.189, 0.511) and weight (0.309, 95% CI: 0.178, 0.439) with
zinc supplementation in the meta-analysis by Brown et al. (15)
suggests that the effectiveness of the multimicronutrient in-
terventions in improving growth may have been due to zinc,
which was included in all interventions. Further, our results
also suggest that recent concerns about the competitive inter-
action between iron and zinc (46,80) may not be a problem, at
TABLE 4
Effect sizes for height and weight gain in multiple
micronutrient trials among children1
Author Height gain Weight gain
Liu (65) 0.34 (0.03, 0.65) ⫺0.08 (⫺0.39, 0.22)
Lartey (66) 0.00 (⫺0.40, 0.40) 0.18 (⫺0.22, 0.58)
Abrams (63) — 0.56 (0.31, 0.80)
Ash (64) 0.35 (0.21, 0.50) 0.46 (0.31, 0.60)
Rivera (62) 0.19 (⫺0.03, 0.41) ⫺0.14 (⫺0.36, 0.08)
ALL2 0.28 (0.16, 0.41) 0.28 (⫺0.07, 0.63)
1 Data are means (95% CI).
2 All interventions contained at least vitamin A, iron, zinc, B vitamins,
and folic acid.
least for growth outcomes, when zinc is included in a multi-
vitamin-mineral supplement.
In summary, interventions with a single nutrient such as
vitamin A or iron, although providing benefits such as im-
proved Hb status and reduced mortality, may not be the
optimal for addressing growth failure, whereas interventions
that provide multiple micronutrients and/or zinc may be the
most effective in improving child growth. The feasibility of
supplementation as the mode of delivery, however, remains a
concern, especially in poor resource settings. More sustainable
food-based approaches such as fortification, improving dietary
quality, and education to improve micronutrient intakes of
young children must be pursued.
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