The Journal of Nutrition

Community and International Nutrition

Provision of Multiple Rather Than Two or Fewer

Micronutrients More Effectively Improves
Growth and Other Outcomes in
Micronutrient-Deficient Children and Adults1–3
Lindsay H. Allen,4,5* Janet M. Peerson,5 and Deanna K. Olney4
4
USDA, Agricultural Research Service Western Human Nutrition Research Center, Davis, CA 95616 and 5Program in International
and Community Nutrition, University of California, Davis, CA 95616

Abstract
Deficiencies of multiple micronutrients (MMN) usually coexist in developing countries, but supplements have usually
provided only 1 or 2 micronutrients (MN). To inform policy, in this article we compared the relative benefits of supplying
MMN vs. a placebo or 1 or 2 MN on the following: children’s growth, health, and development; pregnancy outcome;
nutritional status; and HIV/AIDS mortality and morbidity in adults. Sufficient data were available to perform random-effects
meta-analyses of randomized controlled trials (RCT) for the effects of MMN on child growth and nutritional status. Results
for other outcomes are presented as effect sizes (ES) when available. In children, MMN interventions resulted in small but
significantly greater improvements in length or height (ES ¼ 0.13; 95% CI: 0.055, 0.21) and weight (ES ¼ 0.14; 95% CI:
0.029, 0.25), hemoglobin (ES ¼ 0.39; 95% CI: 0.25, 0.53), serum zinc (ES ¼ 0.23; 95% CI: 0.18, 0.43), serum retinol (ES ¼
0.33; 95% CI: 0.050, 0.61), and motor development. A Cochrane review reported that compared with no supplementation or
a placebo, MMN supplementation during pregnancy reduced the relative risk of low birth weight (0.83), small-for-gestational
age (0.92), and anemia (0.61); however, MMN were not more effective than iron 1 folic acid alone. There is some evidence
that MMN supplementation improves CD4 counts and HIV-related morbidity and mortality in adults. The efficacy of MMN
varies across trials, but overall there is evidence that outcomes are better than when providing #2 MN. The policy
implications of these studies are discussed. J. Nutr. 139: 1022–1030, 2009.

Introduction
Multiple micronutrient (MMN)6 deficiencies are very common,
usually resulting from poor-quality diets. The most prevalent
micronutrient (MN) deficiencies, iron, vitamin A, zinc, vitamin
B-12, riboflavin, vitamin D, and vitamin E, usually occur together
due to a low intake of animal source foods (1,2).
1 preschool and school-aged children, and persons with HIV/
Supported by the United States Agency for International Development (USAID)
through A2Z: The USAID Micronutrient and Child Blindness Project managed by
the Academy for Educational Development under the terms of Cooperative
Agreement No. GHS-A-00-05-00012-00.
2
Author disclosures: L. H. Allen, J. M. Peerson, and D. K. Olney, no conflicts of
interest.
3
Supplemental Tables 1 and 2 are available with the online posting of this paper
at jn.nutrition.org.
6
Abbreviations used: ES, effect size; FA, folic acid; HAART, highly active
antiretroviral therapy; HAZ, height-for-age Z-score; Hb, hemoglobin; MMN,
multiple micronutrients: MN, micronutrient; MTCT, mother-to-child transmis-
sion; RCT, randomized controlled trial; 2RDA, twice the Recommended Daily
Allowance; RR, relative risk; WAZ, weight-for-age Z-score.
* To whom correspondence should be addressed. E-mail: lindsay.allen@
ars.usda.gov.
1022 Manuscript received December 31, 2007. Initial review completed February 25, 2008. Revision accepted February 22, 2009.
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During the last few decades there has been strong interest in
the adverse effects of MN deficiencies on health, growth, and
development, although much of the research has focused on the
effects of single MN. Interventions to improve the status of
MMN simultaneously makes sense from both a biological and a
programmatic perspective, and the cost of adding additional
MN to supplements or fortificants is relatively low. Thus, in the
last 5–10 y, the effects of MMN interventions on health and
development have been evaluated in pregnant women, infants,
AIDS in efficacy trials primarily as well as in a few complemen-
tary feeding programs.
To date there has been no comprehensive review of the effects
of MMN on multiple outcomes, to our knowledge. A few meta-
analyses have been conducted on selected outcomes, including
child growth (3), HIV/AIDS (4), and pregnancy (5). The purpose
of this paper is to review the efficacy of interventions with MMN
supplements or fortified foods on growth, nutrient status,
morbidity, and cognitive and motor development in children,
and on HIV/AIDS and pregnancy outcomes in adults. Meta-
analyses were conducted for outcomes with sufficient data and
effect sizes (ES) calculated for other outcomes where appropriate.
0022-3166/08 $8.00 ª 2009 American Society for Nutrition.
First published online March 25, 2009; doi:10.3945/jn.107.086199.
 Methods
Search strategy. We indentified published articles using PubMed and
the ISI Web of Science, with no language or date restriction. Key words
used to search the literature were: MN(s), vitamins, minerals, pregnancy,
growth, morbidity, mortality, child development, cognitive development,
motor development, HIV, and AIDS. Additional studies were identified
from review articles and personal communications.
Inclusion criteria. Studies varied in many aspects of the MMN inter-
ventions (Supplemental Table 1). These included: duration and frequency
of supplementation, number and type of MN supplemented, control
group (e.g. for pregnancy studies, the control group was usually given iron
or iron 1 folic acid), age of subjects, and delivery system (supplement or
fortified food). Only randomized controlled trials (RCT) lasting at least
4 wk were included in the analysis. The control group could be a placebo
(including unfortified control food or beverage), riboflavin, iron alone,
zinc alone, riboflavin 1 iron, riboflavin 1 zinc, or iron 1 folic acid (the latter
most often in pregnancy), and the intervention could be a supplement or a
fortified food. ‘‘Supplements’’ are defined here as tablets, powders, or
beverages that contain #419 kJ/d (100 kcal/d) of cereal or milk, whereas
the term ‘‘fortified foods’’ refers to MMN preparations containing more
energy and macronutrients, which could theoretically affect MN (MN)
absorption and other outcomes. ‘‘Multiple’’ MN were defined as those
providing .3 MN, because studies containing less than this were usually
designed to explore the individual effects of 1 or 2 MN.
Outcomes. Some studies measured multiple outcomes, but to compare
data across studies, the effects of MMN interventions on specific out-
comes were examined separately. Outcomes included growth of children
(change in length or height, and weight), morbidity of infants and children,
child development, pregnancy outcome, effects on HIV/AIDS, and anemia
and nutritional status. For each outcome, previous reviews and meta-
analyses are referred to when available, followed by the presentation of the
current meta-analysis for each outcome (except pregnancy) using data
from studies meeting the inclusion criteria. For outcomes with insufficient
data to conduct a meta-analysis, the results of individual studies are
described and presented in table format.
Analytical approach. The ES of all interventions meeting the inclusion
criteria were obtained or calculated from each published article. ES were
calculated by dividing the difference between the mean change in
treatment and control groups by the pooled SD, based on the means
and SEM or SD of changes during the study in the control and intervention
groups. An ES of 0.2 is considered small, 0.5 is moderate, and 0.7 is large.
If change means, SEM, or SD were not provided, ES was calculated
from the final minus baseline means and the SD of final values in the
intervention and control groups. If this information was not available,
then the final values were used. When the mean value was not available,
the median was used. When neither SEM nor SD was available, the CI,
minimum and maximum values, or first and 3rd quartiles were used to
calculate the pooled SD. In the case of growth, absolute changes in inches,
cm, or kg were used when available, but if not, Z-scores were used. Ideally
the pooled SD would be calculated in the same way, but sometimes in-
sufficient information was available from the articles. Therefore, to in-
clude as many studies as possible, we chose the methods for obtaining pooled
SD described above; if biased, this would be toward more conservative
estimates.
The overall, mean ES, and 95% CI across all studies were estimated for
each outcome by a random effects model that used the weighted (reci-
procal of the square of the SE of the ES) mean ES of the individual studies.
In addition, overall ES are presented separately for the different types of
studies: fortified vs. unfortified food, daily MMN vs. placebo, weekly MMN
vs. placebo, and daily MMN vs. iron. Meta-regression models were used to
examine the influence of study type, baseline age, height-for-age Z-score
(HAZ), weight-for-age Z-score (WAZ), and initial values of the biochemical
outcomes on the overall ES. P , 0.05 was considered significant.
Baseline values for HAZ, WAZ, hemoglobin (Hb), serum zinc, and
serum retinol are provided, if available, for the studies included in the
meta-analyses (Supplemental Table 2).
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Results
Growth
In 2003, a review of the effect of MN deficiencies on child growth
concluded, based on growth response to supplements in commu-
nity-based trials, that there was good evidence that zinc, vitamin
A, and iron supplements could improve growth in deficient popu-
lations (6). At that time, there were 5 acceptable published trials
with MMN, 4 of which improved growth (7–11). A meta-analysis
in 2004 included 3 of the same 5 MMN trials, plus 2 additional
trials (12,13), and concluded that MMN had a significant positive
effect on child growth, whereas vitamin A alone (14 trials) or iron
alone (21 trials) did not (3). ES for MMN were 0.28 (95% CI:
0.46, 2.51) for height and 0.28 (95% CI: 20.07, 0.63) for weight.
Fortified food was given to young children in 2 trials (12,13),
a fortified beverage to school children in 2 trials (7,8) and
supplements to young children in 1 trial (10).
Since the 2004 meta-analysis, an additional 13 studies have been
published (14–26). Four of these collaborated in a parallel trial (the
InternationalResearchinInfantSupplementationtrial)in4countries,
Indonesia (26), Peru (24), South Africa (25), and Vietnam (23), to test
the ‘‘foodlet,’’ an easily crumbled water dispersible tablet given
without food in 3 countries but added to a maize gruel in South
Africa. A pooled analysis of these 4 studies was also conducted
(27), but the ES of the 4 studies are presented separately here.
The ES for all of the studies that met our inclusion criteria were
calculated in the current meta-analysis and are shown in Figure
1 for length and height and in Figure 2 for weight. The values are
presented in order of the age of the children, from youngest on the
left to oldest on the right. Most of the studies were on infants and
preschoolers, with only 5 on school children (7,8,19,21,22).
Overall, MMN improved length or height, and weight compared
with a control group, with an ES of 0.13 (95% CI: 0.055, 0.21;
P ¼ 0.0015) for length or height and 0.14 (95% CI: 0.029, 0.25;
P ¼ 0.015) for weight. Study type, baseline HAZ, WAZ, and age
did not influence the ES for changes in growth.
Five individual studies showed a significant effect of MMN on
increases in height, for all children in 3 studies (8,14,23) and only
in subgroup analyses in 2 studies (10,11); in Mexico, MMN
increased linear growth only in the children aged ,12 mo (10)
and in Vietnam, only children who were stunted at baseline had a
greater increase in linear growth with a daily or weekly MMN
supplement compared with a placebo (11). The 2 largest ES were
in a subgroup analysis on stunted children (HAZ , 22) in Vietnam
(11) (data not shown). None of the other studies investigated
whether the response was greater in stunted children. Our meta-
regression analysis did not show that children with lower initial
HAZ scores would benefit more than those with higher scores.
Morbidity and mortality of children
MMN interventions were effective in reducing morbidity in some
studies (28,29), but not others (13,17,18,27,30), and data were
unsuitable for use in a meta-analysis. There was a small, 15%
increase in diarrhea in Bangladesh when MMN were compared
with a placebo and (not shown) a 29% increase in severe diarrhea
in Peru when MMN were compared with a zinc control (18). Two
studies, in India (28) and Pakistan (29), reported a significant re-
duction in diarrhea (18 and 11%, respectively). The study in India
also found a significant reduction in fever (7%) and respiratory
infections (26%). There were no studies, to our knowledge, of the
effect of MMN on child mortality.
Mental and motor development of children
A series of papers recently published in The Lancet (31–33)
identified stunting, iodine, and iron deficiency as risk factors for
Multiple micronutrient interventions 1023
 FIGURE 1 Effect of MMN supplementation com-
pared with the control group on children’s linear
growth in individual studies and combined in the
meta-analysis. Values are weighted mean ES 6 2
SE, n ¼ 35. All interventions contained .3 MN
provided for $4 wk. If the control group was not a
placebo, the MN control is given in parentheses.

poor child development and cognitive stimulation as a protective
factor. The impact of MMN interventions was suggested as an
area that needed further research (33).
Although investigators have studied the effects of single
nutrient interventions on the mental and motor development of
children, very few RCT have evaluated the effects of MMN on
these outcomes. The 4 studies all show a positive effect of MMN
on motor development (15,34–36) (Table 1). The interventions
differed in each study, including weekly supplements to young
children (34), a fortified complementary food (15), a MN powder
or a fortified spread (36), or supplementation of HIV-positive
pregnant women followed by assessment of the effects on
development of their children (35). In contrast, neither of the
studies that reported effects on mental development demon-
strated a significant effect of the intervention (34,35).
Pregnancy outcome
A review of RCT of MN efficacy concluded that the only
supplements that affected birthweight were magnesium (which
reduced small-for-gestational age births by 30%) and calcium
(which reduced the risk of low birthweight) (37). No MMN
interventions were included. A Cochrane analysis conducted in
2005 (5) reviewed 9 trials that provided MMN (defined as $3
MN) in pregnancy with a total n of 15,378. The review concluded
that MMN significantly reduce risk of low birthweight [relative
risk (RR) ¼ 0.83], small-for-gestational age (RR ¼ 0.92), and
anemia (RR ¼ 0.61) compared with no supplementation or a
placebo. However, these benefits were not significantly better
than those obtained with iron 1 folic acid alone.
An updated meta-analysis of pregnancy intervention trials
was not conducted here, because the Systematic Review Team of
Multiple Micronutrient Supplements During Pregnancy, under
the Micronutrient Working Group of the Standing Committee on
Nutrition of the United Nations, is currently completing a pooled
analysis of data from trials that used the UNICEF/UNU/WHO
international MMN preparation ‘‘UNIMMAP’’ supplement de-
signed for pregnant and lactating women. They are expected to
provide further information about whether MMN increase per-
inatal and neonatal death, a concern raised by an analysis that
combined the outcomes of 2 separate MMN trials in Nepalese
pregnant women (38).
Few investigators have assessed adequately the effects of
MMN supplements on the MN status of pregnant women. The
most thorough study in this regard revealed that MMN reduced
the prevalence of deficiencies of folate, riboflavin, and vitamins
B-12, B-6, D, and K, but a remarkably high prevalence of de-
ficiency persisted after supplementation (39). This suggests that
higher doses should be considered and tested.

FIGURE 2 Effect of MMN supplementation com-

pared with the control group on children’s weight
gain in individual studies and combined in the meta-
analysis. Values are weighted mean ES 6 2 SE, n ¼
36. All interventions contained .3 MN provided for
$4 wk. If the control group was not a placebo, the
MN control is given in parentheses.

1024 Allen et al.

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 TABLE 1 Efficacy of MMN for improving motor and mental development in children

Reference Country Control group n Child development measure Motor outcome3 Mental outcome

(15) South Africa Unfortified food 266 Gross motor milestones (25 items) ES ¼ 0.29* —
(34) Bangladesh Riboflavin 80 Bayley Scales of Infant Development II ES ¼ 0.39* ES ¼ 0.045
(35) Tanzania Placebo 327 Bayley Scales of Infant Development1 RR ¼ 0.4* RR ¼ 1.3
(36) Ghana Nonintervention group 276 % of children able to walk independently at 12 mo2 24%* —
1
Probability of having a score ,70 on the Bayley Scales of Infant Development Psychomotor or Mental Index.
2
Difference in prevalence of attained walking alone at 12 mo old between the nonintervention group and the Nutributter group.
3
*P , 0.05.

HIV/AIDS in cervicovaginal secretions or semen have been measured in

Five published articles on RCT of the effects of MN supplemen-
tation on morbidity and mortality from HIV infection were
reviewed and published online by the Cochrane Collaboration in
2005 (4). None of these trials tested the effects of MMN in
children and only 2 included MMN. Since then there have been
3 new trials of MMN efficacy in persons with HIV (35,40–45).
Morbidity, mortality, indicators of disease, and transmis-
sion in the absence of highly active antiretroviral therapy.
Three RCT have evaluated the effect of MMN on mortality from
HIVand AIDS (Table 2). One conducted in pregnant HIV-positive
Tanzanian women reported an overall reduction in mortality
(46,47). In that study, pregnant women were supplemented with
MMN, with or without vitamin A, or a placebo from 14 to 27 wk
of gestation and for many years following, although the inclusion
of vitamin A in the supplement was eventually stopped due to
evidence of increased risk of mother-to-child transmission (MTCT)
of HIV in the vitamin A arms of the trial (47). In the other 2 studies,
the benefit was limited to subgroups. In Thailand, for participants
with a baseline CD4 count ,200, there was a reduced risk of
mortality in those who received the MMN supplement compared
with those receiving a placebo (48). Participants in Tanzania had
tuberculosis (of whom one-half were also HIV positive) and
received zinc alone, MMN alone (no zinc), zinc 1 MMN, or a
placebo daily for 8 wk. There was no overall reduction in mortality
due to type of supplement. However, HIV coinfected patients who
received MMN 1 zinc had a 71% reduction in mortality compared
with those who received a placebo (45).
The 1 RCT that examined the effects of MMN on morbidity
in nonpregnant adults found significant reductions in 13 of 15
HIV-related complications (46).
MMN supplementation increased CD4 counts in 3 of the 4
studies in which they were measured (42,46,48,49) and reduced
viral load in the Tanzanian study compared with a placebo (47),
but not in the other 3 studies (42,45,48). MTCT, either apparent
at birth due to transmission during delivery or through breast-
feeding, was reduced in Tanzania in the women at greatest
nutritional risk. Additionally, the effects of MMN on viral loads
3 studies (42,50,51). One reported an increase in cervical shedding
of HIV in the MMN vs. placebo group, which was not significant
in women who were selenium deficient at baseline (42). Neither
of the other 2 studies found a significant effect of MMN on this
outcome (50,51).
In summary, there is some evidence that supplementation with
MMN reduces mortality, and possibly morbidity, in adults with
HIV/AIDS, although additional studies are needed in other
populations.
Morbidity, mortality, and disease indicators in patients
provided highly active antiretroviral therapy. An area that
needs further investigation is whether MMN are a beneficial ad-
junct therapy for people receiving highly active antiretroviral
therapy (HAART). Only 2 RCT (duration . 4 wk) have exa-
mined this question, but both demonstrated a benefit and no ad-
verse effects (41,49). In Poland, adults receiving MMN compared
with a placebo for 6 mo had greater increases in serum vitamin A,
C, and E, less DNA modification, and improved immune function,
but no change in CD4 counts (49). In the US, there were no nega-
tive effects of adding MMN to HAARTon fasting serum glucose,
insulin, or lipids or on kidney or liver function. In addition, people
receiving MMN had 24% higher CD4 counts after 12 wk of
supplementation than those who received a placebo (41). How-
ever, both of these trials were small and included only a few
outcomes.
Hb, anemia, and nutritional status
Most (17/19) studies that included child growth as an outcome
had data on the effects of MMN on Hb concentration, and in
addition, 9 trials reported effects on Hb and anemia but did not
measure other outcomes such as growth (29,30,52–58). Most
studies used a placebo control, some studies included both iron
and placebo controls (23–26,30), and 2 (53) included an iron 1
folic acid control. MMN were given daily, several times a week,
or weekly, with some trials comparing different dosing frequen-
cies. The iron content of the MMN ranged from 5 to 22 mg/d, but
most commonly was 5 to10 mg.

TABLE 2 Efficacy of MMN for improving HIV/AIDS indicators and associated outcomes in adults

Reference Country Population n Mortality (RR)1 Viral load (ES)1 Other significant effects

(48,51) Thailand Adults 481 0.53* 20.11 —

(42) Kenya Nonpregnant women 400 — 20.11 CD4, CD8, [ genital shedding
(46,47) Tanzania Pregnant and lactating women 1083 0.72* 20.19* [ CD4, CD8, CD3, Y risk of diarrhea and
Ymortality in infants; Y MTCT2
(43,44) Tanzania Pregnant and lactating women 1083 — — Y Maternal wasting, [ infant growth
(41) USA Adults taking HAART 40 — — [ CD4 (24%)
1
* P , 0.05.
2
Significant (P , 0.05) decrease in mortality and MTCT in women with low baseline nutritional and immunological status.

Multiple micronutrient interventions 1025

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 FIGURE 3 Effect of MMN supplementation com-
pared with the control group on children’s Hb
concentration in individual studies and combined in
the meta-analysis. Values are weighted mean ES 6
2 SE, n ¼ 46. All interventions contained .3 MN
provided for $4 wk. If the control group was not
a placebo, the MN control is given in parentheses.

The overall ES across the trials show that MMN are certainly
effective at increasing Hb compared with a control group, with a
mean ES of 0.39 (95% CI: 0.25, 0.53; P , 0.001) (Fig. 3). Studies
that used a fortified food were significantly more effective in im-
proving Hb (ES ¼ 0.60, 95% CI: 0.32, 0.88, P-value for fortified
compared with other study types ¼ 0.001). Younger children had
a larger increase in Hb due to MMN than did older children (P ¼
0.0063). Baseline Hb, HAZ, and WAZ were unrelated to the ES.
Fewer studies reported change in the prevalence of anemia.
The mean reduction in the point prevalence of anemia with
MMN vs. a noniron placebo ranged from 10 to 40%. There was
a greater reduction in anemia with a higher amount of iron in the
MMN Fig. 4A), and in populations with a higher prevalence of
anemia at baseline (Fig. 4B).
In the MMN interventions that reported changes in serum (or
plasma) zinc and retinol, the control contained neither of these
nutrients. MMN had a significant effect on serum zinc in 8 of the
12 studies where MMN were given daily. The mean ES was 0.23
overall (95% CI: 0.18, 0.43; P ¼ 0.034) (Fig. 5). There was a
difference in the change in serum zinc by type of study (P ¼
0.006). Daily supplementation compared with either placebo or
iron was significantly better at improving serum zinc compared
with the other study types (ES ¼ 0.45, 95% CI: 0.18, 0.43, P for
difference ¼ 0.001 and ES ¼ 0.42, 95% CI: 20.70, 1.54, P for
difference ¼ 0.013, respectively). In the meta-regression model,
lower HAZ and higher serum zinc at baseline predicted a larger
response to MMN (P ¼ 0.0059 and P ¼ 0.024, respectively).
One paper only reported the effects of MMN on changes in
serum retinol (59); the overall ES was 0.33 (95% CI: 0.05, 0.61;
P ¼ 0.023) (Fig. 6), with no significant difference due to the type
of study. However, children with lower baseline HAZ, WAZ,
and serum retinol had a larger retinol response (P , 0.001, P ¼
0.002 and P , 0.007, respectively).
Discussion
This review shows that the efficacy of MMN varies across trials
and outcomes, but that overall there is substantial evidence that
outcomes are improved compared with 0–2 MN.
Providing MMN vs. 0–2 MN improves growth (in length and
weight) and young child motor development. In addition MMN
reduce anemia, and improve the zinc and vitamin A status of
infants, children and school children. However, the ES of MMN
on Hb and serum zinc differ depending on the type of study.
Somewhat surprisingly fortified food (compared with unfortified
food) had a significantly larger effect on Hb compared with other
interventions, including daily or weekly MMN vs. placebo and
daily MMN vs. iron. For improving serum zinc, daily MMN
supplements were more effective than fortified food or weekly
supplements. Few studies have been conducted on the effects of
MMN on morbidity, and none on mortality. Given our overall
conclusion that MMN interventions support better child growth,
nutritional status and motor development than a placebo, with no
reported adverse effects, it may, however be unnecessary to
conduct more large mortality trials.

FIGURE 4 The percentage point differ-

ence in anemia reduction compared with
a placebo group depends on the mg Fe/d
supplied by the MMN (A) and the baseline
anemia prevalence (B). Data are from
9 studies in children.

1026 Allen et al.

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There is some evidence of benefits of MMN supplements for
reducing adult morbidity and mortality, improving birth out-
comes, and increasing CD4 counts. These results need to be
confirmed in other populations. To date, no studies of MMN have
been conducted, to our knowledge, in children with HIV/AIDS.
More studies are needed to examine patients receiving HAART
and also the effects on MTCT.
For pregnant women, the published meta-analysis shows a
reduction in low birthweight, small-for-gestational age, and
anemia when MMN were compared with no supplementation or
a placebo, but no greater response to MMN when compared with
iron 1 folic acid alone. The important issue of possibly increased
perinatal and neonatal mortality due to maternal MMN supple-
mentation during pregnancy in some populations will be
addressed in the forthcoming publication of the pooled analysis
of the UNIMMAP supplements.
It is undoubtedly necessary to increase the dose of at least some
MMN delivered, both in pregnancy and in other population
groups, to reduce the remaining high prevalence of deficiency and
possibly improve the impact. Only 1 RCT has compared the effect
of supplementing pregnant women with twice the Recommended
Daily Allowance (2RDA) (except for iron) or 1RDA of 15 MN
compared with iron 1 folic acid (60). The 2RDA supplement
caused a significant reduction in birthweights , 3000 g and in low
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FIGURE 5 Effect of MMN supplementation com-
pared with the control group on children’s serum
zinc concentration in individual studies and com-
bined in the meta-analysis. Values are weighted
mean ES 6 2 SE, n ¼ 29. All interventions contained
.3 MN provided for $4 wk. If the control group was
not a placebo, the MN control is given in parentheses.
birthweight infants of women who were anemic (and presumably
more deficient in several MN) at baseline, whereas the 1RDA
supplement was no more effective than the control. Different doses
should be tested systematically in future trials with MMN
supplements, fortified foods, and lipid-based nutrient spreads.
More data are needed on the effects of MMN on other nutritional
status outcomes and cognitive development. In addition, more
attention should be given to the issues of targeting (e.g. whether we
should target stunted children), optimal delivery vehicles (includ-
ing supplements, fortified foods, dry MMN powders, and fortified
spreads), and program efficacy and effectiveness. The benefits from
maternal supplementation in lactation should also be investigated.
Implications for policy. Only 2 current policies on the use of
MMN were identified. WHO’s ‘‘Guiding Principles on Feeding
Non-Breastfed Children 2 to 24 Months of Age’’states: ‘‘as needed,
use fortified foods or vitamin-mineral supplements (preferably
mixed with or fed with food) that contain iron.’’ Also, ‘‘if ade-
quate amounts of animal-source foods are not consumed, these
fortified foods or supplements should also contain other MN,
particularly zinc, calcium and vitamin B-12’’ (61). More recently,
UNICEF/WHO recommended the use of MMN supplements in
populations affected by an emergency (62). In addition to these
specific recommendations, WHO/FAO recommends the fortifi-
FIGURE 6 Effect of MMN supplementation com-
pared with control group on children’s serum retinol
concentration in individual studies and combined in
the meta-analysis. Values are weighted mean ES 6
2 SE, n ¼ 28. All interventions contained .3 MN
provided for $4 wk. If the control group was not a
placebo, the MN control is given in parentheses.
Multiple micronutrient interventions 1027
 cation of food staples with MMN. The selection of MMN and
amounts to add should be based on knowledge of the prevalence
of inadequate intakes in a population group (63).
The limited recommendations on MMN use by policy-making
agencies is in part the result of uncertainty about their efficacy and
safety, an information gap that the current review and analysis
attempts to improve. Ideally, a major policy decision such as
universal or targeted interventions with MMN compared with
#2 MN needs to be supported by evidence to convince agencies,
governments, and individuals that this will produce substantial
improvements in public health, such as reduced mortality or
morbidity, or the prevention of serious mental deficit. Although
WHO recommends iron 1 folic acid supplements for pregnant
women and young children, it is well known that coverage and
compliance is very poor, especially for children. Fortified com-
plementary foods for children, as well as the newer lipid-based
nutrient spreads and powders that can be added to foods, are
potentially more attractive.
Do the results of the efficacy trials to date provide sufficient
evidence to support an international recommendation to use
MMN rather than 0–2 MN? In total, they provide considerable
evidence for relatively small benefits for child growth and deve-
lopment, pregnancy outcome, reduced mortality, and CD4 counts
in HIV/AIDS (but with few studies conducted); a substantial re-
duction in anemia (but not compared with iron 1 folic acid
alone), and improvements in vitamin A and zinc status. These
may be the greatest benefits it is reasonable to expect and MMN
are relatively cheap and feasible to supply. On the other hand, we
are still lacking evidence of major impacts on child mortality and
morbidity and the important question of whether MMN
provided during pregnancy increase perinatal mortality needs
to be resolved. If it is still necessary to obtain such evidence,
perhaps by testing different formulations and amounts of MN,
this needs to be decided and research focused on this question.
Agencies and scientists need to develop a coordinated, systematic
plan that prioritizes research and optimizes and assesses program
efficacy and effectiveness. A huge investment has already been
made in testing MMN interventions, but we still need to answer
important questions such as: when is supplementation or fortifi-
cation with only 1 or 2 MN justified or should MMN always be
supplied; what doses should be delivered; and how do we
prioritize, integrate, and monitor the many available approaches
for delivering MMN? In addition, those responsible for the
delivery of MN should establish a coordinated, systematic plan for
providing and delivering them to relevant population groups in
ways that are effective, cost-effective, feasible, and safe.
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