Zinc, Vitamin A, and Micronutrient Supplementation in Children with

Diarrhea: A Randomized Controlled Clinical Trial of Combination Therapy

versus Monotherapy
Phalguni Dutta, PhD, Utpala Mitra, MBBS, Shanta Dutta, MD, PhD, Trailokya Nath Naik, PhD, Krishnan Rajendran, PhD,
and Mrinal Kanti Chatterjee, MD
Objective To compare the clinical efficacy of supplementation of zinc, zinc plus vitamin A, and zinc plus combination
of micronutrients and vitamins (iron, copper, selenium, vitamin B12, folate, and vitamin A) on acute diarrhea in children.

Study design This was a double-blind, randomized, placebo-controlled trial. Children aged 6 to 24 months with
diarrhea and moderate dehydration were randomized to receive zinc plus placebo vitamin A (group 1), zinc plus
other micronutrients plus vitamin A (group 2), zinc plus vitamin A (group 3), or placebo (group 4) as an adjunct to
oral rehydration solution. Duration, volume of diarrhea, and consumption of oral rehydration solution were compared as outcome variables within the supplemented groups and with the placebo group.
Results The 167 study subjects included 41 in group 1, 39 in group 2, 44 in group 3, and 43 in group 4. All 3 supplemented groups demonstrated a significant reduction in outcome variables (P < .0001) compared with the placebo group. Group 3 had the lowest reduction of outcome variables and group 2 had a speedy recovery, but
differences among the supplemented groups were not statistically significant.
Conclusions Supplementation with a combination of micronutrients and vitamins was not superior to zinc alone,
confirming the clinical benefit of zinc in children with diarrhea. (J Pediatr 2011;159:633-7).

hildhood malnutrition and diarrhea are common in developing countries and responsible for a high proportion of
deaths in children.1 Substantial progress has been made in the treatment of diarrhea in children, with the introduction
of reduced-osmolarity oral rehydration solution (ORS) and zinc supplementation supported by strong scientific evidence.2-8 At present, the World Health Organization (WHO) and United Nations Childrens Fund (UNICEF) jointly recommended zinc supplementation for children with diarrhea.9 Despite strong supportive evidence, zinc has not yet been globally
accepted as a therapeutic agent.10,11
Vitamin A deficiency is a major public health problem in developing countries.12 Vitamin A supplementation trials have
documented reduced severity, duration, and even mortality due to diarrhea.13,14 Deficiencies of copper, iron, folate, vitamin
B12, and selenium are also common in children of most developing countries and are responsible for increased severity of
infection, inflammatory lesions, and reduced antibody response.15-18 The therapeutic effect of combined supplementation
of these micronutrients and vitamins has not yet been studied, however.
We evaluated the therapeutic impact of supplementation with zinc, zinc plus vitamin A, and a combination of micronutrients and vitamins (ie, zinc, iron, copper, selenium, vitamin B12, folate and vitamin A) on diarrhea in children. Our primary
hypothesis was that combined supplementation with micronutrients and vitamins might have a better therapeutic effect compared with supplementation with zinc alone. All micronutrient deficiencies could then be corrected simultaneously.

Methods
We conducted a hospital-based, double-blind, randomized, placebo-controlled clinical trial at the Dr B. C. Roy Memorial Hospital for Children, Kolkata, India between March 1999 and May 2001. The study was not registered in the clinical trial registry as
the study was intra-mural in nature and at the time of initiation of the study registry as not mandatory. Male children were chosen for ease of separate collection of stool and urine samples. The children ranged in age from 6 to 24 months and had a history of
acute watery diarrhea (more than 3 episodes within the last 24 hours) of less than
72 hours duration. All of the children had moderate dehydration, manifested by
From the National Institute of Cholera and Enteric
Diseases, Kolkata, India (P.D., U.M., S.D., T.N., K.R.);
and Department of Pediatric Medicine, Dr. B.C. Roy
Memorial Hospital for Children, Kolkata, India (M.C.)

HIV
ORS
RDA
UNICEF
WHO

Human immunodeficiency virus

Oral rehydration salt solution
Recommended daily allowance
United Nations Childrens Fund
World Health Organization

Supported by the Indian Council of Medical Research, an

intramural project of the National Institute of Cholera and
Enteric Diseases, Kolkata, India. The authors declare no
conflicts of interest.
0022-3476/$ - see front matter. Copyright 2011 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2011.03.028

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clinical signs and symptoms of thirst: irritability; sunken eyes;

dry mouth, lips, and tongue; and loss of skin elasticity.
The sample size was calculated under the assumption that
the average duration of diarrhea in the supplemented groups
will be significantly lower (25%) compared with a mean
duration of 66.4 32.3 hours after initiation of standard
treatment.19 Considering a 5% level of significance, 80%
power, and 10% dropout, the minimum sample size was calculated as 42 children in each of the 4 groups. However, for
fear of more dropouts, we randomized 44 children in each
group from a total of 176 children.
Children clinically diagnosed with severe undernutrition
(wasting) or another systemic illness (eg, septicemia, pneumonia, urinary tract infection, otitis media) or chronic underlying disease (eg, tuberculosis, liver diseases) or needing
intensive care (eg, life support system, blood transfusion, total
parental nutrition) were excluded from the study. Children
who were exclusively breast-fed also were excluded. Children
who had received antibiotics before enrollment or received vitamin A supplementation within the previous 6 months were
excluded. The childrens human immunodeficiency virus
(HIV) status was not assessed, because HIV screening is not
routinely done in children with acute diarrhea. Moreover,
the HIV prevalence in the catchment population of this region
did not warrant routine HIV testing of the study population.
Children who fulfilled the inclusion and exclusion criteria
were randomized to 4 treatment groups according to a random number table. Randomization was done blindly and independently to allocate a patient to specific numbered bottle
of supplementation or placebo. The serial code numbers were
kept in a sealed envelope, and the groups were identified only
after study completion. The children in group 1 received 20
mg elemental zinc (twice the Recommended Daily Allowance
[RDA]) daily and a single oral dose of placebo of vitamin A on
admission. Group 2 children received micronutrient combination (twice the RDA of all micronutrients and vitamins:
zinc, 20 mg; iron, 10 mg; copper, 2 mg; selenium, 40 mg;
vitamin B12, 1.4 mg; folate, 100 mg) daily and a single oral
dose of vitamin A on admission following national guidelines
(age <1 year, 100 000 IU; >1 year, 200 000 IU). Group 3 children received 20 mg of elemental zinc (twice the RDA) daily
and a single oral dose of vitamin A on admission according
to national guidelines. Group 4 children received placebo of
micronutrients and vitamins and a single oral dose of placebo
of vitamin A on admission. Micronutrients, vitamins, or placebo were given in 2 daily doses for 14 days even after recovery. All of the supplemental micronutrients and placebo were
in syrup form with a similar taste and appearance. They were
prepared by Greenco Biologicals (Kolkata, India) according
to our specifications and packaged in identical-looking bottles. Vitamin A and its placebo were prepared in same manner.
This study was approved by the Scientific Advisory Committee and Institutional Ethics Committee of the National Institute of Cholera and Enteric Diseases in Kolkata, India.
Before enrollment, informed written consent was obtained
from the parents of each child after the study procedure
was described in detail. A complete clinical history was
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obtained from the parents, and a thorough physical examination was done. Children were weighed unclothed on a scale
with a sensitivity of 1 g. Length and mid-arm circumference
also were measured. Stool samples were collected on admission in sterile McCartney bottles, using sterile rectal catheters
and were processed for detection of established enteropathogens, including bacteria, viruses, and parasites, using
standard procedures. Children received the WHOrecommended reduced-osmolarity ORS for correction of
initial dehydration and as maintenance therapy, matching
the stool volume and loss in vomitus until cessation of diarrhea.20 Intravenous fluid (ie, Ringers lactate solution)
was available for a child who developed severe dehydration
or intractable vomiting during the hospital stay, in accordance with WHO guidelines.20 No children received any
drug therapy during the study period.
Immediately after correction of initial dehydration, feeding was resumed in all children. Breast-fed children were
allowed to continue breast-feeding; others were allowed to
take formula milk or animal milk. Older children continued
on their normal diet before the onset of illness. Plain water
was offered. Children were followed up in the hospital until
recovery or for 5 days if recovery did not occur within that
time period. Intake and output data were measured every 8
hours and recorded.
The duration of diarrhea was calculated as hours from the
passage of the last liquid stool. Recovery was defined as passage of soft stool, formed stool, or no stool for 18 hours. Stool
loss was measured using preweighed disposable diapers on
a scale with a sensitivity of 1 g. Urine was separated from stool
using a urine collection bag. Vomitus was weighed using preweighed gauze pads. Body weight was recorded after correction of initial dehydration and then every morning between
10 and 10:30 a.m. until recovery. The following measurements were recorded daily: number of stools, number of
vomiting episodes, stool output (g), intake of ORS (mL),
intake of plain water (mL), intake of liquid food (mL), intake
of intravenous fluid (mL) if required for correction of dehydration, and body weight (g). Children were discharged from
the study after the passage of formed stool. Mothers were advised at the time of discharge to bring their children to the
hospital if they developed complications.
The checklist of treatment assignment was decoded for the
experimental groups. The 4 study groups were compared
based on clinical characteristics on admission and isolation
of enteropathogens using the c2 test. The Mantel-Haenszel
c2 test was used for testing recovery rates. One-way analysis
of variance post hoc testing was carried out to compare the
quantitative measures of duration of diarrhea, volume of
stool output, and intake of ORS in the 4 treatment groups.
Survival function analysis was used to assess the recovery
status of the 4 groups.

Results
A total of 176 male children aged 6 to 24 months were initially recruited into the study; however, 9 children dropped
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Table I. Characteristics of children in the 4 study groups at the time of enrollment

Parameters
Age, months
Body weight, kg
Length, cm
MAC, cm
Nutritional status (weight for length z score; WHO standard), n (%)
Normal ($ 1)
Mild undernutrition (< 1 to $ 2)
Moderate undernutrition (< 2 to $ 3)
Duration of diarrhea before admission, hours
Frequency of stool before admission, per 24 hours

Group 1
(n = 41)

Group 2
(n = 39)

Group 3
(n = 44)

Group 4
(n = 43)

12.3 (4.4)
6.9 (0.8)
69.3 (5.1)
12.3 (0.9)

12.1 (4.3)
6.8 (0.9)
69.3 (4.8)
12.1 (4.1)

12.2 (4.4)
6.8 (1.2)
69.3 (5.5)
12.5 (1.3)

12.0 (3.8)
6.9 (0.8)
69.4 (4.6)
12.3 (0.9)

11 (26.8)
14 (34.1)
16 (39.0)
37.2 (18.8)
12.3 (5.3)

4 (10.3)
10 (25.6)
25 (64.1)
37.1 (15.0)
12.1 (4.1)

7 (15.9)
18 (40.9)
19 (43.2)
39.0 (21.8)
12.2 (6.2)

11 (25.6)
11 (25.6)
21 (48.8)
37.3 (17.4)
12.4 (4.0)

MAC, mid-arm circumference.

Results are expressed as mean ( SD) unless indicated otherwise. Children of all groups had moderate dehydration at the time of enrollment.

out because the parents removed them from the hospital before recovery. Thus, the data generated from 167 children
who completed the study procedure were analyzed. These
167 children included 41 in group 1, 39 in group 2, 44 in
group 3, and 43 in group 4.
There were no significant differences at baseline among the
4 groups in any of the variables, except that group 2 had a significantly greater proportion of moderately undernourished
children compared with group 1 (P = .025) (Table I).
Detection of established enteropathogens also was
comparable in all groups (Table II). Enteropathogenic
Escherichia coli and rotavirus were the major pathogens.
Enteric parasites (Giardia lamblia from 3 children and
Cryptosporidium spp from 1 child) were detected as mixed
pathogens.
All of the children were successfully managed with ORS.
None required intravenous fluid or developd any complications during the course of the study. All children in the 3 supplemented groups had significant reduction in the duration
of diarrhea, volume of stool output, and intake of ORS
compared with the placebo group (Table III). Although
the greatest reductions in these outcome variables were
observed in group 3, the differences among the
supplemented groups were not statistically significant. The
difference in cure rate was statistically significant between
the supplemented groups and the placebo group but not
among the supplemented groups.
Table II. Etiologic agents of diarrhea in the children on
admission
Enteropathogen
Sole pathogens, n (%)
Enteropathogenic
Escherichia coli
Rotavirus
Shigella spp
Vibrio cholerae O1/O139
Salmonella typhimurium
Mixed pathogens, n (%)
Rotavirus and bacteria
Mixed bacteria
Bacteria and parasites
No pathogen, n (%)

Group 1
(n = 41)

Group 2
(n = 39)

Group 3
(n = 44)

Group 4
(n = 43)

10 (24.4)

11 (28.2)

11 (25.0)

13 (30.2)

9 (22.0)
1 (2.4)
2 (4.9)
2 (4.9)

10 (25.6)
1 (2.6)
0 (0.0)
0 (0.0)

14 (31.8)
0 (0.0)
1 (2.3)
2 (4.5)

12 (27.9)
0 (0.0)
1 (2.3)
0 (0.0)

4 (9.7)
3 (7.3)
2 (4.9)
8 (19.5)

5 (12.8)
4 (10.2)
1 (2.6)
7 (17.9)

4 (9.1)
2 (4.5)
1 (2.3)
9 (20.4)

5 (11.6)
4 (9.3)
0 (0.0)
8 (18.6)

Survival function analysis of recovery status showed rapid

recovery in all supplemented groups compared with the placebo group. The recovery rate was fastest in group 2, but the
difference in recovery status was not statistically significant
among the supplemented groups (Figure).

Discussion
We evaluated the clinical efficacy of supplementation with
zinc alone versus zinc plus vitamin A and a combination of
micronutrients and vitamins compared with placebo in
a double-blind randomized controlled clinical trial for the
treatment of acute dehydrating diarrhea in children. We
found significant reductions in the major outcome variables
in 3 supplemented groups compared with the placebo group.
The greatest reduction in outcome variables and most rapid
recovery were seen in groups 2 and 3, respectively, but differences among the supplemented groups were not statistically
significant. Combined therapy did not have any added advantage over monotherapy.
The therapeutic effect of zinc supplementation is based
on numerous randomized controlled trials conducted by
several groups worldwide, including ours.3-8 The feasibility
of large-scale use of zinc supplementation was re-examined
by Bhandari and coworkers21,22 and the International Clinical Epidemiology Networks Childnet Zinc Effectiveness
for Diarrhea Group.23
The appropriate dosage of therapeutic zinc is a question of
fundamental importance. Various studies have shown beneficial effects using 20 mg of elemental zinc per day6-8,21-23;
however, other studies found that an inadequate therapeutic
dose (13.9 mg/day) resulted in treatment failure.24,25
Patel and coworkers10,24,25 reported that zinc supplementation had a beneficial effect only in zinc-deficient children
and suggested estimating blood zinc level before providing
supplementation. Although blood zinc level is sufficiently
sensitive for identifying zinc deficiency in the clinical context,
we provided zinc supplementation on an empirical basis with
the view that our study population might have zinc deficiency. The childrens traditional diets had a low zinc content, and the bioavailability of dietary zinc is low due to the
diets high fiber and phytate contents.26 Furthermore, blood

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Table III. Outcome variables of the 4 study groups

Parameter

Group 1
(n = 41)

Group 2
(n = 39)

Group 3
(n = 44)

Group 4
(n = 43)

P value

Patients recovered within 5 days, n (%)

Duration of diarrhea after initiation of therapy, hours
Total ORS consumption, L
Total stool output, L
Total consumption of other fluids (milk and water), L
ORS intake, mL/kg/day
Stool output, mL/kg/day

38 (93)
64.1 (21.7)
1.3 (0.8)
1.2 (0.6)
0.37 (.12)
52.16 (34.34)
51.22 (23.83)

39 (100)
64.1 (16.5)
1.2 (0.3)
1.2 (0.4)
0.36 (.11)
46.60 (19.15)
52.45 (24.17)

43 (98)
59.3 (16.2)
0.9 (0.5)
1.0 (0.4)
0.37 (.10)
37.83 (16.62)
44.56 (16.41)

29 (68)*
88.2 (23.0))*
2.0 (0.8)*
2.0 (0.7)*
0.38 (0.9)*
65.55 (31.14)*
66.83 (4.42)*

<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
<.001

Results are expressed as mean ( SD) unless indicated otherwise.

*Significantly different from groups 1, 2, and 3.

zinc levels may not truly reflect zinc status, because levels may
fluctuate due to changes in diet, degree of hypoproteinaemia,
acute infection, or inflammatory conditions.
Some earlier studies failed to detect a beneficial effect of zinc
supplementation in patients with rotavirus and E coli
associated diarrhea.10,11,24,25 However, the present study
demonstrates the potential impact of zinc on diarrhea when rotavirus and enteropathogenic E coli are the major pathogens.
Patel et al25 suggested that zinc efficacy trials should include
a complete assessment of causative organisms at baseline and
that higher doses of zinc should be considered in E coliassociated diarrhea. In contrast, we observed a beneficial effect of zinc
at the recommended dose (20 mg/day) when E coli was one of
the major pathogens in our study population. Determining the
etiology of diarrhea may be difficult. Identification of a specific
diarrheal agent is complicated by the lack of access to laboratory tests in many developing countries.20
Supplementation with zinc plus vitamin A as a therapeutic
agent in diarrhea remains controversial. A study from Australia
reported no significant benefit,27 whereas another study from
Bangladesh found that a combination of zinc with vitamin A
was more effective than either zinc or vitamin A alone in reducing persistent diarrhea and dysentery.28 The present study
found a trend toward a greater reduction in outcome variables

in patients receiving zinc plus vitamin A supplementation

compared with those receiving zinc supplementation alone.
Children in developing countries are often malnourished
and have deficiencies of multiple micronutrients and vitamins that necessitate supplementation.29 We expected to
find a better therapeutic effect with combined therapy, but
failed to document this effect. However, the trend toward
rapid recovery in the patients receiving combined therapy
is difficult to ignore, given the possible synergistic effect of
these micronutrients and vitamins.
We must acknowledge some limitations of this study. First,
our small sample size might have failed to detect a favorable
impact of combined therapy. Second, the childrens blood
zinc levels were not measured.
In conclusion, the present study has failed to provide substantial evidence of the superiority of combined therapy with
zinc plus vitamin A and micronutrients and vitamins (zinc,
iron, copper, selenium, vitamin B12, folate, vitamin A) on
acute watery diarrhea in children. Our findings do support
the use of zinc supplementation as adjunct therapy in the
treatment of acute diarrhea in children. A short course of
zinc supplementation is a feasible and cost-effective strategy.9
A well-designed clinical trial with larger sample sizes is
needed to better understand the beneficial effect of combined

Figure. Survival function analysis of recovery status of the children in the 4 study groups.
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ORIGINAL ARTICLES

October 2011
therapy with micronutrients and vitamins in children with
diarrhea. n
We thank Mr. P. K. Sinha, Managing Director, Greenco Biological,
Kolkata, India, for preparing the study syrups and placebo used in
this trial.
Submitted for publication Aug 19, 2010; last revision received Jan 19, 2011;
accepted Mar 18, 2011.
Reprint requests: Phalguni Dutta, PhD, National Institute of Cholera and
Enteric Diseases, P33 CIT Road, Scheme XM, Beliaghata, Kolkata-700010,
India. E-mail: drpdutta@yahoo.com

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