The Journal of Nutrition

Community and International Nutrition

Daily Zinc but Not Multivitamin

Supplementation Reduces Diarrhea and Upper
Respiratory Infections in Tanzanian Infants: A
Randomized, Double-Blind, Placebo-Controlled
Clinical Trial1,2
Christine M McDonald,3 Karim P Manji,4 Rodrick Kisenge,4 Said Aboud,5 Donna Spiegelman,6,7
Wafaie W Fawzi,6,8,9 and Christopher P Duggan3,8,9*
3
Division of Gastroenterology, Hepatology and Nutrition, Boston ChildrenÕs Hospital, Boston, MA; Departments of 4Pediatrics and
Child Health and 5Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; and
Departments of 6Epidemiology, 7Biostatistics, 8Nutrition, and 9Global Health and Population, Harvard T.H. Chan School of Public Health,
Boston, MA

Abstract
Background: Although various micronutrient regimens have been shown to prevent and treat common infectious
diseases in children, the effects of daily multivitamin (MV) and/or zinc supplementation have not been widely evaluated in
young African infants.
Objective: The objective was to determine whether daily supplementation of HIV-unexposed Tanzanian infants with MVs
or zinc reduces the risk of infectious morbidity compared with placebo.
Methods: In a 2 3 2 factorial, double-blind, randomized controlled trial, 2400 infants who were 6 wk of age and born to
HIV-negative mothers in a low-malaria setting were randomly assigned to receive daily oral supplementation of MVs
(vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo. Morbidity was assessed by study nurses
at monthly visits and by physicians every 3 mo and/or when the child was acutely ill.
Results: No significant differences were found in the percentage of nurse visits during which diarrhea, cough, or any other
symptom were reported throughout the previous month when receiving either zinc or MVs. However, physician
diagnoses of all types of diarrhea (RR = 0.88; 95% CI: 0.81, 0.96; P = 0.003), dysentery (RR = 0.84; 95% CI: 0.74, 0.95; P =
0.006), and acute upper respiratory infection (RR = 0.92; 95% CI: 0.88, 0.97; P = 0.0005) were significantly lower for
infants supplemented with zinc than for those who did not receive zinc. Among the 2360 infants for whom vital status was
obtained, there was a nonsignificant increase in all-cause mortality among infants who received zinc (HR = 1.80; 95% CI:
0.98, 3.31; P = 0.06) compared with those who did not receive zinc. MVs did not alter the rates of any recorded physician
diagnoses or mortality. Neither zinc nor MVs reduced hospitalizations or unscheduled outpatient visits.
Conclusions: Daily zinc supplementation of Tanzanian infants beginning at the age of 6 wk may lower the burden of
diarrhea and acute upper respiratory infections, but provision of MVs using the regimen in this trial did not confer additional
benefit. This trial was registered at clinicaltrials.gov as NCT00421668. J Nutr 2015;145:2153–60.

Keywords: multivitamins, zinc, child morbidity, diarrhea, respiratory infection

Introduction
for the deaths of 1.9 million children <5 y of age in 2011 (1).
Diarrheal diseases and respiratory infections are among the Low birth weight and early childhood undernutrition are major
leading causes of child mortality globally and were responsible risk factors for morbidity and mortality from these and other
infectious diseases, particularly in resource-limited areas of the
1
Supported by the Eunice Kennedy Shriver National Institute of Child Health and world. Recent estimates indicate that 45% of all child deaths
Human Development (NICHD R01 HD048969-01 and K24HD058795). result from fetal growth restriction, anthropometric deficits,
2
Author disclosures: CM McDonald, KP Manji, R Kisenge, S Aboud, D Spiegelman,
micronutrient deficiencies, or suboptimal breastfeeding (2).
WW Fawzi, and CP Duggan, no conflicts of interest.
* To whom correspondence should be addressed. E-mail: christopher.duggan@childrens. Therefore, interventions to improve nutritional status have
harvard.edu. great potential to reduce child morbidity and mortality.
ã 2015 American Society for Nutrition.
Manuscript received February 13, 2015. Initial review completed April 4, 2015. Revision accepted, June 29, 2015. 2153
First published online July 22, 2015; doi:10.3945/jn.115.212308.
 Micronutrient supplementation is one such strategy and is
particularly compelling given the important role of numerous
vitamins and minerals in systemic immune function and the
maintenance of local defenses, coupled with its relative cost-
effectiveness (3, 4).
Several studies have evaluated the efficacy of different
micronutrient regimens in preventing and/or treating common
infectious diseases, including respiratory and gastrointestinal
diseases. However, differences in study design and location,
baseline nutritional status of the study population, composition
and duration of supplementation, and disease background have
led to varying results. There is clear evidence that therapeutic
zinc supplementation has beneficial effects on the duration and
severity of diarrhea and other morbidities (5), and the WHO has
included zinc supplementation in its guidelines for clinical
management of acute diarrhea for the past decade (6). However,
policy recommendations do not yet exist for preventive zinc
supplementation. A meta-analysis showed that preventive zinc
supplementation in children reduced the incidence of diarrhea
and respiratory infections by ~20% and 14%, respectively (7). A
notable finding, however, was that this effect was generally not
observed in infants <12 mo of age. In addition, few studies
included in the analysis were conducted in sub-Saharan Africa
(7). Given regional differences in maternal nutritional status,
birth outcomes, and morbidity patterns, it is critical that micro-
nutrient supplementation trials be conducted in a diversity of
settings, including sub-Saharan Africa, before global recommen-
dations can be developed.
Because zinc insufficiency may coexist with other vitamin and
mineral deficiencies, simultaneous supplementation with other
micronutrients may be an effective strategy. Two recent trials in
Tanzania and Pakistan examined whether the provision of
multiple micronutrients in addition to zinc confers additional
benefits against diarrhea and other morbidities (8, 9). Both trials,
however, were restricted to children $6 mo of age, both included
iron as part of the micronutrient supplement, and both reported
that multiple micronutrients either increased diarrhea morbidity
or conferred no additional benefit in comparison with zinc
alone. To our knowledge, there have not been any investigations
of preventive zinc and multivitamin (MV) supplementation on
infectious disease morbidity that have included African children
<6 mo of age. Initiation of supplementation earlier in infancy
may be appropriate given the fact that many lactating mothers
are deficient in several micronutrients (10). To evaluate the
potential role of zinc or MV supplementation in early infancy,
we performed a randomized trial to determine whether daily
supplementation of HIV-unexposed Tanzanian infants with
MVs, zinc, or both reduced the risk of infectious morbidity
compared with placebo.
Methods
Study design and participants. The study was a randomized, double-
blind, 2 3 2 factorial design trial that took place in periurban Dar es
Salaam, Tanzania (clinicaltrials.gov NCT 00421668). Mothers of poten-
tially eligible infants were recruited into the study in 1 of 2 ways: 1)
pregnant women #34 wk gestation presenting at 1 of 3 prenatal clinics
in Dar es Salaam were informed about the study and consented
prenatally or 2) women were recruited from the labor ward of
Muhimbili National Hospital within 12 h of delivering a healthy
singleton baby. In both cases, written informed consent was obtained
and mothers were asked to present at a study clinic within 1–2 wk of
delivery for HIV testing. Maternal HIV status was determined using 2
sequential ELISAs that used the Murex HIV antigen/antibody (Abbott
Murex) followed by the Enzygnost anti-HIV-1/2 Plus (Dade Behring) or
2154 McDonald et al.
the Enzygnost HIV Integral II Antibody/Antigen (Siemens). Any dis-
crepancy between the first and second ELISA was resolved by a Western
blot assay. Consenting mothers who were confirmed to be HIV-negative
were enrolled into the study and their infants were randomly assigned to
1 of 4 regimens between 5 and 7 wk of age. Infants of multiple births and
infants with congenital anomalies or other conditions that would
interfere with the study procedures were excluded. Birth characteristics
were obtained immediately after delivery whenever possible. We used
reference data from Oken et al. (11) to calculate the percentile of birth
weight for each completed week of gestation and defined small-for-
gestational age as #10th percentile. At the time of randomization,
clinical examination was performed by a study physician, history of
morbidity and infant feeding practices was conducted by a study nurse,
infant blood was drawn for a complete blood count, and anthropometric
measurements were performed.
Institutional approval was granted by the Harvard T.H. Chan School
of Public Health Human Subjects Committee, the Muhimbili University
of Health and Allied Science Committee of Research and Publications,
the Tanzanian National Institute of Medical Research, and the Tanzanian
Food and Drugs Authority. Over the course of the study, a Data Safety and
Monitoring Board met twice annually.
Randomization and masking. Infants were randomly assigned in a
factorial design to receive a daily oral dose of 1 of the following 4
regimens for 18 mo from the time of randomization: 1) zinc, 2) MVs, 3)
zinc + MVs, or 4) placebo. The biostatistician in Boston prepared a
randomization list from 1 to 2400 that used blocks of 20 and was
stratified by study clinic. Capsules were packaged in a blister pack of 15
each and numbered boxes containing 6 blister packs were prepared
containing the corresponding treatments. Each eligible infant was
assigned the next numbered box of capsules at his/her respective site.
The supplement used was an orange-flavored powder encapsulated in an
opaque gelatinous capsule and was manufactured by Nutriset. All 4
regimens were field tested and the taste, smell, and appearance were
found to be indistinguishable between groups. All study personnel and
participants were blinded to treatment assignment for the duration of
the study.
Procedures. From the time of randomization to 6 mo of age, infants
received 1 capsule/d, and from 7 mo of age to the end of follow-up, 2
capsules were provided daily. For infants in the zinc group, the capsule
contained 5 mg of zinc. For infants in the MV group, the capsule
contained 60 mg of vitamin C, 8 mg of vitamin E, 0.5 mg of thiamine, 0.6 mg
of riboflavin, 4 mg of niacin, 0.6 mg of vitamin B-6, 130 mg of folate,
and 1 mg of vitamin B-12. Infants in the MV + zinc group received
1 capsule containing the micronutrients listed in both the MV and the
zinc groups. For children 0–6 mo of age, these doses represented between
150% and 600% of the RDA or Adequate Intake, and for children 7–12 mo
of age, the doses were equivalent to 200–400% of the RDA or Adequate
Intake. Mothers were shown how to push the capsule through the back
of the blister pack, open the capsule, decant the powder into a small
plastic cup, mix the powder with 5 mL of sterile water, and administer
the solution to the child orally.
Our choice of supplement composition was based on several con-
siderations including: 1) previous research that found deficiencies in
vitamin B-12, folate, zinc, vitamin A, and vitamin E among breastfeeding
women in South Africa (10) and, therefore, suggests that infant micro-
nutrient status may be low in sub-Saharan Africa; 2) a previous clinical
trial involving pregnant Tanzanian women that confirmed improved
birth outcomes with supplementation of vitamin B complex, vitamin E,
and vitamin C (12); and 3) findings from our previous trial of MV
supplementation involving HIV-exposed children, which revealed lower
rates of fever and vomiting among supplemented children (13). Dar es
Salaam has been described as a malaria-endemic area, although studies
have suggested that rates of malaria are declining (14). Nonetheless,
owing to the potential that iron supplementation of nonanemic children
may have adverse consequences in malaria-endemic regions (15), the MV
supplement did not include iron.
Mothers and children were followed from the time of randomization
for 18 mo, until the childÕs death, or until loss to follow-up. Mothers who
were enrolled during pregnancy received standard prenatal care
including anthropometric assessment, intermittent prophylaxis for
malaria, tetanus toxoid immunization, deworming using mebendazole,
anemia assessment, and iron-folic acid supplementation. During this
follow-up period, mothers and children were asked to return to the
study clinic every 4 wk for data collection and standard clinical care,
including growth monitoring, immunizations, routine medical treat-
ment for illnesses, and periodic vitamin A supplementation (100,000 IU
at 9 mo and 200,000 IU at 15 mo). Children who were diagnosed with
anemia were treated with iron supplementation. At ~12 mo of age,
CD4 and CD8 T cell counts and percentages were measured from a
subset of 428 children using FACSCalibur system (Becton Dickinson)
in order to determine any potential immune effect of micronutrient
supplementation.
At each of the monthly follow-up visits study nurses assessed
compliance by counting the number of unconsumed capsules, assessed
infant feeding practices, and conducted a morbidity history with the
aid of pictorial diaries that mothers were instructed to complete daily
in order to document the occurrence of any of the following symptoms:
diarrhea; common cold; cough; difficulty breathing; fever; refusal to
eat, drink, or breastfeed; pus draining from ears; and vomiting. They
also assessed symptoms that were present on the day of the visit,
recorded vital signs (including measurement of the childÕs temperature
and respiratory rate and detection of chest indrawing), and inquired
about the occurrence of any unscheduled clinic visits or hospitaliza-
tions in the past month. Diarrhea was defined as $3 loose or watery
stools within a 24-h period. Rapid respiratory rate was defined as
>50 breaths/min in infants 2–11 mo of age and >40 breaths/min among
infants $12 mo of age.
At baseline, every 3 mo, and/or when acute illnesses were noted by
the study nurse a study physician conducted a physical examination,
diagnosed illnesses, and provided necessary medical treatment. Physi-
cians underwent regular training so that they used standardized
diagnostic criteria and treatment guidelines consistent with the WHO
and Tanzanian Ministry of Health and Social Welfare policies. For the
purposes of the analysis of physician diagnosis, ‘‘any form of diarrhea’’
included persistent diarrhea, acute diarrhea, dysentery, and/or intestinal
parasites. Acute upper respiratory infection was defined as pharyngitis or
rhinitis (both without fast breathing or chest indrawing). Acute lower
respiratory infection was defined as cough or difficulty breathing, rapid
respiratory rate (based on the same definition described previously),
and either a fever of >38.3°C or chest retractions. ‘‘Any form of res-
piratory infection’’ included acute upper respiratory infection, acute
lower respiratory infection, pulmonary tuberculosis, or other causes of
pneumonia.
Children who missed their scheduled monthly follow-up appoint-
ment were visited at home and their vital status was confirmed through
contact with immediate family members. In cases of child death, a verbal
autopsy was performed to determine the cause of death. The cause of
death forms were then coded by 2 independent pediatricians (KPM and
CPD), and any differences were resolved by a third pediatrician.
Data management and analysis. The primary outcomes of the study
were the incidence of clinical symptoms of diarrhea and lower res-
piratory infection. Power was calculated for 1 factor in the factorial
design, which represented either the zinc or MV arm. Based on findings
from our previous trial, we estimated that the mean (SD) number of
diarrheal and lower respiratory illnesses per child per year in the placebo
group would be 3.4 (4.2) and 2.1 (1.0), respectively (16). After applying
a 2-sided a-value of 0.025 to yield an overall type I error rate of 0.05 for
each primary outcome and allowing for a 15% loss to follow-up and
minimum power of 80%, we calculated that we would require 2400
subjects to detect a reduction of 18% in the mean number of diarrheal
episodes per year. We then calculated that with this sample size we would
have 90% power to detect an 8% reduction in the mean number of
episodes of lower respiratory illness per year.
Data were double entered using Microsoft Access software (Micro-
soft Corp.) at the central study site and then converted to SAS data sets
and uploaded to a secured UNIX-based server for analysis. Intent-to-
treat analyses were conducted according to a pre-established data
analysis plan. Descriptive statistics were used to summarize baseline
characteristics of the study population. Frequencies were reported for
categorical variables and the mean 6 SD for continuous variables. The
x2-test and ANOVA were used to detect any differences among treatment
groups. We used generalized estimating equations with the log link,
binomial variance, and exchangeable correlation matrix to compare the
proportion of follow-up visits in which the illness symptom had occurred
in the previous 4 wk between factors. For physician diagnoses that were
made during routine visits every 3 mo or during unscheduled visits
during acute illness episodes, the mean number of diagnoses over the
follow-up period was compared between factors using Poisson regres-
sion. In both sets of analyses we introduced interaction terms to test for
joint effects between the zinc and MV factors. We also tested for effect
modification by each factor and sex and low birth weight. When the
P-interaction term was <0.10, stratified analyses were performed.
Although the study was not powered to detect differences in mortal-
ity, we used Cox proportional hazards modeling to explore differences in
all-cause and cause-specific mortality by factor. Values in the text are
means 6 SDs unless otherwise indicated. All analyses were performed
using SAS software (version 9.2; SAS Institute).
Results
Figure 1 shows the study profile. Between August 2007 and
December 2009, 2400 infants were randomly assigned, and
follow-up ended in May 2011. Median (25th and 75th percen-
tiles) regimen compliance among children was 96 (91, 99) of the
allocated regimen. With the exception of length-for-age z score,
there were no significant differences in any maternal, socioeco-
nomic, or child characteristics between the 4 groups at baseline
(Table 1). Mean maternal age was ~26 y, about three-quarters of
mothers had #7 y of education, and ~30% had not been
pregnant previously. The prevalences of low birth weight and
preterm birth in all groups were ~3% and 13%, respectively.
One child was enrolled outside of the age criteria (at 2.4 wk) but
was kept in the trial after review and approval by the Data Safety
and Monitoring Board and the Institutional Review Board.
Table 2 shows the effect of MV and zinc supplementation on
the occurrence of common infectious morbidities, hospitaliza-
tions, and unscheduled outpatient visits, as recorded by the
study nurses at the monthly clinic visits. When children who
received zinc were compared with children who did not receive
zinc, there were no significant differences in the percentage of
visits during which diarrhea (RR: 0.93; 95% CI: 0.82, 1.05;
P = 0.26), cough (RR: 0.95; 95% CI: 0.90, 1.01; P = 0.10), or
any other symptom had been experienced during the previous
month. In addition, the occurrence of hospitalizations (RR:
1.50; 95% CI: 0.83, 2.70; P = 0.18) and unscheduled outpatient
visits (RR: 1.18; 95% CI: 0.98, 1.43; P = 0.08) did not vary
significantly in children receiving zinc. With the exception of
pus draining from the ears, MVs did not affect the occurrence
of any of the morbidity symptoms, hospitalizations (RR: 1.18;
95% CI: 0.67, 2.11; P = 0.56), or unscheduled outpatient visits
(RR: 1.11; 95% CI: 0.92, 1.34; P = 0.28). There was, however,
a nonsignificant interaction between treatment groups in the
case of diarrhea (P-interaction = 0.06). Subsequent stratified
analysis revealed that in comparison with the placebo group,
children in the zinc group had significantly fewer reported cases
of diarrhea (RR: 0.83; 95% CI: 0.69, 0.99; P = 0.04), whereas
children in the MV (RR: 0.91; 95% CI: 0.77, 1.08; P = 0.28)
and zinc + MV (RR: 0.95; 95% CI: 0.80, 1.13; P = 0.59) groups
did not.
Examination of effect modification showed that zinc lowered
the burden of diarrhea in boys (RR: 0.84; 95% CI: 0.71, 0.99;
P = 0.04) but not in girls (RR = 1.07; 95% CI: 0.89, 1.29; P = 0.49;
Effects of multivitamins and zinc on child health 2155

FIGURE 1 Study profile of a randomized trial of MV and/or zinc
supplementation to infants in Dar es Salaam, Tanzania. MV, multivitamin.
P-interaction = 0.05). Conversely, zinc increased the occurrence of
fever among low birth weight infants (RR: 1.66; 95% CI: 1.09,
2.53; P = 0.02) but had no effect among infants born with a birth
weight of $2.5 kg (RR: 0.95; 95% CI: 0.87, 1.02; P = 0.17;
P-interaction = 0.02). The occurrence of unscheduled outpatient
visits was also higher among low birth weight infants who received
zinc (RR: 5.00; 95% CI: 1.15, 21.69; P = 0.03); however, no
differences were observed among infants with birth weights of
$2.5 kg (RR: 1.17; 95% CI: 0.96, 1.41; P = 0.11; P-interaction =
0.009). Similarly, low birth weight infants who received MVs had
a cough more often than those who did not receive MVs (RR:
1.48; 95% CI: 1.08, 2.02; P = 0.02), whereas there was no
difference among infants with a birth weights of $2.5 kg (RR:
1.00; 95% CI: 0.94, 1.06; P = 0.94; P-interaction = 0.02).
The effect of MVs and zinc on infectious morbidities
diagnosed by the study physician is shown in Table 3. The low
burden of malaria in the study setting is worth noting: the
2156 McDonald et al.
average number of physician diagnoses over the course of
follow-up was <1/child across all treatment groups. Rates of any
type of respiratory infection (RR: 0.93; 95% CI: 0.89, 0.97; P =
0.0006), acute upper respiratory infection (RR: 0.92; 95% CI:
0.88, 0.97; P = 0.0005), any form of diarrhea (RR: 0.88; 95%
CI: 0.81, 0.96; P = 0.004), and dysentery (RR: 0.84; 95% CI:
0.74, 0.95; P = 0.006) were significantly lower among children
who received zinc compared with children who did not receive
zinc. MVs did not significantly change the rates of physician
diagnosis of acute upper respiratory infection, acute lower
respiratory infection, pulmonary tuberculosis or other causes of
pneumonia, any form of respiratory infection, acute diarrhea,
dysentery, persistent diarrhea, intestinal parasites, any form of
diarrhea, uncomplicated malaria, severe malaria, or pallor/
anemia. There were no significant interactions between treat-
ment arms for any of the morbidities.
Stratified analyses illustrated that zinc reduced the rate of
dysentery in boys (RR: 0.73; 95% CI: 0.61, 0.84; P = 0.004) but
not girls (RR: 0.98; 95% CI: 0.81, 1.17; P = 0.79; P-interaction =
0.02). The sex of the child also modified the effect of zinc on
uncomplicated malaria. Girls who received zinc had a reduced
rate of uncomplicated malaria compared with girls who did not
receive zinc (RR: 0.86; 95% CI: 0.75, 0.98; P = 0.02); however,
no difference was observed among boys (RR: 1.06; 95% CI:
0.93, 1.20; P = 0.39; P-interaction = 0.02). Birth weight did not
modify the effect of zinc on any physician diagnoses. Likewise,
the sex of the child or the birth weight did not influence the effect
of MVs on any physician diagnoses.
Among the subgroup of study participants with immunologic
measures available at 51.3 6 2.2 wk, CD4 T cell percent was
35.0 6 7.4 in infants who received zinc compared with 34.5 6
8.0 in those not receiving zinc (P = 0.51). However, infants who
received zinc and MVs had a CD4 T cell percentage of 36.7 6
7.4 compared with 34.3 6 8.0 among children who received
placebo (P = 0.03). There were no group differences in mean
CD8 T cell percentages or CD4:CD8 ratios noted (all, P > 0.20).
After a median follow-up of 17.8 mo, there were 45 deaths
among the 2360 study participants with a known vital status. Of
the 40 children who were lost to follow-up, 8 received the
placebo, 11 received zinc only, 15 received MVs only, and 6
received zinc and MVs. We observed a nonsignificant increase in
all-cause mortality among children who received zinc compared
with children who did not receive zinc (HR: 1.80; 95% CI: 0.98,
3.31; P = 0.06). MVs did not significantly alter the risk of all-
cause mortality (HR: 0.73; 95% CI: 0.40, 1.32; P = 0.30).
Information on the cause of death was available for 39 study
participants. Respiratory illness (n = 13), diarrheal disease (n = 5),
malaria (n = 7), other infectious diseases (n = 8), and neonatal
conditions (n = 2) were the primary causes of deaths. There were
no significant differences in cause-specific mortality between
treatment groups (all, P > 0.05).
Discussion
In this randomized, double-blind trial in 2400 HIV-unexposed
Tanzanian infants, we found that zinc supplementation signif-
icantly lowered rates of physician diagnoses of diarrhea and
acute upper respiratory infections. Zinc specifically reduced the
rates of dysentery, particularly among boys. The occurrence of
diarrhea, as reported at monthly clinic visits with study nurses,
was also significantly reduced among children who received
only zinc in comparison with placebo. MVs did not alter the
occurrence of any recorded morbidities, and neither zinc nor
TABLE 1 Baseline characteristics of enrolled Tanzanian infants and their mothers by supplementation group1

Placebo (n = 604) Zinc only (n = 596) MVs only (n = 598) Zinc + MVs (n = 602)

Maternal characteristics
Age, y 26.5 6 5.0 26.8 6 5.1 26.2 6 5.0 26.1 6 5.0
Formal education, n (%)
None 9 (1.5) 8 (1.4) 10 (1.7) 9 (1.5)
1–7 y 453 (75.3) 421 (71.1) 416 (70.2) 441 (73.4)
$8 y 140 (23.3) 163 (27.5) 167 (28.2) 151 (25.1)
Employment, n (%)
Housewife without income 386 (64.4) 365 (62.3) 337 (56.7) 357 (59.8)
Housewife with income 176 (29.4) 175 (29.9) 212 (35.7) 201 (33.7)
Other 37 (6.2) 46 (7.9) 45 (7.6) 39 (6.5)
Married or cohabitating with partner, n (%) 537 (90.0) 534 (90.5) 542 (91.4) 542 (90.5)
Prior pregnancies, n (%)
None 184 (30.6) 169 (28.6) 205 (34.5) 187 (31.2)
1–4 398 (66.2) 410 (69.3) 375 (63.1) 396 (66.1)
$5 19 (3.2) 13 (2.2) 14 (2.4) 16 (2.7)
Midupper arm circumference, cm 27.0 6 3.1 27.1 6 3.1 27.1 6 3.1 26.7 6 3.2
Recruited prenatally, n (%) 86 (14.2) 76 (12.8) 90 (15.1) 92 (15.3)
Socioeconomic characteristics
Daily food expenditure per person in household is ,1000 TSh, n (%) 158 (27.6) 162 (28.6) 164 (28.8) 170 (29.4)
Household possessions,2 n (%)
None 171 (28.4) 192 (32.7) 173 (29.2) 180 (30.0)
1–3 358 (59.5) 308 (52.4) 330 (55.7) 339 (56.5)
.3 73 (12.1) 88 (15.0) 90 (15.2) 81 (13.5)
Child characteristics
Age at randomization, wk 5.9 6 0.4 5.9 6 0.4 5.9 6 0.4 5.9 6 0.4
Male, n (%) 293 (48.5) 296 (49.7) 282 (47.2) 313 (52.0)
Low birth weight (,2500 g), n (%) 18 (3.0) 21 (3.6) 21 (3.6) 22 (3.7)
Born ,37 wk gestational age, n (%) 77 (14.0) 80 (14.6) 66 (12.0) 67 (12.1)
Born ,34 wk gestational age, n (%) 15 (2.7) 14 (2.6) 12 (2.2) 22 (4.0)
Born small for gestational age (,10th percentile), n (%) 45 (8.4) 47 (8.7) 52 (9.7) 47 (8.7)
Apgar score #7 at 5 min after birth, n (%) 9 (1.6) 17 (3.1) 5 (0.9) 10 (1.8)
Hemoglobin, g/dL 10.7 6 1.6 10.6 6 1.6 10.7 6 1.4 10.6 6 1.4
Length-for-age z score3 20.17 6 1.28a 20.33 6 1.92a,b 20.26 6 1.20a,b 20.37 6 1.23b
Weight-for-length z score 0.05 6 1.32 0.16 6 1.33 0.14 6 1.29 0.15 6 1.31
Weight-for-age z score 20.16 6 1.05 20.23 6 0.97 20.17 6 0.99 20.26 6 1.03
1
According to the x2-test or ANOVA, there were no significant differences in baseline characteristics among treatment groups (P . 0.05) with the exception of length-for-age
z score (P = 0.03). Values are means 6 SDs or percentages. MV, multivitamin; TSh, Tanzanian shilling.
2
From a list that includes sofa, television, radio, refrigerator, and fan.
3
Labeled means in a row without a common letter differ, P , 0.05.

MVs reduced hospitalizations or unscheduled outpatient visits.
Although our study was not powered to detect differences in
mortality, we observed a nonsignificant increase in mortality
among infants who received zinc. Furthermore, in a subset of
children with immunologic measures available at 12 mo of age,
mean CD4 T cell percent was slightly but significantly higher
among children who received zinc and MVs in comparison with
placebo. To our knowledge, this is the first study of preventive
zinc and MV supplementation to be conducted among young
infants in sub-Saharan Africa. Given the large global burden of
diarrhea and acute respiratory infections in young children, we
believe that the 12% reduction in diarrhea, 16% reduction in
dysentery, and 8% reduction in acute upper respiratory infec-
tions among children who received zinc are clinically significant
and potentially of major public health importance.
Although, to our knowledge, no other studies have assessed
the effects of daily zinc supplementation in tandem with MVs
from such a young age, our findings can be compared with
trials of zinc vs. placebo on infant morbidity. Osendarp et al.
(17) reported that daily zinc supplementation from 4 to 24 wk
of age did not reduce morbidity from diarrhea or respiratory
infections in Bangladeshi infants. Likewise, a large trial of
preventive zinc and/or folic acid supplementation involving
Nepalese children 1–35 mo of age saw no differences in the
frequency or duration of diarrhea or acute lower respiratory
infection between treatment groups (18). However, weekly
zinc supplementation for 12 mo was found effective in re-
ducing the incidence of diarrhea and pneumonia among urban
Bangladeshi infants aged 2–12 mo (19). Similarly, a study in
Delhi, India, involving infants 6–11 mo of age, reported that a
short course of daily zinc supplementation for 2 wk effectively
reduced the subsequent number and duration of diarrhea
episodes (20). In contrast, a multicenter study involving infants
1–5 mo of age with acute diarrhea found that infants who
received therapeutic zinc supplementation for 14 d had more
days of diarrhea and similar prevalence of pneumonia and
respiratory infection compared with the placebo group (21).
Differences in the age of study participants, dose and duration of
supplementation, and length of follow-up make it difficult to
identify the reasons behind these contrasting results. However, it
Effects of multivitamins and zinc on child health 2157
TABLE 2 Effect of daily MVs and zinc on the occurrence of common infectious morbidities in Tanzanian infants by nurse evaluation1

Received zinc2 Received MV3

Morbidity reported in Yes (n = 1198) No (n = 1202) Yes (n = 1200) No (n = 1200)

the past 4 wk % (n event/visit) 4
% (n event/visit) 4
RR (95% CI) 5
P 5
% (n event/visit) 4
% (n event/visit)4 RR (95% CI)5 P5 Pint6

Diarrhea 3.7 (547/14,703) 4.0 (584/14,725) 0.93 (0.82, 1.05) 0.26 3.9 (566/14,611) 3.8 (565/14,817) 1.02 (0.90, 1.16) 0.74 0.06
Cough 22.1 (3266/14,782) 23.4 (3474/14,823) 0.95 (0.90, 1.01) 0.10 22.8 (3,350/14,697) 22.7 (3,390/14,908) 1.01 (0.95, 1.07) 0.73 0.78
Difficulty breathing 1.1 (159/14,777) 1.0 (141/14,818) 1.15 (0.89, 1.47) 0.29 1.1 (161/14,692) 0.9 (139/14,903) 1.16 (0.90, 1.49) 0.25 0.51
Cough + fever 4.9 (723/14,782) 5.3 (789/14,823) 0.90 (0.81, 1.01) 0.08 5.2 (760/14,697) 5.0 (752/14,908) 1.02 (0.91, 1.13) 0.78 0.53
Cough plus7 1.7 (247/14,782) 1.8 (261/14,823) 0.95 (0.78, 1.15) 0.57 1.8 (268/14,697) 1.6 (240/14,908) 1.14 (0.94, 1.39) 0.17 0.80
Cough with rapid respiratory rate8 0.1 (16/14,782) 0.1 (14/14,823) 0.98 (0.40, 2.43) 0.97 0.1 (15/14,697) 0.1 (15/14,908) 0.85 (0.34, 2.10) 0.72 0.99
Fever 10.0 (1471/14,780) 10.4 (1539/14,821) 0.95 (0.88, 1.03) 0.18 10.3 (1,514/14,694) 10.0 (1,496/14,907) 1.01 (0.94, 1.09) 0.78 0.80
Cold 21.3 (3153/14,782) 22.5 (3329/14,822) 0.95 (0.90, 1.01) 0.09 22.0 (3,226/14,697) 21.8 (3,256/14,907) 1.01 (0.95, 1.07) 0.82 0.82
Vomiting 1.8 (261/14,779) 1.7 (249/14,819) 1.05 (0.87, 1.26) 0.60 1.9 (272/14,691) 1.6 (238/14,907) 1.16 (0.97, 1.39) 0.11 0.79
Refusal to eat, drink, or breastfeed 2.3 (336/14,780) 2.5 (368/14,817) 0.90 (0.77, 1.06) 0.22 2.5 (363/14,691) 2.3 (341/14,906) 1.07 (0.91, 1.26) 0.38 0.75
Pus draining from ears 0.5 (74/14,778) 0.5 (73/14,817) 1.06 (0.74, 1.52) 0.75 0.4 (59/14,691) 0.6 (88/14,904) 0.65 (0.45, 0.93) 0.02 0.91
Hospitalizations 0.2 (34/14,620) 0.1 (21/14,669) 1.50 (0.83, 2.70) 0.18 0.2 (29/14,528) 0.1 (26/14,761) 1.18 (0.67, 2.11) 0.56 0.63
Unscheduled outpatient visits 2.0 (282/14,286) 1.7 (237/14,358) 1.18 (0.98, 1.43) 0.08 1.90 (270/14,194) 1.72 (249/14,450) 1.11 (0.92, 1.34) 0.28 0.46
1
MV, multivitamin.
2
Received zinc ‘‘yes’’ refers to children who received zinc alone as well as those who received zinc and MVs. Received zinc ‘‘no’’ refers to all children who received MVs alone
and those who received the placebo.
3
Received MVs ‘‘yes’’ refers to children who received MVs alone as well as those who received zinc and MVs. Received MVs ‘‘no’’ refers to all children who received zinc alone
and those who received the placebo.
4
Total number of events occurring during follow-up, defined as being reported in the 28 d (4 wk) before visit or being present on the day of the evaluation.
5
RR, 95% CI, and corresponding P values were obtained from generalized estimating equations with the binomial variance, log link, and exchangeable working covariance structure.
6
P-interaction effect.
7
Cough plus defined as cough with one or more of the following events: difficult breathing, chest retractions, and refusal to eat, drink, or breastfeed.
8
Cough with rapid breathing on the day of the evaluation (respiratory rate: .60/min in infants ,2 mo old, .50/min in infants 2–11 mo old, .40/min in infants 12–59 mo old).

is important to note that, to our knowledge, our study provided
supplementation for the longest period of time and followed
infants well into their second year of life, capturing the period
during which the incidence of infectious morbidities typically
rises.
Our findings build on previous investigations into the pos-
sible effects associated with the addition of multiple micronu-
trients to zinc supplementation regimens among older infants
and children. We previously reported that the same MV regi-
men did not affect the risk of mortality among HIV-exposed

TABLE 3 Effect of daily MVs and zinc on the incidence of common infectious morbidities in Tanzanian infants by physician diagnosis1

Received zinc2 Received MV3

Yes No Yes No
Physician diagnosis n Diagnosis, n 4
n Diagnosis, n 4
RR (95% CI) 5
P 5
n Diagnosis, n 4
n Diagnosis, n4 RR (95% CI)5 P 5 Pint6

Acute upper respiratory infection 1094 3.39 6 2.60 1072 3.70 6 2.80 0.92 (0.88, 0.97) 0.0005 1082 3.52 6 2.68 1084 3.57 6 2.73 0.98 (0.94, 1.03) 0.43 0.35
Acute lower respiratory infection 1040 0.63 6 0.95 1034 0.63 6 0.95 1.01 (0.91, 1.13) 0.86 1039 0.64 6 0.96 1035 0.62 6 0.94 1.02 (0.92, 1.14) 0.69 0.56
Pulmonary tuberculosis or other 1027 0.003 6 0.07 1022 0.001 6 0.03 3.01 (0.31, 28.86) 0.34 1027 0.002 6 0.06 1023 0.002 6 0.04 0.99 (0.14, 7.05) 0.99 —
causes of pneumonia
Diagnosis of any form of 1096 3.94 6 2.91 1074 4.26 6 3.06 0.93 (0.89, 0.97) 0.0006 1083 4.09 6 2.97 1087 4.11 6 3.01 0.99 (0.95, 1.03) 0.62 0.26
respiratory infection
Acute diarrhea 1033 0.46 6 0.77 1028 0.50 6 0.85 0.91 (0.81, 1.03) 0.15 1032 0.48 6 0.79 1029 0.47 6 0.83 1.02 (0.90, 1.16) 0.75 0.29
Dysentery 1048 0.43 6 0.79 1040 0.52 6 0.87 0.84 (0.74, 0.95) 0.006 1045 0.49 6 0.85 1043 0.46 6 0.80 1.05 (0.93, 1.19) 0.42 0.25
Persistent diarrhea 1028 0.003 6 0.05 1022 0.009 6 0.10 0.33 (0.09, 1.23) 0.10 1027 0.009 6 0.10 1023 0.003 6 0.05 1.99 (0.81,11.01) 0.10 0.71
Intestinal parasites 1030 0.14 6 0.38 1023 0.15 6 0.40 0.94 (0.74, 1.17) 0.56 1029 0.14 6 0.39 1024 0.14 6 0.39 0.97 (0.77, 1.21) 0.76 0.33
Diagnosis of any form of 1054 1.00 6 1.18 1043 1.14 6 1.33 0.88 (0.81, 0.96) 0.003 1049 1.09 6 1.29 1048 1.05 6 1.23 1.03 (0.95, 1.12) 0.43 0.24
diarrhea
Uncomplicated malaria 1052 0.87 6 1.08 1037 0.91 6 1.08 0.96 (0.87, 1.05) 0.33 1048 0.88 6 1.07 1041 0.90 6 1.09 0.98 (0.89, 1.07) 0.63 0.92
Severe malaria 1032 0.06 6 0.24 1023 0.06 6 0.24 1.05 (0.73, 1.52) 0.79 1028 0.05 6 0.22 1027 0.06 6 0.25 0.79 (0.55, 1.15) 0.22 0.34
Pallor/anemia 1029 0.16 6 0.45 1026 0.15 6 0.42 1.10 (0.88, 1.37) 0.41 1030 0.15 6 0.42 1025 0.16 6 0.45 0.88 (0.70, 1.09) 0.25 0.42
1
MV, multivitamin.
2
Received zinc ‘‘yes’’ refers to children who received zinc alone as well as those who received zinc and MVs. Received zinc ‘‘no’’ refers to all children who received MVs alone
and those who received the placebo.
3
Received MVs ‘‘yes’’ refers to children who received MVs alone as well as those who received zinc and MVs. Received MVs ‘‘no’’ refers to all children who received zinc alone
and those who received the placebo.
4
Mean 6 SD diagnoses over the course of follow-up.
5
RRs, 95% CIs, and corresponding P values were obtained from generalized estimating equations with the Poisson distribution and log link and by using the log of the follow-up
time as the offset variable.
6
P-interaction term.

2158 McDonald et al.

Tanzanian infants, but it did reduce episodes of vomiting and
fever (13). A different study of daily zinc and/or multiple
micronutrient supplementation involving rural Tanzanian chil-
dren 6–60 mo of age showed that zinc supplementation
significantly decreased the rate of diarrhea and protected against
fever without localizing signs; however, multiple micronutrient
supplementation actually increased the rate of diarrhea by
approximately one-quarter (9). Similarly, in a trial of micro-
nutrient powders with or without zinc among Pakistani children
6–18 mo of age, Soofi et al. (8) observed an increase in the
proportion of days with diarrhea as well as higher rates of
bloody diarrhea and chest indrawing among children in the 2
micronutrient groups compared with a nonsupplemented con-
trol group. An earlier, relatively small study that provided zinc
with or without multiple micronutrients to Peruvian children
6–35 mo of age with persistent diarrhea showed similar results:
zinc supplementation tended to reduce morbidity, whereas the
addition of MVs increased morbidity (22). However, it is worth
noting that iron was included in the multiple micronutrient
supplement that was evaluated in these 3 trials (8, 9, 22),
whereas our MV regimen did not include iron. When taken as a
whole, these findings do not support routine MV supplementa-
tion as an effective means of reducing infant and child morbidity,
even in resource-limited settings where diets are likely poor.
Our findings of increased CD4 T cell percentage with zinc
and MV supplementation suggest one possible immune effect of
supplementation. Although evidence on the topic is particularly
limited in HIV-negative children, we previously reported an
increase in CD4 counts among HIV-infected pregnant women in
Tanzania who received a similar MV regimen (23). Zinc and
multiple micronutrients have also been shown to increase CD4
counts in HIV-infected adults receiving highly active antiretro-
viral therapy (24, 25). However, in a safety and efficacy study
involving 96 HIV-infected children in South Africa, daily supple-
mentation with 10 mg of elemental zinc for 6 mo did not
significantly change the percentage of CD4+ T lymphocytes (26).
In an HIV-negative elderly population, Fortes et al. (27) reported
that zinc increased the number of CD4 cells. Although the
compilation of these findings is encouraging, more research is
needed to better understand the potential mechanisms by which
certain nutrients could be affecting this marker of immunologic
function.
Although not statistically significant, our finding of a possible
increase in the risk of all-cause mortality among children who
received zinc is generally inconsistent with the bulk of the
published evidence on this topic. Our results were unexpected,
especially considering the fact that zinc reduced rates of diarrhea
and acute upper respiratory infections, and we saw no differences
in rates of hospitalizations or unscheduled clinic visits between
treatment groups. Our trial did not have sufficient power to assess
cause-specific mortality, which could have helped to elucidate
possible causal pathways driving this apparent effect. A meta-
analysis concluded that therapeutic zinc supplementation for
the treatment of diarrhea significantly reduces child mortality
(5). Although the effect of preventive zinc supplementation on
mortality appears to be weaker, Brooks et al. (19) reported a
17% reduction in all-cause mortality among children who
received weekly zinc supplementation for 12 mo, and most other
studies, including a large study from Pemba Island, Tanzania,
have reported a nonsignificant reduction in mortality (18, 28,
29). Clearly, more research is needed to better understand the
mechanisms through which zinc may affect certain causes of
mortality and to resolve differences that could be attributed to
variations in study design and subject characteristics.
Several strengths and limitations of our study deserve
comment. As previously noted, to our knowledge, our study is
the first to examine the effects of preventive zinc and MV
supplementation in African infants 6 wk of age. We enrolled
a large number of participants and conducted intensive,
monthly follow-up activities over an extended period of
time. This allowed us to evaluate the effects of supplementa-
tion during the period when rates of morbidity typically
increase. We also assessed morbidity in a comprehensive
manner, using symptom diaries, monthly nurse evaluations,
and regular physician examinations. The discordance in
results between the nurse evaluations and the physician diag-
noses is notable. One possible explanation is that mild illnesses
were only detected by study nurses at the monthly follow-up
visits, whereas more severe symptoms prompted a visit with
study physicians (30). Other possible limitations include lack
of vitamin D in the supplement regimen and what might be
considered a low dose of zinc given the possibility of impaired
zinc absorption in African children (31).
In summary, daily zinc supplementation of HIV-unexposed
Tanzanian infants at 6 wk of age significantly reduced physician-
diagnosed cases of diarrhea and acute upper respiratory tract
infections. Simultaneous provision of MVs did not appear to
confer additional benefit. Further investigation into the optimal
timing, frequency, and duration of supplementation is needed
before policy recommendations can be formulated.
Acknowledgments
We are grateful to the field and study staff for their tireless ef-
forts: Esther Kibona (deceased), Frank Killa, Michel Alexander,
Phares Zawadi, Susie Welty, Rachel Steinfeld, Anne Marie
Darling, James Okuma, Angela Jardin, Elizabeth Long, Jenna
Golan, and Emily Dantzer. We thank Roland Kupka for ex-
pert advice. We thank the members of the Data Safety and
Monitoring Board: Paul Jacques, Davidson Hamer, Roger
Mbise, and Zul Premji.
CMM analyzed the data and wrote the manuscript; KPM
designed the study, supervised data collection, and provided
input to the manuscript; RK provided input to the study design,
oversaw data collection, and reviewed the manuscript; SA
oversaw all laboratory aspects of the study and reviewed the
manuscript; DS supervised the statistical analysis and reviewed
the manuscript; WWF designed the study, provided input to the
statistical analysis, and reviewed the manuscript; CPD designed
the study, oversaw study implementation, contributed to the
statistical analysis, and provided input to the manuscript. All
authors read and approved the final manuscript.
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