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in the total number of days that a child suffered from diarrhea, and Address correspondence to Akash Malik, MBBS, Department of
Community Medicine, Maulana Azad Medical College and
reduction of 36% in duration per episode of diarrhea (IRR 0.64, 95% CI Associated Hospitals, Bahadur Shah Zafar Marg, New Delhi, India.
0.560.74) during the 5 months of follow-up. E-mail: drakashmalik28@gmail.com
CONCLUSIONS: Short-course prophylactic zinc supplementation for PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
2 weeks may reduce diarrhea morbidity in infants of 6 to 11 months Copyright 2013 by the American Academy of Pediatrics
for up to 5 months, in populations with high prevalence of wasting FINANCIAL DISCLOSURE: The authors have indicated they have
and stunting. Pediatrics 2013;132:e46e52 no nancial relationships relevant to this article to disclose.
FUNDING: Supported by the Indian Council of Medical Research,
Department of Health Research (Ministry of Health and Family
Welfare), Government of India. Reference No. 3/2/2011/PG-thesis-
MPD-10.
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Zinc is required for multiple cellular recruited from the similar adjacent area Each 5 mL of the preparation containing
tasks and the immune system depends of Gangavihar. The study was approved by placebo (syrup base) or zinc (20 mg
on the sufcient availability of this es- the Institutional Ethical Committee of elemental zinc as zinc sulfate) was
sential trace element.1 Zinc deciency Maulana Azad Medical College, New Delhi, packed in similar-looking bottles. The
is common in several developing coun- and Associated Lok Nayak Hospitals. The syrups were of similar color, taste, and
tries, including India. This is because the trial is registered with the Clinical Trial consistency. During the survey, after
commonly consumed staple foods have Registry-India, number CTRI/2010/091/ ascertaining the eligibility and obtaining
low zinc contents and are rich in phytates, 001417. informed consent, the infants were en-
which inhibit the absorption and utiliza- We hypothesized that zinc prophylaxis rolled sequentially. The mother received
tion of zinc.2 Randomized controlled trials for 2 weeks would reduce the incidence the bottles with prelabeled serial num-
have shown that zinc supplementation of diarrhea in subsequent months. bers. The eld investigator administered
during acute diarrhea reduces the du- Thus, we excluded any child receiving the rst dose of the intervention at the
ration and severity, as well as the zinc supplement at the time of study or time of enrollment and advised the
incidence of subsequent diarrheal epi- who had received it in the preceding mother to give 5 mL of syrup (using
sodes.37 However, recently published 3 months, those who were severely a standard 5-mL plastic spoon) daily to
meta-analyses conclude that pro- malnourished, immune-decient, cur- the infant for the remaining 13 days.
phylactic zinc supplementation signi- rently on steroid therapy, severely ill Subsequently, visits were made on the
cantly reduces the incidence of diarrhea requiring hospitalization, or of families 7th and the 14th days to ensure com-
only in children .12 months of age.810 likely to migrate from the study area. A pliance. If the syrup had not been given
Because the incidence of diarrhea is house-to-house survey was done at the regularly, a maximum of 1 week was
comparatively high in children 6 to 12 beginning of the study to identify and given to complete the dosages. We col-
months of age (4.8 episode per year),11 recruit the eligible infants. The study lected data for any possible side effects
coinciding with the starting of comple- purpose was explained to the family and as reported by the caregivers during
mentary feeding, the current study an informed consent was obtained from these visits. To ensure that the child did
aimed to evaluate whether zinc pro- parents of all infants before they were not receive additional doses of zinc, we
phylaxis for a short duration has any included in the trial. The recruitment provided mothers with identity cards
role in reducing the morbidity due to was done during the rst 2 weeks of indicating the study title and that the
diarrhea in this age group. Although the January and July, followed by subsequent infants had received zinc syrup. These
original trial included additional out- 5 months of follow-up, respectively. This cards were to be produced whenever
comes, such as acute respiratory tract ensured the assessment of outcomes for the child was taken to any medical
infections and growth, the results of a complete year from January 2011 to practitioner.
these will be reported separately. January 2012, to minimize the effect of
Outcomes and Follow-up
seasonality.
METHODS The primary outcome was the incidence
Randomization and Blinding of diarrhea per child-year. Diarrhea
Study Setting and Participants was dened as 3 or more loose, liquid,
Random sequence was generated by
This is a community-based, randomized, simple randomization method using or watery stools or any change in
double-blind, parallel-arm placebo- computer-generated random numbers consistency or frequency of stools or
controlled trial, conducted from Jan- (Excel 2010). The bottles were labeled at least 1 loose stool containing blood
uary 1, 2011, to January 15, 2012. We with serial numbers in the Department in a 24-hour period.12 Secondary out-
included all children 6 to 11 months of of Community Medicine, Maulana Azad comes included incidence density of
age residing in Gokulpuri, an urban Medical College, by DKT, without the acute diarrhea, dysentery, and persis-
resettlement colony in the northeast dis- knowledge of the eld investigator (AM). tent diarrhea; duration of diarrhea;
trict of Delhi, India, who were likely to stay The eld investigator and parents were and side effects. Acute diarrhea was
untilthecompletionofthestudy.Gokulpuri blinded to the treatment allocation and dened as an episode of diarrhea
has 2500 houses divided into 4 blocks, A, unblinding was done at the end of the lasting up to 14 days. If an episode
B, C, and D, with a predominantly migrant follow-up period for all 272 infants. lasted for .14 days, it was dened as
population of 23 000. Most of the pop- persistent diarrhea.12 The episode was
ulation belongs to the middle and lower Intervention classied as dysentery if the stool con-
socioeconomic strata. To achieve the - The zinc and placebo syrups were pre- tained blood.12 Duration was assessed
nal sample size, additional children were pared by Abyss Pharma (Delhi, India). as the number of days with diarrhea
e48 MALIK et al
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(Table 1). Seven families (n = 4 in the (Table 2). Generalized estimating equa- Zinc signicantly reduced the mean
zinc group and n = 3 in the placebo tion regression model showed that there episodes of diarrhea for each of the
group, respectively) migrated during was a reduction of 39% (adjusted IRR 5 months (Table 4). However, the level of
the study period. The mean number of 0.61, 95% CI 0.530.71) in episodes of signicance decreased after the third
follow-ups was 10 in each group (zinc: diarrhea in the zinc group as compared month.
10.0 6 0.75, placebo: 10.0 6 0.76, P = with the placebo group after the model
.721). The nal analyses included 134 was adjusted for wasting. Side Effects
infants in the zinc group and 124 in the When types of diarrhea were analyzed Reported side effects were diarrhea,
placebo group, who had completed the separately (Table 2), we found a signif- vomiting, and constipation. The per-
study. A total of 19 infants (13.5%) in icant decrease of 31% in the episodes centage of children reporting these
the zinc group and 26 infants (20%) of acute diarrhea (adjusted IRR 0.69, were 9.0%, 10.4%, and 1.5%, respectively,
in the placebo group were given an 95% CI 0.590.81), 70% in the episodes in the zinc group and 7.3%, 4.8%, and 0%,
additional 1 week to complete the in- of persistent diarrhea (adjusted IRR respectively, in the placebo group, and
tervention, as they were found to be 0.30, 95% CI 0.170.51), and more than the difference was nonsignicant in the
initially noncompliant. 95% in the episodes of dysentery (ad- 2 groups.
justed IRR 0.03, 95% CI 0.010.24) in the Onedeathduetodiarrheawasreportedin
Effect on Diarrhea zinc group. thezincgroup3monthsafterrecruitment.
Zinc supplementation for 14 days caused Zinc supplementation led to a signicant Verbal autopsy revealed severe de-
a signicant reduction in the number of reduction of 39% (adjusted rate ratio [RR] hydrationduetononadministrationoforal
episodes of diarrhea. Of the total 829 0.61, 95% CI 0.540.69) in overall days rehydrationsolutionor theavailablehome
episodes observed, 329 episodes oc- with diarrhea. There was also a signi- uids were the cause of death. The fact
curred in the zinc group and 500 in the cant reduction of 36% in duration per that the death took place 3 months after
placebo group, accounting for an in- episode of diarrhea (adjusted RR 0.64, intervention, and the incorrect man-
cidence of 6.07 and 9.90 per child year 95% CI 0.560.74) observed in the zinc agement revealed in the verbal autopsy,
respectively, at the end of 5 months group (Table 3). rules out any possible role of zinc.
DISCUSSION
In the current trial, we report that
prophylactic zinc supplementation for
2 weeks signicantly reduced the in-
cidence and duration of diarrhea dur-
ing follow-up of 5 months. Although we
studied additional outcomes (ie, acute
respiratory tract infections and growth),
the results of these will be reported
separately.
Zinc depletion leads to upregulation of
neuropeptides, such as cyclic guanosine
monophosphate, and acute-phase reac-
tants, such as interleukin 1, which cre-
ates secretory conditions in the intestine
leading to diarrheal episodes.16 Thus,
zinc prophylaxis in zinc-decient pop-
ulations reduces diarrheal morbidity.
The major limitation of this study is that
serum zinc levels were not done to as-
sess the deciency and the subsequent
FIGURE 1 effect on serum zinc levels. Nevertheless,
Trial Prole. previous studies in similar populations
e50 MALIK et al
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A study with short-course zinc sup- arrhea is seen in the age group of 6 slum populations, and thus keep suf-
plementation showed a nonsignicant to 11 months,11 may have been re- fering from repeated episodes of di-
reduction in incidence of dysentery sponsible for such signicant results arrhea. The difculty of having to give
in the age group of 12 to 35 months.18 in the current study. zinc to apparently healthy children is
Of the 2 meta-analyses, 1 is in agree- that the delivery strategy has to be
ment with the current trial, although community based, thus requiring ad-
the age group is wide in this meta- CONCLUSIONS ditional time and work on the part
analysis and studies with only con- Previous trials and meta-analyses have of the health workers/community
tinuous zinc supplementation have shown the benecial effect of zinc volunteers.
been included.9,27 prophylaxis on diarrhea either by The results of this study have important
Among the previous studies in similar continuous supplementation for a long cost and operational implications, as
populations, we found that 1 study duration, ranging from 3 months to short-course prophylaxis of zinc in an
may have insufcient power to detect 1 year, or in age groups of .12 months. adequate dose might be more feasible
a signicant decrease in diarrhea The current study was able to show than continuous therapies.
morbidity in infants 6 to 11 months of signicant reduction in diarrhea mor- The results of this study may be
age.25 In other studies, zinc pro- bidity in infants of 6 to 11 months, extrapolated to similar zinc-decient
phylaxis was given to a subset of the even 5 months after short-course zinc populations only. Future trials on the
population that had already received prophylaxis. effect of zinc prophylaxis on diarrhea
therapeutic zinc for acute diarrhea, The advantage of zinc given as a should concentrate on zinc-decient
which might have led to reduced ef- community-based prophylactic interven- pockets in both developed and de-
fectiveness of the subsequent zinc tion is that all children in the target veloping countries. It is desirable that
prophylaxis.5,7,24,28 However, the cur- population will be covered. This in turn such trials follow a standardized pro-
rent study was done in a population will reduce the overall incidence of cedure regarding the duration and dose
that had not received zinc supple- diarrhea in the community compared of zinc prophylaxis. This would ensure
mentation for the preceding 3 months, with administration of zinc only to that policy makers have reliable and
was apparently healthy, and had children who seek treatment for di- valid evidence to implement zinc pro-
a high proportion of wasted and arrhea. This is because many children phylaxis programs for those child
stunted infants. This, coupled with the suffering from diarrhea may not come populations that will benet the most
fact that the maximum burden of di- to a health facility, as is common in the from them.
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e52 MALIK et al
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Short-Course Prophylactic Zinc Supplementation for Diarrhea Morbidity in
Infants of 6 to 11 Months
Akash Malik, Davendra K. Taneja, Niveditha Devasenapathy and K. Rajeshwari
Pediatrics 2013;132;e46; originally published online June 3, 2013;
DOI: 10.1542/peds.2012-2980
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