Widayati et al.

/ Meta-analysis on the effect on Zinc on reducing diarrhea

Meta-Analysis on the Effect of Zinc on Reducing

Diarrhea Episode in Toddlers

Purwika Widayati1), Setyo Sri Rahardjo2), Vitri Widyaningsih2)

1)Masters Program in Public Health, Universitas Sebelas Maret
2)Faculty of Medicine, Universitas Sebelas Maret

ABSTRACT

Background: Diarrhea is a major cause of mortality and morbidity in toddlers in the world. A
number of studies have shown that zinc supplements can reduce the severity and duration of
diarrhea in toddlers. This study aimed to examine the effectiveness of zinc on reducing diarrhea
episode in toddlers.
Subjects and Method: This was a meta-analysis conducted using PRISMA systematic guideline.
Articles published between year 2000 and 2019 were selected from PubMed, Science Direct, and
Springer Link databases. Six articles met the Randomized Controlled Trial (RCT) criteria. These
studies were conducted in developing countries. A sample of 692 children divided into two groups
of 348 zinc and 344 placebo. The data were analyzed by Review Manager (RevMan) 5.3 program.
The results were assessed for Mean difference (MD) and the analysis was carried out for
heterogeneity.
Results: There was a high heterogeneity between experiments (I2 = 91%; p <0.001) so that
Random Effects Model (REM) was used. Zinc administration reduced the duration of diarrhea 0.89
days faster than placebo, and it was statistically significant (MD= -0.89; 95% CI= -1.52 to -0.26; p=
0.006).
Conclusion: Zinc supplementation is more effective than placebo in reducing the duration of
diarrhea in children.

Keywords: effectiveness, zinc, diarrhea, toddlers, meta analysis

Correspondence:
Purwika Widayati. Masters Program in Public Health, Universitas Sebelas Maret. Jl. Ir. Sutami
36A, Surakarta 57126, Central Java. Email: [email protected]. Mobile: 081231153131.

BACKGROUND and can cause mental loss especially in

Diarrhea is a major cause of mortality and children and people who were malnou-
morbidity and is a major cause of mal- rished or have weak immunity, diarrhea can
nutrition in toddlers in the world. In 2017, be prevented and treated (WHO, 2016).
around 525,000 children die from diarrhea The cause of diarrhea is a virus (rota
(WHO, 2017). Deaths due to diarrhea occur virus); bacteria, including Shigella, Salmo-
among children less than 2 years who live in nella, Esheresia choli, Vibrio, and stomach
South Asia and Sub-Saharan Africa parasites (worms). Diarrhea is transmitted
(UNICEF, 2018). through food or drinks contaminated with
Diarrhea was usually a symptom of a bacteria. The shoot period is very acute and
gastrointestinal infection that can be caused short, from several hours to several days
by bacteria, viruses and parasites. Infection (between 8 hours to 5 days), depending on
spreads through contaminated food or the cause of the illness (Pudiastuti, 2011).
drinking water, can also spread from person Poor behavior can also be a means of
to person due to poor personal hygiene. transmitting diarrhea. For example the
Severe diarrhea might lead to loss of fluids

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habit of defecating in an open place which SUBJECTS AND METHOD

resulted in polluting the water, polluting the a. Study Design
soil, and becoming a place to flies. Not This study was a systematic review and
washing hands or washing hands without meta-analysis. Study data was sought from
soap. Not using clean water facilities. In a systematic and comprehensive database of
children, diarrhea was usually caused by several indexes including; PubMed, Science
parasites, bacterial infections or viruses, Direct, and Springer Link. The keywords
antibiotics, or food (Pudiastuti, 2011). used for database searches were "diarrhea
Zinc tablets: micronutrients that func- in children", "zinc and placebo", "probiotics
tion in cell growth, as antioxidants, form the and placebo", "zinc and probiotic",
body's immunity, and perform intestinal "diarrhea and randomized control trials".
functions. Zinc in infants less than 2 b. Inclusion Criteria
months was given at a dose of 10 mg/day The inclusion criteria in this study were full
for 10 days. In children, zinc was given at a paper articles with Randomized Controlled
dose of 20 mg / day for 10 days. Giving zinc Trial (RCT). The therapy given was zinc
according to dosage can reduce the intensity (gluconate, sulfate, and acetate) with a com-
of subsequent diarrhea. WHO recommend- parison of placebo. The study subjects were
ed zinc in diarrhea to accelerate healing and toddlers (0-60 months) with diarrheal
prevent complications such as chronic disease. The dosage given is ≥ 20 mg / day.
diarrhea and malnutrition. However, it Articles were published in English.
turned out the benefits of zinc are not only c. Exclusion Criteria
obtained when children experienced acute The study was conducted in cross sectional
diarrhea. Zinc given to persistent diarrhea (cross sectional), case control (case control),
also has the same effect (Prihaningtyas, quasi experimental. The study subjects were
2014). toddlers with chronic diarrhea. Therapy was
Zinc soluble salts in gluconate and given zinc with other additions. The control
sulfate/acetate were used as supplements in group was not a placebo.
the form of tablets or syrup to prevent zinc d. Definition Operational of Variables
deficiency and to treat diarrhea in children Diarrhea was a change in bowel habits,
(Wegmüller et al., 2014). Over the past 10 indicated by an increase in frequency (defe-
years, more than 40 zinc sulphate ran- cation more than 3 times 1 day) marked
domized controlled trials (RCTs) have been changes in feces from solid to liquid occur
carried out in developing countries around less than 14 days in toddlers or diarrhea
the world (Duke, 2011). that occurred more than 14 days in infants.
Study by Galvao explained that the Provision of zinc supplements was dose <20
prevalence on days 3, 5 and 7 was lower in mg/day or ≥ 20 mg/day.
the zinc recipient group than in the control This study involved two treatment
group (Galvao et al., 2013). groups to be compared. The zinc group
This study aimed to examine the included gluconate, sulfate, and acetate and
effectiveness of zinc use compared to pla- the control group was placebo. The measu-
cebo in reducing the duration of diarrhea in rement scale of results from zinc and
children in developing countries. placebo was the duration of diarrhea.
e. Study Instrument
Published articles between year 2000 and
2019 were selected in developing countries

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from PubMed, Science Direct, dan Springer article, there were 548 articles that had to
Link databases. be issued and 26 articles that were con-
f. Data Analysis sidered fulfilling the requirements for sub-
Data analysis was carried out using the sequent full text review process.
Review Manager (Rev-Man) software 5.3 After an assessment of full text
released by the Cochrane Collaboration. articles, there were some articles that were
RevMan was used to calculate Mean not targeted for toddlers but for children
Difference (MD) as a whole. over the age of 5 years old. Outcomes from
the study did not meet the requirements
RESULTS because it was not the duration of diarrhea
There were 606 articles identified can be but the frequency of diarrhea, volume of
seen in Figure 1. After going through the diarrhea, body weight, complications after
process of deleting multiple articles found treatment, satisfaction after treatment, and
32 articles then the article filtered 574 others.
articles. Based on the results of the filtered

Figure 1. Flowchart of Review Process

Comparison in the study obtained was probiotics, and others. Giving therapy for
not placebo but with zinc, non-placebo, less than 3 days and was done not in the

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hospital. Giving therapy was not to children and 60 children receiving a placebo. The
for less than 5 years. Published articles were Bangladesh state involved 86 children
not included in developing countries, such receiving zinc and 89 children receiving
as Italy, the United States, Poland and placebo. The country of Peru involved 80
Australia. children who received zinc and 79 children
Articles that fulfill the qualitative received a placebo. India involved 85
requirements were reviewed and one article children received zinc and 79 children
was issued because it did not include the received placebo.
average after treatment and standard devia- The results of the meta-analysis were
tion (SD) needed to determine the effects of presented in the form of a forest plot. The
treatment. The article only included the forest plot was a diagram that showed
difference in improvement after treatment information from each study studied and
so that analysis cannot be done using the estimates of overall results (Akobeng in
mean difference (MD). Murti, 2018). In addition to the forest plot,
The final results of the article review this meta-analysis also showed that the
process contained six articles that fulfilled funnel plot was a diagram that illustrated
the quantitative requirements for a meta- the possibility of publication bias by
analysis of the effectiveness of zinc adminis- displaying relations between the size of the
tration in the management of diarrhea in effect and the sample size of the various
children. Articles obtained from the review studies. The publication bias in the funnel
were studies originating from countries plot can be assessed by looking at the funnel
belonging to developing countries. The shape asymmetry, the number of points on
following was an overview of the study area the right and left side compared to the
obtained from articles that have fulfilled the standard error (Murti, 2018).
requirements: there was one study Based on the articles identified from
conducted in Brazil, Turkey, Bangladesh, the review results, 6 articles fulfilled the
Peru and India. requirements as a source for the meta-
It can be seen that in the lower middle analysis of the effectiveness of zinc use
income countries that were included in this compared to placebo in reducing the
meta-analysis consisted of Brazil, Turkey, duration of diarrhea in children. Next the
Bangladesh, Peru and India. The country of articles that have been obtained would be
Brazil included in the subject of this study analyzed by using RevMen 5.3 and the
consisted of 37 children receiving zinc and results would be presented in the form of a
37 children receiving a placebo. The Turkish forest plot which can be seen in Figure 2.
state involved 60 children receiving zinc

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Table 1. Summary Source of the Effectiveness of Using Zinc in the Management of Diarrhea in Children
Type and Dosage Result
Author (Years) Country Inclusion Criteria
Zinc Placebo Zinc Placebo
(Dutta et al., 2000) India 40 mg zinc ORS The study subjects were children Mean: 2.93 Mean: 4.3
aged 3-24 months old at Dr. B.C. SD: 0.41 SD: 0.71
Roy Memorial Hospital of Kolkata
City in India, giving therapy more
than 3 days.
(Al-Sonboli et al., Brazil 25 mg zinc Lactobacillus Study on toddlers, the study was Mean: 3.3 Mean: 3.7
2003) GG conducted at Joao Alves Hospital, SD: 2.0 SD: 2.0
giving therapy for more than 3
days.
(Mary et al., 2004) Peru 20 mg zinc micronutrient Study in Shanty Hospital, Peru, Mean: 2.7 Mean: 2.7
gluconate the subject of study were children SD: 1.1 SD: 1.1
aged 6-35 months old, giving
therapy for more than 3 days.
(Brooks et al., 2005) Bangladesh 20 mg zinc 5 ml placebo The study was conducted on Mean: 5 Mean: 5
acetate children aged 1-6 months old, SD: 4.6 SD: 4.6
performed at the hospital.
(Dutta et al., 2011) India 20 mg zinc Micronutrient This study was in children aged 6- Mean: 2.49 Mean: 3.67
24 months old, it was conducted SD: 0.67 SD: 0.95
at Dr. B.C. Roy Memorial
Hospital, Kolkata City in India
(Dalgic et al., 2011) Turkey 20 mg zinc ORS The study was conducted at Sisli Mean: 3.41 Mean: 5.35
acetate Etfal Training and study Hospital, SD: 1.38 SD: 1.80
the Study subjects aged 1-28
months old

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The results of the analysis in Figure 2. was statistically significant (MD -0.89; CI
can be seen that 6 articles reported that zinc 95% -1.52 to -0.26).
administration was one way to reduce the Based on figure 3, the plot of zinc used
duration of diarrhea in children. Based on plots in the management of diarrhea, plots
the results of the analysis, there was a high on the right and left sides were not
heterogeneity between experiments (I2 = symmetrical with each other and did not
91%; p <0.001) so that Random Effects form an inverted funnel. The left plot has a
Model (REM) was used. Giving zinc was standard error >0.2 and the right plot has a
able to reduce the duration of diarrhea by standard error >0.6, this indicated that
0.89 days faster than giving placebo, and it there was publication bias in the study.

Figure 2. Forest plot of zinc administration in reducing diarrhea episode

Figure 3. Funnel plot of zinc administration in reducing diarrhea episode

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DISCUSSIONS Study done by Penny (2013) showed

Diarrhea was a major cause of malnutrition that there was a reduction of up to 9% in the
and death in children under five (Tungga et duration of diarrhea. Zinc was also effective
al., 2018). About 525.000 of child deaths in reducing dysentery and exact diarrhea.
every year due to diarrhea (Susanti, 2018). Provision of zinc was estimated to reduce
Diarrhea was the leading cause of death diarrhea deaths by 13%, so it was advisable
among infants and children in underdeve- to make national-level programs in com-
loped and developing countries (Agegnehu bating zinc deficiency in childhood, should
et al., 2019). Better management of diarrhea be accelerated. The results of study done by
and prevention of hospital-acquired diar- Jiang et al. (2016) stated that oral zinc as an
rhea were important for reducing mortality adjunctive therapy was effective in treating
(Grenov et al., 2019). Diarrhea was most infants and young children with rotavirus
common in toddlers (Zicof et al., 2018). enteritis, and reduced the incidence and
Zinc supplements during diarrhea incidence of recurrence of diarrhea in the
were currently recommended by the World next three months.
Health Organization (WHO) and the United
Nations Children's Fund (UNICEF) (Lazze- AUTHOR CONTRIBUTIONS
rini, 2016). Zinc was needed for physio- Purwika Widayati, the main author who
logical processes including defense against played a role in collecting and processing
infection. Zinc deficiency was responsible study data; Vitri Widyaningsih examined
for up to 4% of global child morbidity and the conceptual framework and study
mortality (Penny, 2013). methodology and interpreted the results of
Based on the results of an analysis of 6 data analysis; Setyo Sri Rahardjo wrote the
articles regarding the duration of diarrhea interpretation of data analysis.
in zinc use and placebo, it was reported that
zinc administration was one way to reduce FUNDING AND SPONSORSHIP
the duration of diarrhea in children. Based
This study did not use costs due to
on the results of the analysis, there was a secondary data and used databases that can
high heterogeneity between experiments be accessed and provided open access
(I2= 91%; p <0.001) so that Random Effects journals.
Model (REM) was used. Giving zinc was
able to reduce the duration of diarrhea by
CONFLICT OF INTEREST
0.89 days faster than giving placebo, and it
The authors did not have any conflict of
was statistically significant (MD -0.89; 95%
interest.
CI= -1.52 to -0.26).
The results were supported by Lukacik
et al., (2008) which showed that zinc ACKNOWLEDGEMENT
supplements reduced the duration of The authors would like to thank Pubmed,
diarrhea and the severity of acute diarrhea Science Direct, and Springer Link databases
and persistent diarrhea. A study by Yazar et for providing information and data to
al. (2016) showed that zinc supplementa- published journals.
tion reduced the duration of diarrhea, with
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