**Oral Zinc Supplementation for the Treatment of Acute Diarrhea in Children: A Systematic Review and Meta-Analysis**

**Laura M. Lamberti 1 , Christa L. Fischer Walker 1,\*, Kit Y. Chan 2,3, Wei-Yan Jian 2 and Robert E. Black <sup>1</sup>**


*Received: 4 September 2013; in revised form: 9 October 2013 / Accepted: 4 November 2013 / Published: 21 November 2013* 

**Abstract:** Evidence supporting the impact of therapeutic zinc supplementation on the duration and severity of diarrhea among children under five is largely derived from studies conducted in South Asia. China experiences a substantial portion of the global burden of diarrhea, but the impact of zinc treatment among children under five has not been well documented by previously published systematic reviews on the topic. We therefore conducted a systematic literature review, which included an exhaustive search of the Chinese literature, in an effort to update previously published estimates of the effect of therapeutic zinc. We conducted systematic literature searches in various databases, including the China National Knowledge Infrastructure (CNKI), and abstracted relevant data from studies meeting our inclusion and exclusion criteria. We used STATA 12.0 to pool select outcomes and to generate estimates of percentage difference and relative risk comparing outcomes between zinc and control groups.

We identified 89 Chinese and 15 non-Chinese studies for the review, including studies in 10 countries from all WHO geographic regions, and analyzed a total of 18,822 diarrhea cases (9469 zinc and 9353 control). None of the included Chinese studies had previously been included in published pooled effect estimates. Chinese and non-Chinese studies reported the effect of therapeutic zinc supplementation on decreased episode duration, stool output, stool frequency, hospitalization duration and proportion of episodes lasting beyond three and seven days. Pooling Chinese and non-Chinese studies yielded an overall 26% (95% CI: 20%íUHGXFWLRQLQWKHHVWLPDWHGUHODWLYHULVNRI diarrhea lasting beyond three days among zinc-treated children. Studies conducted in and outside China report reductions in morbidity as a result of oral therapeutic zinc supplementation for acute diarrhea among children under five years of age. The WHO recommendation for zinc treatment of diarrhea episodes should be supported in all low- and middle-income countries.

**Keywords:** zinc; children; global health; China

#### **1. Introduction**

In response to mounting evidence supporting the efficacy and effectiveness of therapeutic zinc supplementation for diarrhea among children under five years of age, the World Health Organization (WHO) and the United Nation's Children Fund (UNICEF) issued a global recommendation in 2004, which advised zinc supplementation in addition to oral rehydration solution (ORS) for the treatment of all diarrhea episodes among children <5 years of age [1,2]. Systematic reviews have quantified the association between therapeutic zinc supplementation and a reduction in the duration and severity of childhood diarrhea episodes in low- and middle-income countries (LMICs) [1,3,4]. Many of the studies contributing to this body of evidence were conducted in South Asia [5–7], but literature stemming from East Asia has not been included in past reviews. In 2011, Zhang published a systematic review which identified 11 Chinese studies assessing zinc treatment for diarrhea and signified the need to update previous meta-analyses with literature published in languages other than English [8].

We sought to conduct an extensive search for studies of oral therapeutic zinc supplementation published in Chinese and any other language. We also aimed to combine evidence across regions in order to generate global estimates of the effect of oral therapeutic zinc supplementation on selected morbidity and mortality outcomes among children under five years of age.

#### **2. Methods**

We conducted a systematic literature search for studies published in any language between 1980 and November 2012 using the MeSH search terms "zinc" and "diarrhea" limited to "humans" in the following databases: Biosis, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, the WHO International

Clinical Trials Registry Platform (ICTRP), Global Health, Latin American and Caribbean Health Sciences Literature (LILACS), PubMed, Scopus, Web of Science, IndMed, Egyptian Universities Library Consortium, Index Medicus for the Eastern Mediterranean Region (IMEMR), China National Knowledge Infrastructure (CNKI), WanFang, and Chinese BioMedical (CBM) database.

Titles and abstracts were reviewed by two independent reviewers, and complete manuscripts were obtained for further review of pertinent studies. Discrepancies were resolved in consultation with a third reviewer. We restricted inclusion to individually randomized controlled trials (RCTs) of children under five years of age with acute diarrhea, including dysentery, where diarrhea was defined as the passage of at least three loose or watery stools in a 24-h period. We excluded cluster RCTs, studies that exclusively enrolled a particular subgroup of children (e.g., HIV-infected children; preterm infants), and studies of persistent diarrhea. We included RCTs assessing oral zinc supplementation of any zinc salt in comparison to a control group receiving placebo supplement. For studies conducted in China, where placebo supplements may not have been readily available, we included trials in which cases received the same supportive therapy regardless of zinc allocation. For all studies, administration of minerals (excluding iron), vitamins, and supporting therapy beyond zinc were only considered acceptable if these were received by both the intervention and control groups. Studies that used supplements that included iron, zinc-fortified ORS, or zinc-fortified foods were excluded.

Included studies were reviewed for the following outcomes: diarrhea duration; the proportion of diarrhea episodes lasting >3 and >7 days; duration of hospitalization; duration of fever; duration of vomiting; proportion of cases vomiting; stool frequency (number per day); stool output (mL); and death from diarrhea or any cause. Two independent reviewers entered data into structured tables, and discrepancies were resolved in consultation with a third reviewer.

We conducted independent analyses for studies assessing diarrhea due to unspecified causes and those assessing specific pathogens (e.g., rotavirus) that were laboratory confirmed prior to enrollment. All data analyses were conducted in STATA 12.0 [9]. We fit Poisson and logistic regression models to continuous and binary outcomes, respectively, weighting all outcomes by sample size. These models generated pooled estimates and 95% confidence intervals lower bound by zero for all outcomes and upper bound by one for proportions.

For continuous outcomes, we calculated the overall percentage difference between the pooled estimates for the zinc and control groups. For binary outcomes, we calculated estimates of relative risk (RR) with placebo as the reference group and conducted random effects meta-analyses to combine RRs across studies [9].

We conducted hypothesis testing to assess the equivalence of pooled outcomes and of effect estimates by placebo and non-placebo controlled trials. To compare effect estimates, we tested the difference of mean percentage differences for continuous outcomes and the ratio of relative risks (RRR) for binary outcomes [10]. We subsequently pooled placebo and non-placebo controlled trials for outcomes with no statistically significant difference in effect size.

We assessed the association between the dose of oral zinc supplement and diarrhea duration by regressing the mean percentage difference in diarrhea duration comparing the zinc and control groups onto a categorical variable which indicated whether zinc dose was lower than, equal to, or greater than the WHO recommendation.

During the course of our analyses, we identified a zinc product called Licorzinc that appeared to be unique to China. To determine whether outcomes for Chinese studies were generalizable comparing Licorzinc to other better established zinc products, we conducted hypothesis testing to assess the equivalence of the mean percentage difference in episode duration between zinc and placebo. We also calculated the RRR to compare the RR of episodes lasting >3 days between studies using Licorzinc and other zinc products.

We plotted funnel plots to assess our primary outcomes for publication bias. We also employed the Child Health Epidemiology Reference Group (CHERG) grading system to assess the quality of evidence for each outcome on a four-point scale ("high", "moderate", "low", "very low") [11].
