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ORAL ZINC FOR TREATING DIARRHOEA IN CHILDREN

Lazzerini Marzia, Ronfani Luca

Lazzerini Marzia, Ronfani Luca

Cochrane Database of Systematic Reviews, Issue 3, 2009 (Status in this issue: UNCHANGED)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD005436.pub3

This review should be cited as: Lazzerini Marzia, Ronfani Luca. Oral zinc for treating diarrhoea in children.Cochrane Database of Systematic Reviews. In: The Cochrane Library, Issue 3, Art. No. CD005436. DOI:

10.1002/14651858.CD005436.pub3

A B S T R A C T

Background

Diarrhoea causes around two million child deaths annually. Zinc supplementation could help reduce the duration andseverity of diarrhoea, and is recommended by the World Health Organization and UNICEF.

Objective

To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.

Criter ia for considering studies for this review

In November 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (TheCochrane Library 2007, Issue 4), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contactedresearchers.

Selection criteria

Randomized controlled trials comparing oral zinc supplementation ( 5 mg/day for any duration) with placebo in

children aged one month to five years with acute or persistent diarrhoea, including dysentery.

Data collection and analysis

Both authors assessed trial eligibility and methodological quality, extracted and analysed data, and drafted the review.Diarrhoea duration and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios(RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate,we combined data in meta-analyses (using the fixed- or random-effects model) and assessed heterogeneity.

Main results

Eighteen trials enrolling 6165 participants met our inclusion criteria. In acute diarrhoea, zinc resulted in a shorterdiarrhoea duration (MD -12.27 h, 95% CI -23.02 to -1.52 h; 2741 children, 9 trials), and less diarrhoea at day three(RR 0.69, 95% CI 0.59 to 0.81; 1073 children, 2 trials), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children, 2trials), and day seven (RR 0.71, 95% CI 0.52 to 0.98; 4087 children, 7 trials). The four trials (1458 children) thatreported on diarrhoea severity used different units and time points, and the effect of zinc was less clear. Subgroupanalyses by age (trials with only children aged less than six months) showed no benefit with zinc. Subgroup analysesby nutritional status, geographical region, background zinc deficiency, zinc type, and study setting did not affect the

results' significance. Zinc also reduced the duration of persistent diarrhoea (MD -15.84 h, 95% CI -25.43 to -6.24 h;529 children, 5 trials). Few trials reported on severity, and results were inconsistent. No trial reported serious adverseevents, but vomiting was more common in zinc-treated children with acute diarrhoea (RR 1.71, 95% 1.27 to 2.30;4727 children, 8 trials).

COCHRANE BVS

BIREME OPASOMS

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Authors' conclusions

In areas where diarrhoea is an important cause of child mortality, research evidence shows zinc is clearly of benefit inchildren aged six months or more.

P L A I N L A N G U A G E S U M M A RY

In developing countries, millions of children suffer from severe diarrhoea every year. This is due to infection andmalnutrition, and many die from dehydration due to the diarrhoea. Giving fluids by mouth (using an oral rehydrationsolution) has been shown to save children's lives, but it seems to have no effect on the length of time the childrensuffer with diarrhoea. Children in developing countries are often zinc deficient. Zinc supplementation is a possibletreatment for diarrhoea though it can have adverse effects if given in high doses. The review of trials identified 18trials involving 6165 children of all ages. Zinc reduced the time that children over the age of six months suffered fromsymptoms of acute or persistent diarrhoea. However, there were insufficient data to see any impact on the number ofchildren who died. More children vomited when given zinc, but it was considered that the benefits outweighed theseadverse effects. Zinc seemed to have no impact on children aged less than six months. In areas where diarrhoea is animportant cause of child mortality, research evidence shows zinc is clearly of benefit in children aged six months ormore with diarrhoeal diseases.

B A C K G R O U N D

O B J E C T I V E S

To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.

M E T H O D S O F T H E R E V I E W

C R I T E R I A F O R CO N S I D E R I N G S T U D I E S F O R T H I S R EV I E W

Types of studies

Randomized controlled trials.

Types of participants

Children aged between one month and five years with acute or persistent diarrhoea, including dysentery.

We excluded trials of infants below one month and studies that exclusively enrolled children with particular conditionssuch preterm or low birthweight infants and children with HIV.

Acute diarrhoea is usually defined as three or more loose stools in a 24-hour period. Persistent diarrhoea is defined asdiarrhoea lasting more than 14 days. Dysentery is a diarrhoeal illness in which blood is observed in the stool. The finalday of diarrhoea is usually defined as the last day meeting the above definition followed by 48 hours withoutdiarrhoea.

Types of intervention

Types of outcom e m easures

Primary

Measures of diarrhoea durat ion

Diarrhoea duration.

Diarrhoea at three, five, and seven days after starting intervention.

Measures of diarrhoea severity

Stool frequency.

Stool output.

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Secondary

Hospitalization.

Death (from any cause and diarrhoea specific).

Adverse event s

Serious adverse events (life-threatening or requiring hospitalization).

Any adverse event that results in the discontinuation of treatment.

Other adverse events, such as vomiting and reduced copper levels.

SE A RC H M E T H O D S F O R I D E N T I F I C A T I O N O F ST U D I E S

Search m ethods for ident ification of studies

We will attempt to identify all relevant trials regardless of language or publication status (published, unpublished, inpress, and in progress).

Databases of published trials

We searched the following databases using the search terms and strategy described in : Cochrane Infectious DiseasesGroup Specialized Register (November 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published inThe Cochrane Library (2007, Issue 4); MEDLINE (1966 to November 2007); EMBASE (1974 to November 2007);LILACS (1982 to November 2007); CINAHL (1982 to November 2007); and the metaRegister of Current ControlledTrials (mRCT; November 2007).

Researchers an d orga nizations

For unpublished and ongoing trials, we contacted individual researchers working in the field, including researchers atthe WHO.

Reference lists

We checked the reference lists of all studies identified by the above methods.

D A T A C O L L E CT I O N A N D A N A L Y S I S

Data collection and analysis

Selection of stu dies

All trials identified by the search strategy were screened by both authors, and full articles were retrieved for all

potentially relevant trials. Both authors independently applied the inclusion criteria to the full reports using a pilot-tested form and scrutinized publications to ensure each trial was included once. Trial authors were contacted forclarification if necessary, and any disagreements were resolved through discussion and consensus after referring tothe protocol; their solutions were recorded and reported.

Data extraction and managem ent

Both authors independently extracted data using a pilot-tested data extraction form and entered the data into ReviewManager 4.2. When data were missing or unclear, we contacted the trial authors for clarification. For dichotomousoutcomes, the number of participants experiencing the event and the number assessed in each group were recorded.For continuous outcomes, the arithmetic means, standard deviations, and number assessed in each group wereextracted. If continuous data were reported using geometric means, the standard deviations on the log scale wereextracted; medians and ranges were extracted and reported in a table.

Assessme nt of risk of bias in included studies

Both authors independently assessed the methodological quality for each trial. Generation of allocation sequence and

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allocation concealment were classified as adequate, inadequate, or unclear according to Jni 2001. Descriptive datawere collected on whether participants, care providers, or outcome assessors were blinded. Inclusion of all randomizedparticipants was classified as adequate if 90% or more of all participants randomized into the trial were included in theanalysis; otherwise it was classified as inadequate or unclear. If data were missing or unclear, we contacted the trialauthors.

Data synthesis

Data were analysed using Review Manager 4.2. All results are presented with 95% confidence intervals (CI).

For dichotomous data, outcome measures were reported using risk ratio (RR). Given the high variation in control eventrates, we did not calculate the number needed to treat (NNT). For continuous data summarized by arithmetic meansand standard deviations, we used the mean difference (MD) to combine the results in a meta-analysis. Continuousdata summarized using other summary statistics that could not be combined in a meta-analysis were presented in atable. We calculated geometric mean ratios and transformed them in the log scale for analysis, and presented them onthe natural scale.

Subgroup ana lysis and investigation of het erogeneity

We assessed heterogeneity among trials by visually inspecting the forest plot, using the chi-squared test forheterogeneity with a 5% level of statistical significance, and the I2 test with a value of 50% representing a moderatelevel of heterogeneity. If we detected significant heterogeneity but felt it was appropriate to pool data, we used the

random-effects model (REM).

We stratified the analyses for acute diarrhoea or persistent diarrhoea as these are different conditions. We alsostratified the results by age (children aged less than and greater than six months) because we observed clear adifference in zinc effect according to the age of children enrolled and significant heterogeneity if all the trials werepooled together. We explored the following potential sources of heterogeneity using subgroup analyses: nutritionalstatus (malnourished children versus well-nourished plus moderate malnourished); geographical region (by continentand by high versus medium estimated risk of zinc deficiency as defined by the International Zinc Nutrition ConsultativeGroup (IZiNCG 2004)); zinc dose (< versus > 20 mg/day); zinc salt (zinc sulfate versus zinc acetate versus zincgluconate versus other type); concomitant copper or iron supplementation; and trial setting (hospital versuscommunity trials). We also explored the effect of sex, although this was not specified in our original protocol.

Sensitivity ana lysis

We conducted a sensitivity analysis in which we limited the analyses to those trials with adequate allocation

concealment, blinding (excluded those trials classified as unclear), and those that included an adequate number ofrandomized participants in the analysis (excluded those trials classified as inadequate or unclear).

M E T H O D O L O G I C AL Q U A L I T Y

R E S U L T S

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Eighteen trials enrolling 6165 children met our inclusion criteria (see 'Characteristics of included studies'). The processof trials selection is reported in , and the reasons for excluding 80 studies are given in the ' Characteristics of excludedstudies'.

Three of the included trials presented results divided in two or more subgroups: one trial presented two interventiongroups of zinc 20 mg and zinc 5 mg, and one control group (Brooks 2005a); one trial presented data for threedifferent study sites (Fischer Walker 2006); and one trial presented the results as children with low and normal zincserum levels (Polat 2003). For these three trials there was no way to combine means and standard deviations, andthus we had to enter the data separately as Brooks 2005a (20 mg), Brooks 2005a (5 mg), Fischer Walker 2006 ETH,Fischer Walker 2006 IND, Fischer Walker 2006 PAK, Polat 2003 low Zn, and Polat 2003 normal Zn. Thus the number oftotal comparisons is 22.

Type of diarrhoea

Thirteen trials enrolled children with acute diarrhoea: eight used this review's definition for acute diarrhoea (Faruque1999; Dutta 2000; Strand 2002; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Brooks 2005a; Fischer Walker2006); one defined diarrhoea as presence of four unformed stools in 24 hours ( Sazawal 1995); one shigellosis trial

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included patients with bloody mucoid diarrhoea (dysentery) or febrile diarrhoea less than five-days' duration (Roy2007a); and three trials did not report the definition of acute diarrhoea (Sachdev 1988; Roy 1997; Larson 2005). Fivetrials were on children with persistent diarrhoea (Sachdev 1990; Roy 1998; Bhutta 1999b; Penny 1999; Khatun2001).

Ag e

Two trials enrolled only children under six months (Brooks 2005a; Fischer Walker 2006). Nine trials only enrolledchildren over six months (Sachdev 1988; Sachdev 1990; Sazawal 1995; Bhutta 1999b; Faruque 1999; Penny 1999;Khatun 2001; Strand 2002; Roy 2007a). Seven trials included children of different ages greater than two months ( Roy1997; Roy 1998; Dutta 2000; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Larson 2005).

Nutritional status

Seven trials enrolled only malnourished children (Roy 1997; Roy 1998; Bhutta 1999b; Dutta 2000; Khatun 2001; Polat2003; Roy 2007a), and one enrolled children regardless of nutritional status (Larson 2005). The remaining 10 trialsenrolled children who were well nourished or with moderate malnutrition. No trial included only well-nourished childrenor only severe malnourished children. There was some variability between trials in the definitions of malnutrition (mostused 'weight/age'; only some used 'weight/height'); therefore we were unable to follow the definition of malnutritionproposed in the protocol.

Se x

Fifteen trials enrolled children of both sexes, while three trials included only males (Dutta 2000; Bhatnagar 2004a;Brooks 2005a).

Geographical region

Fifteen trials were conducted in Asia, two in South America and one multicentred trial in Asia and Africa (FischerWalker 2006). Thus, participants were from Bangladesh (Roy 1997; Roy 1998; Faruque 1999; Khatun 2001; Brooks2005a; Larson 2005; Roy 2007a), India (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta 2000; Bhatnagar2004a; Fischer Walker 2006 IND), Pakistan (Bhutta 1999b; Fischer Walker 2006 PAK), Nepal (Strand 2002), Turkey(Polat 2003), Brazil (Al-Sonboli 2003), Peru (Penny 1999), and Ethiopia (Fischer Walker 2006 ETH).

Risk of zinc deficiency

All the trials were held in countries ranked as high risk for zinc deficiency ( IZiNCG 2004), except for three trials, whichwere conducted in countries at medium risk: Nepal (Strand 2002); Turkey (Polat 2003); and Brazil (Al-Sonboli 2003).

Zinc dose

The zinc dose was 20 mg/day in nine trials. Only two trials administered higher zinc doses: 40 mg/day ( Dutta 2000);and 22 or 45 mg/day (Al-Sonboli 2003). Two trials, of which one in children aged less than six months only, gave zinc10 mg/day (Fischer Walker 2006; Roy 2007a). One trial used zinc 5 mg and 20 mg, but only in children aged less thansix months (Brooks 2005a).

Three trials used different doses depending on age (zinc < 20 mg in infants under 12 months and > 20 mg in childrengreater than 12 months), but they did not report result separately for each treatment group (Faruque 1999; Strand2002; Bhatnagar 2004a). We classified these trials as 'not assignable' and could not include them in the sensitivityanalysis for zinc dose. One trial reported a per kilo dose (3 mg/kg/day) (Bhutta 1999b); we included this in the meta-analysis for stool output but were not able to include it in the subgroup analyses.

Type of z inc salt

Nine trials used zinc sulfate, seven trials used zinc acetate (Roy 1997; Roy 1998; Faruque 1999, Khatun 2001; Strand2002; Brooks 2005a; Roy 2007a), and two used zinc gluconate (Sazawal 1995; Penny 1999).

Concom itant copper or iron supplem enta tion

None of the trials looked at this concomitant supplementation.

Study setting

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Most trials were conducted in hospitals, with the exception of three community-based studies ( Penny 1999; Strand2002; Fischer Walker 2006), and one trial was held both in hospital and community ( Larson 2005).

Treatm ent regimen

Duration of treatm ent

Eight trials administered zinc for two weeks. Of the remaining 10 trials, two gave zinc for seven days after recovery(Strand 2002; Polat 2003), two gave zinc until recovery (Al-Sonboli 2003; Brooks 2005a), and one gave zinc for sevendays (Khatun 2001). Four trials were unclear in respect of duration of zinc supplementation (Sachdev 1988; Sachdev1990; Sazawal 1995; Dutta 2000). One trial on adverse events administered only one dose of zinc ( Larson 2005).

Formulation

Zinc was administered as syrup in most trials; only three used powder (Sachdev 1988; Sachdev 1990; Penny 1999),and three used dispersible tablets (Al-Sonboli 2003; Larson 2005; Fischer Walker 2006).

Dose frequency

The zinc dose was administered once a day in half of the trials, while the other half administered it twice a day(Sachdev 1988; Sachdev 1990; Khatun 2001; Roy 2007a) or three times a day (Roy 1997; Roy 1998; Dutta 2000;Polat 2003; Bhatnagar 2004a).

Addit ional treatm ents

Ten trials administered zinc alone; seven studies used zinc and multivitamin, which did not contain iron (Sazawal1995; Roy 1997; Roy 1998; Bhutta 1999b; Khatun 2001; Bhatnagar 2004a; Roy 2007a). One trial used zinc andvitamin A (Faruque 1999). No trial used concomitant copper.

Outcomes

Fourteen trials reported data on diarrhoea duration (Sachdev 1988; Sachdev 1990; Roy 1997; Roy 1998; Bhutta

1999b; Faruque 1999; Penny 1999; Dutta 2000; Khatun 2001; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a;Brooks 2005a; Fischer Walker 2006). Data were presented as means and standard deviations or means, and 95% CI.One trial reported data as medians and ranges (Roy 2007a), and we could not compare these to the data from othertrials.

Three trials reported on diarrhoea at day three (Penny 1999; Strand 2002; Polat 2003), three trials on diarrhoea atday five (Penny 1999; Dutta 2000; Bhatnagar 2004a), and nine at day seven (Sazawal 1995; Faruque 1999; Penny1999; Khatun 2001; Strand 2002; Polat 2003; Bhatnagar 2004a; Fischer Walker 2006; Roy 2007a)

Stool frequency was reported in five trials (Sachdev 1988; Sachdev 1990; Al-Sonboli 2003; Brooks 2005a; FischerWalker 2006). Two trials did not report cumulative data for the whole hospitalization period (Bhutta 1999b; Polat2003); instead they reported data on some given days (respectively, days two and four, and days one, seven, and14), and these data could not be compared to the data from other trials.

Six trials reported data on stool output (Roy 1997; Bhutta 1999b; Dutta 2000; Khatun 2001; Bhatnagar 2004a;Brooks 2005a). Definitions and measurement units varied consistently between trials (see ). Stool output wasevaluated using pre-weighed disposable diapers with urine collected separately in two trials ( Dutta 2000; Bhatnagar

2004a) and using pre-weighed containers with urine collected separately in one trial (Roy 1997). In one trial, stoolweight was measured by using metabolic beds, and urine was collected separately using urine bags. The methodswere not clearly stated in two trials (Bhutta 1999b; Khatun 2001).

Three community trials reported information on hospitalization (Penny 1999; Strand 2002; Fischer Walker 2006). Thedeclared follow-up period for these trials was "until recovery from diarrhoea" in two trials (Strand 2002; FischerWalker 2006), and 15 days in another trial (Penny 1999).

Death was reported in six trials. These trials had as follow-up times the duration of hospital stay (Roy 1998; Khatun2001; Brooks 2005a), 15 days (Penny 1999), until the diarrhoea episode was over (Fischer Walker 2006), and sixmonths (Roy 2007a).

Data on vomiting were available in 12 trials. All these trials reported percentage of children who vomited. Only onetrial stated case definitions with vomiting defined as a forceful emptying of stomach contents, and regurgitation as theunforced return of any amount of the swallowed syrup, liquids, or foods (Larson 2005).

Three trials reported on copper plasma levels (Bhutta 1999b; Strand 2002; Bhatnagar 2004a), but the data were not

comparable because they used different units of measurement

Risk of bias in included studies

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See for a summary of the risk of bias in included studies.

Generation of allocation sequence

Fifteen trials used adequate methods to generate the allocation sequence. The methods used in the other three trialswere unclear (Sachdev 1988; Sachdev 1990; Khatun 2001).

Allocation concealm ent

Twelve trials reported methods that assured adequate allocation concealment. The remaining six were unclear(Sachdev 1988; Sachdev 1990; Roy 1998; Khatun 2001; Al-Sonboli 2003; Brooks 2005a).

Blinding

Fifteen trials were double blinded. The use of blinding was unclear in the remaining three (Sachdev 1988; Sachdev1990; Khatun 2001).

I nclusion of all random ized participants

Eleven trials included more than 90% of the randomized participants in the analysis. Three included less than 90%,which we assessed as inadequate (Roy 1997; Bhutta 1999b; Roy 2007a), and the number included was unclear in theremaining four trials (Sachdev 1988; Sachdev 1990; Roy 1998; Dutta 2000).

Effects of interventions

1. I n chi ldren w ith acute diarrhoea

1.1 . Diarrhoea duration

Diarrhoea duration was reduced with zinc by -12.27 h (mean difference, 95% CI -23.02 to -1.52 h, ) in a comparisoninvolving nine trials (13 comparisons) and 2741 children, although there was significant heterogeneity between trials

(P = < 0.00001, I2 84.3%). When stratified by age, no benefit was evident in children under six months (1334children, 2 trials), but it was evident in trials of older children (MD -16.67 h, 95% CI -31.03 to -2.31 h; 731 children, 2trials); no statistical heterogeneity was detected. One trial conducted in infants less than six months stratified forbreastfeeding, but it did not detect a difference between exclusively and not exclusively breastfed infants (FischerWalker 2006, 1074 children).

1.2 . Diarrhoea on days three, f ive, and seven

Treatment with zinc also resulted in less diarrhoea at day three (RR 0.69, 95% CI 0.59 to 0.81; 1073 children, 2 trials,3 comparisons, ), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children, 2 trials, ), and day seven (RR 0.71, 95% CI0.51 to 0.98, REM; 4087 children, 7 trials, 10 comparisons, ). There was significant heterogeneity between trials (P =0.0001, I2 73%), although this was markedly reduced if results were stratified by age: no benefit of zinc was detectedin children under six months (1074 children, 3 comparisons), while zinc had a benefit in children older than six months(RR 0.70, 95% CI 0.57 to 0.85, REM; 2565 children, 4 trials).

1.3 . Stool frequency

There was no evidence of a difference in stool frequency (1458 children, 4 trials, Analysis 1.5). Most trials reportingthis outcome only enrolled participants aged less than six months, and the results of the one small trial that did enrolchildren over six months did not reach statistical significance.

1.4 . Stool output

Stool output was measured using different units at different time points, thus results could not be pooled together ().Results are expressed as arithmetic mean difference (AMD) or geometric mean ratio (GMR).

One trial reported on children aged less than six months with no evidence of a difference ( Brooks 2005a). Three trials

reported on children aged less than and greater than six months; two trials showed a reduction in stool output withzinc (Dutta 2000; Bhatnagar 2004a), while one trial showed no evidence of an effect (Roy 1997).

1.5 . Hospitalization

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Only community trials reported on hospitalization; one reported no difference between groups (Strand 2002, 891participants), and the second reported no hospitalizations in the zinc group and one in the placebo group (FischerWalker 2006, 1074 participants).

1.6 . Death

Three trials reported on death: two trials (316 children) did not observe any deaths ( Brooks 2005a; Roy 2007a); andone trial (1034 children) reported one death in each treatment group (Fischer Walker 2006).

1.7 . Adverse events

Eight trials reported vomiting, which was significantly more common in the zinc group (RR 1.71, 95% CI 1.27 to 2.30,REM; 4727 children, 8 trials, 10 comparisons, ), and across all age groups. There was significant heterogeneity amongtrials (P = 0.001, I2 69.3%), and differences in control event rates.

Two trials reported on copper levels, with no significant differences between the zinc and placebo groups. The meanserum copper after 14 days was 121 mg/L in zinc group versus 127 mg/L in the control in one trial ( Bhatnagar2004a), while the mean change in serum copper on the last day of supplementation (seven days after recovery) was -1.1 5.5 mol/dL in the zinc group versus -1.5 4.2 mol/dL in the placebo group in the second trial (Strand 2002).

1.8 . Stat istical heterogeneity

Reasons for heterogeneity were explored for mean diarrhoea duration and diarrhoea at day seven, after excludingtrials only enrolling children aged under six months (Analysis 2.1 and Analysis 3.1). Adjusting for nutritional status,geographical region, background zinc deficiency, zinc type (acetate or sulfate), and study setting did not alter thesignificance of the result. A zinc dose of 20 mg/day did not reduce mean diarrhoea duration, but it significantlyreduced diarrhoea at day seven (Analysis 1.1, no higher doses used for this outcome). It was not possible to draw anyconclusions on the role of gender as separate results for male and female participants were not available. All thesubgroups presented significant heterogeneity, and this indicates that no single feature can explain heterogeneityalone. We were unable to construct funnel plots to look for evidence of publication bias as none of the outcomes hadsufficient numbers of trials to do this.

1.9 . Sensitivity a nalysis

The sensitivity analysis against markers of methodological quality did not affect the direction of results. There wassome loss of significance with diarrhoea duration, but overall the analysis did not change the point estimate of effects.The intention-to-treat analysis for worst-case/best-case scenarios altered the statistical significance only for diarrhoeaat day five in the worst-case scenario, but there were no changes in point estimate of effects.

2. I n children w ith persistent diarrhoea

All trials of persistent diarrhoea enrolled trials aged over six months.

2.1 . Diarrhoea duration

Zinc supplementation reduced the duration of persistent diarrhoea (MD -15.83 h, 95% -25.43 to -6.24 h; 529children, 5 trials, ), with no evidence of heterogeneity.

2.2 . Diarrhoea on days three, f ive, and seven

There was no evidence of a benefit with zinc in the one trial that reported on diarrhoea at days three ( Analysis 4.2)and five (Analysis 4.3) (Penny 1999), and two trials that reported on diarrhoea at day seven (Analysis 4.4) (Penny1999; Khatun 2001).

2.3 . Stool frequency

One small trial reported on stool frequency (Sachdev 1990), but the result did not reach significance (40 participants,Analysis 4.5)

2.4 . Stool output

Stool output was measured using different units at different time points, thus results could not be pooled together ().Results are expressed as the arithmetic mean difference (AMD) or geometric mean ratio (GMR). Two trials reported on

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children aged greater than six months, with five comparisons, and only one (Khatun 2001) reported a significantreduction in cumulative stool output at day seven in the zinc group (AMD -338 mg/kg bodyweight, 95% CI -413.6 to -262.4 mg/kg bodyweight; P = < 0.001).

2.5 . Hospitalization

The only community trial reporting on hospitalization did not observe any hospitalizations in the zinc or placebo group(Penny 1999, 275 participants).

2.6 . Death

One trial reported one death in the zinc group compared to five deaths in the placebo group, out of 95 participants ineach group (Roy 1998). Two trials did not observe deaths in any participants, irrespective of their allocated group(Penny 1999; Khatun 2001).

2.7 . Adverse events ( Analysis 04 .06 )

Four trials that reported on vomiting (505 children) showed no difference between the zinc and placebo groups(Analysis 4.6); three of the trials reported no incidences of vomiting in either group. One trial using zinc 3 mg/kg/dayfor 14 days in moderately malnourished and severely malnourished children reported a significantly lower plasma

copper levels in the zinc-treated group by the end of the second week of therapy (56.2 17.8 g/dL versus 72.7 18.3 g/dL, P = 0.02; Bhutta 1999b, 87 children).

2.8 . Stat istical heterogeneity

There was heterogeneity between two trials for diarrhoea at day seven. This may be explained by differences in thegeographical regions (India and Peru) or to other factors not explored in the review. Reporting of vomiting washeterogeneous between trials, and this may be due to difference in the population or in the definition of event, or toreporting bias.

2.9 . Sensitivity a nalysis

The sensitivity analyses did not affect the direction of results. There was some loss of significance with diarrhoea

duration, but no changes in the point estimate of effects. An intention-to-treat analysis for worst-case/best-casescenarios did not alter the point estimate or the significance of results.

D I S C U S S I O N

Discussion

We identified 18 randomized controlled trials that compared zinc with placebo in young children. Thirteen trials focusedon acute diarrhoea and the other five on persistent diarrhoea. Overall, zinc was effective for diarrhoea in children agedover six months. Two large trials were conducted in children aged less than six months with acute diarrhoea, and theyshowed no evidence of an effect on any of the outcomes.

Zinc reduced acute diarrhoea duration. The size of the effect was clinically important, particularly for diarrhoea at dayseven, which is an indicator for the risk of persistent diarrhoea. This benefit withstood extensive subgroup analysis for

nutritional status, geographic region, background zinc deficiency, zinc type, and study setting. Evidence on diarrhoeaseverity was less clear, as fewer trials reported on this, and different units and time points were used.

Zinc also reduced the duration of persistent diarrhoea, but evidence was inconsistent regarding the severity ofpersistent diarrhoea.

No conclusions regarding zinc's impact on hospitalization or death can be drawn from this review as trials were notdesigned to look at these outcomes, and most were conducted in hospital where death rates were low. Largecommunity trials would be needed to explore whether zinc treatment for diarrhoea reduces hospitalization rates.

Treatment with zinc was associated with an increase in vomiting, although the reduction in diarrhoea seems tooutweigh this. This increase was consistent across trials in all age groups, including one large trial with adequateallocation concealment that was designed to look at safety. This trial reported that vomiting was limited to one episodein most children and mainly occurred within 10 minutes of administration (Larson 2005). Zinc has a metallic after-taste, and development of a more palatable formulation may minimize this. There was no clear evidence of copperdeficiency resulting from zinc supplementation at the regimens used.

In general, the methodological quality of the trials included in this review was good. Most trials were conducted incountries with a high risk of zinc deficiency, but the few trials in countries at 'medium risk' also showed a benefit ofzinc. Applicability of these results to countries is likely to depend on local zinc deficiency and populationcharacteristics, such as the degree of malnutrition. Nearly all trials were conducted in hospital where participants were

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likely to adhere to the intervention, although one large community trial also showed a benefit with zinc.

Our results agree with those of an earlier systematic review of zinc for treating diarrhoea (Bhutta 2000b), except forthe new finding of no effect of zinc in children aged less than six months. The review adds several new trials, includesa more extensive subgroup analysis, and reports on diarrhoea at different time points, diarrhoea severity, and adverseevents.

The results of this review in children over six months support the current WHO/UNICEF policy to give zinc to childrenwith diarrhoea (WHO/UNICEF 2004).

A U T H O R S' C O N C L U SI O N S

Implications for practice

In areas where diarrhoea is an important cause of child mortality, research evidence shows zinc is clearly of benefit inchildren aged six months or more with diarrhoeal diseases.

Implications for research

None identified.

A C K N O W L E D G E M E N T S

Acknowledgements

The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for InternationalDevelopment (DFID) for the benefit of developing countries. We thank Katharine Jones for her help in reviewing thetext.

N O T E S

R E F E R E N C E S

References to studies included in this review

Al-Sonboli 200 3 { published data only}

Al-Sonboli N, Gurgel RQ, Shenkin A, Hart CA, Cuevas LE. Zinc supplementation in Brazilian children withacute diarrhoea. Annals of Tropical Paediatrics 2003;23:3-8.

Cuevas LE, Al Sonboli NN, Gurgel RQ, Shenkins A, Hart CA. Impact of zinc on duration of acutediarrhoea in children [Abstract]. Journal of Infection 2000;40:A29-.

Bhatnagar 2004 a { published data only}

Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan MK. Zinc with oral rehydration therapyreduces stool output and duration of diarrhea in hospitalized children: a randomized controlled trial.Journal of Pediatric Gastroenterology and Nutrition 2004;38:34-40.

Bhut ta 1999 b { published data only}

Bhutta ZA, Nizami SQ, Isani Z. Zinc supplementation in malnourished children with persistent diarrheain Pakistan. Pediatrics 1999;103:e42-.

Brooks 2005a { published data only}

Brooks WA, Santosham M, Roy SK, Faruque AS, Wahed MA, Nahar K. Efficacy of zinc in young infantswith acute watery diarrhea. American Journal of Clinical Nutrition 2005;82:605-10.

Brooks 200 5a (2 0 mg) { published data only}

See Brooks 2005a. . :-.

Brooks 200 5a ( 5 mg) { published data only}

Page 10 of 25



11/25

See Brooks 2005a. . :-.

Dutta 2000 { published data only}

Dutta P, Mitra U, Datta A, Niyogi SK, Dutta S, Manna B. Impact of zinc supplementation inmalnourished children with acute watery diarrhoea. Journal of Tropical Pediatrics 2000;46:259-63.

Faruque 199 9 { published data only}

Faruque AS, Mahalanabis D, Haque SS, Fuchs GJ, Habte D. Double-blind, randomized, controlled trial ofzinc or vitamin A supplementation in young children with acute diarrhoea. Acta Paediatrica1999;88:154-60.

Fischer Wa lker 200 6 { published data only}

Fischer Walker CL, Bhutta ZA, Bhandari N, Teka T, Shahid F, Taneja S. Zinc supplementation for thetreatment of diarrhea in infants in Pakistan, India and Ethiopia. Journal of Pediatric Gastroenterologyand Nutrition 2006;43:357-63.

Fischer W alker 20 06 ETH { published data only}

See Fischer Walker 2006. . :-.

Fischer Walker 200 6 I ND { published data only}


Fischer Wa lker 200 6 PAK { published data only}


Khatun 200 1 { published data only}

Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA, Fuchs G. A randomized controlled clinical trial

of zinc, vitamin A or both in undernourished children with persistent diarrhea in Bangladesh. ActaPaediatrica 2001;90:376-80.

Roy SK. A randomized four cell clinical trial of zinc and vitamin A in undernourished children withpersistent diarrhoea in Bangladesh. Journal of Pediatric Gastroenterology and Nutrition 1998;26:595-.

Larson 200 5 { published data only}

Larson CP, Hoque AB, Larson CP, Khan AM, Saha UR. Initiation of zinc treatment for acute childhooddiarrhoea and risk for vomiting or regurgitation: a randomized, double-blind, placebo-controlled trial.Journal of Health, Population, and Nutrition 2005;23:311-9.

Penny 199 9 { published data only}

Penny ME, Peerson JM, Marin RM, Duran A, Lanata CF, Lonnerdal B. Randomized, community-basedtrial of the effect of zinc supplementation, with and without other micronutrients, on the duration ofpersistent childhood diarrhea in Lima, Peru. Journal of Pediatrics 1999;135:208-17.

Polat 200 3 { published data only}

Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration ofdiarrhea in malnourished Turkish children. Pediatrics International 2003;45:555-9.

Polat 200 3 low Zn { published data only}

Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration ofdiarrhea in malnourished Turkish children. Pediatrics International 2003;45:555-9.

Polat 20 03 normal Zn { published data only}

Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration of

Page 11 of 25



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diarrhea in malnourished Turkish children. Pediatrics International 2003;45:555-9.

Roy 199 7 { published data only}

Roy SK. Effect of zinc supplementation in patients with acute and persistent diarrhoea. Glimpse1991;13:2-.

Roy SK, Tomkins AM, Akramuzzaman SM, Behrens RH, Haider R, Mahalanabis D. Randomised controlledtrial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Archives ofDisease in Childhood 1997;77:196-200.


Roy SK. Effect of zinc supplementation in patients with acute and persistent diarrhoea. Glimpse1991;13:2-.

Roy SK, Tomkins AM, Mahalanabis D, Akramuzzaman SM, Haider R, Behrens RH. Impact of zincsupplementation on persistent diarrhoea in malnourished Bangladeshi children. Acta Paediatrica1998;87:1235-9.

Roy 2007 a { published and unpublished data}

Roy SK, Raqib R, Khatun W, Azim T, Chowdhury R, Fuchs GJ. Zinc supplementation in the managementof shigellosis in malnourished children in Bangladesh. European Journal of Clinical Nutrition :-.

Sachdev 1988 { published data only}

Sachdev HP, Mittal NK, Mittal SK, Yadav HS. A controlled trial on utility of oral zinc supplementation inacute dehydrating diarrhea in infants. Journal of Pediatric Gastroenterology and Nutrition 1988;7:877-81.

Sachdev 1990 { published data only}

Sachdev HP, Mittal NK, Yadav HS. Oral zinc supplementation in persistent diarrhoea in infants. Annalsof Tropical Paediatrics 1990;10:63-9.

Sazawal 1995 { published data only}

Darmon N, Briend A, Desjeux JF. Zinc in the treatment of diarrhea. Journal of PediatricGastroenterology and Nutrition 1997;25:363-5.

Folwaczny C. Role of zinc in treatment of acute diarrhea. Zeitschrift fr Gastroenterologie 1996;34:260-2.

Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young childrenwith acute diarrhea in India. New England Journal of Medicine 1995;333:839-44.

Strand 200 2 { published data only}

Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N. Effectiveness and efficacy of zincfor the treatment of acute diarrhea in young children. Pediatrics 2002;109:898-903.

* indicates the major p ublication for the study

References to studies excluded from this review

Adu Afarwuah 2 007 { published data only}

Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Randomized comparison of 3types of micronutrient supplements for home fortification of complementary foods in Ghana: Effects ongrowth and motor development. American Journal of Clinical Nutrition 2007;86:412-20.

Agustina 200 7 { published data only}

Agustina R, Lukito W, Firmansyah A, Suhardjo HN, Murniati D, Bindels J. The effect of early nutritional

supplementation with a mixture of probiotic,prebiotic, fiber and micronutrients in infants with acutediarrhea in Indonesia. Asia Pacific Journal of Clinical Nutrition 2007;16:435-42.

Alarcon 20 04 { published data only}

Page 12 of 25



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Alarcon K, Kolsteren PW, Prada AM, Chian AM, Velarde RE, Pecho IL. Effects of separate delivery of zincor zinc and vitamin A on hemoglobin response, growth, and diarrhea in young Peruvian childrenreceiving iron therapy for anemia. American Journal of Clinical Nutrition 2004;80:1276-82.

Awasthi 200 6 { published data only}

Awasthi S. Zinc supplementation in acute diarrhea is acceptable, does not interfere with oralrehydration, and reduces the use of other medications: a randomized trial in five countries. Journal of

Pediatric Gastroenterology and Nutrition 2006;42:300-5.

Bahl 200 2 { published data only}

Bahl R, Bhandari N, Saksena M, Strand T, Kumar GT, Bhan MK. Efficacy of zinc-fortified oral rehydrationsolution in 6- to 35-month-old children with acute d iarrhea. Journal of Pediatrics 2002;141:677-82.

Baqui 2002 { published data only}

Baqui AH, Black RE, Arifeen S, Yunus M, Chakraborty J, Ahmed S. Effect of zinc supplementationstarted during diarrhoea on morbidity and mortality in Bangladeshi children: community randomisedtrial. BMJ 2002;325:1059-64.

Baqui AH, Black RE, Arifeen S, Yunus M, Zaman K, Begum N. Zinc therapy for diarrhoea increased the

use of oral rehydration therapy and reduced the use of antibiotics in Bangladeshi children. Journal ofHealth, Population, and Nutrition 2004;22:440-2.


Baqui AH, Zaman K, Persson LA, Arifeen S, Yunus M, Begum N. Simultaneous weekly supplementationof iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infectionin Bangladeshi infants. Journal of Nutrition 2003;133:4150-7.


Baqui AH, Black RE, Fischer Walker CL, Arifeen S, Zaman K, Yunus M. Zinc supplementation and serumzinc during diarrhea. Indian Journal of Pediatrics 2006;73:493-7.

Behrens 1990 { published data only}

Behrens RH, Tomkins AM, Roy SK. Zinc supplementation during diarrhoea, a fortification againstmalnutrition?. Lancet 1990;336:442-3.

Bhandar i 200 2 { published data only}

Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ. Substantial reduction in severe diarrhealmorbidity by daily zinc supplementation in young north Indian children. Pediatrics 2002;109:e86-.


Bhandari N, Mazumder S, Taneja S, Dube B, Black RE, Fontaine O. A pilot test of the addition of zinc to

the current case management package of diarrhea in a primary health care setting. Journal of PediatricGastroenterology and Nutrition 2005;41:685-7.


Bhandari N, Taneja S, Mazumder S, Bahl R, Fontaine O, Bhan MK. Adding zinc to supplemental iron andfolic acid does not affect mortality and severe morbidity in young children. Journal of Nutrition2007;137:112-7.

Bhatnagar 2004 b { published data only}

Bhatnagar S, Natchu UC. Zinc in child health and disease. Indian Journal of Pediatrics 2004;71:991-5.

Bhut ta 2000 a { published data only}

Bhutta ZA, Raza F, Nizami SQ, Issani Z. Does zinc supplementation influence appetite in malnourishedchildren with persistent diarrhoea? A randomized controlled trial in Pakistan. Journal of Pediatric

Page 13 of 25



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Gastroenterology and Nutrition 2000;31 Suppl 2:23-.

Black 200 1 { published data only}

Black RE, Sazawal S. Zinc and childhood infectious disease morbidity and mortality. British Journal ofNutrition 2001;85 Suppl 2:125-9.

Bobat 200 5 { published data only}

Bobat R, Coovadia H, Stephen C, Naidoo KL, McKerrow N, Black RE. Safety and efficacy of zincsupplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial. Lancet 2005;366:1862-7.

Borges 20 07 { published data only}

Borges Dantas CV, Veiga Black AP, Barroso dos Santos G, Jesus Oliveira EF, Serpa Barbosa RF, MoreiraS. Association among serum concentration of minerals, anthropometric indices and diarrhea in low-income children in the metropolitan region of Rio de Janeiro, Brazil. Revista de Nutricao 2007;20:159-69.

Brooks 2005b { published data only}

Brooks WA, Santosham M, Naheed A, Goswami D, Wahed MA, Diener-West M. Effect of weekly zincsupplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban,low-income population in Bangladesh: randomised controlled trial. Lancet 2005;366:999-1004.

Brown 2007 { published data only}

Brown KH, Romana DL, Arsenault JE, Peerson JM, Penny ME. Comparison of the effects of zinc deliveredin a fortified food or a liquid supplement on the growth morbidity and plasma zinc concentrations ofyoung Peruvian children. American Journal of Clinical Nutrition 2007;85:538-47.

Carbaja l 20 00 { published data only}

Carbajal C. Micronutrients: An option in the treatment of acute diarrheal diseases. Revista Cubana dePediatra 2000;72:261-6.

Carcamo 2006 { published data only}

Carcamo C, Hooton T, Weiss NS, Gilman R, Wener MH, Chavez V. Randomized controlled trial of zincsupplementation for persistent diarrhea in adults with HIV-1 infection. Journal of Acquired ImmuneDeficiency Syndromes 2006;43:197-201.

Doherty 199 8 { published data only}

Doherty CP, Sarkar MA, Shakur MS, Ling SC, Elton RA, Cutting WA. Zinc and rehabilitation from severeprotein-energy malnutrition: higher-dose regimens are associated with increased mortality. AmericanJournal of Clinical Nutrition 1998;68:742-8.

Ebrahimi 2 00 6 { published data only}

Ebrahimi S, Pormahmodi A, Kamkar A. Study of zinc supplementation on growth of schoolchildren inYasuj, Southwest of Iran. Pakistan Journal of Nutrition 2006;5:341-2.

Ellis 2007 { published data only}

Ellis AA, Winch P, Daou Z, Gilroy KE, Swedberg E. Home management of childhood diarrhoea insouthern Mali-Implications for the introduction of zinc treatment. Social Science & Medicine2007;64:701-12.

Gardner 200 5 { published data only}

Gardner JM, Powell CA, Baker-Henningham H, Walker SP, Cole TJ, Grantham-McGregor SM. Zincsupplementation and psychosocial stimulation: effects on the development of undernourished Jamaicanchildren. American Journal of Clinical Nutrition 2005;82:399-405.

Page 14 of 25



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Garenne 200 7 { published data only}

Garenne M, Becher H, Ye Y, Kouyate B, Muller O. Sex-specific responses to zinc supplementation inNouna, Burkina Faso. Journal of Pediatric Gastroenterology and Nutrition 2007;44:619-28.

Gregorio 2007 { published data only}

Gregorio GV, Dans LF, Cordero CP, Panelo CA. Zinc supplementation reduced cost and duration of acutediarrhea in children. Journal of Clinical Epidemiology 2007;60:560-6.

Gupta 200 3 { published data only}

Gupta DN, Mondal SK, Ghosh S, Rajendran K, Sur D, Manna B. Impact of zinc supplementation ondiarrhoeal morbidity in rural children of West Bengal, India. Acta Paediatrica 2003;92:531-6.

Gupta 200 7 { published data only}

Gupta DN, Rajendran K, Mondal SK, Ghosh S, Bhattacharya SK. Operational feasibility of implementingcommunity-based zinc supplementation:impact on childhood diarrheal morbidity. Pediatric InfectiousDisease Journal 2007;26:306-10.

Heinig 20 06 { published data only}

Heinig MJ, Brown KH, Lonnerdal B, Dewey KG. Zinc supplementation does not affect growth morbidityor motor development of US term breastfed infants at 4-10 mo of age. American Journal of ClinicalNutrition 2006;84:594-601.

Hidayat 199 8 { published data only}

Hidayat A, Achadi A, Sunoto , Soedarmo SP. The effect of zinc supplementation in children under threeyears of age with acute diarrhea in Indonesia. Medical Journal of Indonesia 1998;7:237-41-.

Hoque 200 6 { published data only}

Hoque KM, Binder HJ. Zinc in the treatment of acute diarrhea: current status and assessment.Gastroenterology 2006;130:2201-5.

Jimenez 2000 { published data only}

Jimenez R, Sagaro E, Lafita Y. How growth infants supplemented with zinc sulfate after an episode ofpersistent diarrhea. Journal of Pediatric Gastroenterology and Nutrition 2000;31 Suppl 2:26-.

Kelly 1999 { published data only}

Kelly P, Musonda R, Kafwembe E, Kaetano L, Keane E, Farthing M. Micronutrient supplementation in theAIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial. AIDS 1999;13:495-500.

Lind 2004 { published data only}

Lind T, Lonnerdal B, Stenlund H, Gamayanti IL, Ismail D, Seswandhana R. A community-basedrandomized controlled trial of iron and zinc supplementation in Indonesian infants: effects on growthand development. American Journal of Clinical Nutrition 2004;80:729-36.

Lira 199 8 { published data only}

Lira PI, Ashworth A, Morris SS. Effect of zinc supplementation on the morbidity, immune function, andgrowth of low-birth-weight, full-term infants in northeast Brazil. American Journal of Clinical Nutrition1998;68 2 Suppl:418-24.

Long 200 6 { published data only}

Long KZ, Montoya Y, Hertzmark E, Santos JI, Rosado JL. A double-blind, randomized, clinical trial of theeffect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections inchildren in Mexico City, Mexico. American Journal of Clinical Nutrition 2006;83:693-700.

Page 15 of 25



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Lopez 200 5 { published data only}

Lopez de Romana G, Cusirramos S, Lopez de Romana D, Gross R. Efficacy of multiple micronutrientsupplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants.Journal of Nutrition 2005;135:646-52.

Luabeya 200 7 { published data only}

Luabeya KK, Mpontshane N, Mackay M, Ward H, Elson I, Chhagan M. Zinc or multiple micronutrientsupplementation to reduce diarrhea and respiratory disease in South African children: a randomizedcontrolled trial. PLoS ONE 2007;2:e541-.

Makonnen 2003a { published data only}

Makonnen B, Venter A, Joubert G. A randomized controlled study of the impact of dietary zincsupplementation in the management of children with protein-energy malnutrition in Lesotho. I:Mortality and morbidity. Journal of Tropical Pediatrics 2003;49:340-52.

Makonnen 2003b { published data only}

Makonnen B, Venter A, Joubert G. A randomized controlled study of the impact of dietary zinc

supplementation in the management of children with protein-energy malnutrition in Lesotho. II: Specialinvestigations. Journal of Tropical Pediatrics 2003;49:353-60.

Meeks 19 98 { published data only}

Meeks Gardner J, Witter MM, Ramdath DD. Zinc supplementation: effects on the growth and morbidityof undernourished Jamaican children. European Journal of Clinical Nutrition 1998;52:34-9.

Mller 200 1 { published data only}

Mller O, Becher H, Zweeden AB, Ye Y, Diallo DA, Konate AT. Effect of zinc supplementation on malariaand other causes of morbidity in west African children: randomised double blind placebo controlled trial.BMJ 2001;322:1567-.

Nasr in 200 5 { published data only}

Nasrin D, Larson CP, Sultana S, Khan TU. Acceptability of and adherence to dispersible zinc tablet in thetreatment of acute childhood diarrhoea. Journal of Health, Population, and Nutrition 2005;23:215-21.

Osendarp 2002 { published data only}

Osendarp SJ, Santosham M, Black RE, Wahed MA, Raaij JM, Fuchs GJ. Effect of zinc supplementationbetween 1 and 6 mo of life on growth and morbidity of Bangladeshi infants in urban slums. AmericanJournal of Clinical Nutrition 2002;76:1401-8.

Pate l 20 05 { published data only}

Patel AB, Dhande LA, Rawat MS. Therapeutic evaluation of zinc and copper supplementation in acutediarrhea in children: double blind randomized trial. Indian Pediatrics 2005;42:433-42.

Penny 2004a { published data only}

Penny ME, Marin RM, Duran A, Peerson JM, Lanata CF, Lonnerdal B. Randomized controlled trial of theeffect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, andmicronutrient status of young Peruvian children. American Journal of Clinical Nutrition 2004;79:457-65.

Penny 2004b { published data only}

Penny ME, Black RE, Brown KH, Lnnerdal B. Reply to RJ Walden [Letter to the Editor]. AmericanJournal of Clinical Nutrition 2004;80:1084-5.

Polat 200 6 { published data only}

Polat TB, Uysalol M, Cetinkaya F. Impact of zinc supplementation in children with acute diarrhoea in

Page 16 of 25



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Turkey. Archives of Disease in Childhood 2006;91:296-9.

Rahman 2001 { published data only}

Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Simultaneous zinc and vitaminA supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ2001;323:314-8.

Rahman 2005 { published data only}

Rahman MJ, Sarker P, Roy SK, Ahmad SM, Chisti J, Azim T. Effects of zinc supplementation as adjuncttherapy on the systemic immune responses in shigellosis. American Journal of Clinical Nutrition2005;81:495-502.

Raqib 200 4 { published data only}

Raqib R, Roy SK, Rahman MJ, Azim T, Ameer SS, Chisti J. Effect of zinc supplementation on immuneand inflammatory responses in pediatric patients with shigellosis. American Journal of Clinical Nutrition2004;79:444-50.

Richard 20 06 { published data only}

Richard SA, Zavaleta N, Caulfield LE, Black RE, Witzig RS, Shankar AH. Zinc and iron supplementationand malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. American Journalof Tropical Medicine and Hygiene 2006;75:126-32.

Rosado 199 7 { published data only}

Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, butneither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers.American Journal of Clinical Nutrition 1997;65:13-9.

Rosado 199 8 { published data only}

Rosado JL. Zinc deficiency and its functional implications. Salud Pblica de Mxico 1998;40:181-8.


Roy SK, Akramuzzaman SM, Haider R, Mahalanabis D, Behrens RH, Wahed MA. Zinc supplementation indiarrhoea: Nutritional implication on clinical recovery and intestinal permeability [Abstract]. Journal ofGastroenterology and Hepatology 1994;9:A166-.

Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA. Impact of zincsupplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistentdiarrhoea syndrome. Journal of Pediatric Gastroenterology and Nutrition 1992;15:289-96.


Roy SK, Tomkins AM, Haider R, Behren RH, Akramuzzaman SM, Mahalanabis D. Impact of zinc

supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea.European Journal of Clinical Nutrition 1999;53:529-34.

Roy 2007 b { published data only}

Roy SK, Tomkins AM, Akramuzzaman SM, Chakraborty B, Ara G, Biswas R. Impact of zincsupplementation on subsequent morbidity and growth in Bangladeshi children with persistent diarrhoea.Journal of Health, Population, and Nutrition 2007;25:67-74.

Roy 2007 c { published data only}

Roy SK, Hossain MJ, Khatun W, Chakraborty B, Chowdhury S, Begum A. Zinc supplementation inchildren with cholera in Bangladesh: randomised controlled trial. BMJ 2008;336:266-8.

Ruel 199 7 { published data only}

Ruel MT, Rivera JA, Santizo MC, Lonnerdal B, Brown KH. Impact of zinc supplementation on morbidity

Page 17 of 25



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from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997;99:808-13.

Sabat ier 19 97 { published data only}

Sabatier Garca FJ, Izquierdo Estvez A, Len Garca RE, Daz Fernndez L. Benefits of zinc in thetreatment of infants presenting with diarrhea. Revista Cubana de Pediatra 1997;69:197-200.

Samuel 19 95 { published data only}

Samuel MJ. Paediatrics Forum. Acute diarrhoea. Africa Health 1995;17:27, 29-30-.

Sazawal 1996 { published data only}

Sazawal S, Black RE, Bhan MK, Jalla S, Bhandari N, Sinha A. Zinc supplementation reduces theincidence of persistent diarrhea and dysentery among low socio-economic children in India. Journal ofNutrition 1996;126:443-50.

Sazawal 1997a { published data only}

Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efficacy of zinc supplementation inreducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled

trial. American Journal of Clinical Nutrition 1997;66:413-8.


Sazawal S, Marwah D, Sazawal S, Black RE, Deb S, Dhingra U. Efficacy of zinc and iron fortification ofmilk in prevention of anemia, diarrhea pneumonia, and iron deficiency- a community based doublemasked randomized trial. Journal of Pediatric Gastroenterology and Nutrition 2004;39 Suppl 1:417-8.


Sazawal S, Dhingra U, Dhingra P, Hiremath G, Kumar J, Sarkar A. Effects of fortified milk on morbidityin young children in north India: community based randomised double masked placebo controlled trial.BMJ 2007;334:140-.

Sazawal 2007b { published data only}

Sazawal S, Dhingra U, Deb S, Bhan MK, Menon VP, Black RE. Effect of zinc added to multi-vitaminsupplementation containing low-dose vitamin A on plasma retinol level in children--a double-blindrandomized, controlled trial. Journal of Health, Population, and Nutrition 2007;25:62-6.

Sazawal 2007c { published data only}

Sazawal S, Black RE, Ramsan M, Chwaya HM, Dutta A, Dhingra U. Effect of zinc supplementation onmortality in children aged 1-48 months: a community-based randomised placebo-controlled trial. Lancet2007;369:927-34.

Shamir 200 5 { published data only}

Shamir R, Makhoul IR, Etzioni A, Shehadeh N. Evaluation of a diet containing probiotics and zinc for thetreatment of mild diarrheal illness in children younger than one year of age. Journal of the AmericanCollege of Nutrition 2005;24:370-5.

Shankar 199 8 { published data only}

Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance toinfection. American Journal Clinical Nutrition 1998;68 Suppl 2:447-63.

Sharieff 2006 { published data only}

Sharieff W, Bhutta Z, Schauer C, Tomlinson G, Zlotkin S. Micronutrients (including zinc) reduce

diarrhoea in children: the Pakistan Sprinkles Diarrhoea Study. Archives of Disease in Childhood2006;91:573-9.

Sur 200 3 { published data only}

Page 18 of 25



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Sur D, Gupta DN, Mondal SK, Ghosh S, Manna B, Rajendran K. Impact of zinc supplementation ondiarrheal morbidity and growth pattern of low birth weight infants in Kolkata, India: a randomized,double-blind, placebo-controlled, community-based study. Pediatrics 2003;112:1327-32.

Tielsch 20 06 { published data only}

Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R. Effect of routine prophylacticsupplementation with iron and folic acid on preschool child mortality in southern Nepal: community-

based, cluster-randomised, placebo-controlled trial. Lancet 2006;367:144-52.

Tielsch 20 07 { published data only}

Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R. Effect of daily zinc supplementationon child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial.Lancet 2007;370:1230-9.

U m et a 2000 { published data only}

Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. Zinc supplementation and stunted infants inEthiopia: a randomised controlled trial. Lancet 2000;355:2021-6.

Untoro 200 5 { published data only}

Untoro J, Karyadi E, Wibowo L, Erhardt MW, Gross R. Multiple micronutrient supplements improvemicronutrient status and anemia but not growth and morbidity of Indonesian infants: a randomized,double-blind, placebo-controlled trial. Journal of Nutrition 2005;135 Suppl:639-45.

Valery 200 5 { published data only}

Valery PC, Torzillo PJ, Boyce NC, White AV, Stewart PA, Wheaton GR. Zinc and vitamin Asupplementation in Australian Indigenous children with acute diarrhoea: a randomised controlled trial.Medical Journal of Australia 2005;182:530-5.

Walden 2004 { published data only}

Walden RJ. Supplementation with zinc and other minerals. American Journal of Clinical Nutrition2004;80:1084-.

Walker 2007 { published data only}

Walker CL, Bhutta ZA, Bhandari N, Teka T, Shahid F, Taneja S. Zinc during and in convalescence fromdiarrhea has no demonstrable effect on subsequent morbidity and anthropometric status among infants


20/25

Life Sciences 1981;28:1425-38.

Bhut ta 2000 b

Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A. Therapeutic effects of oral zinc inacute and persistent diarrhea in children in developing countries: pooled analysis of randomizedcontrolled trials. American Journal of Clinical Nutrition 2000;72:1516-22.

Bray 199 0

Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radical Biology & Medicine1990;8:281-91.

Brown 2003

Brown KH. Diarrhea and malnutrition. Journal of Nutrition 2003;133 Suppl:328-32.

Bryce 2 00 5

Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet2005;365:1147-52.

Dijkhuizen 200 1

Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal . Effects of iron and z inc supplementation inIndonesian infants on micronutrient status and growth. Journal of Nutrition 2001;131:2860-5.

Fischer Wa lker 200 5

Fischer Walker C, Kordas K, Stoltzfus RJ, Black RE. Interactive effects of iron and zinc on biochemicaland functional outcomes in supplementation trials. American Journal Clinical Nutrition 2005;82:5-12.

Fontaine 2001

Fontaine O. Effect of zinc supplementation on clinical course of acute diarrhoea. Journal of Health,Population, and Nutrition 2001;19:339-46.

Garenne 200 5

Garenne M, Becher H, Ye Y, Kouyate B, Muller O. Sex-specific responses to zinc supplementation inNouna, Burkina Faso. Journal of Pediatric Gastroenterology and Nutrition 2007;44:619-28.

Gunshin 199 7

Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF. Cloning and characterization ofa mammalian proton-coupled metal-ion transporter. Nature 1997;388:482-8.

Higgins 200 6

Higgins JPT, Green S. Highly sensitive search strategies for identifying reports of randomized controlledtrials in MEDLINE. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updatedSeptember 2006]; Appendix 5b. :-.

Hoque 200 5

Hoque KM, Rajendran VM, Binder HJ. Zinc inhibits cAMP-stimulated Cl secretion via basolateral K-channel blockade in rat ileum. American Journal of Physiology. Gastrointestinal and Liver Physiology2005;288:956-63.

I qba l 2001

Iqbal AS, Shahidullah M, Islam MN, Akhter S, Banu S. Serum zinc and copper levels in the maternalblood and cord blood of neonates. Indian Journal of Pediatrics 2001;68:523-6.

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Hotz C, Brown KH. Assessment of the risk of zinc deficiency in population and options for its control[Technical Document]. Food and Nutrition Bulletin 2004;25:94-204.

Jones 200 3

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Jni 2001

Jni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlledclinical trials. BMJ 2001;323:42-6.

Kordas 200 4

Kordas K, Stoltzfus RJ. New evidence of iron and zinc interplay at the enterocyte and neural tissues.Journal of Nutrition 2004;134:1295-8.

Kosek 2003

Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studiespublished between 1992 and 2000. Bulletin of the World Health Organization 2003;81:197-204.

Krebs 1999

Krebs NF. Zinc transfer to the breastfed infant. Journal of Mammary Gland Biology and Neoplasia1999;4:259-68.

Review Manager 4 .2

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Sazawal 1997b

Sazawal S, Jalla S, Mazumder S, Sinha A, Black RE, Bhan MK. Effect of zinc supplementation on cell-mediated immunity and lymphocyte subsets in preschool children. Indian Pediatrics 1997;34:589-97.

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Wagstaff A, Bustreo F, Bryce J, Claeson M. Child health: reaching the poor. American Journal of PublicHealth 2004;94:726-36.

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In: Clinical management of acute diarrhoea: WHO/UNICEF joint statement [WHO/FCH/CAH/04.7;

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Zlotkin S, Arthur P, Schauer C, Antwi KY, Yeung G, Piekarz A. Home-fortification with iron and zincsprinkles or iron sprinkles alone successfully treats anemia in infants and young children. Journal ofNutrition 2003;133:1075-80.

G R A P H S

Graphs and Tables

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To view a graph or table, cl ick on t he outcome ti t le of the summ ary table below.

Zinc vs placebo for acute diarrhoea

Outcome t it leNo. of

studiesNo. of

part icipantsStat ist ica l m ethod Effect size

1 Diarrhoea duration (h) 13 2741Mean Difference (IV, Random,95% CI)

-12.27 [-23.02, -1.52]

1.1 Age < 6 months 5 1334Mean Difference (IV, Random,95% CI)

5.23 [-2.00,14.45]

1.2 Age > 6 months 2 731Mean Difference (IV, Random,95% CI)

-16.67 [-31.03, -2.31]

1.3 Ages both < and > 6months

6 676Mean Difference (IV, Random,95% CI)

-22.41 [-35.08, -9.74]

2 Diarrhoea on day 3 3 1073Risk Ratio (M-H, Fixed, 95%CI)

0.69 [0.59, 0.81]

2.1 Age > 6 months 1 891Risk Ratio (M-H, Fixed, 95%CI)

0.75 [0.62, 0.92]

2.2 Ages both < and > 6

months2 182

Risk Ratio (M-H, Fixed, 95%

CI)0.55 [0.42, 0.72]


0.55 [0.32, 0.95]


2 346Risk Ratio (M-H, Fixed, 95%CI)

0.55 [0.32, 0.95]

4 Diarrhoea on day 7 10 4087Risk Ratio (M-H, Random, 95%CI)

0.71 [0.52, 0.98]

4.1 Age < 6 months 3 1074Risk Ratio (M-H, Random, 95%CI)

1.21 [0.91, 1.60]

4.2 Age > 6 months 4 2565Risk Ratio (M-H, Random, 95%CI)

0.70 [0.57, 0.85]

4.3 Ages both < and > 6months 3 448 Risk Ratio (M-H, Random, 95%CI) 0.33 [0.19, 0.57]

5 Stool frequency(stools /day)

7 1458Mean Difference (IV, Fixed,95% CI)

-0.02 [-0.19, 0.15]

5.1 Age < 6 months 5 1334Mean Difference (IV, Fixed,95% CI)

Not estimable

5.2 Age > 6 months 1 50Mean Difference (IV, Fixed,95% CI)

-1.70 [-4.00, 0.60]



-5.9 [-9.44, -2.36]

6 Adverse events(vomiting)

10 4727Risk Ratio (M-H, Random, 95%CI)

1.71 [1.27, 2.30]

6.1 Age < 6 months 3 1334 Risk Ratio (M-H, Random, 95%CI)

1.54 [1.05, 2.24]

6.2 Age > 6 months 3 1878Risk Ratio (M-H, Random, 95%CI)

1.72 [1.36, 2.17]


4 1515Risk Ratio (M-H, Random, 95%CI)

2.01 [1.06, 3.81]

Zinc vs placebo for me an acute diarrhoea durat ion: subgroup analysis excluding children < 6 m onths


studiesNo. of

part icipantsStat ist ica l m eth od Effect size

1 Diarrhoea duration (h) 8Mean Difference (IV,

Random, 95% CI)Subtotals only

1.1 Nutritional status: well-nourishedplus moderately malnourished

4 1071Mean Difference (IV,Random, 95% CI)

-17.49 [-29.25,-5.74]

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1.2 Nutritional status: malnourished 4 336Mean Difference (IV,Random, 95% CI)

-26.98 [-39.34,-14.62]

1.3 Sex: male 2 346Mean Difference (IV,Random, 95% CI)

-21.22 [-44.93,2.49]

1.4 Sex: male and female 6 1061Mean Difference (IV,Random, 95% CI)

-20.85 [-33.65,-8.06]

1.5 Region: Asia 7 1333 Mean Difference (IV,Random, 95% CI)

-19.51 [-31.43,-7.59]

1.6 Region: South America 1 74Mean Difference (IV,Random, 95% CI)

-31.20 [-46.43,-15.97]

1.7 Region: countries ranked as highrisk of zinc deficiency


-19.21 [-32.29,-6.14]

1.8 Region: countries ranked as mediumrisk of zinc deficiency


-24.34 [-47.88,-0.80]

1.9 Zinc dose: 20 mg 4 306Mean Difference (IV,Random, 95% CI)

-17.69 [-36.86,1.49]

1.10 Zinc dose: > 20 mg 2 154Mean Difference (IV,Random, 95% CI)

-32.74 [-38.57,-26.90]

1.11 Zinc type: zinc acetate 2 755Mean Difference (IV,Random, 95% CI)

-20.79 [-34.90,-6.68]

1.12 Zinc type: zinc sulfate 6 652Mean Difference (IV,Random, 95% CI)

-21.07 [-34.11,-8.03]

Zinc vs placebo for acute diarrhoea on da y 7: subgroup analysis excluding children < 6 months


studies

No. of

part icipantsSt at ist ica l m et hod Ef fe ct size

1 Diarrhoea on day 7 7Risk Ratio (M-H, Fixed,95% CI)

Subtotalsonly

1.1 Nutritional status: well nourished plus

moderately malnourished 4 2775

Risk Ratio (M-H, Fixed,

95% CI)

0.68 [0.55,

0.83]

1.2 Nutritional status: malnourished 3 238Risk Ratio (M-H, Fixed,95% CI)

0.37 [0.22,0.61]

1.3 Sex: male 1 266Risk Ratio (M-H, Fixed,95% CI)

0.11 [0.01,0.88]

1.4 Sex: male and female 6 2747Risk Ratio (M-H, Fixed,95% CI)

0.64 [0.53,0.77]

1.5 Region: countries ranked as high risk ofzinc deficiency

4 1940Risk Ratio (M-H, Fixed,95% CI)

0.70 [0.56,0.88]

1.6 Region: countries ranked as mediumrisk of zinc deficiency

3 1073Risk Ratio (M-H, Fixed,95% CI)

0.49 [0.35,0.68]

1.7 Zinc type: zinc acetate 3 1628 Risk Ratio (M-H, Fixed,95% CI) 0.60 [0.45,0.79]

1.8 Zinc type: zinc sulfate 4 1385Risk Ratio (M-H, Fixed,95% CI)

0.64 [0.50,0.83]

1.9 Study setting: hospital 6 2122Risk Ratio (M-H, Fixed,95% CI)

0.64 [0.52,0.78]

1.10 Study setting: community 1 891Risk Ratio (M-H, Fixed,95% CI)

0.58 [0.38,0.87]

Zinc vs placebo for persistent diarrhoea


studies

No. of

part icipantsStat ist ica l m et hod Effect size

1 Diarrhoea duration (h) 5 529Mean Difference (IV, Fixed,95% CI)

-15.84 [-25.43, -6.24]

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C O V E R S H E E T

1.1 Age > 6 months 4 388Mean Difference (IV, Fixed,95% CI)

-16.01 [-26.16, -5.86]



-14.40 [-43.77,14.97]

2 Diarrhoea on day 3 1Risk Ratio (M-H, Fixed, 95%CI)

Totals not selected

2.1 Age > 6 months 1 Risk Ratio (M-H, Fixed, 95%CI)

Not estimable

3 Diarrhoea on day 5 1Risk Ratio (M-H, Fixed, 95%CI)

Totals not selected

3.1 Age > 6 months 1Risk Ratio (M-H, Fixed, 95%CI)

Not estimable


0.52 [0.27, 1.02]


0.52 [0.27, 1.02]

5 Stool frequency(stools/day)

1Mean Difference (IV, Fixed,95% CI)

Totals not selected

5.1 Age > 6 months 1Mean Difference (IV, Fixed,95% CI)

Not estimable

6 Adverse events(vomiting)


1.97 [0.37, 10.59]


1.97 [0.37, 10.59]



Not estimable

Oral zinc for treating diarrhoea in children

Reviewer(s) Lazzerini Marzia, Ronfani Luca

Contribution of Reviewer( s)

I ssue protocol first published 2005 issue 3

I ssue review f irst published 2008 issue 3

Date of last minor am endment Information not supplied by reviewer

Date of last substantive amendm ent Information not supplied by reviewer

Most recent changes

Date new studies sought but none found Information not supplied by reviewer

Date new studies found but not yet included/ excluded Information not supplied by reviewer

Date new studies found and included/ excluded Information not supplied by reviewer

Date reviewe rs' conclusions section am ended Information not supplied by reviewer

Contact address LazzeriniVia dei Burlo 1,34123Via dei Burlo 1TriesteTrieste

ItalyItaly

34100

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S O U R C E S O F S U P P O R T

External sources of support

Department for International Development (DFID), UK.

Internal sources of support

No sources of support supplied

K E Y W O R D S

Child; Child, Preschool; Humans; Infant; Diarrhea[*drug therapy][mortality]; Randomized Controlled Trials asTopic; Time Factors; Zinc[deficiency][*therapeutic use]

H I S T O R Y

HistoryProtocol first published: Issue 3, 2005Review first published: Issue 3, 2008

Imprimir | Cerrar

Copyright: The Cochrane Library

Telephone:Facsimile:E-mail: [email protected]

Cochrane Library number CD005436

Editorial group Cochrane Infectious Diseases Group

Editorial group code HM-INFECTN

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Zinc Cochrane

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Transcript of Zinc Cochrane