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Oral zinc for treating diarrhoea in children

  1. Marzia Lazzerini1,*,
  2. Luca Ronfani2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 31 JAN 2013

Assessed as up-to-date: 20 FEB 2012

DOI: 10.1002/14651858.CD005436.pub4

How to Cite

Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD005436. DOI: 10.1002/14651858.CD005436.pub4.

Author Information

  1. 1

    WHO Collaborating Centre for Maternal and Child Health, Institute for Maternal and Child Health, Unit for Health Services Research and International Health, Trieste, Italy

  2. 2

    Institute for Maternal and Child Health, Unit of Epidemiology and Biostatistics, Trieste, Italy

*Marzia Lazzerini, Unit for Health Services Research and International Health, WHO Collaborating Centre for Maternal and Child Health, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, 8232, Italy. lazzerini@burlo.trieste.it.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 31 JAN 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison. Summary of findings table 1

Zinc compared to placebo for children aged > 6 months with acute diarrhoea

Patient or population: children with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placeboZinc

Death---864
(2 studies)
⊕⊝⊝⊝
very low1,2

Hospitalization---891
(1 study)
⊕⊝⊝⊝
very low3,4

Duration of diarrhoea

 
all trials

The mean duration of diarrhoea ranged from 41 to 170 hoursZinc reduced the mean duration of diarrhoea by 10.44 hours
(21.13 hours shorter to 0.25 hours longer)
 2175
(6 studies)
⊕⊕⊝⊝
low5,6

trials limited to children with signs of moderate malnutrition

The mean duration of diarrhoea ranged from 103 to 147 hoursZinc reduced the mean duration of diarrhoea by 26.98 hours
(39.34 to 14.62 hours shorter)
 336
(3 studies)
⊕⊕⊕⊕

high7,8

Diarrhoea on day 7128 per 100093 per 1000
(78 to 113)
RR 0.73
(0.61 to 0.88)
3865
(6 studies)
⊕⊕⊕⊝

moderate9

Adverse events (vomiting)131 per 1000204 per 1000
(173 to 242)
RR 1.56
(1.32 to 1.85)
2340
(5 studies)
⊕⊕⊕⊕

high8

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for indirectness: Only two trials specifically stated that deaths occurred; one was conducted in hospital and so likely to underestimate death, and the effect of zinc if given at community level.
2 Downgraded by 2 for imprecision: Only three deaths occurred in these two studies, consequently the trials are significantly underpowered to detect or exclude an effect.
3 Downgraded by 1 for indirectness: Only one community based trial reports on hospitalisation rates. No statistically significant effect was seen but this result is not easily generalised to other settings.
4 Downgraded by 2 for imprecision: The trials reports that no statistically significant difference in hospitalisation was seen but did not present the data.
5 Downgraded by 1 for indirectness: The majority of data is from Asia. In the single trial from Africa (Nigeria) no effect was seen. The data may therefore be poorly generalised globally.
6 Downgraded by 1 for inconsistency: There remains moderate unexplained heterogeneity between trials. Some trials show a statistically significant benefit and some do not.
7 The effect of zinc appears to be largest in malnourished children, and with no effect seen in the one trial which only included well nourished children. The three trials were conducted in India, Bangladesh, and Turkey but it seems likely that this effect is still present in malnourished children elsewhere.
8 There was no reason to downgrade for risk of bias, inconsistency, indirectness or imprecision.
9 Downgraded by 1 for indirectness: These trials were all conducted in Asia in countries at high risk of zinc deficiency.

 Summary of findings 2 Summary of findings table 2

 Summary of findings 3 Summary of findings table 3

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Problem

Despite improving trends in mortality rates, diarrhoea still causes 15% of all deaths in children under five years and accounts for nearly 1.4 million child deaths in developing countries every year (Black 2010). It is estimated that on average a child under five years will have approximately 3.2 episodes of diarrhoea each year (Kosek 2003). Diarrhoea is also an important cause of malnutrition, particularly when it is prolonged (Brown 2003).

Treatment of diarrhoea with oral rehydration solution (ORS) reduces mortality due to dehydration. Zinc supplementation could help reduce the duration and the severity of diarrhoea, and therefore have an additional benefit over ORS in reducing children mortality (Bhutta 2008).

 

Biological functions

There are several different mechanism of action of zinc on acute diarrhoea (Berni Canani 2010). Zinc influences the activity of over 300 enzymes, some of which are responsible for DNA replication and transcription (IZiNCG 2004). Zinc promotes immunity, skin and mucosal resistance to infection, growth, and development of the nervous system (Hess 2009, MacDonald 2000, Prasad 2008). It is also an important anti-oxidant and preserves cellular membrane integrity (O' Dell 2000, Powell 2000). At the level of gastrointestinal system, zinc restores mucosal barrier integrity and enterocyte brush-border enzyme activity (Roy 1992; Shankar 1998), it promotes the production of antibodies and circulating lymphocytes against intestinal pathogens (Sazawal 1997b; Albert 2003; Raqib 2004), and has a direct effect on ion channels, acting as a potassium channel blocker of adenosine 3-5-cyclic monophosphate-mediated chlorine secretion (Hoque 2009, Hoque 2005).

 

Rationale for supplementation

Zinc deficiency is mainly due to inadequate dietary intake and is estimated to be common in many countries (IZiNCG 2004; Wagstaff 2004; Hess 2009). High levels of zinc are found in 'expensive foods' (eg meat and fish). Zinc is also present in nuts, seeds, legumes, and whole grain cereal, but the high phytate content of these foods interferes with its absorption. Zinc cannot be stored in the body, and nearly 50% of zinc excretion takes place through the gastrointestinal tract and is increased during episodes of diarrhoea. Young children who are regularly exposed to gastrointestinal pathogens and have diets low in animal products and high in phytate-rich foods are most at risk.

 

Factors that could influence the effects of supplementation

There are a number of factors that could influence the size of any effect when using zinc to treat diarrhoea, and these will be explored in this review.

 

Type of diarrhoea

Acute and persistent diarrhoea are very different conditions. Acute diarrhoea in children in developing countries is usually infectious, while persistent diarrhoea has a number of causes including malnutrition, parasitic infections, tuberculosis, human immunodeficiency virus (HIV), food intolerance, and malabsorption.

 

Age

Zinc requirement varies with age and is highest in children due to their rapid rates of growth. Infants, however, have lower requirements (IZiNCG 2004) as healthy normal birthweight infants have adequate zinc levels at birth from maternal sources even if maternal stores are sub optimal (Iqbal 2001). Infants may be able to mobilize hepatic stores accumulated during gestation (Zlotkin 1988) and are less likely to have had a zinc-depleting illness. Breastfeeding will provide zinc supplementation and protective immune factors against infections (Krebs 1999).

 

Nutritional status

The recommended daily allowance for zinc is markedly higher for malnourished children (2 to 4 mg/kg/day) than healthy children (3 to 5 mg/day for children under five years) (IZiNCG 2004). This is because zinc deficiency is considered more severe in malnourished children and thus the benefit of zinc supplementation may be greater.

 

Geographical region

Zinc supplementation may have different effects according to the level of zinc deficiency in the country. It is important to verify whether zinc supplementation is effective in countries with high, or even medium or low risk of zinc deficiency (IZiNCG 2004).

 

Zinc dose

The World Health Organization (WHO) and United Nations Children's Fund (UNICEF) recommend 10 to 20 mg of zinc per day for children with diarrhoea, at least twice the recommended daily allowance (WHO/UNICEF 2004).

 

Types of zinc salt

Zinc is usually given as zinc sulphate, zinc acetate, or zinc gluconate, which are all water-soluble compounds (IZiNCG 2004).

 

Concomitant iron or copper supplementation

Iron and zinc deficiencies often co-exist. These two compounds may compete for the same absorptive pathways, and iron may interfere with zinc utilization (Gunshin 1997; Kordas 2004). A review of combined supplementation showed that giving zinc with iron resulted in a lower increase in iron levels compared to giving iron alone; iron supplementation alone had no effect on zinc status (Fischer Walker 2005). A trial that assessed combined supplementation on diarrhoea and malaria morbidity showed that zinc combined with iron reduced zinc's protective effect against diarrhoea (Richard 2006). Several trials have also reported a negative interaction of the combined supplementation on physical growth and development (Rosado 1997; Dijkhuizen 2001; Zlotkin 2003; Lind 2004; Bhandari 2007). Some protocols suggest supplementing malnourished children also with copper because these children are also prone to copper deficiency (Beshgetoor 1998).

 

Setting

Zinc effect may vary according to the study setting (hospital or community), due to differences in adherence rates, and other factors such as diet.

 

Adverse effects

Zinc can cause vomiting because of its metallic taste (Fontaine 2001). In high doses, zinc can also cause epigastric pain, lethargy, and fatigue (IZiNCG 2004). One small study suggested a possible increase in mortality in malnourished children supplemented with 6 mg/kg/day of zinc compared to those supplemented with 1.5 mg/kg/day (Doherty 1998). Copper deficiency with zinc supplementation can occur although usually only when zinc is consumed in very high doses (100 to 300 mg/day for adults) over a long period of time (IZiNCG 2004), and malnourished children are at particularly high risk of this due to lower basal copper levels.

 

Previous systematic reviews

Previous meta-analysis indicated that zinc supplementation in diarrhoea is effective (Bhutta 2000b;Lukacik 2008 ;Patro 2008; Haider 2009). This Cochrane Review will have an up-to-date search for trials and will explore more outcome measures of interest and more possible sources of heterogeneity.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

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 conditions such 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 as diarrhoea lasting more than 14 days. Dysentery is a diarrhoeal illness in which blood is observed in the stool. The final day of diarrhoea is usually defined as the last day meeting the above definition followed by 48 hours without diarrhoea.

 

Types of interventions

 

Intervention

Oral zinc supplementation of any zinc salt at doses of 5 mg/day or more for any duration.

 

Control

Placebo.

Concurrent supplementation of other minerals and vitamins are eligible only if administered to both intervention and control group.

ORS plus zinc and food fortification interventions (such as milk fortification) are excluded as the amount of ORS/food consumed, and hence the zinc intake, would be less certain.

 

Types of outcome measures

 

Primary

 
Measures of diarrhoea duration

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

 
Measures of diarrhoea severity

  • Stool frequency.
  • Stool output.

 

Secondary

  • Hospitalization.
  • Death (from any cause and diarrhoea specific).

 

Adverse events

  • 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.

 

Search methods for identification of studies

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

 

Databases of published trials

We searched the following databases using the search terms and strategy described in  Table 1: Cochrane Infectious Diseases Group Specialized Register (20 February 2012); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2012, Issue 2); MEDLINE (1966 to February 2012); EMBASE (1974 to February 2012); LILACS (1982 to 20 February 2012); CINAHL (1982 to 20 February 2012), the metaRegister of Current Controlled Trials (mRCT; February 2012), ClinicalTrials.gov (February 2012), and the WHO International Clinical Trials Registry Platform (ICTRP) (February 2012).

 

Researchers and organizations

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

 

Reference lists

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

 

Data collection and analysis

 

Selection of studies

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 for clarification if necessary, and any disagreements were resolved through discussion and consensus after referring to the protocol; their solutions were recorded and reported.

 

Data extraction and management

Both authors independently extracted data using a pilot-tested data extraction form and entered the data into Review Manager 5. When data were missing or unclear, we contacted the trial authors for clarification. For dichotomous outcomes, 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 were extracted. If continuous data were reported using geometric means, the standard deviations on the log scale were extracted; medians and ranges were extracted and reported in a table.

 

Assessment of risk of bias in included studies

Both authors independently assessed the risk of bias for each trial using the 'The Cochrane Collaboration's tool for assessing the risk of bias' (Higgins 2008). We have categorized our judgments as low risk of bias, high risk of bias, or unclear risk of bias, and this information has been used to guide the interpretation of the results. Where our judgement for efficacy trials was unclear we attempted to contact the trial authors for clarification and any differences of opinion were resolved through discussion. If data were missing or unclear, we contacted the trial authors.

 

Data synthesis

Data were analysed using Review Manager 5. 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 event rates, we did not calculate the number needed to treat (NNT). For continuous data summarized by arithmetic means and standard deviations, we used the mean difference (MD) to combine the results in a meta-analysis. Continuous data summarized using other summary statistics that could not be combined in a meta-analysis were presented in a table. We calculated geometric mean ratios and transformed them in the log scale for analysis, and presented them on the natural scale.

 

Assessment of evidence quality

The quality of evidence has been assessed using the GRADE methodology (GRADE 2008). The GRADE system considers ‘quality’ to be a judgment of the extent to which we can be confident that the estimates of effect are correct. The level of ‘quality’ is judged on a 4-point scale. Evidence from randomized controlled studies is initially graded as high and downgraded by one, two or three levels after full consideration of: any limitations in the design of the studies, the directness (or applicability) of the evidence, the consistency and precision of the results, and the possibility of publication bias.

The estimates of effect, and the GRADE assessments of our confidence in these estimates are displayed in 'summary of findings tables' for the main comparisons. Where we have downgraded the evidence our reasons for doing so are displayed in footnotes.

When making conclusions about the relative effects of the interventions we have used language which reflects the GRADE assessments and our confidence in the estimates, ie if the evidence is high quality we would say "zinc reduces..."; moderate quality "zinc probably reduces..."; low quality "zinc may reduce..."; and where the evidence is very low quality we have not drawn conclusions.

 

Subgroup analysis and investigation of heterogeneity

We assessed heterogeneity among trials by visually inspecting the forest plot, using the Chi2 test for heterogeneity with a 5% level of statistical significance, and the I2 statistic with a value of 50% representing a moderate level of heterogeneity. If we detected significant heterogeneity but felt it was appropriate to pool data, we used the random-effects model.

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

 

Sensitivity analysis

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 of randomized participants in the analysis (excluded those trials classified as inadequate or unclear). To take into account the participants for whom no outcome data were obtained we also conducted an intention-to-treat analysis for worst-case/best-case scenarios.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

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

Twenty-four trials enrolling 9128 children met our inclusion criteria (see 'Characteristics of included studies'). The process of trials selection is reported in  Table 2, and the reasons for excluding 127 studies are given in the 'Characteristics of excluded studies'.

Three of the included trials presented results divided in two or more subgroups: one trial presented two intervention groups of zinc 20 mg and zinc 5 mg, and one control group (Brooks 2005a); one trial presented data for three different study sites (Fischer Walker 2006); and one trial presented the results as children with low and normal zinc serum levels (Polat 2003). For these three trials there was no way to combine means and standard deviations, and thus 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 of total comparisons is 26.

 

Type of diarrhoea

Nineteen trials enrolled children with acute diarrhoea: 11 used this review's definition for acute diarrhoea (Faruque 1999; Dutta 2000; Strand 2002; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Brooks 2005a; Fischer Walker 2006; Dutta 2011); two trials respectively defined diarrhoea as presence of four (Sazawal 1995) or five (Bahl 2002) unformed stools in 24 hours; one shigellosis trial included patients with bloody mucoid diarrhoea (dysentery) or febrile diarrhoea less than five-days' duration (Roy 2008); one trial enrolled only children with diarrhoea and/or vomiting due to rotavirus infection (Dalgic 2011) and three trials did not report the definition of acute diarrhoea (Sachdev 1988; Roy 1997; Larson 2005). Five trials were on children with persistent diarrhoea (Sachdev 1990; Roy 1998; Bhutta 1999b; Penny 1999; Khatun 2001).

 

Age

Two trials enrolled only children under six months (Brooks 2005a; Fischer Walker 2006). Thirteen trials only enrolled children over six months (Sachdev 1988; Sachdev 1990; Sazawal 1995; Bhutta 1999b; Faruque 1999; Penny 1999; Khatun 2001; Bahl 2002; Strand 2002; Roy 2008; Fajolu 2008; Patel 2009; Dutta 2011). Eight trials included children of different ages greater than one months (Roy 1997; Roy 1998; Dutta 2000; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Larson 2005; Patro 2010; Dalgic 2011).

 

Nutritional status

Seven trials enrolled only malnourished children (Roy 1997; Roy 1998; Bhutta 1999b; Dutta 2000; Khatun 2001; Polat 2003; Roy 2008). One trial included only well-nourished children (Patro 2010), and one enrolled children regardless of nutritional status (Larson 2005). The remaining 14 trials enrolled children who were well nourished or with mild or moderate malnutrition. No trial included only severe malnourished children. There was some variability between trials in the definitions of malnutrition (most used 'weight/age'; only some used 'weight/height'); therefore we were unable to follow the definition of malnutrition proposed in the protocol.

 

Sex

Twenty trials enrolled children of both sexes, while four trials included only males (Dutta 2000; Bhatnagar 2004a; Brooks 2005a; Dutta 2011).

 

Geographical region

Nineteen trials were conducted in Asia, two in South America, one in Europe (Patro 2010), one in Africa (Fajolu 2008), and one multicenter trial in Asia and Africa (Fischer Walker 2006) Thus, participants were from Bangladesh (Roy 1997; Roy 1998; Faruque 1999; Khatun 2001; Brooks 2005a; Larson 2005; Roy 2008), India (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta 2000; Bahl 2002; Bhatnagar 2004a; Fischer Walker 2006 IND, Patel 2009), Pakistan (Bhutta 1999b; Fischer Walker 2006 PAK), Nepal (Strand 2002), Turkey (Polat 2003), Brazil (Al-Sonboli 2003), Peru (Penny 1999), Ethiopia (Fischer Walker 2006 ETH), Nigeria (Fajolu 2008) and Poland (Patro 2010).

 

Risk of zinc deficiency

All the trials were conducted in countries ranked as high risk for zinc deficiency (IZiNCG 2004), except for five trials conducted in countries at medium risk: Nepal (Strand 2002);Turkey (Polat 2003; Dalgic 2011); Brazil (Al-Sonboli 2003), and Nigeria (Fajolu 2008), and one recent trial from Poland, where zinc deficiency is considered rare (Patro 2010).

 

Zinc dose

The zinc dose was 20 mg/day in eleven 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 zinc 10 mg/day (Fischer Walker 2006; Roy 2008), and another two trials used 10 mg for infants and 20 mg for children over six months (Fajolu 2008, Patro 2010). One trial used zinc 5 mg and 20 mg, but only in children aged less than six months (Brooks 2005a).

Four trials used different doses depending on age (zinc < 20 mg in infants and ≥ 20 mg in older children), but they did not report results separately for each treatment group (Faruque 1999; Bahl 2002; Strand 2002; Bhatnagar 2004a). We classified these trials as 'not assignable' and could not include them in the sensitivity analysis for zinc dose. Two trials reported a per kilo dose (2 mg/kg/day; 3 mg/kg/day;) (Bhutta 1999b, Patel 2009), and we were not able to include it in the subgroup analyses.

 

Type of zinc salt

Twelve trials used zinc sulphate, eight trials used zinc acetate (Roy 1997; Roy 1998; Faruque 1999, Khatun 2001; Strand 2002; Brooks 2005a; Roy 2008; Dalgic 2011), three used zinc gluconate (Sazawal 1995; Penny 1999; Bahl 2002), and one did not specify (Dutta 2011).

 

Concomitant copper or iron supplementation

One trial compared zinc alone versus zinc and copper versus placebo (Patel 2009).

 

Study setting

Most trials were conducted in hospitals, with the exception of four community-based studies (Penny 1999; Bahl 2002; Strand 2002; Fischer Walker 2006), and one trial held both in hospital and community (Larson 2005).

 

Treatment regimen

 

Duration of treatment

Eleven trials administered zinc for two weeks. Of the remaining 12 trials, three gave zinc for seven days after recovery (Bahl 2002; Strand 2002; Polat 2003), two gave zinc until recovery (Al-Sonboli 2003; Brooks 2005a), one gave zinc for seven days (Khatun 2001), and one gave zinc for 10 days (Patro 2010). Five trials were unclear in respect of duration of zinc supplementation (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta 2000; Dalgic 2011). One trial on adverse events administered only one dose of zinc (Larson 2005).

 

Formulation

Zinc was administered as syrup in most trials; only four used powder (Sachdev 1988; Sachdev 1990; Penny 1999; Dalgic 2011), three used dispersible tablets (Al-Sonboli 2003; Larson 2005; Fischer Walker 2006), and one did not specify (Fajolu 2008).

 

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 2008; Patro 2010) or three times a day (Roy 1997; Roy 1998; Dutta 2000; Polat 2003; Bhatnagar 2004a). One study administered zinc twice a day to infants, and a single dose to children over six months (Dalgic 2011). Two studies did not specify (Fajolu 2008; Patel 2009).

 

Additional treatments

Twelve trials administered zinc alone; seven studies used zinc and multivitamin, which did not contain iron (Sazawal 1995; Roy 1997; Roy 1998; Bhutta 1999b; Khatun 2001; Bhatnagar 2004a; Roy 2008). One trial used zinc and vitamin A (Faruque 1999). One trial used concomitant copper (Patel 2009).

 

Outcomes

Twenty trials reported data on diarrhoea duration (Sachdev 1988; Sachdev 1990; Roy 1997; Roy 1998; Bhutta 1999b; Faruque 1999; Penny 1999; Dutta 2000; Khatun 2001; Bahl 2002; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Brooks 2005a; Fischer Walker 2006; Fajolu 2008; Patel 2009; Patro 2010; Dalgic 2011; Dutta 2011). Data were presented as means and standard deviations, or means and 95% CI. One trial reported data as medians and ranges (Roy 2008), and we could not compare these to the data from other trials.

Five trials reported on diarrhoea at day three (Penny 1999; Bahl 2002; Strand 2002; Polat 2003; Patel 2009), six trials on diarrhoea at day five (Penny 1999; Dutta 2000; Bahl 2002; Bhatnagar 2004a; Patel 2009; Dutta 2011), and 12 at day seven (Sazawal 1995; Faruque 1999; Penny 1999; Khatun 2001; Bahl 2002; Strand 2002; Polat 2003; Bhatnagar 2004a; Fischer Walker 2006; Roy 2008; Patel 2009; Patro 2010)

Stool frequency was reported in seven trials (Sachdev 1988; Sachdev 1990; Bahl 2002; Al-Sonboli 2003; Brooks 2005a; Fischer Walker 2006; Fajolu 2008). Three trials did not report cumulative data for the whole hospitalization period (Bhutta 1999b; Polat 2003; Patro 2010); instead they reported data on some given days (as number of stool on day two or four or other days), and these data could not be compared to the data from other trials.

Eight trials reported data on stool output (Roy 1997; Bhutta 1999b; Dutta 2000; Khatun 2001; Bhatnagar 2004a; Brooks 2005a; Patel 2009; Dutta 2011). Definitions and measurement units varied consistently between trials (see  Table 3). Stool output was evaluated using pre-weighed disposable diapers with urine collected separately in three trials (Dutta 2000; Bhatnagar 2004a; Dutta 2011) and using pre-weighed containers with urine collected separately in one trial (Roy 1997). In one trial, stool weight was measured by using metabolic beds, and urine was collected separately using urine bags. The methods were not clearly stated in two trials (Bhutta 1999b; Khatun 2001).

One hospital trial (Dalgic 2011) and three community trials reported information on hospitalization (Penny 1999; Strand 2002; Fischer Walker 2006). The declared follow-up period for these trials was at least "until recovery from diarrhoea" in three trials (Strand 2002; Fischer Walker 2006; Dalgic 2011), and 15 days in another trial (Penny 1999).

Death was reported in seven trials. These trials had as follow-up times the duration of hospital stay (Roy 1998; Khatun 2001; Brooks 2005a), two weeks (Penny 1999, Patel 2009), until the diarrhoea episode was over (Fischer Walker 2006), and six months (Roy 2008).

Data on vomiting, as percentage of children who vomited, were available in 13 trials. Only one trial stated the case definition, with vomiting defined as a forceful emptying of stomach contents, and regurgitation as the unforced return of any amount of the swallowed syrup, liquids, or foods (Larson 2005). One trial on diarrhoea due to rotavirus reported the duration of vomiting (Dalgic 2011).

Four trials reported on copper plasma levels (Bhutta 1999b; Strand 2002; Bhatnagar 2004a;Patel 2009 ), but the data were not comparable because they used different units of measurement

 

Risk of bias in included studies

See Figure 1 and Figure 2 for the risk of bias in included studies.

 FigureFigure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Generation of allocation sequence

Twenty trials used adequate methods to generate the allocation sequence. The methods used in the other four trials were unclear (Sachdev 1988; Sachdev 1990; Khatun 2001; Fajolu 2008).

 

Allocation concealment

Sixteen trials reported methods that assured adequate allocation concealment. The remaining eight were unclear (Sachdev 1988; Sachdev 1990; Roy 1998; Khatun 2001; Al-Sonboli 2003; Brooks 2005a; Fajolu 2008; Dalgic 2011).

 

Blinding

Nineteen trials were double blinded. The use of blinding was unclear in the remaining five (Sachdev 1988; Sachdev 1990; Khatun 2001; Fajolu 2008; Dalgic 2011).

 

Inclusion of all randomized participants

Fifteen trials included more than 90% of the randomized participants in the analysis. Four included less than 90%, which we assessed as inadequate (Roy 1997; Bhutta 1999b; Roy 2008; Patro 2010), and the number included was unclear in the remaining five trials (Sachdev 1988; Sachdev 1990; Roy 1998; Dutta 2000; Fajolu 2008).

 

Effects of interventions

See:  Summary of findings for the main comparison Summary of findings table 1;  Summary of findings 2 Summary of findings table 2;  Summary of findings 3 Summary of findings table 3

 

1. In children with acute diarrhoea

 

1.1. Diarrhoea duration

Overall, diarrhoea duration was reduced in children given zinc by about 12 hours (mean difference -12.63, 95% CI -21.05 to -4.21 hours, 4446 children, 15 trials, 19 comparisons, Figure 3), but there was significant heterogeneity between trials (I2 = 87%). Stratification by age reduced this statistical heterogeneity and revealed that no benefit was evident in children under six months (1334 children, two trials, Figure 3). The pooled point estimate suggests a benefit with zinc for children > six months although this was not statistically significant and moderate heterogeneity remained (MD -10.44.h, 95% CI -21.13 to 0.25 hours; 2175 children, six trials, Figure 3). In studies enrolling both age-groups a statistically significant benefit is seen (MD -22.53 hours, 95% CI -34.77 to -10.293 hours; 937 children, seven trials, Figure 3) but again with severe heterogeneity. The causes of this statistical heterogeneity are further explored in paragraph 1.8.

 FigureFigure 3. Zinc vs placebo for acute diarrhoea: diarrhoea duration (h)

 

1.2. Diarrhoea on days three, five, and seven

Treatment with zinc resulted in fewer children continuing to have diarrhoea at day three (RR 0.77, 95% CI 0.67 to 0.89; 1568 children, three trials, four comparisons, Figure 4), at day five (RR 0.67, 95% CI 0.51 to 0.89;1730 children, five trials, four comparisons, Figure 5) and at day seven (RR 0.82, 95% CI 0.72 to 0.94; 5528 children, 10 trials, 13 comparisons, Figure 6). For all the three outcomes there was overall significant heterogeneity between trials. For diarrhoea at day three and five there were few trials, and it was difficult to explore heterogeneity. For diarrhoea at day seven heterogeneity was markedly reduced if results were stratified by age. No benefit of zinc was detected in children under six months (1074 children, three comparisons, Figure 6), while zinc had a benefit in children older than six months (RR 0.73, 95% CI 0.61 to 0.8; 3865 children, six trials, Figure 6) and in trials recruiting both age groups (RR 0.31, 95% CI 0.18 to 0.52; 589 children, three trials, four comparisons, Figure 6).

 FigureFigure 4. Zinc vs placebo for acute diarrhoea: diarrhoea on day 3
 FigureFigure 5. Zinc vs placebo for acute diarrhoea: diarrhoea on day 5
 FigureFigure 6. Zinc vs placebo for acute diarrhoea: diarrhoea on day 7

 

1.3. Stool frequency

There was no evidence of a benefit of zinc on stool frequency overall (2323 children, six trials,  Analysis 1.5). Stratification by age reduced heterogeneity, and zinc was only shown to have a statistically significant benefit in the single trial which recruited both age groups (MD -5.90 stool/day, 95% CI -9.44 to -2.36, 74 children, one study,  Analysis 1.5).

 

1.4. Stool output

Stool output was measured using different units at different time points, thus results could not be pooled together ( Table 3). 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). Two trials reported on children aged more than six months with inconsistent results (Patel 2009, Dutta 2011). Three trials reported on children aged less than and greater than six months: two of these studies showed a reduction in stool output with zinc (Dutta 2000; Bhatnagar 2004a), while one showed no evidence of an effect (Roy 1997).

 

1.5. Hospitalization

One hospital trial showed a significant reduction in the duration of hospitalization in children treated with zinc compared to those given placebo (MD 4.33 days ± 1.38 vs 5.81 ± 2.08 days). Of the two community trials reporting on hospitalization, one found no difference between groups (Strand 2002, 891 participants), and the second reported no hospitalizations in the zinc group and only one in the placebo group (Fischer Walker 2006, 1074 participants under 6 months of age).

 

1.6. Death

Four trials specified the numbers of child deaths: two studies (316 children) did not observe any deaths (Brooks 2005a; Roy 2008); one trial (1032 children) reported one death in each treatment group (Fischer Walker 2006), and one trial (754 children) reported one death in the zinc group, no death in the zinc plus copper group, and two deaths in the placebo group (Patel 2009a (zinc)).

 

1.7. Adverse events

Eight trials reported vomiting, which was significantly more common in those given zinc across all age groups (RR 1.59, 95% CI 1.27 to 1.99 REM; 5189 children, 10 trials, 12 comparisons, Figure 7). There was significant heterogeneity among trials (P = 0.001, I2 = 69.3%), and differences in control event rates.

 FigureFigure 7. Zinc vs placebo for acute diarrhoea: Adverse events (vomiting)

One single trial on gastroenteritis due to rotavirus found no difference in time to resolution of vomiting between zinc and placebo (13.63 ± 10.33 hours vs 16.35 ± 11.34 hours, P = 0.1; Dalgic 2011)

Three trials reported on copper levels, with no significant differences between the zinc and placebo groups. Two studies reported the mean change in serum copper on the last day of supplementation (seven and 14 days after recovery): -1.1 ± 5.5 µmol/dL in the zinc group versus -1.5 ± 4.2 µmol/dL in the placebo group in one trial (Strand 2002), and -41.2 ± 418.8 µg/dL in the zinc group versus -79.4 ± 429.2 µg/dL in the placebo group in the second trial (Patel 2009). Mean serum copper after 14 days was 121 mg/L in zinc group versus 127 mg/L in the control in one trial (Bhatnagar 2004a),

 

1.8. Statistical heterogeneity

In the trials in children under six months no significant heterogeneity was detected in any outcome (Figure 3, Figure 6, Figure 7). One multicenter study further subgrouped by sex, breastfeeding practices, length for age, and age (under or above three months), and no significant differences were detected (Fischer Walker 2006).

We explored heterogeneity in the two groups of children > six months and children of all ages for the two outcomes mean diarrhoea duration and diarrhoea at day seven for which there were enough trials (Figure 8 and Figure 9). Each subgroup presented significant heterogeneity, and this indicates that no single feature could explain overall heterogeneity alone. In all the subgroups a significant effect of zinc over placebo was observed, with a few exceptions: 1) one trial in well-nourished children held in Poland, where there is a low risk of zinc deficiency, did not show any benefit of zinc (Patro 2010, 141 children, Figure 8, Figure 9); 2) one single study on zinc gluconate did not show a significant advantage for zinc over placebo (Bahl 2002, 805 children, Figure 8, Figure 9 ); 3) one recent factorial study (Patel 2009) reporting on zinc plus copper in India did not observe a benefit for the association of the two micronutrients but also for zinc alone (Figure 8 Figure 9).

 FigureFigure 8. Forest plot of comparison: 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months, outcome: 2.1 Diarrhoea duration (h).
 FigureFigure 9. Forest plot of comparison: 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months, outcome: 3.1 Diarrhoea on day 7.

We were unable to construct funnel plots to look for evidence of publication bias as none of the outcomes had sufficient numbers of trials to do this.

 

1.9. Sensitivity analysis

The sensitivity analysis against markers of methodological quality did not affect the direction of results. There was some 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 did not altered the statistical significance of the results.

 

2. In children with persistent diarrhoea

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

 

2.1. Diarrhoea duration

Zinc supplementation reduced the duration of persistent diarrhoea (MD -15.83 hours, 95% -25.43 to -6.24 hours; 529 children, five trials, Figure 10), with no evidence of heterogeneity.

 FigureFigure 10. Zinc vs placebo for persistent diarrhoea: diarrhoea duration (h)

 

2.2. Diarrhoea on days three, five, 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) (Penny 1999; 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 ( Table 3). Results are expressed as the arithmetic mean difference (AMD) or geometric mean ratio (GMR). Two trials reported on children aged greater than six months, with five comparisons, and only one (Khatun 2001) reported a significant reduction 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 in each 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

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/day for 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 µg/dL versus 72.7 ± 18.3 µg/dL, P = 0.02; Bhutta 1999b, 87 children).

 

2.8. Statistical heterogeneity

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

 

2.9. Sensitivity analysis

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-case scenarios did not alter the point estimate or the significance of results.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

We identified 24 randomized controlled trials that compared zinc with placebo in young children. Nineteen trials evaluated acute diarrhoea and the other five evaluated persistent diarrhoea. Overall, zinc was effective for acute and persistent diarrhoea in children aged over six months ( Summary of findings for the main comparison,  Summary of findings 2). Two large trials were conducted in children aged less than six months with acute diarrhoea, and they showed no evidence of an effect on any of the outcomes ( Summary of findings 3).

Zinc reduced the duration of acute diarrhoea. The size of the effect was clinically important particularly for diarrhoea at day seven, 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, with the exception of well-nourished children in country with low risk of zinc deficiency. Evidence on diarrhoea severity 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 of persistent diarrhoea.

No firm conclusions regarding zinc's impact on hospitalization or death can be drawn from this review as trials were not designed to look at these outcomes, and most were conducted in hospital where death rates were low. Large community 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 duration seems to outweigh this. This increase was consistent across trials in all age groups, including one large trial with adequate allocation concealment that was designed to look at safety. However, the trial reported that vomiting was limited to one episode in 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 copper deficiency resulting from zinc supplementation in the regimens used.

In general, the methodological quality of the trials included in this review was good. Most trials were conducted in countries with moderate to high risk of zinc deficiency, with the only study held in a country with a low risk of zinc deficiency showing no effect of zinc over placebo.

Applicability of these results to countries is likely to depend on local zinc deficiency and other population characteristics, such as the degree of malnutrition. Nearly all trials were conducted in hospital where participants were likely to adhere to the intervention, although one large community trial also showed a benefit with zinc.

Our results agree with those of other systematic reviews of zinc for treating diarrhoea (Bhutta 2000b, Lukacik 2008, Patro 2008, Haider 2009), except for the new finding of no effect of zinc in children aged less than six months. This review adds several new trials, includes a more extensive subgroup analysis, and reports on diarrhoea at different time points, diarrhoea severity, and adverse events.

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

 

Summary of main results

Twenty-four trials, enrolling 9128 children, met our inclusion criteria. The majority of the data is from Asia, from countries at high risk of zinc deficiency, and may not be applicable elsewhere.

 

Acute diarrhoea

There is currently not enough evidence from well conducted randomized controlled trials to be able to say whether zinc supplementation during acute diarrhoea reduces death or hospitalization (very low quality evidence).

In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (high quality evidence).

Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no impact (low quality evidence), or even increase the proportion of children whose diarrhoea persists until day seven (moderate quality evidence).

No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (high quality evidence).

 

Persistent diarrhoea

In children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (moderate quality evidence),

 

Overall completeness and applicability of evidence

Most trials were conducted in hospital where death rates were low, and were consequently not powered to detect an effect on mortality. Large community trials are needed to explore whether zinc treatment for diarrhoea reduces hospitalization and death.

Most trials were conducted in Asian countries with moderate to high risk of zinc deficiency and high rates of mild and moderate malnutrition. The two studies available from Africa have shown no benefits of zinc over placebo, but this may be affected by other characteristics of the population or of the study (one study enrolled only children under six months, the other enrolled only 60 children). Only one study has been conducted in well-nourished children in countries at low risk of zinc deficiency, showing, as expect, no impact of zinc. The applicability of the results of this systematic review to countries is therefore likely to depend on the local prevalence of zinc deficiency or other population characteristics, such as the prevalence of malnutrition.

Nearly all trials were conducted in hospital where participants are more likely to adhere to the intervention; however one large community trial also showed a benefit with zinc.

The observed increase in vomiting was consistent across trials in all age groups. One large trial with adequate allocation concealment that was designed to look at safety reports that vomiting was limited to one episode in 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 adverse effect.

 

Quality of the evidence

The quality of evidence has been assessed using the GRADE methodology and is displayed in three summary of findings tables:  Summary of findings for the main comparison;  Summary of findings 2;  Summary of findings 3.

The evidence for benefits on diarrhoea duration in children aged > 6 months is of low to moderate quality. This implies that we can have some confidence in the results but further research may alter the estimates of benefit and harm. The main reasons to downgrade were 'indirectness' and 'inconsistency' in the results. Zinc is currently recommended in Asia and Africa but almost all the evidence is from Asia. There is sufficient doubt that micronutrient deficiencies may be different across settings to consider this evidence 'indirect' for application to Africa. In addition, heterogeneity or 'inconsistency' between trials is very high, with many trials failing to show any evidence of benefit. This is perhaps not surprising given the variations in populations, settings, and interventions. However we were unable to completely explain this heterogeneity through subgroup analysis, and so our confidence that zinc supplementation can be broadly applied is decreased.

 

Agreements and disagreements with other studies or reviews

Our results agree with those of other systematic reviews of zinc for treating diarrhoea (Bhutta 2000b, Lukacik 2008, Patro 2008, Haider 2009), except for the new finding of no effect of zinc in children aged less than six months. This review adds several new trials, includes a more extensive subgroup analysis, and reports on diarrhoea at different time points, diarrhoea severity, and adverse events.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

In areas where diarrhoea is an important cause of child mortality, and the prevalence of zinc deficiency or mild/moderate malnutrition is high, zinc may be of benefit in children aged six months or more.

 
Implications for research

Causes of heterogeneity in the effect of zinc in children over six months should be further explored, and further research is necessary to justify continued supplementation in children less than 6 months.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries. We thank Katharine Jones and David Sinclair for their help in reviewing the text.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Zinc vs placebo for acute diarrhoea

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)194446Mean Difference (IV, Random, 95% CI)-12.63 [-21.05, -4.21]

    1.1 Age < 6 months
51334Mean Difference (IV, Random, 95% CI)5.23 [-2.00, 14.45]

    1.2 Age > 6 months
62175Mean Difference (IV, Random, 95% CI)-10.44 [-21.13, 0.25]

    1.3 Ages both < and > 6 months
8937Mean Difference (IV, Random, 95% CI)-22.53 [-34.77, -10.29]

 2 Diarrhoea on day 341568Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.67, 0.89]

    2.1 Age > 6 months
21386Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 0.99]

    2.2 Ages both < and > 6 months
2182Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.42, 0.72]

 3 Diarrhoea on day 551730Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.51, 0.89]

    3.1 Age > 6 months
31384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.52, 1.01]

    3.2 Ages both < and > 6 months
2346Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.32, 0.95]

 4 Diarrhoea on day 7135528Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.94]

    4.1 Age < 6 months
31074Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.99, 1.54]

    4.2 Age > 6 months
63865Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.61, 0.88]

    4.3 Ages both < and > 6 months
4589Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.18, 0.52]

 5 Stool frequency (stools /day)92323Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.20, 0.10]

    5.1 Age < 6 months
51334Mean Difference (IV, Fixed, 95% CI)0.0 [-0.17, 0.17]

    5.2 Age > 6 months
3915Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.47, 0.15]

    5.3 Ages both < and > 6 months
174Mean Difference (IV, Fixed, 95% CI)-5.9 [-9.44, -2.36]

 6 Adverse events (vomiting)125189Risk Ratio (M-H, Random, 95% CI)1.59 [1.27, 1.99]

    6.1 Age < 6 months
31334Risk Ratio (M-H, Random, 95% CI)1.54 [1.05, 2.24]

    6.2 Age > 6 months
52340Risk Ratio (M-H, Random, 95% CI)1.56 [1.32, 1.85]

    6.3 Ages both < and > 6 months
41515Risk Ratio (M-H, Random, 95% CI)2.01 [1.06, 3.81]

 
Comparison 2. Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)15Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Nutritional status: only well-nourished
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.2 Nutritional status: well-nourished plus moderately malnourished
92635Mean Difference (IV, Random, 95% CI)-16.77 [-27.59, -5.94]

    1.3 Nutritional status: malnourished
4336Mean Difference (IV, Random, 95% CI)-26.98 [-39.34, -14.62]

    1.4 Sex: male
3430Mean Difference (IV, Random, 95% CI)-22.35 [-36.40, -8.31]

    1.5 Sex: male and female
112682Mean Difference (IV, Random, 95% CI)-16.04 [-26.97, -5.11]

    1.6 Region: Africa
160Mean Difference (IV, Random, 95% CI)-2.40 [-33.25, 28.45]

    1.7 Region: Asia
112837Mean Difference (IV, Random, 95% CI)-18.88 [-29.33, -8.43]

    1.8 Region: South America
174Mean Difference (IV, Random, 95% CI)-31.20 [-46.43, -15.97]

    1.9 Region: Europe
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.10 Region: countries ranked as high risk of zinc deficiency
82535Mean Difference (IV, Random, 95% CI)-14.97 [-26.21, -3.72]

    1.11 Region: countries ranked as medium risk of zinc deficiency
5436Mean Difference (IV, Random, 95% CI)-25.92 [-44.80, -7.04]

    1.12 Region: countries ranked as low risk of zinc deficiency
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.13 Zinc dose:≤ 20 mg
8711Mean Difference (IV, Random, 95% CI)-18.72 [-32.02, -5.43]

    1.14 Zinc dose: > 20 mg
3959Mean Difference (IV, Random, 95% CI)-23.52 [-42.09, -4.94]

    1.15 Zinc type: zinc acetate
3875Mean Difference (IV, Random, 95% CI)-30.55 [-49.29, -11.82]

    1.16 Zinc type: gluconate
1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]

    1.17 Zinc type: zinc sulphate
91348Mean Difference (IV, Random, 95% CI)-14.04 [-26.76, -1.32]

    1.18 Study setting: hospital
132307Mean Difference (IV, Random, 95% CI)-18.46 [-28.61, -8.30]

    1.19 Study setting:community
1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]

    1.20 Concomitant treatment: zinc alone
142988Mean Difference (IV, Random, 95% CI)-17.58 [-26.64, -8.52]

    1.21 Concomitant treatment: zinc plus copper
1383Mean Difference (IV, Random, 95% CI)2.20 [-5.08, 9.48]

 
Comparison 3. Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea on day 711Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Nutritional status: only well nourished
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.2 Nutritional status: well nourished plus moderately malnourished
64075Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]

    1.3 Nutritional status: malnourished
3238Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.22, 0.61]

    1.4 Sex: male
1266Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 0.88]

    1.5 Sex: male and female
94188Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.58, 0.81]

    1.6 Region: Asia
94313Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.56, 0.79]

    1.7 Region: Europe
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.8 Region: countries ranked as high risk of zinc deficiency
63240Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]

    1.9 Region: countries ranked as medium risk of zinc deficiency
31073Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.35, 0.68]

    1.10 Region: countries ranked as low risk of zinc deficiency
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.11 Zinc dose: 20 mg
83154Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.74]

    1.12 Zinc dose: >20mg
1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]

    1.13 Zinc type: zinc acetate
31628Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.45, 0.79]

    1.14 Zinc type:gluconate
1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]

    1.15 Zinc type: zinc sulphate
62021Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.57, 0.90]

    1.16 Study setting: hospital
82758Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.56, 0.84]

    1.17 Study setting: community
21696Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.44, 0.85]

    1.18 Concomitant treatment: zinc alone
104330Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.55, 0.78]

    1.19 Concomitant treatment: zinc plus copper
1383Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.45]

 
Comparison 4. Zinc vs placebo for persistent diarrhoea

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)5529Mean Difference (IV, Fixed, 95% CI)-15.84 [-25.43, -6.24]

    1.1 Age > 6 months
4388Mean Difference (IV, Fixed, 95% CI)-16.01 [-26.16, -5.86]

    1.2 Ages both < and > 6 months
1141Mean Difference (IV, Fixed, 95% CI)-14.40 [-43.77, 14.97]

 2 Diarrhoea on day 31Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Age > 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Diarrhoea on day 51Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Age > 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Diarrhoea on day 72221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]

    4.1 Age > 6 months
2221Risk Ratio (M-H, Fixed, 95% CI)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)0.0 [0.0, 0.0]

 6 Adverse events (vomiting)4505Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]

    6.1 Age > 6 months
3364Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]

    6.2 Ages both < and > 6 months
1141Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 20 February 2012.


DateEventDescription

6 December 2012AmendedAn error was spotted in the abstract (number of participants and number of studies was incorrect). This has been corrected and the review republished to ensure the correct details are documented.

6 December 2012New citation required but conclusions have not changedcorrected abstract



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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


DateEventDescription

22 March 2012New search has been performedThe search was updated on 20 February 2012. Two new studies were included. The background was updated and a more detailed assessment of the risk of bias in all included trials was undertaken. Summary of findings tables were updated according to GRADE methodology.

22 March 2012New citation required but conclusions have not changedUpdate

11 February 2011New search has been performedThe search was updated on 1 December 2010. Four new studies were included. The background was updated and a more detailed assessment of the risk of bias in all included trials was undertaken. Summary of findings tables were added according to GRADE methodology.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Both authors contributed equally to the preparation of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Department for International Development (DFID), UK.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

2011

We used the GRADE profiler, version 3.2.2 to create ’Summary of findings’ tables for the primary outcomes in the review.

 

2007, Issue 4 (first review version)

We made the following modifications while conducting the review.

  • Changed inclusion criteria for participant age to "children over one month old" (rather than "two months") to avoid arbitrarily losing trials.
  • Moved death to a secondary outcome measure following feedback from referees.
  • Stratified the results by age categories since we observed significant heterogeneity when trials were pooled, and a clear difference in zinc effect was evident according to age.
  • For subgroup analysis by nutritional status, it was not possible to refer to the definition of malnutrition given in the protocol (weight/height) as most included trials used another definition (weight/age), which is easier to measure. The difference between the two definition is that the first identifies children with acute weight loss or 'wasted', while the second includes both children with acute and chronic malnutrition ('wasted' and 'stunted').
  • Two categories of 'zinc dose' were used (20 mg and > 20 mg) as most trials used zinc 20 mg/day, and only two trials used more than 20 mg/day.
  • Gender was added since subgroup as it was recently identified as a possible effect modifier (Garenne 2005).

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Al-Sonboli 2003 {published data only}
  • Al-Sonboli N, Gurgel RQ, Shenkin A, Hart CA, Cuevas LE. Zinc supplementation in Brazilian children with acute diarrhoea. Annals of Tropical Paediatrics 2003;23(1):3-8.
  • Cuevas LE, Al Sonboli NN, Gurgel RQ, Shenkins A, Hart CA. Impact of zinc on duration of acute diarrhoea in children [Abstract]. Journal of Infection 2000;40:A29.
Bahl 2002 {published data only}
  • Bahl R, Bhandari N, Saksena M, Strand T, Kumar GT, Bhan MK, et al. Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old children with acute diarrhea. Journal of Pediatrics 2002;141(5):677-82.
Bhatnagar 2004a {published data only}
  • Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan MK. Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: a randomized controlled trial. Journal of Pediatric Gastroenterology and Nutrition 2004;38(1):34-40.
Bhutta 1999b {published data only}
  • Bhutta ZA, Nizami SQ, Isani Z. Zinc supplementation in malnourished children with persistent diarrhea in Pakistan. Pediatrics 1999;103(4):e42.
Brooks 2005a {published data only}
  • Brooks WA, Santosham M, Roy SK, Faruque AS, Wahed MA, Nahar K, et al. Efficacy of zinc in young infants with acute watery diarrhea. American Journal of Clinical Nutrition 2005;82(3):605-10.
Brooks 2005a (20 mg) {published data only}
  • See Brooks 2005a.
Brooks 2005a (5 mg) {published data only}
  • See Brooks 2005a.
Dalgic 2011 {published data only}
  • Dalgic N, Sancar M, Bayraktar B, Pullu M, Hasim O. Probiotic, zinc andlactose-free formula in children with rotavirus diarrhea: are they effective?. Pediatrics International 2011;53(5):677-82.
Dutta 2000 {published data only}
  • Dutta P, Mitra U, Datta A, Niyogi SK, Dutta S, Manna B, et al. Impact of zinc supplementation in malnourished children with acute watery diarrhoea. Journal of Tropical Pediatrics 2000;46(5):259-63.
Dutta 2011 {published data only}
  • Dutta P, Mitra U, Dutta S, Naik TN, Rajendran K, Chatterjee MK. Zinc, vitamin A, and micronutrient supplementation in children with diarrhea: a randomized controlled clinical trial of combination therapy versus monotherapy. Journal of Pediatrics 2011;159(4):633-7.
Fajolu 2008 {published and unpublished data}
  • Fajolu IB, Emokpae A, Oduwole AO, Silva BO, Abidoye RO, Renner JK. Zinc supplementation in children with acute diarrhoea. Nigerian Quarterly Journal of Hospital Medicine. Nigerian Quarterly Journal of Hospital Medicine. 2008;18(2):101-3.
Faruque 1999 {published data only}
  • Faruque AS, Mahalanabis D, Haque SS, Fuchs GJ, Habte D. Double-blind, randomized, controlled trial of zinc or vitamin A supplementation in young children with acute diarrhoea. Acta Paediatrica 1999;88(2):154-60.
Fischer Walker 2006 {published data only}
  • Fischer Walker CL, Bhutta ZA, Bhandari N, Teka T, Shahid F, Taneja S, et al. Zinc supplementation for the treatment of diarrhea in infants in Pakistan, India and Ethiopia. Journal of Pediatric Gastroenterology and Nutrition 2006;43(3):357-63.
Fischer Walker 2006 ETH {published data only}
  • See Fischer Walker 2006.
Fischer Walker 2006 IND {published data only}
  • See Fischer Walker 2006.
Fischer Walker 2006 PAK {published data only}
  • See Fischer Walker 2006.
Khatun 2001 {published data only}
  • Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA, Fuchs G, et al. A randomized controlled clinical trial of zinc, vitamin A or both in undernourished children with persistent diarrhea in Bangladesh. Acta Paediatrica 2001;90(4):376-80.
  • Roy SK. A randomized four cell clinical trial of zinc and vitamin A in undernourished children with persistent diarrhoea in Bangladesh. Journal of Pediatric Gastroenterology and Nutrition 1998;26(5):595.
Larson 2005 {published data only}
  • Larson CP, Hoque AB, Larson CP, Khan AM, Saha UR. Initiation of zinc treatment for acute childhood diarrhoea and risk for vomiting or regurgitation: a randomized, double-blind, placebo-controlled trial. Journal of Health, Population, and Nutrition 2005;23(4):311-9.
Patel 2009 {published and unpublished data}
  • Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Medicine 2009;5(7):22.
Patel 2009a (zinc) {published and unpublished data}
  • Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Medicine 2009;5(7):22.
Patel 2009b (zinc+copper) {published and unpublished data}
  • Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Medicine 2009;5(7):22.
Patro 2010 {published and unpublished data}
  • Patro B, Szymanski H, Szajewska H. Oral zinc for the treatment of acute gastroenteritis in polish children: a randomized, double-blind, placebo-controlled trial. Journal of Pediatrics 2010;157(6):984-8.
Penny 1999 {published data only}
  • Penny ME, Peerson JM, Marin RM, Duran A, Lanata CF, Lonnerdal B, et al. Randomized, community-based trial of the effect of zinc supplementation, with and without other micronutrients, on the duration of persistent childhood diarrhea in Lima, Peru. Journal of Pediatrics 1999;135(2 Pt 1):208-17.
Polat 2003 {published data only}
  • Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration of diarrhea in malnourished Turkish children. Pediatrics International 2003;45(5):555-9.
Polat 2003 low Zn {published data only}
  • Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration of diarrhea in malnourished Turkish children. Pediatrics International 2003;45(5):555-9.
Polat 2003 normal Zn {published data only}
  • Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration of diarrhea in malnourished Turkish children. Pediatrics International 2003;45(5):555-9.
Roy 1997 {published data only}
  • Roy SK. Effect of zinc supplementation in patients with acute and persistent diarrhoea. Glimpse 1991;13(3):2.
  • Roy SK, Tomkins AM, Akramuzzaman SM, Behrens RH, Haider R, Mahalanabis D, et al. Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Archives of Disease in Childhood 1997;77(3):196-200.
Roy 1998 {published data only}
  • Roy SK. Effect of zinc supplementation in patients with acute and persistent diarrhoea. Glimpse 1991;13(3):2.
  • Roy SK, Tomkins AM, Mahalanabis D, Akramuzzaman SM, Haider R, Behrens RH, et al. Impact of zinc supplementation on persistent diarrhoea in malnourished Bangladeshi children. Acta Paediatrica 1998;87(12):1235-9.
Roy 2008 {published and unpublished data}
  • Roy SK, Raqib R, Khatun W, Azim T, Chowdhury R, Fuchs GJ, et al. Zinc supplementation in the management of shigellosis in malnourished children in Bangladesh. European Journal of Clinical Nutrition 2008;62(7):849-55.
Sachdev 1988 {published data only}
  • Sachdev HP, Mittal NK, Mittal SK, Yadav HS. A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants. Journal of Pediatric Gastroenterology and Nutrition 1988;7(6):877-81.
Sachdev 1990 {published data only}
  • Sachdev HP, Mittal NK, Yadav HS. Oral zinc supplementation in persistent diarrhoea in infants. Annals of Tropical Paediatrics 1990;10(1):63-9.
Sazawal 1995 {published data only}
  • Darmon N, Briend A, Desjeux JF. Zinc in the treatment of diarrhea. Journal of Pediatric Gastroenterology and Nutrition 1997;25(3):363-5.
  • Folwaczny C. Role of zinc in treatment of acute diarrhea. Zeitschrift für Gastroenterologie 1996;34(4):260-2.
  • Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young children with acute diarrhea in India. New England Journal of Medicine 1995;333(13):839-44.
Strand 2002 {published data only}
  • Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, et al. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children. Pediatrics 2002;109(5):898-903.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Adu Afarwuah 2007 {published data only}
  • Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Randomized comparison of 3 types of micronutrient supplements for home fortification of complementary foods in Ghana: Effects on growth and motor development. American Journal of Clinical Nutrition 2007;86(2):412-20.
Adu-Afarwuah 2008 {published data only}
  • Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Home fortification of complementary foods with micronutrient supplements is well accepted and has positive effects on infant iron status in Ghana. The American journal of clinical nutrition 2008;87(4):929-38.
Aggarwal 2007 {published data only}
  • Aggarwal R, Sentz J, Miller MA. Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: a meta-analysis. Pediatrics 2007;119(6):1120-30.
Agustina 2007 {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 acute diarrhea in Indonesia. Asia Pacific Journal of Clinical Nutrition 2007;16(3):435-42.
Alam 2010 {published data only}
  • Alam DS, Yunus M, El Arifeen S, Chowdury HR, Larson CP, Sack DA, Baqui AH, Black RE. Zinc treatment for 5 or 10 days is equally efficacious in preventing diarrhea in the subsequent 3 months among Bangladeshi children. Journal of Nutrition 2010;141(2):312-5.
Alarcon 2004 {published data only}
  • Alarcon K, Kolsteren PW, Prada AM, Chian AM, Velarde RE, Pecho IL, et al. Effects of separate delivery of zinc or zinc and vitamin A on hemoglobin response, growth, and diarrhea in young Peruvian children receiving iron therapy for anemia. American Journal of Clinical Nutrition 2004;80(5):1276-82.
Awasthi 2006 {published data only}
  • Awasthi S, INCLEN Childnet Zinc Effectiveness for Diarrhea (IC-ZED) Group. Zinc supplementation in acute diarrhea is acceptable, does not interfere with oral rehydration, and reduces the use of other medications: a randomized trial in five countries. Journal of Pediatric Gastroenterology and Nutrition 2006;42(3):300-5.
Baqui 2002 {published data only}
  • Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S, et al. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ 2002;325(7372):1059-64.
  • Baqui AH, Black RE, El Arifeen S, Yunus M, Zaman K, Begum N, et al. Zinc therapy for diarrhoea increased the use of oral rehydration therapy and reduced the use of antibiotics in Bangladeshi children. Journal of Health, Population, and Nutrition 2004;22(4):440-2.
Baqui 2003 {published data only}
  • Baqui AH, Zaman K, Persson LA, El Arifeen S, Yunus M, Begum N, et al. Simultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants. Journal of Nutrition 2003;133(12):4150-7.
Baqui 2006 {published data only}
  • Baqui AH, Black RE, Fischer Walker CL, Arifeen S, Zaman K, Yunus M, et al. Zinc supplementation and serum zinc during diarrhea. Indian Journal of Pediatrics 2006;73(6):493-7.
Baum 2010 {published data only}
  • Baum MK, Lai S, Sales S, Page JB, Campa A. Randomized, controlled clinical trial of zinc supplementation to prevent immunological failure in HIV-infected adults. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010;50(12):1653-60.
Behrens 1990 {published data only}
  • Behrens RH, Tomkins AM, Roy SK. Zinc supplementation during diarrhoea, a fortification against malnutrition?. Lancet 1990;336(8712):442-3.
Bhandari 2002 {published data only}
  • Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, et al. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics 2002;109(6):e86.
Bhandari 2005 {published data only}
  • Bhandari N, Mazumder S, Taneja S, Dube B, Black RE, Fontaine O, et al. A pilot test of the addition of zinc to the current case management package of diarrhea in a primary health care setting. Journal of Pediatric Gastroenterology and Nutrition 2005;41(5):685-7.
Bhandari 2007 {published data only}
  • Bhandari N, Taneja S, Mazumder S, Bahl R, Fontaine O, Bhan MK. Adding zinc to supplemental iron and folic acid does not affect mortality and severe morbidity in young children. Journal of Nutrition 2007;137(1):112-7.
Bhandari 2008 {published data only}
  • Bhandari N, Mazumder S, Taneja S, Dube B, Agarwal RC, Mahalanabis D, et al. Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial. Pediatrics 2008;121(5):e1279-85.
Bhatnagar 2004b {published data only}
  • Bhatnagar S, Natchu UC. Zinc in child health and disease. Indian Journal of Pediatrics 2004;71(11):991-5.
Bhutta 2000a {published data only}
  • Bhutta ZA, Raza F, Nizami SQ, Issani Z. Does zinc supplementation influence appetite in malnourished children with persistent diarrhoea? A randomized controlled trial in Pakistan. Journal of Pediatric Gastroenterology and Nutrition 2000;31 Suppl 2:23.
Bilenko 2010 {published data only}
  • Bilenko N, Belmaker I, Vardi H, Fraser D. Efficacy of multiple micronutrient supplementations on child health: study design and baseline characteristics. The Israel Medical Association journal : IMAJ 2010;12(6):342-7.
Black 2001 {published data only}
  • Black RE, Sazawal S. Zinc and childhood infectious disease morbidity and mortality. British Journal of Nutrition 2001;85 Suppl 2:125-9.
Bobat 2005 {published data only}
  • Bobat R, Coovadia H, Stephen C, Naidoo KL, McKerrow N, Black RE, et al. Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial. Lancet 2005;366(9500):1862-7.
Borges 2007 {published data only}
  • Borges Dantas CV, Veiga Black AP, Barroso dos Santos G, Jesus Oliveira EF, Serpa Barbosa RF, Moreira S, et al. Association among serum concentration of minerals, anthropometric indices and diarrhea in low-income children in the metropolitan region of Rio de Janeiro, Brazil [Associação entre concentrações séricas de minerais, índices antropométricos e ocorrência de diarréia entre crianças de baixa renda da região metropolitana do Rio de Janeiro]. Revista de Nutricao 2007;20(2):159-69.
Brooks 2005b {published data only}
  • Brooks WA, Santosham M, Naheed A, Goswami D, Wahed MA, Diener-West M, et al. Effect of weekly zinc supplements 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(9490):999-1004.
Brown 2007 {published data only}
  • Brown KH, de Romana DL, Arsenault JE, Peerson JM, Penny ME. Comparison of the effects of zinc delivered in a fortified food or a liquid supplement on the growth morbidity and plasma zinc concentrations of young Peruvian children. American Journal of Clinical Nutrition 2007;85(2):538-47.
Brown 2007a {published data only}
  • Brown KH, Lopez de Romana D, Arsenault JE, Peerson JM, Penny ME. Comparison of the effects of zinc delivered in a fortified food or a liquid supplement on the growth, morbidity, and plasma zinc concentrations of young Peruvian children. The American Journal of Clinical Nutrition 2007;85(2):538-47.
Carbajal 2000 {published data only}
  • Carbajal C. Micronutrients: An option in the treatment of acute diarrheal diseases [Micronutrientes: una opción en el tratamiento de las enfermedades diarreicas agudas]. Revista Cubana de Pediatría 2000;72(4):261-6.
Carcamo 2006 {published data only}
  • Carcamo C, Hooton T, Weiss NS, Gilman R, Wener MH, Chavez V, et al. Randomized controlled trial of zinc supplementation for persistent diarrhea in adults with HIV-1 infection. Journal of Acquired Immune Deficiency Syndromes 2006;43(2):197-201.
Chandyo 2010 {published data only}
  • Chandyo RK, Shrestha PS, Valentiner-Branth P, Mathisen M, Basnet S, Ulak M, et al. Two weeks of zinc administration to Nepalese children with pneumonia does not reduce the incidence of pneumonia or diarrhea during the next six months. The Journal of Nutrition 2010;140(9):1677-82.
Chang 2010 {published data only}
  • Chang S, El Arifeen S, Bari S, Wahed MA, Rahman KM, Rahman MT, et al. Supplementing iron and zinc: double blind, randomized evaluation of separate or combined delivery. European Journal of Clinical Nutrition 2010;64(2):153-60.
Chen 2010 {published data only}
  • Chen K, Zhang X, Li TY, Chen L, Wei XP, Qu P, et al. Effect of vitamin A, vitamin A plus iron and multiple micronutrient-fortified seasoning powder on infectious morbidity of preschool children. Nutrition 2010, June 1;27(4):428-34.
Chhagan 2009 {published data only}
  • Chhagan MK, Van den Broeck J, Luabeya KK, Mpontshane N, Tucker KL, Bennish ML. Effect of micronutrient supplementation on diarrhoeal disease among stunted children in rural South Africa. European Journal of Clinical Nutrition 2009;63(7):850-7.
Chhagan 2010 {published data only}
  • Chhagan MK, Van den Broeck J, Luabeya KK, Mpontshane N, Tomkins A, Bennish ML. Effect on longitudinal growth and anemia of zinc or multiple micronutrients added to vitamin A: a randomized controlled trial in children aged 6-24 months. BMC Public Health 2010;10:145.
Christian 2009 {published data only}
  • Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP Jr, et al. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. American Journal of Epidemiology 2009;170(9):1127-36.
CIGNIS 2010 {published data only}
  • The Chilenje Infant Growth, Nutrition and Infection (CIGNIS) Study Team. Micronutrient fortification to improve growth and health of maternally HIV-unexposed and exposed Zambian infants: a randomised controlled trial. PLoS ONE 2010;5(6):e11165.
Cross 2009 {published data only}
  • Cross AJ, Heath AL, Ferguson EL, Gray AR, Szymlek-Gay EA. Rates of common communicable illnesses in non-anaemic 12-24 month old South Island, New Zealand children. The New Zealand Medical Journal 2009;122(1290):24-35.
Dhingra 2009 {published data only}
  • Dhingra U, Hiremath G, Menon VP, Dhingra P, Sarkar A, Sazawal S. Zinc deficiency: descriptive epidemiology and morbidity among preschool children in peri-urban population in Delhi, India. Journal of Health, Population, and Nutrition 2009;27(5):632-9.
Doherty 1998 {published data only}
  • Doherty CP, Sarkar MA, Shakur MS, Ling SC, Elton RA, Cutting WA. Zinc and rehabilitation from severe protein-energy malnutrition: higher-dose regimens are associated with increased mortality. American Journal of Clinical Nutrition 1998;68(3):742-8.
Ebrahimi 2006 {published data only}
  • Ebrahimi S, Pormahmodi A, Kamkar A. Study of zinc supplementation on growth of schoolchildren in Yasuj, Southwest of Iran. Pakistan Journal of Nutrition 2006;5(4):341-2.
Ellis 2007 {published data only}
  • Ellis AA, Winch P, Daou Z, Gilroy KE, Swedberg E. Home management of childhood diarrhoea in southern Mali-Implications for the introduction of zinc treatment. Social Science and Medicine 2007;64(3):701-12.
Ferraz 2007 {published data only}
  • Ferraz IS, Daneluzzi JC, Vannucchi H, Jordão Jr AA, Ricco RG, Del Ciampo LA, Martinelli CE Jr, Engelberg AA, Bonilha LR, Custódio VI. Zinc serum levels and their association with vitamin A deficiency in preschool children [Nível sérico de zinco e sua associação com deficiência de vitamina A em crianças pré-escolares]. Jornal de Pediatria (Rio J) 2007;83(6):512-17.
Ferrufino 2007 {unpublished data only}
  • Ferrufino B, Sagrario A. Acceptability of mothers of zinc sulphate supplementation in children under 5 years in the municipality of Jinotega. November 2006 to March 2007. [Aceptabilidad de las madres de la suplementación del sulfato de zinc en el manejo de las enfermedades diarreicas en menores de 5 años, municipio de Jinotega. Noviembre del año 2006 a marzo del año 2007]. Thesis, Universidad Nacional Autónoma de Nicaragua, Managua, 2007.
Fischer Walker 2008 {published data only}
  • Fischer Walker CL, Black RE, Baqui AH. Does age affect the response to zinc therapy for diarrhoea in Bangladeshi infants?. Journal of Health, Population, and Nutrition 2008;26(1):105-9.
Gardner 2005 {published data only}
  • Gardner JM, Powell CA, Baker-Henningham H, Walker SP, Cole TJ, Grantham-McGregor SM. Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children. American Journal of Clinical Nutrition 2005;82(2):399-405.
Garenne 2007 {published data only}
  • Garenne M, Becher H, Ye Y, Kouyate B, Muller O. Sex-specific responses to zinc supplementation in Nouna, Burkina Faso. Journal of Pediatric Gastroenterology and Nutrition 2007;44(5):619-28.
Gregorio 2007 {published data only}
  • Gregorio GV, Dans LF, Cordero CP, Panelo CA. Zinc supplementation reduced cost and duration of acute diarrhea in children. Journal of Clinical Epidemiology 2007;60(6):560-6.
Gupta 2003 {published data only}
  • Gupta DN, Mondal SK, Ghosh S, Rajendran K, Sur D, Manna B. Impact of zinc supplementation on diarrhoeal morbidity in rural children of West Bengal, India. Acta Paediatrica 2003;92(5):531-6.
Gupta 2007 {published data only}
  • Gupta DN, Rajendran K, Mondal SK, Ghosh S, Bhattacharya SK. Operational feasibility of implementing community-based zinc supplementation:impact on childhood diarrheal morbidity. Pediatric Infectious Disease Journal 2007;26(4):306-10.
Habib 2010 {published data only}
  • Habib MA, Soofi SB, Bhutta ZA. Effect of zinc in tablet and suspension formulations in the treatment of acute diarrhoea among young children in an emergency setting of earthquake affected region of Pakistan. Journal of College of Physicians and Surgeons Pakistan 2010;20(12):837-8..
Heinig 2006 {published data only}
  • Heinig MJ, Brown KH, Lonnerdal B, Dewey KG. Zinc supplementation does not affect growth morbidity or motor development of US term breastfed infants at 4-10 mo of age. American Journal of Clinical Nutrition 2006;84(3):594-601.
Hettiarachchi 2008 {published data only}
  • Hettiarachchi M, Liyanage C, Wickremasinghe R, Hilmers DC, Abrams SA. The efficacy of micronutrient supplementation in reducing the prevalence of anaemia and deficiencies of zinc and iron among adolescents in Sri Lanka. European Journal of Clinical Nutrition 2008;62(7):856-65.
Hidayat 1998 {published data only}
  • Hidayat A, Achadi A, Sunoto, Soedarmo SP. The effect of zinc supplementation in children under three years of age with acute diarrhea in Indonesia. Medical Journal of Indonesia 1998;7:237–41.
Hoque 2006 {published data only}
  • Hoque KM, Binder HJ. Zinc in the treatment of acute diarrhea: current status and assessment. Gastroenterology 2006;130(1):2201-5.
Hyder 2007 {published data only}
  • Hyder SM, Haseen F, Khan M, Schaetzel T, Jalal CS, Rahman M, et al. A multiple-micronutrient-fortified beverage affects hemoglobin, iron, and vitamin A status and growth in adolescent girls in rural Bangladesh. The Journal of Nutrition 2007;137(9):2147-53.
Iannotti 2010 {published data only}
  • Iannotti LL, Zavaleta N, Leon Z, Huasquiche C, Shankar AH, Caulfield LE. Maternal zinc supplementation reduces diarrheal morbidity in peruvian infants. Journal of Pediatrics 2010;156(6):960-4, 964.e1-2.
Islam 2010 {published data only}
  • Islam MN, Chowdhury MA, Siddika M, Qurishi SB, Bhuiyan MK, Hoque MM, et al. Effect of oral zinc supplementation on the growth of preterm infants. Indian Pediatrics 2010;47(10):845-9.
Jimenez 2000 {published data only}
  • Jimenez R, Sagaro E, Lafita Y. How growth infants supplemented with zinc sulfate after an episode of persistent 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 the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial. AIDS 1999;13(4):495-500.
Kelly 2010 {published data only}
  • Kelly P, Shawa T, Mwanamakondo S, Soko R, Smith G, Barclay GR, et al. Gastric and intestinal barrier impairment in tropical enteropathy and HIV: limited impact of micronutrient supplementation during a randomised controlled trial. BMC Gastroenterology 2010;10:72.
Larson 2010 {published data only}
  • Larson CP, Nasrin D, Saha A, Chowdhury MI, Qadri F. The added benefit of zinc supplementation after zinc treatment of acute childhood diarrhoea: a randomized, double-blind field trial. Tropical Medicine and International Health 2010;15(6):754-61.
Lin 2008 {published data only}
  • Lin CA, Manary MJ, Maleta K, Briend A, Ashorn P. An energy-dense complementary food is associated with a modest increase in weight gain when compared with a fortified porridge in Malawian children aged 6-18 months. Journal of Nutrition 2008;138(3):593-8.
Lind 2004 {published data only}
  • Lind T, Lonnerdal B, Stenlund H, Gamayanti IL, Ismail D, Seswandhana R, et al. A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: effects on growth and development. American Journal of Clinical Nutrition 2004;80(3):729-36.
Lind 2008 {published data only}
  • Lind T, Seswandhana R, Persson LA, Lonnerdal B. Iron supplementation of iron-replete Indonesian infants is associated with reduced weight-for-age. Acta paediatrica 2008;97(6):770-5.
Lira 1998 {published data only}
  • Lira PI, Ashworth A, Morris SS. Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil. American Journal of Clinical Nutrition 1998;68 Suppl 2:418s-24s.
Long 2006 {published data only}
  • Long KZ, Montoya Y, Hertzmark E, Santos JI, Rosado JL. A double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico. American Journal of Clinical Nutrition 2006;83(3):693-700.
Long 2007 {published data only}
  • Long KZ, Rosado JL, Montoya Y, de Lourdes Solano M, Hertzmark E, DuPont HL, et al. Effect of vitamin A and zinc supplementation on gastrointestinal parasitic infections among Mexican children. Pediatrics 2007;120(4):e846-55.
Lopez 2005 {published data only}
  • Lopez de Romana G, Cusirramos S, Lopez de Romana D, Gross R. Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants. Journal of Nutrition 2005;135(3):646-52.
Luabeya 2007 {published data only}
  • Luabeya KK, Mpontshane N, Mackay M, Ward H, Elson I, Chhagan M, et al. Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial. PLoS ONE 2007;2(6):e541.
Lukacik 2008 {published data only}
  • Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics 2008;121(2):326-36.
Makonnen 2003a {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. I: Mortality and morbidity. Journal of Tropical Pediatrics 2003;49(6):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: Special investigations. Journal of Tropical Pediatrics 2003;49(6):353-60.
Manger 2008 {published data only}
  • Manger MS, McKenzie JE, Winichagoon P, Gray A, Chavasit V, Pongcharoen T, et al. A micronutrient-fortified seasoning powder reduces morbidity and improves short-term cognitive function, but has no effect on anthropometric measures in primary school children in northeast Thailand: a randomized controlled trial. The American Journal of Clinical Nutrition 2008;87(6):1715-22.
Mazariegos 2010 {published data only}
  • Mazariegos M, Hambidge KM, Westcott JE, Solomons NW, Raboy V, Das A, et al. Neither a zinc supplement nor phytate-reduced maize nor their combination enhance growth of 6- to 12-month-old Guatemalan infants. The Journal of Nutrition 2010;140(5):1041-8.
Mazumder 2010 {published data only}
  • Mazumder S, Taneja S, Bhandari N, Dube B, Agarwal RC, Mahalanabis D, et al. Effectiveness of zinc supplementation plus oral rehydration salts for diarrhoea in infants aged less than 6 months in Haryana state, India. Bulletin of the World Health Organization 2010;88(10):754-60.
Mda 2010 {published data only}
  • Mda S, van Raaij JM, de Villiers FP, MacIntyre UE, Kok FJ. Short-term micronutrient supplementation reduces the duration of pneumonia and diarrheal episodes in HIV-infected children. The Journal of Nutrition 2010;140(5):969-74.
Meeks 1998 {published data only}
  • Meeks Gardner J, Witter MM, Ramdath DD. Zinc supplementation: effects on the growth and morbidity of undernourished Jamaican children. European Journal of Clinical Nutrition 1998;52(1):34-9.
Müller 2001 {published data only}
  • Müller O, Becher H, van Zweeden AB, Ye Y, Diallo DA, Konate AT, et al. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomised double blind placebo controlled trial. BMJ 2001;322(7302):1567.
Naheed 2009 {published data only}
  • Naheed A, Walker Fischer CL, Mondal D, Ahmed S, Arifeen SE, Yunus M, et al. Zinc therapy for diarrhoea improves growth among Bangladeshi infants 6 to 11 months of age. Journal of Pediatric Gastroenterology and Nutrition 2009;48(1):89-93.
Nasrin 2005 {published data only}
  • Nasrin D, Larson CP, Sultana S, Khan TU. Acceptability of and adherence to dispersible zinc tablet in the treatment of acute childhood diarrhoea. Journal of Health, Population, and Nutrition 2005;23(3):215-21.
Nga 2009 {published data only}
  • Nga TT, Winichagoon P, Dijkhuizen MA, Khan NC, Wasantwisut E, Furr H, et al. Multi-micronutrient-fortified biscuits decreased prevalence of anemia and improved micronutrient status and effectiveness of deworming in rural Vietnamese school children. The Journal of Nutrition 2009;139(5):1013-21.
Osendarp 2002 {published data only}
  • Osendarp SJ, Santosham M, Black RE, Wahed MA, van Raaij JM, Fuchs GJ. Effect of zinc supplementation between 1 and 6 mo of life on growth and morbidity of Bangladeshi infants in urban slums. American Journal of Clinical Nutrition 2002;76(6):1401-8.
Ouedraogo 2008 {published data only}
  • Ouedraogo HZ, Dramaix-Wilmet M, Zeba AN, Hennart P, Donnen P. Effect of iron or multiple micronutrient supplements on the prevalence of anaemia among anaemic young children of a malaria-endemic area: a randomized double-blind trial. Tropical Medicine and International Health 2008;13(10):1257-66.
Passariello 2010 {published data only}
  • Passariello A, Terrin G, De Marco G, Cecere G, Ruotolo S, Marino A, et al. Efficacy of a New Hypotonic Oral Rehydration Solution Containing Zinc and Prebiotics in the Treatment of Childhood Acute Diarrhea: A Randomized Controlled Trial. The Journal of Pediatrics 2011;158(2):288-92.e1.
Patel 2005 {published data only}
  • Patel AB, Dhande LA, Rawat MS. Therapeutic evaluation of zinc and copper supplementation in acute diarrhea in children: double blind randomized trial. Indian Pediatrics 2005;42(5):433-42.
Patel 2010 {published data only}
  • Patel AB, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Influence of zinc supplementation in acute diarrhea differs by the isolated organism. International Journal of Pediatrics 2010;2010:671587.
Patel 2010a {published data only}
  • Patel A, Mamtani M, Dibley MJ, Badhoniya N, Kulkarni H. Therapeutic value of zinc supplementation in acute and persistent diarrhea: a systematic review. PLoS ONE 2010;5(4):e10386.
Patro 2008 {published data only}
Penny 2004a {published data only}
  • Penny ME, Marin RM, Duran A, Peerson JM, Lanata CF, Lonnerdal B, et al. Randomized controlled trial of the effect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of young Peruvian children. American Journal of Clinical Nutrition 2004;79(3):457-65.
Penny 2004b {published data only}
  • Penny ME, Black RE, Brown KH, Lönnerdal B. Reply to RJ Walden [Letter to the Editor]. American Journal of Clinical Nutrition 2004;80(4):1084-5.
Polat 2006 {published data only}
  • Polat TB, Uysalol M, Cetinkaya F. Impact of zinc supplementation in children with acute diarrhoea in Turkey. Archives of Disease in Childhood 2006;91(4):296-9.
Rahman 2001 {published data only}
  • Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ 2001;323(7308):314-8.
Rahman 2005 {published data only}
  • Rahman MJ, Sarker P, Roy SK, Ahmad SM, Chisti J, Azim T, et al. Effects of zinc supplementation as adjunct therapy on the systemic immune responses in shigellosis. American Journal of Clinical Nutrition 2005;81(2):495-502.
Raqib 2004 {published data only}
  • Raqib R, Roy SK, Rahman MJ, Azim T, Ameer SS, Chisti J, et al. Effect of zinc supplementation on immune and inflammatory responses in pediatric patients with shigellosis. American Journal of Clinical Nutrition 2004;79(3):444-50.
Richard 2006 {published data only}
  • Richard SA, Zavaleta N, Caulfield LE, Black RE, Witzig RS, Shankar AH. Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. American Journal of Tropical Medicine and Hygiene 2006;75(1):126-32.
Rollins 2007 {published data only}
  • Rollins NC, van den Broeck J, Kindra G, Pent M, Kasambira T, Bennish ML. The effect of nutritional support on weight gain of HIV-infected children with prolonged diarrhoea. Acta Paediatrica 2007;96(1):62-8.
Rosado 1997 {published data only}
  • Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. American Journal of Clinical Nutrition 1997;65(1):13-9.
Rosado 1998 {published data only}
  • Rosado JL. Zinc deficiency and its functional implications [Deficiencia de zinc y sus implicaciones funcionales]. Salud Pública de México 1998;40(2):181-8.
Rosado 2009 {published data only}
  • Rosado JL, Caamano MC, Montoya YA, de Lourdes Solano M, Santos JI, Long KZ. Interaction of zinc or vitamin A supplementation and specific parasite infections on Mexican infants' growth: a randomized clinical trial. European Journal of Clinical Nutrition 2009;63(10):1176-84.
Roy 1992 {published data only}
  • Roy SK, Akramuzzaman SM, Haider R, Mahalanabis D, Behrens RH, Wahed MA, et al. Zinc supplementation in diarrhoea: Nutritional implication on clinical recovery and intestinal permeability [Abstract]. Journal of Gastroenterology and Hepatology 1994;9(6):A166.
  • Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. Journal of Pediatric Gastroenterology and Nutrition 1992;15(3):289-96.
Roy 1999 {published data only}
  • Roy SK, Tomkins AM, Haider R, Behren RH, Akramuzzaman SM, Mahalanabis D, et al. Impact of zinc supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea. European Journal of Clinical Nutrition 1999;53(7):529-34.
Roy 2007 {published data only}
  • Roy SK, Tomkins AM, Akramuzzaman SM, Chakraborty B, Ara G, Biswas R, et al. Impact of zinc supplementation on subsequent morbidity and growth in Bangladeshi children with persistent diarrhoea. Journal of Health, Population, and Nutrition 2007;25(1):67-74.
Roy 2008a {published data only}
  • Roy SK, Hossain MJ, Khatun W, Chakraborty B, Chowdhury S, Begum A, et al. Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial. BMJ 2008;336(7638):266-8.
Ruel 1997 {published data only}
  • Ruel MT, Rivera JA, Santizo MC, Lonnerdal B, Brown KH. Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997;99(6):808-13.
Sabatier 1997 {published data only}
  • Sabatier García FJ, Izquierdo Estévez A, León García RE, Díaz Fernández L. Benefits of zinc in the treatment of infants presenting with diarrhea [Beneficios del cinc en el tratamiento de niños con diarrea]. Revista Cubana de Pediatría 1997;69(3/4):197-200.
Samuel 1995 {published data only}
  • Samuel MJ. Paediatrics Forum. Acute diarrhoea. Africa Health 1995;17(5):27, 29-30.
Sancho Martinez 2007 {published data only}
  • Sancho Martinez A, Saenz De Pipaon Marcos M, Quero Jimenez J. Effects of supplementation with zinc in the first year of life [Efectos de la suplementacion con cinc en el primer ano de vida]. Revista Espanola De Pediatria 2007;63(6):464-82.
Sazawal 1996 {published data only}
  • Sazawal S, Black RE, Bhan MK, Jalla S, Bhandari N, Sinha A, et al. Zinc supplementation reduces the incidence of persistent diarrhea and dysentery among low socio-economic children in India. Journal of Nutrition 1996;126(2):443-50.
Sazawal 1997a {published data only}
  • Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea - a community-based, double-blind, controlled trial. American Journal of Clinical Nutrition 1997;66(2):413-8.
Sazawal 2004a {published data only}
  • Sazawal S, Marwah D, Sazawal S, Black RE, Deb S, Dhingra U, et al. Efficacy of zinc and iron fortification of milk in prevention of anemia, diarrhea pneumonia, and iron deficiency- a community based double masked randomized trial. Journal of Pediatric Gastroenterology and Nutrition 2004;39 Suppl 1:417-8.
Sazawal 2007a {published data only}
  • Sazawal S, Dhingra U, Dhingra P, Hiremath G, Kumar J, Sarkar A, et al. Effects of fortified milk on morbidity in young children in north India: community based randomised double masked placebo controlled trial. BMJ 2007;334(7585):140.
Sazawal 2007b {published data only}
  • Sazawal S, Dhingra U, Deb S, Bhan MK, Menon VP, Black RE. Effect of zinc added to multi-vitamin supplementation containing low-dose vitamin A on plasma retinol level in children--a double-blind randomized, controlled trial. Journal of Health, Population, and Nutrition 2007;25(1):62-6.
Sazawal 2007c {published data only}
  • Sazawal S, Black RE, Ramsan M, Chwaya HM, Dutta A, Dhingra U, et al. Effect of zinc supplementation on mortality in children aged 1-48 months: a community-based randomised placebo-controlled trial. Lancet 2007;369(9565):927-34.
Shamir 2005 {published data only}
  • Shamir R, Makhoul IR, Etzioni A, Shehadeh N. Evaluation of a diet containing probiotics and zinc for the treatment of mild diarrheal illness in children younger than one year of age. Journal of the American College of Nutrition 2005;24(5):370-5.
Shankar 1998 {published data only}
  • Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. 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 Childhood 2006;91(7):573-9.
Sheikh 2010 {published data only}
  • Sheikh A, Shamsuzzaman S, Ahmad SM, Nasrin D, Nahar S, Alam MM, et al. Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea. Journal of Nutrition 2010;140(5):1049-56.
Sur 2003 {published data only}
  • Sur D, Gupta DN, Mondal SK, Ghosh S, Manna B, Rajendran K, et al. Impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight infants in Kolkata, India: a randomized, double-blind, placebo-controlled, community-based study. Pediatrics 2003;112(6 Pt 1):1327-32.
Taneja 2009 {published data only}
  • Taneja S, Bhandari N, Rongsen-Chandola T, Mahalanabis D, Fontaine O, Bhan MK. Effect of zinc supplementation on morbidity and growth in hospital-born, low-birth-weight infants. American Journal of Clinical Nutrition 2009;90(2):385-91.
Taneja 2010 {published data only}
  • Taneja S, Strand TA, Sommerfelt H, Bahl R, Bhandari N. Zinc supplementation for four months does not affect growth in young north Indian children. The Journal of Nutrition 2010;140(3):630-4.
Tielsch 2006 {published data only}
  • Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R, et al. Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial. Lancet 2006;367(9505):144-52.
Tielsch 2007 {published data only}
  • Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R, et al. Effect of daily zinc supplementation on child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial. Lancet 2007;370(9594):1230-9.
Umeta 2000 {published data only}
  • Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. Zinc supplementation and stunted infants in Ethiopia: a randomised controlled trial. Lancet 2000;355(9220):2021-6.
Untoro 2005 {published data only}
  • Untoro J, Karyadi E, Wibowo L, Erhardt MW, Gross R. Multiple micronutrient supplements improve micronutrient status and anemia but not growth and morbidity of Indonesian infants: a randomized, double-blind, placebo-controlled trial. Journal of Nutrition 2005;135 Suppl(3):639-45.
Valery 2005 {published data only}
  • Valery PC, Torzillo PJ, Boyce NC, White AV, Stewart PA, Wheaton GR, et al. Zinc and vitamin A supplementation in Australian Indigenous children with acute diarrhoea: a randomised controlled trial. Medical Journal of Australia 2005;182(10):530-5.
Veenemans 2011 {published data only}
  • Veenemans J, Mank T, Ottenhof M, Baidjoe A, Mbugi EV, Demir AY, et al. Protection against diarrhea associated with Giardiaintestinalis Is lost with multi-nutrient supplementation: a study in Tanzanian children. PLoS Negleted Tropical Diseases 2011;5(6):e1158.
Wadhwa 2011 {published data only}
  • Wadhwa N, Natchu UC, Sommerfelt H, Strand TA, Kapoor V, Saini S, et al. ORS containing zinc does not reduce duration or stool volume of acute diarrhea in hospitalized children. Journal of Pediatric Gastroenterology and Nutrition 2011;53(2):161-7.
Walden 2004 {published data only}
  • Walden RJ. Supplementation with zinc and other minerals. American Journal of Clinical Nutrition 2004;80(4):1084.
Walker 2007 {published data only}
  • Walker CL, Bhutta ZA, Bhandari N, Teka T, Shahid F, Taneja S, et al. Zinc during and in convalescence from diarrhea has no demonstrable effect on subsequent morbidity and anthropometric status among infants <6 mo of age. American Journal of Clinical Nutrition 2007;85(3):887-94.
Wieringa 2010 {published data only}
  • Wieringa FT, Dijkhuizen MA, Muhilal, Van der Meer JW. Maternal micronutrient supplementation with zinc and beta-carotene affects morbidity and immune function of infants during the first 6 months of life. European Journal of Clinical Nutrition 2010;64(10):1072-9.
Winch 2006 {published data only}
  • Winch PJ, Gilroy KE, Doumbia S, Patterson AE, Daou Z, Coulibaly S, et al. Prescription and administration of a 14-day regimen of zinc treatment for childhood diarrhea in Mali. American Journal of Tropical Medicine and Hygiene 2006;74(5):880-3.
Winch 2008 {published data only}
  • Winch PJ, Gilroy KE, Doumbia S, Patterson AE, Daou Z, Diawara A, et al. Operational issues and trends associated with the pilot introduction of zinc for childhood diarrhoea in Bougouni district, Mali. Journal of Health, Population, and Nutrition 2008;26(2):151-62.
Wuehler 2008 {published data only}
  • Wuehler SE, Sempertegui F, Brown KH. Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency. American Journal of Clinical Nutrition 2008;87(3):723-33.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
NCT01140074 {unpublished data only}
  • Efficacy of Zinc Sulfate With Probiotics for the Treatment of Acute diarrhoea in Children. Ongoing study July 2010 (not yet recruiting in December 2010).
NCT01198587 {unpublished data only}
  • A Double Blind Randomized Placebo Controlled Trial of Oral Zinc for Children With Acute diarrhoea in a Developed Nation.. Ongoing study September 2010.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Albert 2003
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