Oral zinc for treating diarrhoea in children

 

Characteristics of included studies [ordered by study ID]

Al-Sonboli 2003

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Methods	RCT
Participants	Number: 81 Inclusion criteria: age 3 to 60 months; diarrhoea < 7 days or 1 or more loose stool containing blood in the previous 24 h and at least mild dehydration Exclusion criteria: suspected or confirmed severe systemic infections; antimicrobial or antidiarrhoeal treatment within 72 h before admission; severe malnutrition (< 60% median for weight for age of the NCHC standards)
Interventions	1. Zinc sulphate: 22.5 mg (3 to 6 months) or 45 mg (7 to 60 months) 2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Stool frequency
Notes	Location: Brazil Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	8.6% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Bahl 2002

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Methods	RCT
Participants	Number: 1219 Inclusion criteria: age 6 to 35 months; acute diarrhoea (less than 4 days duration) Exclusion criteria: visible blood in stools; likely to emigrate in the next 4 weeks; required hospitalization; previously enrolled; sibling  concurrently enrolled; refusal of consent
Interventions	1. Zinc gluconate 30 mg (>12 months) or 15 mg (<12 months)   2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 3 3. Diarrhoea at day 5 4. Diarrhoea at day 7 5. Stool frequency 6. Adverse events (vomiting)
Notes	Location: India Setting: Community
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomization lists
Allocation concealment (selection bias)	Low risk	The glass bottles containing the products were labelled with the patient’s number corresponding to the randomization list by an independent individual who was not involved in patient enrolment. Randomization codes were secured until the completion of data collection and initial analysis.There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.
Blinding (performance bias and detection bias) All outcomes	Low risk	Four-blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	2% lost to follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Bhatnagar 2004a

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Methods	RCT
Participants	Number: 287 Inclusion criteria: male; 3 to 36 months; acute diarrhoea (< 72 h) with mild dehydration Exclusion criteria: severe malnutrition (weight/height < 65% of NCHS median); visible blood in stool; severe systemic illness
Interventions	1. Zinc sulphate: 15 mg (< 12 months) or 30 mg (> 12 months) syrup 2. Placebo Both groups: multivitamin
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 5 3. Diarrhoea at day 7 4. Stool output 5. Adverse events (vomiting) 6. Adverse events (copper levels)
Notes	Location: India Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers
Allocation concealment (selection bias)	Low risk	Central randomization performed at a site remote from trial location (World Health Organization, Geneva)
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	7% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Bhutta 1999b

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Methods	RCT
Participants	Number: 87 Inclusion criteria: 6 to 36 months; persistent diarrhoea (> 4 unformed stools/day for at least 14 days); malnutrition (weight-for-age z score < -2.0) Exclusion criteria: kwashiorkor; clinical signs of vitamin A or zinc deficiency; needing intravenous fluids or unable to tolerate oral feeds after a 24-h period of stabilization
Interventions	1. Zinc sulphate: 3 mg/kg/day 2. Placebo Both groups: multivitamins
Outcomes	1. Average duration of diarrhoea 2. Stool output 3. Adverse events (copper levels)
Notes	Location: Pakistan Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Central randomization by independent pharmacy; table block randomization maintained in the pharmacy
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	High risk	11% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Brooks 2005a

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Methods	RCT
Participants	Number: 275 Inclusion criteria: male, 1 to 6 months; onset < 72 h; some dehydration or > 100 mL of watery stool within a 4-observation period Exclusion criteria: clinical signs of zinc deficiency; kwashiorkor, weight/age < 60% NCHS; grossly bloody stool comorbidity; cholera
Interventions	1. Zinc acetate: 20 mg 2. Zinc acetate: 5 mg 3. Placebo
Outcomes	1. Death 2. Average duration of diarrhoea 3. Stool output 4. Stool frequency 5. Adverse events (vomiting)
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Unclear risk	Bottles labelled with randomization numbers; no other details
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	5% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Brooks 2005a (20 mg)

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Methods	See Brooks 2005a
Participants	Number: 91 (5% lost at follow up)
Interventions	1. Zinc acetate: 20 mg 2. Placebo
Outcomes	See Brooks 2005a
Notes	See Brooks 2005a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Brooks 2005a for all descriptions
Allocation concealment (selection bias)	Unclear risk	See Brooks 2005a for all descriptions
Blinding (performance bias and detection bias) All outcomes	Low risk	See Brooks 2005a for all descriptions
Incomplete outcome data (attrition bias) All outcomes	Low risk	5% lost at follow up
Selective reporting (reporting bias)	Unclear risk	See Brooks 2005a for all descriptions
Other bias	Unclear risk	See Brooks 2005a for all descriptions

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Brooks 2005a (5 mg)

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Methods	See Brooks 2005a
Participants	Number: 91 (7% lost at follow up)
Interventions	1. Zinc acetate: 5 mg 2. Placebo
Outcomes	See Brooks 2005a
Notes	See Brooks 2005a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Brooks 2005a for all descriptions
Allocation concealment (selection bias)	Unclear risk	See Brooks 2005a for all descriptions
Blinding (performance bias and detection bias) All outcomes	Low risk	See Brooks 2005a for all descriptions
Incomplete outcome data (attrition bias) All outcomes	Low risk	7% lost at follow up
Selective reporting (reporting bias)	Unclear risk	See Brooks 2005a for all descriptions
Other bias	Unclear risk	See Brooks 2005a for all descriptions

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Dutta 2000

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Methods	RCT
Participants	Number: 80 Inclusion criteria: male, 3 to 24 months; malnourished (< 80% Harvard Standard weight for age); clinical signs of dehydration Exclusion criteria: antibiotics; systemic infections; chronic diseases; need for intensive care; exclusively breastfed
Interventions	1. Zinc sulphate: 40 mg/day 2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 5 3. Stool output
Notes	Location: India Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Code numbers kept in a sealed envelope; zinc and placebo bottles identical
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The number of lost at follow up is not specified
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Fajolu 2008

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Methods	RCT
Participants	Number: 60 Inclusion criteria: age 6 to 24 months; acute diarrhoea (less than 14 days duration) Exclusion criteria: refusal of consent; Protein Energy Malnutrition; use of stool hardeners, anti-motility drugs ant antibiotics; other medical condition requiring hospitalization
Interventions	1. zinc sulphate 20 mg (>12 months) or 10 mg (<12 months)   2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Stool frequency
Notes	Location: Nigeria Setting: hospital (follow up in the community)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not detailed
Allocation concealment (selection bias)	Unclear risk	Not detailed
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not detailed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Number of lost at follow up not specified
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Faruque 1999

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Methods	RCT
Participants	Number: 684 Inclusion criteria: children 6 to 24 months with acute diarrhoea, some dehydration and no severe dehydration; underweight or stunted children were not excluded Exclusion criteria: marasmus; kwashiorkor; systemic illnesses
Interventions	1. Zinc acetate: 14.2 mg (first 417 children) or 40 mg (other 273 children randomized) 2. Placebo Both groups: vitamin A
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 7
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Bottles serially numbered according to the randomization schedule to correspond to the serial number of the participant; supplements prepared by pharmaceutical company and provided in dark-coloured bottles
Blinding (performance bias and detection bias) All outcomes	Low risk
Incomplete outcome data (attrition bias) All outcomes	Low risk	4% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Fischer Walker 2006

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Methods	RCT
Participants	Number: 1110 Inclusion criteria: infants 1 to 5 months of age with acute diarrhoea (< 72 h) Exclusion criteria: severe malnutrition (< -3 z score weight for age); signs of pneumonia if < 2 months (cough and difficult or fast breathing with a respiratory rate of > 60 breaths/min); signs severe pneumonia if 2 to 5 months of age (cough or difficult fast breathing and chest indrawing, nasal flaring, or grunting); required hospitalization (overnight stay at a healthcare facility) for any reason; known major congenital malformation; any other serious pre-existing medical condition; lived out of or planned to move out of study area within following 3 months; previously enrolled in the study
Interventions	1. Zinc sulphate: 10 mg 2. Placebo
Outcomes	1. Death 2. Average duration of diarrhoea 3. Diarrhoea at day 7 4. Stool frequency 5. Hospitalisation 6. Adverse events (vomiting)
Notes	Location: Ethiopia, India, and Pakistan Setting: community
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Randomization scheme assigned in Geneva and kept secure until completion of data collection and initial analysis; upon enrolment, infants assigned chronological study identifiers corresponding to a pre-labelled blister pack of either zinc or placebo tablets
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	3% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Fischer Walker 2006 ETH

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Methods	See Fischer Walker 2006
Participants	Number: 177 (8% lost at follow up)
Interventions	See Fischer Walker 2006
Outcomes	See Fischer Walker 2006
Notes	Location: Ethiopia
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Fischer Walker 2006
Allocation concealment (selection bias)	Low risk	See Fischer Walker 2006
Blinding (performance bias and detection bias) All outcomes	Low risk	See Fischer Walker 2006
Incomplete outcome data (attrition bias) All outcomes	Low risk	8% lost at follow up
Selective reporting (reporting bias)	Unclear risk	See Fischer Walker 2006
Other bias	Unclear risk	See Fischer Walker 2006

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Fischer Walker 2006 IND

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Methods	See Fischer Walker 2006
Participants	Number: 373 (1% lost at follow up)
Interventions	See Fischer Walker 2006
Outcomes	See Fischer Walker 2006
Notes	Location: India
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Fischer Walker 2006
Allocation concealment (selection bias)	Low risk	See Fischer Walker 2006
Blinding (performance bias and detection bias) All outcomes	Low risk	See Fischer Walker 2006
Incomplete outcome data (attrition bias) All outcomes	Low risk	1% lost at follow up
Selective reporting (reporting bias)	Unclear risk	See Fischer Walker 2006
Other bias	Unclear risk	See Fischer Walker 2006

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Fischer Walker 2006 PAK

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Methods	See Fischer Walker 2006
Participants	Number: 560 (3% lost at follow up)
Interventions	See Fischer Walker 2006
Outcomes	See Fischer Walker 2006
Notes	Location: Pakistan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Fischer Walker 2006
Allocation concealment (selection bias)	Low risk	See Fischer Walker 2006
Blinding (performance bias and detection bias) All outcomes	Low risk	See Fischer Walker 2006
Incomplete outcome data (attrition bias) All outcomes	Low risk	3% lost at follow up
Selective reporting (reporting bias)	Unclear risk	See Fischer Walker 2006
Other bias	Unclear risk	See Fischer Walker 2006

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Khatun 2001

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Methods	RCT
Participants	Number: 100 Inclusion criteria: 6 to 36 months; moderately malnourished (61% to 75% of the median NCHS median weight for age); persistent diarrhoea Exclusion criteria: systemic infection; clinical signs of vitamin A deficiency; received vitamin A supplementation within 3 months; received prior antibiotics therapy; bloody mucoid diarrhoea; kwashiorkor; no longer received breast milk
Interventions	1. Zinc acetate: 20 mg 2. Placebo Both groups: multivitamins
Outcomes	1. Death 2. Average duration of diarrhoea 3. Diarrhoea at day 7 4. Stool output 5. Adverse events (vomiting)
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	No details
Allocation concealment (selection bias)	High risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Low risk	4% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Larson 2005

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Methods	RCT
Participants	Number: 1067 Inclusion criteria: child aged 3 to 59 months; acute diarrhoea; having taken oral rehydration solution as instructed; no vomiting in the past 2 h for the short-stay ward or 30 minutes in the outpatient clinic, and no longer dehydrated Exclusion criteria: returning to the hospital with diarrhoea; receiving zinc
Interventions	1. Zinc sulphate: 20 mg 2. Placebo
Outcomes	1. Adverse events (vomiting)
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Opaque envelopes numbered in which the assigned zinc tablet, placebo tablet, or a similar-sized button was placed; randomization schedule kept in a locked cabinet
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	None lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Patel 2009

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Methods	RCT
Participants	Number: 808 Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 h); ability to accept oral fluids or feeds   Exclusion criteria: severe dehydration and unable to drink,chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study
Interventions	1. zinc sulcates 2 mg/kg/die 2. zinc sulphate 2 mg/kg/die + copper 0.2 mg/kg/die 3. Placebo
Outcomes	1. Death 2. Average duration of diarrhoea 3. Diarrhoea at day 3 4. Diarrhoea at day 5 5. Diarrhoea at day 7
Notes	Location: India Setting: hospital (follow up in the community)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Single-site, blocked randomization procedure with blocks of sizes three, six and nine in equal proportions
Allocation concealment (selection bias)	Low risk	Randomization list generated off site by an investigator not directly involved in the data collection. The code list of the placebo and the treatment groups was secured and held only by the pharmacist at the Universal Medicaments Pvt. Ltd, Nagpur, until initial data analysis was completed
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind: bottle packs sequentially labelled according to the treatment allocation list and assigned to patients by the research physician
Incomplete outcome data (attrition bias) All outcomes	Low risk	7% lost at follow up
Selective reporting (reporting bias)	Low risk	Protocol available. Trial registered in metaRegister of Controlled Trials (ISRCTN85071383)
Other bias	Unclear risk	No information available

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Patel 2009a (zinc)

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Methods	RCT
Participants	Number: 808 Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 h); ability to accept oral fluids or feeds   Exclusion criteria: severe dehydration and unable to drink,chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study
Interventions	1. zinc sulphate 2 mg/kg/die 2. zinc sulphate 2 mg/kg/die + copper 0.2 mg/kg/die 3. Placebo
Outcomes	1. Death 2. Average duration of diarrhoea 3. Diarrhoea at day 3 4. Diarrhoea at day 5 5. Diarrhoea at day 7
Notes	Location: India Setting: hospital (follow up in the community)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Patel 2009
Allocation concealment (selection bias)	Low risk	See Patel 2009
Blinding (performance bias and detection bias) All outcomes	Low risk	See Patel 2009
Incomplete outcome data (attrition bias) All outcomes	Low risk	See Patel 2009
Selective reporting (reporting bias)	Low risk	See Patel 2009
Other bias	Unclear risk	See Patel 2009

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Patel 2009b (zinc+copper)

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Methods	See Patel 2009a
Participants	See Patel 2009a
Interventions	See Patel 2009a
Outcomes	See Patel 2009a
Notes	See Patel 2009a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Patel 2009
Allocation concealment (selection bias)	Low risk	See Patel 2009
Blinding (performance bias and detection bias) All outcomes	Low risk	See Patel 2009
Incomplete outcome data (attrition bias) All outcomes	Low risk	See Patel 2009
Selective reporting (reporting bias)	Low risk	See Patel 2009
Other bias	Unclear risk	See Patel 2009

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Patro 2010

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Methods	RCT
Participants	Number: 160 Inclusion criteria: age 3 to 48 months diagnosed with acute diarrhoea lasting less than 5 days, with at least some degree of dehydration. Exclusion criteria: diarrhoea lasting <1 day or >5 days, recent history of diarrhoea (last 2 weeks before enrolment day), chronic gastrointestinal disease with diarrhoea manifestation, (eg, food allergy, celiac disease), weight-to-height ratio <5^th percentile, severe dehydration, coexistence of serious systemic disease(s), coadministration of antibiotics, exclusive or >50% breastfeeding, immunodeficiency, immunosuppressive therapy.
Interventions	1. Zinc sulphate (20 mg in children >6 months or 10 mg in children <6 months)   2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 7
Notes	Location:Poland Setting: hospital (90% of children) and outpatient (10%)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Two different randomization lists for each centre were computer-generated by an investigator at the Medical University of Warsaw.
Allocation concealment (selection bias)	Low risk	The glass bottles containing the products were labelled with the patient’s number corresponding to the randomization list by an independent individual who was not involved in patient enrolment. Randomization codes were secured until the completion of data collection and initial analysis. The placebo was identically supplied and formulated. There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.
Blinding (performance bias and detection bias) All outcomes	Low risk	Investigators, participants, outcome assessors, and data analysts
Incomplete outcome data (attrition bias) All outcomes	High risk	11.8% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	Note: source of funding: Nutricia.

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Penny 1999

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Methods	RCT
Participants	Number: 413 Inclusion criteria: 6 to 36 months, persistent diarrhoea Exclusion criteria: vitamins or minerals within 6 weeks; major congenital malformation affecting growth; severe dehydration; requiring hospitalization
Interventions	1. Zinc gluconate: 20 mg 2. Placebo
Outcomes	1. Death 2. Hospitalization 3. Diarrhoea at day 3 4. Diarrhoea at day 5 5. Diarrhoea at day 7 6. Adverse events (vomiting)
Notes	Location: Peru Setting: community
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer-generated random numbers
Allocation concealment (selection bias)	Low risk	Randomization numbers linked to letter codes, each indicating 1 treatment group; codes kept secret; supplements provided by independent laboratories
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	None lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Polat 2003

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Methods	RCT
Participants	Number: 200 Inclusion criteria: 2 to 29 months; malnourished children (weight for age scale, score < 76% according to NCHS standards); acute non-bacterial diarrhoea Exclusion criteria: concomitant illness or oedema
Interventions	1. Zinc sulphate: 20 mg 2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Diarrhoea at day 3 3. Diarrhoea at day 7 4. Adverse events (vomiting)
Notes	Location: Turkey Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Bottles labelled with randomization numbers, no other details
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	9% lost to follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Polat 2003 low Zn

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Methods	See Polat 2003
Participants	Number: 76 Children with low zinc serum levels
Interventions	See Polat 2003
Outcomes	See Polat 2003
Notes	See Polat 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Polat 2003
Allocation concealment (selection bias)	Low risk	See Polat 2003
Blinding (performance bias and detection bias) All outcomes	Low risk	See Polat 2003
Incomplete outcome data (attrition bias) All outcomes	Low risk	See Polat 2003
Selective reporting (reporting bias)	Unclear risk	See Polat 2003
Other bias	Unclear risk	See Polat 2003

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Polat 2003 normal Zn

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Methods	See Polat 2003
Participants	Number: 106 Children with normal zinc serum levels
Interventions	See Polat 2003
Outcomes	See Polat 2003
Notes	See Polat 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See Polat 2003
Allocation concealment (selection bias)	Low risk	See Polat 2003
Blinding (performance bias and detection bias) All outcomes	Low risk	See Polat 2003
Incomplete outcome data (attrition bias) All outcomes	Low risk	See Polat 2003
Selective reporting (reporting bias)	Unclear risk	See Polat 2003
Other bias	Unclear risk	See Polat 2003

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Roy 1997

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Methods	RCT
Participants	Number: 111 Inclusion criteria: 2 to 24 months; weight below the 76^th centile of weight-for-age according to the NCHS standard 18 (by Gomez classification, protein energy malnutrition grades II and III included) Exclusion criteria: systemic infection or oedema
Interventions	1. Zinc acetate: 20 mg 2. Placebo Both groups: multivitamin
Outcomes	1. Average duration of diarrhoea 2. Stool output
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers
Allocation concealment (selection bias)	Low risk	Bottles labelled with randomization numbers
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	High risk	32.4% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Roy 1998

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Methods	RCT
Participants	Number: 190 Inclusion criteria: 3 to 24 months; persistent diarrhoea; underweight (low weight-for-age) using a cut-off of 70% weight/age of the 50th centile of the NCHS standard; wasted (low weight/height) using a cut-off of 80%; short (low height/age) using a cut-off of less than 95% of the height/age standard Exclusion criteria: none stated
Interventions	1. Zinc acetate: 20 mg 2. Placebo Both groups: multivitamin
Outcomes	1. Death 2. Average duration of diarrhoea 3. Adverse events
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if any lost to follow up; 11% discontinued intervention
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Roy 2008

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Methods	RCT
Participants	Number: 56 Inclusion criteria: aged 12 to 59 months; moderately malnourished (weight/age 61% to 75% of NCHS median); history suggestive of dysentery (eg bloody-mucoid diarrhoea or febrile diarrhoea less than 5-days' duration); with culture-proven shigellosis Exclusion criteria: severe malnutrition; receiving zinc supplementation; measles in the last 6 months; living beyond 2 h of travel time; complications such as haemolytic uraemic syndrome or other systemic illness, including pneumonia, meningitis, and septicaemia
Interventions	1. Zinc acetate: 10 mg 2. Placebo Both groups: multivitamins
Outcomes	1. Death 2. Average duration of diarrhoea 3. Diarrhoea at day 7
Notes	Location: Bangladesh Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers
Allocation concealment (selection bias)	Low risk	Bottles identical labelled with sequential numbers that had earlier been allocated to either intervention or control according to the randomization
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	High risk	11% lost at follow up
Selective reporting (reporting bias)	Low risk	Trial registered in ClinicalTrial.gov (NCT00321126)
Other bias	Unclear risk	No information available

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Sachdev 1988

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Methods	RCT
Participants	Number: 50 Inclusion criteria: children 6 to 18 months; dehydration secondary to acute diarrhoea of < 4 days' duration Exclusion criteria: antibiotics; severe malnutrition (grades III and IV); concomitant features (meningitis, pneumonia, liver disease, otitis media, fever > 39 °C)
Interventions	1. Zinc sulphate: 20 mg 2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Stool frequency 3. Adverse events (vomiting)
Notes	Location: India Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No details
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Sachdev 1990

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Methods	RCT
Participants	Number: 40 Inclusion criteria: 6 to 18 months; persistent diarrhoea Exclusion criteria: another diarrhoeal episode 1 month prior; critically ill; obvious parenteral infections; severe malnutrition (grade III and IV)
Interventions	1. Zinc sulphate: 20 mg 2. Placebo
Outcomes	1. Average duration of diarrhoea 2. Stool frequency 3. Adverse events (vomiting)
Notes	Location: India Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No details
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

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Sazawal 1995

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Methods	RCT
Participants	Number: 947 Inclusion criteria: 6 to 35 months; diarrhoea for 7 days; permanent resident in study area; stunted defined (length for age less than -2 standard deviation) Exclusion criteria: second visit; malnutrition requiring hospitalization; not provide consent
Interventions	1. Zinc gluconate: 20 mg 2. Placebo Both groups: multivitamin
Outcomes	1. Diarrhoea at day 7 2. Stool frequency 3. Adverse events (vomiting)
Notes	Location: India Setting: hospital
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Children allocated to sequential numbers indicating zinc or placebo; code kept by World Health Organization, not available for investigators
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	2% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

---

Strand 2002

---

Methods	RCT
Participants	Number: 899 Inclusion criteria: 6 to 35 months; diarrhoea < 96 h Exclusion criteria: massive dose of vitamin A; requiring hospitalization; family intended to leave Bhaktapur within 2 months
Interventions	1. Zinc gluconate: 15 mg for infants; 30 mg for older children 2. Placebo
Outcomes	1. Diarrhoea at day 3 2. Diarrhoea at day 7 3. Adverse events (vomiting) 4. Adverse events (copper levels)
Notes	Location: Nepal Setting: community
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers
Allocation concealment (selection bias)	Low risk	Packing with serial number; list kept in Copenhagen; capsule identical in appearance; syrup identical in appearance and taste
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	1% lost at follow up
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No information available

---

 NCHS: National Center for Health Statistics.
RCT: randomized controlled trial.

 

Characteristics of excluded studies [ordered by study ID]

---

Study	Reason for exclusion
Adu Afarwuah 2007	Not concerning the intervention of interest (3 types of micronutrients for food fortification)
Adu-Afarwuah 2008	Not concerning the intervention of interest (zinc fortification)
Aggarwal 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Agustina 2007	Not concerning the intervention of interest (probiotic, prebiotic, fibre, and micronutrients mixture)
Alarcon 2004	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Awasthi 2006	Not concerning the intervention of interest (zinc in oral rehydration solution)
Baqui 2002	Community RCT without a placebo group
Baqui 2003	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Baqui 2006	Not concerning any outcome of interest (serum zinc)
Baum 2010	Not concerning the population of interest (adults, HIV positive)
Behrens 1990	Not concerning any outcome of interest (nutritional status)
Bhandari 2002	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2005	Not a RCT
Bhandari 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2008	RCT without a placebo group
Bhatnagar 2004b	Not a RCT
Bhutta 2000a	Not concerning any outcome of interest (appetite)
Bilenko 2010	Not concerning the intervention of interest (multiple micronutrients in sprinkles)
Black 2001	Not a RCT
Bobat 2005	Not concerning the population of interest (only children with HIV enrolled)
Borges 2007	Not a RCT
Brooks 2005b	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Brown 2007	Not concerning the Intervention of interest (food fortification)
Brown 2007a	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Carbajal 2000	Not a placebo-controlled RCT
Carcamo 2006	Not concerning the population of interest (adults with HIV)
Chandyo 2010	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chang 2010	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chen 2010	Not concerning the intervention of interest (food fortification with multiple micronutrients)
Chhagan 2009	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chhagan 2010	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Christian 2009	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, on a different population (pregnant women)
CIGNIS 2010	Not concerning the intervention of interest (food fortification with multiple micronutrients)
Cross 2009	Not RCT
Dhingra 2009	Not RCT
Doherty 1998	Not a placebo-controlled RCT, and criteria for inclusion of children was malnutrition, not diarrhoea
Ebrahimi 2006	Not concerning any outcome of interest (growth)
Ellis 2007	Not a RCT
Ferraz 2007	Not RCT
Ferrufino 2007	Not RCT
Fischer Walker 2008	Secondary analysis of a previously excluded study (Baqui 2002)
Gardner 2005	Not a RCT
Garenne 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gregorio 2007	Not concerning the intervention of interest (zinc-fortified oral rehydration solution)
Gupta 2003	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gupta 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Heinig 2006	Not concerning any outcome of interest (growth, morbidity, and motor development)
Hettiarachchi 2008	Not concerning the population of interest (children 12-16 years), nor the outcomes
Hidayat 1998	Community RCT, but results could not be compared with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea)
Hoque 2006	Not RCT (review)
Hyder 2007	Not concerning the population of interest (adolescent girl), the intervention (multiple micronutrients), nor the outcomes.
Iannotti 2010	Not concerning the population of interest (pregnant women)
Islam 2010	Not concerning the population of interest (preterm infants), nor any outcome of interest (growth)
Jimenez 2000	Not concerning any outcome of interest (growth)
Kelly 1999	Intervention and the population (micronutrient supplementation in AIDS diarrhoea-wasting syndrome) considered in this RCT not relevant
Kelly 2010	Not concerning any outcome of interest (intestinal function)
Larson 2010	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lin 2008	Not placebo controlled, not outcomes of interest (weight)
Lind 2004	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lind 2008	Secondary analysis of a previously excluded study (Lind 2004)
Lira 1998	Not concerning the population of interest (low birthweight infants)
Long 2006	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Long 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Lopez 2005	Not concerning the intervention of interest (multiple micronutrient), nor the outcomes (anaemia, micronutrient status, growth, and morbidity)
Luabeya 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lukacik 2008	Not RCT (meta-analysis)
Makonnen 2003a	Not concerning any outcome of interest
Makonnen 2003b	Not concerning any outcome of interest
Manger 2008	No placebo controlled, different intervention (multiple micronutrients), prevention study
Mazariegos 2010	Not concerning any outcome of interest (linear growth)
Mazumder 2010	Secondary analysis of a previously excluded study (Bhandari 2008)
Mda 2010	Not concerning population of interest (only children with HIV), different intervention (multiple micronutrient)
Meeks 1998	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Müller 2001	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Naheed 2009	Secondary analysis of a previously excluded study (Baqui 2002)
Nasrin 2005	Not a RCT
Nga 2009	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Osendarp 2002	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Ouedraogo 2008	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Passariello 2010	Not concerning the intervention of interest (zinc in oral rehydration solution)
Patel 2005	Not concerning the intervention of interest (zinc and copper in oral rehydration solution)
Patel 2010	Secondary analysis of an included study (Patel 2009), with no outcome of interest (by isolated micro-organism)
Patel 2010a	Not a RCT (review)
Patro 2008	Not RCT (meta-analysis)
Penny 2004a	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Penny 2004b	Not a RCT
Polat 2006	Not a placebo-controlled RCT
Rahman 2001	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rahman 2005	Not concerning any outcome of interest
Raqib 2004	Not concerning any outcome of interest (immune and inflammatory responses)
Richard 2006	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rollins 2007	Not concerning the population of interest (only HIV infected children), and different outcomes (growth, immunity)
Rosado 1997	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rosado 1998	Not a RCT
Rosado 2009	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Roy 1992	Not concerning any outcome of interest (intestinal permeability)
Roy 1999	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2008a	Not concerning the population of interest (children aged between 3 and 14 years)
Ruel 1997	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sabatier 1997	Not a placebo-controlled RCT
Samuel 1995	Not a RCT
Sancho Martinez 2007	Not RCT (review)
Sazawal 1996	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 1997a	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2004a	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2007a	Not concerning the intervention of interest (milk fortification)
Sazawal 2007b	Not concerning any outcome of interest (plasma retinol)
Sazawal 2007c	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Shamir 2005	Not concerning the interventions (zinc and probiotics) considered in this RCT not relevant
Shankar 1998	Not RCT (Review)
Sharieff 2006	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sheikh 2010	Not a RCT
Sur 2003	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Taneja 2009	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, in a different population (low birth weight infants)
Taneja 2010	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (growth)
Tielsch 2006	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Tielsch 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Umeta 2000	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Untoro 2005	Not concerning the intervention of interest (multiple micronutrient), nor any outcome(anaemia, micronutrient status, growth, and morbidity)
Valery 2005	Not concerning the population of interest (all children aged under 11 years)
Walden 2004	Not a RCT
Walker 2007	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Wieringa 2010	Not concerning the population of interest (pregnant women)
Winch 2006	Not a RCT
Winch 2008	Not a RCT
Wuehler 2008	RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

---

 AIDS: acquired immune deficiency syndrome.
HIV: human immunodeficiency virus.
RCT: randomized controlled trial.

 

Characteristics of ongoing studies [ordered by study ID]

NCT01140074

---

Trial name or title	Efficacy of Zinc Sulfate With Probiotics for the Treatment of Acute diarrhoea in Children
Methods	Study design: Randomised Controlled Trial
Participants	Inclusion Criteria: Age 1-36 months Acute diarrhoea defined as 3 or more watery stools per day Informed consent (parents) Exclusion Criteria: Severe dehydration (> 10%) Coexisting severe infection (e.g. sepsis, pneumonia, meningitis) Immune deficiency Chronic digestive tract disease (e.g. celiac diseases, food allergy) Antibiotic therapy
Interventions	1. Zinc sulphate 10-20 mg per day orally plus probiotics 2. Zinc sulphate 10-20 mg per day orally 3.Placebo
Outcomes	1. Period of diarrhoea in hours [ Time Frame: 15 days ] [ Designated as safety issue: No ] 2. Number of stools in consequent days [ Time Frame: 15 days ] 3. Hospitalization 4. Tolerability 5. Adherence to the therapy
Starting date	July 2010 (not yet recruiting in December 2010)
Contact information	Contact: Leszek Szenborn, Prof [e-mail] (principal investigator) Contact: Ernest P. Kuchar, MD [e-mail]
Notes	Location: Poland Registration number: NCT01140074 Source of funding: unclear Sponsor: University Hospital No 1 Wroclaw

---

NCT01198587

---

Trial name or title	A Double Blind Randomized Placebo Controlled Trial of Oral Zinc for Children With Acute diarrhoea in a Developed Nation.
Methods	Study design: randomised controlled trial
Participants	Inclusion Criteria: Healthy Children with non-bloody diarrhoea illness defined as loose or watery stools Symptoms must be present for greater than 24 hours but less than 72 hours. Comorbid conditions including; Asthma, Gastroesophageal reflux (unless followed by a Gastroenterologist), Mild speech, language, motor delays, Benign heart murmurs, Isolated atrial septal defect (ASD) or ventricular septal defect VSD, Epilepsy (unless developmentally delayed), Children born Prematurely between 33-37 weeks without long term sequelae, Repaired tetralogy of Fallot (no cardiac issues for >6 months), Diabetes may be enrolled in the study. Exclusion Criteria: Children with symptoms less than 24 hours Children with symptoms greater than 24 hours Failure to thrive G or J tube Major surgery within last 3 months Minor surgery (tonsillectomy, ear tubes, skin lesion removals etc) within last 1 month Followed by GI service for any reason (Crohn, ulcerative colitis, constipation Developmental delay, patient >1 year behind milestones Current brain tumour Currently being treated for cancer or in remission < 6 months Intussuception Antibiotics in the last 14 days or currently taking antibiotics for any reason Autism Children born premature <33 weeks Cystic Fibrosis Major congenital Heart Disease (any disease where child's baseline oxygen saturations <93%) Short Gut Liver disease History of bowel resection Age minimum: 6 Months Age maximum: 6 Years Gender: Both
Interventions	1. Zinc Sulfate For children ages 6month to 1 year, 12.5mg orally daily for 14 days mixed in 60 mL of fluid. For children aged 1 year and above 25mg orally daily for 14 days mixed in 60 mL of fluid. 2. Placebo
Outcomes	1. Duration of diarrhoea in acute diarrhoeal illnesses in a developed nation while taking zinc or placebo.[Time Frame: 14 days] 2. Length of hospitalization for children with diarrhoeal illness taking zinc or placebo.[Time Frame: 14 days of study medication]
Starting date	September 2010
Contact information	Michelle L Niescierenko, MD [e-mail] Children's Hospital Boston
Notes	Location: USA Registration number: NCT01198587 Source of funding: unclear Sponsor: Children's Hospital Boston

---

 

Comparison 1. Zinc vs placebo for acute diarrhoea

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Diarrhoea duration (h)

17

4242

Mean Difference (IV, Random, 95% CI)

-9.60 [-18.25, -0.96]

---

1.1 Age < 6 months

5

1334

Mean Difference (IV, Random, 95% CI)

5.23 [-2.00, 14.45]

---

1.2 Age > 6 months

5

2091

Mean Difference (IV, Random, 95% CI)

-5.62 [-13.88, 2.63]

---

1.3 Ages both < and > 6 months

7

817

Mean Difference (IV, Random, 95% CI)

-19.05 [-31.65, -6.44]

---

 2 Diarrhoea on day 3

4

1568

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

0.77 [0.67, 0.89]

---

2.1 Age > 6 months

2

1386

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

0.84 [0.71, 0.99]

---

2.2 Ages both < and > 6 months

2

182

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

0.55 [0.42, 0.72]

---

 3 Diarrhoea on day 5

4

1646

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

0.74 [0.55, 0.99]

---

3.1 Age > 6 months

2

1300

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

0.83 [0.59, 1.18]

---

3.2 Ages both < and > 6 months

2

346

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

0.55 [0.32, 0.95]

---

 4 Diarrhoea on day 7

13

5528

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

0.82 [0.72, 0.94]

---

4.1 Age < 6 months

3

1074

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

1.24 [0.99, 1.54]

---

4.2 Age > 6 months

6

3865

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

0.73 [0.61, 0.88]

---

4.3 Ages both < and > 6 months

4

589

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

0.31 [0.18, 0.52]

---

 5 Stool frequency (stools /day)

9

2323

Mean Difference (IV, Fixed, 95% CI)

-0.05 [-0.20, 0.10]

---

5.1 Age < 6 months

5

1334

Mean Difference (IV, Fixed, 95% CI)

0.0 [-0.17, 0.17]

---

5.2 Age > 6 months

3

915

Mean Difference (IV, Fixed, 95% CI)

-0.16 [-0.47, 0.15]

---

5.3 Ages both < and > 6 months

1

74

Mean Difference (IV, Fixed, 95% CI)

-5.9 [-9.44, -2.36]

---

 6 Adverse events (vomiting)

12

5189

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

1.59 [1.27, 1.99]

---

6.1 Age < 6 months

3

1334

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

1.54 [1.05, 2.24]

---

6.2 Age > 6 months

5

2340

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

1.56 [1.32, 1.85]

---

6.3 Ages both < and > 6 months

4

1515

Risk 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 title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Diarrhoea duration (h)

13

Mean Difference (IV, Random, 95% CI)

Subtotals only

---

1.1 Nutritional status: only well-nourished

1

141

Mean Difference (IV, Random, 95% CI)

1.80 [-13.55, 17.15]

---

1.2 Nutritional status: well-nourished plus moderately malnourished

7

2431

Mean Difference (IV, Random, 95% CI)

-10.38 [-19.18, -1.57]

---

1.3 Nutritional status: malnourished

4

336

Mean Difference (IV, Random, 95% CI)

-26.98 [-39.34, -14.62]

---

1.4 Sex: male

2

346

Mean Difference (IV, Random, 95% CI)

-21.22 [-44.93, 2.49]

---

1.5 Sex: male and female

10

2562

Mean Difference (IV, Random, 95% CI)

-12.47 [-21.83, -3.12]

---

1.6 Region: Africa

1

60

Mean Difference (IV, Random, 95% CI)

-2.40 [-33.25, 28.45]

---

1.7 Region: Asia

9

2633

Mean Difference (IV, Random, 95% CI)

-15.11 [-26.46, -3.75]

---

1.8 Region: South America

1

74

Mean Difference (IV, Random, 95% CI)

-31.20 [-46.43, -15.97]

---

1.9 Region: Europe

1

141

Mean Difference (IV, Random, 95% CI)

1.80 [-13.55, 17.15]

---

1.10 Region: countries ranked as high risk of zinc deficiency

7

2451

Mean Difference (IV, Random, 95% CI)

-13.54 [-26.26, -0.82]

---

1.11 Region: countries ranked as medium risk of zinc deficiency

4

316

Mean Difference (IV, Random, 95% CI)

-20.27 [-40.62, 0.08]

---

1.12 Region: countries ranked as low risk of zinc deficiency

1

141

Mean Difference (IV, Random, 95% CI)

1.80 [-13.55, 17.15]

---

1.13 Zinc dose: 20 mg

6

507

Mean Difference (IV, Random, 95% CI)

-12.18 [-26.79, 2.43]

---

1.14 Zinc dose: > 20 mg

3

959

Mean Difference (IV, Random, 95% CI)

-23.52 [-42.09, -4.94]

---

1.15 Zinc type: zinc acetate

2

755

Mean Difference (IV, Random, 95% CI)

-20.79 [-34.90, -6.68]

---

1.16 Zinc type: gluconate

1

805

Mean Difference (IV, Random, 95% CI)

-7.20 [-15.33, 0.93]

---

1.17 Zinc type: zinc sulphate

9

1348

Mean Difference (IV, Random, 95% CI)

-14.04 [-26.76, -1.32]

---

1.18 Study setting: hospital

11

2103

Mean Difference (IV, Random, 95% CI)

-15.14 [-26.25, -4.04]

---

1.19 Study setting:community

1

805

Mean Difference (IV, Random, 95% CI)

-7.20 [-15.33, 0.93]

---

1.20 Concomitant treatment: zinc alone

12

2784

Mean Difference (IV, Random, 95% CI)

-14.40 [-24.06, -4.75]

---

1.21 Concomitant treatment: zinc plus copper

1

383

Mean 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 title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Diarrhoea on day 7

11

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

Subtotals only

---

1.1 Nutritional status: only well nourished

1

141

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

0.35 [0.04, 3.26]

---

1.2 Nutritional status: well nourished plus moderately malnourished

6

4075

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

0.72 [0.60, 0.86]

---

1.3 Nutritional status: malnourished

3

238

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

0.37 [0.22, 0.61]

---

1.4 Sex: male

1

266

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

0.11 [0.01, 0.88]

---

1.5 Sex: male and female

9

4188

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

0.68 [0.58, 0.81]

---

1.6 Region: Asia

9

4313

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

0.67 [0.56, 0.79]

---

1.7 Region: Europe

1

141

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

0.35 [0.04, 3.26]

---

1.8 Region: countries ranked as high risk of zinc deficiency

6

3240

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

0.75 [0.62, 0.92]

---

1.9 Region: countries ranked as medium risk of zinc deficiency

3

1073

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

0.49 [0.35, 0.68]

---

1.10 Region: countries ranked as low risk of zinc deficiency

1

141

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

0.35 [0.04, 3.26]

---

1.11 Zinc dose: 20 mg

8

3154

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

0.62 [0.51, 0.74]

---

1.12 Zinc dose: >20mg

1

805

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

0.67 [0.38, 1.19]

---

1.13 Zinc type: zinc acetate

3

1628

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

0.60 [0.45, 0.79]

---

1.14 Zinc type:gluconate

1

805

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

0.67 [0.38, 1.19]

---

1.15 Zinc type: zinc sulphate

6

2021

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

0.72 [0.57, 0.90]

---

1.16 Study setting: hospital

8

2758

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

0.69 [0.56, 0.84]

---

1.17 Study setting: community

2

1696

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

0.61 [0.44, 0.85]

---

1.18 Concomitant treatment: zinc alone

10

4330

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

0.65 [0.55, 0.78]

---

1.19 Concomitant treatment: zinc plus copper

1

383

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

1.03 [0.43, 2.45]

---

 

Comparison 4. Zinc vs placebo for persistent diarrhoea

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Diarrhoea duration (h)

5

529

Mean Difference (IV, Fixed, 95% CI)

-15.84 [-25.43, -6.24]

---

1.1 Age > 6 months

4

388

Mean Difference (IV, Fixed, 95% CI)

-16.01 [-26.16, -5.86]

---

1.2 Ages both < and > 6 months

1

141

Mean Difference (IV, Fixed, 95% CI)

-14.40 [-43.77, 14.97]

---

 2 Diarrhoea on day 3

1

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

Totals not selected

---

2.1 Age > 6 months

1

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

0.0 [0.0, 0.0]

---

 3 Diarrhoea on day 5

1

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

Totals not selected

---

3.1 Age > 6 months

1

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

0.0 [0.0, 0.0]

---

 4 Diarrhoea on day 7

2

221

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

0.52 [0.27, 1.02]

---

4.1 Age > 6 months

2

221

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

0.52 [0.27, 1.02]

---

 5 Stool frequency (stools/day)

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

---

5.1 Age > 6 months

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

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 6 Adverse events (vomiting)

4

505

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

1.97 [0.37, 10.59]

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6.1 Age > 6 months

3

364

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

1.97 [0.37, 10.59]

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6.2 Ages both < and > 6 months

1

141

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

0.0 [0.0, 0.0]

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Summary of findings for the main comparison. Zinc compared to placebo for children with acute diarrhoea

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Zinc compared to placebo for children with acute diarrhoea
Patient or population: children with acute diarrhoea Settings: all countries Intervention: zinc Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	Zinc
Diarrhoea duration (h) hours	The mean diarrhoea duration (h) ranged across control groups from 59 to 170 hours	The mean diarrhoea duration (h) in the intervention groups was 9.6 lower (18.25 to 0.96 lower)		4242 (17 studies)	⊕⊕⊕⊝ moderate^1
Diarrhoea on day 3	Study population		RR 0.77 (0.67 to 0.89)	1568 (4 studies)	⊕⊕⊕⊝ moderate^2
	374 per 1000	288 per 1000 (251 to 333)
	Medium risk population
	547 per 1000	421 per 1000 (366 to 487)
Diarrhoea on day 5	Study population		Range from 0.55 to 0.99	1646 (4 studies)	⊕⊕⊝⊝ low^2,3
	114 per 1000	See comment
	Medium risk population
	118 per 1000	See comment
Diarrhoea on day 7	Study population		RR 0.82 (0.72 to 0.94)	5528 (13 studies)	⊕⊕⊕⊝ moderate^1,3
	146 per 1000	120 per 1000 (105 to 137)
	Medium risk population
	156 per 1000	128 per 1000 (112 to 147)
Stool frequency (stools /day) (Copy)	The mean stool frequency (stools /day) (copy) ranged across control groups from 4 to 10 stools/day	The mean stool frequency (stools /day) (Copy) in the intervention groups was 0.05 lower (0.2 lower to 0.1 higher)		2323 (9 studies)	⊕⊕⊕⊕ high
Mortality (Copy) number of death	3 per 1000	1 per 1000 (0 to 9)	RR 0.30 (0.03 to 2.92)	1885 (4 studies)	⊕⊕⊝⊝ low
Adverse events (vomiting) (Copy)	Study population		RR 1.59 (1.27 to 1.99)	5189 (12 studies)	⊕⊕⊕⊝ moderate
	134 per 1000	213 per 1000 (170 to 267)
	Medium risk population
	79 per 1000	126 per 1000 (100 to 157)
*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.

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 ^1 Stratification by age significantly reduced heterogeneity.
^2 There was significant heterogeneity among trials.
^3 95% CIs include both negligible effect and appreciable benefit

 

Summary of findings 2. Zinc compared to placebo for children with persistent diarrhoea

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Zinc compared to placebo for children with persistent diarrhoea
Patient or population: children with persistent diarrhoea Settings: all countries Intervention: zinc Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	Zinc
Diarrhoea duration (h)	The mean diarrhoea duration (h) ranged across control groups from 84 to 168 hours	The mean diarrhoea duration (h) in the intervention groups was 15.84 lower (25.43 to 6.24 lower)		529 (5 studies)	⊕⊕⊕⊝ moderate^1
Diarrhoea on day 7	Study population		RR 0.52 (0.27 to 1.02)	221 (2 studies)	⊕⊝⊝⊝ very low^1,2,3
	191 per 1000	99 per 1000 (52 to 195)
	Medium risk population
	317 per 1000	165 per 1000 (86 to 323)
Mortality	25 per 1000	5 per 1000 (0 to 39)	RR 0.19 (0.02 to 1.55)	402 (3 studies)	⊕⊝⊝⊝ very low^1,4
Adverse events (vomiting)	Study population		RR 1.97 (0.37 to 10.59)	505 (4 studies)	⊕⊕⊝⊝ low^1,3,5
	8 per 1000	16 per 1000 (3 to 85)
	Medium risk population
	0 per 1000	0 per 1000 (0 to 0)
*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.

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 ^1 Most trials had limitations in design
^2 Significant heterogeneity (I^2=74%)
^3 95% CIs include both benefit and harm
^4 Trials were not designed to measure mortality
^5 Not applicable: only one study reported events (vomiting).

 

Summary of findings 3. zinc compared to placebo for children < 6 months with acute diarrhoea

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zinc compared to placebo for children < 6 months with acute diarrhoea
Patient or population: children < 6 months with acute diarrhoea Settings: low and middle income countries Intervention: zinc Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	zinc
Diarrhoea duration (h)	The mean diarrhoea duration (h) ranged across control groups from 98 to 133 hours	The mean diarrhoea duration (h) in the intervention groups was 5.23 higher (4 lower to 14.45 higher)		1334 (5 studies)	⊕⊕⊕⊝ moderate^1,2
Diarrhoea on day 7	203 per 1000	252 per 1000 (201 to 313)	RR 1.24 (0.99 to 1.54)	1074 (3 studies)	⊕⊕⊕⊝ moderate^1,3
Stool frequency (stools /day)	The mean stool frequency (stools /day) ranged across control groups from 4 to 6 stools/day	The mean stool frequency (stools /day) in the intervention groups was 0 higher (0.17 lower to 0.17 higher)		1334 (5 studies)	⊕⊕⊕⊕ high^1
Adverse events (vomiting)	64 per 1000	99 per 1000 (67 to 143)	RR 1.54 (1.05 to 2.24)	1334 (3 studies)	⊕⊕⊕⊝ moderate^1,3
*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.

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 ^1 All studies were held in low and middle income countries
^2 95% CIs include both negligible effect and appreciable harm
^3 95% CIs include both negligible effect and appreciable harm

 

Table 1. Detailed search strategies

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Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b	CINAHL	CCT
1	zinc	zinc	zinc	zinc	zinc	zinc	zinc
2	diarrhoea	diarrhoea	ZINC	ZINC	diarrhoea	diarrhoea	diarrhoea
3	vomiting	morbidity	1 or 2	1 or 2	morbidity	morbidity	vomiting
4	adverse effects	2 or 3	diarrhoea	diarrhoea	2 or 3	2 or 3	adverse effects
5	—	1 and 4	diarrhoea	morbidity	1 and 4	1 and 4	—
6	—	vomiting	morbidity	4 or 5	vomiting	vomiting	—
7	—	adverse effects	MORBIDITY	3 and 6	adverse effects	adverse effects	—
8	—	6 or 7	4 or 5 or 6 or 7	Limit 7 to human	6 or 7	6 or 7	—
9	—	1 and 2 and 8	3 and 8	vomiting	1 and 2 and 8	1 and 8	—
10	—	—	Limit 9 to human	adverse effects	—	—	—
11	—	—	vomiting	9 or 10	—	—	—
12	—	—	adverse effects	3 and 4 and 11	—	—	—
13	—	—	11 or 12	—	—	—	—
14	—	—	3 and (4 or 5) and 13	—	—	—	—

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 ^aCochrane Infectious Diseases Group Specialized Register.
^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

 

Table 2. Results of the study selection

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Studies identified through the search	218
Excluded as clearly not concerning the topic of interest	64 trials
Further evaluated and excluded ^a	127
Not RCTs: 24 trials Not placebo-controlled RCTs: 8 trials RCTs on prevention of diarrhoea, not on treatment: 46 trials Not concerning the population of interest (eg studies on low birthweight, HIV): 13 trials Not concerning the interventions of interest (eg studies on zinc in oral rehydration solution, multiple micronutrients, probiotics, food fortification):16 trials Concerning different outcomes (eg studies on serology, appetite, mental or motor development, malnutrition): 14 trials Could not be compared with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea): 1 trial Secondary analysis of other studies: 5
Duplicate of included studies	5 trials
Folwaczny 1996; Darmon 1997 are review articles of the same trial (Sazawal 1995) Roy 1991 is a duplication of Roy 1997 and Roy 1998 Roy 1998b is an abstract of Khatun 2001 Cuevas 2000 is an abstract of Al-Sonboli 2003
Independent trials included in the review	22 RCTs (8924 participants)

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 ^aSee 'Characteristics of excluded studies'
HIV: human immunodeficiency virus
RCT: randomized controlled trial

 

Table 3. Stool output

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Study	Outcome	Units	N zinc	Values zinc	N placebo	Values placebo	Mean difference or rate ratio	Statistical test
ACUTE DIARRHOEA
Age < 6 months
Brooks 2005a (5 mg)	Total (mL)	Mean (95% CI)	85	229 (180 to 256)	45	202 (180 to 246)	27 (-23.3 to 77.3)^a	Not significant
Brooks 2005a (20 mg)	Total (mL)	Mean (95% CI)	86	240 (200 to 266)	44	202 (180 to 246)	38 (-8.6 to 84.6)^a	Not significant
Age > 6 months
Patel 2009a (zinc)	Total (g)	Mean (SD)	248	972 (858 to 1087)	247	877 (728 to 1026)	-95 (-283 to 92)	Not significant
Ages < and > 6 months
Bhatnagar 2004a	Total (g/kg)	Geometric mean (95% CI)	132	111 (86 to 147)	134	148 (116 to 190)	0.69 (0.48 to 0.99)^b	P < 0.05
	Per day of diarrhoea (g/kg/day)	Geometric mean (95% CI)	132	62 (51 to 78)	134	78 (68 to 91)	0.76 (0.59 to 0.98)^b	P < 0.05
Dutta 2000	Total (kg)	Mean (95% CI)	44	1.5 (1.3 to 1.7)	36	2.4 (2.2 to 2.6)	-0.9 (-1.2 to -0.6)^a	P = 0.0001
Roy 1997	Per day of diarrhoea (g/kg/day)	Median (range)	37	238 (35 to 2416)	37	329 (32 to 1464)		P = 0.06
PERSISTENT DIARRHOEA
Age > 6 months
Bhutta 1999b	Per day of diarrhoea, day 1 (g/kg/day)	Mean (95% CI)	43	116.8 (85.8 to 147.8)	44	141.9 (91.2 to 192.6)	-25.1 (-84.5 to 34.3)^a	Not significant
	Per day of diarrhoea, day 7 (g/kg/day)	Mean (95% CI)	43	66.7 (40.9 to 92.4)	44	43.9 (32.1 to 55.7)	22.8 (-5.5 to 51.1)^a	Not significant
	Per day of diarrhoea, day 14 (g/kg/day)	Mean (95% CI)	43	24.9 (20.1 to 29.7)	44	27.8 (18.5 to 37.1)	-2.9 (-13.4 to 7.6)^a	Not significant
Khatun 2001	Cumulative day 1 (mg/kg)	Mean (95% CI)	24	127 (113 to 141)	24	137 (121 to 153)	-10 (-31.6 to 11.6)^a	Not significant
	Cumulative day 7 (mg/kg)	Mean (95% CI)	24	528 (472 to 584)	24	866 (815 to 917)	-338 (-413.6 to -262.4)^a	P = < 0.001

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 ^aArithmetic mean difference (95% CI) for means.
^bGeometric mean ratio (95% CI) for geometric means, adjusted for confounders. (Stool output using zinc is 0.69 and 0.76 times that of participants using placebo, which means a 31% and 24% less stool output under zinc treatment.)
CI: confidence intervals.