Oral zinc for treating diarrhoea in children

Marzia Lazzerini; Humphrey Wanzira

doi:10.1002/14651858.CD005436.pub5

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

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Figure 4

Zinc versus placebo for acute diarrhoea: diarrhoea duration (h)

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Figure 5

Zinc versus placebo for acute diarrhoea: diarrhoea on day 7

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Figure 6

Zinc versus placebo for acute diarrhoea: adverse events (vomiting)

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Figure 7

Funnel plot of comparison: 1 Zinc versus placebo for children with acute diarrhoea, outcome: 1.1 Diarrhoea duration (hours).

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Figure 8

Funnel plot of comparison: 1 Zinc versus placebo for children with acute diarrhoea, outcome: 1.12 Diarrhoea on day 7.

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Analysis 1.1

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 1 Diarrhoea duration (hours).

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Analysis 1.2

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 2 Diarrhoea duration (hours): subgrouped by nutritional status.

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Analysis 1.3

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 3 Diarrhoea duration (hours): subgrouped by sex.

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Analysis 1.4

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 4 Diarrhoea duration (hours); subgrouped by continent.

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Analysis 1.5

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 5 Diarrhoea duration (hours): subgrouped by national risk of zinc deficiency.

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Analysis 1.6

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 6 Diarrhoea duration (hours): subgrouped by zinc dose.

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Analysis 1.7

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 7 Diarrhoea duration (hours): subgrouped by zinc type.

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Analysis 1.8

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 8 Diarrhoea duration (hours): subgrouped by study setting.

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Analysis 1.9

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 9 Diarrhoea duration (hours): subgrouped by concomitant treatment.

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Analysis 1.10

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 10 Diarrhoea on day 3.

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Analysis 1.11

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 11 Diarrhoea on day 5.

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Analysis 1.12

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 12 Diarrhoea on day 7.

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Analysis 1.13

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 13 Diarrhoea on day 7: subgrouped by nutritional status.

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Analysis 1.14

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 14 Diarrhoea on day 7: subgrouped by sex.

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Analysis 1.15

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 15 Diarrhoea on day 7: subgrouped by continent.

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Analysis 1.16

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 16 Diarrhoea on day 7: subgrouped by national risk of zinc deficiency.

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Analysis 1.17

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 17 Diarrhoea on day 7: subgrouped by zinc dose.

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Analysis 1.18

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 18 Diarrhoea on day 7: subgrouped by zinc type.

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Analysis 1.19

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 19 Diarrhoea on day 7: subgrouped by study setting.

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Analysis 1.20

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 20 Diarrhoea on day 7: subgrouped by concomitant treatment.

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Analysis 1.21

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 21 Stool frequency (stools /day).

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Analysis 1.22

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 22 Death.

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Analysis 1.23

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 23 Adverse events (vomiting).

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Analysis 1.24

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 24 Difficulties in treatment administration.

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Analysis 2.1

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 1 Diarrhoea duration (hours).

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Analysis 2.2

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 2 Diarrhoea on day 3.

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Analysis 2.3

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 3 Diarrhoea on day 5.

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Analysis 2.4

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 4 Diarrhoea on day 7.

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Analysis 2.5

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 5 Stool frequency (stools/day).

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Analysis 2.6

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 6 Adverse events (vomiting).

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

Zinc compared to placebo for children more than 6 months of age 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)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Zinc
Duration of diarrhoea	All trials		MD −11.46 (−19.72 to −3.19)	2581 (9 trials)	⊕⊕⊝⊝ low^1,2	No comment
	The mean duration of diarrhoea among placebo ranged from 31.2 to 169.5 hours	The mean duration of diarrhoea among zinc ranged from 28.8 to 147.6 hours
	Trials limited to children with signs of malnutrition		MD −26.39 (−36.54 to −16.23)	419 (5 trials)	⊕⊕⊕⊕ high	No comment
	The mean duration of diarrhoea among placebo ranged from 103.4 to 146.4 hours	The mean duration of diarrhoea among zinc ranged from 70.4 to 120.0 hours
Diarrhoea on day 7	128 per 1000	93 per 1000 (78 to 113)	RR 0.73 (0.61 to 0.88)	3865 (6 trials)	⊕⊕⊕⊝ moderate³	No comment
Number of children hospitalized (community trials only)	—	—	—	276 (1 trial)	⊕⊝⊝⊝ very low^4,5	No events
Death	5 per 1000	1 per 1000 (0 to 11)	RR 0.29 (0.04 to 2.20)	1134 (4 trials)	⊕⊝⊝⊝ very low^6,7	Few events
Adverse events (vomiting)	119 per 1000	188 per 1000 (173 to 242)	RR 1.57 (1.32 to 1.86)	2605 (6 trials)	⊕⊕⊕⊝ moderate⁸	No comment
The basis for the assumed risk* (for example, 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). Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: we are very uncertain about the estimate.
¹Downgraded by 1 for indirectness: all trials were conducted in Asia. ²Downgraded by 1 for serious imprecision: wide CI. ³Downgraded by 1 for serious indirectness: these trials were all conducted in Asia in countries at high risk of zinc deficiency. ⁴Downgraded by 1 for serious indirectness: only one small community trial reported on number of children hospitalized. ⁵Downgraded by 2 for very serious imprecision: no hospitalizations occurred in this trial. ⁶Downgraded by 1 for serious indirectness: the included trials were mostly conducted in hospitals and are therefore likely to underestimate death at the community level. ⁷Downgraded by 2 for very serious imprecision: only three deaths occurred in these two trials, consequently the trials are significantly underpowered to detect or exclude an effect. ⁸Downgraded by 1 for serious risk of bias: two trials reported no details on sequence generation, allocation concealment, blinding, and incomplete outcome data, while one did not give any details regarding allocation concealment.

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

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Summary of findings 2. 'Summary of findings' table 2

Zinc compared to placebo for children aged less than 6 months with acute diarrhoea
Patient or population: children aged less than 6 months with acute diarrhoea Settings: all countries Intervention: zinc Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Zinc
Duration of diarrhoea	The mean duration of diarrhoea among placebo ranged from 97.9 to 133.2 hours	The mean duration of diarrhoea among zinc ranged from 105.6 to 133.2 hours	MD 5.23 (−4.00 to 14.45)	1334 (2 trials)	⊕⊕⊝⊝ low^1,2	No comment
Diarrhoea on day 7	203 per 1000	252 per 1000 (201 to 313)	RR 1.24 (0.99 to 1.54)	1074 (1 trial)	⊕⊕⊝⊝ low^3,4	No comment
Number of children hospitalized (community trials only)	—	—	—	1074 (1 trial)	⊕⊝⊝⊝ very low^5,6	No events
Death	2 per 1000	2 per 1000 (0 to 32)	RR 1.00 (0.06 to 15.89)	1334 (2 trials)	⊕⊝⊝⊝ very low^7,8	Only 1 event in each treatment group
Adverse events (vomiting)	64 per 1000	104 per 1000 (67 to 143)	RR 1.54 (1.05 to 2.24)	1334 (2 trials)	⊕⊕⊕⊝ moderate⁹	No comment
The basis for the assumed risk* (for example, 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). Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: we are very uncertain about the estimate.
¹Downgraded by 1 for inconsistency: only two trials were done and both had inconsistent results. ²Downgraded by 1 for imprecision: large CI. ³Downgraded by 1 for inconsistency: different results in the subgroups. ⁴Downgraded by 1 for indirectness: only one trial (although multi‐country) as it is not possible to generalize these results. ⁵Downgraded by 2 for imprecision: only one hospitalization was recorded in 1074 participants. Much larger trials would be necessary to prove or exclude an effect. ⁶Downgraded by 1 for imprecision: the result is not statistically significant. ⁷Downgraded by 1 for indirectness: most of this data is from Asia and may not be applicable elsewhere. ⁸Downgraded by 2 for imprecision: in these two trials deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality. ⁹Downgraded by 1 under consistency because only two trials were done.

Summary of findings 2. 'Summary of findings' table 2

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Summary of findings 3. 'Summary of findings' table 3

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)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Zinc
Duration of diarrhoea	The mean duration of diarrhoea among placebo ranged from 84 to 132	The mean duration of diarrhoea among zinc ranged from 69.4 to 122.4 hours	MD −15.84 (−25.43 to −6.24)	529 (5 trials)	⊕⊕⊕⊝ moderate¹	No comment
Diarrhoea on day 7	191 per 1000	99 per 1000 (52 to 195)	RR 0.52 (0.27 to 1.02)	221 (2 trials)	⊕⊕⊝⊝ low^1,2	No comment
Hospitalization	—	—	—	275 (1 trial)	⊕⊝⊝⊝ very low^1,3	No events
Death	—	—	—	402 (3 trials)	⊕⊝⊝⊝ very low^1,4	No events
Adverse events (vomiting)	8 per 1000	16 per 1000 (3 to 85)	RR 1.97 (0.37 to 10.59)	505 (4 trials)	⊕⊝⊝⊝ very low^1,5	No comment
The basis for the assumed risk* (for example, 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). Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: we are very uncertain about the estimate.
¹Downgraded by 1 for indirectness: most of this data is from Asia and may not be applicable elsewhere. ²Downgraded by 1 for imprecision: the result does not reach statistically significance, and the number of recorded events is low. ³Downgraded by 2 for imprecision: no hospitalizations were recorded. Much larger trials would be necessary to prove or exclude an effect. ⁴Downgraded by 2 for imprecision: in these three trials deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality. ⁵Downgraded by 2 for imprecision: vomiting was very uncommon in these trials.

Summary of findings 3. 'Summary of findings' table 3

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Table 1. Detailed search strategies

Search set	CIDG SR¹	CENTRAL	MEDLINE²	EMBASE²	LILACS²	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	—	—	—	—
¹Cochrane Infectious Diseases Group Specialized Register. ²Search terms used in combination with the search strategy for retrieving trials developed by Cochrane (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

Table 1. Detailed search strategies

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Table 2. Results of the study selection

Total number of studies identified through the search (up to 30 September 2016)	306 trials
Total number of studies excluded as clearly did not concern the topic of interest	126 trials
Studies further evaluated and excluded¹ Not RCTs: 25 trials Not placebo‐controlled RCTs: 8 trials RCTs on prevention of diarrhoea, not on treatment: 51 trials Not concerning the population of interest (for example, studies on low birthweight, HIV): 13 trials Not concerning the interventions of interest (for example, studies on zinc in oral rehydration solution (ORS), multiple micronutrients, probiotics, food fortification): 19 trials Concerning different outcomes (for example, studies on serology, appetite, mental or motor development, malnutrition): 16 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: 8	141 trials
Duplicates of included studies 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 1998 is an abstract of Khatun 2001 Cuevas 2000 is an abstract of Al‐Sonboli 2003 Patel 2013 is a cost effectiveness analysis based on data reported in Patel 2009	6 trials
Independent trials included in the review	33 trials (10,841 participants)
¹See the 'Characteristics of excluded studies' section. Abbreviations: HIV: human immunodeficiency virus; RCT: randomized controlled trial.

Table 2. Results of the study selection

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Table 3. Stool output: acute diarrhoea

Trial ID	Outcome	Units	Zinc		Placebo		Mean difference	Statistical test
Trial ID	Outcome	Units	N	Values	N	Values	Mean difference	Statistical test
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)¹	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)¹	Not significant
Age > 6 months
Patel 2009a (zinc)	Total (g)	Mean (95% CI)	248	972 (858 to 1087)	247	877 (728 to 1026)	−95 (−283 to 92)	Not significant
Dutta 2011	Total (L)	Mean (95% CI)	41	1.2 (0.6 to 1.8)	43	2.0 (1.3 to 2.7)	‐ 0.8 (‐1.1 to 1.5)	P < 0.0001
Dutta 2011	Per day (ml/kg/day)	Mean (95% CI)	41	51.22 (27.39 to 79.05)	43	66.83 (42.41 to 71.25)	‐ 15.61 (‐22.9 to ‐8.2)	P = 0.0001
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)²	P < 0.05
Bhatnagar 2004a	Per day (g/kg/day)	Geometric mean (95% CI)	132	62 (51 to 78)	134	78 (68 to 91)	0.76 (0.59 to 0.98)²	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)¹	P = 0.0001
Roy 1997	Per day (g/kg/day)	Median (range)	37	238 (35 to 2416)	37	329 (32 to 1464)	−91 (NA)	P = 0.06
¹Arithmetic mean difference (95% CI) for means. ²Geometric 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.) Abbreviations: CI: confidence interval; NA: not applicable.

Table 3. Stool output: acute diarrhoea

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Table 4. Stool output: persistent diarrhoea

Trial ID	Outcome	Zinc		Placebo		Mean difference ¹	Statistical test
Trial ID	Outcome	N	Mean (95% CI)	N	Mean (95% CI)	Mean difference ¹	Statistical test
Age > 6 months
Bhutta 1999	Per day of diarrhoea, day 1 (g/kg/day)	43	116.8 (85.8 to 147.8)	44	141.9 (91.2 to 192.6)	−25.1 (−84.5 to 34.3)	Not significant
	Per day of diarrhoea, day 7 (g/kg/day)	43	66.7 (40.9 to 92.4)	44	43.9 (32.1 to 55.7)	22.8 (−5.5 to 51.1)	Not significant
	Per day of diarrhoea, day 14 (g/kg/day)	43	24.9 (20.1 to 29.7)	44	27.8 (18.5 to 37.1)	‐2.9 (−13.4 to 7.6)	Not significant
Khatun 2001	Cumulative day 1 (mg/kg)	24	127 (113 to 141)	24	137 (121 to 153)	−10 (−31.6 to 11.6)	Not significant
Khatun 2001	Cumulative day 7 (mg/kg)	24	528 (472 to 584)	24	866 (815 to 917)	−338 (−413.6 to −262.4)	P ≤ 0.001
¹Arithmetic mean difference (95% CI) for means. Abbreviations: CI: confidence interval; ID: identification.

Table 4. Stool output: persistent diarrhoea

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Comparison 1. Zinc versus placebo for children with acute diarrhoea

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea duration (hours) Show forest plot	24	5096	Mean Difference (IV, Random, 95% CI)	‐13.42 [‐20.52, ‐6.31]

1.1 Age < 6 months	5	1334	Mean Difference (IV, Random, 95% CI)	5.23 [‐2.00, 14.45]
1.2 Age > 6 months	9	2581	Mean Difference (IV, Random, 95% CI)	‐11.46 [‐19.72, ‐3.19]
1.3 Ages both < and > 6 months	10	1181	Mean Difference (IV, Random, 95% CI)	‐22.18 [‐32.57, ‐11.78]
2 Diarrhoea duration (hours): subgrouped by nutritional status Show forest plot	17	3518	Mean Difference (IV, Random, 95% CI)	‐17.54 [‐25.49, ‐9.58]

2.1 Nutritional status: only well‐nourished	2	406	Mean Difference (IV, Random, 95% CI)	‐6.79 [‐23.84, 10.26]
2.2 Nutritional status: well‐nourished plus moderately malnourished	10	2693	Mean Difference (IV, Random, 95% CI)	‐15.46 [‐25.55, ‐5.36]
2.3 Nutritional status: malnourished	5	419	Mean Difference (IV, Random, 95% CI)	‐26.39 [‐36.54, ‐16.23]
3 Diarrhoea duration (hours): subgrouped by sex Show forest plot	18	3621	Mean Difference (IV, Random, 95% CI)	‐17.33 [‐25.03, ‐9.62]

3.1 Sex: male	3	430	Mean Difference (IV, Random, 95% CI)	‐22.35 [‐36.40, ‐8.31]
3.2 Sex: male and female	15	3191	Mean Difference (IV, Random, 95% CI)	‐16.13 [‐24.71, ‐7.55]
4 Diarrhoea duration (hours); subgrouped by continent Show forest plot	18	3621	Mean Difference (IV, Random, 95% CI)	‐17.33 [‐25.03, ‐9.62]

4.1 Continent: Africa	1	60	Mean Difference (IV, Random, 95% CI)	‐2.40 [‐33.25, 28.45]
4.2 Continent: Asia	13	3205	Mean Difference (IV, Random, 95% CI)	‐19.01 [‐28.19, ‐9.82]
4.3 Continent: South America	1	74	Mean Difference (IV, Random, 95% CI)	‐31.20 [‐46.43, ‐15.97]
4.4 Continent: Europe	2	224	Mean Difference (IV, Random, 95% CI)	‐10.19 [‐34.29, 13.91]
4.5 Continent: Australia	1	58	Mean Difference (IV, Random, 95% CI)	‐2.40 [‐20.93, 16.13]
5 Diarrhoea duration (hours): subgrouped by national risk of zinc deficiency Show forest plot	16	3253	Mean Difference (IV, Random, 95% CI)	‐16.99 [‐25.49, ‐8.50]

5.1 Region: countries ranked as high risk of zinc deficiency	8	2535	Mean Difference (IV, Random, 95% CI)	‐14.97 [‐26.21, ‐3.72]
5.2 Region: countries ranked as medium risk of zinc deficiency	5	436	Mean Difference (IV, Random, 95% CI)	‐25.92 [‐44.80, ‐7.04]
5.3 Region: countries ranked as low risk of zinc deficiency	3	282	Mean Difference (IV, Random, 95% CI)	‐7.63 [‐22.74, 7.48]
6 Diarrhoea duration (hours): subgrouped by zinc dose Show forest plot	13	2018	Mean Difference (IV, Random, 95% CI)	‐20.24 [‐28.84, ‐11.63]

6.1 Zinc dose:≤ 20 mg	9	976	Mean Difference (IV, Random, 95% CI)	‐18.45 [‐30.19, ‐6.71]
6.2 Zinc dose: > 20 mg	4	1042	Mean Difference (IV, Random, 95% CI)	‐23.33 [‐38.30, ‐8.35]
7 Diarrhoea duration (hours): subgrouped by zinc type Show forest plot	16	3454	Mean Difference (IV, Random, 95% CI)	‐16.50 [‐25.11, ‐7.89]

7.1 Zinc type: zinc acetate	3	875	Mean Difference (IV, Random, 95% CI)	‐30.55 [‐49.29, ‐11.82]
7.2 Zinc type: gluconate	2	908	Mean Difference (IV, Random, 95% CI)	‐14.51 [‐30.84, 1.81]
7.3 Zinc type: zinc sulphate	11	1671	Mean Difference (IV, Random, 95% CI)	‐13.21 [‐24.16, ‐2.27]
8 Diarrhoea duration (hours): subgrouped by study setting Show forest plot	18	3621	Mean Difference (IV, Random, 95% CI)	‐17.33 [‐25.03, ‐9.62]

8.1 Study setting: hospital	15	2468	Mean Difference (IV, Random, 95% CI)	‐17.86 [‐27.01, ‐8.70]
8.2 Study setting:community	3	1153	Mean Difference (IV, Random, 95% CI)	‐12.65 [‐21.76, ‐3.54]
9 Diarrhoea duration (hours): subgrouped by concomitant treatment Show forest plot	18	3777	Mean Difference (IV, Random, 95% CI)	‐15.68 [‐23.53, ‐7.82]

9.1 Concomitant treatment: zinc alone	17	3394	Mean Difference (IV, Random, 95% CI)	‐16.95 [‐24.85, ‐9.05]
9.2 Concomitant treatment: zinc plus copper	1	383	Mean Difference (IV, Random, 95% CI)	2.20 [‐5.08, 9.48]
10 Diarrhoea on day 3 Show forest plot	9	2063	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.69, 0.86]

10.1 Age > 6 months	4	1599	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.72, 0.94]
10.2 Ages both < and > 6 months	5	464	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.56, 0.79]
11 Diarrhoea on day 5 Show forest plot	8	2307	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.64, 0.91]

11.1 Age > 6 months	3	1384	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.52, 1.01]
11.2 Ages both < and > 6 months	5	923	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.64, 0.96]
12 Diarrhoea on day 7 Show forest plot	13	5528	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.72, 0.94]

12.1 Age < 6 months	3	1074	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.99, 1.54]
12.2 Age > 6 months	6	3865	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.61, 0.88]
12.3 Ages both < and > 6 months	4	589	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.18, 0.52]
13 Diarrhoea on day 7: subgrouped by nutritional status Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13.1 Nutritional status: only well‐nourished	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.26]
13.2 Nutritional status: well‐nourished plus moderately malnourished	6	4075	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.60, 0.86]
13.3 Nutritional status: malnourished	3	238	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.22, 0.61]
14 Diarrhoea on day 7: subgrouped by sex Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

14.1 Sex: male	1	266	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 0.88]
14.2 Sex: male and female	9	4188	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.58, 0.81]
15 Diarrhoea on day 7: subgrouped by continent Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

15.1 Region: Asia	9	4313	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.56, 0.79]
15.2 Region: Europe	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.26]
16 Diarrhoea on day 7: subgrouped by national risk of zinc deficiency Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

16.1 Region: countries ranked as high risk of zinc deficiency	6	3240	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.62, 0.92]
16.2 Region: countries ranked as medium risk of zinc deficiency	3	1073	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.35, 0.68]
16.3 Region: countries ranked as low risk of zinc deficiency	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.26]
17 Diarrhoea on day 7: subgrouped by zinc dose Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 Zinc dose: 20 mg	8	3154	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.51, 0.74]
17.2 Zinc dose: >20mg	1	805	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.38, 1.19]
18 Diarrhoea on day 7: subgrouped by zinc type Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

18.1 Zinc type: zinc acetate	3	1628	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.45, 0.79]
18.2 Zinc type:gluconate	1	805	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.38, 1.19]
18.3 Zinc type: zinc sulphate	6	2021	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.57, 0.90]
19 Diarrhoea on day 7: subgrouped by study setting Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

19.1 Study setting: hospital	8	2758	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.56, 0.84]
19.2 Study setting: community	2	1696	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.44, 0.85]
20 Diarrhoea on day 7: subgrouped by concomitant treatment Show forest plot	11		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

20.1 Concomitant treatment: zinc alone	10	4330	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.55, 0.78]
20.2 Concomitant treatment: zinc plus copper	1	383	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.43, 2.45]
21 Stool frequency (stools /day) Show forest plot	10	2643	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.25, 0.04]

21.1 Age < 6 months	5	1334	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.17, 0.17]
21.2 Age > 6 months	4	1235	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.58, ‐0.06]
21.3 Ages both < and > 6 months	1	74	Mean Difference (IV, Fixed, 95% CI)	‐5.9 [‐9.44, ‐2.36]
22 Death Show forest plot	8	2609	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.09, 1.07]

22.1 Age < 6 months	2	1334	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.06, 15.89]
22.2 Age > 6 months	5	1134	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.04, 2.20]
22.3 Ages both < and > 6 months	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.55]
23 Adverse events (vomiting) Show forest plot	15	5942	Risk Ratio (M‐H, Random, 95% CI)	1.54 [1.28, 1.85]

23.1 Age < 6 months	3	1334	Risk Ratio (M‐H, Random, 95% CI)	1.54 [1.05, 2.24]
23.2 Age > 6 months	6	2605	Risk Ratio (M‐H, Random, 95% CI)	1.57 [1.32, 1.86]
23.3 Ages both < and > 6 months	6	2003	Risk Ratio (M‐H, Random, 95% CI)	1.63 [1.14, 2.34]
24 Difficulties in treatment administration Show forest plot	1	87	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.44, 2.41]

Comparison 1. Zinc versus placebo for children with acute diarrhoea

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Comparison 2. Zinc versus placebo for children with persistent diarrhoea

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea duration (hours) Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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) Show forest plot	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]
6 Adverse events (vomiting) Show forest plot	4	505	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.37, 10.59]

6.1 Age > 6 months	3	364	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.37, 10.59]
6.2 Ages both < and > 6 months	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Zinc versus placebo for children with persistent diarrhoea

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