Oral zinc for treating diarrhoea in children

  • Review
  • Intervention

Authors

  • Marzia Lazzerini,

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

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  • Luca Ronfani

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

Background

In developing countries, diarrhoea causes around two million child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization and UNICEF.

Objectives

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

Search methods

In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2011, Issue 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers.

Selection criteria

Randomized controlled trials comparing oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery.

Data collection and analysis

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

The quality of evidence has been assessed using the GRADE methods

Main results

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

Acute diarrhoea

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

In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (MD -10.44 hours, 95% CI -21.13 to 0.25; 2175 children, six trials, low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, six trials, moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (MD -26.98 hours, 95% CI -14.62 to -39.34; 336 children, three trials, high quality evidence).

Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no effect on mean diarrhoea duration (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, two trials, low quality evidence), and may even increase the proportion of children whose diarrhoea persists until day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, one trial, moderate quality evidence).

No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (RR 1.59, 95% 1.27 to 1.99; 5189 children, 10 trials, high quality evidence).

Persistent diarrhoea

In children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, five trials, moderate quality evidence).

Authors' conclusions

In areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged six months or more.The current evidence does not support the use of zinc supplementation in children below six months of age.

Résumé scientifique

Le zinc par voie orale pour le traitement de la diarrhée chez l'enfant

Contexte

Dans les pays en développement, la diarrhée cause environ chaque année la mort de deux millions d'enfants. L'Organisation mondiale de la Santé et l'UNICEF recommandent aujourd'hui la supplémentation en zinc lors d'une diarrhée aiguë.

Objectifs

Évaluer la supplémentation orale en zinc dans le traitement des enfants atteints de diarrhée aiguë ou persistante.

Stratégie de recherche documentaire

En février 2012, nous avons effectué une recherche dans le registre spécialisé du groupe Cochrane sur les maladies infectieuses, ainsi que dans CENTRAL (The Cochrane Library 2011, numéro 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT et dans des références bibliographiques. Nous avons également contacté des chercheurs.

Critères de sélection

Des essais contrôlés randomisés comparant la supplémentation orale en zinc à un placebo chez des enfants âgés de un mois à cinq ans souffrant de diarrhée aiguë ou persistante, dysenterie comprise.

Recueil et analyse des données

Les deux auteurs ont évalué l'éligibilité des essais et leurs risques de biais ; ils ont extrait et analysé les données et rédigé la revue. Les principaux critères de jugement étaient la durée et la gravité de la diarrhée. Nous avons résumé les résultats dichotomiques au moyen du risque relatif (RR) et les résultats continus sous la forme de la différence moyenne (DM) avec des intervalles de confiance (IC) à 95 %. Lorsque cela était possible, nous avons combiné les données dans des méta-analyses (au moyen d'un modèle à effets fixes ou à effets aléatoires) et évalué l'hétérogénéité.

La qualité des preuves a été évaluée au moyen de l'échelle GRADE.

Résultats principaux

Vingt-deux essais, impliquant au total 9 128 enfants, remplissaient nos critères d'inclusion. La majorité des données provenant d'Asie, de pays à haut risque de carence en zinc, elles ne sont peut être pas applicables ailleurs.

Diarrhée aiguë

Actuellement, il n'existe pas suffisamment de données issues d'essais contrôlés randomisés bien menés pour permettre de dire si la supplémentation en zinc lors de diarrhée aiguë réduit la mortalité ou l'hospitalisation (données de très faible qualité).

Chez les enfants âgés de plus de six mois atteints de diarrhée aiguë, la supplémentation en zinc peut réduire la durée de la diarrhée d'environ 10 heures (DM -10,44 heures, IC à 95 % -21,13 à 0,25 ; 2175 enfants, six essais, données de faible qualité) et réduit probablement le nombre d'enfants dont la diarrhée persiste jusqu'à sept jours (RR 0,73 ; IC à 95 % 0,61 à 0,88 ; 3 865 enfants, six essais, données de qualité moyenne). Chez les enfants présentant des signes de malnutrition modérée l'effet semble plus grand, la durée de la diarrhée étant réduite d'environ 27 heures (DM -26,98 heures, IC à 95 % -14,62 à -39,34 ; 336 enfants, trois essais, données de bonne qualité).

A l'inverse, chez les enfants âgés de moins de six mois, les données disponibles laissent penser que la supplémentation en zinc n'a aucun effet sur ​​la durée moyenne de la diarrhée (DM 5,23 heures ; IC à 95 % -4,00 à 14,45 ; 1 334 enfants, deux essais, données de faible qualité) et pourrait même augmenter la proportion d'enfants dont la diarrhée persiste jusqu'à sept jours (RR 1,24 ; IC à 95 % de 0,99 à 1,54 ; 1 074 enfants, un essai, données de qualité moyenne).

Aucun essai n'avait fait état d'événements indésirables graves, mais la supplémentation en zinc lors de diarrhée aiguë provoque des vomissements dans les deux groupes d'âge (RR 1,59, IC à 95 % 1,27 à 1,99 ; 5 189 enfants, 10 essais, données de bonne qualité).

Diarrhée persistante

Chez les enfants souffrant de diarrhée persistante, la supplémentation en zinc réduit probablement la durée de la diarrhée d'environ 16 heures (DM -15,84 heures, IC à 95 % -25,43 à -6,24 ; 529 enfants, cinq essais, données de qualité moyenne).

Conclusions des auteurs

Dans les régions où la prévalence de la carence en zinc ou bien la prévalence de la malnutrition modérée est élevée, le zinc peut être bénéfique chez les enfants âgés de six mois ou plus. Les données actuelles n'étayent pas l'utilisation de la supplémentation en zinc chez les enfants de moins de six mois.

アブストラクト

小児の下痢の治療を目的とした経口亜鉛

背景

開発途上国では、年間200万人前後の小児が下痢で死亡する。急性の下痢に対する亜鉛の補充は、現在、世界保健機関(WHO)およびユニセフによって推奨されている。

目的

急性または持続性の下痢の小児に対して治療に用いる経口亜鉛補充を評価すること。

検索戦略

2012年2月に、Cochrane Infectious Diseases Group Specialized Register、CENTRAL(コクラン・ライブラリ2011年第11号)、MEDLINE、EMBASE、LILACS、CINAHL、mRCTおよび参考文献リストを検索した。 このほか、研究者らに問い合わせを行った。

選択基準

赤痢を含む急性または持続性の下痢を来たす生後1カ月~5歳の小児を対象に、経口亜鉛補充とプラセボを比較したランダム化比較試験(RCT)。

データ収集と分析

両著者ともに、試験の適格性およびバイアスのリスクを評価し、データの抽出と解析を行い、レビューの原稿を書いた。下痢の期間および重症度が主要アウトカムであった。二値アウトカムはリスク比(RR)を用いてまとめ、連続アウトカムは平均値の差(MD)を95%信頼区間(CI)とともに用いてまとめた。固定効果モデルまたはランダム効果モデルを用いたメタアナリシスで適宜データを統合し、異質性を評価した。

エビデンスの質は、GRADE法を用いて評価した。

主な結果

小児9128例を登録した24件の試験が選択基準を満たした。データの大半はアジアの亜鉛欠乏のリスクが高い国々のもので、他の地域には当てはまらない場合もある。

急性下痢

急性の下痢を来たしているときに亜鉛を補充することによって、死亡または入院を減らすことができるかどうかを明らかにするには、適切に実施されたRCTからのエビデンスが現時点では十分でない(きわめて質の低いエビデンス)。

生後6カ月以上の小児の急性下痢に対する亜鉛補充は、下痢の期間を10時間前後短縮する可能性があり(MD -10.44時間、95%CI -21.13~0.25;小児2175例、試験6件、質の低いエビデンス)、さらに、おそらく下痢が第7日まで持続する小児の数を減らすことができる(RR 0.73、95%CI 0.61~0.88;小児3865例、試験6件、中等度の質のエビデンス)。 中等度の栄養不良の徴候がある小児では、下痢の期間が27時間前後短縮され、効果がさらに大きいように思われる(MD -26.98時間、95%CI -14.62~-39.34;小児336例、試験3件、質の高いエビデンス)。

逆に、生後6カ月未満の小児のエビデンスからは、下痢の期間の平均値に亜鉛補充の効果が認められず(MD 5.23時間、95%CI -4.00~14.45;小児1334例、試験2件、質の低いエビデンス)、さらに下痢が第7日まで持続する小児の割合が増加する可能性すらある(RR 1.24、95%CI 0.99~1.54;小児1074例、試験1件、中等度の質のエビデンス)ことが示唆される。

重篤な有害事象を報告した試験はないが、急性下痢を来たしているときに亜鉛を補充すると、いずれの年齢グループでも嘔吐が引き起こされる(RR 1.59、95%CI 1.27〜 1.99;小児5189 例、試験 10件、質の高いエビデンス)。

持続性の下痢

持続性の下痢がみられる小児に対する亜鉛補充は、おそらく下痢の期間を16時間前後短縮する(MD -15.84時間、95%CI -25.43~-6.24;小児529例、試験5件、中等度の質のエビデンス)。

著者の結論

亜鉛欠乏症の有病割合または中等度の栄養不良の有病割合が高い地域では、亜鉛が生後6カ月以上の小児に利益となる可能性がある。現在のエビデンスは、生後6カ月未満の小児に対する亜鉛補充の使用を支持していない。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.31]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Oral zinc supplementation for treating diarrhoea in children

In developing countries, millions of children suffer from severe diarrhoea every year. This is due to infection and malnutrition, and many die from dehydration due to the diarrhoea. Giving fluids by mouth (using an oral rehydration solution) has been shown to save children's lives, but it seems to have no effect on the length of time the children suffer with diarrhoea. Children in developing countries are often zinc deficient. This systematic review of 24 trials involving more than 9000 children shows that zinc supplementation may reduce the duration of diarrhoea in children aged six months or more.

Résumé simplifié

La supplémentation orale en zinc pour le traitement de la diarrhée chez l'enfant

Dans les pays en développement, des millions d'enfants souffrent chaque année de diarrhée grave. Cela est dû à des infections et à la malnutrition, et beaucoup meurent d'une déshydratation causée par la diarrhée. Il est avéré que l'administration orale de liquides (solution orale de réhydratation) permet de sauver la vie à des enfants, mais il ne semble pas que cela affecte la durée de la diarrhée dont ces enfants souffrent. Les enfants des pays en développement ont souvent une carence en zinc. Cette revue systématique de 24 essais impliquant au total plus de 9 000 enfants montre que la supplémentation en zinc pourrait réduire la durée de la diarrhée chez les enfants âgés de six mois ou plus.

Notes de traduction

Traduit par: French Cochrane Centre 25th June, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

எளியமொழிச் சுருக்கம்

குழந்தைகளில் பேதி சிகிச்சைக்கு வாய்வழி துத்தநாகம் கூடுதல் உட்கொள்ளல்

வளரும் நாடுகளில், இலட்சக்கணக்கான குழந்தைகள் ஒவ்வொரு ஆண்டும் கடுமையான வயிற்றுப்போக்கால் பாதிக்கப்படுகின்றனர். இந்த நோய் தொற்று மற்றும் ஊட்டச்சத்துக்குறைபாடு காரணமாக வரலாம், மேலும் வயிற்றுப்போக்கினால் உண்டாகும் நீரிழப்பு காரணமாக பலர் இறக்க நேரிடலாம். (வாய் வழி நீரேற்றக் கரைசலை பயன்படுத்தி), வாய் மூலம் திரவங்கள் கொடுப்பது குழந்தைகள் உயிர்களை காப்பாற்றும் என்று நிரூபிக்கப்பட்டுள்ளது, ஆனால் அது குழந்தைகள் வயிற்றுப்போக்கு பாதிக்கப்படுகின்ற கால அளவை பாதிப்பதாக தெரியவில்லை. வளரும் நாடுகளில் குழந்தைகள் பெரும்பாலும் துத்தநாகம் குறைபாட்டுடன் உள்ளர். துத்தநாக கூடுதல் உட்கொள்ளல் ஆறு மாதத்தில் இருந்து அதற்கு மேற்பட்ட வயதுயுடைய குழந்தைகளின் வயிற்றுப்போக்கின் கால அளவை குறைக்கலாம் என்று 9000 குழந்தைகள் பங்குபெற்ற 24 ஆய்வுகள் கொண்ட இந்த திட்டமிட்ட திறனாய்வு கூறுகிறது.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: தி. செந்தில்குமார், கீதா மற்றும் சி.இ.பி.என்.அர் குழு

平易な要約

小児の下痢の治療を目的とした経口亜鉛補充

開発途上国では、毎年、何百万人もの小児が重症の下痢に苦しむ。感染症および栄養不良によって引き起こされ、多くの小児が下痢による脱水症で死亡する。経口による水分補給(経口の水分補給用飲料を用いて)が小児の生命を救うことが明らかになっているが、小児が下痢に苦しむ時間の長さには効果がないように思われる。開発途上国の小児は、亜鉛欠乏症を来たしていることが多い。この9千人超の小児を対象にした24件の試験のシステマティック・レビューからは、生後6カ月以上の小児では、亜鉛補充によって下痢の期間が短くなる可能性があることが明らかになった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.31]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

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

Zinc compared to placebo for children aged > 6 months with acute diarrhoea
Patient or population: children with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
placeboZinc
Death---864
(2 studies)
⊕⊝⊝⊝
very low 1,2
 
Hospitalization---891
(1 study)
⊕⊝⊝⊝
very low 3,4
 

Duration of diarrhoea

 

all trials
The mean duration of diarrhoea ranged from 41 to 170 hoursZinc reduced the mean duration of diarrhoea by 10.44 hours
(21.13 hours shorter to 0.25 hours longer)
 2175
(6 studies)
⊕⊕⊝⊝
low 5,6
 
trials limited to children with signs of moderate malnutrition
The mean duration of diarrhoea ranged from 103 to 147 hoursZinc reduced the mean duration of diarrhoea by 26.98 hours
(39.34 to 14.62 hours shorter)
 336
(3 studies)

⊕⊕⊕⊕

high 7,8

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

⊕⊕⊕⊝

moderate 9

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

⊕⊕⊕⊕

high 8

 
*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.

Summary of findings 2 Summary of findings table 2

Summary of findings 2. Summary of findings table 2
  1. 1 Downgraded by 1 for indirectness: The majority of this data is from Asia and may not be applicable elsewhere.
    2 Downgraded by 2 for imprecision: In these two studies deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
    3 Downgraded by 2 for imprecision: Only one being hospitalization was recorded in 1074 patients. Much larger trials would be necessary to prove or exclude an effect.
    4 Downgraded by 1 for imprecision: the result is not statistically significant.
    5 This multi-centre study from India, Pakistan and Ethiopia found that Zinc increased the number of infants with diarrhoea persisting until day 7. The result was consistent across the trial settings and approaches statistical significance. Downgraded by 1 under directness as it is not yet possible to generalise this to all settings.
    6 There was no reason to downgrade under study limitations, consistency, directness or precision.

Zinc compared to placebo for children aged < 6 months with acute diarrhoea
Patient or population: children aged < 6 months with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
placeboZinc
Death---1334
(2 studies)
⊕⊝⊝⊝
very low 1,2
 
Hospitalization---1074
(1 study)
⊕⊝⊝⊝
very low 1,3
 
Duration of diarrhoeaThe mean duration of diarrhoea ranged from
98 to 133 hours
Zinc reduced the mean duration of diarrhoea 5.23 hours
(4 less to 14.45 more )
 1334
(2 studies)
⊕⊕⊝⊝
low 1,4
 
Diarrhoea on day 7203 per 1000252 per 1000
(201 to 313)
RR 1.24
(0.99 to 1.54)
1074
(1 study)

⊕⊕⊕⊝

moderate 5

 
Adverse events (vomiting)64 per 100099 per 1000
(67 to 143)
RR 1.54
(1.05 to 2.24)
1334
(2 studies)

⊕⊕⊕⊕

high 6

 
*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.

Summary of findings 3 Summary of findings table 3

Summary of findings 3. Summary of findings table 3
  1. 1 Downgraded by 1 for indirectness: The majority of this data is from Asia and may not be applicable elsewhere.
    2 Downgraded by 2 for imprecision: In these three studies deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
    3 Downgraded by 2 for imprecision: No hospitalizations were recorded. Much larger trials would be necessary to prove or exclude an effect.
    4 Downgraded by 1 for imprecision: The result does not reach statistically significance, and the number of recorded events is low.
    5 Downgraded by 2 for imprecision: Vomiting was very uncommon in these trials.

Zinc compared to placebo for children with persistent diarrhoea
Patient or population: children with persistent diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
placeboZinc
Death---402
(3 studies)
⊕⊝⊝⊝
very low 1,2
 
Hospitalization---275
(1 study)
⊕⊝⊝⊝
very low 1,3
 

Duration of diarrhoea

 

The mean diarrhoea duration (h) ranged from
84 to 168 hours
Zinc reduced the mean duration of diarrhoea of
15.84
(25.43 to 6.24 less )
 529
(5 studies)
⊕⊕⊕⊝
moderate 1
 
Diarrhoea on day 7191 per 100099 per 1000
(52 to 195)
RR 0.52
(0.27 to 1.02)
221
(2 studies)
⊕⊕⊝⊝
low 1,4
 
Adverse events (vomiting)8 per 100016 per 1000
(3 to 85)
RR 1.97
(0.37 to 10.59)
505
(4 studies)
⊕⊝⊝⊝
very low 1,5
 
*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.

Background

Problem

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

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

Biological functions

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

Rationale for supplementation

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

Factors that could influence the effects of supplementation

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

Type of diarrhoea

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

Age

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

Nutritional status

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

Geographical region

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

Zinc dose

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

Types of zinc salt

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

Concomitant iron or copper supplementation

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

Setting

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

Adverse effects

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

Previous systematic reviews

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

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

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

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

Acute diarrhoea is usually defined as three or more loose stools in a 24-hour period. Persistent diarrhoea is defined as diarrhoea lasting more than 14 days. Dysentery is a diarrhoeal illness in which blood is observed in the stool. The final day of diarrhoea is usually defined as the last day meeting the above definition followed by 48 hours without diarrhoea.

Types of interventions

Intervention

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

Control

Placebo.

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

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

Types of outcome measures

Primary
Measures of diarrhoea duration
  • Diarrhoea duration.

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

Measures of diarrhoea severity
  • Stool frequency.

  • Stool output.

Secondary
  • Hospitalization.

  • Death (from any cause and diarrhoea specific).

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

  • Any adverse event that results in the discontinuation of treatment.

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

Search methods for identification of studies

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

Databases of published trials

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

Table 1. Detailed search strategies
  1. 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.

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSbCINAHLCCT
1zinczinczinczinczinczinczinc
2diarrhoeadiarrhoeaZINCZINCdiarrhoeadiarrhoeadiarrhoea
3vomitingmorbidity1 or 21 or 2morbiditymorbidityvomiting
4adverse effects2 or 3diarrhoeadiarrhoea2 or 32 or 3adverse effects
51 and 4diarrhoeamorbidity1 and 41 and 4
6vomitingmorbidity4 or 5vomitingvomiting
7adverse effectsMORBIDITY3 and 6adverse effectsadverse effects
86 or 74 or 5 or 6 or 7Limit 7 to human6 or 76 or 7
91 and 2 and 83 and 8vomiting1 and 2 and 81 and 8
10Limit 9 to humanadverse effects
11vomiting9 or 10
12adverse effects3 and 4 and 11
1311 or 12
143 and (4 or 5) and 13

Researchers and organizations

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

Reference lists

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

Data collection and analysis

Selection of studies

All trials identified by the search strategy were screened by both authors, and full articles were retrieved for all potentially relevant trials. Both authors independently applied the inclusion criteria to the full reports using a pilot-tested form and scrutinized publications to ensure each trial was included once. Trial authors were contacted for clarification if necessary, and any disagreements were resolved through discussion and consensus after referring to the protocol; their solutions were recorded and reported.

Data extraction and management

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

Assessment of risk of bias in included studies

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

Data synthesis

Data were analysed using Review Manager 5. All results are presented with 95% confidence intervals (CI).

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

Assessment of evidence quality

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

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

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

Subgroup analysis and investigation of heterogeneity

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

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

Sensitivity analysis

We conducted a sensitivity analysis in which we limited the analyses to those trials with adequate allocation concealment, blinding (excluded those trials classified as unclear), and those that included an adequate number of randomized participants in the analysis (excluded those trials classified as inadequate or unclear). To take into account the participants for whom no outcome data were obtained we also conducted an intention-to-treat analysis for worst-case/best-case scenarios.

Results

Description of studies

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

Table 2. Results of the study selection
  1. aSee 'Characteristics of excluded studies'
    HIV: human immunodeficiency virus
    RCT: randomized controlled trial

Studies identified through the search236
Excluded as clearly not concerning the topic of interest76 trials
Further evaluated and excluded a133
  • Not RCTs: 25 trials

  • Not placebo-controlled RCTs: 8 trials

  • RCTs on prevention of diarrhoea, not on treatment: 48 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):17 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 studies5 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 review24 RCTs (9128 participants)

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

Type of diarrhoea

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

Age

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

Nutritional status

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

Sex

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

Geographical region

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

Risk of zinc deficiency

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

Zinc dose

The zinc dose was 20 mg/day in eleven trials. Only two trials administered higher zinc doses: 40 mg/day (Dutta 2000); and 22 or 45 mg/day (Al-Sonboli 2003). Two trials, of which one in children aged less than six months only, gave zinc 10 mg/day (Fischer Walker 2006; Roy 2008), and another two trials used 10 mg for infants and 20 mg for children over six months (Fajolu 2008, Patro 2010). One trial used zinc 5 mg and 20 mg, but only in children aged less than six months (Brooks 2005a).

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

Type of zinc salt

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

Concomitant copper or iron supplementation

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

Study setting

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

Treatment regimen

Duration of treatment

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

Formulation

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

Dose frequency

The zinc dose was administered once a day in half of the trials, while the other half administered it twice a day (Sachdev 1988; Sachdev 1990; Khatun 2001; Roy 2008; Patro 2010) or three times a day (Roy 1997; Roy 1998; Dutta 2000; Polat 2003; Bhatnagar 2004a). One study administered zinc twice a day to infants, and a single dose to children over six months (Dalgic 2011). Two studies did not specify (Fajolu 2008; Patel 2009).

Additional treatments

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

Outcomes

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

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

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

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

Table 3. Stool output
  1. 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.

StudyOutcomeUnitsN zincValues zincN placeboValues placeboMean difference or rate ratioStatistical test
ACUTE DIARRHOEA        
Age < 6 months        
Brooks 2005a (5 mg)Total (mL)Mean (95% CI)85229 (180 to 256)45202 (180 to 246)27 (-23.3 to 77.3)aNot significant
Brooks 2005a (20 mg)Total (mL)Mean (95% CI)86240 (200 to 266)44202 (180 to 246)38 (-8.6 to 84.6)aNot significant
Age > 6 months        
Patel 2009a (zinc)Total (g)Mean (SD)248972 (858 to 1087)247877 (728 to 1026)-95 (-283 to 92)Not significant
Dutta 2011Total (L)Mean (SD)411.2 (0.6)432.0 (0.7) P < 0.0001
Dutta 2011Per day (ml/kg/day)Mean (SD)4151.22 (23.83)4366.83 (4.42) P = 0.0001
Ages < and > 6 months        
Bhatnagar 2004aTotal (g/kg)Geometric mean (95% CI)132111 (86 to 147)134148 (116 to 190)0.69 (0.48 to 0.99)bP < 0.05
Per day (g/kg/day)Geometric mean (95% CI)13262 (51 to 78)13478 (68 to 91)0.76 (0.59 to 0.98)bP < 0.05
Dutta 2000Total (kg)Mean (95% CI)441.5 (1.3 to 1.7)362.4 (2.2 to 2.6)-0.9 (-1.2 to -0.6)aP = 0.0001
Roy 1997Per day (g/kg/day)Median (range)37238 (35 to 2416)37329 (32 to 1464) P = 0.06
PERSISTENT DIARRHOEA        
Age > 6 months        
Bhutta 1999bPer day of diarrhoea, day 1 (g/kg/day)Mean (95% CI)43116.8 (85.8 to 147.8)44141.9 (91.2 to 192.6)-25.1 (-84.5 to 34.3)aNot significant
Per day of diarrhoea, day 7 (g/kg/day)Mean (95% CI)4366.7 (40.9 to 92.4)4443.9 (32.1 to 55.7)22.8 (-5.5 to 51.1)aNot significant
Per day of diarrhoea, day 14 (g/kg/day)Mean (95% CI)4324.9 (20.1 to 29.7)4427.8 (18.5 to 37.1)-2.9 (-13.4 to 7.6)aNot significant
Khatun 2001Cumulative day 1 (mg/kg)Mean (95% CI)24127 (113 to 141)24137 (121 to 153)-10 (-31.6 to 11.6)aNot significant
Cumulative day 7 (mg/kg)Mean (95% CI)24528 (472 to 584)24866 (815 to 917)-338 (-413.6 to -262.4)aP ≤ 0.001

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

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

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

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

Risk of bias in included studies

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

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Generation of allocation sequence

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

Allocation concealment

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

Blinding

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

Inclusion of all randomized participants

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

Effects of interventions

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

1. In children with acute diarrhoea

1.1. Diarrhoea duration

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

Figure 3.

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

1.2. Diarrhoea on days three, five, and seven

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

Figure 4.

Zinc vs placebo for acute diarrhoea: diarrhoea on day 3

Figure 5.

Zinc vs placebo for acute diarrhoea: diarrhoea on day 5

Figure 6.

Zinc vs placebo for acute diarrhoea: diarrhoea on day 7

1.3. Stool frequency

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

1.4. Stool output

Stool output was measured using different units at different time points, thus results could not be pooled together (Table 3). Results are expressed as arithmetic mean difference (AMD) or geometric mean ratio (GMR).

One trial reported on children aged less than six months with no evidence of a difference (Brooks 2005a). Two trials reported on children aged more than six months with inconsistent results (Patel 2009, Dutta 2011). Three trials reported on children aged less than and greater than six months: two of these studies showed a reduction in stool output with zinc (Dutta 2000; Bhatnagar 2004a), while one showed no evidence of an effect (Roy 1997).

1.5. Hospitalization

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

1.6. Death

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

1.7. Adverse events

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

Figure 7.

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

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

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

1.8. Statistical heterogeneity

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

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

Figure 8.

Forest plot of comparison: 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months, outcome: 2.1 Diarrhoea duration (h).

Figure 9.

Forest plot of comparison: 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months, outcome: 3.1 Diarrhoea on day 7.

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

1.9. Sensitivity analysis

The sensitivity analysis against markers of methodological quality did not affect the direction of results. There was some loss of significance with diarrhoea duration, but overall the analysis did not change the point estimate of effects. The intention-to-treat analysis for worst-case/best-case scenarios did not altered the statistical significance of the results.

2. In children with persistent diarrhoea

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

2.1. Diarrhoea duration

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

Figure 10.

Zinc vs placebo for persistent diarrhoea: diarrhoea duration (h)

2.2. Diarrhoea on days three, five, and seven

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

2.3. Stool frequency

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

2.4. Stool output

Stool output was measured using different units at different time points, thus results could not be pooled together (Table 3). Results are expressed as the arithmetic mean difference (AMD) or geometric mean ratio (GMR). Two trials reported on children aged greater than six months, with five comparisons, and only one (Khatun 2001) reported a significant reduction in cumulative stool output at day seven in the zinc group (AMD -338 mg/kg bodyweight, 95% CI -413.6 to -262.4 mg/kg bodyweight; P ≤ 0.001).

2.5. Hospitalization

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

2.6. Death

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

2.7. Adverse events

Four trials that reported on vomiting (505 children) showed no difference between the zinc and placebo groups (Analysis 4.6); three of the trials reported no incidences of vomiting in either group. One trial using zinc 3 mg/kg/day for 14 days in moderately malnourished and severely malnourished children reported a significantly lower plasma copper levels in the zinc-treated group by the end of the second week of therapy (56.2 ± 17.8 µg/dL versus 72.7 ± 18.3 µg/dL, P = 0.02; Bhutta 1999b, 87 children).

2.8. Statistical heterogeneity

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

2.9. Sensitivity analysis

The sensitivity analyses did not affect the direction of results. There was some loss of significance with diarrhoea duration, but no changes in the point estimate of effects. An intention-to-treat analysis for worst-case/best-case scenarios did not alter the point estimate or the significance of results.

Discussion

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

Zinc reduced the duration of acute diarrhoea. The size of the effect was clinically important particularly for diarrhoea at day seven, which is an indicator for the risk of persistent diarrhoea. This benefit withstood extensive subgroup analysis for nutritional status, geographic region, background zinc deficiency, zinc type, and study setting, with the exception of well-nourished children in country with low risk of zinc deficiency. Evidence on diarrhoea severity was less clear, as fewer trials reported on this, and different units and time points were used.

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

No firm conclusions regarding zinc's impact on hospitalization or death can be drawn from this review as trials were not designed to look at these outcomes, and most were conducted in hospital where death rates were low. Large community trials would be needed to explore whether zinc treatment for diarrhoea reduces hospitalization rates.

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

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

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

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

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

Summary of main results

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

Acute diarrhoea

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

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

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

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

Persistent diarrhoea

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

Overall completeness and applicability of evidence

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

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

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

The observed increase in vomiting was consistent across trials in all age groups. One large trial with adequate allocation concealment that was designed to look at safety reports that vomiting was limited to one episode in most children and mainly occurred within 10 minutes of administration (Larson 2005). Zinc has a metallic after-taste, and development of a more palatable formulation may minimize this adverse effect.

Quality of the evidence

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

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

Agreements and disagreements with other studies or reviews

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

Authors' conclusions

Implications for practice

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

Implications for research

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

Acknowledgements

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

Data and analyses

Download statistical data

Comparison 1. Zinc vs placebo for acute diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea duration (h)194446Mean Difference (IV, Random, 95% CI)-12.63 [-21.05, -4.21]
1.1 Age < 6 months51334Mean Difference (IV, Random, 95% CI)5.23 [-2.00, 14.45]
1.2 Age > 6 months62175Mean Difference (IV, Random, 95% CI)-10.44 [-21.13, 0.25]
1.3 Ages both < and > 6 months8937Mean Difference (IV, Random, 95% CI)-22.53 [-34.77, -10.29]
2 Diarrhoea on day 341568Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.67, 0.89]
2.1 Age > 6 months21386Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 0.99]
2.2 Ages both < and > 6 months2182Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.42, 0.72]
3 Diarrhoea on day 551730Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.51, 0.89]
3.1 Age > 6 months31384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.52, 1.01]
3.2 Ages both < and > 6 months2346Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.32, 0.95]
4 Diarrhoea on day 7135528Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.94]
4.1 Age < 6 months31074Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.99, 1.54]
4.2 Age > 6 months63865Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.61, 0.88]
4.3 Ages both < and > 6 months4589Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.18, 0.52]
5 Stool frequency (stools /day)92323Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.20, 0.10]
5.1 Age < 6 months51334Mean Difference (IV, Fixed, 95% CI)0.0 [-0.17, 0.17]
5.2 Age > 6 months3915Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.47, 0.15]
5.3 Ages both < and > 6 months174Mean Difference (IV, Fixed, 95% CI)-5.9 [-9.44, -2.36]
6 Adverse events (vomiting)125189Risk Ratio (M-H, Random, 95% CI)1.59 [1.27, 1.99]
6.1 Age < 6 months31334Risk Ratio (M-H, Random, 95% CI)1.54 [1.05, 2.24]
6.2 Age > 6 months52340Risk Ratio (M-H, Random, 95% CI)1.56 [1.32, 1.85]
6.3 Ages both < and > 6 months41515Risk Ratio (M-H, Random, 95% CI)2.01 [1.06, 3.81]
Analysis 1.1.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 1 Diarrhoea duration (h).

Analysis 1.2.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 2 Diarrhoea on day 3.

Analysis 1.3.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 3 Diarrhoea on day 5.

Analysis 1.4.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 4 Diarrhoea on day 7.

Analysis 1.5.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 5 Stool frequency (stools /day).

Analysis 1.6.

Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 6 Adverse events (vomiting).

Comparison 2. Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea duration (h)15 Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 Nutritional status: only well-nourished1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]
1.2 Nutritional status: well-nourished plus moderately malnourished92635Mean Difference (IV, Random, 95% CI)-16.77 [-27.59, -5.94]
1.3 Nutritional status: malnourished4336Mean Difference (IV, Random, 95% CI)-26.98 [-39.34, -14.62]
1.4 Sex: male3430Mean Difference (IV, Random, 95% CI)-22.35 [-36.40, -8.31]
1.5 Sex: male and female112682Mean Difference (IV, Random, 95% CI)-16.04 [-26.97, -5.11]
1.6 Region: Africa160Mean Difference (IV, Random, 95% CI)-2.40 [-33.25, 28.45]
1.7 Region: Asia112837Mean Difference (IV, Random, 95% CI)-18.88 [-29.33, -8.43]
1.8 Region: South America174Mean Difference (IV, Random, 95% CI)-31.20 [-46.43, -15.97]
1.9 Region: Europe1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]
1.10 Region: countries ranked as high risk of zinc deficiency82535Mean Difference (IV, Random, 95% CI)-14.97 [-26.21, -3.72]
1.11 Region: countries ranked as medium risk of zinc deficiency5436Mean Difference (IV, Random, 95% CI)-25.92 [-44.80, -7.04]
1.12 Region: countries ranked as low risk of zinc deficiency1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]
1.13 Zinc dose:≤ 20 mg8711Mean Difference (IV, Random, 95% CI)-18.72 [-32.02, -5.43]
1.14 Zinc dose: > 20 mg3959Mean Difference (IV, Random, 95% CI)-23.52 [-42.09, -4.94]
1.15 Zinc type: zinc acetate3875Mean Difference (IV, Random, 95% CI)-30.55 [-49.29, -11.82]
1.16 Zinc type: gluconate1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]
1.17 Zinc type: zinc sulphate91348Mean Difference (IV, Random, 95% CI)-14.04 [-26.76, -1.32]
1.18 Study setting: hospital132307Mean Difference (IV, Random, 95% CI)-18.46 [-28.61, -8.30]
1.19 Study setting:community1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]
1.20 Concomitant treatment: zinc alone142988Mean Difference (IV, Random, 95% CI)-17.58 [-26.64, -8.52]
1.21 Concomitant treatment: zinc plus copper1383Mean Difference (IV, Random, 95% CI)2.20 [-5.08, 9.48]
Analysis 2.1.

Comparison 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months, Outcome 1 Diarrhoea duration (h).

Comparison 3. Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea on day 711 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Nutritional status: only well nourished1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
1.2 Nutritional status: well nourished plus moderately malnourished64075Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]
1.3 Nutritional status: malnourished3238Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.22, 0.61]
1.4 Sex: male1266Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 0.88]
1.5 Sex: male and female94188Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.58, 0.81]
1.6 Region: Asia94313Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.56, 0.79]
1.7 Region: Europe1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
1.8 Region: countries ranked as high risk of zinc deficiency63240Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]
1.9 Region: countries ranked as medium risk of zinc deficiency31073Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.35, 0.68]
1.10 Region: countries ranked as low risk of zinc deficiency1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
1.11 Zinc dose: 20 mg83154Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.74]
1.12 Zinc dose: >20mg1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]
1.13 Zinc type: zinc acetate31628Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.45, 0.79]
1.14 Zinc type:gluconate1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]
1.15 Zinc type: zinc sulphate62021Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.57, 0.90]
1.16 Study setting: hospital82758Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.56, 0.84]
1.17 Study setting: community21696Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.44, 0.85]
1.18 Concomitant treatment: zinc alone104330Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.55, 0.78]
1.19 Concomitant treatment: zinc plus copper1383Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.45]
Analysis 3.1.

Comparison 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months, Outcome 1 Diarrhoea on day 7.

Comparison 4. Zinc vs placebo for persistent diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea duration (h)5529Mean Difference (IV, Fixed, 95% CI)-15.84 [-25.43, -6.24]
1.1 Age > 6 months4388Mean Difference (IV, Fixed, 95% CI)-16.01 [-26.16, -5.86]
1.2 Ages both < and > 6 months1141Mean Difference (IV, Fixed, 95% CI)-14.40 [-43.77, 14.97]
2 Diarrhoea on day 31 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Age > 6 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Diarrhoea on day 51 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Age > 6 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Diarrhoea on day 72221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]
4.1 Age > 6 months2221Risk 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 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Adverse events (vomiting)4505Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]
6.1 Age > 6 months3364Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]
6.2 Ages both < and > 6 months1141Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 1 Diarrhoea duration (h).

Analysis 4.2.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 2 Diarrhoea on day 3.

Analysis 4.3.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 3 Diarrhoea on day 5.

Analysis 4.4.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 4 Diarrhoea on day 7.

Analysis 4.5.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 5 Stool frequency (stools/day).

Analysis 4.6.

Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 6 Adverse events (vomiting).

What's new

DateEventDescription
6 December 2012AmendedAn error was spotted in the abstract (number of participants and number of studies was incorrect). This has been corrected and the review republished to ensure the correct details are documented.
6 December 2012New citation required but conclusions have not changedcorrected abstract

History

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

DateEventDescription
22 March 2012New search has been performedThe search was updated on 20 February 2012. Two new studies were included. The background was updated and a more detailed assessment of the risk of bias in all included trials was undertaken. Summary of findings tables were updated according to GRADE methodology.
22 March 2012New citation required but conclusions have not changedUpdate
11 February 2011New search has been performedThe search was updated on 1 December 2010. Four new studies were included. The background was updated and a more detailed assessment of the risk of bias in all included trials was undertaken. Summary of findings tables were added according to GRADE methodology.

Contributions of authors

Both authors contributed equally to the preparation of the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Department for International Development (DFID), UK.

Differences between protocol and review

2011

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

2007, Issue 4 (first review version)

We made the following modifications while conducting the review.

  • Changed inclusion criteria for participant age to "children over one month old" (rather than "two months") to avoid arbitrarily losing trials.

  • Moved death to a secondary outcome measure following feedback from referees.

  • Stratified the results by age categories since we observed significant heterogeneity when trials were pooled, and a clear difference in zinc effect was evident according to age.

  • For subgroup analysis by nutritional status, it was not possible to refer to the definition of malnutrition given in the protocol (weight/height) as most included trials used another definition (weight/age), which is easier to measure. The difference between the two definition is that the first identifies children with acute weight loss or 'wasted', while the second includes both children with acute and chronic malnutrition ('wasted' and 'stunted').

  • Two categories of 'zinc dose' were used (20 mg and > 20 mg) as most trials used zinc 20 mg/day, and only two trials used more than 20 mg/day.

  • Gender was added since subgroup as it was recently identified as a possible effect modifier (Garenne 2005).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al-Sonboli 2003

MethodsRCT
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)

Interventions1. Zinc sulphate: 22.5 mg (3 to 6 months) or 45 mg (7 to 60 months)
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Stool frequency
Notes

Location: Brazil

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk8.6% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Bahl 2002

MethodsRCT
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated randomization lists
Allocation concealment (selection bias)Low riskThe 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 riskFour-blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk2% lost to follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Bhatnagar 2004a

MethodsRCT
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

Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskCentral randomization performed at a site remote from trial location (World Health Organization, Geneva)
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Bhutta 1999b

MethodsRCT
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

Outcomes1. Average duration of diarrhoea
2. Stool output
3. Adverse events (copper levels)
Notes

Location: Pakistan

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskCentral randomization by independent pharmacy; table block randomization maintained in the pharmacy
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
High risk11% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Brooks 2005a

MethodsRCT
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

Interventions1. Zinc acetate: 20 mg
2. Zinc acetate: 5 mg
3. Placebo
Outcomes1. Death
2. Average duration of diarrhoea
3. Stool output
4. Stool frequency
5. Adverse events (vomiting)
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Unclear riskBottles labelled with randomization numbers; no other details
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk5% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Brooks 2005a (20 mg)

MethodsSee Brooks 2005a
ParticipantsNumber: 91 (5% lost at follow up)
Interventions1. Zinc acetate: 20 mg
2. Placebo
OutcomesSee Brooks 2005a
NotesSee Brooks 2005a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions
Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions
Incomplete outcome data (attrition bias)
All outcomes
Low risk5% lost at follow up
Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions
Other biasUnclear riskSee Brooks 2005a for all descriptions

Brooks 2005a (5 mg)

MethodsSee Brooks 2005a
ParticipantsNumber: 91 (7% lost at follow up)
Interventions1. Zinc acetate: 5 mg
2. Placebo
OutcomesSee Brooks 2005a
NotesSee Brooks 2005a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions
Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow up
Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions
Other biasUnclear riskSee Brooks 2005a for all descriptions

Dalgic 2011

MethodsRCT
Participants

Number: 120

Inclusion criteria: 1 to 28 months and, on admission, stool positive for rotavirus antigen.  

Exclusion criteria: severe malnutrition (weight for height< -3SD as for WHO standards): duration of diarrhoea > 96 h; severe dehydration; exclusively breast-feeding; toxic clinical appearance; immunosuppression; any known allergies to any drugs or foods.

Interventions1. Zinc 20 mg/day
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Hospitalization
Notes

Location: Turkey

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Unclear riskNot specified
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDefined as "single blind", but not further specified
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll children completed the study
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Dutta 2000

MethodsRCT
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

Interventions1. Zinc sulphate: 40 mg/day
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 5
3. Stool output
Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskCode numbers kept in a sealed envelope; zinc and placebo bottles identical
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe number of lost at follow up is not specified
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Dutta 2011

MethodsRCT
Participants

Number: 84

Inclusion criteria: age 6 to 24 months, history of acute watery diarrhoea, moderate dehydration.

Exclusion criteria: severe malnutrition (weight on height < -3SD WHO reference); systemic illness; chronic underlying disease (eg, tuberculosis, liver diseases) or needing intensive care; exclusively breastfed; antibiotics before enrolment or vitamin A within the previous 6 months.

Interventions1. Zinc 20 mg/day
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 5
3. Stool output
Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskCode numbers kept in a sealed envelope; zinc and placebo bottles identical
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber of lost at follow up < 10%
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Fajolu 2008

MethodsRCT
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot detailed
Allocation concealment (selection bias)Unclear riskNot detailed
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot detailed
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of lost at follow up not specified
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Faruque 1999

MethodsRCT
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

Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 7
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskBottles 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Fischer Walker 2006

MethodsRCT
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

Interventions1. Zinc sulphate: 10 mg
2. Placebo
Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskRandomization 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk3% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Fischer Walker 2006 ETH

MethodsSee Fischer Walker 2006
ParticipantsNumber: 177 (8% lost at follow up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: Ethiopia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006
Incomplete outcome data (attrition bias)
All outcomes
Low risk8% lost at follow up
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006
Other biasUnclear riskSee Fischer Walker 2006

Fischer Walker 2006 IND

MethodsSee Fischer Walker 2006
ParticipantsNumber: 373 (1% lost at follow up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: India
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006
Incomplete outcome data (attrition bias)
All outcomes
Low risk1% lost at follow up
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006
Other biasUnclear riskSee Fischer Walker 2006

Fischer Walker 2006 PAK

MethodsSee Fischer Walker 2006
ParticipantsNumber: 560 (3% lost at follow up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: Pakistan
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006
Incomplete outcome data (attrition bias)
All outcomes
Low risk3% lost at follow up
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006
Other biasUnclear riskSee Fischer Walker 2006

Khatun 2001

MethodsRCT
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

Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo details
Allocation concealment (selection bias)High riskNo details
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Larson 2005

MethodsRCT
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

Interventions1. Zinc sulphate: 20 mg
2. Placebo
Outcomes1. Adverse events (vomiting)
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskOpaque 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Patel 2009

MethodsRCT
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSingle-site, blocked randomization procedure with blocks of sizes three, six and nine in equal proportions
Allocation concealment (selection bias)Low riskRandomization 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 riskDouble 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 risk7% lost at follow up
Selective reporting (reporting bias)Low riskProtocol available. Trial registered in metaRegister of Controlled Trials (ISRCTN85071383)
Other biasUnclear riskNo information available

Patel 2009a (zinc)

MethodsRCT
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Patel 2009
Allocation concealment (selection bias)Low riskSee Patel 2009
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009
Selective reporting (reporting bias)Low riskSee Patel 2009
Other biasUnclear riskSee Patel 2009

Patel 2009b (zinc+copper)

MethodsSee Patel 2009a
ParticipantsSee Patel 2009a
InterventionsSee Patel 2009a
OutcomesSee Patel 2009a
NotesSee Patel 2009a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Patel 2009
Allocation concealment (selection bias)Low riskSee Patel 2009
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009
Selective reporting (reporting bias)Low riskSee Patel 2009
Other biasUnclear riskSee Patel 2009

Patro 2010

MethodsRCT
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 <5th 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTwo different randomization lists for each centre were computer-generated by an investigator at the Medical University of Warsaw.  
Allocation concealment (selection bias)Low riskThe 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 riskInvestigators, participants, outcome assessors, and data analysts
Incomplete outcome data (attrition bias)
All outcomes
High risk11.8% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNote: source of funding: Nutricia.

Penny 1999

MethodsRCT
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

Interventions1. Zinc gluconate: 20 mg
2. Placebo
Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers
Allocation concealment (selection bias)Low riskRandomization 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Polat 2003

MethodsRCT
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

Interventions1. Zinc sulphate: 20 mg
2. Placebo
Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskBottles labelled with randomization numbers, no other details
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk9% lost to follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Polat 2003 low Zn

MethodsSee Polat 2003
Participants

Number: 76

Children with low zinc serum levels

InterventionsSee Polat 2003
OutcomesSee Polat 2003
NotesSee Polat 2003
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Polat 2003
Allocation concealment (selection bias)Low riskSee Polat 2003
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003
Selective reporting (reporting bias)Unclear riskSee Polat 2003
Other biasUnclear riskSee Polat 2003

Polat 2003 normal Zn

MethodsSee Polat 2003
Participants

Number: 106

Children with normal zinc serum levels

InterventionsSee Polat 2003
OutcomesSee Polat 2003
NotesSee Polat 2003
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Polat 2003
Allocation concealment (selection bias)Low riskSee Polat 2003
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003
Selective reporting (reporting bias)Unclear riskSee Polat 2003
Other biasUnclear riskSee Polat 2003

Roy 1997

MethodsRCT
Participants

Number: 111
Inclusion criteria: 2 to 24 months; weight below the 76th 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

Outcomes1. Average duration of diarrhoea
2. Stool output
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskBottles labelled with randomization numbers
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
High risk32.4% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Roy 1998

MethodsRCT
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

Outcomes1. Death
2. Average duration of diarrhoea
3. Adverse events
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if any lost to follow up; 11% discontinued intervention
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Roy 2008

MethodsRCT
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

Outcomes1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskBottles 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
High risk11% lost at follow up
Selective reporting (reporting bias)Low riskTrial registered in ClinicalTrial.gov (NCT00321126)
Other biasUnclear riskNo information available

Sachdev 1988

MethodsRCT
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)

Interventions1. Zinc sulphate: 20 mg
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Stool frequency
3. Adverse events (vomiting)
Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Sachdev 1990

MethodsRCT
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)

Interventions1. Zinc sulphate: 20 mg
2. Placebo
Outcomes1. Average duration of diarrhoea
2. Stool frequency
3. Adverse events (vomiting)
Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Sazawal 1995

MethodsRCT
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

Outcomes1. Diarrhoea at day 7
2. Stool frequency
3. Adverse events (vomiting)
Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskChildren 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk2% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Strand 2002

  1. a

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

MethodsRCT
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

Interventions1. Zinc gluconate: 15 mg for infants; 30 mg for older children
2. Placebo
Outcomes1. 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskPacking 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 riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low risk1% lost at follow up
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasUnclear riskNo information available

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

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

Adu Afarwuah 2007Not concerning the intervention of interest (3 types of micronutrients for food fortification)
Adu-Afarwuah 2008Not concerning the intervention of interest (zinc fortification)
Aggarwal 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Agustina 2007Not concerning the intervention of interest (probiotic, prebiotic, fibre, and micronutrients mixture)
Alam 2010Prevention study
Alarcon 2004RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Awasthi 2006Not concerning the intervention of interest (zinc in oral rehydration solution)
Baqui 2002Community RCT without a placebo group
Baqui 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Baqui 2006Not concerning any outcome of interest (serum zinc)
Baum 2010Not concerning the population of interest (adults, HIV positive)
Behrens 1990Not concerning any outcome of interest (nutritional status)
Bhandari 2002RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2005Not a RCT
Bhandari 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2008RCT without a placebo group
Bhatnagar 2004bNot a RCT
Bhutta 2000aNot concerning any outcome of interest (appetite)
Bilenko 2010Not concerning the intervention of interest (multiple micronutrients in sprinkles)
Black 2001Not a RCT
Bobat 2005Not concerning the population of interest (only children with HIV enrolled)
Borges 2007Not a RCT
Brooks 2005bRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Brown 2007Not concerning the Intervention of interest (food fortification)
Brown 2007aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Carbajal 2000Not a placebo-controlled RCT
Carcamo 2006Not concerning the population of interest (adults with HIV)
Chandyo 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chang 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chen 2010Not concerning the intervention of interest (food fortification with multiple micronutrients)
Chhagan 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chhagan 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Christian 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, on a different population (pregnant women)
CIGNIS 2010Not concerning the intervention of interest (food fortification with multiple micronutrients)
Cross 2009Not RCT
Dhingra 2009Not RCT
Doherty 1998Not a placebo-controlled RCT, and criteria for inclusion of children was malnutrition, not diarrhoea
Ebrahimi 2006Not concerning any outcome of interest (growth)
Ellis 2007Not a RCT
Ferraz 2007Not RCT
Ferrufino 2007Not RCT
Fischer Walker 2008Secondary analysis of a previously excluded study (Baqui 2002)
Gardner 2005Not a RCT
Garenne 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gregorio 2007Not concerning the intervention of interest (zinc-fortified oral rehydration solution)
Gupta 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gupta 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Habib 2010Longituidinal cohort study
Heinig 2006Not concerning any outcome of interest (growth, morbidity, and motor development)
Hettiarachchi 2008Not concerning the population of interest (children 12-16 years), nor the outcomes
Hidayat 1998Community 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 2006Not RCT (review)
Hyder 2007Not concerning the population of interest (adolescent girl), the intervention (multiple micronutrients), nor the outcomes.
Iannotti 2010Not concerning the population of interest (pregnant women)
Islam 2010Not concerning the population of interest (preterm infants), nor any outcome of interest (growth)
Jimenez 2000Not concerning any outcome of interest (growth)
Kelly 1999Intervention and the population (micronutrient supplementation in AIDS diarrhoea-wasting syndrome) considered in this RCT not relevant
Kelly 2010Not concerning any outcome of interest (intestinal function)
Larson 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lin 2008Not placebo controlled, not outcomes of interest (weight)
Lind 2004RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lind 2008Secondary analysis of a previously excluded study (Lind 2004)
Lira 1998Not concerning the population of interest (low birthweight infants)
Long 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Long 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Lopez 2005Not concerning the intervention of interest (multiple micronutrient), nor the outcomes (anaemia, micronutrient status, growth, and morbidity)
Luabeya 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lukacik 2008Not RCT (meta-analysis)
Makonnen 2003aNot concerning any outcome of interest
Makonnen 2003bNot concerning any outcome of interest
Manger 2008No placebo controlled, different intervention (multiple micronutrients), prevention study
Mazariegos 2010Not concerning any outcome of interest (linear growth)
Mazumder 2010Secondary analysis of a previously excluded study (Bhandari 2008)
Mda 2010Not concerning population of interest (only children with HIV), different intervention (multiple micronutrient)
Meeks 1998RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Müller 2001RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Naheed 2009Secondary analysis of a previously excluded study (Baqui 2002)
Nasrin 2005Not a RCT
Nga 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Osendarp 2002RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Ouedraogo 2008RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Passariello 2010Not concerning the intervention of interest (zinc in oral rehydration solution)
Patel 2005Not concerning the intervention of interest (zinc and copper in oral rehydration solution)
Patel 2010Secondary analysis of an included study (Patel 2009), with no outcome of interest (by isolated micro-organism)
Patel 2010aNot a RCT (review)
Patro 2008Not RCT (meta-analysis)
Penny 2004aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Penny 2004bNot a RCT
Polat 2006Not a placebo-controlled RCT
Rahman 2001RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rahman 2005Not concerning any outcome of interest
Raqib 2004Not concerning any outcome of interest (immune and inflammatory responses)
Richard 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rollins 2007Not concerning the population of interest (only HIV infected children), and different outcomes (growth, immunity)
Rosado 1997RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rosado 1998Not a RCT
Rosado 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Roy 1992Not concerning any outcome of interest (intestinal permeability)
Roy 1999RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2008aNot concerning the population of interest (children aged between 3 and 14 years)
Ruel 1997RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sabatier 1997Not a placebo-controlled RCT
Samuel 1995Not a RCT
Sancho Martinez 2007Not RCT (review)
Sazawal 1996RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 1997aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2004aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2007aNot concerning the intervention of interest (milk fortification)
Sazawal 2007bNot concerning any outcome of interest (plasma retinol)
Sazawal 2007cRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Shamir 2005Not concerning the interventions (zinc and probiotics) considered in this RCT not relevant
Shankar 1998Not RCT (Review)
Sharieff 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sheikh 2010Not a RCT
Sur 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Taneja 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, in a different population (low birth weight infants)
Taneja 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (growth)
Tielsch 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Tielsch 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Umeta 2000RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Untoro 2005Not concerning the intervention of interest (multiple micronutrient), nor any outcome(anaemia, micronutrient status, growth, and morbidity)
Valery 2005Not concerning the population of interest (all children aged under 11 years)
Veenemans 2011Prevention study
Wadhwa 2011Study on zinc enriched ORS
Walden 2004Not a RCT
Walker 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Wieringa 2010Not concerning the population of interest (pregnant women)
Winch 2006Not a RCT
Winch 2008Not a RCT
Wuehler 2008RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Characteristics of ongoing studies [ordered by study ID]

NCT01140074

Trial name or titleEfficacy of Zinc Sulfate With Probiotics for the Treatment of Acute diarrhoea in Children
MethodsRCT
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 dateJuly 2010 (not yet recruiting in December 2010)
Contact information

Contact: Leszek Szenborn, Prof szenborn@zak.am.wroc.pl (principal investigator)

Contact: Ernest P. Kuchar, MD kuchar@zak.am.wroc.pl

Notes

Location: Poland

Registration number: NCT01140074

Source of funding: unclear

Sponsor: University Hospital No 1 Wroclaw

NCT01198587

Trial name or titleA Double Blind Randomized Placebo Controlled Trial of Oral Zinc for Children With Acute diarrhoea in a Developed Nation.
Methods

RCT

 

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 dateSeptember 2010
Contact information

Michelle L Niescierenko, MD

michelle.niescierenko@childrens.harvard.edu

Children's Hospital Boston

Notes

Location: USA

Registration number: NCT01198587

Source of funding: unclear

Sponsor: Children's Hospital Boston

Ancillary