Papers

Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial

Abdullah H Baqui, associate research professor ^a, Robert E Black, chairman ^a, Shams El Arifeen, head ^c, Mohammad Yunus, head ^d, Joysnamoy Chakraborty, senior manager ^d, Saifuddin Ahmed, assistant scientist ^b, J Patrick Vaughan, professor ^e. 

^a Department of International Health, Johns Hopkins Bloomberg School of Public Heath, 615 N Wolfe Street, Baltimore, MD 21205, USA, ^b Department of Population and Family Health, Johns Hopkins Bloomberg School of Public Heath, ^c Child Health Program, ICDDR,B: Centre for Health and Population Research, GPO Box 128, Dhaka 1000, Bangladesh, ^d Matlab Health Research Program, ICDDR,B: Centre for Health and Population Research, ^e London School of Hygiene and Tropical Medicine, London WC1A 7HT

Correspondence to: A H Baqui abaqui{at}jhsph.edu

	Abstract

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Objective: To evaluate the effect on morbidity and mortality of providing daily zinc for 14 days to children with diarrhoea.
Design: Cluster randomised comparison.
Setting: Matlab field site of International Center for Diarrhoeal Disease Research, Bangladesh.
Participants: 8070 children aged 3-59 months contributed 11 881 child years of observation during a two year period.
Intervention: Children with diarrhoea in the intervention clusters were treated with zinc (20 mg per day for 14 days); all children with diarrhoea were treated with oral rehydration therapy.
Main outcome measures: Duration of episode of diarrhoea, incidence of diarrhoea and acute lower respiratory infections, admission to hospital for diarrhoea or acute lower respiratory infections, and child mortality.
Results: About 40% (399/1007) of diarrhoeal episodes were treated with zinc in the first four months of the trial; the rate rose to 67% (350/526) in month 5 and to >80% (364/434) in month 7 and was sustained at that level. Children in the intervention cluster received zinc for about seven days on average during each episode of diarrhoea. They had a shorter duration (hazard ratio 0.76, 95% confidence interval 0.65 to 0.90) and lower incidence of diarrhoea (rate ratio 0.85, 0.76 to 0.96) than children in the comparison group. Incidence of acute lower respiratory infection was reduced in the intervention group but not in the comparison group. Admission to hospital of children with diarrhoea was lower in the intervention group than in the comparison group (0.76, 0.59 to 0.98). Admission for acute lower respiratory infection was lower in the intervention group, but this was not statistically significant (0.81, 0.53 to 1.23). The rate of non-injury deaths in the intervention clusters was considerably lower (0.49, 0.25 to 0.94).
Conclusions: The lower rates of child morbidity and mortality with zinc treatment represent substantial benefits from a simple and inexpensive intervention that can be incorporated in existing efforts to control diarrhoeal disease.

What is already known on this topic Zinc deficiency is highly prevalent in children in developing countries Zinc supplements given during diarrhoea reduce the duration and severity of treated episodes If given for 14 days during and after diarrhoea, zinc reduces the incidence of diarrhoea and pneumonia in the subsequent two to three months What this study adds Zinc used as a treatment for diarrhoea reduces mortality in children Zinc reduces admissions to hospital for diarrhoea The impact of zinc on mortality and morbidity can be achieved in a realistic large scale public health programme

	Introduction

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Zinc deficiency is highly prevalent in children in developing countries.¹ Inadequacy of dietary zinc intake is exacerbated by the net loss of zinc during diarrhoea.² Zinc supplements given during diarrhoea reduce the duration and severity of treated episodes³ and, if given for 14 days during and after diarrhoea, can reduce the incidence of diarrhoea and acute lower respiratory infection in the subsequent two to three months.⁴ Provision of zinc during diarrhoea may thus be a feasible strategy for both treatment of diarrhoea and prevention of subsequent morbidity and mortality. The therapeutic trials of zinc supplementation conducted to date have been small and conducted in clinical settings. We aimed to evaluate the impact on morbidity and mortality of zinc treatment during diarrhoea in a realistic large scale public health programme.

	Methods

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Study design and population
We conducted this community based, prospective, cluster randomised controlled trial in the Matlab field area of the International Center for Diarrhoeal Disease Research, Bangladesh (ICDDR,B). In 1998 infant mortality in the Matlab area was 60.6 per 1000 live births, and mortality in children aged 1-4 years was 5.2 per 1000 children. Diarrhoea accounted for about 12% of infant deaths and about a third of all deaths in children aged 1-4 years.⁵

Oral rehydration treatment and referral for patients with diarrhoea are provided in the villages by community health workers and by Bari motherscommunity volunteers who distribute oral rehydration solution packets and provide advice to patients with diarrhoea. The community health workers also provide treatment and referral services for acute lower respiratory infection. On average, there is one community health worker for every 2000 people and one Bari mother for every 50 people. We selected for the study 30 service areas (clusters) of community health workers around Matlab treatment centre, each with about 200 children aged 3-47 months.

We initially enrolled children aged 3-47 months who were permanent residents of the study cluster areas. We also included all babies as they became 3 months old and all babies in the age range of 3-59 months moving into the area during the period of the study, November 1998 to October 2000. Children with a mid-upper arm circumference of <110 mm were excluded and referred to the Matlab treatment centre for care. When study children became 60 months old they were excluded.

Intervention
The community health workers and Bari mothers in the intervention clusters taught the mothers how to use the zinc syrup. As soon as diarrhoea was reported, study children in the intervention villages were to receive 20 mg of elemental zinc as acetate each day for 14 days, regardless of the duration of the episode, in a once daily dose of 5 ml. The children in the intervention and comparison clusters received oral rehydration solution, and their mothers received advice on feeding during diarrhoea and on referral to the Matlab treatment centre, if needed.

Outcome definitions and follow up
Data collectors who were not involved in the implementation of the intervention made bi-monthly home visits (six monthly in the second year of the study) to collect data on morbidity from diarrhoea and acute lower respiratory infection and adherence to zinc treatment. Diarrhoea was defined as three or more loose, liquid, or watery stools or at least one loose stool containing blood in a 24 hour period. If the stool contained blood, the episode was classified as dysentery. Acute lower respiratory infection was diagnosed if the child had reported symptoms of cough, difficult breathing and rapid breathing, or chest in-drawing. Data on hospital admissions (diagnosis made by physician) were collected by surveillance in the Matlab treatment centre. Data on deaths in study children were collected by the health and demographic surveillance system of ICDDR,B. Verbal autopsy was conducted with parents for all reported deaths.⁶

We used a Cox's hazards regression to assess the therapeutic effect of zinc on the duration of diarrhoeal episodes, and we estimated the effects of zinc treatment on other outcomes in two ways. Firstly, using children as the unit of analysis, we calculated rates, rate ratios, and 95% confidence intervals, adjusting for covariates with random effect Poisson regression. Secondly, we conducted a cluster level analysis in which we compared the mean rates in the intervention and comparison clusters adjusted for the distribution of selected characteristics of children.

	Results

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A total of 8070 children contributed 11 881 child years of observation (see bmj.com). The age distribution of children in the intervention cluster was similar to that in the comparison cluster. Significantly more boys were in the intervention clusters than the comparison clusters. The distribution of children's age and birth order, mothers' education, homestead land size, and baseline diarrhoea hospital admission rates were similar in the intervention and comparison clusters.

About 40% (399/1007) of episodes were treated with zinc in the first four months of the trial. Use of zinc increased to about 67% (350/526) of episodes by month 5 of the trial and to more than 80% (364/434) by month 7, and was sustained at that level. On average, intervention children received zinc for about seven days during each episode of diarrhoea.

The duration of diarrhoea in children from the intervention clusters was 24% shorter than that in the comparison group. The duration was significantly shorter for both non-dysenteric diarrhoea and dysentery (table 1).

The incidence of diarrhoea was 15% lower in the intervention clusters than in the comparison clusters (table 2). A slightly lower incidence of acute lower respiratory infection in the intervention clusters was evident by the end of the study, but the difference in rates between the intervention and comparison groups over the full study period was not significant. The intervention clusters had a much higher incidence of acute lower respiratory infection than the comparison clusters at the start, and this incidence declined significantly over the study period. No such trend was observed in the comparison clusters (figure). The trends in incidence of acute lower respiratory infection in the intervention and comparison clusters were significantly different (P<0.001).

View larger version (21K): [in this window] [in a new window]   Incidence of acute lower respiratory infection by area and study period

Children in the intervention clusters had a 24% lower diarrhoea related admission rate than children in the comparison clusters, which was a significant difference in the individual level analysis but not in the cluster analysis. The admission rate for acute lower respiratory infection was also lower (by 19%) in the intervention clusters, but the difference was not statistically significant (table 3).

A total of 70 children died33 in the intervention clusters and 37 in the comparison clusters. Thirty deaths were due to drowning, and the remaining 40 were not injury related. The non-injury death rate was 51% (95% confidence interval 6 to 75%) lower in the zinc intervention clusters than in the comparison clusters. The lower non-injury death rate in the intervention clusters was almost entirely due to fewer deaths from diarrhoea and acute lower respiratory infection. Diarrhoea and acute lower respiratory infection together accounted for 10 deaths in the intervention clusters and 20 deaths in the comparison clusters (see bmj.com).

	Discussion

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In our study population, children who received zinc supplementation during and after diarrhoea had 24% shorter duration of diarrhoea, 15% lower incidence of diarrhoea, and a trend suggesting fewer diarrhoea related hospital admissions. The reductions in duration of both non-dysenteric diarrhoea and dysentery were significant. The downward trend in the incidence of acute lower respiratory infection in the zinc treatment group, but not in the comparison group, and the 19% reduction in admissions for acute lower respiratory infection, although not statistically significant, also suggested a benefit of zinc.

The reduction in the duration of diarrhoeal episode is consistent with earlier studies. ^{7 8} A meta-analysis of five studies of zinc treatment for acute diarrhoea found a summary estimate for reduction in duration of 16%.³ Possible mechanisms for the effect of zinc treatment on the duration of diarrhoea include improved absorption of water and electrolytes by the intestine,⁹ faster regeneration of gut epithelium,¹⁰ increased levels of enterocyte brush border enzymes,¹¹ and enhanced immune response,¹² leading to early clearance of diarrhoeal pathogens from the intestine.¹³

Several recent controlled trials have shown a preventive effect of routine zinc supplementation on the incidence of diarrhoea ^{4 14 15} and acute lower respiratory infection. ^{16 17} However, these studies provided daily zinc supplementation for a period of 6-12 months, which is often not feasible in large scale programmes.

The most important aspect of our study is that it shows for the first time a reduction in non-injury deaths from the use of zinc as a treatment for diarrhoea. About half the number of non-injury deaths occurred in the intervention clusters than in the comparison clusters. This difference was significant, even in the rigorous statistical analysis for the cluster level design, controlling for confounding variables. We believe, therefore, that the lower mortality can be attributed to zinc supplementation.

The intervention we evaluated is simple and inexpensive and can be incorporated into existing diarrhoeal disease control efforts. Further study is needed to determine whether zinc should be given as a supplement or can be incorporated into oral rehydration solution.

	Acknowledgments

   Contributors: See bmj.com

	Footnotes

Funding: Johns Hopkins Family Health and Child Survival Cooperative Agreement and ICDDR,B Cooperative Agreement, with funding from the US Agency for International Development.

Competing interests: None declared.

This is an abridged version; the full version is on bmj.com

	References

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(Accepted 24 June 2002)