Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children

Abstract

Objective: To evaluate the impact of 4 months of daily zinc supplementation on the incidence of severe and recurrent diarrhea in children 6 to 30 months of age. Methods: A double-blind, randomized, placebo-controlled trial was conducted on children who were identified by a door-to-door survey to be aged 6 to 30 months and residing in the urban slum of Dakshinpuri, New Delhi. They were randomized to receive daily zinc gluconate (elemental zinc 10 mg to infants and 20 mg to older children) or placebo. A field attendant administered the syrup daily at home for 4 months except on Sundays, when the mother did so. One bottle that contained 250 mL was kept in the child's home and replaced monthly. Field workers visited households every seventh day during the 4-month follow-up period. At each visit, information was obtained for the previous 7 days on history of fever, number and consistency of stools, and presence of cough. When the child was ill, illness characteristics and treatment seeking outside the home were determined. If the child had diarrhea or vomiting, then dehydration was assessed. At household visits, 2 packets of oral rehydration salts were given when a child had diarrhea. Children who visited the study clinic spontaneously for illness or were referred by the field workers were treated according to the standard national program guidelines. Antibiotics were advised only for diarrhea with bloody stools or for associated illnesses. For using generalized estimating equations for longitudinal analysis of a recurring event such as diarrhea, the follow-up data for each child was divided into 17 child-periods of 7 days each and presence or absence of an incident episode of diarrhea or severe diarrhea within each 7-day period was coded. This method of analysis does not assume independence of events and therefore prevents underestimation of variance that results because of correlation of morbidity within the same child. A logistic generalized estimating equations model with exchangeable correlation covariance-variance matrix was then used to estimate the effect size. Results: Zinc or placebo doses were administered on 88.8% and 91.2%, respectively, of study days during the 4 months of follow-up. There was a small but significant increase in the average number of days with vomiting in the zinc group (4.3 [standard deviation (SD): 5.8] vs 2.6 [SD 3.9] days; difference in means: 1.7 [95% confidence interval (CI): 1.3-2.1] days). At the baseline, mean plasma zinc was 62.0 microg/dL (SD: 14.3 microg/dL) in the zinc and 62.0 microg/dL (SD: 11.2 microg/dL) in the placebo group; 45.8% and 42%, respectively, had low plasma zinc levels below 60 microg/dL. At the end of the study, plasma zinc levels were substantially higher in the zinc group (ratio of geometric means: 1.94 [95% CI: 1.86-2.03]) and the proportion with low plasma zinc was lower (difference in proportions: -46.7% [95% CI: -41.8% to -51.4%]). The incidence of diarrhea during follow-up was lower in the zinc-supplemented as compared with the placebo group (odds ratio [OR]: 0.88; 95% CI: 0.82-0.95). The beneficial impact of zinc was greater on the incidence of diarrhea with progressively increasing duration: episodes of diarrhea that lasted 1 to 6 days (OR: 0.92; 95% CI: 0.85-1.00), 7 to 13 days (OR: 0.79; 95% CI: 0.65-0.95), and > or =14 days (OR: 0.69; 95% CI: 0.48-0.98). The impact was also greater on the incidence of episodes with progressively higher stool frequency: 3 to 5 stools per day (OR: 0.90; 95% CI: 0.83-0.98), 6 to 9 stools per day (OR: 0.87; 95% CI: 0.77-0.98), and > or =10 per day (OR: 0.77; 95% CI: 0.63-0.94). In the zinc group, significantly more children experienced no diarrheal episode during the study period (risk ratio [RR]: 1.22; 95% CI: 1.02-1.44). Furthermore, substantially fewer children (RR: 0.51; 95% CI: 0.36-0.73) experienced recurrent diarrhea, defined as >6 diarrheal episodes in the follow-up period as compared with children in the placebo group. The number of children who were hospitalized for any cause tended to be lower in the zinc group, but the difference was not statistically significant (1.79% vs 2.43%; RR: 0.74; 95% CI: 0.43-1.27). The baseline mean plasma copper (microg/dL) was similar in the 2 groups (difference in means: 1.6; 95% CI: -2.9 to 6.1). The end study plasma copper levels were significantly lower in the zinc group (difference in means: -15.5; 95% CI: -19.9 to - 11.1). Conclusions: Zinc supplementation substantially reduced the incidence of severe and prolonged diarrhea, the 2 important determinants of diarrhea-related mortality and malnutrition. This intervention also substantially reduced the proportion of children who experienced recurrent diarrhea. Prompt measures to improve zinc status of deficient populations are warranted. The potential approaches to achieve this goal include food fortification, dietary diversification, cultivation of plants that are zinc dense or have a decreased concentration of zinc absorption inhibitors, and supplementation of selected groups of children. Future studies should assess the impact of increased zinc intakes on childhood mortality in developing countries. For facilitating intervention, there is a need to obtain reliable estimates of zinc deficiency, particularly in developing countries. The functional consequences of the effect of various doses of zinc on plasma copper levels merits additional study.