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meta-regression of randomized trials. Int J Epidemiol. 2010; 39(3):795-808 (ISSN: 1464-3685) Roth DE; Richard SA; Black RE Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. BACKGROUND: Routine zinc supplementation is a potential intervention for the prevention of acute lower respiratory infection (ALRI) in developing countries. However, discrepant findings from recent randomized trials remain unexplained. METHODS: Randomized trials of zinc supplementation in young children in developing countries were identified by a systematic literature review. Trials included in the metaanalysis met specific criteria, including participants <5 years of age, daily/weekly zinc and control supplementation for greater than 3 months, active household surveillance for respiratory morbidity and use of a case definition that included at least one sign of lower respiratory tract illness. ALRI case definitions were classified on the basis of specificity/severity. Incidence rate ratios (IRRs) were pooled by random-effects models. Meta-regression and sub-group analysis were performed to assess potential sources of between-study heterogeneity. RESULTS: Ten trials were eligible for inclusion (n = 49 450 children randomized). Zinc reduced the incidence of ALRI defined by specific clinical criteria [IRR 0.65, 95% confidence interval (CI) 0.52-0.82], but had no effect on lower-specificity ALRI case definitions based on caregiver report (IRR 1.01, 95% CI 0.91-1.12) or World Health Organization 'non-severe pneumonia' (0.96, 95% CI 0.86-1.08). By meta-regression, the effect of zinc was associated with ALRI case definition, but not with mean baseline age, geographic location, nutritional status or zinc dose. CONCLUSIONS: Routine zinc supplementation reduced the incidence of childhood ALRI defined by relatively specific clinical criteria, but the effect was null if lower specificity case definitions were applied. The choice of ALRI case definition may substantially influence inferences from community trials regarding the efficacy of preventive interventions.
© 2006 American Society for Clinical Nutrition Zinc and pneumonia1,2 K Michael Hambidge
1. 1From the University of Colorado Health Sciences Center, Denver, CO Recent experience with lower mortality and morbidity due to infectious disease in welldesigned, randomized, controlled trials of zinc supplements in young children has highlighted zinc deficiency as a public health problem of global proportions (1). This experience applies especially to diarrhea and pneumonia, the most prevalent causes worldwide of infectious disease mortality in young children. The most extensive and
63. the use of zinc supplements as a preventive modality has been associated with lower mortality.72. Breastfed infants delivered at term with birth weights appropriate for gestational age are likely to have adequate zinc intakes for at least the first 4 mo of life.” The typically low dietary zinc intake of older infants .93) and 0. serum zinc was significantly higher at discharge than at baseline in all 3 studies. Comparable benefits of zinc supplementation. In the placebo groups. at least currently. In this issue of the Journal. who received the same antimicrobial therapy but no zinc (5). however. In contrast.impressive data relate to the use of zinc as a preventive measure. which has been categorized as a “problem nutrient.83). As has been typical for the reported studies of zinc administration used to prevent or treat diarrhea or pneumonia. The data for pneumonia prevention were even more impressive: the OR was 0. but in male children only (6). which was attributed to a cessation of the effects of the acute phase response. as in the report by Bose et al. and the mean for the former was well within a normal range. The mean baseline serum zinc concentration in their study was higher than that in the 2 studies they discussed that had positive results (5. and zinc-unfortified. were reported from a study in Kolkarta.82 (95% CI: 0. Bose et al do not include data on habitual dietary zinc intake or. but.41. 0. India.75 (0. provide adequate zinc. no apparent explanation was forthcoming. Zinc administered as a therapeutic agent to young children with acute or persistent diarrhea also reduces the duration of the diarrhea and is associated with a lower rate of treatment failure or death (4). The differential between the study of Bose et al (7) and the 2 positive studies (5. The quantity of zinc derived from breast milk by 6 mo is very limited. dietary zinc during hospitalization.88) for diarrheal incidence and prevalence. it is almost certain that dietary zinc intakes in infants >6 mo old in developing countries will fail to meet requirements. although not identical in the affected variables. In a recent study in Bangladesh. but a wide range of mean baseline serum or plasma zinc concentrations has been reported in studies in which zinc supplements have had a positive effect in preventing diarrhea and pneumonia (2) or in treating diarrhea (4). Although they were quite thorough in reviewing factors that may have accounted for their negative result. 0. zinc given together with antimicrobial therapy to young children with pneumonia was associated with a significant reduction in the duration of pneumonia compared with that in the control group. 0. notably that due to pneumonia (3). plant-based complementary foods do not. India.59 (0. 6). indeed. Hence. A pharmacologic effect of zinc is plausible (5). results of studies of zinc administered as adjuvant therapy for pneumonia have been more limited. However. A pooled analysis of the results of trials in 9 countries and on 4 continents showed odds ratios (ORs) in zincsupplemented groups of 0. Moreover. 6) was maintained. it is widely accepted that the beneficial effects of zinc supplements in the prevention and treatment of diarrhea and pneumonia are most likely to be due to the prevention or correction of zinc deficiency. beneficial effects of zinc supplements in the acute management of pneumonia are not to be expected unless the infant or child is zinc deficient. who typically depend on long-term breastfeeding as well as on the consumption of plant-based complementary foods. Bose et al (7) report no benefits of a zinc supplement in the management of pneumonia in young children in Tamilnadu. The adequacy of dietary zinc varies with age in young children in developing countries. respectively (2).
Zinc requirements in all low-birth-weight infants are higher than those in normalweight infants. Davis. University of California. Trisakti University. it would be unfortunate if this discouragement extended to the low-birth-weight infant. Indonesia. Pakistan.A. United Kingdom. Peru. PhD. California. the study of Bose et al leaves doubt about the more general benefits to be derived from the routine administration of zinc as an adjuvant therapy for pneumonia in young children in the developing world and. Medical Research Council Biostatistics Unit. Bangladesh. R. Mexico. Bangladesh. therefore. Vietnam. benefit from zinc supplements commencing early in infancy (9). Mona. as the authors conclude.E. Brown. Dhaka Medical College. Cambridge. Maryland. the young age of all participants in a recent trial by Brooks et al (8) provides a plausible explanation for the negative results with zinc supplementation. o . Karachi. Zinc Investigators’ Collaborative Group* Aga Khan University Medical Centre. Hence. MBBS. Although there are extensive reassuring data about the safety of zinc supplements in typical doses of 10–20 mg Zn/d. Jakarta. MD. Nutrition Research Institute. this is not the first instance in which zinc supplements have been associated with undesirable negative results. International Centre for Diarrhoeal Disease Research. MD. Mexico City. J. however. especially those identified as small-for-gestational age. Baltimore. This was a well-documented negative study on the value of short-term zinc therapy during the management of acute diarrhea in infants <6 mo old. Although the information on the lack of a treatment effect with age in the study of Bose et al indicates that additional insights are unlikely to be gained from a different agebased subdivision in their study. National Institute of Nutrition. Georgia. Black. Emory University. From a nutritional perspective. MPH. an argument can be made for a different subdivision by age than that selected by Bose at al and other investigators. PhD.Meeks Gardner. The significant treatment effect in subgroup analysis of the hot season that favors the placebo group should be considered when balancing the potential benefits and risks of zinc supplementation.H. Atlanta. Low-birth-weight infants. and the infants' ability to absorb the needed quantities of zinc appears to be limited (10). Jamaica. K. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: Pooled analysis of randomized controlled trials Z. Lima. One important piece of information missing from the report by Brooks et al.suggests that zinc supplements for the treatment of pneumonia are more likely to be effective in infants aged >6 mo. indicates the priority of the need for additional studies in representative populations. Dhaka. Hanoi. University of the West Indies. Bhutta. National Institute of Nutrition. Johns Hopkins School of Public Health. if the report by Brooks et al (8) discouraged the use of zinc supplements in infants aged <6 mo with diarrhea. was the birth weight of the participants. Finally.
Conclusions: Zinc supplementation in children in developing countries is associated with substantial reductions in the rates of diarrhea and pneumonia. Study design: Trials included were those that provided oral supplements containing at least one half of the United States Recommended Daily Allowance (RDA) of zinc in children <5 years old and evaluated the prevention of serious infectious morbidity through household visits. Bangladesh.66. and All India Institute of Medical Sciences.72 to 0.82 (95% CI 0. the pooled ORs for diarrheal incidence and prevalence were 0.37) were similar to those in the continuous trials. The analysis used random effects hierarchical models to calculate odds ratios (OR) and 95% CIs. The effects on diarrhea and pneumonia were analyzed overall and in subgroups defined by age. Results: For the zinc-supplemented children compared with the control group in the continuous trials. Zincsupplemented children had an OR of 0. In the short-course trials the OR for the effects of zinc on diarrheal incidence (OR 0. New Delhi.40 to 1. 95% CI 0. the 2 leading causes of death in these settings.Dhaka. 95% CI 0. Analysis included 7 “continuous” trials providing 1 to 2 RDA of elemental zinc 5 to 7 times per week throughout the period of morbidity surveillance and 3 “short-course” trials providing 2 to 4 RDA daily for 2 weeks followed by 2 to 3 months of morbidity surveillance.93) and 0. (J Pediatr 1999.62 to 1. Guatemala City.74.89. India Abstract Objectives: This study assessed the effects of zinc supplementation in the prevention of diarrhea and pneumonia with the use of a pooled analysis of randomized controlled trials in children in developing countries. respectively.52 to 0.83) for pneumonia. nutritional status. No significant differences were seen in the effects of the zinc supplement between the subgroups examined for either diarrhea or pneumonia. Guatemala. and sex. baseline plasma zinc concentration.88).59 (95% CI 0.135:689-97) .41 to 0.63 to 0.75 (95% CI 0. Institute of Nutrition of Central America and Panama.28) and prevalence (OR 0. 95% CI 0.83) and pneumonia incidence (OR 0.
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