Short-Course Prophylactic Zinc Supplementation for Diarrhea Morbidity in Infants of 6 to 11 Months Akash Malik, Davendra K.

Taneja, Niveditha Devasenapathy and K. Rajeshwari Pediatrics 2013;132;e46; originally published online June 3, 2013; DOI: 10.1542/peds.2012-2980

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Short-Course Prophylactic Zinc Supplementation for Diarrhea Morbidity in Infants of 6 to 11 Months

WHAT S KNOWN ON THIS SUBJECT: Randomized controlled trials have shown that zinc supplementation during diarrhea substantially reduces the incidence and severity. However, the effect of short-course prophylactic zinc supplementation has been observed only in children .12 months of age. WHAT THIS STUDY ADDS: The current study was able to show that short-course prophylactic zinc supplementation signicantly reduced diarrhea morbidity in apparently healthy infants of 6 to 11 months even after 5 months of follow-up.
AUTHORS: Akash Malik, MBBS,a Davendra K. Taneja, MD,a Niveditha Devasenapathy, MBBS, MSc,b and K. Rajeshwari, MDc
Departments of aCommunity Medicine, and cPaediatrics, Maulana Azad Medical College, New Delhi, India; and bIndian Institute of Public Health-Delhi, Public Health Foundation of India, New Delhi, India KEY WORDS zinc, diarrhea, infants, randomized control trial ABBREVIATIONS CIcondence interval IRRincident rate ratio RRrate ratio Dr Malik formulated the research question and contributed to designing the study, wrote the research grants, carried out the eld investigations, carried out the initial data analyses, and drafted the initial manuscript; Dr Taneja contributed to designing the study, contributed to developing the standard operating procedures, implemented randomization and blinding, and reviewed and revised the manuscript; Dr Devasenapathy supervised the data collection and managed the data, analyzed the data, and interpreted the ndings; Dr Rajeshwari supervised the clinical data collection and management, and contributed to developing the standard operating procedures; and all authors approved the nal manuscript as submitted. This trial was registered with the Clinical Trial Registry-India, No. CTRI/2010/091/001417. The Indian Council of Medical Research, Department of Health Research (Ministry of Health and Family Welfare), Government of India, which funded the study, had no role in the study design, data collection, analysis, interpretation of results, or decision to publish this research. AK, DKT, ND and KR had full access to all the data in the study and had nal responsibility for the decision to submit for publication. www.pediatrics.org/cgi/doi/10.1542/peds.2012-2980 doi:10.1542/peds.2012-2980 Accepted for publication Mar 25, 2013 Address correspondence to Akash Malik, MBBS, Department of Community Medicine, Maulana Azad Medical College and Associated Hospitals, Bahadur Shah Zafar Marg, New Delhi, India. E-mail: drakashmalik28@gmail.com PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2013 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose. FUNDING: Supported by the Indian Council of Medical Research, Department of Health Research (Ministry of Health and Family Welfare), Government of India. Reference No. 3/2/2011/PG-thesisMPD-10.

abstract
BACKGROUND: Zinc supplementation during diarrhea substantially reduces the incidence and severity of diarrhea. However, the effect of short-course zinc prophylaxis has been observed only in children .12 months of age. Because the incidence of diarrhea is comparatively high in children aged 6 to 11 months, we assessed the prophylactic effect of zinc on incidence and duration of diarrhea in this age group. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled infants aged 6 to 11 months from an urban resettlement colony in Delhi, India, between January 1, 2011, and January 15, 2012. We randomly assigned 272 infants to receive either 20 mg of zinc or a placebo suspension orally every day for 2 weeks. The primary outcome was the incidence of diarrhea per child-year. All analyses were done by intention-to-treat. RESULTS: A total of 134 infants in the zinc and 124 in the placebo groups were assessed for the incidence of diarrhea. There was a 39% reduction (crude incident rate ratio [IRR] 0.61, 95% condence interval [CI] 0.53 0.71) in episodes of diarrhea, 39% (adjusted IRR 0.61, 95% CI 0.540.69) in the total number of days that a child suffered from diarrhea, and reduction of 36% in duration per episode of diarrhea (IRR 0.64, 95% CI 0.560.74) during the 5 months of follow-up. CONCLUSIONS: Short-course prophylactic zinc supplementation for 2 weeks may reduce diarrhea morbidity in infants of 6 to 11 months for up to 5 months, in populations with high prevalence of wasting and stunting. Pediatrics 2013;132:e46e52

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Zinc is required for multiple cellular tasks and the immune system depends on the sufcient availability of this essential trace element.1 Zinc deciency is common in several developing countries, including India. This is because the commonly consumed staple foods have low zinc contents and are rich in phytates, which inhibit the absorption and utilization of zinc.2 Randomized controlled trials have shown that zinc supplementation during acute diarrhea reduces the duration and severity, as well as the incidence of subsequent diarrheal episodes.37 However, recently published meta-analyses conclude that prophylactic zinc supplementation signicantly reduces the incidence of diarrhea only in children .12 months of age.810 Because the incidence of diarrhea is comparatively high in children 6 to 12 months of age (4.8 episode per year),11 coinciding with the starting of complementary feeding, the current study aimed to evaluate whether zinc prophylaxis for a short duration has any role in reducing the morbidity due to diarrhea in this age group. Although the original trial included additional outcomes, such as acute respiratory tract infections and growth, the results of these will be reported separately.

recruited from the similar adjacent area of Gangavihar. The study was approved by the Institutional Ethical Committee of Maulana Azad Medical College, New Delhi, and Associated Lok Nayak Hospitals. The trial is registered with the Clinical Trial Registry-India, number CTRI/2010/091/ 001417. We hypothesized that zinc prophylaxis for 2 weeks would reduce the incidence of diarrhea in subsequent months. Thus, we excluded any child receiving zinc supplement at the time of study or who had received it in the preceding 3 months, those who were severely malnourished, immune-decient, currently on steroid therapy, severely ill requiring hospitalization, or of families likely to migrate from the study area. A house-to-house survey was done at the beginning of the study to identify and recruit the eligible infants. The study purpose was explained to the family and an informed consent was obtained from parents of all infants before they were included in the trial. The recruitment was done during the rst 2 weeks of January and July, followed by subsequent 5 months of follow-up, respectively. This ensured the assessment of outcomes for a complete year from January 2011 to January 2012, to minimize the effect of seasonality. Randomization and Blinding Random sequence was generated by simple randomization method using computer-generated random numbers (Excel 2010). The bottles were labeled with serial numbers in the Department of Community Medicine, Maulana Azad Medical College, by DKT, without the knowledge of the eld investigator (AM). The eld investigator and parents were blinded to the treatment allocation and unblinding was done at the end of the follow-up period for all 272 infants. Intervention The zinc and placebo syrups were prepared by Abyss Pharma (Delhi, India).

Each 5 mL of the preparation containing placebo (syrup base) or zinc (20 mg elemental zinc as zinc sulfate) was packed in similar-looking bottles. The syrups were of similar color, taste, and consistency. During the survey, after ascertaining the eligibility and obtaining informed consent, the infants were enrolled sequentially. The mother received the bottles with prelabeled serial numbers. The eld investigator administered the rst dose of the intervention at the time of enrollment and advised the mother to give 5 mL of syrup (using a standard 5-mL plastic spoon) daily to the infant for the remaining 13 days. Subsequently, visits were made on the 7th and the 14th days to ensure compliance. If the syrup had not been given regularly, a maximum of 1 week was given to complete the dosages. We collected data for any possible side effects as reported by the caregivers during these visits. To ensure that the child did not receive additional doses of zinc, we provided mothers with identity cards indicating the study title and that the infants had received zinc syrup. These cards were to be produced whenever the child was taken to any medical practitioner. Outcomes and Follow-up The primary outcome was the incidence of diarrhea per child-year. Diarrhea was dened as 3 or more loose, liquid, or watery stools or any change in consistency or frequency of stools or at least 1 loose stool containing blood in a 24-hour period.12 Secondary outcomes included incidence density of acute diarrhea, dysentery, and persistent diarrhea; duration of diarrhea; and side effects. Acute diarrhea was dened as an episode of diarrhea lasting up to 14 days. If an episode lasted for .14 days, it was dened as persistent diarrhea.12 The episode was classied as dysentery if the stool contained blood.12 Duration was assessed as the number of days with diarrhea

METHODS
Study Setting and Participants This is a community-based, randomized, double-blind, parallel-arm placebocontrolled trial, conducted from January 1, 2011, to January 15, 2012. We included all children 6 to 11 months of age residing in Gokulpuri, an urban resettlement colony in the northeast district of Delhi, India, who were likely to stay untilthecompletionofthestudy.Gokulpuri has 2500 houses divided into 4 blocks, A, B, C, and D, with a predominantly migrant population of 23 000. Most of the population belongs to the middle and lower socioeconomic strata. To achieve the nal sample size, additional children were

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and as mean number of days a diarrheal episode lasted. A baseline assessment (Table 1) was done at the time of recruitment, which included weight and length measurements using a Salter weighing scale (up to 100 g [Model no. 235 6M; Salter India Ltd, Daryaganj, New Delhi, India]) and an Infantometer (up to 1 mm [model no: AM 1744; ATICO Medical Pvt Ltd, Haryana, India]) respectively. All the outcomes were assessed by a trained eld investigator. Follow-up for diarrhea began on the 15th day after intervention. Each child was followed-up fortnightly 63 days and the follow-up continued for 5 months after the completion of zinc/ placebo supplementation. At each follow-up, the mother/caregiver was asked about the occurrence of diarrhea during the previous 15 days. Recovery from a diarrheal episode was considered when the last day of diarrhea was followed by a 72-hour diarrhea-free period.6 Subsequent episodes were considered to be new diarrheal episodes.

Sample Size The sample size was calculated taking into account 4 primary outcomes: decrease in incidence of diarrhea, acute respiratory tract infections, and increase in length and weight. For diarrhea, previous studies in similar populations estimated an incidence of 9.1 episodes (SD = 4.5) per child-year.7,9 Thus, for a 20% reduction in the incidence of diarrhea (a = 0.05 and power 80%), we required 90 infants in each group. However, the largest sample size required (for acute respiratory tract infection) was 258; thus, we recruited the entire population of 216 infants from Gokulpuri and an additional 56 infants from Gangavihar (total = 272). The outcomes for diarrhea were assessed for all recruited infants. Statistical Analysis The data were collected and checked for accuracy on a daily basis and entered into SPSS version 16 (IBM SPSS Statistics, IBM Corporation, Chicago, IL). The incidence density was expressed as

episodes per child per year. The counts were expressed by means and SD. Difference between means was tested using t-test, for normally distributed data, or Mann-Whitney U test, for skewed data. Generalized estimating equations were used to obtain an incident rate ratio (IRR) with 95% condence intervals (CIs), to compare monthwise number of episodes and duration of diarrhea using Poisson log linear distribution, by intention-to-treat analysis. The exchangeable working correlation matrix was selected for all the outcomes. We included all children who had taken at least 2 doses of the intervention for the analyses. The follow-up visits for which the infant outcomes were not available were imputed using the worst-case (2 episodes of diarrhea) and best-case scenarios (no episodes). However, this did not change the study results; thus, we present in this article results from complete data set analysis. We decided to adjust the IRRs for covariates that appeared to be different at baseline in the 2 groups. We also decided to compare the monthwise mean episodes of diarrhea in the 2 groups. Socioeconomic status was assessed by using the Modied Kuppuswamy Scale (based on education and occupation of family head and total family income) modied for Consumer Price Index for industrial workers of India for 2011.13 The z-scores for length and weight were calculated by using World Health Organization reference tables for length and weight.14,15 Observation and Results From a total of 3155 households identied during the house to house survey, we assessed 272 infants for eligibility (Fig 1). As there were no exclusions and refusals, all the infants were recruited. A total of 141 infants received zinc and 131 received placebo. Both groups shared similar baseline characteristics

TABLE 1 Baseline Characteristics of the Study Subjects at the Time of Recruitment

Characteristic Gender, n (%) Male Female Age, mo, mean 6 SD Socioeconomic status, n (%) Upper Upper Middle Lower Middle Lower Average oor space per person, square meters 6 SD Household water purication device, n (%) Yes No Feeding type, n (%) Exclusive breastfeeding Complementary feeding Both Length, cm, mean 6 SD Mean z score Stunted (,2Z WHO) , n (%) Weight, kg, mean 6 SD Mean Z score Wasted (,2Z WHO) , n (%)
WHO, World Health Organization.

Zinc (n = 141) 67 (47.5) 74 (52.5) 8.77 6 1.73 4 (2.8) 39 (27.7) 65 (46.1) 33 (23.4) 7.75 6 4.13 31 (22.0) 110 (78.0) 13 (9.2) 12 (8.5) 116 (82.3) 67.4 6 3.86 21.76 6 1.46 51 (36.0) 7.26 6 1.1 21.50 6 1.15 44 (31.2)

Placebo (n = 131) 68 (51.9) 63 (48.1) 8.76 6 1.86 4 (3.1) 30 (22.9) 58 (44.3) 39 (29.8) 8.26 6 5.21 23 (17.6) 108 (82.4) 16 (12.2) 11 (8.4) 104 (79.4) 67.6 6 3.82 21.69 6 1.48 54 (41.0) 7.21 6 1.2 21.58 6 1.21 53 (41.0)

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(Table 1). Seven families (n = 4 in the zinc group and n = 3 in the placebo group, respectively) migrated during the study period. The mean number of follow-ups was 10 in each group (zinc: 10.0 6 0.75, placebo: 10.0 6 0.76, P = .721). The nal analyses included 134 infants in the zinc group and 124 in the placebo group, who had completed the study. A total of 19 infants (13.5%) in the zinc group and 26 infants (20%) in the placebo group were given an additional 1 week to complete the intervention, as they were found to be initially noncompliant. Effect on Diarrhea Zinc supplementation for 14 days caused a signicant reduction in the number of episodes of diarrhea. Of the total 829 episodes observed, 329 episodes occurred in the zinc group and 500 in the placebo group, accounting for an incidence of 6.07 and 9.90 per child year respectively, at the end of 5 months

(Table 2). Generalized estimating equation regression model showed that there was a reduction of 39% (adjusted IRR 0.61, 95% CI 0.530.71) in episodes of diarrhea in the zinc group as compared with the placebo group after the model was adjusted for wasting. When types of diarrhea were analyzed separately (Table 2), we found a significant decrease of 31% in the episodes of acute diarrhea (adjusted IRR 0.69, 95% CI 0.590.81), 70% in the episodes of persistent diarrhea (adjusted IRR 0.30, 95% CI 0.170.51), and more than 95% in the episodes of dysentery (adjusted IRR 0.03, 95% CI 0.010.24) in the zinc group. Zinc supplementation led to a signicant reduction of 39% (adjusted rate ratio [RR] 0.61, 95% CI 0.540.69) in overall days with diarrhea. There was also a signicant reduction of 36% in duration per episode of diarrhea (adjusted RR 0.64, 95% CI 0.560.74) observed in the zinc group (Table 3).

Zinc signicantly reduced the mean episodes of diarrhea for each of the 5 months (Table 4). However, the level of signicance decreased after the third month. Side Effects Reported side effects were diarrhea, vomiting, and constipation. The percentage of children reporting these were 9.0%, 10.4%, and 1.5%, respectively, in the zinc group and 7.3%, 4.8%, and 0%, respectively, in the placebo group, and the difference was nonsignicant in the 2 groups. Onedeathduetodiarrheawasreportedin thezincgroup3monthsafterrecruitment. Verbal autopsy revealed severe dehydrationduetononadministrationoforal rehydrationsolutionor theavailablehome uids were the cause of death. The fact that the death took place 3 months after intervention, and the incorrect management revealed in the verbal autopsy, rules out any possible role of zinc.

DISCUSSION
In the current trial, we report that prophylactic zinc supplementation for 2 weeks signicantly reduced the incidence and duration of diarrhea during follow-up of 5 months. Although we studied additional outcomes (ie, acute respiratory tract infections and growth), the results of these will be reported separately. Zinc depletion leads to upregulation of neuropeptides, such as cyclic guanosine monophosphate, and acute-phase reactants, such as interleukin 1, which creates secretory conditions in the intestine leading to diarrheal episodes.16 Thus, zinc prophylaxis in zinc-decient populations reduces diarrheal morbidity. The major limitation of this study is that serum zinc levels were not done to assess the deciency and the subsequent effect on serum zinc levels. Nevertheless, previous studies in similar populations

FIGURE 1

Trial Prole.

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TABLE 2 Effect of Zinc Supplementation on Incidence of Diarrhea on the Study Subjects

Intervention Child Years Observed Incidence (Episodes Child1year21) 6.07 9.90 5.77 8.33 0.28 1.01 0.02 0.58 Crude IRR (95% CI) 0.61 (0.560.74) 1.00 0.68 (0.570.83) 1.00 0.29 (0.170.51) 1.00 0.032 (0.0040.24) 1.00 Adjusted IRRa (95% CI) 0.61 (0.530.71) 1.00 0.69 (0.590.81) 1.00 0.30 (0.180.53) 1.00 0.030 (0.010.24) 1.00

All forms of diarrhea Zinc 54.08 Placebo 50.25 Acute diarrhea Zinc 54.08 Placebo 50.25 Persistent diarrhea Zinc 54.08 Placebo 50.25 Dysentery Zinc 54.08 Placebo 50.25
a

Zinc prophylaxis was shown to reduce the incidence of diarrhea in both continuous as well as short-course supplementation trials, in 2 meta-analyses.8,9 However, the benecial effect was limited to children .12 months of age. In the current trial, a signicant reduction of days with diarrhea per child and duration per episode of diarrhea was observed. In contrast, results of 2 previous trials have shown no effect of continuous zinc prophylaxis on the duration of diarrhea. Of these, 1 study was done in the age group of 6 to 9 months and another in the age group of 18 to 36 months.19,26 Of the 2 metaanalyses, 1 with continuous zinc supplementation trials showed fewer total days with diarrhea,27 whereas the other, which included studies with continuous and short-course zinc supplementation, showed no effect on duration of diarrhea.7 A signicant reduction in incidence was seen when diarrhea was further classied into acute diarrhea, persistent diarrhea, and dysentery in the current trial. In the past, only 1 study concluded that the incidence of acute diarrhea was reduced signicantly by zinc supplementation, but in a wider age group (635 months).28 Three studies, which had a similar age group or analyzed results for children ,12 months of age, showed no signicant decrease in persistent diarrhea in the zinc group.6,22,24 Although both the meta-analyses show that risk of persistent diarrhea did decrease with zinc supplementation, subgroup analysis for the 6 to 11 months age group is not available.9,27 Also one of these meta-analyses included studies with continuous zinc supplementation only. Regarding dysentery, only 1 study showed signicant reduction in incidence of dysentery following zinc supplementation, that too in a wide age group of 6 to 35 months with continuous supplementation.24

Adjusted for wasting.

TABLE 3 Effect of Zinc Supplementation on Days with Diarrhea and Duration per Episode of
Diarrhea
Duration Intervention Zinc (n = 118)a Placebo (n = 116)a ,.001 ,.001 P Valueb Crude RR (95% CI) Adjusted RRc (95% CI)

Mean 6 SD of days with diarrhea 10.10 6 7.06 23.19 6 13.8 Mean 6 SD days per episode 3.60 6 2.23 5.34 6 2.16
RRrate ratio. a The children with 0 episodes were excluded. b Mann-Whitney U test, P , .05 considered signicant. c Adjusted for wasting.

0.60 (0.530.76) 0.61 (0.540.69) 0.63 (0.550.77) 0.64 (0.560.74)

TABLE 4 Monthwise Episodes of Diarrhea in

the 2 Study Groups
Month Zinc Mean (SD) First Second Third Fourth Fifth
a

Placebo Mean (SD) 0.85 (0.84) 0.83 (0.87) 0.88 (0.77) 0.82 (0.78) 0.77 (0.73)

P Valuea

0.44 (0.60) 0.40 (0.56) 0.49 (0.65) 0.58 (0.65) 0.61 (0.80)

,.0001 ,.0001 ,.0001 .014 .037

Mann-Whitney U test, P , .05 considered signicant.

of Delhi have shown high prevalence of zinc deciency (normal: 11.522.2 mM) to the extent of 73.3% for values ,10.4 mM and 33.8% for values ,9.0 mM.3 Moreover, in our study, the proportion of stunted infants was .20%, which suggests an elevated risk of zinc deciency, because stunting is a proxy indicator of zinc deciency in population studies.17 Also, baseline data on incidence density of diarrhea in this age group were not available. Among the studies in which shortcourse zinc prophylaxis of 2 weeks

was used, only 1 study had shown signicant reduction in the incidence of diarrhea in a 12- to 35-month age group.18 Previous studies, which were carried out in infants of 6 to 11 months, have shown similar results to the current trial but after continuous zinc supplementation.1922 One of these trials was carried out in a cohort of low birth weight infants.20 Trials have also shown the effectiveness of continuous zinc prophylaxis among wider age groups (641 months and 635 months, respectively), but subgroup analysis for children ,12 months of age was not done.23,24 In a large study done in a similar population of Delhi as the current trial, zinc prophylaxis of 4 months was found to be effective only in children .12 months of age.25 Thus, unlike the previous studies, the current trial showed that short-course zinc prophylaxis signicantly reduced diarrheal incidence in an age group of 6 to 11 months.

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A study with short-course zinc supplementation showed a nonsignicant reduction in incidence of dysentery in the age group of 12 to 35 months.18 Of the 2 meta-analyses, 1 is in agreement with the current trial, although the age group is wide in this metaanalysis and studies with only continuous zinc supplementation have been included.9,27 Among the previous studies in similar populations, we found that 1 study may have insufcient power to detect a signicant decrease in diarrhea morbidity in infants 6 to 11 months of age.25 In other studies, zinc prophylaxis was given to a subset of the population that had already received therapeutic zinc for acute diarrhea, which might have led to reduced effectiveness of the subsequent zinc prophylaxis.5,7,24,28 However, the current study was done in a population that had not received zinc supplementation for the preceding 3 months, was apparently healthy, and had a high proportion of wasted and stunted infants. This, coupled with the fact that the maximum burden of di-

arrhea is seen in the age group of 6 to 11 months,11 may have been responsible for such signicant results in the current study.

CONCLUSIONS
Previous trials and meta-analyses have shown the benecial effect of zinc prophylaxis on diarrhea either by continuous supplementation for a long duration, ranging from 3 months to 1 year, or in age groups of .12 months. The current study was able to show signicant reduction in diarrhea morbidity in infants of 6 to 11 months, even 5 months after short-course zinc prophylaxis. The advantage of zinc given as a community-based prophylactic intervention is that all children in the target population will be covered. This in turn will reduce the overall incidence of diarrhea in the community compared with administration of zinc only to children who seek treatment for diarrhea. This is because many children suffering from diarrhea may not come to a health facility, as is common in the

slum populations, and thus keep suffering from repeated episodes of diarrhea. The difculty of having to give zinc to apparently healthy children is that the delivery strategy has to be community based, thus requiring additional time and work on the part of the health workers/community volunteers. The results of this study have important cost and operational implications, as short-course prophylaxis of zinc in an adequate dose might be more feasible than continuous therapies. The results of this study may be extrapolated to similar zinc-decient populations only. Future trials on the effect of zinc prophylaxis on diarrhea should concentrate on zinc-decient pockets in both developed and developing countries. It is desirable that such trials follow a standardized procedure regarding the duration and dose of zinc prophylaxis. This would ensure that policy makers have reliable and valid evidence to implement zinc prophylaxis programs for those child populations that will benet the most from them.

REFERENCES
1. Beisel WR. Single nutrients and immunity. Am J Clin Nutr. 1982;35(suppl 2):417468 2. Black RE. Zinc deciency, immune function, and morbidity and mortality from infectious disease among children in developing countries. Food Nutr Bull. 2001;22: 155162 3. Baqui AH, Black RE, El Arifeen S, et al. Effect of zinc supplementation started during diarrhea on morbidity and mortality in Bangladeshi children: community randomized trial. BMJ. 2002;325(7372):1059 4. Walker CL, Black RE. Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes. Int J Epidemiol. 2010;39(suppl 1): i63i69 5. Sazawal S, Black RE, Bhan MK. Effect of zinc supplementation during acute diarrhea on duration and severity of the episode a community based double-blind controlled trial. N Engl J Med. 1995;333:839844 6. Sazawal S, Black RE, Bhan MK, et al. Zinc supplementation reduces the incidence of persistent diarrhea and dysentery among low socioeconomic children in India. J Nutr. 1996;126(2):443450 7. Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efcacy of zinc supplementation in reducing the incidence and prevalence of acute diarrheaa communitybased, double-blind, controlled trial. Am J Clin Nutr. 1997;66(2):413418 8. Brown KH, Peerson JM, Baker SK, Hess SY. Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Food Nutr Bull. 2009;30(suppl 1): S12S40 9. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators Collaborative Group. J Pediatr. 1999;135(6): 689697 10. Brown KH, Rivera JA, Bhutta Z, et al; International Zinc Nutrition Consultative Group (IZiNCG). Assessment of the risk of zinc deciency in populations. Food Nutr Bull. 2004;25(1 suppl 2):S99S203 11. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ. 2003;81: 197204 12. World Health Organization. Diarrhoeal disease. Available at: www.who.int/mediacentre/

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Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on March 12, 2014

13. 14.

15.

16.

17.

18.

19.

factsheets/fs330/en/index.html. Accessed October 7, 2010 Kuppuswamy B. Manual of Socioeconomic Status (Urban). Delhi, India: Manasayan; 1981 World Health Organization. Child growth standards. Weight-for-age. Available at: www. who.int/childgrowth/standards/weight_for_ age/en/index.html. Accessed July 23, 2011 World Health Organization. Child growth standards. Length/height-for-age. Available at: www.who.int/childgrowth/standards/ height_for_age/en/index.html. Accessed July 23, 2011 Wapnir RA. Zinc deciency, malnutrition and the gastrointestinal tract. J Nutr. 2000; 130(suppl 5S):1388S1392S de Benoist B, Darnton-Hill I, Davidsson L, Fontaine O, Hotz C. Conclusions of the joint WHO/UNICEF/IAEA/IZiNCG interagency meeting on zinc status indicators. Food Nutr Bull. 2007;28(suppl 3):S480S484 Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ. 2001;323 (7308):314318 Ruel MT, Rivera JA, Santizo MC, Lnnerdal B, Brown KH. Impact of zinc supplementation

20.

21.

22.

23.

on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics. 1997;99(6):808813 Sur D, Gupta DN, Mondal SK, et al. Impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight infants in Kolkata, India: a randomized, double-blind, placebo-controlled, community-based study. Pediatrics. 2003; 112(6 pt 1):13271332 Brooks WA, Santosham M, Naheed A, et al. Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial. Lancet. 2005; 366(9490):9991004 Long KZ, Montoya Y, Hertzmark E, Santos JI, Rosado JL. A double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico. Am J Clin Nutr. 2006; 83(3):693700 Gupta DN, Mondal SK, Ghosh S, Rajendran K, Sur D, Manna B. Impact of zinc supplementation on diarrhoeal morbidity in rural children of West Bengal, India. Acta Paediatr. 2003;92(5):531536

24. Penny ME, Marin RM, Duran A, et al. Randomized controlled trial of the effect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of young Peruvian children. Am J Clin Nutr. 2004;79(3):457 465 25. Bhandari N, Bahl R, Taneja S, et al. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics. 2002;109(6). Available at: www.pediatrics. org/cgi/content/full/109/6/e86 26. Rosado JL, Lpez P, Muoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr. 1997;65:1319 27. Aggarwal R, Sentz J, Miller MA. Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: a metaanalysis. Pediatrics. 2007;119(6):11201130 28. Larson CP, Nasrin D, Saha A, Chowdhury MI, Qadri F. The added benet of zinc supplementation after zinc treatment of acute childhood diarrhoea: a randomized, doubleblind eld trial. Trop Med Int Health. 2010;15 (6):754761

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MALIK et al

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Short-Course Prophylactic Zinc Supplementation for Diarrhea Morbidity in Infants of 6 to 11 Months Akash Malik, Davendra K. Taneja, Niveditha Devasenapathy and K. Rajeshwari Pediatrics 2013;132;e46; originally published online June 3, 2013; DOI: 10.1542/peds.2012-2980
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/132/1/e46.full.ht ml This article cites 24 articles, 14 of which can be accessed free at: http://pediatrics.aappublications.org/content/132/1/e46.full.ht ml#ref-list-1 This article has been cited by 1 HighWire-hosted articles: http://pediatrics.aappublications.org/content/132/1/e46.full.ht ml#related-urls This article, along with others on similar topics, appears in the following collection(s): Gastroenterology http://pediatrics.aappublications.org/cgi/collection/gastroente rology_sub Pharmacology http://pediatrics.aappublications.org/cgi/collection/pharmacol ogy_sub Therapeutics http://pediatrics.aappublications.org/cgi/collection/therapeuti cs_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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