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Therapeutic Zinc and Copper Supplementation in Acute Diarrhea Does Not Influence Short-Term Morbidity and Growth

Double-Blind Randomized Controlled Trial

Patel, Archana B. MD, DNB, MSCE*‡; Dibley, Michael J. MB BS, MPH; Mamtani, Manju MD*; Badhoniya, Neetu MSc*; Kulkarni, Hemant MD§

Author Information
The Pediatric Infectious Disease Journal: January 2013 - Volume 32 - Issue 1 - p 91-93
doi: 10.1097/INF.0b013e31826fb32d

Abstract

Zinc deficiency is widespread among children in developing countries. It has been observed that the populations with zinc supplementation show a higher incidence and prevalence of diarrheal and respiratory morbidities. It has therefore been argued that preventive zinc supplementation may be beneficial in that it can conceptually improve the overall health and growth of children. Four meta-analyses of preventive zinc supplementation trials have reported a 9–20% reduction in the incidence of diarrhea and a 8–40% reduction in the incidence of respiratory illness attributable to zinc supplementation,1–3 although there exists a significant heterogeneity among the published trials in this area. Moreover, 2 meta-analyses have assessed the effect of zinc supplementation on growth and reported that zinc supplementation can stimulate better growth, especially if there is a preexisting growth deficit.3,4 Again, there was significant heterogeneity among studies. Another study published after the review, showed no impact of zinc on growth of low birth weight babies.5 Thus, the role of preventive zinc supplementation, albeit conceptually appealing and attractive, is neither clear nor established. The aim of this study was to evaluate the effect of therapeutic zinc and copper supplementation on the secondary outcomes of morbidity and growth during 12 weeks of follow-up after the index diarrhea episode. This study was conducted in children with acute watery or bloody diarrhea in a hospital-based double-blind randomized controlled trial.

MATERIALS AND METHODS

Study Design

Details about the study subjects, the trial design and its rationale are provided elsewhere.6 Briefly, the eligibility criteria were all children aged 6–59 months attending the Indira Gandhi Government Medical College and Hospital, in Nagpur, India, with >3 unformed stools in the prior 24 hours; duration of diarrhea <72 hours; and ability to accept oral fluids or feeds. The consent procedure was administered to parents or guardians of the children, and those who gave informed consent were enrolled and randomized. Written consent was taken. The Ethics Committee of Indira Gandhi Government Medical College and the Human Research Ethics Committee of the University of Newcastle, New South Wales, Australia (HREC Approval No: H-500-0203) approved the study protocol, and the treatment effects monitoring committee monitored the trial for safety. Each recruited child was sequentially assigned to 1 of the following 3 treatment arms using a randomization protocol fixed a priori: placebo (Pl, n = 271) arm, zinc (Zn 2mg/kg/d, n = 264) only arm, and zinc and copper (Zn 2mg/kg/d and Cu 0.2mg/kg/d, n = 273) arm.

Protocol

The syrups were administered during the hospital stay and continued after discharge to complete a total duration of 2 weeks from enrollment in the trial. Treatment adherence was measured by weighing the bottles at enrollment, at discharge and on the 14th day of follow-up. The infants were then followed up fortnightly (6 visits) for 3 months. The mother was trained to record every day of diarrhea (>3 unformed stools in the prior 24 hours), cough, breathlessness and fever on a pictorial 2-week chart. Every effort was made to retain the infant in the study and find missing enrollees. The trial is registered with International Standard Randomized Controlled Trial with the unique identifier ISRCTN85071383.

Outcomes

We followed up the children for the following 11 outcomes—5 diarrhea-related, 3 related to respiratory morbidity and 3 related to growth. The diarrhea-related outcomes included proportion with at least 1 or 2 episodes of diarrhea or an episode of dysentery, the number and duration of diarrheal episodes per child. The respiratory outcomes included duration of episodes of acute lower respiratory infection or fever and the mean number of sick days. Finally, the growth-related outcomes included gain in weight-for-age Z score, weight-for-height Z score and height-for-age Z score.

An episode of diarrhea was defined as >1 day of reported diarrhea. The episode was not considered over until there were consecutive 3 diarrhea-free days. Any infant was reported as having an acute lower respiratory infection during the past 2 weeks, if the mother reported the following signs or symptoms: cough, fast breathing and breathlessness. Febrile days were estimated based on the mother’s report. Mothers were asked to report care-seeking at any healthcare facility, including hospitalization or overnight stay at any health care facility.

Statistical Analysis

χ2 tests were used for categorical variables and analysis of variance (or the nonparametric equivalent Kruskal–Wallis test) for continuous variables. Multivariate analyses were conducted using multiple regression (logistic for binary outcomes and linear for continuous outcomes) after adjusting for baseline covariates like age, gender, prior duration of diarrhea, weight-for-age <−2 Z score, dehydration status, any type of stool, serum zinc and serum copper levels. Anthropometric indicators were calculated using the World Health Organization’s 2005 Anthro software.7 All analyses were performed per protocol by using Stata 10/IC (Stata Corporation, College Station, TX).

RESULTS

A total of 1200 children were screened from August 2003 to October 2006 at the hospital outpatient department for eligibility, and 808 were randomized to receive either placebo, zinc or zinc and copper for 14 days during a diarrheal episode. The attrition rate at the end of 3 months was 11%, 9% and 7% in the Pl, Zn and Zn + Cu groups, respectively.

Baseline Characteristics and Compliance

Imbalance by chance across trial arms was observed in the following baseline characteristics: dehydration status, oral rehydration solution received by the child before enrollment and serum zinc (Table, Supplementary Digital Content 1, https://links.lww.com/INF/B318, which shows detailed baseline comparisons). The overall mean duration of diarrhea before enrollment was 35.5 hours and balanced across the groups. There was no significant difference in nutritional status and sanitation indicators across the groups. The 14th day zinc (µg/dL, mean ± standard deviation) in the 3 groups was 76.3±32.9, 76.6±35 and 74.3±40 in the Pl, Zn and Zn + Cu groups, respectively.

The proportion of children who completed 14 days of oral syrup intake in the Pl, Zn and Zn + Cu groups after discharge was 96.8%, 90.3% and 97.7%, respectively. Overall, 66.6% children consumed more than 80% of the prescribed amount of syrup. In hospital, more than 80% of the supplements were observed to be consumed in 76.6%, 63.7% and 60.3% of the Pl, Zn and Zn + Cu groups, respectively, and, at home, in 46.4%, 42.4% and 41.5%, respectively. This level of adherence corresponded to an average daily intake of 14.3mg of zinc in the Zn group, and 13.5mg of zinc and 1.3mg copper in the Zn + Cu group over 14 days.

Outcomes

Table 1 shows the univariate and multivariate results of follow-up. We observed that all the diarrhea-related outcomes and respiratory outcomes were nondifferentially distributed across the study arms. Even after adjusting for the aforementioned potential confounders, none of these outcomes achieved statistical significance.

T1-29
TABLE 1:
Comparison of Outcomes at the End of the 3-month Follow-up Period Across the Trial Arms*

At enrollment, there was no difference in the nutritional status (Table 1). Although a clear growth in terms of all the outcomes was observed in the study subjects, there was no significant difference in the growth profiles of the 3 trial arms. The weight gain in the Zn group was more than the weight gain in the Pl group at the end of first month (see Fig., Supplementary Digital Content 2, https://links.lww.com/INF/B319, which shows the weight-for-age Z score profile at all follow-up visits). At the end of 2nd month, both supplemented groups had improved weight-for-age Z scores as compared with the Pl group and remained so till end of follow-up. However, when adjusted for baseline covariates these differences were not significant.

DISCUSSION

The results of this study indicate that providing zinc or zinc and copper supplementation to children 14 days during the diarrheal episode neither reduced their subsequent risk of diarrhea or acute lower respiratory infection nor improved their growth performance. Zn supplementation is expected to be beneficial because of its immune-modulating effects for 2–3 months after the 14 days of daily zinc.5,6 Our study mirrors similar observations by other authors. For example, a similar study from Ethiopia, India and Pakistan (not included in the published meta-analyses)8 and another recently published study from New Delhi, India, also found no difference in morbidity.5 Because these aforementioned studies were not included in 3 previously published meta-analyses, a fourth updated meta-analysis of 38 studies was recently published, which showed that the estimate of the protective benefit of zinc supplementation was consistently lower (9% as compared with 14%) than that reported in all previous meta-analyses.9

It is unclear if the lack of observed benefit of zinc and copper supplementation may have been confounded by undertreatment (70% of the recommended dose received), prerecruitment differential prevalence of zinc deficiency or potentially differential diarrheal etiology. It should also be noted that majority of our study subjects did not have severe diarrhea. Nevertheless, our results afford additional support to the continued efforts for improving zinc supplementation practices in developing countries.

ACKNOWLEDGMENTS

The authors thank all the women, children and their families who participated in the trial. The authors also thank the following members of the research team who contributed to the successful implementation of the study: Mr. Hussaini Ali and Mr. Gadkari (Universal Medicaments Pharmacists), Ms. Smita Puppulwar and Ms. Shubhangi Puranik. The authors also thank Professor Catherine D’Este, Dr. A.V. Shrikhande and Dr. Nitin Kimmatkar, the members of the treatment effects monitoring committee, who reviewed the unexpected trial events and conducted an interim analysis.

REFERENCES

1. 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;135:689–697
2. Aggarwal R, Sentz J, Miller MA. Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: a meta-analysis. Pediatrics. 2007;119:1120–1130
3. Brown KH, Peerson JM, Baker SK, et al. Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Food Nutr Bull. 2009;30(1 suppl):S12–S40
4. Brown KH, Peerson JM, Rivera J, et al. Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2002;75:1062–1071
5. Taneja S, Bhandari N, Rongsen-Chandola T, et al. Effect of zinc supplementation on morbidity and growth in hospital-born, low-birth-weight infants. Am J Clin Nutr. 2009;90:385–391
6. Patel A, Dibley MJ, Mamtani M, et al. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Med. 2009;7:22
7. Baqui AH, Black RE, El Arifeen S, et al. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ. 2002;325:1059
8. Walker CL, Bhutta ZA, Bhandari N, et al. Zinc during and in convalescence from diarrhea has no demonstrable effect on subsequent morbidity and anthropometric status among infants <6 mo of age. Am J Clin Nutr. 2007;85:887–894
9. Patel AB, Mamtani M, Badhoniya N, et al. What zinc supplementation does and does not achieve in diarrhea prevention: a systematic review and meta-analysis. BMC Infect Dis. 2011;11:122
Keywords:

acute diarrhea; zinc; randomized controlled trial; morbidity; growth

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