Therapeutic zinc supplementation | GiveWell

# Therapeutic zinc supplementation

Published: July 2012

# In a nutshell

• The Program: Short term zinc supplementation to treat diarrhea episodes in children under five, often administered in conjunction with oral rehydration solution.
• Track Record: Evidence from numerous randomized controlled trials (RCTs) indicates that zinc supplements moderately decrease the duration of acute and persistent diarrhea. One RCT has found that they cause a large and statistically significant reduction in mortality, though we have significant reservations about this study. Deployment of this intervention so far has mostly been limited to small-scale studies.
• Cost-Effectiveness: We do not have sufficient information to create a credible cost-effectiveness estimate. The one published cost-effectiveness estimate suggests that zinc supplementation could be amongst the most cost-effective programs. However, we believe this estimate is likely to overstate the cost-effectiveness of zinc supplementation in multiple ways.

## Basics of the program

### What is the program? What problem does it target?

Therapeutic zinc supplementation is a program aimed at treating diarrhea in children under the age of five, one of the leading causes of death in children in the developing world.1 The World Health Organization and UNICEF recommend that children with diarrhea take zinc supplementation for 10-14 days along with oral rehydration solution.2

## Program track record

### Micro evidence: Has this program been rigorously evaluated and shown to work?

#### Diarrhea duration

In the Cochrane Review on zinc supplementation for treating diarrhea in children under five years old, Lazzerini and Ronfani review the results of 24 randomized, placebo-controlled trials, finding that therapeutic zinc supplementation may cause a moderate reduction in the duration of diarrhea.3 In particular, they find that oral zinc treatment reduced the average duration of diarrhea in children with acute diarrhea by 12 hours (against a control average duration ranging from 41 to 170 hours),4 and reduced the average duration of diarrhea in children with persistent diarrhea by 15.8 hours (against a control average duration ranging from 84 to 168 hours);5 both of these results were statistically significant at the conventional 95% level. Results for the effectiveness of zinc in reducing the severity of diarrhea, as opposed to its duration, were inconsistent.6

#### Mortality

Of the 24 studies included in the Cochrane Review, only seven reported mortality results, of which four had no mortality in either the control or treatment groups.7 Amongst those studies that observed some mortality, there were a total of three deaths in the zinc treatment groups and eight deaths in the placebo groups, too few for statistical significance.8

However, Lazzerini and Ronfani exclude two large cluster-randomized controlled experiments because their control groups did not receive placebos.9 One of these studies, conducted by Baqui et al. in Bangladesh, recorded 13 non-injury deaths in the treatment group, compared with 27 non-injury deaths amongst the control group.10 These deaths translate into a mortality rate of 2.22 per 1,000 per year for the treatment group and 4.49 per 1,000 per year for the control groups; controlling for age, sex, and a few other covariates, treatment is associated with a 51% decrease in the risk of non-injury mortality (with a 95% confidence interval stretching from 6% to 75%).11

Note, however, that there were also a large number of deaths due to drowning in the Baqui et al. study, asymmetrically distributed across the treatment and control groups (20 in the treatment group, 10 in the control group).12 If these deaths are included, Baqui et al. find no statistically significant difference between the treatment and control groups in the all-cause mortality.13 We find this significantly more concerning than we do the lack of a placebo amongst the control group. The ex-post nature of the emphasis on non-injury (rather than total) deaths makes data mining a strong concern and implies that the estimate for averted non-injury mortality is likely biased upwards (i.e. that zinc supplementation is actually less effective than this study suggests).

#### Representativeness of large-scale deployment

While the Cochrane Review demonstrates that zinc reduces the duration of diarrhea under certain experimental circumstances, the programs included in the review may not represent realistic conditions of full-scale deployment. Both of the large-scale cluster-randomized controlled trials excluded from the Cochrane review because they did not give placebos to the control group involved mechanisms that might be more representative of large-scale deployments, such as training community health workers, and both found significant positive effects on diarrhea morbidity.14 As discussed previously, one of these studies found a large reduction in non-injury mortality, while the other did not report mortality results.15

However, these papers do not describe the details of program implementation and it is not clear to us that regional- or national-scale therapeutic zinc supplementation programs would be similar to these ones.

More on our interpretation of “micro evidence” here.

### Macro evidence: Has this program played a role in large-scale success stories?

We have not identified any large-scale success stories in developing countries. Usage of zinc supplements to treat diarrhea appears to be relatively rare in most developing countries.16

More on our interpretation of “macro evidence” here.

## Recommendations and concerns

### Do expert reviews of the comparative merits of interventions endorse this one?

The Lancet series on maternal and child undernutrition describes therapeutic zinc supplementation as a “core” intervention for preventing child mortality and undernutrition,17 and the Copenhagen Consensus recommends therapeutic zinc supplementation to address diarrhea.18

### What are the potential downsides of the intervention?

Though no serious side effects have been detected, therapeutic zinc supplementation has been reported to cause vomiting in many clinical trials.19

## Cost-effectiveness

We have not found sufficient information to calculate a credible estimate of this program's cost effectiveness.

The only cost-effectiveness study for therapeutic zinc supplementation we have seen in the academic literature (Robberstad et al. 2004) relies on extremely limited data about both the costs and the benefits of zinc supplementation to generate an estimate. Amongst other issues,20 it appears to exclude a number of incremental costs that should be included21 and takes the key mortality reduction estimate from a single study (Baqui et al. 2002) which we believe is likely to be biased.22

Using these assumptions, both of which would point in the direction of overstating the cost-effectiveness of zinc supplementation, Robberstad et al. report a cost-effectiveness range that includes our current estimate for the most cost-effective interventions (e.g. distributing insecticide-treated bednets).23

## Sources

• 1.

Diarrhea accounted for 15% of deaths of children under 5 in 2002. WHO/UNICEF, "WHO/UNICEF Joint Statement: Clinical Management of Acute Diarrhoea," Pg 2.

• 2.
• "More than 1.5 million children under five continue to die each year as a result of acute diarrhoea. The number can be dramatically reduced through critical therapies such as prevention and treatment of dehydration with ORS and fluids available in the home, breastfeeding, continued feednorsing, selective use of antibiotics and zinc supplementation for 10–14 days." WHO/UNICEF, "WHO/UNICEF Joint Statement: Clinical Management of Acute Diarrhoea," Pg 3.
• "Mothers and other caregivers should [...] provide children with 20 mg per day of zinc supplementation for 10–14 days (10 mg per day for infants under six months old)." WHO/UNICEF, "WHO/UNICEF Joint Statement: Clinical Management of Acute Diarrhoea," Pg 4.
• 3.

“This systematic review of 24 trials involving more than 9000 children shows that zinc supplementation may reduce the duration of diarrhoea in children aged six months or more.” Lazzerini and Ronfani 2012, Pg 2.

• 4.
• “Acute diarrhoea is usually defined as three or more loose stools in a 24-hour period.” Lazzerini and Ronfani 2012, Pg 6.
• “Overall, diarrhoea duration was reduced in children given zinc by about 12 hours (mean difference -12.63, 95% CI -21.05 to -4.21 hours, 4446 children, 15 trials, 19 comparisons, Figure 3), but there was signiﬁcant heterogeneity between trials (I2= 87%).” Lazzerini and Ronfani 2012, Pg 13.
• For the control averages, see Lazzerini and Ronfani 2012, Pg 3.
• 5.
• “Persistent diarrhoea is defined as diarrhoea lasting more than 14 days.” Lazzerini and Ronfani 2012, Pg 6.
• “Zinc supplementation reduced the duration of persistent diarrhoea (MD -15.83 h, 95% -25.43 to -6.24 h; 529 children, five trials, Figure 10), with no evidence of heterogeneity.” Lazzerini and Ronfani 2012, Pg 21.
• For the control averages, see Lazzerini and Ronfani 2012, Pg 25.
• 6.
• In children with acute diarrhea:
“Evidence on diarrhoea severity was less clear, as fewer trials reported on this, and different units and time points were used.” Lazzerini and Ronfani 2012, Pg 27.
• In children with persistent diarrhea: “Zinc also reduced the duration of persistent diarrhoea, but evidence was inconsistent regarding the severity of persistent diarrhoea.” Lazzerini and Ronfani 2012, Pg 27.
• 7.
• In children with acute diarrhea: “Four trials specified the numbers of death children: two studies (316 children) did not observe any death (Brooks 2005a; Roy 2008); one trial (1032 children) reported one death in each treatment group (Fischer Walker 2006), and one trial (754 children) reported one death in the zinc group, no death in the zinc plus copper group, and two deaths in the placebo group (Patel 2009a (zinc)).” Lazzerini and Ronfani 2012, Pg 17.
• In children with persistent diarrhea: “One trial reported one death in the zinc group compared to five deaths in the placebo group, out of 95 participants in each group (Roy 1998). Two trials did not observe deaths in any participants, irrespective of their allocated group (Penny 1999; Khatun 2001).” Lazzerini and Ronfani 2012, Pg 22.
• 8.
• See the previous footnote for the tally of deaths across studies.
• “No firm conclusions regarding zinc’s impact on hospitalization or death can be drawn from this review as trials were not designed to look at these outcomes, and most were conducted in hospitals where death rates were low.” Lazzerini and Ronfani 2012, Pg 27.
• 9.

Baqui et al. 2002 and Bhandari et al. 2008; see Lazzerini and Ronfani 2012, Pg 68.

• 10.

Baqui et al. 2002, Pg 4.

• 11.

Baqui et al. 2002, Table 6, Pg 4.

• 12.

Baqui et al. 2002, Pg 4.

• 13.

Including drowning deaths, there were 33 child deaths in the intervention group and 37 in the control group. Translating into mortality rates at the same rate as for non-injury deaths, we estimate a mortality rate of 5.64 (=33/17*2.22) per 1,000 child-years for the treatment group and a mortality rate of 6.15 (=37/27*4.49) per 1,000 child-years for the control group. The standard error for the comparison between non-injury mortality rates is around .75 (imputed from the confidence interval, see Table 4), the difference in all-cause mortality would not be statistically significant. Baqui et al. 2002, Pg 4.

• 14.
• “We followed 620 diarrhoeal episodes in the intervention clusters and 632 episodes in the comparison clusters. 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 3).” Baqui et al. 2002, Pg 3.
• Bhandari et al. 2008, Table 4, Pg 1284.
• 15.
• See mortality results at Baqui et al. 2002, Table 6, Pg 4.
• Bhandari et al. 2008 do not report (or indicate collecting) mortality results.
• 16.
• “Coverage of zinc supplementation among children who had diarrhea in the 2 weeks that preceded the survey and whose mothers sought treatment at a health facility was extremely low (range: 0.2%–2.4%) (data not shown).... The low coverage of zinc supplementation for treatment of diarrhea might be explained in part by the limited availability of zinc supplements for children on the global market until recently, which has hampered implementation of national policies.” Lutter et al. 2011. Pgs 6-7.
• "International recommendations for the use of therapeutic zinc supplements for diarrhea date from 2004. Although much work is in progress in several countries, only Bangladesh so far is in the process of a national scale-up." Horton et al. 2008, Pg 3.
• "Only about 53 countries have included therapeutic zinc in the diarrhea management policy, and fewer than 30 countries have initiated pilot projects so far. Bangladesh is the only country to attempt a national scale-up, and Nepal is the first country to engage in large-scale social marketing, which now covers half of its population (Fisher, Walker and Black, cited in Dary et al, 2008). Several other countries such as India, Guatemala and Bolivia are in the process of rolling out their programs." Horton, et al. 2008, Pgs 14-15.
• "Despite ample evidence of efficacy and increasingly strong evidence of effectiveness, implementing this intervention at scale is limited and not yet well documented. The most widely recognized effort is the “Scaling Up Zinc for Young Children (SUZY)” project in Bangladesh which reports achieving 20 percent national coverage. The SUZY project worked with a local manufacturer, trained healthcare providers at various levels, and implemented a large education campaign using various media. In 2008, an estimated 53 countries had changed policies to include therapeutic zinc and up to 30 countries had begun the formative research and/or pilot programs needed to develop context-specific mechanisms to deliver this new intervention (C. Fischer Walker, personal communication)." Klemm, et al. 2009, Pg 25.
• 17.

Bhutta et al. 2008, Pg 44.

• 18.

"The 2008 Copenhagen Consensus ranked micronutrient supplements as the top development priority out of more than 40 interventions considered. Specifically, vitamin A supplementation for children (every 4-6 months, from age 6 months to 5 years) and therapeutic zinc supplementation for diarrhea (10-14 days of supplementation, up to the age of 5) were considered." Horton et al. 2008, Pg 3.

• 19.
• “No trial reported serious adverse events, but vomiting was more common in zinc-treated children with acute diarrhoea (RR 1.59, 95% 1.27 to 1.99; 5189 children, 10 trials).” Lazzerini and Ronfani 2012, Pg 2.
• "Rates of vomiting after zinc administration have been reported in 14 comparisons from 10 trials [25,34,35,36,37,40,44,46,47,48] representing 6,779 children. In a quantitative synthesis of these results (Figure 4), we observed that the risk of vomiting was significantly increased after zinc administration (19.2% in the zinc supplemented group and 9.2% in the zinc withheld group) summary OR 2.13, 95% CI 1.37–3.31). However, this zinc effect was significantly heterogeneously distributed across the trials." Patel et al. 2010, Pg. 5.
• 20.

Other issues include:

• The “total costs” data comes from only one paper covering four health centers in Tanzania. The paper states:
“For standard case management, costs were calculated as the mean cost of diarrhoea management at four different dispensaries in the United Republic of Tanzania (37). The cost items included staff, drugs and medical supplies, utilities, stationery, uniforms and linen, cleaning, maintenance, travel, and annual costs of build- ings, equipment, furniture and transportation (37).” (Robberstad et al. 2004, Pg 525)
• The case-fatality rate for untreated dysentery is assumed to be four times the rate for treated cases, without citation. The paper states,
“We assumed untreated dysentery to be four times more likely to result in death than dysentery appropriately treated with antibiotics, and that one third of the cases are treated adequately with antibiotics (35). The resulting estimates are reported in Table 1, and correspond well with the findings of the above-mentioned meta-analysis (22).” (Robberstad et al. 2004, Pg 525)
Reference 35 (Muhuri, Anker and Bryce 1996) does not contain any justification for the assumption that untreated dysentery is four times more likely to result in death than appropriately treated dysentery. Additionally, their estimate that only one third of cases are adequately treated with antibiotics comes from Demographic and Health Surveys conducted between 1991 and 1993; it seems quite likely that the rate of adequate treatment would have increased over the past twenty years, making the marginal returns to zinc supplements lower. See Muhuri, Anker, and Bryce 1996, Table 3, Pg 142.
• The case-fatality rate for non-dysenteric diarrhea is reported at 0.15% in one place and 0.18% elsewhere, and other estimates for these quantities vary by an order of magnitude:
• “We computed a mean CFR of 0.15% for diarrhoea in children aged less than 5 years from a median of 3.2 episodes per child per year and a yearly mortality rate from diarrhoea of 4.9 children per 1000 as reported in a recent meta-analysis (22).” Robberstad et al. 2004, Pg 524.
• The 0.18% estimate appears in Robberstad et al. 2004, Table 1, Pg 525.
• The “recent meta-analysis” Robberstad et al. cite reports widely varying case-fatality rate estimates: "Case-fatality ratios were available from only two studies. One reported a case-fatality ratio of 0.11% in children under the age of 5 years (38). The other reported case-fatality ratios of 1.8% in children under the age of 1 year and 0.75% in children aged 1–3 years (32). The overall calculated case-fatality ratio obtained by dividing the estimated number of diarrhoea-related deaths by the estimated number of diarrhoea disease episodes in children under the age of 5 years was 0.15%, a quarter of that calculated in 1982 (0.6%) (1), half that reported in 1992 (0.3%) (2), and similar to the 0.2% estimated by the US Institute of Medicine in 1986 (74)." Kosek, Bern, and Guerrant 2003, Pg 198.
• 21.

The list of “incremental costs” of adding zinc treatment to standard case management does not include any wastage or organizational overhead costs, or any costs associated with additional training for health workers (Robberstad et al. 2004, Table 3, Pg 527). More generally, the incremental cost estimates are not based on actual costs in any historical implementation, but on linear extrapolation from the costs of the zinc supplements themselves, a methodology that we believe is likely to understate the true incremental cost of zinc treatment in unpredictable ways.

• 22.

See above for why we believe that the Baqui et al. 2002 mortality estimate is likely to be biased in the direction of overstating the impact of zinc supplements.

• 23.

Robberstad et al. 2004 estimate a cost-per-child-life-saved for therapeutic zinc supplementation of between $300 and$2,100, depending on the particular scenario (incremental or total costs and benefits; including or excluding dysentery treatment; see Table 4, Pg 527).

This estimate is in the same ballpark as our current estimate for the insecticide-treated bednets distributed by our top charity.