Non-therapeutic Zinc Supplementation | GiveWell

# Non-therapeutic Zinc Supplementation

Published: May 2012

# In a nutshell

• The Program: Non-therapeutic zinc supplementation on a daily or weekly basis to prevent diarrhea and pneumonia amongst children under the age of 5.
• Track record: While randomized control trials indicate that zinc supplementation can moderately decrease diarrhea and pneumonia incidence, we are not aware of any large-scale non-experimental implementations of the program, and effectiveness (as opposed to efficacy) evidence is limited.
• Cost-effectiveness: Because non-therapeutic zinc supplementation programs have not been implemented on a large scale, adequate cost data is lacking. We believe the cost-effectiveness of zinc supplementation is likely to compare negatively with other programs that seek to improve nutrition in children, such as vitamin A supplementation and deworming.

## Basics of the program

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

Mass zinc supplementation addresses zinc deficiency, a common micronutrient deficiency which has been associated with weakened immune function and increased severity of infection.1 In particular, zinc supplementation appears to decrease the incidence of diarrhea and pneumonia (see below). In this review, we focus on ongoing, non-therapeutic supplementation, though zinc can also be used in combination with oral rehydration salts to treat diarrhea.2

### What are the components required to implement this program - how does it work?

Zinc supplements are typically administered daily or weekly to children under the age of five.3 Zinc is not stored in the body, so supplements have to be administered regularly in zinc-deficient populations.4 Zinc supplements are usually administered orally as dispersible pill or as a syrup, but to date they seem to be used primarily in experimental settings.5 The studies of zinc supplementation that we have seen relied on intensive efforts on the part of the health system: workers appear to have visited children to give them additional zinc at least once a week.6 These study conditions likely include unusually intensive health system involvement, but we have not seen reports from larger-scale non-experimental implementations of non-therapeutic zinc supplementation.7

If health workers are not visiting the house of every child receiving supplements on a regular basis, parents must be given a large supply of supplements all at once with the expectation that they will administer them appropriately, an expectation we have not seen tested.8

## Program track record

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

We reviewed the results of seven meta-analyses of randomized controlled trials on the effects of zinc supplementation, published between 2007 and 2011.9 Three meta-analyses estimate that zinc supplementation decreases diarrhea incidence by between 9% and 20%; all three estimates are statistically significant, though the 9% estimate is the most recent and relies on the largest number of studies. The four meta-analyses discussing pneumonia find that zinc supplementation decreases the incidence by between 8% and 15%; three of the four estimates, including the one by the Cochrane Collaboration, which we regard as the most credible, are statistically significant. Two of the three meta-analyses that consider the effect of zinc supplementation on vertical growth find small statistically significant effects, while the third finds a statistically indistinguishable, but insignificant, effect. The two meta-analyses that consider the effect of zinc supplementation on mortality find reductions of 6% and 10%, but neither is statistically significant.

Our full summary of the meta-analyses is available here (XLS). Overall, we view this evidence as supporting the hypothesis that regular zinc supplementation for children under the age of 5 reduces the frequency of diarrhea and pneumonia and slightly increases vertical growth. However, the studies to date appear to have been overwhelmingly “efficacy” studies, designed to assess the effectiveness of the drugs, not “effectiveness” studies that assess benefits under real-world conditions.10

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. Zinc supplements appear not to be in common non-therapeutic use in the developing world.11

More on our interpretation of “macro evidence” here.

## Recommendations and concerns

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

We are not aware of any serious negative side effects of zinc supplementation. Brown et al. 2009 conducted a meta-analysis of potential negative side effects and did not find any.12 In some cases, zinc supplements appear to have caused vomiting.13

## Cost-effectiveness

We do not have adequate information about the cost-effectiveness of non-therapeutic zinc supplementation. As far as we know, no large-scale non-experimental non-therapeutic zinc supplementation programs have been undertaken, so sufficient information about the total costs of zinc supplementation is lacking.

However, because zinc supplementation has to be provided on an ongoing basis and appears to have relatively limited mortality benefits, we expect that it would compare negatively in terms of cost-effectiveness with vitamin A supplementation, which is typically provided biannually and appears to have stronger mortality benefits.14 More specifically, the drug costs for zinc supplementation appear to be far higher than the drug costs for vitamin A supplementation,15 and we believe that zinc delivery would also be far more expensive.

It appears that the cost-effectiveness of non-therapeutic zinc supplementation would also compare negatively with the cost-effectiveness of deworming. The drug costs for zinc appear to be higher than for deworming,16 and delivery costs would again be expected to be far higher because the zinc supplements are administered daily or weekly instead of biannually or annually.

## Sources

• 1.

“Zinc deficiency is common amongst children in low-income countries, as defined by the World Bank (World Bank 2008) due to a variety of factors such as low food intake, particularly from animal sources; limited zinc bioavailability from local diets; and loss of zinc during recurrent diarrhoeal illnesses (Bhutta 1999; Black 1998). Zinc deficiency is associated with decreased immunocompetence (Shankar 1998) and increased rates of serious infectious diseases (Bahl 1998; Black 1998). The deficiency is widely recognised as contributing to limited growth of children in both low- income and high-income countries (Ploysangam 1997).” Lassi, Haider, and Bhutta 2010. Pg 4.

• 2.

Haider et al. 2009

• 3.

Aggarwal, Sentz, and Miller 2007. Pg. 1122. Table 1.

• 4.

“Because zinc is not stored in the body, adequate zinc supplementations are required.” Lassi, Haider, and Bhutta 2010. Pg 4.

• 5.
• “The treatment groups were placebo, iron and folic acid, zinc, and iron and folic acid with zinc. The doses of the nutrients used were given daily in tablets that were placebos or that contained 12·5 mg elemental iron as ferrous sulphate and 50 μg folic acid, 10 mg elemental zinc as zinc sulphate, or both. Children under 12 months received half a tablet. The supplements were formulated and manufactured as dispersible tablets by Nutriset (Malaunay, France) in conjunction with the Department of Child and Adolescent Health and Development (WHO, Geneva, Switzerland).” Tielsch et al. 2007. Pg. 3.
• “70 mg of zinc weekly reduces pneumonia and mortality in young children. However, compliance with weekly intake might be problematic outside a research programme... Zinc was given orally as a syrup (35 mg zinc acetate per 5 mL)... Fifth, our findings with a weekly dose are an important step forward in our thinking about, and programmatic use of, zinc. Daily regimens, though promising, might not be practical for long-term use. This study suggests that weekly dosing is beneficial and cost effective, even with reduced compliance.” Brooks et al. 2005, Pgs 1000-1003.
• 6.
• “All children were visited twice every week by study staff, who gave tablets for those days directly to the child. Adequate tablets for daily doses until the next visit were left with the child's caregiver. Older children took the tablets directly and caregivers were instructed to dissolve the tablets in clean water or breastmilk for younger children. During the visits, compliance with supplementation was assessed, and the number of tablets consumed in the preceding week was recorded for each child.” Tielsch et al. 2007. Pg 3.
• “Field research assistants (FRAs) did active surveillance, visiting every enrolled child at home once weekly... At the end of each visit, the FRA observed the child take the syrup, and waited at least 5 min before leaving. Compliance required intake of two teaspoons of syrup (10 mL). If the child vomited within 5 min, the syrup was given again once.” Brooks et al. 2005. Pg 1000.
• 7.

Brown et al. 2009 seems to imply that no such implementations have yet taken place:

"The main operational constraints to successful delivery of such supplements have been described elsewhere [112] and include procurement and distribution of supplements, limited access to and poor utilization of health services by the target population, inadequate training and motivation of frontline health workers, inadequate counseling of target recipients or their caregivers, and low compliance of the intended beneficiaries. These are common obstacles that will need to be addressed by any supplementation program, including programs that distribute potential products such as tablets, powders, and pastes, as discussed below."

Brown et al. 2009, Pg S34.

• 8.

“It has been stated previously that zinc needs to be provided on a daily basis for an extended period of time [102], although one study found equivalent beneficial effects when supplemental zinc was provided weekly [94]. In either case, the likely need for frequent administration of zinc supplements presents a number of programmatic challenges related to product delivery over an extended period of time and ensuring compliance. The most common, currently existing supplementation program requiring daily dosing and high compliance is iron and folic acid supplementation for pregnant and lactating women. The main operational constraints to successful delivery of such supplements have been described elsewhere [112] and include procurement and distribution of supplements, limited access to and poor utilization of health services by the target population, inadequate training and motivation of frontline health workers, inadequate counseling of target recipients or their caregivers, and low compliance of the intended beneficiaries. These are common obstacles that will need to be addressed by any supplementation program, including programs that distribute potential products such as tablets, powders, and pastes, as discussed below... Globally, the most successful micronutrient supplementation program for children less than 5 years of age is VAS, which is increasingly integrated into twice-yearly events for child survival (combining such interventions as deworming, vaccinations, distribution of insecticide-treated bednets, etc.) [115]. It is estimated that 79% of children 6 to 59 months of age in sub-Saharan Africa and 71% of children 6 to 59 months of age in South Asia received at least one dose of vitamin A in 2005 [116]. A recent publication that describes the progress and future directions of twice-yearly VAS in West and Central Africa [117] documents the success of such programs and calls for institutionalizing the child health day approach to deliver VAS and other low-cost, high-impact services for child survival and development.VAS programs have been very effective in reaching children 12 to 59 months of age, although they have been somewhat less successful in reaching infants 6 to 11 months of age [118]. This platform probably offers the most promising avenue for rapid scale-up of delivery of preventive zinc products, but a number of issues must be addressed:
» What duration of dosing will caregivers be able to administer correctly if the supplement supply is delivered only once every 6 months?
» What combination of zinc dose and duration of supplementation will result in optimal improvement in zinc status when delivered at 6-month intervals?
» What is the optimal presentation of the product (supplement, powder, paste) to maximize compliance and minimize costs and logistical burden?
» Can existing twice-yearly VAS programs support the additional input and logistical costs of adding preventive zinc supplementation?
» What communication strategies are required during twice-yearly events and as follow-up to these events to support optimal compliance by caregivers?
» Twice-yearly VAS programs only need to address coverage, since doses are consumed at delivery. Com- pliance will be essential for effective preventive zinc programs. How will programs be able to monitor and evaluate compliance?
» What is the effectiveness of these programs?” Brown et al. 2009, Pg S34.

• 9.

Our full summary of the meta-analyses is available here (XLS).

• 10.

Brown et al. 2009. Pg S34 treats the “effectiveness” of zinc supplementation programs as an open question.

• 11.

“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 mar- ket until recently, which has hampered implementation of national policies.” Lutter et al. 2011. Pgs 6-7. Although this article primarily discusses therapeutic use of zinc, our understanding is that non-therapeutic zinc supplementation is even less common. See also Brown at al. 2009, Pg S34.

• 12.

“According to the previous studies that have been used to define the safe upper level of zinc intake [105], the first signs of excessive intake are perturbations of copper and iron metabolism, resulting in impaired status of these nutrients. Thus, we have reviewed available studies that examined the impact of zinc supplementation on indicators of iron and copper status. There are no overall adverse effects of zinc supplementation on concentrations of hemoglobin, serum ferritin, and serum copper.” Brown et al. 2009. Pg S32.

• 13.

“Fourth, zinc was found to be safe in young children at a weekly dose of 70 mg. Apart from vomiting in a small subpopulation, which may have caused early dropouts, there has been concern that long-term zinc supplementation may interfere with iron and copper absorption. If this were the case we would expect to see decreased serum haemoglobin, copper, and white blood cells, none of which we observed.” Brooks et al. 2005. Pg 1000.

• 14.
• "Forty-three trials involving 215,633 children were included. A meta-analysis for all-cause mortality included 17 trials (194,795 children). At follow-up, there was a 24% observed reduction in the risk of all-cause mortality for vitamin A compared with control (Relative risk (RR) = 0.76 (95% confidence interval (CI) 0.69 to 0.83)." Imdad et al. 2011. Pg. 1.
• "On the basis of previous evidence, the WHO has long recommended VAS for young children and pregnant or breastfeeding mothers at a dose of 50,000 IU for infants under 6 months of age, 100,000 IU for infants 6 to 12 months of age and 200,000 IU for children over 12 months of age, every 4 to 6 months (WHO 1997)." Imdad et al. 2011. Pg. 10.
• 15.

Conservatively assuming a daily dose of 10mg zinc costs $0.005, annual drugs costs for zinc would be roughly$1.80, an order of magnitude higher than for vitamin A, which costs $0.02-0.06 per dose but only has to be administered biannually. • Zinc dosage: “The average daily dose (calculated by dividing the total weekly doses by 7) of zinc supplementation ranged from 1 mg/day [41] to 20 mg/day [53] with a median of 10 mg/day. Most studies (n = 28) provided the zinc supplements in the form of zinc sulphate, although 5 used zinc acetate [36,44,48,53,56] and 2 used zinc gluconate [34,55].” Imdad and Bhutta 2011. Pg. 3. Weekly treatment still assumes the same level of daily dosage, since the average daily dose is derived by dividing the total weekly dose by 7. • Zinc costs: World Health Organization 2005, Pgs 11-13 lists the cost of a 20mg dose of zinc sulfate as$0.01, so we simply divide in half to get the daily dose cost.
• Vitamin A costs: “The International Drug Price Indicator Guide include 100 000 IU formulations in both capsule and tablet form. Each capsule is estimated to cost US $0.02. This can be compared to 200 000 IU capsules, such as those currently in use, which have a median price of US$0.06, with a range from US $0.025 to$0.36.” Magrath et al. 2007. Pg. 11.
• 16.

Conservatively assuming a daily dose of 10mg zinc costs $0.005, annual drugs costs for zinc would be roughly$1.80, quite a bit higher than for deworming, which costs roughly $0.50 per dose but only has to be administered annually or biannually. • Zinc dosage: “The average daily dose (calculated by dividing the total weekly doses by 7) of zinc supplementation ranged from 1 mg/day [41] to 20 mg/day [53] with a median of 10 mg/day. Most studies (n = 28) provided the zinc supplements in the form of zinc sulphate, although 5 used zinc acetate [36,44,48,53,56] and 2 used zinc gluconate [34,55].” Imdad and Bhutta 2011. Pg. 3. Weekly treatment still assumes the same level of daily dosage, since the average daily dose is derived by dividing the total weekly dose by 7. • Zinc costs: World Health Organization 2005, Pgs 11-13 lists the cost of a 20mg dose of zinc sulfate as$0.01, so we simply divide in half to get the daily dose cost.
• Deworming costs: see our review of the Schistosomiasis Control Initiative.