Vitamin A for diarrhea | Cochrane Equity

Oral vitamin A reduces deaths from diarrhea by 12% and reduces incidence of diarrhea by 15% in children ages 6 months to 5 years who aren’t getting enough vitamin A in their diet.

Photo Credits: Tran Thi Hoa

Why is vitamin A important?

Vitamin A is an essential nutrient but it is not produced by our bodies so we have to get it from food and supplements. Vitamin A is important for vision, red blood cell production, our immune system, and reproduction. People who don’t get enough vitamin A are at risk for health effects including dry eyes, stunting, anemia, and infections, such as measles. Vitamin A is low in diets that rely heavily on fruits and vegetables although you can get vitamin from these foods.

What are sources of vitamin A?

Animal sources (such as meat and eggs)
Vegetables (especially those orange or dark green in colour, such as sweet potato, carrots, lettuce, and spinach)

Do vitamin A supplements work?

In countries with high Vitamin A deficiency, supplements reduce the number of deaths in children between six months and five years and the number of cases of measles (measles incidence).

Equity: does vitamin A supplementation work in the disadvantaged?

Vitamin A deficiency is more common in developing countries. Vitamin A supplements reduce child deaths and measles among disadvantaged children. In developing countries, many people can’t get enough vitamin A in their diet and need supplements.

Intervention Delivery

Vitamin A supplements can be given orally as capsules or liquid.
The WHO recommends 50,000 IU for infants under 6 months, 100,000 IU for infants 6-12 months, and 200,000 IU for children over 12 months, provided every 4-6 months. Most studies provided between 50,000 and 200,000 IU of vitamin A in a single dose, every 4 months, or every 6 months. A few studies used smaller doses given more frequently.

Population and Setting

45 out of 47 included studies were conducted in low- and middle-income countries.
Children living in the community were included but those in hospital or with diseases or infections were excluded.

Summary of Findings [SOF] Table: Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age

Patient or population: Children aged between 6 months and five years
Settings: Children living in the community
Intervention: Vitamin A supplementation
Comparison: Placebo or usual care

Outcomes

Anticipated absolute effects per year

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Risk without vitamin A supplementation (Control)

Risk with vitamin A supplementation (95% CI)

Mortality from any cause

Follow up 12-96 weeks

26 per 1000

3 fewer deaths per 1000 (from 2 to 4 fewer)

RR 0.88
(0.83 to 0.93)

1,202,382
(19 studies)

high

Diarrhea related mortality

Follow up 18-104 weeks

8 per 1000

1 fewer death per 1000 (from 0 to 2 fewer)

RR 0.88

(0.79 to 0.98)

1,098,538
(9 studies)

high

Measles related mortality

Follow up 52-104 weeks

2 per 10,000

0.2 fewer deaths per 10,000 (up to 1 fewer)

RR 0.88
(0.69 to 1.11)

1,088,261
(6 studies)

low

Lower respiratory tract infection (LRTI) related mortality

Follow up 48-104 weeks

4 per 10,000

0.08 fewer deaths per 10,000 (1 fewer to 1 more death)

RR 0.98
(0.86 to 1.12)

1,098,538
(9 studies)

low

Diarrhea incidence

Mean episodes per child per year

Follow up 24-60 weeks

4 episodes per child per year

3 fewer episodes of diarrhea per child per year (from 3 to 4 fewer episodes)

RR 0.85
(0.82 to 0.87)

77,946

(15 studies)

low

Measles incidence

Mean episodes per child per year

Follow up around 52 weeks

0.2 episodes per child per year

0.015 fewer episodes of diarrhea per child per year (from 0.019 to 0.01 fewer episodes)

RR 0.50
(0.37 to 0.67)

19,566
(6 studies)

moderate

Lower respiratory tract infection (LRTI) incidence

Mean episodes per child per year

Follow up around 52 weeks

0.1 episodes per child per year

0.1 more episodes of LRTI per child per year (0.1 fewer episodes to 0.1 more episodes)

RR 0.99
(0.92 to 1.06)

27,540
(11 studies)

low

Bitot’s spots incidence

Follow up around 80.72 weeks

35 per 1000

20 fewer incidences per 1000 (from 16 to 23 fewer)

RR 0.42
(0.33 to 0.53)

1,063,278
(5 studies)

moderate

Night blindness incidence

Follow up 52 to 68 weeks

4 per 1000

3 fewer incidences per 1000 (from 2 to 3 fewer)

RR 0.32
(0.21 to 0.50)

22,972
(2 studies)

moderate

Vitamin A deficiency

Follow up around 54.5 weeks

509 per 1000

148 fewer vitamin A deficient individuals per 1000 (from 112 to 178 fewer)

RR 0.71
(0.65 to 0.78)

2,262
(4 studies)

moderate

Side effect: Vomiting

Follow up 0.14-52 weeks

31 per 1000

30 more per 1000 (from 14 fewer to 52 more)

RR 1.97
(1.44 to 2.69)

10,541
(4 studies)

moderate

Adverse Events: Short term side effects identified in the review were vomiting (within 48 hours of supplementation) and Fontanelle (soft spots on a baby’s head). An increase in vomiting was identified in four of the included studies. Fontanelle was also identified in four trials but only two trials had insufficient data. Most included studies included children over one year of age and therefore would not have looked for this side effect.

Other outcomes identified in the review were malaria incidence, malaria prevalence, xerophthalmia (a progressive eye disease caused by vitamin A deficiency), and hospitalization. A decrease in malaria incidence was identified in one of the included studies. A decrease in xerophthalmia prevalence was identified in two of the included studies. One of the included studies reported data on hospitalization due to diarrhea and LRTI.

About quality of evidence (GRADE)

High: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low: We are very uncertain about the estimate.

Relevance of the review for disadvantaged communities Vitamin A supplements reduce child deaths, measles, and diarrhea among disadvantaged children Oral vitamin A every 4 months reduces deaths from diarrhea (by 12%) and measles (by 20%) in children ages 6 months to 5 years who aren’t getting enough vitamin A in their diet.
Findings	Interpretation
Equity – Which of the PROGRESS groups examined
All but 2 (45 of 47) of the included studies reporting on mortality from any cause were conducted in developing countries	Populations with more vitamin A deficiency may have greater effects. Vitamin A deficiency tends to be higher in low and middle income countries and therefore may have greater effects in these settings. The results of this review are likely applicable to any population with vitamin A deficiency.
The review reported subgroup analyses for age and sex. The average child was 33 months. The majority of included studies assigned approximately equal numbers of males and females.	Differences in effectiveness for other subgroups have not been determined. For example, are supplements as effective among those in different places of residence, such as rural communities, or low-income urban communities or among families with lower income.
20 of the included studies specifically included children with vitamin A deficiency, and vitamin A status was not clear in 23 of the included studies, so it is likely that vitamin A supplementation may be even more effective for children in developing countries who are at risk of vitamin A deficiency.	Depending on the availability of vitamin A rich foods within the local setting, the effects of vitamin A supplementation on all-cause mortality, cause-specific mortality, cause-specific morbidity, and vitamin A will differ. Locations with greater access to foods containing vitamin A may have smaller effects from vitamin A supplementation. Populations with more vitamin A deficiency may have greater effects. The results of this review are likely applicable to any population with vitamin A deficiency.
Equity Applicability
The review does not report on the effectiveness of delivery mechanisms for vitamin A supplementation. The studies included in this review gave vitamin A supplementation orally, as capsules or liquid. All but five studies provided vitamin A supplementation using the standard dose recommended by the WHO which is 50,000 IU for infants under 6 months, 100,000 IU for infants 6-12 months, and 200,000 IU for children over 12 months, provided every 4-6 months. The other studies provided participants with 3866 IU given three times a week, 8333 IU given once a week, 10,000 IU given once a week, or 25,000 IU given once every two weeks.	Policy makers and practitioners will have to look at other study types to determine the most suitable delivery mechanism within the local setting. Future trials or programs may consider evaluating smaller but likely to be effective doses that may also reduce the risk of vomiting. Other than supplements, vitamin A can be delivered through: food fortification, consumption of vitamin A rich foods, and beta-carotene supplements.
The review summarized findings based on studies in which the level of organization may be higher than what is available outside of research settings.	Factors to consider when assessing whether the intervention effects are transferable to your settings include: The availability of data on who might benefit from the intervention (those who are vitamin A deficient) The financial and organizational resources to provide clinical and managerial support for vitamin A supplementation and to ensure distribution of properly stored and active supplements The supplies to deliver services
The included studies only considered the effects of vitamin A supplementation on healthy children. Those in hospital or with diseases were excluded.	The effects of vitamin A supplementation on children with disease or infection may need to be explored in other studies.
Cost-equity
The review did not report on the cost-effectiveness of vitamin A supplementation overall or in each disadvantaged group. However, the authors state that vitamin A supplementation may be among the most cost-effective public health interventions (p. 24).	The cost of vitamin A supplementation may be variable based on local conditions outside of research settings.
Monitoring & Evaluation for PROGRESS Groups
There is sufficient evidence that vitamin A supplementation prevents mortality.	Vitamin A supplementation is recommended for children under 5 in areas at risk for vitamin A deficiency. The review suggests following the standard dose recommendation by the WHO for children under five years of age in areas at risk of vitamin A deficiency. However, this recommendation should be revisited for populations where vitamin A deficiency and deaths associated with vitamin A deficiency have significantly declined and no longer remain a public health issue.
Implementation data, including the core components of an intervention, the degree of delivery of the intervention in practice, and factors influencing implementation (such as core components of the intervention, the degree to which they are delivered in practice, and aspects of the trial that may have influenced implementation), were underreported in the studies included in the review (p.22). The authors stress the importance of effective distribution and storage of supplements.	Implementation of a vitamin A supplementation program needs to include an evaluation to ensure the effectiveness of the intervention.
The review did not assess the role of co-interventions on effectiveness. Examples of co-interventions in included studies were vitamin A and vitamin E supplements (8 studies), vitamin A and zinc supplementation (4 studies), vitamin A and measles vaccination (4 studies), vitamin A and both measles and polio vaccination (1 study), vitamin A supplementation for both infant and mother (1 study), vitamin A and L-tetramisole (1 study), vitamin A and ferrous sulfate (1 study), and vitamin A and albendazole (1 study).	Other studies are needed for policy makers and practitioners to make decisions on how vitamin A might relate to other nutritional and health interventions.

This summary update was prepared by Janina Ramos.

Comments on this summary? Please contact Jennifer Petkovic.