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clinmed/2001010004v2 (March 8, 2001)
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Vitamin A for the treatment of measles in children - A systematic review

Dr Rennie M D'Souza PhD (corresponding author and guarantor)

Fellow

National Centre for Epidemiology and Population Health

The Australian National University

Canberra, ACT 0200

AUSTRALIA

Telephone: 612 6125 5622

Facsimile: 612 6125 0740

E-mail: rennie.dsouza@anu.edu.au

Ron D'Souza MBA

Review Group Coordinator

Cochrane Acute Respiratory Infections Group

National Centre for Epidemiology and Population Health

Canberra, ACT 0200

AUSTRALIA

Telephone: +61 2 6125 0714

Facsimile: +61 2 6125 5614

E-mail: ron.dsouza@anu.edu.

Reprints will not be available from the authors.

Running footline: Vitamin A for measles



Key messages


Abstract

Objective: To determine whether vitamin A prevents mortality and pneumonia specific mortality in children with measles.

Design: Meta-analysis of randomised controlled trials

Setting: A systematic search of the medical literature identified studies that used vitamin A to treat measles.

Subjects: 492 children aged 6 months to 13 years were supplemented with vitamin A and 536 with placebo in six trials, five of which were conducted in hospitals and one in the community.

Main outcome measures: Mortality and pneumonia specific mortality.

Results:

We found no evidence that a single dose of 200,000 IU of vitamin A was associated with reduced mortality among children with measles; relative risk was 1.25 (95% confidence interval 0.48 to 3.1; heterogeneity, P=0.60). The same dose given for two days was associated with a reduced risk of overall mortality 0.36; (0.14 to 0.82; heterogeneity, P=0.51) and pneumonia specific mortality 0.33 (0.08 to 0.92; heterogeneity, P=0.74) in hospitalised children in areas with high case fatality. The effect was greater in children under the age of two years 0.17 (0.03 to 0.61; heterogeneity, P=0.79). There were no trials comparing a single dose with two doses of vitamin A. There were not enough studies to separate out the individual effects of age, dose, formulation, hospitalisation and case fatality in the study area.

Conclusions:

200,000 IU of vitamin A repeated on two days should be used for the treatment of measles as recommended by WHO in children admitted to hospitals in areas where the case fatality is high.

Keywords: vitamin A, measles, review, meta-analysis, mortality, pneumonia specific mortality
 
 

Introduction

Measles is a leading cause of childhood morbidity and mortality in developing countries with fatality rates in hospitalised children often exceeding 10%.1 An estimated 36.5 million cases and one million deaths caused by measles still occur each year and about half of these deaths occur in Africa.2

Vitamin A deficiency is a recognised risk factor for severe measles.3 It is essential for the maintenance of normal epithelial tissues throughout the body.4 Measles is a viral disease that infects and damages these tissues.1 The disease can also decrease serum concentrations of vitamin A in well nourished children to less than those observed in non-infected malnourished children.5 Measles rapidly depletes vitamin A stores, and children with marginal liver stores may develop acute vitamin A deficiency, leading to increased mortality. In Asia, measles was found to be an important risk factor in severe vitamin A deficiency.6

In 1987, the World Health Organisation (WHO) and the United Nations International Children's Fund (UNICEF) jointly recommended administration of a single oral dose of 200 000 IU (or 100 000 IU in infants) of vitamin A, at the time of initial measles diagnosis, to non-xerophthalmic children who lived in areas where measles case fatality rates were greater than 1%.7 In 1993, the WHO expanded its recommendation that vitamin A be given to all cases of severe measles but the dose remained the same.8 In 1997, WHO and UNICEF recommended 200 000 IU of vitamin A to be given twice to children with measles over the age of 1 year in populations where vitamin A deficiency may be present.9

Three previous meta-analyses10-12 demonstrated the protective effect of vitamin A on mortality but three randomised controlled trials have been published since.13-15 Therefore there are no recent systematic reviews incorporating all trials that have been published. However, the World Bank has declared vitamin A supplementation to be one of the most cost-effective of all health interventions.16 Programs to control vitamin A deficiency are now in place or in planning in more than 60 countries.17

The objective of this review is to determine whether vitamin A is beneficial in preventing mortality and pneumonia specific mortality in children with measles. A more detailed version of this review will be published and updated in the Cochrane Database of Systematic Reviews.18

Methods

Only randomised controlled trials in which children with measles under the age of 15 of either gender were given vitamin A or placebo orally were considered. Several outcomes were determined a priori18 but only mortality and pneumonia specific mortality are reported here.

Search strategy for identification of studies

This review used the search strategy developed for the Cochrane Acute Respiratory Infections Group (Search strategy for specialised register. In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software). A MEDLINE search was done in March 1999 on PubMed for the period 1997 - 1999. The Cochrane Library now includes searches of MEDLINE 1966-97 and EMBASE 1974-1997, and Issue 4, 1999 was searched. Keywords used were measles, vitamin A, randomized, controlled trial, random allocation and clinical trial. Sixty-six references were found using this search strategy. An additional trial15 was found in a subsequent search of MEDLINE in July 1999. A description of the included studies is given in Table 1.

In addition, the references of the available primary studies, review articles, and editorials were checked to identify trials not found in the database searches. One additional trial19 was found. Experts in the field were also contacted for unpublished trials. Trialists were also contacted for missing data.

Methodological quality of included studies

Sixty-eight references were found using the search strategy described. From the abstracts 28 of these appeared to meet the inclusion criteria. Two reviewers rated these blinded, using the Jadad method20 for assessing the methodological quality of trials. An agreement on the scores was reached after discussion if there was a difference in the scores for individual studies. The score was based on randomisation of participants, blinding of patients, and full description of withdrawals and dropouts. The scoring gives one point to each item if present. If randomisation was well described and appropriate and if the method of double blinding was well described and appropriate (identical placebo, active placebo, dummy, etc) the study received one additional point (thus yielding a score with a range of 0 to 5 points) and a point each was deducted if they were considered inappropriate. From this assessment, six trials, each with a score of three or more were included.

Although Ellison is the largest study yet (600 children),19 it is only included in this systematic review as part of the sensitivity analysis as it received a low quality score because it was not randomised and not a blinded study. The other 21 studies were excluded because vitamin A was given to all children in communities and not just children with measles.

For the purposes of this review the outcomes were taken at the time of discharge from hospital. It is assumed that all have been followed up till the time they were discharged from hospital. To assess the strength of the evidence of the benefits of giving vitamin A to all children with measles, a meta-analysis of the selected studies was done in which administration of vitamin A was compared with placebo. As the outcomes had small numbers, the analysis for dichotomous outcomes was done using the StatExact software package (StatExact; Cytel Software Corp. Version 3.1, 1997). Exact odds ratios and their 95% confidence intervals (CI) were used to calculate the relative risks and 95% CI. Heterogeneity was assessed using the Breslow Day test as provided in StatXact. Sub-group analyses were done for dose, formulation, age and pneumonia specific mortality and were determined a priori.18
 
 

Results

There were deaths reported in all studies except Kawasaki.15 When the five studies13,14,21-23 reporting mortality were pooled together, the summary estimate of the effect of vitamin A on the risk of mortality associated with measles was not statistically significant (RR 0.61; 95% confidence interval 0.32 to 1.12; test of heterogeneity, P value = 0.26) even though there was a 39% reduction (Table 2). When the study by Ellison19 which received a lower score was included with the five studies as part of the sensitivity analysis, vitamin A was associated with a 47% reduction in the risk of overall mortality (RR=0.53; 95% confidence interval 0.33 to 0.83; test of heterogeneity, P value =0.21). The argument for including this study is that the magnitude of mortality reduction in the Ellison19 study was remarkably similar to that of the other studies done almost 60 years later in Africa suggesting that basic health care available to patients then was not dissimilar to that available in Africa in the 1980's and 1990's.

Five of the studies were hospital based and only Rosales'13 study was done in a community setting in a group of patients with mild disease i.e. outpatients. Barclay21, Hussey22 and Coutsoudis23 used 200 000 IU of vitamin A on the first day and a second dose the next day. Coutsoudis23 gave two additional doses on days 8 and 42. These three studies21,22,23 were among hospitalised patients, were done in areas where the hospital case fatality rate was more than ten per cent, and used at least two doses of vitamin A. These three studies were associated with a statistically significant 64% reduction in risk of mortality (RR=0.36; 95% confidence interval 0.13 to 0.82; test of heterogeneity, P value = 0.51) (Table 2). Coutsoudis’23 study had only one death and dropping this study did not change the summary estimate.

The formulation of vitamin A ie. water or oil based is an important factor in its absorption. Of the three studies that used two doses, Hussey22 and Coutsoudis23 used water based vitamin A formulations and were associated with a 81% reduction in the risk of mortality (RR=0.19; 95% confidence interval 0.02 to 0.85; test of heterogeneity, P value = 0.67) (Table 2). The study by Barclay21 which used two doses of oil based preparation was associated with a 48% reduction. The studies13,14 that used a single dose of oil based formulation were done in areas where the case fatality was less than six per cent and were not associated with any reduction in risk of mortality (RR=1.25; 95% confidence interval 0.48 to 3.12; test of heterogeneity, P value = 0.60) (Table 2).

Four14,21-23 of the five13,14,21-23 studies reported the ages at death of the children. There was a 83% reduction in risk of mortality in the vitamin A supplemented group in children under 2 years of age in studies that used two doses21-23 (RR=0.17; 95% confidence interval 0.03 to 0.61; test of heterogeneity, P value = 0.79) (Table 2). The oil-based preparation was statistically significant in the study by Barclay21 (RR=0.13; 95% confidence interval 0.002 to 0.95) while the studies22, 23 that used water based vitamin A almost reached statistical significance (RR=0.23; 95% confidence interval 0.02 to 1.008; test of heterogeneity, P value = 0.64). There was no evidence of reduction in the risk of mortality in the age groups older than two years (RR=0.94; 95% confidence interval 0.23 to 3.1) (Table 2). Even when the study by Ellison19 was included as part of the sensitivity analysis, there was no reduction in the risk of mortality in the children older than two years (RR=0.64; 95% confidence interval 0.20 to 1.76; test of heterogeneity, P value = 0.22).

Although the sub-group analyses were determined a priori, these factors were highly correlated and it was difficult to separate out the effects of each factor given the small sample size of the studies. Three significant studies21-23 were represented most frequently in all the 5 sub-group analyses. These studies tended to use two doses of water-based formulations, in hospitalised patients in children under the age of two and done in areas where the case fatality was high. Only Barclay's21 study deviated from the other two studies as he used an oil based preparation. There were no trials comparing mortality reductions in children with measles who were given a single dose compared to two doses of vitamin A. Although the precision of the estimates of trials that used a single dose were similar to the trials that used two doses.

Four studies13, 21-23 specified the causes of death in the children. Most of the deaths in these studies were due to pneumonia. The pooled estimate of the three studies21-23 which used two doses (oil and water based) were associated with a 67% reduction in the risk of pneumonia specific mortality (RR=0.33; 95% confidence interval 0.08 to 0.92; test of heterogeneity P value = 0.74) (Table 2). Water based preparations were associated with a 77% reduction in the risk of pneumonia specific mortality.

Headaches, loss of appetite, vomiting and bulging fontanelles (in infants) are some of the known adverse effects occasionally occurring with the administration of high doses of vitamin A but none of these were reported in any of the studies.

Discussion

The quality of the trials included in this review is high and there was no statistical heterogeneity between trials. This review has shown reductions in overall mortality and pneumonia specific mortality in hospitalised children under the age of two years who were given two doses of 200 000 IU of vitamin A, in areas where the case fatality was high. This review was unable to separate out which factors were associated with greater benefit of vitamin A in preventing mortality. We did not find evidence that a single dose of 200,000 IU of vitamin A per day, given in oil-based formulation in areas with low case fatality, was associated with reduced mortality among children with measles. The evidence supports the WHO recommendation that two doses of 200 000 IU of vitamin A be given to all cases of severe measles.8 In 1991, Rosales13 came to the same conclusion at the end of his trial, as did Sommer,24 who suggested that it was prudent to follow the double dose schedule already proven in the Barclay21, Hussey22 and Coutsoudis23 trials, rather than the WHO single dose recommended at that time.24

One of the main limitations of this review is that we were unable to control for confounding by nutritional status. Nutritional status is an important predictor of mortality and vitamin A deficiency. The small number of studies and sample sizes have made it difficult to stratify or do a meta-regression and therefore the sub-group analyses are very restricted as the same studies are represented in all of them. The apparent differences between trials may be related to the subgroup, but could equally be confounded by some other aspect of trial design.

Five of the studies13,14, 21-23 were done in Africa. The baseline prevalence of vitamin A deficiency and other characteristics vary across the countries and even within the same country as in South Africa. The health services in the five areas could be different and this could be one of the reasons, in addition to dose, that the studies showed different results.

It would have been useful to have baseline incidence of measles in the study populations reported and if there were epidemics during the study period. The cases enrolled during a measles epidemic could vary in severity from measles cases at other times. There was also a lack of reporting on the immunisation status of these children and the immunisation coverage in the study population. Only one study reported on the immunisation coverage in that area. The level of immunisation would have an impact on the severity of measles in the children as it could reduce the intensity of exposure and hence the dose of the infecting virus.25 This would have an impact on the severity of the disease in the children as well as the severity of the epidemics. The severity of measles would be less in already vaccinated children (vaccine failure) and in areas where the immunisation coverage was high.

It is possible that in high doses oil-based and water-based vitamin A have similar effects in children under the age of two years. In these children formulation did not make any difference as the oil based product showed a statistically significant reduction in the risk of mortality and the water based vitamin A almost reached statistical significance. The study by Markowitz et al26 highlighted the fact that children aged less than two years of age and who had low vitamin A levels had a higher risk of dying than those with higher levels.

Hospitalisation may be a measure of severity of illness. There is the possibility that more severe clinical cases of measles are more likely to benefit from vitamin A treatment. An absence of a vitamin A effect or a smaller effect in the community study than that found in other studies may be due to the study population being healthier than previous studies as stated by Rosales.13 It raises an issue of whether the decrease in mortality was a result of the higher dose, or whether the vitamin A supplementation in higher case fatality areas had a greater effect as there was greater potential for mortality decline in those populations. It may be possible that there would be a mortality decline even with a single dose of vitamin A in high case fatality areas and this needs to be further explored.

The evidence of oil based vitamin A having a protective effect on mortality is demonstrated when a study with a lower score by Ellison19 was included as part of the sensitivity analysis. Although this study used small doses of vitamin A i.e. 300 Carr and Price units for 7-21 days, the supplemented group had statistically significant reductions in risks of mortality even in the absence of antibiotics and immunisation 70 years ago. The participants in this study could be comparable to the African children enrolled in the other 5 studies almost 55-65 years later. The case fatality rates in the Ellison19 study are very similar and in some cases lower than the case fatality in the placebo and supplemented groups in some recent studies.

Additional evidence of the effect of oil based vitamin A can be drawn from the community trials. When these trials were pooled, periodic vitamin A supplementation of children who were apparently healthy at baseline resulted in a 39% reduction in measles-related mortality, in addition to a decrease in overall mortality11.

The conclusions of this review are in keeping with the previous three reviews10-12 which were done at a time when only three trials21-23 were available. These were also the studies using two doses that showed a protective effect on measles mortality in children treated with vitamin A. Later studies by Rosales13 and Ogaro14 used a single dose of oil based vitamin A and did not show reduced measles mortality. Hence authors of earlier reviews were not able to compare dosage in a sub-group analysis. In addition, Fawzi's11 meta-analysis included Ellison's19 study of 1932. The objectives of those reviews were also different from the objective of this review.

The findings of this review are also consistent with one of the largest observational studies which was a retrospective hospital record review of 1720 cases of measles during 1985-86 and 1989-90. There were 651 children in the latter time period who received two doses of 200 000 IU of vitamin A and had a shorter hospital stay, lower requirement for intensive care and lower death rate as compared to 1069 children during 1985-86 who received a single dose of 3000 IU.27

In these trials it was not always apparent as to which day vitamin A was administered after the onset of measles. One of the limitations of this review is that the follow-up period was not the same in all studies. As mortality was assessed at different times, it is difficult to make comparisons across these studies for delayed mortality.

The evidence from these studies can only be generalised to developing countries as there is limited information to generalise to developed countries. The only study done in a developed country (Japan ) used one-fourth the recommended dose (100 000 IU), showed no mortality, and no toxicity was reported.15 Should children with measles in developed countries be given vitamin A in high doses? As seen in the US in 1989-1990, five of the 226 children admitted to hospital with measles died. 28 In another study, children with measles in an urban United States community had depressed serum retinol concentrations and the degree of depression was associated with illness severity. 29 Therefore there may be some patients at greater risk of measles mortality who would benefit from vitamin A in high doses.

Given the limited number of trials, our conclusion would be that the single-dose, water soluble and oil based preparations need to be compared to a two dose schedule. Although the data do not allow us to examine the individual effects of dose and formulation, these are issues that need to be considered. The trade off of using high dose oil based vitamin A versus a water-based formula has to be viewed in terms of the advantages of each product. As the water based product may be associated with greater mortality reductions, the advantage may be offset by its lower stability, higher cost, and non-availability.

Acknowledgments

We would like to thank Drs Wafaie Fawzi, Mahomed Patel, Owen Tinnion and Keith Dear for comments on the draft review, Prof Greg Hussey for providing unpublished data, and Dr Akira Shimouchi and Ms Kasumi Nishigaya for translation.

Potential conflict of interest

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony). We have no personal, political or academic conflict of interest to declare.

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6. Tielsch JM, Sommer A. The epidemiology of vitamin A deficiency and xerophthalmia. Annu Rev Nutr 1984;4:183-205.

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12. Beaton GH, Martorell R, Aronson KJ, Edmoinston B, McCabe G, Ross AC and Harvey B. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. ACC/SCN State of the art Series 1993; Nutrition Policy Discussion Paper no 13.

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23. Coutsoudis A, Broughton M, Coovadia HM. Vitamin A supplementation reduces measles morbidity in young African children: a randomized, placebo controlled, double blind trial. Am J Clin Nutr 1991;54:890-5.

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28.Havens PL, Butler JC, Day SE, Mohr BA, Davis JP, Chusid MJ. Treating measles: appropriateness of admission to a Wisconsin children’s hospital. Am J Public Health. 1993; 83: 379-384.

29. Butler JC, Havens PL, Sowell AL, Huff DL, Peterson DE, Day SE, Chusid MJ, Bennin RA, Circo R and Davis JP. Measles severity and serum retinol (vitamin A) concentrations among children in the United States. Pediatrics 1993; 91 (6): 1176-1181.





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