Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries*

* A project of the International Nutrition Program, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Funded by the Canadian International Development Agency (CIDA)

A Summary Report of Research Findings Presented at the Micronutrient Forum held at the ACC/SCN 20th Session, 15-16 February 1993, at the World Health Organization, Geneva. The Full Report will be published as SCN State-of-the-Art Nutrition Policy Discussion Paper No. 13 (see inside front cover).

G.H. Beaton, R. Martorell, K.A. L'AbbB. Edmonston, G. McCabe, A.C. Ross and B. Harvey

This paper presents a summary of the main findings, and their interpretation, of a review of controlled studies on the effect of vitamin A supplementation on young child morbidity and mortality. In presenting interpretations, special emphasis has been placed on findings and interpretations that appear particularly relevant to policy development and programme design.

While most of the studies available for review involved vitamin A supplementation in the form of the periodic administration of high potency doses, the reviewers have interpreted the analyses and conclusions in terms of the effects of improvement in vitamin A status and suggest that such benefits are likely to be achieved in any programme approach that is as effective as, or more effective than, the reviewed studies in improving vitamin A status. This summary, then, should not be taken as an evaluation or endorsement of a particular approach to improvement of vitamin A status.

Specific Goals of the Review of Experience

Under the original contractual agreement, there were three goals specified. These are set forth below.

· to review and assess the available experience with regard to the effect of vitamin A supplementation on young child morbidity and mortality;

· to advise CIDA on the apparent effectiveness of vitamin A supplementation in young children in developing countries; and

· to estimate, to the extent possible, the range of effects for mortality and morbidity outcomes expected under various nutritional and ecological circumstances and for various subgroups of the population.

These goals were to be addressed in the connotation of informing policy decisions, but the review, assessment, and formulation of policy were not included in the assigned mandate. It is understood that another group, with different composition and with additional background documents, will address policy implications of the report. The following summary is presented under the headings of the three specific objectives, rephrased as questions that were addressed.

Identify and Review Controlled Trials.

We were able to identify and examine 10 mortality trials and 19 morbidity trials (including morbidity results from the 10 mortality trials). This included both published and unpublished studies for which we were able to obtain descriptions from the primary investigators. For published studies, we often obtained supplementary information from original investigators. We are aware of additional morbidity trials still under way, and of plans for further analyses of existing trials. However, we are unaware of any further mortality trials now under way or approved for implementation in the near future. Therefore, for the mortality outcome, we think we have captured the total experience and our only shortfall is with regard to two studies, one in Bombay, India and one in Haiti, for which we could not obtain the level of detailed information needed for inclusion in our formal analyses. In contrast, we expect that substantial additional information will be forthcoming in the next year or two and therefore urge that our morbidity conclusions be seen as a valid interpretation of experience to date but subject to possible modification when further information becomes available.

Did Vitamin A Supplementation Have an Effect on Young Child Morbidity and Mortality?

Mortality Effect

We have provided a definitive YES answer with regard to not mortality. Vitamin A supplementation resulted in an average reduction of 23% in mortality rates of infants and children between 6 months and five years (see figure 1). The effect was highly significant under the two conceptual models examined, a fixed effect and a random effect model, RR=0.77 for both, although the 95% confidence intervals were somewhat wider for the latter (0.68 to 0.88 vs 0.71 to 0.84). Also shown in that figure is the Prediction Interval relating to the effect to be expected in a future programme or study in a new setting. This is discussed later in this summary and is presented in figure 1 only to provide perspective.

For infants under the age of 6 months, the point estimate of effect was also a 23% reduction. However, because of an extremely small sample size, the confidence interval was very wide and statistical significance was achieved. Thus we were unable to answer the question clearly for infants under 6 months.

Figure 1 Impact of Vitamin A Supplementation on Mortality of Infants and Children 6 months to 5 years. Shown are the point estimates and 95% Confidence Intervals for the eight original studies reviewed in detail. Also shown are two summary estimates for the relative effect, taking into account all 8 studies. These have the same point estimates, a 23% reduction in mortality, but differ in the estimated Confidence Intervals. The second estimate (SUMMARY 2) takes into account the between study variation that we believe exists. Technically it is derived from a random effects model. The Prediction Interval for a future programme or study is also presented. Again the predicted average effect is 23% but the interval describing possible actual effects is greatly expanded (see text for explanation).

Over 6 months of age, the relative effect of vitamin A (% reduction in mortality) was not influenced by age or gender. That is, one would expect to see comparable reductions in males and females and in infants over 6 months as well as children up to five years.

The mortality effect is pronounced for diarrhoeal disease, may be absent or very small for deaths attributed to respiratory disease, and is demonstrable for deaths attributed to measles even though the number of cases is much smaller.

A very important finding was that the effect on mortality was not dependent upon very high potency dosing. One trial was based on fortification of Monosodium Glutamate and another was based on the weekly administration of physiologic doses. This led us to the inference that it was improvement of vitamin A status rather than the method of improving it, that was the important determinant of effect.

Morbidity Effect

In contrast to the very clear effect of vitamin A on mortality, we were forced to conclude that improvement of vitamin A status cannot be expected to impact on incidence, duration or prevalence of diarrhoeal and respiratory infections. Conversely, we conclude that it is likely that improvement of vitamin A status impacts upon the progression of illness to its severe forms, and to its severest form, mortality. This important conclusion about an impact on severity is explicitly documented in only the very recent Ghana VAST morbidity trial where it can be seen as having impact on referrals and clinical admissions as well as on reported occurrence of severe morbidity per se. The phenomenon is seen also in studies of vitamin A administration in children presenting with measles; both severity of the illness and case fatality rates are reduced. Since we know that hospital admission and clinical referral data were collected, but not yet analyzed, by other projects, we expect that further information, likely confirmatory in nature, will be forthcoming.

The converse of these findings is that for the control of young child morbidity, vitamin A is not a panacea. The attack will have to focus upon the environment in which morbidity occurs. We can only suggest that vitamin A status appears to affect the child's ability to respond appropriately and adequately once infection has developed and hence appears to impact on the course of morbidity. As for mortality, there may well be differentials in the effect across different types of illness. Available evidence did not permit a conclusion in this on this matter.

One aspect of the morbidity analysis that has direct relevance to field programmes was the fact that vitamin A intervention after the onset of measles impacted favourably upon the development of severe complications and reduced the case fatality rate. In the main mortality trials reviewed, it was not possible to ascertain when the vitamin A had been administered in relation to measles onset. We infer that it is vitamin A status during infection that is important but infer also that this can be addressed before or after the onset of infection.

What Can be Expected in Future Programmes?

The third goal specified in the contract is perhaps the most important. It addresses the important planning question of what should we expect in a new programme in a new setting? Below we divide our response to the third goal into two sub-questions: Where (in what population setting(s)) can one expect vitamin A to be effective? and What is the range of effect to be expected?

Where is Improvement of Vitamin A Status Most Likely to Affect Morbidity and Mortality?

The obvious answer to this question is “Where vitamin A deficiency is now a serious problem.” For the mortality trials, all of which had been conducted in settings where it had been assumed vitamin A was a public health problem under the WHO definition, we attempted to ask about population-level predictors of the relative effect. For these analyses we had only 8 studies and with such a small sample, subtle effects might go undetected. However, any major effects should have been seen.

We found no relationship between the baseline prevalence of xerophthalmia and the relative effect of vitamin A. Thus we have to conclude that while the existence of clinically apparent deficiency was a marker for all programmes, the actual prevalence added very little additional information in predicting outcome. One very important question is unanswered. There were no studies conducted in populations with biochemical evidence of vitamin A depletion but without associated evidence of clinical manifestations of deficiency (Ghana came closest to this situation). Thus we can reach no firm conclusion about the impact of vitamin A to be expected in populations where there is evidence of depletion but not evidence that depletion is severe enough to produce clinical lesions in at least a small proportion of individuals. This, unfortunately leaves as judgemental the potential impact of programmes in a very substantial part of the developing world.

We found no impact of the prevalence of stunting or wasting or of the interaction with xerophthalmia prevalence on the prediction of the relative effect of vitamin A. We note however that all of the population groups studied exhibited a high prevalence of stunting and shared the common feature of representing the poorer segments of the population exhibiting the stigmata of early deprivations and undoubtedly also a common social/biological environment favouring high morbidity and mortality. Thus, stunting was seen more as a marker of the environment of early growth and development than as an index of current nutritional conditions.

We found no apparent association between the mortality rates of control groups and the relative effectiveness of vitamin A. The recorded mortality rates ranged between a low of about 5 per thousand to a high of 126 per thousand.

As mentioned earlier, neither gender nor age appeared to influence relative effectiveness.

The only factor we found that would serve to predict relative effectiveness of vitamin A was evidence that the effect depended on the attributed cause of mortality. From those analyses we conclude that a large relative effect is more likely to be seen where mortality attributed to diarrhoeal diseases or measles is predominant and that the relative effectiveness would be diminished where deaths attributed to respiratory infection became increasingly prevalent.

From these analyses we can add very little to the starting observations that in populations like those studied (with evidence of poverty, general social and biological deprivation marked by stunting, and with evidence of existing vitamin A deficiency marked by the presence of xerophthalmia), vitamin A can be expected to have an effect.

We can describe the apparent reason that two studies (Hyderabad and Sudan) failed to show an effect of vitamin A supplementation (Hyderabad reported a 6% reduction in mortality; Sudan reported a 4% increase in mortality,: neither was significant and the confidence bounds for both included the estimated average effect for all studies combined). In each case there was minimal difference in vitamin A status (marked by effect on xerophthalmia) generated between the treated and control groups. In the case of Sudan, it appears that the vitamin A administered was not biologically effective although its chemical stability was demonstrated. In the case of Hyderabad, the problem was an unexpected improvement in the vitamin A status of the control group. While these observations may explain why those trials failed to demonstrate effects, it is extremely important to recognize that in neither case could the outcomes have been predicted on the basis of information available to us for examination. We treat these two trials and their reported effects as a part of the collective experience and as contributors to our Summary Estimate of the effect of Vitamin A supplementation. However, from the experience in these two studies, we conclude that it is essential that any future programmes monitor the impact of the programme on vitamin A status (e.g. by repeated clinical surveys or by monitoring serum retinol levels), at least until it is established that the administered vitamin A is biologically active in the particular setting.

We suggest, in keeping with conclusions reported by the Sudan study, that it may be timely to review with care the evidence supporting the existing guidelines for high potency periodic dosing. It may be that the combination of dose (200,000 IU after one year) and frequency (6 months interval) was inadequate in the Sudan setting although apparently adequate in other studies following a similar dosing schedule.

What is the Range of Expected Effects for Future Programmes?

Given that we were unable to explain the variation in reported results among the 8 mortality trials, we must base any prediction on the total experience. In figure 1, we included a portrayal of the Prediction Interval applicable to a new study but based on the review of past experience. This interval includes the possibility that a new study will have no effect on mortality (such was a part of the experience). It includes also the possibility that a new study might have an effect much greater than the average 23% reduction expected. In the main report we developed this concept further and actually developed probabilities that could be attached to various levels of effect. These are portrayed in table 1.

Table 1. Probability That a Vitamin A Effect of Specified Magnitude Will be Present in a Future Study.

MORTALITY REDUCTION	Probability
Any effect	0.98
³10%	0.89
³20%	0.62
³30%	0.23
³40%	0.03

Estimates assume a cluster effect (DEFF = 1.3). No new study sampling variance included in this model of the expected true effect.

These might be interpreted in the following manner. If justification of a vitamin A control programme requires that there be a mortality reduction of at least 10%, then we suggest that there are about 9 chances in 10 (probability = 0.89) of an effect at least this large being present in a programme that does improve vitamin A status to a degree comparable to the reviewed programmes. If a 20% reduction is needed, then the probability of achievement is 0.6 (3 chances in 5). However if reductions of 30% and 40% are sought, the probabilities fall to 0.2 and 0.03. All of these may be contrasted to the probability of better than 97% that some effect will be produced.

We also cautioned, in our main report, that because of the predictable effects of sampling error, in a study of finite size, particularly in a population with low mortality rates, the investigator would not necessarily see an effect even if it were present. Table 2 presents this warning in the form of probability that an effect will not be seen as a function of intervention group size and “baseline” mortality rate.

Table 2. Probability of Failing to See an Effect of Vitamin A as a Function of Group Size and Baseline Mortality Rate

GROUP SIZE	MORTALITY RATE/1000
	5	15	25	45
5,000	0.239	0.135	0.096	0.064
10,000	0.172	0.085	0.060	0.042
50,000	0.061	0.034	0.029	0.025
100,000	0.041	0.023	0.025	0.023
250,000	0.029	0.024	0.023	0.022

All estimates assume a cluster effect (DEFF = 1.3) and provide for sampling variance as a function of group size and mortality rate. All estimates are based on average reduction of 23% (RR=0.77).

What this shows is that if one runs a pilot study in a population group of relatively small size (for mortality trials) and in the presence of a low mortality rate, there is a very high chance that one will fail to see any effect even though the probability that there is an effect remains high (see paragraph above). Interestingly the Hyderabad trial would fall into this category. The opposite also holds, there is a greater chance of seeing an effect as large as that reported for Tamil Nadu (50% reduction) even though it is unlikely that the real effect is that large. Care must be taken in interpreting any pilot studies that are run in the future.

We caution also that our estimation of future effects rests on comparison of control and treated groups. However, the mortality rates observed in the control groups was often much lower than expected (than previously believed to exist as a baseline mortality rate). There are several possible explanations for the discrepancy. These include at least: i) a possible non-specific effect of interventions (an effect operating in both control and treatment groups and unrelated to vitamin A); ii) an effect secondary to treatment of high risk xerophthalmic children with vitamin A (in both groups); iii) a phenomenon related to exclusion of high risk children (by design or by self selection); iv) the fact that the study population was actually different from the regional population for which mortality rates had been described (perhaps the result of selecting a study area that had somewhat better health services or other infrastructure); or v) simply inaccuracies in previously reported local mortality rates (where not directly estimated by the research project). We did not have opportunity to test these hypotheses and warn only that we do not know whether vitamin A treatment is equally effective in children that might have been excluded - hence we do not know whether the predicted effect of vitamin A (23% reduction in mortality) is applicable to true baseline mortality rates. From those studies in which the baseline and control group mortalities appeared comparable, the reported effect of vitamin A appeared comparable. Therefore we think the relative effect is applicable to true baseline mortality rates. It was also reported in the Tamil Nadu study that inclusion or exclusion of children treated for xerophthalmia (and then left in their original treatment group assignments) did not change the estimated relative effect of vitamin A. Thus, although that type of exclusion of a high risk group might alter apparent mortality rates (in both control and treated groups) without influencing the estimate of effect of vitamin A. What the planner must recognize is that in a programme setting, without a concurrent control group, reductions from baseline mortality attributable to any of these causes might appear to be results of the intervention. In this sense our estimates of the real effect could be smaller than the apparent effect seen in an operating programme. Offsetting this, of course, would be lower “compliance” rates expected in an operational programme as compared to a research study.

The Distinction Between Relative and Absolute Effects of Vitamin A on Mortality

All of the results described above refer to the relative effects of vitamin A, the proportional reduction in mortality. We have shown from those analyses that there was no apparent effect of gender, age or mortality rate. However, it is to be recognised that if the relative effect is unchanged, then the absolute effect (number of lives saved) must be directly proportional to the baseline mortality rate:

Lives saved per 1000 treated = RR x Baseline Mortality Rate per 1000

Since mortality rates generally fall with age in young children, and perhaps differ by gender, it follows that one would expect an impact of age and perhaps gender on the absolute effect of vitamin A. The possible effect of age is illustrated in figure 2. Here, for purpose of illustration, the median mortality rates of studies contributing age specific data have been used. Actual rates in a new programme might be quite different but the phenomenon should be similar.

Figure 2. Absolute Impact of Vitamin A Expressed as Lives Saved per 1000 Subjects Covered.

Some Implications for Programme Targeting

Although the present analyses were not designed to address operational programs, there are some apparent implications for targeting programs. In terms of relative effects of vitamin A, the only targeting that we identified as potentially making a difference was with regard to cause-specific mortality. Populations in which deaths attributable to diarrhoeal disease or measles were much higher than deaths attributed to respiratory disease would be expected to show higher relative effects of vitamin A than would be seen under the reverse condition.

In keeping with earlier reviews, we demonstrated also that intervention after the onset of measles was effective in reducing severe morbidity and mortality. This has implications for the design of treatment protocols in primary and secondary health care. It also suggests the importance of determining whether a similar phenomenon holds for diarrhoeal disease and other types of infection. It might have implications for the design of population level control programmes but this would imply the need for infrastructures capable of detecting and treating potentially severe illnesses.

When one thinks of programmes in terms of their impact expressed as lives saved per 1000 infants/children covered, then it seems clear that the following baseline characteristics would increase the probably effect of the programme:

· high baseline mortality rates, particularly for diarrhoeal disease or measles (the latter perhaps in conjunction with low measles immunization rates)

· young ages (under 1 year mortality rates are generally much higher than those in children over the age of 1)

Of course, all of our analyses relate to populations determined in advance to likely benefit from vitamin A, thus our assessments apply to population groups characterised by:

· generalized poverty

· high prevalence of stunting suggestive of disadvantageous social and biological environment and associated early growth failure

· presence of clinical manifestations of vitamin A deficiency at least sufficiently prevalent to meet the WHO criteria of a public health problem

A very important unanswered question is whether such populations, lacking evidence of clinical manifestations of vitamin A deficiency, but presenting biochemical evidence of major vitamin A depletion, would also be responsive to improvement of vitamin A status.

Programme Approaches

This analysis of experience was not designed to compare programme approaches, nevertheless some interesting observations relevant to the topic can be offered. First, it was demonstrated, without doubt, that daily (through fortification of monosodium glutamate, MSG) and weekly intakes of physiological levels of vitamin A (Tamil Nadu) were just as effective as periodic high potency dosing. It follows, in the judgement of the reviewers, that any approach to improving vitamin A status that effectively controlled xerophthalmia would have beneficial impact on mortality comparable to that reported. We noted also a recent report from an Indonesian study that one time dosing of women shortly after birth was effective in raising breast milk vitamin A levels and improving the vitamin A status of the infant for at least 6 months. This might be a strategy worthy of exploration if the target group is young infants.

Finally it must always be remembered that vitamin A is potentially toxic and may be teratogenic during pregnancy. In the studies reviewed there was some evidence of transient side effects of high potency dosing (e.g. reports from Ghana VAST) but no evidence of actual toxicity. Conversely, there was some suggestion (Sudan, and perhaps also Hyderabad) that the 200,000 IU x 6 month interval for children over one year may have been inadequate to evoke a beneficial response. That would be in keeping with an earlier review of oral dosing with vitamin A in the control of xerophthalmia. That review suggested that while the suggested dose level appeared adequate to prevent xerophthalmia, it did not appear adequate to sustain blood and tissue levels over 6 months. It is suggested that there is need for continuing review of the norms for periodic high potency vitamin A dosing if that approach to intervention is chosen. Such review might focus upon the dose x frequency combination required to sustain blood levels (and presumably tissue stores) without necessarily having to document a mortality effect.

Authors of the Report

Dr George Beaton, special advisor to the SCN Chairman, is in the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, Ontario, Canada.

Dr Reynaldo Martorell is Chairman of the AGN -presently at the Center for International Health, Emory University School of Public Health, 1599 Clifton Road, N.E., Atlanta, GA 30329, USA - at the Division of Nutritional Sciences, Cornell University, Ithaca, New York at the time of this research.

Dr Beaton and Dr Martorell were co-chairmen of the project.

Dr Kristan L'Abbe is at the Department of Preventive Medicine and Biostatistics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Dr Barry Edmonston, who also periodically advises the SCN on statistical methods, is at the Committee on National Statistics, National Research Council, Washington, D.C., USA.

Dr George McCabe is at the Department of Statistics, Purdue University, West Lafayette, Indiana, USA.

Dr Bart Harvey is at the Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada.

The project, funded by CIDA, was the first phase of an “Assessment of the Research and Policy Implications of Recent Studies of Vitamin A and Morbidity and Mortality”, initiated following the recommendation of the SCN's Advisory Group on Nutrition in 1990. The second phase led to a meeting on policy implications, organized by the SCN in Ottawa in July 1993 - see “News and Views”.