Basics of the program

What is vitamin A deficiency?

Vitamin A deficiency (VAD) is a common condition in the developing world that can cause stunting, anemia, dry eyes (the leading cause of preventable childhood blindness), susceptibility to infection, and death. VAD is most common in the World Health Organization's Africa and South-East Asia Regions. Infants, children, and pregnant or lactating mothers with low vitamin A intake are at particularly high risk of the negative health impacts of VAD. Deficiency is most likely in diets that include few animal sources and little fortified food.

What is vitamin A supplementation?

Oral vitamin A supplementation is “the most widely practiced approach to controlling VAD in most high risk countries.” The version of the intervention we focus on here is periodic prophylactic vitamin A supplementation (VAS) to pre-school children of ages six months to sixty months who are at risk of VAD. For the remainder of this report, “VAS” refers to the policy of providing all pre-school aged children in an area with the WHO-recommended dose of vitamin A every four to six months.

Vitamin A supplementation is inexpensive—around a dollar per person reached per supplementation round in total costs. Children generally receive VAS in combination with other health services.

UNICEF has defined three categories of priority countries for vitamin A supplementation:

countries with an under-five mortality rate exceeding 70 deaths per 1,000 live births. countries where VAD is a public health problem according to national-level assessments registered in the WHO’s Micronutrient Deficiency System. countries with a history of VAS programming which may have lowered VAD incidence and the under-five mortality rate.

Program track record

Many large, randomized (or quasi-randomized) controlled trials have been conducted to determine the impact of VAS. A 2010 Cochrane meta-analysis of studies that primarily took place in the 1980s and early 1990s, estimated that VAS reduces child mortality by 24%, a large and statistically significant reduction.

However, these results differ from the results of the Deworming and Enhanced Vitamin A Study (DEVTA), a more recent trial that was “the largest randomized trial ever conducted” and “included four times the combined participants of all included studies in [the Cochrane] review.” DEVTA, which took place in Uttar Pradesh, India, estimated that VAS reduced child mortality by a statistically insignificant 4%. DEVTA's confidence interval included the possibility of up to an 11% decline in child mortality and also included the possibility of no effect at all.

We believe that VAS can have a meaningful impact on childhood mortality, but the contrast between the results of the Cochrane review and the outcome of DEVTA leave us uncertain about the size of this impact and the conditions that are necessary to achieve it.

Cochrane review

The Cochrane Collaboration conducted a meta-analysis of randomized (and quasi-randomized) trials of VAS published through October 2010. The primary outcome of interest was all-cause mortality, but analyses of cause-specific mortality and other outcomes were also reported.

All-cause mortality

Cochrane’s meta-analysis of seventeen randomized controlled trials, which reported data on all-cause mortality, estimated that VAS reduces all-cause mortality by 24% with a 95% confidence interval ranging from 17% to 31%. The Cochrane review concludes that the included studies perform well with respect to various potential biases.

The main source of uncertainty around the review’s all-cause mortality estimate was the impact of DEVTA. When the Cochrane review was published, initial results from DEVTA had been reported in a publicly available PowerPoint presentation, but the details of the study and its implementation had not been published. As a sensitivity test, the Cochrane authors added DEVTA’s results to their meta-analysis and found that incorporating DEVTA’s results alongside the other trials in an inverse-variance weighted average reduced the estimated benefit of VAS by half, to a 12% reduction in child mortality (with a 95% confidence interval ranging from 6% to 16%). Unfortunately, because the details of DEVTA’s methods, implementation, and results were not published until 2013, the Cochrane authors could not account for the differences between the results of DEVTA and the results of previous trials. DEVTA is discussed in detail below.

Cause-specific mortality

The estimates of the effect of VAS on cause-specific mortality in the Cochrane review are imprecise and vulnerable to bias and measurement error. These estimates should be interpreted with caution.

The Cochrane review estimated that VAS reduces diarrhea-related mortality by 28% (95% CI: 9% to 43%), measles-related mortality by 20% (not statistically significant; 95% CI: 24% increase to 49% decrease), and lower respiratory tract infection (LRTI)-related mortality by 22% (not statistically significant; 95% CI: 14% increase to 46% decrease).

Other outcomes

Mortality was the primary outcome of interest in most studies of VAS and there is less evidence of VAS’s impact on morbidity. There is, however, moderate evidence that VAS substantially reduces measles morbidity and weak evidence suggesting that VAS somewhat reduces diarrhea morbidity. The Cochrane review found no evidence of an effect on lower respiratory tract infection (LRTI) morbidity. VAS also “reduces night blindness and potential precursors to blindness, namely Bitot’s spots and xerophthalmia.” Because studies may be more likely to report morbidity data when they find positive results, these analyses are potentially affected by selective reporting bias.

Few studies reported data on side effects, so Cochrane’s estimates of side effects are highly uncertain and vulnerable to selective reporting bias. There is some evidence that approximately four percent of children who receive VAS experience short-term vomiting due to the intervention. There was not enough data to include other side-effects in the meta-analysis.

The Deworming and Enhanced Vitamin A (DEVTA) Study

The results from DEVTA, a very large VAS trial in north India, differ substantially from the headline results of the Cochrane review. The results of DEVTA were published in Awasthi et al 2013, which estimates that VAS reduced child mortality by 4% and cannot rule out the possibility that VAS did not affect child mortality at all (the 95% confidence interval ranged from a 3% increase in child mortality to an 11% decrease).

DEVTA was the largest randomized controlled trial ever conducted and included about one million children, roughly four times as many participants as the combined number of participants in all studies included in the Cochrane review, though randomization at the administrative block level limits the statistical power of the study to some extent. The study took place in rural Uttar Pradesh (UP), north India from May 1999 through April 2004. VAS was administered by workers at village anganwadi child-care centers (AWCs) and children in the treatment blocks received 200,000 IU of vitamin A every six months.

By delivering VAS through preexisting government infrastructure, DEVTA tested not only the efficacy of VAS, but also the practicability of implementing large-scale VAS at low cost.

DEVTA’s program design may have limited applicability of the study's findings to remote areas and areas without preexisting government infrastructure.

Why did DEVTA’s results differ from previous trials?

DEVTA’s point estimate fell outside of the confidence interval from meta-analyses of previously executed trials. The researchers who conducted DEVTA “conclude that the apparent discrepancy between DEVTA and previous trials was probably due mainly to the play of chance,” but we believe this explanation is unlikely to account for the entire discrepancy. If the underlying effects were truly the same, the odds of achieving such disparate results due to chance alone would be very slim.

There are at least three potential explanations for DEVTA’s deviation from the results of previous trials (each of which we discuss in greater detail below):

DEVTA’s coverage rate may be lower than reported. DEVTA may have treated a population with less severe or less prevalent VAD than in previous trials. The population treated by DEVTA may have had better overall health than previously studied populations, increasing the probability that mortality that may have been averted by VAS in worse-off populations would already have been averted by other mechanisms in the DEVTA population.

It is also possible that DEVTA’s results were significantly affected by the exclusion of areas without functioning AWCs. VAS might have had greater efficacy in areas without functioning AWCs, which we suspect are more remote (and therefore may have more severe or prevalent VAD and worse overall health) than the areas covered by DEVTA. However, it may also be more costly to implement VAS in these areas, so it is not clear what the net impact on cost-effectiveness would be of extending the program to other areas.

While we do not arrive at a firm conclusion about why DEVTA did not find an effect on child mortality, we examine evidence with respect to each of these explanations. Before doing so, we review some features of the key mortality studies included in the Cochrane review.

Additional detail on the key studies included in the Cochrane review

Five of the seventeen trials included in the Cochrane review account for 80% of the weighted mean in the estimate of VAS’s effect on all-cause mortality. Table 1 presents the outcomes of these studies as well as the mortality rates in the control group and some of the reported baseline characteristics.

Notes:

The definition of xerophthalmia may be inconsistent across studies.

The age range of participants varies slightly from study to study, so mortality and disease rates are not directly comparable (since mortality and disease rates are generally different for different ages within the same population).

Table 1: Characteristics of the five main studies used in the Cochrane review's estimate of the effect of VAS on all-cause mortality

Study Location Age of children in study Baseline Vitamin A Deficiency Baseline Health and Control Group Mortality Mortality Risk Ratio

(95% Confidence Interval) Ross et al 1993 The Kassena-Nankana District, a rural area of Ghana, West Africa. 6 to 90 months No VAS program was in place prior to the study, the local diet was deficient in vitamin A, and VAD was locally recognized as a problem.



At baseline, the prevalence of xerophthalmia was 0.7%. According to retinol concentrations, at baseline 14.4% of children were severely VAD (<0.35 μmol/L) and 42.5%were moderately VAD (0.35-0.69 μmol/L). 0.1% mean daily prevalence of measles in placebo group.



15.9% mean daily prevalence of diarrhea in placebo group. The mortality rate in the placebo group was 29.9/1,000 child-years. 0.81 (0.68 - 0.98) West et al 1991 The district of Sarlahi, a rural flood plain in Nepal, South Asia. 6 to 72 months At baseline, the prevalence of xerophthalmia was 3.0%. 6.2% of children in the control group and 5.1% of children in the treatment group had measles during the four months preceding the study. 1% of children had diarrhea during the week preceding the study.



The preschool child/infant death rate in the year preceding the study was 3.9% in the control group and 4.1% in the treatment group.



The mortality rate in the control group was 16.4/1,000 child-years and 14.2/1,000 child-years for children in this group 12 months and older. 0.70 (0.56-0.88) Herrera et al 1992 Five rural councils in northern Sudan, North Africa. 9 to 72 months VAD was present and there was local awareness of the problem.



At baseline, the prevalence of xerophthalmia was 2.8% in the treatment group and 2.9% in the control group. 0.3% of children had measles in the seven days preceding the study.



16.9% of children in the treatment group and 17.7% of children in the control group had diarrhea in the seven days preceding the study.



The mortality rate in the control group was about 5.3/1,000 child-years. 1.06 (0.82-1.37) Daulaire et al 1992 Jumla District, a remote mountainous region of northwestern Nepal, South Asia. 1 to 59 months A survey of 3,651 children under 5 years found active xerophthalmia in 13.2%. The mortality rate in the control group was 126/1,000 child-years at risk and 101.6/1,000 child-years among children 12 months or older. 0.74 (0.55-0.99) Sommer et al 1986 Aceh Province, an area at the northern tip of Sumatra, Indonesia, Southeast Asia. 12 to 71 months At baseline, 1.9% of children in the treatment group and 2.3% of children in the control group had active xerophthalmia. 1.2% of children in the treatment group and 1.4% of children in the control group had Bitot's spots. 1.1% of children in the treatment group and 1.3% of children in the control group had night-blindness. ______________________________ At baseline, 22.3% of children in the treatment group and 21.7% of children in the control group had measles at any time in the past.



At baseline, 7.1% of children in the treatment group and 8.7% of children in the control group had diarrhea in the past seven days.



The mortality rate among preschoolers (12-71 months or age unknown) in the control group was about 7.4/1,000 preschoolers. The total mortality rate in the control group (aged 0-71 months) was 10.6/1,000 children. ____________________________ 0.73 (0.54-0.99) (among 0-71 month olds)

Trials in rural areas of Ghana, Nepal, and Indonesia have found that VAS meaningfully reduced child mortality, while a trial in Sudan found no effect. Though we have not conducted detailed research about the characteristics of the study sites, the trials generally appear to have taken place in areas with high rates of VAD and with high rates of other life-threatening illnesses. A basic comparison suggests that Herrera et al 1992, the study that found no effect for VAS in Sudan, may have taken place in a location with a lower child mortality rate than the other trials. There is not evidence, however, that Herrera et al 1992 had a noticeably lower rate of VAD.

Coverage

Unlike many previous trials, DEVTA evaluated a large-scale program, where we would expect treatment delivery to be more challenging. If a high proportion of DEVTA participants were not actually receiving treatment, the smaller effect size would be explained.

DEVTA’s published coverage rate was 86%. This rate appears to be only slightly below the rate achieved in previous efficacy trials, though we have not fully investigated the coverage rates of previous trials. However, DEVTA’s coverage data has been called into question by researchers who believe the study was not implemented as rigorously as previous trials and that it is implausible to achieve such high coverage at such low cost.

DEVTA implemented multiple strategies for achieving high coverage and for monitoring the coverage rate. These strategies seem reasonable overall. However, we note that these strategies are not fully documented, may be prone to bias in some cases, and were often not in place until the second half of the study. DEVTA's coverage rate would have to be substantially lower than estimated in order to explain the entire gap between the point estimate in the study and the 95% confidence interval from the meta-analysis of previously executed trials. This seems very unlikely.

Rate of vitamin A deficiency

Reliable, comparable data on VAD is scarce, and we have not fully investigated the data that exists. From what we know, DEVTA’s findings do not appear to be caused by a low rate of VAD among DEVTA participants.

There are at least four theoretical reasons why we might expect DEVTA participants to have a lower rate of VAD than in previous studies:

Prevalence of VAD might have declined over time. DEVTA’s size may have prevented it from narrowly targeting a population with severe VAD. DEVTA’s design may have disproportionately failed to reach children in the study area with high VAD. Some control group members also received some doses of vitamin A.

However, DEVTA reports that 64.8% of children in the control group who underwent biomedical visits were VAD (retinol <0.70 μmol/L) and 13.3% were severely VAD (retinol <0.35 μmol/L). 3.5% of children in a control group who participated in the biomedical survey had Bitot’s spots, 3.6% had Bitot’s spots or night blindness, and 6.2% had Bitot’s spots, night blindness, or conjunctivitis in the past four weeks. When compared with data from Table 1, this data suggests that participants in DEVTA had similar levels of VAD as participants in previous studies.

The manner in which VAD data was collected in DEVTA leaves open the possibility that the reported data is not representative of the overall study population. Our understanding of the data collection process is that the reported rates of deficiency are more likely to be underestimates than overestimates. That said, our guess at the dynamics of the sampling bias could be mistaken, and we cannot entirely rule out the possibility that DEVTA’s participants had a lower incidence of VAD than participants in other studies.

Improved overall health conditions

The absolute risk of death from age 1-6 years in DEVTA's control group was 2.64%, which implies a mortality rate of about 5.3 per 1,000 child-years. This is lower than control group mortality in 4 of the 5 trials that account for 80% of the weight in the Cochrane review (see Table 1) — considerably lower than 3 of the 5 — and the same control group mortality as the study that had the lowest rate of the 5 (and also found the smallest impact of VAS). Note that data for the same age group as DEVTA was available for only 2 of the 5 studies; in the other 3, the age group studied was somewhat younger than in DEVTA. We don't believe the differences in the age group studied undermine our conclusions (see the footnote for more detail).

Table 2: Mortality rate and mortality risk ratio in DEVTA and the five main studies used in the Cochrane review's estimate of the effect of VAS on all-cause mortality

Lower overall child mortality rates may limit the effectiveness of VAS at preventing further mortality if, for instance, the deaths averted in previous trials are already being averted by other improvements in health.

There is moderate evidence that deaths prevented by VAS are in part due to reduced diarrhea mortality, and possibly due to reduced measles mortality. If DEVTA participants were less vulnerable to dying from these diseases than participants in other studies, we would expect VAS to have a smaller effect on mortality. For example, measles vaccination campaigns and access to oral rehydration therapy may have decreased the deadliness of these diseases in some locations in the decade between most of the studies reviewed in the Cochrane report and DEVTA.

However, we do not have specific evidence that measles or diarrhea were less common in DEVTA than previous studies. Among the nonrandom subsample of DEVTA’s control group that received biomedical visits, 1.4% had measles over a period of four weeks and 44.1% had diarrhea. We do not have directly comparable data from the five highly-weighted studies in the Cochrane review, but, when compared to data from Table 1, the prevalence of diarrhea and measles among DEVTA participants does not appear to be very different from the prevalence among participants of other studies. Globally, deaths from diarrhea and measles declined between the time of the earlier studies and the time DEVTA took place.

It is possible that DEVTA’s finding on the effect of VAS on mortality was caused by lower child mortality—or generally improved health—in the DEVTA study population as compared to previously studied populations.

Interpreting the evidence in light of DEVTA

Our overall opinion on VAS depends heavily on our interpretation of the data on VAS’s impact on child mortality. Because of the uncertain and relatively small estimated size of morbidity effects and side effects, other factors are likely to be swamped by the intervention’s effect on mortality (or lack thereof).

We believe that the best available explanation for the discrepancy between the results of the four major studies reviewed by Cochrane that found a large impact on child mortality and the results of DEVTA is the lower baseline child mortality rate – and possibly better overall health – among DEVTA participants. This suggests that implementing VAS in areas with child mortality rates much lower than 10.6/1,000 child-years – the lowest rate among the four major successful studies – may be considerably less effective (and cost-effective) than implementations in settings with higher baseline mortality.

The other plausible explanations for heterogeneity between DEVTA and the trials underlying the Cochrane review have different implications for the likelihood that a charity implementing VAS will be a success:

If DEVTA’s failure to find an effect was due to lack of coverage, charities would need to have a strong argument for why their own coverage rates would be similar to the high rate found in early efficacy trials for us to believe that they could replicate the earlier trials' effects on mortality.

If VAS is only successful in areas with extremely high VAD, extremely high prevalence of diarrhea and measles, or low access to life-saving treatment for these diseases, only charities that could show that they have narrowly targeted such a population would be likely to convince us that their intervention would have higher effects on child mortality than DEVTA.

If DEVTA’s smaller impact were due to chance or other contextual factors that we have not thought of, then Cochrane’s meta-analysis (which found that VAS reduces child mortality by 12% (95% CI: 6% to 16%) once DEVTA is included) might be the best guide to future impact.

Cost-effectiveness

We have investigated Helen Keller International's (HKI) VAS program, and found that its cost-effectiveness is in the range of the cost-effectiveness of our priority programs. See our review of HKI and our most recent cost-effectiveness model for details.

Room for more funding

In our review of Helen Keller International (HKI), we discuss HKI's room for more funding and global room for more funding for VAS programs.

Feedback from scholars

We have discussed this page with Sir Richard Peto and Dr. Simon Read, co-authors of the DEVTA study, as well as with Dr. Evan Mayo-Wilson, co-author of the Cochrane review. See their comments here:

Questions for further investigation

We discuss what we might like to learn more about from the existing literature on VAS:

Further researching possible causes of heterogeneity between DEVTA and previous studies. This would involve collecting data from various sources on diarrhea prevalence, measles prevalence, measles vaccination rates, access to oral rehydration therapy, and baseline child mortality in the locations and time periods where DEVTA and each of the previous studies took place. We would also try to learn whether earlier trials took place in areas that were more remote or had less preexisting infrastructure than the area where DEVTA took place.

Reviewing macro evidence on the success of VAS. This could involve searching for meta-analyses of observational studies on VAS and looking at estimates of whether large-scale VAS programs were followed by changes in mortality rates.

Conducting further research on the AWCs in DEVTA. In particular we would like to know how locations for AWCs are chosen and whether villages with functioning AWCs significantly differ from other villages.

Attempting to access unpublished records or proceedings from the workshop at Oxford where criticisms of DEVTA were aired.

Investigating whether participants in DEVTA control blocks received any doses of VAS in addition to the known dose distributed by Pulse Polio. This could include VAS doses external to the study or any instances where members of the control group accidentally received treatment through DEVTA.

Investigating whether control groups in other studies were contaminated by doses of Vitamin A.

Researching alternative methods of combating VAD including fortification.

Further investigating VAS's impact on vision problems. In particular, we would consider looking into the severity of Bitot's spots and night blindness and the frequency with which VAD leads to blindness.

Investigating dosing schedules for VAS and the rationale for the one recommended by the WHO. We'd also to learn more about what effect the dose distributed by Pulse Polio might have had on the control group.

More thorough adjudication of the competing claims in correspondence to the Lancet regarding DEVTA.

Our process

2013-2015

We relied particularly heavily on Imdad et al 2010, the Cochrane review of the effects of universal vitamin A supplementation on preschool-aged children, because it was comprehensive and clearly presented the results of meta-analysis of high-quality trials. We also relied heavily on the primary publications reporting the results of the five highest-weighted studies from that review and on Awasthi et al 2013, Awasthi et al 2013 DEWORMING, and Awasthi et al 2013 APPENDIX, the published results of DEVTA.

We searched for RCTs or quasi-RCTs published after October 2010 (the last month covered by the Cochrane review) by searching PubMed and Google Scholar for studies that cited the Cochrane review, the DEVTA publications, or any of the five heavily weighted studies from the Cochrane review. We also searched PubMed and Google Scholar for the term “Vitamin A Supplementation” and looked for relevant articles. Lastly, we looked at articles cited by the Cochrane review, the DEVTA publications, and RCTs that we found.

We spoke with Dr. Evan Mayo-Wilson, co-author of Imdad et al 2010, the Cochrane review of the effects of universal vitamin A supplementation, and with Sir Richard Peto and Dr. Simon Read, co-authors of the DEVTA study.

2017-2018

We reviewed a more recently published Cochrane review of the effects of universal vitamin A supplementation on preschool-aged children, Imdad et al. 2017, which combines DEVTA and another smaller recent trial (Fisker et al. 2014) in a meta-analysis with previous trials. Its fixed-effect meta-analysis finds that VAS causes a 12% reduction in child mortality (95% confidence interval 7% to 17% reduction) and its random-effects meta-analysis finds that VAS causes a 24% reduction in child mortality (95% confidence interval 17% to 31% reduction). (See the following footnote for a description of the differences between fixed-effect and random-effects meta-analyses.) Even though the overall effect found in the updated meta-analysis remains statistically significant, it is unlikely that differences between the results of DEVTA and earlier trials were due to random chance alone. Overall, our review of Imdad et al. 2017 did not lead to substantial changes in our views on the evidence base for vitamin A supplementation described above.

We also reviewed research on a few topics that we believed could substantially affect our cost-effectiveness analysis:

Biological plausibility of interactions between vitamin A supplementation and vaccinations: Benn et al. 2009, a re-analysis of data from a vitamin A supplementation RCT in Ghana and Fisker et al. 2014, a vitamin A supplementation RCT from Guinea-Bissau, test the hypotheses that there are interactions between vitamin A supplementation and vaccinations, and that these interactions may increase mortality in some groups. We reviewed research on the biological plausibility of interactions between vitamin A supplementation and vaccinations and summarized our findings in this document. We did not find reasons to believe that harmful impacts are highly plausible.

Benn et al. 2009, a re-analysis of data from a vitamin A supplementation RCT in Ghana and Fisker et al. 2014, a vitamin A supplementation RCT from Guinea-Bissau, test the hypotheses that there are interactions between vitamin A supplementation and vaccinations, and that these interactions may increase mortality in some groups. We reviewed research on the biological plausibility of interactions between vitamin A supplementation and vaccinations and summarized our findings in this document. We did not find reasons to believe that harmful impacts are highly plausible. Possible developmental effects: Reducing exposure to malaria during childhood may have an effect on long-term productivity and earnings. We include these possible benefits in our cost-effectiveness analyses for seasonal malaria chemoprevention and mass distribution of long-lasting-insecticide-treated nets. In 2018, we reviewed research on whether vitamin A supplementation may also lead to long-term effects on productivity and earnings by reducing incidence of various infectious diseases, and decided to also include a developmental effects parameter for vitamin A supplementation in our cost-effectiveness analyses.

Reducing exposure to malaria during childhood may have an effect on long-term productivity and earnings. We include these possible benefits in our cost-effectiveness analyses for seasonal malaria chemoprevention and mass distribution of long-lasting-insecticide-treated nets. In 2018, we reviewed research on whether vitamin A supplementation may also lead to long-term effects on productivity and earnings by reducing incidence of various infectious diseases, and decided to also include a developmental effects parameter for vitamin A supplementation in our cost-effectiveness analyses. Prevention of vision loss and blindness: We reviewed research on the impact of vitamin A supplementation on preventing vision loss (e.g., night blindness) and total blindness. We have not incorporated these benefits into our vitamin A supplementation cost-effectiveness analysis because we expect these benefits to be relatively small and we generally focus our analyses on the core benefits of interventions—see the "Inclusion/exclusion" sheet in our cost-effectiveness analyses for more details.

Sources