Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

Our systematic review contains several major findings. Mortality in trials using individual randomisation, offering the fairest comparison, especially in trials at low risk of bias, is likely not affected by vitamin A. The evidence about the effect of vitamin A on mortality ensuing from cluster randomised trials is very uncertain. Vitamin A did not affect mortality in children and adults. Subgroup analyses in different age groups suggested that vitamin A reduced mortality in trials including children 6–59 months old, but data from trials at low risk of bias, in the specific age group, are needed to conclude with greater certainty. Vitamin A increased bulging fontanelle in neonates and infants and caused other non-serious adverse events. However, based on the certainty of evidence, we are uncertain in the result. We are uncertain whether vitamin A supplementation influenced blindness under the conditions examined. It has been hypothesised that vitamin A supplementation may have beneficial effects on outcomes like child growth and development, immunity and morbidity, but the results of randomised trials have been equivocal.42 74

Certainty of the evidence

We followed our published protocol.22 Our work represents a comprehensive review of the topic, including 120 randomised clinical trials with more than 1.6 million participants, which increases the precision and power of our analyses. Previous meta-analyses of preventive trials of vitamin A supplements have included substantially less information, largely due to their focus on selected age strata.180 181 We conducted a thorough review following Cochrane,21 implementing findings of methodological studies.182–187 We also conducted trial sequential analyses to control the risks of random errors in the cumulative meta-analyses.

The certainty of the evidence in individually randomised trials likely showing no effects of vitamin A supplements on mortality was moderate because of risks of bias. We found comparable results in the individually randomised trials at low risk of bias. Contrary, in the cluster randomised trials, a beneficial effect of vitamin A supplementation on all-cause mortality was only supported by very low certainty evidence which means that we do not know if this result is true. Cluster randomised trials are known to be less reliable compared with individually randomised trials (please see below).

Limitations

As with all systematic reviews, our findings and interpretations are limited by the quality and quantity of available evidence on the effects of vitamin A supplements on mortality. The examined populations varied. In our main analysis, we pooled data from participants of different age strata, coming from different countries, with different socioeconomic status, that can differ in their susceptibility to vitamin A deficiency.

Most of the included trials were considered at high risk of bias, which undermines the validity of their and our results.182–187 Other types of bias like bias from trials with deficiencies in the trial design, small trial bias, vested interests, etc might have influenced our results too (eg, https://www.babymilkaction.org/archives/31386; https://www.gava.org/).

Agreements and disagreements with other studies or reviews

Vitamin A deficiency (defined as serum retinol <0.7 µmol/L or ≤20 µg/dL) may cause night blindness and increase the risk of morbidity and mortality from infections.15 There are three ways to prevent vitamin A deficiency in affected populations: better access to vitamin A-rich foods; fortification of a staple food with vitamin A (where food variety is poor) or periodic delivery of vitamin A supplements.188 189

The WHO recommends vitamin A supplementation in a single dose of 100 000 international units (IU) for infants 6–11 months of age, and 200 000 IU every 4–6 months for children 12–59 months of age in countries where vitamin A deficiency is considered a public health problem (prevalence of serum retinol <0.7 µmol/L ≥20%).15 WHO does not recommend vitamin A supplementation for other age groups.15 The current WHO recommendations for vitamin A supplementation in children15 190 191 are based mainly on the results of some of the older cluster randomised trials in children with flaws in their design and at high risk of bias.41–43 45 124 Extremely positive results of some of these trials have previously been questioned.98 192 Their results drove the final results of subsequent meta-analyses180 181 and of Cochrane reviews.17–19 In contrast, later individually and cluster randomised trials with proper methodology found neutral effects of vitamin A.

Recent literature debates different types of biases that may influence the results of cluster randomised trials.193–195 The comparability of intervention groups is challenged in cluster randomised trials because groups of participants rather than the participants themselves are randomised. The chronology of cluster randomised trials compromises allocation concealment (ie, clusters are recruited and randomised, and then participants are recruited), which can induce imbalances between groups. We lack statistical methods to handle non-recruited participants in cluster randomised trials. Therefore, the principle of intention to treat is also challenged in cluster randomised trials. Consequently, we analysed individually and cluster randomised trials separately. In our review, vitamin A supplementation likely does not reduce mortality in individually randomised trials, and the evidence is very uncertain about the effect of vitamin A supplementation on mortality in cluster randomised trials.

We found neutral effects of vitamin A supplementation vs control on mortality in low birthweight neonates, termed neonates, infants 1–6 months of age, children 5–18 years of age and adults. Our results concur with the results of other systematic reviews and meta-analyses.17 196–198 Moreover, they support recent opinions that universal distribution of high-dose vitamin A to children should cease.199 200

Generally, we found neutral effects of vitamin A supplementation in children of any sex on mortality. However, vitamin A might have beneficial effects in some subgroups and harmful effects in others. Benn et al found some evidence that vaccination status and sex were potential effect modifiers of vitamin A.201 They suggested that vitamin A supplementation in children is reassessed in sufficiently powered randomised trials to detect effect modification by vaccination status, sex and other potential effect modifiers.201 A Cochrane review, on vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age, includes subgroup analyses of vitamin A supplementation in boys compared with girls.19 The authors found neutral effects of vitamin A supplementation on mortality in both subgroups. The test for subgroup differences was not significant (p=0.22).19 A recent article also argues that the time is not right for a change to the vitamin A supplementation programme for children in India202 mainly because the diets of children under 5 years old in India are grossly deficit in vitamin A against their recommended dietary allowances, as their diets are predominantly from plant sources.203 Our review showed that vitamin A supplementation did not reduce mortality in trials administering high-dose vitamin A, nor in trials administering low-dose vitamin A.

Our systematic review included 16 randomised trials with more than 4000 participants in low birthweight neonates. We found a neutral effect of vitamin A supplementation on mortality. Other systematic reviews that even speculate that vitamin A might have beneficial effects on survival in this age group included a significantly smaller number of trials.204 205 A recent umbrella review of systematic reviews and meta-analyses, dealing with interventions to prevent bronchopulmonary dysplasia in preterm neonates, concluded that vitamin A supplementation is not a recommended prevention strategy because of the possibility of increased risk of mortality.206 There are speculations in the literature that neonatal vitamin A supplementation reduces mortality in Asia, but not in Africa where it has almost detrimental effects.207 208 Before accepting such regional effects, more likely reasons, such as risks of bias and design errors, should be considered.

Approximately half a billion vitamin A capsules are manufactured yearly and distributed across 100 countries worldwide. However, we lack evidence that high doses of vitamin A result in sustained shift in serum retinol levels and in an effect on the prevalence of vitamin A deficiency in children.209 International funded programmes are not always driven by science. They may be manipulated by policy-makers and influenced by vested interests.210 211 Furthermore, strong WHO recommendations are frequently based on low-quality evidence, particularly regarding child health.212 213 The sustainability of the WHO recommendation for vitamin A supplementation in 6–59 months old children has been repeatedly questioned. A recent study found that even in limited resource settings, the combination of local foods provides 100% of the recommended daily allowance for vitamin A among children 6–23 months old in Ethiopia.214 Vitamin A liver stores were positively associated with breast feeding but not with vitamin A supplementation in Senegalese urban children 9–23 months old.215 Three recent studies raise concerns of vitamin A excess in children when dietary intake, food fortification and vitamin A supplementation are considered together.216–218 Acute and chronic hypervitaminosis A were associated with suboptimal anthropometric measurements in South African children.219 Furthermore, data on the population vitamin A status are limited or absent. Most of the 82 countries that implemented vitamin A supplementation programmes had no vitamin A deficiency data, or the data they had were more than 10 years old.189 Recently, a meta-analysis of five trials of vitamin A supplementation in Indian children showed no significant effect on mortality.220 Another systematic review found that excessive vitamin A supplementation increased the incidence of acute respiratory tract infections.221

Trials assessing vitamin A supplementation in adults have also produced controversial evidence, associated with potential detrimental effects.13 14 222 A recent systematic review did not find beneficial effects of oral vitamin A supplementation for prevention of viral infections.223 However, the review found encouraging results for the management of human papilloma virus lesions and some measles-related complications.223 Today, more than one-half of adults in high-income countries ingest dietary supplements,5 most frequently in the form of multivitamins with or without minerals.224 When combined with dietary intake, the total intake of vitamin A supplement users in the USA exceeds 100% of the estimated average requirement.224 Consequently, vitamin A may provide benefit, but it may also precipitate harm in adults. Some of the analyses of our systematic reviews showed an association between vitamin A supplements, given as primary or secondary prevention, and increased risk of mortality in adults.222 225

The adequacy of current dietary reference intakes (DRIs) for vitamin A was recently questioned.226 DRIs for vitamin A were developed in 2001 using very sparse data for children and adults.227 DRI values for adults were developed using data from four studies with only 13 participants.227 DRIs for children were developed using limited data for infants and extrapolation of data from adults.227

The assumed cut-off for blood retinol (<0.7 µmol/L) that is used to define vitamin A deficiency is based on a small number of studies.228 There are also ethnic and sex differences in serum retinol levels.229 Afro-Americans and Asian-Americans have lower retinol concentrations in blood compared with Caucasians.229 Adult females have blood retinol concentrations lower than males.230 A recent systematic review analysed which cut-off value should be used for vitamin A deficiency in children aged 3–10 years.231 The results showed that blood concentrations of vitamin A had low accuracy to discriminate the outcomes related to vitamin A deficiency (ie, xerophthalmia, immune dysfunction, impaired growth, anaemia) in children of this age group.231 Therefore, we still lack evidence about the optimal vitamin A status.

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