Intervention Review

You have free access to this content

Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age

  1. Aamer Imdad1,
  2. Kurt Herzer2,
  3. Evan Mayo-Wilson3,
  4. Mohammad Yawar Yakoob1,
  5. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

Published Online: 8 DEC 2010

Assessed as up-to-date: 26 OCT 2010

DOI: 10.1002/14651858.CD008524.pub2

How to Cite

Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008524. DOI: 10.1002/14651858.CD008524.pub2.

Author Information

  1. 1

    Aga Khan University Hospital, Division of Women and Child Health, Karachi, Pakistan

  2. 2

    Johns Hopkins School of Medicine, Baltimore, MD, USA

  3. 3

    University of Oxford, The Centre for Evidence-Based Intervention, Oxford, UK

*Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 DEC 2010

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison.

Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age

Patient or population: Children aged between 6 months and five years

Intervention: Vitamin A supplementation

Comparison: Placebo or usual care

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlVitamin A

All-cause mortality

Follow-up: 12-96 weeks
Low risk populationRR 0.76; 95% CI 0.69 to 0.83194,795

(17 studies)
++++
high
The inclusion of the DEVTA trial reduced the effect size from 0.76 to 0.88 ( Analysis 1.4). The impact on the absolute effect was to reduce the risk of mortality by 2 per 1000 in medium risk and 11 per 1000 in high risk populations.

0 per 100010 per 1000
(0 to 0)

Medium risk population

11 per 100018 per 1000
(7 to 9)

High risk population

90 per 1000168 per 1000
(62 to 75)

Diarrhoea-related mortality

Follow-up: 48-104 weeks
Low risk populationRR 0.72; 95% CI 0.57 to 0.9190,951
(7 studies)
+++O
moderate2
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

3 per 100012 per 1000
(2 to 3)

Medium risk population

4 per 100013 per 1000
(2 to 4)

High risk population

9 per 100016 per 1000
(5 to 8)

Measles-related mortality

Follow-up: 52-104 weeks
Low risk populationRR 0.80; 95% CI 0.51 to 1.2488,261
(5 studies)
+++O

moderate2
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

2 per 10,00012 per 10,000
(1 to 3)

Medium risk population

16 per 10,000113 per 10,000
(8 to 20)

High risk population

44 per 10,000135 per 10,000
(22 to 55)

LRTI-related mortality

Follow-up: 48-104 weeks
Low risk populationRR 0.78; 95% CI 0.54 to 1.1490,951
(7 studies)
++OO
low2, 3
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

4 per 10,00013 per 10,000
(2 to 4)

Medium risk population

11 per 10,00019 per 10,000
(6 to 13)

High risk population

219 per 10,0001171 per 10,000
(118 to 250)

Diarrhoea incidence

Mean episodes per child per year
Follow-up: 24-60 weeks
Mean episodes of diarrhoea in control groups: 1.9/child/year in controls.VAS led to 0.29 episodes fewer per child per year (95% CI 0.34 episodes to 0.25 episodes fewer).Rate ratio 0.85; 95% CI 0.82 to 0.8769,972
(13 studies)
++OO
low4, 5

Measles-morbidity incidence

Mean episodes of measles per child per year
Follow-up: mean 52 weeks
Mean episodes in control groups: 0.028 event per child per year.VAS led to 0.015 fewer episodes per child per year (95% CI 0.019 events fewer per child to 0.01 events fewer per child).Rate ratio 0.50; 95% CI 0.37 to 0.6719,566
(6 studies)
++++
high

LRTI-morbidity incidence

Mean episodes per child per year
Follow-up: mean 52 weeks
Mean episodes in control groups: 0.7 episodes.VAS led to 0.1 more episodes/child/year (95% CI 0.04 episodes fewer to 0.3 episodes more episodes per child per year.Rate ratio 1.14; 95% CI 0.95 to 1.3719,566
(9 studies)
+OOO

very low6,7,8

Bitot's spots

Follow-up: mean 80.72 weeks
Low risk populationRR 0.45; 95% CI 0.33 to 0.6163,278
(4 studies)
+++O
moderate9

4 per 100012 per 1000
(1 to 2)

Medium risk population

14 per 100016 per 1000
(5 to 9)

High risk population

203 per 1000191 per 1000
(67 to 124)

Night blindness

Follow-up: 52 to 68 weeks
Low risk populationRR 0.32; 95% CI 0.21 to 0.5022,972

(2 studies)
+++O

moderate11

4 per 1000101 per 1000
(1 to 2)

High risk population

7 per 1000102 per 1000
(2 to 4)

Vitamin A deficiency

Follow-up: mean 54.5 weeks
Low risk populationRR 0.71; 95% CI 0.65 to 0.782262
(4 studies)
++++
high

93 per 10001066 per 1000
(60 to 72)

Medium risk population

286 per 100010203 per 1000
(186 to 223)

High risk population

588 per 100010417 per 1000
(382 to 458)

Vomiting

Follow-up: 0.14 to 52 weeks
Low risk populationRR 2.75; 95% CI 1.81 to 4.192994
(3 studies)
++OO
low 12, 13

0 per 1000100 per 1000
(0 to 0)

Medium risk population

22 per 10001062 per 1000
(41 to 94)

High risk population

73 per 100010200 per 1000
(132 to 305)

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. CERs identified from the studies for this outcome which report cumulative risk.
2. The wide confidence intervals around the pooled effect estimate included both a reduction and an increase in the risk of mortality with vitamin A.
3. The risk of bias assessments determined that Daulaire 1992 and Herrera 1992 were at high risk of selection bias. Inadequate blinding put the results of Daulaire 1992 at a high risk of detection bias. Incomplete data was considered to put the results of Chowdhury 2002 at a high risk of attrition bias. Baseline imbalance was noted for Agarwal 1995.
4. The risk of bias assessment determined that four studies contributing just over 25% weight of the estimated effect were at risk of selection or attrition bias.
5. The I square was 95%, and the results of Herrera 1992; Cheng 1993 and Chowdhury 2002 demonstrated clear evidence of benefit and were discordant with the results of the other studies.
6. The risk of bias assessment determined that Cheng 1993; Kartasasmita 1995 and Chowdhury 2002 were at high risk of attrition bias.
7. Diagnostic procedures were not consistent across the studies.
8. The CIs around the pooled effect included small benefit and a meaningful increase in the risk of RTIs.
9. The risk of bias assessment determined that there was a risk of attrition bias in Pant 1996, which was assigned 47% weight.
10. Risk based on CERs from the included studies.
11. The larger study was not well described and was of uncertain quality; this puts the results at a high risk of selection bias.
12. The follow-up was spread between 1 day and 52 weeks.
13. There was some evidence of under-reporting of adverse events in some of the studies, and the low number of trials giving data in relation to the large of studies included overall means that this selective reporting of adverse events cannot be excluded.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Vitamin A is required for normal functioning of the visual system, maintenance of cell function for growth, epithelial integrity, red blood cell production, immunity and reproduction (Sommer 1996). Vitamin A deficiency (VAD) impairs body functions and may cause death. Adverse health consequences may also include xerophthalmia (dry eyes), susceptibility to infection, stunting and anaemia (Sommer 1996; Rice 2004). Chronic VAD may develop when animal sources and fortified foods are limited, as in diets that rely heavily on vegetables and fruits (Ramakrishnan 2002). In poor societies, especially lower income countries, dietary deficiency can begin very early in life, as when colostrum is discarded or when breastfeeding is inadequate (Haskell 1999).

VAD is interconnected with a deprived ecological, social and economic environment. People with VAD may be exposed to measles, diarrhoea and respiratory diseases (Sommer 2002; Rice 2004). When these problems are comorbid, intake of vitamin A may be lowered through depressed appetite and poor absorption, and body stores of vitamin A may be depleted through excessive metabolism and excretion (Alvarez 1995; Mitra 1998). This combination of poor diet and infection leads to a vicious cycle that particularly affects young children and pregnant or lactating mothers (Sommer 2002; West KP 2003).

VAD is common in the developing world. About 19.1 million pregnant women and 190 million children under 5 are vitamin A deficient (i.e. serum retinol < 0.70 µmol/l), representing about 33% of children under 5 in populations at risk of VAD (WHO 2009). Based on biochemical VAD in young children, 122 countries have a moderate to severe public health problem (WHO 2009).

Africa and South-East Asia contain the highest proportions of pregnant females and children under 5 with biochemical VAD and night blindness (WHO 2009). Xerophthalmia is the world’s leading preventable cause of blindness, and a cardinal indicator of VAD (Sommer 1996). Of the world’s children with xerophthalmia, nearly half reside in South or South-East Asia, with more than 85% of these living in India (West 2002a).

 

Description of the intervention

Vitamin A is a term used for a subclass of retinoic acids, a family of lipid-soluble compounds (Bates 1995). Vitamin A is found in two main forms: provitamin A carotenoids and preformed vitamin A. Provitamin A carotenoids are found in plants; beta-carotene is the only one that is metabolised by mammals into vitamin A. Though fruits and vegetables are nutritious in other ways, normal dietary intake of plants may not deliver adequate amounts of vitamin A because the intestinal carotenoid-to-retinol conversion ratio is 12:1 (US Institute of Medicine, Food and Nutrition Board). Consequently, VAD can exist in places with high vegetable and fruit consumption (West 2002). Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl esters), is the most active form of vitamin A and is found in animal sources. Supplements usually use Preformed vitamin A (Shenai 1993; Bates 1995).

 

How the intervention might work

Vitamin A is an essential nutrient; it cannot be synthesised by the human body and therefore must be obtained through diet (Bates 1995). Oral supplementation (VAS) and food fortification are the most direct methods for providing vitamin A to people whose diets are deficient.

Vitamin A has been described as an anti-infectious vitamin because of its role in regulating human immune function (Green 1928). Early studies in animals and humans revealed an association between VAD and increased susceptibility to infections (Semba 1999). In addition to its preventive and therapeutic effect against xerophthalmia (Sommer 1996), prophylactic VAS in apparently healthy children (over 6 months of age) residing in developing countries may reduce childhood mortality by as much as 30% (Beaton 1993; Fawzi 1993; Glasziou 1993), particularly by reducing diarrhoea and measles mortality.

Side effects of VAS are rare in children aged 6 months or older; however, vitamin A toxicity can develop if large amounts of vitamin A are used over a prolonged period of time. Symptoms of toxicity include liver damage, headaches, vomiting, skin desquamation, bone abnormalities, joint pain and alopecia (Smith 1976). A very high single dose can also cause transient acute toxic symptoms that may include a bulging fontanelle in children under 1 year, headaches, vomiting, diarrhoea, loss of appetite and irritability. Toxicity from ingestion of food sources of preformed vitamin A is rare (Hathcock 1997). 

 

Why it is important to do this review

Prophylactic and therapeutic supplementation has been the subject of several reviews (Beaton 1993; Fawzi 1993; Glasziou 1993; Gogia 2008a). Three of these are 17 years old. The most recent one (Gogia 2008a) included studies of maternal VAS, neonatal VAS and childhood supplementation in a single meta-analysis. Direct supplementation of children and indirect methods through supplementation of breast-feeding mothers may have variable impacts on children, and supplementation may have different effects at these key developmental stages. These systematic reviews reported statistically significant reductions in all-cause child mortality. VAS appears to be a very cheap intervention that can be easily administered to children. In populations with low vitamin A status and where dietary intake of vitamin A is low, large-scale supplementation might lead to substantial public health benefits, including reduced childhood mortality, infections and blindness. On the basis of previous evidence, the WHO has long recommended VAS for young children and pregnant or breastfeeding mothers at a dose of 50,000 IU for infants under 6 months of age, 100,000 IU for infants 6 to 12 months of age and 200,000 IU for children over 12 months of age, every 4 to 6 months (WHO 1997).

Several studies have been conducted since these recommendations were made over a decade ago, and this review aims to provide an up-to-date assessment of the best available evidence for VAS, including subgroup analyses to identify populations most likely to benefit and the most effective doses. Gogia 2008a did not include several known studies of VAS, so there is a need for a systematic review with a highly sensitive search strategy. The therapeutic role of vitamin A has been evaluated for measles and non-measles pneumonia in two separate Cochrane reviews (Ni 2005; Yang 2009). The prophylactic role of vitamin A has also been or is being evaluated in different Cochrane reviews in different subpopulations of children and mothers (van den Broek 2002; Wiysonge 2005; Oliveira 2006; Darlow 2007; Chen 2008; Gogia 2008; Haider 2008; Bello 2009). However, no Cochrane review has addressed prophylactic VAS in children from 6 months to 5 years of age. Given some of the recent controversies raised on the efficacy/effectiveness of VAS in developing countries (Latham 2010), it is important to review the cumulative evidence to date on the impact on health outcomes of VAS in children aged 6 months to 5 years.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To evaluate the effect of vitamin A supplementation (VAS) in children from 6 months to 5 years of age with respect to the prevention of mortality and morbidity.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised controlled trials (RCTs) and cluster RCTs evaluating the effect of synthetic VAS in children aged 6 months to 5 years. We included data from the first period only of cross-over studies. We considered studies for inclusion irrespective of publication status or language of publication. We excluded quasi-experimental studies, such as before-after designs and observational studies.  

Post hoc, we included two studies in which participants were assigned using a quasi-random method (Herrera 1992; Stansfield 1993). In both cases, the authors and the editorial team agreed that the methods of assignment (i) had the desirable characteristics of randomisation and (ii) were of no greater risk of bias than other included studies. For example, Stansfield 1993 used a random starting point and alternately assigned red or green pills. Participants received a single mega-dose of Vitamin A, so the people delivering the pills had no ongoing contact with participants; both selection bias and recruitment bias seem very unlikely.

Though the authors had access to the results of these studies, the decision to include them was made before data were extracted and before any analyses were undertaken. The search was comprehensive and we are not aware of any other studies similar to these two studies that could have been included in the review.

 

Types of participants

Children living in the community and aged 6 months to 5 years at the time of recruitment were eligible. Children in hospital and children with disease or infection were excluded.

We contacted trial authors if the study population included some participants who were not eligible for this review (for example, children over 5 years) and requested disaggregated data. If such data were not available, we included studies if the majority of participants (51%) met the inclusion criteria. If this could not be determined and the participants met the inclusion criteria on average (for example, the mean age was in the eligible range), then we included these trials.

 

Types of interventions

Synthetic oral VAS was compared to either placebo or treatment-as-usual control groups, including trials of various doses and frequencies. Co-interventions (for example, multiple vitamin or mineral supplementation), must have been identical in both groups. We excluded studies evaluating the effects of (i) food fortification, (ii) consumption of vitamin A rich foods and (iii) beta-carotene supplementation.

If a trial included more than one eligible intervention group (for example, different doses), we combined the groups for the main analysis, although the groups were treated separately for subgroup analyses where appropriate. If a trial included multiple control groups (for example, both placebo and treatment-as-usual), we selected the control group that most closely replicated the non-specific treatment of the intervention group (that is, placebo).

 

Types of outcome measures

The following outcomes were extracted. In studies reporting more than one measure of an outcome, measures were combined for meta-analysis using the methods described below (see Data synthesis).

 

Primary outcomes

All-cause mortality

 

Secondary outcomes

Cause-specific mortality due to:

  • diarrhoea;
  • measles;
  • meningitis;
  • lower respiratory tract infection (LRTI).

Cause-specific morbidity (i.e. incidence and prevalence):

  • diarrhoea;
  • measles;
  • malaria;
  • meningitis;
  • lower respiratory tract infection (LRTI);
  • Bitot's spots;
  • night blindness;
  • xerophthalmia.

Side effects (for example, vomiting or diarrhoea following supplementation).

Vitamin A deficiency status (serum retinol).

 

Search methods for identification of studies

 

Electronic searches

We searched CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE (1950 to April Week 2 2010), EMBASE (1980 to 2010 Week 16), Global Health (1973 to March 2010), Latin American Database (LILACS), metaRegister of Controlled Trials and African Index Medicus. All the searches were conducted on 27 April 2010.

The search strategies for each database are included in Appendix 1. Where possible, searches were limited to clinical trials involving human subjects, and were conducted without language restriction.

 

Searching other resources

To identify ongoing and unpublished trials, we used the World Health Organization International Clinical Trials Registry (ICTRP), which searches multiple trial registries. Reference lists of reviews, included studies and excluded studies were searched for additional citations. We contacted organisations and researchers.

 

Data collection and analysis

 

Selection of studies

Two authors independently screened titles and abstracts for inclusion in the review (AI and KH). We resolved differences of opinion about suitability for inclusion by discussion and through consultation with a third author (EMW). Studies that met the screening criteria but did not meet the full inclusion criteria are listed in the Characteristics of excluded studies table with the reasons for exclusion.

 

Data extraction and management

We used a data extraction sheet to extract the following information from each study:

  • year
  • location (country, urban/rural);
  • method of recruitment;
  • inclusion criteria;
  • unit of analysis; and
  • risk of bias (see below).

Participants:

  • socio-demographics (age, sex); and
  • co-morbidities.

For each intervention and comparison group of interest:

  • dosage;
  • duration;
  • frequency;
  • co-intervention (if any).

 For each outcome of interest:

  • time points (i) collected and (ii) reported;
  • definition;
  • validity;
  • unit of measurement (if relevant); and
  • loss to follow-up.

Data from each eligible study were extracted independently by two people using Distiller software. Extraction was also done by a team at the Cochrane Editorial Unit (Toby Lasserson, Rachel Murphy and Karla Soares-Weiser), but there was always at least one extractor who was an author (AI, KH, YY, EMW). Discrepancies were resolved through discussion among the authors.

The main analyses included the longest reported follow-up in each study. Outcomes were also grouped by time (0 to 12 months; 13 to 60 months, and greater than 60 months since randomisation); when trials reported multiple time points for a period, we extracted the longest outcome interval in a given period.

 

Assessment of risk of bias in included studies

Two authors independently assessed the risk of bias associated with each included study using the Risk of Bias tool (Higgins 2008). For all studies, the following were assessed: sequence generation; allocation concealment; blinding of participants, providers and outcome assessors; incomplete outcome data; and selective outcome reporting. We specifically looked for the possibility of performance bias (differential treatment of the intervention and control groups) and detection bias (for example, differential effort to locate death records for the intervention and control groups). Findings are discussed below and included in the Risk of Bias tables.

 

Measures of treatment effect

Morbidity was measured in different ways, and we combined all available data whenever possible. For example, for diarrhoea we included all types of diarrhoea (mild, moderate and severe). In the case of pneumonia, we included lower respiratory tract infection (but not upper).

To avoid reviewer bias, we predetermined the order of preference for extracting outcomes when data were available in several formats. For studies that randomised individuals, we gave preference to data that required the least manipulation by authors or inference by reviewers. We extracted raw values (for example, means and standard deviations) rather than calculated effect sizes (for example, Cohen’s d). For mortality data, we gave preference to denominators in the following order: number with definite outcome known (or imputed as described below), number randomised, and child-years. For other dichotomous outcomes to which both survivors and non-survivors may contribute data (for example, incidence of measles), we gave preference to child-years, number with definite outcome known, and number randomised. 

In the case of cluster RCTs, we (i) used adjusted estimates reported by the authors or (ii) used raw data and inflated the standard error (SE) using procedures described below.

 

Unit of analysis issues

In studies randomising units other than the individual (i.e. clusters), results should be presented with controls for clustering (for example, robust SEs or hierarchical linear models). We analysed clustered data using procedures outlined in Higgins 2008.

Where results did not control for clustering, we contacted authors to request an estimate of the intra-cluster correlation coefficient (ICC). If the authors were unable to provide an ICC, we used design effects calculated previously (Beaton 1993) to calculate the ICC, and we estimated the ICC for studies that did not publish a value (see below). For estimated values, we conducted sensitivity analyses using larger and smaller design effects to determine if the results were robust.

 

Dealing with missing data

Differential dropout can lead to biased estimates of effect size, and bias may arise if reasons for dropout differ across groups. 

Missing data are described, including dropouts and reasons for dropout where given. If data were missing for some cases, or if reasons for dropout were not reported, we contacted the authors. When analyses were reported for completers as well as controlling for dropout (for example, imputed using regression methods), we extracted the latter.

 

Assessment of heterogeneity

Included studies were assessed for clinical heterogeneity by comparing the distribution of important factors, such as study participants, study setting, dose and duration of intervention and co-interventions. Methodological heterogeneity was assessed by comparing data included in the Risk of Bias tables. Statistical heterogeneity was assessed by visual inspection of forest plots, by performing the Chi2 test (assessing the P value) and by calculating the I2 statistic. If the P value was less than 0.10 and I2 exceeded 50%, we considered heterogeneity to be substantial.

 

Assessment of reporting biases

To assess the possibility of small study bias, funnel plots were drawn for outcomes with 10 or more studies and random effects estimates were compared to the fixed effect estimate (see below).

 

Data synthesis

We performed meta-analysis using Review Manager Software Version 5 (RevMan 2008).  When data were extracted in several formats that could not be combined directly in RevMan, we used the generic inverse variance option; data were entered into Comprehensive Meta-Analysis Version 2 and the log RR and SE were entered into RevMan.  

All outcomes are reported with 95% confidence intervals (CI), and overall effects are weighted by the inverse of variance using a fixed-effect model; although there may be some differences across trials (for example, dose and population), the biological mechanism should be similar across trials and we will explore differences through analyses described elsewhere.

For dichotomous outcomes, we calculated the overall Risk Ratio (RR). For incidence data, Risk Ratio (events per child) and Rate Ratio (events per child-year) were combined because these ratios use the same scale and can be interpreted in the same way for these studies (the duration of studies was short, there was no interaction between the intervention and time at risk). In some cases, we estimated time at risk, as when authors reported incidence rate, duration of the study and number of children in the group.

For continuous outcomes we calculated Hedges g

 

Subgroup analysis and investigation of heterogeneity

Effectiveness may differ across members of populations (for example, due to differences in baseline vitamin A status) and may be affected by other interventions (for example, immunisation or deficiency of other micronutrients). For example, neonatal VAS is thought to have different effects in Asia versus Africa (Klemm 2009). Unlike trial-level factors (such as dose), associations between individual-level moderators (such as vitamin A status) and outcomes should be analysed using individual patient data from RCTs and observational studies. With two exceptions, we did not include subgroup analyses based on individual-level moderators in this review, as such analyses are at high risk of the ecological fallacy (for example, lack of variation between studies would not indicate there was no variation within them). We included subgroups of age and gender; trials commonly report separate effects for these groups. 

The following subgroup analyses were prespecified, and differences were tested using the Chi2 test in RevMan:

  1. Dose: Standard (up to 100,000 IU for children 6 to 11 months of age, and 200,000 IU for children 12 months to 5 years of age) versus High (greater than standard).
  2. Frequency: High (doses within 6 months) versus Low (1 dose or 6+ month interval).
  3. Location: Continent.
  4. Age: 6 to 12 months versus 1 to 5 years.
  5. Sex: males versus females.

 

Sensitivity analysis

Sensitivity analyses were performed as follows:

1) To test for bias, the primary analysis was repeated without studies at high risk of bias for sequence generation. To test for small study bias, the analysis was repeated using a random-effects model and funnel plots were drawn for all outcomes with 10 or more studies.

2) Imputed ICC (a post-hoc analysis described below).

3) Studies awaiting assessment (a post-hoc analysis described below).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

 

Results of the search

Electronic searches identified 6683 citations; 4600 citations remained after duplicates were removed. 

Additionally, we reviewed 129 studies from reference lists. There were 371 relevant citations, and all full texts were reviewed, see Figure 1.

 FigureFigure 1. Flow diagram for selection of studies

 

Included studies

Forty-three trials reported in 90 papers met the inclusion criteria, including factorial studies that were treated as two trials for meta-analysis (described below). More than one report was available for 16 (37%) trials.  Where multiple reports existed for an included trial, we extracted data from all reports. Further information about individual studies is included in the Characteristics of included studies tables.

Thirty-nine trials (91%) reported data that could be included in a meta-analysis; four trials reported either outcomes that were not relevant to the review (Cherian 2003), or data that were not available by group (Lima 2010) or were incomplete (van Agtmaal 1988; Smith 1999).

 

Sample size

Trials assigned approximately 215,633 participants, with sample sizes ranging between 35 (van Agtmaal 1988) and approximately 29,236 (Sommer 1986), and a median sample size of 480. The 39 trials that could be analysed included 215,043 participants (99.7% of children included in the review).

The ten largest studies randomised about 200,214 children, 93% of participants in the review (Sommer 1986; Rahmathullah 1990; Vijayaraghavan 1990; West 1991; Daulaire 1992; Herrera 1992; Ross 1993 SURVIVAL; Stansfield 1993; Agarwal 1995; Pant 1996). 

 

Comparisons

Six (14%) studies compared VAS to treatment-as-usual; 37 (86%) compared VAS to placebo. One large trial reported they did not use a placebo because it was forbidden by government (Sommer 1986).

 

Multiple trial arms

Twelve trials (28%) had multiple arms, 7 of which were relevant to the review (Reddy 1986; Florentino 1990; Benn 1997; Smith 1999; Rahman 2001; Long 2006; Lin 2009).

Four trials used factorial designs, combining vitamin A with other treatments such as zinc (Smith 1999; Rahman 2001; Long 2006) or deworming (Reddy 1986); data were extracted for comparisons that differed only in the provision of vitamin A (for example, vitamin A versus placebo; and vitamin A plus zinc versus zinc only).  In one trial (Rahman 2001), raw data were not available and we could not identify outcome data for an eligible comparison. Different doses were combined in one study (Florentino 1990). 

 

Unit of randomisation

Two studies (Herrera 1992; Stansfield 1993) randomised by household and we treated participants as if they were individually randomised.  A sensitivity analysis was conducted for all-cause mortality, using ICCs of 0 and 0.01 for those studies in which the mean design effect was estimated.

Previously reported design effects from Beaton 1993 were used to calculate ICCs for clustered studies (Sommer 1986; Rahmathullah 1990; Vijayaraghavan 1990; West 1991; Daulaire 1992; Ross 1993 SURVIVAL). The ICCs were consistent around a value of 0.002. We imputed an ICC value of 0.002 for all studies in which clustering was not accounted for in the original analysis.

 

Allocation ratio

Participants were evenly allocated to the intervention and control groups in 35 studies (81%) and the number assigned to each group was unclear in 8 trials (19%) (Reddy 1986; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Stansfield 1993; Biswas 1994; Dibley 1994; Ramakrishnan 1995; Pant 1996). 

 

Location/setting

Trials were conducted in 19 countries: 27 (63%) in Asia, 15 of these in India; 7 (16%) in Africa; 7 (16%) in Latin America, and 2 (5%) in Australia. Sixteen (37%) of the studies were conducted in urban/peri-urban settings and 24 (56%) in rural settings, while three studies did not explicitly described their urban/rural setting.

 

Age

Average age was reported in 19 trials (44%). The median of the mean ages was 30.5 months.

 

Sex

Sex was reported in 32 trials (72%). The majority assigned approximately equal numbers of males and females. Three studies (Semba 1992; Ranjini 2001; Lin 2008) favoured males by more than 10%. The median study included 51% males.

 

Time

Outcomes measured at different times (0 to 12 months, 13 to 60 months, and 60 or more months) were collapsed for one overall analysis. Most studies lasted about a year, and dividing studies of similar length created potentially confusing/misleading subgroups. In the event that a single study reported data in more than one time point interval, the data from the longest interval was used in the overall analysis.

 

Excluded studies

After reviewing articles, 328 papers were excluded; eight nearly met the inclusion criteria, and reasons for exclusion are provided in Characteristics of excluded studies.

 

Studies awaiting assessment

Two trials could not be assessed at this time.

One trial (Aklamati 2006) was reported in a conference abstract.  It appeared to meet the inclusion criteria, but reported impossible results. For example, the study included 36 children and reported an outcome of 1.2% of 17; though 1 child out of 17 is nearly 6%. We have contacted the authors for clarification and the study may be included in future versions of this review.

Importantly, one completed trial appears likely to meet the eligibility criteria and may be included in further updates of this review (DEVTA trial 2007). DEVTA is the largest randomised controlled trial ever conducted, including approximately one million children. That is, the trial included four times the combined participants of all included studies in this review. We contacted the authors of this trial several times prior to the completion of this review for information required to evaluate the conduct of the study and its outcomes. They provided an early analysis of the primary outcome, mortality, as well as cause-specific mortality and vitamin A serum level.

To assess how the results of DEVTA might impact the conclusions of this review, a sensitivity analysis was conducted. Due to lack of additional information, reasons for differences between this trial and other trials in the review could not be assessed.

 

Risk of bias in included studies

The risk of bias in each of the five domains was assessed for each study as High, Low or Unclear, see Figure 2.

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

 

Sequence generation

All included studies were randomised or quasi-randomised controlled trials: 19 (44%) specified the method of randomisation and 16 (37%) were at Low risk of bias for sequence generation.  

Three trials (7%) were at High risk of bias for sequence generation (Herrera 1992; Stansfield 1993; Arya 2000). These included 41,139 participants (19% of those included in the review). 

One described assignment as random, but participants may have been assigned in order of arrival at hospital (Arya 2000).  

Though technically quasi-random, we included two trials post hoc (Herrera 1992; Stansfield 1993) because the generation of the allocation sequence was not likely to result in systematically different groups. Given the design of the interventions and the placebos and steps to blind those administering the sequence, the reviewers do not think these studies are meaningfully different from randomised trials. In the first, participants were assigned alternately by household (Herrera 1992). The second used a random starting point and alternating distribution of red or green pills (Stansfield 1993). Lack of a truly random sequence was not related to other sources of bias (for example, performance bias) as individuals delivering the capsules had no ongoing contact with participants and the manufacturer (Roche) held the code until the study was completed. Though post-hoc, the decision to include these studies was made before data were extracted and before any analyses had been conducted; a sensitivity analysis was conducted (below) to determine if the decision had any impact on the results and it did not.

 

Allocation concealment

Allocation concealment is adequate when (i) trial staff and potential participants are unaware of assignments at the time of recruitment into the trial and (ii) the generation of the allocation sequence is protected from the influence of anyone aware of the participants’ characteristics.  Allocation concealment was coded as High risk of bias for only one study (Daulaire 1992) and Unclear for 27 studies (63%). In most studies it was impossible to assess allocation concealment. Efforts to blind participants and providers suggest the overall risk of bias is minimal, and any impact on the primary outcome (all-cause mortality) is likely to be small.

 

Blinding

The intervention was conducive to blinding. Though there is some evidence that very large doses of vitamin A can lead to short-term side effects, participants and providers would not normally become aware of assignment after delivery of vitamin A in the form of pills, capsules or liquid solution. Efforts to blind participants and providers were described in 29 of the studies (67%), which were at Low risk of bias. In some trials, staff delivering the intervention also conducted assessments. Blinding of assessors was at High risk of bias in two studies (Daulaire 1992; Lin 2009) and Unclear in 14 (Reddy 1986; Sommer 1986; van Agtmaal 1988; Semba 1992; Agarwal 1995; Kartasasmita 1995; Stabell 1995; Pant 1996; Donnen 1998; Smith 1999; Ranjini 2001; Chowdhury 2002; Cherian 2003; Lin 2008). 

In some trials, children interacted with researchers or clinicians who were aware of their assignment. Two studies (5%) were at High risk of performance bias, mostly because of failure to adequately blind staff, whereas 28 (65%) were at Low risk of performance bias. The reviewers considered bias due to inadequate blinding to be low and, if anything, likely to underestimate effects; for example, a teacher would be more likely to give extra food to a child receiving placebo rather than the reverse.

The review authors consider the primary outcome, mortality, is very unlikely to have been influenced by lack of blinding. 

 

Incomplete outcome data

For incomplete outcome data, 23 trials (53%) were at Low risk of bias; 8 (17%) were at High risk of bias (van Agtmaal 1988; Kartasasmita 1995; Semba 1995; Pant 1996; Bahl 1999; Arya 2000; Chowdhury 2002; Cherian 2003) and 12 (28%) were Unclear (Sinha 1976; Reddy 1986; Sommer 1986; Vijayaraghavan 1990; West 1991; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Agarwal 1995; Stabell 1995; Venkatarao 1996; Smith 1999; Ranjini 2001).

Missing data are much more likely to influence secondary analyses than the primary outcome. Results for all-cause mortality are known for 91% of randomised participants. Of the 17 studies (40%) that reported this outcome, 7 were Unclear, but 4 of these had minimal attrition (Vijayaraghavan 1990; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Venkatarao 1996) and the others failed to report reasons for dropout.  In 2 studies, missing data were not adequately handled (Pant 1996; Chowdhury 2002), but together these studies contributed only 5% to the pooled estimate.

 

Selective reporting

Most of the trials in the review included multiple outcome measures, and positive results are more likely to be included in reports than negative results. Only 5 (12%) trials appeared to be free of selective outcome reporting (Florentino 1990; Rahmathullah 1990; West 1991; Dibley 1994; Benn 1997). Twenty four (56%) were Unclear, while 14 (33%) were at High risk of bias (Pinnock 1988; van Agtmaal 1988; Vijayaraghavan 1990; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Stansfield 1993; Ramakrishnan 1995; Pant 1996; Bahl 1999; Arya 2000; Cherian 2003; Lin 2008; Lin 2009; Lima 2010).

For the primary outcome, there is no meaningful risk of bias; the outcome was reported for large trials. Data were missing in small studies of short duration, which likely observed few deaths.  For many of the secondary analyses, which included only a few trials representing a small proportion of the overall sample, adding unreported data might influence the observed effects.

 

Other potential sources of bias

Other potential sources of bias were extracted and are noted in the Characteristics of included studies tables, but none were likely to meaningfully influence the results of the review.

 

Effects of interventions

See:  Summary of findings for the main comparison

Results for each outcome are presented below, the most important of which are described in  Summary of findings for the main comparison.

Because most analyses contained a small number of studies, sensitivity analyses were restricted to the primary outcome.

Pneumonia and lower respiratory tract infection (LRTI) outcomes were combined post hoc.  Pneumonia is a type of LRTI, and most of the studies did not test for pneumonia specifically (with a specific clinical criteria). In the event a study reported both pneumonia and LRTI outcomes, the LRTI outcome data were extracted for combination with other studies.

Not all subgroup analyses were conducted. For the primary outcome, only one study used a non-standard dose and this study also used a different frequency. Other analyses with more than 10 studies contained significantly fewer participants (for example, the analysis of serum level included less than 7000) and subgroup analyses for dose and frequency were not conducted because the analyses were clearly underpowered and any effects would be attributable to chance. Results of some of the attempted subgroup analyses are listed in Table 1.

 

1.0 All-cause mortality

Seventeen trials (Sommer 1986; Rahmathullah 1990; Vijayaraghavan 1990; West 1991; Daulaire 1992; Herrera 1992; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Barreto 1994; Dibley 1994; Agarwal 1995; Pant 1996; Venkatarao 1996; Benn 1997; Donnen 1998; Chowdhury 2002; Lin 2008) contributed 194,795 children (90% of the children included in the review) in an overall analysis (using data from the last follow up for trials measuring outcomes multiple times). One reported no events (Lin 2008).

Vitamin A was associated with a 24% reduction in all-cause mortality (RR = 0.76 (95% CI 0.69 to 0.83)), though there was moderate heterogeneity (Chi² = 29.10, df = 15 (P = 0.02); I² = 48%) Figure 3.

 FigureFigure 3. Forest plot of comparison: 1 Vitamin A versus Control, outcome: 1.1 Mortality (all-cause) at Longest Follow-up.

The effect during the first year of life was similar (RR = 0.82 (95% CI 0.74 to 0.91)), but the statistical heterogeneity was substantial (Chi² = 33.85, df = 11 (P = 0.0004); I² = 67%). Only 5 trials (7%) measured mortality between 13 and 60 months, and the effect was similar (RR = 0.75 (95% CI 0.64 to 0.88)) with moderate and significant statistical heterogeneity (Chi² = 9.29, df = 4 (P = 0.05); I² = 57%).

 

Subgroup analyses

 
1. Dose and frequency

Only one study reporting all-cause mortality did not use the standard dose recommended by WHO. Rahmathullah 1990 used weekly dose for 52 weeks. The planned subgroup analysis was not conducted.

 
2. Location

Eleven trials were conducted in Asia (RR = 0.69 (95% CI 0.61 to 0.79)), 5 in Africa (RR = 0.85 (0.73 to 0.98)), and 1 in Latin America (RR = 1.00 (0.14 to 7.08)). These were not significantly different (P = 0.12, see Table 1).

 
3. Age

Four trials (Rahmathullah 1990; West 1991; Daulaire 1992; Benn 1997) reported separate effects for children aged 6 to 12 months (RR = 0.59 (95% CI 0.43 to 0.82)) and children aged 1 to 5 years (RR = 0.68 (0.57 to 0.81)); the subgroups did not differ significantly (P = 0.46). Notably, both effect estimates are larger than the overall result from 17 trials reporting mortality.

 
4. Sex

Five trials (Sommer 1986; West 1991; Daulaire 1992; Herrera 1992; Lin 2008) reported separate effects for males (RR = 0.80 (95% CI 0.66 to 0.97)) and females (RR = 0.79 95% CI 0.65 to 0.95)), which were not significantly different (P = 0.89). Notably, both effect estimates are larger than the overall result from 17 trials reporting mortality.

 

Sensitivity analyses

 
1. Bias

Of the trials at High risk of bias due to sequence generation, only Herrera 1992 contributed to the main mortality analysis and reported no effect (RR = 1.06 (95% CI 0.82 to 1.37)), indicating that these trials were not likely to influence the results in a positive direction.

To test for small study bias, we repeated the analysis using a random-effects model. The overall estimate was slightly larger than the fixed-effect estimate, suggesting that heterogeneity is partially explained by small studies reporting larger effects (RR = 0.71 (0.61 to 0.84)).

There was some evidence of visual asymmetry on the funnel plot we produced, but the overall effect was strongly influenced by five studies that accounted for over 80% of the weighted mean; even if the result was influenced by small study bias, the magnitude of the effect was small. To impact the results, missing studies would need to be very large and show no difference or harmful effects, as demonstrated in the third sensitivity analysis.

 
2. Design effects in cluster trials

Known ICCs were remarkably consistent. For three studies for which the ICC was not known, we estimated ICC = 0.002 and we adjusted SEs using this value and the average cluster size. To determine if this decision had any impact on the results, we repeated the primary analysis using a much larger and much smaller ICC estimate. The size of the effect was slightly smaller when these trials were treated as if they had randomised individuals (RR = 0.81 (95% 0.75 to 0.89)). The effect was virtually unchanged when we increased the ICC to 0.01 (RR = 0.75 (95% CI 0.68 to 0.83)), see Table 1. These results indicate that over-weighting these three studies in the analysis would not impact the conclusions of this review; further inflating their SEs would increase the size of the effect estimate.

 
3. Studies awaiting assessment

One study awaiting assessment was added to the analysis (DEVTA 2007). This trial found no significant effect of VAS on mortality (RR = 0.96 (95% CI 0.89 to 1.03)). 

In our analysis of 18 trials, DEVTA 2007 accounted for 65.2% of the combined effect, which remained significant (RR = 0.88 (95% CI 0.84 to 0.94)) with substantial and significant heterogeneity (Chi² = 44.31, df = 16 (P = 0.0002); I² = 64%). (We assumed the study authors adjusted for clustering. As the results were not significant, inflating the SE would not change our interpretation of the trial’s results, although it would decrease its weight in the analysis.)

Including DEVTA 2007 decreased the estimated benefit of Vitamin A by half (24% to 12%), but the result remained significant and clinically meaningful. As we were unable to assess the trial, we cannot explain this substantially different result.

 

2.0 Diarrhoea mortality

Seven trials (Rahmathullah 1990; Daulaire 1992; Herrera 1992; Ross 1993 SURVIVAL; Agarwal 1995; Venkatarao 1996; Chowdhury 2002) reported a combined 28% reduction in diarrhoea mortality (RR = 0.72 (95% CI 0.57 to 0.91)) with no important heterogeneity (Chi² = 6.12, df = 6 (P = 0.41); I² = 2%), Figure 4.

 FigureFigure 4. Forest plot of comparison: 1 Vitamin A versus Control, outcome: 1.5 Mortality due to Diarrhoea at Longest Follow-up.

 

3.0 Measles mortality

Five trials (Rahmathullah 1990; Daulaire 1992; Herrera 1992; Ross 1993 SURVIVAL; Agarwal 1995) reported a lower risk of measles mortality, but the effect was not statistically significant (RR = 0.80 (95% CI 0.51 to 1.24)). There was no important heterogeneity (Chi² = 0.40, df = 4 (P = 0.98); I² = 0%), Figure 5.

 FigureFigure 5. Forest plot of comparison: 1 Vitamin A versus Control, outcome: 1.6 Mortality due to Measles at Longest Follow-up.

 

4.0 Meningitis mortality

Three trials (Ross 1993 SURVIVAL; Agarwal 1995; Chowdhury 2002) reported a lower risk of meningitis mortality, but the effect was not statistically significant (RR = 0.57 (95% CI 0.17 to 1.88)). There was no important heterogeneity (Chi² = 0.75, df = 2 (P = 0.69); I² = 0%).

 

5.0 Lower Respiratory Tract Infection (LRTI) mortality

Seven trials (Rahmathullah 1990; Daulaire 1992; Herrera 1992; Ross 1993 SURVIVAL; Agarwal 1995; Venkatarao 1996; Chowdhury 2002) reported a lower risk of LRTI mortality, but the effect was not statistically significant (RR = 0.78 (95% CI 0.54 to 1.14)). There was no important heterogeneity (Chi² = 7, df = 6 (P = 0.32); I² = 14%).  

 

6.0 Diarrhoea

Thirteen trials (Florentino 1990; Herrera 1992; Cheng 1993; Barreto 1994; Biswas 1994; Dibley 1994; Ramakrishnan 1995; Venkatarao 1996; Sempertegui 1999; Shankar 1999; Arya 2000; Chowdhury 2002; Long 2007) reported an 18% decrease in diarrhoea incidence (RR = 0.85 (95% CI 0.82 to 0.87)), though statistical heterogeneity was substantial and highly significant (Chi² = 218.62, df = 11 (P < 0.00001); I² = 95%), Figure 6

 FigureFigure 6. Forest plot of comparison: 1 Vitamin A versus Control, outcome: 1.9 Diarrhoea Incidence at Longest Follow-up.

The results of this analysis were highly heterogenous and two studies account for the majority of the overall effect (Cheng 1993; Chowdhury 2002). The observed heterogeneity may be due to measurement error or differences in the effects of VAS across populations and settings. For example, it may reduce susceptibility to particular infections that are prevalent in some places but not others.

Two trials (Stansfield 1993 and Long 2006/Long 2006 (2)) reported no combined effect on diarrhoea prevalence (RR = 1.08 (95% CI 1.05 to 1.12)) though statistical heterogeneity was substantial and highly significant (Chi² = 15.76, df = 2 (P = 0.0004); I² = 87%).

 

Sensitivity analysis

 
1. Bias

To test for small study bias, we repeated the analysis using a random-effects model. The overall estimate was identical to the fixed-effect estimate, though the result bordered on statistical significance, suggesting that heterogeneity is not explained by small studies reporting larger effects (RR = 0.85 (95% CI 0.72 to 1.00)).

The funnel plot we produced was dominated by two studies accounting for 74% of the overall effect, and the plot was relatively flat.

 
2. Design effects in cluster trials

No ICCs were imputed, so sensitivity analysis was not required.

 

7.0 Measles

Six trials (Herrera 1992; Barreto 1994; Semba 1995; Benn 1997; Bahl 1999; Chowdhury 2002) reported a 50% decrease in measles incidence (RR = 0.50 (95% CI 0.37 to 0.67)) with no important heterogeneity (Chi² = 0.55, df = 5 (P = 0.99); I² = 0%), Figure 7.

 FigureFigure 7. Forest plot of comparison: 1 Vitamin A versus Control, outcome: 1.12 Measles Incidence at Longest Follow-up.

No trials reported data on measles prevalence that could be analysed at follow-up.

 

8.0 Malaria

One trial (Shankar 1999) reported a 27% reduction in malaria incidence (RR = 0.73 (95% CI 0.60 to 0.88)). 

Two trials (Ross 1993 HEALTH; Ross 1993 SURVIVAL) reported data on malaria prevalence; the combined effect was not statistically significant (RR = 0.72 (0.42 to 1.23)) and there was no important heterogeneity (Chi² = 0.03, df = 1 (P = 0.87); I² = 0%). Only one study reported data on malaria prevalence that could be analysed at follow-up, the results of which were not significant (RR = 0.73 (0.41 to 1.28)).

 

9.0 Meningitis

No trials reported data on meningitis incidence or prevalence that could be analysed at follow-up.

 

10.0 Lower Respitatory Tract Infection

Nine trials (Rahmathullah 1990; Cheng 1993; Barreto 1994; Biswas 1994; Kartasasmita 1995; Venkatarao 1996; Sempertegui 1999; Chowdhury 2002; Long 2007) reported no combined effect on LRTI incidence (RR = 1.14 (0.95 to 1.37)) with no important heterogeneity (Chi² = 7.66, df = 6 (P = 0.26); I² = 22%). LRT prevalence was reported in a factorial trial (Long 2006) with two relevant comparisons; the combined result of which was inconclusive but suggests benefit (RR = 0.46 (95% CI 0.21 to 1.03)).

 

11.0 Vision

 

11.1 Bitot’s spots

One trial (Herrera 1992) reported no effect on Bitot’s spots incidence (RR = 0.93 (95% CI 0.76 to 1.14)). 

Four trials (Sinha 1976; Sommer 1986; West 1991; Pant 1996) reported a 53% reduction in Bitot’s spots prevalence (RR = 0.45 (95% CI 0.33 to 0.61)) with substantial and significant heterogeneity (Chi² = 8.25, df = 3 (P = 0.04); I² = 64%).

 

11.2 Night blindness

One trial (Herrera 1992) reported a 47% reduction in night blindness incidence (RR = 0.53 (95% CI 0.28 to 0.99)). 

Two trials (Sommer 1986; West 1991) reported a 68% reduction night blindness prevalence (RR = 0.32 (95% CI 0.21 to 0.50)) with no heterogeneity (Chi² = 0.19, df = 1 (P = 0.66); I² = 0%).

 

11.3 Xerophthalmia

Three trials (West 1991; Herrera 1992; Barreto 1994) reported no combined effect on xerophthalmia incidence (RR = 0.85 (95% CI 0.70 to 1.03)), though statistical heterogeneity was substantial and significant (Chi² = 2.69, df = 1 (P = 0.10); I² = 63%). 

Two trials (Sommer 1986; West 1991) reported a 69% reduction in xerophthalmia prevalence  (RR = 0.31 (95% CI 0.22 to 0.45)) with no statistical heterogeneity (Chi² = 0.22, df = 1 (P = 0.64); I² = 0%).

 

12.0 Vitamin A deficiency

 

12.1 Number deficient

Four trials (Ross 1993 HEALTH; Dibley 1994; Shankar 1999; Ranjini 2001) reported a 29% reduction in the number of VAD children (RR = 0.71 (95% CI 0.65 to 0.78)); however, statistical heterogeneity was substantial and significant (Chi² = 13.58, df = 3 (P = 0.004); I² = 78%). 

 

12.2 Serum level

Thirteen studies (Pinnock 1986; Reddy 1986; Pinnock 1988; Semba 1992; Cheng 1993; Ross 1993 HEALTH; Ross 1993 SURVIVAL; Dibley 1994; Kartasasmita 1995; Sempertegui 1999; Shankar 1999; Ranjini 2001; Lin 2009) reported vitamin A serum data at follow-up, including one factorial study contributing two comparisons. Vitamin A serum levels were higher in the Vitamin A group (SMD = 0.31 (95% CI 0.26 to 0.36)), however statistical heterogeneity was substantial and significant (Chi² = 270.23, df = 13 (P < 0.00001); I² = 95%).

 

Sensitivity analysis

 
1. Bias

No studies in this outcome were at high risk of bias for sequence generation.

To test for small study bias, we repeated the analysis using a random-effects model. The overall estimate was considerably larger than the fixed-effect estimate, suggesting small studies report larger effects (RR = 0.53 (95% CI 0.27 to 0.79)).

The funnel plot that we produced was highly asymmetrical.

 
2. Design effects in cluster trials

No ICCs were imputed, so sensitivity analysis was not required.

 

13.0 Hospitalisation

One trial (Ross 1993 HEALTH) reported a reduction of the likelihood of hospitalisations that approached statistical significance (RR = 0.64 (95% CI 0.40 to 1.02)) and a 38% reduction in the number of hospitalisations (RR = 0.62 (95% CI 0.42 to 0.93)).

One trial (Cheng 1993) reported inconclusive evidence on diarrhoea related hospitalisation (RR = 0.25 (95% CI 0.01 to 6.11)).

One trial (Cheng 1993) reported inconclusive evidence on LRTI hospitalisation (RR = 0.11 (95% CI 0.01 to 2.06)).

 

14.0 Side effects

We assessed two short-term side effects:

 

14.1 Vomiting (within 48 hours)

Three trials (Sinha 1976; Florentino 1990; Arya 2000) reported a significant increase in risk of vomiting (RR = 2.75 (95% CI 1.81 to 4.19)) with statistical heterogeneity that was not important (Chi² = 2.53, df = 2 (P = 0.28); I² = 21%). Immediately following the intervention, the rate of vomiting increased from 2% to 6%.

 

14.2 Fontanelle

Three trials (Stabell 1995; Bahl 1999; Arya 2000) reported fontanelle side effects, but only one could be analysed because the others reported insufficient data, which reported no effect (RR = 5.00 (95% CI 0.24 to 103.72)). Most studies included children over 1 year old and would not have assessed this side effect.

Results not contained in the Data and Analyses section are listed below in  Table 1.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

Vitamin A supplementation appeared to reduce all-cause mortality by 24%. There was some statistical heterogeneity in the pooled data.

Much of the reduction in all-cause mortality is explained by reductions in death due to diarrhoea and measles, although many of the cause-specific mortality and morbidity outcomes were characterised by uncertainty. The overall effect for measles mortality was not significant, but the trend was consistent with the overall results and the therapeutic effects of VAS in reducing measles related mortality and morbidity are well established (Yang 2009). Furthermore, VAS resulted in a reduced incidence of diarrhoea and measles. Other reviews have shown that the therapeutic use of VAD may prevent acute diarrhoea from becoming chronic (Imdad 2010). Together, these results suggest that reductions in diarrhoea and measles are potential pathways in the reduction of all-cause mortality.

In addition to reducing death and illness, VAS reduces night blindness and potential precursors to blindness, namely Bitot's spots and xerophthalmia.

Some authors hypothesise that the preventive effect of VAS against infections is related to increased responsiveness to vaccines given around these times, especially in infants (Benn 2003). This has been recently challenged (Kirkwood 2010) and a meta-regression of studies does support the direction of overall effect (Rotondi 2010). A more detailed discussion about this hypothesis is available in the review on neonatal VAS by our group (Haider 2008).

The current review did not locate any trials that compare different co-interventions; policy makers and practitioners should use other types of studies to assess how the delivery and responsiveness to vitamin A might relate to other nutritional and health interventions.

Few studies reported data about side effects, including vomiting, bulging fontanelle and diarrhoea soon after receiving the intervention. VAS may increase short-term vomiting by 4%.

 

Overall completeness and applicability of evidence

This is the first published review to assess systematically both mortality and morbidity associated with VAS.  Other outcomes relevant to VAS, including stunting, could be added to future versions, but few studies have measured these effects.  Nonetheless, observed effects on morbidity suggest that vitamin A may improve overall health, and observational studies might examine the nature of this relationship.

All included studies reporting all-cause mortality were conducted in developing countries. The results appear applicable to developing countries with chronic VAD. The primary analysis is based on many large trials from several countries and locations. It included 90% of the children randomised in this review; risk of selective outcome reporting appears minimal. Statistical heterogeneity suggests that the magnitude of the effect may differ across settings and populations, possibly due to the extent of VAD or the availability of other nutrients. For example, dietary intake of vitamin A will differ across locations and the effects of supplementation may be smaller in places with greater access to vitamin A rich food. Concomitant nutrient deficiencies may also impair the bioavailability of the supplements, since some of these nutrients (including fat, protein and zinc) could be limiting factors for the absorption and utilisation of vitamin A, which is lipid-soluble (Villamor 2000). Comorbid illnesses could also reduce absorption of Vitamin A. That is, if vitamin A reduces mortality by reducing susceptibility to particular pathogens, differences in the prevalence of disease, sanitation, etc. might contribute to heterogeneity in outcomes across trials. Future versions of this review might investigate if VAS reduces both mild and severe episodes of diarrhoea, as the latter are more closely linked to mortality. A few trials have measured malaria mortality, which was not included in the review protocol; this outcome should be added to future versions of the review.

All included studies reporting all-cause mortality were conducted in low- and middle-income countries. The results appear applicable to all such countries with chronic VAD.

Analyses for many of the cause-specific mortality and morbidity outcomes were consistent.  A general weakness of many interventions is the underreporting of implementation data, such as the core components of an intervention, the degree to which they are delivered in practice, and what aspects of the trial may have influenced implementation (Mayo-Wilson 2007). In theory, the putative effect of this intervention relies little on the relationship between the provider and participant (discussed previously in the context of performance bias), but it is essential that large-scale interventions effectively distribute capsules that have been stored properly and remain active. Additionally, the degree to which children were treated for morbidities across trials might influence incidence and prevalence data collected in various trials, and this could contribute to heterogeneity.

Some readers will undoubtedly find these results unsatisfying, particularly because the review does not explain heterogeneity in the results. This review suggests some ways in which vitamin A might work, but it does not describe how effects of vitamin A might differ across subpopulations because trials did not report the data required for such analyses. We decided a priori not to include subgroup analyses based on individual-level moderators for reasons described above; we could not have done much more using study-level data. Co-interventions including other nutrients or vaccinations might interact with vitamin A, but we were unable to review possible interaction effects. We were also unable to compare HIV positive children to HIV negative children. Subgroup analyses by geographical region include few studies; a few studies disaggregated data by gender and age, but these were not representative of the studies overall and the results. Subgroup results were neither significant nor meaningful, and they are vulnerable to reporting bias (i.e. differences are more likely to be reported than similarities). Though a review with individual patient data could be informative, systematic reviews are not the best method for answering all questions, and other studies might explain why results are sometimes different. Furthermore, the observed effects are so large that heterogeneity may be considered unimportant; vitamin A should be given to children whether it reduces childhood mortality by 5% or 25%.

 

Quality of the evidence

The review included 43 studies and an estimated 215,633 children. This is the largest review of VAS for children to date.

The primary outcome was at low risk of bias, and the size and the significance of the effect cannot be explained by bias. While there was some evidence of small study bias for secondary outcomes, further research is unlikely to change the conclusion that VAS, delivered with high quality and coverage, prevents death among children aged 6 to 59 months in the developing world. Despite sensitivity analyses and attempts to explain sources of heterogeneity by comparing the characteristics of the studies, we could not explain reasons for these differences across trials. Observational studies might investigate the mechanisms by which vitamin A reduces mortality.

The DEVTA trial 2007, which includes more than four times the number of children in this review, found no benefit for vitamin A supplementation. However, details that might explain this difference were not available. It is possible that these relatively smaller studies were more prone to bias, but the reviewers find this explanation unlikely to explain the effect in its entirety. When the mortality data for DEVTA trial 2007 are included in the main analysis of this review, a statistically significant benefit for vitamin A is still observed, and that effect remains clinically meaningful. 

 

Potential biases in the review process

This review used clearly specified inclusion and exclusion criteria, a comprehensive search strategy for the identification of relevant studies, and subgroup and sensitivity analyses to explore heterogeneity that were specified a priori. Post-hoc decisions to include quasi-randomised trials and post-hoc analyses are noted, and sensitivity analyses demonstrate that these did not change the results.

The comprehensive search strategy was devised to minimise publication bias by searching for both published and unpublished studies, though none of the included studies were unpublished. While studies with positive results are more likely to be published than studies with negative results, studies large enough to make a difference in this review are very likely to be published. One study awaiting assessment is likely to be published soon (DEVTA trial 2007), and another was too small to affect any analysis (Aklamati 2006). The inclusion of DEVTA in a sensitivity analysis reduces the threat of publication bias and provides evidence that the main finding is robust.

Some secondary outcomes did not contain a majority of the children randomised in the review, and these results may be vulnerable to selective outcome reporting bias. 

 

Agreements and disagreements with other studies or reviews

These results are consistent with the results of other reviews assessing a similar question, though the magnitude of the reduction in risk of death was smaller. Glasziou 1993 reported a 30% reduction in all-cause mortality; Beaton 1993, a 23% reduction, and Fawzi 1993 used an odds ratio rather than risk ratio as the effect statistic so the reported reduction is not directly comparable.

This review contributes a timely update to the status of the evidence; most previous meta-analyses were conducted before publication of the trials contributing 30% of randomised children in the primary analysis. This effect was explored in a post-hoc cumulative meta-analysis which sorted the included trials by year. As reported in Beaton 1993, there was a 23% reduction in all-cause mortality by 1993 (RR = 0.77 (95% CI 0.70 to 0.85)). The trials that occurred after 1993 change the effect by only 1%.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

National and regional programmes of VAS are in place in over 70 countries worldwide and may be among the most cost-effective public health interventions (Fawzi 2006). Worldwide, more than 190 million children are vitamin A deficient; reducing their risk of mortality by 24% could save almost 1 million lives per year. These interventions respond to an immediate need for adequate nutrition, but they are not ideal long-term solutions to the underlying problem.

Fortification, food distribution programs and horticultural developments may provide more permanent relief. For example, vitamin A could be added to rice or growers may aim to increase access to agricultural products such as the orange-fleshed sweet potato (Klemm 2010). Furthermore, if vitamin A reduces mortality by preventing measles, widespread vaccination will reduce the relative contribution of vitamin A supplementation. Until such long-term solutions are in place, supplementation should continue. As access to vitamin A increases, it will be important to continue to identify at-risk groups and deliver supplements to them.

We strongly recommend vitamin A supplementation to children under 5 in areas at risk of VAD. The exact nature of how these programs should be structured and administered - the dose, frequency, and duration of intervention - are less certain. As discussed above, data on implementation for the trials included in this review (and more generally) are lacking. In the absence of this information, concrete recommendations for practice would be speculative at best. Comparative trials may be informative and policymakers should consider including such trials in plans for vitamin A distribution.

 
Implications for research

The effectiveness of VAS for preventing mortality is well-established. The primary result in this review is not meaningfully different from the results of reviews conducted in 1993. Not all studies conducted in the interim were required, and further placebo-controlled studies would be unethical. 

Nevertheless, this review does not answer a number of important questions. There was little variation in dosing among studies reporting the primary outcome. One trial used weekly doses and estimated a 54% reduction in all-cause mortality (Rahmathullah 1990). It would be ethical to conduct trials in which participants receive different doses of vitamin A that are likely to be beneficial, some of which could lead to larger benefits than those observed so far, and might lead to fewer side effects (for example, vomiting).

Reductions in mortality are likely related to reduced incidence and severity of diarrhoea. The effects of VAS on relevant pathogens and disease pathways are not well understood, and these could be examined in observational studies or in trials of other interventions for these problems.

Growth and other developmental outcomes are less important than mortality and have been studied rarely. These outcomes could be added to future versions of this review. Observational studies might elucidate the relationship (if any), between vitamin A and growth.

Despite the primary effect, observed increases in vitamin A serum levels were small, and serum results are more vulnerable to bias than the overall results. Serum level may be a poor indicator of status, and may not be related to more meaningful outcomes like mortality and blindness. On the other hand, oral supplementation may not be the best pathway for delivery. For example, absorption may be better in protein carriers compared to carbohydrate carriers. Further studies might compare synthetic supplementation to fortification or other delivery mechanisms. 

Two additional Cochrane reviews have recently investigated the effects of vitamin A during the neonatal period (Haider 2008) and for infants 1 to 6 months of age (Gogia 2008) and will be available shortly. Further reviews might investigate different delivery channels, including food supplementation, improved access to food, or social programmes to increase uptake of vitamin A rich foods.  Several studies have investigated VAS for pregnant and lactating mothers; these and other efforts to promote delivery of vitamin A (for example, by increased rates and duration of breastfeeding) may require further attention.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

We thank the Cochrane Developmental Psychosocial and Learning Problems Group, including Jo Abbott, Chris Champion and Laura MacDonald. Particularly, Margaret Anderson developed the search strategy and Geraldine Macdonald edited the review. We thank the Cochrane Editorial Unit, particularly Toby Lasserson, Rachel Murphy, and Karla Soares-Weiser for extracting data; we thank David Tovey and Harriet MacLehose for advice and for helping to manage the project. We are also grateful to Toby Lasserson for drafting the summary of findings table. Henry Ebron from DistillerSR provided assistance managing the data. We thank Julian Higgins and the Cochrane Methods Group for statistical advice and assistance. Finally, anonymous peer reviewers offered helpful feedback on the protocol and the review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Vitamin A versus Control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality (all-cause) at Longest Follow-up17Risk Ratio (Fixed, 95% CI)0.76 [0.69, 0.83]

 2 Mortality (all-cause) at Longest Follow-up (by Age)5Risk Ratio (Fixed, 95% CI)Subtotals only

    2.1 6 to 12 months old
4Risk Ratio (Fixed, 95% CI)0.59 [0.43, 0.82]

    2.2 1 to 5 years old
4Risk Ratio (Fixed, 95% CI)0.68 [0.57, 0.81]

 3 Mortality (all-cause) at Longest Follow-up (by Sex)5Risk Ratio (Fixed, 95% CI)Subtotals only

    3.1 Males
5Risk Ratio (Fixed, 95% CI)0.80 [0.66, 0.97]

    3.2 Females
5Risk Ratio (Fixed, 95% CI)0.79 [0.65, 0.95]

 4 Mortality (all-cause) at Longest Follow-up (Sensitivity Analysis including DEVTA trial)18Risk Ratio (Fixed, 95% CI)0.88 [0.84, 0.94]

 5 Mortality due to Diarrhoea at Longest Follow-up7Risk Ratio (Fixed, 95% CI)0.72 [0.57, 0.91]

 6 Mortality due to Measles at Longest Follow-up5Risk Ratio (Fixed, 95% CI)0.80 [0.51, 1.24]

 7 Mortality due to Meningitis at Longest Follow-up3Risk Ratio (Fixed, 95% CI)0.57 [0.17, 1.88]

 8 Mortality due to LRTI at Longest Follow-up7Risk Ratio (Fixed, 95% CI)0.78 [0.54, 1.14]

 9 Diarrhoea Incidence at Longest Follow-up13Risk Ratio (Fixed, 95% CI)0.85 [0.82, 0.87]

 10 Diarrhoea Prevalence at Longest Follow-up3Risk Ratio (Fixed, 95% CI)1.08 [1.05, 1.12]

 11 Measles Incidence at Longest Follow-up6Risk Ratio (Fixed, 95% CI)0.50 [0.37, 0.67]

 12 Malaria Incidence at Longest Follow-up1174132Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.60, 0.88]

 13 Malaria Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.73 [0.41, 1.28]

 14 Lower Respiratory Tract Infection Incidence at Longest Follow-up9Risk Ratio (Fixed, 95% CI)1.14 [0.95, 1.37]

 15 Bitot's Spots Prevalence at Longest Follow-up4Risk Ratio (Fixed, 95% CI)0.45 [0.33, 0.61]

 16 Night Blindness Incidence at Longest Follow-up1Risk Ratio (Fixed, 95% CI)0.53 [0.28, 0.99]

 17 Night Blindness Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.32 [0.21, 0.50]

 18 Xerophthalmia Incidence at Longest Follow-up3Risk Ratio (Fixed, 95% CI)0.85 [0.70, 1.03]

 19 Xerophthalmia Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.31 [0.22, 0.45]

 20 Vitamin A Deficient at Longest Follow-up42262Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.65, 0.78]

 21 Vitamin A Serum Level at Longest Follow-up146623Std. Mean Difference (IV, Fixed, 95% CI)0.31 [0.26, 0.36]

 22 Hospitalisation, Number of Children Hospitalised Once or More at Longest Follow-up11185Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.40, 1.02]

 23 Hospitalisation due to Diarrhoea at Longest Follow-up1172Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.01, 6.11]

 24 Hospitalisation due to Lower Respiratory Tract Infection at Longest Follow-up1172Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.06]

 25 Side effect - Bulging Fontanelle3885Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.24, 103.72]

 26 Side effect - Vomiting32994Risk Ratio (M-H, Fixed, 95% CI)2.75 [1.81, 4.19]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Search strategies

MEDLINE (1950 to April Week 2 2010)

1     exp infant/ or exp child/ or exp child, preschool/

2     (baby or babies or infant$ or toddler$ or child$ or girl$ or boy$ or pre school$ or pre-school$ or preschool$).tw.

3     1 or 2

4     exp Vitamin A/

5     (retinol$ or retinal$ or aquasol a or vitamin a).ab,ti.

6     4 or 5

7     randomised controlled trial.pt.

8     controlled clinical trial.pt.

9     randomized.ab.

10     placebo.ab.

11     drug therapy.fs.

12     randomly.ab.

13     trial.ab.

14     groups.ab.

15     7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

16     exp animals/ not humans.sh.

17     15 not 16

18     3 and 6 and 17

Global Health (1973 to March 2010)

For the search of Global Health database, replacement subject headings mapped to the Global Health database were used when possible, otherwise the text was used similar to the MEDLINE searches conducted previously.

1     exp school children/ or exp children/ or exp preschool children/

2     (baby or babies or infant$ or toddler$ or child$ or girl$ or boy$ or pre school$ or pre-school$ or preschool$).tw.

3     1 or 2

4     retinol.sh.

5     (retinol$ or retinal$ or aquasol a or vitamin a).ab,ti.

6     4 or 5

7     exp randomized controlled trials/ or exp clinical trials/

8     random*.mp.

9     placebo.mp.

10     trial.mp.

11     7 or 8 or 9 or 10

12     3 and 6 and 11

EMBASE (1980 to 2010 Week 16)

EMTREE index terms were used when possible.  The UK Cochrane Centre’s suggested combination of EMTREE and free text words were used to search for randomized-controlled trials. 

1     exp infant/ or exp child/ or exp child, preschool/

2     (baby or babies or infant$ or toddler$ or child$ or girl$ or boy$ or pre school$ or pre-school$ or preschool$).tw.

3     1 or 2

4     exp Vitamin A/

5     (retinol$ or retinal$ or aquasol a or vitamin a).ab,ti.

6     4 or 5

7     exp crossover-procedure/ or exp double-blind procedure/ or exp randomized controlled trial/ or exp single-blind procedure/

8     (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).mp.

9     7 or 8

10     3 and 6 and 9

The Cochrane Central Register of Controlled Trials (CENTRAL) 27 April 2010

#1        MeSH descriptor Child explode all trees

#2        MeSH descriptor Infant explode all trees

#3        MeSH descriptor Child, Preschool explode all trees

#4        (baby or babies or infant* or toddler* or child* or (pre next school*) or preschool* or girl* or boy*):ti,ab,kw

#5        (#1 OR #2 OR #3 OR #4)

#6        MeSH descriptor Vitamin A explode all trees

#7        retinol* or retinal$ or “aquasol a” or “vitamin a”

#8        (#6 OR #7)

#9        (#5 AND #8)

Latino Americana e do Caribe em Ciências da Saúde (LILACS) 27 April 2010

Mh vitamin a or tw retinol$ or tw aquasol$ or tw retinal$ [Words] AND [Tw baby or Tw babies or Tw child$ or Tw infant$ or Tw toddler$ or Tw girl$ or Tw boy$ or Tw prescshool$ or Tw pre-school$ or Tw niño or Tw niños or Tw niña or Tw niñas or Tw bebé or Tw bebés or Tw preescolar or Tw prescolares [Words]

AND ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]

African Index Medicus 27 April 2010

1. retinol$ or retinal$ or aquasol a or vitamin a [Descriptor] 

metaRegister of Controlled Trials 27 April 2010

(baby or babies or infant  or child) and (vitamin a or aquasol or retinol or retinal)

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 26 October 2010.


DateEventDescription

7 December 2010AmendedEdited to correct typographical errors and improve readability.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 5, 2010
Review first published: Issue 12, 2010

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

AI and EMW contributed to the background. EMW, KH and AI were primarily responsible for the methods. Margaret Anderson (from CDPLPG) developed the search strategy and KH conducted the literature search. AI, YY and KH reviewed citations for inclusion, disagreements were resolved through consultation with EMW.  AI, KH, YY and EMW extracted data with three members from the Cochrane Editorial Unit (Toby Lasserson, Rachel Murphey, and Karla Soares-Weiser). KH and EMW entered outcome data into RevMan, analysed the data and wrote results. AI made the included studies and risk of bias tables. KH, EMW and AI contributed to writing the discussion. Toby Lasserson drafted the summary of findings table, which was agreed by all authors. ZB provided supervision and contributed to the writing and analyses.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • Aamer Imdad, Mohammad Yawar Yakoob and Zulfiqar A Bhutta are supported by Aga Khan University, Karachi, Pakistan.
  • Kurt Herzer and Evan Mayo-Wilson are supported by the Centre for Evidence-Based Intervention, University of Oxford, UK.

 

External sources

  • Funding for the review was provided by Department of Nutrition for Health and Development, World Health Organization, Switzerland.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

1) Sensitivity analyses are performed only for all-cause mortality, diarrhoea incidence and vitamin A serum levels.

2) Post-hoc analyses were performed for Imputed ICC and studies awaiting assessment.

3) Subgroup analysis based on baseline HIV status was not performed as none of the included studies gave a baseline status of study population on HIV and we excluded studies conducted on children with HIV.

4) Post-hoc, we included two studies in which participants were assigned using a quasi-random method.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractResumenRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
Agarwal 1995 {published data only}
  • Agarwal DK, Pandey CM, Agarwal KN. Vitamin A administration and preschool child mortality. Nutrition Research. Nutrition Research. 15(5)(pp 669-680), 1995. Date of Publication: 1995., 1995; Vol. 15, issue 5:669-80. [: 0271-5317]
Arya 2000 {published data only}
  • Arya S, Chellani H, Pandey J. Evaluation of safety of oral vitamin 'A' megadose co-administered with measles vaccination. Indian Pediatrics . 2000/12/19 2000; Vol. 37, issue 12:1341-7. [0019-6061: (Print)]
Bahl 1999 {published data only}
  • Bahl R, Kumar R, Bhandari N, Kant S, Srivastava R, Bhan MK. Vitamin A administered with measles vaccine to nine-month-old infants does not reduce vaccine immunogenicity. Journal of Nutrition 1999; Vol. 129, issue 8:1569-73. [: 0022-3166]
Barreto 1994 {published data only}
  • Andreozzi VL, Bailey TC, Nobre FF, Struchiner CJ, Barreto ML, Assis AM, et al. Random-effects models in investigating the effect of vitamin A in childhood diarrhea. Annals of Epidemiology 2006; Vol. 16, issue 4:241-7. [: 1047-2797]
  • Barreto ML, Santos LM, Assis AM, Araujo MP, Farenzena GG, Santos PA, et al. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 1994; Vol. 344, issue 8917:228-31. [: 0140-6736]
Benn 1997 {published data only}
  • Benn CS, Aaby P, Bale C, Olsen J, Michaelsen KF, George E, et al. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, west Africa. Lancet 1997; Vol. 350, issue 9071:101-5. [: 0140-6736]
  • Benn CS, Lisse IM, Bale C, Michaelsen KF, Olsen J, Hedegaard K, et al. No strong long-term effect of vitamin A supplementation in infancy on CD4 and CD8 T-cell subsets. A community study from Guinea-Bissau, West Africa. Annals of Tropical Paediatrics 2000; Vol. 20, issue 4:259-64. [: 0272-4936]
Biswas 1994 {published data only}
  • Biswas R, Biswas AB, Manna B, Bhattacharya SK, Dey R, Sarkar S. Effect of vitamin A supplementation on diarrhoea and acute respiratory tract infection in children. A double blind placebo controlled trial in a Calcutta slum community. European Journal of Epidemiology 1994, issue 1:57-61.
Cheng 1993 {published data only}
  • Cheng L, Chang Y, Wang EL, Brun T, Geissler C. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. European Journal of Clinical Nutrition 1993; Vol. 47, issue 2:88-96. [: 0954-3007]
Cherian 2003 {published data only}
  • Cherian T, Sneha V, Raghupathy P, Ratnam S, Chandra RK. Effect of vitamin A supplementation on the immune response to measles vaccination. Vaccine 2003; Vol. 21, issue 19:2418-20. [: 0264-410X]
Chowdhury 2002 {published data only}
  • Chowdhury S, Kumar R, Ganguly NK, Kumar L, Walia BN. Effect of vitamin A supplementation on childhood morbidity and mortality. Indian Journal of Medical Sciences 2002, issue 6:259-64.
Daulaire 1992 {published data only}
  • Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992; Vol. 304, issue 6821:207-10. [: 0959-8138]
DEVTA 2007 {published data only}
  • See Studies awaiting classification.
Dibley 1994 {published data only}
  • Dibley MJ, Sadjimin T, Kjolhede CL, Moulton LH. Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. Journal of Nutrition 1996; Vol. 126, issue 2:434-42. [: 0022-3166]
  • Hadi H, Dibley MJ, West KP. Complex interactions with infection and diet may explain seasonal growth responses to vitamin A in preschool aged Indonesian children. European Journal of Clinical Nutrition 2004, issue 7:990-9.
  • Hadi H, Stoltzfus RJ, Dibley MJ, Moulton LH, West KP Jr, Kjolhede CL, et al. Vitamin A supplementation selectively improves the linear growth of Indonesian preschool children: results from a randomized controlled trial. American Journal of Clinical Nutrition 2000; Vol. 71, issue 2:507-13. [: 0002-9165]
  • Hadi H, Stoltzfus RJ, Moulton LH, Dibley MJ, West KP Jr. Respiratory infections reduce the growth response to vitamin A supplementation in a randomized controlled trial. International Journal of Epidemiology 1999; Vol. 28, issue 5:874-81. [: 0300-5771]
Donnen 1998 {published data only}
  • Donnen P, Brasseur D, Dramaix M, Vertongen F, Zihindula M, Muhamiriza M, et al. Vitamin A supplementation but not deworming improves growth of malnourished preschool children in eastern Zaire. Journal of Nutrition 1998; Vol. 128, issue 8:1320-7. [: 0022-3166]
  • Donnen P, Dramaix M, Brasseur D, Zihindula M, Muhamiriza M, Hennart P. Malnourished children morbidity following vitamin A supplementation or deworming in Democratic Republic of Congo. Archives of Public Health 1998; Vol. 56, issue 3:109-24. [: 0003-9578]
Florentino 1990 {published data only}
  • Florentino RF, Tanchoco CC, Ramos AC, Mendoza TS, Natividad EP, Tangco JB, et al. Tolerance of preschoolers to two dosage strengths of vitamin A preparation. American Journal of Clinical Nutrition 1990; Vol. 52, issue 4:694-700. [: 0002-9165]
Herrera 1992 {published data only}
  • Fawzi WW, Herrera MG, Willett WC, el Amin A, Nestel P, Lipsitz S, et al. Vitamin A supplementation and dietary vitamin A in relation to the risk of xerophthalmia. American Journal of Clinical Nutrition. American Journal of Clinical Nutrition. 58(3)(pp 385-391), 1993. Date of Publication: 1993., 1993; Vol. 58, issue 3:385-91. [: 0002-9165]
  • Fawzi WW, Herrera MG, Willett WC, Nestel P, el Amin A, Lipsitz S, et al. Dietary vitamin A intake and the risk of mortality among children. American Journal of Clinical Nutrition 1994; Vol. 59, issue 2:401-8. [: 0002-9165]
  • Fawzi WW, Herrera MG, Willett WC, Nestel P, el Amin A, Mohamed KA. Dietary vitamin A intake and the incidence of diarrhea and respiratory infection among Sudanese children. Journal of Nutrition. 1995/05/01 1995; Vol. 125, issue 5:1211-21. [0022-3166: (Print)]
  • Fawzi WW, Herrera MG, Willett WC, Nestel P, el Amin A, Mohamed KA. The effect of vitamin A supplementation on the growth of preschool children in the Sudan. American Journal of Public Health 1997; Vol. 87, issue 8:1359-62. [: 0090-0036]
  • Herrera MG, Nestel P, el Amin A, Fawzi WW, Mohamed KA, Weld L. Vitamin A supplementation and child survival. Lancet 1992; Vol. 340, issue 8814:267-71. [: 0140-6736]
Kartasasmita 1995 {published data only}
  • Kartasasmita CB, Rosmayudi O, Deville W, Demedts M. Plasma retinol level, vitamin A supplementation and acute respiratory infections in children of 1-5 years old in a developing country. Tubercle and Lung Disease 1995; Vol. 76, issue 6:563-9. [: 0962-8479]
Lima 2010 {published data only}
  • Lima AA, Soares AM, Lima NL, Mota RM, Maciel BL, Kvalsund MP, et al. Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial. Journal of Pediatric Gastroenterology & Nutrition 2010; Vol. 50, issue 3:309-15.
Lin 2008 {published data only}
  • Lin J, Song F, Yao P, Yang X, Li N, Sun S, et al. Effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency in China. European Journal of Clinical Nutrition 2008, issue 12:1412-8.
Lin 2009 {published data only}
  • Lin J, Lai X, Qin J, Song F, Zhang Y, Yao P, et al. Effect of beta-carotene supplementation on health and growth of vitamin A deficient children in China rural villages: A randomized controlled trial. e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 2009;4(1):e17-e21. [: 1751-4991]
Long 2006 {published data only}
  • Long KZ, Montoya Y, Hertzmark E, Santos JI, Rosado JL. A double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico. American Journal of Clinical Nutrition 2006; Vol. 83, issue 3:693-700. [: 0002-9165]
  • Rosado JL, Caamano MC, Montoya YA, Solano MdL, Santos JI, Long KZ. Interaction of zinc or vitamin A supplementation and specific parasite infections on Mexican infants' growth: a randomized clinical trial. European Journal of Clinical Nutrition 2009; Vol. 63, issue 10:1176-84. [: 0954-3007]
Long 2006 (2) {published data only}
  • As above.
Long 2007 {published data only}
  • Long KZ, Estrada-Garcia T, Rosado JL, Santos JI, Haas M, Firestone M, et al. The effect of vitamin A supplementation on the intestinal immune response in Mexican children is modified by pathogen infections and diarrhea. Journal of Nutrition 2006; Vol. 136, issue 5:1365-70. [: 0022-3166]
  • Long KZ, Rosado JL, DuPont HL, Hertzmark E, Santos JI. Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children. British Journal of Nutrition 2007; Vol. 97, issue 2:337-43. [: 0007-1145]
  • Long KZ, Santos JI, Rosado JL, Lopez-Saucedo C, Thompson-Bonilla R, Abonce M, et al. Impact of vitamin A on selected gastrointestinal pathogen infections and associated diarrheal episodes among children in Mexico City, Mexico. Journal of Infectious Diseases 2006; Vol. 194, issue 9:1217-25. [: 0022-1899]
Pant 1996 {published data only}
  • Pant CR, Pokharel GP, Curtale F, Pokhrel RP, Grosse RN, Lepkowski J, et al. Impact of nutrition education and mega-dose vitamin A supplementation on the health of children in Nepal. Bulletin of the World Health Organization 1996; Vol. 74, issue 5:533-45. [: 0042-9686]
  • Pokharel GP, Pant CR, Tilden RL, Pokhrel RP, Atmarita, Curtale F. Nutrition education and mega-dose vitamin A supplementation in Nepal. Indian Journal of Pediatrics 1998; Vol. 65, issue 4:547-55. [: 0019-5456]
Pinnock 1986 {published data only}
  • Pinnock CB, Douglas RM, Badcock NR. Vitamin A status in children who are prone to respiratory tract infections. Australian Paediatric Journal. 1986/05/01 1986; Vol. 22, issue 2:95-9. [0004-993X: (Print)]
Pinnock 1988 {published data only}
  • Pinnock CB, Douglas RM, Martin AJ, Badcock NR. Vitamin A status of children with a history of respiratory syncytial virus infection in infancy. Australian Paediatric Journal. 1988/10/01 1988; Vol. 24, issue 5:286-9. [0004-993X: (Print)]
Rahman 2001 {published data only}
  • Rahman MM, Fahmida T, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Short-term supplementation with zinc and vitamin A has no significant effect on the growth of undernourished Bangladeshi children. American Journal of Clinical Nutrition 2002; Vol. 75, issue 1:87-91. [: 0002-9165]
  • Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ 2001; Vol. 323, issue 7308:314-8. [: 0959-8138]
  • Rahman MM, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Synergistic effect of zinc and vitamin A on the biochemical indexes of vitamin A nutrition in children. American Journal of Clinical Nutrition 2002; Vol. 75, issue 1:92-8. [: 0002-9165]
Rahmathullah 1990 {published data only}
  • Rahmathullah L. Effect of receiving a weekly dose of vitamin A equivalent to the recommended dietary allowances among pre school children on mortality in south India. Indian Journal of Pediatrics 1991, issue 6:837-47.
  • Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC. Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. American Journal of Clinical Nutrition 1991; Vol. 54, issue 3:568-77. [: 0002-9165]
  • Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. New England Journal of Medicine 1990; Vol. 323, issue 14:929-35. [: 0028-4793]
  • Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, et al. Vitamin a supplementation reduces childhood mortality. National Medical Journal of India 1991; Vol. 4, issue 4:187-9.
Ramakrishnan 1995 {published data only}
  • Ramakrishnan U, Latham MC, Abel R. Vitamin A supplementation does not improve growth of preschool children: a randomized, double-blind field trial in south India. Journal of Nutrition 1995; Vol. 125, issue 2:202-11. [: 0022-3166]
  • Ramakrishnan U, Latham MC, Abel R, Frongillo EA Jr. Vitamin A supplementation and morbidity among preschool children in South India. American Journal of Clinical Nutrition 1995; Vol. 61, issue 6:1295-303. [: 0002-9165]
Ranjini 2001 {published data only}
  • Ranjini EK, Cherian T, Balasubramaniam KA, Raghupathy P. Vitamin A supplementation in children with recurrent respiratory infections. Indian Pediatrics 2001; Vol. 38, issue 7:771-4. [: 0019-6061]
Reddy 1986 {published data only}
  • Reddy V, Vijayaraghavan K, Mathur KK. Effect of deworming and vitamin A administration on serum vitamin A levels in preschool children. Journal of Tropical Pediatrics 1986; Vol. 32, issue 4:196-9. [: 0142-6338]
Reddy 1986 (2) {published data only}
  • As above.
Ross 1993 HEALTH {published data only}
  • Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial. American Journal of Clinical Nutrition 2009; Vol. 90, issue 3:629-39.
  • Binka FN, Ross DA, Morris SS, Kirkwood BR, Arthur P, Dollimore N, et al. Vitamin A supplementation and childhood malaria in northern Ghana. American Journal of Clinical Nutrition 1995; Vol. 61, issue 4:853-9. [: 0002-9165]
  • Dollimore N, Cutts F, Binka FN, Ross DA, Morris SS, Smith PG. Measles incidence, case fatality, and delayed mortality in children with or without vitamin A supplementation in rural Ghana. American Journal of Epidemiology 1997; Vol. 146, issue 8:646-54. [: 0002-9262]
  • Filteau SM, Morris SS, Raynes JG, Arthur P, Ross DA, Kirkwood BR, et al. Vitamin A supplementation, morbidity, and serum acute-phase proteins in young Ghanaian children. American Journal of Clinical Nutrition 1995; Vol. 62, issue 2:434-8. [: 0002-9165]
  • Filteau SM, Morris SS, Tomkins AM, Arthur P, Kirkwood BR, Ross DA, et al. Lack of association between vitamin A status and measures of conjunctival epithelial integrity in young children in northern Ghana. European Journal of Clinical Nutrition 1994; Vol. 48, issue 9:669-77. [: 0954-3007]
  • Kirkwood BR, Ross DA, Arthur P, Morris SS, Dollimore N, Binka FN, et al. Effect of vitamin A supplementation on the growth of young children in northern Ghana. American Journal of Clinical Nutrition 1996; Vol. 63, issue 5:773-81. [: 0002-9165]
  • Kirkwood BR, Ross DA, Arthur P, Morris SS, Dollimore N, Binka FN, et al. Effect of vitamin A supplementation on the growth of young children in northern Ghana. Early Human Development 1996, issue 3:279.
  • Ross DA, Binka FN, Dollimore N, Smith PG, Addy HA, Tomkins AM, et al. Vitamin A supplementation in northern Ghana: Effects on clinic attendances, hospital admissions, and child mortality. Lancet. Lancet. 342(8862)(pp 7-12), 1993. Date of Publication: 1993., 1993; Vol. 342, issue 8862:7-12. [: 0140-6736]
  • Ross DA, Kirkwood BR, Binka FN, Arthur P, Dollimore N, Morris SS, et al. Child morbidity and mortality following vitamin A supplementation in Ghana: time since dosing, number of doses, and time of year. American Journal of Public Health 1995; Vol. 85, issue 9:1246-51. [: 0090-0036]
Ross 1993 SURVIVAL {published data only}
  • Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial. American Journal of Clinical Nutrition 2009; Vol. 90, issue 3:629-39.
  • Binka FN, Ross DA, Morris SS, Kirkwood BR, Arthur P, Dollimore N, et al. Vitamin A supplementation and childhood malaria in northern Ghana. American Journal of Clinical Nutrition 1995; Vol. 61, issue 4:853-9. [: 0002-9165]
  • Dollimore N, Cutts F, Binka FN, Ross DA, Morris SS, Smith PG. Measles incidence, case fatality, and delayed mortality in children with or without vitamin A supplementation in rural Ghana. American Journal of Epidemiology 1997; Vol. 146, issue 8:646-54. [: 0002-9262]
  • Filteau SM, Morris SS, Raynes JG, Arthur P, Ross DA, Kirkwood BR, et al. Vitamin A supplementation, morbidity, and serum acute-phase proteins in young Ghanaian children. American Journal of Clinical Nutrition 1995; Vol. 62, issue 2:434-8. [: 0002-9165]
  • Filteau SM, Morris SS, Tomkins AM, Arthur P, Kirkwood BR, Ross DA, et al. Lack of association between vitamin A status and measures of conjunctival epithelial integrity in young children in northern Ghana. European Journal of Clinical Nutrition 1994; Vol. 48, issue 9:669-77. [: 0954-3007]
  • Kirkwood BR, Ross DA, Arthur P, Morris SS, Dollimore N, Binka FN, et al. Effect of vitamin A supplementation on the growth of young children in northern Ghana. American Journal of Clinical Nutrition 1996; Vol. 63, issue 5:773-81. [: 0002-9165]
  • Kirkwood BR, Ross DA, Arthur P, Morris SS, Dollimore N, Binka FN, et al. Effect of vitamin A supplementation on the growth of young children in northern Ghana. Early Human Development 1996, issue 3:279.
  • Ross DA, Binka FN, Dollimore N, Smith PG, Addy HA, Tomkins AM, et al. Vitamin A supplementation in northern Ghana: Effects on clinic attendances, hospital admissions, and child mortality. Lancet. Lancet. 342(8862)(pp 7-12), 1993. Date of Publication: 1993., 1993; Vol. 342, issue 8862:7-12. [: 0140-6736]
  • Ross DA, Kirkwood BR, Binka FN, Arthur P, Dollimore N, Morris SS, et al. Child morbidity and mortality following vitamin A supplementation in Ghana: time since dosing, number of doses, and time of year. American Journal of Public Health 1995; Vol. 85, issue 9:1246-51. [: 0090-0036]
Semba 1992 {published data only}
  • Semba R, Muhilal, Scott A, Natadisastra G, Wirasasmita S, Griffin D, et al. Immune status in children with mild vitamin A deficiency in Indonesia. Investigative Ophthalmology and Visual Science 1991.
  • Semba RD, Muhilal, Scott AL, Natadisastra G, West KP, Sommer A. Effect of vitamin A supplementation on immunoglobulin G subclass responses to tetanus toxoid in children. Clinical and Diagnostic Laboratory Immunology 1994, issue 2:172-5.
  • Semba RD, Muhilal, Scott AL, Natadisastra G, Wirasasmita S, Mele L, et al. Depressed immune response to tetanus in children with vitamin A deficiency. Journal of Nutrition. 1992/01/11 1992; Vol. 122, issue 1:101-7. [0022-3166: (Print)]
  • Semba RD, Muhilal MPH, West KP Jr. Impact of vitamin A supplementation on hematological indicators of iron metabolism and protein status in children. Nutrition Research 1992; Vol. 12, issue 4:469-78. [: 0271-5317]
Semba 1995 {published data only}
  • Semba RD, Munasir Z, Beeler J, Akib A, Muhilal, Audet S, et al. Reduced seroconversion to measles in infants given vitamin A with measles vaccination. Lancet. 1995/05/27 1995; Vol. 345, issue 8961:1330-2. [0140-6736: (Print)]
Sempertegui 1999 {published data only}
  • Sempertegui F, Estrella B, Camaniero V, Betancourt V, Izurieta R, Ortiz W, et al. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Pediatrics 1999; Vol. 104, issue 1.
Shankar 1999 {published data only}
  • Shankar AH, Genton B, Semba RD, Baisor M, Paino J, Tamja S, et al. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial. Lancet 1999, issue 9174:203-9.
Sinha 1976 {published data only}
  • Sinha DP, Bang FB. The effect of massive doses of vitamin A on the signs of vitamin A deficiency in preschool children. American Journal of Clinical Nutrition 1976; Vol. 29, issue 1:110-5. [: 0002-9165]
Smith 1999 {published data only}
  • Smith JC, Makdani D, Hegar A, Rao D, Douglass LW. Vitamin A and zinc supplementation of preschool children. Journal of the American College of Nutrition 1999; Vol. 18, issue 3:213-22. [: 0731-5724]
Sommer 1986 {published data only}
  • Abdeljaber MH, Monto AS, Tilden RL, Schork MA, Tarwotjo I. The impact of vitamin A supplementation on morbidity: a randomized community intervention trial. American Journal of Public Health 1991; Vol. 81, issue 12:1654-6. [: 0090-0036]
  • Djunaedi E, Sommer A, Pandji A, Kusdiono, Taylor HR. Impact of vitamin A supplementation on xerophthalmia. A randomized controlled community trial. Archives of Ophthalmology 1988; Vol. 106, issue 2:218-22. [: 0003-9950]
  • Sommer A, Tarwotjo I, Djunaedi E, West KP Jr, Loeden AA, et al. Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet 1986; Vol. 8491, issue 31.
  • Tielsch JM, West KP. Cost and efficiency considerations in community-based trials of vitamin A in developing countries. Statistics in medicine 1990; Vol. 9, issue 1-2:35-41; discussion 41-3.
  • West KP Jr, Djunaedi E, Pandji A. Vitamin A supplementation and growth: a randomized community trial. American Journal of Clinical Nutrition 1988; Vol. 48, issue 5:1257-64. [: 0002-9165]
Stabell 1995 {published data only}
  • Stabell C, Bale C, Pedro da Silva A, Olsen J, Aaby P. No evidence of fontanelle-bulging episodes after vitamin A supplementation of 6- and 9-month-old infants in Guinea Bissau. European Journal of Clinical Nutrition 1995; Vol. 49, issue 1:73-4. [: 0954-3007]
Stansfield 1993 {published data only}
  • Stansfield SK, Muller PL, Lerebours G, Augustin A. Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections. Lancet 1993; Vol. 342, issue 8871:578-82. [: 0140-6736]
van Agtmaal 1988 {published data only}
  • van Agtmaal EJ, Bloem MW, Speek AJ, Saowakontha S, Schreurs HP, van Haeringen NJ. The effect of vitamin A supplementation on tear fluid retinol levels of marginally nourished preschool children. Current Eye Research 1988;7(1):43-8.
Venkatarao 1996 {published data only}
  • Venkatarao T, Ramakrishnan R, Nair NG, Radhakrishnan S, Sundaramoorthy L, Koya PK, et al. Effect of vitamin A supplementation to mother and infant on morbidity in infancy. Indian Pediatrics 1996; Vol. 33, issue 4:279-86. [: 0019-6061]
Vijayaraghavan 1990 {published data only}
  • Vijayaraghavan K, Radhaiah G, Surya Prakasam B, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990; Vol. 336, issue 8727:1342-5. [: 0140-6736]
West 1991 {published data only}
  • Bishai D, Kumar KCS, Waters H, Koenig M, Katz J, Khatry SK, et al. The impact of vitamin A supplementation on mortality inequalities among children in Nepal. Health Policy and Planning 2005; Vol. 20, issue 1:60-6. [: 0268-1080]
  • Katz J, West KP Jr, Khatry SK, Thapa MD, LeClerq SC, Pradhan EK, et al. Impact of vitamin A supplementation on prevalence and incidence of xerophthalmia in Nepal. Investigative Ophthalmology and Visual Science 1995; Vol. 36, issue 13:2577-83. [: 0146-0404]
  • Pokhrel RP, Khatry SK, West KP, Shrestha SR, Katz J, Pradhan EK, et al. Sustained reduction in child mortality with vitamin A in Nepal. Lancet 1994, issue 8909:1368-9.
  • Shih JH, Lu SE. Analysis of failure time data with multilevel clustering, with application to the child vitamin a intervention trial in Nepal. Biometrics 2007; Vol. 63, issue 3:673-80. [: 0006-341X]
  • West KP Jr, LeClerq SC, Shrestha SR, Wu LSF, Pradhan EK, Khatry SK, et al. Effects of vitamin A on growth of vitamin A-deficient children: Field studies in Nepal. Journal of Nutrition 1997; Vol. 127, issue 10:1957-65. [: 0022-3166]
  • West KP Jr, Pokhrel RP, Katz J, LeClerq SC, Khatry SK, Shrestha SR, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; Vol. 338, issue 8759:67-71. [: 0140-6736]

References to studies excluded from this review

  1. Top of page
  2. AbstractResumenRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
Bahl 1997 {published data only}
  • Bahl R, Bhandari N, Taneja S, Bhan MK. The impact of vitamin A supplementation on physical growth of children is dependent on season. European Journal of Clinical Nutrition. 1997/01/01 1997; Vol. 51, issue 1:26-9. [0954-3007: (Print)]
Bhaskaram 1997 {published data only}
  • Bhaskaram P, Rao KV. Enhancement in seroconversion to measles vaccine with simultaneous administration of vitamin A in 9-months-old Indian infants. Indian Journal of Pediatrics. 1997/07/01 1997; Vol. 64, issue 4:503-9. [0019-5456: (Print)]
Bloem 1990 {published data only}
  • Bloem MW, Wedel M, Agtmaal EJ, Speek AJ, Saowakontha S, Schreurs WHP. Vitamin A intervention: short-term effects of a single, oral, massive dose on iron metabolism. American Journal of Clinical Nutrition 1990; Vol. 51, issue 1:76-9. [: 0002-9165]
Kothari 1991 {published data only}
  • Kothari G. The Effect of Vitamin A Prophylaxis on Morbidity and Mortality Among Children in Urban Slums in Bombay. Journal of Tropical Pediatrics 1991; Vol. 37:141.
Semba 1990 {published data only}
  • Semba RD, Wirasasmita S, Natadisastra G, Muhilal, Sommer A. Response of Bitot's spots in preschool children to vitamin A treatment. American Journal of Ophthalmology. 1990/10/15 1990; Vol. 110, issue 4:416-20. [0002-9394: (Print)]
Semba 2005 {published data only}
  • Semba RD, Ndugwa C, Perry RT, Clark TD, Jackson JB, Melikian G, et al. Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: A controlled clinical trial. Nutrition. 2005/01/22 2005; Vol. 21, issue 1:25-31. [0899-9007: (Print)]
Wu 2007 {published data only}
  • Z. Wu, L. Lin, Ouyang L. Impact of vitamin A on the immune function of infants. China Tropical Medicine 2007;7(4):540-1.
Yang 2002 {published data only}
  • Yang YX, Han JH, Shao XP, He M, Bian LH, Wang Z, et al. Effect of micronutrient supplementation on the growth of preschool children in China. Biomedical and Environmental Sciences. 2002/12/26 2002; Vol. 15, issue 3:196-202. [0895-3988: (Print)]

References to studies awaiting assessment

  1. Top of page
  2. AbstractResumenRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
Aklamati 2006 {published data only}
  • Aklamati E, Brown KH, Mulenga M, Kafwembe E, Peerson JM, Stephensen C, et al. Impact of high-dose vitamin A supplements on vitamin A status of 3-4 year old Zambian boys. FASEB Journal 2006; Vol. 20, issue 5, Part 2.
DEVTA trial 2007 {published data only}
  • Awasthi S, Peto R, Bundy D, Read S, Kourellias K, Clark S, et al. Six-monthly vitamin A supplementation from 1 to 6 years of age. Abstract of talk at ILSI Micronutrient Forum, Istanbul, 16-18 April 2007. http://www.ctsu.ox.ac.uk/projects/devta/index_html.

Additional references

  1. Top of page
  2. AbstractResumenRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
Alvarez 1995
  • Alvarez JO, Salazar-Lindo E, Kohatsu J, Miranda P, Stephensen CB. Urinary excretion of retinol in children with acute diarrhoea. American Journal of Clinical Nutrition 1995;61(6):1273-6.
Bates 1995
Beaton 1993
  • Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, et al. Effectiveness of Vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN State of the Art Series, Nutrition 1993;Policy Discussion Paper:No. 13.
Bello 2009
Benn 2003
  • Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines?. International Journal of Epidemiology. 2003/10/16 2003; Vol. 32, issue 5:822-8. [0300-5771: (Print)]
Chen 2008
Darlow 2007
Fawzi 1993
Fawzi 2006
Glasziou 1993
Gogia 2008
Gogia 2008a
  • Gogia S, Sachdev HPS. Web Appendix 10. Review of vitamin A supplementation in pregnancy and childhood. In: Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008;371(9610):417-40.
Green 1928
  • Green H, Mellanby E. Vitamin A as an anti-infective agent. British Medical Journal 1928;2:691-6.
Haider 2008
Haskell 1999
Hathcock 1997
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
Imdad 2010
  • Imdad A, Yakoob MY, Haider BA, Bhutta ZA. Preventive and Therapeutic Effects of Vitamin A Supplementation on Infant and Childhood Morbidity and Mortality: A Systematic Review. In: Bhutta ZA editor(s). Nutrition Interventions for Maternal and Child Health and Survival. Vol. 1, Oxford University Press, 2010:125-39.
Kirkwood 2010
  • Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet 2010;6737(10):61895-8.
Klemm 2009
  • Klemm RD, West KJ, Tielsh J, Wu L, Katz J. Pooled analysis of Asian newborn vitamin A supplementation trials to assess differential effects of early infant mortality. Micronutrients, health and development: Evidence-based programs. Beijing, China, 2009.
Klemm 2010
  • Klemm RD, West KP Jr, Palmer AC, Johnson Q, Randall P, Ranum P, et al. Vitamin A fortification of wheat flour: considerations and current recommendations. Food and Nutrition Bulletin 2010;31(1 Suppl):S47-61.
Latham 2010
  • Latham M. The great vitamin A fiasco. World Nutrition May 2010;1(1):12-45.
Mayo-Wilson 2007
  • Mayo-Wilson E. Reporting implementation in randomized trials: proposed additions to the consolidated standards of reporting trials statement. American Journal of Public Health. 2007/03/03 2007; Vol. 97, issue 4:630-3. [1541-0048: (Electronic)]
Mitra 1998
  • Mitra AK, Alvarez JO, Guay-Woodford L, Fuchs GJ, Wahed MA, Stephenson CB. Urinary retinol excretion and kidney function in children with shigellosis. American Journal of Clinical Nutrition 1998;68(5):1095-103.
Ni 2005
  • Ni J, Wei J, Wu T. Vitamin A for non-measles pneumonia in children. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: 10.1002/14651858.CD003700.pub2]
Oliveira 2006
Ramakrishnan 2002
  • Ramakrishnan U, Darnton-Hill I. Assessment and control of vitamin A deficiency disorders. Journal of Nutrition 2002;132(9 Suppl):2947-53.
RevMan 2008
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
Rice 2004
  • Rice AL, West KP Jr, Black RE. Vitamin A deficiency. In: Global and regional burden of disease attributable to selected major risk factors. Vol. 1, Geneva: World Health Organization, 2004.
Rotondi 2010
  • Rotondi MA, Khobzi N. Vitamin A supplementation and neonatal mortality in the developing world: a meta-regression of cluster-randomized trials. Bulletin of the World Health Organization 2010;88(9):697-702.
Semba 1999
Shenai 1993
  • Shenai JP. Vitamin A. In: Tsang RC, Lucas A, Uauy R editor(s). Nutritional needs of the preterm infant: scientific basis and practical guidelines. Baltimore: Williams and Williams, 1993:87-100.
Smith 1976
Sommer 1996
  • Sommer A, West KP Jr. Vitamin A deficiency: Health, Survival and Vision. New York: Oxford University Press, 1996.
Sommer 2002
  • Sommer A, Davidson FR. Assessment and Control of Vitamin A Deficiency: The Annecy Accords. Journal of Nutrition 2002;132(9):2845-50.
US Institute of Medicine, Food and Nutrition Board
  • US Institute of Medicine, Food, Nutrition Board. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington DC: National Academy Press, 2000.
van den Broek 2002
Villamor 2000
  • Villamor E, Fawzi WW. Vitamin A supplementation: implications for morbidity and mortality in children. Journal of Infectious Diseases. 2000/08/17 2000; Vol. 182 Suppl 1:S122-33. [0022-1899: (Print)]
West 2002
  • West CE, Eilander A, van Lieshout M. Consequences of revised estimates of carotenoid bioefficacy for dietary control of vitamin A deficiency in developing countries. Journal of Nutrition 2002;132(9 Suppl):2920-6.
West 2002a
  • West KP Jr. Extent of vitamin A deficiency among preschool children and women of reproductive age. Journal of Nutrition 2002;132(9):2857-66.
West KP 2003
  • West KP Jr. Vitamin A deficiency disorders in children and women. Food and Nutrition Bulletin 2003;4(suppl 4):S78-S90.
WHO 1997
  • WHO. Vitamin A supplements; A guide to their use in prevention and treatment of vitamin A deficiency and xerophthalmia. Geneva: World Health Organization, 1997.
WHO 2009
  • WHO. Global prevalence of vitamin A deficiency in populations at risk 1995–2005. WHO Global Database on Vitamin A Deficiency 2009.
Wiysonge 2005
Yang 2009
  • Yang HM, Mao M, Wan CM. Vitamin A for treating measles in children. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD001479.pub3]