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Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less

  1. Siddhartha Gogia1,*,
  2. Harshpal S Sachdev2

Editorial Group: Cochrane Neonatal Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 29 NOV 2010

DOI: 10.1002/14651858.CD007480.pub2


How to Cite

Gogia S, Sachdev HS. Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007480. DOI: 10.1002/14651858.CD007480.pub2.

Author Information

  1. 1

    Max Hospital, Pediatrics, Gurgaon, Haryana, India

  2. 2

    Sitaram Bhartia Institute of Science and Research, Pediatrics and Clinical Epidemiology, New Delhi, India

*Siddhartha Gogia, Pediatrics, Max Hospital, Gurgaon, Haryana, India. gogiasiddhartha@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 5 OCT 2011

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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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison. Maternal vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants up to six weeks of age

Maternal Vitamin A Supplementation compared to Placebo for the prevention of morbidity and mortality in infants up to six weeks of age

Patient or population: patients with the prevention of morbidity and mortality in infants up to six weeks of age
Settings: Low and middle income countries
Intervention: Maternal Vitamin A Supplementation
Comparison: Placebo

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

Assumed riskCorresponding risk

PlaceboMaternal Vitamin A Supplementation

All-cause mortality in the first year of life
Follow-up: 6-12 months
Low risk population1RR 1
(0.94 to 1.06)
96203
(7 studies)
⊕⊕⊕⊕
high2
Trials gave vitamin A to mothers in developing countries, reflecting the main question of the review. CER from external sources.

41 per 100041 per 1000
(39 to 43)

Medium risk population1

62 per 100062 per 1000
(58 to 66)

High risk population1

81 per 100081 per 1000
(76 to 86)

All-cause mortality at 1 month
Follow-up: 1 months
Medium risk population3RR 0.98
(0.87 to 1.11)
84537
(2 studies)
⊕⊕⊕⊝
moderate4
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CER from external sources.

30 per 100029 per 1000
(26 to 33)

ARI-related mortality in the first year of life
verbal autopsy or lay reporting
Follow-up: 12 months
Low risk population5RR 1.59
(0.84 to 2.99)
5207
(2 studies)
⊕⊝⊝⊝
very low6,7,8
The studies reported risk ratios and 95% confidence intervals. In the absence of dichotomous data CERs were calculated based on external data.

9 per 100015 per 1000
(8 to 28)

High risk population5

11 per 100018 per 1000
(9 to 33)

Diarrhoea-related mortality in the first year of life
verbal autopsy or lay reporting
Follow-up: 12 months
Low risk population9RR 2.57
(0.72 to 9.12)
5207
(2 studies)
⊕⊝⊝⊝
very low6,8,10
The studies reported risk ratios and 95% confidence intervals. In the absence of dichotomous data CERs were calculated based on external data.<BR/>

8 per 100020 per 1000
(6 to 71)

High risk population9

9 per 100024 per 1000
(7 to 85)

Morbidity due to acute respiratory infections11
Follow-up: mean 12 months
Study populationRate ratio 0.96
(0.85 to 1.08)
598
(1 study)
⊕⊝⊝⊝
very low11,12
Data were analysed as ratios of rates. No estimates of cumulative risk available. Estimates of morbidity not available from external sources.

See commentSee comment

Medium risk population


Morbidity due to diarrhoea11
Follow-up: mean 12 months
Study populationRR 1.10
(0.99 to 1.23)
598
(1 study)
⊕⊝⊝⊝
very low11,12
Data were analysed as ratios of rates. No estimates of cumulative risk available. Estimates of morbidity not available from external sources.

See commentSee comment

Medium risk population


Adverse effectsStudy populationRR 0
(0 to 0)
700
(2 studies)
See commentNo adverse events were reported in two trials providing this information (Bhaskaram 1998, Venkatarao 1996).

See commentSee comment

Medium risk population


*The basis for the assumed risk (e.g. 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 Control group risk taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) for mortality before 1 year of age recorded in 2008 in the countries where included studies were conducted (Bangladesh, Ghana, India, Kenya, Nepal, Zimbabwe). The lowest, medium and highest mortality rates were entered for these countries.
2 Trial design was adequately reported in all but three trials that accounted for 6.6% of the weight in the pooled analysis (Klemm 2008, Newton 2005, Venkatarao 1996). Three trials were cluster randomised with adjustment for the design effect (Katz 2000, Kirkwood 2010, Klemm 2008). The cumulative vitamin A dose received by the postpartum mothers was similar in all but one study (Newton 2005).
3 Control group risk taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) for neonatal mortality rate. Estimates of neonatal mortality were based on rates of 30/1000 live births for Ghana (Kirkwood 2010) and Nepal (Katz 2000) recorded in 2008.
4 Two out of seven studies reporting mortality. Both studies had very large sample sizes.
5 Information taken from two sources. The World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the low and high mortality rates at 1 year of age in the countries of the included studies (India and Zimbabwe). Based on the proportion of global all cause mortality attributed to pneumonia (18%, reported in Black 2010), the CERs entered represent 18% of the national rates of mortality.
6 Venkatarao 1996 had inadequate concealment of allocation. Both studies failed to address missing data appropriately.
7 The confidence intervals include a 16% reduction and 300% increase (appreciable harm) in the risk of ARI related death
8 Only two trials reported this outcome, and the meta-analysis may be affected by the non-disclosure of cause-specific mortality in the remaining studies.
9 Information taken from two sources. The World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the low and high mortality rates at 1 year of age in the countries of the included studies for 2008(India and Zimbabwe). Based on the proportion of global all cause mortality attributed to diarrhoea (15% reported in Black 2010), the events entered represent 15% of the national rates of mortality.
10 The confidence intervals include a 28% reduction (appreciable benefit) and 900% increase (appreciable harm) in the risk of diarrhoea-related death.
11 Single study (Venkatarao 1996) on which randomisation procedure and method of allocation concealment were not described, and incomplete outcome data was not addressed.
12 A single small trial reported this outcome.

 Summary of findings 2 Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

 Summary of findings 3 Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

Vitamin A deficiency (VAD) is a significant public health problem in low and middle income countries, especially in Africa and Southeast Asia. It is most serious when it affects young children and pregnant women. Estimates suggest that there are 127 million pre-school children with VAD (serum retinol < 0.70 mmol/L or displaying abnormal impression cytology) and 4.4 million pre-school children with xerophthalmia in the developing world (West 2002). More than 7.2 million pregnant women in the developing world are vitamin A deficient (serum or breast milk vitamin A concentrations < 0.70 µmol/L) and another 13.5 million have low vitamin A status (0.70 to 1.05 µmol/L) (West 2002). Annually, more than six million women develop night blindness (XN) during pregnancy (West 2002).

The main causes of childhood vitamin A deficiency in the developing world include maternal vitamin A deficiency resulting in low concentrations of vitamin A in breast milk, inadequate dietary intake of vitamin A during and after weaning, and repeated bouts of infectious illnesses, which further decrease vitamin A levels (Miller 2002). The current US recommended dietary allowance (RDA) established by the Institute of Medicine (IOM) for non-pregnant, non-lactating women aged 19 to 50 years is 700 µg of vitamin A per day (IOM 2001). The recommended dietary allowance increases to only 770 µg/d during pregnancy but nearly doubles to 1300 µg/d during lactation. Mothers in developing countries are commonly vitamin A deficient because they consume diets low in vitamin A. Median dietary intake of vitamin A is 403 µg/d in rural Bangladeshi women; which provides 57% of their RDA if they are not pregnant or lactating and only 31% of their RDA during lactation (Zeitlin 1992). Maternal vitamin A deficiency seems to have little effect on fetal status since even well-nourished women transfer very little vitamin A to the infant. Therefore, all babies are physiologically vitamin A 'depleted' at birth, having little in the way of vitamin A stores in their livers. Young infants in developing countries have even lower vitamin A stores (Miller 2002). However, during lactation well-nourished women transfer about 71,500 µg of vitamin A to their infant (130 L of breast milk consumed during the entire period of lactation containing 55 µg/dL vitamin A), whereas women in developing countries transfer only about half that amount because the average milk vitamin A concentrations are about 30 µg/dL (Wallingford 1986). As a result, during lactation breast-fed babies of well-nourished women accrue adequate stores whereas breast-fed babies of vitamin A-deficient women remain depleted. Furthermore, if weaning foods are lower in vitamin A than the breast milk they partially replace, the child's risk of vitamin A deficiency increases further when breast feeding stops. Dietary vitamin A reference intakes for infants and young children, established by the IOM in the United States and by the Food and Agricultural Organization (FAO), recommend intakes from 350 to 500 µg/d for infants and from 300 to 400 µg/d for one to six year old children (FAO/WHO 1988; IOM 2001). In studies of pre-school children in Egypt, Mexico, Kenya and India median intakes of animal sources of vitamin A were 174, 119, 50 and 33 µg/d, respectively, providing only 11% to 58% of the RDA and leaving these children largely dependent on plant sources (Calloway 1993; Ramakrishnan 1999). In a study of Bangladeshi children, virtually the only source of pre-formed vitamin A consumed was breast milk; weaned children consumed only negligible amounts of vitamin A from animal sources (Zeitlin 1992).

 

Description of the intervention

There are two approaches to supplementing vitamin A intake during the first half of infancy. Firstly, to supplement all lactating mothers so that their infants can increase vitamin A intake through breast milk. Secondly, to give vitamin A supplements to all infants when they come in contact with the healthcare system. Such possible contacts occur immediately after birth, during postnatal visits or during immunization visits. The International Vitamin A Consultative Group (IVACG) recommends that three 50,000 international unit (IU) doses of vitamin A should be given at the same time as infant vaccines during the first six months of life. Recent kinetic studies have indicated that this regimen would be safe and would maintain the infant's vitamin A stores even when the mother is also given 400,000 IU within the first six weeks after delivery (Ross 2002).

 

How the intervention might work

VAD is believed to cause an increased susceptibility to infections by impeding normal regeneration of damaged mucosal barriers and by diminishing the function of neutrophils, macrophages and natural killer cells. Vitamin A is required for adaptive immunity and plays a role in the development of T-helper (Th) cells and B-cells (Stephensen 2001). Vitamin A deficiency also diminishes antibody-mediated responses directed by Th2 cells, although some aspects of Th1-mediated immunity are also diminished (Stephensen 2001). These factors may account for the increased mortality seen in vitamin A-deficient infants, young children and pregnant women. Deficiency of vitamin A causes xerophthalmia and significantly increases the risk of severe illness and death from such common childhood infections as diarrhoeal disease and measles (Christian 2001; Humphrey 1992). An estimated 250,000 to 500,000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight (West 2002).

 

Why it is important to do this review

The role of prophylactic vitamin A supplementation, given to apparently healthy children (more than six months of age) residing in low and middle income countries, in reducing childhood mortality has been the subject of several systematic and narrative reviews. For deficient children more than six months of age, vitamin A supplementation is estimated to reduce mortality by between 23% and 30% overall. Most of the reduction is due to the effect on diarrhoea and measles mortality (Beaton 1993; Fawzi 1993; Glasziou 1993). Periodic vitamin A supplementation to children over six months old is being implemented in more than 70 countries and is considered by many international agencies to be one of the most effective public health interventions ever undertaken (Fawzi 2006). Supplementation with a standard WHO protocol (200,000 IU to mothers early postpartum, 100,000 IU to infants at nine months and 200,000 IU at four to six month intervals thereafter) has been adopted as national policy in most developing countries (Darboe 2007). Side-effects of vitamin A supplementation are rare in children aged six months or older but there are reports of toxic effects in the first six months of life, such as raised intracranial pressure manifested by vomiting, bulging of the anterior fontanelle and irritability (Agoestina 1994; Baqui 1995; de Francisco 1993).

Because infants are at a higher risk of mortality when compared to older children, improving the vitamin A status of infants could potentially save the greatest number of lives. Therefore, the available evidence on the beneficial effects on mortality and morbidity of this intervention during the first six months of life needs to be systematically reviewed. Moreover, concern about the safety of vitamin A supplementation in young infants, particularly during the neonatal period, needs to be addressed and the optimum dose determined. Furthermore, the differential effects on mortality and morbidity with respect to the vitamin A status of mothers, birthweight and infant mortality rate need to be studied.

A focused review on vitamin A supplementation in term neonates in developing countries irrespective of maternal HIV status is under preparation (Haider 2008b).

Therefore, we have undertaken a systematic review of randomised controlled trials to evaluate the effect of prophylactic vitamin A supplementation on mortality and morbidity in infants six months of age or less in developing countries, with particular reference to supplementation of mothers during lactation and of infants at different times during the first half of infancy.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

  1. To evaluate the effect of synthetic vitamin A supplementation in postpartum breast feeding mothers in low and middle income countries, irrespective of antenatal vitamin A supplementation status, on mortality, morbidity, and adverse effects in their infants until the age of one year (Comparison 1).
  2. To evaluate the effect of synthetic vitamin A supplementation initiated in the first half of infancy (< 6 months of age) in low and middle income countries, irrespective of maternal antenatal or postnatal vitamin A supplementation status, on mortality, morbidity, and reactions until the age of one year (Comparison 2).

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised or quasi-randomised placebo controlled trials which randomised at the level of the mother or infant or cluster (such as village) that involved synthetic vitamin A supplementation to the postpartum mother or infant (< 6 months of age), or both.

 

Types of participants

 
Comparison 1: Maternal supplementation

Mothers from low and middle income countries receiving synthetic vitamin A supplementation initiated in the postpartum period (< 6 weeks) irrespective of antenatal vitamin A supplementation.

 
Comparison 2: Infant supplementation

Apparently healthy infants from low and middle income countries, breast-fed or non-breast fed, receiving vitamin A supplementation initiated before the age of six months (irrespective of maternal supplementation during pregnancy and lactation).

We excluded trials which recruited selected subgroups of infants, such as those who were very low birth weight (< 1500 grams), who were born to known HIV positive mothers, or who were sick or hospitalised. Although such studies may be of clinical interest, they do not address the research question of this review and have been the subject of previously published Cochrane reviews (Darlow 2007; Shey 2002; Wiysonge 2005).

 

Types of interventions

Synthetic oral vitamin A supplementation in one or more of the following forms were compared against a placebo.

  1. Maternal supplementation (Comparison 1): synthetic vitamin A supplementation to lactating mothers (first six weeks postpartum). Synthetic oral vitamin A supplementation initiated in the postpartum mother within six weeks of delivery, irrespective of the antenatal vitamin A supplementation status, was compared against a placebo. Infants in intervention and placebo groups should not have been supplemented with vitamin A but could have received placebo.
  2. Infant supplementation (Comparison 2): synthetic vitamin A supplementation to infants less than six months of age (breast-fed or non-breast fed). Synthetic oral vitamin A supplementation initiated in infants below six months of age, irrespective of maternal postpartum vitamin A supplementation status, was compared against a placebo administered to the infant and either placebo or no supplementation in the mother. If such a comparison group was not available for the mother infant dyad, the intervention group was compared with the group in which the infant had received placebo while the mother had received supplementation identical to the intervention group.

Trials providing additional interventions were considered if the only difference between the treatment arms was vitamin A supplementation. In studies assessing different doses of vitamin A and placebo, we combined the intervention groups to create a single pair-wise comparison in order to avoid double-counting data. We excluded studies which evaluated food fortification, consumption of vitamin A rich foods or beta-carotene supplementation.

 

Types of outcome measures

 

Primary outcomes

Mortality:

  1. during infancy, in the period between initiation of intervention and the last follow-up, until the age of one year;
  2. during the neonatal period between initiation of intervention and the last follow-up, until the age of one month.

 

Secondary outcomes

Cause-specific mortality (as defined by the authors, irrespective of ascribing a single or multiple causes of death) due to:

  1. diarrhoea;
  2. acute respiratory infections;
  3. other causes.

Morbidity during infancy (as defined by the authors, irrespective of ascribing a single or multiple causes) in the period between initiation of intervention and the last follow-up, until the age of one year:

  1. diarrhoea;
  2. acute respiratory infection or respiratory difficulty;
  3. cough or running nose;
  4. ear infection;
  5. fever;
  6. vomiting.

Adverse effects within one week following the intervention:

  1. bulging fontanel;
  2. vomiting;
  3. irritability;
  4. diarrhoea;
  5. fever.

 

Search methods for identification of studies

 

Electronic searches

We used the standard search strategy of the Cochrane Neonatal Review Group. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), EMBASE and MEDLINE (1966 to October 15, 2010) via PubMed and clinical trials websites for example clinicaltrials.gov were searched using the following search terms:

(Newborn OR infan* OR neonat*) AND ("vitamin A" OR retino*).

We limited the search to "humans" and "clinical trial" without language restriction. We did a lateral search using the related articles link in PubMed for the articles initially included from the search strategy.

 

Searching other resources

We reviewed the reference lists of identified articles and handsearched reviews, bibliographies of books and abstracts. We contacted donor agencies, 'experts' and authors of recent vitamin A supplementation trials to identify any additional unpublished or ongoing trials.

 

Data collection and analysis

 

Selection of studies

Both review authors independently assessed the eligibility of the trials. We selected studies as being potentially relevant by screening the titles and abstracts, if available. The full text of the article was retrieved and reviewed if a decision could not be made by screening the title and the abstract. We retrieved the full texts of all potentially relevant articles and independently assessed study eligibility with forms designed in accordance with the specified inclusion criteria. We resolved disagreements by discussion. We requested additional data and information regarding definitions of outcomes from study investigators when required. In the case of conference abstracts we used the information provided in the abstract if additional data were not forthcoming.

 

Data extraction and management

We collected data using a data extraction form which we designed and piloted. We extracted data independently, and resolved differences by discussion. We contacted study investigators for additional information or data as required. For dichotomous outcomes, the total number of participants for each group and the number of participants experiencing an event were extracted. The relative risks and 95% confidence intervals (or standard errors) of treatment effects for the outcomes were extracted.

 

Assessment of risk of bias in included studies

We undertook a risk of bias assessment in accordance with recommendations from Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We assessed the included studies for their risk of bias against the following key criteria:

  1. adequate sequence generation;
  2. allocation concealment;
  3. blinding;
  4. incomplete outcome data;
  5. selective outcome reporting;
  6. other biases.

Both review authors independently evaluated and agreed the risk of bias for the individual studies; help with the interpretation was made available by the Cochrane Collaboration Editorial Unit. We resolved disagreements by mutual discussion. Following this, another teleconference was arranged between the authors and the Cochrane Collaboration Editorial Unit to resolve disagreements with another ongoing review of neonatal vitamin A supplementation (Haider 2008b) for some domains in studies that were in both reviews.

 

Measures of treatment effect

Analysis of the outcome was based on the available case analysis. We used risk ratio (RR) to analyse data for dichotomous outcomes. In a hierarchical pattern, preference was given to the RR provided by authors with a recalculation using the stated 'raw' numbers. If the RR was not stated, it was computed with the following preference order for the denominator:

  1. stated child-years;
  2. numbers with definite outcome known, until completion of intervention period;
  3. number randomised.

The RR and standard error (SE) were extracted or calculated for individually randomised trials and cluster randomised trials. We entered the SEs for cluster randomised studies which had taken account of the effect of clustering (see below).

 

Unit of analysis issues

 
Cluster randomised trials

The design effect-corrected SEs were calculated from the published data or we contacted the authors for the intra-cluster correlation (ICC) estimates. If required, the design effect for a study was calculated and the SE of the treatment effect was adjusted for use in the analysis based on the formula provided in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

 
Studies with multiple treatment groups

In studies with multiple intervention groups (different methods or doses of vitamin A supplementation), the vitamin A groups were combined to create a single pair-wise comparison with the control (placebo) group.

 

Dealing with missing data

In studies where intention-to-treat data were available, the same was used in case the authors had reported otherwise.

 

Assessment of heterogeneity

We assessed heterogeneity among the trials by the visual inspection of forest plots and by measurement of the I 2 statistic.

 

Assessment of reporting biases

We evaluated publication bias and other reporting biases by preparing a funnel plot.

 

Data synthesis

Statistical meta-analyses were undertaken using Revman 5 (RevMan). We used Intercooled Stata version 9.2 for Windows Stata for the meta-regression (see Subgroup analysis and investigation of heterogeneity).

We calculated the RR and its standard error (SE) for individually randomised trials and combined these estimates with the RRs and SEs from cluster randomised trials (adjusted for the effect of clustering). We used the generic inverse variance method to permit the aggregation of the data.

We developed 'Summary of findings' tables in GRADEpro software for outcomes relating to mortality, morbidity and adverse effects. The quality ratings assigned to the outcome results were based on our assessments of study limitations, consistency and precision of the result, indirectness (such as population, intervention or definition of outcome not of primary interest to the review question) and possible impact of publication bias. More information on recommendations for the methods we applied are provided from GRADE.

 

Subgroup analysis and investigation of heterogeneity

 
Subgroup analyses

The proposed subgroup analyses for the infant mortality component in the maternal postpartum supplementation (Comparsion 1) analysis were:

  • cumulative vitamin A dose received by the mother: low dose (≤ 200,000 IU) versus high dose (≥ 200,000 IU);
  • baseline maternal vitamin A status: maternal night blindness prevalences of < 5% (low) versus ≥ 5% (high), and mean maternal antenatal or postpartum serum retinol levels of ≥ 1.1 µmol/L (low) versus < 1.1 µmol/L (high);
  • birth weight: < 2500 grams (low birth weight) versus ≥ 2500 grams (normal birth weight).

The proposed subgroup analyses for the infant mortality component in the infant supplementation analysis (Comparison 2) were:

  • age at initiation of prophylactic vitamin A supplementation: neonatal period (0 to 1 month) versus post-neonatal period (1 to 6 months);
  • cumulative vitamin A dose received by the infant until the age of six months: low dose (≤ 50,000 IU) versus high dose (≥ 50,000);
  • maternal postpartum vitamin A supplementation: received versus not received;
  • baseline maternal vitamin A status: maternal night blindness prevalences of < 5% (low) versus ≥ 5% (high), and mean maternal antenatal or postpartum serum retinol levels of ≥ 1.1 µmol/L (low) versus < 1.1 µmol/L (high);
  • birth weight: < 2500 grams (low birth weight) versus ≥ 2500 grams (normal birth weight).

 
Investigation of heterogeneity

We considered heterogeneity to be substantial if the I2 statistic exceeded 25% and visual inspection of the forest plot was indicative. We sought to explain heterogeneity in terms of subgroup analyses which considered the possible sources of variation as:

  1. time point of initiation of vitamin A supplementation;
  2. maternal postpartum vitamin A supplementation for Comparison 1 (yes or no);
  3. cumulative dose of vitamin A supplementation;
  4. vitamin A status of mother;
  5. birth weight of neonate;
  6. high baseline infant mortality.

Meta-regression was used to further explore heterogeneity.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

 

Results of the search

The search strategy identified 42 potentially eligible trials; of these we excluded 24 and 18 met the inclusion criteria of the review. In addition, we identified four ongoing trials (Bhandari 2010; Bhutta 2010; Edmond 2010; Fawzi 2010).

 

Included studies

A total of 18 studies were included because these supplied information on one or more of the outcomes for the maternal and infant supplementation analyses.

 
Comparison 1: Maternal supplementation

Information on outcomes was available from eight trials. Mortality was available from seven trials (Ayah 2007; Katz 2000; Kirkwood 2010; Klemm 2008; Malaba 2005; Newton 2005; Venkatarao 1996), morbidity from one trial (Venkatarao 1996) and adverse effects from two trials (Bhaskaram 1998; Venkatarao 1996).

 
Comparison 2: Infant supplementation

Information on outcomes was available from 15 trials. Mortality was available from nine trials (Benn 2008; Benn 2010; Humphrey 1996; Klemm 2008; Malaba 2005; Newton 2005; Rahmathullah 2003; West 1995; WHO 1998), morbidity in seven trials (Benn 2008; Benn 2010; Humphrey 1996; Rahmathullah 2003; Semba 2001; Venkatarao 1996; WHO 1998) and adverse effects in 13 trials (Ayah 2007; Baqui 1995; Benn 2008; de Francisco 1993; Humphrey 1996; Klemm 2008; Malaba 2005; Rahmathullah 2003; Semba 2001; Stabell 1995; Venkatarao 1996; West 1995; WHO 1998). The mortality analysis was done on 10 independent analytic components (that is 10 sets of comparisons) from nine trials to aid the subgroup analysis as one trial yielded two independent analytic components according to the age at which an infant received vitamin A supplementation (0 to 1 month and one to six months) (West 1995).

Characteristics of included studies summarizes the baseline characteristics of the trials included for all the outcomes for the maternal and young infant supplementation analyses.

 
Characteristics of included studies of maternal supplementation (Comparison 1)

All the seven trials reporting mortality (Ayah 2007; Katz 2000; Kirkwood 2010; Klemm 2008; Malaba 2005; Newton 2005; Venkatarao 1996) were conducted in developing countries (three in Asia, four in Africa). Only three trials (Katz 2000; Kirkwood 2010; Klemm 2008) were cluster randomised, and in all of them the cluster design-adjusted results were available. All of the trials were assessed to be double blind; allocation concealment was adequate in six studies; and loss to follow-up was below 10% in two trials. Antenatal vitamin A supplementation had also been given in three studies (Katz 2000; Kirkwood 2010; Klemm 2008). The cumulative vitamin A dose received by the postpartum mother was < 200,000 IU in Newton 2005 and > 200,000 IU in the other six studies. The intervention had been given as a single dose in four studies and as multiple doses in three (Katz 2000; Kirkwood 2010; Klemm 2008). Information on prevalence of maternal night blindness was available in only three studies (> 5% in Malaba 2005 and < 5% in Klemm 2008 and Kirkwood 2010). Mean maternal (antenatal or postnatal) serum retinol levels (micromoles per liter) in placebo group were documented in five trials, and were < 1.1 in two (Ayah 2007; Katz 2000) and > 1.1 in three (Kirkwood 2010; Klemm 2008; Malaba 2005). Information on mean birth weight was available in three studies, and was above 2500 grams in two of them. The infants’ follow-up age was < 6 months in four trials and > 6 months in three studies (Kirkwood 2010; Malaba 2005; Venkatarao 1996).

 
Characteristics of included studies of infant supplementation (Comparison 2)

Nine trials reported mortality in 10 independent analytic components. All these studies (Benn 2008; Benn 2010; Humphrey 1996; Klemm 2008; Malaba 2005; Newton 2005; Rahmathullah 2003; West 1995; WHO 1998) were conducted in low and middle income countries (five in Asia, three in Africa, and one involved multiple centres from Asia, Africa and Latin America). Only two trials (Klemm 2008; West 1995) providing three analytic components were cluster randomised, and in all of them the cluster design-adjusted results were available. All the trials were assessed to be double blind; allocation concealment was adequate in nine of the 10 analytic components; and loss to follow-up was below 10% in seven. Infant vitamin A supplementation had been initiated between birth and one month of age in seven analytic components, and between one and six months of life in three (Newton 2005; West 1995; WHO 1998). In five studies participants were followed up to the age of < 6 months, and in five they were followed up to > 6 months. Simultaneous maternal postpartum vitamin A supplementation (> 30% mothers in the intervention arm) had been used in four of the 10 analytic components (Benn 2008; Humphrey 1996; Rahmathullah 2003; West 1995). The cumulative vitamin A dose received by the infant in the first six months of life was < 50,000 IU in seven analytic components and > 50,000 IU in three analytic components. This had been administered as a multiple dose in three analytic components (Newton 2005; Rahmathullah 2003; WHO 1998). Information on prevalence of maternal night blindness was available in only four analytic components; of these two recorded a prevalence > 5% (Malaba 2005; WHO 1998) and two < 5% (Klemm 2008; Rahmathullah 2003). Mean maternal serum retinol levels (µmol/L) in the placebo group were documented in two analytic components, and were < 1.1 in both. The mean infant serum retinol level in the placebo group was reported in only the multi-centre trial (WHO 1998), and was > 0.6 µmol/L. The mean birth weight was above 2500 grams in four of the six analytic components that had documented this information. However, three trials had presented results separately for low birth weight and non-low birth weight infants. One trial had been conducted exclusively in low birth weight infants (Benn 2010).

The notable general and individual study specific features in relation to data abstraction are summarized in Appendix 1.

 

Excluded studies

The reasons for excluding the 24 studies are summarised in the table Characteristics of excluded studies. The reasons were: relevant outcomes not reported (N = 13 studies), conducted in HIV positive women (N = 5), not placebo controlled (N = 3), conducted on infants treated for diarrhea (N = 2), and only antenatal vitamin A supplementation (N = 1).

 

Risk of bias in included studies

The risk of bias table for individual included studies is summarised in the table Characteristics of included studies and Figure 1.

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

 
Comparison 1: Maternal supplementation

In the seven trials providing information on mortality the risk of bias for sequence generation was low in four and unclear in three trials, of which two were relatively small studies (Newton 2005; Venkatarao 1996). The allocation concealment was assessed to be adequate (low risk) in four trials and of unclear risk in three trials. The only trial providing information on morbidity had unclear risk of bias for sequence generation and allocation concealment. The two trials providing information on adverse effects had unclear risk of bias for sequence generation and allocation concealment.

 
Comparison 2: Infant supplementation

The risk of bias for sequence generation in trials providing data on mortality outcome was low in four trials while it was unclear in five trials (Humphrey 1996; Klemm 2008; Newton 2005; Rahmathullah 2003; West 1995). The allocation concealment was assessed to be adequate (low risk) in five trials and unclear in four trials. In the seven trials providing information on morbidity, sequence generation was adequate (low risk) in three and unclear in four studies; allocation concealment was adequate (low risk) in four and unclear in three trials. In the 13 trials providing information on adverse effects, sequence generation was adequate (low risk) in five and unclear in eight studies; allocation concealment was adequate (low risk) in six, inadequate (high risk) in one small trial, and unclear in six studies.

 

Blinding

 
Comparison 1: Maternal supplementation

In the seven trials providing information on mortality, blinding was adequate in all. The trial providing information on morbidity also had adequate (low risk) blinding. In the two trials providing information on adverse effects, blinding was adequate (low risk) and inadequate (high risk) in one trial each.

 
Comparison 2: Infant supplementation

All the nine trials providing data on mortality were adequately blinded. Similarly, in all the seven trials providing information on morbidity, blinding was assessed to be adequate (low risk). In the 13 trials providing information on adverse effects, blinding was adequate (low risk) in 12 trials and unclear in one study (Stabell 1995).

 

Incomplete outcome data

 
Comparison 1: Maternal supplementation

In the seven trials providing information on mortality, incomplete outcome data were addressed adequately (low risk) in four, it was unclear in one and inadequately (high risk) in two trials. The trial providing information on morbidity had not adequately addressed incomplete outcome data. In the two trials providing information on adverse effects: the risk of bias for incomplete outcome data was high and unclear in one trial each.

 
Comparison 2: Infant supplementation

In the nine trials providing data on mortality, incomplete outcome data were addressed adequately in seven, unclear in one and inadequately in one trial. Incomplete outcome data were addressed adequately in five trials and inadequately in two studies providing information on morbidity. In the 13 trials providing information on adverse effects, the risk of bias for incomplete data was low in seven studies, high in four studies and unclear in two studies.

 

Selective reporting

 
Comaprison 1: Maternal supplementation

In the seven trials providing information on mortality, the risk of bias for selective reporting was low in three, high in three and unclear in one. The trial providing information on morbidity was free of selective reporting. In the two trials providing information on adverse effects, the risk of bias for selective reporting was high and low in one trial each.

 
Comaprison 2: Infant supplementation

In the nine trials providing information on mortality, the risk of bias for selective reporting was low in five, high in one and unclear in three. In the seven trials providing information on morbidity, the risk of bias for selective reporting was low in five trials, high in one trial and unclear in one trial. In the 13 trials providing information on adverse effects, the risk of bias for selective reporting was low in five trials, high in four trials and unclear in four trials.

 

Other potential sources of bias

 
Comparison 1: Maternal supplementation

In the seven trials providing information on mortality, the risk of bias for other potential sources was low in two, high in two and unclear in three. In the trial providing information on morbidity it was unclear if there were other potential sources of bias. In the two trials providing information on adverse effects the risk of bias from other potential sources was high and unclear in one trial each.

 
Comparison 2: Infant supplementation

In the nine trials providing information on mortality, the risk of bias from other potential sources was low in two, high in four and unclear in three. In the seven trials providing information on morbidity, the risk of bias from other potential sources was low in one, high in three and unclear in three. In the 13 trials providing information on adverse effects, the risk of bias from other potential sources was low in two, high in four and unclear in seven.

 

Effects of interventions

See:  Summary of findings for the main comparison Maternal vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants up to six weeks of age;  Summary of findings 2 Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less;  Summary of findings 3 Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

 

Comparison 1: Maternal vitamin A supplementation

 

Primary outcomes

The pertinent details of the vital events and denominators for the mortality analysis for each study are summarised in  Table 1.

 
Outcome 1.1 (Mortality in the first year of life)

Relevant data for evaluating the pooled relative risk of all-cause mortality during infancy, in the period between initiation of intervention and the last follow-up until the age of one year, were available from seven studies.

 
Outcome 1.1.1 (Mortality after postpartum vitamin A supplementation)

There was no evidence of a reduced risk of mortality during infancy ( Analysis 1.1). The pooled risk ratio for mortality was 1.00 (95% CI 0.94 to 1.06, P = 0.9; test for heterogeneity I2 = 0%, P = 0.9). The result was identical with fixed-effect and random-effects models.

The funnel plot for the seven trials included in the main analysis was symmetrical suggesting the absence of publication bias, which was confirmed using the Egger’s (weighted regression) method (P = 0.202) and the Begg’s (rank correlation) method (continuity corrected P = 1.0) in Stata 9.2 (Figure 2).

 FigureFigure 2. Funnel plot of comparison: Maternal vitamin A supplementation versus placebo, outcome: 1.1.1 Mortality in the first year of life for the main analysis.

 
Outcome 1.1.2 (Mortality after postpartum vitamin A supplementation in presence of night blindness, prevalence < 5%)

In the two trials providing data (Kirkwood 2010; Malaba 2005), there was no evidence of a reduced risk of mortality in the presence of maternal night blindness, prevalence < 5% (random-effects model RR 1.02, 95% CI 0.85 to 1.22, P = 0.83; I2 = 28%, test for heterogeneity P = 0.24) ( Analysis 1.1). Similar estimates were derived from the fixed-effect model.

 
Outcome 1.1.3 (Mortality after postpartum vitamin A supplementation in presence of night blindness, prevalence ≥ 5%)

Only one trial had relevant data (Klemm 2008) and the effect was not significant (RR 1.02, 95% CI 0.79 to 1.32).

 
Outcome 1.1.4 (Mortality with cumulative vitamin A dose < 200,000 IU)

Only one trial had relevant data (Newton 2005) and the effect was not significant (RR 1.54, 95% CI 0.31 to 7.63).

 
Outcome 1.1.5 (Mortality with cumulative vitamin A dose > 200,000 IU)

There was no evidence of a reduced risk of mortality in six trials providing a cumulative vitamin A dose > 200,000 IU (random-effects model RR 1.00, 95% CI 0.93 to 1.06, P = 0.89; I2= 0%, test for heterogeneity P = 0.86) (. Analysis 1.1). Similar estimates were derived with the fixed-effect model.

 
Outcome 1.1.6 (Mortality with maternal serum retinol ≤ 1.1 µmol/L)

From two studies (Ayah 2007; Katz 2000), there was no evidence of a reduced risk of mortality if maternal serum retinol was ≤ 1.1 µmol/L (random-effects model RR 1.04, 95% CI 0.88 to 1.23, P = 0.66; I2= 0%, test for heterogeneity P = 0.73) (. Analysis 1.1). Similar estimates were derived with the fixed-effect model.

 
Outcome 1.1.7 (Mortality with maternal serum retinol > 1.1 µmol/L)

From three trials providing data, there was no evidence of a reduced risk of mortality if maternal serum retinol was > 1.1 µmol/L (random-effects model RR 0.99, 95% CI 0.92 to 1.06, P = 0.76; I2 = 0%, test for heterogeneity P = 0.49) (. Analysis 1.1). Similar estimates were derived from the fixed-effect model.

With a univariate meta-regression neither the cumulative vitamin A dose received by the mother nor mean maternal serum retinol emerged as a significant predictor of heterogeneity ( Table 2).

Disaggregated data for low birth weight (< 2500 grams) and normal birth weight (> 2500 grams) were not available for subgroup analysis.

 
Outcome 1.2 (Mortality in the first month of life)

In two trials providing data (Katz 2000; Kirkwood 2010), there was no evidence of a reduced risk of neonatal mortality (random-effects model RR 0.98, 95% CI 0.87 to 1.11, P = 0.47; I2= 28%, test for heterogeneity P=0.24) ( Analysis 1.2).

 

Secondary outcomes

 
Outcome 1.3 (Cause-specific mortality in the first year of life)

Among the six trials providing data on mortality, only two documented information on the cause of death (Malaba 2005; Venkatarao 1996). We have requested information on this outcome from another recent trial (Benn 2010). The cause of death was ascertained by verbal autopsy or lay reporting.

With a random-effects model, there was no evidence of a reduced risk of deaths due to respiratory causes (outcome 1.3.1: RR 1.59, 95% CI 0.84 to 2.99, P = 0.154; I2=0%, test for heterogeneity P = 0.321), diarrhoeal etiology (outcome 1.3.2: RR 2.65, 95% CI 0.83 to 8.50, P = 0.10; I2=11.8%, test for heterogeneity P = 0.287), or causes other than respiratory or diarrhoeal morbidities (outcome 1.3.3: RR 1.04, 95% CI 0.51 to 2.10, P = 0.92; I2 = 64.5%, test for heterogeneity P = 0.093) ( Analysis 1.3). Similar results were obtained with fixed-effect modelling for both outcomes. The estimated RR for causes other than respiratory and diarrhoeal etiologies was 0.62 (95% CI 0.09 to 4.09, P = 0.618; I2 = 64%, test for heterogeneity P = 0.09).

 
Morbidity during infancy

The following morbidity details were available only in one study, for diarrhoeal and acute respiratory infections (Venkatarao 1996). In relation to infant follow-up from birth to six months of age, the two intervention arms (only maternal supplementation and both maternal and child supplementation) were combined, as the child supplementation had been done at six months of age, and compared with the placebo group. There was no evidence of a decrease in either of the recorded morbidities, namely diarrhoeal (RR 1.08, 95% CI 0.94 to 1.24) or acute respiratory infection (RR 1.08, 95% CI 0.98 to 1.19). The morbidity comparison between six and 12 months of age was in relation to only maternal supplementation and placebo groups. In this age group there was no evidence of a decrease in either diarrhoeal (RR 1.10, 95% CI 0.99 to 1.23) or acute respiratory infection (RR 0.96, 95% CI 0.85 to 1.08).

 
Adverse effects within one week

Relevant information was reported in two studies (Bhaskaram 1998; Venkatarao 1996), but no adverse effects were observed in both the trials, in either the intervention or the control groups, during the follow-up.

 

Comparison 2: Infant vitamin A supplementation in the first six months of life

 

Primary outcomes

The pertinent details of the vital events and denominators for the mortality analysis for each study are summarised in  Table 3.

 
Outcome 2.1 (Mortality in the first year of life)

Relevant data for evaluating the pooled relative risk of mortality during infancy, in the period between initiation of intervention and the last follow-up until the age of one year, were available from nine trials, which contributed 10 independent analytic components for the subgroup analyses.

The funnel plot for the nine trials included in the main analysis was symmetrical suggesting the absence of publication bias. This was confirmed using the Egger’s (weighted regression) method (P for bias = 0.566) and the Begg’s (rank correlation) method (continuity corrected P = 0.118) in Stata 9.2 (Figure 3).

 FigureFigure 3. Funnel plot of comparison: 2 Young Infant vitamin A supplementation versus placebo, outcome: 2.1.1 Mortality in the first year of life for the main analysis.

We preferred to report the random-effects model for the pooled estimates in view of I2 values which were above 25% in several of the analyses. The results from the fixed-effect model estimates are also reported for comparison.

The pertinent details of the vital events for the mortality analysis are summarised in  Table 3.

 
Outcome 2.1.1 (Mortality after vitamin A supplementation in first six months)

In the main analysis of nine trials, the pooled risk ratio was 0.97 (95% CI 0.83 to 1.12, P = 0.65; test for heterogeneity I2= 49%, P = 0.05) by the random-effects model and 0.95 (95% CI 0.86 to 1.05, P = 0.32) by the fixed-effect model ( Analysis 2.1).

 
Outcome 2.1.2 (Mortality after neonatal vitamin A supplementation)

From the seven analytic components in which the intervention had been initiated in the neonatal period (0 to < 1 month), the pooled risk ratio was 0.94 (95% CI 0.79 to 1.12, P = 0.49; I2 = 50%, test for heterogeneity P = 0.06) by the random-effects model and 0.92 (95% CI 0.82 to 1.03, P = 0.16) by the fixed-effect model ( Analysis 2.1).

 
Outcome 2.1.3 (Mortality after vitamin A supplementation in one to six months)

From the three analytic components in which the intervention had been initiated between one to six months of life, the pooled risk ratio was 1.05 (95% CI 0.84 to 1.32, P = 0.66; test for heterogeneity I2 = 13%, P = 0.32) by the random-effects model and 1.05 (95% CI 0.86 to 1.28, P = 0.66) by the fixed-effect model. The probability value from the test for statistical heterogeneity between the two subgroups (supplementation initiated in neonatal period and one to six months) was 0.285 (Stata 9.2).

 
Outcome 2.1.4 (Mortality after vitamin A supplementation, cumulative dose ≤ 50,000 IU)

From the seven analytic components, the pooled risk ratio was 0.94 (95% CI 0.79 to 1.12, P = 0.49; I2 = 50%, test for heterogeneity P = 0.06) with random-effects modelling and 0.92 (95% CI 0.82 to 1.03, P = 0.16) with the fixed-effect model ( Analysis 2.1).

 
Outcome 2.1.5 (Mortality after vitamin A supplementation, cumulative dose > 50,000 IU)

From the three analytic components, the pooled risk ratio was 1.05 (95% CI 0.84 to 1.32, P = 0.66; I2 = 13%, test for heterogeneity P = 0.32) by random-effects modelling and 1.05 (95% CI 0.86 to 1.28, P = 0.66) with the fixed-effect model. The probability value for the test for statistical heterogeneity between the two subgroups (cumulative dose ≤ 50,000 and > 50,000) was 0.285 (Stata 9.2).

 
Outcome 2.1.6 (Mortality with concomitant maternal vitamin A supplementation)

From four trials, the pooled risk ratio was 1.0 (95% CI 0.81 to 1.23, P = 0.97; I2 = 31%, test for heterogeneity P = 0.23) by random-effects modelling and 0.97 (95% CI 0.83 to 1.13, P = 0.70) with the fixed-effect model.

 
Outcome 2.1.7 (Mortality without concomitant maternal vitamin A supplementation)

From five trials, the pooled risk ratio was 0.93 (95% CI 0.74 to 1.17, P = 0.54; I2 = 64%, test for heterogeneity P = 0.03) by random-effects modelling and 0.94 (95% CI 0.83 to 1.07, P = 0.34) by the fixed-effect model.

 
Outcome 2.1.8 (Mortality with vitamin A supplementation of low birthweight infants)

From four trials providing this data, the pooled risk ratio was 0.84 (95% CI 0.65 to 1.07, P = 0.16; I2 = 58%, test for heterogeneity P = 0.07) by random-effects modelling and 0.85 (95% CI 0.74 to 0.97, P = 0.02) with the fixed-effect model.

 
Outcome 2.1.9 (Mortality with vitamin A supplementation of normal birthweight infants)

From three trials providing this data, the pooled risk ratio was 0.78 (95% CI 0.43 to 1.40, P = 0.40; I2 = 64%, test for heterogeneity P = 0.06) by random-effects modelling and 0.92 (95% CI 0.70 to 1.19, P = 0.51) with the fixed-effect model.

 
Outcome 2.1.10 (Mortality with vitamin A supplementation in presence of night blindness in < 5% mothers)

From two trials providing this data, the pooled risk ratio was 1.06 (95% CI 0.83 to 1.34, P = 0.66; I2 = 13%, test for heterogeneity P = 0.28) by random-effects modelling and 1.05 (95% CI 0.84 to 1.31, P = 0.66) by the fixed-effect model.

 
Outcome 2.1.11 (Mortality with vitamin A supplementation in presence of night blindness in ≥ 5% mothers)

In two trials providing this data, the pooled risk ratio was 0.83 (95% CI 0.71 to 0.96, P = 0.01; I2 = 0%, test for heterogeneity P = 0.43). Results were identical with random-effects and fixed-effect modelling.

On univariate meta-regression none of these pre-specified variables (time point of initiation of vitamin A supplementation, simultaneous maternal administration of vitamin A supplementation, cumulative dose of vitamin A supplementation, vitamin A status of mother, and birth weight of neonates) could be identified as a statistically significant (P > 0.05) predictor of heterogeneity ( Table 4).

 
Outcome 2.2 (Mortality in the first month of life)

In three trials providing this data, the pooled risk ratio was 0.90 (95% CI 0.75 to 1.08, P = 0.27; I2= 0%, test for heterogeneity P = 0.83). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.2).

 
Outcome 2.3 (Cause-specific mortality in the first year of life)

Among the nine trials providing data on mortality, only seven documented information on the cause of death. All of these studies were conducted in low and middle income countries: three in Asia (Humphrey 1996; Rahmathullah 2003; West 1995); three in Africa (Benn 2008; Benn 2010; Malaba 2005); and one was multi-centre, from Asia, Africa and Latin America (WHO 1998). The cause of death had been ascertained by verbal autopsy or lay reporting. In the trial with two independent analytic components for the all-cause mortality analysis, information on the cause of death was not available by the strata for the age group when intervention was initiated (West 1995).

 
Outcome 2.3.1 (Cause-specific mortality due to diarrhoea)

The pooled risk ratio was 1.01 (95% CI 0.72 to 1.41, P = 0.96; I2 = 33%, test for heterogeneity P = 0.17) by random-effects modelling and 1.01 (95% CI 0.79 to 1.30, P = 0.92) by the fixed-effect model ( Analysis 2.3).

 
Outcome 2.3.2 (Cause-specific mortality due to acute respiratory infection)

The pooled risk ratio was 1.12 (95% CI 0.91 to 1.39, P = 0.29; I2 = 0%, test for heterogeneity P = 0.99). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.3).

 
Outcome 2.3.3 (Cause-specific mortality due to other causes)

The pooled risk ratio was 0.81 (95% CI 0.64 to 1.02, P = 0.07; I2 = 63%, test for heterogeneity P = 0.01) by the random-effects model and 0.85 (95% CI 0.75 to 0.97, P = 0.01) with a fixed-effect model ( Analysis 2.3).

In the trial of neonatal supplementation from India (Rahmathullah 2003), one report (Tielsch 2007) had recorded relative case fatality rates following episodes of common morbidities with follow-up to 60 days after onset. It could not be ascertained whether death during follow-up was causally related to the specific morbidity. At the last follow-up (60 days post-onset) case fatalities for diarrhoea and fever were significantly reduced in the vitamin A group compared with placebo (relative case fatality of 0.50, 95% CI 0.27 to 0.90; and 0.60, 95% CI 0.40 to 0.88, respectively). However, the relative case fatality rates were not statistically different during the episode of diarrhoea and fever (relative case fatality 0.54, 95% CI 0.24 to 1.22; 1.20, 95% CI 0.59 to 2.43, respectively). Also at the last follow-up (60 days post-onset) there were no significant differences for relative case fatality for dysentery (relative case fatality 0.83, 95% CI 0.25 to 2.70) and various definitions of acute respiratory infections, namely cough and fever (0.66, 95% CI 0.35 to 1.21); difficulty breathing and fever (0.52, 95% CI 0.22 to 1.21); and cough, difficulty breathing and fever (0.40, 95% CI 0.12 to 1.28). The numbers of deaths from this data set (assuming that the morbidities occurred independently) were only 249 out of a total of 334 (75%) deaths recorded in the primary study. There was no evidence that the treatment effects were modified by birth weight.

 
Outcome 2.4 (Morbidity in the first year of life)

We evaluated seven trials for the morbidities outcome, all of which were conducted in low and middle income countries: four in Asia (Humphrey 1996; Rahmathullah 2003; Semba 2001; Venkatarao 1996), two in Africa (Benn 2008; Benn 2010), and one was multi-centre from Asia, Africa and Latin America (WHO 1998). There were no cluster randomised studies. Simultaneous maternal vitamin A supplementation had been given in two trials (Rahmathullah 2003; Venkatarao 1996). Infant intervention had been initiated in the neonatal period in four studies (Benn 2008; Benn 2010; Humphrey 1996; Rahmathullah 2003). The total vitamin A dose received by the infant was < 50,000 IU in four trials (Benn 2008; Benn 2010; Humphrey 1996; Rahmathullah 2003) and > 50,000 IU in three studies. A single intervention dose had been given in four trials (Benn 2008; Benn 2010; Humphrey 1996; Rahmathullah 2003) and multiple doses in the other three studies. The follow-up age was > 6 months in four trials.

 
Outcome 2.4.1 (Diarrhea)

In six trials providing this data, the pooled risk ratio was 1.02 (95% CI 0.99 to 1.06, P = 0.19; I2= 0%, test for heterogeneity P = 0.55). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.4).

 
Outcome 2.4.2 (Acute respiratory infection or respiratory distress)

In four trials providing this data, the pooled risk ratio was 1.04 (95% CI 0.95 to 1.15, P = 0.38; I2 = 61%, test for heterogeneity P = 0.05) by random-effects modelling and 1.07 (95% CI 1.02 to 1.13, P = 0.004) with the fixed-effect model ( Analysis 2.4).

 
Outcome 2.4.3 (Cough or running nose)

In three trials providing data the pooled risk ratio was 0.98 (95% CI 0.85 to 1.13, P = 0.77; I2 = 69%, test for heterogeneity P = 0.04) by random-effects modelling and 1.01 (95% CI 0.99 to 1.04, P = 0.34) with the fixed-effect model ( Analysis 2.4).

 
Outcome 2.4.4 (Ear infection)

No trial provided data for this outcome.

 
Outcome 2.4.5 (Fever)

In three trials providing this data, the pooled risk ratio was 0.92 (95% CI 0.76 to 1.11, P = 0.39; I2 = 69%, test for heterogeneity P = 0.04) by random-effects modelling and 1.02 (95% CI 0.98 to 1.07, P = 0.24) with the fixed-effect model ( Analysis 2.4).

 
Outcome 2.4.6 (Vomiting)

No trial provided data for this outcome (classified as morbidity).

 
Outcome 2.5 (Adverse effects)

Of the 13 trials reporting adverse effects, three (Rahmathullah 2003; Stabell 1995; Venkatarao 1996) had not recorded any adverse effect (including bulging fontanelle) in either group during the follow-up. In a companion publication to one of these trials (Rahmathullah 2003), it was stated that “side effects, defined as morbidity of the infant associated close in time to the receipt of the study treatment, were uncommon, with six cases occurring in the placebo group and three cases in the vitamin A group” (Tielsch 2007); specific adverse effect data could not therefore be extracted. Pooled estimates of adverse effects were based on data from 10 trials. All these studies were conducted in developing countries (six in Asia, three in Africa, and one was multi-centre from Asia, Africa and Latin America). Klemm 2008 and West 1995 were cluster randomised. Of the 10 trials, nine were assessed to be double blind, all had adequate allocation concealment, and loss to follow-up was < 10% in 8, > 10% in one, and unknown in one. Simultaneous maternal postpartum vitamin A supplementation (> 30% mothers in the intervention arm) had been resorted to in four studies. The vitamin A dose received by the infant was < 50,000 IU in three trials and > 50,000 IU in seven studies. A physician had recorded the adverse effect (bulging fontanelle) in five trials.

 
Outcome 2.5.1 (Bulging fontanelle following any dose of vitamin A)

In the 10 trials providing this data, the pooled risk ratio was 1.55 (95% CI 1.05 to 2.28, P = 0.03; I2 = 68%, test for heterogeneity P = 0.0009) by random-effects modelling and 1.16 (95% CI 0.99 to 1.35, P = 0.06) with the fixed-effect model ( Analysis 2.5).

 
Outcome 2.5.2 (Bulging fontanelle following first dose of vitamin A)

From seven trials providing data, the pooled risk ratio was 1.37 (95% CI 0.98 to 1.91, P = 0.06; I2 = 63%, test for heterogeneity P = 0.01) by random-effects modelling and 1.12 (95% CI 0.96 to 1.31, P=0.15) with the fixed-effect model ( Analysis 2.5).

 
Outcome 2.5.3 (Bulging fontanelle following second dose of vitamin A)

In the two trials providing this data, the pooled risk ratio was 3.60 (95% CI 1.65 to 7.87, P = 0.001; I2 = 0%, test for heterogeneity P = 0.82). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.5).

 
Outcome 2.5.4 (Bulging fontanelle following third dose of vitamin A)

In the two trials providing this data, the pooled risk ratio was 3.14 (95% CI 1.72 to 5.74, P = 0.0002; I2 = 0%, P = 0.32). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.5).

 
Outcome 2.5.5 (Vomiting)

In the four trials providing this data, the pooled risk ratio was 0.81 (95% CI 0.58 to 1.12, P = 0.20; I2= 77%, test for heterogeneity P = 0.005) by the random-effects model and 0.88 (95% CI 0.78 to 0.99, P = 0.03) by the fixed-effect model ( Analysis 2.5).

 
Outcome 2.5.6 (Irritability)

In the four trials providing this data, the pooled risk ratio was 0.98 (95% CI 0.87 to 1.11, P = 0.78; I2 = 0%, test for heterogeneity P = 0.50). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.5).

 
Outcome 2.5.7 (Diarrhea)

In the five trials providing this data, the pooled risk ratio was 0.99 (95% CI 0.75 to 1.31, P = 0.94; I2= 73%, test for heterogeneity P = 0.03) by random-effects modelling and 0.97 (95% CI 0.84 to 1.12, P = 0.69) with the fixed-effect model ( Analysis 2.5).

 
Outcome 2.5.8 (Fever)

In the three trials providing this data, the pooled risk ratio was 1.07 (95% CI 0.96 to 1.20, P = 0.21; I2= 0%, test for heterogeneity P = 0.79). Results were identical with random-effects and fixed-effect modelling ( Analysis 2.5).

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

The main results are depicted in the summary of findings tables, separately for the maternal ( Summary of findings for the main comparison) and young infant ( Summary of findings 2;  Summary of findings 3) supplementation components of the review.

 
Comparison 1: Maternal supplementation

( Summary of findings for the main comparison)

There was no evidence of a reduced risk of all-cause mortality during infancy (high quality evidence) or the neonatal period (moderate quality evidence). Limited data from one to two trials did not indicate a reduced risk of mortality and morbidity due to diarrhoea or acute respiratory infections (ARI) but the quality of evidence was very low (very uncertain of effect). Only two studies reported on adverse effects but no events were recorded in either of them.  

 
Comparison 2: Infant supplementation

( Summary of findings 2)

There was no evidence of a reduced risk of all-cause mortality during infancy (moderate quality evidence with possibilities including 17% benefit and 12% harm). There was considerable heterogeneity between the results of the nine trials (I2 = 49%, P = 0.05), which could not be explained by any of the pre-specified variables including timing of supplementation (neonatal or post-neonatal). The pre-specified subgroup estimates for supplementation within the neonatal and post-neonatal periods did not identify strong evidence of a reduced risk of all-cause mortality during infancy ( Summary of findings 3; moderate quality evidence; a possible 21% reduction and 12% increase in the risk for neonatal supplementation; a possible 16% reduction and 32% increase in the risk for post-neonatal supplementation). There was considerable heterogeneity between the results of the seven trials for neonatal supplementation (I2 = 50%, P = 0.06). There was no strong evidence that vitamin A reduced the risk of neonatal mortality (the confidence interval around the estimated RR included a possible 25% reduction and 8% increase in the risk of mortality ( Summary of findings 2; very low quality evidence). There was no evidence of a reduced risk of mortality and morbidity due to diarrhoea or ARI (moderate quality evidence for ARI-related mortality and low quality evidence for others). However, in 10 trials (32,978 participants) there was weak evidence of an increased risk of bulging fontanelle following any dose of vitamin A (random-effects model RR 1.55, 95% CI 1.05 to 2.28, P = 0.03) but the quality of evidence was graded as low due to limitations in design and inconsistency (I2 = 68%, P = 0.0009).

 

Overall completeness and applicability of evidence

The ensuing description is pertinent to understanding how the results of the review fit into the context of current global practice. The current WHO guidelines on vitamin A supplementation (WHO 2009) were published in 1997 (WHO/UNICEF/IVACG 1997) and 1998 (WHO/MI 1998). In 2000, WHO commissioned reviews of the scientific literature to examine the current state of knowledge concerning the use of vitamin A supplements to control vitamin A deficiency and convened a Technical Consultation on vitamin A supplementation in Yverdon-les-Bains, Switzerland (March 1 to 3, 2000). The objectives of the Consultation were to undertake a critical review of the safety and efficacy of vitamin A supplementation in order to provide WHO with guidance on the use of vitamin A supplementation as a public health measure to prevent and treat vitamin A deficiency. The review and conclusions of the Consultation were published in a special issue of the Food and Nutrition Bulletin in 2001 (de Benoist 2001). However, these have not been published as formal WHO guidelines. Additional research has been conducted since 2001 and the official WHO guidelines on vitamin A supplementation are currently being revised in a systematic manner using the current evidence (WHO 2008).

 
Comparison 1: Maternal supplementation

The studies were conducted in participants and settings directly relevant to the review, namely in low and middle income countries in Asia and Africa, which have endemic vitamin A deficiency and high neonatal and infant mortality rates. However, data specifically restricted to high risk groups (high prevalence of maternal night blindness and low birth weight) were relatively limited.

The WHO/MI 1998 guidelines on supplementation for mothers in the first six months postpartum recommend "single high-dose supplement above 25,000 IU, and usually at a level 200,000 IU, during the safe period of postpartum infertility for mothers in vitamin A deficient areas". These recommendations have not as yet been adopted universally at national levels. The subsequent technical consultation (de Benoist 2001) suggested that: (i) "the postpartum dose of vitamin A to mothers should be increased to 400,000 IU and should be given as two doses of 200,000 IU" and (ii) "as an alternative to large-dose supplementation, mothers can receive vitamin A at any time postpartum, given as a low dose not exceeding 10,000 IU per day or 25,000 IU per week". These recommendations too are not widely adopted in low and middle income countries. In this review, the cumulative dose of vitamin A received by the postpartum mothers was 200,000 IU or more; it was delivered as a single megadose in four studies and as weekly low-dose supplementation in three trials. Thus, the included trials address interventions relevant to the current WHO guidelines for supplementation in vitamin A deficient areas.

Mortality during infancy was reported in seven trials (96,203 participants) whereas neonatal mortality was documented in two large studies (84,537 participants). The identified studies thus sufficiently addressed mortality outcomes, and in particular mortality during infancy, which is the main question of our review. However, cause-specific mortality (two studies), morbidities (one study) and adverse effects (two studies) were not addressed sufficiently to develop firm recommendations.

 
Comparison 2: Infant supplementation

The studies were conducted in participants and settings directly relevant to the review, namely in Asia and Africa in low and middle income countries which had endemic vitamin A deficiency and high neonatal and infant mortality rates. Vitamin A supplementation was either initiated in the neonatal period (seven analytic components) or between one to six months of life (three analytic components). Data on low birth weight babies was available in three studies while one trial was conducted exclusively on low birth weight babies. However, data specifically restricted to mothers with high prevalence of night blindness was relatively limited.

The WHO/MI 1998 guidelines on direct supplementation of infants before six months of age in areas of endemic vitamin A deficiency state that "firm evidence of benefits to breast-feeding infants of direct supplementation before six months of age is insufficient. Studies are in progress to clarify the benefits/risks of single supplementation at 50,000 IU at birth or thereafter, or multiple supplementation at 25,000 IU. Infants who are not breast-fed and who are not given fortified breast-milk substitutes should receive a 50,000 IU supplement, preferably by about 2 months of age - otherwise at any time within the first six months of life. As an alternative two doses of 25,000 IU can be given within an interval of a month or more in between". The subsequent technical consultation (de Benoist 2001) suggested that: "Infants should receive three 50,000 IU (15,000 µgRE) doses of vitamin A within the first six months of life. The three diphtheria-tetanus-pertussis (DTP) immunization contacts at 6, 10, and 14 weeks are thought to be some of the best opportunities to deliver and record these doses". In this review, the cumulative dose of vitamin A received was 25,000 IU to 50,000 IU in trials involving neonatal supplementation and more than 50,000 IU in trials involving supplementation to infants between one to six months of age. Thus the included trials address interventions relevant to framing the current WHO guidelines (WHO 2009) for supplementation in vitamin A-deficient areas.

Mortality during infancy was reported in nine trials (59,402 participants); the identified studies thus sufficiently addressed the main question of the review. Neonatal mortality (three trials), cause-specific mortality (seven studies) and morbidities (four to six studies) were partially addressed but not in a robust manner. The critical safety outcome of bulging fontanelle (10 trials) was addressed in a sufficient number of participants but not in a robust manner.

 

Quality of the evidence

 
Comparison 1: Maternal supplementation

Data on all-cause mortality in the first year of life were available for 96,203 participants from seven trials; the quality of evidence was high with no serious limitations. Neonatal mortality was documented for 84,537 participants in two large trials; the quality of evidence was rated as moderate due to publication bias. The data on cause-specific mortality (5207 participants in two studies) and morbidities (598 participants in one study) were assessed to have very low quality due to serious limitations of study design (allocation concealment and addressing incomplete outcome data) and imprecision or publication bias. Interpretation was not feasible for adverse effects as no events were recorded in the intervention and control groups amongst 700 participants in two studies ( Summary of findings for the main comparison).

 
Comparison 2: Infant supplementation

Data on all-cause mortality in the first year of life were available for 59,402 participants from nine trials. We downgraded the quality of evidence due to inconsistency which could not be adequately explained (I2 = 49%, P = 0.05). Neonatal mortality was documented for 17,000 participants in three trials; the quality of evidence was rated as very low due to limitations in design, imprecision and publication bias. The data on cause-specific mortality (47,998 participants in seven studies) were assessed to have low to moderate quality due to imprecision. The data on morbidities (diarrhoea in 24,802 participants in six studies and respiratory infections in 24,019 participants in four studies) were assessed to have low quality due to limitations of study design and publication bias. Data on adverse effects (bulging fontanelle following any dose of vitamin A in 32,978 participants in 10 studies) were also assessed to have low quality due to serious limitations of study design (one or more aspects in several studies) and inconsistency (heterogeneity I2 = 68%, P = 0.0009) ( Summary of findings 2).

For the pre-specified subgroup analyses for supplementation during the neonatal and post-neonatal periods, data on all-cause mortality in the first year of life were available for 38,865 participants from seven analytic components for neonatal supplementation and 20,537 participants from three analytic components for post-neonatal supplementation. The quality of evidence was rated as moderate due to inconsistency (unexplained heterogeneity I2 = 50%, P = 0.06) and imprecision, respectively ( Summary of findings 3).

 

Potential biases in the review process

 
Comparison 1: Maternal supplementation

 
Strengths

The main conclusion regarding all-cause mortality during the first year of life remained stable over a large spectrum of pre-specified subgroup analyses and there was no heterogeneity (I2 = 0%). The results were invariably synchronous with the use of either random-effects or fixed-effect models. Analysis of seven trials, though admittedly not robust proof, did not indicate evidence of publication bias. Cluster and individually randomised trials were appropriately combined by design effect correction for the primary outcome. Diligent efforts were made to include all relevant trials.

 
Limitations

There were only a few studies providing information on specific high risk groups (maternal night blindness prevalence > 5% and low birth weight infants), which limited the statistical power to detect differences in treatment effect in such participants. Similarly, due to the small number of trials for meta-regression analysis, the statistical power was limited. The initiation of intervention and the follow-up duration were variable, which precluded constitution of a uniform measure across the studies to explore the possibility of a lower RR of mortality in settings with high baseline infant mortality. For cause-specific mortality, we pooled data from studies reporting single or multiple reasons for death, with the underlying philosophy that the assessed cause had contributed to mortality either partially or wholly. We did multiple subgroup and meta-regression analyses for important pre-specified variables, which increased the possibility of false positive results.

Breast feeding is the sole link in transferring vitamin A to the neonate. Breast feeding rates could be documented only in three trials reporting mortality and were 100%. The authors of three other trials were contacted for relevant data but this information was not available. Trials without breast feeding rates were also conducted in countries with a high traditional prevalences of breast feeding and there is no reason to believe that the breast feeding rates in these studies would be any different.

We excluded trials in which participants were HIV positive to factor for potential effect modification by an immunosuppressive condition. In some settings, however, for public health programmes it would be impossible to distinguish such participants from HIV negative participants. However, on including infants born to HIV positive mothers also (Coutsoudis 1999; Fawzi 2002; Humphrey 2006), there was no evidence of a reduced risk of mortality during infancy (random-effects model RR 1.02, 95% CI 0.96 to 1.08, P = 0.597; I2 = 0%) (Figure 4).

 FigureFigure 4. Forest plot for all cause mortality during infancy following maternal postpartum supplementation of Vitamin A after including HIV positive mothers also. The report Humphrey 2006 also includes the data for HIV negative mothers from Malaba 2005.

We excluded controlled trials that did not provide placebo to obviate the possibility of bias due to non-blinding and the 'Hawthorne effect', which has been a contentious issue in relation to defining child survival effect associated with vitamin A supplementation (Adamson 2006; Cravioto 1990; Gopalan 1992; Kapil 2005). Only two trials were excluded due to this reason (Basu 2003; Roy 1997), and in neither of these was information on the primary outcomes available.

 
Comparison 2: Infant supplementation

 
Strengths

Analysis of nine trials, though admittedly not robust proof, indicated no formal evidence of publication bias. Cluster and individually randomised trials were appropriately combined by design effect correction for the primary outcomes. Diligent efforts were made to include all relevant trials. Subgroup and meta-regression analyses relevant to public health policy were performed.

 
Limitations

There were only a few studies providing information on the specific high risk group of maternal night blindness prevalence > 5%, which limited the statistical power to detect differences in mortality risk in such participants. Similarly, due to the small number of trials for meta-regression analysis, the statistical power was limited.The adverse effects were unadjusted for design effect in the two cluster randomised trials. The follow-up duration was variable, which precluded constitution of a uniform measure to explore baseline mortality as a predictor. To evaluate cause-specific mortality, we pooled data from trials reporting a single cause or multiple causes of death, with the underlying philosophy that the assessed cause had contributed to mortality. We did multiple subgroup and meta-regression analyses for important pre-specified variables, which increased the possibility of false positive results.

A moderate to high level of heterogeneity (I2 = 49%, P = 0.05) was observed between the results of the studies. This could not be explained by the pre-specified variables including supplementation age (neonatal or post-neonatal), maternal postpartum vitamin A supplementation, total dose received, maternal night blindness and birth weight at baseline. Additional variables, not examined by us, have been proposed to explain the observed differences.

  1. Effects of micronutrient supplementation are hypothesized to be different between boys and girls, possibly due to variations in micronutrient deficiency prevalences (Webb 2007; Wieringa 2007).
  2. Divergent results may be explained by differences in vaccination intensity because vitamin A supplementation may interact negatively with DPT vaccine in girls (Benn 2008a). In the Guinea-Bissau trial (Benn 2008), a post hoc analysis suggested that once children received DPT vaccine, mortality in girls who had received VAS at birth was significantly two-fold higher compared with girls who had received placebo at birth (Benn 2008a). We could not explore this hypothesis due to paucity of relevant information in the included trials.
  3. The possibility of a strong interaction with season in one trial (Benn 2008) could not be examined in other trials.
  4. The relationship with infant feeding practices was not analysed in the trials.

We excluded controlled trials that did not provide placebo to obviate the possibility of bias due to non-blinding and the 'Hawthorne effect', which has been a contentious issue in relation to defining the child survival effect of vitamin A supplementation (Adamson 2006; Cravioto 1990; Gopalan 1992; Kapil 2005). However, no such additional trial was identified.

We excluded trials conducted on HIV positive participants and neonates born to HIV positive mothers to factor for potential effect modification by an immune-suppressive condition. However, programmatically in some settings, it would be impossible to distinguish such participants from normal HIV negative participants. There was no evidence of a reduced risk of all-cause mortality during infancy on including data from HIV positive mothers (Humphrey 2006) (random-effects model RR 0.99, 95% CI 0.87 to 1.14, P = 0.934; I2 = 55%, P = 0.019) (Figure 5).

 FigureFigure 5. Forest plot for all cause mortality during the first year of life following vitamin A supplementation from birth to six months of age including participants born to HIV positive mothers. Random-effects model estimate was used for pooling.

A key issue for data abstraction in multi-arm and factorial design trials is the choice of the comparison group. The following reasoning influenced our choice of the control group, which comprised participants who were given placebo and whose mothers had received either placebo or no supplementation.

  1. The most satisfactory comparison for policy should replicate envisaged programmatic intervention, and currently simultaneous neonatal or young infant and maternal supplementation is not formally recommended by the WHO and nor is it widely practised. Thus for an appropriate control group, neither the mothers nor the infants should have received the intervention.
  2. Vitamin A transferred through breast milk may interact with the neonatal intervention. Postpartum Vitamin A supplementation to HIV positive mothers whose infants remained polymerase chain reaction-negative at six weeks (Miller 2006) increased their mortality by two years of age (hazards ratio 1.82, 95% CI 0.99 to 3.31, P = 0.05). Other trials of antenatal or postnatal maternal supplementation (Katz 2000; Malaba 2005) also documented an increased mortality risk for offspring (RR 1.05 and 1.26; P > 0.05). Including maternal supplementation in the control group could thus conceivably inflate survival benefit by increasing mortality in the neonatal placebo group.
  3. Relevant factorial-designed trials (Klemm 2008; Malaba 2005) were only powered to detect effect sizes pooled across the various subgroups (maternal supplementation arms). Such pooling is usually justified by post hoc subgroup analyses that show no significant interaction between maternal and newborn supplementation. However, these analyses are underpowered to reveal realistic interactions; the power was only 10% to detect an interaction term (0.88) equivalent to the observed effect size in the maternal placebo subgroup in one study (Klemm 2008). Trials with 80% power for the overall effect have only 29% power to detect an interaction effect of the same magnitude, and even less power for the smaller interactions that are more likely to occur in practice (Brookes 2004). We evaluated the stability of our estimate (random-effects model) by altering the chosen comparison and control groups in the two relevant factorial-designed trials (Klemm 2008; Malaba 2005). On choosing neonatal intervention and control groups irrespective of maternal supplementation status, the sample size of the control component increased in these two trials while the pooled estimate was similar (random-effects model RR 0.98, 95% CI 0.86 to 1.11, P = 0.729; I2 = 58%, P = 0.011). On restricting the analysis to neonatal intervention and control groups whose mothers were either receiving placebo or no supplementation, the sample size of the intervention component diminished in these two trials while the pooled estimates increased marginally (random-effects model RR 0.99, 95% CI 0.86 to 1.13, P = 0.865; I2 = 53%, P = 0.022). Thus the conclusion regarding mortality during infancy remained stable irrespective of the chosen comparison and control groups.

In the Indian trial (Rahmathullah 2003), it is stated that “all analyses were based on intention to treat”. However, for a 'purist' intention-to-treat analysis (Higgins 2008), their mortality risk estimate should also have included “infants whose mothers were randomised but who were not enrolled and received supplementation with vitamin A” (vide Figure 3 of the publication). With such intention-to-treat analysis reconstruction, the trial RR was actually 0.87 (95% CI 0.74 to 1.03, P = 0.109; fixed-effect model), which marginally strengthened the meta-analysis conclusion regarding mortality during infancy (RR 0.98, 95% CI 0.86 to 1.11, P = 0.74; I2 = 40%, P for heterogeneity 0.10; random-effects model).  

 

Agreements and disagreements with other studies or reviews

 
Comparison 1: Maternal supplementation

We were unable to identify a similar systematic review for comparison. However, a recent systematic review evaluated the effect of prenatal or postnatal vitamin A supplementation, or both, on the risk of mother-to-child transmission (MTCT) of HIV and other pregnancy outcomes (Kongnyuy 2009). The review included five trials totaling 7528 women (four trials of prenatal and one trial of postnatal supplementation). Overall, there was no evidence of an effect of prenatal or postnatal vitamin A supplementation on the risk of MTCT of HIV (RR 1.06, 95% CI 0.89 to 1.26). However, prenatal vitamin A supplementation significantly improved birth weight (WMD 89.78, 95% CI 84.7 to 94.8), but there was no evidence of an effect on stillbirths (RR 0.99, 95% CI 0.68 to 1.43), preterm births (RR 0.88, 95% CI 0.65 to 1.19), death before 24 months among live births (RR 1.08, 95% CI 0.91 to 1.29) and maternal death (RR 0.83, 95% CI 0.59 to 1.17). These findings are in agreement with our results for mortality during infancy among live births in non-HIV infected mothers.

 
Comparison 2: Infant supplementation

We could not identify an earlier systematic review focusing on vitamin A supplementation in participants aged between zero and six months or one and six months.

The findings of this review for the subgroup analysis for neonatal supplementation are concordant with our recent systematic review on neonatal vitamin A supplementation (Gogia 2009) for mortality and morbidity outcomes. However, our earlier review did not document an increased risk of bulging fontanelle, which could be related to exclusion of trials providing the intervention between one to six months of age.

The findings of our subgroup analysis for neonatal supplementation are at variance with a recent review (Bhutta 2008) which states “we identified three reported trials of vitamin A supplementation in the neonatal period in low income countries; they showed a 20% reduction in mortality in babies younger than six months (RR 0.80, 95% CI 0.66 to 0.96)”. The following factors could explain the variation from this earlier estimate.

  1. The authors did not explicitly state the inclusion and exclusion criteria, time window of supplementation, choice of control group and analytic plan to derive their estimate (Haider 2008), which makes direct comparison nebulous.
  2. Their comparison group was probably neonatal placebo irrespective of maternal supplementation status, which is different from ours.
  3. Relevant but negative data from four trials (Benn 2008; Benn 2010; Malaba 2005; West 1995) were excluded from their pooling (Haider 2008). In a subsequent reappraisal following correspondence questioning their finding (Sachdev 2008), the authors included data from two of the earlier excluded sources (Bhutta 2008b). This pooled estimate also did not document any convincing evidence of mortality reduction (RR 0.88, 95% CI 0.73 to 1.06, P = 0.19) following supplementation within three days of birth, which is in consonance with our findings.
  4. They selectively evaluated mortality reduction until six months of age (Bhutta 2008b) when three (now four) trials had follow-up extending until one year.

A recent meta-analysis (Kirkwood 2010b) assessed the survival effect of vitamin A given to neonates within a few days of birth in six trials. It documented a pooled RR of 0.93 (95% CI 0.80 to 1.07; I2= 58%, P for heterogeneity 0.005; random-effects model). These findings are in consonance with our subgroup analysis for neonatal supplementation despite exclusion of older neonates from a trial (West 1995) and inclusion of newborns of HIV positive mothers (Humphrey 2006).

It is difficult to explain the differences between the earlier systematic reviews (Beaton 1993; Fawzi 1993; Glasziou 1993) documenting 23% to 30% reduction in childhood mortality following intervention after the age of six months and the findings of our review. However, the following possibilities deserve consideration.

  1. These systematic reviews are quite old and do not take account of several relevant trials which have become available.
  2. There was no evidence of child survival benefit in a trial conducted recently on one million Indian rural children (RR 0.96, 99% CI 0.88 to 1.05), which as yet remains unpublished (Awasthi 2007).
  3. Trials included in the current systematic review have been more recent, when the magnitude and severity of vitamin A deficiency in populations may have diminished.
  4. Causes of mortality in the neonatal period and in early infancy are different from those after six months of age.
  5. In high risk settings, a vitamin A-deficient state is much more likely after the age of six months, when supplementation is more likely to have a beneficial effect.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice
Comparison 1: Maternal supplementation

Public health programmes in developing countries can opt for adopting postpartum VAS for maternal or infant benefits (improving vitamin A nutriture, or reducing morbidity or mortality). As there is no evidence of a mortality (high quality evidence) or morbidity (very low quality evidence) benefit to the infant, these considerations would not alone be sufficient justification for initiating this intervention in public health programmes. However, policy formulation would be based on deliberation of additional consequences including improvement of maternal and infant vitamin A status, maternal benefits (morbidity or mortality), safety and cost-effectiveness.

Comparison 2: Infant supplementation

It is very difficult to justify a public health programme of VAS in the first six months of life because there is no convincing evidence of a mortality (moderate quality evidence) or morbidity (low quality evidence) benefit and simultaneously there is a possibility of an increased risk of an adverse effect of bulging fontanelle (low quality evidence). However, policy formulation would be based on deliberation of additional consequences including infant vitamin A status, long-term safety and cost-effectiveness. The four ongoing studies, on over 100,000 participants, are likely to provide further quality evidence on these issues and address the information gaps. It would therefore be logical to await the results of these trials before formulating any policy.

 
Implications for research
Comparison 1: Maternal supplementation

Considerable research has already been conducted to evaluate the effect of maternal postpartum VAS on infant outcomes. The quality of available evidence for mortality during infancy was rated as high and that for neonatal mortality as moderate. The need for conducting further studies designed solely to evaluate mortality outcomes is therefore questionable. However, there are some information gaps, which must be addressed if any future trials are contemplated: (i) population-based studies examining the role of VAS in specific high risk conditions like high prevalence of maternal night blindness and low birth weight infants; (ii) effect on morbidities, and (iii) adverse reactions.

Comparison 2: Infant supplementation

Considerable research has already been conducted to evaluate the effect of VAS in the first six months of life on infant outcomes. The quality of available evidence for mortality during infancy was rated as moderate, for neonatal mortality as very low, and for other outcomes as low. There is also limited information in participants with a high prevalence of maternal night blindness. The four ongoing studies on over 100,000 participants are designed to address the outstanding issues of quality and information gaps. It would therefore be logical to await the results of these trials before any further research is contemplated.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

The authors thank the Cochrane Editorial Unit, especially Toby Lasserson, Karla Soares-Weiser and Harriet MacLehose, for their advise and tremendous support in preparing the table on 'Characteristics of included studies', the 'Risk of bias' tables and the 'Summary of findings' tables for this 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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Maternal vitamin A supplementation versus placebo

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

 1 Mortality in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    1.1 Postpartum vitamin A supplementation
7Risk Ratio (Random, 95% CI)1.00 [0.94, 1.06]

    1.2 Maternal nightblindness prevalence <5%
2Risk Ratio (Random, 95% CI)1.02 [0.85, 1.22]

    1.3 Maternal nightblindness prevalence >5%
1Risk Ratio (Random, 95% CI)1.02 [0.79, 1.32]

    1.4 Cumulative vitamin A dose<200000 IU
1Risk Ratio (Random, 95% CI)1.54 [0.31, 7.63]

    1.5 Cumulative vitamin A dose>200000 IU
6Risk Ratio (Random, 95% CI)1.00 [0.93, 1.06]

    1.6 Maternal serum retinol ≤1.1 µmol/l
2Risk Ratio (Random, 95% CI)1.04 [0.88, 1.23]

    1.7 Maternal serum retinol>1.1µmol/l
3Risk Ratio (Random, 95% CI)0.99 [0.92, 1.06]

 2 Mortality in the first month of life2Risk Ratio (Random, 95% CI)0.98 [0.87, 1.11]

 3 Cause specific mortality in the first year of life2Risk Ratio (Random, 95% CI)Subtotals only

    3.1 ARI
2Risk Ratio (Random, 95% CI)1.59 [0.84, 2.99]

    3.2 Diarrhoea
2Risk Ratio (Random, 95% CI)2.57 [0.72, 9.12]

    3.3 Others
2Risk Ratio (Random, 95% CI)0.62 [0.09, 4.09]

 
Comparison 2. Young infant vitamin A supplementation versus placebo

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

 1 Mortality in the first year of life9Risk Ratio (Random, 95% CI)Subtotals only

    1.1 Vitamin A supplementation in first 6 months of life
9Risk Ratio (Random, 95% CI)0.97 [0.83, 1.12]

    1.2 Neonatal vitamin A supplementation
7Risk Ratio (Random, 95% CI)0.94 [0.79, 1.12]

    1.3 Post neonatal Vitamin A supplementation
3Risk Ratio (Random, 95% CI)1.05 [0.84, 1.32]

    1.4 Cumulative vitamin A dose received <=50,000 IU
7Risk Ratio (Random, 95% CI)0.94 [0.79, 1.12]

    1.5 Cumulative vitamin A dose received >50,000 IU
3Risk Ratio (Random, 95% CI)1.05 [0.84, 1.32]

    1.6 With concomitant maternal vitamin A supplementation
4Risk Ratio (Random, 95% CI)1.00 [0.81, 1.23]

    1.7 Without concomitant maternal vitamin A supplementation
5Risk Ratio (Random, 95% CI)0.93 [0.74, 1.17]

    1.8 Low birthweight
4Risk Ratio (Random, 95% CI)0.84 [0.65, 1.07]

    1.9 Normal birthweight
3Risk Ratio (Random, 95% CI)0.78 [0.43, 1.40]

    1.10 Maternal nightblindness prevalence <5%
2Risk Ratio (Random, 95% CI)1.06 [0.83, 1.34]

    1.11 Maternal nightblindness prevalence>5%
2Risk Ratio (Random, 95% CI)0.83 [0.71, 0.96]

 2 Mortality in the first month of life3Risk Ratio (Random, 95% CI)0.90 [0.75, 1.08]

 3 Cause specific mortality in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    3.1 Diarrhoea
7Risk Ratio (Random, 95% CI)1.01 [0.72, 1.41]

    3.2 ARI
7Risk Ratio (Random, 95% CI)1.12 [0.91, 1.39]

    3.3 Others
7Risk Ratio (Random, 95% CI)0.81 [0.64, 1.02]

 4 Morbidity in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    4.1 Diarrhoea
6Risk Ratio (Random, 95% CI)1.02 [0.99, 1.06]

    4.2 Acute respiratory infection or respiratory difficulty
4Risk Ratio (Random, 95% CI)1.04 [0.95, 1.15]

    4.3 Cough or running nose
3Risk Ratio (Random, 95% CI)0.98 [0.85, 1.13]

   4.4 Ear infection
0Risk Ratio (Random, 95% CI)0.0 [0.0, 0.0]

    4.5 Fever
3Risk Ratio (Random, 95% CI)0.92 [0.76, 1.11]

   4.6 Vomiting
0Risk Ratio (Random, 95% CI)0.0 [0.0, 0.0]

 5 Adverse effects of vitamin A supplementation10Risk Ratio (Random, 95% CI)Subtotals only

    5.1 Bulging fontanelle following any dose of vitamin A
10Risk Ratio (Random, 95% CI)1.55 [1.05, 2.28]

    5.2 Bulging fontanelle following first dose of vitamin A
7Risk Ratio (Random, 95% CI)1.37 [0.98, 1.91]

    5.3 Bulging fontanelle following second dose of vitamin A
2Risk Ratio (Random, 95% CI)3.60 [1.65, 7.87]

    5.4 Bulging fontanelle following third dose of vitamin A
2Risk Ratio (Random, 95% CI)3.14 [1.72, 5.74]

    5.5 Vomiting
4Risk Ratio (Random, 95% CI)0.81 [0.58, 1.12]

    5.6 Irritability
4Risk Ratio (Random, 95% CI)0.98 [0.87, 1.11]

    5.7 Diarrhoea
3Risk Ratio (Random, 95% CI)0.99 [0.75, 1.31]

    5.8 Fever
5Risk Ratio (Random, 95% CI)1.07 [0.96, 1.20]

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Data Abstraction

General

  • For computing the summary relative risk, we required individual study risk ratio (RR) and 95% CI or standard error (SE). In a hierarchical pattern, we gave preference to the RR stated by authors with a recheck of the calculations from the stated numbers. If RR was not stated, it was computed with the following preference order for the denominator - stated child-years, numbers with definite outcome known till completion of intervention period, or number randomized.
  • Where necessary and possible, an intention to treat analysis was reconstructed from the available data.
  • In the case where no events (or all events) were observed in both groups the trial provided no information about relative probability of the event and was automatically omitted from the meta-analysis.
  • If stratified data in relation to time point of starting supplementation was not available, then supplementation grouping was done as per the initiation time in >75% of participants.
  • The term apparently healthy was used for the group of participants who had no obvious clinical morbidity and in whom HIV serology, if performed, was negative in > 75% of subjects.

Specific

Ayah 2007

Mortality outcome is available only till 14 weeks of age, the time point of initiating infant vitamin A supplementation. Thus for evaluating effect of maternal vitamin A supplementation in comparison to placebo, both groups of maternal supplementation (irrespective of infant vitamin A supplementation later) and both groups of maternal placebo (irrespective of infant vitamin A supplementation later) were merged for calculating RR and 95% CI. 

Benn 2008

Actual death counts in the first seven days of life are available. However, the quantification of the small number of subjects recruited after seven days of life is not available. Thus the denominator for risk calculations was taken as the vital status known at the end of the study.

Benn 2010

The numbers for Additional  Table 3 were derived from Figure 2 and  Table 4 of the report.

The cause specific mortality, ascertained by verbal autopsy as a single cause of death, was depicted only as graph in Figure 5 in the publication. The authors responded to our request to provide detailed data. The rate ratios are adjusted for gender, randomization to BCG vaccine and inter-dependency for multiple births. Mortality due to diarrhea had a RR 1.0; 95% CI 0.42 to 2.38 (Vitamin A: 10/757 and Placebo: 10/762). Mortality due to respiratory infections had a RR 0.87; 95% CI 0.42 to 1.82 (Vitamin A: 13/757 and Placebo: 15/762). Mortality due to causes other than diarrhea and respiratory infections had a RR 1.15; 95% CI 0.79 to 1.67 (Vitamin A: 60/757 and Placebo: 53/762).

The morbidity data on diarrhea was reported in Diness 2010 for a subsample of 287 infants during annual rotavirus epidemic from Januray through March 2005. We extracted the data for all diarrheal episodes (irrespective of etiology) till infancy from Tables 3 and 5 by combining non-rotavirus diarrhea and rota virus diarrhea for both age groups (1-5 months and 6-9 months). The calculated RR was 1.02; 95% CI 0.79 to 1.31 (Vitamin A:123/7377 and Placebo 137/8396 days at risk).

Humphrey 1996

Mean birth weight was calculated from percentages of birth-weight categories in  Table 2 (page 492), assuming the mid point of birth-weight distributions for 1500-2499 g (2000 g), 2500 3499 g (3000 g), and 3500 g for the category > 3500 g. The average of Vitamin A and control groups was computed as the mean birth-weight, which was 2.97 kg.

Klemm 2008

A recalculation of the RRs and 95% CIs was required for the two reviews, which was based on the stratified data provided by the authors of this study in the detailed  Table 1. For this recalculation, appropriate adjustment was made for the design effect calculated (1.01769) from the numbers, and the stated RR and 95% CI for the mortality effect of neonatal vitamin A supplementation irrespective of maternal supplementation status. In the maternal supplementation review comparison, the intervention group comprised maternal vitamin A supplementation and neonatal placebo whereas the control group comprised placebo administration to both the newborn and the mother; the calculated RR and 95% CI were 1.0193 (0.7861, 1.3216). The numbers for Additional  Table 1 of this review were derived from the  Table 1 of the report; as this table or the text or tables elsewhere in the report do not mention the loss to follow-up in these sub-groups specifically, it is not possible to calculate the number randomized. In the young infant supplementation review comparison, the intervention group comprised neonatal vitamin A supplementation irrespective of maternal supplementation status whereas the control group comprised placebo administration to both the newborn and the mother; the calculated RR and 95% CI were 0.8806 (0.7080, 1.0953). The numbers for Additional  Table 3 of this review were derived from the Figure 2 and  Table 1 of the report; as this table or the text or tables elsewhere in the report do not mention the loss to follow-up in control subgroup specifically, it is not possible to calculate the number randomized for controls. A similar recalculation was not possible for the adverse effects analysis, in which the actual numbers were used (without design effect) for neonatal vitamin A supplemented and placebo groups irrespective of the maternal supplementation status.

 

Malaba 2005

For recalculation of the RRs according to all cause mortality, the number of deaths due to congenital abnormalities and injuries were added to each factorial group results in  Table 4, page 459 (3 in Aa and 2 each in other groups) and the denominator taken as person years in Statsdirect software for RR meta-analysis. For infant mortality the intervention numbers were 93/4195 (Aa + Pa) and pure placebo (Pp) numbers were 38/2120; the calculated RR and 95% CI were 1.2368 (0.8534, 1.7942). For maternal mortality the intervention numbers (Ap) were 48/2119; the calculated RR and 95% CI were 1.2638 (0.8319, 1.9202). Mean maternal serum retinol values (postpartum) are not available. However, the percentage of serum retinol deficient women with the cut-off level of 1.05 micro moles/L was similar to that of Klemm, 2008 (18) for the first trimester. Assuming the same distribution of serum retinol, the mean serum retinol levels were presumed to be equal to this study. 

Rahmathullah 2003

In the report Tielsch 2007, case fatality data is available following common morbidities for 60 day period following the episode, and numbers of deaths for this data (assuming no overlap of morbidities) are only 249 out of a total of 334 (75%) deaths recorded in the primary study . It is not possible to derive cause specific mortality data from this information. Information on the specific type of adverse effect recorded is missing as also the specific time period for recording adverse effects after the intervention.

The cause specific mortality was extracted from the web table of the publication. Mortality due to diarrhea had a RR 0.5; 95% CI 0.25 to 1.0 (Vitamin A: 12/2713 and Placebo: 24/2719 person-years). Moratlity due to respiratory causes (aspiration pneumonia, bronchopneumonia and respiratory distress syndrome) had a RR 1.13; 95% CI 0.76 to 1.67 (Vitamin A: 53/2713 and Placebo: 47/2719 person years). Mortality due to causes other than diarrhea and respiratory infections had a RR 0.69; 95% CI 0.52 to 0.92 (Vitamin A: 81/2713 and Placebo: 117/2719 person years).

For morbidity outcome, diarrhea and dysentery ( Table 2) were combined as the two were mutually exclusive by definition; the pooled RR and 95% CI were calculated by generic inverse variance (fixed and random estimates were identical). ARI1 was categorized as cough or running nose and ARI2 as acute respiratory infection or respiratory difficulty. 

Semba 2001

For the morbidity analyses, the two vitamin A intervention groups (25,000 IU and 50,000 IU) were pooled by the approximate method feasible in SPSS software. 

Venkatarao 1996

For the maternal supplementation comparison, the data on mortality outcome pertains to AP and PP groups only as the mortality after 6 months age cannot be ascertained according to the different treatment arms. For the infant supplementation comparison, the data on mortality after initiating vitamin A supplementation (mortality after 6 months) cannot be extracted, and hence this outcome could not be included. For recalculating for the morbidity analyses, for AP + AA groups versus PP for 0-6 months, AP versus PP for 6-12 months, and AA versus PP for 6-12 months, the total number of person years was taken from the number stated by the author (denominator) in  Table 2 (page 283).

No adverse effects were observed in any of the three groups. 

West 1995

In the two independent analytic components (split according to the age of initiation of vitamin A supplementation, namely 0-1 months and 1-6 months), the RRs and 95% CIs were calculated according to the person-year follow-up given in  Table 4 and inflated by 10% for cluster correction as per the methods section. The calculated RR and 95% CI for the mortality analysis in the 1-6 months group was 1.12 (0.83, 1.51). 

WHO 1998

Of the 233 infants who had died by age 12 months, information on the cause of death was available for 203 deaths, which was sought from and received from the authors.

 

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 4, 2008
Review first published: Issue 10, 2011

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Both the authors prepared the protocol, applied the search strategy, retrieved the articles, extracted data, performed the risk of bias assessment, and did the statistical analysis. Both authors contributed to the drafting of the final version of the paper and act as joint guarantors.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. 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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • Sitaram Bhartia Institute of Science and Research, B-16 Qutab Institutional Area, Delhi 110016, India.
    for time support for Prof. Sachdev and Dr. Gogia till December 2009.
  • Max Hospital, Gurgaon, Haryana, India.
    for time support for Dr. Gogia from January 2010.

 

External sources

  • Department of Nutrition for Health and Development, World Health Organization, Switzerland.
    for providing funding for the preparation and update of this review.
  • Child and Adolescent Health Division, World Health Organization, Switzerland.
    for providing funding for the initial preparation of this review.

 

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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Search strategy was reapplied on October 15, 2010 to include all relevant studies till that period. The Risk of Bias assessment was increased to include all the six headings now followed by The Cochrane Collaboration instead of the four specified earlier.

 

Index terms

  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. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Medical Subject Headings (MeSH)

*Developing Countries; *Dietary Supplements [adverse effects]; *Infant Mortality; Breast Feeding; Cause of Death; Diarrhea [epidemiology]; Infant, Newborn; Lactation; Milk, Human [chemistry]; Postpartum Period; Randomized Controlled Trials as Topic; Respiratory Tract Infections [epidemiology]; Vitamin A [*administration & dosage; adverse effects; physiology]; Vitamin A Deficiency [mortality; *therapy]; Vitamins [*administration & dosage; adverse effects]

MeSH check words

Female; Humans; Infant

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  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. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Ayah 2007 {published data only}
  • Ayah RA, Mwaniki DL, Magnussen P, Tedstone AE, Marshall T, Alusala D, et al. The effects of maternal and infant vitamin A supplementation on vitamin A status: a randomised trial in Kenya. The British Journal of Nutrition 2007;98(2):422-30. [PUBMED: 17391562]
Baqui 1995 {published data only}
  • Baqui AH, de Francisco A, Arifeen SE, Siddique AK, Sack RB. Bulging fontanelle after supplementation with 25,000 IU of vitamin A in infancy using immunization contacts. Acta Paediatrica (Oslo, Norway: 1992) 1995;84(8):863-6. [PUBMED: 7488807]
Benn 2008 {published and unpublished data}
  • Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, et al. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ 2008;336(7658):1416-20. [PUBMED: 18558641]
  • Nante JE, Diness BR, Ravn H, Roth A, Aaby P, Benn CS. No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette-Guerin vaccination to normal-birth-weight newborns in Guinea-Bissau. European Journal of Clinical Nutrition 2008;62(7):842-8. [PUBMED: 17538544]
Benn 2010 {published data only (unpublished sought but not used)}
  • Benn CS, Fisker AB, Napirna BM, Roth A, Diness BR, Lausch KR, et al. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial. BMJ 2010;340:c1101. [PUBMED: 20215360]
  • Diness BR, Christoffersen D, Pedersen UB, Rodrigues A, Fischer TK, Andersen A, et al. The effect of high-dose vitamin A supplementation given with Bacille Calmette-Guerin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau. Journal of Infectious Diseases 2010;202(Supplement):S241-51.
Bhaskaram 1998 {published data only}
  • Bhaskaram P, Balakrishna N. Effect of administration of 200,000 IU of vitamin A to women within 24 hrs after delivery on response to PPV administered to the newborn. Indian Pediatrics 1998;35(3):217-22. [PUBMED: 9707874]
de Francisco 1993 {published data only}
  • de Francisco A, Chakraborty J, Chowdhury HR, Yunus M, Baqui AH, Siddique AK, et al. Acute toxicity of vitamin A given with vaccines in infancy. Lancet 1993;342(8870):526-7. [PUBMED: 8102669]
Humphrey 1996 {published data only}
  • Agoestina T, Humphrey JH, Taylor GA, Usman A, Subardja D, Hidayat S, et al. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Bulletin World Health Organisation 1994;72(6):859-68.
  • Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. Journal of Pediatrics 1996;128(4):489-96.
Katz 2000 {published data only}
  • Katz J, West KP Jr, Khatry SK, Pradhan EK, LeClerq SC, Christian P, et al. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. The American Journal of Clinical Nutrition 2000;71(6):1570-6. [PUBMED: 10837300]
Kirkwood 2010 {published data only}
  • Kirkwood BR, Hurt L, Amenga-Etego S, Tawiah C, Zandoh C, Danso S, et al. Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial. Lancet 2010;375(9726):1640-9. [PUBMED: 20435345]
Klemm 2008 {published data only}
  • Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008;122(1):e242-50. [PUBMED: 18595969]
Malaba 2005 {published data only}
  • Iliff PJ, Humphrey JH, Mahomva AI, Zvandasara P, Bonduelle M, Malaba L, et al. Tolerance of large doses of vitamin A given to mothers and their babies shortly after delivery. Nutrition Research 1999;19(10):1437-46.
  • Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. The American Journal of Clinical Nutrition 2005;81(2):454-60.
Newton 2005 {published data only}
  • Newton S, Cousens S, Owusu-Agyei S, Filteau S, Stanley C, Linsell L, et al. Vitamin a supplementation does not affect infants' immune responses to polio and tetanus vaccines. The Journal of Nutrition 2005;135(11):2669-73. [PUBMED: 16251628]
Rahmathullah 2003 {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;58(6):837-47. [PUBMED: 1818881]
  • Rahmathullah L, Tielsch JM, Thulasiraj RD, Bloem MW, Osrin D. Supplementing newborn infants with vitamin A reduces mortality at age 6 months. Evidence-Based Healthcare 2004;8:30-2.
  • Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003;327(7409):254.
  • Tielsch JM, Rahmathullah L, Thulasiraj RD, Katz J, Coles C, Sheeladevi S, et al. Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India. The Journal of Nutrition 2007;137(11):2470-4.
Semba 2001 {published data only}
  • Semba RD, Munasir Z, Akib A, Melikian G, Permaesih D, Muherdiyantiningsih, et al. Integration of vitamin A supplementation with the Expanded Programme on Immunization: lack of impact on morbidity or infant growth. Acta Paediatrica 2001;90(10):1107-11. [PUBMED: 11697418]
Stabell 1995 {published data only}
  • Stabell C, Balé 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;49(1):73-4. [PUBMED: 7713054]
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;33(4):279-86. [PUBMED: 8772901]
West 1995 {published data only}
  • West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, et al. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. The American Journal of Clinical Nutrition 1995;62(1):143-8. [PUBMED: 7598058]
  • West KP Jr, Khatry SK, LeClerq SC, Adhikari R, See L, Katz J, et al. Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal. Bulletin of the World Health Organization 1992;70(6):733-9. [PUBMED: 1486669]
WHO 1998 {published and unpublished data}
  • WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 1998;352(9136):1257-63. [PUBMED: 9788455]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  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. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Basu 2003 {published data only}
  • Basu S, Sengupta B, Paladhi PK. Single megadose vitamin A supplementation of Indian mothers and morbidity in breastfed young infants. Postgraduate Medical Journal 2003;79(933):397-402. [PUBMED: 12897218]
Benn 2000 {published data only}
  • 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;20(4):259-64. [PUBMED: 11219162]
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;64(4):503-9.
Coles 2001 {published data only}
  • Coles CL, Rahmathullah L, Kanungo R, Thulasiraj RD, Katz J, Santhosham M, et al. Vitamin A supplementation at birth delays pneumococcal colonization in South Indian infants. The Journal of Nutrition 2001;131(2):255-61. [PUBMED: 11160543]
Coutsoudis 1999 {published data only}
  • Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. South African Vitamin A Study Group. AIDS 1999;13(12):1517-24.
  • Kennedy CM, Coutsoudis A, Kuhn L, Pillay K, Mburu A, Stein Z, et al. Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and postpartum among HIV-infected women. Journal of Acquired Immune Deficiency Syndromes 2000;24(1):37-44. [PUBMED: 10877493]
Dimenstein 2007 {published data only}
  • Dimenstein R, Lourenco RM, Ribeiro KD. Impact on colostrum retinol levels of immediate postpartum supplementation with retinyl palmitate [Impacto da suplementacao com retinil palmitato no pos-parto imediato sobre os niveis de retinol do colostro ]. Revista Panamericana de Salud Publica = Pan American Journal of Public Health 2007;22(1):51-4. [PUBMED: 17931488]
Fawzi 2002 {published data only}
  • Fawzi WW, Msamanga GI, Hunter D, Renjifo B, Antelman G, Bang H, et al. Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality. AIDS 2002;16(14):1935-44.
  • Fawzi WW, Msamanga GI, Spiegelman D, Urassa EJ, McGrath N, Mwakagile D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998;351(9114):1477-82. [PUBMED: 9605804]
Humphrey 2006 {published data only}
  • Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. The Journal of Infectious Diseases 2006;193(6):860-71. [PUBMED: 16479521]
Kumwenda 2002 {published data only}
  • Kumwenda N, Miotti PG, Taha TE, Broadhead R, Biggar RJ, Jackson JB, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clinical Infectious Diseases 2002;35(5):618-24.
Mahalanabis 1997 {published data only}
  • Mahalanabis D, Rahman MM, Wahed MA, Islam MA, Habte D. Vitamin A megadoses during early infancy on serum retinol concentration and acute side effects and residual effects on 6 month follow-up. Nutrition Research 1997;17(4):649-9.
Miller 2006 {published data only}
  • Miller MF, Stoltzfus RJ, Iliff PJ, Malaba LC, Mbuya NV, Humphrey JH. Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study. The American Journal of Clinical Nutrition 2006;84(1):212-22. [PUBMED: 16825698]
Newton 2007 {published data only}
  • Newton S, Owusu-Agyei S, Ampofo W, Zandoh C, Adjuik M, Adjei G, et al. Vitamin A supplementation enhances infants' immune responses to hepatitis B vaccine but does not affect responses to Haemophilus influenzae type b vaccine. The Journal of Nutrition 2007;137(5):1272-7. [PUBMED: 17449592]
Rahman 1995 {published data only}
  • Rahman MM, Mahalanabis D, Wahed MA, Islam MA, Habte D. Administration of 25,000 IU vitamin A doses at routine immunisation in young infants. European Journal of Clinical Nutrition 1995;49(6):439-45. [PUBMED: 7656887]
Rahman 1996 {published data only}
  • Rahman MM, Mahalanabis D, Alvarez JO, Wahed MA, Islam MA, Habte D, et al. Acute respiratory infections prevent improvement of vitamin A status in young infants supplemented with vitamin A. The Journal of Nutrition 1996;126(3):628-33. [PUBMED: 8598547]
Rahman 1997 {published data only}
  • Rahman MM, Mahalanabis D, Alvarez JO, Wahed MA, Islam MA, Habte D. Effect of early vitamin A supplementation on cell-mediated immunity in infants younger than 6 mo. The American Journal of Clinical Nutrition 1997;65(1):144-8. [PUBMED: 8988926]
Rahman 1998 {published data only}
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Rahman 1999 {published data only}
  • Rahman MM, Mahalanabis D, Hossain S, Wahed MA, Alvarez JO, Siber GR, et al. Simultaneous vitamin A administration at routine immunization contact enhances antibody response to diphtheria vaccine in infants younger than six months. The Journal of Nutrition 1999;129(12):2192-5. [PUBMED: 10573548]
Rao 1976 {published data only}
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Rice 1999 {published data only}
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Rice 2000 {published data only}
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Roy 1997 {published data only}
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Schmidt 2002 {published data only}
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Stoltzfus 1993 {published data only}
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Vinutha 2000 {published data only}
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References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  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. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Bhandari 2010 {unpublished data only}
  • Bhandari N, et al. Efficacy of neonatal vitamin A supplementation in improving child survival in Haryana, India: generation of evidence necessary for informing global policy - NeoVitA Trial. Ongoing study June 2010.
Bhutta 2010 {unpublished data only}
  • Bhutta ZA, et al. Newborn Vitamin A (VA) Supplementation Pilot Project, Pakistan. Ongoing study January 2007.
Edmond 2010 {unpublished data only}
  • Edmond K, et al. Efficacy of newborn vitamin A supplementation in improving child survival in rural Ghana: generation of evidence necessary for informing global policy - - NeoVitA. Ongoing study August 2010.
Fawzi 2010 {unpublished data only}
  • Fawzi W, et al. Efficacy of newborn vitamin A supplementation in improving child survival in Tanzania: generation of evidence necessary for informing global policy - Neovita. Ongoing study August 2010.

Additional references

  1. Top of page
  2. AbstractRésumé
  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. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
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