Routine vitamin A supplementation for the prevention of blindness due to measles infection in children

 

Summary of findings    [Explanations]

 

Summary of findings for the main comparison.

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Vitamin A compared with placebo or no vitamin A for prevention of blindness
Patient or population: children with measles infection and no clinically demonstrable vitamin A deficiency Settings: resource-limited countries Intervention: vitamin A Comparison: placebo or no vitamin A
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Vitamin A
Blindness	See comment		Not estimable	260 (2 studies)	See comment	None of the studies reported blindness as an end point
Serum retinol (1 week post-intervention) (mean X [µg/dL] ± standard error SE)	X ± SE in the placebo group was 29.0 ± 2.2 (95% CI 24.8 to 33.3)	X ± SE in the intervention group was 38.5 ±3.0 (95% CI 32.6 to 44.4)	9.5 higher (2.2 higher to 16.7 higher)	17 (1 study)	+++O moderate
Serum retinol (2 weeks post-intervention) (mean X [µg/dL] ± standard error SE)	X ± SE in the placebo group was 19.0 ± 0.7 (95% CI 17.6 to 20.3)	X ± SE in the intervention group was 21.6 ± 1.1 (95% CI 19.5 to 23.7)	2.7 higher (0.3 lower to 5.6 higher)	155 (1 study)	+++O moderate
Serum retinol (6 weeks post-intervention) (mean X [µg/dL] ± standard error SE)	X ± SE in the placebo group was 28.5 ± 2.4 (95% CI 23.86 to 33.12)	X ± SE in the intervention group was 31.1 ± 3.2 (95% CI 24.7 to 37.4)	2.6 higher (5.3 lower to 10.4 higher)	39 (1 study)	+++O moderate
Serum retinol (mean change 1 week post-intervention (mean X [µg/dL] ± standard error SE)	X ± SE in the placebo group was 17.3 ± 1.9 (95% CI 13.7 to 21.0)	X ± SE in the placebo group was 26.0 ± 3.3 (95% CI 19.6 to 32.4)	8.6 higher (1.2 higher to 16.0 higher)	17 (1 study)	+++O moderate
Weight gain 6 weeks post-intervention (mean X [kg] ± standard error SE)	X ± SE in the placebo group was 0.9 ± 0.1 (95% CI 0.6 to 1.2)	X ± SE in the intervention group was 1.3 ± 0.2 (95% CI 1.3 to 1.3)	0.4 higher (0.04 lower to 0.8 higher)	48 (1 study)	+++O moderate
Weight gain 6 months post-intervention (mean X [kg] ± standard error SE)	X ± SE in the placebo group was 2.4 ± 0.2 (95% CI 2.0 to 2.8)	X ± SE in the intervention group was 2.9 ± 0.2 (95% CI 2.4 to 3.3)	0.5 higher (0.1 lower to 1.1 higher)	36 (1 study)	+++O moderate
Other ocular morbidities (night blindness, conjunctival xerosis, Bitot's spot, corneal xerosis, xerophthalmia, corneal ulceration, corneal scars)	See comment		Not estimable	260 (2 studies)	See comment	None of the studies reported ocular morbidities as end points.
Adverse events	See comment		Not estimable	260 (2 studies)	See comment	0 participants had adverse events
*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; SE: standard error; GRADE: GRADE Working Group grades of evidence (see explanations)

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 Assumed risk and corresponding risk in the table are from a single study in each case, and are not the usual combined mean or median risks across multiple studies.
GRADE Working Group grades of evidence
High quality (++++): Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality (+++O): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality (++OO): 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 (+OOO): We are very uncertain about the estimate.

 

Background

 

Description of the condition

The World Health Organization (WHO) defines blindness as a corrected visual acuity in the better eye of less than 3/60 (Gilbert 2001). The measles virus causes blindness by reducing the serum concentration of vitamin A, which is needed for maintenance of epithelial surfaces such as corneas. Vitamin A deficiency subsequently causes dryness and scarring of the cornea. Serum vitamin A concentrations in well-nourished children with measles have been reported to be lower than those in malnourished children without measles (Chan 1990).

The major causes of blindness in children vary widely from region to region and are related to the level of socio-economic development of the community. In high-income countries, lesions of the optic nerve and higher visual pathways predominate as the cause of blindness, while corneal scarring from measles, vitamin A deficiency, use of harmful traditional eye remedies and ophthalmia neonatorium are the major causes in low-income countries (Gilbert 2001). 

The prevalence of blindness also has a direct correlation with the level of socio-economic development and the under five mortality rate (Gilbert 2003). The prevalence ranges from about 3 per 10,000 in high-income communities to 15 per 10,000 in low-income communities. Annually 500,000 children become blind worldwide, 75% of them living in low-income countries (Gilbert 2003; Nemer 2001). Blind children have a high death rate and the prevalence, therefore, markedly underestimates the burden of disease (Gilbert 2003). Vitamin A deficiency has been strongly implicated as a major cause of blindness in children, especially in low-income countries.

 

Description of the intervention

Vitamin A is a fat-soluble substance stored in the liver and is released as needed into the blood stream (Al-Kubaisy 2002). It is required for the maintenance of epithelial surfaces, immune competence, normal functioning of the retina, growth and development and reproduction (Potter 1997). As vitamin A levels decrease, total body reserves of vitamin A are depleted first, followed by a diminished concentration of serum retinol. This leads to abnormalities in tissue function. Xerophthalmia (drying of the conjunctiva from changes resulting from vitamin A deficiency) results in ocular manifestations: night blindness, corneal ulceration, scarring and consequent blindness (Al-Kubaisy 2002; Potter 1997). The WHO cut-off value indicative of sub-clinical vitamin A deficiency is a serum retinol level of < 20 µg/dL (0.7 µmol/L) (Al-Kubaisy 2002). 

Vitamin A deficiency is a major cause of paediatric ocular morbidity and the leading cause of childhood blindness. Annually, over five million children develop xerophthalmia and 250,000 children become blind. Vitamin A deficiency is caused by dietary inadequacy, unmet physiological needs and cultural factors.

Measles is a precipitating factor in blindness from vitamin A deficiency, particularly in Africa (Sommer 1990). Measles causes corneal blindness through several mechanisms, including vitamin A deficiency (Gilbert 2003). When mild or severe forms of vitamin A deficiency are present, it is associated with increased morbidity and mortality from respiratory and diarrhoeal complications of measles. These complications not only increase the requirement for vitamin A but decrease its intake by reduced appetite (Nemer 2001). 

Vitamin A deficiency is widespread and particularly prevalent in Africa and South East Asia, where about three million children under the age of five show signs of xerophthalmia. In 1998 the WHO estimated that vitamin A deficiency was a problem in 118 countries. Annually, an estimated 250,000 to 500,000 children with the severest deficiencies become blind and even larger numbers die of preventable infectious diseases such as diarrhoea and measles (Nemer 2001).

 

How the intervention might work

Supplying vitamin A to children suffering measles may reverse the mechanism of blindness. Some evidence suggests that vitamin A supplements may be a cheap and effective way of preventing death and complications in children with measles (Chan 1990). 

 

Why it is important to do this review

The control of blindness in children is considered a high priority within the WHO's VISION 2020 The Right to Sight Program (Gilbert 2001). The benefit of vitamin A in reducing mortality in children with measles has been widely reported (Yang 2009). We aim to determine the benefit or otherwise of vitamin A in preventing blindness in children with measles infection. 

 

Objectives

To assess the efficacy of vitamin A in preventing blindness in children infected with measles. 

 

Methods

 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs) that assess the efficacy of vitamin A in preventing blindness in children diagnosed with measles but with no prior clinical features of vitamin A deficiency and who are not malnourished. We excluded studies with participants that had clinically demonstrable vitamin A deficiency.

 

Types of participants

Children 18 years or younger diagnosed with measles, with no prior clinical features of vitamin A deficiency. We excluded studies that included children with ocular abnormalities unrelated to vitamin A deficiency.

 

Types of interventions

Vitamin A versus placebo or no vitamin A.

 

Types of outcome measures

 

Primary outcomes

Blindness as defined by the WHO: corrected visual acuity in the better eye of less than 3/60 (Gilbert 2001).

 

Secondary outcomes

Other clinical manifestations of vitamin A deficiencies:

1. Night blindness
   
2. Conjunctival xerosis
   
3. Bitot's spot
   
4. Corneal xerosis
   
5. Xerophthalmia
   
6. Corneal ulceration
   
7. Corneal scars
   
8. Serum retinol level
   
9. Nutritional status
   
10. Adverse events
    
    1. Vitamin A toxicity
       
    2. Other adverse events
       

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1950 to January week 3, 2011), EMBASE.com (1974 to January 2011) and LILACS (1985 to January 2011). We used the following search strategy to search MEDLINE and CENTRAL. We did not use a filter to identify randomised trials in MEDLINE as there were too few studies. We adapted the search terms accordingly for EMBASE (see Appendix 1) and LILACS (see Appendix 2).

 

MEDLINE (OVID)

1 exp Measles/
2 exp Measles virus/
3 measles.tw.
4 rubeola.tw.
5 morbilli*.tw.
6 or/1-5
7 exp Vitamin A/
8 vitamin a.tw,nm.
9 retinol.tw,nm.
10 exp Dietary Supplements/
11 or/7-10
12 exp Blindness/
13 Xerophthalmia/
14 Night Blindness/
15 (bitot* adj1 spot*).tw.
16 xerosis*.tw.
17 keratomalacia.tw.
18 blind*.tw.
19 xerophthalmia*.tw.
20 exp Vision Disorders/
21 (vision* or visual* or eye* or sight*).tw.
22 or/12-21
23 6 and 11 and 22

 

Searching other resources

There were no publication or language restrictions. We also searched the following ongoing database registers: http://www.controlled-trials.com/, http://www.clinicaltrials.gov, http://www.trialscentral.org/ and http://ctr.glaxowellcome.co.uk/welcome.asp (3 February 2011). We also contacted experts in the field for information on ongoing and unpublished trials. We did not find any ongoing trials in the database registers. Efforts at contacting experts also proved unsuccessful as some of the email contacts were no longer active. We are yet to receive any response from those whose emails were still active.

 

Data collection and analysis

 

Selection of studies

Two review authors (SB, OO) reviewed the results from the initial literature search, excluded non-relevant studies, retrieved the full text of these articles and designed a study eligibility form. Two review authors (SB, MM) reviewed the full texts of the publications using the eligibility form.

 

Data extraction and management

Two review authors (SB, OO) designed and piloted a data extraction form. The following were included in the data extraction form.

1. Verification of the eligibility of study, including the inclusion and exclusion criteria.
   
2. Study characteristics, including the quality criteria.
   
3. Information on the participants; number in each group, number lost to follow up, duration of follow up.
   
4. The interventions given, including dose and preparation/form of vitamin A used.
   
5. Outcome measures of interest to the review.
   
6. Publication status.
   
7. Date and location of the study.
   

One review author (MM) supervised data extraction. Two review authors (SB, OO) independently extracted the data.

 

Assessment of risk of bias in included studies

Two review authors (SB, OO) used a quality assessment form to rank the studies as low, moderate and high risk of bias, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We assessed the quality of the studies using the following criteria.

1. Generation of allocation sequence; secure or not.
   
2. Allocation concealment; whether adequate, inadequate or unclear.
   
3. Blinding of care giver; yes, no or unclear.
   
4. Blinding of outcome assessors; yes, no or unclear.
   
5. Differential loss to follow up/attrition/exclusion; whether all randomised participants were included in the analysis.
   

 

Measures of treatment effect

Both studies used per protocol analysis. They reported mean and standard error of mean (SE) for serum retinol levels and weight gain. We converted the standard error of mean to standard deviation by multiplying SE by √n for separate arms. We report the per protocol analysis found in both studies and the mean difference with 95% confidence interval (CI). Due to the clinical heterogeneity of the included studies, we did not pool any of the estimates.

 

Results

 

Description of studies

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

 

Results of the search

The searches identified 147 records.

 

Included studies

We retrieved seven full articles out of which two studies (Coutsoudis 1991; Rosale 1996) (in four publications) were found eligible and were included in the review. Both of these studies were randomised, double-blind, placebo-controlled trials of vitamin A. One trial (Coutsoudis 1991) was conducted in Durban, South Africa in 1989 while the other (Rosale 1996) was carried out in Ndola, Zambia in 1991. Total sample size for both studies was 260. Coutsoudis 1991 enrolled 200 children and Rosale 1996 enrolled 60 children; the number enrolled in the vitamin A arm was 90 and 29 respectively.

In the Coutsoudis 1991 study, participants were aged four to 24 months. In the Rosale 1996 study, participants were aged five months to 17 years with measles. However, Coutsoudis 1991 enrolled children whose illness was severe enough to warrant hospital admission in contrast to Rosale 1996 who enrolled children with mild illness and excluded cases that required hospital admission. Both studies excluded children with clinical signs of vitamin A deficiency and severe under-nutrition. In addition to clinical judgement, Rosale 1996 confirmed measles cases by a four-fold increase in measles antibody titre two weeks after enrolment.

The intervention given in both studies was vitamin A. Coutsoudis 1991 administered standard WHO recommended dosage (54.5 mg for children < 12 months, 109 mg for children > 12 months) on days two, eight and week six, while Rosale 1996 administered a single dose of 200,000 IU (210 µmol). Co-interventions consisted essentially of standard treatment administered to both groups in both studies. In addition, the formulation used by one study (Rosale 1996) contained vitamin E (40 mg/ml)

None of the studies reported ocular morbidities, although one (Rosale 1996) indicated that eye examination was done at baseline and subsequent follow up. Both studies reported other measles-related complications seen and serum retinol levels post-intervention. One study (Coutsoudis 1991) measured nutritional status post-intervention.

 

Excluded studies

We excluded two studies for reasons documented in the Characteristics of excluded studies table. One (CID 1993) was an advocacy document and not a study.

 

Risk of bias in included studies

The quality of both studies was moderate (Figure 1; Figure 2).

Figure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Allocation

Both included studies (Coutsoudis 1991; Rosale 1996) generated allocation sequence with the use of a table of random numbers. Allocation concealment was adequate in both trials.

 

Blinding

Both studies were double-blind.

 

Incomplete outcome data

All participants enrolled were well-accounted for by both studies.

 

Selective reporting

One study (Coutsoudis 1991) reported all outcomes stated in the objectives of the study while the other (Rosale 1996) indicated that eye examination was done at follow-up visits but ocular outcomes were not reported.

 

Other potential sources of bias

Neither study included all randomised participants in the final analysis. Rosale 1996 included 77.5% of enrolled participants in the final analysis, while Coutsoudis 1991 included 28% (one week post-intervention), 65% (for serum retinol) and 80% (for weight gain) at six weeks and 60% at six months post-intervention.

 

Effects of interventions

See:  Summary of findings for the main comparison

Both studies were clinically heterogenous in several ways (see Characteristics of included studies). Only the time of study and duration of study and the geographical location were similar. The age groups enrolled, the formulation of vitamin A used, doses of vitamin A given and the time point of outcome assessment were widely different between the two studies. One (Coutsoudis 1991) was hospital-based. None of the studies reported ocular morbidities. We could therefore not assess the following outcomes: blindness, night blindness, conjunctival xerosis, Bitot's spot, corneal xerosis, xerophthalmia, corneal ulceration and corneal scars. No adverse event was reported in either study. Only serum retinol levels post-intervention were reported in both studies. A measure of nutritional status (weight gain) was reported by Coutsoudis (Coutsoudis 1991).

 

Serum retinol levels

Rosale measured and reported a summary estimate for serum retinol level at two weeks post-intervention (Rosale 1996). There was no significant difference in the mean serum retinol level of both groups (mean difference (MD) 2.7 µg/dL; 95% CI -0.3 to 5.6, 155 participants). Coutsoudis reported a significantly higher serum retinol level (measured on day eight) in the vitamin A group (MD 9.45 µg/dL; 95% CI 2.2 to 16.7, 17 participants) (Coutsoudis 1991). The mean change in serum retinol level on day eight compared to baseline was also significantly higher in the vitamin A group (MD 8.6 µg/dL; 95% CI 1.2 to 16.02, 17 participants). However, there was no strong evidence to show that there was a difference in the serum retinol level between the vitamin A and the placebo groups on day 42 post-intervention (MD 2.6 µg/dL; -5.3 to 10.4, 39 participants) ( Analysis 1.3).

 

Nutritional status

One study (Coutsoudis 1991) measured and reported weight gain post-intervention. There was no significant difference in weight gain between both groups at six weeks (MD 0.39 kg; 95% CI -0.04 to 0.8) and six months (MD 0.5 kg; 95% CI -0.1 to 1.1).

It is possible that a larger effect of serum retinol and weight gain could have been observed if the sample size of both studies was larger. This is depicted in the wide CIs (smaller precision) of the reported estimates.

 

Discussion

 

Summary of main results

The serum retinol level increased significantly one week after two doses of vitamin given on two consecutive days at the WHO recommended dosage. A single dose of 200,000 IU did not increase the serum retinol significantly two weeks after administration. However, administration of three doses of vitamin within one week did not result in a significant increase in serum retinol level six weeks post-intervention. Likewise, there was no significant difference in weight gain between vitamin A group and the placebo group six weeks and six months post-administration of three doses of vitamin A.

Blindness, other ocular morbidities and adverse events were not reported in the included studies.

 

Overall completeness and applicability of evidence

None of the studies included assessed the primary outcome of this review. There is therefore insufficient evidence to address this question.

 

Quality of the evidence

The quality of the evidence and methodology of both studies were moderate. There was a possible reporting bias in Rosale 1996 because ocular examinations were carried out but not reported.

 

Potential biases in the review process

The sample size in the included studies was small and this could affect the precision of the estimates given. We reported the per protocol analysis as given in the studies. This could have produced an over-estimate of effects of intervention. One study (Rosale 1996) indicated that eye examination was performed but did not report ocular outcomes. We were unable to obtain information from the trial authors about this outcome. It could be that the findings were not significant and so were not reported.

 

Agreements and disagreements with other studies or reviews

We found insufficient data in these trials to attempt any comparison with other studies.

 

Authors' conclusions

 

Implications for practice

None of the included studies assessed blindness (primary outcome of this review) and other ocular morbidities as end points. There is insufficient evidence to demonstrate the benefit or otherwise of vitamin A in the prevention of blindness in children infected with measles. However, since the benefit of vitamin A in reducing the risk of death in children with measles (of different levels of severity) has been demonstrated in other trials (Yang 2009) its use in children with measles should be encouraged for these proven clinical benefits.

 

Implications for research

New placebo-controlled vitamin A studies in children with measles will pose a significant ethical challenge since the beneficial effect of vitamin A on measles mortality and morbidity has been demonstrated in a Cochrane Review (Yang 2009). In light of dose-related differences in serum level of vitamin A, there could be some benefit in conducting more randomised controlled trials to asses the efficacy of different dosage schedules (single, double or triple doses of vitamin A) for the prevention of blindness and other ocular morbidities in measles infection. Serum retinol levels and other study outcomes should also be measured at similar time points during follow up to ensure comparability of the study results. Studies should also address dosage for level of severity and age groups. Larger studies would enable analysis of these subgroups.

 

Acknowledgements

The review authors wish to thank the following people for commenting on the draft protocol: Chanpen Choprapawon, Rita Sitorus, Francisco Espinosa, Nelcy Rodriguez and Anthony Harnden and the draft review: Emmanuel Effa, Chanpen Choprapawon, Rita Sitorus, Elaine Beller and Matthew Thompson. We also acknowledge the efforts of the Review for Africa Program (RAP Nigeria) and the Nigerian Branch of the South African Cochrane Centre in securing a dedicated time for the authors to complete this review.

 

Data and analyses

Download statistical data

 

Comparison 1. Vitamin A versus placebo

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum retinol 2 weeks post-intervention	1	155	Mean Difference (IV, Fixed, 95% CI)	2.67 [-0.29, 5.63]
2 Serum retinol 1 week post-intervention	1	17	Mean Difference (IV, Fixed, 95% CI)	9.45 [2.19, 16.71]
3 Serum retinol 6 weeks post-intervention	1	39	Mean Difference (IV, Fixed, 95% CI)	2.56 [-5.28, 10.40]
4 Serum retinol mean change day 8 (1 week post-intervention)	1	17	Mean Difference (IV, Fixed, 95% CI)	8.62 [1.22, 16.02]
5 Weight gain 6 weeks post-intervention	1	48	Mean Difference (IV, Fixed, 95% CI)	0.39 [-0.04, 0.82]
6 Weight gain 6 months post-intervention	1	36	Mean Difference (IV, Fixed, 95% CI)	0.52 [-0.08, 1.12]

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Appendices

 

Appendix 1. Embase.com search strategy

19. #6 AND #11 AND #18
18. #12 OR #13 OR #14 OR #15 OR #16 OR #17
17. blind*:ab,ti OR xerosis*:ab,ti OR keratomalacia:ab,ti OR xerophthalmia*:ab,ti OR vision*:ab,ti OR visual*:ab,ti OR eye*:ab,ti OR sight*:ab,ti
16. 'xerosis'/de
15. (bitot* NEAR/1 spot*):ab,ti
14. 'night blindness'/de
13. 'xerophthalmia'/de
12. 'blindness'/exp OR 'visual impairment'/de OR 'visual disorder'/de
11. #7 OR #8 OR #9 OR #10
10. 'nutrient'/de OR 'vitamin'/de OR 'carotenoid'/exp
9. retinol:ab,ti
8. 'vitamin a':ab,ti
7. 'retinol'/exp
6. #1 OR #2 OR #3 OR #4 OR #5
5. morbilli*:ab,ti
4. rubeola:ab,ti
3. measles:ab,ti
2. 'measles virus'/de
1. 'measles'/exp

 

Appendix 2. LILACS search strategy

Mh measles or Tw measles$ or Tw sarampion or Tw sarampo or Mh measles virus or Tw rubeola or Tw morbilli$ [Words] and Mh vitamin a or Tw vitamin a or Tw vitamina a or Tw retinol or Mh dietary supplements or Tw suplementos dieteticos [Words] and Mh blindness or Tw blind$ or Tw ceguera or Tw cegueira or Mh xerophthalmia or Tw xerophthalmia or Tw xeroftalmia or Tw bitot spot or Tw xerosis or Tw keratomalacia or Mh vision disorders or Tw vision$ or Tw visao$ or Tw visual$ or Tw vista$ or Tw eye$ or Tw ojo$ or Tw olho$ [Words]

 

History

Protocol first published: Issue 2, 2009
Review first published: Issue 4, 2011

 

Contributions of authors

The final review was written by all review authors.
SB searched the ongoing databases of trials.
SB and OO conducted trial selection, data extraction and quality assessment under the guidance of MMM.
OO and RIE edited the final draft of this review.

 

Declarations of interest

None known.

 

Sources of support

 

Internal sources

• Institute of Tropical Diseases Research and Prevention, University of Calabar Teaching Hospital, Calabar, Nigeria.
  
  Training
  IT support
  
• Nigerian Branch, South African Cochrane Centre, Calabar, Nigeria.
  
  Training
  IT support
  

 

External sources

• Acute Respiratory Infections (ARI) Group editorial base, Australia.
  
  Cochrane materials
  Information and technical support
  

 

Differences between protocol and review

The age of the participants was increased to < 18 years.

 

Index terms

Medical Subject Headings (MeSH)

Adolescent; Blindness [etiology; *prevention & control]; Measles [*complications]; Randomized Controlled Trials as Topic; Vitamin A [*administration & dosage]; Vitamins [*administration & dosage]

MeSH check words

Child; Child, Preschool; Humans; Infant

* Indicates the major publication for the study