Health Evidence™ hosted a 60 minute webinar examining the effectiveness of vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Click here for access to the audio recording for this webinar: https://youtu.be/fuWd7TJQYEI Dr. Aamer Imdad, MBBS, MPH, Assistant Professor of Pediatrics, SUNY Upstate Medical University led the session and presented findings from their recent Cochrane review: Imdad A, Mayo-Wilson E, Herzer K, & Bhutta Z. (2017). Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database of Systematic Reviews, 2017(3), CD008524. Vitamin A deficiency is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. This review examines the effectiveness of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years. Forty-seven randomized control trials involving approximately 1,223,856 children were included in this review. VAS was associated with a clinically meaningful reduction in morbidity and mortality in children.

1. Welcome!
Effectiveness of vitamin A
supplementation for
preventing morbidity and
mortality in children: What's
the evidence?
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3

4. What’s the Evidence?
Imdad A, Mayo-Wilson E, Herzer K, & Bhutta Z.
(2017). Vitamin A supplementation for
preventing morbidity and mortality in children
from six months to five years of age. Cochrane
Database of Systematic Reviews, 2017(3),
CD008524.
https://healthevidence.org/view-
article.aspx?a=vitamin-supplementation-
preventing-morbidity-mortality-children-
months-years-age-30222

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National Collaborating Centre for Methods and Tools. Evidence-Informed
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14. Searchable Questions Think “PICOS”
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15. How often do you use systematic reviews
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Poll Question #3

16. Aamer Imdad
PhD, MBBS, FRCPCH, FAAP, Co-Director,
Director of Research Centre for Global
Child Health, The Hospital for Sick
Children, Senior Scientist, Research
Institute, Professor Department of
Nutritional Sciences, Professor, University
of Toronto, Division of Epidemiology Dalla
Lana School of Public Health
MBBS, MPH, Assistant Professor of
Pediatrics, SUNY Upstate Medical
University
Zulfiqar Bhutta

17. Vitamin A supplementation for preventing morbidity and
mortality in children from six months to five years of age
• Imdad A, Mayo-Wilson E, Herzer K, Bhutta ZA. Vitamin A supplementation for
preventing morbidity and mortality in children from six months to five years of
age. Cochrane Database Syst Rev. 2017 Mar 11;3:CD008524.
• Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A
supplementation for preventing morbidity and mortality in children from 6
months to 5 years of age. Cochrane Database Syst Rev. 2010 Dec
8;(12):CD008524.
• Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements
for preventing mortality, illness, and blindness in children aged under 5:
systematic review and meta-analysis. BMJ. 2011 Aug 25;343:d5094.
• Imdad A, Ahmed Z, Bhutta ZA. Vitamin A supplementation for the prevention of morbidity
and mortality in infants one to six months of age. Cochrane Database Syst Rev. 2016 Sep
28;9:CD007480.
• Haider BA, Sharma R, Bhutta ZA. Neonatal vitamin A supplementation for the prevention
of mortality and morbidity in term neonates in low and middle income countries.
Cochrane Database Syst Rev. 2017 Feb 24;2:CD006980.

18. Background
• What is vitamin A?
– Essential micronutrient, subclass of retinoic acids, lipid-
soluble compounds
• What is the normal function of vitamin A?
– Required for visual system, maintenance of cell function
for growth, epithelial integrity, red blood cell production,
immunity, and reproduction
• What are the consequences of Vitamin A Deficiency (VAD)?
– Xerophthalmia (dry eyes), Bitot spots, blindness,
susceptibility to infection including diarrhea, pneumonia,
measles, stunting, and anemia, and may cause death

19.  WHO estimates: 2009
 19.1 million pregnant women
 190 million (33%) children < 5 years
 Most common cause of nutritional blindness in children
 122 countries have a moderate to severe VAD public health problem
 Recent estimates showed that VAD is decreasing but still prevalent in
South East Asia and Sub-Saharan Africa
How common is the VAD?
Stevens et. Al Lancet Global Health 2015;3 (9):e528-36.

20. Background
• What are the common sources of vitamin A?
 Naturally: plants: inactive retinoids (provitamin: green leafy vegetables,
yellow vegetables, and yellow/orange non-citrus fruits
 Active form: animal based: retinol, retinal and retinoic acid: glandular
meats, liver, fish liver oils, egg yolk, whole milk, dairy products and
human milk
• Why do we need to supplement vitamin A?
 Bioavailability: carotenoid-to-retinol conversion ratio varies with type of
food, ranging from 6:1 to 26:1
 Increased losses due to increased burden of infectious disease, low
consumption and increased losses due to diarrheal disease
 Food insecurity

21. Objective
To assess the effects of vitamin A
supplementation (VAS) for preventing
morbidity and mortality in children aged six
months to five years.

22. Methods

23. Methods
• Study design: Systematic review and meta-analysis
• Type of studies: Individual and cluster randomized
controlled trials
• Participants: Children 6 months to 5 years
• Intervention: Preventive, synthetic vitamin A
supplementation
• Comparison: Placebo or no intervention

24. Methods
• Outcomes:
 Primary:
– All-cause mortality
 Secondary outcomes:
– Cause-specific mortality: Diarrhea, pneumonia, measles
– Cause-specific morbidity: Diarrhea, pneumonia, measles, night
blindness
– Side effects
– Vitamin A deficiency status (based on serum retinol level)

25. Literature Searches
• Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) (searched 1 March
2016).
• MEDLINE Ovid (1946 to February Week 3 2016).
• Medline In-Process & Other Non-Indexed Citations Ovid (29 February 2016).
• Embase Ovid (1980 to 2016 Week 9).
• Science Citation Index Web of Science (SCI; 1970 to 27 February 2016).
• Conference Proceedings Citation Index - Science Web of Science (CPCI-S; 1990 to 27 February
2016).
• Cochrane Database of Systematic Reviews (CDSR; 2016, Issue 2) in the Cochrane Library.
• Database of Abstracts of Reviews of Effects (DARE; 2015 Issue 2) in the Cochrane Library.
• LILACS (Latin American and Caribbean Health Science Information database (searched 1
March 2016).
• African Index Medicus (searched 1 March 2016).
• ClinicalTrials.gov (clinicaltrials.gov; searched 1 March 2016).
• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP;
searched 1 March 2016).

26. Data Synthesis
• Data extraction: Double data abstraction
• Risk of bias: Cochrane handbook of systematic
reviews
• Meta-analysis: Generic inverse variance: fixed
effect models
• Dichotomous variables: Risk ratios (95 %
confidence interval)
• Continuous variables: Standardized Mean
difference with 95 % CI
• Overall quality: GRADE criteria

27. Results

28. PRISMA Flow Diagram

29. Characteristics of Included Studies
• Most of the studies were conducted in low and
middle income countries
• Sample size ranged from 35 to 1 million and
overall sample size: 1,223,856
• Dose ranged: 50,000 IU to 200,000 IU, one study
used weekly dose of 3866
• Retinol palmitate was the most commonly used
compound
• Most of the studies lasted about one year or
less and about 11 studies lasted for 5 years

30. Risk of Bias in the Included Studies

31. Vitamin A vs. Control: All-Cause Mortality

32. Diarrhea Mortality: Vitamin A vs. Control

33. Measles Mortality: Vitamin A vs. Control

34. LRTI Mortality: Vitamin A vs. Control

35. Diarrhea Incidence: Vitamin A vs. Control

36. Measles Incidence: Vitamin A vs. Control

37. LRTI Incidence: Vitamin A vs. Control

38. Bitot’s Prevalence: Vitamin A vs. Control

39. Night Blindness Prevalence: Vitamin A vs.
Control

40. Side Effects: Vomiting

41. Vitamin A Deficiency

42. Vitamin A: Serum Retinol Level

43. GRADE: Summary of Findings Table

44. GRADE: Summary of Findings Table

45. GRADE: Summary of Findings Table

46. Strengths/Limitations
• Study included 47 RCT representing 1,223,856
children
• Standard methods of Cochrane collaboration were
used
• Both morbidity and mortality outcomes were assessed
• The primary analysis for all-cause mortality: 19 trials
and included 1,202,382 children randomized in this
review

47. Strengths/Limitations
• Inclusion of a recent large trial from India (DEVTA
trial) changed the summary estimate from 24 % to 12
%, but overall results remained statistically
significant
• Overall, there was substantial heterogeneity in the
pooled data and the analysis performed in this review
could not fully explain the variation of effect
• Growth outcomes were not measured in this review

48. Implications for Public Health
• Vitamin A has a robust effect on prevention of
mortality in young children
• The World Health Organization recommends
vitamin A for children 6 and 59 months of age,
in a dose of 100,000 IU for children aged 6 to 12
months and a dose of 200,000 IU for children
aged 1 to 5 years, every six months

49. Implications for Public Health
• We suggested to continue this policy and WHO used
the first publication of this review to issue its
guideline and an update is expected soon based on
latest evidence
• We, however, acknowledge that synthetic vitamin A
supplementation may not be a long term solution and
other strategies such as fortification, food
distribution programs, and horticultural
developments should be encouraged

50. Take Home Message
Vitamin A supplementation in
children 6-59 months of age reduces
all-cause and diarrhea related
mortality and it reduces night
blindness and illness due to diarrhea
and measles

51. Acknowledgements
Prof. Zulfiqar Ahmed Bhutta: The Hospital for Sick Children, Toronto
Dr. Kurt Herzer: John Hopkins’ School of Public Health
Dr. Evan Mayo Wilson: John Hopkins’ School of Public Health
Dr. Mohammad Yawar Yakoob: Aga Khan University, Pakistan
Cochrane Developmental Psychosocial and Learning Problems
group (CDPLG): Jo Abbott, Chris Champion, Joanne Wilson, Margaret
Anderson and Geraldine Macdonald
Cochrane Editorial Unit: Toby Lasserson, Rachel Murphy, and Karla
Soares-Weiser
World Health Organization: Provided partial funding

52. Questions?

53. Additional slides

54. All-Cause Mortality: Subgroup Analysis:
Age

55. All-Cause Mortality: Subgroup Analysis:
Gender

56. All-Cause Mortality: Funnel Plot

57. Poll Question #4
The information presented today was
helpful
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C.Neutral
D.Disagree
E.Strongly disagree

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59. Poll Question #5
What are your next steps? [Check all
that apply]
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review on www.healthevidence.org
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D. Tell a colleague about the evidence

60. Thank you!
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