Dr. Ron’s Research Review – November 16, 2016

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This week’s research review focuses on vitamin A with vaccination.

The World Health Organization recommends vitamin A supplementation (VAS) at routine vaccination contacts after 6 months of age based on the assumption that it reduces mortality by 24%. 
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Vitamin A supplementation was associated with a reduced incidence of diarrhea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). (Mayo-Wilson et al., 2011)

A recent study randomized 7587 children aged 6 to 23 months 1:1 to VAS (100,000 IU if aged 6-11 months, 200,000 IU if aged 12-23 months) or placebo. Within 6 months of follow-up 80 non-accident deaths occurred (VAS: 38; placebo: 42). The mortality rate ratio (MRR) comparing VAS versus placebo recipients was 0.91 (95% confidence interval 0.59-1.41) and differed significantly between boys (MRR 1.92 [0.98-3.75]) and girls (MRR 0.45 [0.24-0.87]) (P = .003 for interaction between VAS and gender). At enrollment, 42% (3161/7587) received live measles vaccine, 29% (2154/7587) received inactivated diphtheria-tetanus-pertussis-containing vaccines, and 21% (1610/7587) received both live and inactivated vaccines. The effect of VAS did not differ by vaccine group. VAS had no overall effect, but the effect differed significantly by gender. (Fisker et al., 2014)

A meta-analysis found that vaccination was 85% effective in preventing measles disease for countries vaccinating before one year of age, and possibly 95% when vaccinating at 1 year or later and 98% for two doses of vaccine based on serology reviews. Also included were six high-quality trials in the meta-analysis of vitamin A treatment of measles which found no significant reduction in measles morality. However, when stratifying by vitamin A treatment dose, at least two doses were found to reduce measles mortality by 62% (95% CI 19-82).  Measles vaccine and vitamin A treatment are effective interventions to prevent measles mortality in children. (Sudfeld et al., 2010)

Dr. Ron


 

Articles

High-dose vitamin A with vaccination after 6 months of age: a randomized trial.
            (Fisker et al., 2014) Download
BACKGROUND:  The World Health Organization recommends vitamin A supplementation (VAS) at routine vaccination contacts after 6 months of age based on the assumption that it reduces mortality by 24%. The policy has never been evaluated in randomized controlled trials for its effect on overall mortality. We conducted a randomized double-blind trial to evaluate the effect of VAS with vaccines. METHODS:  We randomized children aged 6 to 23 months 1:1 to VAS (100000 IU if aged 6-11 months, 200000 IU if aged 12-23 months) or placebo at vaccination contacts in Guinea-Bissau. Mortality rates were compared in Cox proportional-hazards models overall, and by gender and vaccine. RESULTS:  Between August 2007 and November 2010, 7587 children were enrolled. Within 6 months of follow-up 80 nonaccident deaths occurred (VAS: 38; placebo: 42). The mortality rate ratio (MRR) comparing VAS versus placebo recipients was 0.91 (95% confidence interval 0.59-1.41) and differed significantly between boys (MRR 1.92 [0.98-3.75]) and girls (MRR 0.45 [0.24-0.87]) (P = .003 for interaction between VAS and gender). At enrollment, 42% (3161/7587) received live measles vaccine, 29% (2154/7587) received inactivated diphtheria-tetanus-pertussis-containing vaccines, and 21% (1610/7587) received both live and inactivated vaccines. The effect of VAS did not differ by vaccine group. CONCLUSIONS:  This is the first randomized controlled trial to assess the effect of the policy on overall mortality. VAS had no overall effect, but the effect differed significantly by gender. More trials to ensure an optimal evidence-based vitamin A policy are warranted.

Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis.
            (Mayo-Wilson et al., 2011) Download
OBJECTIVE:  To determine if vitamin A supplementation is associated with reductions in mortality and morbidity in children aged 6 months to 5 years. DESIGN:  Systematic review and meta-analysis. Two reviewers independently assessed studies for inclusion. Data were double extracted; discrepancies were resolved by discussion. Meta-analyses were performed for mortality, illness, vision, and side effects. DATA SOURCES:  Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, Global Health, Latin American and Caribbean Health Sciences, metaRegister of Controlled Trials, and African Index Medicus. Databases were searched to April 2010 without restriction by language or publication status. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:  Randomised trials of synthetic oral vitamin A supplements in children aged 6 months to 5 years. Studies of children with current illness (such as diarrhoea, measles, and HIV), studies of children in hospital, and studies of food fortification or β carotene were excluded. RESULTS:  43 trials with about 215,633 children were included. Seventeen trials including 194,483 participants reported a 24% reduction in all cause mortality (rate ratio=0.76, 95% confidence interval 0.69 to 0.83). Seven trials reported a 28% reduction in mortality associated with diarrhoea (0.72, 0.57 to 0.91). Vitamin A supplementation was associated with a reduced incidence of diarrhoea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). Three trials reported an increased risk of vomiting within the first 48 hours of supplementation (2.75, 1.81 to 4.19). CONCLUSIONS:  Vitamin A supplementation is associated with large reductions in mortality, morbidity, and vision problems in a range of settings, and these results cannot be explained by bias. Further placebo controlled trials of vitamin A supplementation in children between 6 and 59 months of age are not required. However, there is a need for further studies comparing different doses and delivery mechanisms (for example, fortification). Until other sources are available, vitamin A supplements should be given to all children at risk of deficiency, particularly in low and middle income countries.

Effectiveness of measles vaccination and vitamin A treatment.
            (Sudfeld et al., 2010) Download
BACKGROUND:  The current strategy utilized by WHO/United Nations Children's Fund (UNICEF) to reach the Global Immunization Vision and Strategy 2010 measles reduction goal includes increasing coverage of measles vaccine, vitamin A treatment and supplementation in addition to offering two doses of vaccine to all children. METHODS:  We conducted a systematic review of published randomized controlled trials (RCTs) and quasi-experimental (QE) studies in order to determine effect estimates of measles vaccine and vitamin A treatment for the Lives Saved Tool (LiST). We utilized a standardized abstraction and grading format in order to determine effect estimates for measles mortality employing the standard Child Health Epidemiology Research Group Rules for Evidence Review. RESULTS:  We identified three measles vaccine RCTs and two QE studies with data on prevention of measles disease. A meta-analysis of these studies found that vaccination was 85% [95% confidence interval (CI) 83-87] effective in preventing measles disease, which will be used as a proxy for measles mortality in LiST for countries vaccinating before one year of age. The literature also suggests that a conservative 95% effect estimate is reasonable to employ when vaccinating at 1 year or later and 98% for two doses of vaccine based on serology reviews. We included six high-quality RCTs in the meta-analysis of vitamin A treatment of measles which found no significant reduction in measles morality. However, when stratifying by vitamin A treatment dose, at least two doses were found to reduce measles mortality by 62% (95% CI 19-82). CONCLUSION:  Measles vaccine and vitamin A treatment are effective interventions to prevent measles mortality in children.

References

Fisker, AB, et al. (2014), ‘High-dose vitamin A with vaccination after 6 months of age: a randomized trial.’, Pediatrics, 134 (3), e739-48. PubMed: 25136048
Mayo-Wilson, E, et al. (2011), ‘Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis.’, BMJ, 343 d5094. PubMed: 21868478
Sudfeld, CR, AM Navar, and NA Halsey (2010), ‘Effectiveness of measles vaccination and vitamin A treatment.’, Int J Epidemiol, 39 Suppl 1 i48-55. PubMed: 20348126