Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials

West, Keith P.; Wu, Lee; Ali, Hasmot; Klemm, Rolf; Edmond, Karen; Hurt, Lisa; Kirkwood, Betty; Newton, Sam; Shannon, Caitlin; Taneja, Sunita; Mazumder, Sarmila; Bhatia, Kiran; Bhandari, Nita; Katz, Joanne; Tielsch, James M.; Humphrey, Jean H.; Agoestina, T; Soofi, Sajid Bashir; Ariff, Shabina; Bhatti, Zaid; Bhutta, Zulfiqar A; Ntozini, Robert; Masanja, Honorati; Smith, Emily R.; Muhihi, Alfa; Fawzi, Wafaie W.; Bahl, Rajiv; Martines, José; Yoshida, Sachiyo

doi:10.1136/archdischild-2018-315242

Cited by 27 publications

(27 citation statements)

References 33 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…12 Micronutrients and their relation to pneumonia have been the subject of research interest for many years. The consensus is that mass infant vitamin A preventative supplementation reduces subsequent all-cause mortality, 13 but that adjunctive treatment in acute pneumonia does not alter disease trajectory. 14 The role of zinc, another key micronutrient, remains controversial.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of zinc as adjunctive pneumonia treatment in children aged 2 to 60 months in low-income and middle-income countries: a systematic review and meta-analysis

Brown

Kukka²,

Mårtensson³

2020

bmjpo

View full text Add to dashboard Cite

BackgroundDespite advances in vaccination and case management, pneumonia remains the single largest contributor to early child mortality worldwide. Zinc has immune-enhancing properties, but its role in adjunctive treatment of pneumonia in low-income and middle-income countries (LMICs) is controversial and research still active.MethodsSystematic review and meta-analysis of randomised controlled trials of zinc and placebo in pneumonia in children aged 2 to 60 months in LMICs. Databases included MEDLINE, the Cochrane Library, EMBASE, LILACS, SciELO, the WHO portal, Scopus, Google Scholar and ClinicalTrials.gov. Inclusion criteria included accepted signs of pneumonia and clear measure of outcome. Risk of bias was independently assessed by two authors. ORs with 95% CI were used for calculating the pooled estimate of dichotomous outcomes including treatment failure and mortality. Time to recovery was expressed as HRs. Sensitivity analyses considering risk of bias and subgroup analyses for pneumonia severity were performed.ResultsWe identified 11 trials published between 2004 and 2019 fulfilling the a priori defined criteria, 7 from South Asia and 3 from Africa and 1 from South America. Proportional treatment failure was comparable in both zinc and placebo groups when analysed for all patients (OR 0.95 (95% CI 0.80 to 1.14)) and only for those with severe pneumonia (OR 0.93 (95% CI 0.75 to 1.14)). No difference was seen in mortality between zinc and placebo groups (OR 0.64 (95% CI 0.31 to 1.31)). Time to recovery from severe pneumonia did not differ between the treatment and control groups for patients with severe pneumonia (HR 1.01 (95% CI 0.89 to 1.14)). Removal of four studies with high risk of bias made no difference to the conclusions.ConclusionThere is no evidence that adjunctive zinc treatment improves recovery from pneumonia in children in LMICs.Trial registration numberCRD42019141602.

show abstract

Section: Resultsmentioning

confidence: 99%

Efficacy of zinc as adjunctive pneumonia treatment in children aged 2 to 60 months in low-income and middle-income countries: a systematic review and meta-analysis

Brown

Kukka²,

Mårtensson³

2020

bmjpo

View full text Add to dashboard Cite

show abstract

“…In 2014, WHO arranged an analytical workshop including all the PIs of NVAS trials. Based on 11 trials (excluding the Nepalese NVAS trial [10], which did not provide NVAS in the first days of life) the meta-pooled RR with a random effects model was 0.97 (95% CI 0.89–1.06) by 6 months of age and 1.00 (0.93–1.08) by 12 months of age [20]. There was considerable heterogeneity across trials.…”

Section: Resultsmentioning

confidence: 99%

“…Potential NVAS trials for inclusion in the review were identified using the same methods as in a recent meta-analysis [20]. Individual or cluster randomized trials assessing the effect of early NVAS (25,000–50,000 IU intended to be given within the first 2–3 days of life) compared with placebo, with follow-up through at least 6 months of age, were eligible.…”

Section: Methodsmentioning

confidence: 99%

Lessons Learned from the Testing of Neonatal Vitamin A Supplementation

2019

View full text Add to dashboard Cite

A total of 12 trials have tested the effect of neonatal vitamin A supplementation (NVAS) on mortality. Overall, NVAS had no effect on mortality, but results were heterogeneous. Two competing hypotheses have been put forward to explain the divergent effects: A) NVAS works by preventing vitamin A deficiency (VAD) and not all countries have VAD; B) NVAS interacts negatively with subsequent diphtheria-tetanus-pertussis (DTP) vaccine, increasing mortality in females; in countries with low DTP coverage NVAS may have a beneficial effect. Only hypothesis A was tested in a recent meta-analysis; there is no strong empirical support for hypothesis A and it would not explain observed negative effects in some settings. Hypothesis B accounts for most observations. However, so far it has only been tested properly in a few trials. If hypothesis B is correct, it has major consequences for the understanding of the effects of vitamin A, and for the VAS policy in older children. As a WHO priority, the DTP coverage is bound to increase, and therefore hypothesis B urgently needs to be tested.

show abstract

“…Thirteen of the studies were conducted in the community settings and three studies were conducted in the hospital settings. We initially planned subgroup analyses for neonatal vitamin A supplementation however we did not perform any subgroup analysis because a recent individual participant analysis (IPD) conducted subgroup analyses for 6-month mortality at individual and trial level data [21].…”

Section: Discussionmentioning

confidence: 99%

“…We rated the quality of the body of evidence for each key outcome as 'high', 'moderate', 'low' or 'very low' [20]. We intended to perform numerous subgroup analyses for neonatal vitamin A supplementation; however, a recent IPD analysis [21] covered those analyses, so we decided not to perform any subgroup analysis for vitamin A supplementation.…”

Section: Methodsmentioning

confidence: 99%

Effect of Synthetic Vitamin A and Probiotics Supplementation for Prevention of Morbidity and Mortality during the Neonatal Period. A Systematic Review and Meta-Analysis of Studies from Low- and Middle-Income Countries

et al. 2020

View full text Add to dashboard Cite

Background: Suboptimal nutritional status of a newborn is a risk factor for short-and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89-1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.

show abstract

Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials

Cited by 27 publications

References 33 publications

Efficacy of zinc as adjunctive pneumonia treatment in children aged 2 to 60 months in low-income and middle-income countries: a systematic review and meta-analysis

Efficacy of zinc as adjunctive pneumonia treatment in children aged 2 to 60 months in low-income and middle-income countries: a systematic review and meta-analysis

Lessons Learned from the Testing of Neonatal Vitamin A Supplementation

Effect of Synthetic Vitamin A and Probiotics Supplementation for Prevention of Morbidity and Mortality during the Neonatal Period. A Systematic Review and Meta-Analysis of Studies from Low- and Middle-Income Countries

Contact Info

Product

Resources

About