Vitamin A supplementation to prevent mortality and short and long‐term morbidity in very low birthweight infants
Abstract
Background
Vitamin A is necessary for normal lung growth and the ongoing integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with increased risk of developing chronic lung disease. Several studies have been undertaken to assess whether vitamin A supplementation beyond that routinely given in multivitamin preparations can reduce the incidence of this outcome.
Objectives
To assess the benefit and risk of supplementation with vitamin A in very low birthweight infants.
Search methods
Searches were made of the Oxford Database of Perinatal Trials, MEDLINE up to November 2006, Cochrane Central Register of Controlled Trials Register (CENTRAL, The Cochrane Library, Issue 4, 2006), and Science Citation Index. The reference lists of relevant trials, recent issues of paediatric and nutrition journals, abstracts and proceedings from relevant conferences in the English language were hand searched.
Selection criteria
Randomised controlled trials which compared the effects of supplemental vitamin A with standard vitamin A regimes in infants with birthweight </= 1500 g and reported clinical outcomes (death, chronic lung disease or bronchopulmonary dysplasia, long‐term neurodevelopmental status) and/or vitamin A concentrations were considered for the review, as were trials which compared vitamin A dosing regimes and reported biochemical outcomes (retinol concentrations at 28 days).
Data collection and analysis
Data on mortality, requirement for supplemental oxygen at one month of age and at 36 weeks postmenstrual age, retinopathy of prematurity, nosocomial sepsis and follow‐up at 18 to 22 months, as well as retinol concentrations at 28 days in trials comparing dosage regimes, were excerpted by both reviewers independently. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group.
Main results
Eight eligible trials comparing vitamin A supplementation with standard regimes were identified, one having a much larger sample size than the others combined. The meta‐analysis suggests supplementation with vitamin A is beneficial in reducing death or oxygen requirement at one month of age [typical RR 0.93 (95% CI 0.88, 0.99), RD ‐0.05 ( 95% CI ‐0.10, ‐0.01), NNT 20 (10, 100) and oxygen requirement at 36 weeks postmenstrual age [typical RR 0.87 (95% CI 0.77, 0.98), RD ‐0.08 ( 95% CI ‐0.14, ‐0.01), NNT 13 (7, 100)], and trends towards reduction in oxygen requirement in survivors at one month of age [typical RR 0.93 (95% CI 0.86, 1.01) and death or oxygen requirement at 36 weeks postmenstrual age [typical RR 0.91 (95% CI 0.82, 1.00)]. Meta‐analysis of the three studies from which data on retinopathy of prematurity are available suggests a trend towards reduced incidence in vitamin A supplemented infants. Neurodevelopmental assessment of 85% of surviving infants participating in the largest trial showed no differences in outcome between supplementation and placebo groups at 18 to 22 months corrected age.
Authors' conclusions
Supplementing very low birthweight infants with vitamin A is associated with a reduction in death or oxygen requirement at one month of age and oxygen requirement among survivors at 36 weeks postmenstrual age, with this latter outcome being confined to infants with birthweight less than 1000 g. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in this outcome, balanced against the lack of other proven benefits and the acceptability of treatment. Information on long‐term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention. The benefits, in terms of vitamin A status, safety and acceptability of delivering vitamin A in an intravenous emulsion compared with repeat intramuscular injections, should be assessed in a further trial.
PICOs
Plain language summary
Vitamin A supplementation to prevent mortality and short and long‐term morbidity in very low birthweight infants
Vitamin A is a group of fat soluble compounds used by the body for regulation and promotion of growth and differentiation of many cells, including cells in the retina of the eye and the cells that line the lung. Preterm infants have low vitamin A levels at birth. This may contribute to an increased risk of developing chronic lung disease. It is possible that additional vitamin A supplement may reduce complications of prematurity, including abnormal development of the retina (retinopathy), bleeding in the brain (intraventricular haemorrhage) and damage to the gut from inflammation (necrotising enterocolitis) as well as reducing respiratory infections. Too much vitamin A is potentially harmful as it can raise intracranial pressure and cause skin and mucous membrane changes (injury or lesions) and vomiting. In this review of eight trials, supplementing very low birthweight infants with vitamin A by intramuscular injection or in the milk formula was associated with a trend toward a reduced number of deaths or oxygen requirement at one month of age. For surviving infants with birthweight less than 1000 g (three studies, 824 infants in total of which at least 96% had a birthweight less than 1000 g), fewer infants required oxygen at 36 weeks postmenstrual age. The number needed to treat for one to benefit was 13 (7 to 100). Three studies with information on retinopathy of prematurity suggested a trend towards reduced incidence in vitamin A supplemented infants. The one study which investigated neurodevelopmental status at 18 to 22 months of age correcting for prematurity found no evidence of benefit or harm associated with vitamin A supplementation. No side effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful.
