1. Budesonide used for prevention of bronchopulmonary dysplasia in extremely preterm infants showed no difference in rate of neurodevelopmental disability at two years compared to placebo treated infants.
2. There was an increased risk of mortality at two years amongst infants receiving budesonide.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Bronchopulmonary dysplasia is a common complication of preterm birth that is associated with multisystem complications and higher mortality rates. A randomized trial in 2015 investigated inhaled budesonide for the prevention of bronchopulmonary dysplasia in preterm infants, and found no effect on the composite outcome of bronchopulmonary dysplasia or death at 36 weeks. It remains unclear, however, whether inhaled glucocorticoids have a detrimental effect on neurodevelopmental outcomes later in life. The authors of this study tracked a pre-specified secondary composite outcome of neurodevelopmental disability in the previously mentioned trial. After two years of follow-up, no difference was found between the placebo and budesonide treatment arm in this secondary outcome. However, an elevated risk of mortality in the budesonide arm at two years was observed. This study offers high quality evidence that, amongst infants similar to those enrolled in this trial, exposure to inhaled corticosteroids is not a causal risk factor for neurodevelopmental disability at two years.
A major strength of this study is the randomized trial design, which allows for estimation of the causal effect of inhaled budesonide on risk of neurodevelopmental disability. Limitations include multiple hypothesis testing with numerous exploratory outcomes, which may reduce the likelihood that significant findings are true.
In-Depth [randomized controlled trial]: This was an extended follow-up of 629 infants enrolled in a multi-site randomized controlled trial testing the efficacy of budesonide (n = 308) compared to placebo (n = 321) for the prevention of bronchopulmonary dysplasia in premature infants. Eligible infants had a gestational age between 23 weeks 0 days and 27 weeks 6 days, and their chronological age at the time of enrollment was less than twelve hours. Randomization was stratified by gestational age. Patients received budensonide or placebo until supplemental oxygen was no longer required (mean 33.9 days in treatment group). The pre-specified secondary outcome tracked during follow-up was a composite of cerebral palsy, cognitive delay, deafness, and blindness.
There was no evidence of a difference in risk of composite neurodevelopmental disability between the study (48.1%) and placebo (51.4%) arms (relative risk, 0.93; 95% confidence interval, 0.80 to 1.09; p = 0.40). The risks for the individual components of the composite outcome were also not significantly different between the treatment and placebo groups. There was evidence of excess mortality in the budesonide arm (19.9% vs 14.5%; RR, 1.37; 95% CI, 1.01 to 1.86; p = 0.04), but no clear signal for overrepresented etiologies of death in this difference. Numerous other secondary outcomes, including rate of hospital admissions and weight percentile, were not different between the study arms.
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