Inhaled Budesonide May Yield Mixed Results in Premature Infants

By Gene Emery

January 11, 2018

NEW YORK (Reuters Health) - Inhaled-glucocorticoid therapy does not appear to boost the longer-term risk of neurodevelopmental disability in extremely premature infants, but might increase mortality, according to a randomized controlled trial.

"Thanks to the new study results, neonatologists can now make informed decisions regarding the use of inhaled glucocorticoids for the prevention of” bronchopulmonary dysplasia (BPD), chief author Dr. Dirk Bassler, chief of neonatology at University Hospital Zurich told Reuters Health by email.

"When making this decision," he said, "they need to carefully balance the risks of potentially increased mortality owing to early inhaled corticosteroids against those of decreased rates of BPD with no effect on neurodevelopment in survivors at 2 years of age."

BDP itself is the most common chronic complication of extremely preterm birth. It is associated with higher mortality, growth failure, neurodevelopmental delay and both chronic respiratory and cardiovascular impairment.

It can be prevented with systemic glucocorticoids, but those carry a higher risk of neurodevelopmental impairment such as cerebral palsy, and intestinal perforation. So doctors often try inhaled glucocorticoids.

"Despite much study and progress in neonatology in recent years and some modest improvements in survival, both the incidence and severity of BPD have not changed much. To this day, approximately half of the infants born with a gestational age of less than 28 weeks suffer from BPD," Dr. Bassler said.

The popularity of glucocorticoid treatment varies widely. It was estimated a few years ago that it was prescribed for about 25% of premature infants in the United States versus about 70% in Japan.

The latest findings, reported January 10 online in The New England Journal of Medicine, are a follow-up to the group's 2015 study in the Journal, which found that while inhaled budesonide lowered the dysplasia risk, it elevated the mortality rate.

The new work evaluated data on 629 babies randomly assigned to placebo or budesonide at a corrected age of 18 to 22 months. All were at a gestational age of at least 23 weeks and less than 28 weeks at the time therapy began.

In the trial, done at 40 centers in nine countries, the budesonide babies received 400 micrograms of the inhaled drug every 12 hours, with the daily dose reduced to 200 micrograms from day 15 until the babies didn't need respiratory support. Drug treatment ended at 32 weeks.

The rate of neurodevelopmental disability - a composite of cognitive delay, deafness, blindness or cerebral palsy - was 48.1% among the 308 budesonide recipients and 51.4% among the 321 who got placebo (P=0.40).

The Bassler team also found no evidence that individual elements of that composite scale were affected by inhaled budesonide therapy.

Budesonide recipients were more likely to die during the study (19.9% vs. 14.5%, P=0.04).

"This is unexpected," Dr. Bassler said, and "there is no biologically plausible hypothesis to explain the seeming excess of deaths in treated infants, and the causes of death in our study did not differ considerably between the groups. The mortality findings may be attributed to chance, but we can’t be sure about this assumption."

He said the results need to be seen in the context of other studies.

"There are now updated meta-analyses including our short-term outcomes that address the use of inhaled glucocorticoids as compared with placebo or no intervention," Dr. Bassler said. "All updated systematic reviews and meta-analyses found a modest, but significant reduction in the composite outcome of death or BPD at 36 weeks. In these updated meta-analyses, inhaled glucocorticoids were associated with a significant reduction in BPD with no effect on mortality."


N Engl J Med 2018.