Lung Drug Works But Is Risky for Preterm Infants

Giving extremely preterm infants inhaled budesonide may lower the risk of bronchopulmonary dysplasia, but may also increase the risk of mortality, according to a recent study published in the New England Journal of Medicine. Dirk Bassler, MD, of the Department of Neonatology at the University Hospital Zurich in Zurich, Switzerland, and colleagues conducted the study to find out if “inhaled budesonide administered within 24 hours after birth would decrease the incidence of bronchopulmonary dysplasia and death at 36 weeks of postmenstrual age” in preterm babies born before 28 weeks of gestation.

The study was randomized and multinational and “Infants with a gestational age of 23 weeks 0 days to 27 weeks 6 days and a chronologic age of 12 hours or less who required any form of positive-pressure support were eligible.” The primary measure was “a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age.”

A set of secondary outcomes was also prespecified: “death for any reason at 36 weeks of postmenstrual age; bronchopulmonary dysplasia in survivors at 36 weeks of postmenstrual age; the duration of positive-pressure respiratory support or supplemental oxygen; ventriculomegaly with or without intraventricular hemorrhage; patent ductus arteriosus requiring drug treatment or surgery; and intestinal perforation or necrotizing enterocolitis.”

There were 856 infants included in the final analysis, drawn from 40 study centers located in 9 countries. In the budesonide group, 40% of the infants developed bronchopulmonary dysplasia, and 46.3% of the placebo group developed the condition. However, the benefit “was offset by a nonsignificant excess in mortality with budesonide as compared with placebo.” The researchers observed that “no single cause of death recorded on death certificates or on autopsy reports explained the difference in mortality between the two groups.”

As for secondary outcomes, the frequency of a patent ductus arteriosus that required surgical ligation was “significantly lower among the infants assigned to budesonide than among those assigned to placebo.” There were no other significant differences in the other prespecified secondary outcomes.

The researchers did not expect the possibility that budesonide could raise the risk of mortality. They note that, “on the basis of a biologic rationale and the available clinical evidence, there was reason to hypothesize that inhaled glucocorticoids might reduce the incidence of bronchopulmonary dysplasia, but there was no indication that they might increase mortality among preterm infants.” After examining prior reviews and trials, they conclude “The difference between the rate of death in the budesonide group and the placebo group may be explained by chance.”