Dirk Bassler1, Eric S Shinwell1, Mikko Hallman1, Pierre-Henri Jarreau1, Richard Plavka1, Virgilio Carnielli1, Christoph Meisner1, Corinna Engel1, Alexander Koch1, Karen Kreutzer1, Johannes N van den Anker1, Matthias Schwab1, Henry L Halliday1, Christian F Poets1. 1. From the Department of Neonatology, University Hospital Zurich, University of Zurich, Zurich (D.B.), and the Division of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel (J.N.A.) - both in Switzerland; Ziv Medical Center, Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat Gan, Israel (E.S.S.); the Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, Oulu, Finland (M.H.); Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire Risques et Grossesse, Université Paris Descartes, Hôpital Cochin, Service de Médecine et Réanimation Néonatales de Port-Royal, Paris (P.-H.J.); Charles University, General Faculty Hospital and 1st Faculty of Medicine in Prague, Prague, Czech Republic (R.P.); Polytechnical University of Marche, Salesi Children's Hospital, Ancona, Italy (V.C.); Institute for Clinical Epidemiology and Applied Biometry (C.M.), University Children's Hospital Tübingen, Center for Pediatric Clinical Studies (C.E.), Department of Neonatology, University Children's Hospital (A.K., K.K., C.F.P.), and Department of Clinical Pharmacology and Department of Pharmacy and Biochemistry, University Hospital and University of Tübingen (M.S.), Tübingen, and Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart (M.S.) - all in Germany; Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, the Netherlands (J.N.A.); the Division of Clinical Pharmacology, Children's National Health System, Washington, DC (J.N.A.); and the Department of Child Health at Queen's University Belfast, Institute of Clinical Science, Belfast, United Kingdom (H.L.H.).
Abstract
BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).
RCT Entities:
BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).
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