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Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus
Quick Takes
- This randomized, controlled trial demonstrated that expectant management of patent ductus arteriosus in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks’ gestational age.
- Moderate-to-severe bronchopulmonary dysplasia occurred in a lower percentage of infants in the expectant management group (33.3%) as compared with the early ibuprofen group (50.9%).
Study Questions:
What is the benefit of early ibuprofen in the management of premature infants with patent ductus arteriosus (PDA)?
Methods:
A multicenter, randomized, noninferiority trial was performed. Inclusion criteria included PDA diameter >1.5 mm with left-to-right shunting and extreme prematurity (<28 weeks’ gestation). Infants were randomized to receive either expectant management or early ibuprofen with repeated dose to achieve ductal closure. The composite primary endpoint included necrotizing enterocolitis (Bell’s stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks’ postmenstrual age.
Results:
A total of 273 infants were randomized, with a median gestational age of 26 weeks and median birth weight of 845 grams (29.8 ounces). A primary outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; p < 0.001 for noninferiority). Necrotizing enterocolitis occurred in 17.6% of infants in the expectant-management group and 15.3% in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1). Bronchopulmonary dysplasia occurred in 33.3% of infants in the expectant-management group and 50.9% in the early-ibuprofen group (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 14% in the expectant-management group and 18.2% in the early-ibuprofen group (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4).
Conclusions:
The authors conclude that expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks’ postmenstrual age.
Perspective:
PDA is common in extremely premature infants. Empiric early closure with cyclooxygenase inhibitors has been proposed to decrease morbidity and mortality related to PDA in this patient population. This randomized trial studied the role of expectant management as compared with early medical therapy to close PDA and demonstrated noninferiority of expectant management. The study did not meet enrollment targets but nonetheless provides valuable information, suggesting that the practice of routine early closure with ibuprofen should be reconsidered. Given improved transcatheter therapies for closure of PDA in extremely small and premature infants, the study of alternative methods of closure may be considered.
Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Congenital Heart Disease
Keywords: Bronchopulmonary Dysplasia, Cyclooxygenase Inhibitors, Ductus Arteriosus, Patent, Enterocolitis, Necrotizing, Gestational Age, Heart Defects, Congenital, Ibuprofen, Infant, Extremely Premature, Infant, Premature, Infant, Newborn, Pregnancy, Prostaglandin-Endoperoxide Synthases
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