Expectant management of patent ductus arteriosus noninferior to early ibuprofen use
1. In this randomized controlled trial, expectant management of patent ductus arteriosus (PDA) in extremely premature infants required no active intervention unless complications arose.
2. Expectant management was shown to be noninferior to early ibuprofen in terms of preventing adverse neonatal outcomes.
Evidence Rating Level: 1 (Excellent)
Study Rundown: PDA is a common complication of premature delivery, where the vessel connecting the aorta and the pulmonary artery present in utero does not close properly. Notably, PDA is associated with adverse neonatal outcomes and mortality. Although cyclooxygenase inhibitors, such as ibuprofen, can induce PDA closure, their clinical benefits are uncertain. Considering the potential adverse effects of these agents, expectant management has been increasingly employed, but with limited evidence. The current study was a trial to compare expectant management with early administration of ibuprofen in severely premature infants with confirmed PDA. In this randomized controlled trial, it was demonstrated that expectant management, which did not involve active intervention unless pre-specified indications were met, was noninferior to early ibuprofen with regards to the incidence of such as bronchopulmonary dysplasia, necrotizing enterocolitis, and death, as well as other adverse outcomes at 36 weeks postmenstrual age. Specific adverse outcomes were more common in the ibuprofen recipients. The study was limited by its unblinded design, narrow inclusion criteria, and sample size. Nevertheless, it provided evidence to support expectant management for PDA in premature infants in clinically appropriate circumstances.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: This study was an international, multicenter, randomized controlled trial assessing the noninferiority of expectant management against early ibuprofen for premature infants with PDA. Extremely premature infants, at 28 weeks gestational age or less, with an echocardiographically confirmed PDA were eligible for inclusion. Exclusion criteria included contraindications to ibuprofen, persistent pulmonary hypertension, neurodevelopment anomaly, and life-threatening defects. Overall, 273 infants were randomized 1:1 to complete an ibuprofen regimen to close the PDA (early-ibuprofen group) or to be managed expectantly (expectant-management group). The pharmacologic intervention was only considered if cardiovascular failure associated with a significant left-to-right shunt was suspected. The primary outcome was a composite of necrotizing enterocolitis, moderate-to-severe bronchopulmonary dysplasia, or death at 36 weeks postmenstrual age. The median gestational age of included infants was 26 weeks, and the median birth weight was 845g. Overall, the primary outcome occurred in 46.3% of infants in the expectant-management group and 63.5% in the early-ibuprofen group (Absolute Risk Difference [ARD], -17.2 percentage points; upper boundary of one-sided 95% confidence interval [CI], -7.4; p<0.001 for noninferiority). Necrotizing enterocolitis occurred in 17.6% of the expectant-management group and 15.3% in the early-ibuprofen group (ARD, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1) while bronchopulmonary dysplasia occurred in 33.3% and 50.9% in each group, respectively (ADR, -17.6 percentage points; 95% CI, -30.2 to -5.0). The mortality rate was 14.0% and 18.2%, respectively (ADR, -4.3 percentage points; 95% CI, -13.0 to 4.4). In summary, these results demonstrated that for comparable clinical settings, expectant management was noninferior to early ibuprofen administration in extremely premature infants with PDA.
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