Early ibuprofen administration did not help babies born preterm with patent ductus arteriosus (PDA), as waiting for the heart defect to close on its own was associated with non-inferior, perhaps even better clinical outcomes, in a randomized trial.
For infants born with moderate or larger PDAs, expectant management worked at least as well as early ibuprofen for the trial’s composite primary endpoint at 36 weeks postmenstrual age, at 46.3% versus 63.5% for early ibuprofen (risk ratio [RR] 0.73, 95% CI 0.59-0.91, P
- Necrotizing enterocolitis: 17.6% vs 15.3% (RR 1.15, 95% CI 0.67-1.97)
- Moderate-to-severe bronchopulmonary dysplasia: 33.3% vs 50.9% (RR 0.66, 95% CI 0.48-0.90)
- Death: 14.0% vs 18.2% (RR 0.77, 95% CI 0.44-1.32)
Rates of other adverse outcomes were similar between the two study groups, according to Willem-Pieter de Boode, MD, PhD, of Radboud University Nijmegen Medical Center in the Netherlands, and colleagues. Findings from the BeNeDuctus study were published in the New England Journal of Medicine and presented at the 2002 Hot Topics in Neonatology meeting.
A common finding in preterm infants, PDA occurs when the vessel connecting the aorta and the pulmonary artery does not close normally and results in a left-to-right shunt. Ibuprofen and other cyclooxygenase inhibitors have been used to close PDAs in newborns, though they have not been shown to improve neonatal morbidity and mortality in placebo-controlled, randomized trials.
“The results of this trial should not be interpreted to suggest that there is no causal relationship between PDA and neonatal morbidity in extremely preterm infants,” de Boode and colleagues wrote.
“Rather, it is plausible that an attempt to close the PDA with ibuprofen may be more harmful than the condition itself,” they said, citing prior observational data consistent with the suggestion of excess bronchopulmonary dysplasia with ibuprofen use due to the inhibition of angiogenesis.
The researchers called for further study of potentially safer and more effective treatments for PDA.
BeNeDuctus was a non-inferiority trial conducted at 17 neonatal ICUs in the Netherlands, Belgium, and Denmark. Included were 273 babies who were born extremely preterm (
Infants were randomized soon after birth to expectant management or early ibuprofen.
Expectant management comprised withholding treatment to close PDA unless criteria were met for cardiovascular failure associated with a left-to-right shunt. Peers assigned early ibuprofen received it starting at a median postnatal age of 63 hours at a median dose of 10 mg/kg, followed by two subsequent doses of 5 mg/kg.
The study cohort had a median gestational age of 26 weeks and birth weight of 845 g (1.86 lbs). Baseline maternal and neonatal characteristics were similar except for a greater preponderance of mothers with hemolysis, elevated liver enzymes, and low platelets in the expectant management group.
Results may not be generalizable to infants of different races or gestational ages or to those receiving prolonged invasive ventilation, de Boode and colleagues warned. They also had to stop enrollment after randomizing less than half of the planned sample size due to slow recruitment and funding issues.
“Our trial focused on the short-term effects of PDA management in the neonatal period and cannot inform management beyond this period, including whether neonatal follow-up should include routine echocardiographic screening for potentially prolonged exposure to transductal left-to-right shunting,” they added.
Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow
The study was funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center.
de Boode disclosed no relationships with industry.