Preterm Infants Treated Early for Patent Ductus Arteriosus Had Worse Outcomes

Active treatment of hemodynamically significant patent ductus arteriosus (PDA) in preterm infants within the first 2 weeks of life was associated with worse outcomes than expectant management.Incidence of the composite outcome of death at 36 weeks or at discharge, or moderate to severe bronchopulmonary dysplasia (BPD) was higher in the active treatment group than in the expectant management group.Deaths at 36 weeks were higher in the active treatment group.

Active treatment of hemodynamically significant patent ductus arteriosus (PDA) in preterm infants within the first 2 weeks of life was associated with worse outcomes than expectant management, a meta-analysis suggested.

In the analysis of 10 randomized clinical trials (RCTs), incidence of the composite outcome of death at 36 weeks or at discharge, or moderate to severe bronchopulmonary dysplasia (BPD) was higher in the active treatment group than in the expectant management group (56.2% vs 50.8%, relative risk [RR] 1.10, 95% CI 1.01-1.19, P=0.02), reported Jiun Lee, MBBS, MMed, of the National University Health System in Singapore, and colleagues.

Deaths at 36 weeks were higher in the active treatment group (14.3% vs 11.2%, RR 1.27, 95% CI 1.01-1.61, P=0.04), they noted in JAMA Pediatrics. There was a nonsignificant increase in moderate to severe BPD (47.4% vs 43.3%, RR 1.08, 95% CI 0.95-1.23, P=0.25).

“In our meta-analysis of 10 RCTs we found that active closure of preterm PDA was associated [with] a significantly higher risk of mortality, as well as the composite outcome of death or chronic lung disease (bronchopulmonary dysplasia),” Lee told MedPage Today in an email. “In evidence-based medicine, meta-analysis of all relevant RCTs is considered the highest level of evidence (Level I),” Lee added. “As far as we are aware, ours is the first such meta-analysis that shows potential harm in actively closing the preterm PDA.”

For decades, conventional management for hemodynamically significant PDA in preterm infants has been using prostaglandin inhibitors to attempt closure. If that fails, surgical ligation is usually done, Lee and colleagues explained.

“Since the 2000s, however, there has been a shift toward less aggressive treatment for PDA because despite some success with pharmacologic closure, no other benefit could be conclusively demonstrated,” they added. “The pharmacologic agents used also have some serious adverse effects. In addition, rates of spontaneous PDA closure in infants with a birth weight of 1,000 g or more were very high in previous studies.”

“Surgical ligation of PDA is accompanied by substantial risks and does not guarantee a good outcome,” they continued. “Nevertheless, in the majority of neonatal intensive care units, infants with a birth weight of less than 1,000 g are still being routinely treated for hemodynamically significant PDA, despite reports of noninferiority of an expectant management approach.”

However, in an accompanying editorial, Ronald Clyman, MD, of the University of California San Francisco wrote, “It is important to remember that the results of ongoing RCTs and future meta-analyses need to be interpreted in their historical contexts.”

“Whether early use of newer pharmacologic or procedural therapies, like transcatheter device closure, are as safe and offer a benefit over expectant management will need to be addressed in future trials,” Clyman added. “Given the ever-changing nature and context of neonatal care, these too will require reevaluation by additional trials in the future.”

In the trial, there was a nonsignificant increase in periventricular leukomalacia (5.7% vs 3.5%, RR 1.50, 95% CI 0.98-2.30, P=0.06) in the active treatment group versus the expectant management group, though there was a significant risk difference between the groups, favoring expectant management (risk difference 1.8%, 95% CI 0.4%-3.2%, P=0.01). Differences between groups for other secondary outcomes, which included intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, were not statistically significant.

RCTs included in the meta-analysis were sourced from PubMed (MEDLINE), Embase, and Cochrane Library databases, and were published between January 2010, and July 2024. There were 2,035 infants enrolled in the trials, with 1,018 infants in the active treatment group and 1,017 infants in the expectant management group, evenly split between female and male infants.

Overall, the mean gestational age of infants was about 26 weeks in both groups; mean birth weight was 874.7 g in the active treatment group and 897.7 g in the expectant management group.

Limitations included that, because PDA treatment was started during the first 2 weeks of life, findings may not be generalizable to infants who received treatment at a later time, Lee and colleagues noted.

Additionally, open-label medical treatment was greater in the expectant management group than in the active treatment group, and less use of NSAIDs or paracetamol and longer PDA exposure with expectant management was associated with better outcomes. Also, BPD definitions varied among included trials, and subgroup analyses for other clinical points of interest did not show significant differences for the composite outcome, but there were few studies reporting these data.