Highlight
– In a multicenter randomized trial of 482 infants born at 22–28 weeks’ gestation with a protocol-defined PDA, expectant management and active pharmacologic treatment produced similar rates of the composite outcome death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age (PMA).
– Expectant management was associated with significantly lower early mortality: death before 36 weeks’ PMA occurred in 4.1% of infants randomized to expectant management vs 9.6% randomized to active treatment (adjusted risk difference −5.6%; 95% CI −10.1% to −1.2%; P = .01).
Background
Patent ductus arteriosus (PDA) is common in very preterm infants and has long been implicated in adverse outcomes including respiratory morbidity, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and prolonged need for respiratory support. Management strategies vary widely and include routine pharmacologic closure (indomethacin, ibuprofen, or acetaminophen), surgical or catheter-based closure, or conservatively observing (expectant management) to allow spontaneous closure. Observational data and physiologic rationale have supported both earlier closure to reduce pulmonary overcirculation and conservative approaches to avoid drug-related adverse effects and the risks of intervention. High-quality, contemporary randomized evidence comparing routine active treatment of an identified PDA with expectant care in extremely preterm infants has been limited, leaving clinical equipoise.
Study design
This trial (NICHD Neonatal Research Network) randomized infants born at 22 to 28 weeks’ gestation who had a protocol-defined PDA identified between 48 hours and 21 days of life. Between December 2018 and December 2024, 482 infants at 33 NICHD sites were randomized to either expectant management (n = 242) or active pharmacologic treatment to close the PDA (n = 240). Active treatments included acetaminophen, ibuprofen, or indomethacin per protocol. The primary outcome was the composite of death or BPD at 36 weeks’ PMA. Secondary outcomes included the individual components of the composite outcome and other prematurity-related morbidities. The trial was registered at ClinicalTrials.gov (NCT03456336).
Key findings
Population characteristics: Median gestational age was 25 weeks (IQR 24–27 weeks) and median birth weight was 760 g (IQR 620–935 g).
Primary outcome: Death or BPD at 36 weeks’ PMA occurred in 80.9% (195/241) of infants randomized to expectant management versus 79.6% (191/240) of infants randomized to active treatment. The adjusted risk difference was 1.2% (95% CI, −5.7% to 8.1%; P = .73), indicating no statistically significant difference between strategies for the composite outcome.
Mortality: The trial was stopped early (after a planned 50% interim analysis) for futility and safety because of higher survival observed in the expectant management arm. Death before 36 weeks’ PMA occurred in 4.1% (10/241) of infants in the expectant management group compared with 9.6% (23/240) in the active treatment group. The adjusted risk difference was −5.6% (95% CI, −10.1% to −1.2%; P = .01), a clinically and statistically significant reduction in early mortality favoring expectant management.
Cause-specific findings: Infections resulting in death were reported in 0.8% (2/241) of expectant management infants versus 3.8% (9/240) of actively treated infants. Detailed safety profiles, including rates of NEC, IVH, renal adverse events, and other complications, were prespecified secondary outcomes in the trial report; the primary safety signal prompting early stopping related to differential survival.
Interpretation and expert commentary
These results provide high-quality randomized evidence that routine pharmacologic closure of a protocol-defined PDA in extremely preterm infants does not reduce the combined outcome of death or BPD at 36 weeks’ PMA compared with expectant management. More strikingly, active treatment was associated with a higher early mortality rate. The trial’s early stopping for futility and safety strengthens the signal that routine active pharmacologic closure, as applied in this trial, may confer harm in terms of survival during the neonatal period.
Clinical plausibility and potential mechanisms
Pharmacologic agents used to close the ductus (cyclooxygenase inhibitors such as indomethacin and ibuprofen, or acetaminophen acting via alternative pathways) affect prostaglandin-mediated physiology. Known adverse effects include reductions in renal perfusion and urine output, altered platelet function, and potential impacts on intestinal perfusion — theoretical mechanisms that could increase susceptibility to NEC, renal dysfunction, or bleeding. Additionally, treatment may necessitate central access, contribute to exposure to other interventions, or interact with hemodynamic instability in extremely preterm infants. However, the precise pathways linking active pharmacologic PDA treatment to higher early mortality observed here remain to be elucidated and require careful secondary analyses and mechanistic investigation.
Strengths
This was a large, multicenter, randomized trial conducted within the NICHD Neonatal Research Network, increasing generalizability to high-resource NICU settings. The study enrolled a high-risk cohort (22–28 weeks’ gestation), used prespecified definitions and endpoints clinically relevant to neonatology, and included a preplanned interim analysis with stopping rules for efficacy, futility, and safety.
Limitations and cautions
– Early stopping: The trial was stopped after the interim analysis for safety and futility, which can complicate interpretation of both positive and null results. Early stopping may overestimate treatment effects or yield imprecise estimates for subgroups and secondary outcomes.
– Treatment heterogeneity: The active-treatment arm permitted different agents (acetaminophen, ibuprofen, indomethacin). Differential effects by drug class or dosing regimen are possible and may dilute or obscure agent-specific benefits or harms.
– Composite endpoint complexity: The primary composite (death or BPD) is driven in large part by BPD rates, which remain high in this population. A null composite result can obscure divergences in individual components; in this trial, mortality diverged while the composite did not.
– Applicability: Results apply to extremely preterm infants with protocol-defined PDA managed in high-resource NICUs; extrapolation to older preterm infants, infants with differing PDA hemodynamics, or low-resource settings requires caution.
Clinical implications
For clinicians caring for extremely preterm infants, this trial challenges the routine use of pharmacologic PDA closure for all infants meeting protocol-defined PDA criteria. The findings support consideration of expectant management as a default strategy in similar patient populations, reserving active pharmacologic or surgical interventions for infants with specific, refractory hemodynamic compromise attributable to the PDA. Clinical judgment should incorporate individual hemodynamics, respiratory status, risk of drug-related adverse effects, and center-level expertise.
Practically, centers and guideline committees should review local practice patterns, weighing the new randomized evidence when drafting recommendations. Shared decision-making with families, emphasizing the lack of benefit on death or BPD and the observed early survival advantage with expectant care, is warranted.
Research implications and next steps
Key unanswered questions include the mechanism(s) by which active pharmacologic treatment was associated with increased early mortality, whether specific agents differ in risk/benefit profiles, and the long-term neurodevelopmental outcomes of expectant versus active strategies. Subgroup and per-protocol analyses from the trial, longer-term follow-up (beyond 36 weeks’ PMA), and trials focused on infants with clear hemodynamic compromise are needed. Biomarker and physiologic studies to identify which infants are most likely to benefit or be harmed by active treatment would facilitate precision approaches to PDA management.
Conclusion
The PDA Randomized Clinical Trial found no difference between expectant management and active pharmacologic treatment in the composite outcome of death or BPD at 36 weeks’ PMA among extremely preterm infants with a protocol-defined PDA. Importantly, expectant management was associated with substantially higher early survival. These findings support a more conservative approach to routine pharmacologic closure in this population and call for individualized care, further mechanistic work, and longer-term outcome data to guide practice refinements.
Funding and clinicaltrials.gov
This trial was performed within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trial registration: ClinicalTrials.gov Identifier: NCT03456336.
References
Laughon MM, Thomas SM, Watterberg KL, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial. JAMA. 2025 Dec 9:e2523330. doi:10.1001/jama.2025.23330. PMID: 41364689; PMCID: PMC12690482.