Selective Early PDA Pharmacotherapy Feasible in Extremely Preterm Infants

Navigating Patent Ductus Arteriosus Management in Extremely Preterm Infants

Management of patent ductus arteriosus (PDA) remains a persistent challenge in neonatal intensive care, particularly for extremely preterm infants born before 26 weeks' gestational age [1, 2]. As the most common cardiovascular condition in this vulnerable population, PDA is associated with significant morbidity and mortality [2, 3]. Yet, a consensus on optimal management remains elusive, with clinical practice varying widely from conservative observation to early pharmacologic or surgical intervention [3, 4]. This uncertainty is compounded by systematic reviews suggesting that early, routine medical treatment may not improve, and could potentially worsen, outcomes like bronchopulmonary dysplasia or death [5, 6]. This clinical equipoise highlights the need for evidence to guide clinicians in selecting which infants benefit from intervention and determining the appropriate timing. A recent pilot trial offers new insight into the feasibility of a more selective, evidence-guided treatment strategy.

Evaluating a Targeted Intervention Strategy

To bring clarity to this debate, a multicenter, open-label, parallel-design pilot randomized controlled trial was conducted across seven tertiary and quaternary neonatal intensive care units. The study's primary goal was to assess the feasibility of recruiting for a larger trial comparing two distinct management approaches for infants born at less than 26 weeks gestational age with a PDA diagnosed within 72 hours of birth. The trial contrasted an early selective medical treatment (SMART) strategy against a control arm of no intervention during the first 7 postnatal days. The SMART protocol involved early echocardiographic screening within 72 hours to grade the PDA shunt, with subsequent pharmacotherapy initiated only for infants with a moderate-to-severe shunt. Beyond feasibility, the investigators also evaluated a composite clinical endpoint of survival without major morbidity, a clinically relevant measure that captures the balance between survival and long-term health in this fragile population.

Recruitment and Protocol Adherence

The trial successfully demonstrated that a study of this nature is feasible in a real-world clinical setting. Investigators met their primary recruitment objective by enrolling 116 of 185 eligible infants, representing 63% (95% CI 56% to 70%) of the potential pool. Of those enrolled, 104 infants (90%) were randomized, with 51 assigned to the selective medical treatment (SMART) arm and 53 to the control arm. The cohort's mean gestational age of 24.3 weeks and mean birth weight of 714 g confirm that the study successfully reached its intended high-risk population. Furthermore, the protocol proved highly practical for implementation, evidenced by a protocol deviation rate of only 1.9%. A key finding was that the screening algorithm effectively stratified risk; 24% of infants in the SMART arm never met the criteria for intervention, thereby avoiding unnecessary medication. For those who were treated, the median age at treatment initiation was 2 days (interquartile range 1–2.5 days), confirming the strategy's early and targeted application.

Preliminary Outcome Signals

While designed primarily to assess feasibility, the pilot trial also generated preliminary data on clinical outcomes. The analysis showed that the selective medical treatment (SMART) strategy had an 85% probability of yielding a better Win ratio (1.34, 95% Credible Interval 0.73 to 2.5) compared to the control group. The Win ratio is a patient-centered statistical method that compares outcomes between two groups by ranking them in order of clinical importance, such as survival without major morbidity being superior to survival with morbidity, which is in turn superior to death. It then determines which group had more favorable outcomes overall. Although the point estimate favors the SMART strategy, the wide credible interval, which crosses 1.0, indicates statistical uncertainty and means a definitive conclusion on efficacy cannot be drawn from this pilot study. These findings should be interpreted as hypothesis-generating, providing a rationale for a larger, adequately powered trial.

Clinical Implications and Future Directions

This multicenter pilot trial establishes that a randomized trial of selective, early PDA pharmacotherapy is feasible to conduct in extremely preterm infants. The high recruitment rate and minimal protocol deviation (1.9%) suggest that the SMART-PDA algorithm, which uses clinical and echocardiographic grading to guide treatment, is a practical strategy for tertiary and quaternary neonatal intensive care units. The clinical relevance of this approach is significant. The authors suggest that early echocardiography screening and selective pharmacotherapy using the SMART-PDA algorithm may enhance the probability of survival with fewer morbidities in infants born at less than 26 weeks gestational age. By identifying and treating only those with a moderate-to-severe PDA shunt, this strategy provides a potential framework to avoid both the risks of an untreated, hemodynamically significant PDA and the potential harms of unnecessary pharmacotherapy. These findings provide a strong foundation and a clear methodological roadmap for a definitive, large-scale trial to confirm the clinical benefits of this targeted approach. The trial registration number is NCT05011149.

References

1. Mitra S, Hebert A, Castaldo MP, et al. Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial (SMART-PDA).. Archives of disease in childhood. Fetal and neonatal edition. 2026. doi:10.1136/archdischild-2026-330462

2. Mitra S, Hébert A, Castaldo M, et al. Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial protocol (SMART-PDA).. BMJ open. 2024. doi:10.1136/bmjopen-2024-087998

3. Mitra S, Boode WPD, Weisz DE, Shah PS. Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. Cochrane Database of Systematic Reviews. 2023. doi:10.1002/14651858.cd013588.pub2

4. Sherif DFE, Raggal NME, Nasef MW, Saleh GA, Youssef NH, Metwally MH. Oral ibuprofen versus placebo in closure of patent ductus arteriosus in preterm neonates, a randomized control trial.. Journal of neonatal-perinatal medicine. 2024. doi:10.1177/19345798241302264

5. Gupta S, Subhedar NV, Bell J, et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. New England Journal of Medicine. 2024. doi:10.1056/nejmoa2305582

6. Parikh NA, Velu S. Patent ductus arteriosus: emerging trial evidence firmly supports conservative management in preterm infants.. Current opinion in pediatrics. 2026. doi:10.1097/MOP.0000000000001543