A small but rigorous randomized trial suggests paracetamol may be a feasible alternative to ibuprofen for late PDA treatment, while underscoring the need for larger multicenter studies to guide neonatal care.
Study: Paracetamol or ibuprofen? A pilot study comparing rescue therapy for PDA in preterm infants within the first month. Image Credit: Jana Kollarova / Shutterstock
In a recent article published in the journal Frontiers in Pediatrics, researchers presented findings from the Paracetamol and Ibuprofen Research (PAIR) trial, which analyzed differences between the two medications as treatments for hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants.
They found no statistically significant differences between the two therapies in adverse effects, prematurity-related complications, or PDA closure rates, although the study was not powered to detect superiority or equivalence in clinical efficacy.
Clinical Context of Patent Ductus Arteriosus
PDA remains a common and debated clinical problem in preterm infants, particularly when it becomes hemodynamically significant and contributes to respiratory and systemic instability. In infants with hsPDA, a blood vessel that should close after birth remains open, allowing abnormal blood flow between the heart and lungs. This extra blood flow can strain these organs, reduce blood supply to other parts of the body, and cause clinical symptoms such as poor circulation and breathing difficulties.
Ibuprofen is the established pharmacological treatment for symptomatic hsPDA in the UK, but growing evidence suggests that paracetamol may be a potential alternative. National surveys indicate widespread off-label use of paracetamol in neonatal intensive care units (NICUs), although uncertainty persists regarding its effectiveness, optimal dosing, and safety profile.
There is no current evidence to support very early or routine prophylactic treatment of PDA, and many infants experience spontaneous closure. However, a subset of extremely preterm infants develops persistent, symptomatic hsPDA requiring rescue treatment within the first month of life, a period during which pharmacological responsiveness may already be declining.
PAIR Trial Design and Eligibility Criteria
The PAIR trial was a single-center, prospective pilot randomized controlled study conducted in a UK neonatal intensive care unit.
Preterm infants with a birth weight below 1,500 g or gestational age under 32 weeks were eligible if they were 28 days of age or younger and had echocardiographically confirmed hsPDA with clinical symptoms warranting treatment. A pragmatic sample size of 32 infants was selected to assess feasibility rather than treatment superiority, reflecting the exploratory nature of the trial.
hsPDA was defined according to standardized echocardiographic criteria adapted from the European Neonatologist Performed Echocardiography guidelines. Eligible infants were randomized to receive either paracetamol or ibuprofen.
Treatment Protocols and Outcome Measures
Infants who received paracetamol received an initial dose of 20 mg/kg, administered once to quickly achieve an effective drug level, followed by maintenance doses of 10 mg/kg every 6 hours over 3 days. Infants receiving ibuprofen received 10 mg/kg on the first day and 5 mg/kg each on the second and third days.
Both ibuprofen and paracetamol were administered intravenously. Echocardiograms were repeated within 72 hours after treatment completion and were interpreted by blinded pediatric cardiologists.
The primary outcome that researchers measured was reduction to non-hsPDA or PDA closure. Secondary outcomes included complications associated with prematurity, including necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP), each of which can influence survival and long-term outcomes, and medication-related adverse effects. Recruitment, retention, and data completeness were evaluated as part of the pilot design.
Treatment Response and Safety Outcomes
Over two years, the research team successfully enrolled 32 infants, representing 91.4% of the eligible infants, with a 100% completion rate. Baseline characteristics were broadly similar across groups, although infants assigned to the ibuprofen group tended to be smaller, more premature, and significantly more likely to require mechanical ventilation prior to treatment, indicating greater baseline illness severity.
Following treatment, 37.5% of infants who received paracetamol converted from hsPDA to non-hsPDA, compared with 25.0% in those who received ibuprofen; this difference was not statistically significant. Complete PDA closure occurred in 25.0% of paracetamol-treated infants and 12.5% of ibuprofen-treated infants.
No significant differences were observed between groups in major complications of prematurity, including BPD, NEC, IVH, or overall ROP incidence. A higher proportion of infants receiving ibuprofen developed severe ROP requiring treatment. However, confidence intervals were wide, and findings should be interpreted cautiously given the small sample size and baseline imbalance between groups. Adverse effects were uncommon and similar between groups, with one case of transient renal impairment in the ibuprofen group and no significant hepatic or gastrointestinal complications in either group. One death occurred in each treatment group due to severe NEC, with no temporal association identified between the study medications and mortality.
Approximately one-third of infants received an additional open-label course of pharmacological treatment for persistent hsPDA. This protocol allowance reflects real-world practice but may have influenced secondary outcome comparisons.
Interpretation and Implications for Future Trials
In this pilot trial, researchers found no statistically significant differences in efficacy or safety between intravenously administered paracetamol and ibuprofen as rescue treatment for hsPDA in very preterm infants during the first four weeks of life. Because the study was designed to assess feasibility rather than clinical superiority, these findings should not be interpreted as evidence of equivalence between therapies. Overall closure rates were lower than those reported in studies treating PDA earlier in life, supporting existing evidence that pharmacological treatment becomes less effective with increasing postnatal age. Importantly, the trial demonstrated excellent feasibility, with high parental consent and complete follow-up.
Key strengths include a robust randomized design, standardized echocardiographic definitions, blinded outcome assessment, and real-world clinical relevance. Limitations include a small sample size, lack of blinding, baseline imbalance between groups, and the allowance of open-label rescue treatment, which may have influenced secondary outcomes. The study was also not designed to assess long-term neurodevelopmental outcomes.
In conclusion, the PAIR trial provides valuable feasibility and short-term safety data. These findings support a larger multicenter clinical trial to determine the optimal pharmacological management of hsPDA diagnosed in preterm infants.
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