Highlights
The TREOCAPA trial, a large-scale randomized clinical trial across 14 European countries, investigated whether prophylactic intravenous acetaminophen could improve survival without severe morbidities in extremely preterm infants. The key highlights include:
- Prophylactic acetaminophen did not significantly improve the primary outcome of survival without severe neonatal morbidity at 36 weeks’ postmenstrual age (PMA) compared to placebo.
- While the treatment significantly increased the rate of ductus arteriosus closure by day 7, this anatomical success did not translate into better clinical outcomes.
- Acetaminophen treatment was associated with a significantly higher incidence of cholestasis (6.4% vs. 2.6%) compared to the placebo group.
- The results challenge the routine use of prophylactic paracetamol for patent ductus arteriosus (PDA) management in the extremely preterm population.
Background: The PDA Management Dilemma
The management of patent ductus arteriosus (PDA) remains one of the most debated topics in neonatal intensive care. In extremely preterm infants, the failure of the ductus arteriosus to close shortly after birth can lead to significant hemodynamic instability. This condition, characterized by a left-to-right shunt, may result in pulmonary overcirculation and systemic hypoperfusion, which are theoretically linked to complications such as intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD).
Historically, nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin and ibuprofen have been the mainstays of treatment. However, these agents are associated with significant adverse effects, including renal impairment and gastrointestinal perforations. Acetaminophen (paracetamol) emerged as a promising alternative because it inhibits prostaglandin synthesis through a different mechanism (the peroxidase segment of prostaglandin H2 synthase) and was perceived to have a more favorable safety profile. Despite its increasing use off-label, high-quality evidence regarding its prophylactic efficacy in improving long-term clinical outcomes has been lacking until the publication of the TREOCAPA trial.
Study Design and Methodology
The TREOCAPA (Trial of Prophylactic Acetaminophen) was a double-blind, randomized, placebo-controlled clinical trial conducted across 43 neonatal intensive care units (NICUs) in 14 European countries. The study enrolled preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation.
Intervention and Stratification
The trial utilized a weight-based dosing regimen that was refined after a phase 2 dose-finding study. Infants were stratified by gestational age (GA):
- Infants born at 27–28 weeks GA: Received a 20-mg/kg loading dose followed by 7.5 mg/kg every 6 hours for 5 days.
- Infants born at 23–26 weeks GA: Received a 25-mg/kg loading dose followed by 10 mg/kg every 6 hours for 5 days.
The control group received an equivalent volume of isotonic sodium chloride (placebo). Treatment was initiated within the first 12 hours of life to capture the prophylactic window.
Endpoints
The primary outcome was survival without severe neonatal morbidities evaluated at 36 weeks’ PMA. Severe morbidities included grade 3 or 4 intraventricular hemorrhage, cystic periventricular leukomalacia, stage 2 or 3 necrotizing enterocolitis, or moderate-to-severe bronchopulmonary dysplasia. The secondary exploratory outcome focused on the anatomical closure of the ductus arteriosus, assessed via echocardiography on postnatal day 7.
Key Findings: Efficacy and Safety Analysis
A total of 778 infants were included in the final analysis (391 in the acetaminophen group and 387 in the placebo group). The median gestational age was 26 weeks, and the population was nearly evenly split by sex.
Primary Outcome: Survival Without Morbidity
The study found no statistically significant difference in the primary composite outcome. Survival without severe morbidities at 36 weeks’ PMA occurred in 66.2% of the acetaminophen group compared to 63.6% in the placebo group. The absolute risk difference (ARD) was 2.7 percentage points (95% CI, -4.0 to 9.3), and the relative risk (RR) was 1.04 (95% CI, 0.94 to 1.16). This indicates that early administration of acetaminophen does not provide a superior clinical benefit regarding overall survival or the prevention of major neonatal complications.
Secondary Outcome: PDA Closure
Interestingly, acetaminophen was highly effective at achieving the physiological goal of ductus closure. By day 7, the ductus arteriosus was closed in 71.2% of infants in the acetaminophen group compared to only 52.2% in the placebo group (ARD, 19.0; 95% CI, 12.0 to 25.7). This confirms that acetaminophen is a potent ductal constrictor, yet this anatomical success did not translate into a reduction in clinical morbidities.
Safety and Adverse Events
While most safety parameters were comparable between the two groups, a significant safety signal was detected regarding liver function. Cholestasis was reported in 6.4% of infants treated with acetaminophen compared to 2.6% in the placebo group (ARD, 3.8; 95% CI, 0.9 to 6.9). This finding suggests that even at standard neonatal doses, the immature liver of an extremely preterm infant may be susceptible to acetaminophen-induced hepatotoxicity or altered bile flow.
Expert Commentary and Clinical Implications
The results of the TREOCAPA trial add to a growing body of evidence suggesting that “closing the duct” does not necessarily equate to “improving the baby.” This phenomenon, often referred to as the PDA paradox, suggests that while a large PDA is associated with poor outcomes, the act of pharmacologically closing it—especially prophylactically—may not mitigate those risks and might introduce new ones.
Mechanistic Insights
The lack of clinical benefit despite successful ductal closure may be due to several factors. First, the morbidities associated with extreme prematurity (like BPD and NEC) are multifactorial; the PDA is likely only one small contributor. Second, the potential side effects of the medication (such as the observed cholestasis) might offset any hemodynamic benefits gained from ductal closure. Finally, many PDAs in the placebo group closed spontaneously or remained hemodynamically insignificant, suggesting that a more selective, conservative approach to PDA management may be safer.
Comparison with Previous Trials
The findings align with other recent studies, such as the PDA-TOLERATE trial, which suggested that routine treatment of a PDA in the first week of life does not reduce the risk of BPD or other complications. The TREOCAPA study provides the most robust evidence to date specifically regarding the prophylactic use of intravenous acetaminophen, effectively closing the door on its use as a standard preventive measure in this population.
Conclusion
The TREOCAPA trial provides high-quality evidence that prophylactic intravenous acetaminophen started within 12 hours of birth does not increase survival without severe neonatal morbidities in extremely preterm infants. Although the drug is effective at inducing ductus arteriosus closure, its use is associated with an increased risk of cholestasis and offers no clear clinical advantage over placebo. Clinicians should reconsider the routine use of prophylactic acetaminophen and instead focus on individualized management strategies for symptomatic patent ductus arteriosus.
Funding and ClinicalTrials.gov
This study was supported by various European national health research grants and the TREOCAPA Study Group. ClinicalTrials.gov Identifier: NCT04459117.
References
- Rozé JC, Cambonie G, Flamant C, et al. Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen: A Randomized Clinical Trial. JAMA Pediatr. 2026;180(2):e256150. doi:10.1001/jamapediatrics.2025.6150.
- Hundscheid T, Onland W, Kooi EMW, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2023;388(11):980-990.
- Clyman RI, Liebowitz M, Kaempf J, et al. PDA-TOLERATE Trial: Is Early Treatment of the Patent Ductus Arteriosus Necessary? J Pediatr. 2019;206:102-108.e3.
- Ohlsson A, Shah PS. Paracetamol (acetaminophen) for prevention or treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2020;1(1):CD010061.