TY - JOUR
T1 - Prophylactic Treatment of Patent Ductus Arteriosus with Acetaminophen
T2 - A Randomized Clinical Trial
AU - TREOCAPA Study Group
AU - Rozé, Jean-Christophe
AU - Cambonie, Gilles
AU - Flamant, Cyril
AU - Patkaï, Juliana
AU - Mühlbacher, Tobias
AU - Gascoin, Geraldine
AU - Rideau Batista Novais, Aline
AU - Tauzin, Manon
AU - Le Duc, Kevin
AU - Beuchée, Alain
AU - Joye, Sebastien
AU - Babacheva, Evgeniya
AU - Bouissou, Antoine
AU - Ligi, Isabelle
AU - Tammela, Outi
AU - Plourde, Marion
AU - Dempsey, Eugene
AU - Tosello, Barthelemy
AU - Nguyen, Kim
AU - Vincent, Marine
AU - Andresson, Pille
AU - Binder, Christoph
AU - Kruse, Charlotte
AU - Barcos Munoz, Francisca
AU - Kuhn, Pierre
AU - Proença, Elisa
AU - Bartocci, Marco
AU - Kermorvant-Duchemin, Elsa
AU - Nellis, Georgi
AU - Lumia, Mirka
AU - Giapros, Vasileios
AU - Rigo, Vincent
AU - Sankilampi, Ulla
AU - Mendes Da Graça, André
AU - Rønnestad, Arild
AU - Soukka, Hanna
AU - Mondì, Vito
AU - Aikio, Outi
AU - Torre-Monmany, Nuria
AU - Rüegger, Christoph
AU - Baud, Olivier
AU - Zeitlin, Jennifer
AU - Morgan, Andrei Scott
AU - Baruteau, Alban Elouen
AU - Ancel, Pierre Yves
AU - Carbajal, Ricardo
AU - Bouazza, Naim
AU - Diallo, Alpha
AU - Levoyer, Lea
AU - Kemper, Ruth
N1 - Publisher Copyright:
© 2026 American Medical Association.
PY - 2026/2/16
Y1 - 2026/2/16
N2 - Importance: Controversies persist about management of the ductus arteriosus by nonsteroidal anti-inflammatory drugs in extremely preterm infants. Acetaminophen (paracetamol) appears to be a promising alternative with possibly fewer adverse effects. Objective: To evaluate whether prophylactic intravenous acetaminophen started within 12 hours of birth increases survival without neonatal severe morbidities at 36 weeks' postmenstrual age. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled clinical trial was conducted among preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation in 43 neonatal intensive care units of 14 European countries between October 2020 (October 2021 for infants born at 23-26 weeks' gestation, after the phase 2 study identified the optimal dose of acetaminophen) and April 2024. Data analysis was conducted from January to June 2025. Intervention: In the acetaminophen group, patients born at 27 to 28 weeks' gestation received a 20-mg/kg loading dose of acetaminophen followed by 7.5 mg/kg every 6 hours for 5 days, and patients born at 23 to 26 weeks' gestation received a 25-mg/kg loading dose of acetaminophen followed by 10 mg/kg every 6 hours for 5 days. In the placebo group, isotonic sodium chloride was administered. Main Outcomes and Measures: The primary outcome was survival without neonatal morbidity evaluated at 36 weeks' postmenstrual age. The secondary exploratory outcome was ductus arteriosus closure, assessed by echocardiography on day 7. Results: A total of 778 patients (median [IQR] gestational age, 26 [25-27] weeks; 375 [48.2%] female) were included in the study, with 391 in the acetaminophen group and 387 in the placebo group. Survival without severe morbidities at 36 weeks' postmenstrual age occurred in 259 infants (66.2%) in the acetaminophen group and 246 (63.6%) in the placebo group (absolute risk difference [ARD], 2.7 [95% CI, -4.0 to 9.3] percentage points; relative risk [RR], 1.04 [95% CI, 0.94 to 1.16]). The ductus arteriosus was considered closed on day 7 in 264 of 371 infants (71.2%) assigned to acetaminophen and 191 of 366 infants (52.2%) assigned to placebo (ARD, 19.0 [95% CI, 12.0 to 25.7] percentage points; RR, 1.36 [95% CI, 1.21 to 1.53]). In the safety analysis, adverse events were not different except for a higher cholestasis rate in the acetaminophen group (25 of 392 infants [6.4%]) vs the placebo group (10 of 386 infants [2.6%]) (ARD, 3.8 [95% CI, 0.9 to 6.9]) percentage points. Conclusions and Relevance: This study found that prophylactic acetaminophen treatment for patent ductus arteriosus did not increase survival without neonatal morbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT04459117.
AB - Importance: Controversies persist about management of the ductus arteriosus by nonsteroidal anti-inflammatory drugs in extremely preterm infants. Acetaminophen (paracetamol) appears to be a promising alternative with possibly fewer adverse effects. Objective: To evaluate whether prophylactic intravenous acetaminophen started within 12 hours of birth increases survival without neonatal severe morbidities at 36 weeks' postmenstrual age. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled clinical trial was conducted among preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation in 43 neonatal intensive care units of 14 European countries between October 2020 (October 2021 for infants born at 23-26 weeks' gestation, after the phase 2 study identified the optimal dose of acetaminophen) and April 2024. Data analysis was conducted from January to June 2025. Intervention: In the acetaminophen group, patients born at 27 to 28 weeks' gestation received a 20-mg/kg loading dose of acetaminophen followed by 7.5 mg/kg every 6 hours for 5 days, and patients born at 23 to 26 weeks' gestation received a 25-mg/kg loading dose of acetaminophen followed by 10 mg/kg every 6 hours for 5 days. In the placebo group, isotonic sodium chloride was administered. Main Outcomes and Measures: The primary outcome was survival without neonatal morbidity evaluated at 36 weeks' postmenstrual age. The secondary exploratory outcome was ductus arteriosus closure, assessed by echocardiography on day 7. Results: A total of 778 patients (median [IQR] gestational age, 26 [25-27] weeks; 375 [48.2%] female) were included in the study, with 391 in the acetaminophen group and 387 in the placebo group. Survival without severe morbidities at 36 weeks' postmenstrual age occurred in 259 infants (66.2%) in the acetaminophen group and 246 (63.6%) in the placebo group (absolute risk difference [ARD], 2.7 [95% CI, -4.0 to 9.3] percentage points; relative risk [RR], 1.04 [95% CI, 0.94 to 1.16]). The ductus arteriosus was considered closed on day 7 in 264 of 371 infants (71.2%) assigned to acetaminophen and 191 of 366 infants (52.2%) assigned to placebo (ARD, 19.0 [95% CI, 12.0 to 25.7] percentage points; RR, 1.36 [95% CI, 1.21 to 1.53]). In the safety analysis, adverse events were not different except for a higher cholestasis rate in the acetaminophen group (25 of 392 infants [6.4%]) vs the placebo group (10 of 386 infants [2.6%]) (ARD, 3.8 [95% CI, 0.9 to 6.9]) percentage points. Conclusions and Relevance: This study found that prophylactic acetaminophen treatment for patent ductus arteriosus did not increase survival without neonatal morbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT04459117.
UR - https://www.scopus.com/pages/publications/105030727659
U2 - 10.1001/jamapediatrics.2025.6150
DO - 10.1001/jamapediatrics.2025.6150
M3 - Article
C2 - 41697673
AN - SCOPUS:105030727659
SN - 2168-6203
JO - JAMA Pediatrics
JF - JAMA Pediatrics
ER -