Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen
Jean-Christophe Rozé, Gilles Cambonie, Cyril Flamant, Juliana Patkaï, Tobias Mühlbacher, Geraldine Gascoin, Aline Rideau Batista Novais, Manon Tauzin, Kévin Le Duc, Alain Beuchée, Sébastien Joye, Evgeniya Babacheva, Antoine Bouissou, Isabelle Ligi, O Tammela, Marion Plourde, EM Dempsey, Barthélémy Tosello, Kim An Nguyen, Marine Vincent, Pille Andresson, Christoph Binder, Charlotte Kruse, Francisca Barcos Munoz, Pierre Kuhn, Elisa Proença, Marco Bartocci, Elsa Kermorvant-Duchemin, Georgi Nellis, Mirka Lumia, Vasileios Giapros, Vincent Rigo, Ulla Sankilampi, André Mendes da Graça, Arild Rønnestad, Hanna Soukka, Vito Mondı̀, Outi Aikio, Núria Torre-Monmany, C M Rüegger, Olivier Baud, J ZEITLIN, Andreï S. Morgan, Alban-Elouen Baruteau, Pierre-Yves Ancel, Ricardo Carbajal, Naïm Bouazza, Alpha Oumar Diallo, Léa Levoyer, Ruth Kemper, Mikko Hallman, Corinne Alberti, Moreno Ursino, TREOCAPA Study Group, Pierre‐Henri Jarreau, Aure Vanhecke, Victorine Desplebin, Naouel Bouafia, Héloïse Torchin, Elisa Proença, Nadia Mazille, Magali Reynold de Seresin, Georgi Nellis, Laure Simon, Arnaud Callies, Maria Fintzou, Marina Malakozi, Marie Moreau, Anne Murray, Katja Ovaskainen, Sauli Palmu, Siw Helen Eger, Louis Baraton, Susanne Kirschenhofer, Kelly Mellul, Gaelle Sorin, Ludovic Tréluyer, David Healy, Mari Liis Ilmoja, Dimitrios Rallis, Hélène Yager, Elodie Zana-Taieb, Laure Carneiro, Cécile Cipierre, Araceli Corredera, Gilles Dassieu, Rim Debbiche, Fabrice Decobert, Leif Evaggelidis, Aurélie Garbi, Maarja Hallik, Emilie Jourdes, Claire Langlet Muteau, Bertrand Leboucher, Jurate Panaviene, Géraldine Apprioual, Clemence Auzet, Claire Bellanger, Mélinda Bénard, V. Biran
Abstract
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.