Year: 2026
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
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.
Authors: Jean-Christophe Rozé, Gilles Cambonie, Cyril Flamant, Juliana Patkaï, Tobias Mühlbacher, Geraldine Gascoin, Aline Rideau Batista Novais, Manon Tauzin, Kevin Le Duc, Alain Beuchée, Sebastien Joye, Evgeniya Babacheva, Antoine Bouissou, Isabelle Ligi, Outi Tammela, Marion Plourde, Eugene Dempsey, Barthelemy Tosello, Kim 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 Mondì, Outi Aikio, Nuria Torre-Monmany, Christoph Rüegger, Olivier Baud, Jennifer Zeitlin, Andrei Scott Morgan, Alban-Elouen Baruteau, Pierre-Yves Ancel, Ricardo Carbajal, Naim Bouazza, Alpha Diallo, Lea Levoyer, Ruth Kemper, Mikko Hallman, Corinne Alberti, Moreno Ursino, TREOCAPA Study Group, Pierre-Henri Jarreau, Aure Vanhecke, Victorine Desplebin, Naouel Bouafia, Heloise Torchin, Elisa Proenca, 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 Treluyer, David Healy, Mari Liis Ilmoja, Dimitrios Rallis, Helene Yager, Elodie Zana-Taieb, Laure Carneiro, Cecile Cipierre, Araceli Corredera, Gilles Dassieu, Rim Debbiche, Fabrice Decobert, Leif Evaggelidis, Aurelie Garbi, Maarja Hallik, Emilie Jourdes, Claire Langlet Muteau, Bertrand Leboucher, Jurate Panaviene, Geraldine Apprioual, Clemence Auzet, Claire Bellanger, Melinda Benard, Valerie Biran, Farid Boubred, Marine Butin, Melissa David, Marie Amelie Detristan, Odile Dicky, Laurence Dillenseger, Izaskun Dorronsoro, Xavier Durrmeyer, Sophie Laborie, Carine Lallemant, Noemie Lefevre, Sandra Lescure, Nathalie Montjaux, Corinne Ragouilliaux, Marta Sarda, Helene Schieber, Hans Jorgen Stensvold, Kenneth Strommen, Joao Virtuoso, Noura Zayat, Julie Abbal, Nahla Ahmed, Alberto Berenguer, Roberto Chioma, Sophie Delorme, Elodie Garnier, Joana Gil, Raquel Gouveia, Isabelle Grand Vuillemin, Shushanik Hovhannisyan, Piermichele Paoulillo, Chiara Passarella, Anne Sophie Pellot, Simonetta Picone, Nikolaos Podimatas, Ana Rita Prior, Monica Rebelo, Marine Robert de Saint Vincent, Angela Sainz, Edmundo Santos, Juliette Suhard, Camille Theveniaut, Tiina Ukkonen, Mathilde Yverneau
Institutions: Inserm, Centre Hospitalier Universitaire de Nantes, Centre d'Investigation Clinique de Nantes, Centre Hospitalier Universitaire de Montpellier, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, University of Zurich, University Hospital Zurich, Centre Hospitalier Universitaire de Toulouse, Hôpital Robert-Debré, Hôpital Intercommunal de Créteil, Centre Hospitalier Universitaire de Lille, Laboratoire Traitement du Signal et de l'Image, Centre Hospitalier Universitaire de Rennes, Université de Rennes, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Université de Tours, Centre Hospitalier Universitaire de Tours, Assistance Publique Hôpitaux de Marseille, Tampere University, University of Tampere, Centre Hospitalier Universitaire d'Angers, Université d'Angers, University College Cork, Infant, Hôpital Nord, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, East Tallinn Central Hospital, Medical University of Vienna, Rigshospitalet, University Hospital of Geneva, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Hospital de Santo António, Karolinska University Hospital, Hôpital Necker-Enfants Malades, Tartu University Hospital, Helsinki University Hospital, University of Ioannina, Centre Hospitalier Universitaire de Liège, Kuopio University Hospital, University of Lisbon, Hospital de Santa Maria, Oslo University Hospital, University of Turku, Turku University Hospital, Policlinico Casilino, Oulu University Hospital, University of Oulu, Corporació Sanitària Parc Taulí, Université Paris Cité, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Université Sorbonne Paris Nord, Centre de Recherche Épidémiologie et Statistique, University College London, Nantes Université, Hôpital Armand-Trousseau, Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte, Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Evaluation et recherche en services et politiques en santé pour les populations vulnérables, Institut national de recherche en sciences et technologies du numérique, Heka : Méthodes basées sur les données et modèles en santé pour l'acquisition de connaissances
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7129052174