[en] [en] 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.
Disciplines :
Pediatrics
Author, co-author :
Rozé, Jean-Christophe; Department of Neonatal Medicine, Nantes University Hospital, Inserm, Centre d'Investigation Clinique 1413, Nantes, France
Cambonie, Gilles; Department of Neonatal Medicine, Montpellier University Hospital, Montpellier, France
Flamant, Cyril; Department of Neonatal Medicine, Nantes University Hospital, Inserm, Centre d'Investigation Clinique 1413, Nantes, France
Patkaï, Juliana; Department of Neonatal Medicine, Cochin Port-Royal Hospital, Fédération Hospitalo-Universitaire PREMA, Assistance Publique-Hôpitaux de Paris Centre, Paris, France
Mühlbacher, Tobias; Newborn Research, Department of Neonatology, University Hospital and University of Zürich, Zürich, Switzerland
Gascoin, Geraldine; Neonatal Intensive Care, University Hospital, Toulouse, France
Rideau Batista Novais, Aline; Department of Neonatology, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Tauzin, Manon; Neonatal Intensive Care Unit, Centre Hospitalier Intercommunal de Créteil, Créteil, France
Le Duc, Kevin; Department of Neonatology, Lille University Hospital, Lille, France
Beuchée, Alain; Neonatology, University of Rennes, CHU Rennes, Inserm, LTSI-UMR 1099, Rennes, France
Joye, Sebastien; Department of Mother-Woman-Child, Clinic of Neonatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Babacheva, Evgeniya; Second Department of Neonatology and Neonatal Intensive Care Unit, General Hospital of Papageorgiou, Aristotle University of Thessaloniki, Thessaloniki, Greece
Bouissou, Antoine; Department of Neonatology, CHU Tours, Tours University, Tours, France
Ligi, Isabelle; Department of Neonatalogy, Assistance Publique Hôpitaux de Marseille, Marseille, France
Tammela, Outi; Department of Neonatalogy, Tampere University, Tampere, Finland
Plourde, Marion; Department of Neonatal Medicine, Angers University Hospital, Angers, France
Dempsey, Eugene; Department of Paediatrics and Child Health, INFANT Centre, University College Cork, Cork, Ireland
Tosello, Barthelemy; Department of Neonatology, North Hospital, Assistance Publique des Hôpitaux de Marseille, Marseille, France
Nguyen, Kim; Department of Neonatology and Neonatal Reanimation, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France
Vincent, Marine; Department of Neonatology, Hospices Civils de Lyon, Hôpital de la Croix Rousse, Lyon, France
Andresson, Pille; Department of Neonatology, East Tallinn Central Hospital, Tallinn, Estonia
Binder, Christoph; Division of Neonatology, Department of Pediatrics, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
Kruse, Charlotte; Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark
Barcos Munoz, Francisca; Neonatal Intensive Care Unit, University Hospital of Geneva, Geneva, Switzerland
Kuhn, Pierre; Department of Neonatal Medicine, University Hospital of Strasbourg, University of Strasbourg, Strasbourg, France
Proença, Elisa; Department of Neonatology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
Bartocci, Marco; Department of Neonatology, Karolinska University Hospital, Stockholm, Sweden
Kermorvant-Duchemin, Elsa; Pédiatrie et Réanimation Néonatales, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
Nellis, Georgi; Neonatal Unit, Tartu University Hospital, Children's Clinic, Tartu, Estonia
Lumia, Mirka; New Children's Hospital, Clinical Trial Unit and Department of Neonatology, Helsinki University Hospital, Helsinki, Finland
Giapros, Vasileios; Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, Ioannina, Greece
Rigo, Vincent ; Université de Liège - ULiège > Département des sciences cliniques > Néonatologie
Sankilampi, Ulla; Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
Mendes da Graça, André; Division of Neonatology, Hospital de Santa Maria, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Rønnestad, Arild; Department of Neonatal Intensive Care, Oslo University Hospital, Oslo, Norway
Soukka, Hanna; Department of Pediatrics and Adolescent Medicine, University Hospital of Turku and Turku University, Turku, Finland
Mondì, Vito; Neonatology and Neonatal Intensive Care Unit, Policlinico Casilino, Rome, Italy
Aikio, Outi; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, and Research Unit of Clinical Medicine and MRC Oulu, University of Oulu, Oulu, Finland
Torre-Monmany, Nuria; Department of Neonatology, Parc Taulí University Hospital, Sabadell, Barcelona
Rüegger, Christoph; Newborn Research, Department of Neonatology, University Hospital and University of Zürich, Zürich, Switzerland
Baud, Olivier; Department of Neonatal Medicine, Cochin Port-Royal Hospital, Fédération Hospitalo-Universitaire PREMA, Assistance Publique-Hôpitaux de Paris Centre, Paris, France ; Neonatal Intensive Care Unit, University Hospital of Geneva, Geneva, Switzerland
Zeitlin, Jennifer; Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Centre for Research for Epidemiology and Statistics (CRESS-UMR1153) Obstetrical, Perinatal Paediatric and Life Course Epidemiology (OPPaLE) Team, Paris, France
Morgan, Andrei Scott; Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Centre for Research for Epidemiology and Statistics (CRESS-UMR1153) Obstetrical, Perinatal Paediatric and Life Course Epidemiology (OPPaLE) Team, Paris, France ; Department of Neonatology, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK
Baruteau, Alban-Elouen; Department of Pediatric Cardiology and Pediatric Cardiac Surgery, Fédération Hospitalo-Universitaire PRECICARE, Nantes Université, CHU Nantes, Nantes, France
Ancel, Pierre-Yves; Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Centre for Research for Epidemiology and Statistics (CRESS-UMR1153) Obstetrical, Perinatal Paediatric and Life Course Epidemiology (OPPaLE) Team, Paris, France
Carbajal, Ricardo; Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Centre for Research for Epidemiology and Statistics (CRESS-UMR1153) Obstetrical, Perinatal Paediatric and Life Course Epidemiology (OPPaLE) Team, Paris, France ; Paediatric Emergency Department, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France
Bouazza, Naim; Pharmacologie et évaluations des thérapeutiques chez l'enfant et la femme enceinte, URP7323, Université Paris Cité, Paris, France
Diallo, Alpha; Clinical Trial Safety and Public Health, ANRS, Emerging Infectious Diseases, Paris, France ; Clinical Research Safety Department, Inserm, Paris, France
Levoyer, Lea; Clinical Trial Safety and Public Health, ANRS, Emerging Infectious Diseases, Paris, France ; Clinical Research Safety Department, Inserm, Paris, France
Kemper, Ruth; Global Foundation for the Care of Newborn Infants, Munich, Germany
Hallman, Mikko; Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, and Research Unit of Clinical Medicine and MRC Oulu, University of Oulu, Oulu, Finland
Alberti, Corinne; Université Paris Cité, Unité d'épidémiologie clinique, Hôpital Robert Debré, Partners FCRIN, Assistance Publique-Hôpitaux de Paris, Inserm, Centre d'Investigation Clinique 1426, ECEVE, Paris, France
Ursino, Moreno; Université Paris Cité, Unité d'épidémiologie clinique, Hôpital Robert Debré, Partners FCRIN, Assistance Publique-Hôpitaux de Paris, Inserm, Centre d'Investigation Clinique 1426, ECEVE, Paris, France ; Inserm, Université Paris Cité, Inria, HeKA, Paris, France
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