Cerebral Oximetry in Extremely Preterm Infants: 2-Year Follow-Up of the SafeBoosC-III Randomized Clinical Trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice JAMA Pediatr . 2026 Apr 20;180(6):619–627. doi: 10.1001/jamapediatrics.2026.1066 Search in PMC Search in PubMed View in NLM Catalog Add to search Cerebral Oximetry in Extremely Preterm Infants 2-Year Follow-Up of the SafeBoosC-III Randomized Clinical Trial Marie Isabel Skov Rasmussen Marie Isabel Skov Rasmussen , MD, PhD 1 Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Find articles by Marie Isabel Skov Rasmussen 1, 2, ✉ , Mathias L Hansen Mathias L Hansen , MD, PhD 1 Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Find articles by Mathias L Hansen 1, 2 , Adelina Pellicer Adelina Pellicer , MD, PhD 3 Department of Neonatology, La Paz University Hospital, Madrid, Spain 4 Hospital La Paz Institute for Health Research-IdiPAZ, Madrid, Spain Find articles by Adelina Pellicer 3, 4 , Simon Hyttel-Sørensen Simon Hyttel-Sørensen , MD, PhD 5 Department of Intensive Care, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Find articles by Simon Hyttel-Sørensen 5 , Ebru Ergenekon Ebru Ergenekon , MD, PhD 6 Division of Newborn Medicine, Gazi University Hospital, Ankara, Turkey Find articles by Ebru Ergenekon 6 , Tomasz Szczapa Tomasz Szczapa , MD, PhD 7 2nd Department of Neonatology, Neonatal Biophysical Monitoring and Cardiopulmonary Therapies Research Unit, Chair of Neonatology, Poznan University of Medical Sciences, Poznan, Poland Find articles by Tomasz Szczapa 7 , Cornelia Hagmann Cornelia Hagmann , MD, PhD 8 Pediatric Intensive Care and Neonatology, Children’s University Hospital of Zurich, Zurich, Switzerland Find articles by Cornelia Hagmann 8 , Gunnar Naulaers Gunnar Naulaers , MD, PhD 9 Department of Development and Regeneration, KU Leuven, Leuven, Belgium Find articles by Gunnar Naulaers 9 , Jonathan Mintzer Jonathan Mintzer , MD 10 Department of Pediatrics, Division of Newborn Medicine, Mountainside Medical Center, Montclair, New Jersey Find articles by Jonathan Mintzer 10 , Monica Fumagalli Monica Fumagalli , MD, PhD 11 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 12 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Find articles by Monica Fumagalli 11, 12 , Gabriel Dimitriou Gabriel Dimitriou , MD, PhD 13 NICU, Department of Pediatrics, Patras Medical School, Patras, Greece Find articles by Gabriel Dimitriou 13 , Eugene Dempsey Eugene Dempsey , MD, PhD 14 Infant Centre and Department of Paediatrics and Child Health, University College Cork, Cork, Ireland Find articles by Eugene Dempsey 14 , Jakub Tkaczyk Jakub Tkaczyk , MD 15 Department of Neonatology, University Hospital Motol, Prague, Czech Republic Find articles by Jakub Tkaczyk 15 , Siv Fredly Siv Fredly , MD, PhD 16 Department of Neonatology, Oslo University Hospital, Oslo, Norway Find articles by Siv Fredly 16 , Anne M Heuchan Anne M Heuchan , MD 17 Department of Neonatal Medicine, Royal Hospital for Children, Glasgow, United Kingdom Find articles by Anne M Heuchan 17 , Gerhard Pichler Gerhard Pichler , MD 18 Department of Pediatrics, Medical University of Graz, Graz, Austria 19 Research Unit for Neonatal Micro- and Macrocirculation, Medical University of Graz, Graz, Austria Find articles by Gerhard Pichler 18, 19 , Hans Fuchs Hans Fuchs , MD, DMSc 20 Division of Neonatology and Pediatric Intensive Care Medicine, Center for Pediatrics and Adolescents Medicine, Medical Center - University of Freiburg, Freiburg, Germany 21 Faculty of Medicine, University of Freiburg, Freiburg, Germany Find articles by Hans Fuchs 20, 21 , Saudamini Nesargi Saudamini Nesargi , DNB 22 Department of Neonatology, St John’s Medical College, Bangalore, India Find articles by Saudamini Nesargi 22 , Gitte H Hahn Gitte H Hahn , MD, PhD 1 Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Find articles by Gitte H Hahn 1 , Salvador Piris-Borregas Salvador Piris-Borregas , MD, PhD 23 Neonatology Department, 12 de Octubre University Hospital, Madrid, Spain Find articles by Salvador Piris-Borregas 23 , Jan Širc Jan Širc , MD, PhD 24 The Institute for the Care of Mother and Child, Prague, Czech Republic 25 Third Faculty of Medicine, Charles University, Prague, Czech Republic Find articles by Jan Širc 24, 25 , Miguel Alsina-Casanova Miguel Alsina-Casanova , MD, PhD 26 Department of Neonatology, Hospital Clínic Barcelona, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine, Barcelona, Spain Find articles by Miguel Alsina-Casanova 26 , Martin Stocker Martin Stocker , MD 27 Intensive Care Unit, Children’s Hospital Lucerne, Lucerne, Switzerland 28 Faculty of Medicine and Medical Science, University of Lucerne, Lucerne, Switzerland Find articles by Martin Stocker 27, 28 , Hilal Ozkan Hilal Ozkan , MD 29 Department of Neonatology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey Find articles by Hilal Ozkan 29 , Kosmas Sarafidis Kosmas Sarafidis , MD, PhD 30 1st Department of Neonatology, Aristotle University of Thessaloniki, Ippokrateion General Hospital of Thessaloniki, Greece Find articles by Kosmas Sarafidis 30 , Nicole J Kraus Nicole J Kraus , DO 31 Division of Neonatology, Department of Pediatrics, Loma Linda University Children’s Hospital, Loma Linda, California Find articles by Nicole J Kraus 31 , Tanja Karen Tanja Karen , MD 27 Intensive Care Unit, Children’s Hospital Lucerne, Lucerne, Switzerland 32 Department of Neonatology, University Hospital Zurich, Zurich, Switzerland Find articles by Tanja Karen 27, 32 , Beata Rzepecka-Weglarz Beata Rzepecka-Weglarz , MD 33 Department of Neonatology, Centrum Medyczne “Ujastek” Sp. z o.o., Krakow, Poland Find articles by Beata Rzepecka-Weglarz 33 , Serife S Oguz Serife S Oguz , MD 34 Department of Neonatology, NICU, University of Health Sciences, Ankara City Hospital, Ankara, Turkey Find articles by Serife S Oguz 34 , Liesbeth Thewissen Liesbeth Thewissen , MD, PhD 9 Department of Development and Regeneration, KU Leuven, Leuven, Belgium Find articles by Liesbeth Thewissen 9 , Luis Arruza Luis Arruza , MD, PhD 35 Department of Neonatology, Hospital Clinico San Carlos–IdISSC, Madrid, Spain Find articles by Luis Arruza 35 , Asli C Memisoglu Asli C Memisoglu , MD 36 Division of Neonatology, Department of Pediatrics, Marmara University Research and Education Hospital, Marmara University, School of Medicine, Istanbul, Turkey Find articles by Asli C Memisoglu 36 , Ruth del Rio Florentino Ruth del Rio Florentino , MD 37 Department of Neonatology, Hospital Sant Joan de Deu, Barcelona, Spain Find articles by Ruth del Rio Florentino 37 , Mariana Baserga Mariana Baserga , MD 38 Division of Neonatology, University of Utah Hospital, Salt Lake City Find articles by Mariana Baserga 38 , Pierre Maton Pierre Maton , MD 39 Service de Néonatologie, Clinique CHC Montlégia-Liège-Belgium, Belgium Find articles by Pierre Maton 39 , Juliane Schneider Juliane Schneider , MD 40 Clinic of Neonatology, Department of Women, Mother and Child, University Hospital Center, Vaud, Switzerland 41 University of Lausanne, Vaud, Switzerland Find articles by Juliane Schneider 40, 41 , M Isabel de las Cuevas M Isabel de las Cuevas , MD, PhD 42 Neonatal Unit, Donostia University Hospital-IIS Biogipuzkoa, Basque Country, Spain Find articles by M Isabel de las Cuevas 42 , Sofie Sommer Hedegaard Sofie Sommer Hedegaard , MD 43 Department of Pediatrics and Adolescent Medicine, Gødstrup Hospital, Denmark Find articles by Sofie Sommer Hedegaard 43 , Pamela Zafra Pamela Zafra , MD 44 Neonatal Intensive Care Unit, Puerta del Mar University Hospital, Cádiz, Spain Find articles by Pamela Zafra 44 , Lars Bender Lars Bender , MD 45 Department of Neonatology, Aalborg University Hospital, Aalborg, Denmark Find articles by Lars Bender 45 , Sarah Farquharson Sarah Farquharson , MD 17 Department of Neonatal Medicine, Royal Hospital for Children, Glasgow, United Kingdom Find articles by Sarah Farquharson 17 , Agnieszka Ochoda-Mazur Agnieszka Ochoda-Mazur , MD 46 Neonatology Clinic, Jagiellonian University Medical College, Kraków, Poland Find articles by Agnieszka Ochoda-Mazur 46 , Chantal Lecart Chantal Lecart , MD 47 Department of Neonatology, GHdC Charleroi, Belgium Find articles by Chantal Lecart 47 , Afif El-Khuffash Afif El-Khuffash , MD 48 Department of Paediatrics, School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland Find articles by Afif El-Khuffash 48 , Caitríona Ní Chathasaigh Caitríona Ní Chathasaigh , MD 49 National Maternity Hospital, Dublin, Ireland Find articles by Caitríona Ní Chathasaigh 49 , Jan Miletin Jan Miletin , MD, PhD 50 The Coombe Hospital, Dublin, Ireland 51 University College Dublin, Dublin, Ireland 52 2nd Faculty of Medicine, Charles University, Prague, Czech Republic Find articles by Jan Miletin 50, 51, 52 , Evangelia Papathoma Evangelia Papathoma , MD, PhD 53 Neonatal Intensive Care Unit, Alexandra University and State Hospital, Athens, Greece Find articles by Evangelia Papathoma 53 , Zachary Vesoulis Zachary Vesoulis , MD 54 Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri Find articles by Zachary Vesoulis 54 , Francesca Serrao Francesca Serrao , MD 55 Unità Operativa Complessa di Neonatologia, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Find articles by Francesca Serrao 55 ; and the SafeBoosC-III Follow-Up Writing Group for the SafeBoosC-III Follow-Up Collaborator Group , Luc Cornette Luc Cornette , MD, PhD 56 Department of Neonatology, AZ St-Jan Bruges, Bruges, Belgium Find articles by Luc Cornette 56 , Beril Yasa Beril Yasa , MD 57 Basaksehir Cam and Sakura City Hospital, Basaksehir, Turkey 58 Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Küçükçekmece/İstanbul, Turkey Find articles by Beril Yasa 57, 58 , Anja Klamer Anja Klamer , MD 59 Department of Pediatrics, Odense University Hospital, Odense, Denmark Find articles by Anja Klamer 59 , Francisca Barcos-Munoz Francisca Barcos-Munoz , MD 60 Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland Find articles by Francisca Barcos-Munoz 60 , Tatiana Boetti Tatiana Boetti , MD 61 SC Neonatologia, Osp. S.Anna - Città della Salute e della Scienza di Torino, Turin, Italy Find articles by Tatiana Boetti 61 , Merih Cetinkaya Merih Cetinkaya , MD, PhD 57 Basaksehir Cam and Sakura City Hospital, Basaksehir, Turkey 58 Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Küçükçekmece/İstanbul, Turkey Find articles by Merih Cetinkaya 57, 58 , Mahmoud Montasser Mahmoud Montasser , MD 62 Neonatology Department, University Hospital Wishaw, Wishaw, Scotland, United Kingdom Find articles by Mahmoud Montasser 62 , Eleftheria Hatzidaki Eleftheria Hatzidaki , MD, PhD 63 Department of Neonatology & NICU, University Hospital of Heraklion, Crete, Greece Find articles by Eleftheria Hatzidaki 63 , Renata Bokiniec Renata Bokiniec , MD 64 Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland Find articles by Renata Bokiniec 64 , Sylwia Marciniak Sylwia Marciniak , MD 65 Neonatal Unit, Specialist Hospital No. 2, Bytom, Poland Find articles by Sylwia Marciniak 65 , Lina Chalak Lina Chalak , MD 66 Division of Pediatrics–Neonatal-Perinatal, UT Southwestern, Dallas, Texas Find articles by Lina Chalak 66 , Shashidhar A Rao Shashidhar A Rao , MD, DM 22 Department of Neonatology, St John’s Medical College, Bangalore, India Find articles by Shashidhar A Rao 22 , Iwona Sadowska-Krawczenko Iwona Sadowska-Krawczenko , MD, PhD 67 Department of Neonatology, Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Torun, Bydgoszcz, Poland Find articles by Iwona Sadowska-Krawczenko 67 , Itziar Serrano-Viñuales Itziar Serrano-Viñuales , MD 68 Neonatology Division, Miguel Servet University Hospital, Zaragoza, Spain Find articles by Itziar Serrano-Viñuales 68 , Barbara Krolak-Olejnik Barbara Krolak-Olejnik , MD, PhD, BS 69 Department of Neonatology, Wroclaw Medical University, Wroclaw, Poland Find articles by Barbara Krolak-Olejnik 69 , Anne Mette Plomgaard Anne Mette Plomgaard , MD, PhD 70 Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark Find articles by Anne Mette Plomgaard 70 , Bo Mølholm Hansen Bo Mølholm Hansen , MD, PhD 71 Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Hilleroed, Denmark Find articles by Bo Mølholm Hansen 71 , Markus Harboe Olsen Markus Harboe Olsen , MD, PhD 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 72 Department of Neuroanaesthesiology, Neuroscience Centre, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark Find articles by Markus Harboe Olsen 2, 72 , Christian Gluud Christian Gluud , MD, DMSc 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 73 Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark Find articles by Christian Gluud 2, 73 , Janus C Jakobsen Janus C Jakobsen , MD, DMSc 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 73 Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark Find articles by Janus C Jakobsen 2, 73 , Gorm Greisen Gorm Greisen , MD, DMSc 1 Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Find articles by Gorm Greisen 1 Author information Article notes Copyright and License information 1 Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 3 Department of Neonatology, La Paz University Hospital, Madrid, Spain 4 Hospital La Paz Institute for Health Research-IdiPAZ, Madrid, Spain 5 Department of Intensive Care, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark 6 Division of Newborn Medicine, Gazi University Hospital, Ankara, Turkey 7 2nd Department of Neonatology, Neonatal Biophysical Monitoring and Cardiopulmonary Therapies Research Unit, Chair of Neonatology, Poznan University of Medical Sciences, Poznan, Poland 8 Pediatric Intensive Care and Neonatology, Children’s University Hospital of Zurich, Zurich, Switzerland 9 Department of Development and Regeneration, KU Leuven, Leuven, Belgium 10 Department of Pediatrics, Division of Newborn Medicine, Mountainside Medical Center, Montclair, New Jersey 11 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 12 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy 13 NICU, Department of Pediatrics, Patras Medical School, Patras, Greece 14 Infant Centre and Department of Paediatrics and Child Health, University College Cork, Cork, Ireland 15 Department of Neonatology, University Hospital Motol, Prague, Czech Republic 16 Department of Neonatology, Oslo University Hospital, Oslo, Norway 17 Department of Neonatal Medicine, Royal Hospital for Children, Glasgow, United Kingdom 18 Department of Pediatrics, Medical University of Graz, Graz, Austria 19 Research Unit for Neonatal Micro- and Macrocirculation, Medical University of Graz, Graz, Austria 20 Division of Neonatology and Pediatric Intensive Care Medicine, Center for Pediatrics and Adolescents Medicine, Medical Center - University of Freiburg, Freiburg, Germany 21 Faculty of Medicine, University of Freiburg, Freiburg, Germany 22 Department of Neonatology, St John’s Medical College, Bangalore, India 23 Neonatology Department, 12 de Octubre University Hospital, Madrid, Spain 24 The Institute for the Care of Mother and Child, Prague, Czech Republic 25 Third Faculty of Medicine, Charles University, Prague, Czech Republic 26 Department of Neonatology, Hospital Clínic Barcelona, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine, Barcelona, Spain 27 Intensive Care Unit, Children’s Hospital Lucerne, Lucerne, Switzerland 28 Faculty of Medicine and Medical Science, University of Lucerne, Lucerne, Switzerland 29 Department of Neonatology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey 30 1st Department of Neonatology, Aristotle University of Thessaloniki, Ippokrateion General Hospital of Thessaloniki, Greece 31 Division of Neonatology, Department of Pediatrics, Loma Linda University Children’s Hospital, Loma Linda, California 32 Department of Neonatology, University Hospital Zurich, Zurich, Switzerland 33 Department of Neonatology, Centrum Medyczne “Ujastek” Sp. z o.o., Krakow, Poland 34 Department of Neonatology, NICU, University of Health Sciences, Ankara City Hospital, Ankara, Turkey 35 Department of Neonatology, Hospital Clinico San Carlos–IdISSC, Madrid, Spain 36 Division of Neonatology, Department of Pediatrics, Marmara University Research and Education Hospital, Marmara University, School of Medicine, Istanbul, Turkey 37 Department of Neonatology, Hospital Sant Joan de Deu, Barcelona, Spain 38 Division of Neonatology, University of Utah Hospital, Salt Lake City 39 Service de Néonatologie, Clinique CHC Montlégia-Liège-Belgium, Belgium 40 Clinic of Neonatology, Department of Women, Mother and Child, University Hospital Center, Vaud, Switzerland 41 University of Lausanne, Vaud, Switzerland 42 Neonatal Unit, Donostia University Hospital-IIS Biogipuzkoa, Basque Country, Spain 43 Department of Pediatrics and Adolescent Medicine, Gødstrup Hospital, Denmark 44 Neonatal Intensive Care Unit, Puerta del Mar University Hospital, Cádiz, Spain 45 Department of Neonatology, Aalborg University Hospital, Aalborg, Denmark 46 Neonatology Clinic, Jagiellonian University Medical College, Kraków, Poland 47 Department of Neonatology, GHdC Charleroi, Belgium 48 Department of Paediatrics, School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland 49 National Maternity Hospital, Dublin, Ireland 50 The Coombe Hospital, Dublin, Ireland 51 University College Dublin, Dublin, Ireland 52 2nd Faculty of Medicine, Charles University, Prague, Czech Republic 53 Neonatal Intensive Care Unit, Alexandra University and State Hospital, Athens, Greece 54 Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri 55 Unità Operativa Complessa di Neonatologia, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy 56 Department of Neonatology, AZ St-Jan Bruges, Bruges, Belgium 57 Basaksehir Cam and Sakura City Hospital, Basaksehir, Turkey 58 Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Küçükçekmece/İstanbul, Turkey 59 Department of Pediatrics, Odense University Hospital, Odense, Denmark 60 Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland 61 SC Neonatologia, Osp. S.Anna - Città della Salute e della Scienza di Torino, Turin, Italy 62 Neonatology Department, University Hospital Wishaw, Wishaw, Scotland, United Kingdom 63 Department of Neonatology & NICU, University Hospital of Heraklion, Crete, Greece 64 Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland 65 Neonatal Unit, Specialist Hospital No. 2, Bytom, Poland 66 Division of Pediatrics–Neonatal-Perinatal, UT Southwestern, Dallas, Texas 67 Department of Neonatology, Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Torun, Bydgoszcz, Poland 68 Neonatology Division, Miguel Servet University Hospital, Zaragoza, Spain 69 Department of Neonatology, Wroclaw Medical University, Wroclaw, Poland 70 Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark 71 Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Hilleroed, Denmark 72 Department of Neuroanaesthesiology, Neuroscience Centre, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark 73 Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark Group Information: Members of the SafeBoosC-III Follow-Up Writing Group appear at the end of the article. Members of the SafeBoosC-III Follow-Up Collaborator Group appear in Supplement 4. Accepted for Publication: February 25, 2026. Published Online: April 20, 2026. doi: 10.1001/jamapediatrics.2026.1066 Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2026 Rasmussen MIS et al. JAMA Pediatrics . ✉ Corresponding Author: Marie Isabel Skov Rasmussen, MD, PhD, Department of Pediatric and Neonatal Intensive Care, Copenhagen University Hospital–Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark ( [email protected] ). The SafeBoosC-III Follow-Up Writing Group: Luc Cornette, MD, PhD; Beril Yasa, MD; Anja Klamer, MD; Francisca Barcos-Munoz, MD; Tatiana Boetti, MD; Merih Cetinkaya, MD, PhD; Mahmoud Montasser, MD; Eleftheria Hatzidaki, MD, PhD; Renata Bokiniec, MD; Sylwia Marciniak, MD; Lina Chalak, MD; Shashidhar A. Rao, MD, DM; Iwona Sadowska-Krawczenko, MD, PhD; Itziar Serrano-Viñuales, MD; Barbara Krolak-Olejnik, MD, PhD, BS; Anne Mette Plomgaard, MD, PhD; Bo Mølholm Hansen, MD, PhD; Markus Harboe Olsen, MD, PhD; Christian Gluud, MD, DMSc; Janus C. Jakobsen, MD, DMSc; Gorm Greisen, MD, DMSc. Affiliations of The SafeBoosC-III Follow-Up Writing Group: Department of Neonatology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark (Greisen); Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark (Olsen, Gluud, Jakobsen); Department of Neonatology, St John’s Medical College, Bangalore, India (Rao); Department of Neonatology, AZ St-Jan Bruges, Bruges, Belgium (Cornette); Basaksehir Cam and Sakura City Hospital, Basaksehir, Turkey (Yasa, Cetinkaya); Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Küçükçekmece/İstanbul, Turkey (Yasa, Cetinkaya); Department of Pediatrics, Odense University Hospital, Odense, Denmark (Klamer); Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland (Barcos-Munoz); SC Neonatologia, Osp. S.Anna - Città della Salute e della Scienza di Torino, Turin, Italy (Boetti); Neonatology Department, University Hospital Wishaw, Wishaw, Scotland, United Kingdom (Montasser); Department of Neonatology & NICU, University Hospital of Heraklion, Crete, Greece (Hatzidaki); Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland (Bokiniec); Neonatal Unit, Specialist Hospital No. 2, Bytom, Poland (Marciniak); Division of Pediatrics–Neonatal-Perinatal, UT Southwestern, Dallas, Texas (Chalak); Department of Neonatology, Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Torun, Bydgoszcz, Poland (Sadowska-Krawczenko); Neonatology Division, Miguel Servet University Hospital, Zaragoza, Spain (Serrano-Viñuales); Department of Neonatology, Wroclaw Medical University, Wroclaw, Poland (Krolak-Olejnik); Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark (Plomgaard); Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Hilleroed, Denmark (Hansen); Department of Neuroanaesthesiology, Neuroscience Centre, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark (Olsen); Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark (Gluud, Jakobsen). Author Contributions: Drs Rasmussen and Greisen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Rasmussen, M. Hansen, Pellicer, Hyttel-Sørensen, Mintzer, Fumagalli, Dimitriou, Dempsey, Fredly, Ozkan, El-Khuffash, Cetinkaya, Montasser, Chalak, Krolak-Olejnik, Plomgaard, B. Hansen, Harboe Olsen, Gluud, Jakobsen, Greisen. Acquisition, analysis, or interpretation of data: Rasmussen, M. Hansen, Pellicer, Ergenekon, Szczapa, Hagmann, Naulaers, Mintzer, Fumagalli, Dempsey, Tkaczyk, Heuchan, Pichler, Fuchs, Nesargi, Hahn, Piris-Borregas, Širc, Alsina, Stocker, Ozkan, Sarafidis, Kraus, Karen, Rzepecka-Węglarz, Oguz, Thewissen, Arruza, Memisoglu, Del Rio, Baserga, Maton, Schneider, Cuevas-Terán, Sommer Hedegaard, Zafra-Rodrigiez, Bender, Farquharson, Ochoda-Mazur, Lecart, Ní Chathasaigh, Miletin, Papathoma, Vesoulis, Serrao, Cornette, Yasa, Klamer, Barcos Munoz, Boetti, Cetinkaya, Montasser, Hatzidaki, Bokiniec, Marciniak, Chalak, Rao, Sadowska-Krawczenko, Serrano-Viñuales, Harboe Olsen, Gluud, Jakobsen, Greisen. Drafting of the manuscript: Rasmussen, M. Hansen, Širc, Ozkan, Memisoglu, El-Khuffash, Serrao, Montasser, Hatzidaki, Plomgaard, Harboe Olsen. Critical review of the manuscript for important intellectual content: Rasmussen, M. Hansen, Pellicer, Hyttel-Sørensen, Ergenekon, Szczapa, Hagmann, Naulaers, Mintzer, Fumagalli, Dimitriou, Dempsey, Tkaczyk, Fredly, Heuchan, Pichler, Fuchs, Nesargi, Hahn, Piris-Borregas, Širc, Alsina, Stocker, Ozkan, Sarafidis, Kraus, Karen, Rzepecka-Węglarz, Oguz, Thewissen, Arruza, Del Rio, Baserga, Maton, Schneider, Cuevas-Terán, Sommer Hedegaard, Zafra-Rodrigiez, Bender, Farquharson, Ochoda-Mazur, Lecart, El-Khuffash, Ní Chathasaigh, Miletin, Papathoma, Vesoulis, Cornette, Yasa, Klamer, Barcos Munoz, Boetti, Cetinkaya, Montasser, Bokiniec, Marciniak, Chalak, Rao, Sadowska-Krawczenko, Serrano-Viñuales, Krolak-Olejnik, Plomgaard, B. Hansen, Harboe Olsen, Gluud, Jakobsen, Greisen. Statistical analysis: Rasmussen, Sarafidis, Harboe Olsen, Jakobsen. Obtained funding: Rasmussen, M. Hansen, Vesoulis, Gluud, Greisen. Administrative, technical, or material support: Rasmussen, M. Hansen, Szczapa, Mintzer, Fumagalli, Alsina, Stocker, Ozkan, Kraus, Karen, Oguz, Memisoglu, Sommer Hedegaard, Bender, El-Khuffash, Miletin, Papathoma, Vesoulis, Serrao, Yasa, Montasser, Hatzidaki, Rao, Sadowska-Krawczenko, Greisen. Supervision: Rasmussen, M. Hansen, Szczapa, Naulaers, Mintzer, Fumagalli, Tkaczyk, Piris-Borregas, Stocker, Arruza, Cuevas-Terán, Ochoda-Mazur, El-Khuffash, Chalak, Plomgaard, B. Hansen, Gluud, Jakobsen, Greisen. Conflict of Interest Disclosures: Dr Maton reported receiving grants from Belgian Health Care Knowledge Centre during the conduct of the study. Dr Vesoulis reported receiving nonfinancial support from Medtronic and Edwards Life Sciences and personal fees from Medtronic outside the submitted work. No other disclosures were reported. Funding/Support: Elsass Foundation, Aage og Johanne Louis-Hansen Fonden, and Svend Andersen Fonden. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information: Members of the SafeBoosC-III Follow-Up Collaborator Group are listed in Supplement 4. Data Sharing Statement: See Supplement 5 . Additional Contributions: We thank the families who consented to participate in the follow-up, as well as the nurses, physicians, and staff from all participating sites for their dedication and care in supporting the infants throughout the trial and follow-up. Beyond usual salary, where applicable, no one received financial compensation for these contributions. ✉ Corresponding author. Received 2025 Oct 22; Accepted 2026 Feb 25; Issue date 2026 Jun. Copyright 2026 Rasmussen MIS et al. JAMA Pediatrics . This is an open access article distributed under the terms of the CC-BY License. PMC Copyright notice PMCID: PMC13097032 PMID: 42008246 See commentary " Cerebral Oximetry-Guided Care for Extremely Preterm Infants. " with doi: 10.1001/jamapediatrics.2026.1063. This randomized clinical trial investigates if treatment guided by cerebral oximetry monitoring during the first 72 hours after birth reduces the risk of death or moderate or severe neurodevelopmental disability and cognitive impairment at 2 years of corrected age in extremely preterm infants. Key Points Question Does treatment guided by cerebral oximetry monitoring during the first 72 hours after birth reduce the risk of death or moderate or severe neurodevelopmental disability and cognitive impairment at 2 years of corrected age in extremely preterm infants? Findings In this 2-year follow-up of the Safeguarding the Brain of Our Smallest Children (SafeBoosC-III) randomized clinical trial including 1438 infants, death or moderate or severe neurodevelopmental disability did not differ between the cerebral oximetry group and the usual-care group, and mean Bayley cognitive scores at 2 years did not differ significantly between groups. Meaning Results reveal that the routine use of cerebral oximetry monitoring during the first 72 hours after birth in extremely preterm infants to reduce death or moderate or severe neurodevelopmental disability and cognitive impairment was not supported by this trial. Abstract Importance Cerebral oximetry monitoring in the first 72 hours after birth has not been shown to reduce death or severe brain injury at 36 weeks’ postmenstrual age in extremely preterm infants. The long-term effects remain uncertain. Objective To determine whether treatment guided by cerebral oximetry monitoring during the first 72 hours after birth reduces the risk of death or longer-term neurodevelopmental outcomes at 2 years’ corrected age, compared with usual care. Design, Setting, and Participants In the phase 3 Safeguarding the Brain of Our Smallest Children (SafeBoosC-III) randomized clinical trial, we compared treatment guided by cerebral oximetry monitoring with usual care for the first 72 hours after birth. Seventy sites across 17 countries randomized 1601 infants within 6 hours of birth. Infants from 56 sites participated in this follow-up. Blinded assessors evaluated outcomes using a predefined 3-tier data model combining formal clinical assessments, parental questionnaires, and informal assessments. Data were analyzed from October to December 2024. Interventions Treatment guided by cerebral oximetry monitoring for the first 72 hours after birth vs usual care. Main Outcomes and Measures The coprimary outcomes were as follows: (1) death or moderate or severe neurodevelopmental disability and (2) Bayley cognitive composite score, both assessed at approximately 2 years’ corrected age. Results A total of 1438 infants (mean [SD] age, 26.0 [1.3] weeks; 758 male [52.7%]) participated in this follow-up study. Participants were followed up from October 2021 to October 2024. Death or moderate or severe neurodevelopmental disability occurred in 292 of 620 infants (47.1%) in the cerebral oximetry group compared with 321 of 669 infants (48.0%) in the usual-care group (relative risk with cerebral oximetry, 0.96; 97.5% CI, 0.85-1.07; P = .45). The mean (SD) Bayley cognitive score was 92.8 (17.0) in the cerebral oximetry group compared with 93.2 (17.3) in the usual-care group (mean difference with cerebral oximetry, −0.14; 97.5% CI, −3.24 to 2.96; P = .92). Conclusions and Relevance In extremely preterm infants, treatment guided by cerebral oximetry monitoring compared with usual care for the first 72 hours after birth did not result in a lower incidence of death or moderate or severe neurodevelopmental disability nor higher Bayley cognitive scores at 2 years’ corrected age. The routine use of cerebral oximetry monitoring during the first 72 hours after birth in extremely preterm infants to reduce neurodevelopmental disability was not supported by this trial. Trial Registration ClinicalTrials.gov Identifier: NCT05134116 Introduction Despite advancements in the care of extremely preterm infants, mortality rates remain around 20%, and up to 25% of survivors experience substantial neurodevelopmental disabilities. 1 These include cerebral palsy, cognitive and neurosensory deficits, and other conditions affecting the daily life of both children and their families. 2 The risk of brain injury is particularly high during the earliest postnatal days due to immature respiratory and circulatory systems as well as impaired autoregulation of the cerebral blood flow. 3 This hemodynamic instability can lead to episodes of cerebral hypoxia, 4 which are associated with an increased risk of death, intracranial hemorrhage, ischemic lesions, and later neurodevelopmental disabilities. 5 Cerebral oximetry monitoring may detect cerebral hypoxia, enabling clinicians to adjust cardiorespiratory support accordingly. 6 The Safeguarding the Brain of Our Smallest Children (SafeBoosC-III) trial randomized 1601 extremely preterm infants across 70 sites in 17 countries and assessed whether treatment guided by cerebral oximetry monitoring during the first 72 hours after birth could reduce these risks. 7 The trial found no differences in the composite primary outcome of death or severe brain injury detected on routine cerebral ultrasound scans at 36 weeks’ postmenstrual age compared with usual care. However, the relationship between neonatal brain injury and long-term neurodevelopmental disability is not simple. 8 The correlation is strong for the most severe brain injuries; while ultrasound scans can detect these conditions, their limited predictive capacity highlights the need for assessing long-term outcomes in neonatal trials. 9 To address these patient-relevant outcomes, we conducted a 2-year follow-up of the SafeBoosC-III trial to evaluate whether treatment guided by cerebral oximetry monitoring improves survival and neurodevelopmental outcomes compared with usual care. Methods Trial Design The SafeBoosC-III follow-up is an investigator-initiated, pragmatic, multinational follow-up study of the participants in a phase 3 randomized clinical trial. 7 The study protocol and statistical analysis plan were published before data analysis ( Supplement 1 and Supplement 2 , respectively). 10 , 11 The protocol received approval from the ethics committees at each participating site, ensuring adherence to regulatory standards, and a list of investigators is available in the eAppendix in Supplement 3 . Prior publications have documented details on randomization, blinding and interventions. 7 , 12 , 13 The SafeBoosC-III follow-up was not prespecified in the original SafeBoosC-III trial and was mentioned as a potential study in the protocol appendix. The follow-up study was deemed feasible to conduct and was initiated 6 months after randomization started when sufficient recruitment and site participation had been achieved. Data were collected from October 2021 to October 2024. This study is reported following the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guidelines. Participants Of the 70 sites that randomized infants in the SafeBoosC-III trial, 56 participated in this follow-up study. Of the 14 nonparticipating sites, 2 withdrew and 12 were excluded due to lack of progress (eMethods in Supplement 3 ). No follow-up data were collected from the excluded sites. Participant race and ethnicity data were not gathered. Eligibility criteria were enrollment in the SafeBoosC-III trial (gestational age at birth less than 28 weeks, decision to provide full life support, possibility to start cerebral oximetry monitoring within 6 hours from birth, and prior informed parental consent unless deferred consent or opt-out was used). Because the follow-up study was not planned from the outset, some sites, particularly those initiating randomization later, were able to include it in their initial ethical approvals and consent procedures. Most sites required separate consent once the follow-up study was initiated, in accordance with local ethical requirements. Informed consent was written and obtained from the families of the participants. Central and local monitoring was conducted following Standard Operating Procedures (eMethods in Supplement 3 ). Randomization and Intervention in the SafeBoosC-III Trial Infants were randomly assigned in a 1:1 ratio to either the cerebral oximetry group or the usual-care group. Randomization was stratified by site and gestational age (above or below 26 weeks of gestational age). In the cerebral oximetry group, infants were monitored for the first 72 hours after birth using a forehead sensor that emitted near-infrared light. A bedside monitor continuously displayed the cerebral oxygen saturation percentage, primarily reflecting oxygen levels in the cerebral veins. If cerebral oxygenation fell below a device-specific hypoxic threshold, a treatment guideline was provided suggesting appropriate clinical actions, ie, potential interventions to normalize cerebral oxygenation. 14 Infants in the usual-care group did not undergo monitoring with cerebral oximetry but received treatment as usual. 12 Primary and Exploratory Outcomes for the 2-Year Follow-Up Study The dichotomous coprimary outcome was a composite of death or moderate or severe neurodevelopmental disability, assessed at approximately 2 years’ corrected age. Death was defined as death occurring before the 2-year follow-up assessment. Moderate or severe neurodevelopmental disability was defined as the presence of 1 or more of the following criteria: cerebral palsy with a Gross Motor Function Classification System score of greater than or equal to 2, a cognitive score below 85 on the Bayley-III/IV cognitive scores or an another neurodevelopmental assessment score below 2 SDs from the mean, visual impairment defined as a diagnosis of moderate reduced vision or worse (blind in 1 eye with good vision in the contralateral eye or blind or can only perceive light or light reflecting objects), and hearing impairment defined as diagnosis of hearing loss corrected with aids or some hearing that is not corrected by aids or no useful hearing even with aids. The continuous coprimary outcome was the cognitive score on the Bayley-III/IV cognitive scores assessment, conducted by a trained professional. All components of the dichotomous coprimary outcome were reported separately as exploratory outcomes. Further exploratory outcomes included head circumference, height, and body weight; daily medication for the last 2 months; and any other chronic illness. 10 Data Collection and Outcome Assessment The SafeBoosC-III follow-up study builds on routinely collected clinical data and parental questionnaires. To minimize missing data, data collection accepted a wider than normal range of age at assessment and followed a prioritized 3-tier model, focusing on the coprimary outcome of death or moderate or severe neurodevelopmental disability (eFigure 1 in Supplement 3 ). Tier 1: Formal Clinical Data The prioritized data source was clinical follow-up records from 18 to 30 months’ corrected age. The collected data included information on cerebral palsy and Gross Motor Function Classification System classification, diagnoses of impaired vision and/or hearing, and assessment of cognitive function. The priority for the cognitive function was the Bayley-III/IV cognitive score. If unavailable, other tests measuring a cognitive domain were used according to predefined selection (eMethods in Supplement 3 ). Exploratory outcomes were also obtained from clinical records. Tier 2: Parental Questionnaires Access to an online questionnaire was distributed to parents of all eligible infants between 23.5 and 27.5 months’ corrected age. If components of the coprimary outcome death or moderate or severe neurodevelopmental disability were missing from the formal clinical data, parental responses were used. The questionnaires included the following (1) The Parent Report of Children’s Abilities-Revised Nonverbal Cognitive (PARCA-R NVC) scale with scores below 2 SDs classified as events and (2) questions regarding general health and development (eFigure 4 in Supplement 3 ). Parental confirmation of any of the following resulted in categorization of moderate or severe neurodevelopmental disability: a physician diagnosis of cerebral palsy, inability to walk independently at 2 years’ corrected age, visual impairment (blindness in 1 or both eyes or poor vision even with correction), or hearing impairment requiring hearing aids or cochlear implants. For exploratory outcomes, these questionnaires additionally gathered data on chronic diseases, daily medication use, hospitalizations since initial discharge, infants thriving, parental concerns regarding infant development, and parental education. Tier 3: Informal Assessments If no formal neurodevelopmental test or PARCA-R NVC scores were available, the cognitive component was assessed informally. If formal clinical data and parental questionnaires were unavailable, all clinical records from 12 months’ corrected age onward were used to determine moderate or severe neurodevelopmental disability. A detailed description of the 3-tier model is available in the eMethods in Supplement 3 . Blinding Parents and clinicians were not blinded to group allocation. A blinded outcome assessor reviewed the infants’ clinical records, decided on the classification of outcomes, and reported findings in the electronic case report form (eFigure 3 in Supplement 3 ). To ensure sufficient blinding of the outcome assessor, a local blinding procedure was developed by each site (eMethods in Supplement 3 ). Statisticians, data managers, and authors were blinded to group allocation. After analysis and prior to unblinding, abstracts for both outcome scenarios were written and agreed on by the authors. Statistical Analysis A total of 1601 infants were included in the SafeBoosC-III trial. 7 Assuming that all 1601 infants participated in this follow-up study, power calculations for the dichotomous, coprimary outcome of death or moderate or severe neurodevelopmental disability determined 80% power to detect an 8% absolute risk difference from an expected 50% incidence 15 of the coprimary outcome, with a 2-sided α level of 2.5%. The Bonferroni adjustment was used to account for 2 coprimary outcomes. 16 This power calculations was done before the results of the SafeBoosC-III trial and site withdrawals/exclusions. Due to the low maximum power for a large effect, a more sensitive but less patient-relevant coprimary outcome was chosen. Based on answers to a questionnaire on systematic routine follow-up, we assumed that two-thirds of the sites participating in SafeBoosC-III would be able to provide data on Bayley-III/IV cognitive score and that these sites would recruit a total of 850 infants. This sample size would provide 90% power to detect a mean difference of 5 points (Cohen d = 0.25) on the mean cognitive score, assuming a SD of 20 points and a 2-sided α level of 2.5%. 10 Statistical analyses were conducted independently by M.H.O. and J.C.J.. The results of these analyses were compared for discrepancies before unblinding. No significant discrepancies were found. All primary outcomes analyses were performed on the intention-to-treat population. Dichotomous outcomes were analyzed using mixed-effects logistic regression, while continuous outcomes were analyzed using mixed-effects linear regression. All regression models included the trial site as a random effect and gestational age below or above 26 weeks’ and group allocation as fixed effects. 13 We assumed data were missing at random and used multiple imputation for missing dichotomous coprimary outcomes based on predefined 36-week covariates. 11 We did not apply imputation to the continuous coprimary outcome due to the high proportion of missing data. 16 Prespecified sensitivity analyses were conducted for the coprimary outcomes, including a per-protocol analysis; a random-effects meta-analysis to account for possible between-site heterogeneity in treatment effect and a generalized estimation equation analysis to account for nonindependence of multiple births. Exploratory outcomes were analyzed without adjustment for multiple testing and results are presented with effect estimates and 95% CIs and should only be hypothesis generating. Statistical assumptions were systematically assessed for each method. Data were analyzed from October to December 2024 using R, version 4.4.2 (R Foundation for Statistical Computing), by M.H.O. and Stata, version 17 (StataCorp) by J.C.J. Results Participants Of the 1601 infants initially randomized from the 70 participating sites, 1438 infants (90%; mean [SD] age, 26.0 [1.3] weeks; 680 female [47.3%]; 758 male [52.7%]) from 56 sites in Asia, Europe, and North America were included in the follow-up study, with 697 in the cerebral oximetry group and 741 in the usual-care group ( Figure ). A total of 149 infants were lost to follow-up due to the following: 8 declined consent to use data, 38 had clinical follow-up in other hospital where outcome data were unavailable, 34 families moved away, 35 were due to other reasons, and 34 were unknown reasons. Characteristics were similar between the cerebral oximetry and usual-care group at birth and 36 weeks’ postmenstrual age ( Table 1 ). Characteristics of infants eligible for the follow-up study and those from sites withdrawn or excluded were similar at 36 weeks’ postmenstrual age as well (eTable 1 in Supplement 3 ). An overview of follow-up times and the health care professionals involved can be found in eTables 14 to 16 in Supplement 3 . Figure. Flowchart Depicting Randomization, 36-Week Follow-Up, and 2-Year Follow-Up. Open in a new tab Table 1. Baseline Characteristics and Neonatal Clinical Characteristics of the Infants Randomized at the 56 Sites Who Took Part in the 2-Year Follow-Up Study. Characteristic Cerebral oximetry (n = 697) Usual care (n = 741) Birth weight, median (IQR), g 800 (660-958) 800 (660-950) Gestational age, median (IQR), wk 26.1 (25.0-27.1) 26.1 (25.0-27.1) Gestational age >26 wk, No. (%) 381 (54.7) 409 (55.2) Twins or triplets, No. (%) a 168 (24.1) 219 (29.6) Sex, No. (%) Female 322 (46.2) 358 (48.3) Male 375 (53.8) 383 (51.7) Apgar score at 5 min, median (IQR) b 7 (6-8) 7 (6-8) Neonatal clinical characteristics Major congenital anomaly, No. (%) 15 (2.2) 17 (2.3) Cardiovascular support within 72 h of life, No. (%) 256 (36.7) 227 (30.6) Mechanical ventilation, No. (%) c 551 (79.1) 577 (77.9) Median days using mechanical ventilation (IQR), No. d 9 (3-23) 9 (3-25) Bronchopulmonary dysplasia, No./total No. (%) e 287/524 (54.6) 340/572 (59.4) Retinopathy of prematurity, No. (%) f 97 (13.9) 88 (11.9) Late-onset sepsis, No. (%) g 425 (61.0) 470 (63.4) Necrotizing enterocolitis, No. (%) h 87 (12.5) 82 (11.1) Severe brain injury at 36 wk PMA, No./total No. (%) i 171/688 (24.8) 170/732 (23.2) Death before 36 wk PMA, No. (%) 150 (21.5) 147 (19.8) Intervention: cerebral oximetry Age at initiation of cerebral oximetry monitoring median (IQR), h 3 (2-4) NA Cerebral oximetry monitoring discontinued >14 h, No. (%) 32 (4.6) NA Change of medical management due to cerebral hypoxia, No. (%) 199 (28.6) NA Cerebral oximetry monitoring in usual care group, No. (%) NA 20 (2.6) Open in a new tab Abbreviations: NA, not applicable; PMA, postmenstrual age. a For twins/triplet status, data were available for 694 in the cerebral oximetry group and 741 in the usual-care group. b For median Apgar score at 5 minutes, data were available for 694 in the cerebral oximetry group and 740 in the usual care group. c Mechanical ventilation was defined as invasive mechanical ventilation delivered by means of an endotracheal tube or tracheostomy tube. d For median days using mechanical ventilation, data were available for 551 in the cerebral oximetry group and 577 in the usual-care group. e Bronchopulmonary dysplasia was defined as the receipt of any respiratory support or supplemental oxygen (or both) at 36 weeks postmenstrual age. f Retinopathy of prematurity was defined as stage 3 or above (as classified according to the International Classification of Retinopathy of Prematurity) or treatment at any time point until 2-year follow-up. g Late-onset sepsis was defined as the initiation of antibiotics later than 72 hours from birth for at least 5 days. h Necrotizing enterocolitis was defined as stage 2 or higher based on the modified Bell staging system or focal intestinal perforation at any time point until 36 weeks follow-up (or both). i Severe brain injury was defined as one or more of the following diagnoses: intraventricular hemorrhage grade 3 or 4, cystic periventricular leukomalacia, posthemorrhagic ventricular dilatation, cerebellar hemorrhage, or cerebral atrophy shown on any routine cerebral ultrasound scan conducted until 36 weeks follow-up. Outcomes The coprimary outcome death or moderate or severe neurodevelopmental disability was available for 1289 of 1438 participants (90%). In total, 1002 infants (77.7%) underwent categorization of cerebral palsy and visual, hearing, and cognitive impairment using formal clinical records (tier 1), 154 (11.9%) were classified using data from parental questionnaires (tier 2), and 133 (10.3%) were classified from informal assessment (tier 3) ( Table 2 ). Bayley-III/IV cognitive scores were available for 533 of 1111 alive infants (48%). Table 2. Distribution of Data Sources Available to Classify the Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability (Percentages Calculated Without Missing Data). Overall (N = 1289) Tier 1: Death or formal clinical records between 18-30 mo 2: Parental questionnaire 3: Informal assessment of clinical records from 12 mo and onward Classification of death or moderate or severe neurodevelopmental disability, No. (%) 1002 (77.7) 154 (11.9) 133 (10.3) Components Classification of death, No. (%) 327 (100) NA NA Classification of cerebral palsy, No. (%) a , b 1186 (93.0) 89 (7.0) NA Classification of visual impairment, No. (%) a , c 1185 (93.1) 88 (6.9) NA Classification of hearing impairment, No. (%) a , d 1184 (92.9) 91 (7.1) NA Classification of cognitive impairment, No. (%) a , e 967 (77.0) 165 (13.1) 124 (9.9) Open in a new tab Abbreviations: NA, not applicable; PARCA-R NVC, Parent Report of Children’s Abilities-Revised Nonverbal Cognitive. a Deaths are classified within tier 1 and are included in the composite outcome of death or moderate or severe neurodevelopmental disability. b Cerebral palsy was defined as a Global Motor Function Classification score ≥2. c Visual impairment was defined as a diagnosis of moderate reduced vision or worse (blind in 1 eye with good vision in the contralateral eye or blind or can only perceive light or light reflecting objects). d Hearing impairment was defined as diagnosis of hearing loss corrected with aids or some hearing but loss not corrected by aids or no useful hearing even with aids. e Cognitive impairment was defined as (1) Bayley-III/IV cognitive score <85 (1st priority); (2) any developmental assessment <−2SD (including the PARCA-R NVC score) (2nd priority); and (3) if none of the above are available, blinded assessment of health care records from 12 months of corrected age and onwards concluding if the child has a cognitive impairment equivalent to moderate or severe neurodevelopmental disability (3rd priority). At 2 years’ corrected age, death or moderate or severe neurodevelopmental disability occurred in 292 of 620 infants (47.1%) in the cerebral oximetry group compared with 321 of 669 infants (48.0%) in the usual-care group (relative risk with cerebral oximetry, 0.96; 97.5% CI, 0.85-1.07; P = .45) ( Table 3 ). The mean (SD) Bayley-III/IV cognitive score was 92.8 (17.3) in the cerebral oximetry group compared with 93.2 (17.0) in the usual-care group (mean difference with cerebral oximetry, −0.14; 97.5% CI, −3.24 to 2.96; P = .92) ( Table 3 ). No important differences were observed when comparing the exploratory outcomes between the cerebral oximetry and usual-care groups ( Table 3 ). Death beyond 36 weeks’ postmenstrual age was rare (eTable 2 in Supplement 3 ). Parental education did not differ between groups (eTable 16 in Supplement 3 ). Table 3. Outcomes at 2 Years’ Corrected Age a . Outcome Cerebral oximetry (n = 697) Usual care (n = 741) Adjusted RR or mean difference (97.5% CI) P value Coprimary outcomes Death or moderate or severe neurodevelopmental disability, No./total No. (%) 292/620 (47.1) 321/669 (48.0) 0.96 (0.85 to 1.07) .58 Bayley III/IV cognitive score, mean (SD) 92.8 (17.3) 93.18 (17.0) −0.14 (−3.24 to 2.96) b .92 No. assessed 249 284 NA NA RR or mean difference (95% CI) Components of dichotomous outcome, No./total No. (%) Death 162/625 (25.9) 165/671 (24.5) 1.01 (0.83 to 1.21) NA Cerebral palsy c 25/453 (5.5) 22/495 (4.4) 1.30 (0.79 to 2.14) NA Visual impairment d 25/453 (5.5) 43/493 (8.7) 0.56 (0.38 to 0.8) NA Hearing impairment e 16/451 (3.5) 14/497 (2.8) 1.15 (0.69 to 1.92) NA Cognitive impairment f 106/442 (24.0) 116/485 (24.0) 0.97 (0.77 to 1.22) NA Moderate or severe neurodevelopmental disability decided by informal assessment 5/60 (8.3) 14/73 (19.2) 0.58 (0.25 to 1.37) NA Exploratory outcomes Head circumference, median (IQR), cm 47.5(46.0 to 49.0) 47.0 (46.0 to 49.0) 0.03 (−0.27 to 0.34) b NA No. assessed 221 256 NA NA Height, median (IQR), cm 85.0 (82.0 to 88.0) 85.0 (82.0 to 88.0) −0.20 (−0.87 to 0.46) b NA No. assessed 222 258 NA NA Body weight, median (IQR), kg 11.1 (10.0 to 12.0) 11.1 (10.0 to 12.3) −0.10 (−0.35 to 0.14) b NA No. assessed 233 274 NA NA Any other chronic illness, No./total No. (%) 117/451 (26.0) 154/488 (31.2) 0.80 (0.65 to 0.98) NA Any daily medication for the last 2 mo, No./total No. (%) 93/451 (20.6) 108/488 (22.0) 0.91 (0.71 to 1.17) NA PARCA-R NVC score, No. assessed (mean score [SD]) 320 (86.4 [21.2]) 337 (87.4 [21.3]) 0.00 (−4.0 to 3.0) a NA Hospitalization since discharge from birth hospitalization, No./total No. (%) 181/349 (52.0) 186/381 (48.8) 1.06 (0.91 to 1.23) NA Parental report of thriving child, No./total No. (%) 337/348 (97.0) 368/381 (96.6) 1.00 (0.97 to 1.03) NA Parental report of worries regarding the child, No./total No. (%) 124/341 (36.0) 144/374 (38.5) 0.96 (0.79 to 1.17) NA Open in a new tab Abbreviations: PARCA-R NVC, Parent Report of Children’s Abilities-Revised Nonverbal Cognitive; RR, relative risk. a Effect estimates for the coprimary outcomes are derived from prespecified regression models. The dichotomous outcome (death or moderate or severe neurodevelopmental disability) was analyzed using mixed-effect logistic regression, while continuous outcome (Bayley III/IV cognitive score mean score) was analyzed using mixed-effect linear regression. Models were adjusted for stratification variables. Two-sided P values correspond to these model-based estimates. CIs for the coprimary outcomes are reported at the 97.5% level to account for multiplicity. b For this outcome, the treatment effect is the mean difference. c Cerebral palsy was defined as a Global Motor Function Classification score ≥2. d Visual impairment was defined as a diagnosis of moderate reduced vision or worse (blind in 2 eye with good vision in the contralateral eye or blind or can only perceive light or light reflecting objects). e Hearing impairment was defined as diagnosis of hearing loss corrected with aids or some hearing but loss not corrected by aids or no useful hearing even with aids. f Cognitive impairment was defined as (1) Bayley-III/IV Cognitive score <85 (1st priority); (2) any developmental assessment below 2 SDs (including the PARCA-R NVC score) (2nd priority); and (3) if none of the above are available, blinded assessment of health care records from 12 months of corrected age and onward concluding that the child has a cognitive impairment equivalent to moderate or severe neurodevelopmental disability (3rd priority). The sensitivity analyses consistently supported the results in the coprimary outcome death or moderate or severe neurodevelopmental disability. Multiple imputation analyses indicated that missing data did not substantially affect results (eTable 4 in Supplement 3 ). The generalized estimation equation sensitivity analysis did not suggest that the result was significantly affected by the high proportion of twins (eTable 10 in Supplement 3 ). The exclusion of informal assessments did not change the results (eTable 6 in Supplement 3 ). The remaining prespecified analyses are presented in eFigure 2 and eTables 3, 5, 7-9, 11-13, and 17 in Supplement 3 . Discussion In this 2-year follow-up of the SafeBoosC-III randomized clinical trial, extremely preterm infants receiving treatment guided by cerebral oximetry monitoring compared with usual care for the first 72 hours after birth did not result in a lower incidence of death or moderate or severe neurodevelopmental disability, nor did it result in higher Bayley cognitive scores. The findings in this follow-up study are consistent with our 36-week outcome results of the SafeBoosC-III trial. 7 The confidence limits for the dichotomous outcome are wide, thus not excluding either important potential benefits or harms, and reflect limited statistical power. In contrast, the confidence limits of the effect size on Bayley-III/IV cognitive scores are narrow, thus excluding a major effect at the population level. Although cognitive tests at school age are more reliable than at 2 years, 17 the likelihood that effects emerge later is low. 18 This is supported by an ancillary study 19 of the SafeBoosC-III trial population, which did not find less abnormalities on magnetic resonance imaging at term equivalent age. Of the exploratory outcomes, visual impairment was reported less frequently in the cerebral oximetry group ( Table 3 ), whereas severe retinopathy of prematurity was slightly higher in the cerebral oximetry group ( Table 1 ). This difference in visual outcomes likely reflects a chance finding rather than a biologically plausible effect and may partly relate to different definitions of visual impairment. No evidence of an effect of cerebral oximetry monitoring may have several possible explanations. Monitoring was limited to the first 72 hours after birth, representing a short exposure relative to the overall duration of neonatal intensive care. Hypoxia may not be the primary driver of brain injury in extremely preterm infants as brain injury in this population is multifactorial. Cerebral oximetry with near-infrared spectroscopy measures only from local and superficial layers of the brain and is subject to significant imprecision particularly after sensor repositioning. 20 To improve the effectiveness of the intervention, a web-based training program was implemented. However, only 39% of staff caring for the participants at the 70 sites obtained certification, as this was not mandatory. This may have led to suboptimal implementation in sites with limited prior clinical experience and modest engagement in the web-based training. 21 Continuous cerebral oximetry data were not collected, hindering estimation of the baseline burden of hypoxia. Only 29% of the experimental group had management changes due to cerebral hypoxia documented in their clinical records, limiting the intervention’s potential effect to this subgroup. Although hypoxic thresholds triggered alerts, there was no standardized or mandated management response. Finally, a targeted 22% relative risk reduction may have been optimistic and smaller effects may not be detectable by a trial of this size. Cerebral oxygenation may be more directly affected in specific clinical scenarios, such as systemic hypotension, significant anemia, mechanical ventilation, or hemodynamically relevant patent ductus arteriosus, where cerebral perfusion and oxygen delivery are compromised. 22 , 23 , 24 , 25 Future studies could target such high-risk populations. Limitations Our study has several limitations. First, the SafeBoosC-III follow-up trial was not prespecified as part of the original trial design, and the available sample size was, therefore, not powered to detect differences in long-term outcomes. The targeted sample size for the 2 coprimary outcomes was not achieved, thereby increasing the risk that the study was underpowered. Second, we encountered 10% missing data for the primary outcome of death or moderate or severe neurodevelopmental disability, which may introduce bias dependent on the missing mechanism. 26 However, the proportion of missing data was similar between the cerebral oximetry and usual-care groups, and multiple imputation analysis did not alter the intervention effect. The Bayley-III/IV cognitive scores were available for only 48% of eligible alive infants. The prespecified sample size calculation targeted a mean difference of 5 points that, while modest at the individual level, may be considered clinically relevant at the population level for an intervention with few adverse effects. Third, routine clinical assessments and reporting of these in the clinical records were not blinded. Group allocation is unlikely to have influenced clinical assessments, as the intervention only lasted the first 3 days after birth, in a hospital stay that for survivors may last several months. To reduce potential bias, extraction of outcome data from clinical records was performed blindly. Fourth, the nonparticipation of 14 sites may reduce external validity, but similarly, the 36-week outcomes between excluded and included sites suggest minimal impact. Fifth, informal assessments provided 10% of the data for the dichotomous coprimary outcome. While subjective, these assessments were blinded, minimizing the risk of systematic bias, and results did not differ materially when these data were excluded. Importantly, our 3-tier model enabled a 90% follow-up rate for the dichotomous coprimary outcome, despite the lack of funding for trial-specific follow-up at local sites. This is both a strength but also a limitation as this pragmatic approach prioritized completeness of follow-up over the uniform data granularity seen in population-based cohorts or studies with dedicated trial-specific assessments. By minimizing missing data, a common challenge in 2-year outcome studies, this model offers potential for adaptation in other neonatal trials assessing similar long-term outcomes. A limitation may also be the pragmatic design of the trial: the intervention was limited to the first 72 hours after birth, training in the use of cerebral oximetry was variable across sites, and no details were collected on the clinical actions taken when hypoxic thresholds were reached, the response, nor on other patient monitoring data. These methodological limitations should be considered when interpreting the results. Conclusions In this follow-up study of the SafeBoosC-III randomized clinical trial, in extremely preterm infants, treatment guided by cerebral oximetry monitoring compared with usual care for the first 72 hours after birth did not result in a lower incidence of death or moderate or severe neurodevelopmental disability, nor did it result in higher Bayley cognitive scores at 2 years’ corrected age. The routine use of cerebral oximetry monitoring during the first 72 hours after birth in extremely preterm infants to reduce death or moderate or severe neurodevelopmental disability and cognitive impairment was not supported by this trial. Supplement 1. Trial Protocol. jamapediatr-e261066-s001.pdf (405KB, pdf) Supplement 2. Statistical Analysis Plan. jamapediatr-e261066-s002.pdf (166.4KB, pdf) Supplement 3. eAppendix. List of Investigators eMethods. eTable 1. Death or Severe Brain Injury at 36 Weeks’ Postmenstrual Age and at 2-Year Follow-Up in Included and Excluded Sites eTable 2. Causes of Death Beyond 36 Weeks’ Postmenstrual Age eTable 3. Per-Protocol Analysis eTable 4. Multiple Imputation Analysis on Death or Moderate or Severe Neurodevelopmental Disability eTable 5. Best-Worst and Worst-Best Case Analysis on Death or Moderate or Severe Neurodevelopmental Disability eTable 6. Exclusion of Informal Assessment (Tier 3) for the Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability eTable 7. Number of Events in Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability for Informal Assessments (Tier 3) eTable 8. Comparison of Sites With High Follow-Up Rates (≥90%) vs Low Follow-Up Rates (<90%) for the Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability eTable 9. Comparison of Sites With High Follow-Up Rates (≥90 vs Low Follow-Up Rates (<90%) for the Coprimary Outcome Bayley III/IV Cognitive Score eTable 10. Generalized Estimation Equation (Twin Sensitivity Analysis) eTable 11. Proportion of Missingness Between Cerebral Oximetry Group and Experimental Group for the 2 Coprimary Outcomes eTable 12. Analysis of all PARCA-R Nonverbal Cognitive Scores Including Extrapolated Scores eTable 13. Death or Moderate or Severe Neurodevelopmental Disability With PARCA-R Nonverbal Cognitive Extrapolated Scores eTable 14. Follow-Up Times of Randomized Infants eTable 15. Clinical Data Based on Information From Health Care Professional eTable 16. Parental Education Level Based on ISCED Classification eTable 17. Number of Randomizations per Site eFigure 1. Prioritization of Data for the Coprimary Outcome Moderate or Severe Neurodevelopmental Disability eFigure 2. Random Effect Meta-Analysis for Coprimary Outcome Moderate or Severe Neurodevelopmental Disability and Bayley III/IV Cognitive Score eFigure 3. Extract From the Electronic Case Report Form for 2-Year Clinical Data eFigure 4. 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Death or Severe Brain Injury at 36 Weeks’ Postmenstrual Age and at 2-Year Follow-Up in Included and Excluded Sites eTable 2. Causes of Death Beyond 36 Weeks’ Postmenstrual Age eTable 3. Per-Protocol Analysis eTable 4. Multiple Imputation Analysis on Death or Moderate or Severe Neurodevelopmental Disability eTable 5. Best-Worst and Worst-Best Case Analysis on Death or Moderate or Severe Neurodevelopmental Disability eTable 6. Exclusion of Informal Assessment (Tier 3) for the Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability eTable 7. Number of Events in Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability for Informal Assessments (Tier 3) eTable 8. Comparison of Sites With High Follow-Up Rates (≥90%) vs Low Follow-Up Rates (<90%) for the Coprimary Outcome Death or Moderate or Severe Neurodevelopmental Disability eTable 9. Comparison of Sites With High Follow-Up Rates (≥90 vs Low Follow-Up Rates (<90%) for the Coprimary Outcome Bayley III/IV Cognitive Score eTable 10. Generalized Estimation Equation (Twin Sensitivity Analysis) eTable 11. Proportion of Missingness Between Cerebral Oximetry Group and Experimental Group for the 2 Coprimary Outcomes eTable 12. Analysis of all PARCA-R Nonverbal Cognitive Scores Including Extrapolated Scores eTable 13. Death or Moderate or Severe Neurodevelopmental Disability With PARCA-R Nonverbal Cognitive Extrapolated Scores eTable 14. Follow-Up Times of Randomized Infants eTable 15. Clinical Data Based on Information From Health Care Professional eTable 16. Parental Education Level Based on ISCED Classification eTable 17. Number of Randomizations per Site eFigure 1. Prioritization of Data for the Coprimary Outcome Moderate or Severe Neurodevelopmental Disability eFigure 2. Random Effect Meta-Analysis for Coprimary Outcome Moderate or Severe Neurodevelopmental Disability and Bayley III/IV Cognitive Score eFigure 3. Extract From the Electronic Case Report Form for 2-Year Clinical Data eFigure 4. Parental Questionnaire Used for the SafeBoosC-III Follow-Up Study eReferences. jamapediatr-e261066-s003.pdf (4.4MB, pdf) Supplement 4. Nonauthor Collaborators. SafeBoosC-III Follow-Up Collaborator Group jamapediatr-e261066-s004.pdf (125.7KB, pdf) Supplement 5. Data Sharing Statement. jamapediatr-e261066-s005.pdf (15.6KB, pdf) Articles from JAMA Pediatrics are provided here courtesy of American Medical Association ACTIONS View on publisher site Cite Collections Permalink PERMALINK Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Add to Collections Create a new collection Add to an existing collection Name your collection * Choose a collection Unable to load your collection due to an error Please try again Add Cancel Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top