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Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth
  1. Olivier Baud1,2,
  2. Clémence Trousson1,
  3. Valérie Biran1,3,
  4. Emilie Leroy1,
  5. Damir Mohamed4,
  6. Corinne Alberti4
  7. for the PREMILOC Trial group
    1. 1Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, Paris, France
    2. 2Division of Neonatology and Paediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland
    3. 3Inserm U1141, University Paris Diderot, Sorbone Paris-Cité, Paris, France
    4. 4Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, Inserm U1123 and CIC-EC 1426, University Paris Diderot, Sorbonne Paris-Cité, Paris, France
    1. Correspondence to Professor Olivier Baud, Division of Neonatology and Paediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland; olivierfrancois.baud{at}hcuge.ch

    Abstract

    Objective To determine whether early hydrocortisone treatment in extremely preterm infants affects neurodevelopmental outcomes at 2 years of age according to gestational age at birth.

    Patients and methods This is an exploratory analysis of neurodevelopmental outcomes by gestational age strata from the PREMILOC trial, in which patients were randomly assigned to receive either placebo or low-dose hydrocortisone and randomisation was stratified by gestational age groups (24–25 and 26–27 weeks of gestation). Neurodevelopmental impairment (NDI) was assessed using a standardised neurological examination and the revised Brunet-Lézine scale at 22 months of corrected age.

    Results A total of 379 of 406 survivors were evaluated, 96/98 in the gestational age group of 24–25 weeks and 283/308 in the gestational age group of 26–27 weeks. Among surviving infants born at 24–25 weeks, significant improvement in global neurological assessment was observed in the hydrocortisone group compared with the placebo group (P=0.02) with a risk of moderate-to-severe NDI of 2% and 18%, respectively (risk difference 16 (95% CI −28% to −5%)). In contrast, no statistically significant difference between treatment groups was observed in infants born at 26–27 weeks (P=0.95) with a similar risk of moderate-to-severe NDI of 9% in both groups. The incidence of cerebral palsy or other major neurological impairments were found similar between treatment groups in each gestational group.

    Conclusions In an exploratory analysis of neurodevelopmental outcomes from the PREMILOC trial, early low-dose hydrocortisone was associated with a statistically significant improvement in neurodevelopmental outcomes in infants born at 24 and 25 weeks of gestation.

    • hydrocortisone
    • extremely preterm neonate
    • neurodevelopmental impairment

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    Footnotes

    • Contributors OB and CA designed the study. CéT, EL and VéB performed neurological assessments. DM and CA analysed the data. OB wrote the first draft of the paper. All authors revised and approved the final version of the manuscript.

    • Funding This work was funded by a research grant from the French Ministry of Health and sponsored by the Délégation à la Recherche Clinique et à l’Innovation, Assistance Publique-Hôpitaux de Paris (AOM 06 025 and AOM 11 129). The funders had no role in the design and conduct of the study; analysis and interpretation of the data; preparation, review or approval of the manuscript and decision to submit the manuscript for publication. No honorarium, grant or other form of payment was given to anyone to produce the manuscript.

    • Competing interests None declared.

    • Patient consent Parental/guardian consent obtained.

    • Ethics approval The trial was approved by the national ethics committee (Comité de Protection des Personnes, Ile-de-France II, Necker), the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament, EudraCT number 2007-002041-20) and the French data protection authority (Commission Nationale de l’Informatique et des Libertés).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Additional members of the PREMILOC Trial group are listed below: Caroline Farnoux, M.D., Laure Maury, M.D., Sophie Soudée, M.D (Neonatal intensive care unit and INSERM U1141, Assistance Publique-Hôpitaux de Paris, CHU Robert Debré, Paris, France); Michèle Granier, M.D., Florence Lebail, M.D (Neonatal intensive care unit, CH Corbeil-Essonnes, France); Duksha Ramful, M.D., Sylvain Samperiz, M.D (Neonatal and pediatric intensive care unit, CHR Saint-Denis, La Réunion, France); Alain Beuchée, M.D., Ph.D., Karine Guimard, M.D (Neonatal intensive care unit, CHU Rennes, France); Pascal Boileau, M.D., Ph.D., Florence Castela, M.D., Fatima El Moussawi, M.D (Neonatal intensive care unit, CHI Poissy, France); Claire Nicaise, M.D., Renaud Vialet, M.D (Neonatal intensive care unit, Assistance Publique-Hôpitaux de Marseille, CHU Hôpital Nord, Marseille,France); Pierre Andrini, M.D., Thierry Debillon, M.D., Ph.D (Neonatal intensive care unit, CHU Grenoble, France); Hasinirina Razafimahefa, M.D., Véronique Zupan-Simunek, M.D (Neonatal intensive care unit, Assistance Publique-Hôpitaux de Paris, CHU Antoine Béclère, Paris, France); Anne Coursol, M.D., Saïd Merbouche, M.D.: Neonatal intensive care unit, CH Pontoise, France); Pascal Bolot, M.D., Jean-Marc Kana, M.D (Neonatal intensive care unit, CH Saint-Denis, France); Julie Guichoux, M.D., Olivier Brissaud, M.D., Ph.D (Neonatal and pediatric intensive care unit, CHU Bordeaux, France); Gérard Thiriez, M.D., Ph.D., Olivier Schulze, M.D (Neonatal and pediatric intensive care unit, CHU Besançon, France); Mickael Pomedio, M.D., Patrice Morville, M.D (Neonatal and pediatric intensive care unit, CHU Reims, France); Thierry Blanc, M.D., Stéphane Marret, M.D., Ph.D (Neonatal and pediatric intensive care unit, CHU Rouen, France); Bernard Guillois, M.D., Ph.D., Cénéric Alexandre, M.D (Neonatal intensive care unit, CHU Caen, France); Stéphane Le Bouëdec, M.D., Bertrand Leboucher, M.D (Neonatal intensive care unit, CHU Angers, France); Umberto Simeoni, M.D.,Ph.D., Valérie Lacroze, M.D (Neonatal intensive care unit, Assistance Publique-Hôpitaux de Marseille, CHU Conception, Marseille, France); Pierre Kuhn, M.D., Ph.D., Stéphanie Litzler-Renaud,M.D (Neonatal intensive care unit, CHU, Strasbourg, France); Elodie Zana-Taïeb, M.D., Ph.D., Pierre-Henri Jarreau, M.D., Ph.D (Neonatal intensive care unit Port-Royal, Assistance Publique-Hôpitaux de Paris, CHU Cochin-Broca-Hôtel Dieu, Paris, France); Sylvain Renolleau, M.D., Ph.D., Virginie Meau-Petit, M.D (Neonatal and pediatric intensive care unit, Assistance Publique-Hôpitaux de Paris, CHU Armand Trousseau, Paris, France); Gilles Cambonie, M.D., Ph.D., Aline Rideau Batista Novais, M.D., Ph.D (Neonatal intensive care unit, CHRU Montpellier, France); Annick Tibi, Pharm.D (Département de la santé publique, Université Paris-Descartes, Département des essais cliniques, Agence Générale des Equipements et des Produits de Santé (AGEPS), Assistance Publique-Hôpitaux de Paris, Paris, France) Thierry Lacaze-Masmonteil, M.D., Ph.D (Section Head Neonatology, Regional Director–Calgary Zone, University of Calgary, Canada. Kristi Watterberg, M.D (University of New Mexico School of Medicine, Albuquerque, NM, USA). Other members: Amel Ouslimani, Elodie Soler (Direction de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris, Paris, France); Sandra Argues, Tania Rilcy, Adyla Yacoubi, Sabrina Verchere (Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s hospital, Paris, France); Elena Bombled, Jennifer Gallard, Anne Ménard (Neuropsychologists); Dr. Isabelle Husson, M.D., Ph.D (Pediatric neurologist); Prof. Elizabeth Autret M.D., Ph.D., Prof. Charlotte Casper, M.D., Ph.D., Prof. Bruno Giraudeau Ph.D., Prof. Pierre-Henri Jarreau, M.D., Ph.D (Data Safety Monitoring Board).

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