Objective To determine whether early low-dose hydrocortisone treatment in extremely preterm infants is associated with brain damage assessed by MRI at term equivalent of age (TEA).
Patients and outcomes This is a predefined secondary analysis of brain abnormalities, observed by MRI at TEA, of patients randomly assigned to receive either placebo or hydrocortisone in the PREMILOC trial. Outcomes were based on brain abnormalities graded according to Kidokoro scores.
Results Among 412 survivors at TEA, 300 MRIs were performed and 295 were suitable for analysis. Kidokoro scoring was completed for 119/148 and 110/147 MRIs in the hydrocortisone and placebo groups, respectively. The distribution of the Kidokoro white matter (WM) subscore and other subscores was not significantly different between the two groups. There was, however, a significant association between a higher overall Kidokoro score and hydrocortisone treatment (5.84 (SD 3.51) for hydrocortisone and 4.98 (SD 2.52) for placebo; mean difference, 0.86; 95% CI 0.06 to 1.66; p=0.04). However, hydrocortisone was not statistically associated with moderate-to-severe brain lesions (Kidokoro overall score ≥6) in a multivariate logistic regression model accounting for potential confounding variables (adjusted OR (95% CI) 1.27 (0.75 to 2.14), p=0.38). Bronchopulmonary dysplasia at 36 weeks postmenstrual age significantly predicted both WM damage (adjusted OR (95% CI) 2.70 (1.03 to 7.14), p=0.04) and global brain damage (adjusted OR (95% CI) 2.18 (1.19 to 3.99), p=0.01).
Conclusions Early hydrocortisone exposure in extremely preterm infants is not statistically associated with either WM brain damage or overall moderate-to-severe brain lesions when adjusted for other neonatal variables.
Trial registration number EudraCT number 2007-002041-20, NCT00623740
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Collaborators PREMILOC study group: Valérie Biran, Ali Bilal, Caroline Farnoux, Sophie Soudée, Laure Maury (CHU Robert Debré, Paris); Michèle Granier, Florence Lebail (CH Corbeil-Essonnes); Duksha Ramful, Sylvain Samperiz (CHR Saint-Denis, La Réunion); Alain Beuchée, Karine Guimard (CHU Rennes, France); Fatima El Moussawi, Pascal Boileau, Florence Castela (CHI Poissy); Claire Nicaise, Renaud Vialet (CHU Hôpital Nord, Marseille); Pierre Andrini, Thierry Debillon (CHU Grenoble); Véronique Zupan-Simunek, Hasinirina Razafimahefa (CHU Antoine Béclère, Paris); Anne Coursol, Saïd Merbouche (CH Pontoise); Pascal Bolot, Jean-Marc Kana (CH Saint-Denis); Julie Guichoux, Olivier Brissaud (CHU Bordeaux); Gérard Thiriez, Olivier Schulze (CHU Besançon); Mickael Pomedio, Patrice Morville (CHU Reims); Thierry Blanc, Stéphane Marret (CHU Rouen); Bernard Guillois, Cénéric Alexandre (CHU Caen); Stéphane Le Bouëdec, Bertrand Leboucher (CHU Angers); Umberto Simeoni, Valérie Lacroze (CHU Conception, Marseille); Pierre Kuhn, Stéphanie Litzler-Renaud (CHU Strasbourg); Elodie Zana-Taïeb, Pierre-Henri Jarreau (CHU Cochin-Broca-Hôtel Dieu, Paris); Sylvain Renolleau, Virginie Meau-Petit (CHU Armand Trousseau, Paris); Gilles Cambonie (CHRU Montpellier); Annick Tibi (Agence Générale des Equipements et des Produits de Santé (AGEPS), Paris); Amel Ouslimani, Elodie Soler (Direction de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris, Paris); Sandra Argues, Tania Rilcy, Adyla Yacoubi, Sabrina Verchere (Unit of Clinical Epidemiology, CHU Robert Debré, Paris).
Contributors MA and BT carried out data analyses, and revised the manuscript. AT, AB and DM designed the statistical analytical plan, carried out the analyses and participated in their interpretation. CA co-ordinated and supervised the statistical methods and analyses, and revised the manuscript. VB participated in the interpretation of the analyses and revised the manuscript. OB conceived the study, participated in the interpretation of the analyses and wrote the manuscript. All authors have approved the final manuscript as submitted and agree to be held accountable for all aspects of the work.
Funding This work was supported by a research grant from the French Ministry of Health and sponsored by the Département de la Recherche Clinique et de l’Innovation, Assistance Publique-Hôpitaux de Paris (AOM 06 025 and AOM 11 129).
Competing interests None declared.
Patient consent for publication 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 no. 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.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, the statistical analysis plan and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to firstname.lastname@example.org.