Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial - Inria - Institut national de recherche en sciences et technologies du numérique Access content directly
Journal Articles The Lancet Year : 2022

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial

Thomas Schmitz (1) , Muriel Doret-Dion (2) , Loic Sentilhes (3) , Olivier Parant (4) , Olivier Claris (5) , Laurent Renesme (6) , Julie Abbal (4) , Aude Girault (7, 8, 9) , Héloïse Torchin (8, 10) , Marie Houllier (11) , Nolwenn Le Saché (11) , Alexandre Vivanti (12) , Daniele de Luca (13, 14) , Norbert Winer (15) , Cyril Flamant (15) , Claire Thuillier (16) , Pascal Boileau (17, 16) , Julie Blanc (18, 19) , Véronique Brevaut (20) , Pierre-Emmanuel Bouet (21) , Géraldine Gascoin (21) , Gaël Beucher (22) , Valérie Datin-Dorriere (22) , Stéphane Bounan (23) , Pascal Bolot (23) , Christophe Poncelet (24) , Corinne Alberti (25) , Moreno Ursino (26, 27, 28) , Camille Aupiais (29) , Olivier Baud (30) , Philippe Boize , Charles Garabédian , Florence Flamein , Maela Le Lous , Alain Beuchée , Jean Gondry (31, 32) , Pierre Tourneux (33, 34) , Perrine Coste-Mazeau , Antoine Bedu , Denis Gallot , Karen Coste , Céline Chauleur , Hugues Patural , Gilles Kayem , Delphine Mitanchez , Hélène Heckenroth , Farid Boubred , Jeanne Sibiude , Luc Desfrère , Caroline Bohec , Thierry Mansir , Antoine Koch , Pierre Kuhn , Nadia Tillouche , Fabrice Lapeyre , Franck Perrotin , Géraldine Favrais , Edouard Lecarpentier , Xaxier Durrmeyer , Véronique Equy , Thierry Debillon , Luc Rigonnot , Stéphanie Lefoulgoc , Claudia Brie , Anne-Sophie Pagès , Romy Rayssiguier , Gilles Cambonie , Corinne Cudeville , Doriane Madeleneau , Olivier Morel , Jean-Michel Hascoet , Vincent Letouzey , Massimo Di Maio , Laurent Salomon , Alexandre Lapillonne
1 Hôpital Robert Debré
2 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
3 CHU Bordeaux
4 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
5 HCL - Hospices Civils de Lyon
6 CRCTB - Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux]
7 Maternité Port-Royal [CHU Cochin]
8 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
9 EPOPé [CRESS - U1153 / UMR_A 1125] - Obstetrical, Perinatal and Pediatric Epidemiology | Épidémiologie Obstétricale, Périnatale et Pédiatrique
10 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
11 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
12 AP-HP - Hôpital Antoine Béclère [Clamart]
13 Service de Pédiatrie et Réanimations néonatales [Béclère]
14 HPPIT - Hypertension pulmonaire : physiopathologie et innovation thérapeutique
15 PhAN - Physiopathologie des Adaptations Nutritionnelles
16 CHI Poissy-Saint-Germain
17 PHYSENDO - Physiologie et physiopathologie endocriniennes
18 ENSFEA - École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville
19 EFTS - Education, Formation, Travail, Savoirs
20 Hôpital Nord [CHU - APHM]
21 CHU Angers - Centre Hospitalier Universitaire d'Angers
22 CHU Caen
23 Centre Hospitalier de Saint-Denis [Ile-de-France]
24 Centre Hospitalier René Dubos [Pontoise]
25 Hôpital Robert Debré Paris
26 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
27 HeKA - Health data- and model- driven Knowledge Acquisition
28 CIC 1426 - Centre d'Investigation Clinique 1426
29 ECEVE (U1123 / UMR_S_1123) - Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables
30 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
31 CHU Amiens-Picardie
32 GRAMFC - Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 UPJV
33 PERITOX - Périnatalité et Risques Toxiques - UMR INERIS_I 1 UPJV
34 Soins Intensifs de Néonatologie et Médecine Néonatale / Réanimation et Surveillance Continue de Pédiatrie [CHU Amiens]
Loic Sentilhes
  • Function : Author
Géraldine Gascoin
  • Function : Author
  • PersonId : 1374656
Gaël Beucher
  • Function : Author
Valérie Datin-Dorriere
  • Function : Author
Philippe Boize
  • Function : Author
Charles Garabédian
  • Function : Author
Florence Flamein
  • Function : Author
Maela Le Lous
  • Function : Author
Alain Beuchée
  • Function : Author
Perrine Coste-Mazeau
  • Function : Author
Antoine Bedu
  • Function : Author
Denis Gallot
  • Function : Author
Karen Coste
  • Function : Author
Céline Chauleur
  • Function : Author
Hugues Patural
Gilles Kayem
  • Function : Author
Delphine Mitanchez
  • Function : Author
Hélène Heckenroth
  • Function : Author
Farid Boubred
  • Function : Author
Jeanne Sibiude
  • Function : Author
Luc Desfrère
  • Function : Author
Caroline Bohec
  • Function : Author
Thierry Mansir
  • Function : Author
Antoine Koch
  • Function : Author
Pierre Kuhn
  • Function : Author
Nadia Tillouche
  • Function : Author
Fabrice Lapeyre
  • Function : Author
Franck Perrotin
Géraldine Favrais
  • Function : Author
Edouard Lecarpentier
  • Function : Author
Xaxier Durrmeyer
  • Function : Author
Véronique Equy
  • Function : Author
Thierry Debillon
  • Function : Author
Luc Rigonnot
  • Function : Author
Stéphanie Lefoulgoc
  • Function : Author
Claudia Brie
  • Function : Author
Anne-Sophie Pagès
  • Function : Author
Romy Rayssiguier
  • Function : Author
Gilles Cambonie
Corinne Cudeville
  • Function : Author
Doriane Madeleneau
  • Function : Author
Olivier Morel
  • Function : Author
Jean-Michel Hascoet
  • Function : Author
Vincent Letouzey
  • Function : Author
  • PersonId : 989211
  • IdRef : 13095327X
Massimo Di Maio
  • Function : Author
Laurent Salomon
  • Function : Author
Alexandre Lapillonne
  • Function : Author

Abstract

BackgroundAntenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.MethodsWe designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.FindingsBetween Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.InterpretationBecause non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction.

Dates and versions

hal-03872891 , version 1 (25-11-2022)

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Thomas Schmitz, Muriel Doret-Dion, Loic Sentilhes, Olivier Parant, Olivier Claris, et al.. Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. The Lancet, 2022, 400 (10352), pp.592-604. ⟨10.1016/S0140-6736(22)01535-5⟩. ⟨hal-03872891⟩
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