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1. 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

Author

Thomas Schmitz, Muriel Doret-Dion, Loic Sentilhes, Olivier Parant, Olivier Claris, Laurent Renesme, Julie Abbal, Aude Girault, Héloïse Torchin, Marie Houllier, Nolwenn Le Saché, Alexandre J Vivanti, Daniele De Luca, Norbert Winer, Cyril Flamant, Claire Thuillier, Pascal Boileau, Julie Blanc, Véronique Brevaut, Pierre-Emmanuel Bouet, Géraldine Gascoin, Gaël Beucher, Valérie Datin-Dorriere, Stéphane Bounan, Pascal Bolot, Christophe Poncelet, Corinne Alberti, Moreno Ursino, Camille Aupiais, Olivier Baud, Philippe Boize, Charles Garabédian, Florence Flamein, Maela Le Lous, Alain Beuchée, Jean Gondry, Pierre Tourneux, 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 J. Salomon, Alexandre Lapillonne, Hôpital Robert Debré, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP - Hôpital Antoine Béclère [Clamart], Service de Pédiatrie et Réanimations néonatales [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), CHI Poissy-Saint-Germain, Physiologie et physiopathologie endocriniennes (PHYSENDO), École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA), Education, Formation, Travail, Savoirs (EFTS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA), Hôpital Nord [CHU - APHM], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], Hôpital Robert Debré Paris, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
Respiratory Distress Syndrome, Newborn, Double-Blind Method, Pregnancy, [SDV]Life Sciences [q-bio], Infant, Newborn, Humans, Premature Birth, Female, Infant, Premature, Diseases, General Medicine, Betamethasone
Abstract

International audience; 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.

Published
2022

2. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author

Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract

Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Published
2020

3. Role of fetal ultrasound and magnetic resonance imaging in the prenatal diagnosis of migration disorders

Author

Chrystèle Rubod, Nadia Tillouche, Véronique Houfflin-Debarge, Francis Puech, Yann Robert, and Louise Devisme

Subjects
medicine.medical_specialty, Pathology, Lissencephaly, Gestational Age, Prenatal diagnosis, Context (language use), Ultrasonography, Prenatal, Central nervous system disease, Pregnancy, Prenatal Diagnosis, medicine, Humans, Pathological, Genetics (clinical), Cerebral Cortex, Chromosome Aberrations, medicine.diagnostic_test, business.industry, Obstetrics and Gynecology, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Fetal Diseases, Female, Radiology, Abnormality, business
Abstract

Objectives To evaluate the contribution and limitations of fetal ultrasonography (US) and magnetic resonance imaging (MRI) for the diagnosis and management of migration disorders. Methods Over a 5-year period, 14 fetuses with pathological migration disorders, without an infectious context, were taken care of in our centre. All underwent US; nine underwent MRI as well. Sonographic and MRI data were compared with neuropathological data. Results The diagnosis of gyral disorders was obtained by US in 1/14 cases; other cerebral abnormalities were found suggesting neuronal disorder in the remainder. Cerebral MRI suggested gyral abnormality in eight of the nine cases. Conclusions US performance is increasing. MRI appears to be a promising method for the diagnosis of fetal migration disorders, giving better results than US. It may be recommended in cases of abnormal cerebral US findings or familial clinical history. However, interpretation of MRI can be tricky and the resulting diagnosis occurs late within the pregnancy. Copyright © 2005 John Wiley & Sons, Ltd.

Published
2005

5. O201 HIGH DOSE TRANEXAMIC ACID REDUCES BLOOD LOSS IN POST-PARTUM HAEMORRHAGE

Author

Laurent Mandelbrot, B. Jude, Nadia Tillouche, Cyril Huissoud, Anne-Sophie Ducloy-Bouthors, S. Fontaine, S. Susen, H. Keita-meyer, F. Broisin, and Alain Duhamel

Subjects
Blood loss, business.industry, Anesthesia, Obstetrics and Gynecology, Medicine, General Medicine, business, Tranexamic acid, Post partum, medicine.drug
Published
2012

6. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage

Author

Anne-Sophie Ducloy-Bouthors, Laurent Mandelbrot, Hawa Keita-Meyer, Sandrine Depret-Mosser, Cyril Huissoud, Brigitte Jude, Nadia Tillouche, Sophie Susen, Sylvie Fontaine, Françoise Le Goueff, Benoit Vallet, F. Broisin, and Alain Duhamel

Subjects
Adult, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Loading dose, law.invention, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, Pregnancy, Antifibrinolytic agent, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Dose-Response Relationship, Drug, Vaginal delivery, business.industry, Research, Postpartum Hemorrhage, medicine.disease, Antifibrinolytic Agents, 3. Good health, Treatment Outcome, Tranexamic Acid, Anesthesia, Injections, Intravenous, Female, Packed red blood cells, business, Tranexamic acid, medicine.drug
Abstract

Introduction Our purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss. Methods This was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures. Results A total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03). Conclusions This study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH. Trial registration Controlled Trials ISRCTN09968140.

Published
2011

7. 0.11a Tranexamic acid reduces blood loss in post-partum haemorrhage

Author

H. Keita-meyer, S. Fontaine, Laurent Mandelbrot, Brigitte Jude, Cyril Huissoud, S. Depret-Mosser, S. Susenr, F. le Goueff, Nadia Tillouche, Anne-Sophie Ducloy-Bouthors, F. Broisin, and A. Duhameir

Subjects
Blood loss, business.industry, Anesthesia, medicine, Hematology, business, Tranexamic acid, Post partum, medicine.drug
Published
2011

8. Postpartum acute renal failure: a multicenter study of risk factors in patients admitted to ICU

Author

Marie Jonard, Maryse Aucourt, Virginie Mignaux, Nadia Tillouche, Anne-Sophie Ducloy-Bouthors, Gaëlle Gasan, Eileen M Boyle, Mercé Jourdain, and François Fourrier

Subjects
medicine.medical_specialty, Tranexamic acid, Hyperoncotic albumin, HELLP syndrome, medicine.medical_treatment, Critical Care and Intensive Care Medicine, Postpartum haemorrhage, Acute renal failure, Pregnancy, Anesthesiology, Postpartum Acute Renal Failure, Intensive care, Internal medicine, medicine, Renal replacement therapy, business.industry, Research, medicine.disease, Surgery, Postpartum complications, business, Postpartum period, medicine.drug
Abstract

Background Even in developed countries, severe specific pregnancy complications may occur in the immediate postpartum period and require admission to the ICU. The characteristics and risk factors of acute renal failure (ARF) induced by these complications and their treatments are not well known. Methods We performed a retrospective multicenter study in three intensive care departments linked to level III maternity wards in the north of France. All patients admitted to ICU for postpartum complications over a 5-year period (2008 to 2012) were included. Clinical and biological data, delivery characteristics, type of complications, and treatments were compared by univariate and multivariate analyses according to the occurrence and severity of ARF. Results One hundred eighty-two patients admitted to ICU for postpartum complications were included in the study. Sixty-eight patients (37%) developed an ARF: 49 with a low or medium severity and 19 with a severe ARF requiring renal replacement therapy. Hemolysis, elevated liver enzyme, and low platelet count (HELLP) syndrome on its own (p = 0.047) or combined with postpartum haemorrhage (p = 0.003), previous treatment by hyperoncotic albumin infusion (p = 0.001) and blockade of fibrinolysis by tranexamic acid (p = 0.03), was associated with secondary ARF. By multivariate analysis, the only independent factors were the association of HELLP syndrome with postpartum haemorrhage and the use of hyperoncotic albumin infusion. Conclusions HELLP syndrome associated with postpartum haemorrhage induces a high risk of ARF in the complicated postpartum setting. A particular attention should be given to treatments that could worsen the kidney function in that situation.

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9. Tocolysis in the management of preterm prelabor rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM)

Author

Elsa Lorthe, Gilles Kayem, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Geneva University Hospitals and Geneva University, Service de Gynécologie-Obstétrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), OCOPROM Study Group and the GROG (Groupe de Recherche en Obstétrique et Gynécologie): Gilles Kayem, Elsa Lorthe, Pierre-Yves Ancel, Hendy Abdoul, Nelly Briand, Blandine Lehmann, Clémence Cabanne, Stéphane Marret, Laurence Foix l'Hélias, François Goffinet, Thomas Schmitz, Caroline Charlier, Fanny Autret, Elie Azria, Jadot Balitalike, Kareen Billiemaz, Caroline Bohec, Pascal Bolot, Marie Bornes, Hanane Bouchghoul, Malek Bourennane, Florence Bretelle, Lionel Carbillon, Christine Castel, Céline Chauleur, Romain Corroenne, Karen Coste, Valérie Datin-Dorrière, Raoul Desbriere, Luc Desfrere, Michel Dreyfus, Marc Dommergues, Xavier Durrmeyer, Géraldine Favrais, Cyril Flamant, Denis Gallot, Julie Gries, Bassam Haddad, Laure Julé, Cécile Laffaille, Jacques Lepercq, Emmanuelle Letamendia, Fanny de Marcillac, Caroline Miler, Olivier Morel, Karine Norbert, Franck Perrotin, Christophe Poncelet, Laurent Renesme, Claire Roumegoux, Patrick Rozenberg, Mireille Ruiz, Loïc Sentilhes, Jeanne Sibiude, Damien Subtil, Nadia Tillouche, Héloïse Torchin, Barthélémy Tosello, Eric Verspyck, Alexandre Vivanti, Norbert Winer, Malbec, Odile, and Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
medicine.medical_specialty, Nifedipine, [SDV]Life Sciences [q-bio], Reproductive medicine, Tocolysis, Placebo, law.invention, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Pregnancy, 030225 pediatrics, medicine, Clinical endpoint, Rupture of membranes, media_common.cataloged_instance, European union, media_common, Preterm prelabor rupture of membranes, business.industry, Obstetrics, Obstetrics and Gynecology, Preterm birth, Gynecology and obstetrics, Neonatal outcome, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], RG1-991, Gestation, business, 030217 neurology & neurosurgery
Abstract

Background Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation. Methods A randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 220/7 and 336/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle. Discussion This trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year. Trial registration ClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).

Published
2021

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