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Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE).
BMC Pregnancy Childbirth. 2019 Feb 12; 19(1):67.BP

Abstract

BACKGROUND

Although antenatal betamethasone is recommended worldwide for women at risk of preterm delivery, concerns persist regarding the long-term effects associated with this treatment. Indeed, adverse events, mainly dose-related, have been reported. The current recommended dose of antenatal betamethasone directly derives from sheep experiments performed in the late 60's and has not been challenged in 45 years. Therefore, randomized trials evaluating novel dose regimens are urgently needed.

METHODS

A randomised, double blind, placebo-controlled, non-inferiority trial will be performed in 37 French level 3 maternity units. Women with a singleton pregnancy at risk of preterm delivery before 32 weeks of gestation having already received a first 11.4 mg injection of betamethasone will be randomised to receive either a second injection of 11.4 mg betamethasone (full dose arm) or placebo (half dose arm) administered intramuscularly 24 h after the first injection. The primary binary outcome will be the occurrence of severe respiratory distress syndrome (RDS), defined as the need for exogenous intra-tracheal surfactant in the first 48 h of life. Considering that 20% of the pregnant women receiving the full dose regimen would have a neonate with severe RDS, 1571 patients in each treatment group are required to show that the half dose regimen is not inferior to the full dose, that is the difference in severe RDS rate do not exceed 4% (corresponding to a Relative Risk of 20%), with a 1-sided 2.5% type-1 error and a 80% power. Interim analyses will be done after every 300 neonates who reach the primary outcome on the basis of intention-to-treat, using a group-sequential non-inferiority design.

DISCUSSION

If the 50% reduced antenatal betamethasone dose is shown to be non-inferior to the full dose to prevent severe RDS associated with preterm birth, then it should be used consistently in women at risk of preterm delivery and would be of great importance to their children.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT 02897076 (registration date 09/13/2016).

Authors+Show Affiliations

Service de Gynécologie Obstétrique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 48 boulevard Sérurier, 75019, Paris, France. thomas.schmitz@aphp.fr. Université Paris Diderot, Site Villemin, 10 avenue de Verdun, 75010, Paris, France. thomas.schmitz@aphp.fr. Inserm, U1153, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center, Obstetrical, Perinatal and Pediatric Epidemiology Team, 53 avenue de l'observatoire, 75014, Paris, France. thomas.schmitz@aphp.fr.Université Paris Diderot, Site Villemin, 10 avenue de Verdun, 75010, Paris, France. Unité d'épidémiologie clinique, CIC-EC 1426, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, 48 boulevard Sérurier, 75019, Paris, France. Inserm, U1123, ECEVE, 10 avenue de Verdun, 75010, Paris, France.Inserm, U1138, Equipe 22, Sorbonne Université, Université Paris Descartes, 75006, Paris, France.Service de néonatalogie, Hôpitaux universitaires de Genève, 32 boulevard de la Cluse, 1205, Genève, Switzerland. Inserm, U1141, Hôpital Robert Debré, 48 boulevard Sérurier, 75019, Paris, France.Université Paris Diderot, Site Villemin, 10 avenue de Verdun, 75010, Paris, France. Inserm, U1123, ECEVE, 10 avenue de Verdun, 75010, Paris, France. Inserm, U1138, Equipe 22, Sorbonne Université, Université Paris Descartes, 75006, Paris, France. Service d'Accueil des Urgences Pédiatriques, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, 48 boulevard Sérurier, 75019, Paris, France.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30755164

Citation

Schmitz, Thomas, et al. "Full Versus Half Dose of Antenatal Betamethasone to Prevent Severe Neonatal Respiratory Distress Syndrome Associated With Preterm Birth: Study Protocol for a Randomised, Multicenter, Double Blind, Placebo-controlled, Non-inferiority Trial (BETADOSE)." BMC Pregnancy and Childbirth, vol. 19, no. 1, 2019, p. 67.
Schmitz T, Alberti C, Ursino M, et al. Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). BMC Pregnancy Childbirth. 2019;19(1):67.
Schmitz, T., Alberti, C., Ursino, M., Baud, O., & Aupiais, C. (2019). Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). BMC Pregnancy and Childbirth, 19(1), 67. https://doi.org/10.1186/s12884-019-2206-x
Schmitz T, et al. Full Versus Half Dose of Antenatal Betamethasone to Prevent Severe Neonatal Respiratory Distress Syndrome Associated With Preterm Birth: Study Protocol for a Randomised, Multicenter, Double Blind, Placebo-controlled, Non-inferiority Trial (BETADOSE). BMC Pregnancy Childbirth. 2019 Feb 12;19(1):67. PubMed PMID: 30755164.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). AU - Schmitz,Thomas, AU - Alberti,Corinne, AU - Ursino,Moreno, AU - Baud,Olivier, AU - Aupiais,Camille, AU - ,, Y1 - 2019/02/12/ PY - 2018/09/25/received PY - 2019/01/28/accepted PY - 2019/2/14/entrez PY - 2019/2/14/pubmed PY - 2019/6/4/medline KW - Antenatal betamethasone KW - Antenatal corticosteroids KW - Non-inferiority KW - Preterm birth KW - Preterm delivery KW - Respiratory distress syndrome SP - 67 EP - 67 JF - BMC pregnancy and childbirth JO - BMC Pregnancy Childbirth VL - 19 IS - 1 N2 - BACKGROUND: Although antenatal betamethasone is recommended worldwide for women at risk of preterm delivery, concerns persist regarding the long-term effects associated with this treatment. Indeed, adverse events, mainly dose-related, have been reported. The current recommended dose of antenatal betamethasone directly derives from sheep experiments performed in the late 60's and has not been challenged in 45 years. Therefore, randomized trials evaluating novel dose regimens are urgently needed. METHODS: A randomised, double blind, placebo-controlled, non-inferiority trial will be performed in 37 French level 3 maternity units. Women with a singleton pregnancy at risk of preterm delivery before 32 weeks of gestation having already received a first 11.4 mg injection of betamethasone will be randomised to receive either a second injection of 11.4 mg betamethasone (full dose arm) or placebo (half dose arm) administered intramuscularly 24 h after the first injection. The primary binary outcome will be the occurrence of severe respiratory distress syndrome (RDS), defined as the need for exogenous intra-tracheal surfactant in the first 48 h of life. Considering that 20% of the pregnant women receiving the full dose regimen would have a neonate with severe RDS, 1571 patients in each treatment group are required to show that the half dose regimen is not inferior to the full dose, that is the difference in severe RDS rate do not exceed 4% (corresponding to a Relative Risk of 20%), with a 1-sided 2.5% type-1 error and a 80% power. Interim analyses will be done after every 300 neonates who reach the primary outcome on the basis of intention-to-treat, using a group-sequential non-inferiority design. DISCUSSION: If the 50% reduced antenatal betamethasone dose is shown to be non-inferior to the full dose to prevent severe RDS associated with preterm birth, then it should be used consistently in women at risk of preterm delivery and would be of great importance to their children. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT 02897076 (registration date 09/13/2016). SN - 1471-2393 UR - https://www.unboundmedicine.com/medline/citation/30755164/Full_versus_half_dose_of_antenatal_betamethasone_to_prevent_severe_neonatal_respiratory_distress_syndrome_associated_with_preterm_birth:_study_protocol_for_a_randomised_multicenter_double_blind_placebo_controlled_non_inferiority_trial__BETADOSE__ L2 - https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-019-2206-x DB - PRIME DP - Unbound Medicine ER -