Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized non-inferiority trial - 28/02/24

Doi : 10.1016/j.ajog.2024.02.002

Olivier Baud, PhD ^a,^b,^⁎ , Loic Sentilhes, MD ^c, Moreno Ursino, PhD ^d,^e,^f, Muriel Doret-Dion, MD ^g, Corinne Alberti, PhD ^d,^h, Camille Aupiais, MD ^h,ⁱ, Thomas Schmitz, MD ^j,^k
On behalf of the
BETADOSE trial study group and the GROG (Groupe de Recherche en Obstétrique et Gynécologie)
^a Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva, University of Geneva, Geneva, Switzerland
^b Université Paris Cité, Inserm U1141, Paris, France
^c Department of Obstetrics and Gynecology, Bordeaux University Hospital, Bordeaux, France
^d Clinical Epidemiology Unit, CIC-EC 1426, Robert Debré Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
^e Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France
^f HeKA, Inria Paris, Paris, France
^g Department of Obstetrics and Gynecology, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France
^h Université Paris Cité, Inserm U1123, ECEVE, Paris, France
ⁱ Pediatric Emergency Department, Jean Verdier Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Paris Nord University, Paris, France
^j Department of Obstetrics and Gynecology, Robert Debré Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
^k Université Paris Cité, Centre for Research in Epidemiology and Statistics (CRESS), Inserm, INRAE, Paris, France

^∗Corresponding author: Olivier Baud, PhD.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Wednesday 28 February 2024

Abstract

Background

Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated.

Objective

This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes.

Study Design

We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia.

Results

After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, −5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial.

Conclusion

In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings.

Le texte complet de cet article est disponible en PDF.

Video

(9.1 Mo)

Le texte complet de cet article est disponible en PDF.

Key words : antenatal steroids, betamethasone dose reduction, neonatal morbidities, very preterm neonates

Plan

Introduction

Materials and Methods

Study design and participants

Primary and secondary outcomes

Results in the context of what is known

Clinical and research implications

Strengths and limitations

Conclusion

	Clinical trial registration
	Date of registration: September 13, 2016
	Date of initial participant enrollment: January 2, 2017
	Clinical trial identification number: ClinicalTrials.gov, NCT02897076
	URL of the registration site: NCT02897076
	O.B. reports receiving consulting fees from Aguettant; T.S. receiving consulting fees from Dilafor; and L.S. receiving consulting fees from Dilafor, lecture fees from Bayer, GSK, and Sigvaris, and lecture and consulting fees from Ferring Pharmaceuticals.
	This study was funded by the French Ministry of Health.
	Data sharing
	Data sharing requests will be considered by the management group upon written request to the corresponding author. Deidentified participant data or other prespecified data will be available, subject to a written proposal and a signed data sharing agreement.
	Cite this article as: Baud O, Sentilhes L, Ursino M, et al. Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized noninferiority trial. Am J Obstet Gynecol 2024;XX:x.ex–x.ex.