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
SUMMARY
Antenatal 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. The authors of this article published in The Lancet and led by GCIR member Professor Olivier Baud investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.
They 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 foetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11路4 mg) before 32 weeks' gestation. They 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路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路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.
Findings: Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49路9%]) or the full-dose group (n=1624 [50路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路0%) of 1567 neonates in the half-dose group and 276 (17路5%) of 1574 neonates in the full-dose group (risk difference 2路4%, 95% CI -0路3 to 5路2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2路2%, 95% CI -0路6 to 5路1). No between-group differences appeared in the rates of neonatal death, grade 3-4 intraventricular haemorrhage, stage 鈮�2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.
Interpretation: Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, these results do not support practice changes towards antenatal betamethasone dose reduction.
Funding: French Ministry of Health.
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Why is this article important?
Antenatal corticosteroids, historically given to women at risk of preterm delivery to prevent respiratory distress syndrome, also reduce the incidence of intraventricular haemorrhage, necrotising enterocolitis, and neonatal death in preterm neonates. They are consequently recommended worldwide. In high-resource countries, a course of antenatal corticosteroids usually comprises two intramuscular 12 mg betamethasone injections 24 h apart, for a full dose of 24 mg. This dose regimen comes directly from the preclinical experiments reported by Liggins in the late 1960s and has not been challenged in randomised clinical trials, although indications for treatment and the subsequent number of exposed foetuses have been continuously rising in the past decade.
In a recent population-based retrospective cohort study that included 670鈥�097 children, antenatal steroids - exposed children had significantly higher cumulative incidence rates and hazards for any mental and behavioral disorder in a follow-up to 11 years compared with nonexposed children (hazard ratio, 1.33).
This article describes the first study that, by comparing 12鈥�24 mg of betamethasone, has evaluated a 50% dose reduction of antenatal corticosteroids.
The results showed a small disadvantage (2.4%) of half-dose antenatal betamethasone comparing to the full-dose regimen in preventing the need for exogenous intratracheal surfactant within 48 h after birth in the neonate. However, the betamethasone dose reduction did not result in higher incidences of neonatal mortality or major prematurity-related complications, even in extremely preterm infants.
Results of the 5-year follow-up of the infants enrolled in the trial, to assess the possible neurodevelopment effects of reducing foetal exposure to antenatal corticosteroids, are needed before deciding whether this 50% dose reduction could be recommended. Practice changes towards antenatal betamethasone dose reduction, currently not supported by these neonatal results, will then be reconsidered based on both short-term and long-term outcomes.
6 Sept 2022