Lowering Antenatal Betamethasone Dose Misses in Randomized Trial

Cutting the dose of antenatal betamethasone in half was not equivalent to full-dose antenatal betamethasone when it came to needing to treat respiratory distress in very preterm infants, findings from the randomized BETADOSE trial showed.

Among more than 3,000 neonates in the intention to treat (ITT) analysis, 20% of newborns in the half-dose group required exogenous intratracheal surfactant within 2 days of birth, as compared to 17.5% of those in the full-dose group, which failed to meet criteria for noninferiority (2.4% risk difference, 95% CI -0.3 to 5.2), reported Thomas Schmitz, MD, of Assistance Publique-Hôpitaux de Paris, and colleagues in The Lancet.

There were no differences between the study groups in rates of neonatal death, severe intraventricular hemorrhage, necrotizing enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia, the authors stated.

“Our results do not support practice changes towards antenatal betamethasone dose reduction,” wrote Schmitz and colleagues, noting that most outcomes related to the severity of respiratory illness within the first 2 days of life “tended to disfavor the half-dose group.”

Administration of antenatal corticosteroids among women at risk for preterm birth is standard global practice, although some studies have shown that the medications are associated with poor neurodevelopmental outcomes, suggesting that the current dosing might be too high.

In an accompanying comment, Nir Melamed, MD, MSc, and Elizabeth Asztalos, MD, MSc, both of the University of Toronto, said that the true difference between the half-dose and full-dose groups may be even greater than these primary findings show, underestimating the true effect of full-dose betamethasone. This conclusion was supported by greater differences in need for respiratory distress interventions between the two groups based on administration timing and gestational age, they added.

“It should be recognized that the study might underestimate the true biological differences between the two regimens, and that its findings might not be generalized to settings where the timing of antenatal corticosteroids is better,” said Melamed and Asztalos.

They noted that “antenatal corticosteroids remain the most effective intervention to improve the outcomes of preterm infants, even in the current era of neonatal care,” and added that the current study is a “major step towards making this intervention safer.”

BETADOSE (Reduction of Antenatal Betamethasone Dose) was a randomized, double-blind, noninferiority trial conducted in 37 perinatal care centers in France. From January 2017 to October 2019, a total of 3,244 pregnant women (median age 31; median body mass index 23) at risk of preterm delivery were randomized to either the half-dose or full-dose regimen.

All participants received a first 11.4 mg-dose injection of antenatal betamethasone before 32 weeks’ gestation. Women in the half-dose group received a placebo for their second shot while those in the full-dose group got an additional 11.4-mg betamethasone injection. Along with the primary outcome — need for exogenous intratracheal surfactant within 2 days of birth — investigators also looked at other adverse neonatal outcomes, safety endpoints, and conducted subgroup analyses stratified by gestational age.

Results in the per-protocol analysis for the primary outcome were consistent with those in the ITT analysis.

Secondary respiratory outcomes and prematurity-related outcomes did not differ significantly between the two groups. Also, a post-hoc analysis based on timing of the first betamethasone injection and birth suggested that a half dose was inferior to the full-dose regimen when birth occurred 7 days after the first shot — an optimal window for betamethasone administration — with an 11% risk difference (95% CI 2.3-19.8) for the primary outcome.

Schmitz and colleagues acknowledged that the primary outcome may only represent a short-term surrogate that only partly reflects the illness of the neonate, which may have limited these findings.

The researchers said the data were a good step towards understanding the benefits and risks of antenatal betamethasone on infants, but the results of the follow-up study of these infants at age 5 will better describe the potential effects of reduced fetal exposure to antenatal corticosteroids on early childhood development.