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


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.

This study, led by GCIR member Professor Olivier Baud, 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.

They 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, they 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.

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.

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Why is it important?

Antenatal corticosteroids given to women at risk of preterm birth are recommended worldwide to prevent complications in preterm infants, such as respiratory distress syndrome, brain haemorrhages and intestinal problems. The current dosage of these corticosteroids was established more than 50 years ago and has not changed, despite advances in medical care for preterm infants. Previous studies have shown that prenatal steroid exposure can affect the development of various organs and systems in the child, which can lead to long-term behavioural problems.

In light of these findings, the authors of this work aimed to see if administering half the usual dose of corticosteroids could still prevent these complications while reducing the potential long-term side effects on the child's development.

The study found that there was no significant difference in outcomes between infants who received the full dose and those who received half the dose of steroids. This suggests that using a lower dose may be safe for the newborn when discharged from hospital. However, more research is needed to fully understand their long-term effects on the child's development.

To learn more…

What is meant by a post hoc analysis of a randomised non-inferiority trial?

A "post hoc analysis" refers to an examination or evaluation of data that was not specified or planned in advance in the original design of a study. In other words, it is an analysis conducted after the data have been collected, often in response to observations or questions that arise during or after the study.

In this context, a "randomised non-inferiority trial" is a type of clinical trial in which participants are randomly assigned to different treatment groups, and the objective is to demonstrate that a new treatment is not significantly worse than an existing treatment by more than a predefined margin of "non-inferiority", usually defined by expert consensus.

So when someone talks about a "post hoc analysis of a randomised non-inferiority trial", they are analysing data from a study that was originally designed to compare the efficacy or safety of different treatments with a focus on non-inferiority, but are now conducting additional analyses that were not originally planned. These analyses might bring new insights complementary to main analysis by exploring secondary outcomes, subgroup analyses, or other aspects of the data that were not part of the original study protocol.

1 Mar 2024