Late-Preterm Infants Benefit From Pre-Birth Steroid Exposure

Real-world data on more than 700,000 births add to the evidence suggesting that exposure to steroids shortly before delivery is associated with a reduction in respiratory mortality among late-preterm newborns.

Findings from the cross-sectional analysis confirmed those of the pivotal Antenatal Late Preterm Steroid (ALPS) study, which showed a 20% reduction in the risk of respiratory complications among newborns born at gestational weeks 34 to 36.

The analysis, published in JAMA Network Open, also confirmed that the ALPS trial findings quickly changed clinical practice, with steroid exposure among late-preterm infants more than doubling in the U.S. in the 9 months after the study’s publication.

The recent analysis also showed a 9% decline in assisted ventilation among the population during the period.

"These findings suggest that there was an immediate change in practice of administering antenatal steroids and a reduction in neonatal morbidity among late preterm births associated with the dissemination of the ALPS trial, suggesting that this evidence may be translating into a reduction in immediate respiratory morbidity outside the context of a clinical trial," wrote researcher Mark A. Clapp, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues.

Corticosteroid exposure shortly before birth has long been recognized as a useful strategy for reducing respiratory complications and death in very preterm and preterm infants, due to the treatment’s mechanism of stimulating fetal lung surfactant production.

Prior to the 2016 publication of the ALPS study, led by Cynthia Gyamfi-Bannerman, MD, of the University of California San Diego Health, the practice was not widely used in late preterm deliveries, even though late-preterm infants have been shown to have a higher risk for respiratory complications than term infants born after 36 weeks’ gestation.

The publication of the ALPS findings led numerous obstetrics and gynecological organizations, including the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists (ACOG), to recommend steroid administration for pregnant women at risk for delivering late preterm.

The newly reported cross-sectional study was conducted "to understand whether publication of [the ALPS] study and the related updates to clinical guidelines were associated with real-world practice changes and changes in respiratory outcomes for neonates in the late-preterm period," Clapp and colleagues wrote.

"Leveraging a complete sample of late-preterm births in the U.S., we designed an interrupted time series study that evaluated the hypothesis that publication and dissemination of the ALPS trial findings would be associated with increased use of steroids in the late-preterm period and a corresponding reduction in respiratory morbidity in these neonates," they explained.

Using National Center for Health Statistics birth data collected from early February 2015 through October 2017, the researchers identified live, singleton newborns with gestational ages recorded as between 34 and 36 weeks (considered late-preterm) born to women without gestational diabetes.

The researchers studied the use of steroids prior to delivery among the late preterm infants during the 9-month period after the publication of the ALPS study (Feb. 1 to Oct. 16, 2016), which was considered the ALPS trial dissemination period for the purposes of the cross-sectional analysis.

"To conduct the interrupted time series analysis, we a priori selected a 12-month observational period before (Feb. 1, 2015, to Jan. 30, 2016) and after (Nov. 30, 2016, to Oct. 31, 2017) the dissemination period to quantify whether the trial was associated with changes in obstetric practice and neonatal outcomes," the researchers wrote.

The main study outcomes were steroid use, need for any assisted ventilation, and assisted ventilation use for more than 6 hours.

The adjusted rate of steroid use increased from 5.0% to 11.7% (adjusted incidence rate ratio [IRR]: 2.34; 95% CI: 2.13-2.57) compared with expected rates based on predissemination trends. In addition, assisted ventilation use also decreased, from 8.9% to 8.2% (adjusted IRR: 0.91; 95% CI: 0.85-0.98) after the dissemination period. Finally, there were no changes in the use of assisted ventilation use for more than 6 hours (adjusted IRR: 0.98; 95% CI: 087-1.10).

"Using a robust, quasi-experimental interrupted time series design and a complete sample of late-preterm births in the U.S., this study demonstrated that dissemination of the ALPS trial was associated with changes in obstetric practice and neonatal outcomes, the researchers wrote. "These findings were robust to various sensitivity analyses, and the adjustment for multiple potential confounders only reduced the uncertainty of the estimates, strengthening our confidence in the validity of the results."

The quasi-experimental design was cited by the researchers as a study strength.

"Although randomized clinical trials are often considered the criterion standard for determining causality, their translation into clinical practice can be limited because of issues with generalizability," they wrote. "The use of quasi-experimental methods, such as an interrupted time series analysis, can allow us to examine associations between the dissemination of new evidence and practice changes.

"In our study, we report an increase in steroid use and a decrease in immediate neonatal ventilation use after the release of new evidence without being able to discern the exact timing of steroid administration, the clinical circumstances in which they were administered, or the type and exact duration of assisted ventilation use; these findings enhance the external validity and generalizability of the ALPS trial’s findings."

Clapp and fellow researchers noted that clinical practice adoption of the guideline changes related to the ALPS findings occurred far more quickly than adoption of most other professional society recommendations related to new research.

"We hypothesize that this adoption may be related to the fact that this new evidence was a direct extension of an identical intervention for women with expected preterm deliveries at earlier than 34 weeks of gestation, increasing practitioner familiarity and comfort in adopting the recommendation," they wrote.

Study limitations cited by Clapp and colleagues included concerns about the "validity of certain birth certificate data elements," and the possibility that other practice changes occurring at the same time "coincided with the ALPS trial and that this concurrent change may have affected real or reported rates of assisted ventilation."

"More detailed information on the exposure and outcomes (e.g., exact timing, indications, and duration) would ideally be helpful in better isolating the effectiveness of this intervention, although such types of information are rarely available in population-based analyses," Clapp and colleagues wrote. "Of importance, we were unable to assess other short-term (e.g., neonatal hypoglycemia) or long-term (e.g., neurodevelopmental) outcomes of corticosteroid administration in the late-preterm period, which have been previously reported. Any potential benefit should be considered in tandem of potential reported risks."

Clapp reported serving as a scientific advisory board member and holding private equity in Delfina Care.

The ALPS study was funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

ALPS researcher Gyamfi-Bannerman received speaking fees and grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and speaking fees from Meleda unrelated to this research.

Clapp MA, et al "U.S. incidence of late-preterm steroid use and associated neonatal respiratory morbidity after publication of the antenatal late preterm steroids trial, 2015-2017" JAMA Netw Open 2022; DOI: 10.1001/jamanetworkopen.2022.12702.