Antenatal Corticosteroids: Fresh Answers to Old Questions

Giving corticosteroids to pregnant women at risk for preterm birth before 34 weeks of gestational age has been the standard of care since the 1990s, but a few scenarios for their use remain up for debate. Two studies presented this week at the 2023 annual meeting of the Society for Maternal and Fetal Medicine (SMFM) provided some fresh insight into the practice that could help clinicians better manage pregnant patients.

Neurodevelopmental Outcomes in Late Preterm

First, should antenatal corticosteroids (ACS) be given to mothers who present with late preterm labor, defined as 34-36 weeks gestational age?

A landmark randomized clinical trial published in 2016 demonstrated that use of ACS in mothers in late preterm labor reduced severe respiratory complications. That practice has largely been adopted by clinicians. The only downside, according to the researchers, was that infants whose mothers received steroid therapy were more likely to develop hypoglycemia. The condition is self-limiting, but studies have raised concern about the potential long-term risk of neurocognitive or psychological outcomes in infants with hypoglycemia.

Dr Cynthia Gyamfi-Bannerman

Cynthia Gyamfi-Bannerman, MD, MSc, endowed chair and professor of obstetrics, gynecology, and reproductive sciences at University of California San Diego, led the 2016 study. Her team was unable to secure funding for their originally planned follow-up study of the infants 2 years later. But once the American College of Obstetricians and Gynecologists (ACOG) endorsed the practice and more women received ACS in the late preterm period, Gyamfi-Bannerman and her colleagues felt the need to "follow up the infants just to see what the outcomes are from a neurodevelopmental standpoint," she said.

Gyamfi-Bannerman and colleagues recruited children older than age 6 from the original trial whose parents were willing to have them participate in a follow-up study. A total of 949 from the initial 2831 cohort completed cognitive testing and received assessments for cerebral palsy, social impairment within the autism spectrum, and behavioral and emotional problems.

At the SMFM conference, Gyamfi-Bannerman reported no differences in the primary outcome of cognitive function between those whose mothers had received a single course of betamethasone and those who did not, or any differences in rates of the other outcomes.

Kathy Zhang-Rutledge, MD, a maternal-fetal medicine specialist who practices with Obstetrix Maternal Fetal Medicine Group of Houston, part of Pediatrix Medical Group, said she was glad to see a study that addressed the potential long-term adverse events associated with ACS in the late preterm period.

"Having this pretty large study — with really good neurological testing results — should help reassure clinicians that this is something they should consider adopting in their practice," Zhang-Rutledge said.

Are Boosters Better?

The second unresolved question was if a repeat course of ACS should be administered when a woman at risk for preterm birth receives a course of steroids but does not deliver in the following 7 days.

Any benefits to the initial course of ACS wear off after a week. As a result, clinicians often give booster courses 7 days after the first dose if the infant is likely to be delivered in the following week. A 2009 study showed this approach may protect infants from respiratory problems, but data on long-term outcomes have been weak.

ACOG guidelines say to "consider" a booster dose in women who are less than 34 weeks' gestation at risk for preterm delivery within 7 days.

The exception is when the mother already has experienced preterm prelabor rupture of membranes (PPROM), because ACS may increase the risk for infection for both mother and child. ACOG doesn't take a stand on use of booster doses for PPROM, citing a lack of data to show that potential benefits outweigh the potential risks of this approach.

A recent multicenter, double-blinded, randomized clinical trial attempted to fill that void in knowledge. Between 2016 and 2022, 194 women with PPROM and gestational age less than 32 weeks who had received an initial ACS course at least 7 days prior to randomization received a booster course of ACS or saline placebo.

"Our primary outcome was designed to be like the prior rescue study (in 2009) that we did with patients with intact membranes," said Andrew Combs, MD, PhD, a maternal-fetal medicine specialist at Pediatrix Medical Group in Sunrise, Florida, who participated in the earlier study. "It was a composite of neonatal morbidity that was any one of a variety of outcomes including respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death."

The primary outcome occurred in 64% of women who received booster ACS and 66% with placebo (odds ratio 0.82, 95% CI, 0.43 - 1.57), according to Combs, who presented the findings at SMFM.

Although the study was not powered to detect significant differences in specific outcomes, the rate of neonatal sepsis was not higher in the ACS group, suggesting that ACS may be safe if membranes have ruptured, the researchers reported. But because the booster course of ACS did not prevent respiratory morbidity, clinicians may wonder what to do with the findings.

Niraj Chavan, MD, an associate professor in the Department of Obstetrics, Gynecology and Women's Health at St. Louis University, St. Louis, Missouri, said he was unsure how the study would affect clinical practice.

The relatively small sample number of patients prevented analysis of specific outcomes and subgroup analyses of important variables such as race, ethnicity, gestational age, and other comorbid conditions in the mothers, he said. So clinicians still must weigh potential risks and benefits on a case-by-case basis.

"You have to think about it in buckets," he said, "One is conditions that would increase the risk for neonatal morbidity. The other is the risk for infection, both for the mom and the baby."

But for Combs, the interpretation of the findings was simpler: "We concluded that there's no indication to give a booster course of steroids after a week has elapsed in patients with ruptured membranes."

The study presented by Gyamfi- Bannerman was funded by the National Institute of Child Health and Human Development. The study presented by Combs was funded by MEDNAX Center for Research, Education and Quality, which in 2022 was renamed Pediatrix Center for Research, Education and Quality. Combs is an employee of Pediatrix Medical Group but has no conflicts of interest. Gyamfi- Bannerman , Zhang-Rutledge, and Chavan report no relevant financial relationships.

Society for Maternal-Fetal Medicine 43rd Annual Meeting 2023. Abstract LB02. Presented February 9, 2023.
Society for Maternal-Fetal Medicine 43rd Annual Meeting 2023. Abstract LB07. Presented February 10, 2023.

Ann Thomas is a pediatrician and epidemiologist in Portland, Oregon.

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