Study findings warrant caution in administering antenatal corticosteroids

Findings from a systematic review and meta-analysis of long-term outcomes associated with preterm exposure to antenatal corticosteroids suggest that the timing and dose of administration “should be carefully considered,” researchers said.

The review found that children born extremely preterm who were exposed to a single course of the antenatal corticosteroids betamethasone or dexamethasone had a significantly lower risk for neurodevelopmental impairment. However, children born late preterm or at full term experienced a significantly higher risk for adverse neurocognitive and/or psychological outcomes if they were exposed to single course.

“Given that approximately half of children who were exposed to antenatal corticosteroids exceeded expectations and were born at or after 35 weeks of gestation, we aimed to conduct a systematic review and meta-analysis of long-term outcomes in all children as well as children with preterm (ie, born before 37 weeks of gestation) and full-term (ie, born at or after 37 weeks of gestation) birth,” Sarah McDonald, MD, MSc, professor of obstetrics and gynecology and Canada research chair at McMaster University, and colleagues wrote.

McDonald said some of the findings surprised the researchers.

“We anticipated that a single course of antenatal corticosteroids would be beneficial compared to no steroids in children born extremely preterm, but we were surprised by a few findings,” McDonald told Healio. “[We were surprised] that in children born late and that the use of antenatal steroids was associated with increased adjusted risks of neurocognitive/psychological harm. We were [also] surprised that approximately half of children who are exposed preterm to antenatal corticosteroids exceed expectations and are born at term — but this reflects that preterm birth is very challenging to predict.”

The researchers assessed more than 340 randomized clinical trials, quasi-randomized clinical trials and cohort studies published from 2000 through October 2021 that examined long-term neurodevelopmental, psychological, or other outcomes among children aged 1 year or older who had preterm exposure to antenatal corticosteroids,

They included 30 studies in the final analysis, which included more than 1.25 million children who were at least 1 year old.

From the studies, they found that exposure to a single course of antenatal corticosteroids for children with extremely preterm birth was associated with “a significant reduction in risk of neurodevelopmental impairment” (adjusted OR = 0.69 [95% CI, 0.57-0.84]).

They also found that for children born late preterm, exposure to antenatal corticosteroids was associated with higher risks for investigation for neurocognitive disorders (adjusted HR = 1.12 [95% CI, 1.05-1.20]).

Among children born at full term, exposure to antenatal corticosteroids was associated with a higher risk for mental or behavioral disorders (aHR = 1.47 [95% CI, 1.36-1.60]) and proven or suspected neurocognitive disorders (aHR = 1.16 [95% CI, 1.10-1.21]).

“The findings suggest a need for caution in administering antenatal corticosteroids,” the authors wrote.

McDonald said she hopes the study will give pediatricians a better understanding of the risks of corticosteroids.

“Despite some significant benefits for children born extremely preterm, caution may be required in administering antenatal steroids, given that the appropriate dose has never been established, and animal studies suggest that the dose being used is 2 to 10 times higher than needed,” McDonald said. “Further research on the correct dose of and timing of antenatal corticosteroids is critically important.”

In an accompanying editorial, Andrea F. Duncan, MD, MSCR and Daniel T. Malleske, MD, MS, of The Children’s Hospital of Philadelphia’ division of neonatology; and Nathalie L. Maitre, MD, PhD of the division of neonatology in the department of pediatrics at Emory University in Atlanta, said the timing of antenatal corticosteroids “has long been discussed and, along with dose and gestational age, defines the optimal medication delivery.”

“For the risk of late-preterm birth, a single, carefully timed course of antenatal corticosteroids may also be administered,” they wrote. “Administration of repeated antenatal corticosteroid courses is somewhat controversial, with as many detractors as there are proponents. Antenatal corticosteroids may sometimes be used before 24 weeks’ gestation, depending on a family’s decision and preferences, but is not recommended as standard of care.”

They noted the main finding that children born preterm after antenatal corticosteroid administration had significantly lower adjusted odds of neurodevelopmental impairment but that children born at term after antenatal corticosteroid administration had significantly higher adjusted risks for neurodevelopmental impairment.

“Medical teams and families always hope and strive for a term birth despite preterm pregnancy complications,” they wrote. “Yet term birth after antenatal corticosteroid administration may confer safety risks on long-term fetal development: courses of specific postnatal corticosteroids are known to adversely affect neurodevelopmental outcomes. Therefore, it is possible that receipt of antenatal corticosteroids during a term pregnancy may itself disrupt a complex cascade of developmental gene activation and predispose children to worse development in early childhood.”

They said meta-analyses of research “can help move the field forward.”

“Far from being useless, these reports can impel neonatal researchers to develop new medication approaches and design innovative trial methodologies,” they wrote. “Neonatal science is still an emerging field compared with the millenia of trial and error in adult medicine. Future studies of antenatal corticosteroid management will likely be challenging but critically important in charting an appropriate course forward.”

Reference:

Duncan A, et al. JAMA Pediatrics. 2022;doi: 10.1001/jamapediatrics.2022.0480.

Ninan K, et al. JAMA Pediatrics. 2022;doi:10.1001/jamapediatrics.2022.0483.