Corticosteroids Deemed Safe in Pregnancy but Questions Linger

CHAPEL HILL, N.C., Sept. 19 -- Repeat courses of prenatal corticosteroids, commonly used to speed fetal lung development if there's risk of premature delivery, appear not to hinder mental or physical development.

Two large trials that provided the original evidence of benefit for early lung function and other outcomes with repeat dosing showed no excess impairment in infant growth, neurocognitive development, blood pressure, respiratory morbidity, or behavior through age two.

However, the follow-up analyses reported in the Sept. 20 issue of the New England Journal of Medicine did offer some reason for caution.

Children exposed to repeat corticosteroid doses tended to have higher risk for cerebral palsy in one trial (relative risk 5.7, P=0.12) and more attention problems in the other (P=0.04).

Overall, both studies offered reassurance, but further follow-up of the children through school age is needed, commented Alan D. Stiles, M.D., of the University of North Carolina at Chapel Hill, in an accompanying editorial.

Meanwhile, "if a decision is made to give repeat courses of corticosteroids, it may be prudent to consider the use of lower doses," he said.

"In all cases, we should inform parents of the limited data on long-term outcomes and should follow survivors for long-term neurodevelopmental outcomes," Dr. Stiles added.

In the National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units (MFMU) Network study, Ronald J. Wapner, M.D., of Columbia University, and colleagues, followed 486 children to a corrected age of 29.3 months on average.

In the study, women between 23 and 31 weeks' gestation at high risk for spontaneous preterm delivery and who had already received one course of corticosteroids were randomized to weekly courses of two intramuscular injections of 12 mg betamethasone or placebo given 24 hours apart.

Repeat dosing was restricted during the study to four courses because of theoretical safety concerns.

At follow-up, there were no significant differences between groups in any outcome except that cerebral palsy tended to be more common after repeat dosing (2.9% versus 0.5%, RR 5.7, 95% confidence interval 0.7 to 46.7).

Notably, all but one of the six children with cerebral palsy in the repeat-treatment group had been exposed to a total of five or more courses of corticosteroids, which "raises the possibility of a threshold or dose-response effect," the researchers said.

And, "even more troubling," five of the six were born after at least 34 weeks' gestation, "when cerebral palsy is less likely" and four had normal ultrasound examinations of the head.

Because of this potential harm and lack of long-term benefit in the study, Dr. Wapner's group recommended against more than a single course of prenatal corticosteroids for women at risk of preterm delivery.

But the researchers in Australian Collaborative Trial of Repeat Doses of Steroids came to the opposite conclusion.

In this trial, Caroline A. Crowther, M.D., of the University of Adelaide in Adelaide, Australia, and colleagues, randomized at-risk women who had already had one course of corticosteroids to a lower weekly intramuscular dose -- 11.4 mg once per course -- of betamethasone or placebo.

In follow-up of 1,047 children at a corrected age of two years, there were no significant differences between groups for any outcomes, except attention problems in the range warranting clinical attention. These were more common with repeat dosing (6.0% versus 3.2%, adjusted RR 1.87, P=0.04).

This "may have been a chance finding, since it represents a difference in the sum of five items in a 100-item standardized test," but animal studies have suggested a similar problem, Dr. Crowther and colleagues noted.

They recommended in favor of repeat courses for women who remain at risk for preterm delivery.

However, both groups were unanimous in acknowledging a need for further follow-up.

"Since neurosensory abilities at two years of age are of limited predictive value, particularly for more subtle problems," Dr. Crowther and colleagues concluded, "follow-up of these children is warranted later in childhood, when other important cognitive outcomes, such as executive function, can be determined more completely."

One researcher in Dr. Wapner's group reported receiving consulting fees from Columbia Laboratories, but none of the other researchers or Dr. Stiles reported conflicts of interest.