DALLAS — Multiple courses of antenatal corticosteroids did not offer additional benefits to infants born to mothers at high risk of preterm delivery, and were associated with significantly smaller birth weight, birth length, and head circumference in a phase IV study of 1,858 women.
In 2000, the National Institutes of Health reaffirmed that a single course of antenatal corticosteroids should be considered for pregnant women between 24 and 34 weeks of gestation who are at risk for preterm delivery within 7 days, but concluded that the data available at that time were inadequate to argue for or against repeat or rescue courses of antenatal corticosteroids (ACS) for fetal maturation.
Treatment consists of two doses of 12 mg betamethasone given intramuscularly 24 hours apart or four doses of 6 mg betamethasone given intramuscularly 12 hours apart.
In their latest October 2007 Guidelines for Perinatal Care, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics advise that “repeated corticosteroid courses should not be used routinely because clinical trials show decreased brain size, decreased birth weight, and adrenal insufficiency in neonates exposed to repeated doses.”
In the current study, the primary composite outcome of mortality, severe respiratory distress syndrome, grade 3–4 intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis was similar between infants born to women who received multiple courses of corticosteroids (12.9%) and those born to women receiving placebo (12.5%) after an initial course of corticosteroids. The odds ratio was 1.04.
The rate of still births also was not significantly different between groups (43 vs. 40, OR 1.08), principal investigator Dr. Kellie Murphy reported on behalf of the Women in the Multiple Courses of Antenatal Corticosteroids or Preterm Birth Study (MACS) group at the annual meeting of the Society for Maternal-Fetal Medicine.
The interventional study was conducted at 80 centers and included women at 26–30 weeks of gestation who remained at high risk for early delivery 14 or more days after being given a single course of ACS. At randomization, 937 received two doses of 12 mg betamethasone intramuscularly 24 hours apart every 14 days until 33 6/7 weeks or delivery and 921 received placebo. The mean age in both groups was 29 years.
The 1,164 babies born to women in the repeat-corticosteroid group weighed less (2,216 g vs. 2,330 g), were shorter (44.5 cm vs. 45.4 cm), and had a smaller head circumference (31.1 cm vs. 31.7 cm), compared with the 1,140 babies born to mothers in the placebo group. All the differences were statistically significant.
“What was surprising to us is that even though the majority of patients, 70%, received only one or two [additional] doses, which one wouldn't think was a large amount, there was still a significant decrease in all those parameters,” said Dr. Murphy, a perinatologist at Mount Sinai Hospital, Toronto.
In all, 385 women received one additional course, 305 received two additional courses, and 247 received three to five courses.
An unplanned ad hoc analysis of infants born less than 7 days after study drug exposure and those born less at than 32 weeks' gestational age showed no significant difference in the primary composite outcome between groups.
Dr. Murphy acknowledged during the question-and-answer session that the MACS findings are quite different from those of the recent Australian ACTORDS study in which repeat doses of antenatal steroids reduced neonatal morbidity without changes in body size or survival free of neurosensory disability at 2 years (N. Engl. J. Med. 2007;357:1179–89).
That study used a single intramuscular injection of betamethasone 11.4 mg repeated weekly, not times two; the definition of respiratory distress syndrome was slightly different; and z-scores were used to determine outcomes—all of which may account for the different findings, she said.
The MACS group concluded that multiple courses of ACS should not be given every 14 days to women at increased risk of preterm birth after receiving an initial course. When asked by an audience member about the efficacy of a single course of ACS, Dr. Murphy replied, “I still believe that it is efficacious and beneficial.”
The study was funded by the Canadian Institutes of Health Research. Dr. Murphy disclosed no relevant financial conflicts of interest.