Rescue Course of Antenatal Corticosteroids
Abstract & Commentary
By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis: A recent study supports another investigation suggesting the benefit of a rescue dose of antenatal corticosteroids in patients who will deliver prior to 35 weeks and have had more than 2 weeks elapse after their initial course of therapy.
Source: McEvoy C, et al. Respiratory compliance in preterm infants after a single rescue course of antenatal steroids. Am J Obstet Gynecol 2010;202:544.e1-9.
In 1972, liggins and howie demonstrated that antenatal corticosteroids (ACS) stimulated the production of surfactant in premature human fetuses.1 Since then, it has been accepted that steroids in particular, betamethasone and dexamethasone can reduce the incidence of respiratory distress syndrome (RDS) in preterm infants if given prior to 35 weeks. However, it has not been completely clear how often it can be given to attain its greatest effectiveness, with minimal risk.
McEvoy et al just published a randomized trial that dealt with the efficacy of giving a "rescue" course of betamethasone 2 weeks or more past the initial dosage and prior to 35 weeks' gestation. Rather than gathering large enough numbers of patients to show differences in the rates of respiratory distress syndrome (RDS), they concentrated on two indices of respiratory compliance in the neonate. The study included patients who had an initial course of steroids after 24 weeks.
Forty-four mothers delivering 56 infants (twins were included), all of whom had gotten an initial dose of betamethasone between 24 weeks and 32 weeks, were randomly assigned to receive a two-injection rescue course of betamethasone. Another 41 mothers and 57 infants were given placebos. Both study groups received their study drugs more than 2 weeks after the initial dose. In the end, there were 49 infants in each group that could be tested at about 20 hours post-delivery for passive respiratory compliance (Crs) and functional residual capacity (FRC).
Fewer infants in the treated group had RDS, but, not surprisingly, based on the small numbers of patients involved, the difference was not statistically significant. However, significantly fewer infants in the treated group needed > 30% oxygen or 40% oxygen than controls (13% vs 29%, and 9% vs 23%). Although there were no significant differences in groups for FRC, there was an 18% improvement in Crs in the treated group, demonstrating improved compliance.
The results in those delivered prior to 34 weeks showed an even greater difference in RDS, oxygen requirements, and Crs (a 30% difference).
Commentary
There is now adequate evidence that ACS diminishes the incidence of RDS and associated neonatal morbidity if given before 35 weeks. However, when some studies suggested a loss of its effect after 1 week, there was a movement to respond to the adage "if some is good, more is better," by giving weekly courses of ACS until 34 weeks. The concept was backed up by data from a Cochrane review by Crowther et al,2 which showed a reduction of the severity of the disease when ACS was administered weekly, compared with a single course. However, based on the concept that ACS could suppress DNA synthesis, and evidence that fetal lambs exposed to ACS had a dose-dependent decrease in birth weight, there was a renewed effort to evaluate possible side effects for repeated doses of ACS. In the Cochrane review of 2007, there was only one randomized trial showing a reduction in average birth weight with repeated dosage, but there were two studies that suggested a higher rate of infants born with birth weights below the 10th percentile. One randomized trial addressed long-term follow-up at 2-3 years of age in children exposed to repeated dosage, compared with a single dose.3 There were no differences between the groups with regard to body size, blood pressure, respiratory morbidity, or behavior scores. However, there was a greater tendency for the repeated-dose children to have "attention problems." Another randomized trial conducted by the NIH Perinatal Network had a similar study design.4 Five hundred fifty-six infants, whose mothers, after a standard dose of ACS, were randomized in the same way, underwent neurological testing at 2-3 years of age. There were no differences in Bayley scores between the above groups at age 2-3 years. However, although the numbers were small, there was a higher rate of cerebral palsy (CP) in the repeated-dose group (6 children), compared with the single-dose group (1 child).
Now there are at least two studies underscoring the rationale for a single rescue course of ACS being used as a substitute for repeated dosage. Garite et al demonstrated a 50% decrease in combined neonatal morbidity with a rescue dose after 2 weeks, compared with placebo.5 Also, in the featured study above, McEvoy et al, in addition to showing a better response to respiratory function testing with a rescue dose after 2 weeks, found no differences in head circumferences or birth weight between groups.
As of now, here is what is known about the risks and benefits of ACS:
- There is evidence to back up its efficacy before 35 weeks, but the evidence is shaky at best after that time.
- It seems that more than one dose is needed for maximal benefit if delivery does not occur within 2 weeks of the initial dose.
- Even if the patient delivers within 48 hours of the first injection, there may be some benefit from ACS.
- There is no solid evidence to indicate any long-term ill effects of ACS, in general. However, based on the potential DNA effect, the animal data noted above, and some unresolved concerns about CP and attention deficits, a rescue dose of ACS seems to be a better option than weekly ACS in patients who show signs of delivering prior to 35 weeks.
- Although along the way it has been subject to some tinkering, the standard dosage of betamethasone is 12 mg every 24 hours × 2. Dexamethasone seems to be a suitable substitute, and was used during a period of time when betamethasone was not available in many hospitals.
References
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-525.
- Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory distress. Cochrane Database Syst Rev 2007;3:CD003935.
- Crowther CA, et al. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1179-1189.
- Wapner RJ, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1190-1198.
- Garite TJ, et al; for the Obstetrix Collaborative Research Network. Impact of a 'rescue course' of corticosteroids. Am J Obstet Gynecol 2009;200:248.e1-9.
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