The results of the highly anticipated Antenatal Late Preterm Study recently have become available.1 Data from this randomized controlled trial, conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network, demonstrated that administration of betamethasone to women at risk for preterm delivery between 34 weeks 0 days and 36 weeks 6 days of gestation significantly reduces the rate of neonatal respiratory complications. It may represent the largest study of antenatal corticosteroids (ACS) to date, with 2,827 infants studied, and its results inevitably lead to the logical practical question: Should ACS use be extended beyond the 34 weeks’ gestation limit previously recommended by professional guidelines in the United States2?
There are some issues that bear discussion before such a significant change in standard of care should be promoted.2
The primary outcome in the study was a composite end point describing the need for respiratory support within 72 hours after birth. Based on a pilot study, the investigators had anticipated a 33% decrease in the rate of the primary outcome; however, the reduction was only 20% (relative risk [RR], 0.80; 95% confidence interval [CI], 0.66−0.97). Although the effect size was statistically significant, one could question the clinical relevance of such a small difference.
A 33% reduction effect, more consistent with the preliminary expectations, was noted in the prespecified secondary composite outcome of severe respiratory complications (RR, 0.67; 95% CI, 0.53−0.84). Occurrences included in the secondary composite outcome that also showed significant rate reductions were:
- the use of continuous positive airway pressure (CPAP) or high-flow oxygen via nasal cannula for at least 12 hours (RR, 0.62; 95% CI, 0.48−0.80)
- need for resuscitation at birth (RR, 0.78; 95% CI, 0.66−0.92)
- surfactant use (RR, 0.59; 95% CI, 0.37−0.96)
- transient tachypnea of the newborn (RR, 0.68; 95% CI, 0.53−0.87).
The reported reduction in bronchopulmonary dysplasia (RR, 0.22; 95% CI, 0.02−0.92) cannot plausibly be attributed to ACS. Randomized data aggregated by the Cochrane Database of Systematic Reviews3 do not show improvement in chronic lung disease with ACS use. Moreover, the authors recognize that the assessment for bronchopulmonary dysplasia at only 28 days of life is only partially informative and that longer childhood follow-up is required to confirm the finding.
Your patient’s baby is between 34 weeks’ and 36 weeks’ 5 days’ gestational age. As her physician, you should explain to your patient that the decision not to expose her baby to corticosteroids at this gestational age is based upon the following:
- Although corticosteroids have been shown to reduce the risk of the baby needing breathing support by 20%, they are associated with a 60% increase in risk for low blood sugar in the newborn (hypoglycemia). Hypoglycemia can place the baby at risk for seizures and even brain damage.
- There is an unknown safety profile for corticosteroid administration at this gestational age. The fetal brain is still developing during this period, and there is some information to suggest that corticosteroids could have an unfavorable effect on brain development.
- Corticosteroids are potent hormones and potentially can have undesired hormonal effects at this gestational age.
- If corticosteroids are given and the mother carries the baby to term (37 weeks or later) there are some studies that suggest the baby is at an increased risk for neurologic, cognitive, metabolic, and/or behavioral abnormalities in later life.
We propose prudence with ACS use after 34 weeks’ gestation for the following reasons: the increased risk for neonatal hypoglycemia associated with ACS, the increased risk for ACS-related harm in term-born babies, and safety concerns with ACS in the late preterm period.
The most profound effect modification observed in the study was an adverse effect—namely, a 60% increase in neonatal hypoglycemia with ACS administration (RR, 1.6; 95% CI, 1.37−1.87). The rate of neonatal hypoglycemia was 24% in the ACS group, compared with 15% in the placebo group.
Results of prior studies have demonstrated either no increased risk of hypoglycemia with ACS use4−7 or a much smaller increase (from 4.2% to 5.7%).8 The higher rate of neonatal hypoglycemia seen in this study suggests the possibility that the late preterm population may be more vulnerable to the negative impact of ACS on neonatal glucose/insulin homeostasis. Presumed mechanisms of action are either maternal hyperglycemia or fetal adrenal suppression or both, with potential for fetal adrenal suppression resulting from betamethasone exposure to affect long-term metabolic outcomes.9
