Should we take another look at antenatal corticosteroids?
Potentially exposing hundreds of thousands of late preterm or term pregnancies in the United States alone to ACS is a significant shift from limiting use of the drugs to pregnancies <34 weeks. Following the publication of the ALPS trial and despite the lack of long-term safety data, the Society for Maternal-Fetal Medicine (SMFM) endorsed use of a single course of ACS in late preterm if delivery appears to be imminent.8 They also opined that risk of hypoglycemia could be minimized by routine glucose testing in late-preterm infants as endorsed by the American Academy of Pediatrics.9 The American College of Obstetricians and Gynecologists then expanded their guidelines to include gestations from 23 to 37 weeks.2 Neither organization has advocated for ACS use at term prior to cesarean delivery.
Perspective on safety
Do we have sufficient data to conclude that ACS administration to late preterm or term infants is safe? The field of medicine is full of examples of treatments that were introduced based on short-term outcomes and were later demonstrated to be harmful. In the SMFM consensus statement, 2 studies were cited as evidence of the safety of administering ACS in late preterm and term pregnancies.8 The first was ASTECS2 and the second was a 31-year follow-up of the original Liggins cohort.6,10 Of note, few participants in the original trial were randomized near or at term and there is no mention of when ACS was administered relative to outcomes on follow-up. A total of 192 adults participated (87 betamethasone group and 105 control group). The results were reassuring with regard to perceived long-term health benefits, cognitive performance, and psychiatric illnesses. A larger cohort also participated in cardiovascular follow-up at age 30, which was not cited by SMFM.11 At age 30, there were no major differences in cardiovascular health between betamethasone-exposed and control survivors, which is not surprising as most cardiovascular disease is seen in older adults. Risk factors for insulin resistance were significantly increased in betamethasone recipients. In these 2 studies,5,10 304 cases were exposed to a single course of betamethasone from 24 to 41 weeks’ gestation compared to 295 controls. Those numbers are insufficient to conclude ACS exposure in late preterm infants as safe, a fact that was acknowledged by SMFM with the comment “there is always the potential for unintended consequences with any change in long term practice.”8
In the very low birthweight baby, the majority of data when a single course of ACS therapy was administered prior to 34 weeks’ gestation demonstrates significant benefits in the short term, including potential improvements in long-term neurologic handicap (eg, cerebral palsy).3 However, when all neonates exposed in utero to a single course of ACS at 24–34 weeks’ gestation are considered, follow-up data do not suggest that the positive effects seen in the nursery persist long-term.10,11
The risk-benefit analysis for administering ACS at early gestational ages is not comparable to late preterm or term as the rates of morbidity and mortality are significantly lower at later gestational ages in non-anomalous fetuses. It should not be a surprise that administration of ACS prior to delivery near term or prior to cesarean at term decreased respiratory morbidity in both ASTECs and ALPS, as these studies had adequate power to detect small decreases in short-term respiratory problems in a low-risk population. The impact on a reduction in transient tachypnea of the newborn confirmed what was already known in animal models.12
The risks of administering ACS during late term and term remain unknown. Endogenous corticosteroids surge near term when the fetus is in a critical period of brain and other organ system development in preparation for parturition and transition to life ex utero.12-15 Additional exposure to ACS during the period at or near term is likely to have far greater consequences for normal brain development than at any other time in development. Between 34 weeks’ gestation and term, in a normal human pregnancy, the brain grows by 35%. Cortical volume increases by 50% and 25% of cerebellum development occurs during that time.3,14
Corticoids are crucial for normal development. “Overexposure of the fetus to ACS by using synthetic GC (betamethasone and dexamethasone) during certain stages of pregnancy can profoundly affect the development of the neuroendocrine system, which may lead to life-long effects on endocrine, behavioral, emotional, and cognitive function. These life-long effects on neuroendocrine function are associated with increased risks of developing a wide range or metabolic, cardiovascular, and brain disorders in later life.”14-17