In 1972, Drs. Liggins and Howie published their landmark study demonstrating that antenatal corticosteroids administered to women 24-36 weeks of gestation reduced the incidence of respiratory distress syndrome and neonatal mortality. Liggins had previously noted that lambs, treated with intrafetal ACTH, cortisol, or dexamethasone, delivered prematurely, and sacrificed, demonstrated partially expanded lungs.
Such alveolar stability was not typically noted until later in gestation. It suggested to Liggins that glucocorticoids might cause premature liberation of surfactant into the alveoli and served as the basis for his study. In the trial, the most significant difference in the incidence of respiratory distress syndrome among those treated vs. not treated with corticosteroids occurred in those gestations less than 32 weeks.
Although those gestations treated between 32 and 37 weeks exhibited a decreased incidence of respiratory distress, the number did not reach statistical significance. Nevertheless, even at that time, Liggins postulated that mechanisms in addition to enhanced surfactant production and release might be responsible for the improved pulmonary function noted in more advanced gestations treated with antenatal corticosteroids.
Interestingly, despite the findings of the initial study and similar results in multiple subsequent studies , the 1994 NIH Consensus report on the effect of corticosteroids for fetal maturation on perinatal outcomes found that only 20% of women who delivered newborns 501-1500 grams received the benefit of antenatal steroids. After a thorough review of available evidence, including 12 year neurodevelopmental follow up showing no adverse outcomes, the Consensus Panel felt the benefits of antenatal administration of corticosteroids vastly outweigh the risks and all fetuses between 24 and 34 weeks gestation at risk of preterm delivery should be considered candidates for antenatal treatment.
Only in those few pregnancies where corticosteroids would have an adverse effect on the mother or delivery was imminent should steroid treatment be withheld. In addition, although Grade 1 evidence existed at the time to support the use of antenatal corticosteroids for gestations greater than 34 weeks, it was judged insufficient to recommend their use.
Since the Consensus statement, the use of antenatal corticosteroid use has become common and has resulted in considerable reduction in mortality and morbidity, as well as total health care costs. In addition, further neurodevelopmental follow up, including the original Auckland steroid trial participants, continues to demonstrate no adverse effects on psychological functioning and health-related quality of life. Other studies have demonstrated a decrease in overall respiratory disease in infants born beyond 34 weeks who had previously been exposed to antenatal corticosteroids when compared to unexposed infants born at similar gestations.
More than 300,000 pregnancies deliver in the late preterm period (34 0/7 – 36 6/7 weeks gestation) each year in the United States. Seventy per cent of Intensive Care Nursery admissions are late preterm newborns. Their increasing numbers and the broad range and severity of respiratory disorders with which they present beg for a re-evaluation of antenatal corticosteroid use in this range of gestations. This is especially appropriate with a better understanding of the multiple actions of corticosteroids as gestation approaches term.
A recent study, titled Antenatal Late Preterm Steroids (ALPS), a Randomized Trial to Reduce Neonatal Respiratory Morbidity, was published in The New England Journal of Medicine in April, 2016. The study enrolled over 2800 women with singleton pregnancies at high risk for late preterm delivery.
The participants were randomized to receive antenatal betamethasone by injection or a matching placebo. Greater than 80% of women in the trial delivered prior to 37 weeks gestation. The primary outcome was a neonatal composite of treatment in the first 72 hours (CPAP or High Flow Nasal Cannula for at least 2 hours, supplemental oxygen with fraction of inspired oxygen of at least 0.3 for at least 4 hours, mechanical ventilation, or ECMO) or stillbirth or neonatal death within 72 hours of birth.
The study found a significant decrease in neonatal respiratory complications in the group given the steroid treatment (11.6% vs. 14.4%). In addition, severe respiratory complications occurred significantly less frequently in the betamethasone group. The incidence of neonatal hypoglycemia was increased in those treated with betamethasone (24% vs. 14.9%), but no other adverse neonatal outcomes were noted between the groups.
The study is authoritative due to its size, generalizability, and methodologic rigor. Although the issue of long term follow up cannot be specifically addressed, follow up studies of similar treatment in earlier gestations are reassuring. Late preterm births comprise a high risk group for hypoglycemia regardless of maternal antenatal steroid treatment and warrant vigilant monitoring during the newborn period. In sum, the findings of the Antental Late Preterm Steroids study are consistent with other randomized controlled trials of antenatal corticosteroids administered at gestations less than 34 weeks.
Both the American College of Obstetrics and Gynecology with an endorsement by the American Academy of Pediatrics and the Society for Maternal-Fetal Medicine have addressed and published recommendations based on the study’s findings. Although the recommendations do not establish exclusive standards of care, the organizations approve the use of antenatal corticosteroids in certain defined late preterm pregnancies. It is only with thoughtful application of the recommendations and further studies that the efficacy and safety of antenatal steroids in the late preterm pregnancy will be realized. It is a significant start.
