Antenatal Corticosteroids for Preterm Birth
The discovery of antenatal corticosteroids emerged from experimental work in reproductive endocrinology, not from clinical observation. Graham Liggins, investigating the hormonal triggers of parturition in a sheep model, serendipitously discovered that preterm lambs exposed to corticosteroids in utero had structurally more mature lungs than expected, were viable at an earlier gestational age, and had less severe respiratory distress at birth. Recognizing the potential clinical implications, Liggins collaborated with neonatologist Ross Howie to translate this finding into a human trial.
Liggins and Howie devised a randomized, placebo-controlled trial and began enrolling women in 1969. The first report, covering 282 women, was published in Pediatrics in 1972 — having initially been rejected by The Lancet on the grounds that it “lacked general interest.”The results were substantial. Early neonatal mortality fell from 15% to 3%, and the incidence of respiratory distress syndrome (RDS) from 26% to 9%. The two-injection regimen of 12 mg betamethasone administered 24 hours apart was selected empirically; despite decades of subsequent use, this dosing schedule has never been subjected to rigorous dose-finding trials.
Despite the quality of the evidence, for two decades relatively few preterm infants benefited from antenatal steroid treatment. Concerns about potential adverse effects and reservations about the trial methodology caused many clinicians to be hesitant to adopt the therapy into routine practice. In 1990, Patricia Crowley published a pivotal systematic review. This meta-analysis of 12 randomized controlled trials demonstrated that antenatal corticosteroids significantly reduced RDS, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and overall neonatal mortality.
The NIH convened a consensus conference in 1994 to formally assess the evidence. Citing a meta-analysis of 15 randomized controlled trials, the panel concluded that antenatal corticosteroids significantly reduced neonatal mortality, RDS, and IVH without proven short- or long-term risks, and recommended their administration to all women between 24 and 34 weeks of gestation at risk of preterm delivery. ACOG’s endorsement of these recommendations produced a marked and rapid increase in utilization, and it was considered the standard of care in the US and Europe from 1994 forward.
However, following the 1994 recommendations, repeat and weekly courses became common practice when preterm delivery did not occur after an initial treatment. Animal studies through the late 1990s — particularly sheep studies led by John Newnham and Alan Jobe — demonstrated adverse effects of repeated antenatal corticosteroids on fetal growth and neurological development, raising significant concern. The NIH reconvened in August 2000 and concluded that while a single course retained unequivocal support, available data were insufficient to justify routine use of repeat or rescue courses, which should be reserved for patients enrolled in clinical trials.
For decades, the 34–36 week gestational window was considered insufficiently high-risk to warrant treatment. The 1994 recommendation had not been extended to women at risk of delivery after 34 weeks. This changed with the publication of the ALPS trial in 2016. Guided by results of this large multicenter randomized trial, ACOG issued a practice advisory that betamethasone may be considered for singleton pregnancies between 34 0/7 and 36 6/7 weeks at imminent risk of preterm birth within seven days.
Current ACOG guidance recommends a single course of corticosteroids for women between 24 0/7 and 33 6/7 weeks at risk of preterm delivery within seven days, including those with ruptured membranes and multiple gestations. Administration may also be considered from 23 0/7 weeks based on family decisions regarding resuscitation. Planned multiple courses are not recommended.
Several questions remain active areas of investigation. The overall efficacy of antenatal corticosteroid therapy is highly variable even when preterm risk is accurately assessed; the treatment regimens in common use are largely empirical; and dosing is suprapharmacologic relative to effect. Large population-based retrospective studies have identified associations between antenatal corticosteroid exposure and childhood mental health disorders and neonatal infection, findings that have prompted calls for a third NIH Consensus Conference to reassess the full risk-benefit profile.
Antenatal corticosteroids represent one of the most impactful interventions in the history of perinatal medicine — a therapy born from serendipity in an Auckland sheep shed that, more than five decades later, is administered to hundreds of thousands of pregnant women annually worldwide.
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972 Oct;50(4):515-25. PMID: 4561295.
- Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol. 1990 Jan;97(1):11-25. doi: 10.1111/j.1471-0528.1990.tb01711.x. PMID: 2137711.
- Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement. 1994 Feb 28-Mar 2;12(2):1-24. PMID: 7728157.
Last Updated on 04/05/26