Reproductive Health · 1972
Antenatal corticosteroids for fetal lung maturation (Liggins and Howie trial)
Preterm birth was, through most of the twentieth century, a death sentence for infants delivered before 32 weeks. Respiratory distress syndrome, caused by insufficient pulmonary surfactant in the immature type II pneumocyte, accounted for the majority of deaths in this group. Neonatologists could support ventilation once the infant was born, but preventing the lung injury itself required acting before delivery. The physiological mechanism had been worked out in animal models during the 1960s: glucocorticoids accelerate surfactant synthesis, and fetuses of corticosteroid-treated pregnant animals survived premature delivery at rates that controls did not.
Graham Liggins, an obstetrician in Auckland, New Zealand, had observed the accelerated lung maturation effect serendipitously in sheep experiments. He and pediatrician Ross Howie designed a randomized controlled trial to test the clinical translation. Between 1969 and 1974 they enrolled 282 mothers threatening preterm delivery before 37 weeks at National Women's Hospital in Auckland, assigning them to intramuscular betamethasone or placebo. The primary analysis was published in Pediatrics in 1972, before recruitment was complete, because the interim results were compelling enough to report.
Respiratory distress syndrome fell from 25.8 percent in the placebo group to 9.0 percent in the betamethasone group. Early neonatal death dropped from 15.0 percent to 3.2 percent. The magnitude of those reductions, in a condition where the alternative was largely supportive care with high fatality, was larger than any single pharmacological intervention had achieved in neonatal medicine before or since. The treatment window mattered: benefit was greatest when at least 24 to 48 hours elapsed between the first dose and delivery.
Despite those numbers, adoption was slow. A decade after the trial, surveys found that the majority of eligible preterm deliveries in the United States were not receiving antenatal steroids. Clinicians raised concerns about immunosuppression, growth effects with repeated courses, and whether the New Zealand results would generalize to other settings. It took a 1994 NIH consensus development conference, which reviewed the accumulated evidence and declared omission of treatment in eligible patients unjustifiable, to drive widespread implementation in high-income countries.
Betamethasone for threatened preterm birth is now on the WHO list of essential medicines and is standard of care in obstetrics worldwide for gestations between approximately 24 and 34 weeks. Subsequent research refined the recommendations: repeat courses were found to carry risks that single courses do not, and the treatment interval and gestational age boundaries were specified more precisely. Liggins received numerous honors before his death in 2010, and the 1972 Pediatrics paper remains among the most frequently cited studies in neonatal medicine.
Key People
- Graham Liggins — New Zealand obstetrician who designed and led the betamethasone RCT.
- Ross Howie — Co-investigator and co-author of the 1972 Pediatrics trial.
Pediatrics, 1972
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