A Controlled Trial of Antepartum Glucocorticoid Treatment for Prevention of the Respiratory Distress Syndrome in Premature Infants, by G. C. Liggins, MB, PhD, FRCOG, and R. N. Howie, MB, MRACP, Pediatrics, 1972;50:515–525
A controlled trial of betamethasone therapy was carried out in 282 mothers in whom premature delivery threatened or was planned before 37 weeks' gestation, in the hope of reducing the incidence of neonatal respiratory distress syndrome by accelerating functional maturation of the fetal lung. A total of 213 mothers were in spontaneous premature labor. When necessary, ethanol or salbutamol infusions were used to delay delivery while steroid or placebo therapy was given. Delay for at least 24 hours was achieved in 77% of the mothers. In these unplanned deliveries, early neonatal mortality was 3.2% in the treated group and 15.0% in the control subjects. There were no deaths with hyaline membrane disease or intraventricular cerebral hemorrhage in infants of mothers who had received betamethasone for at least 24 hours before delivery. The respiratory distress syndrome occurred less often in treated babies (9.0%) than in controls (25.8%), but the difference was confined to babies of <32 weeks' gestation who had been treated for at least 24 hours before delivery (11.8% of the treated babies compared with 69.6% of the control babies). There may be an increased risk of fetal death in pregnancies complicated by severe hypertension–edema–proteinuria syndromes and treated with betamethasone, but no other hazard of steroid therapy was noted.
We conclude that this preliminary evidence justifies additional trials, but that additional work is needed before any new routine procedure is established.
The first controlled trial of antepartum glucocorticoids for prevention of respiratory distress syndrome launched more than 25 years of exploration of the hormonal regulation of lung maturation and the optimal means of achieving it in premature infants. Sir Graham Liggins, an obstetrician, and Ross Howie, a neonatologist, in Auckland, New Zealand, tested whether antenatal glucocorticoids given to the mother within 48 to 72 hours before a planned delivery could accelerate fetal lung maturation and prevent deaths from respiratory distress syndrome (also known as hyaline membrane disease).1From December 1969 to early 1972, they embarked on a prospective, blinded, controlled, clinical trial based on Liggins experience with premature delivery of fetal lambs infused with glucocorticoids. In 1969, Liggins had published the observation that such an intervention promoted early onset of labor in the ewe, but the newborn premature lambs, delivered at 117 to 123 days' gestation, had partial aeration of lungs from spontaneous ventilation.2
Meanwhile, deLemos and colleagues at Johns Hopkins, confirmed the observation of Liggins in twin fetal lambs, one of which received dexamethasone and the other saline. The dexamethasone-treated animals all had lungs with accelerated appearance of pulmonary surfactants at least a week earlier than did controls.3
The translation of these findings in lambs to the clinical setting accomplished in New Zealand in 1972, to routine care elsewhere, was slow, for readily understood reasons.4 Most obstetricians were concerned about the appearance of delayed adverse effects on fetal tissues and were reluctant to use steroids before follow-up studies could be reviewed. There also was a question of efficacy in infants born before 32 weeks' gestation, who were not represented in the New Zealand study (average gestational age at delivery, 249 days in treated group, 225 in controls). Many other groups, including the Ballards, found synthetic steroid administration optimal between 26 and 34 weeks.5
Another reason for delay in acceptance of antenatal glucocorticoid therapy was failure of the Collaborative Group on Antenatal Steroid Therapy in 1981 to show efficacy in males or in Caucasian subgroups. Overall, no complications were cited, but the limited benefit in a large multicenter study was discouraging. By 1982, the New Zealand group provided the crucial follow-up of 6-year-old children whose mothers had been treated antenatally with betamethasone,6and by 1984, the Collaborative Group on Antenatal Steroid Therapy reported that no detectable growth or physical, motor, or developmental deficiencies were identified in the first 3 years of life that could be attributed to steroid therapy.7
In the 1990s, additional perspectives on antenatal glucocorticoids, summarized by Jobe and coworkers in 1993,8showed that the combined use of antenatal glucocorticoids and surfactant replacement therapy was better than either alone, and if a choice had to be made, glucocorticoids conferred the greater benefit. By 1994, the National Institutes of Health Consensus Conference, complete with meta-analyses, established the efficacy of glucocorticoids as well as their cost benefit.9 By 1996, the impact on survival of preterm infants by glucocorticoids and surfactant replacement therapy contributed to the lowest neonatal mortality in the United States in history.10
It was a long road from the publication by a New Zealand obstetrician/endocrinologist interested in parturition to life-saving interventions on behalf of preterm infants. The next step will be to reduce preterm births.
- Liggins GC,
- Howie RN
- Liggins GC
- MacArthur BA,
- Howie RN,
- Dezoete JA,
- Elkins J
- Avery ME
- ↵Guyer B, Martin JA, MacDorman MF, Anderson RN, Strobino DM. Annual summary of vital statistics—1996. Pediatrics. 1997;100:905–918
- Copyright © 1998 American Academy of Pediatrics