Antenatal Steroids For Possible Premature Delivery -

Cochrane

The story began in the late 1960s, when Graham ('Mont') Liggins returned to New Zealand from the USA, with a grant to study pregnancy and birth in sheep. Premature birth was of great interest at the time. Liggins had the idea that the fetus might be producing something that triggered premature labour, possibly steroid hormones. He set about testing the effects of different steroids on pregnancy.

Serendipity then intervened. Liggins routinely carried out post-mortems, and he noticed a striking difference in the lungs of two fetal sheep. As Liggins's co-worker Ross Howie describes:

"I still remember the excitement I felt[?]when he handed me the lungs of twin lambs for pressure ? volume studies. The lambs had been delivered very early: one had been infused with glucocorticoids and the other not. Lungs of the infused lamb were perfectly stable after inflation: pink, fluffy and floated in water. In total contrast, the lungs of the other remained solid and liver-like and sank."

At the time, premature birth was a big problem. An infant's underdeveloped lungs left it gasping for air ? respiratory distress that could be fatal or caused permanent brain damage, typically cerebral palsy. Many people were trying to extend pregnancy, to give the infant lungs more time to develop. But what if steroids could accelerate development of the fetal lungs? A baby born prematurely would then have a much greater chance of survival. Liggins immediately realised his chance discovery had clinical potential.

As it happened, Auckland was the ideal place for the research to progress. Liggins was eager to try clinical studies, and he needed to work with a clinician. At the time, Ross Howie was the only paediatrician in the whole of New Zealand who could artificially respirate premature babies. The two set about designing a clinical trial to test the effects of a single injection of steroids in mothers undergoing premature labour ? a conceptually simple randomised controlled trial, half the mothers getting steroids, half a placebo.

Within a few months the trial had begun. The results were crystal clear. More babies were surviving and staying healthy in the treated group. Prenatal steroids were working.

Given that the new treatment was saving babies' lives, one might have expected a rapturous reception for the results. But nothing of the sort happened. The Lancet rejected the paper. Ross Howie recalled the reaction of the Royal College of Obstetricians andGynaecologists in 1972: "They didn?t want to know."

Not that the work was completely ignored. Avery and others began similar studies, in experimental animals and humans. A large trial was coordinated by the US National Institutes of Health (NIH).

Dissemination

Working in Dublin at the time was a young obstetrician, Patricia Crowley. Just as the steroid work was breaking, a premature baby in her care died due to respiratory distress. She became an early convert to steroid treatment and began collecting papers published on the topic (a laborious manual process in those pre-database days). She published a review in a new publication, the Journal of Obstetrics and Gynaecology, a cost?benefit analysis of prenatal steroids (an approach she puts down to the fact she was dating an economist at the time).

At the same time, Iain Chalmers in Oxford was growing convinced of the need for systematic reviews of the literature, to inform clinical practice. He had grown increasingly alarmed at the number of medical calamities that could have been avoided had already published knowledge been applied.

Chalmers established the Cochrane Collaboration to promulgate 'evidence-based medicine?', particularly evidence derived from randomised controlled trials. Moreover, the concept of 'meta-analysis' had emerged in the mid-1970s, a way of pooling data from multiple trials; by themselves, clinical trials (particularly small ones) may throw up spurious associations.

Crowley led the systematic review of prenatal steroid use, covering eight large trials. Again, the results could not have been clearer: steroids had a reproducible beneficial effect. A graphic representation of this study became the Cochrane Centre's logo.

Finally, things began to accelerate. In Birmingham in the 1980s, Professor Richard Lilford was a convert to evidence-based medicine. He suggested to the board of the Royal College of Obstetricians andGynaecologists that it should promote good practice by producing clinical guidelines. To his surprise, they agreed. He drew together a group that spent a long day trawling through a database on perinatal medicine established in Oxford. The group proposed 21 guidelines, in order of clarity of benefit. Number 2 in the list were prenatal steroids.

The guidelines seemed to do the trick. Published in 1992, almost overnight they led to a huge change in clinical practice.

The Effectiveness of Corticosteroids.

Respiratory Distress Syndrome, RDS, is affects 40?50% of babies born before 32 weeks.  Liggins and Howie⁷²⁰¹ published the classic paper in1972 demonstrating that the antenatal administration of corticosteroids prior to preterm delivery reduces the incidence of RDS.

In a metaanalysis of 18 trials⁰⁰⁰¹ data on over 3700 babies were included was analysed. Antenatal administration of 24 milligrams of betamethasone, of 24 milligrams of dexamethasone, or two grams of hydrocortisone to women expected to give birth preterm was associated with a significant reduction in mortality (odds ratio 0.60), respiratory distress syndrome (odds ratio 0.53) and intraventricular haemorrhage in preterm infants. These benefits extended to a broad range of gestational ages and were not limited by gender or race.

The combined use of prenatal corticosteroids, when indicated, and postnatal surfactant improves neonatal outcome.⁹³⁰¹

After 34 weeks 94 women will need to be treated to prevent one case of RDS, while before 31 weeks one case of RDS is prevented for every five women treated.

The effect of treatment is optimal if the baby is delivered more than 24 hours and less than seven days after the start of treatment. However, there is a trend towards benefit in babies delivered before and after the optimal treatment interval has elapsed.

Neonates at 23 weeks of gestation whose mothers complete a course of antenatal corticosteroids had an associated 82% reduction in odds of death.⁰⁸⁰¹

The value of steroids when the membranes have ruptured (PROM) has been called into question particularly in babies weighing < 1000 g.^{9601, 9901} Vermillion et al⁹⁹⁰² found that multiple courses, but not single courses, of antenatal betamethasone administered to patients with preterm premature rupture of membranes were associated with an increased risk of early-onset neonatal sepsis development. Others have produced similarly reassuring evidence on the safety and effectiveness of steroids in the presence of PROM.^{9602, 9903, 0001, 0101}

One study reported no difference in risks for death or major morbidity for the very low birth weight neonates between corticosteroid exposed singleton and multiple infants.0201 Others,^{9904, 0203} however, have found that antenatal steroid therapy did not reduce the incidence of RDS in multiple gestation. Ballabh et al⁰²⁰² concluded that the shorter half-life of betamethasone in twin pregnancy than in singleton pregnancy could cause the level of betamethasone to be sub-therapeutic for lung maturation in twin pregnancy.

A study with very large numbers of preterm twins would be required to demonstrate a statistically significant reduction in perinatal morbidity.