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.RCOG
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.RCOG
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.RCOG
Neonates at 23 weeks of gestation whose mothers complete a course of
antenatal corticosteroids had an associated 82% reduction in odds of death.0801
Premature Rupture Of The
Memebranes (PROM).
|
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.
In a
study of 805 infants of diabetic mothers and 10,152 infants of non-diabetic
mothers the data were examined for a relation between maternal diabetes and
respiratory-distress syndrome of the newborn. The syndrome occurred in 23.4
per cent of the diabetic vs. 1.3 per cent of the non-diabetic group.7601
This may, however, have been attributable to confounding factors such
as gestational age and, with strict control, the incidence of RDS in babies
born to mothers with diabetes is not increased.8701
Women
with diabetes in pregnancy who are at risk of pre-term delivery should
receive antenatal corticosteroids in line with local protocols. If steroids
are clinically indicated for pre-term labour, inpatient supervision by an
experienced team is essential to regulate diabetic control.
SIGN
Studies of long-term outcome for children involved in antenatal steroid
administration for threatened premature labour are ressuring.8201,
8401,
0401and
this extends into adult life.0002,
0501,
0601,
0602
Dose and Route of
Adminisration.
|
A
large observational study suggested that antenatal exposure to
betamethasone, but not dexamethasone, is associated with a decreased risk of
cystic periventricular leucomalacia among premature infants born at 24?31
weeks of gestation.8701
In
the study by Egerman et al,9801
subjects at high risk for preterm delivery between 24 and 33 weeks'
gestation were prospectively randomly assigned to receive either 6 mg
intramuscular dexamethasone or 8 mg oral dexamethasone every 12 hours
for 4 doses. The regimen was repeated weekly until 34 weeks' gestation
if delivery had not yet occurred. The study was discontinued at 39%
enrollment after a blinded review of available outcomes. A total of 170
women with 188 fetuses were randomly assigned. The oral and
intramuscular groups had similar mean gestational ages at enrollment
(29.9 weeks vs 29.2 weeks) and similar median latencies (9.5 vs 10
days). No difference in the frequency of respiratory distress syndrome
was found between the oral and intramuscular groups, (34.3% vs 29.8%).
Neonatal sepsis (10.1% vs 1.2%, P =.01) and intraventricular hemorrhage
(10.1% vs 2. 4%, P =.04) were significantly higher in the oral group.
There were no statistical differences in the frequencies of necrotizing
enterocolitis or neonatal death. A subgroup analysis of 112 patients who
were delivered at <34 weeks' gestation revealed no statistical
difference in respiratory distress syndrome between the groups; however,
oral dexamethasone was associated with a significant increase in sepsis
(15.9% vs 1.6%, P =.009) and intraventricular hemorrhage (15.9% vs 3.3%,
P =.03). It was concluded that oral administration increases neonatal
morbidity without demonstrable benefit and should not at this time be
used clinically for induction of fetal pulmonary maturation.
A postal survey of UK obstetricians
conducted in 1997 reported that 98% of responders prescribed repeated
courses of antenatal corticosteroids.9905
Evidence from randomized controlled trials in animals0204
suggests that repeated doses of antenatal corticosteroids may have
beneficial effects in terms of lung function but may have adverse effects on
brain function and fetal growth.
Although there are possibly beneficial effects of multiple doses of steroids
including lower rates of respiratory distress syndrome and a decrease in
oxygen use, there are adverse outcomes notably reduction in birth head
circumference, birth weights, and increased neonatal and maternal infection
rates.0004,
0102,
0204 and
perinatal mortality.0005
In a
randomized, double-blind, placebo-controlled intention-to-treat trial0103
conducted in 13 academic centres in the United States from February 1996
through April 2000 a total of 502 pregnant women between 24 and 32 completed
weeks' gestation who were at high risk of preterm delivery were aseessed.
All the patients received a complete single course of antenatal
corticosteroids (either betamethasone, 12 mg intramuscularly repeated once
in 24 hours for 2 doses, or dexamethasone, 6 mg intramuscularly repeated
every 12 hours for 4 doses). Participants who had not delivered 1 week after
receipt of the single course were randomly assigned to receive either
betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses
every week until 34 weeks' gestation or delivery, whichever came first (n =
256), or a similarly administered placebo (n = 246). Composite neonatal
morbidity included severe respiratory distress syndrome, bronchopulmonary
dysplasia, severe intraventricular haemorrhage, periventricular
leukomalacia, proven sepsis, necrotizing enterocolitis, or perinatal death.
Composite morbidity occurred in 22.5% of the weekly-course group vs 28.0% of
the single-course group. Neither group assignment nor the number of
treatment courses was associated with a reduction in composite morbidity. It
was concluded that weekly courses of antenatal corticosteroids did not
reduce composite neonatal morbidity compared with a single course of
treatment and that weekly courses of antenatal corticosteroids should not be
routinely prescribed for women at risk of preterm delivery.
Experts have concluded that until data establish a favourable
benefit-to-risk ratio, repeat courses of antenatal corticosteroids,
including rescue therapy, should be reserved for patients enrolled in
clinical trials.0003
Thyrotrophin Releasing
Hormone
|
Thyrotropin-releasing hormones (TRH) added to prenatal corticosteroids
has been suggested as a way to further reduce breathing problems and
neonatal lung disease in infants born preterm.
Crowther et al.0402
reviewed 13 trials involving over 4600 women.
Overall, prenatal TRH, in addition to corticosteroids, did not reduce
the risk of neonatal respiratory disease or chronic oxygen dependence,
and did not improve any of the fetal, neonatal or childhood outcomes
assessed by intention to treat analyses. In the infants, prenatal TRH
increased the risk of needing ventilation (relative risk 1.16), having a
low Apgar score at five minutes (RR 1.48) and, for the two trials
providing data, was associated with poorer outcomes at childhood follow
up. It was concluded that prenatal thyrotropin-releasing hormones, in
addition to corticosteroids, given to women at risk of very preterm
birth do not improve infant outcomes and can cause maternal side effects
and it follows that it cannot be recommended for clinical practice.
The RCOG
Guidelines conclusions are as follows:
- Clinicians should offer antenatal corticosteroid treatment to women at risk
of preterm delivery because antenatal corticosteroids are associated with a significant
reduction in rates of RDS, neonatal death and intraventricular haemorrhage.RCOG
The optimal treatment?delivery interval for administration of antenatal
corticosteroids is more than 24 hours but fewer than seven days after
the start of treatment.
The use of antenatal corticosteroids in multiple pregnancies is
recommended, but a significant reduction in rates of RDS has not been
demonstrated.
The use of antenatal corticosteroids in
pregnancies complicated by maternal diabetes mellitus is recommended,
but a significant reduction in rates of RDS has not been demonstrated.
If commenced, inpatient supervision by an experienced diabetic/obstetric
team is essential to regulate diabetic control.
Women may be advised that the use of a single course of antenatal
corticosteroids does not appear to be associated with any significant
maternal or fetal adverse effects.
In preterm labour it is reasonable not to use tocolytic drugs, as there
is no clear evidence that they improve outcome. However, clinicians
should consider the use of short-term tocolysis if the few days gained
can be put to good use, such as completing a course of corticosteroids,
or in utero transfer.
Every effort should be made to initiate antenatal corticosteroid therapy
in women between 24 and 34 weeks of gestation with any of the following:
-
threatened preterm labour
-
any condition requiring elective preterm delivery.
-
preterm rupture of membranes
- antepartum haemorrhage
Between 35 to 36 weeks obstetricians might want to consider antenatal
steroid use in any of the above conditions although the numbers needed
to treat will increase significantly.
Corticosteroid therapy is contraindicated if a woman suffers from
systemic infection including tuberculosis. Caution is advised if
suspected chorioamnionitis is diagnosed.
Betamethasone is the steroid of choice to enhance lung maturation.
Recommended therapy involves two doses of betamethasone 12 mg, given
intramuscularly 24 hours apart.
If repeat courses of antenatal corticosteroids are contemplated then
senior opinion should be sought as, at present, there is a lack of
evidence to show significant benefit.
The use of thyrotrophin-releasing hormone is not recommended in
combination with antenatal corticosteroids.
