The case for tocolysis

in threatened preterm labour

Clinical Work of Obstetrics and Gynecology

RSUD Tanjung-KLU
Medical Faculty
Islamic University Al-Azhar Mataram
2016
tutor: dr. Dony Rosmana Bimantara SpOG
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abstract
The failure of tocolytics to improve neonatal outcomes in
placebo-controlled trials has wrongly been interpreted as
evidence that they do not work
While delivery is unequivocally prolonged by 24 hours, 48
hours and 7 days, the time gained was not exploited to
optimise neonatal outcome
The largest placebo-controlled study showed clear trends
towards better survival in fetuses <28 weeks, lower rates of
cerebral palsy and higher Bayley mental scores
Finally, there is the Orwellian analogy that tocolytics dont
work, but some work better than others
Development of tocolytics that are safe for mother and baby
should facilitate adequately-powered placebo-controlled
studies
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INTRODUCTION
There are three requirements of a tocolytic

agent:
that it delays labour
that it is safe for mother and fetus
that it improves perinatal outcome

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PROLONGATION OF GESTATION
A recent meta-analysis identified 17 placebo-

controlled trials concerning the use of

tocolytics for the treatment of preterm labour
involving 2284 women
the use of a tocolytic drug was associated with

significantly reduced odds of delivery :

within 24 hours (OR 0.47, CI 0.290.77)
within 48 hours (OR 0.57, CI 0.380.83)
within 7 days (OR 0.60, CI 0.380.95)

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These effects were only significant for beta-

agonists, atosiban, and indomethacin

Despite its popularity in North America, there
is no controlled evidence that magnesium
functions as a tocolytic

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MATERNAL AND FETAL SAFETY

Adverse effects from tocolytics largely result from

their non-specificity for uterine muscle

betasympathomimetic receptors:
maternal palpitations (48% vs 5% placebo)
tremor (39% vs 4%)
hyperglycaemia (39% vs. 6%)
headache (23% vs. 6%)
nausea (20% vs. 12%)
dyspnoea (14% vs. 1%)
vomiting (13% vs. 8%)
chest pain (10% vs. 1%)
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beta-agonists
Pulmonary oedema occurs rarely (1 in 266,

based on three cases in 797 treated women)

Cyclo-oxygenase (COX) inhibitors

fetal oliguria and ductal constriction
Indomethacin
neonatal necrotising enterocolitis (29% vs. 8%)
intraventricular haemorrhage (28% vs. 9%)
patent ductus arteriosus (62% vs. 44%)

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oxytocin/ vasopressin antagonist

nausea (11% vs. 5% placebo) as its only side
effect
In large randomised comparative trials
beta-agonists, atosiban was associated with a
10-fold reduction in maternal cardiovascular
side effects (8% vs. 81%)
much lower rate of discontinuation due to side
effects (1% vs. 15%)

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PERINATAL OUTCOME
The lack of effect of tocolytics on perinatal outcome in

the randomised studies has been wrongly interpreted

as definitive proof that they have no effect
Although it has been known for nearly two decades
that a course of corticosteroid therapy >2448 hours
respiratory distress syndrome (RDS)
periventricular haemorrhage and neonatal death
corticosteroids were infrequently given in these trials

which is hardly surprising given that preterm labour is

proportionately more common at later gestations

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EVIDENCE OF BENEFIT FROM

TOCOLYSIS
trial of any tocolytic agent.
Ritodrine Placebo
P value
Neonatal mortality at 24 27 weeks 12% (14/75) 19% (7/61)
Cerebral palsy at 18 months
1/128
5/121
0.09
Bayley mental score

100.3 F 1.6

95.1 F 1.7

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These trends are not seen with other agents

the trials with atosiban are smaller and

confounded by rescue tocolysis after as little

as an hour
while perinatal outcome after indomethacin is
likely to be confounded by adverse drug
effects on the fetus

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THE ANIMAL FARM ANALOGY

Early attempts at meta-analysis identified a

number of methodological concerns with these

trials
all were unblinded
most lacked intention-to-treat analysis
some used calcium antagonists as second-line

therapy
and others included non-contracting patients with
ruptured membranes

Metaanalysis of these trials comparing calcium

antagonists with beta-agonists revealed

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CONCLUSION AND FUTURE

STUDIES
The

neonatal
effects
of
short-term
prolongation of gestation with tocolytic agents
have not been adequately evaluated in
placebo-controlled trials
which have been characterised by low
corticosteroid usage, no in-utero transfer,
enrolment at late gestations, and lack of
power

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beneficial effect is suggested by:

Bayesian trends towards reduced neonatal
morbidity and mortality, and improved longterm outcome in the beta-agonist trials and
randomised
trials showing that calcium
antagonists improve neonatal outcome and
delay delivery more effectively than betaagonists
The development of tocolytics that are safe for
the mother and baby should facilitate such
trials.
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Journal Analysis
Problem:

A recent meta-analysis identified 17 placebo-controlled

trials concerning the use of tocolytics for the treatment of
preterm labour involving 2284 women in North America.
Intervention:
When tocolytic therapy was introduced, it held great
promise for reducing the perinatal sequelae of preterm
birth. Although tocolytics have been unequivocally
demonstrated to delay preterm delivery in the short term,
to date no perinatal benefit has been demonstrated in
randomized controlled trials. In this trials the sample used
beta-agonists, atosiban, and indomethacin.

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Comparison:

Journal : Adverse effects of tocolytic therapy, the conclusion of

this journal is The ideal labour-inhibiting agents would exclusively
target the myometrium or the labour stimulus itself. It would be
orally active with a rapid onset of action and long duration. The
agent would be devoid of maternal and fetal side effects and
would be highly effective
Out Come:
The neonatal effects of short-term prolongation of gestation with
tocolytic agents have not been adequately evaluated in placebocontrolled trials, which have been characterised by low
corticosteroid usage, no in-utero transfer, enrolment at late
gestations, and lack of power. The development of tocolytics that
are safe for the mother and baby should facilitate such trials.
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THANKYOU

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