Download Mechanism of action

Tocolysis – A clinically based review.
Katie M Groom BSc MB BS *
(Clinical Research Fellow)
Phillip R Bennett PhD MD FRCOG
(Professor of Obstetrics and Gynaecology)
Imperial College Parturition Research Group
Imperial College of Science, Technology and Medicine
Institute of Reproductive and Developmental Biology
Hammersmith Campus
Du Cane Road
London. W12 0HN
*Author for correspondence
Telephone No: 020 7594 2137
Fax No: 020 7594 2189
E-mail: [email protected]
1
Premature birth, the major cause of neonatal morbidity and mortality, complicates up to
10% of all pregnancies. Mortality rates from 32 weeks gestation are similar to those at
term
1
and therefore it is the very early premature deliveries at greatest risk of neonatal
death and serious morbidity, which are most likely to benefit from treatment. This
accounts for 1-2% of the obstetric population. 2
Current treatment of preterm labour is reactive, with tocolytics only being used once
contractions have started. However, it is now well recognised that labour both at term and
preterm resembles an inflammatory reaction with upregulation of inflammatory cytokines
and prostaglandins in the fetal membranes, myometrium and cervix. 3, 4, 5 This is believed
to occur over a period of several weeks with the onset of contractions occurring towards
the end of this complex process. 6 Multiple feed forward mechanisms within this process
mean that once started clinical labour is difficult to stop. Therefore it may be expected
that tocolytic drugs, targeted solely at stopping contractions, will be unsuccessful at
preventing preterm delivery. Indeed meta-analyses of studies of tocolytics, although
showing a prolongation of pregnancy to some degree, do not show a significant impact on
preterm delivery rates or neonatal outcome. 7 In addition these drugs are associated with
significant fetal and / or maternal side effects which should always be considered before
prescribing tocolytic therapy.
There have been recent developments in the prediction of women at risk of preterm
delivery 8, 9, 10 and increasing interest in preventative treatment such as cervical cerclage,
cyclo-oxygenase inhibitors, progestogens and antibiotics. These approaches may be more
successful at reducing overall preterm delivery rates and improving neonatal outcome but
this remains to be seen. For the purpose of this review we have concentrated on the acute
2
management of preterm labour and will consider the mechanisms of action of tocolytic
drugs, the rationale for their use and their possible benefits and side effects.
3
Mechanism of action
Myometrial cell contractility is modulated by the intracellular concentration of calcium.
Increased intracellular calcium, from a variety of different mechanisms (see table 1) binds
with calmodulin and leads to activation of calcium dependent myosin light chain kinase
(CDMLK), this in turn triggers an ATP-dependent phosphorylation of myosin. This
allows interaction with actin filaments and crossbridges form which result in contraction
of the myometrial cell. (see figure 1)
Subgroups of tocolytic drugs act at a variety of different levels of this pathway to cause
inhibition of contractions. This may be via mechanisms specific to labour (oxytocin
receptor antagonists, cyclo-oxygenase inhibitors and possibly nitric oxide donors) or by a
non-specific action on cell contractility (-mimetcs, magnesium sulphate and calcium
channel blockers). (see figure 1)
4
Rationale for tocolytic use
Extreme prematurity is associated with high neonatal mortality and serious morbidity and
therefore the rationale for the use of any intervention must be that it will lead to
improvements in neonatal survival and wellbeing without causing undue risk to either
mother or fetus. It is widely believed that improvement will be achieved by prolonging
pregnancy until the fetus is more mature and / or to allow time for additional therapies to
be administered which will improve neonatal outcome.
Finnström et al studied a population of almost 250 000 births and demonstrated a gain in
infant survival from 8% at 23 weeks gestation to 74% at 26 weeks gestation (see figure
2).
11
This equates to a survival gain of 3% per day at these low gestational ages.
Therefore if tocolytic drugs are successful at delaying delivery for up to seven days 7 then
we would expect to see considerable improvements in survival rates and the risk of
serious morbidity. Further population studies have shown similar large changes in
mortality rates for each additional week of gestation and for each 100g increase in
birthweight at lower gestational ages. However, at higher gestational ages (>32 weeks)
comparable changes in gestation and birthweight only have a relatively small impact on
mortality. 1
Respiratory distress syndrome (RDS) is the most common serious complication of
prematurity and is associated with immediate and long term mortality and morbidity. The
use of antenatal corticosteroids to improve fetal lung maturity is now well documented
and recommended for both its health and cost benefits. 12, 13 A Cochrane review analysed
18 trials covering over 3700 births and demonstrated that antenatal corticosteroids lead to
a significant reduction in mortality (OR 0.6 95% CI 0.48-0.75) and RDS (OR 0.53 95%
5
CI 0.44-0.63). There is a trend towards a reduction in RDS at 24-48 hours and this
becomes significant at 48 hours and up to seven days after administration. This
improvement in fetal lung maturity is associated with a substantial reduction in the risk of
intraventricular haemorrhage (IVH) but has no effect on the risk of necrotising
enterocolitis (NEC) or chronic lung disease (CLD).
14
No adverse consequences of a
single course of corticosteroids were identified by this meta-analysis.
Advances in neonatal care have lead to significant improvements in neonatal survival
despite no change in preterm delivery rates. The introduction of neonatal intensive care
units (NICU) in the 1960s is likely to have been one of the most influential factors
affecting survival rates. Neonatal outcome is also dependent on the infant being delivered
within a maternity unit with NICU services rather than being transferred after delivery.
Several studies have demonstrated better outcomes for inborn infants compared to
outborn infants,
15, 16
although most studies do not adjust for perinatal risk factors,
birthweight and gestational age. A recent study of 3769 singleton infants born at ≤32
weeks gestation admitted to 17 Canadian NICUs controlled for perinatal risks and
admission illness severity. They demonstrated that outborn infants were at higher risk of
death (OR 1.7 95% CI 1.2-2.5), grade III – IV IVH (OR 2.2 95% CI 1.5-3.2), patent
ductus arteriosus (PDA) (OR 1.6 95% CI 1.2-2.1), RDS (OR 4.8 95% CI 3.6-6.3) and
nosocomial infection (OR 2.5 95% CI 1.9-3.3). Although outborn infants were more
likely to be of younger gestational age, neonatal outcome was significantly worse even
with subanalysis of each gestational age group (≤26 weeks, 27-28 weeks and 29-30 weeks
but not at 31-32 weeks gestational age).
17
Therefore any therapy which allows in utero
transfer of mother and baby might be expected to lead to improved mortality and
6
morbidity at very early gestational ages. As we will discuss below however, there is
currently no evidence that this is in fact the case.
7
Tocolytics and Outcome
There are many randomised controlled trials assessing the effectiveness of tocolytic drugs
compared with ‘placebo’ or ‘no tocolytic drug’. The majority are too small to be clinically
significant on their own. The largest meta-analysis of these trials, by Gyetvai et al,
7
retrieved 76 trials of which 18 met the inclusion criteria: all randomised controlled trials
comparing the effect of tocolytic with ‘placebo’ or ‘no tocolytic’ in preterm labour;
perinatal, neonatal or maternal outcome reported, loss to follow up of >20% of total
recruits; data reported on per-patient treated basis. This meta-analysis included trials of mimetics, magnesium sulphate, indomethacin, atosiban and ethanol and demonstrated
that, with the exception of magnesium sulphate, these tocolytics did prolong pregnancy
for up to seven days compared with ‘placebo’ or ‘no tocolytic’.
Evidence discussed previously would suggest that prolonging pregnancy by one week
should improve morbidity and mortality because delivery is later, birthweight is increased
and time is available for antenatal corticosteroids and in utero transfer. However, this
meta-analysis 7 showed that none of these drugs affected perinatal death rates, incidences
of RDS, IVH, NEC, PDA, seizures, hypoglycaemia or neonatal sepsis (see table 2).
Indomethacin was the only drug, in one study,
18
to reduce preterm delivery rates (<37
weeks) and the number of babies born with birthweight <2500g. Overall tocolytics did
not cause a significant reduction in births <30 weeks (OR 1.33 95% CI 0.53-3.33) or
before 32 weeks (OR 0.81 95% CI 0.61-1.07).
7
This analysis did not comment on the
gestational ages at recruitment for each trial or on any differences in outcome according
to gestational age at the time of drug administration.
8
There maybe several reasons why, despite prolongation of pregnancy, there is an apparent
lack of clinical benefit. Firstly it may be that the time gained by the use of tocolytic drugs
is not used appropriately for the administration of corticosteroids or for in-utero transfer
to hospitals with NICU facilities. For example in one recent study, which demonstrated a
delay in delivery of seven days compared to placebo, less than 50% of patients received
antenatal corticosteroids.
19
Many of the tocolytic trials predate the routine use of
corticosteroids and therefore the lack of effect on outcome is not related to lack of effect
of corticosteroids. A trial of tocolysis, corticosteroids and in-utero transfer versus nothing
would be required to fully assess this but is not ethically justifiable and unlikely to be
undertaken!
Some trials included too many women at later gestational ages when the time gained by
the drug does not have a significant impact on neonatal survival or morbidity. In the
Canadian Preterm Labor Investigators Group trial (n=708) 80% of women recruited were
≥28 weeks. 20 It may also be possible that tocolytic drugs are only effective at prolonging
pregnancy at these more advanced gestational ages and that very early preterm labour
does not respond well to tocolytic treatment. The majority of studies do not report
subanalysis of data to assess if prolongation of pregnancy is gestation specific. Romero et
al, in their study of atosiban vs placebo, report that only at gestational ages ≥28 weeks did
more women receiving atosiban stay undelivered at 24 hours, 48 hours and 7 days
compared with placebo. This prolongation of pregnancy was not demonstrated in those
<28 weeks. 19
The causes of preterm labour are diverse and multifactorial and it is not always possible
to make a definitive diagnosis for each individual case. However, it may be that the fetus
9
is compromised in some way and that this is the stimulus for labour. For example, we
know up to 40% of cases of preterm delivery (<32 weeks) are associated with infection 21,
22
and therefore it is possible that a gain in time in-utero is actually detrimental to a fetus.
Finally it should be considered that tocolytics themselves may be harmful and therefore
any significant benefit gained by time in utero may be counteracted.
In addition to improved neonatal outcome a further consideration for using tocolysis may
be a monetary one. Prolongation of pregnancy by tocolysis may not have shown a
reduction in NICU admissions but it may lead to a reduction in number of days in NICU.
Cost of NICU services has not been directly assessed within tocolytic trials, however, St
John et al have studied the cost of neonatal care according to gestational age at birth and
survival. Accounting for number of survivors / non-survivors and cost per survivor / nonsurvivor, the mean cost of neonatal care at 24, 25 or 26 weeks is 75 000 US dollars,
compared with 57 000 US dollars at 28 weeks, 38 000 US dollars at 30 weeks, 21 000 US
dollars at 32 weeks and 8 000 US dollars at 34 weeks. 23 This suggests that a prolongation
of pregnancy for one week may lead to considerable savings. However, it should be
remembered that tocolytics do not reduce the number of admissions to NICU or the
incidence of serious morbidity and therefore this apparent saving may not exist.
10
-mimetics
-mimetics stimulate -2 adrenergic receptors in smooth muscle and, via cAMP, reduce
sensitivity to and absolute levels of intracellular calcium causing myometrial relaxation.
-mimetics have been the most commonly used tocolytic drugs within the UK over recent
years. Meta-analysis of seven randomised trials of -mimetics has shown them to be
significantly better at delaying delivery within 24 hours, 48 hours and seven days (but
bizarrely not 72 hours) than placebo or ‘no drug’. However, this did not lead to any
improvement in preterm delivery rates before 30 weeks, 32 weeks or 37 weeks or in
neonatal outcome in terms of perinatal death, incidence of RDS, IVH, NEC or
birthweight <2500g.
7
This analysis also showed, as have many others, that -mimetics
have a significant maternal side effect profile; commonly causing palpitations, tremor,
chest pain, cardiac arrhythmias, nausea, vomiting, headache, hyperglycaemia and
hypokalaemia. There is also the more serious risk of pulmonary oedema, occurring in up
to 5% of women treated with -mimetics.
24
This occurs as a result of fluid overload
secondary to the antidiuretic effect of -mimetics and excessive intravenous fluid
administration. The short term fetal cardiovascular side effects, tachycardia and increased
output are similar to those in the mother but do not appear to have a detrimental effect on
neonatal morbidity or mortality. 7
Alternative tocolytics , such as atosiban and nifedipine, have been shown to have similar
or improved efficacy to -mimetics with a significantly reduced side effect profile
25, 26
and therefore -mimetics should no longer be the drugs of first choice for tocolysis.
Calcium channel blockers (CCB)
11
CCB block transmembrane influx of calcium through voltage dependent channels leading
to a reduction in intracellular calcium and therefore in myometrial contractility. There is
increasing interest in the use of CCB for the treatment of preterm labour as well as in
hypertension in pregnancy. Tsatsaris et al performed a meta-analysis of nine randomised
controlled trials of 679 patients receiving -mimetics or nifedipine and demonstrated that
nifedipine was better than -mimetics in delaying delivery for at least 48 hours (OR 1.52
95% CI 1.03-2.24) or to gestations over 34 weeks (OR 1.87 95% CI 1.11-3.5). Although
there was no difference in neonatal mortality (OR 1.51 95% CI 0.63-3.65) nifedipine was
well tolerated compared to -mimetics with fewer discontinuations due to side effects
(OR 0.12 95% 0.05-0.29). There was a reduced incidence of RDS (OR 0.57 95% 0.370.97) and admission to NICU (OR 0.65 95% CI 0.43-0.97).
25
Nifedipine is therefore
currently the only tocolytic to be associated with a benefit for the neonate.
Oxytocin receptor antagonists
Atosiban, a competitive oxytocin / vasopressin receptor antagonist, has recently been
licensed for use as a tocolytic in Europe. The rationale for its use is that oxytocin plays a
fundamental role in labour. Therefore inhibition of its receptor, which leads to a reduction
in extracellular calcium influx as well as its release from intracellular stores, should
inhibit myometrial contractility. However, there has been some doubt over the role of
oxytocin in the initiation and maintenance of labour 28.
Romero et al randomly assigned just over 500 women in preterm labour to atosiban or
placebo with rescue therapy of standard tocolysis after one hour if contractions continued.
12
19
There was no significant difference in the primary outcome, which was time from start
of treatment to delivery or therapeutic failure, between atosiban and placebo. There was
an increase in the number of patients remaining undelivered and not requiring alternative
tocolytic therapy at 24 hours (73% vs 58%), 48 hours (67% vs 56%) and seven days (62%
vs 49%) for those receiving atosiban compared to placebo. Infant mortality and morbidity
was similar between the two groups at ≥28 weeks but were increased in the atosiban
group at <28 weeks. This may be explained by more women <24 weeks being assigned to
the atosiban group, however, further investigation would be required to confirm this.
Atosiban and -mimetics have been compared in a large multicenter trial (n=742) and
shown to have similar efficacy in delaying delivery at 48 hours and seven days and with
similar neonatal outcomes.
26
Atosiban did however, have a better maternal cardiac side
effect profile than -mimetics; tachycardia (5.5% vs 75.5%), chest pain (1.1% vs 4.8%)
and palpitations (2.2% vs 15.6%). Pulmonary oedema occurred in two patients in the mimetic group and in one patient in the atosiban group, but this patient had received
seven days of rescue therapy with a -mimetic!
The results of these and a few smaller trials have led to suggestions that atosiban should
become the drug of first choice if tocolytic therapy is to be used, however, the cost of
each drug should also be considered. The cost of 24 hours treatment using standard
regimes for atosiban is approximately £275, compared with £13 for ritodrine and £1.50
for nifedipine. 29
Non steroidal anti-inflammatory (NSAI) drugs
13
NSAI drugs inhibit the cyclo-oxygenase (COX) (prostaglandin synthetase) enzyme which
is responsible for the conversion of arachidonic acid to prostaglandins E2 and F2.
Prostaglandins play an integral role in the initiation and maintenance of labour and have
an effect on contractility in several ways. In preparation for labour they enhance the
development of gap junctions between myometrial cells to allow coordinate uterine
activity and cause upregulation of oxytocin receptors. Prostaglandins also have a direct
effect on calcium influx stimulating myometrial contractility.
Indomethacin, a non-specific COX inhibitor, has been the most commonly used NSAI
drug. It is more effective than placebo at delaying delivery for 48 hours and seven days
and unlike all other tocolytic drugs has been shown to cause a reduction in deliveries
before 37 weeks gestation and the number of low birthweight deliveries (<2500g). 7 It has
relatively few maternal side effects but use has been limited by concerns over potential
fetal side effects. Indomethacin has been associated with constriction of the ductus
arteriosus,
30
oligohydramnios,
31
NEC
32
and IVH.
32
Reports concerning these side
effects have been conflicting, however, a decision model analysis based on published data
regarding fetal adverse effects concluded that the benefits of indomethacin outweigh the
potential risks to the neonate at gestational ages ≤32 weeks.
33
It may be that some of
these adverse neonatal outcomes are related to confounding variables. 34
It is now well established that labour is associated with upregulation of COX-2 and not
COX-1 in the myometrium and fetal membranes
35
and therefore there has been
increasing interest in the newer COX-2 specific inhibitors for the treatment of preterm
labour. Observational studies and case reports support the efficacy of these drugs but
there remains concern over potential fetal side effects, in particular renal effects
36, 37, 38
14
and therefore until the results of randomised controlled trials are available the use of
COX-2 specific inhibitors should be closely supervised and only within a research trial.
Magnesium Sulphate
Magnesium sulphate acts as a calcium antagonist at the neuromuscular junction. It has
been used widely as an anticonvulsant agent in preeclamptic women for many years and
is the most commonly used tocolytic drug in the USA. However, meta-analysis has
shown it to be no better than placebo in delaying delivery 7 and the most recent Cochrane
Review concludes there is insufficient evidence to support its use in the treatment of
preterm labour. 39
Nitric Oxide (NO) Donors
NO donors act by increasing levels of cGMP in uterine smooth muscle cells which leads
to uterine relaxation. There have been few studies of transdermal nitroglycerin, but these
have suggested a reduction in deliveries within 48 hours compared to placebo
similar efficacy to -mimetics with possibly fewer maternal side effects.
41
40
and
However,
there is now increasing evidence that NO donors may be associated with cervical
ripening, making them unsuitable as tocolytic agents. 42, 43
15
16
Conclusion
The rationale for treatment of preterm labour should be that it improves neonatal outcome
without undue risk to the mother or fetus. Sadly current management does not achieve
this. In simple terms all acute tocolytics appear to be little better than placebo or ‘no drug’
and all are associated with almost no clinical benefit. This is illustrated by inconsistencies
in the results of randomised controlled trials. For example, nifedipine is more effective
than -mimetics,
25
which is better than placebo, 7 but similar to magnesium sulphate,
which is no better than placebo.
7
27
Multiple comparisons between studies of ‘drug’ vs
‘drug’, ‘drug’ vs ‘no drug’ and ‘drug’ vs ‘placebo’ make interpretation of data hazardous
and unreliable.
It is reasonable and clinically justifiable not to use tocolytic drugs. However, if tocolysis
is considered it should only be in selected situations where benefit is more likely to be
achieved, for example for antenatal corticosteroid administration and in-utero transfer.
The use of any tocolytic drug should be carefully considered in terms of both potential
benefit and possible harm and fully discussed with the mother before treatment is
instigated.
The choice of drug remains contentious. There is now sufficient evidence to show that
both atosiban and nifedipine are preferable to -mimetics in terms of side effect profile. It
maybe ethically difficult to justify high costs for a drug treatment which has been shown
to make no improvement in outcome and is likely to be administered to many patients
who would ‘respond’ equally well to placebo. Therefore in our opinion, nifedipine, which
is inexpensive and the only tocolytic shown to improve neonatal morbidity, should be the
drug of choice if a tocolytic is to be used.
17
18
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24
Tables and Figures Titles.
Table 1. Mechanisms of intracellular calcium control.
Table 2. Effect of tocolytics compared to ‘placebo’ or ‘no tocolytic drug’ on prolongation
of pregnancy and neonatal outcome.
Figure 1. Control of Myometrial cell contractility and sites of tocolytic drug activity.
Key:
OTR – Oxytocin receptor
PGR – Prostanoid receptor
SR – sarcoplasmic reticulum
V – Voltage dependent Ca channel
R – Receptor dependent Ca channel
-R - -adrenergic receptor
OTRA - Oxytocin receptor antagonist
COXI – Cyclo-oxygenase inhibitor
MgS – Magnesium sulphate
CCB – Calcium channel blocker
 - -mimetcs
NO – nitric oxide donors
Figure 2. Infant survival rates from 23 to 26 weeks gestation.
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Table 1. Mechanisms of intracellular calcium control.
Mechanism
Voltage dependent
calcium channels
Effect on
intracellular (Ca 2+)
 Ca 2+
Receptor dependent
calcium channels
 Ca 2+
Release from
sarcoplasmic
reticulum
 Ca 2+
-adrenoreceptors
 Ca 2+
Membrane depolarisation caused by
inherent membrane instability and
increased number of gap junctions leads to
rapid influx of calcium
Coupled to membrane bound G-proteins
which are activated by endocrine and
paracrine receptors such as oxytocin and
prostanoid receptor
Oxytocin receptor linked to G-proteins
activates phosholipase C which increases
inositol triphosphate (IP3) levels and bind
to SR causing release of Ca 2+
Coupled to G-proteins cause increased
cAMP levels which activates protein
kinase A, this inhibits phosphorylation of
CDMLK and increases SR uptake of Ca 2+
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Table 2. Effect of tocolytics compared to ‘placebo’ or ‘no tocolytic drug’ on prolongation
of pregnancy and neonatal outcome.
-mimetics
Del within 48hrs
OR (95% CI)
Del within 7 days
OR (95% CI)
Perinatal death
OR (95% CI)
RDS
OR (95% CI)
IVH
OR (95% CI)
BW <2500g
OR (95% CI)
Gyetvai 1999
0.56 *
(0.42-0.74)
0.65*
(0.50-0.83)
1.08
(0.72-1.62)
0.76
(0.57-1.01)
0.70
(0.43-1.15)
0.79
(0.61-1.01)
Magnesium
sulphate
0.52
(0.26-1.05)
1.54
(0.85-2.82)
1.83
(0.70-4.77)
1.19
(0.61-2.31)
0.82
(0.25-2.63)
1.06
(0.58-1.93)
Indomethacin
Atosiban
0.12 *
(0.05-0.32)
0.07*
(0.02-0.27)
1.48
(0.24-9.20
0.61
(0.16-2.30)
0.67*
(0.47-0.95)
0.59*
(0.41-0.84)
7.66
(0.78-75.15)
0.07*
(0.02-0.27)
*statistically significant result
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Figure 1.
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Figure 2. Infant survival rates from 23 to 26 weeks gestation.
Finnström 1997.
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