Tocolysis – A clinically based review

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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

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Fax No: 020 7594 2189

E-mail: [email protected]

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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

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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.

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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)

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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.

Finnstrm 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%

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

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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

morbidity at very early gestational ages. As we will discuss below however, there is

currently no evidence that this is in fact the case.

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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-analysis7

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 (


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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


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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 / non-

survivor, 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.

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-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


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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% 0.37-0.97)

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 labour28.

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.

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

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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


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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 (


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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 40 and

similar efficacy to -mimetics with possibly fewer maternal side effects. 41 However, there

is now increasing evidence that NO donors may be associated with cervical ripening,

making them unsuitable as tocolytic agents. 42, 43

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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, 27

which is no better than placebo. 7 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.

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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 OTRA - Oxytocin receptor antagonist

PGR Prostanoid receptor COXI Cyclo-oxygenase inhibitorSR sarcoplasmic reticulum MgS Magnesium sulphate

V Voltage dependent Ca channel CCB Calcium channel blocker

R Receptor dependent Ca channel - -mimetcs-R - -adrenergic receptor 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 Effect onintracellular (Ca 2+)

Voltage dependent

calcium channels

Ca 2+ Membrane depolarisation caused byinherent membrane instability and

increased number of gap junctions leads to

rapid influx of calcium

Receptor dependent

calcium channels

Ca 2+ Coupled to membrane bound G-proteinswhich are activated by endocrine and

paracrine receptors such as oxytocin and

prostanoid receptor

Release from

sarcoplasmic

reticulum

Ca 2+ Oxytocin receptor linked to G-proteinsactivates phosholipase C which increases

inositol triphosphate (IP3) levels and bind

to SR causing release of Ca 2+

-adrenoreceptors Ca 2+ Coupled to G-proteins cause increasedcAMP 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 Magnesiumsulphate

Indomethacin Atosiban

Del within 48hrs

OR (95% CI)

0.56 *

(0.42-0.74)

0.52

(0.26-1.05)

0.12 *

(0.05-0.32)

0.67*

(0.47-0.95)

Del within 7 days

OR (95% CI)

0.65*

(0.50-0.83)

1.54

(0.85-2.82)

0.07*

(0.02-0.27)

0.59*

(0.41-0.84)

Perinatal death

OR (95% CI)

1.08

(0.72-1.62)

1.83

(0.70-4.77)

1.48

(0.24-9.20

RDS

OR (95% CI)

0.76

(0.57-1.01)

1.19

(0.61-2.31)

0.61

(0.16-2.30)

7.66

(0.78-75.15)

IVH

OR (95% CI)

0.70

(0.43-1.15)

0.82

(0.25-2.63)

BW


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Figure 1.

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Figure 2. Infant survival rates from 23 to 26 weeks gestation.

Finnstrm 1997.

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Tocolysis – A clinically based review