Tocolysis a Clinically Based Review

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:

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 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.

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 (b-mimetcs, magnesium sulphate and calcium channel blockers). (see figure 1)

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% 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 morbidity at very early gestational ages. As we will discuss below however, there is currently no evidence that this is in fact the case.

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 b-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.

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 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 / 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.

b-mimetics

b-mimetics stimulate b-2 adrenergic receptors in smooth muscle and, via cAMP, reduce sensitivity to and absolute levels of intracellular calcium causing myometrial relaxation. b-mimetics have been the most commonly used tocolytic drugs within the UK over recent years. Meta-analysis of seven randomised trials of b-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 b-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 b-mimetics. 24 This occurs as a result of fluid overload secondary to the antidiuretic effect of b-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