PREMATURE LABOUR TOCOLYTICS

 

 

 

The onset of labour at term is related to an inflammatory type reaction with upregulation of inflammatory cytokines and prostaglandins in the fetal membranes, myometrium and cervix.^{8501, 9201, 9501}  The aetiology of preterm labour is multifactorial, including withdrawal of progesterone block^,0701 secretion into amniotic fluid of major lung surfactant protein,⁰⁵⁰¹ corticotropin-releasing hormone (CRH)⁰⁴⁰¹ and the influence of the fetal adrenal gland.⁰⁷⁰² 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,⁰⁶⁰¹ do not show a significant impact on preterm delivery rates or neonatal outcome.⁹⁹⁰¹ In addition these drugs may be associated with significant fetal and maternal adverse effects which should always be taken into account before initiating tocolytic therapy. There have been developments in the prediction of women at risk of preterm delivery by assessing the cervical length^{9502,  9801} or looking for the presence of fetal fibronectin.⁹⁶⁰¹  There is increasing interest in preventative treatment such as cervical cerclage, cyclo-oxygenase (COX) inhibitors, progestogens and antibiotics, which may be more successful at reducing overall preterm delivery rates and improving neonatal outcome. Studies examining long-term use of progestogens in women at a high-risk of preterm delivery have returned encouraging results^{.0301, 0302}  Data concerning use of cervical cerclage^{0101, 0102} and antibiotics^{9503, 0103, 0303, 0602}  are conflicting and use of COX-2-specific inhibitors are disappointing.⁰⁵⁰²

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 the mother or fetus. It is widely believed that improvement can be achieved by prolonging pregnancy until the fetus is more mature and to allow time for additional therapies to be administered that will improve neonatal outcome.

A study of the Swedish date from 1990-92,⁹⁷⁰¹ a population of almost 250 000 births, demonstrated a gain in infant survival from 8% at 23 weeks of gestation to 74% at 26 weeks of gestation (Figure 1). There was effectively a survival gain of 3% per day at these low gestational ages. Further population studies have shown similar large changes in mortality rates for each additional week of gestation and for each 100 g increase in birthweight at lower gestational ages. However, at higher gestational ages (> 32 weeks) comparable changes in gestation and birthweight only have an insignificant impact on mortality.

 

The most common serious complication of prematurity is respiratory distress syndrome (RDS) 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.^RCOG 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 respiratory distress syndrome (OR 0.53 95% CI 0.44?0.63).⁰⁰⁰¹ There is a trend towards a reduction in respiratory distress syndrome 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 but has no significant effect on the risk of necrotising enterocolitis or chronic lung disease. No adverse consequences of a single course of corticosteroids were identified by this meta-analysis.

Neonatal intensive care units (NICU), first launched in the 1960s, are 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. Studies have demonstrated better outcomes for inborn infants compared with outborn infants,^{9702, 0002} although most studies do not adjust for perinatal risk factors, birthweight and gestational age.

A study of 3769 singleton infants born at ≤32 weeks of gestation admitted to 17 Canadian NICUs controlled for perinatal risks and admission illness severity.⁰¹⁰⁴ They demonstrated that outborn infants were at higher risk of death (OR 1.7 grade III?IV intraventricular haemorrhage (OR 2.2), patent ductus arteriosus (OR 1.6), respiratory distress syndrome (OR 4.8). 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 of gestational age). 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.

Recent developments such as the use of surfactant may reduce the benefits of in-utero transfer.⁰⁶⁰³

The largest metaanalysis of trials assessing the effectiveness of tocolytic drugs compared with placebo or no tocolytic drug retrieved 76 trials of which 18 met the inclusion criteria.⁹⁹⁰¹ These criteria were: 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 a 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 either the placebo or no tocolytic groups. Perhaps surprisingly, this meta-analysis showed that none of these drugs affected perinatal death rates, incidences of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, patent ductus arteriosus, seizures, hypoglycaemia or neonatal sepsis. Indomethacin⁸⁴⁰¹ was the only drug, in one study, to reduce preterm delivery rates (< 37 weeks) and the number of babies born with birthweight < 2500 g. Overall tocolytics did not cause a significant reduction in births < 32 weeks. The authors 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.

So why is there 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. 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. Secondly, 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. 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. In their study of atosiban versus placebo, Romero et al.,⁰⁰⁰³ reported that only at gestational ages of ≥28 weeks did more women receiving atosiban remain undelivered at 24 hours, 48 hours and seven days compared with those taking a placebo.Finally, there may be direct or indirect adverse effects of tocolytics which counteract their potential gain, including prolongation of pregnancy when this is detrimental to the baby.

The causes of preterm labour are diverse and multifactorial and it is not always possible to definite causation 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 of gestation) are associated with infection^{9101, 9202, 0105}  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 by the possible adverse effects of the drugs administered.

Economics is a further consideration for using tocolysis. In a study conducted in Massachusetts,⁰⁷⁰³ birth certificates for infants who were born between July 1999 and June 2000 were linked to early intervention claims through 2003. Overall, 14,033 of 76,901 surviving infants received early intervention services. Program costs totalled almost $66 million, with mean cost per surviving infant of $857. The mean cost per infant was highest for children who were 24 to 31 weeks' gestational age ($5393), for infants who were 32 to 36 weeks' gestational age ($1578) compared with those who were born at term ($725). At each gestational age, mean cost per surviving infant was higher for multiples than for singletons. The total cost of initial care for the US population of neonates is estimated at $10.2 billion annually, with 11.9% spent on infants born between 24 and 26 weeks' gestation and 42.7% spent on those born at > or = 37 weeks' gestation.⁰⁰⁰⁴ Although costs for an individual surviving extremely premature baby may be high, the costs for extremely low gestational age infants is a relatively small component of total neonatal care costs because so few infants are born at these gestational ages. Costs that are associated with early childhood developmental services must be included when considering the long-term costs of prematurity.

 

 

 

In the early 1950's, alcohol was used in an attempt to suppress premature labour and some success was reported. Side effects, notably nausea limited its use. Its effect was attributed to suppression of the posterior pituitary output of ADH and also oxytocin. Interestingly, in later studies it has proven to be effective.⁹⁹⁰¹

 

Beta-Mimetics

 

 

Beta-mimetics stimulate -2 adrenergic receptors in smooth muscle reducing sensitivity to and absolute levels of intracellular calcium causing myometrial relaxation. The group include isouxuprine, terbutaline, salbutamol and ritodrene. They have been the most commonly used tocolytic drugs within the UK. Meta-analysis of seven randomised trials of beta-mimetics has shown them to be significantly better at delaying delivery within 24 hours, 48 hours and seven days (although not 72 hours) than women on a placebo or no drug. However, this did not lead to any improvement in preterm delivery rates before 30 weeks, 32 weeks or 37 weeks gestation or in neonatal outcome in terms of perinatal death, incidence of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis or birthweight < 2500 g.⁹⁹⁰¹ Beta-mimetics have a significant maternal adverse 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.⁰⁶⁰¹ This occurs as a result of fluid overload secondary to the antidiuretic effect of -mimetics and excessive intravenous fluid administration.

If a tocolytic agent is used, beta-mimetics no longer seem the best choice. Alternatives such as atosiban or nifedipine appear to have comparable effectiveness in terms of delaying delivery for up to seven days and are associated with fewer maternal adverse effects.^RCOG

Calcium Channel Blockers

 

 

Calcium channel blockers block transmembrane influx of calcium leading to a reduction in intracellular calcium and, therefore, in myometrial contractility. There is increasing interest in the use of calcium channel blockers for the treatment of preterm labour as well as hypertension in pregnancy. A metaanalysis⁰¹⁰⁶ of nine randomised controlled trials of 679 women receiving beta-mimetics or nifedipine demonstrated that nifedipine was better in delaying delivery for at least 48 hours (OR 1.52) or to gestations over 34 weeks (OR 1.87). Although there was no difference in neonatal mortality (OR 1.51) nifedipine was well tolerated compared with beta-mimetics with fewer discontinuations due to adverse effects (OR 0.12). There was a reduced incidence of respiratory distress syndrome (OR 0.57) and admission to NICU (OR 0.65). Nifedipine is therefore currently the only tocolytic to be associated with a benefit for the neonate, although this is concluded from relatively small numbers within randomised controlled trials.

When compared with any other tocolytic agent, particularly beta-mimetics, calcium channel blockers reduce the number of women giving birth within seven days of receiving treatment (relative risk (RR 0.76) and prior to 34 weeks' gestation (RR 0.83). Calcium channel blockers also reduce the requirement for women to have treatment ceased for adverse drug reaction (RR 0.14), the frequency of neonatal respiratory distress syndrome (RR 0.63), necrotising enterocolitis (RR 0.21), intraventricular haemorrhage (RR 0.59) and neonatal jaundice (RR 0.73).⁰³⁰⁴

Nifedipine has the advantage of oral use and it is cheap. It is not licensed in the UK for use as a tocolytic agent and so responsibility for its use lies with the prescribing doctor. There is no consensus about the appropriate regimen for nifedipine: the optimal dose has not been defined and the different release characteristics of the formulations available may affect the dosage required. Dosage of 10 mg sublingually every 15 minutes for the first hour, until contractions stopped, then 60?160 mg/day of slow release nifedipine depending on uterine activity has been used.^RCOG

 

 

Oxytocin Receptor Antagonists

 

 

Atosiban, a competitive oxytocin-/vasopressinreceptor antagonist, is 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.

Five hundred women in preterm labour were randomly assigned to atosiban or a placebo, with rescue therapy of standard tocolysis after one hour if contractions continued.⁰⁰⁰³ There was no significant difference in the time from the start of treatment to delivery or therapeutic failure between atosiban and the placebo. There was an increase in the number of women remaining undelivered and not requiring alternative tocolytic therapy at 24 hours (73% versus 58%), 48 hours (67% versus 56%) and seven days (62% versus 49%) for those receiving atosiban when compared with the placebo. Infant mortality and morbidity were similar between the two groups at ≥ 28 weeks but were increased in the atosiban group at < 28 weeks. This may, perhaps, be explained by more women of < 24 weeks gestation being assigned to the atosiban group; further studies are required to establish if this finding is significant.

Atosiban and beta-mimetics were compared in a large multicentre trial of 742 women.⁰¹⁰⁶ they were shown to have similar efficacy in delaying delivery at 48 hours and seven days with similar neonatal outcomes. There were no significant differences between atosiban and beta-agonists in delaying delivery for 48h (88.1% vs 88.9%) or seven days (79.7% versus 77.6%). Tocolytic effectiveness was also similar in terms of mean gestational age at delivery (35.8 weeks vs 35.5 weeks) and mean birthweight (2,491g versus 2,461g). Maternal side effects, particularly cardiovascular adverse events (8.3% vs 81.2%, P < 0.001), were reported more frequently in women given beta-agonists, resulting in more treatment discontinuations due to side effects (1.1% vs 15.4%, P = 0.0001). No statistical differences in neonatal/infant outcomes were observed with either study medication.

The cost of 24 hours of treatment using standard regimens for atosiban is approximately ?275 sterling, compared with ?13 for ritodrine and ?1.50 for nifedipine.

 

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

 

 

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the COX enzyme (prostaglandin synthetase), which is effects 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 they allow coordinated 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. It is more effective than a 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 of gestation and the number of low birthweight deliveries (< 2500 g).⁹⁹⁰¹ It has relatively few maternal adverse effects but use has been limited by concerns over potential fetal adverse effects.

A dramatic yet usually reversible increase in the incidence of indomethacin-induced ductal constriction occurs at 31 weeks' gestation.⁹⁷⁰³ Weekly fetal echocardiography is warranted for the duration of therapy. More indomethacin-exposed infants with a patent ductus arteriosus required surgical ligation because of either a lack of initial response or a reopening of the duct after postnatal indomethacin therapy (50 percent vs. 20 percent of the unexposed infants, P = 0.05).⁹³⁰¹

Prolonged indomethacin therapy results in decreased fetal urine output with resultant oligohydramnios.^{9101, 9301}

Indomethacin appears to increase the risk of serious neonatal complications in infants born at or before 30 weeks' gestation. More indomethacin-exposed infants had necrotizing enterocolitis (29 percent vs. 8 percent, P = 0.005), intracranial haemorrhage grade II to IV (28 percent vs. 9 percent, P = 0.02).⁹³⁰¹

On the basis of current estimates, the benefits of indomethacin outweigh the potential risks to the neonate at gestational ages < or = 32 weeks.⁹⁷⁰⁴ Thus the use of indomethacin for tocolysis at these ages is a reasonable strategy.

In a more recent analysis, Loe et al⁰⁵⁰³ evaluated studies assessing the neonatal outcomes of patients undergoing tocolysis with indomethacin. Observational studies and randomized trials were included in this systematic review. There were 28 studies included; 1,621 were exposed to indomethacin for tocolysis antenatally; 4,387 infants not exposed to indomethacin served as the comparison group. No significant differences in the rates of intraventricular haemorrhage, patent ductus arteriosus, necrotizing enterocolitis, or neonatal mortality between infants exposed to indomethacin antenatally and those not exposed. Meta-analysis of randomized trials revealed increased risk of bronchopulmonary dysplasia. However, the meta-analysis included only 3 randomized clinical trials, one of which showed increased risk. It was concluded that although the pooled results did not identify significantly increased risks of adverse effects, the limited statistical power of published randomized trials did not allow exclusion of  the possibility that indomethacin tocolysis increases the risk of adverse neonatal outcomes.

Cyclooxygenase type 2 and type 1 expression are localized within the amniotic epithelium and amniotic mesoderm. Type 1 but not type 2 enzyme was also expressed in the chorionic mesoderm. Expression of the type 2 enzyme is significantly increased with the onset of labour⁹⁵⁰⁴ and therefore there has been of 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 adverse effects, in particular renal effects. Fetal COX-2 inhibition, due to maternal nimesulide assumption, can be responsible for neonatal chronic renal failure.^{9902, 0604}  In the study by Stika et al⁰²⁰¹ comparing indomethacien with celecoxib mean maximum ductal flow velocity was significantly elevated over baseline (82.9 +/- 4.6 cm/s vs 111.14 +/- 14.3 cm/s; P =.02) after 24 hours of indomethacin, but not celecoxib. Both medications were associated with a transient decrease in amniotic fluid volume, with a greater effect by indomethacin. The medications were equally effective in the maintenance of tocolysis. There were no significant maternal or neonatal adverse events. The safety of short-term celecoxib in women with preterm labor was superior to that of indomethacin. However, in a larger placebo-controlled trial the long-term use of rofecoxib in women at high risk of preterm labour, it was associated with reversible effects on the fetal kidneys and ductus arteriosus. It did not reduce the incidence of early preterm delivery <30 weeks and was associated with an increased risk of delivery before 37 weeks in women at high risk.⁰⁵⁰²

 

Magnesium Sulphate

 

 

Magnesium sulphate acts as a calcium antagonist at the neuromuscular junction. It is the most commonly used tocolytic drug in the USA. However, meta-analysis has shown that betamimetics, indomethacin, atosiban, and ethanol, but not magnesium sulfate, were associated with significant prolongations in pregnancy.⁹⁹⁰¹ Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, and its use is associated with an increased mortality for the infant.⁰²⁰² Another Cochrane review concluded that there is not enough evidence to show that magnesium maintenance therapy is effective in preventing preterm birth after an episode of threatened preterm labour.⁰⁰⁰⁵

 

Nitric Oxide Donors

 

 

 

Nitric oxide donors act by increasing levels of cyclic guanosine monophosphate (cGMP) in uterine smooth muscle cells, and this leads to uterine relaxation. A pilot study⁹⁹⁰³ of 33 women in preterm labour were randomised in a double-blind fashion to receive either transdermal nitroglycerin (n = 17) or placebo (n = 16). Fewer women randomised to nitroglycerin treatment (6/17) were delivered within 48 hours, compared with the placebo treatment (10/16). In a comparison between glyceryl trinitrate and ritodrine,⁹⁹⁰⁴ no overall difference was observed in the acute tocolysis of preterm labour. Glyceryl trinitrate was more effective in reducing the preterm delivery rate. The maternal side effect profile and treatment discontinuation rates were fewer for glyceryl trinitrate, suggesting it was a safer alternative to ritodrine.

Like the prostaglandin analogue gemeprost, glyceryl trinitrate can effect cervical ripening to the extent that it may provide an alternative to prostaglandins for cervical ripening before surgical procedures in the first trimester^;9705 this calls into question its use as a tocolytic.

 

Conclusions

 

 

 

It is reasonable and clinically justifiable not to use tocolytic drugs. 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. There is now sufficient evidence to show that both atosiban and nifedipine are preferable to - mimetics in terms of adverse effect profile. It maybe ethically difficult to justify high costs for a drug treatment that has been shown to make no improvement in outcome and is likely to be administered to many individuals who would respond equally well to a placebo. It would seem that nifedipine, which is inexpensive and the only tocolytic shown to improve neonatal morbidity, should be the drug of choice.

In view of the current lack of evidence for any substantive benefit for the baby from tocolysis, and the possibility of hazard for the mother, the available evidence should be discussed with the woman and her partner and their preferences taken into account in determining her care.

Maintenance tocolysis is not recommended once contractions have been suppressed.^RCOG

 

Sources:

Groom, KM and Bennett, PR. TOG

Tocolytic Drugs For Preterm Labour - RCOG Guideline

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