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: k.groom@ic.ac.uk

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 (-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. 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

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 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 / 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 therefore -mimetics should no longer be the drugs of first choice for tocolysis. Calcium channel blockers (CCB) CCB block transmembrane influx of calcium through voltage dependent channels leading to a reduction in intracellular calcium and therefore in myometrial contractility. There is
25, 26

and

11

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 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.
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

12

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 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 13

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

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.

14

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,

27

which is no better than placebo.

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

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17. Chien YL, Whyte R, Aziz K, Thiessen P, Matthew D, Lee SK. Improved outcome of preterm infants when delivered in tertiary care centers. Obstet Gynecol 2001;98:247252. 18. Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor with indomethacin. Part II double blind study. J Perinat Med 1984;12:25-29. 19. Romero R, Sibai BM, Sanchez-Ramos L, Valenzula GJ, Veille JC, Tabor B. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: A randomized, double blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182:1173-1183. 20. The Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. New Engl J Med 1992;327:308-312. 21. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult fluid infection with gestational age and neonatal outcome among women in preterm labour. Obstet Gynecol 1992;79:351-357. 22. Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J, Silbeman L. Placental pathologic findings in preterm birth. Am J Obstet Gynecol 1991;165:934938. 23. St John EB, Nelson KG, Cliver SP, Bishnoi RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182:170-175. 24. Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytics stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993;168:1247-1259.

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25. Tsatsaris V, Papatsonis D, Goffinet F, Dekker G, Carbonne B. Tocolysis with nifedipine or beta-adrenergic agonists: A meta-analysis. Am J Obstet Gynecol 2001;97:840-847. 26. The World Atosiban versus Beta-agonists Study Group. Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. BJOG 2001;108:133-142. 27. Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulphate for the treatment of preterm labor. Am J Obstet Gynecol 1999;181:1432-1437. 28. Thornton S, Vatish M, Slater D. Oxytocin antagonists: clinical and scientific considerations. Exp Physiol 2001;86.2:297-302. 29. British National Formulary 42. September 2001. Published by British Medical Association and the Royal Pharmaceutical Society of Great Britain. 30. Vermillion ST, Scardo JA, Lashus AG, Wiles HB. The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. Am J Obstet Gynecol 1997;177:256-61. 31. Kirshon B, Moise KJ, Mari G, Willis R. Long-term indomethacin therapy decrease fetal urine output and results in oligohydramnios. Am J Perinatology 1991;8:86-88. 32. Norton ME, Merrill J, Cooper BAB, Kuller JA, Clyman RI. Neonatal complications after the administration of indomethacin for preterm labor. New Engl J Med 1993;329:1602-1607. 33. Macones GA, Robinson CA. Is there justification for using indomethacin in preterm labor? An analysis of neonatal risks and benefits. Am J Obstet Gynecol 1997;177:819824.

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34. Macones GA, Marder SJ, Clothier B, Stamilio DM. The controversy surrounding indomethacin for tocolysis. Am J Obstet Gynecol 2001;184:264-272. 35. Slater DM, Berger LC, Newton R, Moore GE, Bennett PR. Expression of cyclooxygenase types 1 and 2 in human fetal membranes at term. Am J Obstet Gynecol 1995;172:77-82. 36. Sawdy R, Slater D, Fisk N, Edmonds DK, Bennett P. Use of a cyclo-oxygenase type-2 selective non-steroidal anti-inflammatory agent to prevent preterm delivery. Lancet 1997;350:265-266. 37. Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. Neonatal end stage renal failure associated with maternal ingestion of cyclo-oxygenase type-2 selective inhibitor nimesulide as tocolytic. Lancet 1999;354:1615. 38. Groom K, Sawdy R, Elliott C, Shennan A, Bennett P. Experience of the use of Nimesulide, a COX-2 selective NSAI, in the prevention of preterm delivery in high risk cases. J Soc Gynecol Investig 2000;7:60-61A. 39. Crowther CA, Moore V. Magnesium for preventing preterm birth after threatened preterm labour (Cochrane Review). In: The Cochrane Library, Issue 4, 2001: Update Software. 40. Smith GN, Walker MC, Mc Grath MJ. Randomised, double blind, placebo-controlled pilot study assessing nitroglycerin as a tocolytic. Br J Obstet Gynaecol 1999;106:736739. 41. Lees CC, Lojacono A, Thompson C, Danti L, Black RS, Tanzi P, White IR, Campbell S. Glyceryl trinitrate and ritodrine in tocolysis: An international multicenter randomized study. Obstet Gynecol 1999;94:403-408.

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42. Thomson AJ, Burnett Lunan C, Cameron AD, Cameron IT, Greer IA, Norman JE. Nitric oxide donors induce cervical ripening of the human uterine cervix: a randomised controlled trial. Br J Obstet Gynaecol 1997;194:1054-1057. 43. Thomson AJ, Burnett Lunan C, Ledingham M, Howat RCL, Cameron IT, Greer IA, Norman JE. Randomised trial of nitric oxide donor versus prostaglandin for cervical ripening before first-trimester termination of pregnancy. Lancet 1998;352:1093-1096.

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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 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.

25

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 -adrenoreceptors

Ca 2+

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+

26

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 0.12 * (0.05-0.32) 0.07* (0.02-0.27) 1.48 (0.24-9.20 0.61 (0.16-2.30)

Atosiban 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

27

Figure 1.

28

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

Finnstrm 1997.

29