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Acute tocolysis

Edwin Chandraharan and Sabaratnam Arulkumaran

Purpose of review Emergency uterine relaxation may decrease the morbidity and mortality of the mother and her fetus. Obstetricians need to be aware of the indications, pharmacological methods, efcacy and complications of acute tocolysis. Recent ndings A variety of pharmacological agents are used to suppress uterine contractions. Newer agents like cyclo-oxygenase-2 inhibitors (Celecoxib) and oxytocin antagonists (atosiban) have been introduced into clinical practice with the hope of reducing the complications of betasympathomimetic drugs. Calcium-channel blockers are used but there are recent case reports of acute pulmonary oedema with the use of these agents. Most of the trials on tocolytics have been for suppression of preterm labour. Nitroglycerin has been used successfully as an acute tocolytic during Caesarean sections and manual removal of placenta. A recent randomized trial has suggested that atosiban may be an option for acute intrapartum tocolysis. This article will review the recent literature on the use of pharmacological agents used to suppress uterine contractions in emergency obstetric situations. Summary Acute tocolysis may be indicated in antepartum, intrapartum and postpartum periods for a variety of indications. It may help reduce maternal and fetal morbidity and mortality. The ideal tocolytic is yet to be developed. Research is needed to develop a drug which has a greater uterospecicity with no effect on other organs with a rapid onset and a short duration of action. Keywords acute inversion, acute tocolysis, cord prolapse, external cephalic version, fetal distress
Curr Opin Obstet Gynecol 17:151156. # 2005 Lippincott Williams & Wilkins. Division of Obstetrics and Gynaecology, St. Georges Hospital Medical School, London SW17 0RE, UK Correspondence to Professor S. Arulkumaran, Head, Division of Obstetrics and Gynaecology, St. Georges Hospital Medical School, London SW17 0RE, UK e-mail: sarulkum@sghms.ac.uk Current Opinion in Obstetrics and Gynecology 2005, 17:151156 Abbreviation ECV external cephalic version

Introduction
The term tocolysis was coined in 1964 by Mosler [1]. Since its inception, tocolysis has bafed both clinicians and researchers and hence has lived up to its complex terminological origin. Initially, it was intended to stop uterine contractions in threatened or established preterm labour to facilitate the administration of steroids to reduce the incidence of respiratory distress syndrome (RDS) or to ensure in-utero transfer to a tertiary care centre. Acute tocolysis refers to the use of pharmacological agents to relax the uterine myometrium and to abolish uterine contractions that may benet the mother or the fetus. The initial goal of tocolytic therapy was to prevent the adverse consequences of preterm birth. These include neonatal morbidity and mortality, long-term disability (cerebral palsy, neurological sequelae, chronic lung disease) and health-care costs. Unfortunately, the available evidence on the use of tocolytic therapy to prolong pregnancy fails to show any benets in neonatal survival and reduced disability [2]. Over the years the role of tocolytics has been gradually extended to many clinical situations in obstetric practice as an emergency therapeutic measure in antepartum, intrapartum and postpartum periods. In this review we have described clinical situations where acute tocolysis may be employed to improve obstetric and perinatal outcome.

Indications
The use of acute tocolysis may be during the antenatal, intrapartum or postpartum period.
Antenatal period

Apart from suppression of uterine contractions in threatened and established preterm labour, tocolytics are widely used during external cephalic version, during and after fetal surgery and emergency cervical cerclage.
External cephalic version

# 2005 Lippincott Williams & Wilkins 1040-872X

Tocolytics have been used to facilitate external cephalic version (ECV) over the last three decades [3]. Initial studies reported success rates of about 6080% with ECV when tocolytics were used [3,4]. There was also a signicant reduction in the number of vaginal breech deliveries and Caesarean sections [5]. However, subsequent studies questioned the role of tocolytics in external cephalic version and attributed the difference in outcome to parity rather than to the use of tocolytics [6]. There was no difference between the oral and intravenous routes of
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administration of salbutamol [6]. A recent Cochrane Database of Systemic Reviews on interventions to help external cephalic version concluded that routine tocolysis appears to reduce the failure rate of ECV at term [7]. Although the reduction of non-cephalic presentations at birth was not statistically signicant, there was a reduction in the number of Caesarean sections [7]. Betasympathomimetics have been found to be effective, whereas sublingual nitroglycerin was found to be associated with signicant side effects and was not clinically effective [7,8]. Terbutaline is the most commonly used betasympathomimetic agent to achieve tocolysis prior to ECV. It can be administered subcutaneously [9] or intravenously [10] but not by inhalation as it has not been found to be effective when given by this route [11]. Figure 1 illustrates inhibition of uterine activity after the administration of terbutaline by nebulizer and by intravenous route. Effective and rapid uterine relaxation was observed following intravenous administration of terbutaline (250 mg), whereas there was no inhibition with four puffs (1 mg) and minimal inhibition with eight puffs (2 mg) of terbutaline [11]. Intravenous ritodrine was also found to lower Caesarean section rate in breech presentations signicantly by increasing the success rate of ECV [12]. In the light of current evidence, it may be

prudent to use tocolytics selectively prior to ECV. In a primigravida with a tense uterine wall, it may be advisable to relax the uterus prior to the procedure with the use of a betasympathomimetic agent. Conversely, in a multi-gravid patient with lax uterine wall, tocolytics may not be necessary.
Fetal surgery

Figure 1. Percentage change of uterine activity in Groups A, B and C [11]

Group A Group B Group C


140 130

Terbutaline, 4 puffs (1 mg) Terbutaline, 8 puffs (2 mg) Terbutaline, intravenous (250 g)


134.4 135.6 123

120

A
99.7 89.6 100.6 89.5 96.8 90.67

120.8 113.7 106.8

Advances in fetal surgery over the last few decades have contributed to an improvement in perinatal outcome. Fetoscopy is being used increasingly in twin-to-twin transfusion syndrome as well as for corrective procedures. These include in-utero treatment of sacrococcygeal teratomas and correction of cardiac, urological and neural tube defects. Such procedures are associated with the risk of amniorrhexis, intrauterine infections due to the procedures and preterm labour due to inadvertent stimulation of the uterine myometrium. Hence, relaxation of the myometrium by using tocolytic agents prior to, during and after the procedure may help to prevent preterm labour. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia has been found to improve postnatal survival [13]. Recently, intravenous nitroglycerin was found to be effective in maintaining uterine relaxation and placental perfusion during ex-utero intrapartum treatment (EXIT procedure) and this has even furthered their role [14] in obstetric practice. This technique is designed to establish an airway at the time of delivery in fetuses at risk of airway obstruction and requires maintenance of uterine relaxation to continue placental perfusion and prevent placental separation. Recently in-vitro studies using indomethacin have found consistent inhibition or complete arrest of overall myometrial activity [15]. It is hoped that local myometrial delivery of indomethacin through slow-release systems may be developed in future, which may effectively prevent preterm delivery after fetal surgery [15].
Emergency cerclage

Percentage change of uterine activity

110 100 90 80 70 60 50 40 30 20 10 0 0 15 30 45 60 75 16.7 31.7 43.1 43.8 49.1

48.2

90

The effectiveness of prophylactic cerclage in preventing preterm delivery in women with low or medium risk for second trimester pregnancy loss has not been proven [16]. There is a signicant uncertainty among the clinicians with regard to the use of prophylactic cerclage and only about 37% employed adjunctive tocolytics [17]. A recent large multi-centre randomized controlled trial concluded that insertion of cervical cerclage does not substantially reduce the risk of early preterm delivery [18]. Hence, in the light of current evidence, elective cerclage with or without the use of tocolytics cannot be recommended routinely for the prevention of preterm births. Emergency cerclage refers to the insertion of the cervical suture when the cervix is dilated and the membranes are bulging, suggesting that delivery may be imminent. In such circumstances, an emergency cerclage with adjuvant

Minutes

Group A, terbutaline four puffs (1 mg; solid line); Group B, terbutaline eight puffs (2 mg; thin dotted line); Group C, terbutaline intravenous (250 mg; thick dotted line).

Acute tocolysis Chandraharan and Arulkumaran 153

tocolytic therapy may prolong pregnancy and improve neonatal outcome [19]. Fetal survival rates of up to 89% have been reported without any signicant maternal side effects [20]. There is evidence to suggest that although intravenous salbutamol does not prevent or alter the rise in the level of prostaglandins that is found to occur following a cerclage procedure, it was still associated with a good outcome [21]. However, McGahan and Hanson [22] concluded that tocolytics, amniocentesis and cervical cerclage were of little benet in preventing immediate delivery in their small series of patients with prolapsing amniotic membranes through a partially dilated cervix. In the light of current evidence, routine tocolysis cannot be recommended for elective cervical cerclage as recent studies have questioned the very efcacy of this procedure itself [18]. There may be a place for tocolytics in emergency cerclage to delay labour so that measures could be instituted to improve perinatal outcome. A recent randomized cerclage trial concluded that emergency cerclage in combination with tocolysis, antibiotics and bed rest reduced the incidence of preterm delivery before 34 weeks as compared to bed rest and antibiotics alone [23]. The mean interval from randomization to delivery was 54 days in the former group as compared to 20 days in the latter group and this difference was statistically signicant. As most of the studies are limited by small numbers and there were differences in the criteria used to dene the indications for emergency cerclage and tocolysis, it is difcult to determine the efcacy of tocolytics in emergency cerclage and further research is needed to answer this question.
Delayed interval delivery in multiple pregnancies

ritodrine or rectal indomethacin without resorting to cervical cerclage to reduce the risk of chorioamnionitis [27]. There is no doubt that prolonging the delivery interval in multiple pregnancies improves perinatal outcome by reducing the morbidity and mortality associated with extreme prematurity. However, there is insufcient evidence to suggest that tocolytics are solely responsible for the prolongation of pregnancy because most studies have also employed cervical cerclage and antibiotics. A recent multi-centre study on delayed delivery of the second twin reported a mean delivery interval of 47 days and a survival of 7 and 79% for the rst and second fetus, respectively [28]. Acute tocolysis may be a valuable tool in delaying delivery of the second or higher-order fetuses in multiple pregnancies, despite the lack of evidence. It is important to exclude contraindications like chorioamnionitis and fetal malformations prior to instituting this treatment. The patients should also be counseled regarding the possibility of sepsis, coagulation abnormalities and the possibility of long-term neurological sequelae in the surviving fetus.
Intrapartum period

Acute tocolysis may prove to be invaluable in many intrapartum obstetric emergencies like uterine hyperstimulation, cord prolapse, acute fetal distress and previously undiagnosed malpresentations presenting in labour, prior to and during Caesarean sections as well as during the Zavanelli manoeuvre in cases of shoulder dystocia.
Acute relaxation of the uterus

Preterm delivery remains one of the most feared complications of multiple pregnancies resulting in perinatal morbidity and mortality, which are primarily related to the gestational age. The critical period for perinatal morbidity and mortality in twin and other high-order multiple pregnancies is between 23 and 28 weeks. The birth of the rst fetus at an early gestational age is often followed by the unavoidable delivery of the other fetuses. Hence, any successful delay in delivering subsequent fetuses may improve their survival and tocolysis has been used in combination with cervical cerclage and antibiotics in this regard. Their use in triplet pregnancies has been reported with good maternal and perinatal outcome [24]. Recently, aggressive tocolysis has been recommended in high-order multiple pregnancies to improve the outcome provided that there are no signs of chorioamnionitis, fetal distress or maternal compromise [25]. In a review of the literature on delayed interval delivery in twin pregnancies using tocolytics, Wittmann et al. [26] reported a survival rate of 48.9% for the second twin. Similar results have been reported in another series using intravenous

In many clinical situations it may be necessary to cause an immediate uterine relaxation to improve maternal and fetal outcome. Uterine hyperstimulation due to injudicious administration of oxytocic agents (prostaglandins or oxytocin) is one such example. Rarely, it may occur de novo in spontaneous labour. This condition can be detrimental to the mother (uterine rupture in the presence of obstruction or previous uterine scar) as well as the fetus, which may develop acute fetal hypoxia or fetal distress and its consequences, including meconium aspiration syndrome and fetal death. Rapid uterine relaxation with tocolytic agents is required and most often labour can be allowed to progress if the fetal heart rate improves after tocolysis. Hence, acute tocolysis may salvage the fetus as well as help prevent an unnecessary operative procedure. Similarly, acute tocolysis is useful in fetal distress due to cord prolapse or any other reason, when urgent delivery by Caesarean section is contemplated. By relaxing the uterus and improving the uteroplacental circulation, it helps in fetal resuscitation in utero, which may improve the neonatal outcome. The Cochrane Database of Systemic Reviews on Tocolytics for suspected intrapartum fetal distress concluded that betamimetics appeared to reduce the fetal heart-rate abnormalities and perhaps

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reduce uterine activity. However, there was no evidence to suggest an improvement in clinical outcome [29]. To date, there is no evidence to suggest that intrauterine resuscitation with betasympathomimetics is associated with fetal metabolic effects, including lactic acidosis [30]. A recent prospective randomized controlled trial on acute tocolysis and intrauterine resuscitation revealed that both atosiban and hexoprenaline were effective in stopping uterine contractions. Atosiban was associated with more prompt resumption of uterine contractions and low incidence of maternal side effects [31]. Acute tocolysis can be employed to optimize the fetal condition prior to an emergency Caesarean section. The indications include undiagnosed malpresentations, fetal distress in the second of twins and Zavanelli manoeuvre in shoulder dystocia. In such circumstances acute tocolysis, by relaxing the myometrium, ensures adequate uteroplacental circulation and reduces the chances of fetal compromise. Rarely, if the operating theatre is busy, acute tocolysis may be employed for in-utero resuscitation of the fetus while awaiting an emergency Caesarean section.
Acute tocolysis during Caesarean section

section were found to be 1 in 3734 and 1 in 1860, respectively [35]. It was complicated by postpartum haemorrhage in 65% of patients and 47.5% required blood transfusion [35]. Tocolytics like magnesium sulphate, terbutaline and halogenated anaesthetics may be used to relax the uterus and to enable replacement of the fundus. Intravenous nitroglycerin provides an alternative to these traditional tocolytics in acute uterine inversion and offers several pharmacodynamic advantages [36].

Emergency tocolytic drugs in current practice


Halogenated anaesthetic agents were used earlier and these have been largely replaced by betasympathomimetic agents, magnesium sulphate and nitroglycerin. Recently, oxytocin antagonists (atosiban), calcium-channel blockers and cyclo-oxygenase inhibitors are being increasingly used in the suppression of preterm labour. However, there is insufcient evidence regarding their safety and efcacy in suppressing uterine contractions in established labour.
Betasympathomimetics

Technical difculties may be experienced in delivering a fetus during a Caesarean section. Transverse lie or neglected shoulder presentation in advanced labour, preterm breech delivery and second-stage Caesarean section are some examples. Intravenous betasympathomimetics as well as sublingual and intravenous nitroglycerin have been used for this purpose and both these agents have been found to be safe to be used with epidural anaesthesia [32]. A prospective trial concluded that there were no major side effects like postpartum haemorrhage or hypotension with sublingual glyceryl trinitrate and the uterus responded well to standard oxytocic regimens post-delivery [33].
Postpartum period

These are the most frequently used agents for acute tocolysis and act through G proteins, increasing the intracellular concentrations of cAMP, and thereby the enzyme protein kinase A. Release of calcium from the sarcoplasmic reticulum is prevented, leading to muscle relaxation. Intravenous ritodrine (6 mg drawn up in 10 ml of normal saline and administered over 23 min) or terbutaline (250 mg in 5 ml of saline over 5 min) are commonly used. Maternal side effects include tachycardia, hypotension and pulmonary oedema; hence patients on betasympathomimetic drugs should be carefully monitored. Table 1 shows the changes in maternal parameters after the administration of terbutaline by nebulizer and by intravenous route [11]. There were no signicant changes in maternal parameters after four puffs (1 mg)
Table 1. Maternal parameters after administration of terbutaline [11] Time (min). . . Maternal parameters 300 015 1530 3045 4560 6075 Group A Systolic (mmHg) Diastolic (mmHg) Pulse (b.p.m.) Group B Systolic (mmHg) Diastolic (mmHg) Pulse (b.p.m.) Group C Systolic (mmHg) Diastolic (mmHg) Pulse (b.p.m.) 120 78 81 115 79 81 119 76 84 116 78 82 17 80 80 112 72 109 116 79 82 119 80 80 122 73 100 117 79 83 119 80 81 121 75 94 117 79 84 117 80 80 121 77 94 114 78 81 118 79 81 120 77 94

Acute tocolysis may be indicated when the placenta gets retained after being separated from the uterine wall due to the formation of a contraction or retraction ring. Although earlier inhalational relaxants like halothane and general anaesthesia were employed, intravenous nitroglycerin with epidural anaesthesia for pain relief is efcacious and is associated with minimum haemodynamic disturbances [34]. It is also useful in patients with co-morbid chronic heart conditions like rheumatic heart disease and its high efcacy and short duration of action make it a safe alternative. Acute puerperal uterine inversion is a rare but potentially life-threatening complication in the third stage of labour. If unrecognized, it can lead to severe haemorrhage, shock and maternal death. In a recent review the incidence of acute inversion after vaginal delivery and Caesarean

Group A, terbutaline 4 puffs (1 mg); Group B, terbutaline 8 puffs (2 mg); Group C, terbutaline intravenous (250 mg). Signicant rise in the pulse rate up to 30 min (P < 0.05).

Acute tocolysis Chandraharan and Arulkumaran 155

and eight puffs (2 mg) of terbutaline. Intravenous administration of terbutaline (250 mg) was associated with an increase in the pulse rate which gradually returned back to normal [11]. Alternatively, 250 mg of terbutaline may be administered subcutaneously and the National Institute of Clinical Excellence (NICE) and the Royal College of Obstetricians and Gynaecologists have recommended this approach [37]. It has been suggested that 1 mg of propranolol can be injected intravenously to reverse the effects on the myometrium after the delivery [38]. Betasympathomimetics have also been tried for preventing fetal distress in the second stage of labour. A Cochrane Review on tocolysis for preventing fetal distress in second stage of labour concluded that there was no evidence to support their use for this indication [39].
Nitroglycerin

used in the suppression of preterm labour and recently its side-effect prole has been analysed [43]. An initial loading dose of 4 g is given intravenously, followed by an intravenous maintenance dose of 5 g/h. To minimize the side effects, a lower maintenance dose of 2 g/h is sometimes used. However, a recent prospective randomized controlled trial concluded that higher maintenance of magnesium sulphate was associated with more rapid tocolysis without any increase in maternal and neonatal morbidity [44].

Atosiban

This is an ester of nitric acid, which is metabolized rapidly by the liver and hence has a short half-life of 22.5 min. Acting through the cGMP mechanism, it produces smooth muscle relaxation by preventing actinmyosin interaction. Sublingual administration of nitroglycerin (400 mg) using aerosol sprays has been tried but this may not be effective due to unpredictable mucosal absorption during pregnancy. A prospective trial concluded that it is a safe form of uterine relaxation during Caesarean section with minimal side effects [33]. Recently, it has also been used as a sublingual tablet form for manual removal of placenta without any overt side effects [40]. Intravenous administration remains the most preferred route of administration for acute tocolysis in obstetric practice. A dose of 100200 mg often results in rapid and effective uterine relaxation without any signicant side effects to mother and fetus [41]. The effect is usually evident within 90 s and lasts for about 12 min. The dose may have to be repeated every 2 min until adequate uterine relaxation is obtained. Generalized smooth muscle relaxant effect may cause vasodilatation and hypotension; therefore hypovolumia and hypotension should be corrected prior to its administration. It has been reported that the tocolytic effect of nitroglycerin can be easily reversed with oxytocin, ergometrine and prostaglandin F2a [42]. A recent retrospective review has suggested that it is safe to be used in Caesarean breech delivery with epidural anaesthesia when a traumatic delivery is anticipated or encountered [32].
Magnesium sulphate

This is an oxytocin antagonist which binds to the oxytocin receptor and blocks its action on G-protein. This suppresses the activity of the enzyme phospholipase C leading to the inhibition of release of calcium ions from sarcoplasmic reticulum mediated through the inositol phosphate pathway. Reduction in intracellular calcium ion concentration results in muscle relaxation. The Royal College of Obstetricians and Gynaecologists has recommended atosiban as the preferred agent over ritodrine for the suppression of preterm labour [45]. Currently there is limited evidence supporting its use in emergency obstetric situations to bring forth acute uterine myometrial relaxation. Recently a prospective randomized pilot study has suggested that atosiban may be used for acute intrapartum tocolysis for fetal distress [31].

Conclusion
Acute tocolysis is a useful tool in obstetric emergencies. It is important for the practising clinician to be aware of indications, contra-indications and side effects of various tocolytic agents that are available. They are not suitable for patients with cardiovascular disease, hypovolumia and hypotension due to their vasodilator effects. It is also important to realize that reversal of their effects may become necessary to prevent atonic postpartum haemorrhage after their use. Unfortunately, there is insufcient evidence on tocolytic agents used commonly to suppress preterm labour, like calcium-channel blockers, cyclooxygenase inhibitors and oxytocin antagonists (atosiban), with regard to their efcacy on acute tocolysis. Further research is needed to develop a pharmacological agent with greater utero-specicity with minimal maternal and fetal side effects.

References and recommended reading


Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest 1 Keirse MJ. The history of tocolysis. Br J Obstet Gynaecol 2003; 110(Suppl 20):9497.

Magnesium sulphate acts by inhibiting the transport of calcium ions through the voltage-gated calcium channels and by preventing the release of calcium ions from the sarcoplasmic reticulum. The net effect is a reduction in intracellular concentration of calcium ions leading to decreased activity of the calmodulin-dependent myosin light-chain kinase. Actinmyosin interaction is thus prevented, resulting in muscle relaxation. This has been

2 Klam SL, Leduc L. Management options for preterm labour in Canada.  J Obstet Gynaecol Can 2004; 26:339345. This is a review of 32 randomized controlled trials which failed to show any benets in neonatal survival or reduced disability with the use of tocolytic agents.

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7 Hofmeyr GJ. Interventions to help external cephalic version for breech pre sentation at term. Cochrane Database Syst Rev 2004; 1:CD 000184. This review analysed various tocolytic agents used to aid external cephalic version and concluded that routine tocolysis appears to reduce the failure rate of external cephalic version at term. 8 Bujold E, Boucher M, Rinfret D, et al. Sublingual nitroglycerin versus placebo  as a tocolytic for external cephalic version: a randomized controlled trial in parous women. Am J Obstet Gynecol 2003; 189:10701073. A recent randomized controlled trial which concluded that sublingual nitroglycerin did not improve the success rate of external cephalic version. 9 Fernandez CO, Bloom SL, Smullian JC, et al. A randomized placebo-controlled evaluation of terbutaline for external cephalic version. Obstet Gynecol 1997; 90:775779.

10 Ingemarsson I, Arulkumaran S, Ratnam SS. Single injection of terbutaline in term labour. II. Effect on uterine activity. Am J Obstet Gynecol 1985; 153:865869. 11 Kurup A, Arulkumaran S, Tay D, et al. Can terbutaline be used as a nebuliser instead of intravenous injection for inhibition of uterine activity. Gynecol Obstet Invest 1991; 32:8487. 12 Brocks V, Philipsen T, Secher NJ. A randomized trial of external cephalic version with tocolysis in late pregnancy. Br J Obstet Gynaecol 1984; 91:653656. 13 Deprest J, Gratacos E, Nicolaides KH. Fetoscopic tracheal occlusion  (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004; 24:121 126. A recent series of 21 cases, which reported successful treatment of severe congenital diaphragmatic hernia using a minimally invasive technique with improvement in the postnatal outcome. 14 Clark KD, Viscomi CM, Lowell J, Chien EK. Nitroglycerin to establish a fetal airway (EXIT procedure). Gynaecology 2004; 103:11131115. 15 Garza J, Clayton N, Kaviani A, et al. In situ inhibition of uterine activity by indomethacin: Possible relevance to preterm labour prevention after fetal surgery. J Paediatr Surg 2004; 39:11731175. 16 Drakeley AJ, Roberts D, Alfrevic Z. Cervical cerclage for the prevention  of preterm delivery: meta-analysis of randomized controlled trials. Obstet Gynaecol 2003; 102:621627. A recent meta-analysis which questioned the effectiveness of prophylactic cervical cerclage in preventing preterm delivery in women with low or medium risk. 17 Pramod R, Okun N, McKay D, et al. Cerclage for the short cervix demonstrated by transvaginal ultrasound: current practice and opinion. J Obstet Gynaecol Canada 2004; 26:564570. 18 To MS, Alfrevic Z, Heath VC, et al. Cervical cerclage for prevention of preterm  delivery in women with short cervix: a randomized controlled trial. Lancet 2004; 363:18491853. A large multi-centre randomized controlled trial which concluded that insertion of cervical cerclage in women with a short cervix does not substantially reduce the risk of early preterm delivery. 19 Hordnes K, Askvik K, Dalaker K. Emergency McDonald cerclage with application of stay sutures. Eur J Obstet Gynecol Reprod Biol 1996; 64:4349. 20 Novy MJ, Haymond J, Nichols M. Shirodkar cerclage in a multifactorial approach to the patient with advanced cervical changes. Am J Obstet Gynecol 1990; 162:14121419. 21 Toplis PJ, Shepherd JH, Youssesmejadian E, et al. Plasma prostaglandin concentrations after cerclage in early pregnancy. Br J Obstet Gynaecol 1980; 87:669671. 22 McGahan JP, Hanson F. Prolapsing amniotic membranes: detection, sonographic appearances and management. J Perinatol 1987; 7:204209.