- Email: [email protected]
Methods of induction
&&&” i
,GYNAECOLOGYJ Mini-symposium: Induction of labour
Methods of induction
J. E. Brennand
and A. A. Calder
Labour induction should only be employed when the obstetrician believes that it will lead to an improved outcome to the pregnancy for mother or baby. The methods employed should mimic as closely as possible the process of spontaneous labour. The emergence of new pharmacological options such as relaxin and mifepristone raises the prospect of further improvements towards this objective, but for the moment prostaglandins E, administered locally within the genital tract offers the best option for cervical ripening (if required) and induction of labour.
Introduction
to those cases in which the balance of risks to the mother or her offspring or both between continuation or interruption of the pregnancy has tipped in favour of interruption. There is no merit in replacing one set of risks in pregnancy for another set in labour. In some cases of severe fetal compromise elective Caesarean section will be the better option. In most instances, induction of labour will be appropriate but if possible such induced labours should mimic an easy spontaneous labour. The onset of spontaneous labour is not a sudden event, but rather the result of changes which occur in the uterus and cervix that together are known as prelabour. During this phase of prelabour there is an increase in uterine contractility and an alteration in the shape and compliance of the cervix, otherwise known as cervical ripening. Caldeyro-Barcia’ demonstrated that there is a progressive increase in uterine contractility from about 35 weeks gestation culminating in clinical labour at term. In addition to these uterine changes, the cervix transforms from a rigid sphincter to a soft compliant structure capable of undergoing effacement and dilatation. Both of these processes are mandatory for the onset of spontaneous labour and successful expulsion of the fetus. If induction of labour is to be successful it must be as physiological as possible. The changes which
Induction of labour has been practiced by obstetricians for centuries. 20 years ago it became the subject of heated controversy in the media. This coincided with, on the one hand, a rise in the rates of induction in many maternity hospitals to levels that could not be justified on purely clinical grounds and, on the other hand, the rise of consumerism in obstetrics. These last two decades have taught us the imperative of recognising the need to confine induction of labour to pregnancies in which a genuine benefit of induction for the mother or her offspring can be perceived. It is also vital to take time to explain and discuss the situation with the mother and sometimes also with the father. Some mothers may resist the idea of induction from a belief that interference with nature is inherently wrong while others may clamour for delivery against the judgement of the obstetrician and we must take the mother along with us in determining the best management for each individual case. The indications for intervention may be many and varied. Interruption of pregnancy should be confined J. E. Brennand, A. A. Calder*, Department of Obstetrics and Gynaecology, University of Edinburgh, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9EW, UK *Address correspondence to A.A.C. Currenr 0bsterric.v and ~ynaecolo~~ Q 1994 Longman Group Ltd
( 1994, 4, 79-84
79
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CURRENT OBSTETRICS AND GYNAECOLOGY
take place in the cervix occur gradually and, clearly, the later in pregnancy the closer is the spontaneous onset of labour, and therefore the easier a proposed induction will be. It is the woman with an unfavourable cervix who has not undergone any of these changes that represents the greatest challenge with regard to labour induction. It is relatively easy to establish uterine activity in the presence of either a ripe or an unripe cervix. However, only in the former clinical situation is the ensuing labour likely to result in a successful outcome and indeed the amount of uterine activity necessary for cervical dilatation is dependent on the state of the cervix. The ultimate aim of induction is to achieve a vaginal delivery with a healthy mother and baby: the process not merely being a prelude to Caesarean section. Cervical ripening A variety of options are available to enhance the ripeness of the cervix prior to induction of labour. Prostaglandins Prostaglandins are strongly implicated in the process of parturition. The onset of spontaneous labour is associated with an increase in prostaglandin E, and Fza in amniotic fluid’ and in the maternal peripheral circulation.3 Early work on amniotic fluid concentrations of the primary prostaglandins suggested that each has an important but differing role in the labour process with E implicated in early labour and Fzm the major prostaglandin as labour becomes established.4*5 A recent longitudinal study of peripheral plasma prostaglandin metabolite levels throughout labour confirms these findings with the major increase in PGE metabolite occurring in early labour while the increase in PGF metabolite occurred as labour progressed.6 In addition, dysfunctional labour was associated with significantly lower PGF metabolite levels; decreased amniotic fluid PGF2, levels have been found in a similar group of patients. The cervix synthesises prostaglandin E2’, production increasing at the time of labour. Therefore, it may be that PGE, is primarily involved in cervical ripening, whereas PGF2= is responsible for promoting and maintaining uterine activity. Based on these concepts, the pharmacological use of prostaglandins is a logical approach to cervical ripening in the clinical setting. Prostaglandins were first employed for the induction of labour in the late 1960s. These agents had an effect on the consistency of the cervix when used in doses smaller than those required for labour induction itself.* This led to extensive investigation of their potential use as cervical ripening agents. Prostaglandins are currently the most successful pharmacological agents used to promote cervical ripening. A systematic overview’ of all placebo and no treatment-controlled investigations of prostaglandin treatment for cervical ripening has shown that
this treatment does confer considerable benefits. There is a significant effect on cervical ripeness; a reduction in failed induction rates; decreased induction to delivery interval and a reduction in the operative delivery rate. Accepting that prostaglandins are currently the drug of choice attention must be turned to type, vehicle and route of administration of these agents. Prostaglandin E,, which is 5-10 times more potent than PGF,, and will produce similar cervical effects at a much lower dose and so a lower incidence of side effects, is the main prostaglandin employed for ripening. The route of administration of prostaglandins is governed by their physiological properties. Firstly, they are synthesised or released at or near their target organ and secondly they are very rapidly broken down to inactive metabolites. Local application is therefore appropriate for maximum effect. Three options are available; extra-amniotic, endocervical or vaginal routes. Prostaglandin E, was first used for cervical ripening via the extra-amniotic route.8 This technique proved highly successful with regard to reduction in the induction-delivery interval and Caesarean section rate’ and indeed when compared with vaginal or endocervical administration it is the route most likely to result in the onset of spontaneous labour.” However, disadvantages associated with the extraamniotic route include introduction of infection, uterine hypertonus resulting from rapid uptake via the choriodecidual space and, importantly, patient discomfort when introducing the catheter. Because of this it has been superseded by vaginal or endocervical application. The extra-amniotic route may be useful for the extremely unripe cervix, but in such a situation where prompt delivery is necessary it could equally be argued that Caesarean section is the better option. Two preparations of PGE, in a viscous gel are currently available for endocervical administration. One is a triacetin-based gel marketed as Prepedil (Upjohn) and the other is a starch-based gel marketed in Europe as Cerviprost (Organon). The work of Ulmsten and his colleagues in Sweden has led to the increasing popularity of this route for cervical ripening. Its success depends on the volume of gel that remains within the endocervical canal without overspill into either the extra-amniotic space or the vagina. The dose employed is 0.5 mg. The cervical ripening effect of the endocervical route is superior to that of the vaginal route in women with a very low Bishop score (l-3).” In addition, the endocervical route appears to be the most specific in its effect on the cervix, stimulating cervical ripening in the virtual absence of uterine activity. Vaginal application is the route most commonly used for cervical ripening in the UK, and PGE, is available in gel and tablet form for this purpose. The early placebo-controlled trials to determine the efficacy of vaginal gel used home-made preparations
METHODS OF INDUCTION
with the inherent problem of unpredictable pharmacodynamics, hence the wide range of doses investigated. l2 The commercial development of both vaginal gel and tablets has removed these problems and the agents currently favoured are the triacetin based vaginal gels containing a dose of 1 or 2 mg of PGE2 (Upjohn) and the 3 mg lactose vaginal tablet (Upjohn). Studies comparing the two vehicles have shown that the gels have greater efficacy and bioavailability than the tabletsi Our cervical ripening policy is to administer 2 mg of PGE2 gel vaginally in the early evening. If, by morning, there has been no change in the Bishop score, and no regular uterine activity, the 2 mg dose is repeated. A number of women may require a third dose 6 h later, but thereafter there is no benefit from further vaginal applications. At this point the options are to reconsider the indication for induction, resort to extra-amniotic administration, proceed to amniotomy or consider Caesarean section. Relaxin Ideally cervical ripening agents should promote change without simultaneously stimulating uterine activity. This cannot be achieved with exogenous prostaglandins which generally do both. Relaxin is a polypeptide hormone which is involved in connective tissue remodelling and theoretically the inhibition of spontaneous uterine activity. Its exact role in human parturition remains unclear. However, the concept that this hormone could achieve cervical ripening pharmacologically without promoting uterine contractility is an attractive one, and has been the subject of some research. Trials have shown some therapeutic benefit14 although the numbers recruited were small, and the subjects of mixed parity, limiting the conclusions that can be drawn from them. Mifpristone The role of progesterone in the initiation of human parturition remains unclear. In the sheep there is a well documented fall in circulating levels of plasma progesterone prior to the onset of spontaneous labour, but this is not the case in humans. However, plasma levels do not necessarily reflect local changes and a mechanism whereby a local decrease in progesterone occurs may be sufficient to trigger spontaneous labour. Mifepristone (RU 486) is a synthetic steroid compound which has both antiprogestagenic and antiglucocorticoid activity, and it exerts these effects at receptor level. The two main clinical effects of this drug are generation of spontaneous uterine activity with an accompanying increase in sensitivity to oxytocic agents,i5 and promotion of cervical ripening with a corresponding reduction in the force necessary to dilate the cervix.i6 As a result, mifepristone has an established role as a medical abortifacient in both the first and second
81
trimesters of pregnancy. The exact mechanism of action of mifepristone in inducing these effects remains unknown. However, prostaglandins are implicated in the process. In vitro studies of cultured decidual cells have shown increased PGF,, production in response to treatment with mifepristone.17 Similarly, treatment with mifepristone in vivo resulted in increased production of PGF,, and decreased PGF metabolite production by cultured decidual cells. l8 Since mifepristone is clearly capable of terminating pregnancies of early gestation, and has the capacity to promote the changes in cervical compliance that we are aiming to achieve when ripening the cervix pharmacologically at term, it is appropriate to explore its potential at later gestations. The first study looking at mifepristone for labour induction at term has been reported by Frydman et al.19 This was a double-blind, placebo-controlled study of 120 women with a Bishop score less than 4. Patients randomly assigned to the treatment group received 200 mg of mifepristone daily for 2 days, and were then induced on day 4 if spontaneous labour had not already occurred. The onset of spontaneous labour was significantly more frequent in the treatment group compared to the controls (54% vs 18% respectively, p
Induction of labour Oxytocin Based on the work of Turnbull & Anderson2’ oxytocin, in combination with amniotomy, has until recently been the most widely favoured method of labour induction. The success of this approach is dependent on the state of the cervix. Oxytocin has little, if any, effect on cervical compliance and therefore is less efficacious in inducing labour when the cervix is unfavourable. It has proved to be a highly effective method of induction, when the cervix is favourable. Administration is via intravenous infusion which has superseded the buccal or sublingual route and this should not be commenced until amniotomy or spontaneous rupture of the membranes has occurred. Amniotomy results in prostaglandin release from within the uterus, which in turn sensitises the myometrium to oxytocin with the potential hazard of uterine hyperstimulation. The timing of amniotomy is crucial to the induction process. It should be performed when the cervix is ripe, ideally fully effaced and 3 cm dilated. If performed too early, amniotomy will result in a prolonged labour often
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culminating in an operative delivery. Oxytocin infusion can be commenced immediately following amniotomy although some clinicians prefer to wait for about 1 h to assess the uterotonic effect of amniotomy alone. The policy in our department is to administer oxytocin (20 iU/L) as a continuous infusion starting at a rate of 2 mU/min and doubling this every 15 min to a maximum of 32 mU/min. With a clearer understanding of physiological oxytocin secretion the traditional continuous infusion regimes are being questioned. Oxytocin is secreted in a pulsatile fashion during pregnancy and spontaneous labour with approximately three spurts per 10 min during normal parturition.21 It may, therefore, be more rational to deliver oxytocin pharmacologically in a pulsatile manner, particularly since myometrial oxytocin receptor sites are unavailable once occupied. In a comparison of pulsatile with continuous oxytocin infusion Odem et al” showed that there was no significant difference in the time to adequate labour, the induction to delivery interval or the vaginal delivery rate. The peak dose and total amount of oxytocin administered were however significantly lower in the pulsed group (p ~0.05). These findings have been confirmed in a larger prospective study controlled for parity and Bishop score.23 There appear to be two phases of uterine activity induced by oxytocin. 24 Initially an incremental phase of about 2 h followed by a stable phase during which time there is no further increase in uterine activity. Increasing doses of oxytocin in the stable phase will not augment uterine contractions but rather predispose to uterine hyperstimulation. Once the stable phase has been reached and labour is successfully established a much smaller dose of oxytocin (e.g. 8 mU/min) is required to maintain the labour, possibly due to increased myometrial receptiveness or stimulation of prostaglandin production. Prostaglandins
In addition to being the agents of choice for cervical ripening, prostaglandins may also be preferred for induction of labour when the cervix is favourable. The prostaglandin used is E,, applied locally. Prostaglandin F,, should no longer be used and intravenous administration of prostaglandins abandoned. For primigravid women the initial dose of PGE, is usually 2 mg. This can be repeated 6 h later in a dose of 1 or 2 mg depending on the change in Bishop score. Problems with uterine hyperstimulation can be reduced if care is taken with the second dose. If there is no change in the Bishop score, and in the absence of uterine activity, it is usually safe to repeat the 2 mg dose. If there has been improvement in the Bishop score then 1 mg may be enough. In the presence of uterine activity and a changing cervix yet too unfavourable for amniotomy it is safest to wait for a few hours until amniotomy is appropriate. Thereafter labour may progress without further
intervention to delivery, but oxytocin may be required to augment uterine activity in some cases. Parous women should receive 1 mg of PGE2 initially, which is usually sufficient to enable amniotomy 4-6 h later. The timing of amniotomy is not as crucial in these patients and complete effacement of the cervix is not a prerequisite. If a second dose of PGE, is required this should always be 1 mg. An alternative approach for favourable inductions, especially in parous women, is amniotomy followed 2 h later, if labour is not established, by oral PGE2 tablets. The dose is 0.5 mg every 30 min until the onset of regular uterine activity, up to a maximum of six doses. This approach has now lost favour in most departments. Keirse and Van Oppen25 have presented a metaanalysis of 29 controlled trials comparing prostaglandins with oxytocin for labour induction. There is no difference in the likelihood of being delivered by any route within 12 h between prostaglandin or oxytocin induction. However, if undelivered after 12 h, there is more likelihood of remaining undelivered at 24 and 48 h if induced with oxytocin. There was no difference in the Caesarean section rates between the groups, but the incidence of instrumental vaginal delivery was significantly lower in the prostaglandin group. There was also a decreased need for analgesia in the prostaglandin group. These findings, plus the important factor of much improved patient acceptability, have led to the increasing use of prostaglandins in place of oxytocin for induction of labour.
Other clinical settings Previous Caesarean section
As the global rates of Caesarean section continue to rise there is a corresponding increase in the number of women entering a subsequent pregnancy with a uterine scar. Management of these patients is tending to divert from the traditional dogma of ‘once a section always a section’ to anticipation of a vaginal delivery. This is obviously most likely to be successful if spontaneous labour occurs, but, if this is not the case there is the problem of labour induction and the most appropriate method in the presence of a uterine scar. The major concern when inducing these patients is the risk of scar rupture. The following discussion is confined to women with one previous lower segment Caesarean section scar. Prostaglandins induce frequent, low amplitude contractions with a net decrease in total uterine effort required to achieve cervical dilatation when compared with oxytocin, and theoretically this should reduce the risk of scar rupture. MacKenzie et a126administered PGE, intravaginally to 143 women at term with a previous Caesarean section scar. Of the total study population, 76% achieved a vaginal delivery. Importantly, 68% of the patients with an unfavourable cervix (Bishop score O-3) delivered vaginally. However, of those patients whose original section
METHODS
was for failed induction or slow progress, 40% required repeat Caesarean section compared to only 21% of the remaining patients. There were two cases of suspected scar rupture in the study, neither of which was confirmed, and both of these patients had been augmented with oxytocin. In a larger analysis of 439 patients 27 the vaginal delivery rate was 75% with five observed cases of uterine ‘damage’ (1.1%): one case of rupture and four of dehiscence. Three of these patients received two applications of PGE, and all were given intravenous oxytocin. The addition of a second oxytocic agent appears to identify a group at increased risk of scar rupture, however the incidence of uterine rupture/dehiscence reported in this study compares favourably with that found in spontaneous labour and labour induced without prostaglandins. The requirement for large doses of oxytocics should be reduced if cervical ripening is achieved prior to induction and hence the risk of scar rupture minimised. A recent study reported the results of intracervical PGE, for cervical priming prior to induction of labour in patients with one previous Caesarean section.28 PGE, gel 0.5 mg was administered to 30 women with a cervical score of <5. The overall Caesarean section rate for the study was 27% and of these only two were for failed cervical priming. 50% of the patients delivered vaginally within 24 h of treatment and only two of these women required oxytocin augmentation. Only three patients remained undelivered at 48 h post-treatment: one achieved a vaginal delivery and two required repeat Caesarean section. There was no evidence of uterine scar damage at any of the Caesarean sections. Prostaglandins are not contraindicated in the management of women with a previous lower segment Caesarean section scar. Our own policy is to administer 1 mg PGE, gel intravaginally. Opinion varies as to whether a second dose should be given if required, or whether early recourse to repeat section is a safer option. It should be recognised that the addition of a second oxytocic agent apparently increases the risk of uterine scar rupture whilst simultaneously decreasing the chance of a successful vaginal delivery. Early rupture
qf membranes at term
The debate regarding the management of women with early rupture of the membranes at term continues. The main dilemma is whether or not to intervene, and if so, the most effective method. Active management is favoured by some in an attempt to reduce the risk of maternal and neonatal infection, whereas others argue that conservative management decreases the incidence of Caesarean section. Studies have been reported which confirm either view point. Traditionally, intravenous oxytocin has been employed in this clinical setting. However, prostaglandins are not contraindicated in the presence of
OF INDUCTION
83
ruptured membranes. As is the case with intact membranes. the cervical state is the greatest predictor of success. When the Bishop score is favourable, particularly in parous women, oxytocin is still extremely effective. However in the presence of an unfavourable cervix this is not the case. In a comparison of vaginal PGE, and intravenous oxytocin for the management of 29 women with a cervical score 6 5 and PROM at term, Ekman et alz9 reported that 60% of women were delivered within 24 h of PGEz therapy compared with only 10% of the oxytocin group. In addition, there were no Caesarean sections performed in the PGE, group compared with a rate of 40% in the oxytocin group. In fact, all the women in the oxytocin group undelivered after 24 h of treatment had an operative delivery of some form. There were no cases of hyperstimulation and neonatal Apgar scores were slightly better in the PGE, group. They found that the main improvement in cervical score occurred within 5 h of PGE, treatment and therefore a second dose of PGE, should be administered approximately 6-8 h after the initial dose. Once the decision has been made to institute active management of PROM at term the chosen method should be tailored according to the Bishop score. If the cervix is favourable intravenous oxytocin will be successful in most cases. An alternative approach, usually confined to parous women, is oral PGE, tablets administered as previously described. If the cervix is unfavourable, PGE, gel should be administered. In our department this is given intravaginally in an initial dose of 1 mg for parous women and up to 2 mg for primigravidae.
References I. Caldeyro-Barcia 2.
3.
4.
5.
6.
I.
8. 9.
R. Uterine contractility in obstetrics. Proceedings of the Second International Congress of Gvnaecoloev and Obstetrics. Montreal 1: 655x3 Hillier K, &der AA, Embrey MP. Concentrations of prostaglandin F,,__in amniotic fluid and plasma in spontaneous labour and induced labours. J Obstet Gynaeco Br Cwlth 1974; 81: 257-63 Mitchell MD, Flint ADF, Bibby J et al. Plasma concentrations of prostaglandins during late human pregnancy: influence of normal and preterm labour. J Clin Endocrinol Metab 1978: 46: 947.-51 Keirse MJNC. Tumbull AC. E prostaglandins in amniotic fluid during pregnancy and labour. J Obstet Gynaecol Br Cwlth 1973: 80: 970-3 Keirse MJNC, Flint APF. Tumbull AC. F prostaelandins in amniotic fluid during pregnancy and labour. Obsiet Gvnaecol Br Cwlth 1974: 81: 131-S Johnston TA, Greer IA, Kelly RW. Calder AA. Plasma prostaglandin metabolite concentrations in normal and dysfunctional labour. Br J Obstet Gynaecol 1993; 5: 483 -488 Ellwood DA. Mitchell MD, Anderson AB, Tumbull AC. The in vitro production of prostanoids by the human cervix during pregnancy: preliminary observation. Br J Obstet Gynaecol 1980; 87: 210-214 Calder AA, Embrey MP. Prostaglandins and the unfavourable cervix. Lancet 1973; ii: 1322- 1323 Keirse MJNC. Prostaglandins in preinduction cervical ripening-meta-analysis of worldwide clinical experience. J Reprod Med 1993: 38 (1 supp): 899100 L.
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10. Greer IA, Calder AA. Pre-induction cervical ripening with extra-amniotic and vaginal prostaglandin E,. Journal of Obstetrics and Gynaecology 1989; 10: 18-22 11. Ekman G, Forman A, Marsal K, Ulmsten U. Intravaginal versus intracervical application of prostaglandin E, in viscous gel for cervical priming and induction of labour at term in patients with an unfavourable cervical state. Am J Obstet Gynecol 1983; 147: 657-61 12. MacKenzie I, Embrey MP. Cervical ripening with intravaginal PGE, gel. BMJ 1977; ii: 1381-1384 13. Greer IA, McLaren M, Calder AA. Vaginal administration of PGE, for induction of labor stimulates endogenous PGF,, production. Acta Obstet Gynecol Stand 1990; 69: 621-625 14. Evans MI, Dougan MB, Mowad AH et al. Ripening of the human cervix with porcine relaxin. Am J Obstet Gynecol 1983; 147: 410-414 15. Bygdeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 1985; 32: 45-51 16. RBdestad A, Christensen NJ, Stromberg L. Induced cervical ripening with mifepristone in first trimester abortion. A double-blind, random&d, biochemical and biomechanical study. Contraception 1988; 38: 301-312 17. Smith SK, Kelly RW. The effect of the antiprogestins RU 486 and ZK 98734 on the synthesis and metabolism of prostaglandin F1.. and E2 in separated cells from early human decidua. J Clin Endocrinol Metab 1987; 65: 527-534 18. Norman JE, Wu WX, Kelly RW et al. Effects of mifepristone in vivo on decidual prostaglandin synthesis and metabolism. Contraception 1991; 44: 89-98 19. Frydman R, Lelaidier C, Baton-Saint Mleux C et al. Labor induction in women at term with mifepristone (RU 486): a double-blind, randomised, placebo-controlled study. Obstet Gynecol 1992; 80: 972-975
20. Tumbull AC, Anderson ABM. Induction of labour; results with amniotomy and oxytocin titration. Obstet Gynaecol Br Cwlth 1968; 75: 3241 21. Dawood MY, Ylikorkala 0, Trivedi D et al. Oxytocin in maternal circulation and amniotic fluid during pregnancy. J Clin Endocrinol Metab 1979; 49: 429434 22. Odem RR, Work BA, Dawood MY. Pulsatile oxytocin for induction of labor: a randomised prospective controlled study. J Perinat Med 1988; 16: 31-37 23. Cummiskey KC, Dawood MY. Induction of labor with pulsatile oxytocin. Am J Obstet Gynecol 1990; 163: 1868-1874 24. Woolfson J, Steer PJ, Bashford CC et al. The measurement of uterine activity in induced labour. Br J Obstet Gynaecol 1976; 83: 934-937 25. Keirse MJNC, van Oppen ACC. Comparison of prostaglandins and oxytocin for inducing labour. In: Chahner I. Enkin M and Keirse MJNC (eds). Effective Care in Pregnancy and Childbirth. Oxford: Oxford University Press, pp. 1080-l 111 26. MacKenzie IZ, Bradley S, Embrey MP. Vaginal prostaglandins and labour induction for patients previously delivered by Caesarean section. Br J Obstet Gynaecol 1984; 91: 7-10 27. MacKenzie IZ. Previous Caesarean section and labour induction with PGE,. In: Egarter C, Husslein P, eds. Prostaglandins for Cervical-Ripening and/or Induction of Labour. Vienna: Facultas. 1988: 53-57 28. Norman M, Ekman G. Preinductive cervical ripening with prostaglandin E, in women with one previous Cesarean section. Acta Obstet Gynecol Stand 1992; 71: 351-355 29. Ekman-Ordeberg G, Uldbjerg N, Ulmsten U. Comparison of intravenous oxytocin and vaginal prostaglandin E, gel in women with unripe cervixes and premature rupture of the membranes. Obstet Gynecol 1985; 66: 307-310
,GYNAECOLOGYJ Mini-symposium: Induction of labour
Methods of induction
J. E. Brennand
and A. A. Calder
Labour induction should only be employed when the obstetrician believes that it will lead to an improved outcome to the pregnancy for mother or baby. The methods employed should mimic as closely as possible the process of spontaneous labour. The emergence of new pharmacological options such as relaxin and mifepristone raises the prospect of further improvements towards this objective, but for the moment prostaglandins E, administered locally within the genital tract offers the best option for cervical ripening (if required) and induction of labour.
Introduction
to those cases in which the balance of risks to the mother or her offspring or both between continuation or interruption of the pregnancy has tipped in favour of interruption. There is no merit in replacing one set of risks in pregnancy for another set in labour. In some cases of severe fetal compromise elective Caesarean section will be the better option. In most instances, induction of labour will be appropriate but if possible such induced labours should mimic an easy spontaneous labour. The onset of spontaneous labour is not a sudden event, but rather the result of changes which occur in the uterus and cervix that together are known as prelabour. During this phase of prelabour there is an increase in uterine contractility and an alteration in the shape and compliance of the cervix, otherwise known as cervical ripening. Caldeyro-Barcia’ demonstrated that there is a progressive increase in uterine contractility from about 35 weeks gestation culminating in clinical labour at term. In addition to these uterine changes, the cervix transforms from a rigid sphincter to a soft compliant structure capable of undergoing effacement and dilatation. Both of these processes are mandatory for the onset of spontaneous labour and successful expulsion of the fetus. If induction of labour is to be successful it must be as physiological as possible. The changes which
Induction of labour has been practiced by obstetricians for centuries. 20 years ago it became the subject of heated controversy in the media. This coincided with, on the one hand, a rise in the rates of induction in many maternity hospitals to levels that could not be justified on purely clinical grounds and, on the other hand, the rise of consumerism in obstetrics. These last two decades have taught us the imperative of recognising the need to confine induction of labour to pregnancies in which a genuine benefit of induction for the mother or her offspring can be perceived. It is also vital to take time to explain and discuss the situation with the mother and sometimes also with the father. Some mothers may resist the idea of induction from a belief that interference with nature is inherently wrong while others may clamour for delivery against the judgement of the obstetrician and we must take the mother along with us in determining the best management for each individual case. The indications for intervention may be many and varied. Interruption of pregnancy should be confined J. E. Brennand, A. A. Calder*, Department of Obstetrics and Gynaecology, University of Edinburgh, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9EW, UK *Address correspondence to A.A.C. Currenr 0bsterric.v and ~ynaecolo~~ Q 1994 Longman Group Ltd
( 1994, 4, 79-84
79
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CURRENT OBSTETRICS AND GYNAECOLOGY
take place in the cervix occur gradually and, clearly, the later in pregnancy the closer is the spontaneous onset of labour, and therefore the easier a proposed induction will be. It is the woman with an unfavourable cervix who has not undergone any of these changes that represents the greatest challenge with regard to labour induction. It is relatively easy to establish uterine activity in the presence of either a ripe or an unripe cervix. However, only in the former clinical situation is the ensuing labour likely to result in a successful outcome and indeed the amount of uterine activity necessary for cervical dilatation is dependent on the state of the cervix. The ultimate aim of induction is to achieve a vaginal delivery with a healthy mother and baby: the process not merely being a prelude to Caesarean section. Cervical ripening A variety of options are available to enhance the ripeness of the cervix prior to induction of labour. Prostaglandins Prostaglandins are strongly implicated in the process of parturition. The onset of spontaneous labour is associated with an increase in prostaglandin E, and Fza in amniotic fluid’ and in the maternal peripheral circulation.3 Early work on amniotic fluid concentrations of the primary prostaglandins suggested that each has an important but differing role in the labour process with E implicated in early labour and Fzm the major prostaglandin as labour becomes established.4*5 A recent longitudinal study of peripheral plasma prostaglandin metabolite levels throughout labour confirms these findings with the major increase in PGE metabolite occurring in early labour while the increase in PGF metabolite occurred as labour progressed.6 In addition, dysfunctional labour was associated with significantly lower PGF metabolite levels; decreased amniotic fluid PGF2, levels have been found in a similar group of patients. The cervix synthesises prostaglandin E2’, production increasing at the time of labour. Therefore, it may be that PGE, is primarily involved in cervical ripening, whereas PGF2= is responsible for promoting and maintaining uterine activity. Based on these concepts, the pharmacological use of prostaglandins is a logical approach to cervical ripening in the clinical setting. Prostaglandins were first employed for the induction of labour in the late 1960s. These agents had an effect on the consistency of the cervix when used in doses smaller than those required for labour induction itself.* This led to extensive investigation of their potential use as cervical ripening agents. Prostaglandins are currently the most successful pharmacological agents used to promote cervical ripening. A systematic overview’ of all placebo and no treatment-controlled investigations of prostaglandin treatment for cervical ripening has shown that
this treatment does confer considerable benefits. There is a significant effect on cervical ripeness; a reduction in failed induction rates; decreased induction to delivery interval and a reduction in the operative delivery rate. Accepting that prostaglandins are currently the drug of choice attention must be turned to type, vehicle and route of administration of these agents. Prostaglandin E,, which is 5-10 times more potent than PGF,, and will produce similar cervical effects at a much lower dose and so a lower incidence of side effects, is the main prostaglandin employed for ripening. The route of administration of prostaglandins is governed by their physiological properties. Firstly, they are synthesised or released at or near their target organ and secondly they are very rapidly broken down to inactive metabolites. Local application is therefore appropriate for maximum effect. Three options are available; extra-amniotic, endocervical or vaginal routes. Prostaglandin E, was first used for cervical ripening via the extra-amniotic route.8 This technique proved highly successful with regard to reduction in the induction-delivery interval and Caesarean section rate’ and indeed when compared with vaginal or endocervical administration it is the route most likely to result in the onset of spontaneous labour.” However, disadvantages associated with the extraamniotic route include introduction of infection, uterine hypertonus resulting from rapid uptake via the choriodecidual space and, importantly, patient discomfort when introducing the catheter. Because of this it has been superseded by vaginal or endocervical application. The extra-amniotic route may be useful for the extremely unripe cervix, but in such a situation where prompt delivery is necessary it could equally be argued that Caesarean section is the better option. Two preparations of PGE, in a viscous gel are currently available for endocervical administration. One is a triacetin-based gel marketed as Prepedil (Upjohn) and the other is a starch-based gel marketed in Europe as Cerviprost (Organon). The work of Ulmsten and his colleagues in Sweden has led to the increasing popularity of this route for cervical ripening. Its success depends on the volume of gel that remains within the endocervical canal without overspill into either the extra-amniotic space or the vagina. The dose employed is 0.5 mg. The cervical ripening effect of the endocervical route is superior to that of the vaginal route in women with a very low Bishop score (l-3).” In addition, the endocervical route appears to be the most specific in its effect on the cervix, stimulating cervical ripening in the virtual absence of uterine activity. Vaginal application is the route most commonly used for cervical ripening in the UK, and PGE, is available in gel and tablet form for this purpose. The early placebo-controlled trials to determine the efficacy of vaginal gel used home-made preparations
METHODS OF INDUCTION
with the inherent problem of unpredictable pharmacodynamics, hence the wide range of doses investigated. l2 The commercial development of both vaginal gel and tablets has removed these problems and the agents currently favoured are the triacetin based vaginal gels containing a dose of 1 or 2 mg of PGE2 (Upjohn) and the 3 mg lactose vaginal tablet (Upjohn). Studies comparing the two vehicles have shown that the gels have greater efficacy and bioavailability than the tabletsi Our cervical ripening policy is to administer 2 mg of PGE2 gel vaginally in the early evening. If, by morning, there has been no change in the Bishop score, and no regular uterine activity, the 2 mg dose is repeated. A number of women may require a third dose 6 h later, but thereafter there is no benefit from further vaginal applications. At this point the options are to reconsider the indication for induction, resort to extra-amniotic administration, proceed to amniotomy or consider Caesarean section. Relaxin Ideally cervical ripening agents should promote change without simultaneously stimulating uterine activity. This cannot be achieved with exogenous prostaglandins which generally do both. Relaxin is a polypeptide hormone which is involved in connective tissue remodelling and theoretically the inhibition of spontaneous uterine activity. Its exact role in human parturition remains unclear. However, the concept that this hormone could achieve cervical ripening pharmacologically without promoting uterine contractility is an attractive one, and has been the subject of some research. Trials have shown some therapeutic benefit14 although the numbers recruited were small, and the subjects of mixed parity, limiting the conclusions that can be drawn from them. Mifpristone The role of progesterone in the initiation of human parturition remains unclear. In the sheep there is a well documented fall in circulating levels of plasma progesterone prior to the onset of spontaneous labour, but this is not the case in humans. However, plasma levels do not necessarily reflect local changes and a mechanism whereby a local decrease in progesterone occurs may be sufficient to trigger spontaneous labour. Mifepristone (RU 486) is a synthetic steroid compound which has both antiprogestagenic and antiglucocorticoid activity, and it exerts these effects at receptor level. The two main clinical effects of this drug are generation of spontaneous uterine activity with an accompanying increase in sensitivity to oxytocic agents,i5 and promotion of cervical ripening with a corresponding reduction in the force necessary to dilate the cervix.i6 As a result, mifepristone has an established role as a medical abortifacient in both the first and second
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trimesters of pregnancy. The exact mechanism of action of mifepristone in inducing these effects remains unknown. However, prostaglandins are implicated in the process. In vitro studies of cultured decidual cells have shown increased PGF,, production in response to treatment with mifepristone.17 Similarly, treatment with mifepristone in vivo resulted in increased production of PGF,, and decreased PGF metabolite production by cultured decidual cells. l8 Since mifepristone is clearly capable of terminating pregnancies of early gestation, and has the capacity to promote the changes in cervical compliance that we are aiming to achieve when ripening the cervix pharmacologically at term, it is appropriate to explore its potential at later gestations. The first study looking at mifepristone for labour induction at term has been reported by Frydman et al.19 This was a double-blind, placebo-controlled study of 120 women with a Bishop score less than 4. Patients randomly assigned to the treatment group received 200 mg of mifepristone daily for 2 days, and were then induced on day 4 if spontaneous labour had not already occurred. The onset of spontaneous labour was significantly more frequent in the treatment group compared to the controls (54% vs 18% respectively, p
Induction of labour Oxytocin Based on the work of Turnbull & Anderson2’ oxytocin, in combination with amniotomy, has until recently been the most widely favoured method of labour induction. The success of this approach is dependent on the state of the cervix. Oxytocin has little, if any, effect on cervical compliance and therefore is less efficacious in inducing labour when the cervix is unfavourable. It has proved to be a highly effective method of induction, when the cervix is favourable. Administration is via intravenous infusion which has superseded the buccal or sublingual route and this should not be commenced until amniotomy or spontaneous rupture of the membranes has occurred. Amniotomy results in prostaglandin release from within the uterus, which in turn sensitises the myometrium to oxytocin with the potential hazard of uterine hyperstimulation. The timing of amniotomy is crucial to the induction process. It should be performed when the cervix is ripe, ideally fully effaced and 3 cm dilated. If performed too early, amniotomy will result in a prolonged labour often
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culminating in an operative delivery. Oxytocin infusion can be commenced immediately following amniotomy although some clinicians prefer to wait for about 1 h to assess the uterotonic effect of amniotomy alone. The policy in our department is to administer oxytocin (20 iU/L) as a continuous infusion starting at a rate of 2 mU/min and doubling this every 15 min to a maximum of 32 mU/min. With a clearer understanding of physiological oxytocin secretion the traditional continuous infusion regimes are being questioned. Oxytocin is secreted in a pulsatile fashion during pregnancy and spontaneous labour with approximately three spurts per 10 min during normal parturition.21 It may, therefore, be more rational to deliver oxytocin pharmacologically in a pulsatile manner, particularly since myometrial oxytocin receptor sites are unavailable once occupied. In a comparison of pulsatile with continuous oxytocin infusion Odem et al” showed that there was no significant difference in the time to adequate labour, the induction to delivery interval or the vaginal delivery rate. The peak dose and total amount of oxytocin administered were however significantly lower in the pulsed group (p ~0.05). These findings have been confirmed in a larger prospective study controlled for parity and Bishop score.23 There appear to be two phases of uterine activity induced by oxytocin. 24 Initially an incremental phase of about 2 h followed by a stable phase during which time there is no further increase in uterine activity. Increasing doses of oxytocin in the stable phase will not augment uterine contractions but rather predispose to uterine hyperstimulation. Once the stable phase has been reached and labour is successfully established a much smaller dose of oxytocin (e.g. 8 mU/min) is required to maintain the labour, possibly due to increased myometrial receptiveness or stimulation of prostaglandin production. Prostaglandins
In addition to being the agents of choice for cervical ripening, prostaglandins may also be preferred for induction of labour when the cervix is favourable. The prostaglandin used is E,, applied locally. Prostaglandin F,, should no longer be used and intravenous administration of prostaglandins abandoned. For primigravid women the initial dose of PGE, is usually 2 mg. This can be repeated 6 h later in a dose of 1 or 2 mg depending on the change in Bishop score. Problems with uterine hyperstimulation can be reduced if care is taken with the second dose. If there is no change in the Bishop score, and in the absence of uterine activity, it is usually safe to repeat the 2 mg dose. If there has been improvement in the Bishop score then 1 mg may be enough. In the presence of uterine activity and a changing cervix yet too unfavourable for amniotomy it is safest to wait for a few hours until amniotomy is appropriate. Thereafter labour may progress without further
intervention to delivery, but oxytocin may be required to augment uterine activity in some cases. Parous women should receive 1 mg of PGE2 initially, which is usually sufficient to enable amniotomy 4-6 h later. The timing of amniotomy is not as crucial in these patients and complete effacement of the cervix is not a prerequisite. If a second dose of PGE, is required this should always be 1 mg. An alternative approach for favourable inductions, especially in parous women, is amniotomy followed 2 h later, if labour is not established, by oral PGE2 tablets. The dose is 0.5 mg every 30 min until the onset of regular uterine activity, up to a maximum of six doses. This approach has now lost favour in most departments. Keirse and Van Oppen25 have presented a metaanalysis of 29 controlled trials comparing prostaglandins with oxytocin for labour induction. There is no difference in the likelihood of being delivered by any route within 12 h between prostaglandin or oxytocin induction. However, if undelivered after 12 h, there is more likelihood of remaining undelivered at 24 and 48 h if induced with oxytocin. There was no difference in the Caesarean section rates between the groups, but the incidence of instrumental vaginal delivery was significantly lower in the prostaglandin group. There was also a decreased need for analgesia in the prostaglandin group. These findings, plus the important factor of much improved patient acceptability, have led to the increasing use of prostaglandins in place of oxytocin for induction of labour.
Other clinical settings Previous Caesarean section
As the global rates of Caesarean section continue to rise there is a corresponding increase in the number of women entering a subsequent pregnancy with a uterine scar. Management of these patients is tending to divert from the traditional dogma of ‘once a section always a section’ to anticipation of a vaginal delivery. This is obviously most likely to be successful if spontaneous labour occurs, but, if this is not the case there is the problem of labour induction and the most appropriate method in the presence of a uterine scar. The major concern when inducing these patients is the risk of scar rupture. The following discussion is confined to women with one previous lower segment Caesarean section scar. Prostaglandins induce frequent, low amplitude contractions with a net decrease in total uterine effort required to achieve cervical dilatation when compared with oxytocin, and theoretically this should reduce the risk of scar rupture. MacKenzie et a126administered PGE, intravaginally to 143 women at term with a previous Caesarean section scar. Of the total study population, 76% achieved a vaginal delivery. Importantly, 68% of the patients with an unfavourable cervix (Bishop score O-3) delivered vaginally. However, of those patients whose original section
METHODS
was for failed induction or slow progress, 40% required repeat Caesarean section compared to only 21% of the remaining patients. There were two cases of suspected scar rupture in the study, neither of which was confirmed, and both of these patients had been augmented with oxytocin. In a larger analysis of 439 patients 27 the vaginal delivery rate was 75% with five observed cases of uterine ‘damage’ (1.1%): one case of rupture and four of dehiscence. Three of these patients received two applications of PGE, and all were given intravenous oxytocin. The addition of a second oxytocic agent appears to identify a group at increased risk of scar rupture, however the incidence of uterine rupture/dehiscence reported in this study compares favourably with that found in spontaneous labour and labour induced without prostaglandins. The requirement for large doses of oxytocics should be reduced if cervical ripening is achieved prior to induction and hence the risk of scar rupture minimised. A recent study reported the results of intracervical PGE, for cervical priming prior to induction of labour in patients with one previous Caesarean section.28 PGE, gel 0.5 mg was administered to 30 women with a cervical score of <5. The overall Caesarean section rate for the study was 27% and of these only two were for failed cervical priming. 50% of the patients delivered vaginally within 24 h of treatment and only two of these women required oxytocin augmentation. Only three patients remained undelivered at 48 h post-treatment: one achieved a vaginal delivery and two required repeat Caesarean section. There was no evidence of uterine scar damage at any of the Caesarean sections. Prostaglandins are not contraindicated in the management of women with a previous lower segment Caesarean section scar. Our own policy is to administer 1 mg PGE, gel intravaginally. Opinion varies as to whether a second dose should be given if required, or whether early recourse to repeat section is a safer option. It should be recognised that the addition of a second oxytocic agent apparently increases the risk of uterine scar rupture whilst simultaneously decreasing the chance of a successful vaginal delivery. Early rupture
qf membranes at term
The debate regarding the management of women with early rupture of the membranes at term continues. The main dilemma is whether or not to intervene, and if so, the most effective method. Active management is favoured by some in an attempt to reduce the risk of maternal and neonatal infection, whereas others argue that conservative management decreases the incidence of Caesarean section. Studies have been reported which confirm either view point. Traditionally, intravenous oxytocin has been employed in this clinical setting. However, prostaglandins are not contraindicated in the presence of
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ruptured membranes. As is the case with intact membranes. the cervical state is the greatest predictor of success. When the Bishop score is favourable, particularly in parous women, oxytocin is still extremely effective. However in the presence of an unfavourable cervix this is not the case. In a comparison of vaginal PGE, and intravenous oxytocin for the management of 29 women with a cervical score 6 5 and PROM at term, Ekman et alz9 reported that 60% of women were delivered within 24 h of PGEz therapy compared with only 10% of the oxytocin group. In addition, there were no Caesarean sections performed in the PGE, group compared with a rate of 40% in the oxytocin group. In fact, all the women in the oxytocin group undelivered after 24 h of treatment had an operative delivery of some form. There were no cases of hyperstimulation and neonatal Apgar scores were slightly better in the PGE, group. They found that the main improvement in cervical score occurred within 5 h of PGE, treatment and therefore a second dose of PGE, should be administered approximately 6-8 h after the initial dose. Once the decision has been made to institute active management of PROM at term the chosen method should be tailored according to the Bishop score. If the cervix is favourable intravenous oxytocin will be successful in most cases. An alternative approach, usually confined to parous women, is oral PGE, tablets administered as previously described. If the cervix is unfavourable, PGE, gel should be administered. In our department this is given intravaginally in an initial dose of 1 mg for parous women and up to 2 mg for primigravidae.
References I. Caldeyro-Barcia 2.
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R. Uterine contractility in obstetrics. Proceedings of the Second International Congress of Gvnaecoloev and Obstetrics. Montreal 1: 655x3 Hillier K, &der AA, Embrey MP. Concentrations of prostaglandin F,,__in amniotic fluid and plasma in spontaneous labour and induced labours. J Obstet Gynaeco Br Cwlth 1974; 81: 257-63 Mitchell MD, Flint ADF, Bibby J et al. Plasma concentrations of prostaglandins during late human pregnancy: influence of normal and preterm labour. J Clin Endocrinol Metab 1978: 46: 947.-51 Keirse MJNC. Tumbull AC. E prostaglandins in amniotic fluid during pregnancy and labour. J Obstet Gynaecol Br Cwlth 1973: 80: 970-3 Keirse MJNC, Flint APF. Tumbull AC. F prostaelandins in amniotic fluid during pregnancy and labour. Obsiet Gvnaecol Br Cwlth 1974: 81: 131-S Johnston TA, Greer IA, Kelly RW. Calder AA. Plasma prostaglandin metabolite concentrations in normal and dysfunctional labour. Br J Obstet Gynaecol 1993; 5: 483 -488 Ellwood DA. Mitchell MD, Anderson AB, Tumbull AC. The in vitro production of prostanoids by the human cervix during pregnancy: preliminary observation. Br J Obstet Gynaecol 1980; 87: 210-214 Calder AA, Embrey MP. Prostaglandins and the unfavourable cervix. Lancet 1973; ii: 1322- 1323 Keirse MJNC. Prostaglandins in preinduction cervical ripening-meta-analysis of worldwide clinical experience. J Reprod Med 1993: 38 (1 supp): 899100 L.
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10. Greer IA, Calder AA. Pre-induction cervical ripening with extra-amniotic and vaginal prostaglandin E,. Journal of Obstetrics and Gynaecology 1989; 10: 18-22 11. Ekman G, Forman A, Marsal K, Ulmsten U. Intravaginal versus intracervical application of prostaglandin E, in viscous gel for cervical priming and induction of labour at term in patients with an unfavourable cervical state. Am J Obstet Gynecol 1983; 147: 657-61 12. MacKenzie I, Embrey MP. Cervical ripening with intravaginal PGE, gel. BMJ 1977; ii: 1381-1384 13. Greer IA, McLaren M, Calder AA. Vaginal administration of PGE, for induction of labor stimulates endogenous PGF,, production. Acta Obstet Gynecol Stand 1990; 69: 621-625 14. Evans MI, Dougan MB, Mowad AH et al. Ripening of the human cervix with porcine relaxin. Am J Obstet Gynecol 1983; 147: 410-414 15. Bygdeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 1985; 32: 45-51 16. RBdestad A, Christensen NJ, Stromberg L. Induced cervical ripening with mifepristone in first trimester abortion. A double-blind, random&d, biochemical and biomechanical study. Contraception 1988; 38: 301-312 17. Smith SK, Kelly RW. The effect of the antiprogestins RU 486 and ZK 98734 on the synthesis and metabolism of prostaglandin F1.. and E2 in separated cells from early human decidua. J Clin Endocrinol Metab 1987; 65: 527-534 18. Norman JE, Wu WX, Kelly RW et al. Effects of mifepristone in vivo on decidual prostaglandin synthesis and metabolism. Contraception 1991; 44: 89-98 19. Frydman R, Lelaidier C, Baton-Saint Mleux C et al. Labor induction in women at term with mifepristone (RU 486): a double-blind, randomised, placebo-controlled study. Obstet Gynecol 1992; 80: 972-975
20. Tumbull AC, Anderson ABM. Induction of labour; results with amniotomy and oxytocin titration. Obstet Gynaecol Br Cwlth 1968; 75: 3241 21. Dawood MY, Ylikorkala 0, Trivedi D et al. Oxytocin in maternal circulation and amniotic fluid during pregnancy. J Clin Endocrinol Metab 1979; 49: 429434 22. Odem RR, Work BA, Dawood MY. Pulsatile oxytocin for induction of labor: a randomised prospective controlled study. J Perinat Med 1988; 16: 31-37 23. Cummiskey KC, Dawood MY. Induction of labor with pulsatile oxytocin. Am J Obstet Gynecol 1990; 163: 1868-1874 24. Woolfson J, Steer PJ, Bashford CC et al. The measurement of uterine activity in induced labour. Br J Obstet Gynaecol 1976; 83: 934-937 25. Keirse MJNC, van Oppen ACC. Comparison of prostaglandins and oxytocin for inducing labour. In: Chahner I. Enkin M and Keirse MJNC (eds). Effective Care in Pregnancy and Childbirth. Oxford: Oxford University Press, pp. 1080-l 111 26. MacKenzie IZ, Bradley S, Embrey MP. Vaginal prostaglandins and labour induction for patients previously delivered by Caesarean section. Br J Obstet Gynaecol 1984; 91: 7-10 27. MacKenzie IZ. Previous Caesarean section and labour induction with PGE,. In: Egarter C, Husslein P, eds. Prostaglandins for Cervical-Ripening and/or Induction of Labour. Vienna: Facultas. 1988: 53-57 28. Norman M, Ekman G. Preinductive cervical ripening with prostaglandin E, in women with one previous Cesarean section. Acta Obstet Gynecol Stand 1992; 71: 351-355 29. Ekman-Ordeberg G, Uldbjerg N, Ulmsten U. Comparison of intravenous oxytocin and vaginal prostaglandin E, gel in women with unripe cervixes and premature rupture of the membranes. Obstet Gynecol 1985; 66: 307-310