Journal of Obstetrics and Gynaecology (1 988) 8 (Suppl. 1 ) S7-Sll

Induction of labour-a review of the use of prostaglandins

I. Z. MacKenzie Nu ffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford

IT is now almost 20 years since Karim and Embrey independently first explored the use of prostaglan- dins as possible oxytocic agents to induce labour. After the first ten years research into potential roles and routes of administration a variety of different uses in relation to labour induction were defined as a consequence of this effort (Figure I ) . Despite much work, there remains, as might be expected, some debate and uncertainties regarding precise doses and treatment regimens for specific indications, and the true benefit of prostaglandins over oxytocin for uncomplicated uterine stimula- tion has still to be proved objectively for some of the specific circumstances encountered in obstetric practice. However, some reasonably firm conclu- sions can now be drawn.

INDUCTION OF LABOUR WHEN THE CERVIX IS UNFAVOURABLE Since Embrey’s initial observations in 1969 that the results of labour induction with intravenous prostaglandin E, appeared to be improved when compared with intravenous oxytocin or prosta- glandin F2*, the most obvious benefit accruing from the use of prostaglandins-especially Ez- has been in improving the outlook for labour induction when the cervix is unfavourable with a Bishop’s score 4 or less. Although applicable to primiparae as well as multiparae, i t is of par- ticular importance in the former group of patients. Administration needs to be local, and although many techniques have been tried out, instillation extra-amniotically, endocervically or vaginally has

Cervical ripening

Induction wi th a moderately ripe cervix

Induction wi th twins, breech or previous caesarean section

Augmentation with spontaneously ruptured membranes or dysfunctional labour

Induction for fetal death

Control of atonic postpartum haemorrhage

Figure 1. Current uses of prostaglandins related to labour induction.

@ Institute of Obstetrics and Gynaecology Trust, 1988

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58 Journal of Obstetrics and Gynecology (1988) Vol. 8/Suppl. 1

been most widely used (MacKenzie, 1987). Ran- dom controlled trials have been conducted com- paring the results with intravenous oxytocin, and in virtually all it has been shown that local prosta- glandins will reduce the incidence of failed induc- tion and the need for caesarean section by two- thirds, and reduce the mean duration of labour by 33 per cent. In consequence maternal, fetal and neonatal morbidity are reduced. There remain some continuing questions.

First, success in ripening the cervix is not guar- anteed and caesarean section for failed induction is still necessary in 3 to 5 per cent of cases. This could be due to an inadequate dose being used, inadequate release of prostaglandin E, from the preparation administered, o r the uterus being unresponsive. The former two possibilities have been explored with vaginal administration and it appears that the results are similar whether doses of 2 or 7-5mg are used. The rate of release of prostaglandins has been less widely considered but there is evidence of marked variation in release and absorption of prostaglandins E, from the preparations commonly used in clinical practice (Figure 2). This has led to efforts directed towards developing vehicles incorporating the prostaglan- dins that will give a predictable release of the oxytocic (Embrey et al., 1986). This is doubtless important, but it is also probable that the hor- mone milieu controlling the onset of parturition and spontaneous cervical ripening are of greater importance than either of the former two consider- ations. The concept of repeating prostaglandin administration if ripening has not occurred with one treatment is widely practised, but is of unproved advantage compared with early resort to intravenous infusions of oxytocin and amniotomy when the cervix dilates. It is the author's opinion that no benefit accrues from delaying the induc- tion 24 to 48 hours, using further prostaglandin treatments. An adequate time must be allowed after prostaglandin E, treatment for cervical ripen- ing to occur and this appears to be 12 to 18 hours for some patients: attempting induction of labour after only 3 hours is too soon in many cases.

The second uncertainty concerns the need for continuous electronic fetal heart monitoring either during the ripening phase with prostaglandin E, or the subsequent established labours: the place for continuous electronic monitoring has not been established for labour which is induced with oxy- tocin or of spontaneous onset. No trials have been conducted into the advantages of continuous monitoring during the process of prostaglandin induced ripening. Since mobility appears to be an important freedom requested by many parturients

-1 Wax pessary

-I Dry tablet

Gel

Polymer pessary

0 2 4 6 Time (h)

Figure 2. Release of prostaglandin E, from various preparations used for labour induction as assessed by measurement of concentration of prostaglandin E meta- bolite (PGEM) in peripheral plasma. (Redrawn from Castle er al., 1983; means and standard deviations).

which local prostaglandin treatment allows, the need for continuous monitoring still needs to be proved. Although suspected fetal distress may occur in cases of placental insufficiency during the ripening process, the contractions stimulated by the prostaglandins are generally of low amplitude and less likely to result in fetal compromise than is the case during established labour. The use of conventional intermittent auscultation does seem essential during this period when uterine activity is occurring.

INDUCTION OF LABOUR WHEN THE CERVIX IS FAVOURABLE When labour induction is indicated at or near term and the cervix is moderately favourable, with a Bishop's score of 5 or more, prostaglandin E, may be given orally in doses of 0.5-1.5 mg hourly and will stimulate uterine contractions. Following an amniotomy it will result in established progressive labour in virtually all cases. Alternatively, vaginal instillation of 1 to 5 m g as a gel, dry tablet, wax pessary, o r polymer pessary on one occasion or

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MacKenzie: Induction of labour with prostaglandins s9

repeated a t 3 to 6 hour intervals will be equally successful in practically all patients, with a small proportion only requiring additional augmen- tation of uterine contractions with oxytocin. Com- pared with induction using intravenous oxytocin titration and amniotomy alone, the overall duration and outcome of labour appears to be very similar. Incontrovertible evidence of reduced analgesic requirements and enhanced patient acceptance has not been established; a reduced rate of primary postpartum haemorrhage due to uterine hypotonia has been demonstrated with the use of prostaglandins compared with oxytocin (Kennedy et a!., 1982).

Avoiding an oxytocic infusion in the majority of women is an attractive advantage to the patient and the midwifery staff. Although widely accep- ted, local administration, particularly intravagi- nally, may occasionally be associated with over- stimulation of the uterus; this could be due to a rapid absorption of the prostaglandin. This is difficult to predict although it can be anticipated if treatment is given when the cervix is effaced and widely dilated-a situation that represents one of the few contraindications to prostaglandin ad- ministration. While immediate delivery by caesar- ean section may be appropriate, first aid manage- ment with an intravenous tocolytic agent such as rito-drine or salbutamol should be instigated and can be expected to suppress the prostaglandin provoked contractions and reverse any consequent fetal distress. After an hour, the infusion may be discontinued and labour allowed to re-establish and progress. The controlled release polymer pes- saries recently investigated should reduce the chances of this worrying event.

As well as raised prostaglandin metabolite levels being found in the maternal circulation following local prostaglandin treatment, raised levels of the prostaglandin and its metabolite are also found in the fetal cord circulation (MacKenzie et al., 1980; Sellers and MacKenzie, 1985). The precise rele- vance of this is presently not understood, and, to date, a direct adverse effect upon the neonate has not been identified.

PR EVlO U S CAESAREAN S ECTlON With the rising incidence of caesarean sections in many countries, the decision regarding the management of subsequent pregnancies confronts the obstetrician more frequently. The prostaglan- dins have been used in this situation and there are a few series reported in the literature. All are uncontrolled reports giving favourable results but none provides evidence of any objective advantage over intravenous oxytocin beyond avoiding the

need for an intravenous infusion in a high propor- tion of cases. It has been concluded that those patients with an unfavourable cervix that require delivery have a 70 per cent chance of vaginal delivery if given local prostaglandins as part of the induction procedure, a figure that is believed to be higher than if oxytocin alone is used. Indeed many obstetricians might otherwise opt for caesarean section without any attempt a t labour. A random trial comparing the use of vaginal prostaglandins and intravenous oxytocin in this situation is currently in progress in Oxford (Sellers and MacKenzie, unpublished studies) and the early results indicate that there is a definite advantage using the former management compared with the latter by reducing the number of failed induction.

FETAL BREECH PRESENTATION As with patients previously delivered by caesarean section, there is a continuing debate on the most appropriate method of managing the delivery. If induction of labour is required there is no reason why the local administration of prostaglandin should not be used. In one small series of 30 primiparae with an unripe cervix, 77 per cent were delivered vaginally after prostaglandin E,, 2 mg in gel instilled into the vagina, the remainder requir- ing caesarean section for poor progress in labour (O’Herlihy, 1981). In another report of 54 patients of mixed parity and varying cervical scores, 87 per cent were delivered vaginally after 3 m g prosta- glandin Ez pessaries were administered, the re- mainder requiring caesarean section. The majority of the latter patients were in the second stage of labour (Shepherd el al., 1981). A personal series of 177 patients of mixed parity and cervical states was managed with vaginal prostaglandin E,, 2.5- 5.0mg as a gel o r pessary, and 78 per cent deli- vered vaginally without detriment to mother or neonate. The remaining patients required delivery by caesarean section, almost half during the second stage of labour. Unfortunately there have been no random studies comparing prostaglandins with oxytocin induced labour or spontaneous labour and the advantages are thus still specula- tive. It would seem that induction with local prostaglandins, compared with intravenous oxy- tocin and amniotomy, allows a delay in rupturing the fore-waters until the breech has descended well into the maternal pelvis, with the probability of a reduced incidence of cord prolapse. Random trials are required to provide the necessary data to allow an objective comparison of the two approaches.

TWIN PREGNANCIES Apart from occasional anecdotal cases reported in

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s10 Journal of Obstetrics and Gynecology (1988) Vol. 8/Suppl. 1

the literature, there is virtually nothing written concerning the use of prostaglandins in multiple pregnancies. Personal experience suggests that prostaglandins are as effective in multiple preg- nancies as in singleton pregnancies. Since primary postpartum haemorrhage due to uterine hypo- tonia occurs in approximately 12 per cent of twin labours, it could be argued that the use of prosta- glandins as part of the induction procedure is more than justified.

LABOUR AUGMENTATION The prostaglandins have been given to stimulate uterine contractions in cases of spontaneous rup- ture of the membranes without ensuing labour. In the literature, there are a small number of reports either recording the outcome in patients treated with prostaglandins or comparing results with those obtained by intravenous oxytocin titration collected retrospectively or prospectively. The numbers are relatively small in most series and prostaglandins have been administered orally, intravenously and vaginally. It is concluded from these reports, which at present remain inadequate to allow worthwhile conclusions, that no obvious advantage is obtained with prostaglandins.

One area that has not been explored is the value of the prostaglandins in the management of ‘dys- functional labour’- when incoordinate uterine ac- tivity results in a non-progressive labour. Whether local prostaglandins would improve the outcome compared with intravenous oxytocin should be explored in random studies. If successful, the incidence of caesarean sections for secondary arrest of labour in these cases may be reduced.

FETAL DEATH IN UTERO Of all the possible roles for prostaglandins in obstetric practice, the place in the management of fetal death is probably the most widely acknow- ledged. While intravenous infusions are successful, local administration has again provided the best results. Abortion or delivery within 24 hours has been the goal and while extra-amniotic infusions or injections of prostaglandins are successful in the majority of cases there has always been a fear that the introduction of a foreign material into the uterus when the fetus is dead might result in intra- uterine sepsis. Vaginal administration causes mini- mal inconvenience and distress to the patient and permits delaying rupturing the fetal membranes until delivery or abortion is inevitable. Single vaginal instillations of prostaglandin E,, 5-25 mg as a gel or wax pessary results in expulsion within 24 hours in virtually all cases. Intravenous oxyto- cin after 12 to 18 hours is needed in not more than

25 per cent of patients. Instillation of prostaglan- din E,, 20 mg pessaries repeated 3 to 6 hourly, as proposed by workers in the United States is equally effective, although these regimens result in a higher rate of gastro-intestinal side effects. Some of the prostaglandin analogues have been tested in this situation but to date there have been few studies that have indicated a significant improve- ment over the results currently provided with the natural prostaglandins.

PROSTAGLANDINS AND POSTPARTUM HAEMORRHAGE It has been observed that there is a lower rate of primary postpartum haemorrhage from uterine hypotonia following labour induction with prosta- glandins compared with oxytocin. This advantage has been investigated by various workers in con- trolling torrential haemorrhage occasionally observed immediately following delivery (Thiery, 1986). A number of different regimens have been tried, including prostaglandin F,, 0.25-1.0 mg by intramyometrial injection, prostaglandin E,, 5-10 pg per min by intravenous infusion, and the prostaglandin analogue I 5-rnethyl-prostaglandin, F,, 0.5 mg by intramuscular injection. The results obtained are dramatic when all else has failed, and can prevent the need for internal iliac vessel liga- tion or hysterectomy. Whether the use of prosta- glandins as a third stage oxytocic should be con- sidered as routine has not been fully explored. There would seem to be some merit in adopting this approach since the use of ergometrine is being questioned in relation to the recognised effects upon maternal cardiopulmonary function and the potential to induce hypertension in susceptible patients.

FUTURE DEVELOPMENTS Compared to many new treatments that have been introduced into clinical practice, the prostaglan- dins as agents for induction of labour were intro- duced in a scientific manner to assess possible advantages and disadvantages. Unlike the way in which amniotomy or buccal pitocin and even intravenous oxytocin were used with little attempt to evaluate their role objectively, prostaglandins have been subjected to numerous trials, many using the powerful tool of double blind random allocation, and in consequence some firm conclu- sions regarding the true benefit of these powerful oxytocics have been reached.

Much of the clinical research involving prosta- glandins for labour induction has tended to be confined to investigating natural prostaglandins administered alone or in conjunction with intra-

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MacKenzie: Induction of labour with prostaglandins s11

venous oxytocin. While the principle of single drug treatment is preferable to multiple drug treatments it is possible that further consideration of the physiology of parturition might lead to improved results in labour induction with reductions in prostaglandin doses and some of the unpredictable responses. Further investigation of the use of oestrogen as a concomitant treatment (Luther et al., 1980) of the unripe cervix might be worth pursuing and combination treatments using some of the new anti-progesterone preparations which have been shown to enhance induced abortion results (Selinger et al., 1987) could be a particular advantage in cases of suspected placental insuffi- ciency. The possibility of countering the myorne- trial contractions provoked by prostaglandins when the cervix is ripening with simultaneous administration of a tocolytic agent so reducing the chances of labour and possible unexpected fetal distress needs further study (Goeschen er al., 1985). Alternatively some of the newer prostaglan- din analogues with a greater propensity for cervi- cal collagenolysis may provide improved results in cervical ripening with reduced myometrial ac- tivity. This may reduce the risk of caesarean scar rupture and fetal distress occurring during the ripening procedure or subsequent labour induc- tion. Although enormous advantages have been obtained with prostaglandins in the management of labour induction there remain areas where further improvement is still required.

REFERENCES Castle B. M., Bellinger J., Brennecke S. P., Embrey M. P.

and MacKenzie I. Z. (1983) In vivo studies using the bicyclo PGEM assay to assess release of PGE, from vaginal preparations used for labour induction. Abstracts of 23rd British Congrem of Obstetrics and Gynaecology. July. Birmingham, R.C.O.G.

Embrey M. P. (1969) The effect of prostaglandins on the human pregnant uterus. Journal of Obstetrics and Gynaec,ology of the British Commonw’ealth 16, 783- 798.

Embrey M . P., Graham N . B., McNeil M. E. and Hillier K. (1986) In vitro release characteristics and long-term

stability of poly (ethylene oxide) hydrogel vaginal pessaries containing prostaglandin E,. Journal of Con- trolled Release 3, 3 9 4 5 .

Goeschen K., Fuchs F., Rasmussen A. B., Rehnstrom J. V. and Saling E (1985) Effect of p-mimetic tocolysis on cervical ripening and plasma prostaglandin F,, metabolite after endocervical application of prosta- glandin E,. Obstetrics and G~VnecOliJgy 65. 166- 171.

Karim S. M.. Trussell R. R., Patel R. C. and Hillier K . (1968) Response of pregnant human uterus to prosta- glandin F,,-induction of labour. British Medical Jour- nal iv, 621423.

Kennedy J. H., Stewart P., Barlow D. H.. Hillan E. and Calder A. A. (1982) Induction of labour: a comparison of a single prostaglandin E? vaginal tablet with amnio- tomy and intravenous oxytocin. British Journal of Obstetrics and Gynaecology 89, 70&707.

Luther E. R., Roux J . , Popat R., er al. (1980) The effect of oestrogen priming on induction of labour with prostaglandins. American Journal of Obstetrics and Gvnecology 137. 351-354.

MacKenzie I . 2. (1987) The clinical use of prostaglan- dins for cervical ripening and induction of labour. In Eicosanoid.7 and Reproduction. edited by Hillier K, pp. 195-224. Lancaster. MTP Press Ltd.

MacKenzie 1. 2.. Bradley S. G. and Mitchell M. D. (1980) Prostaglandin levels in cord venous plasma at delivery or related to labour. In Advances in Prosta- glandin and Thromboxane Research. volume 8. edited by Samuelsson B.,Ramwell P. W. and Paoletti R., pp. 1401-1405. New York, Raven Press.

O’Herlihy C. (1981) Vaginal prostaglandin E, gel and breech presentation. European Journal of Obstetrics. Cyneco1og.v and Reproductive Biology 11, 299-303.

Selinger M., MacKenzie I . Z . . Gillmer M. D., Phipps S. L. and Ferguson J. F. (1987) Progesterone inhibi- tion in mid-trimester termination of pregnancy: phy- siological and clinical etrects. British Journal of Ohste- trics and Gynecology 94, I2 I8 ~ 1222.

Shepherd J . H., Bennett M., Laurence D., Moore F. and Sims C. D. (1981) Prostaglandin suppositories: a sim- ple and safe approach to the induction of labor. Obstetrics and Gynecology 58, 596 600.

Sellers S. M. and MacKenzie I . 2. (1985) Prostaglandin release following vaginal prostaglandin treatment for labour induction. In The Role o f Prostaglandins in Labour, edited by Wood C. pp, 77-84. Royal Society of Medicine Symposium 92.

Thiery, (1986). Prostaglandins for the treatment of hypo- tonic postpartum haemorrhage. Pro.7taglandin f e r - specrives 2, 1&11

Correspondence should be addressed to: M r I . Z . MacKenzie, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, OX3 9DU.

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