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Title: Evaluation of a controlled release vaginal prostaglandin E2 pessary with a retrieval system for the induction of labour
Authors: Westgate J and Williams JA
Journal: J Obstet Gynaecol 1994 J Obstet Gynaecol Downloaded from informahealthcare.com by ReprintsDesk on 06/22/14 For personal use only. Westgate and Williams: Controlled release prostaglandin EZ 141
Women with a singleton, cephalic, pregnancy mean initial Bishop’s score was 4.2 (primigravi- of at least 38 weeks duration who were thought to dae 4.2, multigravidae 4.1). require induction of labour for medical or obst- etric reasons were recruited for the study if their Ease of removal and patient acceptability modified Bishop’s score was 6 or less. Patients The pessary was removed with little or no with more than three previous full term pregnan- difficulty for either staff or patient in 97 per cent cies, a previous caesarean section, ruptured mem- of cases (Table). All patients who experienced branes, evidence of fetal compromise or asthma slight discomfort during removal likened the sen- were excluded. sation to removal of a tampon. Removal was very At entry, all patients were examined by a single difficult in one case who became very distressed research midwife who allocated a Bishop’s score. at the onset of labour and developed vaginismus. Uterine activity and fetal heart rate were moni- The retrieval system allowed the pessary to be tored by a cardiotocogram at baseline and then removed but a full vaginal examination could not again 1 hour after insertion of the pessary, during be performed until after epidural analgesia was which time the patients remained in bed. The established. No uterine hyperstimulation occurred cardiotocogram was repeated at the onset of tight- and the patient did not have a precipitate labour. enings or contractions. The pessary was removed All 11 1 patients provided information about their by the research midwife after 12 hours, or earlier experience of the pessary in siru. Ninety-eight if there was concern about fetal or maternal con- patients (88 per cent) were unaware of its pres- dition or uterine contraction frequency; or if the ence, 10 (9 per cent) were aware but felt no membranes ruptured or labour ensued. Labour discomfort, two (2 per cent) were aware with mild was defined as the onset of regular painful con- discomfort and one (I per cent) had marked dis- tractions which lasted at least 45 seconds at a comfort with the pessary in frequency of three to four contractions in 10 situ. The pessary fell out in 11 patients. Eight of minutes. In all cases a cervical assessment was these occurred in the first 51 patients when the made at the time of removal. Ease of removal was pessary was left lying longitudinally in the vagina assessed by staff and patients on a 4-point scale. following insertion. In the next 60 patients the Patients also rated their experience of the pessary in situ on a 4-point scale. Treatment was con- insertion technique was modified to leave the sidered effective if labour began during the 12 pessary lying transversely in the posterior fornix. hour observation period or if the Bishop’s scorc After that only three pessaries were lost, all from patients in early labour; one loss with spontaneous For personal use only. increased by three or more points. Patients who rupture of the membranes, one with a heavy did not go into labour or who were unsuitable for mucous show and one with a amniotomy following the 12 hours observation contraction. were managed at the discretion of their attending obstetrician. Efficacy Following removal all pessaries were placed in Treatment success, defined as the onset of labour a plastic bag labelled with the study number, date within 12 hours or an increase in Bishop’s score and time of removal and placed immediately into of at least 3, occurred in 78 (70 per cent) of all a freezer. The pessaries were analysed by high I11 patients (primigravidae 73 per cent; multi- performance liquid chromatography by Con- gravidae, 67 per cent). If the patients in whom the trolled Therapeutics (Scotland) Ltd. (East Kil- pessary was lost (n = 1 1 ) or in whom the pessary
J Obstet Gynaecol Downloaded from informahealthcare.com by ReprintsDesk on 06/22/14 bride, Scotland). The amount of prostaglandin E2 was removed early due to an adverse event released was calculated by subtraction of the (iz = 8) are excluded, treatment success occurred residual prostaglandin from the batch potency. in 70 of 92 patients (76 per cent) of cases (primi- Statistical analysis was by Student’s t test, Mann-Whitney U test, analysis of variance or x2 Table. Ease of pessary removal in 100 patients analysis. Odds ratios and their 95 per cent confidence intervals are given where appropriate. As assessed by
Midwife Patient RESULTS One hundred and eleven patients (63 primigravi- No difficulty 78 88 dae, 48 multigravidae) were recruited. The mean Slight difficulty 19 9 Moderate difficulty 2 2 gestational age at induction was 40.7 weeks Very difficult 1 1 (primigravidae 40.9, multigravidae 40.4) and the 148 Journal of Obstetrics and Gynaecology (1994) Vol. 14/No. 3
gravidae 80 per cent; multigravidae, 71 per cent). in good condition at delivery although one was In this group, although the median pre-treatment postmature and treated for hypoglycaemia neona- Bishop’s scores were the same, patients with a tally. The two other cases had decelerations ac- treatment success tended to have had higher initial companying mild, infrequent contractions (one in scores compared with those with a treatment fail- 5 to 10 minutes) which resolved when the pessary ure (difference, P
For personal use only. Eight (47 per cent) were sent home after failing to Residual prostaglandin EP respond to extra prostaglandin El, two were read- One hundred and three pessaries were recovered mitted in spontaneous labour, five were readmit- for analysis of residual prostaglandin content. The ted for further induction attempts and one was amount released from each pessary is shown in delivered by elective caesarean section. The over- the Figure. all caesarean section rate in this group was 35 per The mean rate of prostaglandin E2 release was cent. 0.33 2 0.15 mg/hour (s.d.; range 0.12 to 0.78; 95 per cent confidence interval 0.30-0.36 mghour). No difference wa5 found in release rates between Adverse events with Propess in situ primigravidae and multigravidae or between treat- The pessary was removed early from six patients ment successes and treatment failures. Less than
J Obstet Gynaecol Downloaded from informahealthcare.com by ReprintsDesk on 06/22/14 because of an abnormal cardiotocogram and from two mg of prostaglandin E2 was released in the 12 two patients because of uterine hyperstimulation. hours in 13 (22 per cent) of the 60 patients who All six cases of cardiotocographic abnormality had the pessary in for that time, nevertheless were associated with uterine activity but none was treatment success occurred in seven cases (54 per hyperstimulated. In two cases the record showed cent). Conversely, five of the 16 patients (31 per an accelerative fetal heart rate pattern which was cent) who received more than 4 mg of misinterpreted as a fetal tachycardia, so the true prostaglandin E2 in the 12 hour period had treat- incidence of fetal heart rate abnormalities with the ment failures. pessary in situ was four cases (3.6 per cent). Contractions did not resolve following removal of the Propess in two cases (one was in early labour, DISCUSSION the other had the membranes ruptured artificially The inability to remove vaginal prostaglandin after removal of Propess) who were delivered by pessaries or gels and terminate drug delivery has emergency caesarean section. Both neonates were always been a concern about these preparations. Westgate and Williams: Controlled release prostaglandin E2 149
.-C a IZ T 4 -m M T T m 0 ‘p 4 1 ffl 0 ‘I 0 T L Grn 0 a 1 0 4 0 I2 3 4 s a 7 I010 11 12 Time(Hours) Figure. The amount of prostaglandin EI released from each pessary according to the number of hours in the vagina and the occurrence of adverse events. Results are shown as means (0)t- 2s.d. Hyperstimulation, + fetal heart rate ahnormalities
This study has demonstrated that the retrieval signal the onset of labour. The painful tightenings system fitted to Propess allows easy removal and with Propess-RS were progressive and did not has a high patient acceptability. The incidence of decline unless the pessary was removed. The on- excessive uterine activity (2 per cent) and fetal set of labour was best judged by the onset of heart rate abnormalities with the pessary in sirri (4 regular painful contractions and not by change in per cent) were low. Furthermore, neither of the the cervix. A slow steady onset of contractions women with hyperstimulation before labour could may be preferable for women who have labour have received more than 1 mg of prostaglandin induced. There is no comparative data available Ez. This suggests an individual sensitivity to exo- for other vaginal prostaglandin E2 preparations, genous prostaglandin rather than an overdose of but it is our impression that analgesia require-
For personal use only. drug and confirms the advantage both of a slow ments with Propess-RS were reduced. Only 20 release preparation and of the ability to rapidly (I 8 per cent) in our study required analgesia with terminate drug delivery. the pessary in situ, the vast majority (1 6) receiving Uterine hyperstimulation with Propess-RS can paracetamol, night sedation, baths or the ‘pulsar’. also occur if the pessary is left in too long after There was no evidence of dose dumping from the onset of labour. This occurred in one case in Propess-RS. The release rate of prostaglandin Ez our study. In two studies where similar controlled found in this study (0.33 mg/hour) was much release preparations were deliberately left in place lower than the 0.9 mg/hour previously reported at the onset of labour, the overall incidences of (Taylor et ul., 1990). The pessary used in that hyperstimulation were 15 per cent (Rayburn et d., study was thinner (0-8 mm thick versus 1.1 mm 1992) and 7 per cent (Witter et al., 1992), but, in this study) which should theoretically have
J Obstet Gynaecol Downloaded from informahealthcare.com by ReprintsDesk on 06/22/14 when removed before the onset of labour. hyper- resulted in an increase in release rate. The main stimulation occurred in only 4 per cent and nil reason for the discrepancy is that the pessary was respectively. In all cases, uterine activity reduced left in situ following amniotomy in several cases with removal of the pessary. Staff must under- in Taylor et al.’s study. Amniotic fluid has a stand that the pattern of uterine activity with the higher pH than the normal vaginal pH during slow release pessary is different to that commonly pregnancy and would cause greater release of seen with other vaginal prostaglandin preparations prostaglandin from the pessary (Johnson et a/., (Miller et al., 1991). We noted a gradual increase 1992). If the release rate is recalculated excluding in uterine activity over a number of hours the amniotomy cases the mean rate of 0.33 mg/ with Propess, as opposed to the frequent painful hour is comparable with the rate found in our uterine activity seen in the first hour after study (Controlled Therapeutics, personal com- prostaglandin Ez pessaries or gel which then often munication). subsides. These pains are not usually associated Vaginal prostaglandin preparations probably with change in the cervix and do not necessarily act by stimulating endogenous prostaglandin 150 Journal of Obstetrics and Gynaecology (1994) Vol. 14/No. 3
production. It has been thought that this is Bex P., Gunasekera P. C. and Phipps J. H. (1990) achieved most successfully by a rapid initial rise Difficulties with controlled release vaginal in prostaglandin EZ (Greer et al., 1990). A single prostaglandin pessaries [letter]. Lancet 336, 1 19. dose of other prostaglandin vaginal preparations Embrey M. P. and MacKenzie I. Z. (1985) Labour induction with a sustained release prostaglandin E2 causes a maximal increase in plasma prosta- polymer vaginal pessary. Journal of Obstetrics and glandin metabolites in the first 40 minutes after Gynaecology 6, 38-N4 1. administration, which may be responsible for the Greer I. A., McLaren M. and Calder A. A. (1990) initial uterine activity described above. Propess- Vaginal administration of PGE2 for induction of RS released an average of 0.3 mg of prostaglandin labour stimulates endodgenous PGF2a production. E2 in the first hour, so a rapid initial rise in Acta Obstetricia et Gynecologica Scandinavica 69, metabolites was unlikely. Our results suggest 621425. that a slow but steady release of exogenous Johnson T. A,, Greer I. A., Kelly R. W. and Calder A. A. (1992) The effect of pH on release of PGE?, from prostaglandin EZ is also effective in stimulating vaginal and endocervical preparations for induction endogenous production. The amount released of labour. Brirish Journal of Obsterrics and Gvnue- from each pessary varied and was not related to dogy 99, 877-880. the success of the induction. Greer et al., (1990) Keirse M. N. and van Oppen A. C. C. (1989) Preparing also found variable absorption rates with the cervix for induction of labour. In: Effective Cure prostaglandin E2 gel. Patients who failed to in Pregnancy and Childbirth, edited by Chalmers I., respond to Propess had a 35 per cent incidence Enkin M. and Kierse, M. J. N. C. chapter 61, pp. of caesarean section (despite receiving additional 988-1 056. Oxford, Oxford University Press. prostaglandin) compared with an 11 per cent inci- Khouzam M. N. and Ledward R. S. (1990) Difficulties dence for those who did respond. with controlled release prostaglandin E2 pessaries [letter]. Lancet 336, 119. This study has demonstrated the safety and Miller A. M., Rayburn W. F. and Smith C. V. (1991) efficacy of a slow release prostaglandin EZ prep- Patterns of uterine activity after intravaginal aration with a retrieval system. It allows the clin- prostaglandin E2 during preinduction cervical ripen- ician to control the dose administered and ing. American Journal of Obstetrics and Gynecology therefore offers particular advantages in cases 165, 1006-1009. where there is concern about fetal condition or a Rayburn W. F., Wapner R. J., Bars V. A., Spitzberg E., risk of uterine over-activity. Molina R. D., Mandsager N. and Yonekura M. L. ( 1992) An intravaginal controlled-release prostaglandin E2 pessary for cervical ripening and initiation of labour at term. Obsrerrics and Gynecol- For personal use only. Acknowledgements We thank the medical and midwifery staff at Freedom ORV 79, 314-379. Fields Hospital, Plymouth for their collaboration and Taylor A. V. G., Boland J. and MacKenzie 1. Z. (1990) support. We acknowledge the support of Controlled The concurrent in-vitro release of PGE2 from a con- Therapeutics who supplied the Propess-RS pessaries trolled release hydrogel polymer pessary for cervical and performed the analysis of residual prostaglandin E2 ripening. Prostaglcmdins 40, 89-98. content. Witter F. R., Rocco I. E. and Johnson T. R. (1992) A randomised trial of prostaglandin E2 in a controlled- release vaginal pessary for cervical ripening at term. American Jourircil of Obstetrics and Gynecology 166, 830-834. Wilson P. (1993) Analysis of 10 rng PGE2 I.lmm REFERENCES hydrogel pessaries fitted with retrieval systems re- J Obstet Gynaecol Downloaded from informahealthcare.com by ReprintsDesk on 06/22/14 Baravilala W. R., Baker C. and Morsrnan J. M. (1990) turned to CTS from clinical trial CTC101-500. Tech- Controlled release prostaglandin E2 pessaries [letter]. nicul Report Number R93008S, pp 3-6. Controlled Lrrncet 336, 431. Therapeutics, (Scotland) Ltd, Glasgow.
Correspondence should 6e addressed ro: Dr J. Westgate, Department of Obstetrics and Gynaecology, Middlemore Hospital, Private Bag 933 I I, Otahuhu, Auckland, New Zealand.