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Re: prostaglandinas endovaginaisFrom: João Batista Marinho de Castro Lima (jblima@horizontes.net)Sat, 13 Feb 1999 18:20:05 -0200
O uso de misoprostol intravaginal na dose de 25 mcg de 3 em 3 horas, para indução do parto em fetos vivos, está sendo estudado em vários serviços internacionais, inclusive com muitos ensaios randomizados controlados sem evidenciar efeitos deletérios nos recém-nascidos. Tais estudos, entretanto, possuem pequenas amostras para se chegar a uma conclusão definitiva sobre os resultados perinatais. O grande impacto da droga seria em relação ao baixo custo e ao seu evidente efeito positivo no amadurecimento do colo e na indução do parto. João Batista jblima@horizontes.net -----Mensagem original----- De: A.C.Reis-Morais <reismorais@mail.telepac.pt> Para: Multiple recipients of list <obstet-l@talk.obgyn.net> Data: Sexta-feira, 12 de Fevereiro de 1999 11:44 Assunto: Re: prostaglandinas endovaginais
>Nós usamos os próprios comprimidos do misoprostol na Misoprostol vaginally for labour induction Misoprostol vaginally for labour induction Vaginal misoprostol for cervical ripening and labour induction in late pregnancy Hofmeyr GJ Date of most recent substantive amendment : 20 April 1998 Objectives: To determine, from the best available evidence, the effects of misoprostol administered vaginally for third trimester cervical ripening or induction of labour. Search strategy: The register of clinical trials maintained and updated by the Cochrane Pregnancy and Childbirth Group. Selection criteria: The criteria for inclusion included the following: 1) clinical trials comparing vaginal misoprostol used for third trimester cervical ripening or labour induction with other methods or placebo/no treatment; 2) random allocation to the treatment or control group; 3) adequate allocation concealment; 4) violations of allocated management not sufficient to materially affect conclusions; 5) clinically meaningful outcome measures reported; 6) data available for analysis according to the random allocation; 7) missing data insufficient to materially affect the conclusions. Data collection and analysis: Trials under consideration were evaluated for methodological quality and appropriateness for inclusion, without consideration of their results. Included trial data were processed as described in: Mulrow CD, Oxman AD (eds). Cochrane Collaboration Handbook [updated 1 March 1997]. In: The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration. Oxford: Update Software; 1996-. Updated quarterly. Main results: Vaginal misoprostol vs placebo: The one small study included in this part of the review [Fletcher 1993] showed a clear effect of misoprostol on increasing cervical ripening and reducing the need for oxytocin (see analysis tables). The numbers studied were too small to assess the impact on obstetric management and maternal and neonatal complications. Misoprostol vs Oxytocin: Misoprostol was more effective than oxytocin for labour induction (relative risk (RR) of failure to achieve vaginal delivery within 24 hours 0.48, 95% confidence interval (CI) 0.35-0.66). However, uterine hyperstimulation was more common both without (RR 2.96, 95% CI 2.11-4.14) and with associated fetal heart rate changes (RR 2.54, 95% CI 1.12-5.77). The results of individual trials with respect to Caesarean section were inconsistent, ranging from a large reduction following misoprostol administration to no significant difference. There were no statistically significant differences in perinatal or maternal outcomes. Misoprostol vs prostaglandins: Failure to achieve vaginal delivery within 24 hours was reduced in four of five trials (RR 0.70, 95% CI 0.61-0.79). The trial which failed to show a difference was the only trial with a misoprostol regimen <25 micrograms three hourly [Wing 1997]. Oxytocin augmentation was used less often with misoprostol (RR 0.66, 95% CI 0.59-0.75). Uterine hyperstimulation without fetal heart rate changes was more common with misoprostol (RR 1.53, 95% CI 1.17-1.99). Uterine hyperstimulation with associated fetal heart rate changes was increased with misoprostol (RR 1.59, 95% CI 1.02-2.48). Meconium stained liquor was increased with misoprostol (RR 1.38, 95% CI 1.06-1.79). The rates of vaginal instrumental delivery and Caesarean section were inconsistent between trials. Overall, there was a reduction in instrumental deliveries with misoprostol (RR 0.75, 95% CI 0.58-0.97). There were no statistically significant differences in perinatal or maternal outcomes. Misoprostol: low dosage regimen versus higher dose. The lower dosage regimens (misoprostol 25µg six hourly versus three hourly, or 25mg versus 50µg three hourly) did not show significantly more failures to achieve delivery within 24 hours (RR 1.08, 95% CI 0.93-1.25). There was significantly more use of oxytocin (RR 1.32, 95% CI 1.11-1.56). There were no differences in mode of delivery, meconium stained liquor or maternal side effects. There was a trend to less uterine hyperstimulation with fetal heart rate changes, and fewer low Apgar scores at five minutes and neonatal intensive care unit admissions. Conclusions: In dosages of 25 micrograms three hourly or more, misoprostol is more effective than conventional methods of cervical ripening and labour induction. The increase in uterine hyperstimulation with fetal heart rate changes found in this review is a matter for concern. Although no differences in perinatal outcome were shown, the studies were not sufficiently large to exclude the possiblility of uncommon serious adverse effects. Thus, though misoprostol shows promise as a highly effective, inexpensive and convenient agent for labour induction, it cannot be recommended for routine use at this stage. It is also not registered for such use in many countries. Because of the enormous economic and possible clinical advantages of misoprostol, there is an urgent need for trials to establish its safety. On the basis of this review, such trials should have the following features: 1. Randomised, double blind. 2. Vaginal misoprostol dose not greater than 25 micrograms four to six hourly (oral misoprostol will be reviewed separately). 3. Sample size sufficient to detect moderate differences in important uncommon complications such as serious perinatal morbidity/mortality. 4. Meconium stained liquor included as an outcome measure. Background Induction of labour in the third trimester of pregnancy may be considered beneficial in many clinical circumstances. The main problems experienced during induction of labour are ineffective labour, and excessive uterine activity which may cause fetal distress. Both problems may lead to an increased risk of Caesarean section. Methods of induction of labour include administration of oxytocin, prostaglandins, prostaglandin analogues and smooth muscle stimulants such as herbs or castor oil (Mitri 1985), or mechanical methods such as digital stretching of the cervix and sweeping of the membranes, hygroscopic cervical dilators, extra-amniotic balloon catheters, artificial rupture of the membranes, and nipple stimulation. Standardised 'scoring' of the cervix prior to labour induction has been recommended (Bishop 1964). Oxytocin has the disadvantages of a high failure rate when the cervix is unfavourable (low cervical score), and requiring monitored continuous intravenous infusion. Artificial rupture of membranes is also less effective or may not be possible when the cervix is unfavourable. It may increase the risk of infection if labour does not proceed promptly. Rupture of membranes may also increase the vertical transmission of specific maternal infections such as HIV. Unsuccessful labour induction is most likely when the cervix is unfavourable and, in this circumstance, prostaglandin preparations have proved to be beneficial (Keirse 1993). Those prostaglandins that have been registered for cervical ripening and labour induction are expensive and unstable, requiring refrigerated storage. Uterine hyperstimulation has been identified as a particular problem during labour induction with prostaglandins, and has been treated with tocolysis (Egarter 1990). Misoprostol (Cytotec, Searle) is a methyl ester of prostaglandin E1 additionally methylated at C-16 and is marketed for use in the prevention and treatment of peptic ulcer disease caused by prostaglandin synthetase inhibitors. It is inexpensive, easily stored at room temperature and has few stored at room temperature and has few systemic side effects. It is rapidly absorbed orally and vaginally. The reported mean peak serum misoprostol acid following oral administration was 227pg/ml versus vaginal route 165pg/ml; the times to peak levels were 34 versus 80 minutes. Vaginally absorbed serum levels are more prolonged (Zieman 1997). Irrespective of serum levels, vaginal misoprostol may have locally mediated effects. Misoprostol has been shown in several studies to be an effective myometrial stimulant of the pregnant uterus, selectively binding to EP-2/EP-3 prostanoid receptors (Senior 1993). Misoprostol has been used widely for obstetric and gynaecological indications despite the fact that it has not been registered for such use. It has therefore not undergone the extensive testing for appropriate dosage and safety required for registration. Misoprostol is an effective abortifacient, both alone and following pretreatment with mifepristone (Norman 1991). Its widespread use in Brazil (Costa 1993) resulted in the identification of teratogenic effects (Fonseca 1991). Use of misoprostol for second trimester termination of pregnancy has been associated with uterine rupture, particularly when combined with oxytocin infusion. In a report of 803 women admitted with abortion complications in Rio de Janeiro, 458 reported using misoprostol (Costa 1993). There was one maternal death from uterine rupture at 16 weeks’ gestation following self-medication with misoprostol. Third trimester cervical ripening and labour induction with misoprostol have been reported using the oral, vaginal and rectal routes. Mariani-Neto et al (Mariani-Neto 1987) first reported using oral misoprostol 400 micrograms four hourly for induction of labour following intrauterine death. In a subsequent paper (Mariani-Neto 1988) they described 'uterine tachysystole' with misoprostol use at term, which appeared unrelated to dosage. Since that time, several small studies have confirmed an increased incidence of uterine tachysystole ( >5 contractions per 10 minutes for at least 20 minutes), uterine hypersystole/hypertonus (a contraction of two minutes or more) and/or uterine hyperstimulation syndrome (uterine tachysystole or hypersystole with fetal heart rate changes such as persistent decelerations, tachycardia or reduced short term variability). The conclusion from a recent meta-analysis was that published data confirmed the safety of intravaginal misoprostol for cervical ripening and labour induction. The data showed an increased incidence of uterine tachysystole (odds ratio 2.70, 95% confidence intervals 1.80-4.04), but there was no statistically significant increase in adverse fetal outcome (Sanchez Ramos 1997). Wing et al [Wing 1995a, Wing 1995b, Wing 1996, Wing 1997] have suggested that uterine hyperstimulation and meconium passage with vaginal misoprostol may be less frequent using a 25 microgram dose, six hourly. Merrell (Merrell 1995) reported a series of 62 inductions of labour with vaginal misoprostol. There were two stillbirths, one apparently due to a tight nuchal cord, and one unexplained. They commented on rapid onset of contractions and described one woman with induction to delivery interval of only two hours. In a subsequent abstract (Merrell 1996) they described labour inductions with vaginal misoprostol in 345 women with live fetuses and 86 with intrauterine deaths. There was one unexplained maternal death; two uterine ruptures, one of which followed a previous Caesarean section; eight Caesarean sections for fetal distress and one for uterine hyperstimulation; and 10 perinatal deaths. The possibility of uterine rupture as a rare complication of labour induction with misoprostol must be considered. We are aware of one unpublished case of uterine rupture in a nulliparous woman following misoprostol use (EM Smith, personal communication). At term +12 days she received misoprostol 100 micrograms vaginally. After six hours her cervix was found to be 7cm dilated, and she progressed to full dilatation within a further 70 minutes. Fetal distress was suspected. Ventouse application produced no descent, so delivery was effected by Caesarean section. The infant showed no signs of life at birth. After resuscitation, life was sustained for a few hours only. A posterior uterine tear arising from the cervix and spiralling up the posterior aspect of the uterus was discovered and repaired. Because such uterine tears are rare in nulliparous women without prolonged labour or syntocinon use, a causal relationship with the use of misoprostol must be considered. This review will focus on the effectiveness and safety of misoprostol administered vaginally for cervical ripening and labour induction in the third trimester of pregnancy. The use of oral misoprostol for cervical priming and labour induction, compared with other methods including misoprostol administered vaginally, will be reviewed separately. Objectives To determine, from the best available evidence, the effectiveness and safety of misoprostol administered vaginally for third trimester cervical ripening and induction of labour. Criteria for considering studies for this review Types of participants Women due for third trimester induction of labour, with a viable fetus. Sub-group analyses were performed for women with membranes intact and ruptured, and sub-groups of these for those with favourable, unfavourable or undefined cervices. Only those outcomes with data appear in the analysis tables. Types of intervention Vaginal administration of misoprostol compared with placebo/no treatment or any other method of cervical ripening or induction of labour. Primary comparisons: Misoprostol vs placebo/no treatment Misoprostol vs oxytocin Misoprostol vs prostaglandins Misoprostol vs mechanical methods (no trials to date) Low dosage misoprostol regimen (less than 25 micrograms, or 25 micrograms less frequently than three hourly) vs higher dosage regimens. In all the studies of misoprostol versus prostaglandins, the prostaglandin used was dinoprostone intravaginally as a gel, tablet or slow-release pessary, or intracervically as a gel. In most of the studies, oxytocin was used with similar protocols for both the misoprostol and the prostaglandin group, except that in one study [Kadanali 1996] oxytocin was started if indicated after six hours in the dinoprostone group and only after 24 hours in the misoprostol group. The effective comparison in this trial is therefore misoprostol versus dinoprostone plus early oxytocin. The results are in keeping with those of other studies. Types of outcome measures Clinically relevant outcomes for trials of methods of cervical ripening/labour induction were prespecified by two authors of labour induction reviews (Justus Hofmeyr and Zarko Alfirevic). Differences were settled by discussion. Five primary outcomes were chosen. Sub-group analyses were limited to the primary outcomes: 1. Vaginal delivery not achieved within 24 hours. 2. Uterine hyperstimulation with fetal heart rate (FHR) changes. 3. Caesarean section. 4. Serious neonatal morbidity or perinatal death. 5. Serious maternal morbidity or death. Secondary outcomes relate to measures of effectiveness, complications and satisfaction: Measures of effectiveness: 1. Cervix unfavourable/unchanged after 12-24 hours. 2. Vaginal delivery not achieved within 24 hours. 3. Oxytocin augmentation. Complications: 4. Uterine hyperstimulation without FHR changes. 5. Uterine hyperstimulation with FHR changes. 6. Uterine rupture. 7. Instrumental vaginal delivery. 8. Caesarean section. 9. Meconium stained liquor. 10. Apgar score <7 at 5 minutes. 11. Neonatal intensive care unit admission. 12. Neonatal encephalopathy. 13. Perinatal death. 14. Disability in childhood. 15. Maternal side effects (eg nausea, vomiting, diarrhoea, pyrexia). 16. Postpartum haemorrhage (as defined by the trial authors). 17. Serious maternal complications (eg uterine rupture, intensive care unit admission, septicaemia). 18. Maternal death. Measures of satisfaction: 19. Woman not satisfied. 20. Caregiver not satisfied. While all the above outcomes were sought, only those with data appear in the analysis tables. The terminology of uterine hyperstimulation is problematic (Curtis 1987). In this review we have used the term 'uterine hyperstimulation without FHR changes' to include uterine tachysystole ( >5 contractions per 10 minutes for at least 20 minutes) and uterine hypersystole/hypertonus (a contraction lasting at least two minutes) and 'uterine hyperstimulation with FHR changes' to denote uterine hyperstimulation syndrome (tachysystole or hypersystole with fetal heart rate changes such as persistent decelerations, tachycardia or decreased short term variability). Outcomes were included in the analysis: if reasonable measures were taken to minimise observer bias; missing data were insufficient to materially influence conclusions; and data were available for analysis according to original allocation. Types of studies Clinical trials comparing misoprostol administered vaginally for cervical ripening or labour induction, with placebo/no treatment or other methods; random allocation to treatment and comparison groups; reasonable measures to ensure allocation concealment; violations of allocated management not sufficient to materially affect outcomes. Search strategy for identification of studies See: Collaborative Review Group search strategy This review has drawn on the search strategy developed for the Pregnancy and Childbirth Group as a whole. Relevant trials were identified in the Group's Specialised Register of Controlled Trials. See Review Group's details for more information. The Cochrane Controlled Trials Register was searched using the word 'misoprostol', and relevant trials extracted by hand. The reference lists of trial reports and reviews were searched by hand. Methods of the review Trials under consideration were evaluated for methodological quality and appropriateness for inclusion according to the prestated selection criteria, without consideration of their results. Allocation concealment was scored as A: adequate (eg double-blind, placebo controlled; envelopes administered centrally) B: unclear (eg numbered sealed envelopes not administered centrally); C: inadequate (eg alternation). Individual outcome data were included in the analysis if they met the prestated criteria in 'Types of outcome measures'. Included trial data were processed as described in: Mulrow CD, Oxman AD (eds). Cochrane Collaboration Handbook [updated 1 March 1997]. In: The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration. Oxford: Update Software; 1996-. Updated quarterly. Data were extracted from the sources and entered onto the Review Manager (RevMan) computer software (Update Software, Oxford, UK), checked for accuracy, and analysed as above using the RevMan software. For dichotomous data, relative risks and 95% confidence intervals were calculated, and in the absence of heterogeneity, results were pooled using a fixed effects model. Predefined possible criteria for sensitivity analysis were: trial quality assessment, dose of misoprostol and parity. Primary analysis was limited to the prespecified outcomes and sub-group analyses. In the event of differences in unspecified outcomes or sub-groups being found in the future, these will be analysed post hoc, but clearly identified as such to avoid drawing unjustified conclusions. Description of studies See table of 'Characteristics of included studies'. Methodological qualities of included studies With the exception of three double blind placebo controlled trials [Fletcher 1993, Surbek 1997, Farah 1997], allocation was by means of sealed envelopes or unspecified, and treatment was not blinded. There is therefore a real possibility of bias affecting both the clinical management of the women (eg decisions to undertake Caesarean section) and the assessment of outcomes. Such biases might operate in either direction (for example, a clinician enthusiastic about the potential of misoprostol might be less likely to perform Caesarean section in the misoprostol group, while one anxious about the experimental nature of misoprostol might be more likely to perform Caesarean section in this group). The possibility of such bias must be kept in mind in the interpretation of the results. However, it is reassuring that for the misoprostol versus prostaglandin comparison, the results of the double-blind study (Surbek 1997) are consistent with the overall results. Results All the outcomes listed under 'Types of outcome measures', and sub-groups defined in 'Types of participants', were sought. Only those with data appear in the analysis tables. Vaginal misoprostol versus placebo: The one small study included in this part of the review [Fletcher 1993] showed a clear effect of misoprostol on cervical ripening and need for oxytocin (see analysis tables). The insertion to delivery interval was reduced (misoprostol mean 15.6 hours, standard deviation 12.4 versus placebo 43.2, 20.5). The numbers studied were too small to assess the impact on obstetric management and maternal and neonatal complications. Vaginal misoprostol versus oxytocin: Misoprostol, in the doses used in these trials, was more effective than oxytocin for labour induction (relative risk (RR) of failure to achieve vaginal to achieve vaginal delivery within 24 hours 0.48, 95% confidence interval (CI) 0.35-0.66). However, uterine hyperstimulation was more common both without (RR 2.96, 95% CI 2.11-4.14) and with associated fetal heart rate changes (RR 2.54, 95% CI 1.12-5.77). The rates of vaginal instrumental delivery were similar. The trial results with respect to Caesarean section were inconsistent, ranging from a large reduction [Campos Peres 1994] following misoprostol administration to no statistically significant difference [Escudero 1997]. Sub-group analysis showed a reduced rate of Caesarean section with misoprostol for the group with intact but not ruptured membranes, though the numbers studied in the latter were small. A possible explanation for differences between trials is that they could be related to differences in management of misoprostol-related uterine hyperstimulation in different centres. A policy of early recourse to Caesarean section for uterine hyperstimulation would increase Caesarean sections in the misoprostol group. There were no differences in perinatal or maternal outcomes. Misoprostol versus prostaglandins: In one trial reporting this outcome [Buser 1997], failure to achieve cervical ripening within 12 hours was reduced with misoprostol (RR 0.68, 95% CI 0.52-0.88). Failure to achieve vaginal delivery within 24 hours was reduced with misoprostol in four of five trials (RR 0.70, 95% CI 0.61-0.79). The trial which showed no difference was the only trial with a misoprostol regimen micrograms three hourly [Wing 1997]. Oxytocin augmentation was used less often with misoprostol (RR 0.66, 95% CI 0.59-0.75). The only trial not consistent with this result was the low dose misoprostol trial [Wing 1997]. Uterine hyperstimulation without fetal heart rate changes was more common with misoprostol (RR 1.53, 95% CI 1.17-1.99), though the findings of the low dose misoprostol trial [Wing 1997] showed no such increase. Uterine hyperstimulation with associated fetal heart rate changes was variable between trials, but all were consistent with the pooled result showing an increase with misoprostol (RR 1.59, 95% CI 1.02-2.48). The latter result was similar for the sub-group of trials studying women with intact membranes and unfavourable cervices (RR 2.36, 95% CI 1.32-4.20). The rates of vaginal instrumental delivery were variable between trials, with an overall significant reduction in the misoprostol group (RR 0.75, 95% CI 0.58-0.97). Caesarean sections were variable between trials, with no significant differences overall. Meconium stained liquor was increased with misoprostol (RR 1.38, 95% CI 1.06-1.79). There were no statistically significant differences in perinatal or maternal outcomes. Misoprostol low dosage regimen versus higher dose: The lower dosage regimens (misoprostol 25µg six hourly versus three hourly, or 25 versus 50µg three hourly) did not show significantly more failures to achieve delivery within 24 hours (RR 1.08, 95% CI 0.93-1.25). There was significantly more use of oxytocin (RR 1.32, 95% CI 1.11-1.56). There were no differences in mode of delivery, meconium stained liquor or maternal side effects. There was a trend to less uterine hyperstimulation with fetal heart rate changes, and fewer low Apgar scores at 5 minutes and neonatal intensive care unit admissions. Serious maternal complications were reported in only one study [Wing 1996]: one maternal death occurred in a primiparous woman, nine hours after a single 25 microgram misoprostol dose and shortly after amnioinfusion and epidural analgesia, from amniotic fluid embolisation. Two Caesarean hysterectomies were performed for atonic uterine haemorrhage, 13 and 30 hours after single 25 microgram doses of misoprostol; in one primiparous woman with uncomplicated labour, and in one nulliparous woman who developed chorioamnionitis following prolonged labour induction attempts by oxytocin augmentation. It is not clear whether these three women were allocated to the low or the higher dosage regimen misoprostol group. No other maternal No other maternal deaths and no uterine ruptures or perinatal deaths were reported. However, most studies have not specifically reported these outcomes. Only those specified in the reports have been included in the data tables. Summary of analyses MetaView: Tables and Figures Discussion There is in general considerable consistency between trials, except with respect to Caesarean section rates and to the low misoprostol dosage regimens. The trials show that vaginal misoprostol in dosages ranging from 25 micrograms two to three hourly, to 50 micrograms four hourly (most studies), to 100 micrograms six to 12 hourly, appear to be more effective than oxytocin or dinoprostone in the usual recommended doses for induction of labour, but with increased rates of uterine hyperstimulation both without and with associated fetal heart rate changes. The rates of Caesarean section were inconsistent, tending to be reduced with misoprostol. No differences in perinatal or maternal outcome were shown. However, the trials were not sufficiently large to assess the likelihood of uncommon, serious adverse perinatal and maternal complications. The possibility of inadvertent bias because of the unblinded nature of these studies should be kept in mind. A lower dosage regimen of misoprostol (25 micrograms six hourly) was less effective than a higher dose (25 micrograms three hourly), with possibly reduced rates of uterine hyperstimulation. The finding of a significant increase in meconium stained liquor with misoprostol is of interest. Wing et al [Wing 1995a] suggested the possibility of meconium passage in response to uterine hyperstimulation or a direct effect of absorbed misoprostol metabolites on the fetal gastrointestinal tract. We have previously observed an increased rate of meconium stained liquor in women who have ingested castor oil, though causality was not proven (Mitri 1987). It is unlikely that the small amount of hydrogenated castor oil found in misoprostol tablets [Chuck 1995] would have any pharmacological effect, but the possibility that misoprostol metabolites may stimulate fetal bowel activity merits further investigation. In countries in which misoprostol is being used for non-registered obstetric indications, there is a need for health authorities to clarify the medicolegal implications. Particularly in countries in which conventional prostaglandins are unaffordable, health authorities need to decide whether misoprostol should be used in specific circumstances and, if so, take steps to legalise and regulate such use. Conclusions Implications for practice The limited information on lower dosage regimens (misoprostol 25 micrograms four to six hourly) suggests that it may be as effective as other prostaglandins, without increased uterine hyperstimulation. In dosages of 25 micrograms three hourly or more, misoprostol is more effective than conventional methods of cervical ripening and labour induction. The increase in uterine hyperstimulation with fetal heart rate changes found in this review is a matter for concern. Although no differences in perinatal outcome were shown, the studies were not sufficiently large to exclude the possiblility of uncommon serious adverse effects. The increase in meconium stained liquor in one study also requires further investigation. Thus, though misoprostol shows promise as a highly effective, inexpensive and convenient agent for labour induction, it cannot be recommended for routine use at this stage. It is also not registered for such use in many countries. Implications for research Because of the enormous economic and possible clinical advantages of misoprostol, there is the need for trials to establish its safety. On the basis of this review, such trials should have the following features: 1. Randomised, double blind. 2. Vaginal misoprostol dose not greater than 25 micrograms four to six hourly (oral misoprostol will be six hourly (oral misoprostol will be reviewed separately). 3. Sample size sufficient to detect moderate differences in important uncommon complications such as serious perinatal morbidity/mortality. 4. Meconium stained liquor included as an outcome measure. Ongoing audit of rare serious complications such as uterine rupture is important, and we would be grateful to receive reports of any such incidents. Potential conflict of interest None known. Acknowledgements Zarko Alfirevic for advice concerning outcome measures. Characteristics of included studies Table: Characteristics of included studies Characteristics of excluded studies Study : Bugalho 1995 Allocation not random. A comparison of vaginal misoprostol and oxytocin for induction of labour. Study : Escalante 1993 Excluded because does not fit the pre-stated comparisons of this review. Labour was induced 'randomly' by either vaginal (n = 68) or intracervical (n = 32) misoprostol 100 micrograms, repeated if necessary (in 4 women) after 24 hours. No statistically significant differences regarding cervical ripening and pregnancy outcome were found, though most of the data presented are for the whole group of 100 women. Maternal side effects occurred in 4 women. Uterine hyperstimulation occurred in 11 women, of whom one developed fetal distress which resolved with tocolytic therapy. There were 12 Caesarean sections. Study : Ngai 1996 Excluded because misoprostol administered orally, not vaginally. To be considered for inclusion in the review 'Oral misoprostol for induction of labour'. Study : Toppozada 1997 For consideration of inclusion in review 'Oral misoprostol for induction of labour'. Women with cervical score <5 were randomly allocated to induction of labour with vaginal misoprostol 100 microgams 3-hourly, increasing to 200 micrograms after 2 doses (maximum 1mg), versus oral misoprostol 100 micrograms 3-hourly, increased to 200 micrograms after the first dose. The induction to delivery interval was: vaginal mean 7.15 (standard deviation 4.39) hours vs oral 9.93 (3.68); side effects (nausea and vomiting) 2/20 vs 4/20; uterine hyperstimulation 8/20 vs 0/20; fetal heart rate changes 10/20 vs 1/20; Caesarean section: 2/20 vs 4/20; instrumental vaginal delivery: 4/20 vs 2/20. Study : Wicker 1995 Study reported as an abstract only. Data are not available in a format suitable for analysis. The first author has been written to for further information. Intravaginal misoprostol gel 25 micrograms 6 hourly was compared with 0.5 mg intracervical dinoprostone gel 6 hourly (maximun 3 doses), in 117 women with cervical scores of 5 or less and reassuring antenatal testing. Women receiving misoprostol had higher cervical scores after the first dose, shorter time from induction to oxytocin use and lower number of doses needed. No differences in complications were noted. Study : Windrim 1997 Excluded because misoprostol administered orally, not vaginally. To be considered for inclusion in the review 'Oral misoprostol for induction of labour'. References References to studies included in this review Buser 1997 {published data only} Buser D, Mora G, Arias F. A randomized comparison between misoprostol and dinoprostone for cervical ripening and labor induction in patients with unfavorable cervices. Obstet Gynecol 1997;89:581-585. [9471] Arias F, Buser D, Mora G. Randomized comparison of misoprostol vs dinoprostone for cervical ripening and labor induction. Am J Obstet Gynecol 1997;176:S41. [9533] Campos Perez 1994 {published data only} Campos GA, Guzman S, Rodriguez JG, Voto LS, Margulies M. [Misoprostol--a PGE1 analog for induction of labor at term: comparative and randomized study with oxytocin] Misoprostol--un analogo de la analogo de la PGE1--para la induccion de parto a termino: estudio comparativo y randomizado con oxitocina. Rev Chil Obstet Ginecol 1994;59:190-196. [9163] Campos Perez GA, Margulies M, Ortega I, Voto LS. Induction of labor with misoprostol, a PGE1 analog. A comparative study. Proceedings of the 2nd European Congress on Prostaglandins in Reproduction, The Hague, Netherlands, April 30-May 3 1991, p97. [6368] Margulies M, Campos Perez G, Voto LS Misoprostol to induce labour [letter] Lancet 1992;339:64. [6874] Chang 1997 {published data only} Chang CH, Chang FM. Randomized comparison of misoprostol and dinoprostone for preinduction cervical ripening and labor induction. J Formos Med Assoc 1997;96:366-369. [9474] Chuck 1995 {published data only} Chuck F, Huffaker J. Labor induction with intravaginal prostaglandin E1 (PGE1) (Misoprostol, Cytotec) vs intracervical prostaglandin E2 (PGE2) (Dinoprostone, Prepidil gel): a randomized comparison. Am J Obstet Gynecol 1995;172:424. [8757] Chuck FJ, Huffaker BJ. Labor induction with intravaginal misoprostol versus intracervical prostaglandin E2 gel (Prepidil gel): randomized comparison. Am J Obstet Gynecol 1995;173:1137-1142. [8943] El-Azeem 1997 {published data only} El-Azeem S, Samuels P, Welch G, Staisch K. Term labor induction with PGE1 misoprostol versus PGE2 dinoprostone. Am J Obstet Gynecol 1997; 176: S113 [9617]. Escudero 1997 {published data only} Escudero F, Contreras H. A comparative trial of labor induction with misoprostol versus oxytocin. Int J Gyn Obstet 1997;57:139-143. [9477] Farah 1997 {published data only} Farah LA, Sanchez-Ramos L, Rosa C, Del Valle GO, Gaudier FL, Delke I, Kaunitz AM. Randomised trial of two doses of the prostaglandin E1 analog misoprostol for labor induction. Am J Obstet Gynecol 1997;177:364-371. [9659] Fletcher 1993 {published data only} Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br-J-Obstet-Gynaecol 1993;100:641-644. [8210] Fletcher 1994 {published data only} Fletcher H, Mitchell S, Frederick J, Simeon D, Brown D. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents. Obstet-Gynecol 1994;83:244-247. [8255] Gottschall 1997 {published data only} Gottschall DS, Borgida AF, Mihalek JJ, Sauer F, Rodis JF. A randomized clinical trial comparing misoprostol with prostaglandin E2 gel for preinduction cervical ripening. Am J Obstet Gynecol 1997;177:1067-1070. [9531] Gottschall D, Borgida AF, Mihalek JJ, Sauer F, Rodis JF. Misoprostol versus prostin E2 gel for preinduction cervical ripening. Am J Obstet Gynecol 1997;176:S141. [9660] Herabutya 1997 {published data only} HerabutyaY, O-Prasertsawat P, Pokpirom J. A comparison of intravaginal misoprostol and intracervical prostaglandin E2 gel for ripening of unfavourable cervix and labor induction. J Obstet Gynaecol Res 1997;23:369-374. [9476] Howarth 1996 {published data only} Howarth GR, Funk M, Steytler P, Pistorius L, Makin J, Pattinson RC. A randomised controlled trial comparing vaginally administered misoprostol to vaginal dinoprostone gel in labour induction. J Obstet Gynaecol 1996;16:474-478. [9194] Kadanali 1996 {published data only} Kadanali S, Kucukozkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs. Oxytocin/prostaglandin E2 in term pregnancy. Int J Gynecol Obstet 1996;55:99-104. [9482] Kramer 1997 {published data only} Kramer RL, Gilson GJ, Morrison DS, Martin D, Gonzales JL, Qualls CR. A CR. A randomized trial of misoprostol and oxytocin for induction of labor: safety and efficacy. Obstet Gynecol 1997;89:387-391. [9472] Kramer RL, Gilson G, Morrison DS, Martin D, Gonzales JL, Curet LB. A randomized trial of misoprostol and oxytocin for induction of labor: safety and efficacy. Obstet Gynecol 1997;176:S111. [9615] Mundle 1996 {published data only} Mundle WR, Young DC. Vaginal misoprostol for induction of labor: a randomized controlled trial. Obstet Gynecol 1996;88:521-525. [9484] S-Ramos 1993 {published data only} Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analog misoprostol vs oxytocin: a randomized trial. Int J Gynecol Obstet 1993;43:229. [8102] Sanchez Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: a randomized trial. Obstet Gynecol 1993;81:332-336. [7669] S-Ramos 1997 {published data only} Sanchez-Ramos L, Chen AH, Kaunitz AM, Gaudier FL, Delke I. Labor induction with intravaginal misoprostol in term premature rupture of membranes: a randomized study. Obstet Gynecol 1997;89:909-912. [9481] Sanchez-Ramos L, Chen A, Briones D, Del Valle GO, Gaudier FL, Delke I. Premature rupture of membranes at term: induction of labor with intravaginal misoprostol tablets (PGE1) or intravenous oxytocin. Am J Obstet Gynecol 1994;170:377. [8424] Srisomboon 1997 {published data only} Srisomboon J, Piyamongkol W, Aiewsakul P. Comparison of intracervical and intravaginal misoprostol for cervical ripening and labour induction in patients with an unfavourable cervix. J Med Assoc Thai 1997;80:189-194. [9479] Surbek 1997 {published data only} Surbek DV, Boesiger H, Hoesli I, Pavic N, Holzgreve W. A double-blind comparison of the safety and efficacy of intravaginal misoprostol and prostaglandin E2 to induce labor. Am J obstet Gynecol 1997;177:1018-1023. [9661] Surbek DV, Bosiger H, Hosli I, Pavic N, Holzgreve W. Cervical priming and labor induction with intravaginal misoprostol versus PGE2: a double-blind randomized trial. Am J obstet Gynecol 1997;176:S112. [9614]. Tabor 1995 {published data only} Tabor B, Anderson J, Stettler B, Wetwiska N, Howard T. Misoprostol vs prostaglandin E2 gel for cervical ripening. Am J Obstet Gynecol 1995;172:425. [8756] Varalakis 1995 {published data only} Varaklis K, Gumina R, Stubblefield PG. Randomized controlled trial of vaginal misoprostol and intracervical prostaglandin E2 gel for induction of labor at term. Obstet Gynecol 1995;86:541-544. [8921] Webb 1997 {published data only} Webb GW, Raynor BD, Huddleston JF, Fandall HW. Induction of labor with an unfavorable cervix: a randomized prospective trial. Am J Obstet Gynecol 1997;176:S22. [9456] Wing 1995a {published data only} Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostaglandin E2 gel for preinduction cervical ripening and labor induction [see comments] Am J Obstet Gynecol 1995;172:1804-1810. [9167] Wing 1995b {published data only} Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: an effective agent for cervical ripening and labor induction [see comments]. Am J Obstet Gynecol 1995;172:1811-1816. [9166] Wing 1996 {published data only} Wing DA, Paul RH. A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1996;175:158-164. [9209] Wing 1997 {published Wing 1997 {published data only} Wing DA, Ortiz-Omphroy G, Paul RH. A comparison of intermittent vaginal administration of misoprostol with continuous dinoprostone for cervical ripening and labor induction. Am J Obstet Gynecol 1997;177:612-618. [9483] Wing DA, Paul RH. Vaginally administered misoprostol (Cytotec) versus the dinoprostone vaginal insert (Cervidil) for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1997;176:S113. [9616] * indicates the major publication for the study References to studies excluded from this review Bugalho 1995 Bugalho A, Bique C, Machungo F, Bergstrom S. Vaginal misoprostol as an alternative to oxytocin for induction of labor in women with late fetal death. Acta Obstet Gynecol Scand 1995;74:194-198. [9478] Escalante 1993 Escalante G, Ribas D, Moya R, Sanchez LO, Pena C. Misoprostol intracervical vs. vaginal: caracteristicas clinicas en la induccion del parto/Misoprostol intracervical or vaginal. Clinics characteristics in delivery induction. Rev costarric cienc med 1993;14:43-50. [9473] Ngai 1996 Ngai SW, To WK, Lao T, Ho PC. Cervical priming with oral misoprostol in pre-labor rupture of membranes at term. Obstet Gynecol 1996;87:923-926. [9121] Toppozada 1997 Toppozada MK, Anwar MY, Hassan HA, el-Gazaerly WS. Oral or vaginal misoprostol for induction of labor. Int J Gynaecol Obstet 1997;56:135-139. [9295] Wicker 1995 Wicker R, Albert J, Laurent S, Bellitt P. Evaluation of misoprostol and dinoprostone in cervical ripening. Am J Obstet Gynecol 1995;172:424. [8759] Windrim 1997 Windrim R, Bennett K, Mundle W, Young DC. Oral administration of misoprostol for labor induction: a randomized controlled trial. Obstet Gynecol 1997;89:392-397. [9480] References to studies awaiting assessment Echeverria 1995 Echeverria E, Rocha M. [Randomised comparative study of induced labor with oxytocin and misoprostol in prolonged pregnancies]. Rev Clin Obstet Gynecol 1995;60:108-111. [9100] Lee 1997 Lee HY. A randomised double-blind study of vaginal misoprostol vs dinoprostone for cervical ripening and labour induction in prolonged pregnancy. Singapore Med J 1997;38:292-294. [9475] Additional references Bishop 1964 Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266-268. Costa 1993 Costa SH, Vessey MP. Misoprostol and illegal abortion in Rio de Janeiro, Brazil. Lancet 1993;341:1258-1261. Curtis 1987 Curtis P, Evans S, Resnick J. Uterine hyperstimulation. The need for standard terminology. J Reprod Med 1987;32:91-95. Egarter 1990 Egarter CH, Husslein PW, Rayburne WF. Uterine hyperstimulation after low-dose prostaglandin E2 therapy: tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990;163:794-796. Fonseca 1991 Fonseca W, Alencar AJC, Mota FSB, Coelho HLL. Misoprostol and congenital malformations. Lancet 1991;338:56. Keirse 1993 Keirse MJNC. Prostaglandins in preinduction cervical ripening: Meta-analysis of worldwide clinical experience. J Reprod Med 1993;38 (suppl):89-98. Mariani Neto 1988 Mariani Neto C, Delbin AL, Val RD. Padrao tocografico desencadeado pelo misoprostol. Rev Paul Med 1988;106:205-208. Mariani-Neto 1987 Mariani-Neto C, Leao EJ, Baretto EM, Kenj G, De Aquino MM. Use of misoprostol for labour induction in stilbirths. Rev Paul Med 1987;105:325-328. Merrell 1995 Merell DA, Koch MAT. Induction of labour with misoprostol in the second and third trimesters of second and third trimesters of pregnancy. S Afr Med J 1995;85:1088-1090. Merrell 1996 Merrell DA, Koch MAT, Thomas PC. Experience with vaginal and rectal misoprostol as an oxytocic agent in pregnancy. PAFMACH Conference, Johannesburg, South Africa 1996 (abstract). Mitri 1987 Mitri F, Hofmeyr G J, Van Gelderen C J. Meconium during labour: self-medication and other associations. S Afr Med J 1987;71:431-433. Norman 1991 Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 1991;338:1233-1236. Sanchez-Ramos 1997 Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol 1997;89:633-642. Senior 1993 Senior J, Marshall K, Sangha R, Clayton JK. In vitro characterisation of prostaniod receptors on human myometrium at term pregnancy. Br J Pharm 1993;108:501-506. Zieman 1997 Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88-92. Coversheet Title Vaginal misoprostol for cervical ripening and labour induction in late pregnancy Short Title Misoprostol vaginally for labour induction Reviewer(s) Hofmeyr GJ Date of most recent amendment : 28 October 1998 Date of most recent substantive amendment : 20 April 1998 This review should be cited as : Hofmeyr GJ. Vaginal misoprostol for cervical ripening and labour induction in late pregnancy (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software. Contact address : Prof G Justus Hofmeyr Department of Obstetrics and Gynaecology Coronation Hospital and University of the Witwatersrand 7 York Road Parktown 2193 Johannesburg South Africa Telephone: +27 11 470 9090 Facsimile: +27 11 470 9092 E-mail: 091just@chiron.wits.ac.za For information on the editorial group see: Cochrane Pregnancy and Childbirth Group Extramural sources of support to the review South African Medical Research Council SOUTH AFRICA UNDP/UNFPA/WHO/World Bank (HRP) SWITZERLAND Intramural sources of support to the review University of the Witwatersrand SOUTH AFRICA Comment, Reply and Editorial notes The title of this review has changed. It was published in 1998 as 'Misoprostol administered vaginally for cervical ripening and labour induction in the third trimester'. Keywords HUMAN; FEMALE; PREGNANCY; LABOR-INDUCED / methods; MISOPROSTOL / adverse-effects; MISOPROSTOL / administration- &-dosage; PLACEBOS; UTERINE-CONTRACTION / chemically-induced; UTERINE-RUPTURE / chemically-induced; LABOR-COMPLICATIONS / chemically-induced; ADMINISTRATION-INTRAVAGINAL; DOUBLE-BLIND-METHOD; RANDOMIZED-CONTROLLED-TRIALS; CRG Code: HM-PREG ----- END OF DOCUMENT -----
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