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
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 -----
