Review: Expert Committee Member

MISOPROSTOL (Low dose for labour induction at term)

Author: Lenita Wannmacher

Application: Misoprostol, a synthetic prostaglandin E1 analogue, is proposed for

inclusion in the 14th WHO Model List of Essential Medicines for labour induction
at term, to be used in a low dose (25mcg 50 mcg).

Dr. Metin Glmezoglu (UNDP/UNFPA/ WHO/World Bank Special Programme of

Research, Development and Research Training in Human Reproduction (HRP),
Department of Reproductive Health and Research) has submitted this
application1.

Background: Sometimes it is necessary to bring on labour artificially because of

safety concerns for the mother or child. Labour induction is an intervention that
artificially initiates uterine contractions leading to progressive dilatation and
effacement of the cervix and birth of the baby, and is to be considered when the
risks of continuing pregnancy are outweighed the risks of terminating it. When
fetal maturity is guaranteed, psychosocial or logistical factors may turn into
indications for labour induction. Labour induction is a procedure used for a broad
range of common conditions: post-term pregnancy, pregnancy induced
hypertension, pre-eclampsia, eclampsia, premature rupture of membranes,
intrauterine fetal growth retardation, chorioamnionitis, fetal death, and maternal
diabetes. Other less common but severe conditions include chronic renal disease,
antiphospholipid syndrome, thromboembolism, severe dermatosis and previous
stillbirth. A prompt delivery reduces maternal or neonatal morbidity and mortality.
Methods of preparing uterine cervix and inducing labour include administration of
oxytocin, prostaglandins, prostaglandin analogues, mifepristone, extra-amniotic
saline solution infusion, or mechanical procedures (amniotomy, intracervical
Foley catheter, hygroscopic cervical dilators, digital stretching of the cervix and
sweeping of the membranes, and nipple stimulation). There is a great concern
about their effectiveness and safety. The main problems experienced during
induction are ineffective labour and excessive uterine activity, which may cause
fetal and maternal distress. Both problems may lead to an increased risk of
caesarean section.
When the cervix is unfavourable (low cervical Bishop score) in the third trimester
or when uterine evacuation is needed in the first or second trimesters (absence
of oxytocin receptors in the pregnant uterus) oxytocin presents a high failure
rate for labour induction. In addition, its continuous intravenous infusion has to be
constantly monitored. In those cases, prostaglandin preparations have proved to
be beneficial, but most of them are expensive and unstable at room temperature.
Prostaglandin analogues (misoprostol, dinoprostone, carboprost) are used in
labour induction and augmentation. Among them misoprostol is preferred for it is
inexpensive, easily stored at room temperature and has few systemic side
effects.2
WHO guidelines3 address induction of labour with misoprostol in highly selected
situations such as severe pre-eclampsia or eclampsia when the cervix is
unfavourable, and a caesarean is unsafe, or the baby is too premature to survive,
or there is in-utero fetal death in woman who have decreasing platelets and no
spontaneous labour after four weeks.
In many countries misoprostol is only approved for prevention and treatment of
NSAID-associated peptic ulcers and management of medical abortion. However,
it has been extensively studied and widely used for obstetric and gynaecological
non-abortive indications, such as pre-induction cervical ripening and labour
induction (3rd trimester, especially at low Bishop scores), evacuation of the uterus
after pregnancy failure or for various medical reasons (2nd trimester), and primary
postpartum haemorrhage4, 5.
In many countries misoprostol tablets have been administered through different
routes (sublingual, oral, vaginal and rectal). Misoprostol is absorbed faster orally
than vaginally, with higher peak serum level, but vaginally absorbed serum levels
are more prolonged. Its oral use may be convenient, but high doses could cause
uterine hyperstimulation and uterine rupture. Vaginal use of lower doses seems
to be associated with less uterine hyperstimulation. Misoprostol is associated
with locally mediated effects. The judicious use of misoprostol for obstetric and
gynaegological indications, in appropriate clinical settings, hope to reduce
maternal mortality.

Aims of the search: To assess the effectiveness, safety and cost-effectiveness

of misoprostol for labour induction at term, in order to decide on its inclusion as
25microg and 50microg tablets in the 14th WHO Model List of Essential
Medicines.

Methods: A Medline search (misoprostol labour induction) for systematic

reviews and randomised controlled trials (RCTs), from 2003 to 2005, yielded 4
systematic reviews and 35 RCTs. These references were reviewed in addition to
those previously commented in a misoprostols application during the last
Committee Meeting in 2003.

Comments
EFFECTIVENESS
Pre-induction cervical ripening
Widespread availability of pre-induction cervical ripening agents has contributed
to the rising trend in labour induction. Approximately half of all women
undergoing an induction of labour will have an unfavorable cervix that will require
some ripening agent. Pharmacologic and mechanical dilator techniques have
been proven to ripen the unfavourable cervix.
A Cochrane Review2 compared intravaginal misoprostol with placebo (5 small
studies), vaginal prostaglandins (23 trials with 3282 participants), intracervical
prostaglandins (13 trials with 1810 participants), and oxytocin (14 trials with 1767
participants). Misoprostol was associated with increased cervical ripening after
12 and 24 hours and reduced failure to achieve vaginal delivery within 24 hours
in all comparisons. Epidural analgesia was used less frequently with misoprostol
in comparison with the other vaginal prostaglandins (six trials, RR: 0.91; 95%CI:
0.84-0.99) and oxytocin (two trials, RR: 0.64; 95%CI: 0.48-0.86). Oxytocin
augmentation was reduced with misoprostol versus vaginal (23 trials, RR: 0.64;
95%CI: 0.56-0.73) and intracervical prostaglandins (10 trials, RR 0.58, 95% CI
0.52 to 0.64). There was a trend towards a reduction in the need for caesarean
sections, but results showed differences among trials. There was a trend towards
fewer admissions to neonatal intensive care units with low-dosage regimens of
misoprostol. No differences in perinatal or maternal outcome were shown. A
meta-analysis8 did not identify significant differences in clinical outcomes
between dinoprostone vaginal inserts and alternatives (including misoprostol)
used for cervical ripening at term. A RCT9 compared the efficacy of intravaginal
misoprostol (50 micrograms) to intracervical dinoprostone gel for pre-induction
cervical ripening in 61 patients whose cervices were unfavourable (Bishop score:
4). The results within 12 hours significantly favour misoprostol (56% versus 17%;
P = 0.007). Fewer doses of misoprostol were required to achieve cervical
ripening, and the interval from induction to delivery was shorter in the misoprostol
group. Another comparison10 between 50 microg vaginal misoprostol 6 hourly
and 0.5 mg intracervical dinoprostone 6 hourly for cervical ripening and induction
of labour evidenced vaginal misoprostol is safer and more effective, with lesser
need of oxytocin augmentation and shorter induction delivery interval.
Another RCT11 compared the efficacy of intravaginal misoprostol tablets with
transcervical Foley catheter for pre-induction cervical ripening in 111 women with
unfavourable cervices. No statistically significant differences were observed in
Bishop score changes, pre-induction cervical ripening times, and total induction
times between groups. There was no statistically significant difference in the
mode of delivery or adverse neonatal outcomes. A comparison12 among
intravaginal misoprostol, intracervical Foley catheter, or a combination
prostaglandin E2 gel and Foley catheter for pre-induction cervical ripening in 205
women with unfavourable cervices showed a lower oxytocin requirement in the
misoprostol group when compared with the other two groups. A study13
compared a single 25-microg outpatient intravaginal dose of misoprostol to
placebo in pregnant women with Bishop scores less than 9 at 40 weeks or
greater. After placement of the study medication, subjects were permitted to go
into spontaneous labor unless an indication for induction developed. The mean
interval to delivery was significantly less in the misoprostol group (P =.04). The
interval to delivery for only the nulliparous patients was significantly less in the
misoprostol group (P =.02). There were no adverse outcomes in either group. In
another trial14 pregnancies that underwent labor induction at > or =37 weeks of
gestation with an unfavorable cervix (Bishop score, < or =6) were randomly
assigned to receive vaginally either a single dose of sustained-release
dinoprostone with concurrent low-dose oxytocin or multidosing of misoprostol (25
microg every 4 hours) followed by high-dose oxytocin. The dinoprostone and
misoprostol groups did not differ statistically in the percent of patients who were
delivered vaginally by 12 hours (36.2% vs 29.7%), 18 hours (63.8% vs 56.3%),
and 24 hours (81.0% vs 81.3%). Excess uterine activity was not more common in
either group, and hyperstimulation syndrome was absent in all cases.

Induction of labour at term

Multiple trials have proven that vaginally applied misoprostol is an effective agent
for labour induction at term pregnancy15. Oral use would be particularly attractive
because of easy and non-invasive administration. A Cochrane Review16 included
RCTs, which compared oral misoprostol with placebo, intravaginal dinoprostone,
intracervical dinoprostone, oxytocin, and vaginal misoprostol for induction of
labour in women with a viable fetus in the third trimester of pregnancy. Compared
with placebo (one trial), oral misoprostol reduced the need for oxytocin infusion
and shortened the time between induction and delivery (the difference was 8.7
hours; 95% CI: 6.0-11.3). Compared with vaginal dinoprostone, induction to
delivery interval was somewhat shorter in the vaginal misoprostol group
(weighted mean difference 2.78 hours; 95%CI: 0.72-4.84). The comparison of a
single 200 microg oral dose of misoprostol with intracervical dinoprostone did not
show a statistically significant difference in achieving vaginal delivery within 24
hours (76% vs. 50%; RR 0.72; 95%CI: 0.52-1.00). In two comparisons with
intravenous oxytocin, there was no significant difference in prespecified
outcomes. The comparison with vaginal misoprostol was performed with different
oral regimens (results discussed below). Oral misoprostol appears to be less
effective than vaginal misoprostol. The caesarean section rate was less in the
oral misoprostol group compared with the vaginal misoprostol group (16.7%
versus 21.7%; RR 0.77, 95%CI: 0.61 - 0.97). The lower caesarean section rate
with oral misoprostol could not be explained by a lower incidence of uterine
hyperstimulation (8.5% versus 7.4%; RR 1.11; 95%CI: 0.78 - 1.59), but the
heterogeneity for this outcome was also significant (P=0.0014). There were no
reported cases of severe neonatal and maternal morbidity and no significant
differences in other clinically relevant outcomes. When oral and vaginal
misoprostol were compared in subgroup with unfavourable cervix there were no
significant differences in reported outcomes. When only women with intact
membranes were analysed, failure to achieve vaginal delivery after 24 hours was
more likely in oral misoprostol group. Also, there was more meconium stained
liquor in the oral misoprostol group. The subgroup of women with intact
membranes and unfavourable cervix had more uterine hyperstimulation with fetal
heart rate changes after oral administration. Compared with vaginal misoprostol,
failure to achieve vaginal delivery after 24 hours after oral misoprostol was more
likely in primiparous women. In multiparous women oral misoprostol was also
less effective.
Compared with oral misoprostol, the effectiveness of mechanical methods was
similar (34% versus 30%; RR: 1.15; 95% CI: 0.80-1.66) 17. Comparing oral
misoprostol, 100 mg, administered every 4 hours up to 6 doses with intravenous
oxytocin infusion for labor induction in 198 women with favorable cervical
examinations (defined as a Bishop score of 6 or more), Wing and associates18
concluded that oral misoprostol offers no benefit over intravenous oxytocin for
labor induction in those women. It is associated with a higher likelihood of uterine
hyperstimulation and may increase the risk of uterine rupture. Another RCT19
compared intravaginal misoprostol (25 microg, every 4 hours, not exceeding 8
doses) versus oxytocin in intravenous continuous infusion for cervical ripening
and labor induction in pregnant women with unripe cervices. The cesarean
section rate, latent period and period from induction to vaginal delivery were
significantly lower for the misoprostol group. With regard to uterine tonus
alterations, tachysystole was significantly more common in the misoprostol group.
However, there was no difference in hypoxia and neonatal morbidity between the
groups.
In pregnancies at high risk of fetal distress20 intravaginal misoprostol and
dinoprostone vaginal insert were compared, and no significant difference was
found in neonatal safety, in neonatal tolerance, in the cesarean delivery rate for
fetal distress or in the incidence of meconium-stained amniotic fluid. Time to
vaginal delivery was shortened by misoprostol (P=0.03). Another study21
concluded that intravaginal misoprostol and dinoprostone vaginal inserts are safe
and effective medications for use in cervical ripening before labor induction.
Misoprostol results in a shorter interval from induction to delivery. However,
Cesarean delivery for a non-reassuring fetal heart rate tracing was more
common with misoprostol.
A more recent Cochrane review22 including three studies (502 participants)
compared buccal/sublingual misoprostol with placebo/no treatment or
respectively with a vaginal regimen (200 g versus 50 g) and with oral
administration (50 versus 50 g and 50 versus 100g) for third trimester cervical
ripening or labour induction. The buccal route was associated with a trend to
fewer caesarean sections than with the vaginal route (18/73 versus 28/79;
RR=0.70; 95%CI: 0.42 - 1.15). There were no significant differences in any other
outcomes. When the same dosage was used sublingually versus orally, the
sublingual route was associated with less failures to achieve vaginal delivery
within 24 hours (12/50 versus 19/50; RR 0.63; 95%CI: 0.34 - 1.16), reduced
oxytocin augmentation (17/50 versus 23/50; RR=0.74; 95%CI: 0.45 - 1.21) and
reduced caesarean section (8/50 versus 15/50; RR=0.53; 95%CI: 0.25 - 1.14),
but the differences were not statistically significant. When a smaller dose was
used sublingually than orally, there were no differences in any of the outcomes.

Protocol comparisons
Route of administration
Misoprostol has been administered through oral, sublingual, buccal, vaginal and
rectal routes. A study23 compared the pharmacokinetic profiles of orally, rectally,
and vaginally administered misoprostol tablets in pregnant women. Vaginal
misoprostol was present in the circulation longer than oral misoprostol and had a
greater area under curve at 240 minutes (P <0.001). Rectal misoprostol had a
similar pattern but a much lower area under curve at 240 minutes. Oral
misoprostol had a significantly greater peak plasma concentration and a shorter
duration to maximum concentration than either rectal or vaginal misoprostol (both
P <0.001). Therefore misoprostol has route-dependent pharmacokinetics and is
best absorbed when administered vaginally.
Oral versus vaginal route
Extensive clinical experience has demonstrated that vaginal administration is
more effective, and is associated with fewer side effects, as nausea and
diarrhoea. A Cochrane review15 compared swallowed misoprostol with vaginal
misoprostol. Different oral regimens of misoprostol seemed to be less effective
than vaginal preparation. More women who used oral misoprostol did not achieve
vaginal delivery within 24 hours compared with those who used vaginal
misoprostol (50% vs.39.7%; RR=1.27; 95%CI: 1.09-1.47). The caesarean section
rate was lower in the oral misoprostol group compared with the vaginal
misoprostol group (16.7% vs. 21.7%; RR: 0.77; 95%CI: 0.61- 0.97). Three
studies suggested that higher oral doses (100 mcg or more) are more effective,
but successful vaginal delivery within 24 hours have to be carefully balanced
against serious adverse outcomes. No significant differences were found for
uterine hyperstimulation with fetal heart rate changes and no severe neonatal or
maternal morbidity was reported.
A RCT24 compared oral (100 microg) versus vaginal misoprostol (25 microg)
given every 3-4 hours for induction. There was no statistical difference in delivery
time, caesarean section rate, adverse effects and neonatal outcomes in vaginal
and oral arms. Another RCT25 compared the efficacy of 100 microg orally with 50
microg vaginally misoprostol every 6 hours for 48 hours for induction of labor at
term. The median induction to vaginal delivery time in the oral group (14.3 h) was
not significantly different from that of the vaginal group (15.8 h). The median
number of doses was also not significantly different in the oral group compared
with the vaginal group. There was a significant higher incidence of uterine
tachysystole in the vaginal group compared to the oral group (17.1% vs. 5.3%, P
= 0.032). There was no hyperstimulation in either group. There were no
significant differences between the groups with respect to oxytocin augmentation,
cesarean section rate, analgesic requirement, and neonatal outcomes. Oral
misoprostol (100 microg) was compared with vaginal misoprostol (25 microg,
every 4 hours to a maximum of five doses) in term labor induction26. Related to
vaginally delivery within 24 hours, oxytocin need and induction to delivery interval,
the 25 microg vaginal misoprostol seems to be more efficacious than the 100
microg oral dose. However there were no differences in the modes of delivery,
uterine hyperstimulation rates or neonatal outcomes.
Oral versus sublingual route
A non-blinded RCT27 compared the efficacy of repeated sublingual (50 microg)
versus oral misoprostol (100 microg). Both schedules had the same efficacy and
safety profile. The women preferred the oral to sublingual route. The authors of a
more recent Cochrane review22 affirmed that there is insufficient evidence to
establish if misoprostol by mouth is more effective swallowed or sublingual.
Buccal versus vaginal misoprostol
A RCT28 compared buccal misoprostol with intravaginal misoprostol for cervical
ripening. The efficacy was similar between the two groups, but the incidence of
tachysystole was higher in the buccal group than in the vaginal group (28
occurrences vs. 15 occurrences; P=0.01).

Dose
Vaginal misoprostol
A Cochrane review2 compared the effects of different doses of vaginal
misoprostol. Lower doses compared to higher doses were associated with more
need for oxytocin augmentation (dose <50 microg), less uterine hyperstimulation,
with and without fetal heart rate changes, and a non-significant trend to fewer
admissions to neonatal intensive care unit. The lower dosage regimens did not
show more failures to achieve delivery within 24 hours. Based on the analysis,
the Cochrane reviewers recommend a starting dose of 25 mcg every four hours.
A comparison29 between 25 mcg and 50 mcg intravaginal misoprostol for cervical
ripening and labour induction showed the higher dose was associated with a
shorter interval to vaginal delivery, greater proportion of deliveries within 24
hours, and less frequent need for oxytocin augmentation, but it is unclear
whether it is as safe as the 25 mcg dose. Another similar study30 showed the
same results in relation to time to delivery and need for oxytocin augmentation. In
contrast, more women achieved vaginal delivery with 25 microg misoprostol
(79.3 vs. 60.7%; P < 0.05). The proportions of patients with tachysystoles and
hypersystoles showed not significant differences between the two groups. The
rate of caesarean sections due to non-reassuring foetal status was higher with
the higher dose (28.6 vs. 10.3%; P < 0.05). The number of neonates with a low
1-min Apgar score (<7) was significantly higher in the 50mcg misoprostol group
(26.8 vs. 8.6%; P < 0.05), but 5-min Apgar scores and umbilical artery blood gas
values at the time of delivery were not significantly different between groups. One
patient in the 25 mcg group suffered uterine rupture. A more recent RCT31
compared two schedules of intravaginal misoprostol: 100 microg, every 6 hours
or 50 microg every 4 hours. In the two groups the number of doses of
misoprostol used was similar. There was no difference between the two groups
in the time to delivery and cesarean rate. Likewise, there was no significant
difference in the rates of 5 min Apgar score and meconium passage. Another
RCT32 compared the effectiveness of 25 microg vs. 50 microg of intravaginal
misoprostol for cervical ripening and labor induction beyond 41 weeks gestation.
The dose was repeated every 4 hours (maximum number of doses limited to six)
until the patient exhibited three contractions in 10 min. There was no significant
difference between the two groups with regard to the inductionvaginal delivery
interval (685201 min in the 25 microg group vs. 627177 min in the 50 microg
group, P=0.09). The proportion of women delivering vaginally with one dose of
vaginal misoprostol was significantly greater in the 50 microg group (0/49 vs.
41/47, P<0.001). There were no differences in the rates of cesarean and
operative vaginal delivery rates, or in the incidences of tachysystole and
hyperstimulation syndrome in the two treatment groups. Neonatal outcomes were
also similar.
Oral misoprostol
A Cochrane review16 focusing oral misoprostol for induction of labour included
two studies that used oral 200 microg misoprostol dose. This dose was
associated with more tachysystole, but without evidence of better effectiveness in
comparison with low-dose vaginal misoprostol. Most of the studies have used an
oral dose of 50 mcg. It seems that higher oral doses (100 microg or more) are
more effective, with more successful vaginal delivery within 24 hours. However,
stronger uterine contractions and shorter labours have to be carefully balanced
against more uterine hyperstimulation, adverse neonatal outcomes and
possibility of uterine rupture.

Pharmaceutical formulation
In many countries oral misoprostol tablets are used vaginally, although they are
not formulated for the vaginal route. Oral tablets may be different from vaginal
tablets. Misoprostol tablets are usually available in 200 microg presentation. The
administration of lower doses thus involves fragmenting tablets which makes it
difficult to guarantee that a uniform dose is being delivered33. In Brazil
misoprostol is registered as vaginal tablets (25, 100 and 200 micrograms) 34. Oral
tablets put inside the vagina may be poorly dissolved, then suffering expulsion
(Personal communication). However Khan and associates23 showed oral
misoprostol tablet being also absorbed by the rectal and vaginal routes. One
trial35 compared vaginal gel versus tablets. The mean intervals from drug
administration to induction of labour onset (13.8 h vs. 18.2 h) and delivery (22.4 h
vs. 29.0 h) were significantly shorter in the tablet group than in the gel group (P <
0.01 for both). Oxytocin augmentation, analgesic epidural use, and the mean
number of misoprostol insertions (1.4 vs. 1.9) were lower in the tablet group than
in the gel group (P < 0.05 for all).

Procedure
Different regimens have been proposed for misoprostol use in labour induction. A
study36 performed in multiparous patients randomised 104 women to either a
single dose of 50 microg of intravaginal misoprostol in 24 hours, or two
consecutive doses of intravaginal 50 microg misoprostol 6 hours apart. The
mean induction-to-delivery interval and delivery rate within 12 hours were higher
in the two-dose group. The oxytocin augmentation rate was higher in the single-
dose group. There was no statistical difference between both regimens with
respect to the rates of tachysystole, hyperstimulation, and meconium staining at
delivery.
A RCT37 estimated the efficacy of 50 microg intravaginal misoprostol as tablets
moistened with 1 ml of 3% acetic acid solution or dry tablets for labour induction.
There was no statistically significant difference for the interval to vaginal delivery,
need for oxytocin augmentation, proportion of patients delivered after a single
dose, intrapartum complications (tachysystole and uterine hyperstimulation),
mode of delivery, or perinatal outcomes.
 Another RCT38 performed for abortive purpose evaluated if the efficacy of
treatment with intravaginal misoprostol was enhanced by the addition of saline
solution. The misoprostol effectiveness is not improved by adding saline solution.

RISKS
There is no consensus on what constitutes an acceptable risk of labour induction,
in the absence of life threatening conditions for mother and baby. It is likely that
most parents and clinicians would not be prepared to accept a 0.5% to 1%
increase in serious adverse outcome on the grounds of convenience or cost. In
fact, it is likely that women would be prepared to spend more time on delivery
suite if this means a safer labour. Unfortunately, currently available data are
nowhere near large enough to address the issue of safety.
Some trials reported uterine contraction abnormalities (tachysystole, hypertonus
and hyperstimulation), increased frequencies of meconium passage, neonatal
acidaemia and caesarean delivery for fetal distress in association with repeated
higher doses (50 microg or more) of vaginal or oral misoprostol given for cervical
ripening and labour induction. However, low-dose vaginal misoprostol (25 microg,
every four or six hours) appears to have a more favourable profile2, 15. Uterine
rupture is considered a rare complication of labour induction with misoprostol, but
it happened even with a low-dosage use. It is important to keep in mind that
uterine rupture could also be associated with other inductive methods. Maternal
and perinatal deaths were rarely reported in RCTs. Other potential
gastrointestinal adverse effects include diarrhoea, abdominal pain, dyspepsia,
flatulence and, nausea and vomiting. Skin rashes headache and dizziness have
also been reported. Hypotension is rarely seen at recommended doses.

COMPARATIVE COST AND COST-EFFECTIVENESS WITHIN THE

PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP
Misoprostol is considerably cheaper than both intravaginal and intracervical
dinoprostone. The Royal College of Physicians found that taking as a reference
the recommended regimen of vaginal dinoprostone tablet, that relative costs
compared with vaginal misoprostol would be 0.18 per 200 mcg tablet of
misoprostol versus 8.13 for a 3 mg dinoprostone tablet. Compared with
dinoprostone, misoprostol reduces the incidence of operative deliveries therefore
a further indirect cost savings would be expected33. In the US a dose of
misoprostol would cost less than one US dollar, whilst dinoprostone costs over
$150 USD39. A comparison40 on cost between dinoprostone and misoprostol as
labor preinduction agents showed that vaginal misoprostol (50 microg every 6
hours for two doses) is more cost-effective than the comparable commercial
dinoprostone preparations (gel and insert) as an adjuvant to labor induction in
women with an unfavorable cervix.

Recommendation
Based on contemporary evidence, misoprostol is effective in cervical ripening
and labour induction, as well as treatment in primary postpartum haemorrhage.
In comparison with other conventional agents, it is stable at room temperature,
less expensive, and has fewer systemic side effects. In an initial dose of 25
micrograms every four or six hours, vaginal misoprostol is more effective than
oral and sublingual misoprostol. On the other hand, intravaginal misoprostol
increases uterine hyperstimulation with or without fetal heart rate changes.
Although no difference in perinatal and maternal outcomes were shown in
systematic reviews and meta-analyses, the studies reviewed were not sufficiently
large to exclude the possibility of uterine rupture, which has been reported
anecdotally following misoprostol use in women with or without previous
caesarian section. At the same time, it is important to remember that uterine
rupture could be associated with other inductive methods. Several studies
showed reduced rate and severity of complications among women who have
used vaginal misoprostol. Vaginal administration of misoprostol seems to be
cost-effective, mainly because it reduces the incidence of operative deliveries.
Therefore a further indirect cost saving would be expected. Finally, for
appropriate clinical indications misoprostol has to be administered through
vaginal route, as 25 or 50 microg vaginal tablets, and used only in organized
health services with conditions to manage negative outcomes.

References
1.Cuervo LG. Misoprostol: low dose for labour induction at term. Received 2
February 2005. Available:
http://www.who.int/medicines/organization/par/edl/expcom14/expcom05add.shtm
l
2. Hofmeyr GJ, Glmezoglu AM. Vaginal misoprostol for cervical ripening and
induction of labour (Cochrane Review). In: The Cochrane Library, Issue 4, 2004.
Oxford: Update Software.
3. WHO Department of Reproductive Health and Research. Induction and
augmentation of labour. In: WHO, UNFPA, UNICEF, World Bank, editors.
Managing complications in pregnancy and childbirth: a guide for midwives and
doctors. Geneva: WHO/RHR/00.7; 2000. P. 17-25.
4. Glmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for prevention
of postpartum haemorrhage (Cochrane Review). In: The Cochrane Library, Issue
4, 2004. Oxford: Update Software.
5. Mousa HA, Alfirevic Z. Treatment for primary postpartum haemorrhage
(Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Oxford: Update
Software.
6. Kirby RS. Trends in labor induction in the United States: is it true that what
goes up must come down? Birth 2004; 31(2): 148-151.
7. Yawn BP, Wollan P, McKeon K, Field CS. Temporal changes in rates and
reasons for medical induction of term labor, 1980-1996. Am J Obstet Gynecol
2001; 184(4): 611-619.
8. Hughes EG, Kelly AJ, Kavanagh J. Dinoprostone vaginal insert for cervical
ripening and labor induction: a meta-analysis. Obstet Gynecol 2001; 97: 847-855.
9. Neiger R, Greaves PC. Comparison between vaginal misoprostol and cervical
dinoprostone for cervical ripening and labour induction. Tenn Med 2001; 94:25-
27.
10. Agarwal N, Gupta A, Kriplani A, Bhatla N, Parul. Six hourly vaginal
misoprostol versus intracervical dinoprostone for cervical ripening and labor
induction. J Obstet Gynaecol Res 2003; 29(3):147-151.
11. Sciscione AC, Nguyen L, Manley J, Pollock M, Maas B, Colmorgen G. A
randomized comparison of transcervical Foley catheter to intravaginal
misoprostol for pre-induction cervical ripening. Obstet Gynecol 2001; 97: 603-607.
12. Greybush M, Singleton C, Atlas RO, Balducci J, Rust OA. Pre-induction
cervical ripening techniques compared. J Reprod Med 2001; 46:11-17.
13. McKenna DS, Ester JB, Proffitt M, Waddell KR. Misoprostol outpatient
cervical ripening without subsequent induction of labor: a randomized trial.
Obstet Gynecol 2004; 104 (3): 579-584.
14. Bolnick JM, Velazquez MD, Gonzalez JL, Rappaport VJ, McIlwain-Dunivan G,
Rayburn WF. Randomized trial between two active labor management protocols
in the presence of an unfavorable cervix. Am J Obstet Gynecol 2004; 190 (1):
124-128.
15. Wing DA. A benefit-risk assessment of misoprostol for cervical ripening and
labour induction. Drug Saf 2002; 25: 665-676.
16. Alfirevic Z. Oral misoprostol for induction of labour (Cochrane Review). In:
The Cochrane Library, Issue 4, 2004. Oxford: Update Software.
17. ( Boulvain M, Kelly A, Lohse C, Stan C, Irion O. Mechanical methods for
induction of labour (Cochrane Review). In: The Cochrane Library, Issue 4, 2004.
Oxford: Update Software.
18. Wing DA, Fassett MJ, Guberman C, Tran S, Parrish A, Guinn G. A
comparison of orally administered misoprostol to intravenous oxytocin for labor
induction in women with favorable cervical examinations. Am J Obstetr Gynecol
2004; 190: 1689-1694.
19. AquinoMMA, Cecatti JG. Misoprostol versus oxytocin for labor induction in
term and post-term pregnancy: randomized controlled trial. Sao Paulo Med. J
2003; 121: 102-106.
20. Patrick Rozenberg P, Chevret S, Snat M-V, Bretelle F, Bonnal AP, Ville Y. A
randomized trial that compared intravaginal misoprostol and dinoprostone
vaginal insert in pregnancies at high risk of fetal distress. Am J Obstet Gynecol
2004; 191: 247-253.
21. Garry D, Figueroa R, Kalish RB, Catalano CJ, Maulik D. Randomized
controlled trial of vaginal misoprostol versus dinoprostone vaginal insert for labor
induction. J Matern Fetal Neonatal Med 2003; 13(4): 254-259.
22. Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical
ripening and induction of labour (Cochrane Review). In: The Cochrane Library,
Issue 4, 2004. Oxford: Update Software.
23. Khan RU, El-Refaey H, Sharma S, Sooranna D, Stafford M. Oral, rectal, and
vaginal pharmacokinetics of misoprostol. Obstet Gynecol 2004; 103 (5 Pt 1):
866-870.
24. Hall R, Duarte-Gardea M, Harlass F. Oral versus vaginal misoprostol for
labour induction. Obstet Gynecol 2002; 99: 1044-1048.
25. Paungmora N, Herabutya Y, O-Prasertsawat P, Punyavachira P. Comparison
of oral and vaginal misoprostol for induction of labor at term: a randomized
controlled trial. J Obstet Gynaecol Res 2004;30 (5):358-362.
26. Shetty A, Livingstone I, Acharya S, Rice P, Danielian P, Templeton A. Oral
misoprostol (100 microg) versus vaginal misoprostol (25 microg) in term labor
induction: a randomized comparison. Acta Obstet Gynecol Scand 2003; 82 (12):
1103-1106.
27. Shetty A, Mackie L, Danielian P, Rice P, Templeton A. Sublingual compared
with oral misoprostol in term labour induction: a randomised controlled trial.
BJOG 2002; 109: 645-650.
28. Carlan SJ, Blust D, OBrien WF. Buccal versus intravaginal administration for
cervical ripening. Am J Obstet Gynecol 2002; 186: 229-233.
29. Sanchez-Ramos L, Kaunitz AM, Delke I. Labour induction with 25 microg
versus 50 microg intravaginal misoprostol: a systematic review. Obstet Gynecol
2002; 99: 145-151.
30. Has R, Batukan C, Ermis H, Cevher E, Araman A, Kilic G, Ibrahimoglu L.
Comparison of 25 and 50 microg vaginally administered misoprostol for pre-
induction of cervical ripening and labour induction. Gynecol Obstet Invest 2002;
53:16-21.
31. Ozsoy M, Ozsoy D. Induction of labor with 50 and 100 microg of misoprostol:
comparison of maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol
2004; 113: 41-44.
32. Meydanli MM, alkan E, Burak F, Narin MA, Atmaca R. Labor induction
post-term with 25 micrograms vs. 50 micrograms of intravaginal misoprostol. Int J
Gynecol Obstetr 2003; 81: 249-255.
33. Royal College of Obstetricians and Gynaecologists. Induction of labour:
evidence-based clinical guideline number 9. 2001. London. Available in: Http://
www.nelh.nhs.uk/guidelinesdb/html / AFinductionof labour.htm
34. Brazil. Ministry of Health. National Health Surveillance Agency. Resolution
RE number 905, June 21, 2001 and Resolution RE number 365, October 13,
2004. Available in http://e- legis.bvs.br/ leisref/public/
showAct.php?id=12916&word=Prostokos#'
35. Carlan SJ, Bouldin S, O'Brien WF. Extemporaneous preparation of
misoprostol gel for cervical ripening: a randomized trial. Obstet Gynecol 1997; 90:
911-915.
36. Lokugamage AU, Forsyth SF, Sullivan KR, El Refaey H, Rodeck CH.
Randomized trial in multiparous patients: investigating a single vs. two-dose
regimen of intravaginal misoprostol for induction of labor. Acta Obstet Gynecol
Scand 2003; 82(2):138-142.
37. Sanchez-Ramos L, Danner CJ, Delke I, Kaunitz AM. The effect of tablet
moistening on labour induction with intravaginal misoprostol: a randomized trial.
Obstet Gynecol 2002; 99:1080-1084.
38. Gilles JM, Creinin MD , Barnhart K, Westhoff C, Frederick MM, Zhang J, for
the National Institute of Child Health and Human Development Management of
Early Pregnancy Failure Trial. A randomized trial of saline solutionmoistened
misoprostol versus dry misoprostol for first-trimester pregnancy failure. American
Journal of Obstetrics and Gynecology 2004; 190: 389-394.
39. Baxley EG. Labor induction: a decade of change. Am Fam Physician 2003;
67(10): 2076, 2078, 2083-2076, 2078, 2084.
40. Ramsey PS, Harris DY, Ogburn PL, Heise RH, Magtibay PM, Ramin KD.
Comparative efficacy and cost of the prostaglandin analogs dinoprostone and
misoprostol as labor preinduction agents. Am J Obstet Gynecol 2003; 188: 560-
565.