THE HONG KONG MEDICAL DIARY

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VOL.10 NO.4 APRIL 2005
Drug Review
Clinical Uses of Misoprostol in Obstetrics
and Gynaecology
Dr. Suk-wai Ngai MBBS, MRCOG, MD
Associate Professor
Department of Obstetrics & Gynaecology, The University of Hong Kong
Introduction
Misoprostol is a synthetic prostaglandin E1 analogue
approved by the Food and Drug Administration (FDA)
for the prevention and treatment of gastroduodenal ulcers.
Norman et al. first demonstrated its uterocontractive
abortifacient properties in 1991
1
. This publi cati on
generated great interest in the search for the potential uses
of misoprostol in Obstetrics and Gynecology. Misoprostol
has since been proven to be an effective agent for cervical
priming prior to surgical abortion, medical abortion,
induction of labour and prevention of postpartum
haemorrhage. In contrast to other synthetic prostaglandin
analogues, it is substantially less expensive. It does not
require refrigeration and can be administered orally,
rectally, vaginally, as well as by the sublingual route. The
purpose of this chapter is to summarise the evidences of
its efficacy in clinical use.
Cervical Priming Prior to Surgical Abortion
Cervical preparation is critical to the success of surgical
abortion. It reduces the need for rapid mechanical
dilatation of the cervix which carries a significant risk of
cervical laceration with immediate morbidity, and the
possibility of remote complications such as cervical
incompetence
2
. Misoprostol was extensively investigated
as a cervical priming agent before surgical abortion.
Bulgalho et al.
3
compared the use of vaginal misoprostol
versus pl acebo i n 1994. Our group subsequentl y
published a series of studies to investigate its efficacy
when used as a cervical priming agent by the oral route.
We showed that when given orally 12 h prior to vacuum
aspiration, 400ug misoprostol was more effective than
pl acebo
4
and gemepros t
5
, and as ef f ect i ve as
mifepristone
6
for cervical priming. Dose finding studies
have determined that 400 ug vaginal misoprostol, given
3-4 hours prior to the procedure, is probably the optimal
treatment for achieving adequate dilation in over 95%
of women prior to suction evacuation
7
.
First Trimester Medical Abortion
Medical abortion has become an alternative method of
first trimester pregnancy termination with the availability
of prost agl andi ns i n the earl y 1970s and ant i -
progesterones in the 1980s. Studies on the use of
misoprostol alone for first trimester medical abortion have
largely been unsatisfactory. Repeated doses were required
Dr. Suk-wai Ngai
and it took a few days for the effect to complete. The
overall successful rate ranged from 40-90%
8-10
. The results
were difficult to compare because different studies
adopted different dosing regimens. In most of the studies,
the daily doses of misoprostol vary from 600-1000 ug
11-13
.
The success rate of abortion was also not uniformly
defi ned. In contrast, the combinati on regi men of
mifepristone and misoprostol gave much more promising
results. Jain et al.
14
compared women who received
misoprostol alone to women who had received 600 mg
mifepristone and 400 ug oral misoprostol. Successful
abortion occurred in 88% with misoprostol alone and in
94% with the combi nation regimen. A subsequent
randomised controlled trial compared misoprostol alone
to 200 mg mifepristone combined with 800 ug vaginal
misoprostol, and found a success rate for the single drug
of 88%; versus 95.7% for the combination
15
. Misoprostol
is currently the prostaglandin used most commonly in
combination with mifepristone. In standard regimens
approved by national regulatory agencies, mifepristone
600 mg orally is followed by approximately 48h later by
400 ug oral misoprostol given in the clinic for first trimester
medical abortion.
However, mifepristone is not widely available. The use
of the misoprostol-alone regimen remains attractive in
many countries. Our group performed a pilot study on
the use of sublingual misoprostol for medical abortion.
We achieved 95% complete abortion rate by using 400 ug
misoprostol every 4 hours for a maximal of five doses
16
.
Our finding suggested that large scale prospective
randomised trials should be conducted to work out the
optimal dosing regimen.
Second Trimester Medical Abortion
Abortion-related mortality and morbidity increase
significantly as gestation increases. Induction of abortion
after 14 weeks of gestation is associated with a sharp rise
in the rates of complications and in the consequent medical
costs. Such abortions constitute only 10-15% of all induced
abortions but they are responsible for two-thirds of all
major complications and 50% of all abortion-related
maternal deaths
17
. Different management protocols are
continuously revised, aiming to achieve improved success
rates and reduced discomfort to the patients. Medical
abortion using prostaglandin analogues alone or in
combination with mifepristone has been proven to be
effective for second trimester abortion and the termination
of pregnancy with intrauterine death
18-22
.
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Drug Review
Most of the misoprostol-only regimens used in second
trimester abortion involved vaginal administration. In the
literature, the dosage of misoprostol used in the studies
involving misoprostol alone varied from 100-200 ug and
the dosing interval ranged from 3 to 12 hours
23, 24-29
.
Misoprostol at a dose of 100-200 ug every 6-12 hours gives
a lower abortion rate at 48 hours and a longer induction-
to-abortion interval than gemeprost
24
. The induction-to-
abortion interval was still long even if the dosage of
misoprostol was increased to 400-600 ug every 12 hours
25,27
.
A randomised study demonstrated that misoprostol 400
ug given vaginally every 3 hours was probably the optimal
regimen for second trimester abortion
29
. The complete
abortion rate and induction-to-abortion interval were
compromised if the dosing interval extends to 6 hours. This
regimen of misoprostol had been shown by a randomised
study to be more effective when compared with the
standard regimen of gemeprost
29
. Recently, sublingual
administration of misoprostol has been investigated. One
pilot study using 400 ug misoprostol every 3 hours for a
maximum of five doses achieved 100 percent second
trimester abortion rate with a median induction-to-abortion
interval of 11.6 h
30
. In addition, the majority of women
preferred the oral route to the vaginal route because the
former is more convenient and offers more privacy.
Intrauterine Death
Induction of labour for intrauterine death can be difficult
particularly when the cervix is unripe. The success rates of
misoprostol alone regimen range from 67% to 100%
3,31
. Most
of the published regimens have recommended the vaginal
route. More recently, mifepristone has also been
successfully used in this aspect. Fletcher et al. reported
successful induction of labour using mifepristone 200 mg
12 hourly for two days
31
, and subsequently a prospective
double blind trial confirmed that mifepristone can be useful
in the management of intrauterine death
32
. In the latter
study 43 women with a silent miscarriage or stillbirth
received mifepristone 200 mg three times a day for two
days resulting in 63% of them delivering within 72 hours
of commencing treatment compared with only 17% in the
placebo group. Wahaarachchi et al. first reported a
combination of vaginal and oral route
19
. Women received a
single dose of 200 mg mifepristone following which a 24-
48 hours interval was recommended before administration
of misoprostol. For gestations of 24-34 weeks, 200 ug of
intravaginal misoprostol was administered, followed by
four oral doses of 200 ug at three hourly intervals. Gestations
over 34 weeks were given a similar regimen but a reduced
dose of 100 ug misoprostol. The average induction-to-
delivery interval was 8.5 hours which was the shortest
among t he previ ous regi men. Improved pati ent
acceptability and reduced risk of introducing intrauterine
infection are potential advantages of oral over vaginal route.
Induction of Labour
Induction of labour requires a fine balance between
inducing effective uterine contraction and maintaining
foetal wellbeing. In this field the dosage and the frequency
of drug administration are the two main issues that have
to be examined. A variety of methods have been used for
this intervention, which include catheter balloon insertion,
laminaria tent insertion, prostaglandin E2 analogs, and
oxytocin infusion. Many clinical trials have demonstrated
that misoprostol is effective for induction of labour at term,
including prelabour rupture of membranes. These trials
compared misoprostol with oxytocin
33-35
, and other
prostaglandins
36-39
. Systematic review and meta-analysis
supported than misoprostol is more effective than placebo
or other prostaglandin for labour induction
40,41
. It can
achieve a higher rate of vaginal delivery within 24 hours, a
shorter induction-to-delivery interval, and significantly
lower overall caesarean section rates than pooled figures
for the control groups. However, the efficacy between oral
and vaginal routes remains controversial. Adair et. al.
showed that both routes were comparable as labour
induction agents
42
. Others reported that the vaginal route
was able to achieve a shorter induction-to-delivery interval,
lower number of doses, and lower oxytocin use
43,44
. The
dosing regimen of labour induction has been extensively
investigated as well. The available data suggest that the
optimal dose of mosoprostol for labour induction is 25 ug
given vaginally every 4 to 6 hours. Although the 50-ug dose
results in shorter induction-to-delivery interval and a higher
rate of vaginal delivery
45,46
, the 25-ug dose was associated
with lower inci dence of tachysystol e and uterine
hyperstimulation. The lower-dose regimen achieved a
comparable induction-delivery interval when compared
with the high dose regimen
45-49
. Doses higher than 50 ug
should not be given because it has been associated with an
increased risk of serious complications
50
.
Induction of labour with previous uterine scar is always
challenged. No matter what method is used, there are
higher risks of uterine rupture than those without a scar.
The first randomised controlled trial of 25 ug vaginal
misoprostol for induction of labour in women with one
prior caesarean section was terminated after two women
in the misoprostol group had disruption of their uterine
scar. No further prospective trials in this area has been
published. Plaut et al. reported a 5.5% rate of scar rupture
associated with the use of misoprostol compared with
0.2% in patients attempting vaginal birth after caesarean
section with no stimulation in a retrospective study
51
. With
the rising caesarean section rate, there will be an increasing
number of women undergoing termination of pregnancy
or labour induction with a previous uterine scar. Current
evidence would suggest that they are at an increased risk
of scar rupture. Women shoul d be appropriatel y
counselled about the risks and consequences.
Prevention for Postpartum Haemorrhage
Postpartum haemorrhage (PPH) continues to be a leading
cause of maternal morbidity and mortality worldwide.
Uterotonic agents administered during the third stage of
labour have been shown to reduce the incidence of PPH
by 40%
52,53
. Misoprsotol administered by oral, vaginal and
rectal routes had been investigated. The World Health
Organization (WHO) conducted the largest scale study
involving nine countries with altogether 20,000 women
were recruited
54
. This trial was to compare the use of oral
misoprostol (600 ug) to 10 IU of oxytocin. The sample size
was of adequate power to measure two outcomes: blood
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VOL.10 NO.4 APRIL 2005
Drug Review
loss of 1000 ml or more and the use of additional uterotonic
agents. Unfortunately, the trial had several problems: 1.
it was unclear whether the women received intravenous
or intramuscular oxytocin; 2. there was an unexplained
statistical heterogenicity between the individual centres
for the primary outcome of measured blood loss. The
finding of this large trial is often quoted as a 1% difference
between oral misoprostol and oxytocin. The WHO trial,
however proved the safety of misoprostol administered
orally at doses up to 600 ug. The alternative administered
route incl udi ng vaginal and rectal route has been
investigated. The pilot study by O'Brien et al reported that
mi soprostol 1000 ug given rectall y i s an effecti ve
intervention in women with PPH who are unresponsive
to standard uterotonic agents
55
. Subsequent observations
studies and a recent randomised study support the use of
rectal misoprostol (800 ug) in the treatment of PPH
56,57
.
Side Effects and Complications
Minor side effects including nausea, vomiting, and
di arrhoea, are characteri sti cs of prost agl andi n
administration and are due to prostaglandins stimulatory
effect on the gastrointestinal tract. Serious complications
including uterine rupture, major haemorrhage and
cervical tear are rare
48, 57-58
. Cases of uterine rupture were
reported to occur with both misoprostol and gemeprost,
with our without priming by mifepristone
59-61
. Risk factors
of uterine rupture include previous caesarean section,
grand mul ti para, advance gest ati on, prol onged
prostaglandin therapy and use of oxytocin in addition to
prostagl andins. Cardi ovascular compli cations are
uncommon. Long term complications associated with
medical abortion in the second trimester using misoprostol
with or without mifepristone are rarely reported.
Conclusions
Misoprostol is an important medication for Obstetrics and
Gynaecology practice. It is effective for medical abortion
in combination with mifepristone. There is solid evidence
supporting the use of misoprostol for cervical ripening
prior to first trimester suction evacuation. It is also an
effective labour inducing agent. It was proven to be safe
when used i n thi rd stage to prevent postpartum
haemorrhage. However, the use in women with previous
scar should be cautious.
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