Uses of Misoprostol in Obstetrics and Gynecology

Abstract

Misoprostol is a synthetic prostaglandin E(1) analogue that is used off-label for a variety of indications in the practice of obstetrics and gynecology, including medication abortion, medical management of miscarriage, induction of labor, cervical ripening before surgical procedures, and the treatment of postpartum hemorrhage. Due to its wide-ranging applications in reproductive health, misoprostol is on the World Health Organization Model List of Essential Medicines. This article briefly reviews the varied uses of misoprostol in obstetrics and gynecology.

Full text

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 159
TREATMENT UPDATE
Uses of Misoprostol in Obstetrics
and Gynecology
Rebecca Allen, MD, MPH, Barbara M. O’Brien, MD
Department of Obstetrics and Gynecology, Women and Infants’ Hospital and Warren Alpert Medical
School of Brown University, Providence, RI
Misoprostol is a synthetic prostaglandin E
1
analogue that is used off-label
for a variety of indications in the practice of obstetrics and gynecology,
including medication abortion, medical management of miscarriage, induction
of labor, cervical ripening before surgical procedures, and the treatment of
postpartum hemorrhage. Due to its wide-ranging applications in reproductive
health, misoprostol is on the World Health Organization Model List of Essential
Medicines. This article briefly reviews the varied uses of misoprostol in
obstetrics and gynecology.
[Rev Obstet Gynecol. 2009;2(3):159-168 doi: 10.3909/riog0055]
© 2009 MedReviews®, LLC
Key words: Misoprostol • Induced abortion • Induction of labor • Postpartum hemorrhage •
Cervical ripening • Hysteroscopy
Misoprostol is a synthetic prostaglandin E1analogue marketed as an oral
preparation used to prevent and treat gastroduodenal damage induced
by nonsteroidal anti-inflammatory drugs (NSAIDs). However, misopros-
tol is used off-label for a variety of indications in the practice of obstetrics and
gynecology, including medication abortion, medical management of miscarriage,
induction of labor, cervical ripening before surgical procedures, and the treat-
ment of postpartum hemorrhage. Misoprostol’s effects are dose dependent and
include cervical softening and dilation, uterine contractions, nausea, vomiting,
diarrhea, fever, and chills.1Although misoprostol is not approved by the US Food
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160 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY
and Drug Administration (FDA) for
these indications, in 2002, pregnancy
was removed from the label as an ab-
solute contraindication to misoprostol
use.2Misoprostol’s advantages over
other synthetic prostaglandin ana-
logues are its low cost, long shelf life,
lack of need for refrigeration, and
worldwide availability (Figure 1).3
Pharmacokinetics
Routes of misoprostol administration
include oral, vaginal, sublingual, buc-
cal, or rectal. Pharmacokinetics stud-
ies (Figure 2) comparing oral and
vaginal administration have shown
that vaginal misoprostol is associated
with slower absorption, lower peak
plasma levels, and slower clearance,
similar to an extended-release prepa-
ration.4-6 Vaginal misoprostol is also
associated with a greater overall ex-
posure to the drug (area under the
curve [AUC]) and greater effects on the
cervix and uterus.5There is, however,
a wide variation in the absorption of
misoprostol through the vaginal ep-
ithelium among different women.3
There is no clinically significant dif-
ference between vaginal misoprostol
that is administered dry and vaginal
misoprostol moistened with water,
saline, or acetic acid.7-9
The rectal route of administration
shows a similar pattern to vaginal
administration, but has a lower AUC,
including a significantly lower maxi-
mum peak concentration.6The sublin-
gual route of administration has an
AUC similar to vaginal administra-
tion, but more rapid absorption and
higher peak levels than either vaginal
or oral administration (Figure 2).7This
translates into higher rates of gas-
trointestinal side effects. Nevertheless,
the sublingual route also causes uter-
ine contractions at a rate equivalent
to vaginal administration and has less
variation in absorption.10 The buccal
route of administration shows a lower
AUC, a lower peak concentration, and
fewer side effects than sublingual
administration.11 The buccal route has
a pattern of absorption similar to the
vaginal route, but produces lower
serum levels overall. Nonetheless, the
buccal and vaginal routes of adminis-
tration have similar effects on uterine
tone and activity.12 The buccal route
of administration is also thought to be
the least variable in terms of drug
exposure and peak levels. The admin-
istration of NSAIDs for pain relief
does not alter the efficacy of miso-
prostol.13,14 There are no known drug
interactions with misoprostol.1
Teratogenicity
Misoprostol is considered a teratogen.
Congenital defects following prenatal
exposure in early pregnancy to miso-
prostol include skull defects, bladder
exstrophy, arthrogryposis, cranial
nerve palsies, facial malformations,
terminal transverse limb defects, and
Moebius sequence.1,15,16 This constel-
lation of congenital malformations
is thought to be due to a vascular
Approved
Not
approved
Also approved for an
obstetrics-gynecology
indication
Figure 1. World map of misoprostol approval. Produced by Gynuity Health Projects. Reproduced with permission from Gynuity Health Projects.
Copyright ©2008. Access at www.gynuity.org.
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disruption secondary to uterine con-
tractions caused by misoprostol. The
incidence of these abnormalities does
not appear to be high when popula-
tion registries have been studied, es-
pecially given that exposure to miso-
prostol is quite common among some
populations of patients.17,18 The ab-
solute risk of congenital malforma-
tions after prenatal exposure to
misoprostol is estimated to be ap-
proximately 1%.
Pharmacokinetic studies reveal that
misoprostol is excreted into breast
milk with drug levels that rise and fall
very quickly. Levels become unde-
tectable within 5 hours of maternal
ingestion.19 However, breastfeeding
women should be advised that miso-
prostol may cause infant diarrhea.20
Medication Abortion
In 2000, the FDA approved medica-
tion abortion using 600 mg of oral
mifepristone, a progesterone antago-
nist, with 400 g of oral misoprostol
48 hours later for pregnancies up to
49 days of gestation.21 However, there
is excellent evidence of efficacy up to
63 days of gestation using the regi-
mens of 200 mg of mifepristone orally
followed by home administration of
either 800 g of buccal misoprostol in
24 to 36 hours or 800 g of vaginal
misoprostol in 6 to 48 hours.22,23
Women then return 4 to 14 days later
for a clinical evaluation to document
complete abortion. Success rates for
these regimens range from 95% to
98%, with failure due to ongoing
pregnancy in approximately 1%.21 In
the United States, most women un-
dergo ultrasound for pregnancy dat-
ing and confirmation of complete
abortion. However, serial serum
-human chorionic gonadotropin
(hCG) levels can also be used to con-
firm complete abortion.24,25
Candidates for medication abortion
must be able to adhere to the treat-
ment regimen as well as have access
to a telephone and transportation to a
medical facility in case of emergency.
Multiple gestation is not a contraindi-
cation to medication abortion pro-
vided that the pregnancy is no more
than 49 to 63 days, depending on the
regimen being used.22 Contraindica-
tions to mifepristone medication
abortion include hemorrhagic disor-
der; concurrent anticoagulant ther-
apy; inherited porphyrias; chronic
adrenal failure; concurrent long-term
systemic corticosteroid use; con-
firmed or suspected ectopic or molar
pregnancy; allergy to mifepristone,
misoprostol, or other prostaglandin;
and unwillingness to undergo a vac-
uum aspiration if needed.26 If the
woman has an intrauterine device in
place, it must be removed before
treatment. Women with serious sys-
temic illnesses (eg, severe cardiac,
renal, or liver disease or severe ane-
mia) should be evaluated individually
to determine which method of abor-
tion is safest. Rhesus (Rh)-negative
women typically receive Rh immune
globulin on the day of mifepristone
administration.22
Medication abortion necessarily in-
volves heavy bleeding and cramping
as the pregnancy is expelled. Other
transient side effects from misopros-
tol include nausea, vomiting, diar-
rhea, fever, and chills.21 At the follow-
up visit, ongoing pregnancies are
most commonly treated with suction
curettage because of the risk of con-
genital anomalies. Women with per-
sistent nonviable pregnancies may
opt for expectant management, a re-
peat dose of misoprostol, or suction
curettage.27 Mifepristone medication
abortion is safe with an estimated
complication rate of 2.2 per 1000
women.28 The most frequent compli-
cations are heavy bleeding requiring
curettage and/or transfusion and
0
0 100 200
Time (min)
300 400
200
400
Plasma Misoprostol Acid
Concentration (pg/mL)
600
800
Sublingual
Oral
Vaginal
Vaginal  Water
Figure 2. Mean plasma concentrations of misoprostol acid over time (arrow bars 1 SD). Reprinted from Tang
OS et al, “Pharmacokinetics of different routes of administration of misoprostol,” Hum Reprod. 2002;17:332-336.
Copyright ©2002 with permission from Oxford University Press.7
The absolute risk of congenital malformations after prenatal exposure to
misoprostol is estimated to be approximately 1%.
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Misoprostol Use in Obstetrics and Gynecology continued
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infection. The estimated mortality
rate for mifepristone abortion is 1 per
100,000 women, most commonly due
to fatal sepsis.28 Where mifepristone is
not available, medication abortion
can be accomplished with methotrex-
ate and misoprostol or misoprostol
alone.29
Cervical Ripening
Before Surgical Abortion
First Trimester
First-trimester surgical abortion is a
common, safe procedure with a major
complication rate of less than 1%.30
Risk factors for major complications
in the first trimester, such as cervical
laceration and uterine perforation, are
provider inexperience, patient age
less than 18 years, and increasing
gestational age.31, 32 Studies have
shown that the use of laminaria for
cervical ripening reduces the risk of
cervical laceration and, to a lesser
extent, uterine perforation.33,34 Al-
though pharmacologic priming
agents, such as misoprostol, may po-
tentially have the same effects, no
published studies to date have been
large enough to assess these out-
comes. The risk of these injuries dur-
ing first-trimester suction curettage is
very small, given an experienced
provider. Nevertheless, the Society of
Family Planning recommends that
providers consider cervical ripening
for women late in the first trimester
(12-14 weeks of gestation), adoles-
cents, and for women in whom cervi-
cal dilation is expected to be difficult
either due to patient factors or
provider inexperience.35
Misoprostol is a proven cervical
ripening agent prior to first-trimester
surgical abortion.36 Studies have
shown that the optimal dose in terms
of balancing effectiveness and side
effects is 400 g.37 There are data eval-
uating oral, vaginal, and sublingual
routes of administration. Effective
regimens are 400 g of misoprostol
vaginally 3 to 4 hours, 400 g orally
8 to 12 hours, or 400 g sublingually
2 to 4 hours prior to suction curet-
tage.35 Compared with the oral route,
vaginal administration is equally or
more effective and is associated with
fewer side effects.36,38,39 The sublin-
gual route is more effective than oral,
equivalent to or better than vaginal
administration, but is associated with
more side effects than either oral or
vaginal administration.40 Although
not yet studied for first-trimester sur-
gical abortion, buccal administration
is widely used. Buccal misoprostol of-
fers the effectiveness and decreased
side effects of vaginal administration
combined with high acceptability for
both patient and staff. These regimens
significantly increase baseline cervi-
cal dilatation and facilitate further
mechanical dilation compared with
placebo.41 Some studies have also re-
ported decreased procedure time and
estimated blood loss. These differ-
ences are statistically, but not clini-
cally, significant.42,43 There is no clear
evidence to date that misoprostol re-
duces pain during the procedure com-
pared with placebo.35 It is important
to note that if misoprostol is used for
cervical ripening, and the woman is
unable to undergo surgical abortion
as planned, she is at some risk for ex-
pelling the pregnancy. Therefore, be-
fore receiving misoprostol, all women
should give informed consent for the
abortion procedure and be adequately
screened by appropriately trained
personnel.
Second Trimester
Cervical preparation prior to second-
trimester surgical abortion (dilation
and evacuation, D&E) is critical to
prevent complications from forceful
dilation of the cervix.33,34 Providers
have traditionally used osmotic dila-
tors such as laminaria to slowly dilate
the cervix over several hours to days
before the procedure.44 Although
there are fewer studies than in the
first trimester, misoprostol has been
evaluated in the second trimester as a
substitute for laminaria and as an ad-
junct to laminaria. The regimens
studied for second-trimester D&E
vary widely and include 400 g of
vaginal misoprostol for 3 to 4 hours,
400 g and 600 g of buccal miso-
prostol for at least 90 minutes, 600
g of buccal misoprostol for 2 to 4
hours, and 800 g of buccal miso-
prostol for at least 20 minutes but not
more than 90 minutes preopera-
tively.45-48 As a substitute for lami-
naria, misoprostol does not achieve
the same degree of preoperative
cervical dilation and frequently
additional mechanical dilation is
required.47 Although this additional
mechanical dilation may be easily
achieved in most patients, especially
those under 16 weeks of gestation and
multiparous women, there is a higher
rate of difficult or inadequate dilation
when using misoprostol instead of
laminaria.46
The Society of Family Planning recommends that providers consider cervi-
cal ripening for women late in the first trimester (12-14 weeks of gesta-
tions), adolescents, and for women in whom cervical dilation is expected to
be difficult either due to patient factors or provider inexperience.
Cervical preparation prior to second-trimester surgical abortion is critical to
prevent complications from forceful dilation of the cervix.
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The ideal dosing regimen for sec-
ond-trimester procedures is unknown.
In terms of safety, a review of more
than 6000 surgical abortions between
12 and 16 weeks using 400 g of
vaginal or buccal misoprostol 90 min-
utes preprocedure showed a uterine
perforation rate of 0.45 per 1000,
comparable to historical reports for
laminaria use.49 Cervical lacerations,
however, were not reported. The
Society of Family Planning does not
recommend the use of misoprostol as
an alternative to laminaria except by
experienced clinicians in the early
second trimester (before 16 weeks) in
women at low risk for cervical or
uterine injury.44
Misoprostol use as an adjunct to
laminaria has been evaluated in a
randomized, controlled trial using
400 g of misoprostol at least 90
minutes preoperatively in 125 women
between 13 and 20 6/7 weeks of ges-
tation.48 Misoprostol improved preop-
erative dilation in women only at 19
weeks of gestation and above. How-
ever, if women needed subsequent
mechanical dilation after laminaria
had been removed, misoprostol sig-
nificantly improved the subjective
ease of dilation in women at 16 weeks
of gestation and above. Given this,
the Society of Family Planning does
not recommend routine use of miso-
prostol as an adjunct to laminaria
under 16 weeks, but it may be con-
sidered at later gestational ages.44 In
general, misoprostol may be used for
cervical ripening prior to surgical abor-
tion in women with prior cesarean
deliveries in the first and second
trimesters because uterine rupture
rarely occurs in this setting.44
Cervical Ripening Before
Other Procedures
Researchers have studied cervical
ripening prior to other gynecologic
procedures in nonpregnant women,
including hysteroscopy, endometrial
biopsy, and intrauterine device (IUD)
insertion. Similar to cervical ripening
prior to surgical abortion, the aim of
misoprostol use in hysteroscopy is to
prevent complications of mechanical
dilation such as cervical laceration,
uterine perforation, and the creation
of a false passage.50 One meta-analy-
sis of 10 studies concluded that miso-
prostol leads to greater preoperative
dilation, decreased need for addi-
tional dilation, and reduced rates of
cervical laceration in premenopausal
women.51 The greatest benefits were
seen in nulliparous women and with
operative hysteroscopy. However,
women treated with misoprostol had
higher rates of transient vaginal
bleeding, cramping, and fever preop-
eratively. There may also be potential
concerns regarding loss of distension
from excessive cervical dilation
caused by misoprostol.52 More re-
search is needed to determine the
ideal candidate for misoprostol use
before hysteroscopy.
The optimal dosing regimen for
cervical ripening before hysteroscopy
is unclear. In premenopausal women,
studies have found either 200, 400, or
1000 g of vaginal misoprostol or
400 g of oral misoprostol given at
least 9 to 12 hours preoperatively to
be superior to placebo.53-57 Most of
these studies focused on nulliparous
women. There are few trials compar-
ing routes of administration, doses,
and interval to procedure prior to
hysteroscopy. One study that com-
pared 400 g of oral and vaginal
misoprostol given 10 to 12 hours be-
fore operative hysteroscopy found
vaginal misoprostol to be superior in
baseline cervical dilation and time re-
quired for cervical dilation.52 Trials
evaluating vaginal misoprostol for
shorter intervals, 4 to 6 hours preop-
eratively, have not shown evidence of
an effect.58,59 Therefore, it may be that
time to adequate cervical ripening is
different for pregnant and nonpreg-
nant women. For peri- and post-
menopausal women and women
treated with gonadotropin-releasing
hormone agonists, data are conflict-
ing and most studies do not show a
benefit from misoprostol.53,60-63 Miso-
prostol’s actions on the cervix may
require endogenous estrogen. It is not
known if more intensive dosing regi-
mens would affect the post-
menopausal cervix.51
Only a single study has evaluated
misoprostol for endometrial biopsy.
This trial randomized a mixed popu-
lation of 42 premenopausal, peri-
menopausal, and postmenopausal
women to either 400 g of oral miso-
prostol or placebo 3 hours prior to en-
dometrial biopsy.64 This study found
no evidence of an effect on cervical
resistance, success rate for obtaining
the biopsy, and the ease of performing
the biopsy. However, the study was
underpowered for these endpoints.
The study did note significantly more
pain with the biopsy and uterine
cramping in the misoprostol group.
Based on a single, small study, IUD
insertion in nulliparous women may
be facilitated by misoprostol use. A
Swedish trial randomized 80 women
to 400 g of sublingual misoprostol
plus 100 mg of diclofenac or 100 mg
of diclofenac alone 1 hour before
Nova-T IUD insertion.65 Although
baseline cervical dilation was similar
in both groups, providers rated the in-
sertion procedure as “easy” in 74% of
the misoprostol group compared with
The aim of misoprostol use in hysteroscopy is to prevent complications of
mechanical dilation such as cervical laceration, uterine perforation, and the
creation of a false passage.
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55% in the control group (P.04).
However, the majority of the IUD in-
sertions were uncomplicated in both
groups. There was no difference be-
tween the groups in terms of pain
scores during IUD insertion or overall
side effects.
Medical Management of
Miscarriage
Misoprostol is an option for the med-
ical management of early pregnancy
failure, including anembryonic preg-
nancies and embryonic demise, and
incomplete abortion for women at 12
weeks or less of gestation.66,67 Con-
traindications include pelvic infection
or sepsis, hemodynamic instability or
shock, allergy to misoprostol, known
bleeding disorder, concurrent antico-
agulant therapy, and confirmed or
suspected ectopic or molar preg-
nancy.68 If the woman has an IUD in
place, it must be removed before
treatment. Similar to medication
abortion, cramping and bleeding will
occur with pregnancy passage and
side effects such as nausea, vomiting,
diarrhea, fever, and chills may be ex-
perienced.68 Studies have shown,
however, that misoprostol is accept-
able to most women for this indica-
tion.69,70
For early pregnancy failure, the
most commonly used regimen is a
single dose of 800 g of vaginal
misoprostol.68 The success rate is ap-
proximately 85% as long as at least 7
to 14 days is allowed for completion
of expulsion and a second dose of
misoprostol is considered for initial
failures.69 Ultrasound is typically used
to confirm complete abortion. As long
as the gestational sac is absent and
the woman is asymptomatic, there is
no endometrial stripe thickness that
requires intervention.71 Compared
with surgical evacuation, there is no
significant difference in the rates of
infection or hemorrhage.69 For incom-
plete abortion, effective misoprostol
regimens include a single dose of 600
g orally, a single dose of 800 g
vaginally, or a single dose of 400 g
sublingually.68,69 Depending on the
study, success rates range from 66%
to 100% using these doses.
Induction of Labor in the
Second Trimester
Misoprostol is an effective drug for
labor induction in the second
trimester for fetal death or termina-
tion of pregnancy.67 The optimal dose,
schedule, and route of administration
have not been determined. Several
randomized, controlled trials exist ex-
amining the different doses and
schedules.72-75 The doses used in these
randomized trials range from 200 g
to 800 g administered vaginally, and
the interval between dosing ranged
from every 3 to every 12 hours. No
conclusive evidence of superiority of
one dose or schedule over another can
be clearly drawn from these studies.
An important study aimed at answer-
ing the question of dose optimization
was performed by Dickinson and
Evans,76 who administered vaginal
misoprostol either 200 g every 6
hours, 400 g every 6 hours, or a 600
g loading dose followed by 200 g
every 6 hours. Both the 400 g and
600/200 g regimens were superior to
the 200 g regimen in terms of me-
dian time to delivery. The 600/200 g
regimen caused more side effects than
the other 2 dosing schedules. Side ef-
fects of misoprostol noted in several
studies include maternal fever, chills,
and gastrointestinal symptoms such
as nausea, vomiting, diarrhea, and
abdominal pain.1Therefore, it makes
sense to administer the lowest dose of
misoprostol that is most effective,
thereby decreasing the side effects.
Although the optimal dose for fetal
death or termination of pregnancy in
the second trimester has not been
established, a reasonable approach
may be to start with 400 g vaginally
every 6 hours for a 48-hour period.
There is also evidence that the addi-
tion of 200 mg of mifepristone to the
induction protocol decreases the
interval to delivery for termination of
pregnancy.77
Induction of labor with misoprostol
in the setting of a previous cesarean
delivery scar, although contraindi-
cated in the third trimester, can be
safely performed in the second
trimester. The data on the absolute
risk of induction of labor in this
setting are lacking. Many studies on
second-trimester induction with
misoprostol have excluded patients
with a previous cesarean delivery due
to the fear of uterine rupture. Impor-
tantly, however, several randomized
studies did include patients with a
previous cesarean delivery.73,74,78 No
adverse effects occurred in these pa-
tients. Furthermore, several retrospec-
tive studies have specifically ad-
dressed the safety of misoprostol use
for second-trimester induction in the
case of a prior cesarean delivery. In
one of the largest retrospective stud-
ies on the subject, 188 women with a
previous cesarean delivery underwent
induction of labor between 17 and 24
weeks of gestation.79 The dose of
misoprostol was 400 g orally to-
gether with 400 g vaginally for the
first dose followed by 400 g vagi-
nally every 6 hours for a maximum of
5 doses. The main outcomes included
Misoprostol is an option for the medical management of early pregnancy
failure, including anembryonic pregnancies and embryonic demise, and in-
complete abortion for women at 12 weeks or less of gestation.
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hemorrhage requiring transfusion,
postabortal infection, retained pla-
centa, and uterine rupture. There was
no evidence that a previous cesarean
delivery affected the incidence of
complications. Similar results were
found in another study of 80 women
undergoing termination of pregnancy
between 13 and 26 weeks of gestation
for a variety of reasons with 1 or
more cesarean section scars.80 Miso-
prostol, 400 g, was administered to
women up to 20 weeks of gestation
and 200 g for women greater than
20 weeks of gestation, vaginally or
sublingually, every 6 hours up to 24
hours. The mean induction to abor-
tion interval was 16.4 hours and was
not statistically different between
women with and without a prior
cesarean delivery scar. There was no
case of uterine rupture or scar dehis-
cence. No statistically significant
differences were found in rates of
incomplete abortion, blood loss, or
sepsis.
Cervical Ripening and Induction
of Labor With a Viable Fetus
Compared with placebo, misoprostol
causes cervical ripening before induc-
tion with oxytocin.81,82 When used for
cervical ripening, misoprostol can be
administered orally, sublingually, or
vaginally, although there is more evi-
dence for vaginal regimens.83,84 A
commonly used dose is 25 g admin-
istered vaginally every 4 hours as
needed, with a maximum dose of 150
g.85 Doses are withheld if contrac-
tions are more frequent than every 4
minutes. Electronic fetal heart rate
monitoring is used to evaluate fetal
status 20 minutes before administra-
tion and continued for 4 hours after
each dose.
Misoprostol has also been shown to
be effective for induction of labor
with a viable fetus.86,87 The Cochrane
Pregnancy and Childbirth Group re-
viewed randomized trials comparing
vaginal misoprostol with placebo,
oxytocin, or prostaglandin E2for cer-
vical ripening or induction of a viable
fetus in the third trimester.85 Primary
outcomes included rate of vaginal de-
livery within 24 hours, incidence of
uterine hyperstimulation with associ-
ated fetal heart rate changes, rate of
cesarean delivery, and risk of serious
adverse event in mother or fetus.
Vaginal misoprostol was found to be
Misoprostol has also been shown to be effective for induction of labor with
a viable fetus.
Main Points
• Misoprostol is a prostaglandin E1analogue that causes cervical softening and dilation and uterine contractions. Routes of admin-
istration include oral, vaginal, rectal, buccal, and sublingual.
• Medication abortion with 200 mg of mifepristone and 800 g of buccal or vaginal misoprostol is 95% to 98% effective with
evidence-based regimens.
• Misoprostol is an effective cervical ripening agent prior to first-trimester surgical abortion. It is recommended especially for
women between 12 and 14 weeks of gestation, adolescents, and for women in whom cervical dilation is expected to be difficult
either due to patient factors or provider inexperience.
• Misoprostol for cervical ripening as a substitute for laminaria prior to second trimester dilation and evacuation is only recom-
mended under 16 weeks of gestation.
• Misoprostol is an effective cervical ripening agent in premenopausal women prior to hysteroscopy. The greatest benefit is seen in
nulliparous women and for operative hysteroscopy. Whether the routine use of misoprostol prior to hysteroscopy is beneficial is
still unknown.
• Misoprostol for cervical ripening prior to gynecologic procedures in postmenopausal women has not been found to be effective.
• Misoprostol is an option for the management of early pregnancy failure and incomplete abortion in women who are hemody-
namically stable without signs of infection. A single dose of 800 g vaginally is typically used.
• Misoprostol is a proven induction agent in the second trimester for termination of pregnancy or fetal death. One regimen is 400 g
vaginally every 6 hours up to 48 hours.
• For cervical ripening and induction of labor for a viable fetus, 25 g of vaginal misoprostol every 4 to 6 hours is recommended.
• Misoprostol has not been shown to be as effective as injectable uterotonics (oxytocin and methylergotomine) for the prevention
and treatment of postpartum hemorrhage. However, it is a valid option when these are not available or fail.
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166 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY
more effective than prostaglandin E2
or oxytocin for inducing vaginal de-
livery within 24 hours. However, uter-
ine stimulation with associated fetal
heart rate changes was more common
in the group of women receiving
misoprostol than in women receiving
either oxytocin or prostaglandin E2.
Cesarean delivery rate data were con-
flicting with a trend toward decreased
cesareans for failure to progress in
labor and increased cesarean deliver-
ies for fetal distress in the misoprostol
group. There was no difference in se-
rious neonatal or maternal mortality
between women receiving misopros-
tol and women who received
prostaglandin E2or oxytocin; how-
ever, most studies were underpowered
for this assessment. Optimal dosing of
misoprostol that will achieve effective
induction without uterine hyperstim-
ulation and resultant fetal heart rate
changes has been the topic of many
studies. As with cervical ripening, an
effective dose of misoprostol without
high rates of uterine hyperstimulation
is 25 g administered every 4 to 6
hours.1,85
Postpartum Hemorrhage
Misoprostol has been used both as
prevention and treatment of postpar-
tum hemorrhage secondary to its
uterotonic properties. Several ran-
domized, controlled trials88-90 and a
large, prospective, observational
study91 have examined the use of
misoprostol as an agent for the pre-
vention of postpartum hemorrhage.
There are insufficient data to support
the use of misoprostol as a primary
preventive measure for postpartum
hemorrhage when conventional in-
jectable uterotonics (such as oxytocin
and/or methylergotomine) are avail-
able as part of the management of the
third stage of labor.1,92 Misoprostol
has also not yet been found to be bet-
ter than oxytocin or ergotamine in
well-controlled, randomized trials for
the treatment of postpartum hem-
orrhage.93 However, it remains an
important option for treating postpar-
tum hemorrhage when other agents
are not available or fail. A descriptive
study showed that 1000 g of rectally
administered misoprostol, when given
to patients who failed to respond to
oxytocin and ergotamine, controlled
postpartum hemorrhage within 3
minutes.94 However, further studies,
with randomized designs, are needed.
Conclusions
Misoprostol has many applications in
the practice of obstetrics and gyne-
cology. Off-label use of approved
medications is supported by the FDA
as long as it is based on sound med-
ical evidence. Researchers and
providers must continue to work to
further refine the indications for
misoprostol in many areas. However,
several indications are already sup-
ported by high-quality evidence.
Given its low cost and ease of use,
misoprostol has the potential to im-
prove women’s health worldwide.
References
1. Goldberg AB, Greenberg MB, Darney PD.
Misoprostol and pregnancy. N Engl J Med. 2001;
344:38-47.
2. ACOG Committee Opinion. Number 283, May
2003. New U.S. Food and Drug Administration
labeling on Cytotec (misoprostol) use and preg-
nancy. Obstet Gynecol. 2003;101:1049-1050.
3. Tang OS, Ho PC. The pharmacokinetics and
different regimens of misoprostol in early first-
trimester medical abortion. Contraception. 2006;
74:26-30.
4. Zieman M, Fong SK, Benowitz NL, et al. Absorp-
tion kinetics of misoprostol with oral or vaginal
administration. Obstet Gynecol. 1997;90:88-92.
5. Danielsson KG, Marions L, Rodriguez A, et al.
Comparison between oral and vaginal adminis-
tration of misoprostol on uterine contractility.
Obstet Gynecol. 1999;93:275-280.
6. Khan RU, El-Refaey H, Sharma S, et al. Oral, rec-
tal, and vaginal pharmacokinetics of misopros-
tol. Obstet Gynecol. 2004;103:866-870.
7. Tang OS, Schweer H, Seyberth HW, et al. Phar-
macokinetics of different routes of administration
of misoprostol. Hum Reprod. 2002;17:332-336.
8. Singh K, Fong YF, Prasad RN, Dong F. Does an
acidic medium enhance the efficacy of vaginal
misoprostol for pre-abortion cervical priming?
Hum Reprod. 1999;14:1635-1637.
9. Creinin MD, Carbonell JL, Schwartz JL, et al. A
randomized trial of the effect of moistening
misoprostol before vaginal administration when
used with methotrexate for abortion. Contracep-
tion. 1999;59:11-16.
10. Aronsson A, Bygdeman M, Gemzell-Danielsson
K. Effects of misoprostol on uterine contractility
following different routes of administration.
Hum Reprod. 2004;19:81-84.
11. Schaff EA, DiCenzo R, Fielding SL. Comparison
of misoprostol plasma concentrations following
buccal and sublingual administration. Contra-
ception. 2005;71:22-25.
12. Meckstroth KR, Whitaker AK, Bertisch S, et al.
Misoprostol administered by epithelial routes:
drug absorption and uterine response. Obstet
Gynecol. 2006;108:582-590.
13. Fiala C, Swahn ML, Stephansson O, Gemzell-
Danielsson K. The effect of non-steroidal anti-
inflammatory drugs on medical abortion with
mifepristone and misoprostol at 13-22 weeks
gestation. Hum Reprod. 2005;20:3072-3077.
14. Li CF, Wong CY, Chan CP, Ho PC. A study of
co-treatment of nonsteroidal anti-inflammatory
drugs (NSAIDs) with misoprostol for cervical prim-
ing before suction termination of first trimester
pregnancy. Contraception. 2003;67:101-105.
15. Orioli IM, Castilla EE. Epidemiological assess-
ment of misoprostol teratogenicity. BJOG. 2000;
107:519-523.
16. Yedlinsky NT, Morgan FC, Whitecar PW. Anom-
alies associated with failed methotrexate and
misoprostol termination. Obstet Gynecol. 2005;
105:1203-1205.
17. Tang OS, Gemzell-Danielsson K, Ho PC. Miso-
prostol: pharmacokinetic profiles, effects on the
uterus and side-effects. Int J Gynaecol Obstet.
2007;99(suppl 2):S160-S167.
18. Pastuszak AL, Schüler L, Speck-Martins CE, et al.
Use of misoprostol during pregnancy and
Möbius’ syndrome in infants. N Engl J Med.
1998;338:1881-1885.
19. Vogel D, Burkhardt T, Rentsch K, et al. Miso-
prostol versus methylergometrine: pharmacoki-
netics in human milk. Am J Obstet Gynecol.
2004;191:2168-2173.
20. Hale TW. Medications and Mothers’ Milk. 11th
ed. Amarillo, TX: Pharmasoft Publishing; 2004.
21. Fiala C, Gemzel-Danielsson K. Review of medical
abortion using mifepristone in combination with
a prostaglandin analogue. Contraception.
2006;74:66-86.
22. National Abortion Federation (NAF). NAF
Protocol for Mifepristone/Misoprostol in Early
Abortion. Washington, DC: National Abortion
Federation; 2008. http://www.prochoice.org/pubs_
research/publications/downloads/professional_
education/medical_abortion/protocol_mife_miso
.pdf. Accessed January 15, 2009.
23. Winikoff B, Dzuba IG, Creinin MD, et al. Two
distinct oral routes of misoprostol in mifepris-
tone medical abortion: a randomized controlled
trial. Obstet Gynecol. 2008;112:1303-1310.
24. Paul M, Schaff E, Nichols M. The roles of clini-
cal assessment, human chorionic gonadotropin
assays, and ultrasonography in medical abortion
practice. Am J Obstet Gynecol. 2000;183(2
suppl):S34-S43.
7. RIOG0055_09-14.qxd 9 /14/09 8:57 PM Page 166

Misoprostol Use in Obstetrics and Gynecology
VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 167
25. Walker K, Schaff E, Fielding S, Fuller L. Moni-
toring serum chorionic gonadotropin levels after
mifepristone abortion. Contraception. 2001;64:
271-273.
26. Davey A. Mifepristone and prostaglandin for
termination of pregnancy: contraindications for
use, reasons and rationale. Contraception. 2006;
74:16-20.
27. Kruse B, Poppema S, Creinin MD, Paul M. Man-
agement of side effects and complications in
medical abortion. Am J Obstet Gynecol.
2000;183(2 suppl):S65-S75.
28. Henderson JT, Hwang AC, Harper CC, Stewart
FH. Safety of mifepristone abortions in clinical
use. Contraception. 2005;72:175-178.
29. Moreno-Ruiz NL, Borgatta L, Yanow S, et al. Al-
ternatives to mifepristone for early medical abor-
tion. Int J Gynaecol Obstet. 2007;96:212-218.
30. Bartlett LA, Berg CJ, Shulman HB, et al. Risk fac-
tors for legal induced abortion-related mortality
in the United States. Obstet Gynecol. 2004;103:
729-737.
31. Royal College of General Practitioners, Royal
College of Obstetricians and Gynaecologists. In-
duced abortion operations and their early seque-
lae. J R Coll Gen Pract. 1985;35:175-180.
32. Cates W Jr, Schulz KF, Grimes DA. The risks as-
sociated with teenage abortion. N Engl J Med.
1983;309:621-624.
33. Grimes DA, Schulz KF, Cates WJ Jr. Prevention
of uterine perforation during curettage abortion.
JAMA. 1984;251:2108-2111.
34. Schulz KF, Grimes DA, Cates W Jr. Measures to
prevent cervical injury during suction curettage
abortion. Lancet. 1983;1:1182-1185.
35. Allen RH, Goldberg AB; Board of Society of
Family Planning. Cervical dilation before first-
trimester surgical abortion (<14 weeks’ gesta-
tion). SFP Guideline 20071. Contraception.
2007;76:139-156.
36. Blanchard K, Clark S, Winikoff B, et al. Miso-
prostol for women’s health: a review. Obstet
Gynecol. 2002;99:316-332.
37. Singh K, Fong YF. Preparation of the cervix for
surgical termination of pregnancy in the first
trimester. Hum Reprod Update. 2000;6:442-448.
38. Carbonell JL, Velazco A, Rodriguez Y, et al. Oral
versus vaginal misoprostol for cervical priming
in first-trimester abortion: a randomized trial.
Eur J Contracept Reprod Health Care. 2001;6:
134-140.
39. MacIsaac L, Grossman D, Balistreri E, Darney P.
A randomized controlled trial of laminaria, oral
misoprostol, and vaginal misoprostol before
abortion. Obstet Gynecol. 1999;93:766-770.
40. Hamoda H, Ashok PW, Flett GM, Templeton A. A
randomized controlled comparison of sublingual
and vaginal administration of misoprostol for
cervical priming before first-trimester surgical
abortion. Am J Obstet Gynecol. 2004;190:55-59.
41. Fiala C, Gemzell-Danielsson K, Tang OS, von
Hertzen H. Cervical priming with misoprostol
prior to transcervical procedures. Int J Gynaecol
Obstet. 2007;99(suppl 2):S168-S171.
42. Saxena P, Salhan S, Sarda N. Role of sublingual
misoprostol for cervical ripening prior to vac-
uum aspiration in first trimester interruption of
pregnancy. Contraception. 2003;67:213-217.
43. Ngai SW, Tang OS, Lao T, et al. Oral misoprostol
versus placebo for cervical dilatation before vac-
uum aspiration in first trimester pregnancy. Hum
Reprod. 1995;10:1220-1222.
44. Fox MC, Hayes JL; Society of Family Planning.
Cervical preparation for second-trimester surgi-
cal abortion prior to 20 weeks of gestation. Con-
traception. 2007;76:486-495.
45. Todd CS, Soler M, Castleman L, et al. Buccal
misoprostol as cervical preparation for second
trimester pregnancy termination. Contraception.
2002;65:415-418.
46. Patel A, Talmont E, Morfesis J, et al. Adequacy
and safety of buccal misoprostol for cervical
preparation prior to termination of second-
trimester pregnancy. Contraception. 2006;73:
420-430.
47. Goldberg AB, Drey EA, Whitaker AK, et al. Miso-
prostol compared with laminaria before early
second-trimester surgical abortion: a random-
ized trial. Obstet Gynecol. 2005;106:234-241.
48. Edelman AB, Buckmaster JG, Goetsch MF, et al.
Cervical preparation using laminaria with ad-
junctive buccal misoprostol before second-
trimester dilation and evacuation procedures: a
randomized clinical trial. Am J Obstet Gynecol.
2006;194:425-430.
49. Nucatola D, Roth N, Saulsberry V, Gatter M. Se-
rious adverse events associated with the use of
misoprostol alone for cervical preparation prior
to early second trimester surgical abortion (12-
16 weeks). Contraception. 2008;78:245-248.
50. Bradley LD. Complications in hysteroscopy: pre-
vention, treatment and legal risk. Curr Opin Ob-
stet Gynecol. 2002;14:409-415.
51. Crane JM, Healey S. Use of misoprostol before
hysteroscopy: a systematic review. J Obstet Gy-
naecol Can. 2006;28:373-379.
52. Batukan C, Ozgun MT, Ozcelik B, et al. Cervical
ripening before operative hysteroscopy in pre-
menopausal women: a randomized, double-blind,
placebo-controlled comparison of vaginal and
oral misoprostol. Fertil Steril. 2008;89:966-973.
53. Oppegaard KS, Nesheim BI, Istre O, Qvigstad E.
Comparison of self-administered vaginal miso-
prostol versus placebo for cervical ripening prior
to operative hysteroscopy using a sequential trial
design. BJOG. 2008;115:663, e1-e9.
54. Preutthipan S, Herabutya Y. A randomized con-
trolled trial of vaginal misoprostol for cervical
priming before hysteroscopy. Obstet Gynecol.
1999;94:427-430.
55. Preutthipan S, Herabutya Y. Vaginal misoprostol
for cervical priming before operative hys-
teroscopy: a randomized controlled trial. Obstet
Gynecol. 2000;96:890-894.
56. Ngai SW, Chan YM, Liu KL, Ho PC. Oral miso-
prostol for cervical priming in non-pregnant
women. Hum Reprod. 1997;12:2373-2375.
57. Waddell G, Desindes S, Takser L, et al. Cervical
ripening using vaginal misoprostol before hys-
teroscopy: a double-blind randomized trial. J
Minim Invasive Gynecol. 2008;15:739-744.
58. Singh N, Ghosh B, Naha M, Mittal S. Vaginal
misoprostol for cervical priming prior to diag-
nostic hysteroscopy–efficacy, safety and patient
satisfaction: a randomized controlled trial. Arch
Gynecol Obstet. 2009;279:37-40.
59. Fernandez H, Alby JD, Tournoux C, et al. Vagi-
nal misoprostol for cervical ripening before op-
erative hysteroscopy in pre-menopausal women:
a double-blind, placebo-controlled trial with
three dose regimens. Hum Reprod. 2004;19:
1618-1621.
60. Barcaite E, Bartusevicius A, Railaite DR, Nadis-
auskiene R. Vaginal misoprostol for cervical
priming before hysteroscopy in perimenopausal
and postmenopausal women. Int J Gynaecol Ob-
stet. 2005;91:141-145.
61. Fung TM, Lam MH, Wong SF, Ho LC. A ran-
domised placebo-controlled trial of vaginal
misoprostol for cervical priming before hys-
teroscopy in postmenopausal women. BJOG.
2002;109:561-565.
62. Ngai SW, Chan YM, Ho PC. The use of misopros-
tol prior to hysteroscopy in postmenopausal
women. Hum Reprod. 2001;16:1486-1488.
63. Thomas JA, Leyland N, Durand N, Windrim RC.
The use of oral misoprostol as a cervical ripen-
ing agent in operative hysteroscopy: a double-
blind, placebo-controlled trial. Am J Obstet Gy-
necol. 2002;186:876-879.
64. Perrone JF, Caldito G, Mailhes JB, et al. Oral
misoprostol before office endometrial biopsy.
Obstet Gynecol. 2002;99:439-444.
65. Sääv I, Aronsson A, Marions L, et al. Cervical
priming with sublingual misoprostol prior to in-
sertion of an intrauterine device in nulliparous
women: a randomized controlled trial. Hum Re-
prod. 2007;22:2647-2652.
66. Chen BA, Creinin MD. Contemporary manage-
ment of early pregnancy failure. Clin Obstet
Gynecol. 2007;50:67-88.
67. Neilson JP, Hickey M, Vazquez J. Medical treat-
ment for early fetal death (less than 24 weeks).
Cochrane Database Syst Rev. 2006;3:CD002253.
68. Consensus Statement. Instructions for Use—
Misoprostol for the Treatment of Incomplete
Abortion and Miscarriage. Expert Meeting on
Misoprostol, June 9, 2004. New York: Reproduc-
tive Health Technologies Project and Gynuity
Health Projects; 2008.
69. Zhang J, Gilles JM, Barnhart K, et al; National
Institute of Child Health Human Development
(NICHD) Management of Early Pregnancy Fail-
ure Trial. A comparison of medical management
with misoprostol and surgical management for
early pregnancy failure. N Engl J Med. 2005;
353:761-769.
70. Lee DT, Cheung LP, Haines CJ, et al. A compari-
son of the psychologic impact and client satis-
faction of surgical treatment with medical treat-
ment of spontaneous abortion: a randomized
controlled trial. Am J Obstet Gynecol. 2001;
185:953-958.
71. Reeves MF, Lohr PA, Harwood BJ, Creinin MD.
Ultrasonographic endometrial thickness after
medical and surgical management of early preg-
nancy failure. Obstet Gynecol. 2008;111:106-112.
72. Carbonell JL, Torres MA, Reyes R, et al. Second-
trimester pregnancy termination with 600-mi-
crog vs. 400-microg vaginal misoprostol and
systematic curettage postexpulsion: a random-
ized trial. Contraception. 2008;77:50-55.
73. Wong KS, Ngai CS, Yeo EL, et al. A comparison
of two regimens of intravaginal misoprostol for
7. RIOG0055_09-14.qxd 9 /14/09 8:57 PM Page 167

Misoprostol Use in Obstetrics and Gynecology continued
168 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY
termination of second trimester pregnancy: a
randomized comparative trial. Hum Reprod.
2000;15:709-712.
74. Herabutya Y, Chanrachakul B, Punyavachira P. A
randomised controlled trial of 6 and 12 hourly
administration of vaginal misoprostol for second
trimester pregnancy termination. BJOG. 2005;
112:1297-1301.
75. Herabutya Y, Chanrachakul B, Punyavachira P.
Second trimester pregnancy termination: a com-
parison of 600 and 800 micrograms of intra-
vaginal misoprostol. J Obstet Gynaecol Res.
2001;27:125-128.
76. Dickinson JE, Evans SF. The optimization of in-
travaginal misoprostol dosing schedules in sec-
ond-trimester pregnancy termination. Am J Ob-
stet Gynecol. 2002;186:470-474.
77. Kapp N, Borgatta L, Stubblefield P, et al. Mifepri-
stone in second-trimester medical abortion: a
randomized controlled trial. Obstet Gynecol.
2007;110:1304-1310.
78. Dickinson JE, Evans SF. A comparison of oral
misoprostol with vaginal misoprostol adminis-
tration in second-trimester pregnancy termina-
tion for fetal abnormality. Obstet Gynecol.
2003;101:1294-1299.
79. Daskalakis GJ, Mesogitis SA, Papantoniou NE, et
al. Misoprostol for second trimester pregnancy
termination in women with prior caesarean sec-
tion. BJOG. 2005;112:97-99.
80. Bhattacharjee N, Ganguly RP, Saha SP. Miso-
prostol for termination of mid-trimester post-
Caesarean pregnancy. Aust N Z J Obstet
Gynaecol. 2007;47:23-25.
81. Fletcher HM, Mitchell S, Simeon D, et al. Intra-
vaginal misoprostol as a cervical ripening agent.
Br J Obstet Gynaecol. 1993;100:641-644.
82. Ngai SW, To WK, Lao T, Ho PC. Cervical priming
with oral misoprostol in pre-labor rupture of mem-
branes at term. Obstet Gynecol. 1996;87:923-926.
83. Alfirevic Z. Oral misoprostol for induction of labour.
Cochrane Database Syst Rev. 2001;(2):CD001338.
84. Muzonzini G, Hofmeyr GJ. Buccal or sublingual
misoprostol for cervical ripening and induction
of labour. Cochrane Database Syst Rev. 2004;(4):
CD004221.
85. Hofmeyr GJ, Gülmezoglu AM. Vaginal misopros-
tol for cervical ripening and induction of labour.
Cochrane Database Syst Rev. 2003;(1):CD000941.
86. Sanchez-Ramos L, Kaunitz AM. Misoprostol for
cervical ripening and labor induction: a system-
atic review of the literature. Clin Obstet Gynecol.
2000;43:475-488.
87. Wing DA, Gaffaney CA. Vaginal misoprostol ad-
ministration for cervical ripening and labor in-
duction. Clin Obstet Gynecol. 2006;49:627-641.
88. Bamigboye AA, Hofmeyr GJ, Merrell DA. Rectal
misoprostol in the prevention of postpartum he-
morrhage: a placebo-controlled trial. Am J Ob-
stet Gynecol. 1998;179:1043-1046.
89. Hofmeyr GJ, Nikodem VC, de Jager M, Gelbart
BR. A randomised placebo controlled trial of oral
misoprostol in the third stage of labour. Br J Ob-
stet Gynaecol. 1998;105:971-975.
90. Surbek DV, Fehr PM, Hösli I, Holzgreve W. Oral
misoprostol for third stage of labor: a random-
ized placebo-controlled trial. Obstet Gynecol.
1999;94:255-258.
91. El-Refaey H, O’Brien P, Morafa W, et al. Use of
oral misoprostol in the prevention of postpartum
haemorrhage. Br J Obstet Gynaecol. 1997;104:
336-339.
92. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ.
Prostaglandins for preventing postpartum haem-
orrhage. Cochrane Database Syst Rev. 2007;(3):
CD000494.
93. Mousa HA, Alfirevic Z. Treatment for primary
postpartum haemorrhage. Cochrane Database
Syst Rev. 2007;(1):CD003249.
94. O’Brien P, El-Refaey H, Gordon A, et al. Rectally
administered misoprostol for the treatment of
postpartum hemorrhage unresponsive to oxy-
tocin and ergometrine: a descriptive study. Ob-
stet Gynecol. 1998;92:212-214.
7. RIOG0055_09-14.qxd 9 /14/09 8:57 PM Page 168