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Authors:

Caitlin Shannon, MPH


Beverly Winikoff, MD, MPH
Section Editor:
Jody Steinauer, MD, MAS
Deputy Editor:
Sandy J Falk, MD, FACOG
Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2016. | This topic last updated: Jul 28, 2014.
INTRODUCTION Medical methods for induced abortion have emerged over the past two
decades as safe, effective, and feasible alternatives to surgery. Nonsurgical alternatives expand
a woman's treatment options and, in turn, the quality of care [1]. Moreover, in some settings,
surgical options are not available to women or are not medically feasible.
In first trimester abortion, combined treatment with misoprostol with mifepristone appears to be
more effective than misoprostol-alone regimens, and thus, are considered the gold standard for
medical induction [2,3]. However, misoprostol-alone regimens may be the treatment of choice in
settings in which mifepristone is not available or is too costly.
Misoprostol is commonly used as a single agent for second trimester induced abortion in the
United States and many other parts of the world [4,5].
This topic review will discuss use of misoprostol in pregnancy termination. Use of mifepristone
and other medical and surgical approaches to pregnancy termination and use of misoprostol for
fetal demise or labor induction are reviewed separately. (See "First-trimester medication abortion
(termination of pregnancy)" and "Overview of pregnancy termination" and "Spontaneous
abortion: Management" and "Fetal death and stillbirth: Incidence, etiology, and prevention" and
"Techniques for ripening the unfavorable cervix prior to induction".)

PHARMACOKINETICS Misoprostol is a synthetic E1 prostaglandin (PGE1) developed and


approved originally for the prevention of gastric ulcers. Misoprostol is not approved by the United
States Food and Drug Administration for uterine evacuation in pregnant women.
Misoprostol administration in pregnancy induces cervical effacement and uterine contractions at
all gestational ages, thereby facilitating uterine evacuation [6]. The potency of misoprostol's
effect, however, varies with gestational age, as well as with route of administration, dose, dosing
interval, and cumulative dose.
Gestational age The sensitivity of the uterus to prostaglandins increases with
gestational age [6]. For this reason, providers generally use decreasing amounts of
misoprostol with increasing gestational age.
Route of administration Misoprostol can be administered by the following routes:
vaginal, oral, sublingual, buccal, or rectal [7-12].
Serum level The pharmacokinetic profile varies by route [7,8,11,12]. Oral or
sublingual administration leads to a rapid peak in serum level, which appears to
decrease in one to three hours. Conversely, with vaginal or buccal dosing, serum levels
peak later and remain elevated longer [11,12].
Uterine activity Regular and sustained uterine activity is more likely following vaginal,
sublingual, or buccal compared with oral administration [12].
Moist versus dry tablets Moistening of misoprostol tablets does not appear to
increase clinical effectiveness [13-16]. A randomized trial evaluated first trimester
abortion using methotrexate followed by wet versus dry misoprostol; no difference was
found between the two groups [13].
CONTRAINDICATIONS
Absolute contraindications
Suspected or confirmed ectopic pregnancy
Gestational trophoblastic disease

High risk of uterine rupture (ie, second or third trimester inductions in women with more
than one prior hysterotomy, a prior classical or T-shaped uterine incision, or extensive
transfundal uterine surgery)
Intrauterine device (IUD, must be removed before misoprostol is administered)
Allergy to prostaglandins
Contraindications to medical or surgical uterine evacuations (eg, hemodynamically
unstable, coagulopathy) (see "Overview of pregnancy termination")
Relative contraindications Misoprostol-alone regimens should be used with caution in
women who are at risk for complications of pregnancy termination (eg, coagulopathy).
Precautions specific to misoprostol are considered here. A full discussion of abortion
complications is presented separately. (See "Overview of pregnancy termination", section on
'Complications'.)
Risk factors for uterine rupture Uterine rupture is a risk of misoprostol use at any time
during pregnancy. While the risk is likely higher in women with a uterine scar, there are few
reports of this complication (table 1) [17]. In a systematic review of available studies, the risk of
rupture was 0.3 percent among women with a prior cesarean delivery who were undergoing
second trimester misoprostol-induced abortion [18]. Advanced gestational age, high gravidity
(3 pregnancies) or uterine anomalies may also increase risk of rupture.
Uterine rupture has only been reported once in women undergoing first trimester ruptures [19].
In the second trimester, uterine rupture is rare, but has been reported more frequently than in
the first trimester [20-28]. Case reports of uterine rupture in women undergoing second trimester
abortion with misoprostol include women with scarred [20-25] and unscarred uteri [25-28].
Scarred uterus There are no high quality data regarding the risk of uterine rupture
with use of misoprostol for first or second trimester pregnancy termination. Among five
published case series of women with a prior cesarean section who were undergoing
second trimester misoprostol abortion (n = 858), two cases of uterine rupture were

reported [20,21,29-31]; however, they were underpowered to detect this rare


complication.

According to observational data regarding obstetric labor induction, misoprostol induction


is contraindicated in women with more than one hysterotomy, a prior classical or Tshaped uterine incision, or extensive transfundal uterine surgery. It has not been
established whether these risks apply equally to patients undergoing first or second
trimester induction. (See "Choosing the route of delivery after cesarean birth", section on
'Inappropriate candidates'.)

We counsel women that a uterine scar is not a contraindication for first trimester
misoprostol induction, but that the risk may increase with increasing gestational age,
particularly in the late second trimester. We counsel women about risk and monitor them
for signs of rupture.
Unscarred uterus In reports of uterine rupture in women without previous uterine
surgery, risk factors included grand multiparity [25,26], gestational age greater than 23
weeks [24], and use of oxytocin in addition to misoprostol [25]. However, oxytocin can
generally be used safely in combination with misoprostol [26]. For pregnancies at 23 or
more weeks, it is controversial whether it is necessary to decrease the misoprostol dose
or increase dosing interval, though it may be prudent to do so [32,33].
Breastfeeding Misoprostol is excreted transiently and at low levels in human breast milk [34].
It appears that the levels rise and decline within three to five hours of administration [6,34]. It is
reasonable to counsel women who receive misoprostol while breastfeeding to pump and discard
all milk produced within five hours after each dose.
PRETREATMENT EVALUATION AND PREPARATION All women should undergo an initial
evaluation, including a medical history and a physical examination confirming gestational age.
Ultrasound is necessary only if there is uncertainty about gestational age, pregnancy location or
the presence of gestational trophoblastic disease. If an ultrasound is not performed, the

pregnancy should be confirmed with a urine or serum human chorionic gonadotropin (hCG).
Blood type and antibody status are checked and Rh immune globulin given if indicated. If a
patient has an IUD, it must be removed.
One of the advantages of misoprostol induction is that it can be performed safely and effectively
without mechanical dilation (eg, rigid or osmotic dilators). Some providers augment the
procedure with pretreatment laminaria for inductions after 15 weeks. However, two randomized
trials in women undergoing second trimester termination reported that use of laminaria
compared with no mechanical dilation did not reduce (16 and 17 hours) [35] and may prolong
(14 versus 11 hours) [36] induction time; one trial found an increase in the use of morphine in
patients treated with laminaria [36]. A full discussion of cervical preparation for pregnancy
termination can be found separately. (See "Overview of pregnancy termination", section on
'Cervical preparation'.)
There is no high quality evidence regarding the use of antibiotic prophylaxis for medical abortion
(ie, no invasive methods for cervical preparation or uterine evacuation). However, due to several
deaths due to clostridial sepsis in the United States in patients who received vaginal misoprostol
in combination with mifepristone, some organizations, such as Planned Parenthood (the largest
abortion provider in the United States), have introduced the use of prophylactic antibiotics
[37,38]. However, deaths due to clostridial infection have been reported among women
administering misoprostol both vaginally and buccally [39]. (See "First-trimester medication
abortion (termination of pregnancy)", section on 'Prophylactic antibiotics'.)
Pretreatment evaluation for pregnancy termination is discussed in detail separately. (See
"Overview of pregnancy termination", section on 'Preoperative considerations' and "Prevention
of Rh(D) alloimmunization in pregnancy".)
DATA ON DRUG ADMINISTRATION The optimal misoprostol regimen at any gestational age
is determined by achieving a balance among effectiveness, adverse effects, and acceptability to
patients. As an example, higher doses and shorter dosing intervals increase effectiveness, but
also may result in higher rates of adverse effects and complications [6].

Route of administration Effectiveness (defined as complete abortion without surgical


intervention) is higher with vaginal compared with oral administration in both first and second
trimesters [40-43]. However, in a randomized trial, women preferred oral rather than vaginal
dosing [10].
Accumulating evidence regarding sublingual administration appears promising regarding
effectiveness and patient acceptability [44-46]. Buccal misoprostol is also used frequently in
combination with mifepristone. As a single agent, two studies have found that buccal
misoprostol can be effective for first trimester induction and may be effective in second trimester
abortion [47,48]. Its use has not been compared to either vaginal administration or sublingual
administration, which are preferable [47,48].
Oral versus vaginal dosing At 8 or less weeks of gestation, a comparative study
evaluated three oral and four vaginal regimens in 260 women showed that the rate of
complete abortion is higher with vaginal compared with oral administration (43 to 80
versus 39 to 50 percent) [40].

For pregnancies between 9 and 12 weeks, there are no high quality data comparing
vaginal with oral administration. However, observational studies of vaginal misoprostol
use have reported consistently high rates of complete abortion (85 to 90 percent) [4958].

At 13 or more weeks, randomized trials comparing vaginal with oral dosing found that the
vaginal route was more effective (86 to 100 versus 45 to 89 percent) and had a shorter
induction-to-delivery interval (10 to 15 hours versus 12 to 35 hours) [5,42,43,59].
Adverse effects were similar between the two routes, with the possible exception of a
higher incidence of fever with vaginal dosing [42], and of nausea and diarrhea with oral
dosing [59]. Findings on adverse effects are not consistent and thus do not provide high
quality evidence for guiding route of administration.

At 24 to 28 weeks, one randomized trial of women with a fetal demise compared oral and
vaginal regimens and found a slightly longer time to expulsion in women receiving oral
misoprostol [60].
Sublingual versus vaginal dosing In pregnancies at 12 weeks of gestation or less,
data suggest that the sublingual route may be as effective as the vaginal route when
dosed appropriately [40,44,61]. In a randomized trial that compared two vaginal and two
sublingual regimens in 2000 women, vaginal misoprostol administered every 3 or 12
hours and sublingual misoprostol every three hours were similarly effective (83 to 85
percent), but sublingual misoprostol every 12 hours was less effective (78 percent) [61].
Women preferred sublingual to vaginal administration. Side effects tended to be more
common among women taking misoprostol at 3-hour compared to 12-hour intervals,
vaginal or sublingual; and this finding was significant for incidence of fever. Diarrhea and
chills were slightly more common in women taking misoprostol sublingually compared to
vaginally, but this difference was not statistically significant and, regardless, may not be
clinically relevant.

Similarly, the sublingual route may be as effective as the vaginal route for termination
after 12 weeks [46,59,62-66]. One meta-analysis demonstrated that efficacy at 24 hours
was similar (pooled RR 1.04, 95% CI 0.93-1.7), but that vaginal misoprostol may be
more successful at 48 hours (pooled RR 0.96; 95% CI 0.93-0.99) and may shorten the
induction-to-abortion interval (WMD -4.54, 95% CI -8.03 to -1.05) [65]. A second metaanalysis of 40 randomized trials examining medical methods of uterine evacuation for
women 12 to 28 weeks pregnant found that while misoprostol was more frequently
vaginally administered, sublingual administration was equally effective [66]. Rates of
adverse effects are similar between the two types of dosing; however, patients prefer the
sublingual route [46,62,63].
Buccal versus oral or vaginal dosing Buccal administration of misoprostol as a single
agent for medical termination of pregnancy in the first trimester appears promising
[67,68]. Randomized trial data for administration of misoprostol in combination with

mifepristone for pregnancy up to eight to nine weeks of gestation have found that the
efficacy of buccal dosing is similar to vaginal and better than oral dosing [69,70]. Buccal
administration was associated with a slight increase in nausea over either oral or vaginal
dosing. Patient satisfaction was high across all routes. Used as a single agent, buccal
misoprostol was found to have an efficacy of 76 percent among women less than 9
weeks pregnant (n = 147) [47].

Studies regarding buccal dosing in the second trimester have also yielded favorable
results, but there are no studies regarding use of buccal misoprostol as a single agent for
second trimester pregnancy termination [71,72]. In one randomized trial, the initial
misoprostol dose was administered vaginally, and subsequent doses were given either
buccally or vaginally [73]. The median time to abortion in the buccal group did not differ
significantly in the buccal compared with vaginal dosing groups (15 versus 12 hours); no
difference was found in patient preference for route of administration.
Combined-route regimens for second trimester terminations Regimens that combine
an initial vaginal misoprostol dose followed by oral doses have been commonly used for
terminations after 12 weeks and appear to be as effective as vaginal-only regimens
[36,43,74-76]. The rationale is to maximize effectiveness and acceptability, while
minimizing induction-to-delivery interval, adverse effects and complications. In a
randomized trial of 43 women at 13 to 23 weeks of gestation, an initial 800 mcg vaginal
misoprostol dose was followed every eight hours by 400 mcg given either orally or
vaginally; effectiveness (82 and 87 percent) and induction-to-delivery interval (16 and 21
hours) were similar between the oral and vaginal groups [76]. A randomized trial
demonstrated that 200 mcg buccal doses repeated at six-hour intervals, following an
initial 400 mcg vaginal dose, result in a similar induction-to-delivery interval (15 versus
12 hours, respectively) [73].
Dose and dosing interval The optimal regimen is a dose and dosing interval balance which
generate sufficient and sustained uterine activity while minimizing adverse effects [77]. Longer
dosing intervals have the benefit of exposing a woman to a decreased risk of adverse effects.

Conversely, shorter dosing intervals (closer to three hours) may be necessary to generate
sufficient uterine activity, in particular if misoprostol is given via a route with a rapid rise and fall
in serum levels (ie, oral and sublingual) [8]. Uterine hyperstimulation is rare; however, the risk
may increase with shorter dosing intervals.
9 or less weeks Vaginal administration of misoprostol appears to be more effective at
800 mcg (generally 80 to 90 percent) than 200 or 400 mcg (23 to 46 percent), according
to observational data [51].

A vaginal dosing interval of 3 to 24 hours (800 mcg PV; total of three to five doses) is
typically used to terminate pregnancies up to nine weeks, with reported success rates of
85 to 93 percent in non-comparative studies [77].

There are no high quality data comparing different doses of sublingual misoprostol for
terminations at 12 weeks. In studies of sublingual-dosing alone and comparative trials
with vaginal dosing, 400 to 800 mcg SL is typically used [40,44,61]. As noted above, 3rather than 12-hour dosing interval was found to be significantly more effective in a
randomized trial (84 versus 78 percent) [61].
10 to 12 weeks Lower success rates for misoprostol-alone have been reported for
pregnancies at 10 to 12 weeks of gestation (84 to 87 percent) in a few descriptive
studies [51,56,57,78,79]. The most effective regimen appears to be 800 mcg PV every
12 to 24 hours for a maximum of three doses [56,57].

Data from a case series of 50 women suggest that sublingual administration is also
effective; the regimen used was 600 mcg SL every three hours up to five doses [44].
13 to 22 weeks Two misoprostol regimens, 400 mcg PV every three hours OR 600
PV mcg every 12 hours were safe, effective, and resulted in low induction-to-delivery
interval in randomized trials [80-82]. However, these two regimens have not been
compared to each other.

As noted above, it is unclear whether sublingual administration is more or less effective


than vaginal in this gestational age range. More research is needed to determine
whether sublingual administration should be used among women with gestations 13 to
22 weeks, and the appropriate regimen. (See 'Route of administration' above.)
23 to 28 weeks Many studies have examined the use of misoprostol-alone regimens
beyond 23 weeks of gestation, and data show that the method, employing a variety of
regimens, can be safely and effectively used in women with advanced gestations
[43,74,81-86]. In general, however, termination after 23 weeks is not common in the
United States, and an optimal regimen has not been established. When pregnancy
termination is performed at 24 weeks, the indication is generally a fetal anomaly.
The Society for Family Planning (SFP) has published a systematic review and guidelines
for pregnancy termination from 24 to 28 weeks; these include data and
recommendations for pregnancy termination and labor induction for fetal demise [87].
For misoprostol-only regimens, 11 studies (7 were randomized trials) were included, and
showed that a dosing regimen of misoprostol PV 100 mcg or 200 mcg given every 4
hours was associated with a 24-hour expulsion rate of 84 to 100 percent, with mean or
median expulsion times of 10 to 14 hours. Longer dosing intervals were associated with
a longer time to expulsion. Use of a higher dose (400 mcg) was not associated with an
increase in efficacy. In addition, a subsequent randomized trial of women with a fetal
demise found that a 200 mcg dose was significantly more effective than a 100 mcg dose
(76.7 versus 89.5 percent completion at 48 hours) [88].

As noted above, uterine sensitivity to prostaglandins and risk of uterine rupture increase
with gestational age. Therefore, it may be prudent to use a decreased dose or increased
dosing interval in this gestational age range [89] (see 'Pharmacokinetics' above). Uterine
rupture is rare, however. There no uterine ruptures reported among the 700 cases
included in the SFP review [87].
A retrospective review of second trimester terminations among women with prior
cesarean section found that, among the 279 women undergoing termination, there were

3 cases of rupture [90]. All three cases of rupture were among women with two or more
prior cesarean sections. The type of prior incision, termination regimen used, and the
length of induction were not specified. In another study, no significant increased risk of
uterine rupture was found in women with a prior uterine scar compared to those with no
uterine scar (1/44 versus 2/457) in a population of 518 women undergoing second
trimester medical termination with a combination of methods, including misoprostol alone
[91].
Number of doses In pregnancies at 12 or less weeks, it appears that there is little increase
in effectiveness after the second dose of misoprostol [58,92], although most studies have
evaluated regimens of three to five doses [77]. As an example, in one study, effectiveness after
a second or third dose were similar (86 and 88 percent) [92].
Data on second trimester medical terminations with misoprostol show that multiple doses are
highly effective compared to single doses. As noted above, recommended doses are lower than
doses used for first trimester terminations since the uterine is more sensitive to misoprostol and
the risk of rupture appears greater [65,66,93]. As an example, 25 to 50 mcg doses are generally
used for labor induction in the third trimester. The need for repeat doses should be evaluated
prior to administration and based on lack of relevant clinical signs of progression (eg, insufficient
uterine activity or cervical dilation).
CLINICAL REGIMEN The regimens listed below are consistent with the regimens proposed
by a meeting convened by the World Health Organization (WHO) as a prelude to WHO
guidelines (table 2) [77,89,94]. All gestational ages refer to weeks of amenorrhea.
9 or less weeks Misoprostol may be administered either in a clinic or at home.
800 mcg SL every three hours for up to three doses [61] OR
800 mcg PV every 3 to 12 hours for up to three doses [40,61] OR
800 mcg buccally every two to three hours

10 to 12 weeks We suggest administration in a clinic only due to increased risk of excessive


bleeding and possibly of uterine rupture [77].
800 mcg PV every 3 to 12 hours for up to three doses [56,57]
13 to 22 weeks Treatment should be administered only in a clinic setting with immediate
access to emergency surgery and blood transfusion. If delivery has not occurred at 24 hours,
the protocol may be repeated [80,81].
400 mcg PV every three to four hours (max five doses) [80] OR
600 mcg PV every 12 hours [81]
23 or more weeks Treatment should be administered only in a clinic setting with immediate
access to emergency surgery and blood transfusion. As noted above, there is no wellestablished regimen for this gestational age range. The Society for Family planning has
published the following regimen [87]:
100 to 200 mcg vaginal or buccal misoprostol every 4 to 6 hours for 24 hours
Pretreatment with mifepristone Mifepristone (200 mg) should be administered 24 to
48 hours prior to the administration of misoprostol, where available (see "Second
trimester pregnancy termination: Induction (medication) termination")
MONITORING DURING TREATMENT Women are monitored during treatment whether it
occurs at home or in a clinic setting. The goals of monitoring are to assess treatment efficacy
and assess for complications.
At-home treatment A woman undergoing medical termination at home should have easy
access to a clinician who can answer questions and manage complications medically or
surgically. Patient education should include how to recognize complications (eg, fever,
abdominal pain, or prolonged or excessive bleeding) (table 2).
In addition, a woman should also call her provider if it does not seem that the treatment has
been effective. Typically, if 48 hours have passed since completion of treatment and a woman

has not had bleeding greater than a menstrual period, it is likely that she may have an
incomplete abortion or continuing pregnancy [95].
In-clinic treatment Examination of presumed products of conception or pelvic examination
are performed before each additional misoprostol dose is administered in order to determine
whether the fetus has been expelled. The frequency and strength of uterine contractions are
also monitored, and additional doses should be deferred if uterine contractions are strong
(strong to palpation or by patient report) and/or too frequent (>3 contractions/10 min) [89].
In pregnancies at 13 weeks or greater, if a woman does not abort after 24 hours, the option of a
second course of misoprostol treatment or surgical evacuation can be offered [80,82]. There are
insufficient data on the safety and effectiveness of augmentation with other uterotonics (eg,
prostaglandins or oxytocin) [89]. As with misoprostol, if additional uterotonics are used,
precautions should be taken to avoid uterine hyperstimulation, as it may lead to rupture.
Expulsion of the placenta should be confirmed. Expulsion usually occurs shortly after the fetus
is delivered. After expulsion, the placenta should be examined to see whether it is complete.
Advice regarding time interval to wait for placental expulsion varies from 30 minutes to four
hours; in a retrospective study, there was no morbidity associated with a waiting period of four
hours [96]. If two or more hours have passed and the placenta has not delivered, an infusion of
oxytocin 10 units in 500 mL of normal saline administered intravenously at a rate of 20 to 30
drops per minute may be given [89]. If the placenta has not delivered after infusion of oxytocin or
the woman starts bleeding excessively, manual or surgical removal of the placenta may be
required.
Before discharge from the clinic, clinicians should observe women for at least four hours to
monitor vital signs and observe for severe abdominal pain or excessive vaginal bleeding.
If 48 hours have passed and abortion is not complete, surgical evacuation is typically performed
[89].

FOLLOW-UP After treatment, women should be educated about how to recognize


complications (eg, fever, abdominal pain, or prolonged or excessive bleeding) (table 2). A followup visit is conducted at one to two weeks post-treatment. A thorough clinical history and
bimanual pelvic examination is performed to evaluate uterine size, bleeding, and assess for
infection.
The most important questions to ask at the follow-up visit are:
Do you feel pregnant?
Did you see the expulsion of the gestational sac or fetus?
How much bleeding did you have?
Are you still bleeding?
These questions and a pelvic examination to determine uterine size are sufficient to detect most
women in need of further treatment for incomplete abortion (retained products of conception, no
or inconsistent uterine growth, and lack of cardiac activity on ultrasound) or ongoing pregnancy
(uterine growth consistent with the time elapsed between the first and follow-up visits and
cardiac activity on vaginal ultrasound).
If there is uncertainty about whether there is an incomplete abortion (retained products of
conception, no or inconsistent uterine growth, and lack of cardiac activity on ultrasound) or
ongoing pregnancy (uterine growth consistent with the time elapsed between the first and followup visits and cardiac activity on vaginal ultrasound), a vaginal ultrasound examination may be
necessary. Generally speaking, a serum hCG is only used when there is concern about nonuterine pregnancy and/or when ultrasound is not available.
While hCG concentration may remain elevated for weeks after complete abortion, a
measurement that falls to less than 20 percent of its pre-procedure value generally indicates
successful pregnancy termination [97]. Also, there is no consensus regarding the upper limit of
endometrial thickness associated with a successful medical abortion; therefore, it is not a good
diagnostic tool for determining whether further intervention may be required [98-102]. (See
"First-trimester medication abortion (termination of pregnancy)", section on 'Follow-up'.)

Contraceptive method can be started as soon as possible. (See "Overview of pregnancy


termination", section on 'Contraception'.)
OUTCOME In early pregnancy, some studies suggest that pregnancy termination efficacy
may be higher among women at six weeks and less [103,104] compared with those at six to
eight weeks [103,104]. This trend toward higher effectiveness with decreasing gestational age is
similar to the results seen in large trials of combined mifepristone-misoprostol.
Effectiveness (defined as complete abortion) of misoprostol alone for pregnancy termination is
as follows.
9 weeks (weeks of amenorrhea): 75 to 85 percent [61,77]
10 to 12 weeks: 80 to 85 percent [77]
13 weeks: 80 to 90 percent [89]
ADVERSE EFFECTS Misoprostol is a safe and well-tolerated medication [105].
Gastrointestinal symptoms (nausea, diarrhea) and fever are the most common adverse effects
of misoprostol. These are generally transient and self-limiting.
Gastrointestinal symptoms Diarrhea is the major adverse reaction that has been reported
consistently, but it is usually mild and self-limiting. Nausea and vomiting may also occur [105].
The majority of cases can be managed expectantly or with anti-emetic or anti-/diarrheal
medication.
These symptoms have been observed with all four routes of administration; severity may be
dose and interval dependent (ie, higher doses and shorter dosing intervals may lead to
increased symptoms) [61,77,103].
Fever Fever, even in the absence of infection is a common effect of misoprostol, reported in 5
to 88 percent of patients undergoing first trimester abortion [6,51,77]. There is one case report
of severe hyperthermia (41.9 C/107.4 F) in a woman who received misoprostol for postpartum
hemorrhage prophylaxis [106]. Fever associated with misoprostol should subside within 24

hours, and antipyretics may be given as needed. If fever persists beyond 24 hours, a women
should be evaluated for infection.
Concern has emerged in North America following the reports of six cases of Clostridiaassociated fatal toxic shock syndrome following use of mifepristone and misoprostol for early
pregnancy termination (five cases associated with sordellii and one with perfringens) [107-110].
An additional case (of perfringens) was recently reported in a woman who used laminaria and
misoprostol for second trimester termination. Although several hypotheses on the mechanism of
infection have been put forth, no consensus has been reached [111-113]. (See "First-trimester
medication abortion (termination of pregnancy)", section on 'Fever and infection'.)
Prevention of adverse effects Pretreatment with antipyretic and antidiarrheal medications
may slightly reduce the severity of gastrointestinal adverse effects [114]. In a randomized trial of
women undergoing pregnancy termination at 7 weeks, pretreatment with loperamide 4 mg and
acetaminophen 500 mg prior to misoprostol 800 mcg pv compared to no pretreatment led to a
significant reduction in incidence of diarrhea (23 versus 44 percent), but no difference in
vomiting or fever/chills.
COMPLICATIONS Complications specific to misoprostol-only pregnancy termination are
discussed below. As with any uterine evacuation procedure, bleeding or infection may occur.
(See "Overview of pregnancy termination", section on 'Complications'.)
Incomplete abortion
First trimester For women undergoing first trimester inductions, management of ongoing
pregnancy (cardiac activity on ultrasound) or incomplete abortion (sac or other evidence of
products of conception, but no gestational growth and no cardiac activity on ultrasound) are
generally different. We assess women at the follow-up visit (one to two weeks) and advise
surgery for all ongoing pregnancies. For incomplete abortion, we advise expectant management
or a second dose of misoprostol. For women who receive a second dose, we schedule a second
follow-up assessment at one to two weeks.

We generally don't give more than one additional dose. This is because the cumulative benefit
of additional doses is not established and requiring multiple follow-up visits increases the
chance of loss-to-follow-up.
Second trimester For women in second trimester, management of retained products of
conception (POCs) depends on the point in the process at which they are suspected or
diagnosed.
After fetal expulsion and before discharge from the hospital or clinic, clinicians should confirm
that the fetus and placenta have been completely expelled.
Many clinicians manage retained products of conception (POCs) with surgical evacuation.
Clinicians can choose either dilatation and curettage or manual vacuum aspiration, depending
on the clinical situation. (See "Surgical termination of pregnancy: First trimester" and "Overview
of second-trimester pregnancy termination".)
However, some clinicians treat retained POCs after a second trimester induction with an
additional dose or two of misoprostol. The efficacy of this practice has not been established in
the literature, but avoiding surgical intervention is always recommended, and there are no
known dangers of giving additional misoprostol doses after fetal expulsion.
It is rare for retained POCs to be detected only after discharge from the clinic, and there is no
standard approach. Management (expectant management, additional misoprostol, or surgery)
should be tailored to the patient's preferences and the clinical situation.
Uterine rupture Misoprostol, and other agents which stimulate uterine contractions (eg,
oxytocin, other prostaglandins), may increase risk of dehiscence of a prior uterine scar or uterine
rupture. (See 'Risk factors for uterine rupture' above.)
Preprocedure screening of patients for risk factors and close observation during treatment are
crucial to prevent or detect early signs of uterine rupture. In addition, the minimum cumulative
misoprostol dose should be used (ie, lowest dose, longest dosing interval, lowest number or
total doses).

Clinical manifestations of uterine rupture following medical termination of pregnancy are


variable. In women with known uterine scarring, uterine rupture should always be strongly
considered if severe and persistent abdominal pain and/or signs of intraabdominal hemorrhage
are present. Vaginal bleeding is not a cardinal symptom, as it may be modest, despite major
intraabdominal hemorrhage. Other clinical manifestations include hypotension ranging from
subtle to severe (hypovolemic shock), cessation of uterine contractions, and uterine tenderness.
Hematuria may occur if the rupture extends to the bladder. In a stable patient, ultrasound
examination may confirm the diagnosis [22,115]. (See "Choosing the route of delivery after
cesarean birth", section on 'Inappropriate candidates'.)
Rupture or dehiscence is managed with exploratory laparotomy, with either uterine repair or
hysterectomy. Conservative surgery also requires completion of the pregnancy termination.
Teratogenicity Questions regarding the teratogenicity of misoprostol may arise in cases
where complete abortion is not achieved after one or more doses and a woman does not followup or chooses to continue a pregnancy. The teratogenic risk of misoprostol appears to be low
and generally limited to first trimester exposure, according to a review of case reports [116].
Despite the low risk, women who do not abort after induction with misoprostol should be
counseled about the risk of fetal malformation.
The mechanism for misoprostol-associated fetal malformations appears to be vascular
disruption, possibly due to alteration of fetal blood flow due to uterine contractions [89,116-119].
MISOPROSTOL-ALONE COMPARED TO OTHER REGIMENS
Misoprostol versus other prostaglandins Compared with other prostaglandins,
misoprostol has less adverse effects, is orally active, temperature stable, less expensive, and
widely available, including: PGE2 (dinoprostone) and PGF2alpha (carboprost) [120].
In a systematic review of randomized trials in women undergoing pregnancy termination in the
second or third trimester, vaginal misoprostol compared with gemeprost (another PGE1) was

associated with reduced narcotic analgesia (RR 0.64, 95% CI 0.49-0.84) and surgical
evacuation of the uterus (RR 0.71, 95% CI 0.53-0.95) [121].
Misoprostol versus mifepristone/misoprostol A combined regimen of mifepristone and
misoprostol is more effective than misoprostol-alone in a randomized trial [92]; the misoprostolonly regimen would be of use in those settings where mifepristone is not available.
In addition, compared with combined therapy, women who administer misoprostol-alone may
experience more fever and chills (probably due to higher and repeated doses), whereas women
administered the combined therapy may experience more nausea and vomiting [104].
Pretreatment with mifepristone may also reduce the pain associated with the procedure.
Misoprostol versus methotrexate/misoprostol Choice of misoprostol-alone and combined
methotrexate/misoprostol is controversial [3]. Data from randomized trials regarding the
comparative efficacy of the two regimens are variable. Data from a large retrospective series
reported that use of methotrexate with misoprostol was more effective than misoprostol-alone
[2]. However, methotrexate is not widely available and is more cumbersome to use than
mifepristone and misoprostol and misoprostol alone. Also, it can only be used safely through 7
weeks of gestation.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
The Basics and Beyond the Basics. The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written at
the 10th to 12th grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on patient info and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Abortion (pregnancy termination)
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Pretreatment considerations
In women seeking pregnancy termination at nine or less weeks of gestation, we
recommend mifepristone with misoprostol versus misoprostol alone (Grade 1A).
However, in settings where other medications are not accessible, use of misoprostolalone for early pregnancy termination is an appropriate and effective choice. (See
'Misoprostol-alone compared to other regimens' above.)
Misoprostol is commonly used as a single agent for second trimester induced abortion
in the United States and many other parts of the world. (See 'Introduction' above.)
In women undergoing pregnancy termination at 14 or more weeks, we recommend
misoprostol over gemeprost (Grade 1A). (See 'Misoprostol versus other prostaglandins'
above.)
In women undergoing second trimester pregnancy termination who are at high risk of
uterine rupture (more than one hysterotomy, a prior classical or T-shaped uterine
incision, or extensive transfundal uterine surgery [eg, myomectomy]), we suggest against
using misoprostol (Grade 2B). Misoprostol induction for pregnancy termination appears
to be safe in women with one prior low transverse hysterotomy. Rupture is rarely
associated with misoprostol use in first trimester. (See 'Risk factors for uterine rupture'
above and "Choosing the route of delivery after cesarean birth", section on 'Inappropriate
candidates'.)
Clinical protocol
In women undergoing pregnancy termination with misoprostol-alone, we suggest
sublingual, rather than vaginal or oral, misoprostol dosing (Grade 2B). Buccal dosing
may be a reasonable alternative to sublingual. Sublingual and vaginal administration

appear to be comparable in effectiveness and safety in randomized trials. Vaginal


administration is more effective than oral, however, equivalent safety has not been
confirmed. (See 'Route of administration' above.)
For women at nine or less weeks, misoprostol can be administered at home or in a
clinic setting. At 10 or more weeks, we conduct misoprostol treatment and monitoring in
a clinic. (See 'Clinical regimen' above.)
The potency of the effect of misoprostol varies with gestational age, as well as with
route of administration, dose, dosing interval, and cumulative dose. Clinical protocols
vary by gestational age (see 'Data on drug administration' above and 'Clinical regimen'
above) (table 2).
Gastrointestinal symptoms (nausea, vomiting, diarrhea) and fever are the most
common adverse effects of misoprostol. These are generally transient and self-limiting. It
is reasonable to give prophylactic anti-diarrheal medication to decrease the incidence of
diarrhea; pretreatment does not appear to decrease other side effects. (See 'Adverse
effects' above.)
Posttreatment issues
Women should be educated about how to recognize complications (eg, fever,
abdominal pain, or prolonged or excessive bleeding). (See 'Follow-up' above.)
Incomplete abortion or continuing pregnancy are the most common complications of
medical abortion. This can be managed expectantly, medically, or surgically. (See
'Complications' above.)
Uterine rupture should be suspected in a woman with severe or persistent abdominal
pain and signs of intraabdominal bleeding. Prompt laparotomy is indicated in patients
with a presumptive diagnosis of uterine rupture. (See 'Complications' above.)
ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Wesley
Clark, MD, MPH, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 5434 Version 13.0

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