Vous êtes sur la page 1sur 10

7. RIOG0055_09-14.

qxd 9/14/09 8:57 PM Page 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 E1 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

M
isoprostol is a synthetic prostaglandin E1 analogue 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.1 Although misoprostol is not approved by the US Food

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 159


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 160

Misoprostol Use in Obstetrics and Gynecology continued

and Drug Administration (FDA) for misoprostol through the vaginal ep- administration.11 The buccal route has
these indications, in 2002, pregnancy ithelium among different women.3 a pattern of absorption similar to the
was removed from the label as an ab- There is no clinically significant dif- vaginal route, but produces lower
solute contraindication to misoprostol ference between vaginal misoprostol serum levels overall. Nonetheless, the
use.2 Misoprostol’s advantages over that is administered dry and vaginal buccal and vaginal routes of adminis-
other synthetic prostaglandin ana- misoprostol moistened with water, tration have similar effects on uterine
logues are its low cost, long shelf life, saline, or acetic acid.7-9 tone and activity.12 The buccal route
lack of need for refrigeration, and The rectal route of administration of administration is also thought to be
worldwide availability (Figure 1).3 shows a similar pattern to vaginal the least variable in terms of drug
administration, but has a lower AUC, exposure and peak levels. The admin-
Pharmacokinetics including a significantly lower maxi- istration of NSAIDs for pain relief
Routes of misoprostol administration mum peak concentration.6 The sublin- does not alter the efficacy of miso-
include oral, vaginal, sublingual, buc- gual route of administration has an prostol.13,14 There are no known drug
cal, or rectal. Pharmacokinetics stud- AUC similar to vaginal administra- interactions with misoprostol.1
ies (Figure 2) comparing oral and tion, but more rapid absorption and
vaginal administration have shown higher peak levels than either vaginal Teratogenicity
that vaginal misoprostol is associated or oral administration (Figure 2).7 This Misoprostol is considered a teratogen.
with slower absorption, lower peak translates into higher rates of gas- Congenital defects following prenatal
plasma levels, and slower clearance, trointestinal side effects. Nevertheless, exposure in early pregnancy to miso-
similar to an extended-release prepa- the sublingual route also causes uter- prostol include skull defects, bladder
ration.4-6 Vaginal misoprostol is also ine contractions at a rate equivalent exstrophy, arthrogryposis, cranial
associated with a greater overall ex- to vaginal administration and has less nerve palsies, facial malformations,
posure to the drug (area under the variation in absorption.10 The buccal terminal transverse limb defects, and
curve [AUC]) and greater effects on the route of administration shows a lower Moebius sequence.1,15,16 This constel-
cervix and uterus.5 There is, however, AUC, a lower peak concentration, and lation of congenital malformations
a wide variation in the absorption of fewer side effects than sublingual is thought to be due to a vascular

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.

Approved
Not
approved
Also approved for an
obstetrics-gynecology
indication

160 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 161

Misoprostol Use in Obstetrics and Gynecology

Candidates for medication abortion


800 must be able to adhere to the treat-
Sublingual ment regimen as well as have access
Oral to a telephone and transportation to a
Vaginal medical facility in case of emergency.
600
Plasma Misoprostol Acid

Vaginal  Water
Concentration (pg/mL)

Multiple gestation is not a contraindi-


cation to medication abortion pro-
vided that the pregnancy is no more
400
than 49 to 63 days, depending on the
regimen being used.22 Contraindica-
tions to mifepristone medication
200 abortion include hemorrhagic disor-
der; concurrent anticoagulant ther-
apy; inherited porphyrias; chronic
0
adrenal failure; concurrent long-term
systemic corticosteroid use; con-
0 100 200 300 400
firmed or suspected ectopic or molar
Time (min)
pregnancy; allergy to mifepristone,
Figure 2. Mean plasma concentrations of misoprostol acid over time (arrow bars  1 SD). Reprinted from Tang misoprostol, or other prostaglandin;
OS et al, “Pharmacokinetics of different routes of administration of misoprostol,” Hum Reprod. 2002;17:332-336. and unwillingness to undergo a vac-
Copyright © 2002 with permission from Oxford University Press.7
uum aspiration if needed.26 If the
woman has an intrauterine device in
disruption secondary to uterine con- mifepristone, a progesterone antago- place, it must be removed before
tractions caused by misoprostol. The nist, with 400 g of oral misoprostol treatment. Women with serious sys-
incidence of these abnormalities does 48 hours later for pregnancies up to temic illnesses (eg, severe cardiac,
not appear to be high when popula- 49 days of gestation.21 However, there renal, or liver disease or severe ane-
tion registries have been studied, es- is excellent evidence of efficacy up to mia) should be evaluated individually
pecially given that exposure to miso- 63 days of gestation using the regi- to determine which method of abor-
prostol is quite common among some mens of 200 mg of mifepristone orally tion is safest. Rhesus (Rh)-negative
women typically receive Rh immune
globulin on the day of mifepristone
The absolute risk of congenital malformations after prenatal exposure to
administration.22
misoprostol is estimated to be approximately 1%. Medication abortion necessarily in-
volves heavy bleeding and cramping
populations of patients.17,18 The ab- followed by home administration of as the pregnancy is expelled. Other
solute risk of congenital malforma- either 800 g of buccal misoprostol in transient side effects from misopros-
tions after prenatal exposure to 24 to 36 hours or 800 g of vaginal tol include nausea, vomiting, diar-
misoprostol is estimated to be ap- misoprostol in 6 to 48 hours.22,23 rhea, fever, and chills.21 At the follow-
proximately 1%. Women then return 4 to 14 days later up visit, ongoing pregnancies are
Pharmacokinetic studies reveal that for a clinical evaluation to document most commonly treated with suction
misoprostol is excreted into breast complete abortion. Success rates for curettage because of the risk of con-
milk with drug levels that rise and fall these regimens range from 95% to genital anomalies. Women with per-
very quickly. Levels become unde- 98%, with failure due to ongoing sistent nonviable pregnancies may
tectable within 5 hours of maternal pregnancy in approximately 1%.21 In opt for expectant management, a re-
ingestion.19 However, breastfeeding the United States, most women un- peat dose of misoprostol, or suction
women should be advised that miso- dergo ultrasound for pregnancy dat- curettage.27 Mifepristone medication
prostol may cause infant diarrhea.20 ing and confirmation of complete abortion is safe with an estimated
abortion. However, serial serum complication rate of 2.2 per 1000
Medication Abortion -human chorionic gonadotropin women.28 The most frequent compli-
In 2000, the FDA approved medica- (hCG) levels can also be used to con- cations are heavy bleeding requiring
tion abortion using 600 mg of oral firm complete abortion.24,25 curettage and/or transfusion and

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 161


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 162

Misoprostol Use in Obstetrics and Gynecology continued

infection. The estimated mortality surgical abortion.36 Studies have unable to undergo surgical abortion
rate for mifepristone abortion is 1 per shown that the optimal dose in terms as planned, she is at some risk for ex-
100,000 women, most commonly due of balancing effectiveness and side pelling the pregnancy. Therefore, be-
to fatal sepsis.28 Where mifepristone is effects is 400 g.37 There are data eval- fore receiving misoprostol, all women
not available, medication abortion uating oral, vaginal, and sublingual should give informed consent for the
can be accomplished with methotrex- routes of administration. Effective abortion procedure and be adequately
ate and misoprostol or misoprostol regimens are 400 g of misoprostol screened by appropriately trained
alone.29 vaginally 3 to 4 hours, 400 g orally personnel.
8 to 12 hours, or 400 g sublingually
Cervical Ripening 2 to 4 hours prior to suction curet- Second Trimester
Before Surgical Abortion tage.35 Compared with the oral route, Cervical preparation prior to second-
First Trimester vaginal administration is equally or trimester surgical abortion (dilation
First-trimester surgical abortion is a more effective and is associated with and evacuation, D&E) is critical to
common, safe procedure with a major fewer side effects.36,38,39 The sublin- prevent complications from forceful
complication rate of less than 1%.30 gual route is more effective than oral, dilation of the cervix.33,34 Providers
Risk factors for major complications
in the first trimester, such as cervical
Cervical preparation prior to second-trimester surgical abortion is critical to
laceration and uterine perforation, are
provider inexperience, patient age prevent complications from forceful dilation of the cervix.
less than 18 years, and increasing
gestational age.31,32 Studies have equivalent to or better than vaginal have traditionally used osmotic dila-
shown that the use of laminaria for administration, but is associated with tors such as laminaria to slowly dilate
cervical ripening reduces the risk of more side effects than either oral or the cervix over several hours to days
cervical laceration and, to a lesser vaginal administration.40 Although before the procedure.44 Although
extent, uterine perforation.33,34 Al- not yet studied for first-trimester sur- there are fewer studies than in the
though pharmacologic priming gical abortion, buccal administration first trimester, misoprostol has been
agents, such as misoprostol, may po- is widely used. Buccal misoprostol of- evaluated in the second trimester as a
tentially have the same effects, no fers the effectiveness and decreased substitute for laminaria and as an ad-
published studies to date have been side effects of vaginal administration junct to laminaria. The regimens
large enough to assess these out- combined with high acceptability for studied for second-trimester D&E
comes. The risk of these injuries dur- both patient and staff. These regimens vary widely and include 400 g of
ing first-trimester suction curettage is significantly increase baseline cervi- vaginal misoprostol for 3 to 4 hours,
very small, given an experienced cal dilatation and facilitate further 400 g and 600 g of buccal miso-
prostol for at least 90 minutes, 600
The Society of Family Planning recommends that providers consider cervi- g of buccal misoprostol for 2 to 4
hours, and 800 g of buccal miso-
cal ripening for women late in the first trimester (12-14 weeks of gesta-
prostol for at least 20 minutes but not
tions), adolescents, and for women in whom cervical dilation is expected to more than 90 minutes preopera-
be difficult either due to patient factors or provider inexperience. tively.45-48 As a substitute for lami-
naria, misoprostol does not achieve
provider. Nevertheless, the Society of mechanical dilation compared with the same degree of preoperative
Family Planning recommends that placebo.41 Some studies have also re- cervical dilation and frequently
providers consider cervical ripening ported decreased procedure time and additional mechanical dilation is
for women late in the first trimester estimated blood loss. These differ- required.47 Although this additional
(12-14 weeks of gestation), adoles- ences are statistically, but not clini- mechanical dilation may be easily
cents, and for women in whom cervi- cally, significant.42,43 There is no clear achieved in most patients, especially
cal dilation is expected to be difficult evidence to date that misoprostol re- those under 16 weeks of gestation and
either due to patient factors or duces pain during the procedure com- multiparous women, there is a higher
provider inexperience.35 pared with placebo.35 It is important rate of difficult or inadequate dilation
Misoprostol is a proven cervical to note that if misoprostol is used for when using misoprostol instead of
ripening agent prior to first-trimester cervical ripening, and the woman is laminaria.46

162 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 163

Misoprostol Use in Obstetrics and Gynecology

The ideal dosing regimen for sec- biopsy, and intrauterine device (IUD) evaluating vaginal misoprostol for
ond-trimester procedures is unknown. insertion. Similar to cervical ripening shorter intervals, 4 to 6 hours preop-
In terms of safety, a review of more prior to surgical abortion, the aim of eratively, have not shown evidence of
than 6000 surgical abortions between misoprostol use in hysteroscopy is to an effect.58,59 Therefore, it may be that
12 and 16 weeks using 400 g of prevent complications of mechanical time to adequate cervical ripening is
vaginal or buccal misoprostol 90 min- dilation such as cervical laceration, different for pregnant and nonpreg-
utes preprocedure showed a uterine uterine perforation, and the creation nant women. For peri- and post-
perforation rate of 0.45 per 1000, of a false passage.50 One meta-analy- menopausal women and women
comparable to historical reports for sis of 10 studies concluded that miso- treated with gonadotropin-releasing
laminaria use.49 Cervical lacerations, prostol leads to greater preoperative hormone agonists, data are conflict-
however, were not reported. The
Society of Family Planning does not
The aim of misoprostol use in hysteroscopy is to prevent complications of
recommend the use of misoprostol as
an alternative to laminaria except by mechanical dilation such as cervical laceration, uterine perforation, and the
experienced clinicians in the early creation of a false passage.
second trimester (before 16 weeks) in
women at low risk for cervical or dilation, decreased need for addi- ing and most studies do not show a
uterine injury.44 tional dilation, and reduced rates of benefit from misoprostol.53,60-63 Miso-
Misoprostol use as an adjunct to cervical laceration in premenopausal prostol’s actions on the cervix may
laminaria has been evaluated in a women.51 The greatest benefits were require endogenous estrogen. It is not
randomized, controlled trial using seen in nulliparous women and with known if more intensive dosing regi-
400 g of misoprostol at least 90 operative hysteroscopy. However, mens would affect the post-
minutes preoperatively in 125 women women treated with misoprostol had menopausal cervix.51
between 13 and 20 6/7 weeks of ges- higher rates of transient vaginal Only a single study has evaluated
tation.48 Misoprostol improved preop- bleeding, cramping, and fever preop- misoprostol for endometrial biopsy.
erative dilation in women only at 19 eratively. There may also be potential This trial randomized a mixed popu-
weeks of gestation and above. How- concerns regarding loss of distension lation of 42 premenopausal, peri-
ever, if women needed subsequent from excessive cervical dilation menopausal, and postmenopausal
mechanical dilation after laminaria caused by misoprostol.52 More re- women to either 400 g of oral miso-
had been removed, misoprostol sig- search is needed to determine the prostol or placebo 3 hours prior to en-
nificantly improved the subjective ideal candidate for misoprostol use dometrial biopsy.64 This study found
ease of dilation in women at 16 weeks before hysteroscopy. no evidence of an effect on cervical
of gestation and above. Given this, The optimal dosing regimen for resistance, success rate for obtaining
the Society of Family Planning does cervical ripening before hysteroscopy the biopsy, and the ease of performing
not recommend routine use of miso- is unclear. In premenopausal women, the biopsy. However, the study was
prostol as an adjunct to laminaria studies have found either 200, 400, or underpowered for these endpoints.
under 16 weeks, but it may be con- 1000 g of vaginal misoprostol or The study did note significantly more
sidered at later gestational ages.44 In 400 g of oral misoprostol given at pain with the biopsy and uterine
general, misoprostol may be used for least 9 to 12 hours preoperatively to cramping in the misoprostol group.
cervical ripening prior to surgical abor- be superior to placebo.53-57 Most of Based on a single, small study, IUD
tion in women with prior cesarean these studies focused on nulliparous insertion in nulliparous women may
deliveries in the first and second women. There are few trials compar- be facilitated by misoprostol use. A
trimesters because uterine rupture ing routes of administration, doses, Swedish trial randomized 80 women
rarely occurs in this setting.44 and interval to procedure prior to to 400 g of sublingual misoprostol
hysteroscopy. One study that com- plus 100 mg of diclofenac or 100 mg
Cervical Ripening Before pared 400 g of oral and vaginal of diclofenac alone 1 hour before
Other Procedures misoprostol given 10 to 12 hours be- Nova-T IUD insertion.65 Although
Researchers have studied cervical fore operative hysteroscopy found baseline cervical dilation was similar
ripening prior to other gynecologic vaginal misoprostol to be superior in in both groups, providers rated the in-
procedures in nonpregnant women, baseline cervical dilation and time re- sertion procedure as “easy” in 74% of
including hysteroscopy, endometrial quired for cervical dilation.52 Trials the misoprostol group compared with

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 163


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 164

Misoprostol Use in Obstetrics and Gynecology continued

55% in the control group (P  .04). the woman is asymptomatic, there is the other 2 dosing schedules. Side ef-
However, the majority of the IUD in- no endometrial stripe thickness that fects of misoprostol noted in several
sertions were uncomplicated in both requires intervention.71 Compared studies include maternal fever, chills,
groups. There was no difference be- with surgical evacuation, there is no and gastrointestinal symptoms such
tween the groups in terms of pain significant difference in the rates of as nausea, vomiting, diarrhea, and
scores during IUD insertion or overall infection or hemorrhage.69 For incom- abdominal pain.1 Therefore, it makes
side effects. plete abortion, effective misoprostol sense to administer the lowest dose of
regimens include a single dose of 600 misoprostol that is most effective,
Medical Management of g orally, a single dose of 800 g thereby decreasing the side effects.
Miscarriage vaginally, or a single dose of 400 g Although the optimal dose for fetal
Misoprostol is an option for the med- sublingually.68,69 Depending on the death or termination of pregnancy in
ical management of early pregnancy study, success rates range from 66% the second trimester has not been
failure, including anembryonic preg- to 100% using these doses. established, a reasonable approach
nancies and embryonic demise, and may be to start with 400 g vaginally
incomplete abortion for women at 12 Induction of Labor in the every 6 hours for a 48-hour period.
weeks or less of gestation.66,67 Con- Second Trimester There is also evidence that the addi-
traindications include pelvic infection Misoprostol is an effective drug for tion of 200 mg of mifepristone to the
or sepsis, hemodynamic instability or labor induction in the second induction protocol decreases the
interval to delivery for termination of
pregnancy.77
Misoprostol is an option for the medical management of early pregnancy Induction of labor with misoprostol
failure, including anembryonic pregnancies and embryonic demise, and in- in the setting of a previous cesarean
complete abortion for women at 12 weeks or less of gestation. delivery scar, although contraindi-
cated in the third trimester, can be
safely performed in the second
shock, allergy to misoprostol, known trimester for fetal death or termina- trimester. The data on the absolute
bleeding disorder, concurrent antico- tion of pregnancy.67 The optimal dose, risk of induction of labor in this
agulant therapy, and confirmed or schedule, and route of administration setting are lacking. Many studies on
suspected ectopic or molar preg- have not been determined. Several second-trimester induction with
nancy.68 If the woman has an IUD in randomized, controlled trials exist ex- misoprostol have excluded patients
place, it must be removed before amining the different doses and with a previous cesarean delivery due
treatment. Similar to medication schedules.72-75 The doses used in these to the fear of uterine rupture. Impor-
abortion, cramping and bleeding will randomized trials range from 200 g tantly, however, several randomized
occur with pregnancy passage and to 800 g administered vaginally, and studies did include patients with a
side effects such as nausea, vomiting, the interval between dosing ranged previous cesarean delivery.73,74,78 No
diarrhea, fever, and chills may be ex- from every 3 to every 12 hours. No adverse effects occurred in these pa-
perienced.68 Studies have shown, conclusive evidence of superiority of tients. Furthermore, several retrospec-
however, that misoprostol is accept- one dose or schedule over another can tive studies have specifically ad-
able to most women for this indica- be clearly drawn from these studies. dressed the safety of misoprostol use
tion.69,70 An important study aimed at answer- for second-trimester induction in the
For early pregnancy failure, the ing the question of dose optimization case of a prior cesarean delivery. In
most commonly used regimen is a was performed by Dickinson and one of the largest retrospective stud-
single dose of 800 g of vaginal Evans,76 who administered vaginal ies on the subject, 188 women with a
misoprostol.68 The success rate is ap- misoprostol either 200 g every 6 previous cesarean delivery underwent
proximately 85% as long as at least 7 hours, 400 g every 6 hours, or a 600 induction of labor between 17 and 24
to 14 days is allowed for completion g loading dose followed by 200 g weeks of gestation.79 The dose of
of expulsion and a second dose of every 6 hours. Both the 400 g and misoprostol was 400 g orally to-
misoprostol is considered for initial 600/200 g regimens were superior to gether with 400 g vaginally for the
failures.69 Ultrasound is typically used the 200 g regimen in terms of me- first dose followed by 400 g vagi-
to confirm complete abortion. As long dian time to delivery. The 600/200 g nally every 6 hours for a maximum of
as the gestational sac is absent and regimen caused more side effects than 5 doses. The main outcomes included

164 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 165

Misoprostol Use in Obstetrics and Gynecology

hemorrhage requiring transfusion, incomplete abortion, blood loss, or status 20 minutes before administra-
postabortal infection, retained pla- sepsis. tion and continued for 4 hours after
centa, and uterine rupture. There was each dose.
no evidence that a previous cesarean Cervical Ripening and Induction Misoprostol has also been shown to
delivery affected the incidence of of Labor With a Viable Fetus be effective for induction of labor
complications. Similar results were Compared with placebo, misoprostol with a viable fetus.86,87 The Cochrane
found in another study of 80 women causes cervical ripening before induc- Pregnancy and Childbirth Group re-
undergoing termination of pregnancy tion with oxytocin.81,82 When used for viewed randomized trials comparing
between 13 and 26 weeks of gestation
for a variety of reasons with 1 or
Misoprostol has also been shown to be effective for induction of labor with
more cesarean section scars.80 Miso-
prostol, 400 g, was administered to a viable fetus.
women up to 20 weeks of gestation
and 200 g for women greater than cervical ripening, misoprostol can be vaginal misoprostol with placebo,
20 weeks of gestation, vaginally or administered orally, sublingually, or oxytocin, or prostaglandin E2 for cer-
sublingually, every 6 hours up to 24 vaginally, although there is more evi- vical ripening or induction of a viable
hours. The mean induction to abor- dence for vaginal regimens.83,84 A fetus in the third trimester.85 Primary
tion interval was 16.4 hours and was commonly used dose is 25 g admin- outcomes included rate of vaginal de-
not statistically different between istered vaginally every 4 hours as livery within 24 hours, incidence of
women with and without a prior needed, with a maximum dose of 150 uterine hyperstimulation with associ-
cesarean delivery scar. There was no g.85 Doses are withheld if contrac- ated fetal heart rate changes, rate of
case of uterine rupture or scar dehis- tions are more frequent than every 4 cesarean delivery, and risk of serious
cence. No statistically significant minutes. Electronic fetal heart rate adverse event in mother or fetus.
differences were found in rates of monitoring is used to evaluate fetal Vaginal misoprostol was found to be

Main Points
• Misoprostol is a prostaglandin E1 analogue 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.

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 165


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 166

Misoprostol Use in Obstetrics and Gynecology continued

more effective than prostaglandin E2 the treatment of postpartum hem- 9. Creinin MD, Carbonell JL, Schwartz JL, et al. A
randomized trial of the effect of moistening
or oxytocin for inducing vaginal de- orrhage.93 However, it remains an misoprostol before vaginal administration when
livery within 24 hours. However, uter- important option for treating postpar- used with methotrexate for abortion. Contracep-
ine stimulation with associated fetal tum hemorrhage when other agents tion. 1999;59:11-16.
10. Aronsson A, Bygdeman M, Gemzell-Danielsson
heart rate changes was more common are not available or fail. A descriptive K. Effects of misoprostol on uterine contractility
in the group of women receiving study showed that 1000 g of rectally following different routes of administration.
misoprostol than in women receiving administered misoprostol, when given Hum Reprod. 2004;19:81-84.
11. Schaff EA, DiCenzo R, Fielding SL. Comparison
either oxytocin or prostaglandin E2. to patients who failed to respond to of misoprostol plasma concentrations following
Cesarean delivery rate data were con- oxytocin and ergotamine, controlled buccal and sublingual administration. Contra-
flicting with a trend toward decreased postpartum hemorrhage within 3 ception. 2005;71:22-25.
12. Meckstroth KR, Whitaker AK, Bertisch S, et al.
cesareans for failure to progress in minutes.94 However, further studies, Misoprostol administered by epithelial routes:
labor and increased cesarean deliver- with randomized designs, are needed. drug absorption and uterine response. Obstet
ies for fetal distress in the misoprostol Gynecol. 2006;108:582-590.
13. Fiala C, Swahn ML, Stephansson O, Gemzell-
group. There was no difference in se- Conclusions Danielsson K. The effect of non-steroidal anti-
rious neonatal or maternal mortality Misoprostol has many applications in inflammatory drugs on medical abortion with
between women receiving misopros- the practice of obstetrics and gyne- mifepristone and misoprostol at 13-22 weeks
gestation. Hum Reprod. 2005;20:3072-3077.
tol and women who received cology. Off-label use of approved 14. Li CF, Wong CY, Chan CP, Ho PC. A study of
prostaglandin E2 or oxytocin; how- medications is supported by the FDA co-treatment of nonsteroidal anti-inflammatory
ever, most studies were underpowered as long as it is based on sound med- drugs (NSAIDs) with misoprostol for cervical prim-
ing before suction termination of first trimester
for this assessment. Optimal dosing of ical evidence. Researchers and pregnancy. Contraception. 2003;67:101-105.
misoprostol that will achieve effective providers must continue to work to 15. Orioli IM, Castilla EE. Epidemiological assess-
induction without uterine hyperstim- further refine the indications for ment of misoprostol teratogenicity. BJOG. 2000;
107:519-523.
ulation and resultant fetal heart rate misoprostol in many areas. However, 16. Yedlinsky NT, Morgan FC, Whitecar PW. Anom-
changes has been the topic of many several indications are already sup- alies associated with failed methotrexate and
studies. As with cervical ripening, an ported by high-quality evidence. misoprostol termination. Obstet Gynecol. 2005;
105:1203-1205.
effective dose of misoprostol without Given its low cost and ease of use, 17. Tang OS, Gemzell-Danielsson K, Ho PC. Miso-
high rates of uterine hyperstimulation misoprostol has the potential to im- prostol: pharmacokinetic profiles, effects on the
is 25 g administered every 4 to 6 prove women’s health worldwide. uterus and side-effects. Int J Gynaecol Obstet.
2007;99(suppl 2):S160-S167.
hours.1,85 18. Pastuszak AL, Schüler L, Speck-Martins CE, et al.
References Use of misoprostol during pregnancy and
Postpartum Hemorrhage 1. Goldberg AB, Greenberg MB, Darney PD. Möbius’ syndrome in infants. N Engl J Med.
Misoprostol and pregnancy. N Engl J Med. 2001; 1998;338:1881-1885.
Misoprostol has been used both as 344:38-47. 19. Vogel D, Burkhardt T, Rentsch K, et al. Miso-
prevention and treatment of postpar- 2. ACOG Committee Opinion. Number 283, May prostol versus methylergometrine: pharmacoki-
tum hemorrhage secondary to its 2003. New U.S. Food and Drug Administration netics in human milk. Am J Obstet Gynecol.
labeling on Cytotec (misoprostol) use and preg- 2004;191:2168-2173.
uterotonic properties. Several ran- nancy. Obstet Gynecol. 2003;101:1049-1050. 20. Hale TW. Medications and Mothers’ Milk. 11th
domized, controlled trials88-90 and a 3. Tang OS, Ho PC. The pharmacokinetics and ed. Amarillo, TX: Pharmasoft Publishing; 2004.
large, prospective, observational different regimens of misoprostol in early first- 21. Fiala C, Gemzel-Danielsson K. Review of medical
trimester medical abortion. Contraception. 2006; abortion using mifepristone in combination with
study91 have examined the use of 74:26-30. a prostaglandin analogue. Contraception.
misoprostol as an agent for the pre- 4. Zieman M, Fong SK, Benowitz NL, et al. Absorp- 2006;74:66-86.
vention of postpartum hemorrhage. tion kinetics of misoprostol with oral or vaginal 22. National Abortion Federation (NAF). NAF
administration. Obstet Gynecol. 1997;90:88-92. Protocol for Mifepristone/Misoprostol in Early
There are insufficient data to support 5. Danielsson KG, Marions L, Rodriguez A, et al. Abortion. Washington, DC: National Abortion
the use of misoprostol as a primary Comparison between oral and vaginal adminis- Federation; 2008. http://www.prochoice.org/pubs_
preventive measure for postpartum tration of misoprostol on uterine contractility. research/publications/downloads/professional_
Obstet Gynecol. 1999;93:275-280. education/medical_abortion/protocol_mife_miso
hemorrhage when conventional in- 6. Khan RU, El-Refaey H, Sharma S, et al. Oral, rec- .pdf. Accessed January 15, 2009.
jectable uterotonics (such as oxytocin tal, and vaginal pharmacokinetics of misopros- 23. Winikoff B, Dzuba IG, Creinin MD, et al. Two
and/or methylergotomine) are avail- tol. Obstet Gynecol. 2004;103:866-870. distinct oral routes of misoprostol in mifepris-
7. Tang OS, Schweer H, Seyberth HW, et al. Phar- tone medical abortion: a randomized controlled
able as part of the management of the macokinetics of different routes of administration trial. Obstet Gynecol. 2008;112:1303-1310.
third stage of labor.1,92 Misoprostol of misoprostol. Hum Reprod. 2002;17:332-336. 24. Paul M, Schaff E, Nichols M. The roles of clini-
has also not yet been found to be bet- 8. Singh K, Fong YF, Prasad RN, Dong F. Does an cal assessment, human chorionic gonadotropin
acidic medium enhance the efficacy of vaginal assays, and ultrasonography in medical abortion
ter than oxytocin or ergotamine in misoprostol for pre-abortion cervical priming? practice. Am J Obstet Gynecol. 2000;183(2
well-controlled, randomized trials for Hum Reprod. 1999;14:1635-1637. suppl):S34-S43.

166 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 167

Misoprostol Use in Obstetrics and Gynecology

25. Walker K, Schaff E, Fielding S, Fuller L. Moni- 43. Ngai SW, Tang OS, Lao T, et al. Oral misoprostol 59. Fernandez H, Alby JD, Tournoux C, et al. Vagi-
toring serum chorionic gonadotropin levels after versus placebo for cervical dilatation before vac- nal misoprostol for cervical ripening before op-
mifepristone abortion. Contraception. 2001;64: uum aspiration in first trimester pregnancy. Hum erative hysteroscopy in pre-menopausal women:
271-273. Reprod. 1995;10:1220-1222. a double-blind, placebo-controlled trial with
26. Davey A. Mifepristone and prostaglandin for 44. Fox MC, Hayes JL; Society of Family Planning. three dose regimens. Hum Reprod. 2004;19:
termination of pregnancy: contraindications for Cervical preparation for second-trimester surgi- 1618-1621.
use, reasons and rationale. Contraception. 2006; cal abortion prior to 20 weeks of gestation. Con- 60. Barcaite E, Bartusevicius A, Railaite DR, Nadis-
74:16-20. traception. 2007;76:486-495. auskiene R. Vaginal misoprostol for cervical
27. Kruse B, Poppema S, Creinin MD, Paul M. Man- 45. Todd CS, Soler M, Castleman L, et al. Buccal priming before hysteroscopy in perimenopausal
agement of side effects and complications in misoprostol as cervical preparation for second and postmenopausal women. Int J Gynaecol Ob-
medical abortion. Am J Obstet Gynecol. trimester pregnancy termination. Contraception. stet. 2005;91:141-145.
2000;183(2 suppl):S65-S75. 2002;65:415-418. 61. Fung TM, Lam MH, Wong SF, Ho LC. A ran-
28. Henderson JT, Hwang AC, Harper CC, Stewart 46. Patel A, Talmont E, Morfesis J, et al. Adequacy domised placebo-controlled trial of vaginal
FH. Safety of mifepristone abortions in clinical and safety of buccal misoprostol for cervical misoprostol for cervical priming before hys-
use. Contraception. 2005;72:175-178. preparation prior to termination of second- teroscopy in postmenopausal women. BJOG.
29. Moreno-Ruiz NL, Borgatta L, Yanow S, et al. Al- trimester pregnancy. Contraception. 2006;73: 2002;109:561-565.
ternatives to mifepristone for early medical abor- 420-430. 62. Ngai SW, Chan YM, Ho PC. The use of misopros-
tion. Int J Gynaecol Obstet. 2007;96:212-218. 47. Goldberg AB, Drey EA, Whitaker AK, et al. Miso- tol prior to hysteroscopy in postmenopausal
30. Bartlett LA, Berg CJ, Shulman HB, et al. Risk fac- prostol compared with laminaria before early women. Hum Reprod. 2001;16:1486-1488.
tors for legal induced abortion-related mortality second-trimester surgical abortion: a random- 63. Thomas JA, Leyland N, Durand N, Windrim RC.
in the United States. Obstet Gynecol. 2004;103: ized trial. Obstet Gynecol. 2005;106:234-241. The use of oral misoprostol as a cervical ripen-
729-737. 48. Edelman AB, Buckmaster JG, Goetsch MF, et al. ing agent in operative hysteroscopy: a double-
31. Royal College of General Practitioners, Royal Cervical preparation using laminaria with ad- blind, placebo-controlled trial. Am J Obstet Gy-
College of Obstetricians and Gynaecologists. In- junctive buccal misoprostol before second- necol. 2002;186:876-879.
duced abortion operations and their early seque- trimester dilation and evacuation procedures: a 64. Perrone JF, Caldito G, Mailhes JB, et al. Oral
lae. J R Coll Gen Pract. 1985;35:175-180. randomized clinical trial. Am J Obstet Gynecol. misoprostol before office endometrial biopsy.
32. Cates W Jr, Schulz KF, Grimes DA. The risks as- 2006;194:425-430. Obstet Gynecol. 2002;99:439-444.
sociated with teenage abortion. N Engl J Med. 49. Nucatola D, Roth N, Saulsberry V, Gatter M. Se- 65. Sääv I, Aronsson A, Marions L, et al. Cervical
1983;309:621-624. rious adverse events associated with the use of priming with sublingual misoprostol prior to in-
33. Grimes DA, Schulz KF, Cates WJ Jr. Prevention misoprostol alone for cervical preparation prior sertion of an intrauterine device in nulliparous
of uterine perforation during curettage abortion. to early second trimester surgical abortion (12- women: a randomized controlled trial. Hum Re-
JAMA. 1984;251:2108-2111. 16 weeks). Contraception. 2008;78:245-248. prod. 2007;22:2647-2652.
34. Schulz KF, Grimes DA, Cates W Jr. Measures to 50. Bradley LD. Complications in hysteroscopy: pre- 66. Chen BA, Creinin MD. Contemporary manage-
prevent cervical injury during suction curettage vention, treatment and legal risk. Curr Opin Ob- ment of early pregnancy failure. Clin Obstet
abortion. Lancet. 1983;1:1182-1185. stet Gynecol. 2002;14:409-415. Gynecol. 2007;50:67-88.
35. Allen RH, Goldberg AB; Board of Society of 51. Crane JM, Healey S. Use of misoprostol before 67. Neilson JP, Hickey M, Vazquez J. Medical treat-
Family Planning. Cervical dilation before first- hysteroscopy: a systematic review. J Obstet Gy- ment for early fetal death (less than 24 weeks).
trimester surgical abortion (<14 weeks’ gesta- naecol Can. 2006;28:373-379. Cochrane Database Syst Rev. 2006;3:CD002253.
tion). SFP Guideline 20071. Contraception. 52. Batukan C, Ozgun MT, Ozcelik B, et al. Cervical 68. Consensus Statement. Instructions for Use—
2007;76:139-156. ripening before operative hysteroscopy in pre- Misoprostol for the Treatment of Incomplete
36. Blanchard K, Clark S, Winikoff B, et al. Miso- menopausal women: a randomized, double-blind, Abortion and Miscarriage. Expert Meeting on
prostol for women’s health: a review. Obstet placebo-controlled comparison of vaginal and Misoprostol, June 9, 2004. New York: Reproduc-
Gynecol. 2002;99:316-332. oral misoprostol. Fertil Steril. 2008;89:966-973. tive Health Technologies Project and Gynuity
37. Singh K, Fong YF. Preparation of the cervix for 53. Oppegaard KS, Nesheim BI, Istre O, Qvigstad E. Health Projects; 2008.
surgical termination of pregnancy in the first Comparison of self-administered vaginal miso- 69. Zhang J, Gilles JM, Barnhart K, et al; National
trimester. Hum Reprod Update. 2000;6:442-448. prostol versus placebo for cervical ripening prior Institute of Child Health Human Development
38. Carbonell JL, Velazco A, Rodriguez Y, et al. Oral to operative hysteroscopy using a sequential trial (NICHD) Management of Early Pregnancy Fail-
versus vaginal misoprostol for cervical priming design. BJOG. 2008;115:663, e1-e9. ure Trial. A comparison of medical management
in first-trimester abortion: a randomized trial. 54. Preutthipan S, Herabutya Y. A randomized con- with misoprostol and surgical management for
Eur J Contracept Reprod Health Care. 2001;6: trolled trial of vaginal misoprostol for cervical early pregnancy failure. N Engl J Med. 2005;
134-140. priming before hysteroscopy. Obstet Gynecol. 353:761-769.
39. MacIsaac L, Grossman D, Balistreri E, Darney P. 1999;94:427-430. 70. Lee DT, Cheung LP, Haines CJ, et al. A compari-
A randomized controlled trial of laminaria, oral 55. Preutthipan S, Herabutya Y. Vaginal misoprostol son of the psychologic impact and client satis-
misoprostol, and vaginal misoprostol before for cervical priming before operative hys- faction of surgical treatment with medical treat-
abortion. Obstet Gynecol. 1999;93:766-770. teroscopy: a randomized controlled trial. Obstet ment of spontaneous abortion: a randomized
40. Hamoda H, Ashok PW, Flett GM, Templeton A. A Gynecol. 2000;96:890-894. controlled trial. Am J Obstet Gynecol. 2001;
randomized controlled comparison of sublingual 56. Ngai SW, Chan YM, Liu KL, Ho PC. Oral miso- 185:953-958.
and vaginal administration of misoprostol for prostol for cervical priming in non-pregnant 71. Reeves MF, Lohr PA, Harwood BJ, Creinin MD.
cervical priming before first-trimester surgical women. Hum Reprod. 1997;12:2373-2375. Ultrasonographic endometrial thickness after
abortion. Am J Obstet Gynecol. 2004;190:55-59. 57. Waddell G, Desindes S, Takser L, et al. Cervical medical and surgical management of early preg-
41. Fiala C, Gemzell-Danielsson K, Tang OS, von ripening using vaginal misoprostol before hys- nancy failure. Obstet Gynecol. 2008;111:106-112.
Hertzen H. Cervical priming with misoprostol teroscopy: a double-blind randomized trial. J 72. Carbonell JL, Torres MA, Reyes R, et al. Second-
prior to transcervical procedures. Int J Gynaecol Minim Invasive Gynecol. 2008;15:739-744. trimester pregnancy termination with 600-mi-
Obstet. 2007;99(suppl 2):S168-S171. 58. Singh N, Ghosh B, Naha M, Mittal S. Vaginal crog vs. 400-microg vaginal misoprostol and
42. Saxena P, Salhan S, Sarda N. Role of sublingual misoprostol for cervical priming prior to diag- systematic curettage postexpulsion: a random-
misoprostol for cervical ripening prior to vac- nostic hysteroscopy–efficacy, safety and patient ized trial. Contraception. 2008;77:50-55.
uum aspiration in first trimester interruption of satisfaction: a randomized controlled trial. Arch 73. Wong KS, Ngai CS, Yeo EL, et al. A comparison
pregnancy. Contraception. 2003;67:213-217. Gynecol Obstet. 2009;279:37-40. of two regimens of intravaginal misoprostol for

VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY 167


7. RIOG0055_09-14.qxd 9/14/09 8:57 PM Page 168

Misoprostol Use in Obstetrics and Gynecology continued

termination of second trimester pregnancy: a termination in women with prior caesarean sec- 88. Bamigboye AA, Hofmeyr GJ, Merrell DA. Rectal
randomized comparative trial. Hum Reprod. tion. BJOG. 2005;112:97-99. misoprostol in the prevention of postpartum he-
2000;15:709-712. 80. Bhattacharjee N, Ganguly RP, Saha SP. Miso- morrhage: a placebo-controlled trial. Am J Ob-
74. Herabutya Y, Chanrachakul B, Punyavachira P. A prostol for termination of mid-trimester post- stet Gynecol. 1998;179:1043-1046.
randomised controlled trial of 6 and 12 hourly Caesarean pregnancy. Aust N Z J Obstet 89. Hofmeyr GJ, Nikodem VC, de Jager M, Gelbart
administration of vaginal misoprostol for second Gynaecol. 2007;47:23-25. BR. A randomised placebo controlled trial of oral
trimester pregnancy termination. BJOG. 2005; 81. Fletcher HM, Mitchell S, Simeon D, et al. Intra- misoprostol in the third stage of labour. Br J Ob-
112:1297-1301. vaginal misoprostol as a cervical ripening agent. stet Gynaecol. 1998;105:971-975.
75. Herabutya Y, Chanrachakul B, Punyavachira P. Br J Obstet Gynaecol. 1993;100:641-644. 90. Surbek DV, Fehr PM, Hösli I, Holzgreve W. Oral
Second trimester pregnancy termination: a com- 82. Ngai SW, To WK, Lao T, Ho PC. Cervical priming misoprostol for third stage of labor: a random-
parison of 600 and 800 micrograms of intra- with oral misoprostol in pre-labor rupture of mem- ized placebo-controlled trial. Obstet Gynecol.
vaginal misoprostol. J Obstet Gynaecol Res. branes at term. Obstet Gynecol. 1996;87:923-926. 1999;94:255-258.
2001;27:125-128. 83. Alfirevic Z. Oral misoprostol for induction of labour. 91. El-Refaey H, O’Brien P, Morafa W, et al. Use of
76. Dickinson JE, Evans SF. The optimization of in- Cochrane Database Syst Rev. 2001;(2):CD001338. oral misoprostol in the prevention of postpartum
travaginal misoprostol dosing schedules in sec- 84. Muzonzini G, Hofmeyr GJ. Buccal or sublingual haemorrhage. Br J Obstet Gynaecol. 1997;104:
ond-trimester pregnancy termination. Am J Ob- misoprostol for cervical ripening and induction 336-339.
stet Gynecol. 2002;186:470-474. of labour. Cochrane Database Syst Rev. 2004;(4): 92. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ.
77. Kapp N, Borgatta L, Stubblefield P, et al. Mifepri- CD004221. Prostaglandins for preventing postpartum haem-
stone in second-trimester medical abortion: a 85. Hofmeyr GJ, Gülmezoglu AM. Vaginal misopros- orrhage. Cochrane Database Syst Rev. 2007;(3):
randomized controlled trial. Obstet Gynecol. tol for cervical ripening and induction of labour. CD000494.
2007;110:1304-1310. Cochrane Database Syst Rev. 2003;(1):CD000941. 93. Mousa HA, Alfirevic Z. Treatment for primary
78. Dickinson JE, Evans SF. A comparison of oral 86. Sanchez-Ramos L, Kaunitz AM. Misoprostol for postpartum haemorrhage. Cochrane Database
misoprostol with vaginal misoprostol adminis- cervical ripening and labor induction: a system- Syst Rev. 2007;(1):CD003249.
tration in second-trimester pregnancy termina- atic review of the literature. Clin Obstet Gynecol. 94. O’Brien P, El-Refaey H, Gordon A, et al. Rectally
tion for fetal abnormality. Obstet Gynecol. 2000;43:475-488. administered misoprostol for the treatment of
2003;101:1294-1299. 87. Wing DA, Gaffaney CA. Vaginal misoprostol ad- postpartum hemorrhage unresponsive to oxy-
79. Daskalakis GJ, Mesogitis SA, Papantoniou NE, et ministration for cervical ripening and labor in- tocin and ergometrine: a descriptive study. Ob-
al. Misoprostol for second trimester pregnancy duction. Clin Obstet Gynecol. 2006;49:627-641. stet Gynecol. 1998;92:212-214.

168 VOL. 2 NO. 3 2009 REVIEWS IN OBSTETRICS & GYNECOLOGY