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SPECIAL ARTICLE
WHO recommendations for misoprostol use for obstetric and gynecologic indications
Jennifer Tang
a
, Nathalie Kapp
b,
⁎, Monica Dragoman
b
, Joao Paulo de Souza
b
a
Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, USA
b
Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
abstractarticle info
Article history:
Received 2 November 2012
Received in revised form 10 December 2012
Accepted 22 January 2013
Keywords:
Abortion
Guidelines
Labor induction
Misoprostol
Postpartum hemorrhage
Recommendations
Background: Misoprostol, a prostaglandin E
1
analog, stimulates uterine contractility and cervical ripening. A
number of randomized trials and systematic reviews have evaluated its use in obstetric and gynecologic condi-
tions. Misoprostol is inexpensive, stableat room temperature, and available in more than 80 countries, making it
particularly useful in resource-poor settings. WHO recognizes the crucial role of misoprostol in reproductive
health andhas incorporated recommendationsfor its use into 4 reproductive healthguidelines focusedon induc-
tion of labor, prevention and treatment of postpartum hemorrhage, and management of spontaneous and in-
duced abortion. Methods and results: All guidelines were prepared in accordance with the WHO Handbook for
Guideline Development. The process included: identification of priority questions and critical outcomes; retrieval
of evidence; assessment and synthesis of evidence; formulation of recommendations; and planning for dissem-
ination, implementation, impact evaluation, and updating. The present report summarizes recommendations
for misoprostol use in line with each guideline. Conclusion: The present comprehensive reference document
was designed to enable clinicians and policy makers to quickly access and compare recommendations for the
use of misoprostol in various reproductive health settings.
© 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Misoprostol is a prostaglandin E
1
analog that was first marketed in
the 1980s to prevent gastric ulcers. Because of its effects on uterine
contractility and cervical ripening, a number of randomized trials and
systematic reviews have evaluated its use in obstetric and gynecologic
conditions. Misoprostol is inexpensive, stable at room temperature,
and available in more than 80 countries, making it particularly useful
in resource-poor settings [1].
WHO endorses the important role of misoprostol in reproduc-
tive health by including it in the WHO Model List for Essential Med-
icines [2] and incorporating its use into 4 separate WHO reproductive
health guidelines.
Indications for use include: induction of labor (where appropriate
facilities are available); prevention and treatment of postpartum hemor-
rhage (PPH [where oxytocin is not available]); management of incom-
plete and spontaneous abortion (requires close medical supervision);
and termination of pregnancy, in combination with mifepristone
(where permitted under national law and where culturally acceptable).
The present report summarizes and clarifies the various uses, dosing
strategies, and routes of administration for misoprostol recommended
by each WHO guideline. Combining these recommendations into a sin-
gle comprehensive reference document will enable clinicians and policy
makers to quickly access and compare recommendations for the use of
misoprostol in reproductive health settings.
2. Materials and methods
All guidelines referenced in the present document were prepared
according to standard procedures included in the WHO Handbook for
Guideline Development [3]. Details regarding the methods governing
specific guideline development canbe found in the referenced materials
[4–6]. In summary, theprocess included: identification of priority ques-
tions and critical outcomes; retrieval of evidence; assessment and syn-
thesis of evidence; formulation of recommendations; and planning for
dissemination, implementation, impact evaluation, and updating.
3. Summary of recommendations
3.1. Misoprostol use for induction of labor
3.1.1. Recommendations for induction of labor at term
The general principle for misoprostol use for induction of labor at
term is that it should be used at a low dose (25 μg), given the increasing
sensitivity of uterine receptors to misoprostol with increasinggestation-
al age. Evidence for misoprostol use in this setting was derived from 3
systematic reviews, which included a large number of randomized
controlled trials [7–9]. Based on the results of these trials, either low-
dose vaginal misoprostol (every 6 hours) or oral misoprostol (every
2 hours) are recommended for induction of labor at term in women
who have not had a previous cesarean delivery (Table 1). It should be
International Journal of Gynecology and Obstetrics 121 (2013) 186–189
⁎Corresponding authorat: Avenue Appia 20, Room X119,1211 Geneva 27, Switzerland.
Tel.: +41 22 79 13437; fax: +41 22 791 4171.
E-mail address: kappn@who.int (N. Kapp).
0020-7292/$ –see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijgo.2012.12.009
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics
journal homepage: www.elsevier.com/locate/ijgo
noted that women receiving misoprostol for induction of labor should
never be left unattended because the procedure carries the risk of
uterine hyperstimulation, uterine rupture, and fetal distress. Therefore,
induction of labor should be carried out in facilities in which the
wellbeing of mothers and fetuses can be closely monitored. In addition,
wherever possible, induction of labor should be carried out in facilities in
which cesarean delivery can be performed.
3.1.2. Recommendations for termination of pregnancy in cases involving
fetal anomaly or after intrauterine fetal death
Pregnant women experiencing an intrauterine fetal death or a fetal
anomaly requiring pregnancy termination present with a scenario for
clinical management that is different from that for labor induction in
women with a normal live fetus. First, increased uterine contractility
leading to fetal distress is no longer a major concern. Second, induction
of labor in women with an anomalous or dead fetus is often performed
before term, when the uterus may be less responsive to uterotonics. Ev-
idence concerning the use of misoprostol in this setting is summarized
in a systematic review evaluating several comparisons among various
misoprostol preparations and prostaglandins in the second and third
trimesters of pregnancy [10]. Overall, the review contained few trials
with small numbers of participants, which created substantial uncer-
tainty regarding the size of the effect. Based on these limited data, either
oral or vaginal misoprostol is recommended for induction of labor in
women with a dead or anomalous fetus in the third trimester of preg-
nancy, at the same doses and regimens recommended for use of miso-
prostol for induction of labor at term (Table 1).
3.2. Misoprostol use for the prevention of PPH
During the third stage of labor, all women should be administered
a uterotonic to prevent PPH. Intramuscular (IM) or intravenous (IV)
oxytocin (10 IU) is recommended as the uterotonic of choice. In
settings in which oxytocin is not available or its provision is not fea-
sible, alternative uterotonics may be considered for use. These alter-
natives include other injectable medications such as ergometrine/
methylergometrine, the fixed drug combination of oxytocin and
ergometrine, and oral misoprostol (600 μg). Because ergot-derived
medications have clear contraindications for women with hyperten-
sive disorders, caution should be exercised when opting for these
medications in unscreened populations.
Parentally administered oxytocin is considered more effective than
orally administered misoprostol for the prevention of PPH. Therefore,
the use of misoprostol by health workers (including lay health workers
trained in this practice) is considered an alternative in settings in which
the use of oxytocin is not possible. The use of misoprostol as an al-
ternative uterotonic for PPH prevention should not detract from the
objective of making oxytocin widely accessible. Finally, there is insuffi-
cient evidence to recommend advance distribution of misoprostol to
pregnant women during the prenatal period for self-administration
after childbirth.
3.3. Misoprostol use for the management of PPH due to uterine atony
Intravenous oxytocin is recommended for the treatment of PPH. If
IV oxytocin is unavailable or if bleeding persists despite oxytocin, the
use of intravenous ergometrine, the fixed drug combination of oxyto-
cin and ergometrine, or a prostaglandin drug (including misoprostol)
is recommended. The recommended dose for misoprostol is 800 μg
provided sublingually, which is based on the dose studied in the 2
largest trials of misoprostol for the treatment of PPH [11,12] (Table 1).
Intravenous oxytocin is recommended as the first-line uterotonic
drug for the treatment of PPH, including when women have already
received this drug for PPH prophylaxis. In settings in which IV oxyto-
cin is unavailable to women who have received prophylactic IM oxy-
tocin during the third stage of labor, misoprostol is considered a valid
Table 1
Recommended uses, doses, and routes of administration for misoprostol.
Indication Dose Route
Labor and delivery
Induction of labor at term if no prior cesarean delivery 25 μg, 2-hourly Oral
25 μg, 6-hourly Vaginal
Termination of pregnancy involving fetal anomaly or after intrauterine
fetal death in the third trimester of pregnancy
25 μg, 2-hourly Oral
25 μg, 6-hourly Vaginal
Prevention of PPH if oxytocin is not available or feasible 600 μg, once Oral
Management of PPH due to uterine atony if oxytocin has failed or is
not available
800 μg, once Sublingual
Safe abortion care
Treatment of incomplete abortion when uterine size measures
13 weeks or less
400 μg, once Sublingual
600 μg, once Oral
400–800 μg, once Vaginal
a
Mifepristone available
Medical abortion up to 7 weeks (49 days) Oral
•Given 24–48 hours after administration of oral mifepristone 200 mg 400 μg, once
(Or regimen for medical abortion up to 9 weeks)
Medical abortion up to 9 weeks (63 days) Buccal, vaginal, or sublingual
•Given 24–48 hours after administration of oral mifepristone 200 mg 800 μg, once
Medical abortion between 9 and 12 weeks (63 and 84 days)
•Given 36–48 hours after administration of oral mifepristone 200 mg
800 μg, then 400 μg, 3-hourly up to 5 doses Vaginal, then vaginal or sublingual
Medical abortion after 12 weeks (after 84 days)
•Given 36–48 hours after administration of oral mifepristone 200 mg
800 μg, then 400 μg, 3-hourly up to 5 doses Vaginal, then vaginal or sublingual
a
400 μg, then 400 μg, 3 hourly up to 5 doses Sublingual, then vaginal or sublingual
a
Mifepristone not available
Medical abortion up to 12 weeks (up to 84 days) 800 μg, at intervals of 3–12 hours up to 3 doses Vaginal or sublingual
Medical abortion after 12 weeks (after 84 days) 400 μg, 3-hourly up to 5 doses
b
Vaginal or sublingual
Cervical preparation prior to surgical abortion up to 12–14 weeks 400 μg(2–3 hours pre-procedure) Sublingual
400 μg (3 hours pre-procedure) Vaginal
Cervical preparation prior to surgical abortion at 14 weeks or later 400 μg(3–4 hours pre-procedure) Vaginal
Abbreviation: PPH, postpartum hemorrhage.
a
Vaginal route recommended only in the absence of significant vaginal bleeding.
b
For pregnancies beyond 24 weeks, misoprostol dose should be reduced owing to greater uterine sensitivity to prostaglandins; however, the lack of clinical studies prohibits
specific dosing recommendations.
187J. Tang et al. / International Journal of Gynecology and Obstetrics 121 (2013) 186–189
alternative. If PPH prophylaxis with misoprostol has been adminis-
tered and if injectable uterotonics are unavailable, there is insufficient
evidence to guide further misoprostol dosing, and consideration must
be given to the risk of potential toxicity.
There is no added benefit to offering misoprostol simultaneously
to women receiving oxytocin for the treatment of PPH (i.e. adjunct
misoprostol). Additionally, if IV oxytocin has been used for the treat-
ment of PPH and bleeding continues, few data recommend preferences
for second-line uterotonic drug treatment. Similarly, in situations in
which IM oxytocin can be administered and there is no possibility of
IV treatment with ergot alkaloids/injectable prostaglandins, there is a
paucity of data to recommend a preference of IM oxytocin over miso-
prostol orother uterotonics. Decisionsin such situations mustbe guided
by the experience of the provider, the availability of the drugs, and the
known contraindications for a woman's medical condition.
3.4. Misoprostol use in the context of safe abortion
3.4.1. Recommendations for the treatment of incomplete abortion
Incomplete abortion can occur following either spontaneous or
induced abortion. Options for the treatment of incomplete abortion
include expectant management, medical management, and surgical
evacuation. Either vacuum aspiration or medical treatment with mi-
soprostol can be recommended for women with incomplete abortion
at any gestational age when uterine size at time of treatment corre-
sponds to 13 weeks of gestation or less. This recommendation is ex-
trapolated from research conducted among women with reported
spontaneous abortion.
The recommended regimen of misoprostol is a single dose given
either sublingually (400 μg) or orally (600 μg) (Table 1). Misoprostol
may also be used vaginally; however, this route of administration
should be avoided if there is significant bleeding because the pres-
ence of blood could prevent effective absorption of the medication.
Studies of vaginal misoprostol for management of incomplete abor-
tion have used doses ranging from 400 μg to 800 μg; comparative
dosing trials have not been reported.
This guidance does not pertain to the management of missed
abortion, which is a separate entity. WHO guidelines for the use of
misoprostol in this context have not been developed.
3.4.2. Recommendations for medical abortion up to 9 weeks (63 days)
Medical abortion up to 9 weeks (63 days) is well accepted as an alter-
native to surgical abortion in different settings. Randomized controlled
trials have consistently shown that combined regimens are more effec-
tive than single-medication regimens and that the most effective regi-
men is the combination of mifepristone followed by misoprostol. Many
trials have also compared doses and timing for the administration of
mifepristone and misoprostol. The most effective regimen is 200 mg of
mifepristone orally, followed by misoprostol 1–2days (24–48 hours)
later. Misoprostol can be given vaginally, buccally, or sublingually up to
9weeksof gestation(Table 1). Oral misoprostol should be used only
up to 7 weeks of gestation. Vaginal administration has higher effective-
ness and lower rates of adverse effects than other routes of administra-
tion; however, some women may prefer a non-vaginal route.
3.4.3. Recommendations for medical abortion between 9 and 12 weeks
(63 and 84 days)
Currently, there is limited evidence forthe use of misoprostol in med-
ical abortion between 9 and 12 weeks (63 and 84 days) of gestation.
WHO recommendations are derived from only 1 randomized controlled
trial and 1 observational trial; however, the principles for the regimen
are similar to those for medical abortion at other gestational ages
[13,14]. Combined regimens are more effective than single-medication
regimens and they should include misoprostol because it is the most ef-
fective prostaglandin for inducing medical abortion. Studies of medical
abortion after 12 weeks indicate that repeat doses of misoprostol should
be used as gestational age increases (Table 1). There is ongoing research
in this area, and recommendations may change as studies are completed.
3.4.4. Recommendations for medical abortion up to 12 weeks (84 days)
when mifepristone is not available
Mifepristone is currently approved in 50 countries [15]. Therefore,
there are many countries in which mifepristone is not available and al-
ternative methods must be used for medical abortion. Methotrexate
combined with misoprostol is less effective than mifepristone combined
with misoprostol but it is more effective than misoprostol used alone;
therefore, it is sometimes used for medical abortion up to 12 weeks.
However, a WHO Toxicology Panel recommended against the use of
methotrexate for inducing abortion based on concerns about teratoge-
nicity should the pregnancy continue to birth [16]. Instead, in settings
in which mifepristone is not available, the recommended method of
medical abortion for gestations less than 12 weeks is misoprostol
alone, repeated at intervals of at least 3 but no more than 12 hours for
up to 3 doses (Table 1). Women may be offered either vaginal or sublin-
gual administration of misoprostol; however, sublingual misoprostol is
associated with higher rates of adverse effects compared with vaginal
administration. Also, the sublingual route is less efficacious in nullipa-
rous women when repeat doses of misoprostol are provided at intervals
longer than 3 hours.
3.4.5. Recommendations for medical abortion after 12 weeks
(after 84 days)
Medical abortion after 12 weeks is an area of ongoing research and
many different medical regimens have been studied. It is difficult to per-
form studies to determine the most effective regimen for this group be-
cause it may change with gestational age, and fewer abortions occur at
later gestational ages. As with early gestations, combined regimens are
more effective than single-medication regimens. The recommended
regimen is administration of oral mifepristone, followed 36–48 hours
later by repeat doses of misoprostol (Table 1). An interval between ad-
ministration of mifepristone and misoprostol less than 36 hours is asso-
ciated with a longer interval to abortion and higher rates of incomplete
abortion.Women with a uterine scarhave a very low (0.3%) risk of uter-
ine rupture during medical abortion using misoprostol in the second
trimester [17]. Therecommendedmethod of medicalabortion when mi-
fepristone is not available is misoprostol alone, repeated every 3 hours
up to 5 doses (Table 1). Instillation of ethacridine lactate is associated
with an interval to abortion that is similar to that for regimens using
misoprostol alone; however, studies have not compared the safety or
efficacy of its use with that of combined mifepristone and misoprostol.
3.4.6. Recommendations for cervical preparation prior to surgical
abortion up to 12–14 weeks (up to 84–98 days)
Cervical preparation has been found to improve baseline cervical
dilation prior to surgical abortion and can be accomplished using os-
motic dilators or misoprostol. If using misoprostol for cervical prepa-
ration, it can be provided as a single 400-μg dose either sublingually
2 hours pre-procedure or vaginally 3 hours pre-procedure (Table 1).
Methods for cervical preparation may be considered for women of
any gestational age to facilitate cervical dilation; cervical preparation
is recommended for all women undergoing surgical abortion at a ges-
tational age beyond12–14 weeks. In the first trimester, cervical prep-
aration has not been shown to decrease significant adverse events
such as uterine perforation or cervical laceration, although it does de-
crease rates of incomplete abortion following surgical evacuation.
Unavailability of osmotic dilators or misoprostol should not limit access
to abortion services. Consideration should be given to the increase in
time and adverse effects (pain, vaginal bleeding, and precipitous
abortion) associated with cervical preparation. Cost, local availability
of cervical preparatory methods, and training in the use of such
methods will affect the choice of method used.
188 J. Tang et al. / International Journal of Gynecology and Obstetrics 121 (2013) 186–189
3.4.7. Recommendations for cervical preparation prior to surgical
abortion at 14 weeks or later (98 days or later)
All women undergoing dilation and evacuation at 14 weeks or
later should undergo cervical preparation prior to the procedure. The
recommended methods of cervical preparation before dilation and
evacuation include osmotic dilators or misoprostol. Only 1 random-
ized controlled trial has directly compared vaginal misoprostol with
overnight laminaria, showing that osmotic dilators reduced procedure
time and the need for further dilation compared with use of misopros-
tol [18]. Another randomized controlled trial involving women at
13–20 weeks of gestation found that cervical dilation with laminaria
was augmented by preoperative use of buccal misoprostol but this
effect was found only in gestations at 19–20 weeks [19]. The effect
of misoprostol prior to dilation and evacuation after 20 weeks of ges-
tation has not been investigated in comparative studies.
4. Conclusion
In 2010, 287 000 women died during and following pregnancy and
childbirth. The major complications thataccount for 80% of all maternal
deaths are hemorrhage (particularly PPH), puerperal infections, high
blood pressure during pregnancy, and unsafe abortion [20].
Evidence-driven application of the use of misoprostol across a range
of obstetric and gynecologic indications has the potential to reduce ma-
ternal mortality in line with the call to action put forth in the Millenni-
um Development Goals. As discussed, misoprostol can be used as an
agent for labor induction in the third trimester, contributing to expedit-
ed delivery in the setting of maternal and fetal medical conditions such
as hypertensive disorders and infection. There is a role for misoprostol
in the prevention and treatment of PPH; although misoprostol is not a
first-line agent, evidence supports its use when oxytocin is unavailable.
Finally, misoprostol is an essential medication for the safe management
of spontaneous and induced abortion.
All of the WHO recommendations for the use of misoprostol in var-
ious obstetric and gynecologic contexts have been developed based on
the best available evidence through a rigorous guideline development
process. Because the evidence-based regimens for the safe and effective
use of misoprostol vary depending on the indication and may also differ
by setting, the present document summarizes current guidance for
misoprostol use. As new evidence becomes available, WHO will update
recommendations accordingly, in addition to its practical tools for
policy makers and clinicians.
Conflict of interest
The authors have no conflicts of interest.
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