Alternatives to mifepristone for early medical
N.L. Moreno-Ruiza,⁎, L. Borgattaa, S. Yanowb, N. Kappa, E.R. Wiebec,
aDepartment of Obstetrics and Gynecology, Boston University School of Medicine, Boston MA, USA
bAbortion Access Project, Cambridge MA, USA
cDepartment of Family Practice, University of British Columbia, Vancouver, BC, Canada
dGynuity Health Projects, New York, USA
Received 30 May 2006; received in revised form 17 August 2006; accepted 11 September 2006
Objective: To review published reports of first-trimester medical abortion regimens that do not
include mifepristone. Methods: Reports listed in Pubmed and Medline on prospective and
controlled trials of the efficacy of misoprostol, alone or associated with methotrexate, for first-
trimester abortion were analyzed if they included more than 100 participants and were published
since 1990. Results: The efficacy of regimens using misoprostol alone ranged from 84% to 96%,
and when misoprostol was used with methotrexate the efficacy ranged from 70% to 97%. Efficacy
rates were influenced by follow-up interval. Treatment for infection, bleeding, and incomplete
abortion were infrequent with both methods (0.3%–5%). Conclusion: Alone or in combination
with methotrexate, misoprostol is an efficacious alternative to mifepristone for the medical
termination of pregnancy.
© 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
Medical termination of pregnancy, also called medication or
pharmacologic abortion, is an effective and acceptable
alternative to surgical termination of pregnancy.
Mifepristone was the first medication to be approved
specifically for medical abortion, and it has been used in
combination with a prostaglandin analogue, usually mis-
oprostol, to increase its efficacy [1,2]. Mifepristone in
association with misoprostol has a high efficacy (92%–99%
of complete abortions) and an excellent safety profile .
The most frequently reported adverse effects were nausea
and vomiting [1,3,4]. Contraindications to mifepristone use
include long-term corticosteroid use, chronic renal failure,
anticoagulants use, inherited porphyria, allergy to the
medications, suspicion of ectopic pregnancy, and intrauter-
ine device in situ. Coagulopathies and severe anemia are
contraindications for medical abortion with any agent.
⁎ Corresponding author. Department of Obstetrics and Gynecology, Boston University School of Medicine, 85 East Concord St, 6th Floor,
Boston, MA 02118, USA. Tel.: +1 617 414 5112 (work), +1 617 459 5290 (home); fax: +1 617 414 7300.
E-mail address: Nilda.Moreno@bmc.org (N.L. Moreno-Ruiz).
0020-7292/$ - see front matter © 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
available at www.sciencedirect.com
International Journal of Gynecology and Obstetrics (2007) 96, 212–218
Where available, mifepristone/misoprostol regimens are
well accepted. However, mifepristone is not globally avail-
able. Even in countries where abortion is legal and
mifepristone is available, political and economic factors
may restrict its use. The purpose of this article was to review
published reports of medical abortion regimens that do not
2. Classification and follow-up of medical
In studies of medical abortion, success is defined as the
expulsion of all products of pregnancy, with no need for
surgical intervention (uterine aspiration). A medical abortion
is still considered successful if additional doses of medication
are required for complete expulsion. A surgical intervention
is classified as a failure of the medical technique. Uterine
aspiration may be used to end a pregnancy that continues
after a medical intervention, for an incomplete abortion or
unspecified bleeding, or if it is the choice of the woman or
her clinician .
Reported success rates are influenced by surgical inter-
ventions made upon patients' request or clinicians' pre-
ference, often due to the length of the abortion process.
These outcomes do not represent pharmacologic failures,
but decrease the overall success rate as each surgical
intervention is recorded as a bfailure.Q
The timing of follow-up can influence overall success
rates. Women using any medical technique may have
delayed passage of the products of pregnancy (e.g.,
14 days or more after taking the medication). If the regimen
mandates a surgical termination after a fixed period, then
the rate of success is determined at the cut-off date.
Without the cut-off date, some of these pregnancies might
abort completely without surgical intervention. An early
follow-up date without routine surgical intervention might
increase efficacy if it provided an opportunity for additional
medication. In general, if women were willing to wait for the
passage of the products of pregnancy, the wait would
Table 1 Summary of studies of medical abortion using misoprostol alone
Author Year of
No. of days
800 mcg q8h×3⁎⁎ (b)
800 mcg initially+
400 mcg q3h up to
96.3 Zikopoulos 2002 160
<42800 mcg vaginal q
24 h up to 3 doses ⁎⁎⁎(b)
88.0 Jain 2002 125800 mcg vaginal q
24 h up to 3 doses ⁎⁎⁎
800 mcg vaginal q
24 h up to 3 doses ⁎⁎⁎
medication not given
1000 mcg vaginal q
24 h up to 3 doses ⁎⁎(b)
800 mcg vaginal and in
7 days if no abortion ⁎⁎⁎
800 mcg vaginal q
24 h up to 3 doses ⁎⁎ (b)
800 mcg vaginal q
24 h up to 3 doses ⁎⁎(b)
800 mcg vaginal q
48 h up to 3 doses ⁎⁎⁎(c)
800 mcg vaginal q
48 h up to 3 doses ⁎⁎,(b,d)
Jain  2001≤56
100 14 93.0
Carbonell 200130042–63393.0 8.1
Velazco 2000 15035–633 88.76.8
Carbonell 1999720 35–63389.48.0
a. Number of days after first misoprostol dose; interim evaluations may have taken place.
b. Additional medication given if abortion was incomplete at follow-up.
c. Misoprostol, 400 or 600 mcg, 1–3 doses given after abortion depending on ultrasonographic assessment of the uterus.
d. Women with pregnancies less than 63 days had a completion rate of 96%; between 63 and 70 days the completion rate was 83%.
⁎ The first dose was administered by the clinician, second dose self-administered.
⁎⁎ All doses were self-administered; first dose vaginally; other doses orally or vaginally.
⁎⁎⁎ All doses were administered by the clinician.
213 Alternatives to mifepristone for early medical abortion
Table 2 Summary of studies of medical abortion using methotrexate and misoprostol
No. of days
Dose and route of administrationInterval
(No. of days after
Overall success, %
Wiebe 2004300≤4950 mg/m2IM 600 mcg oral
Twice, 24 h apart
600 mcg vaginal
twice, 24 h apart
800 mcg vaginal (c)
800 mcg vaginal
Twice, 24 h apart
600 mcg vaginal
3, 4 or 57 53.5 (b)
3, 4 or 567.5
4 to 6
3 to 6
Wiebe  1999100
5 to 714 88.9 (d)
87800 mcg vaginal
Wiebe  1999 257≤49
800 mcg vaginal, up to
3 doses q 24 h if bleeding
less than menses
800 mcg vaginal moistened
Creinin 1999 240≤4950 mg/m2IM5 to 67
800 mcg vaginal dry (e)
Carbonell 1999 148≤5625 mg oral800 mcg vaginal (e), up to
3 doses q 48 h if no abortion
N.L. Moreno-Ruiz et al.
154 50 mg oral 800 mcg vaginal (e), up to
3 doses q 48 h if no abortion
800 mcg vaginal, repeated in
48 and 96 h if needed (f)
Carbonell 1998 300≤6350 mg oral 3, 4 or 58 91.0 (d)
Creinin  1997100
<4975 mg IM 800 mcg vaginal (e)5 to 614
2, 7, 14 after
Creinin 1997 299≤49 50 mg oral800 mcg vaginal (e) 5 to 6
Carbonell  1997 287≤63 50 mg/m2IM 800 mcg vaginal, repeated in
48 and 96 h if needed
800 mcg vaginal (e,f)
3, 4 or 5
Creinin  1996300≤56 50 mg/m2IM7
Wiebe 1996 100
<56 50 mg/m2IM800 mcg vaginal (e)3
a. Self-administered unless noted.
c. The second dose was administered 24 h later if the bleeding was less than menses.
d. Differences were not significant (P>0.05).
e. Repeated if gestational sac was still present at first follow-up visit.
f. Misoprostol, 400 or 600 mcg, 1 to 3 doses given after abortion depending on ultrasonographic assessment of the uterus.
Alternatives to mifepristone for early medical abortion
increase the success rate by decreasing the number of
In addition, a longer follow-up interval gives more
information about success rates since late failures (in
patients requiring surgical intervention for prolonged bleed-
ing or infection after a diagnosis of complete abortion) are
also included in the final analysis. A study protocol that
evaluated patients 2 weeks and 3 months following admin-
istration of mifepristone found that the success rate
decreased from 99% to 96% owing to surgical interventions
in patients initially diagnosed as having had complete
3. Alternative medical abortion agents to
Misoprostol is a synthetic prostaglandin E1 analogue
approved worldwide for the prevention of gastric ulcers.
Misoprostol tablets are inexpensive and stable at room
temperature, and this medication has no known adverse
interactions with other drugs.
Misoprostol is effective in labor induction, the treatment
of postpartum hemorrhage and early pregnancy failure, and
induction of second-trimester abortion [7–10]. It is also used
for cervical priming prior to hysteroscopy and surgical
abortion in during the first and second trimesters .
However, its use for gynecologic and obstetric indications is
boff-labelQ in most countries.
The most commonly reported adverse effects of mis-
oprostol administration are chills, nausea, vomiting, dizzi-
ness, fever, and diarrhea .
Misoprostol has few medical contraindications. It is
contraindicated in patients allergic to prostaglandins or
when the possible adverse gastro-intestinal effects are
contraindicated, such as in severe inflammatory bowel
disease. Misoprostol has been associated with teratogenicity
in high doses , and a maximum safe dose has not been
Although misoprostol is administered in a variety of
routes, it is almost always labeled for oral use. The
pharmacokinetics of the alternative routes of administration
show different absorption characteristics. One hour follow-
ing administration, the vaginal route produces higher serum
levels ofmisoprostol acid, themain metabolite, than the oral
route , and sublingual administration results in higher
peak serum concentration levels as well as a higher
cumulative dose (barea under the curveQ) than oral admin-
istration . Serum concentrations are not significantly
different following sublingual or buccal administration,
Compared with vaginal administration, oral administra-
tion of misoprostol is associated with increased nausea,
vomiting, abdominal pain, and diarrhea . There are no
differences between the reported incidence of adverse
effects following buccal and vaginal administration, except
that diarrhea may be more common after buccal adminis-
Misoprostol may be administered buccally or intravagi-
nally with no decrease in clinical effectiveness. When used in
combination with mifepristone for termination of pregnan-
cies up to 63 menstrual days' duration, vaginal misoprostol is
more effective . Another study reported similar effec-
tiveness with buccal and vaginal administration of misopros-
tol after mifepristone use (95% vs. 93%, P=0.51) . The
use of buccal or sublingual misoprostol has been reported for
both methods, but there is currently limited documentation.
Moistening misoprostol tablets prior to vaginal adminis-
tration has been used extensively and is believed by some to
improve efficacy. Although cumulative serum levels are
higher after administration of moistened misoprostol, there
were no differences in success rates between moistened and
dry misoprostol in randomized clinical trials [21–23].
Methotrexate is a dihydrofolate reductase inhibitor that
deprives cells of tetrahydrofolic acid, which is essential for
DNA synthesis in rapidly dividing cells. It is approved in the
United States for the treatment of psoriasis, rheumatoid
arthritis, and neoplasia (trophoblastic disease, lymphoma,
and leukemia). It has been used in single or short-term
administration as an alternative treatment for ectopic
pregnancy and for first-trimester medical abortion [1,24].
Used in a single dose, the adverse effects of methotrexate
include nausea, vomiting, headaches, and mouth sores [25–
28]. Complications are rare and thrombocytopenia is an
unusual event [27,29]. Methotrexate is contraindicated in
women with cytopenia, thrombocytopenia, immune or
hematopoetic suppression, or renal or hepatic impairment.
Methotrexate is formulated for oral and intramuscular
administration. Although its price varies by country, it is
generally inexpensive and globally available.
4. Clinical outcomes of alternative methods
4.1. Misoprostol-only methods
Pubmed and Medline were used to search for articles
published since 1990 that described results of misoprostol-
only protocols for pharmacologic first-trimester abortion.
The keywords used were bmedical abortionQ and
bmisoprostol.Q Only prospective series and controlled trials
with more than 100 participants were selected for analysis.
Table 1 summarizes the 13 studies identified. Publication
dates range from 1997 to 2003. In most of these studies, a
dose of 800 mcg of misoprostol was administered vaginally
and the administration was repeated every 24 h for up to 3
doses. The median time for the completion of a misoprostol-
induced abortion ranged from 6 to 9 h after the first dose
(Table 1). The overall success ranged from 84% to 96%.
Misoprostol doses of 1000 mcg in women with a pregnancy
duration less than 63 days had a success rate of 93%, the
midrange being reported for doses of 800 mcg . For
women in whom the abortion was not complete after 2 doses
of misoprostol, a third dose may increase the overall success
rate slightly, by 0.6% to 4% [33,39].
In the analyzed studies, the surgical intervention rates
related to time constraints or patient request ranged
between 5.3% and 15.3% [12,17,19,30–33,37–39]. Surgical
intervention for excessive bleeding ranged between 0.3% and
216N.L. Moreno-Ruiz et al.
3.3% and treatment for infection ranged between 0.3% and
As most women will complete the abortion within 3 days
of the first dose, longer follow-up periods had a small effect
on efficacy rates of misoprostol-only regimens. In a study
with a follow-up period lasting up to 43 days, the final
success rate was 96%, among the highest reported in medical
Self-medication with misoprostol to induce an abortion
has been documented in both legal and illegal contexts
[40,41]. At this point, complications other than incomplete
abortion following self-medication have not been reported,
and there are no estimations of rates of incomplete abortion.
4.2. Methotrexate methods
A similar literature search was used with the keywords
bmedical abortionQ and bmethotrexate.Q The studies selected
were published between 1996 and 2004, and all were
prospective studies including more than 100 women (Table
2). Most of the regimens used a methotrexate dose of 50 mg/
m2intramuscularly followed by 800 mcg of vaginal mis-
oprostol 3 to 7 days later, with some exceptions (Table 2).
Methotrexate doses were calculated using body surface, and
for most women the final dose was between 60 and 100 mg.
Because the doses, routes, and timing of administration
differ among studies for both medications, the relationship
between medication regimen and outcome is complex.
Inclusion criteria, such as gestational age, also vary. The
overall success rate was similar at various gestational ages.
When 50 mg/m2of intramuscular methotrexate was
followed by 800 mcg of vaginal misoprostol 3 to 7 days
later in women with a pregnancy duration of 49 days or less,
the day of misoprostol administration, was not found to have
an effect on outcome [23,27,42–44].
Oral methotrexate, which avoids injection and decreases
exposure risks to health care personnel, has also been used.
Serum levels of methotrexate following oral administration
were 85% of those after intramuscular injection, and were
not affected by ingestion of food . Despite the lower
methotrexate serum levels with oral use, however, clinical
outcomes were similar. Effectiveness and adverse effects for
oral and parenteral administration were found to be similar,
and women reported similar acceptability for the 2 routes.
Intramuscular and oral methotrexate followed by mis-
oprostol administration 3 to 7 days later appear comparable
in efficacy. In women with a pregnancy duration less than
49 days, the reported success rate after administration of
50/m2mg of oral methotrexate followed by 800 mcg of
vaginal misoprostol was between 90% and 91% [26,43]. When
50 mg/m2of intramuscular methotrexate was followed by
800 mcg of vaginal misoprostol in women with a pregnancy
duration less than 49 days, however, the observed success
ranged between 75% and 95% [23,27,42,44].
Most clinicians used a second dose of misoprostol if
abortion had not occurred after the first. Using a third dose
did not significantly increase the success rates .
Surgical interventions for true method failure (continu-
ing pregnancy) ranged from 0.4% to 8% [20,23,25–27,29,
42,43,47,48]. Surgical procedures deemed medically indi-
cated because of excessive bleeding, incomplete abortion,
and infection ranged from 0.3% to 5.0% [20,23,25,42,47].
Misoprostol may be used anywhere from 3 to 7 days after
treatment with methotrexate. Longer follow-up intervals
are associated with higher success rates. In 2 studies
conducted among 539 women with pregnancies of 49 days
or less, success rates increased from 70% to 73% at 7 days, to
81% to 87% at 14 days, and to 91% to 95% at 42 to 44 days
[23,26]. Follow-up up to 42 days without intervention has not
been associated with adverse outcomes.
Ideally, medical abortion should be simple, safe, inexpen-
sive, and accessible. There are a number of situations
when mifepristone may not be used, which include lack of
availability, financial concerns, or personal preference.
The success rates of alternative regimens using misoprostol
alone and methotrexate with misoprostol are around 90%,
and these 2 drugs are inexpensive and available in many
regions. Complications such as incomplete abortion,
bleeding, and infection appear to be similar for these 2
regimens and for mifepristone regimens as well. Although
the methods using misoprostol alone and methotrexate
followed by misoprostol have lower success rates than
those using mifepristone, these methods are safe and
acceptable choices for women who desire an abortion early
in the first trimester.
Methotrexate followed by misoprostol has been widely
used worldwide and many practitioners are familiar with
this method. Misoprostol alone is not as widely used by
clinicians, particularly in the United States, but it has the
advantage of causing a faster complete abortion without
an obvious decrease in effectiveness. Although misopros-
tol is most often used vaginally, other routes for its ad-
ministration may become more widely used. Self-induced
abortion with misoprostol, because of its simplicity and
quick results, is an option for women without other
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