Efficacy of Combination Therapy with Methotrexate and Misoprostol in Termination of Pregnancy in the First Trimester
Abstract Background: Induced abortion is the medical or surgical ter-
mination of pregnancy before fetal viability. It has maternal or fetal indications. The aim of the present study was to evaluate the efficacy of the combination of methotrexate and misopros- tol for termination of the pregnancy in the first trimester. Methods: This analytic study was performed on 100 women at the first trimester of pregnancy (<14th week), during 2004- 2006. Each woman received intramuscular methotrexate (50 mg/m2) and intravaginal misoprostol (800 μg) 72 hours after methotrexate administration. The second dose of misoprostol was administered if abortion did not occur after 24 hours. Ab- dominal ultrasonography was performed 7 days after abortion. Results: Of the 100 women, 76 had gestational age >9 weeks
and 24 has gestational age<9 weeks. Eighty one women (81%)
had successful medical abortion and 19% women required cu-
rettage. Fifty nine patients with gestational age>9 weeks and
22 patients with gestational age <9 weeks had complete abor-
tion. Failure rate was higher in missed abortion. Required dose
of misoprostol and duration of conceptus expulsion were
higher in pregnancies with missed abortion.
Conclusion: Combination therapy with methotrexate and mi-
soprostol represents a safe and effective alternative to invasive
methods for termination of the pregnancy in the first trimester.
Iran J Med Sci 2009; 34(2): 116-120.
1Department of Obstetrics & Gynecology,
Keywords● Medical abortion ● misoprostol ● methotrexate ●
first trimester of pregnancy ● induced abortion ● missed abortion
Department of Community Medicine, Ghaem Hospital,
Introduction
urgical termination of pregnancy (dilatation and curet-
tage) has been the standard management of early
PCorr espondence: S pregnancy failure. Medical management of early
Department of Obstetrics & Gynecology,
pregnancy termination using prostaglandin analogues has
been proposed as an alternative to surgery. Prostaglandin ana-
logues combined with mifepristone (RU486) for elective abor-
Mashhad, Iran. Tel: +98 511 8417493
tion at the first trimester of pregnancy result in success rate of
Fax: +98 511 8409612
about 95% (complete uterine evacuation without surgery).1
Email: sed_ayati @ yahoo.com
Published studies using various prostaglandins for early abor-
tion report success rates ranging from 13% to 95%.2-5 The
Revised: 27 December 2008 Accepted: 14 February 2009
widely varying success rates may reflect the inclusion of
116 Iran J Med Sci June 2009; Vol 34 No 2
Methotrexate and misoprostol for first trimester termination
different types of pregnancy failure (missed
Medical Sciences from October 2004 to March
abortion, blighted ovum, or incomplete abor-
tion). The efficacy diminishes with missed abor-
tion because of placental fibrotic tissues, firm
1- Gestational age of 12 weeks or less, with
residual adhesion, duration of pregnancy (effi-
intrauterine pregnancy on the basis of abdomi-
cacy to be decreased after 49 days of gestation),
and different treatment protocols (vaginal v oral;
2- Specific reasons for pregnancy termination
vaginal route has more efficacy, presumably be-
(legal abortion, missed abortion, blighted ovum).
cause of greater tissue bioavailability).1
Three medications have been used for early
eases, asthma or hematologic disorders were
medical abortion, including the antiprogestin
excluded from the study, with the exception of
mifepristone, the antimetabolite methotrexate,
the cases that the dosage of misoprostol and
and the prostaglandin misoprostol. These
methotrexate was safe for them. If medical
agents cause abortion by increasing uterine
termination failed or resulted in incomplete
contractility, either by direct stimulation of the
abortion, or severe hemorrhage, surgical ter-
myometrium (misoprostol) or by reversing the
progesterone-induced inhibition of uterine con-
traction (mifepristone and methotrexate).6
Human Investigation Unit of Ethical Committee
Recently, medical termination of pregnancy
of the University, and all the women provided
has been the suitable replacement for surgical
methods in China and Europe. Methotrexate is a
A data sheet was completed for each patient
cytotoxic drug for the placental tissue and there-
including the gestational age, the dose of miso-
fore it is prescribed for the treatment of malignant
prostol, the time of spontaneous expulsion,
trophoblastic tumors. Also it is applied as a safe
need for curettage, reason for abortion, pres-
and effective drug in unruptured ectopic preg-
ence or absence of fetal heart activity, uterine
nancy. Methotrexate has been used for a long
cramp, and bleeding patterns after abortion.
time in the treatment of benign diseases such as
Data collection was performed according to
the patients’ responses and observing the out-
Iamakov and his colleagues reported a suc-
cess rate of 96% in terminating the pregnancy
Three clinic visits were scheduled. At the
until 9th week of gestation by the combination
first visit (day 1), each patient received an in-
of methotrexate and misoprostol. They con-
cluded that medical abortion with these two
drugs was safe and effective and this protocol
from the first day of the last menstrual period,
could be recommended to the gynecologists.8
and by using abdominal ultrasonography and
Burgata co-workers studied the women aged
pelvic examination. Blood group, Rh, complete
15-21 years for induced abortion, and compared
blood count (CBC), blood urea nitrogen, hema-
them with women older than 21 years. They
tocrit (Hct), creatinine, and liver function tests
reached the better results in the younger women
were requested before initiating the study. At
(89.4% v 83%); however satisfaction rate with
the second visit (day 4), the patients received
this method was similar in both groups.9
800 microgram (as 200-microgram tablets)
In different studies, the success rate of the
misoprostol intravaginally. After taking miso-
medical abortion in the first 7 to 9 weeks of
prostol, the women were monitored for 4 hours
pregnancy with methotrexate (50 mg/m2, in-
for potential adverse events such as nausea,
tramuscular) and misoprostol (800 μg vagi-
vomiting, diarrhea, and abdominal pain. At the
nally, repeated as needed), has been reported
third visit (day 5), the same dose of misopros-
tol was prescribed unless the complete abor-
The aim of the present study was to evalu-
ate the efficacy of the combination of meth-
otrexate and misoprostol for termination of the
groups: blighted ovum, missed abortion and
fetus with heart activity. The relations between
the type of pregnancy and curettage, dose of
Patients and Methods
misoprostol and time needed for expulsion of
The present study was an interventional ana-
Vaginal bleeding, uterine cramp, and expul-
lytic study. A total of 100 women with gesta-
sion of conceptus were recorded on a diary
tional age of 14 weeks or less who needed ter-
mination of pregnancy and referred to teaching
Follow-up was extended to the fourth visit
hospitals affiliated to Mashhad University of
(day 12) if bleeding continued or if there was
Iran J Med Sci June 2009; Vol 34 No 2 117
F. Vahid Roudsari, S. Ayati, MT. Shakeri uncertainty about the completeness of abortion
of misoprostol, and 21 patients (25.9%) had
complete abortion by receiving the second
Efficacy was defined as the termination of
dose. There was a significant correlation be-
pregnancy with complete expulsion of concep-
tween the prescribed dose of misoprostol and
tus without the need for surgical procedure.
The need for surgical methods (dilatation and
There were 76 women in > 9 weeks and 24
curettage) was considered as failure. Surgical
women in < 9 weeks of gestational age groups.
procedure was performed as needed if the in-
vestigators believed there was a threat for
tween gestational age and curettage rate, dose
women’s life (severe hemorrhage), or at the
of misoprostol, and the time needed for expul-
end of the study for an ongoing pregnancy or
incomplete abortion. Endometrial thickness
<10 mm was considered as complete abortion.
tween the presence or absence of fetal heart
Statistical analysis was performed by descrip-
activity and curettage (P=0.223), dose of mi-
tive statistics and frequency distribution in
soprostol (P=0.347), and the time needed for
SPSS software version 11. The study’s find-
ings were analysed by χ2 test. P< 0.05 was
In the present study, the duration between
considered as statistically significant.
misoprostol administration, onset of uterine
cramps and the time needed for conceptus
expulsion, was divided into < 12 hours and >
In the present study, 100 pregnant women
There was significant correlation between
were evaluated for termination of pregnancy at
the first trimester. Mean age of the patients was
27.3±2.6 years, mean gravidity was 2.8±1.6 and
Spotting duration after abortion was divided
mean gestational age was 9±1.9 weeks (6-12
into < 10 days and > 10 days. There was a
weeks). Among the patients, 14 had therapeutic
significant correlation between the time needed
abortion with live fetuses. From a total of 100
for conceptus expulsion and duration of spot-
patients, 81 women had successful abortion by
ting after abortion (P=0.001). There was a sig-
methotrexate and first or second administration
nificant relationship between the type of preg-
of misoprostol and 19 patients required surgical
nancy and curettage (P=0.010), dose of miso-
intervention. Among the 81 patients, 60 (74.7%)
prostol (P<0.001), and the time needed for
had successful abortion following the first dose
Table 1: The correlation between gestational age and curettage, dose of misoprostol, and the time needed for conceptus expulsion Gestational age > 9 weeks < 9 weeks < 9 weeks
Table 2: The correlation between the type of pregnancy, doses of misoprostol, and the time of expulsion and curettage Type of pregnancy Blighted Live fetus abortion
118 Iran J Med Sci June 2009; Vol 34 No 2
Methotrexate and misoprostol for first trimester termination
Discussion
needed time for medical abortion. This relation
has not been shown in the previous studies.
Termination of pregnancy has been practiced
Rock and coworkers studied the efficacy of
since antiquity. Although many societies
misoprostol 3, 4, or 5 days after methotrexate
accept this practice, some reject it and it is
administration at the gestational age of 63
sometimes considered as a crime. The most
days or less. The success rate was 92% and
widely used methods for terminating pregnancy
there was no significant relationship with the
in the first trimester are surgical, primarily vac-
uum aspiration, which is safer and less painful
others in 1996 represented a significant rela-
The study performed by Hausknecht in 1995
tion ship between the gestational age (more
showed the efficacy of 800 microgram vaginal
or less than 56 days) and success rate with
misoprostol 5-7 days after intramuscular injection
of methotrexate. Among 178 pregnant women
otrexate).16 But in the present study, there
with gestational age of <9 weeks, 171 cases
was no significant relationship between ges-
(96%) had successful abortion and seven patients
tational age (more or less than 9 weeks),
required curettage.7 The higher success rate in the
dose of the drugs and the needed time for
study compared with our study may be due to
conceptus expulsion. This may be due to the
lower gestational age and less study population. In
presence of live fetus in other studies and
the present study, all pregnant women up to 12
One of the limitations of the present study
Borgatta and coworkers in 2001 evaluated
was difficult access to misoprostol tablets that
the efficacy of methotrexate and misoprostol
are not easily available in Iran drug market.
on 1973 women with gestational age 7 weeks
The other limitation was the ambiguity about
or less. The rate of complete abortion was
maternal outcomes after exposure with meth-
84.1% and the need for curettage was 14.9%.9
otrexate. However, no important side effects
have been reported in the present study and
in 1999 on 108 patients with gestational age of
9 weeks or less in three groups. For the first
group, methotrexate, for the second group, mi-
Conclusion
soprostol and for the third group, a combination
of methotrexate and misoprostol were adminis-
Pregnancy termination with low dose of meth-
tered. The success rate was 69%, 57% and
otrexate and misoprostol is safe and effective.
89%, respectively. They concluded that the
There is no need for hospitalization and this
combination of methotrexate and misoprostol
method is accepted completely in outpatient
was a safe and suitable method for pregnancy
settings. Therefore we suggest that this method
termination at the first trimester of pregnancy.11
is suitable alternative to surgical methods. Fur-
Of course, in the most performed studies so far,
ther studies with focus on the medical abortion
this method was considered for fetus with heart
with different methods will be worthwhile.
activity (live fetus) and as a method for elective
abortion.8 In the present study, however, missed
Acknowledgements
abortion and blighted ovum were studied as
well. And the gestational age of the pregnant
The authors would like to thank Mrs. Touran
women in our study was higher than other stud-
Makhdoomi for editing the present paper, Dr.
ies.9-14 Low success rate in the present study
Ghorbani for collecting the data, and Mrs.
may be due to the types of pregnancy and ter-
Moshtaghi for typewriting this collection. This
study has been financially supported by Medi-
The present study, for the first time, studied
the effects of medical termination of pregnancy
with methotrexate and misoprostol on missed
Conflict of Interest: None declared
abortion. The results showed that the failure
rate was higher in pregnancies with missed
References
abortion. The dose of misoprostol and the
needed time for conceptus expulsion in missed
abortion were also higher than blighted ovum
al. Bleeding patterns after vaginal miso-
prostol for treatment of early pregnancy
Moreover, we showed that there was no sig-
failure. Hum Reprod 2004; 19: 1655-8.
nificant correlation between live or dead fetus in
Allen RH, Westhoff C, De Nonno L, et al.
regard to curettage, dose of misoprostol and the
Curettage after mifepristone-induced abor-
Iran J Med Sci June 2009; Vol 34 No 2 119
F. Vahid Roudsari, S. Ayati, MT. Shakeri
tion: frequency, timing and indications.
years. J Pediatr Adolesc Gynecol 2001;
10 Ozeren M, Bilekli C, Avdemir V, Bozokaya
vacuum aspiration. J Am Med Womens
alone or in combination for early abortion.
Gilles JM, Creinin MD, Barnhart K, et al. A
prostol for first-trimester pregnancy failure.
prostol for medical abortion. Indian med sci Am J Obstet Gynecol 2004; 190: 389-94.
Muffley PE, Stitely ML, Gherman RB. Early
intrauterine pregnancy failure: a randomized
otrexate and misoprostol for early abortion
trial of medical versus surgical treatment. Am
in adolescent women. J Pediatr Adolesc J Obstet Gynecol 2002; 187: 321-6.
13 Christin-Maitre S, Bouchard Ph, Spitz IM.
Medical termination of pregnancy. N Engl J
14 Stubblefield PG, Carr-Ellis S, Borgatta L.
Methods for induced abortion. Obstet Gy-
prostol to terminate early pregnancy. N
15 Rock JA, Jones HW. Telindes Operative
Gynecology. 9th ed. Lippincott Williams &
[Medical abortion using methotrexate and
misoprostol. Efficacy and tolerability].
16 Carbonell I Esteve JL, Velazco A, Varela
Akush Ginekol (sofiia) 2005; 44: 16-8.
L, et al. Misoprostol 3, 4, or 5 days after
Borgatta L, French A, vragovic O, Burnhill
methotrexate for early abortion. A random-
ized trial. Contraception 1997; 56: 169-74.
120 Iran J Med Sci June 2009; Vol 34 No 2
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