Vahid Roudsari, F., Ayati, S., Saghafy, N., Shakeri, M. (2010). Misoprostol Alone or in Combination with Methotrexate for Termination of Pregnancy at First Trimester. Iranian Journal of Pharmaceutical Research, Volume 9(Number 1), 89-94. doi: 10.22037/ijpr.2010.841
F Vahid Roudsari; S Ayati; N Saghafy; M Shakeri. "Misoprostol Alone or in Combination with Methotrexate for Termination of Pregnancy at First Trimester". Iranian Journal of Pharmaceutical Research, Volume 9, Number 1, 2010, 89-94. doi: 10.22037/ijpr.2010.841
Vahid Roudsari, F., Ayati, S., Saghafy, N., Shakeri, M. (2010). 'Misoprostol Alone or in Combination with Methotrexate for Termination of Pregnancy at First Trimester', Iranian Journal of Pharmaceutical Research, Volume 9(Number 1), pp. 89-94. doi: 10.22037/ijpr.2010.841
Vahid Roudsari, F., Ayati, S., Saghafy, N., Shakeri, M. Misoprostol Alone or in Combination with Methotrexate for Termination of Pregnancy at First Trimester. Iranian Journal of Pharmaceutical Research, 2010; Volume 9(Number 1): 89-94. doi: 10.22037/ijpr.2010.841
Misoprostol Alone or in Combination with Methotrexate for Termination of Pregnancy at First Trimester
Abortion is an important problem in obstetrics throughout the world. The common and standard method for pregnancy termination at first trimester is surgery (curettage). Nowadays, an effective method of pregnancy termination at first trimester is medical treatments. The aim of this study is to compare misoprostol alone or in combination with methotrexate for pregnancy termination at first trimester. This study is a randomized clinical trial. A total of 200 pregnant women at first trimester were randomizedly divided into two groups for termination of pregnancy. The first group received 800 µg vaginal misoprostol. If conceptus residual remained, the same dose of misoprostol was repeated. The second group received 50 mg/m² intramuscular methotrexate, and then 800 µg vaginal misoprostol was administered after 72 h. If conceptus residual remained, the same dose of misoprostol was repeated after 24 h. Abdominal ultrasonography was performed at seventh day for both groups. Should conceptus residual remained or if pregnancy continued, curettage was performed. The results were analyzed statistically in terms of chi-square, and student’s t-test, using the SPSS software. A P-value equal or smaller than 0.05, was considered statistically significant. In this study, 83% of the first group and 81% of the second group had successful abortion. There was a significant correlation between the dose of misoprostol and abortion (P = 0.001) and between type of pregnancy and need for curettage (P < 0.000) in both groups, but there was no significant correlation between gestational age and the numberof doses administered (P = 0.932).In conclusion it seems that pregnancy termination by misoprostol alone or in combination with methotrexate is a safe and cost-effective method.
Acute and Subchronic Toxicity?of Teucrium polium Total Extract in Rats
Iranian Journal of Pharmaceutical Research
(2010), 9 (1): 89-94
Received: Janury 2008
Accepted: April 2009
Copyright ? 2010 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services
Original Article
Misoprostol Alone or in Combination with
Methotrexate
for Termination of Pregnancy at First Trimester
Fatemeh Vahid Roudsaria, Sedigheh Ayatia*,
Nafiseh Saghafya and Mohamadtaghi Shakerib
aDepartment of Obstetrics and Gynecology, Mashhad University of Medical
Sciences, Women?s Health Research Center, Ghaem Hospital, Mashhad, Iran.
bDepartment of Medicosocial, Biostatics Unit, Mashhad University of Medical
Sciences, Ghaem Hospital, Mashhad, Iran.
Abstract
Abortion is an important problem in obstetrics throughout the world. The common
and standard method for pregnancy termination at first trimester is surgery
(curettage). Nowadays, an effective method of pregnancy termination at first
trimester is medical treatments. The aim of this study is to compare misoprostol
alone or in combination with methotrexate for pregnancy termination at first
trimester. This study is a randomized clinical trial. A total of 200 pregnant
women at first trimester were randomizedly divided into two groups for
termination of pregnancy. The first group received 800 ?g vaginal misoprostol.
If conceptus residual remained, the same dose of misoprostol was repeated. The
second group received 50 mg/m? intramuscular methotrexate, and then 800 ?g
vaginal misoprostol was administered after 72 h. If conceptus residual remained,
the same dose of misoprostol was repeated after 24 h. Abdominal ultrasonography
was performed at seventh day for both groups. Should conceptus residual remained
or if pregnancy continued, curettage was performed. The results were analyzed
statistically in terms of chi-square, and student?s t-test, using the SPSS
software. A P-value equal or smaller than 0.05, was considered statistically
significant. In this study, 83% of the first group and 81% of the second group
had successful abortion. There was a significant correlation between the dose of
misoprostol and abortion (P = 0.001) and between type of pregnancy and need for
curettage (P < 0.000) in both groups, but there was no significant correlation
between gestational age and the numberof doses administered (P = 0.932).In
conclusion it seems that pregnancy termination by misoprostol alone or in
combination with methotrexate is a safe and cost-effective method.
Keywords: Missed abortion; Misoprostol; Methotrexate; Early medical abortion;
Pregnancy termination.
Introduction
The management of normal pregnancy without any side-effects, with the purpose of
saving the life of mother and fetus, is one of the important duties of
physician. However, but sometimes despite the desire of mother for continuing
pregnancy, the physician should perform abortion, for example in cases that
mother is complicated by pulmonary hypertension or a fetus that has severe
anomaly (including anencephaly or Down?s syndrome) (1).
In the recent decades, medical pregnancy termination methods have become a
suitable replacement for surgical methods. Three medications for early medical
abortion have been studied: the antiprogestin mifepristone, the antimetabolite
methotrexate, and the prostaglandin misoprostol. These agents cause abortion by
increasing uterine contractility, either by stimulating the myometrium directly
(misoprostol) or by reversing the progesterone-induced inhibition of contraction
( mifepristone and methotrexate) (1).
Methotrexate has been used safely and successfully to treat unruptured ectopic
pregnancy (2-4). It has long been known that methotrexate is cytotoxic to
proliferative trophoblastic tissue. Hence, so it has been used to treat
malignant trophoblastic and other epithelial tumors (5). In addition,
misoprostol has been approved by the Food and Drug Administration for the
prevention of gastric ulcer disease. Creinin and Vittinghoff used misoprostol
either alone or in combination with methotrexate up to 56 days from the last
menstrual period (6). They reported that 90 percent of their patients had
complete abortion. Lamakov and coworkers have reported a success rate of 96% in
termination of pregnancies which were less than 7 weeks, by the use of
misoprostol in combination with methotrexate. They concluded that these two
drugs are safe and effective in medical abortion and suggested them to
obstetricians (7). In another study performed in 2004 at South Africa, 104
patients were compared for the efficacy of medical abortion and expectant
management (8). The success rate of treatment with misoprostol was found to be
87% and in the expectant management 29%, in this study.
The aim of this study is to compare misoprostol alone or in combination with
methotrexate for termination of pregnancy at first trimester.
Experimental
The present study is a randomized clinical trial. The study population included
200 pregnant women at their first trimester (gestational age <13 weeks), who had
referred to teaching hospitals related to Mashhad University of Medical Sciences
during 2004-2007 for pregnancy termination.
The inclusion criteria of this study were:
a) Complete awareness of patients from both medical and surgical methods for
pregnancy termination and its side-effects.
b) An intrauterine pregnancy < 13 weeks on the basis of last menstruation period
or abdominal ultrasonography.
c) Specific reasons for pregnancy termination (missed abortion, blighted ovum
and therapeutic abortion).
The exclusion criteria of this study were hypersensitivity to misoprostol,
severe anemia (hemoglubin < 10g/dL), coagulopathy disorders or the use of
anticoagulant drugs, acute liver and adrenal disease, cardiovascular diseases,
uncontrolled seizure, and the use of corticosteroids.
The patients were randomisedly divided into two groups of 100 patients. The
first group was treated with vaginal misoprostol alone and the second group with
misoprostol and methotrexate. Misoprostol (Cytotec?) was manufactured by Pfizer
(Madrid) and methotrexate by the Ebeve Pharama (Austria). The study?s protocol,
the side-effects and benefits of medical abortion, the visit schedule and
informed consent were reviewed with each subject. Informed consent included both
the patient and her husband?s consent to perform an elective abortion with the
understanding that there would be a surgical abortion if the medical abortion
failed. All the women were asked to stop taking vitamin supplements containing
folate. The estimated gestational age was based on the last menstrual period and
abdominal ultrasonography. Baseline values of complete blood count, platelet
count, liver function tests and serum creatinine were measured and if there was
any abnormality in laboratory tests, the patients were excluded from the study.
Moreover, both methods had been approved by the Ethics Committee of Mashhad
University of Medical Sciences. A questionnaire was completed for each patient,
including age, gestational age, gravidity, type of pregnancy, doses of
misoprostol administration, need for curettage and drug side-effects.
The first group received 800 ?g vaginal misoprostol in the posterior fornix of
vagina by clinician without any additional intervention. The patients were
controlled for 4 h and if no complication appeared, they were discharged.
If conceptus expulsion did not occur based on patient's report, they received
another 800 ?g vaginal doses of misoprostol. After one week, abdominal
ultrasonography was performed and curettage was carried out if residue remained
or if pregnancy continued. Moreover, BG + Rh and liver and renal tests were
determined at first visit for both groups.
The second group received an intramuscular administration of 50 mg/m? of
methotrexate at first visit and returned after 72 h (second visit) for vaginal
administration of 800 ?g misoprostol. At the third visit (24 h later), if
expulsion did not occur, 800 ?g of vaginal misoprostol was again inserted in the
posterior fornix of vagina. After one week, abdominal ultrasonography was
performed and curettage was conducted if residue remained or if pregnancy
continued.
The assessed outcomes were including abortion success, duration of vaginal
bleeding, and side-effects. A successful abortion was defined as complete
abortion, confirmed by ultrasound examination without the requirement for a
surgical procedure.
Following the collection of study data, they were analyzed statistically
(chi-square, and student's t-test), using SPSS software. A P-value equal to or
less than 0.05 was considered statistically significant. Quantitative variables
were calculated as mean ? SD.
Results
In this study, there was no significant correlation between the two groups, as
they were compared in terms of age, number of pregnancy and gestational age
(Table 1).
In the first group, among 83 patients that had abortion, 55 (62%) cases had
successful abortion with one dose of misoprostol and 28 (34%) with two doses
(chi-square = 8.78, P < 0.001).
In the second group, among 81 patients that had abortion, 60 (79%) cases had
successful abortion with one dose of misoprostol and 21 (40%) with two doses
(chi-square=18.71, P< 0.001) (Table 2).
There was no significant correlation between dose of misoprostol and the need to
curettage in both groups (chi-square = 1.19, P = 0.275).
In terms of gestational age, patients were divided into two groups: gestational
age of ≤9 weeks and gestational age of > 9 weeks. In both groups, there was no
significant correlation between the gestational age and the dose of misoprostol
(chi-square = 0.007 , P = 0.934 in the first group and chi-square = 0.585 ,
P=0.44 in the second group respectively) (Table 3).
In the first group, there was a significant correlation between the gestational
age and the need to curettage (chi-square = 4.264, P = 0.039). However in the
second group, there was no significant correlation between these two variables
(chi- square= 2.335, P = 0.127) (Table 4).
In terms of the type of pregnancy, the patients were divided into two groups:
(a) missed abortion and (b) blighted ovum or therapeutic abortion. In the first
group, there was no significant correlation between the type of pregnancy and
the dose of misoprostol (chi-square=0.618, P=0.439) and in the second group,
there was a significant correlation between these two variables (chi-square=
15.425, P < 0.001).
In both groups, there was a significant correlation between the type of
pregnancy and curettage (chi-square= 3.83 and P = 0.051in the first group, and
chi-square= 4.258 and P = 0.038 in the second group).
In the present study, no important side-effects were observed with the use of
misoprostol or methotrexate.
Discussion
The clinical experience of this study suggests that early pregnancy termination
with misoprostol alone or the combination of low-doses of methotrexate and
vaginal misoprostol is both safe and effective. Although the toxicity of
methotrexate therapy for cancer is extensive, the doses used for cancer
treatment are much larger than those in this study.
In the present study, misoprostol alone was effective in medical abortion in 83%
of the subjects. There have been relatively few trials, which have evaluated the
use of misoprostol alone for early pregnancy termination (9). In a clinical
study using with 800 ?g vaginal misoprostol, there were 47% complete abortion,
27% incomlplete abortion and 27% ongoing pregnancy (6). Koopersmith and Mishell
have reported an extent of 61% complete abortion with doses of 200 and 400 ?g
misoprostol alone, as did Bugalho et al. who showed success rates of 66% and 46%
with 400 and 200?g misoprostol alone, respectively (10, 11). In a large series,
Carbonell et al. found a high success rate of 94% by using repeated doses of
misoprostol and reported this method would increase the efficacy and help to
progress incomplete abortion to complete abortion (12). In a study performed in
Florida in 2004, vaginal misoprostol was administered to 41 pregnant women for
first trimester abortion, and the rate of success obtained was 78% (13). This
rate of success observed is lower than our study, which could be due to the
fewer numbers of studied patients in their study.
The combination of misoprostol and methotrexate resulted in a complete and safe
termination of pregnancy, as demonstrated previously (14-17). In the present
study, the rate of success with this method was 81%. In the study performed in
2001 by Borgatta et al., methotrexate in combination with vaginal misoprostol
was administered in pregnancy with a gestational age of < 49 days, and 84% of
cases was found to have complete abortion (18). In the present study, the rate
of success with this method in cases with a gestational age of < 9 weeks was 83%
and for patients with a gestational age of ≤ 7 weeks was 100%. Creinin et al, in
USA, evaluated the efficacy of misoprostol and methotrexate in 300 pregnant
women with a maximum gestational age of 56 days. They reported that 90% of women
with a gestational age of 49 days and 81.6% with a gestational age of 50-56 days
had complete abortion (19). In our study, following the administration of
misoprostol and methotrexate in women with a gestational age of 9 weeks, 83% had
complete abortion and following the administration of misoprostol alone in the
same gestational age, 92.5% had complete abortion. The differences obtained
between these two studies are most probably due to the variation in the type of
patients. All the studied patients by Creinin et al. had live fetus, but in the
present study, the patients with missed abortion and blighted ovum also entered
the study. In the performed study by Beucher in 2004, vaginal misoprostol (800
?g) was administered for 102 pregnant women at first trimester. They showed that
72 cases had missed abortion and 30 patients threatened abortion. The rate of
success was reported to be 78.4% (20). Our study is statistically similar to the
study performed by Beucher et al. in 2004 which could be due to the similar
number and type of patients in both studies. Previous studies using methotrexate
followed 3-7 days later by vaginally administered misoprostol, had success rates
of 72% to 98% (21). Misoprostol had been reported to be more effective, when
given 7 days instead of 3, 4 or 5 days after administration of methotrexate
(16). In the study performed by Jahangir et al. at 2005, the efficacy of
misoprostol for termination of pregnancy in missed abortion was evaluated. They
suggested this method as an effective policy without side-effects, and a good
replacement for surgical methods (22).
Misoprostol alone or in combination with methotrexate could be an acceptable
method for the first trimester abortion. Since the rate of success is similar in
both methods, it is possible to eliminate the administration of methotrexate
which is a cytotoxic drug with many potential side-effects. Of course, it should
be mentioned that side-effects of methotrexate appear in large doses for
chemotherapy and for our patients that have received low doses (50 mg/m?), no
important side-effects was observed. For administration of methotrexate, it is
necessary to perform liver and renal tests and CBC ,which would all bear extra
costs. However, with the use of misoprostol alone, the cost of medical abortion
and the number of visits are effectively decreased and there is no need for
intramuscular injection.
In conclusion, the use of methotrexate in low dose in combination with
misoprostol or alone for the first trimester termination are both safe and
effective methods without important side-effects. These two methods can be used
alternatively, but the results of the present study suggest misoprostol alone is
easier. This is due to the fact that the number of visits is decreased, there is
no need for intramuscular injection and possible side-effects of methotrexate
that is a cytotoxic drug are eliminated. Most of the patients expressed their
consent of this method and suggested it to other patients.
Acknowledgements
The authors would like to thank the medical faculty of Mashhad University for
financial support of this study. Mrs. Touran Makhdoomi is thanked for editing
this manuscript, Mrs Ebrahim zadeh and Zahra Davarnia are also thanked for
following up the patients and Mrs. Moshtaghi for typing this manuscript.
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