06-dr. ayati.doc

Original Article

Efficacy of Combination Therapy with
Methotrexate and Misoprostol in Termination
of Pregnancy in the First Trimester

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
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
Live fetus
118 Iran J Med Sci June 2009; Vol 34 No 2 Methotrexate and misoprostol for first trimester termination
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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