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Methotrexate and misoprostol when surgical abortion fails
Methotrexate and Misoprostol When Surgical Abortion Fails ERIC A. SCHAFF, MD, MORRIS WORTMAN, MD, STEVEN H. EISINGER, MD, AND PETER FRANKS, MD Objective: To describe the use of methotrexate and misoprostol to induce abortion in pregnancies up to 8 w e e k s w h e n uterine or cervical anomalies make suction curettage difficult or impossible. Methods: Four consecutive w o m e n , 8 w e e k s pregnant or less and with failed suction curettage, were given methotrexate 50 m g per square meter intramuscularly f o l l o w e d by a misoprostol 800-/zg vaginal suppository 72 hours later. A repeat dose of a misoprostol 800-/~g suppository was administered on day 4 if there was no bleeding, and an additional dose was given if the repeat/3-hCG titer had not decreased by at least 50%. Subjects were followed-up with serum or urine hCG assays. Complete abortion was defined by vaginal bleeding and a negative urine pregnancy test. Subjects completed a daily s y m p t o m log and a satisfaction questionnaire w h e n the abortion was complete. Results: The four w o m e n referred after failed suction curettage had the f o l l o w i n g anatomic problems: a uterus bicornis bicollis, a bicornuate uterus, uterine leiomyomas, and cervical stenosis resulting from previous laser surgery. All subjects had a complete abortion from methotrexate and misoprostol. Mild gastrointestinal side effects were reported by all four subjects: nausea (two subjects), vomiting (two), and diarrhea (two). The satisfaction questionnaire revealed that all subjects agreed with the statements that "Overall, the procedure went well" and "I w o u l d recommend this procedure over a surgical abortion." Conclusion: Methotrexate and misoprostol can induce an abortion w h e n uterine or cervical anomalies make suction curettage difficult or impossible. (Obstet Gynecol 199&87: 450 -2)
Suction curettage is a safe surgical method to induce first-trimester abortion, with a reported complication rate of 0.3%. 1 Surgical abortion is more likely to fail under the following circumstances: very early gestational age, extreme vaginismus, cervical stenosis, endo-
metrial distortion secondary to leiomyomas, or a congenital structural abnormality of the uterus. The combination of methotrexate and misoprostol represents a major new development for early firsttrimester abortion. 2-5 Methotrexate is a folic acid antagonist and a competitive inhibitor of dihydrofolate reductase, thereby inhibiting the production of reduced folates required for de novo purine and pyrimidine synthesis and other transmethylation reactions. 6 It is a wellknown anti-neoplastic agent often used in the treatment of gestational trophoblastic disease 7 and used for immunosuppressive therapy for severe rheumatoid arthritis, systemic lupus erythematosus, Crohn disease, and psoriasis. The use of methotrexate is now considered an acceptable alternative to surgery for early unruptured ectopic pregnancies, with an efficacy rate of approximately 95%. 8,9 Misoprostol, a prostaglandin E 1 analogue, has been used successfully for the treatment of nonsteroidal anti-inflammatory drug-induced peptic ulcers. Known to cause uterine contractions, misoprostol has also been shown to ripen the cervix and induce labor for early, safe vaginal delivery in cases when the cervix is unripe and delivery is indicated, m'~l Creinin and Darney 12 found that when misoprostol is combined with methotrexate to induce an abortion, the vaginal route of misoprostol administration is more effective than the oral route. We examined the role of misoprostol and methotrexate, specifically in patients who had failed surgical abortion. These w o m e n were referred to the ongoing trial of methotrexate and misoprostol to induce abortion in w o m e n 8 weeks pregnant or less. The study was approved by the University of Rochester Research Subjects Review Board that began in July 1994.
Materials and Methods From tile Departments of Family Medicine and Obstetrics and Gyuecology, University of Rochester, Rochester, New York.
450
0029-7844/96/$15.00 SSDI 0029-7844(95)00406-8
The protocol has been reported in two previous reports. 4"5 In brief, w o m e n had to be 1) age 18 or older, 2)
Obstetrics & Gynecology
Table 1. Reason for Surgical Failure and Baseline Demographic and Clinical Variables
Subject Reason for surgical failure 1
Doublecervix and double uterus 2 Unicollisbicornis 3 Cervicalstenosis from laser surgery 4 Uterineleiomyoma LMP - last menstrual period.
Days hCG Age from day 1 (y) Parity LMP (IU/L) 22
0
52
104,000
22 45
0 2
49 49
55,300 126,472
29
0
56
85,946
in good health, 3) 56 days or less from the beginning of their last menstrual period (LMP) (initially, up to 49 days for the first 48 subjects), and 4) willing to comply with the visit schedule and phlebotomies. Each w o m a n had a urine pregnancy test, Rh type, hematocrit, and fi-hCG level measured. Gestational dating was determined by the first day of the LMP and uterine sizing by bimanual examination, using ultrasound when clinical dating was uncertain. Subjects were given 1) methotrexate 50 mg per square meter of body surface area, intramuscularly in the gluteal muscle; 2) a misoprostol 800/~g-compounded vaginal suppository to self-administer in 3 days; and 3) ten tablets of a c e t a m i n o p h e n with codeine p h o s p h a t e (300 rag/30 mg) to use for abdominal cramping as needed. All w o m e n had their/3-hCG level monitored until it was negative by a sensitive urine pregnancy test (below 25 IU/L). A repeat gynecologic examination was performed on day 14 or day 7 if no bleeding occurred. Subjects who had no bleeding within 24 hours after the administration of misoprostol were given a second dose to use the following day. Those whose /3-hCG level failed to decline by at least 50% at the 1-week follow-up visit were also given an additional misoprostol dose. Subjects maintained a daily log of s y m p t o m s and any medications used for abdominal cramping. When the abortion was complete, they completed a satisfaction questionnaire.
Results Four patients were referred after failed surgical abortion procedures. Table 1 provides the reason for surgical failure and baseline demographic and clinical variables. Examination of subject 1 revealed a vaginal septum and a double cervix. Transvaginal ultrasound suggested a uterus bicornis bicollis. Subject 2 had a transvaginal ultrasound that revealed a uterus unicolis bicornis with a gestational sac located in the right hemi-uterus. Subject 3 had an 11-year history of cervical dysplasia treated with five cryosurgeries and two car-
VOL. 87, NO. 3, MARCH 1996
bon dioxide laser vaporizations. On examination, the cervix was hypoplastic and the cervical os stenotic. Subject 4 had multiple uterine leiomyomas, the largest measuring 8.2 × 7.1 cm, with a uterus measuring 11 × 9 cm. The surgical procedure was stopped after a 7-mm flexible suction curette was inserted completely, raising the concern of either perforation or a distorted endometrial cavity due to the fibroids. Table 2 describes the dose of methotrexate, the number of doses of misoprostol and the day administered, the day of initial bleeding, and length of bleeding. All four subjects had complete medical abortions with methotrexate and misoprostol. Mild gastrointestinal side effects were reported by all four subjects: nausea (two subjects), vomiting (two), and diarrhea (two). The results of the satisfaction questionnaire revealed that all subjects agreed with the statements that "Overall, the procedure went well" and "I would recommend this procedure over a surgical abortion." Three of the four subjects agreed that "If I needed another abortion, I would choose this procedure," and the remaining subject was neutral. One subject found the cramping pain unacceptable.
Discussion Physicians who perform first-trimester abortions occasionally encounter difficulty in accessing the uterine cavity. This may be due to extreme vaginismus, a patient's inability to cooperate, marked anteflexion or retroflexion of the uterus, cervical stenosis, uterine myomas, or congenital abnormalities of the uterus. Methotrexate with misoprostol offers an alternative to surgery in these cases, potentially avoiding repeated surgical attempts, and general anesthetics and their resultant complications. Methotrexate injection followed by intravaginal misoprostol is simple to administer, well tolerated, easy to monitor with ]3-hCG titers or vaginal ultrasound, readily available, and inexpensive. Mifepristone m a y have similar benefits if it becomes available in the United States. An additional benefit of methotrexateand misoprostol-induced abortion is that it treats an early unsuspected ectopic pregnancy. Table 2. Methotrexate Dose, Day(s) of Misoprostol Administration, and Bleeding Response
Subject
Methotrexate dose (rag)
Day(s) of Initial Total misoprostol day of days of administration bleeding bleeding
1
72
3, 6
7
2
77
3 4
76 100
3 3, 16 3, 6
3 3 7
Schaff et al
Methotrexate for Abortion
11 14 24 19
451
References 1. Buehler JW, Schulz KF, Grimes DA, Hogue CJ. The risk of serious complications from induced abortions: Do personal characteristics make a difference? Am J Obstet Gynecol 1985;153:14-20. 2. Creinin MD. Methotrexate for abortion at <-42 days gestation. Contraception 1993;48:519-25. 3. Creinin MD, Vittinghoff E. Methotrexate and misoprostol vs misoprostol alone for early abortion, a randomized controlled trial. JAMA 1994;272:1190-5. 4. Hauseknecht RU. Methotrexate and misoprostol for induced abortion. New Engl J Med 1995;333:537 40. 5. Schaff EA, Eisinger S, Franks P, Kim S. Combined methotrexate and misoprostol for early induced abortion. Arch Fam Med 1995;4:774-9. 6. Sznol M, Ohnuma T, Holland JF. Hepatic toxicity of drug used for hematologic neoplasia. Semin Liver Dis 1987;7:237-56. 7. Ross GT, Goldstein DP, Hertz R, Lipsett MB, Odell WD. Sequential use of methotrexate and actinomycin D in the treatment of metastatic choriocarcinoma and related trophoblastic diseases in women. Am J Obstet Gynecol 1965;93:223-9. 8. Lindblom B. Ectopic pregnancy: Laparoscopic and medical treatment. Curt Opin Obstet Gynecol 1992;4:400-5. 9. Stoval TG, Ling FW. Single-dose methotrexate: An expanded clinical trial. Am J Obstet Gynecol 1993;168:1759-62. 10. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intra-
452
S c h a f f et al
Methotrexate for Abortion
vaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 11. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E~ methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81:332- 6. 12. Creinin MD, Darney PD. Methotrexate and misoprostol for early abortion. Contraception 1993;48:339 47.
A d d r e s s r e p r i n t r e q u e s t s to:
Eric A. Schaff, MD Department of Family Medicine University of Rochester 885 South Avenue Rochester, N Y 14620
Received ]Hly 27, 1995. Received in revised form October 11, 1995. Accepted October 23, 1995. Copyright © 1996 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
Obstetrics & Gynecology
Suction curettage is a safe surgical method to induce first-trimester abortion, with a reported complication rate of 0.3%. 1 Surgical abortion is more likely to fail under the following circumstances: very early gestational age, extreme vaginismus, cervical stenosis, endo-
metrial distortion secondary to leiomyomas, or a congenital structural abnormality of the uterus. The combination of methotrexate and misoprostol represents a major new development for early firsttrimester abortion. 2-5 Methotrexate is a folic acid antagonist and a competitive inhibitor of dihydrofolate reductase, thereby inhibiting the production of reduced folates required for de novo purine and pyrimidine synthesis and other transmethylation reactions. 6 It is a wellknown anti-neoplastic agent often used in the treatment of gestational trophoblastic disease 7 and used for immunosuppressive therapy for severe rheumatoid arthritis, systemic lupus erythematosus, Crohn disease, and psoriasis. The use of methotrexate is now considered an acceptable alternative to surgery for early unruptured ectopic pregnancies, with an efficacy rate of approximately 95%. 8,9 Misoprostol, a prostaglandin E 1 analogue, has been used successfully for the treatment of nonsteroidal anti-inflammatory drug-induced peptic ulcers. Known to cause uterine contractions, misoprostol has also been shown to ripen the cervix and induce labor for early, safe vaginal delivery in cases when the cervix is unripe and delivery is indicated, m'~l Creinin and Darney 12 found that when misoprostol is combined with methotrexate to induce an abortion, the vaginal route of misoprostol administration is more effective than the oral route. We examined the role of misoprostol and methotrexate, specifically in patients who had failed surgical abortion. These w o m e n were referred to the ongoing trial of methotrexate and misoprostol to induce abortion in w o m e n 8 weeks pregnant or less. The study was approved by the University of Rochester Research Subjects Review Board that began in July 1994.
Materials and Methods From tile Departments of Family Medicine and Obstetrics and Gyuecology, University of Rochester, Rochester, New York.
450
0029-7844/96/$15.00 SSDI 0029-7844(95)00406-8
The protocol has been reported in two previous reports. 4"5 In brief, w o m e n had to be 1) age 18 or older, 2)
Obstetrics & Gynecology
Table 1. Reason for Surgical Failure and Baseline Demographic and Clinical Variables
Subject Reason for surgical failure 1
Doublecervix and double uterus 2 Unicollisbicornis 3 Cervicalstenosis from laser surgery 4 Uterineleiomyoma LMP - last menstrual period.
Days hCG Age from day 1 (y) Parity LMP (IU/L) 22
0
52
104,000
22 45
0 2
49 49
55,300 126,472
29
0
56
85,946
in good health, 3) 56 days or less from the beginning of their last menstrual period (LMP) (initially, up to 49 days for the first 48 subjects), and 4) willing to comply with the visit schedule and phlebotomies. Each w o m a n had a urine pregnancy test, Rh type, hematocrit, and fi-hCG level measured. Gestational dating was determined by the first day of the LMP and uterine sizing by bimanual examination, using ultrasound when clinical dating was uncertain. Subjects were given 1) methotrexate 50 mg per square meter of body surface area, intramuscularly in the gluteal muscle; 2) a misoprostol 800/~g-compounded vaginal suppository to self-administer in 3 days; and 3) ten tablets of a c e t a m i n o p h e n with codeine p h o s p h a t e (300 rag/30 mg) to use for abdominal cramping as needed. All w o m e n had their/3-hCG level monitored until it was negative by a sensitive urine pregnancy test (below 25 IU/L). A repeat gynecologic examination was performed on day 14 or day 7 if no bleeding occurred. Subjects who had no bleeding within 24 hours after the administration of misoprostol were given a second dose to use the following day. Those whose /3-hCG level failed to decline by at least 50% at the 1-week follow-up visit were also given an additional misoprostol dose. Subjects maintained a daily log of s y m p t o m s and any medications used for abdominal cramping. When the abortion was complete, they completed a satisfaction questionnaire.
Results Four patients were referred after failed surgical abortion procedures. Table 1 provides the reason for surgical failure and baseline demographic and clinical variables. Examination of subject 1 revealed a vaginal septum and a double cervix. Transvaginal ultrasound suggested a uterus bicornis bicollis. Subject 2 had a transvaginal ultrasound that revealed a uterus unicolis bicornis with a gestational sac located in the right hemi-uterus. Subject 3 had an 11-year history of cervical dysplasia treated with five cryosurgeries and two car-
VOL. 87, NO. 3, MARCH 1996
bon dioxide laser vaporizations. On examination, the cervix was hypoplastic and the cervical os stenotic. Subject 4 had multiple uterine leiomyomas, the largest measuring 8.2 × 7.1 cm, with a uterus measuring 11 × 9 cm. The surgical procedure was stopped after a 7-mm flexible suction curette was inserted completely, raising the concern of either perforation or a distorted endometrial cavity due to the fibroids. Table 2 describes the dose of methotrexate, the number of doses of misoprostol and the day administered, the day of initial bleeding, and length of bleeding. All four subjects had complete medical abortions with methotrexate and misoprostol. Mild gastrointestinal side effects were reported by all four subjects: nausea (two subjects), vomiting (two), and diarrhea (two). The results of the satisfaction questionnaire revealed that all subjects agreed with the statements that "Overall, the procedure went well" and "I would recommend this procedure over a surgical abortion." Three of the four subjects agreed that "If I needed another abortion, I would choose this procedure," and the remaining subject was neutral. One subject found the cramping pain unacceptable.
Discussion Physicians who perform first-trimester abortions occasionally encounter difficulty in accessing the uterine cavity. This may be due to extreme vaginismus, a patient's inability to cooperate, marked anteflexion or retroflexion of the uterus, cervical stenosis, uterine myomas, or congenital abnormalities of the uterus. Methotrexate with misoprostol offers an alternative to surgery in these cases, potentially avoiding repeated surgical attempts, and general anesthetics and their resultant complications. Methotrexate injection followed by intravaginal misoprostol is simple to administer, well tolerated, easy to monitor with ]3-hCG titers or vaginal ultrasound, readily available, and inexpensive. Mifepristone m a y have similar benefits if it becomes available in the United States. An additional benefit of methotrexateand misoprostol-induced abortion is that it treats an early unsuspected ectopic pregnancy. Table 2. Methotrexate Dose, Day(s) of Misoprostol Administration, and Bleeding Response
Subject
Methotrexate dose (rag)
Day(s) of Initial Total misoprostol day of days of administration bleeding bleeding
1
72
3, 6
7
2
77
3 4
76 100
3 3, 16 3, 6
3 3 7
Schaff et al
Methotrexate for Abortion
11 14 24 19
451
References 1. Buehler JW, Schulz KF, Grimes DA, Hogue CJ. The risk of serious complications from induced abortions: Do personal characteristics make a difference? Am J Obstet Gynecol 1985;153:14-20. 2. Creinin MD. Methotrexate for abortion at <-42 days gestation. Contraception 1993;48:519-25. 3. Creinin MD, Vittinghoff E. Methotrexate and misoprostol vs misoprostol alone for early abortion, a randomized controlled trial. JAMA 1994;272:1190-5. 4. Hauseknecht RU. Methotrexate and misoprostol for induced abortion. New Engl J Med 1995;333:537 40. 5. Schaff EA, Eisinger S, Franks P, Kim S. Combined methotrexate and misoprostol for early induced abortion. Arch Fam Med 1995;4:774-9. 6. Sznol M, Ohnuma T, Holland JF. Hepatic toxicity of drug used for hematologic neoplasia. Semin Liver Dis 1987;7:237-56. 7. Ross GT, Goldstein DP, Hertz R, Lipsett MB, Odell WD. Sequential use of methotrexate and actinomycin D in the treatment of metastatic choriocarcinoma and related trophoblastic diseases in women. Am J Obstet Gynecol 1965;93:223-9. 8. Lindblom B. Ectopic pregnancy: Laparoscopic and medical treatment. Curt Opin Obstet Gynecol 1992;4:400-5. 9. Stoval TG, Ling FW. Single-dose methotrexate: An expanded clinical trial. Am J Obstet Gynecol 1993;168:1759-62. 10. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intra-
452
S c h a f f et al
Methotrexate for Abortion
vaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 11. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E~ methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81:332- 6. 12. Creinin MD, Darney PD. Methotrexate and misoprostol for early abortion. Contraception 1993;48:339 47.
A d d r e s s r e p r i n t r e q u e s t s to:
Eric A. Schaff, MD Department of Family Medicine University of Rochester 885 South Avenue Rochester, N Y 14620
Received ]Hly 27, 1995. Received in revised form October 11, 1995. Accepted October 23, 1995. Copyright © 1996 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
Obstetrics & Gynecology