[ original research * nouveaute's en recherche I

IABORTION INDUCED WVITH MAETHOTREXATE

AND MISOPROSTOL
Ellen R. Wiebe, MO

Objective: To determine the outcome and side effects of a new drug protocol to induce abortion. Design: Case series. Setting: An urban primary care practice. Patients: One hundred consecutive patients who requested elective termination of pregnancies of less
than 8 weeks' gestation. Intervention: Subjects received methotrexate (50 mg/m2 body surface area, administered intramuscularly) and, 3 days afterward, misoprostol (800 pg, given vaginally). Outcome measures: Number of abortions induced within 24 hours and within 10 days of misoprostol administration, number of surgical aspirations conducted because of incomplete abortion, mean amount of bleeding and pain and the number of women who, if faced with the same situation, said they would again choose a drug-induced abortion over a surgical one. Results: Abortion occurred within 24 hours of misoprostol administration among 48 women and within 10 days among 69 women. In total, 89 women had an abortion without surgical aspiration. Of these women, 71 said they would choose a drug-induced abortion if faced with the choice again. Conclusion: Abortion induced with methotrexate and misoprostol appears to be a feasible alternative to surgical abortion and deserves further study.

Objectifs D&terminer les r-6sultats

provoquer un avortement.

et les effets secondaires d'un nouveau

protocole pharmaceutique pour

Conception Se'ie de cas. Contexte :Pratique urbaine de soins primaires.

Patientes C ent patientes cons6cutives qui ont demand6 linterruption volontaire de grossesses de momns de 8 semaines. Intervention Les sujets ont requ du m6thotrexate (50 mg/m2 de surface corporelle, administr-6 par voie intramusculaire) et, 3 jours apr~s, du misoprostol (800 pg, administre' par voie vaginale). Mesures des re'sultats : Nombre d'avortements provoqu6s dans les 24 heures et dans les 10 jours suivant ladministration de misoprostol, nombre d'aspiratinns chirurgicales effectui6es hi cause d'un avortement incomplet, volume moyen de saignement, douleur moyenne et nombre de femmes qui, dans Ia meme situation, ont affirm6 qu'elles choisiraient de nouveau un avortement par m6dicament plut6ot que par intervention chirurgicale. Re'sultats L'avortement s'est produit dans les 24 heures suivant ladministration du misoprostol chez 48 femmes et dans les 10 jours chez 69. Au total, 89 femmes ont subi un avortement sans aspiration chirurgicale, et 71 d'entre elles ont d6clar6 qu'elles choisiraient un avortement par m6dicament si elles devaient faire de nouveau le meme choix. Conclusion L'avortement provoqu6 par le m6thotrexate et le misoprostol semble une solution de rechange possible aux avortements chirurgicaux et m6rite de~tre 6tudi6 plus ha fond.

M edical abortion (induced with the use of drugs) has been available as an alternative to surgical abortion in Europe since 1990. Medical abortion has several advantages: it allows women to avoid the risks of surgery and anesthesia, and it can be performed very

early in a pregnancy (at 4 to 7 weeks' gestation). It can be managed in the privacy of the physician's office and the woman's home, thus making it less likely to be the
target of anti-abortion activities. Since 1991 selected ectopic pregnancies have been

Dr. Wiebe is clinical assistant professor, Department of Family Practice, University of British Columbia, Vancouver, BC.

Reprint requests to: Dr. Ellen R. Wiebe, 1310 750 W Broadway, Vancouver BC V5Z 1.13; fax 604 873-8304

CAN MED ASSOC J * JAN. 15, 1996; 154 (2)

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successfully terminated with the use of methotrexate.' This regimen consists of a single dose of 50 mg/m2 body surface area, administered intramuscularly; it has a success rate of 94.3% and minimal side effects.2 The rate of patients' return to fertility after methotrexate treatment is greater than that after surgical intervention in ectopic pregnancies.' In Europe, medical abortion of intrauterine pregnancy is induced with the use of mifepristone (also known as RU486) in combination with various prostaglandins. However, mifepristone is not available in Canada. In terms of the choice of prostaglandins, misoprostol has been shown to be less expensive than, to be equally effective as and to have fewer side effects than gemeprost, when used with mifepristone.45 In 1993 Creinin and Darney6 published the first reports of abortion of intrauterine pregnancy induced with methotrexate and misoprostol. They used a protocol of methotrexate (50 mg/m2 body surface area given intramuscularly) with misoprostol (800 j.g given vaginally) 72 hours later. Further reports have shown that this regimen is safe and effective and has few side effects.` Methotrexate is cytotoxic to trophoblast and hence causes abortion; however, when methotrexate is used alone, abortion takes a mean 24 days after drug administration.7 Prostaglandin analogues increase the contractility of the smooth muscle in the uterus and cause expulsion of the conceptus. Used alone, misoprostol results in completed abortion in only 47% of women.' However, when methotrexate and misoprostol have been used together, the rate of completed abortion has been 90%. Methotrexate affects bone marrow, liver and kidney function when used for some other indications, but the single dose used in these studies' 267 did not have any effect on hematologic, hepatic or renal function. Studies conducted in France," Scotland12'3 and Hong Kong'4 have compared medical abortion with surgical abortion. The investigators found that women who were single, had more education and were pregnant for the first time were more likely than other women to choose medical abortion. Fewer women who had had a medical abortion (87.7%) were satisfied with their care than those who had had a surgical abortion (95.3%).1 The rate of psychiatric morbidity after abortion was similar in the two groups.'3 The costs of medical and surgical abortion have been compared and found to be similar.'1-'7 There has been concern about the possible teratogenic effects of methotrexate and misoprostol. There are reports that four infants born to women treated with methotrexate during the first trimester had a very rare and characteristic pattern of congenital anomalies, indicating that methotrexate is probably teratogenic.'8,9 However, there are also reports of healthy children born to such women.202 Seven cases of limb abnormalities
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have been reported among children born to women who attempted to abort the pregnancy with the use of misoprostol, indicating that misoprostol may be teratogenic.22-24 In Europe, women who choose medical abortion have a surgical abortion if the medical abortion fails, so the risk of children being born with congenital anomalies as the result of a failed medical abortion is low. This article describes the first 100 cases in Canada of abortion induced with methotrexate and vaginally administered misoprostol. When this study began, there were only four previous cases reported.6 The aim of this study was to determine whether a protocol of a single dose of methotrexate followed by administration of misoprostol is a feasible method of inducing abortion.

METHODS
This study was conducted in an urban primary care practice. Women who requested termination of a pregnancy of 7 weeks' gestation or less were recruited. Approval was granted by the Clinical Screening Committee for Research Involving Human Subjects of the University of British Columbia. Inclusion criteria were a request for elective abortion, ability to understand the consent form, pregnancy of less than 8 weeks' gestation on the first day of treatment and willingness to comply with schedules for visits and blood tests. Exclusion criteria were a hemoglobin concentration of less than 95 g/L, a leukocyte count of less than 3.0 x i09/L, active liver disease (indicated by an aspartate aminotransferase level of more than twice the normal level), renal insufficiency (indicated by a serum creatinine level of more than 120 amol/L), inflammatory bowel disease or a history of intolerance to methotrexate or misoprostol. The study protocol, the risks and benefits of medical abortion, the visit schedule and informed consent were reviewed with each potential subject. Informed consent included an agreement that the patient would have a surgical abortion if the medical abortion failed. For each patient results of the following tests were obtained and reviewed: a complete blood count, an aspartate aminotransferase level, a serum creatinine level, urinalysis, a quantitative serum level of human chorionic gonadotropin (hCG) and a test for Rh factor. A history was taken and a physical examination performed. All women were asked to stop taking vitamin supplements containing folate. For the first 15 patients a baseline ultrasonographic examination was performed to confirm the estimated gestational age. Because of the difficulty in obtaining ultrasonographic examinations, for the rest of the subjects baseline examinations were performed only if more than 6 weeks had elapsed since the first day of

the patient's last period, the menstrual dates were uncertain or the pelvic examination failed to confirm the gestational age. I used the same protocol as that used by Creinin and Darney.6 All subjects received 50 mg/m2 body surface area of methotrexate, administered intramuscularly, on the first day of treatment (day 1). Women with Rh-negative blood also received 120 pg of Rh(D) immune globulin on this day. The first five patients returned 3 days later (day 4) to have the misoprostol (800 pg given as four tablets) inserted into the vagina. The rest of the subjects were given the dose of misoprostol to insert vaginally at home on the appropriate day. The take-home dose consisted of a #00 gelatin capsule filled with 800 pg of misoprostol, in the form of tablets that had been ground into a powder, to be inserted with a vaginal applicator. Subjects were given acetaminophen with codeine tablets (Tylenol No. 3) to take as required for pain. Three days after the misoprostol was administered (day 7), a quantitative serum hCG measurement was obtained. The first 15 subjects also underwent a second ultrasonographic examination. All subjects returned to the office 4 days after the misoprostol was given (day 8). If the subject had not had a completed abortion by this day, she was given a second dose of misoprostol. Among the first 15 subjects, those who had not had a completed abortion after 2 weeks underwent surgical aspirations. The remaining 85 subjects visited the physician's office weekly, and quantitative serum hCG levels were taken until they had had a completed abortion. Among these patients, only those in whom the hCG levels were not falling or who had pregnancy symptoms, prolonged bleeding or pain had an ultrasonographic examination. A surgical abortion was performed if medical abortion was incomplete. Approximately 2 weeks after each abortion, a vaginal examination was performed to ensure that the patient had a normal uterus with no tenderness or indications of pregnancy. Abortion was assumed to be completed on the basis of the falling hCG level and clinical history and was confirmed by the final pelvic examination. If there was any doubt, an ultrasonographic examination was performed. The women were asked to fill out a daily symptom log of pain, measured on an 11-point numeric scale, bleeding, measured by pad count, and other symptoms such as nausea. They were questioned about side effects at each visit. At the last visit, they handed in their symptom log and were asked a question concerning their satisfaction with the procedure (If you had to undergo this procedure again and had a choice, do you think you would choose a surgical abortion or a medical abortion?). They were also counselled about contraception. Those choosing oral contraceptives started taking them after the abortion, when the bleeding became light. For those wishing to use

intrauterine devices or levonorgestrel implants, these were inserted at least 2 weeks after the abortion. Women who did not return for follow-up visits were contacted by telephone. Outcome measures were the number of abortions induced within 24 hours (day 5) and within 10 days (by day 14) of misoprostol administration, the number of surgical aspirations, the mean amount of bleeding and pain and the number of women who, if faced with the same situation, would again choose a medical abortion over a surgical one. STATISTICAL ANALYSIS
Statistical analysis was carried out with the use of Number Cruncher Statistical System software (version 5, Number Cruncher, copyright by Dr. Jerry Hintz, Utah). Descriptive statistics and frequency distributions were compiled for the entire sample. Student's t-tests and X2 tests were used to assess the ability of characteristics (gestational age, baseline hCG level and change in hCG level) to predict the outcome of the procedure. The upper bound of the true percentage of serious side effects was computed with the use of a one-tailed confidence interval for a binomial parameter when no occurrences are observed. The sample size was calculated on the basis of the proportion of a particular item (in this case, a serious side effect) in a population of independent trials, assuming that no serious side effects are observed. For very large populations, a sample size of 100 results in an upper limit of a 95% confidence interval that represents a true occurrence (of serious side effects, in this case) of 3% in the population.

RESULTS
PATIENT CHARACTERISTICS

All 100 women who consented to participate in the study received both drugs and made at least one followup visit. The mean age of the subjects was 28.2 years (range 15 to 46). The mean gestational age was 5.6 weeks (range 4 to 8 weeks). It was the first pregnancy for 42 of the women; approximately one third had had at least one previous surgical abortion and one third had given birth at least once (Table 1). OUTCOME

Of the 100 women, 48 had a completed abortion within 24 hours of the first dose of misoprostol (by day 5). The 50 women who had not had an abortion by the visit on day 8 received a second dose of misoprostol. By day 14, 69 women had had a completed abortion; an additional 15 women had a completed abortion between
CAN MED ASSOC J * JAN. 15, 1996; 154 (2)
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days 15 and 28, as did 5 more women between days 29 and 44. There were 11 surgical aspirations performed during the study, 4 among the first 15 subjects but only 7 among in the next 85. This difference in the rate of surgical abortion reflects the investigator's learning curve in managing delayed reactions to medical treatment. Of the 11 surgical aspirations, 7 involved continuing pregnancies, 1 involved an incomplete abortion with symptoms (cramping pain for 5 days and ultrasonographic evidence of nonviable gestation) and 3 involved patients with delayed reactions who did not wish to wait any longer. There were no serious or prolonged side effects. The only side effect noted after methotrexate injections was nausea. After the insertion of misoprostol, there were 11 reports of increased nausea, 9 of diarrhea (usually mild and lasting only a few hours), 8 of fever, 8 of headache, 3 of chills and 2 of vomiting. Nine of the 11 surgical aspirations were scheduled on a nonurgent basis at a freestanding abortion clinic. The other two were performed urgently as a result of visits to the emergency depart-

ment by the patients, one of whom had heavy bleeding (but did not require a transfusion) and the other of whom had intractable pain. The mean worst pain score was 5.8 on a scale of 0 (no pain) to 10 ("pain as bad as it can be"); 14 women rated their worst pain at 9 or 10. The women reported a mean 12 days of bleeding (Table 2). Fetuses from three of the surgical aspirations involving continuing pregnancies could be examined for anomalies. In each case there were limb defects. Potential factors predicting outcome were analysed. It proved impossible to predict successful outcome on the basis of gestational age. An analysis of hCG levels among the subjects showed that the women who underwent surgical aspirations had a significantly higher baseline hCG level (mean 64 232 IU/L) than the other women (mean 28 006 lU/L, p = 0.0019). A decrease of at least 50% in quantitative hCG levels between the first test, taken before treatment was started, and the test taken on day 7 indicated a completed abortion. No other result was definitive. However, hCG levels fell during the first week of treatment in two of the seven women with continuing pregnancies, and 28 of the women who had successful medical abortions had rising hCG levels.

PATIENT ACCEPTANCE
15-24 .25-34.

33
50` 17

35-46

Gestatlonalage, wk
4-5'

5.5-6 6.5-7 7.5-8 Baseline human chorionic gonadotropin inve, lU/L:-:

35 44 17

140-1000-00 10`001-50 000 50 001-100 Q000100001-150000 > 150000 Obstetric history

First pregnancy 1 previous surgical abortion > I previous surgical abortion

45 35 12.
5

2
42

Of the 89 women who had successful medical abortions, only 6 said they would choose a surgical abortion if faced with the choice again; they gave as reasons that medical abortion was too painful or too long or that the uncertainty was too stressful. One of these six women had had a previous surgical abortion. Seven women said they were uncertain whether they would have a medical abortion and five did not answer the question. The 71 women who were satisfied with their experience gave the following reasons: they did not need to wait for an abortion in a clinic (which are performed only after 7 weeks' gestation), they wanted to avoid surgery, they were afraid of the protesters around the clinics, they wanted to be at home with their support person, and they found that medical abortion "felt more natural" than surgical abortion or that it was "no worse than my normal period." Patient satisfaction could not be predicted on the basis of a history of previous abortion, patient age or gestational age.

23 6

DISCUSSION
The main results of this case series on medical abortion are that 48% of the women had a completed abortion within 24 hours of the first misoprostol dose (by day 5) and that 69% had a completed abortion by day 14; 1 1 % of the women eventually underwent surgical as-

1 previous live birth 16 16 l previou's live birth *The baseline human chorionic.gonadotropin level was not obtained from one patient; the number *f patients in categoies df obstetric histoy sums to mbre than 100 Ocouse somnepatients were in more than one categry.

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piration. Patient satisfaction was high despite the long process involved. There were no serious side effects. There are limitations to this study: it is only descriptive and does not include a control group. The success rate was 89% (the percentage of women who had an abortion without surgical aspiration); however, three of the surgical aspirations were considered unnecessary, raising the theoretic effectiveness of the drug protocol to 92%. This is similar to the 90% rate shown in a study of the same protocol by Creinin and Vittinghoff.8 However, these rates are not as high as those of medical abortion induced with mifepristone (which has a 95% to 97% success rate).45 The high degree of patient satisfaction was surprising, in view of the bleeding and pain patients experienced. The amount of bleeding and pain caused by medical abortion is greater than that caused by surgical abortion. The mean amount of pain shown in this study was 5.8 on the 1 1-point pain scale; by contrast, a previous study showed a mean pain score of 4.2 among 211 women undergoing a surgical abortion with local anesthesia.25 The delay, uncertainty and amount of bleeding associated

with medical abortion was distressing to many women, especially the 20% of subjects who had delayed reactions. However, the side effects of the drugs were infrequent, mild and transient. Despite all of the disadvantages, most of the women were satisfied and said they would choose a medical over a surgical abortion if faced with the same situation again. These women were highly motivated to avoid surgery; many were very grateful to have the choice of a medical abortion. The teratogenic effect of the agents is worrisome; it is therefore crucial that every woman having a medical abortion be followed up. In this study there was a problem with women failing to come in for their final followup visit. Each one was contacted by telephone, at the least, to ensure that there were no late complications. On the basis of these 100 cases, we can conclude, with 95% confidence, that this procedure is 97% safe (that is, free of serious complications). When other cases published by Creinin and collaborators6"0 in the United States are taken into account, we can say that it is safe 99% of the time.

Outcome, side effect or

preference
Outome..

Abort.^io.n coinpeteui,. 'no of days of drug protocol elapsed. Surgical 4-5; 6-14. 15-4. aspiration* 421 .. : : ..8 20:. 11
5 4 .. 4 16 2
3

Total
-100

SWdeefhect.Nausea

4
1

Diarrhea
Fever Duration of bleding < lOd

1 7

0 1 1

11. 9 8
31 32 26

8.
7

>than10.d.

N4detat - :: eore for .. p Pailn,

O 1.-7

19 ; .13.
0 16 14 18
41 1 3

6
2 11 4 4

6 7 0 7 7 6
15
5

NAt NA NA
NA NA

8-10 Nodatd Prefrernce Prefer.medical abortion

NA NA
NA N.A
NA

2 34 25 28
71 7

Uncertain Prefer surgical abortion Nodata *2 1 *strgical aspiration was performed because of incomplete abortion.
tN = not applicable.
tPain was scored on a scale of 0 (no pain) to 10 (pain as bad as it can be).

15 1 3

0 2

NA

6 5

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CONCLUSION

Medical abortion induced with methotrexate and misoprostol appears to be a feasible alternative to surgiNaji SA, Russell IT al: Comparison of cal abortion. More research is needed to determine the 12. Henshaw RC,with surgical vacuumetaspiration; women's medprefical abortion best timing and dosages of the drugs and to compare erences and acceptability of treatment. BMJ 1993; 307: medical abortion induced with mifepristone with that in714-717 duced with methotrexate and with surgical abortion.
I thank Cheryl Couldwell, my office assistant, for providing enthusiastic support and encouragement to me and my patients, and Jonathan Berkowitz for providing statistical support.

11. Bachelot A, Cludy L, Spira A: Conditions for choosing between drug-induced and surgical abortions. Contraception 1992;45: 547-559

13. Urquhart DR, Templeton A: Psychiatric morbidity and acceptability following medical and surgical methods of induced abortion. Br J Obstet Gynaecol 1991; 98: 396-399

14. Tang GWK: A pilot study of acceptability of RU 486 and ONO 802 in a Chinese population. Contraception 1991; 44: 523-532 1. Stovall TG, Ling FW, Gray LA: Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991; 77: 754-757
2. Stovall TG, Ling FW: Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993; 168:
1759-1765

15. Doherty P: Medical abortion. [letter] BMJ 1992; 304: 573

16. Kidd GM: Medical abortion. [letter] BMJ 1992; 304: 1380
17. Thong KJ, Baird DT: Medical abortion. [letter] BMJ 1992; 305: 187-188 18. Milunsky A, Graef JW, Gaynor MF: Methotrexate-induced congenital malformations. JPediatr 1968; 72: 790-795
19. Powell HR, Ekert H: Methotrexate-induced congenital malformations. Med J Aust 1971; 2: 1076-1077

3. Stovall TG, Ling FW, Buster JE: Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol 1990; 162: 1620-1624

4. Peyron R, Aubeny E, Targosz V et al: Early termination of pregnancy with mifepristone (ru 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993; 328: 1509-15 13
5. Thong KJ, Dewar MH, Baird DT: What do women want during medical abortion? Contraception 1992; 46: 435-442
6. Creinin MD, Darney PD: Methotrexate and misoprostol for early abortion. Contraception 1993; 48: 339-348
7. Creinin MD: Methotrexate for abortion at < or = 42 days gestation. Contraception 1993; 48: 519-525

20. Ross GT: Congenital anomalies among children born of mothers receiving chemotherapy for gestational.trophoblastic neoplasms. Cancer 1976; 37: 1043-1047

21. Kozlowski RD, Steinbrunner JV, MacKenzie AH et al: Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990; 88: 589-592
22. Gonzalez CH, Vargas FR, Perez AB et al: Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy. Am J Med Genet 1993; 47 (1): 59-64
23. Schuler L, Ashton PW, Sanseverino MT: Teratogenicity of misoprostol. [letter] Lancet 1992; 339: 437 24. Fonseca W, Alencar AJ, Mota FS et al: Misoprostol and congenital malformations. [letter] Lancet 1991; 338: 56

8. Creinin MD, Vittinghoff E: Methotrexate and misoprostol vs misoprostol alone for early abortion. A randomized controlled trial. JAMA 1994; 272: 1190-1195
9. Creinin MD: Methotrexate and misoprostol for abortion at 57-63 days gestation. Contraception 1994; 50: 511-515 10. Creinin MD, Vittinghoff E, Galbraith S et al: A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Am J Obstet Gynecol 1995;
173: 1578-1584

25. Wiebe ER, Rawling M: Pain control in abortion. Int J Gynecol Obstet (in press)

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