Ellen R. Wiebe, MD
Canadian Medical Association Journal 1996; 154; 165-170
[résumé]
Paper reprints may be obtained from: Dr. Ellen R. Wiebe, 1310750 W Broadway, Vancouver BC V5Z 1J3; fax 604 873-8304
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 µg, 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.
Conception : Série de cas.
Contexte : Pratique urbaine de soins primaires.
Patientes : Cent patientes consécutives qui ont demandé l'interruption volontaire de grossesses de moins de 8 semaines.
Intervention : Les sujets ont reçu du méthotrexate (50 mg/m2 de surface corporelle, administré par voie intramusculaire) et, 3 jours après, du misoprostol (800 µg, administré par voie vaginale).
Mesures des résultats : Nombre d'avortements provoqués dans les 24 heures et dans les 10 jours suivant l'administration de misoprostol, nombre d'aspirations chirurgicales effectuées à cause d'un avortement incomplet, volume moyen de saignement, douleur moyenne et nombre de femmes qui, dans la même situation, ont affirmé qu'elles choisiraient de nouveau un avortement par médicament plutôt que par intervention chirurgicale.
Résultats : L'avortement s'est produit dans les 24 heures suivant l'administration 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 déclaré qu'elles choisiraient un avortement par médicament si elles devaient faire de nouveau le même choix.
Conclusion : L'avortement provoqué par le méthotrexate et le misoprostol semble une solution de rechange possible aux avortements chirurgicaux et mérite d'être étudié plus à fond.
Since 1991 selected ectopic pregnancies have been successfully terminated with the use of methotrexate.[1] 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.[3]
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.[4,5] In 1993 Creinin and Darney[6] 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 µg given vaginally) 72 hours later. Further reports have shown that this regimen is safe and effective and has few side effects.[710]
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.[8] 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[1,2,6,7] did not have any effect on hematologic, hepatic or renal function.
Studies conducted in France,[11] Scotland[12,13] and Hong Kong[14] 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%).[11] The rate of psychiatric morbidity after abortion was similar in the two groups.[13] The costs of medical and surgical abortion have been compared and found to be similar.[1517]
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.[18,19] However, there are also reports of healthy children born to such women.[20,21] Seven cases of limb abnormalities 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.[2224] 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.
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 × 109/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 µmol/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 µg of Rh(D) immune globulin on this day. The first five patients returned 3 days later (day 4) to have the misoprostol (800 µg 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 µg 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.
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 free-standing abortion clinic. The other two were performed urgently as a result of visits to the emergency department 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 IU/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.
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).[4,5]
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 11-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 follow-up 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 collaborators[610] in the United States are taken into account, we can say that it is safe 99% of the time.