Canadian Medical Association Journal 1996; 154: 185-187
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Introduction
In this issue (see pages 165 to 170 [abstract]) Dr. Ellen R. Wiebe reports the results of the first Canadian study to examine the use of methotrexate and misoprostol in combination for the early termination of intrauterine pregnancy. This research, based on a series of 100 cases, raises important questions for physicians and patients who would consider medical options for early abortion.
In Europe mifepristone (also known as RU486), a potent antiprogestin, is used in combination with various prostaglandins to induce abortion. Because this agent is not available in Canada, other agents with abortifacient properties -- notably methotrexate, a folic-acid antagonist used to treat cancer, psoriasis and rheumatoid arthritis, and misoprostol, a prostaglandin used in the prevention of gastric ulcer -- have been promoted by some clinicians for "off-label" use in medical abortion. However, the use of methotrexate and misoprostol in combination for this purpose has been subject to limited investigation.
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The protocols used in the studies of the methotrexate-misoprostol combination were similar. First, methotrexate (50 mg/m2 body surface area) was administered by intramuscular injection. Misoprostol (800 µg) was given intravaginally 3 to 7 days later, followed by a second dose of misoprostol 1 to several days later if abortion was incomplete. If pregnancy continued after the second misoprostol dose a surgical abortion was usually performed.
Because of the small number of patients involved in these studies, the failure rate of medical abortion has not been firmly established. The two larger studies revealed that 2% and 4% of patients required surgery.(5,6) The results reported by Wiebe (surgical abortion was performed in 11 of 100 women, but was strictly necessary in only 8) are consistent with the rates of required surgical intervention reported by Creinin and associates.(1,3,4) Ulmann and Silvestre(9) reported a failure rate of 4.7% for mifepristone used with a prostaglandin analogue among approximately 15 700 patients. These results were obtained at approved centres for voluntary pregnancy termination governed by France's strict distribution control of mifepristone.
Wiebe's finding that a large proportion of patients required more than one dose of misoprostol is congruent with findings from other studies.(1-6) Of the pregnancies that were not terminated despite the use of methotrexate and misoprostol in Wiebe's study, it is uncertain what proportion would have continued to the third trimester had surgical aspiration not been performed. In 1 of 100 cases followed by Schaff and colleagues,(5) a sizing error led to continuing pregnancy in a patient who was found to have initially been at 9.5 weeks' gestation. All seven of the women in Hausknecht's study(6) who required surgical abortion had characteristics indicative of inevitable abortion. Two of the three pregnancies that failed to abort in Creinin and Vittinghoff's study(4) were at 54 and 55 days' gestation at the time methotrexate was administered. Wiebe reports 7 cases of continuing pregnancy in her series of 100 cases. The corresponding rate reported by Ulmann and Silvestre(9) of continuing pregnancy after mifepristone and prostaglandin administration was 1.2%.
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Unlike mifepristone, methotrexate is an antimetabolite that can cause congenital malformations to a fetus carried to term after intrauterine exposure. Congenital malformations occurred when larger, cumulative doses of methotrexate were given to treat cancer in pregnant women.(13) Congenital anomalies in continuing pregnancies have also been associated with misoprostol.(14,15) Wiebe, whose study of methotrexate and misoprostol is the only one to have examined teratogenicity, found limb defects in all three fetuses that could be examined after surgical aspiration.
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As with any medical procedure, there exists the risk of loss to follow-up. The rate of loss to follow-up after treatment with mifepristone and a prostaglandin analogue reported by Ulmann and Silvestre was 2.8%.(9) To date, studies of the use of methotrexate and misoprostol for medical abortions have been conducted under conditions in which women are selected carefully, follow-up is rigorous and participants consent to undergo surgical abortion should the medical abortion fail. Nevertheless, the evidence suggests that it is difficult to follow patients this closely in such interventions. Wiebe notes that there were problems with patient attendance at follow-up visits. The feasibility of duplicating or improving on research conditions in clinical practice settings in Canada has not been established.
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Incorporating this regimen into clinical practice, or counselling women about its availability as off-label therapy for early termination of intrauterine pregnancy, is currently insupportable. Although Wiebe's work makes a valuable contribution, larger clinical studies are required to establish further the safety, acceptability and efficacy of this regimen. If it is approved for clinical practice, safeguards to ensure quality of care to the woman and to minimize the potential for continued pregnancy resulting in congenital abnormality will be needed. At a minimum, it should be required that this protocol is administered only in registered centres.
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Results of research to date
In 1993 and 1994 results were reported from the first studies of combined methotrexate and misoprostol for early induction of abortion -- three case series of 10 patients each(1-3) and a small randomized trial comparing the use of this combination in 31 patients to the use of misoprostol alone in 30 patients.(4) Recently in two larger case series(5,6) the rates of completed abortions were determined among 278 patients. Before these studies were done, methotrexate treatment had been used in selected cases of ectopic pregnancy.(7,8) Misoprostol is routinely used in combination with mifepristone in France and the United Kingdom for termination of intrauterine pregnancy.
Side effects of methotrexate
and misoprostol
Because methotrexate is used to treat other medical conditions, it has undergone rigorous testing to establish its safety. A single dose of methotrexate (50 mg/m2) injected intramuscularly has been used for termination of ectopic pregnancies,(8) and research protocols for early termination of intrauterine pregnancies have employed the same dosage. Severe adverse effects to the woman resulting from single-dose methotrexate have not been reported. Side effects such as abdominal cramping, headache, dizziness, nausea and vomiting have been reported,(2) although some of these could have been related to the pregnancy itself. Wiebe's assessment of patient preferences, like that of Creinin and Park,(10) suggests that many women would prefer a medical abortion to a surgical procedure, but these findings have not been confirmed in direct comparative studies. Misoprostol has been shown to be preferable to other prostaglandin analogues when used with mifepristone.(9) Although side effects of diarrhea and vomiting have been reported,(11,12) the dosages used for terminating pregnancies did not result in severe adverse outcomes for the women.
Concerns for practice
The high potential for teratogenicity in continued pregnancy with the use of methotrexate and misoprostol for early termination of intrauterine pregnancies raises the concern that a woman may not complete the medical regimen or may not have a surgical abortion in the event that the drug treatment fails.
Conclusion
If the combined use of methotrexate and misoprostol to induce abortion is found acceptable in Canada, it will be essential that surgical treatment and emergency care are immediately available in the event of incomplete abortion or an emergency. This precludes the adoption of this technique as an alternative to surgical abortion in geographic areas where surgical abortions are not available and where making a return visit would be difficult for the patient. Moreover, the feasibility of requiring women to agree to surgery should medical abortion fail is questionable. Because accurate gestational dating is essential, it is also necessary to have access to laboratory facilities that can provide results quickly to support clinical judgements about whether to use additional doses of misoprostol or to resort to surgical abortion. Ongoing contact with patients during the course of treatment and aggressive follow-up with those who miss appointments are also required. The use of this regimen should therefore be limited to approved facilities that can meet these standards for quality assurance.
References