- Email: [email protected]
Medical Abortion
, , , , , ,
GYNAECOLOGY
, , , , , ,
MEDICAL ABORTION Victoria]. Davis, MD, FRCSC, Assistant Professor, University of Toronto, Department of Obstetrics and Gynaecology, Associate Staff, Hospital for Sick Children, Active Staff, Toronto East General Hospital, Toronto, Ontario ABSTRACT
Objective: to review medical abortion with empha.sis on studies using methotrexate and misoprostol. Data Sources: a MEDLINE search and bibUographies from relevant articles were used. Only studies in EngUsh and French with medical abortion using mifepristone, methotrexate and misoprostol were reviewed. Data selection: only studies using mifepristone with 100 or more women were included. AU studies using methotrexate and misoprostol alone or in combination were reviewed. Results: in early pregnancy, combinations of mifepristone with prostaglandin or methotrexate with misoprostol are effective for pregnancy termination. When misoprostol is used to augment mifepristone or methotrexate, its vaginal application appears to be superior to the oral route. Vaginal misoprostol (BOO},tg) is more effective applied five to seven days after the methotrexate than three days after. For inevitable or incomplete abortions, misoprostol alone may be used effectively to avoid surgery. When surgical abortion fails, medical abortion is an excellent back-up treatment. Conclusion: medical abortion with mifepristone or methotrexate plus misoprostol is a safe and effective method of pregnancy termination. Because the complete abortion rate with medical abortion is less than with vacuum aspiration, surgery cannot be completely avoided. Commitment on behalf of both physician and patient is necessary to ensure safety. If mifepristone becomes available in Canada, studies comparing its use to methotrexate wiU be of paramount importance to help to determine the best method. Further research into medical abortion is important to women's health as this method is highly acceptable and ha.s the potential to increase access to safe abortion. RESUME
Objectif : Examiner I' avortement therapeutique en insistant sur les etudes portant sur le methotrexate et le misoprostol. Sources des donnees: Une recherche dans MEDLINE et les bibUographies d' articles pertinents. On n' a examine que les etudes en ang/ais et en fraTlfais portant sur les avortements therapeutiques realises au moyen de Ia mi[epristone, du methotrexate et du misoprostol. Selection des donnees: On n' a examine que les etudes portant sur 100 femmes ou plus ayant utiUse Ia mi[epristone. On a examine routes les etudes portant sur le methotrexate et le misoprostol, utiUses seuls ou en association. Resultats : Au'debut de Ia grossesse, les associations de mi[eprostone et de prostaglandine ou de methotrexate et de misoprostol sont efficaces pout provoquer un avortement. Quand le misoprostol sert aaccroltre I' effet de Ia mi[epristone ou du methotrexate, I' application vaginale semble donner de meilleurs resultats que Ia voie orale. Le misoprostol par voie vaginale (BOOttg) est plus efficace si on I' appUque cinq a sept jours apres le methotrexate, plutOt que trois jours apres le methotrexate. En cas d' avortements inevitables ou incomplets, le misoprostol seul peut etre utiUse efficacement pour eviter Ia chirurgie. En cas d' echec de I' avortement chirurgical, I' avortement therapeutique constitue un excellent traitement de rechange. Conclusion: L' avortement therapeutique au moyen de Ia mi[epristone ou du methotrexate et du misoprostol est une methode sure et efficace pour mettre fin aIa grossesse. Puisque le taux d' avortements complets obtenu au moyen de I' avortement therapeutique est inferieur a
JOURNALSOGC
739
JULY 1998
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, , , celui obtenu au moyen de l' avortement par aspiration, on ne peut pas eviter completement Ia chirurgie. L' engagement ilia fois du medecin et de Ia patiente est necessaire pour garantir I'innocuite. Si Ia mifepristone est commercialisee au Canada, des etudes sur son utilisation par comparaison avec celle du methotrexate auront une importance capitale pour determiner Ia meilleure methode. D'autres recherches sur I' avortement therapeutique sont importantes pour Ia sante des femmes puisque cette methode est tres acceptable et parce qu' elle pourrait accroftre I' acces il un avortement sur. J soc OBSTET GYNAECOL CAN 1998;20(8):739·47 KEYWORDS
Medical abortion, methotrexate, misoprostol, mifepristone. Received on October 1st, 1997. Revised and accepted on December 15th, 1997.
INTRODUCTION
labour. Therapeutic use of mefipristone for luteal phase and emergency postcoital contraception appears to be safe and effective. 3 Mifepristone has additional properties that may be useful for the treatment of breast cancer, gynaecologic malignancy and some forms of Cushing's syndrome.4
Since women began to regulate their fertility, they have looked for potions to bring on their menses or cause abortion. None of these elixirs has been safe or successful. In the 1980s, chemical termination of pregnancy was described, and continued research in this area has led to refinements in making medical abortion a safe, easy, private and accessible procedure.
2.
In Europe, the prostaglandin, sulprostone (PGEZ analogue) , was initially used intramuscularly with mifepristone, until reports associated sulprostone with serious cardiovascular complications including death. 5 Gemeprost (PGE1 analogue), PGOS (PGF z alpha analogue) and misoprostol (PGE1 analogue) are the current prostaglandins used vaginally to augment mifepristone effects in medically induced abortions. These prostaglandins cause uterine contractions and the expulsion of the products of conception. In North America, available prostaglandins with uterotonic activity are carboprost tromethamine (lS-methyl PGF z alpha), dinoprostone (PGE z) and misoprostol. Prostaglandins are associated with gastro-intestinal side effects including nausea, vomiting and diarrhoea.6 Misoprostol was first marketed for the prevention of gastric ulcers in individuals using non-steroidal antiinflammatory medications. The recognized uterotonic activity of misoprostolled to subsequent expansion of its applications. In some countries, notably Brazil, where abortion is illegal, women are currently using misoprostol to induce abortion or bleeding, before presenting themselves for medical care.) Several infants exposed to misoprostol in the first trimester have been born-some with limb or skull defects with or without Mobius sequence which may be associated with misoprostol. 8•9 The usual daily dose of misoprostol for ulcer prophylaxis is 800 llg and this dose is not exceeded in medical abortions. Uterine sensitivity to the uterotonic activity of misoprostol increases with increasing gestational age. In the second trimester, pregnancies complicated by ruptured membranes, fetal demise or anomalies can be evacuated
PHARMACOLOGY OF AGENTS USED FOR MEDICAL ABORTION 1.
MIFEPRISTONE
(RU 486)
Mifepristone was first developed in the 1970s from norethindrone. This steroid has anticorticosteroid activity and a high affinity for progesterone receptors. Mefipristone acts as a false transmitter, inhibiting the action of progesterone which is necessary to support early embryonic development. In 1982, it was demonstrated that this orally active agent could induce abortion in pregnancies of less than 49 days gestation. l Mifepristone alone has a high incomplete abortion rate (15 to 40%) and as such is a poor alternative to vacuum aspiration. The addition of prostaglandin (PG) after 36 to 48 hours of mifepristone markedly improves the complete abortion rate to about 9S percent, with only five percent of women requiring vacuum aspiration (failure). In one of the largest studies involving 16,369 women, indictions for vacuum aspiration included incomplete abortion (2.8%), continuing pregnancy (1.2%) and excessive bleeding (0.7%).2 Outside abortion itself, there are no known side effects or long term sequelae associated with the use of mifepristone. There has been no reported association between mifepristone and birth defects. In France, the indications for mifepristone use are currently expanding. Because mifepristone causes cervical softening and dilation, it may be used prior to vacuum aspiration and for induction of
JOURNAL SOGC
PROSTAGLANDINS
741
JULY 1998
, , , with misoprostol as an alternate to intra-amniotic prostaglandins. 10 Although the use of misoprostol for the induction oflabour in viable gestations appears to be efficient, inexpensive and safe, the procedure will continue to be experimental until details of safety, dosage and administration route can be established.l1,ll Misoprostol has been used instead oflaminaria tents to dilate and soften the cervix prior to vacuum aspiration to avoid the complications associated with tent insertion i.e. perforation, infection and pain. 13 Problems encountered with this method include bleeding, cramps, and occasionally incomplete abortion if the drug is given more than 12 hours prior to vacuum aspiration.
3.
Claude Evin, declared mifepristone to be "the moral property of women, not just the property of a drug company," and ordered the company to resume distribution. Since that time there have been several studies looking at the dosage of mifepristone and the type and route of prostaglandin administration. In a recent review of seven studies of a total of 3,556 women, 200 mg of mifepristone was found to be as effective as 600 mg when given orally followed by prostaglandin at less than 63 days gestation. 19 The first use of misoprostol in combination with mifepristone for medical abortion was described in 1991,2° Misoprostol is reportedly more effective when administered vaginally. In a recent report, a combination of oral mifepristone with vaginal misoprostol (800llg) resulted in a complete abortion rate of 95 percent, and one percent continuing pregnancy. In contrast, the abortion and continuing pregnancy rates with oral misoprostol were 87 percent and seven percent, respectively. Zl Moreover, vaginal misoprostol is associated with fewer gastro-intestinal side effects. When compared to gemeprost and PG05, misoprostol is stable at room temperature, less expensive and its use is not associated with bronchospasm. Since the introduction of medical abortions in France, there has been no increase in the total number of abortions performed per year. The combination of mifepristone and misoprostol has also been used to evacuate missed abortion and anembryonic pregnancies of up to thirteen weeks with 94 percent success. Z2
METHOTREXATE
Methotrexate is an analogue of folic acid that competitively inhibits dihydrofolate reductase, an important step in DNA synthesis. Since 1952, methotrexate has been known to be cytotoxic to neoplastic and nonneoplastic trophoblastic tissue, and has been used to treat molar pregnancies and choriocarcinoma, as well as in chemotherapy for haematologic neoplasia. 14 Methotrexate is also used in the treatment of rheumatoid arthritis and psoriasis. Since 1982, selected ectopic pregnancies have been treated medically with intramuscular methotrexate (50mg/m 2) with a success rate as high as 95 percent. 15,16 The success rate in the medical treatment of ectopic pregnancy may be improved if methotrexate is given in the deltoid rather than the gluteus muscle. This ensures placement of the drug in muscle and not adipose tissue where absorption is less than optimal. Side effects seen with methotrexate are dose related and rarely seen with single dose regimes used for ectopic pregnancies. If side effects occur, they include bone marrow depression (primarily leucopaenia), mucositis (primarily stomatitis), alopecia, nausea and vomiting. In utero exposure to methotrexate has been inconsistently associated with malformations of the skull, face and limb as normal infants have also been deliveredY,IB
2.
Medical abortion with mifepristone and prostaglandin has been available in France, The United Kingdom (UK), Sweden and China since 1989, and will soon be available in other European countries. In North America, political and social issues have delayed the introduction and testing of mifepristone. The Population Council has recently acquired the patent for mifepristone, and in 1996 filed an application with the Food and Drug Administration (FDA) for approval. Although the FDA has apparently found mifepristone to be safe and effective as an abortifacient and full approval is expected, the Population Council has been having difficulties in locating a manufacturer for the drug. These delays have led to the alternative combination of methotrexate and misoprostol being developed in North America. The reported success of methotrexate in the treatment of ectopic pregnancies led Creinin and Darney in 1993 to
REGIMENS USED FOR MEDICAL ABORTION
1.
MIFEPRISTONE AND PROSTAGLANDIN
The 1989 introduction of mifepristone for clinical use in France was challenged by an intense religious campaign which led to withdrawal of the medication by the developers Roussel Uclaf. The health minister at that time,
JOURNALSOGC
METHOTREXATE AND MISOPROSTOL
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JULY1998
, , , use methotrexate (50mg/m2) and misoprostol (800J..lg) in early intra-uterine gestations to induce abortion.23 Since then there have been several studies using these medications to induce abortion in early gestations, all having success rates of 90 percent or more (Table 1) y4-26 In all of these studies, a second application of misoprostol was given if no bleeding occurred within twenty-four hours of the first dose. When used with methotrexate, misoprostol at 800J..lg per vagina on the fifth, sixth or seventh day is more effective than earlier applications.27 The use of oral methotrexate (50mg) with vaginal misoprostol (800J..lg) to terminate pregnancies at less than 49 days has been described. 28 In a study involving three hundred women, there was a complete abortion rate of 91 percent with a delayed rate of 13 percentsimilar to results with parenteral methotrexate. However, such side effects as vomiting, diarrhoea and headaches occurred with greater frequency. Further studies with oral methotrexate are needed to determine if this will prove to be a viable alternative to the parenteral route. Misoprostol alone can induce abortion in the first trimester, though large and repeated doses may be required. In one study, up to three doses of vaginal misoprostol, 800J..lg every 48 hours at less than 70 days gestation, had a complete abortion rate of 93 percent. 29 Other studies have reported less success with misoprostol alone as an early abortifacient (Table 2).30,31 The absorption and efficacy of vaginal misoprostol may improve if subjects are instructed to douche prior to misoprostol insertion. 29 Misoprostol has been also used in attempts to evacuate the uterus when pregnancy fails in the first trimester, as with missed, inevitable and incomplete abortions. The success under these conditions, defined as no surgery, is highly variable. Complete abortion rates of 62 to 88 percent, depending on the dose and route of the misoprostol administration, have been reported (Table 3 ).32.34
The "off label" use of medication, as with methotrexate and ectopic pregnancy, aspirin and atherosclerosis, is used routinely by physicians and may help to advance the practice of medicine. The Health Protection Branch of Canada has no jurisdiction over "off label" usage of medications once they have been approved for other applications in Canada.
SAFETY
There are few contra-indications to medical abortion with mifepristone or misoprostol. With methotrexate, exclusion criteria include active liver disease, active renal disease, blood dyscrasia or inflammatory bowel disease. Medical terminations are associated with greater blood loss than suction aspiration, though no clinically significant decrease in haemoglobin is seenY Women with anaemia (haemaglobin less than 95gm/L) may not be appropriate candidates for medical abortion. Most women (76%) abort within twelve hours of prostaglandin application, and bleeding similar to menstruation continues for approximately ten days.25 Haemorrhage requiring dilatation and curettage occurs in less than one percent of medical terminations and is associated with increased gestational age. The low dose methotrexate regime (50 mg/m2) has not been associated with serious side effects, although transient mild stomatitis (less than 1%) and rarely reversible alopecia and neutopaenia have been reported. 25 ,36,37 In those women treated with methotrexate as a chemotherapeutic agent or for ectopic pregnancy, studies have shown that future fertility is not impaired. 38,39 Surgical abortion is complicated by infection, perforation, cervical laceration or haemorrhage in 0.3 percent of procedures. One-half of these incidents are perforations. 40.4 1These complications are avoided when medical abortion is successful. When medical abortion fails, vacuum aspiration should be arranged as there are concerns that the agents used may be teratogenic in the event of an ongoing viable gestation (1 %). There are some studies describing limb defects in assoTABLE 1 ciation with misoprostol use in the first trimester METHOTREXATE AND MISOPROSTOL AS EARLY ABORTIFACIENTS with or without methotrexate.9,24 No relationship Complete Abortion Rate (%) vs Day between birth defects and use of mifepristone or of Misoprostol low-dose methotrexate has been established. 42 ,43 Gestational age Investigator Day 3 Day 5 Day 7 -t Once interruption of pregnancy has begun, it 89 (89/100) < 56 Wiebe, 199624 96 (171/176) Hausknecht, 199525 < 63 should be taken to completion to avoid poten< 56 98 (39/40) tially grave complications. Safety is improved and < 56 complications avoided when gestational dating
I
JOURNALSOGC
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JULY 1998
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, , , DISADVANTAG ES
TABLE 2 MISOPROSTOL ALONE AS AN EARLY ABORTIFACIENT
Although medical abortion is technically simple, it is logistically more complex because of Creinin & Vittinghoff. 199430 800l1g pv q24h X 2 < 56 days 47 (14/30) I • • the need for follow-up and for commitment by • 800l1g pv q48h X 3 1< 70 days 1 93.6 (1321141) Carbonell et at. 1997 29 31 both the physician and patient. Confirmation of Bugalho et a/. 1996 200l1g pv q12h X 4 < 77 days 46 (47/101) a complete abortion is not immediate, taking r 400l1g pv q12h X4 77 days1 66 (88/133) days to weeks. During this time, diligent attenis accurate; dating should be verified by an ultrasound if dance to weekly follow-up tests (~hCG and/or ultrathere is any doubt after pelvic examination. sound) by the patient and clinician are critical to avoid ongoing viable gestations or retained products of conADVANTAGES OF MEDICAL ABORTION ception. Those women who cannot commit to follow-up should be offered suction curettage. Incomplete abortions Medical abortion is technically simple and can be perare much higher (3 to 10%) with medical abortion so the formed as a private office procedure; this has the potenneed for surgical intervention is not completely removed. tial to increase the number of providers and improve When counselling women, physicians must make this access to safe abortion in rural areas. Medical abortion clear so that informed decisions can be made. avoids surgical complications and is less costly than vacUp to ten percent of successful medical terminations uum aspiration performed in hospitals. Mifepristone costs will be "delayed," and complete evacuation of the uterus between $200 and $300, whereas the total cost of may take several days and, on occasion, weeks. If the methotrexate and misoprostol is approximately $60. woman seeking medical abortion is aware of this, she will Some physicians prefer to wait until 63 days gestabe more likely to withstand the delay and avoid premature tion if they are planning a vacuum aspiration, to avoid surgical intervention. Miscarriage occurs in approximately the small risk of a failed attempt associated with early 80 percent of women within 24 hours after insertion of the gestation. 44 For those women who are aware of their 5There are cramps of varying severity, bleedmisoprostol.Z pregnancy early, there is relatively little waiting time ing with clots and the passage of tissue. Women who canwith medical abortion. Women feel that they have not tolerate these symptoms or the sight of the products of more autonomy with medical abortion and find the conception should be offered surgical abortion. process less frightening. 19 Studies in Europe and in North America indicate that medical abortion is highly acceptA PROTOCOL FOR MEDICAL ABORTION able to women and that they will tolerate multiple visits A history and physical examination must be perand waiting for the conceptus to pass in order to avoid 19 formed to determine the gestational age and to identify a psychologically and physically invasive operation. any condition which may contra-indicate medical aborSeventy percent of women who have experienced both medical and surgical abortion preferred the former. tion. These include emotional instability, risk of loss to follow-up, a gestation greater than 63 days, a medical When surgical abortion fails, medical abortion is an condition, known intolerance or allergy to methotrexexcellent back-up. This is particularly true if the probate or misoprostol. There is evidence to suggest that the lem involves access to the uterine contents secondary to efficacy of medical abortion decreases with increasing uterine leiomyoma, cervical stenosis or congenital uterine anomaly.45 gestational age, increasing gravity (over 4) and in Asian women. 6 Medical abortion can be offered up to 63 days TABLE 3 gestation as long as the woman is aware that the risk of MISOPROSTOL AND EARLY PREGNANCY FAILURE failure is increased with advancing gestational age. For Complete abortion. % Investigator Dosage this reason, accurate determination of gestational age is 400l1g po q4h X 3 62 (88/141) Chung et a/. 199534 important, with confirmation by ultrasound if necessary. .Henshaw et a/. 199333 400119 po q4h X 3 91(21/23) Routine screening of haemoglobin, white blood cell Creinin et a/. 1997 32 400l1g po 25 (4/12) count, Rh factor, aspartamine transaminase and creati88 (7/8) 800l1g pv nine are recommended. Other screening procedures
-
Investigator
.
Dosage' Gestation Abortion rate.% . .
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r<
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JOURNALSOGC
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JULY1998
, , , should be arranged for rubella, sexually transmitted diseases and cervical cytology, if not previously performed. Although medical abortion is not a surgical procedure, the woman's written consent should be obtained. The physician must be sure that she understands the nature and the consequences of the procedure and is making an informed decision. Counselling is the key to success. The patient should feel free to contact the office to ask questions, receive reassurance and to report her progress. It should be clear that she can request suction curettage at any time, and in the event of complications, surgery should be arranged without delay.
an inexpensive and effective alternative. However, the overall effectiveness, cost and safety of methotrexate in comparison to mifepristone, when available, should be evaluated so that the most appropriate drug can be selected. Not every woman is a candidate for medical abortion. The physician must take care that the woman is emotionally stable and reliable. There is always a worry that a patient will be lost to follow-up, and pregnancy will continue with the delivery of an infant with birth defects. A well-informed patient is more committed, and will have a higher threshold of intervention in the event of a delayed reaction or heavy/prolonged bleeding. Physicians in Canada are currently preforming medical abortions using methotrexate and misoprostol. Care must be taken that this combination is not used indiscrimtnately and that the providers are trained to deal with potential complications. Medical abortion is not a magic elixir to banish all worries, but continued research should improve its efficacy and availability. A complete gUideline on medical termination of pregnancy will be soon published by the Society of Obstetricians and Gynaecologists of Canada.
PROTOCOL
1. Methotrexate 50 mg/m 2 1M (deltoid). Rh immune globulin if Rh negative. Analgesics, an anti-emetic and eight 200llg tablets of misoprostol prescribed. Woman are asked to abstain from intercourse and avoid foods containing folic acid i.e. green vegetables, legumes, oranges. 2. On the fifth, sixth or seventh day afrer methotrexate, the woman places four misoprostol tablets high in the vagina. If there is no bleeding or passage of tissue afrer 24 hours, four more tablets should be insetted. 3. Two days after first application of misoprostol a quantitative ~hCG is drawn. 4. Repeat ~hCG after seven days followed by an office visit. If ~hCG has fallen by more than 80 percent over the seven days, then the procedure was a success. If /3hCG has decreased by less than this amount, weekly /3hCGs should be done until the level approaches zero or there is an interval decrease of greater than 80 percent. This represents a delayed reaction. If ~hCG plateaus or increases, a vacuum aspiration should be arranged immediately. This indicates an incomplete abortion or an ongoing viable gestation. 5. Once the termination is complete, confirm a nonpregnant, non-tender uterus by bimanual examination. Oral contraceptives can be started, an intra-uterine contraceptive device placed or Depo Provera given.
7.
SUMMARY
8.
REFERENCES 1.
2.
3. 4. 5. 6.
The ability to terminate early pregnancy medically represents a major development in women's health. Even though mifepristone is not available in Canada, the combination of methotrexate with misoprostol appears to be
JOURNAL SOGC
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Herrmann W, Wyss R, Riondel A et al. Effect d'un steroide anti progesterone chez la femme: interruption du cyele menstrual et de la grossesse au debut. Cr Acad Sci Paris 1982;294:933-8. Ulmann A, Silvestre L, Chemama L et al. Medical termination of pregnancy with mifepristone (RU-486) followed by a prostaglandin analogue: study in 16,369 women. Acta Obstet Gynecol Scand 1992;7:278-83. Heikinheimo 0, Archer DF. Mifepristone: a potential contraceptive. Clin Obstet Gynecol 1996;39(2):461-8. Kitsch M. Antiprogestins and the abortion controversy: a progress report. Fam Plann Perspect 1991;337:969-70. Anonymous. A death associated with mifepristone/ sulprostone. Lancet 1991 ;337:969-70. Creinin MD, Vittinghoff E, Keder L, Darney PD, Tiller G. Methotrexate and misoprostol for early abortion: a multicenter trial. I. Safety and efficacy. Contraception 1996;53:321-7. Coelho HL, Teixeira AC, Santos AP et al. Misoprostol and illegal abortion in Fortalela, Brazil. Lancet 1993;341 :1261-3. Fonseca W, Alencar AJ, Mota FS, Coelho HL. Misoprostol and congenital malformations [letter] Lancet 1991 ;338:56. Gonzalez CH, Vargus FR, Perez AB et al. Limb deficiencies with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy. Am J Med Genet 1993;47:59-64.
JULY 1998
, , , 10. Yapar EG, Senoz S, Urkutar M, Batioglu S, Gokem o. Second trimester pregnancy termination including fetal death: comparison of five different methods. Eur J Obstet Gynecol Reprod Bioi 1996;69(2):97-102. 11. Windrim R, Bennett K, Mundie W, Young DC. Oral administration of misoprostol for labor induction: a randomized control trial. Obstet GynecoI1997;89:392-7. 12. Sanchez-Ramos L, Kaunitz AM, Wears RL, Deike I, Gaudier FL. Misoprostol for cervical ripening and labor induction: a meta-analysis. Obstet GynecoI1997;89:633-42. 13. Lawie A, Penney G, Templeton A. A randomized comparison of oral and vaginal misoprostol for cervical priming before suction termination of pregnancy. Br J Obstet GynaecoI1996;103:1117-9. 14. Thiersch JB. Therapeutic abortions with a folic acid antagonist, 4-aminopteroyglutamic acid (4-Amino PGA) administered by the oral route. Am J Obstet GynecoI19S2;63:1298-1306. 15. Tanaka T, Hayashi H, Kutsuzawa T et a/. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril1982;37:851-2 16. Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet GynecoI1993;168:1759-65. 17. Reich EW, Cox RP, Becker MH, Genieser NB, McCarthy JG, Converse JM. Recognition in adult patients of malformations induced by folic-acid antagonist. Birth Defects 1978;14:139-60. 18. O'Neil E, Pelegrina I, Hammond CB, Vicens R, Almodovar AR. Normal pregnancy and delivery after cerebral metastases of choriocarcinoma: case report. Cancer 1976;38:984-6. 19. Grimes D. Medical abortion in early pregnancy: a review of evidence. Obstet Gynecol1997; 89:790-6. 20. Norman J, Thong K, Bairn DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 1991 ;(ii);338:1233-6. 21. EI-Refaey H, Rajasekar D, Abdalla M, Calder L, Templeton A. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med 1995; 332:983-7. 22. EI-Refaey H, Hinshaw K, Henshaw R, Smith N, Templeton A. Medical management of missed and anembryonic pregnancy. BMJ 1992;305:1399. 23. Creinin MD, Darney PD. Methotrexate and misoprostol for early abortion. Contraception 1993;48:339-48. 24. Wiebe ER. Abortion induced with methotrexate and misoprostol. Can Med AssocJ 1996;154:165-70. 25. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40. 26. Schaff EA, Eisinger SH, Franks P, Kim SS. Combined methotrexate for early induced abortion. Arch Fam Med 1995;4:774-9. 27. Creinin MD, Vittinghoff E, Galbraith S, Klaisle C. A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Am J Obstet Gynecol 1995; 173: 1578-84. 28. Creinin MD, Vittinghoff E, Schaff E, Klaisle C, Darney PD, Dean C. Medical abortion with oral methotrexate and vaginal misoprostol. Obstet GynecoI1997;90:611-6.
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29. Carbonell JLL, Varela L, Velazco A, Fernandez C. The use of misoprostol for the terrnination of early pregnancy. Contraception 1997;55: 165-8. 30. Creinin MD, Vittinghoff E. Methotrexate and misoprostol versus misoprostol alone for early abortion: a randomized control trial. JAMA 1994;272:1190-5. 31. Bugalho A, Faundes A, Jamisse L, Usfa M, Maria E, Bique C. Evaluation of vaginal misoprostol to induce first trimester abortion. Contraception 1996;53:243-6. 32. Creinin MD, Moyer R, Guido R. Misoprostol for medical evaluation of early pregnancy failure. Obstet Gynecol 1997;89:768-72. 33. Henshaw RC, Cooper K, EI-Refaey H, Smith NC, Templeton A. Medical management of miscarriage: non-surgical uterine evacuation of incomplete and inevitable spontaneous abortion. BMJ 1993;306:894-5. 34. Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang AMZ. Misoprostol in the management of spontaneous abortion. Br J Obstet GynaecoI1995;102:832-5. 35. Thonneau P, Poi rei H, Fougeyrollas B et al. A comparative analysis of fall in haemoglobin following abortions conducted by mifepristone (600mg) and vacuum aspiration. Hum Reprod 1995;10:1512-5. 36. Trout S, Kemmann E. Reversible alopecia after single dose methotrexate treatment in a patient with ectopic pregnancy. Fert Steril1995;64:866-7. 37. Isaacs JD, McGehee RP, Cowan BD. Life-threatening neutropenia following methotrexate treatment of an ectopic pregnancy: a report of two cases. Obstet Gynecol 1996;88:694-6. 38. Walden PAM, Bagshawe KD. Reproductive performance of women successfully treated for gestational trophoblastic tumor. Am J Obstet GynecoI1976;125:11 08. 39. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet GynecoI1990;162:1620-4. 40. Buehler JW, Schulz KF, Grimes DA, Hogue CJ. The risk of serious complication from induced abortion: do personal characteristics make a difference? Am J Obstet Gynecol 1985;153:14-20. 41. Lindell G, Flam F. Management of uterine perforations in connection with legal abortions. Acta Obstet Gynecol Scand 1995;74:373-5. 42. Lim BH, Lees DA, Bjornsson S et a/. Normal development after exposure to mifepristone in early pregnancy. Lancet 1990;336:257 -8. 43. Coalesce 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;88:589-92. 44. Kaunitz AM, Rovira EZ, Grimes DA, Schulz KF. Abortions that fail. Obstet GynecoI1985;80:533-7. 45. Schaff EA, Wortman M, Eisinger S, Franks P. Methotrexate and misoprostol when surgical abortion fails. Obstet GynecoI1996;87:450-2.
747
JULY 1998
GYNAECOLOGY
, , , , , ,
MEDICAL ABORTION Victoria]. Davis, MD, FRCSC, Assistant Professor, University of Toronto, Department of Obstetrics and Gynaecology, Associate Staff, Hospital for Sick Children, Active Staff, Toronto East General Hospital, Toronto, Ontario ABSTRACT
Objective: to review medical abortion with empha.sis on studies using methotrexate and misoprostol. Data Sources: a MEDLINE search and bibUographies from relevant articles were used. Only studies in EngUsh and French with medical abortion using mifepristone, methotrexate and misoprostol were reviewed. Data selection: only studies using mifepristone with 100 or more women were included. AU studies using methotrexate and misoprostol alone or in combination were reviewed. Results: in early pregnancy, combinations of mifepristone with prostaglandin or methotrexate with misoprostol are effective for pregnancy termination. When misoprostol is used to augment mifepristone or methotrexate, its vaginal application appears to be superior to the oral route. Vaginal misoprostol (BOO},tg) is more effective applied five to seven days after the methotrexate than three days after. For inevitable or incomplete abortions, misoprostol alone may be used effectively to avoid surgery. When surgical abortion fails, medical abortion is an excellent back-up treatment. Conclusion: medical abortion with mifepristone or methotrexate plus misoprostol is a safe and effective method of pregnancy termination. Because the complete abortion rate with medical abortion is less than with vacuum aspiration, surgery cannot be completely avoided. Commitment on behalf of both physician and patient is necessary to ensure safety. If mifepristone becomes available in Canada, studies comparing its use to methotrexate wiU be of paramount importance to help to determine the best method. Further research into medical abortion is important to women's health as this method is highly acceptable and ha.s the potential to increase access to safe abortion. RESUME
Objectif : Examiner I' avortement therapeutique en insistant sur les etudes portant sur le methotrexate et le misoprostol. Sources des donnees: Une recherche dans MEDLINE et les bibUographies d' articles pertinents. On n' a examine que les etudes en ang/ais et en fraTlfais portant sur les avortements therapeutiques realises au moyen de Ia mi[epristone, du methotrexate et du misoprostol. Selection des donnees: On n' a examine que les etudes portant sur 100 femmes ou plus ayant utiUse Ia mi[epristone. On a examine routes les etudes portant sur le methotrexate et le misoprostol, utiUses seuls ou en association. Resultats : Au'debut de Ia grossesse, les associations de mi[eprostone et de prostaglandine ou de methotrexate et de misoprostol sont efficaces pout provoquer un avortement. Quand le misoprostol sert aaccroltre I' effet de Ia mi[epristone ou du methotrexate, I' application vaginale semble donner de meilleurs resultats que Ia voie orale. Le misoprostol par voie vaginale (BOOttg) est plus efficace si on I' appUque cinq a sept jours apres le methotrexate, plutOt que trois jours apres le methotrexate. En cas d' avortements inevitables ou incomplets, le misoprostol seul peut etre utiUse efficacement pour eviter Ia chirurgie. En cas d' echec de I' avortement chirurgical, I' avortement therapeutique constitue un excellent traitement de rechange. Conclusion: L' avortement therapeutique au moyen de Ia mi[epristone ou du methotrexate et du misoprostol est une methode sure et efficace pour mettre fin aIa grossesse. Puisque le taux d' avortements complets obtenu au moyen de I' avortement therapeutique est inferieur a
JOURNALSOGC
739
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, , , celui obtenu au moyen de l' avortement par aspiration, on ne peut pas eviter completement Ia chirurgie. L' engagement ilia fois du medecin et de Ia patiente est necessaire pour garantir I'innocuite. Si Ia mifepristone est commercialisee au Canada, des etudes sur son utilisation par comparaison avec celle du methotrexate auront une importance capitale pour determiner Ia meilleure methode. D'autres recherches sur I' avortement therapeutique sont importantes pour Ia sante des femmes puisque cette methode est tres acceptable et parce qu' elle pourrait accroftre I' acces il un avortement sur. J soc OBSTET GYNAECOL CAN 1998;20(8):739·47 KEYWORDS
Medical abortion, methotrexate, misoprostol, mifepristone. Received on October 1st, 1997. Revised and accepted on December 15th, 1997.
INTRODUCTION
labour. Therapeutic use of mefipristone for luteal phase and emergency postcoital contraception appears to be safe and effective. 3 Mifepristone has additional properties that may be useful for the treatment of breast cancer, gynaecologic malignancy and some forms of Cushing's syndrome.4
Since women began to regulate their fertility, they have looked for potions to bring on their menses or cause abortion. None of these elixirs has been safe or successful. In the 1980s, chemical termination of pregnancy was described, and continued research in this area has led to refinements in making medical abortion a safe, easy, private and accessible procedure.
2.
In Europe, the prostaglandin, sulprostone (PGEZ analogue) , was initially used intramuscularly with mifepristone, until reports associated sulprostone with serious cardiovascular complications including death. 5 Gemeprost (PGE1 analogue), PGOS (PGF z alpha analogue) and misoprostol (PGE1 analogue) are the current prostaglandins used vaginally to augment mifepristone effects in medically induced abortions. These prostaglandins cause uterine contractions and the expulsion of the products of conception. In North America, available prostaglandins with uterotonic activity are carboprost tromethamine (lS-methyl PGF z alpha), dinoprostone (PGE z) and misoprostol. Prostaglandins are associated with gastro-intestinal side effects including nausea, vomiting and diarrhoea.6 Misoprostol was first marketed for the prevention of gastric ulcers in individuals using non-steroidal antiinflammatory medications. The recognized uterotonic activity of misoprostolled to subsequent expansion of its applications. In some countries, notably Brazil, where abortion is illegal, women are currently using misoprostol to induce abortion or bleeding, before presenting themselves for medical care.) Several infants exposed to misoprostol in the first trimester have been born-some with limb or skull defects with or without Mobius sequence which may be associated with misoprostol. 8•9 The usual daily dose of misoprostol for ulcer prophylaxis is 800 llg and this dose is not exceeded in medical abortions. Uterine sensitivity to the uterotonic activity of misoprostol increases with increasing gestational age. In the second trimester, pregnancies complicated by ruptured membranes, fetal demise or anomalies can be evacuated
PHARMACOLOGY OF AGENTS USED FOR MEDICAL ABORTION 1.
MIFEPRISTONE
(RU 486)
Mifepristone was first developed in the 1970s from norethindrone. This steroid has anticorticosteroid activity and a high affinity for progesterone receptors. Mefipristone acts as a false transmitter, inhibiting the action of progesterone which is necessary to support early embryonic development. In 1982, it was demonstrated that this orally active agent could induce abortion in pregnancies of less than 49 days gestation. l Mifepristone alone has a high incomplete abortion rate (15 to 40%) and as such is a poor alternative to vacuum aspiration. The addition of prostaglandin (PG) after 36 to 48 hours of mifepristone markedly improves the complete abortion rate to about 9S percent, with only five percent of women requiring vacuum aspiration (failure). In one of the largest studies involving 16,369 women, indictions for vacuum aspiration included incomplete abortion (2.8%), continuing pregnancy (1.2%) and excessive bleeding (0.7%).2 Outside abortion itself, there are no known side effects or long term sequelae associated with the use of mifepristone. There has been no reported association between mifepristone and birth defects. In France, the indications for mifepristone use are currently expanding. Because mifepristone causes cervical softening and dilation, it may be used prior to vacuum aspiration and for induction of
JOURNAL SOGC
PROSTAGLANDINS
741
JULY 1998
, , , with misoprostol as an alternate to intra-amniotic prostaglandins. 10 Although the use of misoprostol for the induction oflabour in viable gestations appears to be efficient, inexpensive and safe, the procedure will continue to be experimental until details of safety, dosage and administration route can be established.l1,ll Misoprostol has been used instead oflaminaria tents to dilate and soften the cervix prior to vacuum aspiration to avoid the complications associated with tent insertion i.e. perforation, infection and pain. 13 Problems encountered with this method include bleeding, cramps, and occasionally incomplete abortion if the drug is given more than 12 hours prior to vacuum aspiration.
3.
Claude Evin, declared mifepristone to be "the moral property of women, not just the property of a drug company," and ordered the company to resume distribution. Since that time there have been several studies looking at the dosage of mifepristone and the type and route of prostaglandin administration. In a recent review of seven studies of a total of 3,556 women, 200 mg of mifepristone was found to be as effective as 600 mg when given orally followed by prostaglandin at less than 63 days gestation. 19 The first use of misoprostol in combination with mifepristone for medical abortion was described in 1991,2° Misoprostol is reportedly more effective when administered vaginally. In a recent report, a combination of oral mifepristone with vaginal misoprostol (800llg) resulted in a complete abortion rate of 95 percent, and one percent continuing pregnancy. In contrast, the abortion and continuing pregnancy rates with oral misoprostol were 87 percent and seven percent, respectively. Zl Moreover, vaginal misoprostol is associated with fewer gastro-intestinal side effects. When compared to gemeprost and PG05, misoprostol is stable at room temperature, less expensive and its use is not associated with bronchospasm. Since the introduction of medical abortions in France, there has been no increase in the total number of abortions performed per year. The combination of mifepristone and misoprostol has also been used to evacuate missed abortion and anembryonic pregnancies of up to thirteen weeks with 94 percent success. Z2
METHOTREXATE
Methotrexate is an analogue of folic acid that competitively inhibits dihydrofolate reductase, an important step in DNA synthesis. Since 1952, methotrexate has been known to be cytotoxic to neoplastic and nonneoplastic trophoblastic tissue, and has been used to treat molar pregnancies and choriocarcinoma, as well as in chemotherapy for haematologic neoplasia. 14 Methotrexate is also used in the treatment of rheumatoid arthritis and psoriasis. Since 1982, selected ectopic pregnancies have been treated medically with intramuscular methotrexate (50mg/m 2) with a success rate as high as 95 percent. 15,16 The success rate in the medical treatment of ectopic pregnancy may be improved if methotrexate is given in the deltoid rather than the gluteus muscle. This ensures placement of the drug in muscle and not adipose tissue where absorption is less than optimal. Side effects seen with methotrexate are dose related and rarely seen with single dose regimes used for ectopic pregnancies. If side effects occur, they include bone marrow depression (primarily leucopaenia), mucositis (primarily stomatitis), alopecia, nausea and vomiting. In utero exposure to methotrexate has been inconsistently associated with malformations of the skull, face and limb as normal infants have also been deliveredY,IB
2.
Medical abortion with mifepristone and prostaglandin has been available in France, The United Kingdom (UK), Sweden and China since 1989, and will soon be available in other European countries. In North America, political and social issues have delayed the introduction and testing of mifepristone. The Population Council has recently acquired the patent for mifepristone, and in 1996 filed an application with the Food and Drug Administration (FDA) for approval. Although the FDA has apparently found mifepristone to be safe and effective as an abortifacient and full approval is expected, the Population Council has been having difficulties in locating a manufacturer for the drug. These delays have led to the alternative combination of methotrexate and misoprostol being developed in North America. The reported success of methotrexate in the treatment of ectopic pregnancies led Creinin and Darney in 1993 to
REGIMENS USED FOR MEDICAL ABORTION
1.
MIFEPRISTONE AND PROSTAGLANDIN
The 1989 introduction of mifepristone for clinical use in France was challenged by an intense religious campaign which led to withdrawal of the medication by the developers Roussel Uclaf. The health minister at that time,
JOURNALSOGC
METHOTREXATE AND MISOPROSTOL
742
JULY1998
, , , use methotrexate (50mg/m2) and misoprostol (800J..lg) in early intra-uterine gestations to induce abortion.23 Since then there have been several studies using these medications to induce abortion in early gestations, all having success rates of 90 percent or more (Table 1) y4-26 In all of these studies, a second application of misoprostol was given if no bleeding occurred within twenty-four hours of the first dose. When used with methotrexate, misoprostol at 800J..lg per vagina on the fifth, sixth or seventh day is more effective than earlier applications.27 The use of oral methotrexate (50mg) with vaginal misoprostol (800J..lg) to terminate pregnancies at less than 49 days has been described. 28 In a study involving three hundred women, there was a complete abortion rate of 91 percent with a delayed rate of 13 percentsimilar to results with parenteral methotrexate. However, such side effects as vomiting, diarrhoea and headaches occurred with greater frequency. Further studies with oral methotrexate are needed to determine if this will prove to be a viable alternative to the parenteral route. Misoprostol alone can induce abortion in the first trimester, though large and repeated doses may be required. In one study, up to three doses of vaginal misoprostol, 800J..lg every 48 hours at less than 70 days gestation, had a complete abortion rate of 93 percent. 29 Other studies have reported less success with misoprostol alone as an early abortifacient (Table 2).30,31 The absorption and efficacy of vaginal misoprostol may improve if subjects are instructed to douche prior to misoprostol insertion. 29 Misoprostol has been also used in attempts to evacuate the uterus when pregnancy fails in the first trimester, as with missed, inevitable and incomplete abortions. The success under these conditions, defined as no surgery, is highly variable. Complete abortion rates of 62 to 88 percent, depending on the dose and route of the misoprostol administration, have been reported (Table 3 ).32.34
The "off label" use of medication, as with methotrexate and ectopic pregnancy, aspirin and atherosclerosis, is used routinely by physicians and may help to advance the practice of medicine. The Health Protection Branch of Canada has no jurisdiction over "off label" usage of medications once they have been approved for other applications in Canada.
SAFETY
There are few contra-indications to medical abortion with mifepristone or misoprostol. With methotrexate, exclusion criteria include active liver disease, active renal disease, blood dyscrasia or inflammatory bowel disease. Medical terminations are associated with greater blood loss than suction aspiration, though no clinically significant decrease in haemoglobin is seenY Women with anaemia (haemaglobin less than 95gm/L) may not be appropriate candidates for medical abortion. Most women (76%) abort within twelve hours of prostaglandin application, and bleeding similar to menstruation continues for approximately ten days.25 Haemorrhage requiring dilatation and curettage occurs in less than one percent of medical terminations and is associated with increased gestational age. The low dose methotrexate regime (50 mg/m2) has not been associated with serious side effects, although transient mild stomatitis (less than 1%) and rarely reversible alopecia and neutopaenia have been reported. 25 ,36,37 In those women treated with methotrexate as a chemotherapeutic agent or for ectopic pregnancy, studies have shown that future fertility is not impaired. 38,39 Surgical abortion is complicated by infection, perforation, cervical laceration or haemorrhage in 0.3 percent of procedures. One-half of these incidents are perforations. 40.4 1These complications are avoided when medical abortion is successful. When medical abortion fails, vacuum aspiration should be arranged as there are concerns that the agents used may be teratogenic in the event of an ongoing viable gestation (1 %). There are some studies describing limb defects in assoTABLE 1 ciation with misoprostol use in the first trimester METHOTREXATE AND MISOPROSTOL AS EARLY ABORTIFACIENTS with or without methotrexate.9,24 No relationship Complete Abortion Rate (%) vs Day between birth defects and use of mifepristone or of Misoprostol low-dose methotrexate has been established. 42 ,43 Gestational age Investigator Day 3 Day 5 Day 7 -t Once interruption of pregnancy has begun, it 89 (89/100) < 56 Wiebe, 199624 96 (171/176) Hausknecht, 199525 < 63 should be taken to completion to avoid poten< 56 98 (39/40) tially grave complications. Safety is improved and < 56 complications avoided when gestational dating
I
JOURNALSOGC
743
JULY 1998
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, , , DISADVANTAG ES
TABLE 2 MISOPROSTOL ALONE AS AN EARLY ABORTIFACIENT
Although medical abortion is technically simple, it is logistically more complex because of Creinin & Vittinghoff. 199430 800l1g pv q24h X 2 < 56 days 47 (14/30) I • • the need for follow-up and for commitment by • 800l1g pv q48h X 3 1< 70 days 1 93.6 (1321141) Carbonell et at. 1997 29 31 both the physician and patient. Confirmation of Bugalho et a/. 1996 200l1g pv q12h X 4 < 77 days 46 (47/101) a complete abortion is not immediate, taking r 400l1g pv q12h X4 77 days1 66 (88/133) days to weeks. During this time, diligent attenis accurate; dating should be verified by an ultrasound if dance to weekly follow-up tests (~hCG and/or ultrathere is any doubt after pelvic examination. sound) by the patient and clinician are critical to avoid ongoing viable gestations or retained products of conADVANTAGES OF MEDICAL ABORTION ception. Those women who cannot commit to follow-up should be offered suction curettage. Incomplete abortions Medical abortion is technically simple and can be perare much higher (3 to 10%) with medical abortion so the formed as a private office procedure; this has the potenneed for surgical intervention is not completely removed. tial to increase the number of providers and improve When counselling women, physicians must make this access to safe abortion in rural areas. Medical abortion clear so that informed decisions can be made. avoids surgical complications and is less costly than vacUp to ten percent of successful medical terminations uum aspiration performed in hospitals. Mifepristone costs will be "delayed," and complete evacuation of the uterus between $200 and $300, whereas the total cost of may take several days and, on occasion, weeks. If the methotrexate and misoprostol is approximately $60. woman seeking medical abortion is aware of this, she will Some physicians prefer to wait until 63 days gestabe more likely to withstand the delay and avoid premature tion if they are planning a vacuum aspiration, to avoid surgical intervention. Miscarriage occurs in approximately the small risk of a failed attempt associated with early 80 percent of women within 24 hours after insertion of the gestation. 44 For those women who are aware of their 5There are cramps of varying severity, bleedmisoprostol.Z pregnancy early, there is relatively little waiting time ing with clots and the passage of tissue. Women who canwith medical abortion. Women feel that they have not tolerate these symptoms or the sight of the products of more autonomy with medical abortion and find the conception should be offered surgical abortion. process less frightening. 19 Studies in Europe and in North America indicate that medical abortion is highly acceptA PROTOCOL FOR MEDICAL ABORTION able to women and that they will tolerate multiple visits A history and physical examination must be perand waiting for the conceptus to pass in order to avoid 19 formed to determine the gestational age and to identify a psychologically and physically invasive operation. any condition which may contra-indicate medical aborSeventy percent of women who have experienced both medical and surgical abortion preferred the former. tion. These include emotional instability, risk of loss to follow-up, a gestation greater than 63 days, a medical When surgical abortion fails, medical abortion is an condition, known intolerance or allergy to methotrexexcellent back-up. This is particularly true if the probate or misoprostol. There is evidence to suggest that the lem involves access to the uterine contents secondary to efficacy of medical abortion decreases with increasing uterine leiomyoma, cervical stenosis or congenital uterine anomaly.45 gestational age, increasing gravity (over 4) and in Asian women. 6 Medical abortion can be offered up to 63 days TABLE 3 gestation as long as the woman is aware that the risk of MISOPROSTOL AND EARLY PREGNANCY FAILURE failure is increased with advancing gestational age. For Complete abortion. % Investigator Dosage this reason, accurate determination of gestational age is 400l1g po q4h X 3 62 (88/141) Chung et a/. 199534 important, with confirmation by ultrasound if necessary. .Henshaw et a/. 199333 400119 po q4h X 3 91(21/23) Routine screening of haemoglobin, white blood cell Creinin et a/. 1997 32 400l1g po 25 (4/12) count, Rh factor, aspartamine transaminase and creati88 (7/8) 800l1g pv nine are recommended. Other screening procedures
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Investigator
.
Dosage' Gestation Abortion rate.% . .
-'--
r<
~
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, , , should be arranged for rubella, sexually transmitted diseases and cervical cytology, if not previously performed. Although medical abortion is not a surgical procedure, the woman's written consent should be obtained. The physician must be sure that she understands the nature and the consequences of the procedure and is making an informed decision. Counselling is the key to success. The patient should feel free to contact the office to ask questions, receive reassurance and to report her progress. It should be clear that she can request suction curettage at any time, and in the event of complications, surgery should be arranged without delay.
an inexpensive and effective alternative. However, the overall effectiveness, cost and safety of methotrexate in comparison to mifepristone, when available, should be evaluated so that the most appropriate drug can be selected. Not every woman is a candidate for medical abortion. The physician must take care that the woman is emotionally stable and reliable. There is always a worry that a patient will be lost to follow-up, and pregnancy will continue with the delivery of an infant with birth defects. A well-informed patient is more committed, and will have a higher threshold of intervention in the event of a delayed reaction or heavy/prolonged bleeding. Physicians in Canada are currently preforming medical abortions using methotrexate and misoprostol. Care must be taken that this combination is not used indiscrimtnately and that the providers are trained to deal with potential complications. Medical abortion is not a magic elixir to banish all worries, but continued research should improve its efficacy and availability. A complete gUideline on medical termination of pregnancy will be soon published by the Society of Obstetricians and Gynaecologists of Canada.
PROTOCOL
1. Methotrexate 50 mg/m 2 1M (deltoid). Rh immune globulin if Rh negative. Analgesics, an anti-emetic and eight 200llg tablets of misoprostol prescribed. Woman are asked to abstain from intercourse and avoid foods containing folic acid i.e. green vegetables, legumes, oranges. 2. On the fifth, sixth or seventh day afrer methotrexate, the woman places four misoprostol tablets high in the vagina. If there is no bleeding or passage of tissue afrer 24 hours, four more tablets should be insetted. 3. Two days after first application of misoprostol a quantitative ~hCG is drawn. 4. Repeat ~hCG after seven days followed by an office visit. If ~hCG has fallen by more than 80 percent over the seven days, then the procedure was a success. If /3hCG has decreased by less than this amount, weekly /3hCGs should be done until the level approaches zero or there is an interval decrease of greater than 80 percent. This represents a delayed reaction. If ~hCG plateaus or increases, a vacuum aspiration should be arranged immediately. This indicates an incomplete abortion or an ongoing viable gestation. 5. Once the termination is complete, confirm a nonpregnant, non-tender uterus by bimanual examination. Oral contraceptives can be started, an intra-uterine contraceptive device placed or Depo Provera given.
7.
SUMMARY
8.
REFERENCES 1.
2.
3. 4. 5. 6.
The ability to terminate early pregnancy medically represents a major development in women's health. Even though mifepristone is not available in Canada, the combination of methotrexate with misoprostol appears to be
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