ORIGINAL RESEARCH ARTICLE. Introduction Medical abortion using mifepristone combined

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1 ORIGINAL RESEARCH ARTICLE Low-Dose Mifepristone 200 mg and Vaginal Misoprostol for Abortion Eric A. Schaff,* Steven H. Eisinger,* Lisa S. Stadalius, Peter Franks,* Bernard Z.Gore, and Suzanne Poppema The objectives of this study were to determine the effectiveness, side effects, and acceptability of one-third the standard 600 mg dose of mifepristone (200 mg) to induce abortion. A prospective trial at seven sites enrolled women 18 years, up to 8 weeks pregnant, and wanting an abortion. The women received 200 mg mifepristone orally, selfadministered 800 g misoprostol vaginally at home 48 h later, and returned 1 4 days later for ultrasound evaluation. Surgical intervention was indicated for continuing pregnancy, excessive bleeding, persistent products of conception 5 weeks later, or other serious medical conditions. Of the 933 subjects, 906 (97%) had complete medical abortions, 22 had surgical intervention, two were protocol failures, and three were lost to follow up. Of the 746 subjects who had no or minimal bleeding before misoprostol, 80% bled within 4 h and 98% within 24 h of using misoprostol. By day 7, 95% of women had a complete abortion. Side effects were acceptable in 85% of subjects, and 94% found the procedure acceptable. Low-dose mifepristone followed by vaginal misoprostol was highly effective as an abortifacient. CONTRACEPTION 1999 Elsevier Science Inc. All rights reserved. KEY WORDS: abortion, mifepristone, misoprostol *Department of Family Medicine, University of Rochester School of Medicine, Rochester, New York; School of Nursing, University of Rochester School of Medicine, Rochester, New York; Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California; and Department of Family Medicine, University of Washington, Seattle, Washington Name and address for correspondence: Eric Schaff, MD, Department of Family Medicine, University of Rochester, 885 South Avenue, Rochester, NY 14620; Tel.: (716) ext 509; Pager: (716) ; Fax: (716) ; eschaff@aol.com Submitted for publication September 22, 1998 Revised December 7, 1998 Accepted for publication December 11, 1998 Introduction Medical abortion using mifepristone combined with a synthetic prostaglandin has been available in Europe since 1989, with efficacy rates of 92% 96%. 1 3 In 1997, a US Food and Drug Administration (FDA) Advisory Committee found oral 600 mg mifepristone with office-administered oral misoprostol 400 g to be approvable pending additional labeling and manufacturing information. Mifepristone, a synthetic antiprogesterone, is used to competitively block the effects of progesterone and weaken the attachment of an early pregnancy on the endometrium. Progesterone is a hormone essential to maintain an early pregnancy. Misoprostol, a synthetic prostaglandin, is used h after mifepristone to induce cervical softening and dilatation, and uterine contractions to assist in the expulsion of the pregnancy. The optimal dose of mifepristone has not been established. Mifepristone serum levels do not increase proportionally with increasing oral doses. 4 European studies have shown that smaller doses of mifepristone are as effective as the 600-mg standard dose to induce abortion. 5 7 The advantages of a lower dose of mifepristone include reduced manufacturing costs and less exposure to potential side effects. The optimal dose and delivery of misoprostol are still evolving. After 600 mg mifepristone, vaginal misoprostol was as effective as oral misoprostol up to 7 weeks gestation, but had fewer gastrointestinal side effects and was more effective in 7- to-9-week gestations. 8 Vaginal misoprostol s effectiveness is probably due to the sustained blood level rather than the quick peak and rapid metabolism noted after oral misoprostol. 9 In 1996, investigators from the Department of Family Medicine at the University of Rochester initiated the second US multicenter trial with mifepristone sponsored by the Abortion Rights Mobilization (ARM) of New York City. ARM is a nonprofit advocacy organization that received FDA approval to manufacture mifepristone for research. The initial report from a single site demonstrated the effectiveness and acceptability of home-administered vaginal misoprostol after 600 mg oral mifepristone in 166 subjects. 10 The present trial evaluates both a lower dose of mifepristone and home use of the vaginal route of misoprostol for abortion up to 8 weeks gestation. The rationale for this trial was to produce sufficient information to help with FDA labeling: a lower dose of 1999 Elsevier Science Inc. All rights reserved. ISSN /99/$ Avenue of the Americas, New York, NY PII S (98)

2 2 Schaff et al. Contraception mifepristone, home use of misoprostol, and use of this combination for up to 56 days of amenorrhea. Materials and Methods All sites in this prospective multicenter trial had institutional review board approval. Sites were chosen for geographically diverse settings. The women enrolled met the following criteria: age 18 years; good health; a single, intrauterine pregnancy of 56 days from first day of last menstrual period, confirmed by sonogram; willingness to return on day 4 8 after mifepristone and, if the abortion was not complete, on days 15 and 36; access to a telephone and emergency transportation; ability to give informed consent; willingness to have a surgical abortion if treatment failed; and no allergy to study medications. Exclusion criteria included: compromised health related to the adrenal gland, liver, lung, kidney, heart or blood pressure; specific diseases such as severe asthma, glaucoma, sickle cell anemia, anemia (Hgb 10 gm/dl), blood clotting defect, and insulin-dependent diabetes mellitus; and chronic medications such as warfarin, glucocorticoids, antipsychotic medications, and prostaglandin-inhibiting medications such as ibuprofen. Study medications were provided by Abortion Rights Mobilization, the sponsor, but the subject or her health insurance was responsible for the costs of the clinical care. On day 1, a medical history, gynecologic examination, and office-based transvaginal sonogram were performed, and Rh-type and hemoglobin were determined. Rh-negative subjects received RH O (D) immune globulin. The formula for ultrasound gestational dating in days was 42 plus embryonic crownrump length (in millimeters) or, if a fetal pole was not identified, 30 plus the mean gestational sac (in millimeters). 11 The number of days from the first day of the last menstrual period (LMP) was used for the study gestational age if it corresponded to within 3 days of the ultrasound results. If not, the ultrasound gestational dating was used as the study gestational age. After informed consent, investigators administered 200 mg mifepristone orally. Subjects were offered the option to self-administer vaginal misoprostol at home or to return to the office for the investigator to administer misoprostol by placing four tablets in the vagina during speculum examination with up to 4 h of observation in the office. On day 1, subjects who elected home administration of misoprostol received 800 g misoprostol as four 200- g tablets, instructions on how to insert the misoprostol tablets with a finger in the vagina 2 days after using mifepristone, a description of possible symptoms, instructions to avoid syncope by drinking fluids and raising from a recumbent position slowly, a specific plan for emergency situations such as heavy bleeding that soaked more than four thick sanitary napkins in 2 h, and a recommendation for a support person to be available during misoprostol administration. Subjects received either 10 tablets of acetaminophen with codeine (300 mg/30 mg) or acetaminophen with hydrocodone (500 mg/5 mg) to use liberally for cramping pain. If bleeding similar to menses occurred before misoprostol, subjects were to return to the clinic to determine by ultrasound whether the abortion was complete. An on-call provider was available 24 h a day. The first follow-up visit occurred from day 4 8 at the subject s discretion. Subjects were queried about any additional medications used and any symptoms made worse from mifepristone and from misoprostol. Subjects could report vaginal bleeding as either spotting or bleeding. Subjects had a repeat transvaginal ultrasound to determine whether the abortion was complete (defined as the absence of the gestational sac). If the pregnancy had not passed, an additional dose of 800- g misoprostol tablets was inserted in the vagina by the investigator and the subject was scheduled to return on day 15. A surgical procedure was performed if embryonic cardiac activity was present at study day 15, a nonviable gestational sac was still present at study day 36, bleeding became excessive (soaking more than four thick sanitary pads over 2 h), 1 other medical indications, such as severe nausea, warranted intervention, or the subject elected not to wait any longer. When the abortion was complete, depo-medroxyprogesterone acetate (Depo-Provera ) was provided or oral contraceptives were started the following Sunday. A final mail or phone contact occurred to determine when vaginal bleeding ceased. When the abortion was confirmed by ultrasound, subjects responded by five choices, from strongly disagree to strongly agree, to statements regarding acceptability: whether they would recommend overall procedure to a friend, cramping pain, bleeding, side effects, wait until the abortion was over, whether they would recommend using misoprostol at home, whether they would recommend the procedure, and whether they would choose the procedure again. Cronbach s to determine internal consistency of the questions was previously found to be The analysis consisted of a description of the initial clinical presentation and the effectiveness, side effects, and acceptability of the trial. T tests, 2, and Fisher s exact tests were used as appropriate. Statistical significance was defined as having a p 0.05.

3 Contraception Mifepristone 200 mg for Abortion 3 Table 1. Number of subjects who had surgical intervention or who failed the protocol by gestational age (n 933) Gestation <49 days (n 660 [%]) Gestation days (n 273 [%]) Surgical intervention Excessive bleeding 6 2 Continuing pregnancy 2 3 Acute hemorrhage post misoprostol 2 2 Nausea and epigastric pain 2 Ectopic pregnancy 2 Patient s request for intervention 1 Protocol failure Persistent gestational sac 35 days 1 Opted to continuing pregnancy 1 Lost to follow-up 1 2 Total 17 (3) 10 (4) Results Nine-hundred-thirty-three subjects were enrolled from November 1996 through October There were seven enrolling sites: 562 (60%) subjects were enrolled in Rochester, New York; 144 (15%) in San Francisco; 104 (11%) in Seattle; 83 (9%) in New York City; 13 (1%) in Bellevue, Nebraska; 25 (3%) Burlington, Vermont; and 2 ( 1%) in Kalispell, Montana. Of the 933 subjects, 77.4% were white, 10.6% black; 7.1% Asian, 4.3% Hispanic, and 1% other. Subjects had a mean age of 27.8 years (SD 6.1; range 18 41) and a mean gestational age at onset of the study of 46 days with 660 (71%) subjects 49 days and 273 (29%) between days. Seventy-one percent of subjects had had a prior pregnancy, 46% a prior birth, and 49% a prior induced abortion. Enrollment varied at each site because of delays in initiating enrollment, the geographical location and potential number of subjects to recruit, and the experience and staffing of each site. Nine-hundred-six (97%) subjects had a documented complete abortion with study medications. Table 1 describes the 27 (3%) subjects by initial gestational age up to 49 days and from days pregnant who had surgical intervention, failed to complete the protocol, or were lost to follow-up. The most common reason for surgical intervention was persistent or heavy bleeding, which occurred in eight subjects, for, on average, 38.7 days (SD 10.4; range 26 59). There was no difference in surgical intervention by study site, gestational age, mean age of subjects, or prior pregnancy or abortion. One subject who failed the protocol had a persistent gestational sac at day 36, refused surgical intervention, and passed the gestational sac spontaneously on day 50, which was confirmed by ultrasound. Another subject received 200 mg mifepristone orally, vomited within 30 min, decided to continue her pregnancy, and delivered a healthy newborn. Two subjects were enrolled with occult ectopic pregnancies that became apparent at first follow-up visit. Both had amenorrhea 35 days by LMP, and a small amount of fluid in the endometrium misinterpreted as a gestational sac (in retrospect, pseudogestational sac). In neither subject was there a bleeding response to misoprostol warranting further ectopic evaluation. One had an aspiration curettage and no chorionic villi were identified. The subject was treated successfully with methotrexate. The other subject developed right-sided pain, had a formal ultrasound that found an adnexal mass, and required a salpingectomy. In addition to the subjects who were considered treatment failures or required surgery, there were several adverse reactions. Four of the subjects who required surgical intervention required intravenous fluids though none required an overnight hospitalization or transfusion. One subject with an uneventful medical abortion presented with extreme fatigue and dizziness within days of the abortion, requiring a 30-day hospitalization; there was no definitive diagnosis though a psychologic cause was most probable. Another subject had a generalized urticaria reaction after misoprostol, and a last subject had a syncopal experience while bleeding after using misoprostol and fell and broke her nose. Two women had treatment for mild endometritis with an oral antibiotic. One woman had an emergency visit for intravenous fluids for severe nausea. Of those using misoprostol (913), 893 (98%) subjects self-administered the misoprostol vaginally at home. At the first follow-up visit, 25 (2.7%) subjects had not passed the pregnancy and eight (0.9%) had persistent embryonic cardiac activity. Sixteen (2%) subjects used a second dose of misoprostol. Four-hundred-forty-five subjects (47.5%) experienced some vaginal bleeding before using misoprostol. Twenty-six (3.0%) subjects passed the pregnancy before misoprostol use. Of the 746 subjects who had minimal or no bleeding before misoprostol, 593 (80%) reported bleeding within 4 h and 731 (98%) had bleeding within 24 h after using misoprostol. The mean time until the initiation of bleeding after misoprostol was 3.3 h (SD 3.2). Subjects with no prior pregnancy had an onset of bleeding after misoprostol of 2.7 h (SD 2.9), compared with subjects with a prior pregnancy, who had an onset of bleeding of 3.7 h (SD 5.5), p Subjects with no prior live birth began to bleed at 3.2 h (SD 3.1), compared with subjects with at least one live birth, who began to bleed at 3.9 h (SD 4.4), p There was no difference in the

4 4 Schaff et al. Contraception Table 2. Number of subjects reporting symptoms made worse by mifepristone and misoprostol (n 933) Symptoms made worse by Mifepristone (n 929 [99.6%]) Misoprostol (n 903 [96/8%]) Nausea 414 (44.6%) 385 (42.5%) Cramping 339 (36.5%) 830 (91.8%) Dizziness 139 (15.0%) 254 (28.1%) Fever/chill 131 (14.1%) 291 (32.2%) Headaches 125 (13.5%) 118 (13.0%) Vomiting 123 (13.2%) 231 (26.2%) Diarrhea 99 (10.7%) 210 (23.2%) onset of bleeding in subjects with a prior history of an abortion. Of the 828 (89%) subjects with a documented bleeding cessation date, the mean length of bleeding was 17.4 days (SD 10.8). There was no difference in the length of bleeding in the 294 subjects who planned to use a hormonal contraceptive method (17.5 days, SD 11.4), which was started no later than the Sunday after the initial negative ultrasound. The side effects reported for each medication are noted in Table 2. The most common symptoms due to mifepristone were nausea and cramping and the most common symptoms due to misoprostol were cramping, fever, and chills. Table 3 shows the responses to the acceptability questionnaire by whether the subject had a prior surgical abortion. Overall, 94% of subjects found the procedure acceptable and 85% would recommend the procedure to a friend. Seventy-three percent of subjects used an oral narcotic for pain. Seventy-four percent of subjects found the pain related to the procedure acceptable, whereas 13% (121) were neutral and 13% (124) found the pain unacceptable despite using the narcotic medication. Table 3. Number of acceptable responses by history of prior surgical abortion (n 920) Variable Acceptable responses in subjects with prior abortion (n 449) Acceptable responses in subjects with no prior abortion (n 471) Procedure was acceptable 416 (92.7%) 447 (94.9%) Home use of misoprostol was acceptable 401 (90.1%) 429 (92.1%) Bleeding was acceptable 399 (88.9%) 425 (90.2%) Side effects were acceptable 387 (86.4%) 398 (84.5%) Would choose procedure again 382 (85.3%) 420 (89.4%) Waiting was acceptable 380 (84.6%) 407 (86.4) Would recommend procedure 377 (84.2%) 403 (86.1%) Pain was acceptable 336 (74.8%) 345 (73.2%) Of the 124 subjects who found the pain unacceptable, 26 (21%) also reported the procedure to be unacceptable. Unacceptable pain was unrelated to the age of the subject, but correlated with first pregnancies (45/268 or 17%), p 0.001, no prior births (100/504 or 20%), p 0.001, and later gestations of days (55/273 or 20%), p Discussion The participating sites were quite varied as to the number and type of providers, the population served, and the geographic location. Enrollment also varied considerably. There were no statistical differences noted in effectiveness rates across sites. There were fewer failures in the present trial than in the first US multicenter mifepristone trial conducted by the Population Council of NYC in This may be explained by the different regimens. The present trial administered one-third the mifepristone dose, twice the misoprostol dose, misoprostol vaginally rather than orally, misoprostol at home versus under medical supervision, and a second dose of misoprostol if needed. In addition, first follow-up occurred on day 4 8 rather than day 15, and surgical intervention was not performed for a nonviable pregnancy until day 36. The clinical experience gained from the Population Council s trial and from studies of methotrexate abortions likely decreased the number of unnecessary surgical interventions. The high effectiveness rates up to 8 weeks gestation and the consistent bleeding response to misoprostol were likely due to the vaginal administration of misoprostol with its sustained serum levels. 9 Bleeding occurred in almost half the subjects before misoprostol. However, most of these women required the use of misoprostol despite the bleeding. This finding has been incorporated into the routine counseling. Given the choice, almost all subjects used misoprostol at home and 91% found home misoprostol use acceptable. Acute hemorrhage, the most serious problem that might benefit from a 4-h office observation period, occurred in 1% of subjects. Although the additional medical supervision and emotional support from office-administered misoprostol may be ideal, it adds a substantial barrier to this service for both the provider and patient. Women presenting with persistent, delayed heavy bleeding requiring an aspiration curettage for retained products of conception often have a negative or nonspecific ultrasound. Although the -human chorionic gonadotropin (hcg) should rapidly decline about 50% every 48 h after a complete abortion, a persistent level should raise suspicion of retained products of conception. If medical management for persistent bleeding

5 Contraception Mifepristone 200 mg for Abortion 5 with several birth control pills per day for several days or methergine for 2 days fails, curettage should be performed. Subjects who choose to self-administer misoprostol at home at 48 h should have a plan for obtaining emergency care if excessive bleeding occurs. A major advantage of mifepristone is that 95% of subjects had a negative ultrasound at 7 days and 97% within 14 days compared with methotrexate, which can take up to a month to achieve effectiveness rates 90% Because the actions of both mifepristone and misoprostol occur relatively quickly, subjects with an ongoing pregnancy after a second dose of misoprostol can be offered surgical intervention. In contrast, methotrexate s toxic effects on trophoblastic tissue may take up to 2 weeks. It is prudent not to intervene during this period. Continuing pregnancies and other adverse reactions were very rare in the present trial, supporting a high safety profile for mifepristone. Mifepristone is not known to be teratogenic, whereas methotrexate and misoprostol are. Subjects can change their minds and continue their pregnancy, as happened once in the present trial. On the other hand, advantages of methotrexate include its relative low costs, wide availability, and effectiveness as a treatment for early, unruptured ectopic pregnancy. Fever and chills occurred in almost onethird of subjects after misoprostol, a common prostaglandin effect. Unlike methotrexate, mifepristone does not affect early ectopic pregnancy. 15 The acceptability results are consistent with other nonrandomized reports indicating that the majority of participants find medical abortion acceptable and preferable to surgical abortion, whether or not they had a prior surgery. 16,17 The postprocedure questionnaire was performed at the time of the negative ultrasound and, therefore, the acceptability of prolonged bleeding was not assessed. The most unacceptably rated feature of the procedure was the cramping after misoprostol. Of interest, only one-fifth of women who objected to the pain rated the overall procedure as unacceptable. One might conclude that although the pain was unacceptable to a small proportion of women, the pain was expected and the overall experience was acceptable. Unacceptable pain was statistically related to women with no prior pregnancies and later gestational age. The acceptability of the average 17 days of bleeding found postprocedure was not assessed. Women will need to be prepared for this length of bleeding and providers must be aware that excessive bleeding as much as 30 days later may be due to retained products of conception requiring an aspiration curettage. Access to a provider who can perform a surgical completion of the abortion must be available in the case of excessive bleeding. Suction machines are commonly found in emergency rooms and surgical suites. An alternative technique is using manual aspiration with a specially designed 60-cc hand-held syringe. It is simple, portable, and inexpensive for performing early abortions and completions of failed medical abortions. 18 Low-dose mifepristone was highly effective, safe, and acceptable to women. Vaginal misoprostol was associated with a high response of bleeding within 24 h and allowed the regimen to be effective up to 8 weeks gestation. Home administration of misoprostol was safe and acceptable. Other studies are underway to determine the upper gestational limit of effectiveness of this regimen and whether administering misoprostol at 24 or 72 h is as effective as at 48 h. Acknowledgments We acknowledge the contributions of Larry Lader, President of the Abortion Rights Mobilization, for making this study possible and David Horne, PhD, Assistant Professor of Chemistry, Columbia University, New York, for overseeing the manufacturing process. Collaborating investigators include LeRoy Carhart, MD, Bellevue, Nebraska; James Armstrong, MD, Kalispell, Montana; Carolyn Westhoff, MD, Associate Professor of Obstetrics and Gynecology, Columbia University, New York; and Elisabeth K. Wegner, MD, Assistant Professor of Obstetrics and Gynecology, University of Vermont. References 1. Peyton R, Aubeny E, Tarzus V, et al. Early termination of pregnancy with mifepristone (RU486) and orally active prostaglandin misoprostol. N Engl J Med 1993; 328: Silvestre L, Dubois C, Renault M, et al. Voluntary interruption of pregnancy with mifepristone (RU486) and a prostaglandin analog: a large scale French experience. N Engl J Med 1990;322: Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Eng J Med 1998;338: Heikinheimo O, Kekkonen R. Dose-response relationships of RU486. Ann Intern Med 1993;25: World Health Organization Task Force on Postovulatory Methods of Fertility Regulation. Termination of pregnancy with reduced doses of mifepristone. Br Med J 1993;307: World Health Organization. Pregnancy termination with mifepristone and gemeprost: a multicenter comparison between repeated doses and a single dose of mifepristone. Fertil Steril 1991;56: Birgerson L, Odlind V. Early pregnancy termination with antiprogestins: a comparative clinical study of RU486 given in dose regimens and Epostane. Fertil Steril 1987;48:

6 6 Schaff et al. Contraception 8. El-Refaey H. Rajasekar D, Abdalla M, et al. Induction of abortion with mifepristone (RU486) and oral or vaginal misoprostol. N Engl J Med 1995; Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90: Schaff EA, Stadalius LS, Eisinger SH, Franks P. Vaginal misoprostol administered at home after mifepristone for abortion. J Fam Pract 1997;44: Goldstein SR. Embryonic ultrasonographic measurements: crown-rump length revisited. Am J Obstet Gynecol 1991;165: Creinin MD, Vittinghoff E, Keder L, et al. Methotrexate and misoprostol for early abortion: a multicenter trial. I. Safety and efficacy. Contraception 1996;53: Hausknecht RU. Methotrexate and misoprostol for induced abortion. N Engl J Med 1995;333: Schaff EA, Eisinger SH, Franks P, Kim S. Methotrexate and misoprostol for early abortion. Fam Med 1996;28: Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993;168: Henshaw RC, Naji SA, Russell IT, Templeton AA. Comparison of medical abortion with surgical vacuum aspiration: women s preferences and acceptability of treatment. Br Med J 1993;307: Creinin MD, Burke AE. Methotrexate and misoprostol for early abortion: a multicenter trial. Acceptability. Contraception 1996;54: Edwards J, Carson SA. New technologies permit safe abortion at less than six weeks gestation and provide timely detection of ectopic gestation. Am J Obstet Gynecol 1997;176: