Mifepristone in Abortion Care

Transcription

1 Mifepristone in Abortion Care Courtney Schreiber, M.D., 1,3 and Mitchell Creinin, M.D. 2,3 ABSTRACT With the addition of a prostaglandin analog, mifepristone allows for successful outpatient termination of pregnancy up to 63 days gestation in 92 99% of women. In the inpatient setting, studies have shown that mifepristone in combination with a prostaglandin analog is also effective as an abortifacient in the late first trimester. In the second trimester, the addition of mifepristone to a prostaglandin regimen has been shown to expedite induction time. At all stages of pregnancy, the use of mifepristone facilitates and ameliorates prostaglandins expulsive effects on the uterine contents. The rich literature regarding mifepristone in the setting of abortion care has made an important contribution to how physicians treat undesired and problem pregnancies. As with any area of medicine, treatment options provide important flexibility for patients and clinicians alike. KEYWORDS: Mifepristone, misoprostol, medical abortion Antiprogestins have been explored for their practical application to fertility control since the 1960s. 1 In 1982, French researchers developed RU 486 (mifepristone), a compound similar to norethindrone with high progesterone receptor affinity that inhibits progesterone s support of a pregnancy. With the addition of a prostaglandin analog, mifepristone allows for successful outpatient termination of pregnancy up to 63 days gestation in 92 to 99% of women. 2 6 In the inpatient setting, studies have shown that mifepristone in combination with a prostaglandin analog is also effective as an abortifacient in the late first trimester Although dilation and evacuation (D&E) is the safest and most effective way in which to evacuate the uterus in the second trimester, the addition of mifepristone to a prostaglandin regimen has been shown to expedite induction for second-trimester abortion. 14,15 This article reviews the history, the mode of action, efficacy, and the evidence that supports the clinical use of mifepristone in abortion care. HISTORY In recent years, mifepristone has been used in abortion care predominantly in two arenas: medical abortion, a term that refers to the medical termination of a pregnancy before 9 weeks gestation, 16 and induction, a term that refers to the medical termination of a pregnancy in the second trimester. For centuries, women have attempted to limit child-bearing through abortion by a variety of means. Hippocrates advised, jumping up and down so that the buttocks are touched with the feet to induce an abortion. Americans in the 19th century used poisons in doses that were supposed to be sufficient to kill the fetus, but still able to spare the woman. 17 Despite its lengthy history, the scientific approach to medical abortion has only been cultivated during the last 50 years, and it is only in the last 20 years that regimens comparably effective to vacuum aspiration have become available. The agents of scientific focus fall into three main categories: uterotonics (predominantly prostaglandins and their analogs), antiprogestins, and Progesterone Receptor Antagonists and Selective Progesterone Receptor Modulators (SPRMs); Editor in Chief, Bruce R. Carr, M.D.; Guest Editor, Irving M. Spitz, M.D., D.Sc., F.R.C.P. Seminars in Reproductive Medicine, Volume 23, Number 1, Address for correspondence and reprint requests: Courtney Schreiber, M.D., Contraception Research and Family Planning, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee Womens Hospital, 300 Halket Street, Pittsburgh, PA cschreiber@mail. magee.edu. 1 Contraception Research and Family Planning; 2 Gynecologic Specialties, and Family Planning; 3 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee Womens Hospital, Pittsburgh, Pennsylvania. Copyright # 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) ,p;2005,23,01,082,091,ftx,en;sre00302x. 82

2 MIFEPRISTONE IN ABORTION CARE/SCHREIBER, CREININ 83 antimetabolites (methotrexate). Mifepristone is the only antiprogestin that has been used clinically. PHARMACOKINETICS Mifepristone is well absorbed orally and reaches peak serum concentration in pregnant women within 2 hours. The pharmacokinetics are similar for any dose over 100 mg, and similar peak serum concentrations of 2.0 to 2.5 mg/ml are found in women given 100, 200, and 800 mg. 18 The half-life of mifepristone is approximately 19 hours in pregnant women. The principal serum-binding protein to which it binds is a-1-acid gylcoprotein. 19 MECHANISM OF ACTION Progesterone plays an important role in human reproduction, and the ability to inhibit its activity likewise has the potential to influence reproductive capacity at many levels. In 1982, investigators of glucocorticoid antagonists, Baulieu and collaborators at the pharmaceutical company Roussel-Uclaf (France), developed a compound that antagonizes progesterone at the receptor level. Mifepristone, a derivative of norethindrone, works at the progesterone receptor as an antiprogestin. By competitively binding with the progesterone receptor, mifepristone inhibits progestin activity, alters the endometrium, and decidual necrosis, and causes the trophoblast to separate from the deciduas. 19,20 In addition, mifepristone sensitizes the pregnant uterus and cervix to endogenous and exogenous prostaglandins, which allows for increased uterine activity and cervical softening. Human studies have suggested that uterine contractility does not increase until 24 to 36 hours after mifepristone administration. 21 At this point, the myometrium is five times more sensitive to the stimulatory effects of exogenous prostaglandins. 21 However, a recent study 22 in which the time interval between mifepristone and misoprostol for early abortion was decreased suggests that some or all of these actions occur sooner. A 24- to 36-hour interval between mifepristone and prostaglandin analog administration is not necessary for the medical abortion to be successful, tolerable, and acceptable to the patient. The exact manner in which mifepristone contributes to the abortion process is not entirely understood, and warrants further investigation. MIFEPRISTONE ALONE FOR EARLY ABORTION Because of the effects of mifepristone on a pregnancy and the pregnant uterus and cervix, clinical trials were initiated to evaluate the efficacy of mifepristone alone as an abortifacient. Oral doses ranging from 50 to 400 mg were tested in women with gestations less than 49 days; complete abortion occurred in 60 to 80% of pregnancies, and 7 to 40% of patients had continuing pregnancies These rates were not clinically acceptable when compared with complete abortion rates from vacuum aspiration. Because mifepristone weakens the implantation site and increases myometrial sensitivity to prostaglandins, investigators began to add small doses of uterotonic agents on the last day of mifepristone treatment in an attempt to increase complete abortion rates. The addition of small doses of prostaglandin analogs had a synergistic effect, resulting in complete in nearly 100% of women. 24,28 Importantly, these prostaglandin analog doses were lower than those required when using the prostaglandin analog alone. Complete abortion could be achieved with potentially fewer side effects, primarily because mifepristone treatment allowed for lower doses of prostaglandin to be used to induce an abortion successfully. In 1988, mifepristone, in combination with a prostaglandin analog, was licensed for use in France. China, England, and Sweden followed suit soon thereafter. After years of political delay, the U.S. Food and Drug Administration (FDA) finally approved the use of mifepristone as an abortifacient in September Since then, researchers have been working to refine its acceptability and efficacy, and more than 130,000 American women have used mifepristone in combination with a prostaglandin to achieve an abortion. 29 PROSTAGLANDINS ALONE To understand the clinical utility of mifepristone in the setting of abortion, one should first have an appreciation for the efficacy of prostaglandins alone for uterine evacuation. This section focuses on misoprostol, a prostaglandin E 1 (PGE 1 ) methyl analog, because it is the least expensive, most convenient to store, and most widely accessible of the prostaglandin analogs. However, in Europe, the use of gemeprost is still common. Oral misoprostol alone has not been studied extensively, but it appears to be an ineffective abortifacient, inducing abortion in only 5% of women < 56 days gestation. 30 Vaginal misoprostol has been studied more extensively. It has been given in a variety of dosing regimens, along with a variety of administration techniques (such as with vaginal cleansing, misoprostol moistening, and repeat dosing at different time intervals.) Success rates, with varying definitions, ranged from 19 to 97% In general, the more time that is allowed to elapse before the decision of success or failure is made, the higher the success rate. The highest success rates are seen in those regimens using repeated doses of 800 mg vaginally (47 to 94%) at < 63 days gestation, 31,35 with some evidence that success is increased by moistening the misoprostol (85 to 97%). 35 Side effects, such as vomiting and diarrhea, occur in as many as 40% of

3 84 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 23, NUMBER women and increase with repeated does of prostaglandin. Clearly, the range of success rates with vaginal misoprostol alone is wide, and women may not be willing to wait for days to weeks to complete the abortion procedure. As we will review, the addition of mifepristone to misoprostol regimens allows for increased complete abortions at a faster rate up to 63 days gestation. MIFEPRISTONE AND MISOPROSTOL FOR EARLY ABORTION The most commonly used medical abortion regimen throughout the world today is mifepristone followed by a prostaglandin analog. In the United States, the current standard, FDA-approved regimen consists of 600 mg of oral mifepristone followed by a prostaglandin analog, usually misoprostol, 36 to 48 hours later. A review of the literature and an understanding of the pharmacology can explain why some experienced clinicians have varied this regimen. The standard, FDA-approved regimen has been reported to effect complete abortion in 92 to 99% of women. 2 5 Consistent with rates of abortion using mifepristone alone, between 2 and 5% of women will abort before misoprostol administration. 2 4 The largest clinical trial combining mifepristone 600 mg and misoprostol 400 mg orally was the U.S. Population Council study. 4 All participants had a vaginal ultrasound examination to confirm gestational dating, and all participants underwent observation after misoprostol administration for a minimum of 4 hours. The overall effectiveness in the 2015 women evaluated was significantly worse using this treatment regimen for women with gestations more than 49 days. Vaginal bleeding lasted days; 9% of women had bleeding lasting more than 30 days. Four (0.2%) women received blood transfusions: one subject each through 49 days and at 57 to 63 days gestation, and two subjects at 50 to 56 days gestation. A randomized trial in Canada compared the efficacy and side effects of mifepristone 600 mg followed 36 to 48 hours later by misoprostol 400 mg orally (n ¼ 518) and methotrexate 50 mg/m 2 intramuscularly followed 4 to 6 days later by misoprostol 800 mg vaginally (n ¼ 524) in women up to 49 days gestation. 37 All misoprostol doses were self-administered by the women and repeated 24 hours later if bleeding was less than the typical menstrual flow. Subjects returned 7 days after the initiation of treatment, at which time vaginal ultrasonography was performed; misoprostol 800 mg was administered vaginally if the examination demonstrated persistence of a gestational sac. A suction aspiration was performed if a viable gestation was present at a second follow-up visit 2 weeks after initiation of treatment or if the gestational sac had not been expelled by 5 weeks after initiation of treatment. The abortion rate by the 1-week follow-up examination was 75% in the methotrexate group and 90% in the mifepristone group (p < 0.001). Notably, the overall surgery rates were 4% in both groups. Although some subtle differences in the rate of some side effects were present, the most interesting was a statistically greater mean pain score (using an 11-point scale) with the methotrexate regimen (6.3 v 5.8; p ¼ 0.003), although this small difference is not likely clinically significant. Inspired by the early efficacy of the standard regimen of mifepristone 600 mg followed 48 hours later by a prostaglandin analog in the clinic or office in women up to 49 days gestation, 38 investigators looked toward alternative regimens that might ease side effects, be less expensive, or be more acceptable to providers and patients. The innovations studied have involved using lower doses of mifepristone, using misoprostol vaginally, administering misoprostol at home, and altering the timing of the misoprostol dose. As expected on the basis of mifepristone pharmacokinetics, lower doses of mifepristone are equally as effective as the 600-mg dose when combined with either gemeprost or misoprostol Because mifepristone is the more expensive of the medications, lower-dose regimens are more economical. El-Rafaey et al 36 first reported equivalence in 220 women treated with mifepristone 200 or 600 mg (110 subjects per group) followed by misoprostol 600 mg orally 48 hours later. The overall effectiveness was 97.5% at up to 49 days gestation, 91.3% at 50 to 56 days gestation, and 84.4% at 57 to 63 days gestation. A large trial performed by the World Health Organization (WHO) 42 included women up to 63 days gestation who received either mifepristone 200 mg (n ¼ 792) or 600 mg (n ¼ 797) followed 48 hours later by misoprostol 400 mg orally. Complete abortion rates were similar for both groups (89 and 88%, respectively) and, as in the U.S. Population Council study, 4 were dependent on gestational age: the rates of incomplete abortion were 5% in the 64; 49 days gestation group, 7% in the 57- to 63-days gestation group, and 8% in the 50- to 56-days gestation group. Side effects were not different between the groups. In addition to these randomized trials, three large studies using mifepristone 200 mg combined with misoprostol 800 mg vaginally in more than 4000 women have also confirmed the efficacy of the lower dose of mifepristone. 6,43,44 Both vaginal and sublingual dosing of misoprostol have been evaluated in combination with mifepristone for medical abortion. However, the data available for sublingual dosing is scant, and additional investigations are needed before sublingual misoprostol should be used in clinical practice. 45,46 Overall, administering misoprostol vaginally, as compared with the standard oral route, allows the effective use of mifepristone regimens through 63 days. Because women prefer the oral

4 MIFEPRISTONE IN ABORTION CARE/SCHREIBER, CREININ 85 route, 47 continued evaluation of sublingual, buccal, and other nonvaginal routes of administration is highly warranted. El-Rafaey et al 48 first reported the use of vaginal misoprostol in combination with mifepristone in Of 100 women up to 63 days gestation, 99 completely aborted within 4 hours of misoprostol administration and 67% did not require any pain medication. A followup study randomly assigned women up to 63 days gestation to receive misoprostol 800 mg orally or vaginally (130 and 133 subjects, respectively, per group) 48 hours after mifepristone 600 mg. 36 Abortion occurred more rapidly in the vaginal misoprostol group, with an expulsion rate of 93% within 4 hours as compared with 78% in the oral group. Complete abortion occurred in 95% of women using vaginal misoprostol and 87% with oral misoprostol. In addition, three large studies including more than 4000 women have reported the high efficacy and low rates of continuing viable pregnancy with regimens using misoprostol 800 mg vaginally. 43,44 A multicenter randomized trial compared misoprostol 800 mg vaginally and gemeprost 0.5 mg vaginally approximately 48 hours after mifepristone 200 mg in women up to 63 days gestation. 49 The complete abortion rate was significantly higher after treatment with misoprostol than gemeprost (98.7 versus 96.2%, respectively; p ¼ 0.02). Importantly, continuing pregnancy was much less common with misoprostol than gemeprost (0.2 versus 1.8%, respectively; p ¼ 0.02). In both groups, failure was more common at higher gestational ages. Side effects were not clinically significantly different between groups. The WHO recently published a study that compared the efficacy, acceptability, and bleeding duration differerences in the route and duration of misoprostol treatment. 50 In the well-powered study of 2219 women, the investigators found that there was no difference in complete abortion rate for women < 56 days gestation in their three arms (vaginal misoprostol 800 mg only, vaginal misoprostol 800 mg followed by oral misoprostol 400 mg, and oral misoprostol 800 mg followed by oral misoprostol 400 mg). For women with a gestation more advanced than 57 days, there was a statistically significant difference between complete abortion rates in the vaginal misoprostol group versus the oral misoprostol group. Patients who had follow-up oral misoprostol had higher efficacy rates still, but also suffered more significant side effects such as diarrhea. There was an approximately 6% increase in the incomplete abortion rate when the oral misoprostol group was compared with the vaginal followed by the oral misoprostol group, with significant findings in the patients with more than 57 days gestation. The duration of bleeding was similar among the three groups. These trials suggest that, based on efficacy, vaginal misoprostol should be the prostaglandin analog of choice (and route of delivery) for use with mifepristone through 63 days gestation. Multiple investigators have published reports of successful use of self-administered misoprostol in mifepristone medical abortion regimens. 6,43,47,51 54 In the three largest trials using mifepristone 200 mg and misoprostol 800 mg vaginally, 3,6,52 90% of subjects in all studies found home use of misoprostol acceptable regardless of prior abortion experience, 6 gestational age, 44 or time between mifepristone and misoprostol use. 54 A total of four (0.1%) participants in two studies experienced adverse events in the hours after misoprostol administration. 6,43 Two of these women presented for an emergent aspiration for heavy bleeding; neither required a blood transfusion. One patient had a vasovagal reaction to cramping and was treated with intravenous fluids. One woman had a syncopal episode while bleeding and fell and broke her nose. Only the latter occurrence (one of approximately 4500 women) would have necessarily been avoided with in-office observation. On the basis of the initial clinical trials using mifepristone and a prostaglandin analog, the standard time to administer the prostaglandin analog after mifepristone is 36 to 48 hours. However, regimens with a shorter interval between mifepristone and misoprostol administration, if effective, would lessen the amount of time necessary for a medical abortion to occur and increase acceptability. 52 In addition, given that approximately half of women bleed during the 48 hours after mifepristone administration, 4,6 administering the drugs on the same day would decrease prolonged bleeding. Schaff et al 52 reported a multicenter randomized trial in 2295 women up to 56 days gestation who selfadministered misoprostol 800 mg vaginally 24, 48, or 72 hours after taking mifepristone 200 mg orally. Follow-up occurred within 8 days after the mifepristone. The misoprostol dose was repeated if vaginal ultrasound examination did not confirm expulsion. Complete medical abortion occurred in 98% (95% CI, 97 to 99%), 98% (95% CI, 97 to 99%), and 96% (95% CI, 95 to 97%), respectively. In addition, the waiting period before expulsion was acceptable in 86, 79, and 76%, respectively ( p ¼ 0.001). The same investigators followed this study with a randomized trial to compare oral and vaginal dosing of misoprostol 24 hours after administration of mifepristone 200 mg. 47 Women up to 63 days gestation were randomly assigned to use either two doses of oral misoprostol 400 mg taken 2 hours apart or misoprostol 800 mg vaginally. Women returned for follow-up within 5 days and received vaginal misoprostol if a continuing pregnancy was present. Of the 1144 women who complied with their random assignment, complete abortion

5 86 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 23, NUMBER by the first follow-up visit occurred in 90% of the oral misoprostol group, and 97% in the vaginal misoprostol group (p ¼ 0.001). By the second follow-up visit, the complete abortion rates were 95% and 99%, respectively (p ¼ 0.001). There were minimal differences in side effects. This trial verified the efficacy of vaginal misoprostol 24 hours after mifepristone dosing with a complete abortion rate that approximates vacuum aspiration. However, the time-lapse between the administrations of the two medications (which, for the patient, contributes to the time it takes to complete the abortion), might be considered a disadvantage of the method. A recent equivalency trail 22 set out to address whether or not a further decrease in the time interval between the administrations of the two drugs allows for the same efficacy. This study randomly assigned 1080 women to 200 mg mifepristone followed by 800 mg vaginal misoprostol at either 6 to 8 hours or 24 hours later. The complete abortion rates were statistically equivalent between the two groups: 96% (95% CI, 93 to 97) in the 6- to 8-hour group and 98% (95% CI, 97 to 99) in the 24-hour group. The complete abortion rate did not vary statistically by gestational age in either group. The duration of bleeding was not different between the two groups; however, those in the 6- to 8-hour group experienced statistically significantly fewer side effects such as nausea, vomiting, and diarrhea. In summary, the standard regimen for medical abortion is 600 mg of mifepristone combined with oral misoprostol 36 to 48 hours later. However, the evidence demonstrates that 200 mg of misoprostol fosters the same efficacy, and this is supported by the pharmacokinetics of the drug. Vaginal placement of misoprostol is more efficacious for gestations above 49 days, and the difference in efficacy is emphasized with more than 56 days gestation. A decrease in the time interval, with a current lower limit of 6 hours, does not compromise efficacy and does decrease side effects. The efficacy of such evidence-based regimens is comparable to that of vacuum aspiration. POSTMEDICAL ABORTION CARE A follow-up evaluation is typically performed 10 to 15 days after misoprostol administration to ensure that the pregnancy has been expelled. Expulsion can be confirmed by clinical history or ultrasonography. Most commonly, European, Chinese, and U.S. clinical trial protocols have included a surgical aspiration if the abortion is not complete by this follow-up visit. Schaff et al 51 have demonstrated that this intervention is not necessary and additional doses of misoprostol or simply waiting (if the pregnancy is not viable) is an acceptable alternative. Clinicians must understand that a normal transvaginal view of the uterine cavity following misoprostol administration will contain obvious clot and, sometimes, fluid (Fig. 1). The main goal of the ultrasound examination is solely the determination of the presence or absence of the gestational sac. Harwood et al 55 demonstrated that the mean endometrial thickness 24 hours after using misoprostol in women with a complete medical abortion was 17.5 mm, but ranged from 7.6 to 29.0 mm. Typically, clinicians define a thickness greater than 15 mm as suspicious for incomplete abortion. One week after the abortion, the mean thickness was 11.3 mm but ranged from 1.6 to 24.9 mm. Fifteen percent of these women had an endometrial lining of 16 mm or greater and might have been diagnosed as having an incomplete abortion. Given that all of the women in this trial had a complete abortion, this study indicates that it is normal to visualize clot and debris in the uterus when transvaginal ultrasound is used to evaluate a patient following medical abortion. The duration of bleeding after a medical abortion using mifepristone varies among studies but, surprisingly, the variation is not due to use of different doses of either medication or the route of administration of the misoprostol. Three studies, including two from France, found an average duration of bleeding of 9 days, 2,3,36 with a range of 1 to 32 days. 34,30 However, the remainder of studies, including those from the United States, report a mean duration of bleeding of 14 to 17 days 6,40,41 with a range of 1 to 69 days. 4,51,56 Figure 1 The thickened endometrial stripe seen after a complete medical abortion. (A) uterus, longitudinal; (B) uterus, transverse.

6 MIFEPRISTONE IN ABORTION CARE/SCHREIBER, CREININ 87 Davis et al 57 developed diaries with the intent of ascertaining accurate bleeding patterns after medical abortion. Mifepristone 200 mg and misoprostol 800 mg vaginally were administered as part of a larger trial comparing misoprostol administration 1, 2, or 3 days after the mifepristone. 52 Subjects reported bleeding for a mean of 14 days and spotting for a mean of 10 days. Overall, women had bleeding or spotting for an average of 24 days, much longer than that typically reported in efficacy studies. Twenty percent of women had bleeding or spotting that lasted more than 35 days. The results were not affected by when the misoprostol was administered. However, gestational age was directly related to the length of bleeding, with a mean total number of days of bleeding or spotting of 19 days in gestations less than 6 weeks and 25 days for gestations equal to or greater than 6 weeks. In addition, there was no significant difference in bleeding duration on the basis of contraceptive method started after expulsion. Use of oral contraceptives after expulsion does not effect duration of vaginal bleeding, blood loss, or abortion outcome. 58,59 COUNSELING FOR MEDICAL ABORTION The success of the medical abortion experience depends a great deal on the counseling process. Because the widespread availability of medical abortion is relatively new, patients may not know what to anticipate regarding their experience. As with any medical intervention, careful review of the process and establishment of appropriate expectations will make the process easier for both the patient and the clinician. Because the abortion process is prolonged and occurs outside of a doctor s office, the counseling for medical abortion is generally more involved than the counseling for a surgical abortion. 60 Manuals for medical abortion providers such as that produced by Planned Parenthood of New York City and the National Abortion Federation offer detailed guidelines about the practicalities of medical abortion. Some important points include a review of what the patient will experience so that she is prepared. Bleeding and cramping are to be expected, as are the potential for nausea, vomiting, diarrhea, and fever and chills. It may help for the woman to arrange for a support person s availability and/or childcare during the few hours after the misoprostol administration. Contraception counseling and prescription is also an important component of the medical abortion process. The average amount of time that it takes for women to ovulate after the administration of the medication is not known. In populations undergoing spontaneous abortion and surgical abortion, ovulation generally occurs between 12 and 39 days after uterine evacuation Many clinicians, therefore, initiate contraception as soon as the pregnancy is expelled. 66 MIFEPRISTONE BETWEEN 9 AND 13 WEEKS GESTATION Although mifepristone has been studied extensively as an abortifacient up to 63 days gestation, it has not been as extensively explored in the late first trimester. There are two potential uses of mifepristone at this gestation: as a cervical primer before vacuum aspiration and as an abortifacient in conjunction with a prostaglandin analog. 10 Given the known effect of mifepristone as a cervical softener, it is not surprising that, when administered 24 to 48 hours before dilation and curettage (D&C), mifepristone is an effective cervical primer. 67 A randomized controlled comparison (n ¼ 60) of mifepristone versus misoprostol preoperatively for women between 7 and 12 weeks gestation demonstrated that the baseline dilation and force necessary to mechanically dilate was equivalent between women who received mifepristone 48 hours or vaginal misoprostol 24 hours before their procedure. There was no statistically significant difference between the two groups regarding patient satisfaction or intraoperative blood loss. Likewise, studies comparing oral misoprostol with mifepristone have shown to be equivalent to cervical priming, and mifepristone may have an advantage over gemeprost in nulliparous women. 7 9 Bleeding and abdominal pain is decreased with mifepristone compared with misoprostol. 7,9 To evaluate the efficacy of mifepristone 200 mg orally followed 36 to 48 hours later by misoprostol 800 mg vaginally between 63 and 83 days gestation, women who presented for abortion with this gestational age range were offered either D&C or the medical regimen. 68 Of the 313 women who presented during the study interval, interestingly, 253 (81%) chose medical abortion over D&C. Success was defined as complete abortion at the 24-hour mark without the need for additional misoprostol dosing or surgical intervention. The success rate in this study was 95%. Four women completed their abortion before the misoprostol was given. 60% of the subjects were nulliparous, and, although the study s power was not calculated with this in mind, there was no difference in success rate based on parity. Seventy-two percent of women neither requested nor received analgesia. One woman required a blood transfusion, and six women (2%) required overnight hospitalization. A similar case series 69 (n ¼ 120) using mifepristone 200 mg followed 36 to 48 hours later by misoprostol 800 mg vaginally (with some women also receiving doses of misoprostol 400 mg orally at the discretion of the investigators) between 9 and 13 weeks gestation also found a success rate of 95% with no major complications reported. The concept that medical abortion is a treatment for undesired pregnancy before 63 days perhaps should be called into question. Further studies to verify these findings may revise the definition of medical

7 88 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 23, NUMBER abortion, and allow women with pregnancies of all gestational ages the flexibility of choice of abortion method. MIFEPRISTONE FOR SECOND-TRIMESTER ABORTION In experienced hands, D&E following cervical preparation with osmotic dilators is the safest, most effective and expeditious way in which to perform a secondtrimester abortion Complication rates increase with advanced gestational age and surgical inexperience. 13 Because the skills and equipment necessary to perform surgical second-trimester uterine evacuation are not always available, medical management is often necessary. Furthermore, a small subset of patients may prefer this mode of delivery, depending on the circumstances involved. The introduction of prostaglandin analogs in the 1970s allowed for departure from the use of intraamniotic infusion and oxytocin for the care of patients in the second trimester. A variety of such analogs are effective, with misoprostol possessing the favorable profile of being inexpensive, effective, and stable at room temperature. Induction to abortion time is comparable to that with other prostaglandin analogs, approximately 12 to 28 hours. 70 The use of mifepristone 36 to 48 hours before prostaglandin can improve outcomes. Several investigators have demonstrated a decreased induction-toabortion interval and increased success rate when misoprostol administration is preceded by oral mifepristone, in either 200 or 600 mg dosing. 71 The equivalence of the efficacy of the 200-mg dose as compared with the 600-mg dose, as with early medical abortion, has been demonstrated in a randomized controlled trial (n ¼ 7); mean induction to abortion interval, 6.9 hours). 15 Although some studies have shown equivalent induction-to-abortion times with misoprostol alone, the number of repeat doses of prostaglandin makes this regimen less desirable than when it is accompanied by mifepristone. In a study done to compare oral versus vaginal misoprostol in women pretreated with 200 mg mifepristone for pregnancies between 13 and 20 weeks gestation, 72 the induction-to-abortion interval was shorter with vaginal misoprostol (200 mg vaginally every 3 hours for a maximum of five doses), but acceptability was greater in the oral misoprostol group (400 mg every 3 hours for a maximum of five doses). Of note, the induction-to-abortion interval for the vaginal group was still 15.2 hours on average. Although this was an improvement over the oral misoprostol group (32 hours on average), it is still significantly longer than the 6- to 8-hour interval cited by other studies. 15,73,74 When used in combination with gemeprost, mifepristone significantly reduced both the induction-toabortion interval and the amount of gemeprost necessary to complete the induction. 72 In this study, in which women 14 to 20 weeks gestation (n ¼ 62) were randomly assigned to pretreatment with mifepristone 600 mg or laminaria tent before prostaglandin treatment, side effects were similar between the two groups. COUNSELING FOR SECOND-TRIMESTER INDUCTION In centers where D&E is available, or referral to such services is available, patients should be counseled regarding the very different experience of undergoing a D&E versus induction in the second trimester. D&E remains the safest and most effective manner in which to perform a second-trimester abortion Little is known about patient preferences, however, and older data using prolonged induction techniques such as intra-amniotic infusion may not apply to patients who undergo induction with mifepristone followed by a prostaglandin analog. A randomized comparison of second-trimester abortion with mifepristone/prostaglandin and D&E has not been performed. Given the dramatically shortened induction interval fostered by mifepristone, patient preference, and even safety and efficacy, may not be predictable based on historic data. As with any second-trimester induction, patients who undergo mifepristone/prostaglandin analog inductions must be prepared for a process that mimics labor, and the possibility of a live-born fetus. Both of these aspects of induction can be difficult for patients and staff. However, appropriate pain control, emotional support, and discretion on the part of the clinicians can ease this process, and should be considered a priority in this setting. TERATOGENICITY Patients who choose to undergo abortion with mifepristone and a prostaglandin must be clear about their decision to terminate the pregnancy. The patient s expectation should be that a failed abortion would be completed by an aspiration procedure and that continuation of the pregnancy is not an alternative. In terms of the teratogenic effects of the mediations used to induce abortion, there are no data to support insults secondary to use of mifepristone. In France, 91,665 pregnancies during 2 years resulted in 3452 fetal anomalies, but none of the women had taken mifepristone during their pregnancies. 75 A great deal of information on the teratogenicity of misoprostol comes from Brazil, where women use misoprostol in attempts to perform illegal abortions. Misoprostol has been associated with two types of anomalies: skull defects and limb abnormalities.

8 MIFEPRISTONE IN ABORTION CARE/SCHREIBER, CREININ 89 Some of these infants have Mobius sequence, 76 which is defined as mask-like facies, bilateral sixth and seventh nerve palsy, and possible micrognathia. 77 The efficacy of the two-drug medical abortion regimen increases success rates and decreases failure rates, thereby decreasing the likelihood of possible associated fetal anomalies. 78 Both patients and providers must understand the important relationship between efficacy, failure, and commitment to the termination of the pregnancy. CONCLUSION This article reviewed the utility of mifepristone in abortion care. Its efficacy has been studied most extensively in combination with misoprostol in pregnancies up to 9 weeks gestation, but there is evidence that it can facilitate uterine evacuation at all stages of pregnancy. 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