043098 early pregnancy termination with mifepristone

C o py r ig h t , 1 9 9 8 , by t h e Ma s s a c h u s e t t s Me d i c a l S o c i e t y V O L U M E 3 3 8
N U M B E R 1 8
causes abortion by competitively blocking have been used successfully to terminate pregnancy progesterone receptors.1-3 For maximal ef- in Europe and China. We report the results of a large fectiveness, a prostaglandin should be giv- U.S. study of mifepristone and misoprostol in wom- en 48 hours after mifepristone.1,3,4 The rates of en with pregnancies of up to nine weeks’ duration.
termination of pregnancies 49 days old or less are Methods
similar, ranging from 96 to 99 percent, whether and then 400 mg of misoprostol two days later to mifepristone is used with gemeprost or misoprostol, 2121 women seeking termination of their pregnan- both prostaglandin E compounds.1,3,5-7 Gemeprost cies at 17 centers. The women were observed for is expensive, requires refrigeration, and is not widely four hours after the administration of misoprostol available, but misoprostol is inexpensive, stable at and returned on day 15 for final assessment.
room temperature, and obtainable in many coun- the final assessment. Among them, pregnancy was terminated in 762 of the 827 women pregnant for Many American women do not have access to р49 days (92 percent), 563 of the 678 women preg- abortion,8 and in developing countries up to 200,000 nant for 50 to 56 days (83 percent), and 395 of the women die annually of complications after illegal 510 women pregnant for 57 to 63 days (77 percent) abortions.9 The availability of medical abortion in (PϽ0.001). Termination occurred within 4 hours after the United States and elsewhere could lead to great- the administration of misoprostol in 49 percent of er access to safer abortion services. We conducted a the women and within 24 hours in 75 percent. Fail- multicenter trial of mifepristone and misoprostol to ures, defined as cases requiring surgical intervention determine whether this combination could be used for medical reasons or because the patient request- to terminate pregnancies of up to 63 days’ duration.
ed it, the abortion was incomplete, or the pregnancywas ongoing, increased with increasing duration of pregnancy. The largest increase was in failures rep-resenting ongoing pregnancy, which increased from Participating Centers
1 percent in the р49-days group to 9 percent in the From September 1994 to September 1995, we enrolled 2121 57-to-63-days group (PϽ0.001). Abdominal pain, nau- women, each with a documented pregnancy of 63 days’ duration sea, vomiting, diarrhea, and vaginal bleeding also in- or less, requesting termination of pregnancy. Women with liver, creased with advancing gestational age. Two percent respiratory, renal, adrenal, or cardiovascular disease, thromboem- of the women in the р49-days group, as compared bolism, hypertension, anemia, insulin-dependent diabetes melli- with 4 percent in each of the other two groups, were tus, coagulopathy, or known allergy to prostaglandins were ex- hospitalized, underwent surgical intervention, and cluded, as were women less than 18 years of age or those morethan 35 years of age who smoked more than 10 cigarettes per day received intravenous fluids (Pϭ0.008).
and had another cardiovascular risk factor. Women were also ex- Conclusions
cluded if they had in situ intrauterine devices, were breast-feed- men is effective in terminating pregnancies, espe-cially in women with pregnancies of 49 days’ dura-tion or less. (N Engl J Med 1998;338:1241-7.)1998, Massachusetts Medical Society.
From the Center for Biomedical Research, Population Council, 1230 York Ave., New York, NY 10021, where reprint requests should be ad-dressed to Dr. Robbins. The principal investigators and centers participating in the study are list- Downloaded from www.nejm.org at WELCH MEDICAL LIBRARY-JHU on April 17, 2005 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e ing, were receiving anticoagulation or long-term glucocorticoid with respect to age (mean, 27 years; range, 18 to therapy, had adnexal masses, had ectopic pregnancies, or had 45), gravidity, parity, number of spontaneous or signs or symptoms suggesting they might abort spontaneously.
previous elective abortions, and ethnic or racial dis- All the women agreed to undergo surgical termination of preg-nancy if the medical method failed. Among the 2121 women, tribution (white, 71 percent; black, 15 percent; His- 915 were enrolled at eight Planned Parenthood clinics, 538 at panic, 9 percent; Asian, 5 percent). Seventy-three four university-hospital clinics, and 668 at five free-standing abor- percent of the women had had previous pregnancies, tion clinics. The protocol was approved by the human investiga- 51 percent elective abortions, and 15 percent spon- tional review board at each participating institution, and all thewomen gave informed consent.
Study Design
Pregnancy was measured from the first day of the last menstrual Among the 2015 women who returned for the period according to menstrual history, pelvic examination, and third visit, the rates of pregnancy termination were vaginal ultrasonography. On the basis of the investigator’s final 92 percent in the р49-days group, 83 percent in the assessment of these three measures, the women were assigned tothe following arbitrarily defined gestational-age groups: the р49- 50-to-56-days group, and 77 percent in the 57-to- days group (859 women); the 50-to-56-days group (722); and 63-days group (PϽ0.001) (Table 1). Of the 59 wom- en who did not receive misoprostol, 56 had termi- Three clinic visits were scheduled. At visit 1 (day 1), the wom- nation of their pregnancies after mifepristone alone.
en were assessed clinically and took 600 mg of mifepristone oral- In the remaining three women, it subsequently be- ly. At visit 2 (day 3), they took 400 mg of misoprostol orally un-less a complete abortion had already occurred. After taking came apparent that their pregnancies had not been misoprostol, the women were monitored for four hours for ad- terminated after mifepristone and they should have verse events, such as nausea, vomiting, diarrhea, and abdominal been given misoprostol; they later underwent surgi- pain. These events were rated by the women and recorded as mild cal termination. The rate of termination after mife- (felt but easily tolerated), moderate (uncomfortable enough tointerfere with usual activity), or severe (incapacitating, preventing pristone alone also decreased significantly with in- usual activity). Vaginal bleeding was recorded on a diary card and creasing gestational age, from 5 percent to 0.8 percent rated by each woman on days 1 through 15 of the study as spot- ting (less than normal menstrual bleeding), normal (similar to The rates of incomplete abortion were 8 percent normal menstrual bleeding), or heavy (more than normal men- in the 50-to-56-days group and 7 percent in the 57- strual flow). During this period, the women were also monitoredfor expulsion of the conceptus. At visit 3 (day 15), the treatment to-63-days group, as compared with 5 percent in the р49-days group (Table 1). The failures for all other Efficacy was defined as the termination of pregnancy with com- reasons were significantly higher in both the 50-to- plete expulsion of the conceptus without the need for a surgical 56- and 57-to-63-days groups than in the р49-days procedure. The need for a surgical procedure (either vacuum as-piration or dilation and curettage) constituted a failure, and such group. The largest increase was in failures represent- a procedure was performed at any time if the investigator believed ing ongoing pregnancy, which rose from 1 percent there was a threat to a woman’s health (medically indicated), at a in the р49-days group to 9 percent in the 57-to-63- woman’s request, or at the end of the study for an ongoing preg- days group. Ninety percent of the surgical termina- nancy or incomplete abortion. Follow-up was extended beyond tions performed for medical reasons were for vaginal visit 3 if there was uncertainty about the completeness of theabortion or if bleeding persisted.
bleeding. A patient’s request was the reason least of- A total of 106 women were excluded from the efficacy analysis because they did not return for visit 3. Evidence suggesting a suc- Although the study design called for analysis ac- cessful outcome was available for 92 of these women, and evi- cording to the three discrete gestational-age groups, dence of failure for 1. The remaining 13 women were lost to fol-low up; 5 had continuing pregnancies when last seen at visit 2.
there was in fact a steady decline in the frequency of The analyses of efficacy therefore included 2015 women.
termination of pregnancy with increasing durationof gestation (Fig. 1). Logistic-regression analysis in- Statistical Analysis
dicated that the rates decreased with increasing ges- Statistical analysis was performed with the use of Statistical tational age, from more than 95 percent before day Analysis System software (SAS Institute, Cary, N.C.). One-way 40 to less than 90 percent after day 47 and to less analysis of variance and Kruskal–Wallis tests were used to compare than 80 percent after day 59. The only other factor mean values in the gestational-age groups, and Pearson’s chi-square tests were used to compare the distributions of categorical that was related to outcome was the number of pre- variables. Fisher’s exact test was used to compare rates in the ges- vious elective abortions (Fig. 1); the termination tational-age groups. Stepwise logistic-regression analysis was used rates were higher for women with no previous abor- to evaluate the relation between success or failure and various tions than for those with previous abortions. The base-line patient characteristics; the significance level required fora variable to stay in the model was 0.10. All statistical tests were differences in rates were less than 2 percent up to day 35, 2 to 3 percent from days 36 to 42, 3 to 4 percentfrom days 43 to 48, 4 to 6 percent from days 49 to 55, and 6 to 10 percent from days 56 to 63. The There were 859 women in the р49-days group, outcomes were unrelated to other base-line charac- 722 in the 50-to-56-days group, and 540 in the 57- teristics, including age, race, body weight, gravidity, to-63-days group. The three groups were similar Downloaded from www.nejm.org at WELCH MEDICAL LIBRARY-JHU on April 17, 2005 . Copyright 1998 Massachusetts Medical Society. All rights reserved. E A R LY P R E G N A N CY T E R M I N AT I O N W I T H M I F E P R I STO N E A N D M I S O P RO STO L I N T H E U N I T E D STAT E S
р49 DAYS
50 TO 56 DAYS
57 TO 63 DAYS
number (percent [95% confidence interval]) 563 (83 [80–86])* 395 (77 [74–81])*† *PϽ0.001 for the comparison with the р49-days group.
†Pϭ0.02 for the comparison with the 50-to-56-days group.
‡0.001рPϽ0.03 for the comparison with the р49-days group.
§PϽ0.001 for the comparison with the 50-to-56-days group.
Complete expulsion of the conceptus occurred before the administration of misoprostol in 76 wom-en (4 percent). This group included the 56 women who received only mifepristone and an additional 20women who received misoprostol because their ex- pulsion status was considered uncertain at the be-ginning of visit 2. It was subsequently determined that these 20 women had had complete expulsions before they took misoprostol. During the four hours of observation after the administration of misopros-tol, 49 percent of the women expelled the concep- tus, and during the fifth hour an additional 11 per- cent expelled the conceptus. By 24 hours after misoprostol administration, 75 percent of the wom-en had expelled the conceptus (Fig. 2).
Figure 1. Logistic-Regression Analysis of the Predicted Proba-
bility of Successful Pregnancy Termination, According to the
Vaginal Bleeding
Duration of Pregnancy for All the Women and for the WomenWho Had and Those Who Had Not Had Previous Elective Abor- Vaginal bleeding is a natural consequence of the abortion process, and it occurred in all the womenwhose pregnancies were terminated medically. Themedian duration of bleeding or spotting was 13 daysin the р49-days group and 15 days in the other two ventions, and intravenous-fluid administration were groups (PϽ0.001). The proportions of women who reported for 2 percent of the women in the р49-days reported heavy bleeding did not differ significantly group and for 4 percent of those in each of the other in the three groups, were highest on day 3, and then groups (Pϭ0.008). Bleeding was managed by the decreased steadily. By day 15, 77 percent of all re- administration of uterotonic agents, such as oxyto- ported bleeding was considered spotting (Fig. 3).
cin, methylergonovine, or vasopressin, in 41 women Nine percent of the women reported some type of (5 percent) in the р49-days group, 50 (7 percent) in bleeding after 30 days, and 1 percent after 60 days.
the 50-to-56-days group, and 55 (10 percent) in the Excessive bleeding necessitated blood transfusions in four women and accounted for 25 of 27 hospital-izations (including emergency-room visits), 56 of 59 Other Adverse Events
surgical interventions, and 22 of 49 administrations Almost all the women (99 percent) reported at of intravenous fluid. Hospitalizations, surgical inter- least one adverse event during the study period (Ta- Downloaded from www.nejm.org at WELCH MEDICAL LIBRARY-JHU on April 17, 2005 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Figure 2. Times of Expulsion of the Conceptuses in 1720 Women with Successful Termination of Their Pregnancies.
The women received mifepristone at visit 1 and misoprostol two days later (visit 2). “Uncertain” indicates that expulsion occurredwithin the first 24 hours after misoprostol was given, but the exact time was not known. “Unknown” indicates that expulsion oc-curred more than 24 hours after misoprostol was given, but the exact time was not known.
ble 2). Nearly all had abdominal pain; its overall in- In the four-hour observation period after the ad- cidence did not differ among the three groups.
ministration of misoprostol, the number of adverse However, 53 percent of the women in the 50-to-56- events and the percentage classified as severe were days group and 54 percent in the 57-to-63-days similar to those reported during the entire study pe- group had abdominal pain reported as severe, as riod. During these four hours, nausea (PϽ0.001) compared with 43 percent in the р49-days group and vomiting (PϽ0.001) were significantly more fre- (PϽ0.001). Sixty-eight percent of the women re- quent in the 50-to-56- and 57-to-63-days groups ceived at least one medication for abdominal pain than in the р49-days group, and abdominal pain (usually acetaminophen), and 29 percent also re- (Pϭ0.009) and diarrhea (Pϭ0.006) were more se- ceived opiates (usually acetaminophen with hydro- codone or codeine). The women in the 50-to-56- The frequency of adverse events declined signifi- and 57-to-63-days groups received significantly more cantly with increasing gravidity and parity (Table 2).
analgesia and opiates than the women in the р49- Nulliparous women received significantly more anal- days group (PϽ0.001). Abdominal pain resulted in gesia (PϽ0.001), opiate analgesia (PϽ0.001), and one hospitalization and was the reason for two med- medications for nausea (PϽ0.001) and diarrhea (PϽ ically indicated surgical interventions.
0.001) than parous women. Chronologic age was As compared with the р49-days group, the 50-to- not consistently related to the frequency of adverse 56- and 57-to-63-days groups had significantly more nausea and vomiting, and diarrhea was more fre- Other adverse events reported included headache quent in the 57-to-63-days group. The overall per- (32 percent); dizziness, encompassing light-headed- centages of events reported as severe were 3 percent ness and faintness (12 percent); back pain and fatigue for diarrhea, 10 percent for vomiting, and 20 percent (9 percent each); fever, vaginitis, and viral infections for nausea. Medications for these adverse events were (4 percent each); rigors and dyspepsia (3 percent taken by 1 percent, 4 percent, and 19 percent of the each); and asthenia, leg pain, anxiety, insomnia, ane- women, respectively, with no differences among the mia, syncope, leukorrhea, and sinusitis (2 percent gestational-age groups. Severe vomiting resulted in each). Endometritis occurred in 19 women; it was one hospitalization and was the reason for one med- considered study-related in 10, in 1 of whom it was ically indicated surgical intervention.
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Figure 3. Types of Vaginal Bleeding as Recorded by the Women from Day 1 (Administration of Mife-
pristone) to Day 15.
The data are from 1506 women who did not undergo surgical termination of pregnancy and who re-corded the types of bleeding they had from study day 1 to day 15 on menstrual-diary cards. Bleedingwas characterized as spotting, as similar to normal menstrual bleeding (normal), or as heavier thannormal menstrual bleeding (heavy).
*PϽ0.001 for the comparison with the р49-days group (by Fisher’s exact test).
†Pϭ0.01 for the comparison with the р49-days group (by Fisher’s exact test).
‡0.001рPр0.03 for the comparison with the women who had had three or more pregnancies (by §0.001рPр0.004 for the comparison with the women who had had no children (by Fisher’s exact Downloaded from www.nejm.org at WELCH MEDICAL LIBRARY-JHU on April 17, 2005 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e DISCUSSION
did almost half the expulsions, and some women In this large, multicenter U.S. trial, the success of may prefer to be in the clinic during these events.
medical termination of pregnancy decreased gradu- Moreover, in the women with pregnancies of longer ally with advancing gestational age. We confirmed duration, the majority of the hospitalizations or sur- the international experience that mifepristone and gical interventions occurred on day 3, whereas in the misoprostol can terminate pregnancies of up to 49 women with pregnancies of shorter duration, these days’ duration, although the success rate was lower events were evenly distributed throughout the 15- than previously described.7,10-12 As noted in other day study period. Thus, the four-hour visit may be countries,13 this lower success rate may be related to most appropriate for women with pregnancies of the lack of experience with medical abortion in the longer duration. Nonetheless, on the basis of the re- United States as well as to the design of our study.
sults of a small study, mifepristone combined with We considered the need for surgical intervention on home application of vaginal misoprostol is a safe al- day 15 as representing failure, but abortion might ternative in women with pregnancies of up to 56 have occurred later.13,14 Also, a surgical termination performed at the woman’s request was classified as a Careful medical follow-up is essential to ensure that failure instead of being excluded from the efficacy surgical termination is performed in cases of failed analysis.10,12,13 Unexpectedly, success was also less fre- medical abortion. In this study, 5 percent of the quent among women who had previous elective women did not return for final confirmation of the abortions. Although the reason is unknown, this fac- outcomes of their pregnancies, and five of these wom- tor could also have contributed to the differences, en had continuing pregnancies when last seen at visit because 51 percent of the women in our study had 2. The ultimate outcome of these pregnancies is un- had previous elective abortions, as compared with known, despite our repeated attempts to contact the 25 to 27 percent in two British studies.12,13 women. In other studies, the loss to follow-up has Efficacy decreased after 49 days’ gestation. A sim- ranged from 3 to 11 percent.5-7,10,12,21 Although mife- ilar trend has previously been reported with miso- pristone is not teratogenic in rats, mice, or mon- prostol but not with gemeprost.10-15 Thus, the lower keys,22,23 skull deformities attributed to uterine con- success rates later in gestation are probably related tractions occurred in rabbits.24 Misoprostol, on the to the prostaglandin component of the regimen.
other hand, has been reported to be teratogenic in Such lower rates were not found when misoprostol was given by the vaginal route,16,17 presumably be- Recently, other methods of medical abortion have cause of greater tissue bioavailability.18 Higher doses been evaluated. Oral misoprostol alone is not effec- of oral misoprostol increase uterine contractility19 tive.19,27 The efficacy of vaginal misoprostol in the and are also associated with improved results.11,12,15 first trimester varies widely, from 47 to 94 per- Efficacy is not, however, related to differences in cent,28,29 but it is highly effective in the second tri- the dose of mifepristone, and similarly good results mester.30 Success rates with methotrexate and vagi- have been reported with single doses as low as 200 nal misoprostol range from 83 to 98 percent.31-35 As compared with mifepristone, this latter regimen has The incidence of adverse events rose with the du- the advantage of being an effective treatment for ec- ration of pregnancy.7,10,13 These events included both topic pregnancy.36 However, misoprostol has to be subjective symptoms (abdominal pain, nausea, and given three to seven days after methotrexate, de- vomiting) and more objective markers (hospitaliza- laying the abortion process.35 Unlike mifepristone, tions and surgical interventions). The majority of methotrexate is cytotoxic to proliferating trophoblast hospitalizations and surgical interventions were for tissue, and persisting pregnancies may represent a vaginal bleeding. With advancing pregnancy, the du- ration of bleeding increased, as did the administra- In conclusion, the regimen of mifepristone and tion of uterotonic drugs and intravenous fluids. De- misoprostol is safe and effective for women seeking spite the increases in the numbers of failures and medical abortions of pregnancies of 49 days’ dura- adverse events, the majority of the women in this tion or less. With longer durations of pregnancy, the study reported that they were satisfied with their regimen is less effective and the incidence of adverse medical abortions, regardless of whether the out- come was successful (Winikoff B, et al.: unpublisheddata).
One drawback of this method of pregnancy termi- We are indebted to Dr. Elof Johansson for his helpful advice and nation is the inconvenience of the four-hour clinic continuing support; to Dr. Brigid M. O’Connor, Dr. Charlotte El- stay after the administration of misoprostol. In its fa- lertson, Dr. Beverly Winikoff, and Ms. Batya Elul for their contri-butions to the data analysis; to Mr. Evan Read for preparation of vor is the fact that many adverse events, including the figures; and to Mr. Peter Conlon and Ms. Irina Shmerlin for those rated as severe, occurred during this period, as Downloaded from www.nejm.org at WELCH MEDICAL LIBRARY-JHU on April 17, 2005 . Copyright 1998 Massachusetts Medical Society. All rights reserved. E A R LY P R E G N A N CY T E R M I N AT I O N W I T H M I F E P R I STO N E A N D M I S O P RO STO L I N T H E U N I T E D STAT E S
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