Original Article
Mifepristone (RU 486) Compared with High-Dose Estrogen and Progestogen for Emergency Postcoital Contraception
N Engl J Med 1992; 327:1041-1044October 8, 1992
- Abstract
- Abstract
Background.
Mifepristone (RU 486) is a synthetic steroid with potent antiprogestational and antiglucocorticoid properties that provides an effective medical method of inducing abortion in early pregnancy. Since progesterone is essential for implantation, we tested the use of mifepristone for emergency postcoital contraception.
Methods.
We studied 800 women and adolescents requesting emergency postcoital contraception who had had unprotected intercourse within the preceding 72 hours. A total of 398 women and adolescents were randomly assigned to treatment with 100 μg of ethinyl estradiol and 1 mg of norgestrel, each given twice 12 hours apart (standard therapy), and 402 women and adolescents were randomly assigned to receive 600 mg of mifepristone.
Results.
None of the women and adolescents who received mifepristone became pregnant, as compared with four of those who received standard therapy; the difference in failure rates between the two regimens was not statistically significant. The number of pregnancies in each group was significantly lower than the number expected according to calculations based on the day of the cycle during which intercourse had taken place (P<0.001). In many subjects the stage of the cycle as calculated by menstrual history was inconsistent with measurements of plasma progesterone or urinary pregnanediol excretion. The subjects treated with mifepristone reported less nausea (40 percent vs. 60 percent) and vomiting (3 percent vs. 17 percent) on the day of treatment, as well as lower rates of other side effects, than the subjects treated with the standard regimen, but they were more likely to have a delay in the onset of the next menstrual period (42 percent vs. 13 percent).
Conclusions.
Mifepristone is a highly effective postcoital contraceptive agent that, if used more widely, could help reduce the number of unplanned and unwanted pregnancies. (N Engl J Med 1992;327:1041–4.)
Media in This Article
Table 1
Characteristics of the Four Women Who Became Pregnant after Receiving the Standard Regimen for Postcoital Contraception.Table 2
Incidence of Side Effects among Women and Adolescents Treated with Mifepristone or the Standard Estrogen—Progestogen Regimen for Postcoital Contraception.*Article Activity
- Article
DESPITE the availability of highly effective methods of contraception, many conceptions are unplanned.1 Many women who request an abortion have become pregnant as a result of either the lack of forethought or contraceptive failure.
The report by Yuzpe and Lancee2 that a combination of a large dose of estrogen and a progestogen prevented pregnancy after intercourse led to the development of the now standard regimen of 100 μg of ethinyl estradiol and 1 mg of norgestrel, each given twice 12 hours apart, for emergency contraception. Fasoli et al.,3 in a review of the results of published studies of this regimen, reported a wide variation (from 0.2 to 7.4 percent) in the rate of failure. The side effects of the combined administration of estrogen and progestogen are those commonly associated with estrogen; most studies report nausea in 50 percent of women and vomiting in up to 25 percent. When these symptoms occur within the first 12 hours after treatment is initiated, they may impair compliance and efficacy. The postcoital insertion of an intrauterine device is highly effective in preventing pregnancy (failure rate, 0.1 percent), but the process of insertion is invasive and associated with side effects. Other oral agents used for this purpose include danazol and high-dose levonorgestrel, but the failure rates of these agents have been as high as 10 percent.4 , 5
Progesterone is necessary for the formation of secretory endometrium and therefore for the establishment and maintenance of pregnancy. Mifepristone (RU 486) is a synthetic steroid with potent antiprogestational and antiglucocorticoid activity. When given in combination with a prostaglandin, it has proved to be a safe, convenient alternative to surgical termination of early pregnancy.6 7 8 9 Reflecting the importance of progesterone in many biologic processes, mifepristone has many other potential uses, such as the inhibition of ovulation,10 , 11 prevention of the development of secretory endometrium,12 induction of labor,13 and treatment of endometriosis and breast cancer.14
We compared the efficacy and side effects of a 600-mg dose of mifepristone with those of the standard regimen of estrogen and progestogen as emergency postcoital contraceptive agents in a randomized trial of 800 women and adolescents. A preliminary report describing the results in the first 379 subjects in this study has been published.15
Methods
We studied 800 women and adolescents ranging in age from 16 to 45 years who were recruited from the Dean Terrace Centre in Edinburgh (752 subjects) and the Accident and Emergency Department of the Royal Infirmary of Edinburgh (48 subjects). All the women and adolescents were seeking emergency postcoital contraception. All had a history of regular menstrual cycles of 21 to 35 days for the preceding three months, were seen within 72 hours after a single act of unprotected intercourse, and were willing to use a condom or abstain from intercourse for the rest of the current cycle. We excluded women and adolescents who were taking an oral-contraceptive preparation, had a medical contraindication to the standard estrogen—progestogen regimen (a history of cardiovascular disease, thromboembolism, or liver disease), were regularly using prescription drugs (anticonvulsant medications or insulin), were certain that they would continue with the pregnancy if emergency contraception failed, or would be unavailable for follow-up.
The project was approved by the local ethics committee, and written informed consent was obtained from each subject, who was informed that there was a risk of failure no matter which treatment she received. Mifepristone was supplied by the World Health Organization, and the use of the drug for emergency contraception was approved by the Medicines Control Agency of the United Kingdom.
A careful menstrual history was obtained from each subject, and the interval between intercourse and presentation was recorded. The estimated day of ovulation was calculated as being 14 days before the estimated day of onset of the next menstrual period; each subject's usual cycle length was taken into account. On the basis of these data we determined whether a subject was treated at midcycle (one day before or after ovulation), in the follicular phase of the cycle (two or more days before ovulation), or in the luteal phase of the cycle (two or more days after ovulation). A pelvic examination was undertaken only if clinically indicated. Each subject's height and weight were recorded.
To allow for differences in fertility and therefore possible differences in failure rates with age, the women and adolescents were divided into three age groups: 16 to 25 years, 26 to 34 years, and 35 to 45 years. The women and adolescents in each age group were randomly assigned to receive either 600 mg of mifepristone as a single dose taken at the time of enrollment or two 100-μg doses of ethinyl estradiol and two 1-mg doses of norgestrel, the second dose of each being taken at home 12 hours after the first.
Blood or urine samples were collected at the time of enrollment for the measurement of the plasma progesterone concentration and urinary pregnanediol excretion. Each subject was asked to complete a diary chart recording the occurrence and severity of nausea, vomiting, breast tenderness, headache, and vaginal bleeding each day for seven days after treatment, and each made an appointment to return to the clinic within five days of the expected date of the next menstrual period. Each subject was given a stamped, addressed envelope in which to return the diary chart and to inform the clinic of the date of the next menstrual period should she be unable to return. Attempts were made to contact the women and adolescents who did not return or mail in a completed diary chart. After three unsuccessful attempts the subject was classified as lost to follow-up.
At the follow-up visit the diary chart and date of menstrual bleeding were checked by a member of the clinic staff. If menstrual bleeding had not occurred, blood was taken for the measurement of the beta subunit of chorionic gonadotropin in the plasma and another appointment was made. The subject returned for additional follow-up every two weeks until she had a normal menstrual period.
Assay Methods
Urinary pregnanediol-3-glucuronide was measured by enzyme-linked immunosorbent assay.16 The sensitivity of the assay was 0.17 ng per milliliter (0.5 nmol per liter), and the interassay and intraassay coefficients of variation were 12 percent and 10 percent, respectively. Plasma progesterone was measured by a radioimmunoassay in which 1-anilino-8-naphthalenesulfonate (pH 4.0) was used to displace progesterone from plasma binding proteins.17 The interassay and intraassay coefficients of variation were 10 percent and 8 percent, respectively. Plasma progesterone concentrations of more than 3 ng per milliliter (>9 nmol per liter) or urinary pregnanediol excretion in excess of 0.5 mmol per mole of creatinine (>2.17 mg per gram of creatinine) were considered to be compatible with ovulation; plasma progesterone concentrations ranging from 1.6 to 2.9 ng per milliliter (5 to 9 nmol per liter) or urinary pregnanediol excretion of 0.3 to 0.4 mmol per mole of creatinine (1.3 to 1.7 mg per gram of creatinine) were considered periovulatory; and plasma progesterone concentrations below 1.6 ng per milliliter (<4 nmol per liter) or urinary pregnanediol excretion below 0.2 mmol per mole of creatinine (<0.9 mg per gram of creatinine) were considered consistent with the absence of ovulation.
Statistical Analysis
Fisher's exact test (two-tailed) was used to compare the efficacy of the two regimens, and chi-square tests were used to compare the incidence of side effects in the two groups.
Results
A total of 402 women and adolescents were treated with mifepristone, and 398 were treated with the standard regimen of ethinyl estradiol and norgestrel. Of the 800 women and adolescents, 566 were 16 to 25 years of age, 192 were 26 to 35 years of age, and 42 were 36 to 45 years of age. Twenty-six women and adolescents (3 percent) were lost to follow-up, of whom seven had had intercourse within three days before or after the estimated day of ovulation and might be considered genuinely at risk for conception; three of these subjects received mifepristone. A further 16 women and adolescents failed to reply to letters or telephone calls but returned for follow-up within three months after treatment. Although unable to recall the date of menstruation, none had become pregnant.
Efficacy
Four women became pregnant, all of whom had received the standard regimen; there were no mifepristone failures. The overall failure rate in the standard-therapy group was 1.0 percent (95 percent confidence interval, 0.3 to 2.5 percent). All four women chose to have the pregnancy terminated. The difference in failure rates between the standard regimen (1.0 percent) and mifepristone (0 percent) was not statistically significant (P = 0.12). The characteristics of the four women who conceived are shown in Table 1Table 1
Characteristics of the Four Women Who Became Pregnant after Receiving the Standard Regimen for Postcoital Contraception..Accurate cycle data were obtained for 733 women and adolescents, of whom 322 (44 percent) had had intercourse within three days before or after the estimated day of ovulation. One hundred sixty-seven of these subjects received mifepristone. All 4 of the women who became pregnant were among the 155 subjects in this group of 322 who were treated with the standard regimen, for a failure rate of 3 percent.
Side Effects
A total of 693 women and adolescents returned completed diary charts. The incidence of side effects is shown in Table 2Table 2
Incidence of Side Effects among Women and Adolescents Treated with Mifepristone or the Standard Estrogen—Progestogen Regimen for Postcoital Contraception.*. All side effects were significantly (P<0.001) more frequent among the subjects treated with the standard regimen, and more of the women and adolescents who were treated with mifepristone reported having no side effects (P<0.001). Among the subjects who had nausea on the day of treatment, 17 percent of those who received the standard regimen described the nausea as being severe, whereas only 2 percent of those who received mifepristone did so.Timing of Menses
The timing of the onset of menstrual bleeding after emergency postcoital contraception is shown in Table 3Table 3
Timing of Menses among Women and Adolescents after Postcoital Contraceptive Treatment with Mifepristone or the Standard Regimen.*. A subject who reported bleeding within three days before or after the expected day of menstruation was described as having menstruated on time. Significantly more (P<0.001) of the women and adolescents who were treated with mifepristone had a delay in the onset of menstruation (range, 4 to 63 days).Discussion
Most published studies of the efficacy of postcoital contraception report failure rates in terms of the number of pregnancies as a function of the total number of women treated, and do not report the number lost to follow-up. Not all women given emergency postcoital contraception are genuinely at risk for pregnancy, since unprotected intercourse that occurs in the early follicular phase or in the luteal phase of the cycle is unlikely to result in conception. On the basis of cycle dates, 44 percent of the women and adolescents in this study were treated within three days before or after the estimated day of ovulation. Silvestre et al.18 argued that the true failure rate should take into account the timing of unprotected intercourse and therefore the probability that a pregnancy will occur. Using a table that provides a probability of pregnancy for each day of the cycle,19 Silvestre et al.18 recalculated the failure rates of the standard estrogen and progestogen regimen reported in a number of studies. Failure rates reported as ranging from 0.2 to 5 percent on the basis of the number of women treated ranged from 6 to 44 percent when the table was used and the probability of pregnancy taken into account. Using the table in the same way, we calculated that we should have expected 23 pregnancies in each treatment group in our study, which would mean a failure rate of 17 percent for the standard regimen and, of course, 0 percent with mifepristone. Both regimens resulted in significantly fewer pregnancies than would have been expected had no treatment been given (P<0.001).
The validity of using the table depends on the accuracy of the menstrual-cycle data. The measurements of plasma progesterone or urinary pregnanediol in 780 women and adolescents on the day of treatment provided the opportunity to determine whether the cycle data were compatible with the biochemical evidence of ovulation. Of the 368 women believed on the evidence of cycle data to be in the luteal phase of the cycle, 187 (51 percent) had a plasma progesterone or urinary pregnanediol value indicating that ovulation had not occurred. Forty-four of the 205 women and adolescents (21 percent) considered to have been treated in the follicular phase had biochemical evidence of ovulation. Ninety women and adolescents who had intercourse four to nine days after the estimated day of ovulation, and who were therefore excluded from our calculations of the fertile phase of the cycle, had not in fact ovulated when they were treated and could therefore have been genuinely at risk for pregnancy. Most women do not keep a record of their menstrual periods, and it is well recognized that estimated dates are likely to be inaccurate. In our study the dates appeared more likely to be accurate in the follicular phase of the cycle when menses had recently occurred.
Regardless of the method by which failure rates are calculated, the fact remains that none of the women and adolescents who were treated with mifepristone conceived. Although the difference in the failure rates was not statistically significant, mifepristone was unquestionably as effective as the standard estrogen—progestogen regimen as emergency postcoital contraception. Although the subjects were aware of which treatment they received, they were not advised that there might be any difference in side effects. It is clear, however, that mifepristone was associated with fewer side effects. Moreover, since it was taken as a single dose, there was no possibility of noncompliance if side effects occurred.
The only apparent disadvantage of mifepristone was that more of the women and adolescents who took it had a delay in the onset of the next menstrual period — an occurrence that would undoubtedly be stressful to a woman who was worried that she might be pregnant. In contrast to the standard regimen, however, it is possible to make some prediction about the timing of the onset of the next menses after the administration of mifepristone. Of the women and adolescents who were treated with mifepristone in whom both cycle and biochemical data suggested that they were in the follicular phase, 52 percent had bleeding more than four days after the expected date of their next menstrual period, indicating that mifepristone inhibited ovulation.10 Of those who were treated in the luteal phase (confirmed biochemically), 84 percent either bled before the estimated date of their next menstrual period or menstruated on time. The administration of mifepristone in the luteal phase is associated with early bleeding in 100 percent of women.20 , 21
In conclusion, we confirmed our preliminary report15 that mifepristone is an effective postcoital contraceptive agent with advantages over the standard estrogen-progestogen regimen. A dose of 600 mg is probably higher than necessary, but no studies have yet been done to determine the optimal dose. The real problem with emergency postcoital contraception is not its failure rate or its side effects but the fact that so few women and adolescents who have had unprotected intercourse actually use it.
Mifepristone has been a center of controversy since the report of the initial clinical study demonstrating its efficacy as an abortifacient agent.13 Research into alternative uses of mifepristone is severely restricted in many countries, including the United States, largely as a result of the activities of those who are opposed to abortion. The results in this paper demonstrate that the drug has the potential to avert unwanted and unplanned pregnancy. More widely available contraceptive services that included mifepristone as a postcoital agent would help reduce the demand for therapeutic abortion.
Supported by a grant from the World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction.
We are indebted to the medical and nursing staff of the Family Planning Service, without whose help the study would not have been possible; to Ms. Vicky Sweeting and Mrs. Sanjukta Chatterjee for technical support; and to Mrs. Maureen Lipscombe for assistance in the preparation of the manuscript.
Source Information
From the Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, University of Edinburgh (A.G., K.J.T., M.D., D.T.B.), and the Dean Terrace Centre, Lothian Health Board (A.G., M.M.), both in Edinburgh, Scotland. Address reprint requests to Dr. Glasier at the Dean Terrace Centre, Lothian Health Board, 18 Dean Terr., Edinburgh EH4 1NL, United Kingdom.
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