Mifepristone as a late post-coital contraceptive

Premila W. Ashok1,3, Prabhath T. Wagaarachchi1, Gillian M. Flett2 and Allan Templeton1

1 Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Cornhill Road, Aberdeen, AB25 2ZL and 2 Grampian Healthcare NHS Trust, Family Planning Clinic, 13 Golden Square, Aberdeen AB10 1RH, UK3


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was undertaken to assess the efficacy of mifepristone as a post-coital contraceptive beyond 72 h and up to 5 days in women who found the intrauterine contraceptive device (IUCD) unacceptable. During a 2 year period 219 consecutive women fulfilling the inclusion criteria and presenting late for emergency contraception were approached and offered a choice of methods. Fifteen (6.8%) women wished to have the IUCD fitted, but 204 (93.2%) who found this unacceptable were offered and accepted mifepristone 200 mg. In one woman there was a technical problem fitting the IUCD and mifepristone was administered. Women who had mifepristone were younger (mean age 21.4 versus 26.9 years, P = 0.004) and more likely to be nulliparous (81 versus 25 %, P < 0.001) than the IUCD group. A total of 155 (75.6%) women who had mifepristone and all 14 who had the coil fitted were followed up. There were no true failures in either group. There was one user failure in the mifepristone group, where pregnancy occurred from an act of intercourse subsequent to treatment, giving a crude pregnancy rate of 0.65%. Mifepristone prevented 85% of expected pregnancies. Most women find the IUCD an unacceptable method of post-coital contraception. Mifepristone is an effective late post-coital contraceptive, which can be offered to women who decline the IUCD.

Key words: emergency or post-coital contraception/IUCD/mifepristone


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The Yuzpe regimen was until recently the only method of oral emergency contraception approved by the Committee on Safety of Medicines (CSM) and is used up to 72 h of unprotected intercourse. However, with this regimen, 50% of women experience nausea and a further 20% vomiting (Yuzpe et al., 1982Go). Early in the year 2000 levonorgestrel obtained a product licence in the UK as an emergency contraceptive. However a recent study has shown that with either regimen there may be decreased efficacy after 24 h of treatment although the levonorgestrel regimen is more effective and better tolerated than the Yuzpe regimen (WHO, 1998).

The intra-uterine contraceptive device (IUCD) is the only method of emergency contraception available to women presenting beyond 72h and within 5 days of unprotected intercourse. However most women requesting emergency contraception are young and nulliparous and perceive the IUCD as an unsuitable method (Pillaye, 1995Go).

Mifepristone is an orally active synthetic 19 norsteroid with potent antiprogestional as well as antiglucocorticoid activity. It acts by competing with progesterone for receptor binding. In normally menstruating women, the effect of mifepristone depends on the timing of administration in relation to the menstrual cycle. In the follicular phase mifepristone inhibits ovulation and significantly delays the onset of menstruation (Glasier et al., 1992Go; Ledger et al., 1992Go). Given in the first half of the luteal phase it is thought to block the progesterone receptors on the endometrium. This prevents the development of secretory endometrium, which results in a hostile environment to pregnancy (Baird and Glasier, 1993Go; Brogden et al., 1993Go; Gemzell-Danielsson et al., 1994Go). Menstrual induction may occur by the direct action of mifepristone on progesterone receptors on the endometrium independent of luteolysis (Schaison et al., 1985Go; Li et al., 1988Go; Gemzell-Danielsson et al., 1993Go).

Mifepristone has proved to be a highly effective post-coital contraceptive given in a single dose of 600 mg within 72 h of unprotected sexual intercourse (Glasier et al., 1992Go; Webb et al., 1992Go). Recently WHO has shown that lower doses (10 and 50 mg) are as effective as a dose of 600 mg of mifepristone in the context of emergency contraception (WHO, 1999).

We undertook a pilot study to assess the efficacy of mifepristone as a late post-coital contraceptive beyond 72 h and up to 5 days in women who found the IUCD an unacceptable method. Outcome measures included crude pregnancy rates and proportion of pregnancies prevented.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was carried out in the Family Planning Clinic in Aberdeen, Scotland. Approval was obtained for the project from Grampian Joint Ethics Committee. Eligible women included those with regular menstrual cycles (21–42 days) who requested emergency contraception between 72–120 h of intercourse, and were willing to use a barrier method or abstain from further acts of unprotected intercourse during the current cycle. The following women were excluded from the study: women taking oral contraceptive preparations, those breast feeding, those with contraindications to the use of mifepristone and those who were certain to continue with the pregnancy should emergency contraception fail.

During a two-year period between December 1997 and November 1999 women requesting emergency contraception between 72–120 h of unprotected intercourse and unwilling to use the IUCD were offered mifepristone as an unproven alternative to the IUCD. Informed written consent was obtained from each participant following which they were included in the study. A detailed gynaecological, obstetric and medical history was obtained from each woman. A menstrual history was also obtained and the time interval between coitus and presentation recorded.

Women who had the IUCD fitted had an infection screen done which included high vaginal and endocervical swabs for Chlamydia trachomatis and additionally each woman was given a course of prophylactic antibiotics (doxycycline and metronidazole). Those declining to have the IUCD inserted were offered mifepristone one tablet (200 mg) orally in clinic.

Women were asked to keep a record of their bleeding pattern and the next menstrual period (cycle in which emergency contraception was taken). A follow-up appointment was made within a week of the expected next menstrual period. At the follow-up visit if menstrual bleeding had not occurred pregnancy was excluded by means of a urine pregnancy test and a further appointment was made in 1–2 weeks time. If the pregnancy test was positive ultrasonography was used to estimate gestational age.

Attempts were made to contact women who failed to attend follow-up. Hospital records (both gynaecology and antenatal) of those who could not be contacted and lost to follow-up were searched to exclude pregnancy since the Grampian University hospital is the only referral hospital for a 50 mile radius for both gynaecology and maternity referrals.

In presenting the results, continuous variables are presented as means with standard deviations and ranges. Comparisons between groups were made using the Fisher exact or {chi}2 tests as appropriate. Differences were regarded as statistically significant if P < 0.05.

The primary outcome measure was unintended pregnancy. The crude pregnancy rate and the expected and prevented pregnancies were calculated. The estimated date of ovulation was calculated by subtracting 14 days from the expected date of the next menstrual period. The expected pregnancies were calculated by multiplying the number of women having sexual intercourse on each day of the menstrual cycle by probability of conception on cycle day using pooled recognisable conception probabilities (Trussell et al., 1998Go). Prevented pregnancies were calculated as follows: 1 – observed pregnancies/expected pregnancies.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient characteristics
During a 24 month period 231 women presented beyond 72 h and within 120 h for emergency contraception. Twelve women were excluded from the study since they did not fulfil the inclusion criteria although mifepristone was administered on a named patient basis. A total of 219 women fulfilled the entry criteria and were included in the study. Fifteen (6.8%) of these women wished to have the IUCD fitted of whom two women were seen earlier in clinic and counselled to use this method as a contraceptive in the subsequent cycle prior to this episode. In one woman there was a technical problem in fitting the device and mifepristone was administered. A total of 204 women (93.2%) declined to have the IUCD fitted and accepted mifepristone (no women declined mifepristone).

Table IGo shows patient characteristics of the women in both treatment groups. Women who had mifepristone were significantly younger (mean age 21.4 versus 26.9 years, P = 0.004) and more likely to be nulliparous (81 versus 25%, P < 0.001) compared to the IUCD group. Forty-eight women had a pregnancy test performed prior to inclusion in the study.


View this table:
[in this window]
[in a new window]
 
Table I. Patient characteristics
 
The reason for requesting emergency contraception was similar in both groups (Table IGo) although in two women who had mifepristone the request was following alleged rape. The mean time from coitus to treatment in both groups is shown in Table IGo. Of those who took mifepristone 80 (51.6%) women presented between 72–96 h and 75 (48.4 %) presented between 96–120 h after unprotected intercourse.

Treatment outcome
Outcome was known in 155 (75.6%) of the women who received mifepristone and all 14 women who had the IUCD fitted. Two women were found to be pregnant after treatment with mifepristone. Dating ultrasonography revealed that one woman was already pregnant at the time of treatment (excluded from analysis). Ultrasonography confirmed that in one woman pregnancy may have occurred 2 weeks or more after the act of intercourse for which treatment was sought; this was considered as a user failure but included in the analysis. Both women had intrauterine pregnancies and opted to have induced abortion.

The crude pregnancy rate with mifepristone was 0.65% and there were no pregnancies with the IUCD. Using the probabilities of conception based on pooled recognisable conception probabilities (Wilcox et al., 1995Go; Trussell et al., 1998Go), in the mifepristone group there was one pregnancy observed with 6.7 pregnancies expected, 85% of expected pregnancies were prevented. There were no observed pregnancies in the IUCD group (expected pregnancies were 0.34).

Timing of menses
Accurate menstrual details were known in 135 (87.1%) of the 155 women who were given mifepristone and in whom follow-up was complete. Of these 93 women (68.9%) had a normal period and 13 (9.6%) had an early period (onset of menstruation within 5 days of the expected period). In 27 (20.0%) women menstruation was delayed more than 5 days. Two (1.5%) women were pregnant. Of the 27 women in whom menstruation was delayed the mean ± SD delay in days was 13 ± 1.7 (5–41). In 16 (11.1%) women bleeding occurred within 5 days of administration of mifepristone.

Of the 14 women who had the IUCD fitted, 10 (71.4%) had a normal period, three (21.4%) had early menstruation and in one (7.1%) menses was delayed.

Side-effects
Fifty women who were administered mifepristone returned questionnaires in relation to side effects. The following were the side effects experienced by the women: eight (16%) had nausea, two (4%) experienced vomiting, 14 (28%) had abdominal pain, 18 (36%) complained of tiredness, six (12%) had breast tenderness and 12 (24%) complained of a headache.

Future contraception
Table IIGo shows the contraception given to women at discharge. Eleven (78.6%) of the 14 women who had the IUCD fitted wished to continue using the coil as a future method of contraception.


View this table:
[in this window]
[in a new window]
 
Table II. Contraception at discharge
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The IUCD is currently the most effective method of emergency contraception, and can be used up to 5 days following unprotected intercourse or calculated day of ovulation. It is the only method of emergency contraception available to women presenting beyond 72 h and within 5 days of unprotected intercourse. This study was undertaken as a pilot to assess the acceptability of the IUCD as an emergency contraceptive as well as to study the efficacy of mifepristone beyond 72 h and up to 120 h of unprotected intercourse.

Although the preferred design for evaluating a new treatment is a randomized controlled study, this was not feasible in this group of women who presented for emergency contraception since 93% of women found the IUCD unacceptable. Women who declined to have the coil fitted were significantly younger and were more likely to be nulliparous compared to the women who had the IUCD fitted.

Mifepristone 600 mg administered within 72 h of unprotected intercourse has been shown to be a highly effective post-coital contraceptive with no pregnancies reported in published studies (Glasier et al., 1992Go; Webb et al., 1992Go). More recently it has been shown that 50 and 10 mg doses were as effective up to 120 h of unprotected intercourse with a failure rate of 1.1–1.3% (WHO Task Force, 1999). Our study shows that mifepristone in a 200 mg dose is an effective post-coital contraceptive beyond 72 h and up to 120 h of unprotected intercourse. The crude pregnancy rate was 0.65% with mifepristone preventing 85% of expected pregnancies. We excluded one woman who was pregnant at treatment, since this woman did not give any information about the efficacy of the method used. We included the woman who became pregnant from an act of intercourse subsequent to treatment (user failure). Should this woman be excluded from further analysis, the true effectiveness of mifepristone would be >85%, with no failures.

The insertion of an IUCD requires skill, and provision of such a service may be a problem when using it as a post-coital contraceptive. In one of the 15 women who agreed to have the IUCD fitted, technical difficulties were encountered when fitting the device and this woman was given mifepristone.

The insertion of an IUCD can lead to pelvic inflammatory disease and its sequelae which include tubal infertility and ectopic pregnancy. The risk of pelvic inflammatory disease is six times higher during the first 20 days of insertion especially in women <25 years of age (Eschenbach, 1992Go; Farley et al., 1992Go). In our study 158 (77.1%) of the women who declined to have the IUCD fitted were <25 years of age. The likelihood of a sexually transmitted disease may be more common after a casual sexual encounter or rape. Two women in the mifepristone group sought emergency contraception following rape. Women who had the IUCD fitted were screened for C. trachomatis and received prophylactic antibiotics. None of these women screened positive for C. trachomatis. The group of women who had the coil fitted were older than the mifepristone group and it is known that C. trachomatis is more prevalent in younger women, particularly those <25 years (CMO Report, 1998).

Levonorgestrel and the Yuzpe regimen for emergency contraception within 72 h of unprotected intercourse has been compared by the WHO (WHO Task Force, 1998). With either regimen there was a decreased efficacy after 24 h of treatment although the levonorgestrel regimen was more effective and better tolerated than the Yuzpe regimen. Hence it has been concluded that the earlier treatment begins, the more effective it is. Delaying the first dose by 12 h increases the odds of pregnancy by almost 50% (Piaggio et al., 1999Go). In the WHO study the failure rates with levonorgestrel and Yuzpe regimen in women presenting between 48–72 h were 2.7 and 4.7% respectively. Hence if women presenting beyond 72 h are offered either the levonorgestrel or the Yuzpe regimen, which are the only oral preparations currently available, the pregnancy rate would likely be higher since a large randomized controlled trial has shown that the efficacy of these methods is related to the time interval from coitus to treatment (WHO, 1998).

Previous studies using a 600 mg dose of mifepristone for post-coital contraception have shown that 37–42% of women can experience a delay in the onset of the next menstrual period. However more recently WHO have shown that lower doses of mifepristone were associated with less menstrual disturbances with only 18% of women having a delay in menses with a 10 mg dose. In this study 20% of women who were given mifepristone 600 mg had a delay in the onset of menstruation. Mifepristone administered in the pre-ovulatory phase of the menstrual cycle inhibits or delays ovulation (Liu et al., 1987Go). Should a delay in ovulation occur there is a substantial risk of pregnancy in women who have further acts of coitus. There was one user failure in our study who had a discrepancy of two weeks between the act of intercourse for which she sought treatment and the estimated date of conception. This woman was administered mifepristone on day 8 of her menstrual cycle.

The WHO recommends a 10 mg dose of mifepristone for emergency contraception since a lower dose would be substantially cheaper. We used a 200 mg dose which is one tablet since mifepristone is currently not available as a single tablet in smaller doses.

Mifepristone is a highly effective post-coital contraceptive up to 120 h unprotected intercourse and should be offered to women who present late for emergency contraception and find the IUCD an unacceptable method.


    Notes
 
3 To whom correspondence should be addressed. E-mail: ashok{at}abdn.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Baird, D.T. and Glasier, A.F. (1993) Hormonal contraception. Drug Therapy, 328, 1543–1549.

Brogden, R.N., Goa, K.L. and Faulds, D. (1993) Mifepristone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic Potential. Drugs, 45, 384–409.[ISI][Medline]

Eschenbach, D.A. (1992) Earth, motherhood and the intrauterine contraceptive device. Fertil. Steril., 57, 1177–1179.[ISI][Medline]

Expert Advisory Group (1998) Chlamydia trachomatis—summary and conclusions of CMO's Expert Advisory Group. 1–22 Department of Health, London, UK.

Farley, T.M., Rosenberg, M.J., Rowe, P. et al. (1992) Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet, 339, 785–788.[ISI][Medline]

Gemzell-Danielsson, K., Swahn, M.L., Svalander, P. et al. (1993) Early luteal treatment with mifepristone (RU 486) for fertility regulation. Hum Reprod., 8, 870–873.[Abstract]

Gemzell-Danielsson, K., Svalander, P., Swahn, M. et al. (1994) Effects of single post-ovulatory dose RU 486 on endometrial maturation in the implantation phase. Hum Reprod., 9, 2398–2404.[Abstract]

Glasier, A., Thong, K.J., Dewar, M. et al. (1992) Mifepristone (RU486) compared with high dose estrogen and progestogen for emergency contraception. N. Engl. J. Med. 327, 1041–1044.[Abstract]

Ledger, W.L., Sweeting, V.M., Hillier, H. et al. (1992) Inhibition of ovulation by low-dose mifepristone (RU 486). Hum Reprod., 7, 945–950.[Abstract]

Li, T., Dockery, P., Thomas, P. et al. (1988) The effects of progesterone receptor blockade in the luteal phase of normal fertile women. Fertil. Steril., 50, 732–742.[ISI][Medline]

Liu, J.H., Garzo, G., Morris, S. et al. (1987) Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J. Clin. Endocrinol. Metab., 65, 1135–1140.[Abstract]

Piaggio, G., von Hertzen, H., Grimes, G.A., et al. (1999) Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet, 353, 721.[ISI][Medline]

Pillaye, J. (1995) Morning-after birth control. Lancet, 346, 251–252.

Schaison, G., George, M., Lestrat, N. et al. (1985) Effects of the antiprogesterone steroid RU 486 during midluteal phase in normal women. J. Clin. Endocrinol. Metab., 61, 484–489.[Abstract]

Trussell, J., Rodriguez, G. and Ellertson, C. (1998) New estimates of the effectiveness of the Yuzpe regimen of emerging contraception. Contraception, 59, 363–369.[ISI]

Webb, A.M., Russell, J. and Elstein, M. (1992) Comparison of Yuzpe regimen, danazol, and mifepristone (RU 486) in oral postcoital contraception. Br. Med. J., 305, 927–931.[ISI][Medline]

WHO Task Force on Postovulatory Methods of Fertility Regulation (1998) Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet, 352, 428–433.[ISI][Medline]

WHO Task Force on Postovulatory Methods of Fertility Regulation (1999) Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Lancet, 353, 697–702.[ISI][Medline]

Wilcox, A.J., Weinberg, C.R. and Baird, D.D. (1995) Timing of sexual intercourse in relation to ovulation. New Eng. J., 333, 1517–1521.[Abstract/Free Full Text]

Yuzpe, A.A., Percival, Smith, R. and Rademaker, A.W. (1982) A multicentre clinical investigation employing ethinylestradiol combined with dl-norgestrel as a postcoital contraceptive agent. Fertil. Steril., 37, 3–7.

Submitted on July 3, 2000; accepted on September 29, 2000.