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
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Abstract |
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Key words: emergency or post-coital contraception/IUCD/mifepristone
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Introduction |
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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, 1995).
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., 1992; Ledger et al., 1992
). 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, 1993
; Brogden et al., 1993
; Gemzell-Danielsson et al., 1994
). Menstrual induction may occur by the direct action of mifepristone on progesterone receptors on the endometrium independent of luteolysis (Schaison et al., 1985
; Li et al., 1988
; Gemzell-Danielsson et al., 1993
).
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., 1992; Webb et al., 1992
). 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.
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Materials and methods |
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During a two-year period between December 1997 and November 1999 women requesting emergency contraception between 72120 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 12 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 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., 1998). Prevented pregnancies were calculated as follows: 1 observed pregnancies/expected pregnancies.
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Results |
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Table I 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.
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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., 1995; Trussell et al., 1998
), 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 (541). 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 II 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.
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Discussion |
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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., 1992; Webb et al., 1992
). 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 1.11.3% (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, 1992; Farley et al., 1992
). 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., 1999). In the WHO study the failure rates with levonorgestrel and Yuzpe regimen in women presenting between 4872 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 3742% 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., 1987). 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.
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Notes |
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References |
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Submitted on July 3, 2000; accepted on September 29, 2000.