Contraceptive Development Network, Department of Reproductive and Development Sciences, The University of Edinburgh, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, EH3 9ET, UK
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Abstract |
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Key words: contraceptive/home use fertility monitor/LH surge/Mifepristone/once-a-month pill
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Introduction |
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Progesterone is essential for the establishment and maintenance of human pregnancy. The anti-progesterone mifepristone is a synthetic 19-norsteroid, which acts by blocking the action of progesterone at the receptor level (Spitz and Bardin, 1993), and thus, has multiple potential anti-fertility actions. When administered in the early luteal phase mifepristone retards endometrial development, without disturbing the timing of menses (Swahn et al., 1988
; Berthois et al., 1991
; Maentausta et al., 1993
). It also alters uterine contractility to a pattern more usually seen in the late luteal phase (Gemzell-Danielsson et al., 1990
). In 1993 Gemzell-Danielsson and colleagues conducted a pilot study in which a single dose of 200 mg of mifepristone was given in the early luteal phase [2 days following the surge of the lutenizing hormone (LH) in urine]. Out of 124 cycles in which coitus took place during the fertile period, only one pregnancy was observed (Gemzell-Danielsson et al., 1993
). There was no disruption of the timing of the subsequent menstrual bleed, although in 35% of the cycles slight vaginal bleeding was reported 23 days after treatment.
The main problem in developing a once-a-month contraceptive is finding a means that, both reliably and easily, identifies the start of the LH surge. Gemzell-Danielsson tried to solve this problem by using the LH sticks for home urine testing (Ovu-quick; Organon). In their study 12 out of 169 cycles were deemed to be anovulatory. However, it is not possible to determine if the LH surge truly was absent, or if the method failed to detect a surge. The woman may have read the test result wrongly or even failed to perform a test on the appropriate day.
Unipath (Bedford, UK) have developed a technology that can be used in the home to monitor changes in urinary hormones. This system comprises disposable test sticks and a hand held monitor, which together are used to detect changes in the levels of oestrone-3-glucuronide (E3G), a urinary metabolite of oestradiol, and LH, to indicate the potentially fertile days leading up to ovulation. The time from the first significant rise of LH in the urine to ovulation is reported to be around 2448 h (Collins, 1996). The monitor thus should provide a convenient method of identifying the early luteal phase. Summary data for up to six consecutive cycles can be stored in the monitor memory and these data can be retrieved.
We investigated the contraceptive efficacy of 200 mg of mifepristone on day LH + 2 in a group of women who used this monitor to identify the LH surge.
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Materials and methods |
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Treatment group
Thirty-two women were recruited to the treatment group. None had been taking hormonal preparations within the 2 months prior to the start of the study and all had had at least two spontaneous menstrual periods since stopping hormonal contraception. All women underwent screening at the time of recruitment including a routine physical and gynaecological examination. A venous blood sample was taken for full blood count, serum biochemistry and liver function. The study started on day 1 of the menstrual period following screening, and lasted for up to seven consecutive menstrual cycles in which subjects took 200 mg mifepristone once per month.
Control group
The control group consisted of 20 healthy women with regular menstrual cycles who were trying to become pregnant (for less than 6 months prior to the enrolment in to the study) and hence, were not using contraception. They were provided with a monitor, which they used according to the manufacturer's instructions. Women were advised that their chance of conception would be higher if they were to have sexual intercourse during the fertile period, identified by the monitor. The controls took part in the study until pregnancy occurred or for a maximum of six cycles if they did not conceive.
Procedure
All subjects and controls were provided with a home use hormone monitoring system (Unipath, Bedford, UK). The system comprises a hand-held monitor and disposable dual-assay urine test sticks, and is used to simultaneously detect LH and E3G levels in early morning urine. The monitor optically measures the intensity of the lines that form on the test sticks after sampling, and the system will delineate three levels of fertility (Low, High and Peak Fertility) according to the optical signal changes detected. Low fertility will be displayed from day 1 of the cycle, until the hormone levels rise above the baseline levels. A change from low to high fertility is triggered by detection of elevated E3G levels, to concentrations typically between 20 and 30 ng/ml. The change from high to peak fertility is triggered by the detection of an LH surge, typically with a concentration >30 IU/l.
Peak fertility is displayed on the day of the LH surge and on the following day. Subsequently high fertility is displayed for 1 day prior to a return to low fertility. At the start of each menses, the subjects pressed the `m' button on their monitor to initiate that cycle of use, at a time suitable for testing the first urine of the day. For the rest of the month, the subjects were required to consult the monitor display each morning (3 h either side of the time when `m' button was set) to determine whether they needed to perform a test that day. Beyond this 6 h time window the monitor would not accept a test. The system requests one test every day for up to a total of 10 or 20 tests, depending on the length of the woman's cycle, and the timing of her LH surge. Embedded software within the monitor collects and analyses data from each cycle to identify and display fertility status to the user, and stores data for several months.
Mifepristone (Laboratories Exelgyn, Paris, France) was taken 2 days after the day of the first day of peak fertility (LH surge). With each cycle, subjects followed the same protocol, and were reviewed by the investigator monthly, on day LH + 2. Just before taking the 200 mg tablet of mifepristone, a venous blood sample was taken, and later assayed for progesterone. At the beginning of the study, if the LH surge was not identified by day 21 of the cycle, the subject was instructed to continue testing, but mifepristone was not given in that cycle. The subject was also advised to use barrier contraception from day 21 until the onset of the next menses. After the second pregnancy (which occurred due to a failure in detecting an LH surge), we changed this practice. We calculated the estimated day of LH surge for each month based on information from the previous cycles. If the women did not detect an LH surge either within 3 days after the anticipated day of LH surge or by day 19, a blood sample was taken for rapid serum progesterone assay. If the progesterone level was >5nmol/l and if the woman was at risk of pregnancy, mifepristone was administered.
All subjects and controls kept a menstrual record card, recording all vaginal bleeding experienced during the study and the days on which they had sexual intercourse. Subjects also marked the first day of the peak fertility as identified by the monitor and the day of taking the study medication.
If menstruation was overdue by more than one week the investigator performed a pregnancy test. Provided this was negative, the subject continued in the study and the next cycle was deemed to start with the onset of menses. Since the effect of mifepristone taken in very early pregnancy is unknown, and teratogenic effects could not be ruled out, women who would not consider terminating any pregnancy were not recruited to the treatment group.
At the end of the study, the subjects attended for a final visit, when a routine physical and gynaecological examination was performed. Full blood count, serum biochemistry and liver function were reassessed.
The following definitions were created for the purpose of the study.
Statistical analysis
Cycle lengths and serum progesterone concentrations were compared by two-sample t-tests. Confidence limits for efficacy were derived from confidence limits for relative risk calculated by the Greenland and Robins method (Greenland and Robins, 1985).
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Results |
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The probability of pregnancy in the control group
Twenty women were recruited to the control group and three withdrew before completing the study. Two withdrew from the study as they found using the system `too stressful' and one withdrew because she no longer wished to plan a pregnancy. Data were collected from 50 control cycles during which 12 pregnancies occurred. Average frequency of intercourse was 1.7 episodes per week in the 39 control cycles in which the women kept a record of their sexual activity. In 37 cycles women had intercourse at least once during the fertile period (FP). In two cycles intercourse did not occur during the FP, while in 11 cycles the exposure status was unknown, as women failed to keep a record of sexual activity. Eight pregnancies occurred in the first exposure cycle.
If we assume that all 11 cycles from which information on sexual activity was lacking were exposure cycles, the probability of pregnancy was 0.25. However if those cycles were all non-exposure cycles, the probability of conception would be 0.32. Therefore among the control group the overall probability of pregnancy if sexual intercourse took place at least once during the fertile period lies between 0.250.32.
Contraceptive efficacy of the method
Thirty-two volunteers were treated with a single dose of 200 mg of mifepristone administered in the luteal phase of the cycle as their sole method of contraception between one and seven cycles. They contributed a total of 178 cycles, and in 167 cycles mifepristone was administered. Eight women withdrew from the study before completion; two women moved out of the area, three ended their relationship, two conceived during the study and one lost confidence in the method.
Two clinical pregnancies occurred in the 178 cycles studied. The first pregnancy was a true treatment failure, which occurred in a woman (para 1) who took mifepristone on day 14 (LH + 2) of her first treatment cycle. She opted for a surgical termination of pregnancy, which was performed at 8 weeks of gestation (confirmed by ultrasound scanning). In the second woman (para 3), an LH surge was not identified in her third study cycle hence she did not receive treatment with mifepristone, menses did not occur and on day 37 after her last menstrual period an ectopic pregnancy was diagnosed and treated surgically. In a third woman a biochemical pregnancy was diagnosed (serum ßHCG only rising to 34 IU/l), which was spontaneously and completely aborted by day 34 of the third study cycle after taking mifepristone on day 14 (LH + 2). This woman continued in the study and completed six treatment cycles.
The mean frequency of sexual intercourse was 1.8 episodes per week in 167 treatment cycles in which sexual activity was recorded. If we assume the probability of pregnancy in the treatment group is similar to the control group (0.250.32), the expected number of clinical pregnancies during the 178 cycles (in which 140 were exposure cycles) studied should be between 3548.3. The observed number was two. Therefore, the efficacy of the method is 94.3% (95% confidence interval 75.498.7) 95.9% (95% CI 82.599.0).
When calculating the efficacy of the method, we excluded the 29 cycles during which women were not exposed to a risk of pregnancy, and the three cycles in which mifepristone was taken in the follicular phase.
Contraceptive efficacy of luteal phase administration of mifepristone
In 145 cycles in which mifepristone was taken in the early luteal phase (within 2 days of the urinary LH surge) 117 were exposure cycles (Table II). Exposure status was unknown in eight cycles and in 20 cycles women were not at risk of pregnancy. In the 117 exposure cycles, there was only one clinical pregnancy.
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If the probability of pregnancy in all exposure cycles in the study is 0.250.32 (the same as that of the control group), between 3446 clinical pregnancies would be expected in the 136 ovulatory cycles in which mifepristone was taken in the luteal phase. The observed number was one. Hence, the contraceptive efficacy of luteal phase mifepristone is between 97.1% (95% CI 78.0099.6) 97.8% (95% CI 83.999.7).
Performance of the home use hormone monitor
In 140 treatment cycles an LH surge was identified by the monitor, which equates to 90.9% LH surge detection when calculated for perfect use cycles; and 80.5% when imperfect use cycles are also included in the total. In 127 cycles this was confirmed by a subsequent rise in serum progesterone of >5 nmol/l in the early luteal phase. This information was not available from nine cycles (blood samples lost or not collected). In the remaining four cycles serum progesterone was between 25 nmol/l, 1 or 2 days following the urinary LH surge as detected by the monitor. This may have been due to an early detection of the first significant rise in urinary LH. None of these five cycles were prolonged after taking mifepristone, hence it is unlikely that they were anovulatory.
There was a total of 38 (21.3%) cycles in which an LH surge was not detected. Among them, one (0.6%) was an anovulatory cycle, defined by serum progesterone not rising above 5 nmol/l in the mid-luteal phase. In three (1.7%) other cycles we administered mifepristone on day 19, before the monitor had identified an LH surge. Serum levels of progesterone (taken on the day of administering mifepristone) confirmed that in these cycles mifepristone was administered in the follicular phase. All three cycles were prolonged (4352 days).
In the remaining 34 cycles an LH surge probably occurred (as suggested by a rise in serum progesterone of >5 nmol/l) but was not identified by the monitor. Fourteen were missed due to monitor method failure (7.9%) and 20 were a consequence of imperfect use of the system (11.2%).
Cycle length
Mifepristone when given in early luteal phase did not significantly affect the cycle length (P = 0.35). The mean of the usual cycle length was 28.3 days (SD ± 1.3) and during the treatment cycles it was 28.0 days (SD ± 1.9).
Side effects
Women kept a record of vaginal bleeding in 139 out of the total 144 cycles where mifepristone was taken on LH + 2. Mifepristone induced vaginal bleeding within 72 h in 21 cycles (15%). In a further 19 cycles, our volunteers took mifepristone in the luteal phase but the LH status was not known. In 17 of those cycles (>89%), mifepristone induced a vaginal bleed.
Serum progesterone values in blood samples taken just prior to mifepristone administration were available for 136 cycles. The mean serum progesterone value was significantly (P < 0.0001) higher in those cycles where mifepristone induced bleeding when compared to the mean value for the cycles without bleeding [21.72 (SD ± 9.04) nmol/l versus 13.33 (SD ± 6.23) nmol/l].
Two women spontaneously reported improvement of their pre-menstrual symptoms during cycles in which mifepristone was administered, while one reported worsening. In one woman hepatic alanine aminotransferase (ALT) was elevated at 103 IU/l (normal range 1040 IU/l) at the end of the study but returned to normal within 2 months. One woman complained of diarrhoea 12 h post mifepristone in one cycle, three reported menstrual cramping within 72 h of taking mifepristone; two women reported a reduction in menstrual blood loss.
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Discussion |
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One criticism of previous work in this field has been the lack of a suitable control group for the subjects studied. Unlike the Gemzell-Danielsson study, we were able to compare the results with a contemporaneous control group using the same methodology in the same cultural setting. In this control group, if sexual intercourse took place on a fertile day the probability of a pregnancy was 0.250.32. The calculated probability of pregnancy in a cohort of couples monitored during a study of natural family planning (WHO, 1983) was 0.486 if intercourse took place 3 days prior to and a day after the peak day of mucus discharge. The difference in the probability of pregnancy between our study and a variety of other published series (Table III) may be explained by the fact that we have extended our definition of the fertile period to 6 days (3 days prior to the urinary LH surge until 2 days after). Other authors (Wilcox et al., 1995
) have calculated that the likelihood of conceiving during an ovulatory cycle to be 0.37 (95% confidence interval 0.310.48) if daily sexual intercourse took place during a 6 day fertile period (four days before and a day after ovulation). The lower frequency of intercourse in our group (untimed intercourse averaging 1.7 per week) may also explain the lower probability of pregnancy.
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During the course of the study we developed an algorithm (Figure 1) for the administration of mifepristone if an LH surge was not identified. In 19 exposure cycles (out of 28 cycles in which an LH surge was not identified) mifepristone was administered using this algorithm and there were no pregnancies. Given that the methods available to be used in real life to time the administration of mifepristone cannot be 100% accurate, such an algorithm will be essential to deal with a missed LH surge.
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Administration of mifepristone in the mid or late luteal phase induces a bleed within a few days of treatment, which may or may not be followed by a second bleed at the time of expected menstruation (Shoupe et al., 1987; Swahn et al., 1988
). In our study, in 17 out of the 19 cycles where mifepristone was taken after ovulation (the LH status unavailable and probably later than on LH + 2), inter- menstrual vaginal bleeding occurred (89.5%). Moreover, there was an increased risk of bleeding seen in those women who may have taken mifepristone slightly later in the LH + 2 window. The mean serum progesterone concentration was significantly higher in those women who had bleeding after taking mifepristone within LH + 2, when compared with those who did not. The higher serum progesterone value in some on LH + 2, could be due to a delayed identification of the first significant rise in urinary LH, or because of a more rapid increase in serum progesterone due to early ovulation. Nevertheless, in our group of women, in all cycles where mifepristone induced a vaginal bleed, a second bleed occurred at the time of the expected menses. Therefore, while the bleeding may have been inconvenient, it did not jeopardise efficacy or continued use of the method. There was less inter-menstrual bleeding (15% of the cycles) reported in our study when mifepristone was taken within LH + 2, less than half of that reported by Gemzell-Danielsson et al. (32%) (Gemzell-Danielsson et al., 1993
). This is possibly due to the fact that the majority of women in our study received mifepristone at the correct time. In their study, in 51% of the cycles, mifepristone was taken between 3 and 5 days after the LH surge.
In conclusion, the use of the combination of home use fertility monitor with once-a-month administration of mifepristone (especially if mifepristone is administered at the early luteal phase) is an attractive contraceptive option with minimal side effects. However, to be an effective contraceptive method, the women have to be committed to using a device, which identifies the LH surge, in order that the pill can be taken at the correct time in the cycle. Whilst this regimen may be acceptable to motivated women, it may be regarded as too complicated for others to adopt on a routine basis. There was evidence of such non-compliance in this study, with 11.2% of LH surges being missed as a consequence of imperfect use of the monitor. Unfortunately, it is difficult to envisage how an easier way of defining the correct timing, which obligated less compliance, could be devised.
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Acknowledgements |
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Notes |
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References |
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Submitted on November 22, 2000; accepted on March 6, 2001.