1 Department of Obstetrics and Gynecology, Huddinge University Hospital, S-141 86 Huddinge, 2 Department of Woman and Child Health, Division for Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden, 3 Shanghai Institute of Planned Parenthood Research, Shanghai, 4 Shanghai Lu Wan District MCH Hospital and 5 Shanghai No. 2 Textile Hospital, China
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Abstract |
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Key words: luteal phase treatment/menstrual regulation/mifepristone/misoprostol
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Introduction |
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The possibility of using the antiprogestin mifepristone for menstrual regulation has been evaluated in a number of studies (Ulmann, 1987; Van Santen and Haspels, 1987
; Dubois et al., 1988
; Lähteenmäki et al., 1988
). The overall failure rate per treatment cycle is ~5% and per pregnant cycle 17% (for review, see Swahn et al., 1996
). The efficacy rate for menstrual regulation in women with a menstrual delay of 7 days was higher if the antiprogestin was combined with the prostaglandin analogue Cervagem® (Rhône-Poulenc Rorer, Helsingborg, Sweden) 48 h later. Efficacy amongst subjects with elevated ß human chorionic gonadotrophin (HCG) was 97.2% and if non-pregnant women were included the overall efficacy was 97.9% (WHO, 1995
).
All available data concerning mifepristone treatment in the luteal phase indicate that repeated use on a monthly basis would hamper the bleeding pattern; only treatment in the very early and very late luteal phase will not cause bleeding disturbances (Croxatto et al., 1987; Swahn et al., 1990
). Studies made in the luteal phase in which a state of pseudo pregnancy was induced by HCG (Gemzell-Danielsson et al., 1993
) indicate that treatment with mifepristone and a prostaglandin analogue just prior to the expected time of menstruation would be well tolerated and not upset the menstrual cycle in a non-pregnant cycle while in the case of pregnancy the combination would be sufficient to induce bleeding and possibly disrupt implantation.
One possible reason why such treatment has not been considered feasible for regular use has been the lack of a suitable oral prostaglandin analogue. A possible one is misoprostol which is effective for the induction of early abortion when used in combination with mifepristone (Aubeny and Baulieu, 1991; Norman et al., 1992; El-Rafaey et al., 1995
)
The objectives of the present study were to evaluate the efficacy, safety and to some extent the acceptability of once-a-month administration of a combination of 200 mg mifepristone and 0.4 mg misoprostol for menstrual regulation in the late luteal phase. The effect on bleeding pattern was of special interest.
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Materials and methods |
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Recruitment started in November 1994 and ended in April 1996.
Assays
In the Chinese centre, analyses of LH in urine was made by enzyme-immunoassay techniques and of serum HCG by radioimmunoassay. In Stockholm immunofluorescence methods with commercial kits from Abbott Diagnostics, Kista, Sweden for IMX equipment were used.
Values for HCG of more than 10 IU/l or 3.1 ng/ml were considered diagnostic for pregnancy.
Statistics
Cycle length was calculated from the first day of the menstrual bleeding to the day before the next bleeding in association with the treatment. In cases of two bleeding episodes after treatment the first one was considered as the menstrual bleeding.
A Pearl Index of 5 was chosen as an acceptable level of efficacy. With a total of 400 cycles the 95% confidence limits would be 0.48 and 9.6. The study was discontinued if the Pearl Index (number of pregnant cycles per 100 woman years) exceeded 9.6. The results were reviewed per 100 treated cycles. Student's t-test was used for comparison of cycle lengths.
The study was approved by the Ethics Committee at each centre and by WHO's Secretariat Committee on Research Involving Human Subjects.
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Results |
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LH surge
Urine samples for analysis of LH were available in 119 cycles. In 16 cycles the LH surge was not possible to identify. In the cycles with identified LH surge the mean day of treatment occurred on cycle day LH + 12 ± 1.9 (SD) and 14.2 ± 2.5 (SD) in Stockholm and Shanghai respectively.
In Shanghai the participating women reported at least one act of intercourse in cycle days LH 3 to LH +2 in 69/84 cycles. The corresponding figure for Stockholm was 39/41 cycles.
Effects on bleeding pattern
In the majority of patients the mean length of the cycles was not affected by the treatment (Table II). Eight subjects (one in Stockholm and seven in Shanghai) discontinued the study due to bleeding irregularities which were seen in 15 cycles. In seven cycles two bleeding episodes with a few days interval were seen after treatment. In four cycles the expected menstruation was delayed for up to 1 week. In one cycle treatment did not cause bleeding and only after treatment 1 month later was menstruation induced. In three cycles an irregular bleeding pattern was observed. Two of these cycles were preceded by a positive serum HCG and in these cycles the bleeding episodes were seen on cycle days 913 plus 1824, and on cycle days 2025 respectively. In the third case a second bleeding was seen on days 1722. Treatment with RU 486 previous to the cycle with irregular bleeding occurred on day 14.8 ± 3.1 (n = 9; SD) (range LH + 10 to LH + 20) after the LH surge whereas in six cycles the day of treatment in relation to LH surge was impossible to identify. In the 13 remaining women with positive HCG, the subsequent cycle was unaffected with regard to duration and bleeding pattern.
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Discussion |
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The combination of 600 mg mifepristone and 1 mg Cervagem® for menstrual regulation (WHO, 1995) in women with a menstrual delay of less than 11 days was highly effective. The overall success rate was 97.4% and for pregnant women 97.9%. These results are more favourable than those achieved in our study. The reason for the lower efficacy rate for administration before rather than after the missed menstrual period is not known, but these present results indicate that research on mechanisms of placentation during this early period between implantation and first missed menstrual period is needed. It is noteworthy that four of the continuing pregnancies were later terminated successfully by a medical method using 600 mg mifepristone and 1 mg Cervagem®. The differences in efficacy in the WHO and the present study may be attributed to the dose of mifepristone used, 200 mg in our study and 600 mg in the WHO study, and also to the type of prostaglandin analogue. However, several studies have confirmed the high efficacy of a single dose of 200 mg mifepristone combined with the prostaglandin analogue misoprostol for the termination of pregnancy (Bygdeman, 1995
) so this explanation does not seem likely to be the only one.
The overall frequency of pregnancies was lower than expected in both centres, 21.4% in Shanghai and 7.3% in Stockholm. With intercourse in the peri-ovulatory period the probability of pregnancy is 3050% (WHO, 1983; Wilcox et al., 1995
). In Stockholm at least one act of intercourse was reported during the peri-ovulatory period from LH 3 to LH +2 in 39 out of 41 cycles. The corresponding figure in Shanghai was 69 cycles out of 84. The lower sexual activity during the fertile period in Shanghai may explain the low rate of pregnancies in that centre whereas the reason for the low pregnancy rate in Stockholm is unclear. One possible reason for the low number of pregnancies detected might be that timing of the plasma sample of ß-HCG in the cycle was not optimal. The fact that the ß-HCG test was negative despite a continuing pregnancy detected 1920 days later might support this hypothesis.
Bleeding disturbances were seen in 15 cycles in the study. The frequency was higher in Shanghai than in Stockholm, where two bleeding episodes were noted in only one cycle. Genetic variations and differences in lean body mass may explain the different effect on bleeding pattern.
It is a well known fact that treatment with mifepristone affects the menstrual cycle. The type of effect is dependent on the timing of drug intake in the cycle. Treatment in the follicular phase inhibits ovulation and folliculogenesis is resumed once treatment is withdrawn and menstruation will be delayed correspondingly. Treatment in the mid-luteal phase may either induce one or two bleeding episodes depending on whether luteolysis occurs or not. In the present study all these predictable effects on the menstrual cycle could be seen. In two cases a positive HCG before treatment seemed to induce bleeding irregularities, although that was not a consistent trait as a positive HCG did not affect the subsequent cycle in 13 cycles.
It has been argued that women would not approve of late luteal contraceptive methods (Rimmer et al., 1992). Our problem with the slow recruitment rate to this study may indicate that women prefer contraceptive methods with other modes of action, but that there would still be a need for alternate methods for a minority of women.
In summary, late luteal phase treatment with 200 mg mifepristone the day before the expected menstruation followed by 0.4 mg misoprostol orally 48 h later every month is not effective enough to be used for menstrual regulation. Also the effect on bleeding pattern makes the timing of treatment impossible in too many cases.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 22, 1998; accepted on November 12, 1998.