 For
the past ten years, the Special Programme of Research, Development and Research
Training of the World Health Organization has been in the forefront of research
on new technologies for Emergency Contraception. This research has led to the
development of two new methods, a levonorgestrel-only regimen1 and a low-dose
mifepristone regimen2. Both have advantages when compared to the Yuzpe regimen,
the current standard in hormonal emergency contraception. This presentation will
focus on research on mifepristone as an emergency contraceptive.
Mifepristone is the first antiprogestogen which was synthesized in 1980 by
the French Pharmaceutical Company, Roussel-Uclaf. The chemical structure of mifepristone
resembles that of progesterone, and mifepristone has a high affinity to progesterone
receptors. It blocks the receptor and thus interferes with the action of progesterone3.
This has several consequences as progesterone is essential for a number of reproductive
functions. It is needed, for example, for follicular maturation and in the process
leading to ovulation and fertilization. It causes changes in the endometrium that
are essential for successful implantation and it is indispensable for the continuation
of pregnancy. As a consequence, administration of mifepristone during
the preovulatory phase of the cycle either disrupts follicular development or
blocks ovulation. In fact, it was shown that administration of 5 mg at the time
when follicular size was 14 mm retarded its growth for 12-84 hours after treatment4.
On the other hand, a high dose [3 mg/kg] blocked ovulation, collapsed the dominant
follicle, and forced reinitiation of follicular recruitment, which prolonged the
follicular phase and thus the whole cycle5. Mifepristone may also prevent
pregnancy by influencing the development and transport of the fertilized egg.
In rats, mifepristone accelerated egg transport through the tube and caused the
loss of fertilized eggs from the uterus before implantation6. When administered
after ovulation, mifepristone affects endometrial maturation to an extent considered
to be incompatible with implantation7. The timing may be more important than the
actual dose: the earlier mifepristone is administered during the secretory phase,
the more marked is its effect on the endometrium8. These modes of action
of mifepristone suggested that it could be effective when used for Emergency Contraception.
And, in fact, the results of the first two studies9,10, which compared the efficacy
and side-effects of 600 mg of mifepristone to those of the Yuzpe regimen, were
very promising. There were no pregnancies (method failures) among 597 women who
were treated with mifepristone, while 9 pregnancies occurred in the group of 589
women treated with the Yuzpe regimen. (Table-1)
Table-1 : Efficacy of Emergency Contraception | | Mifepristone1 | Yuzpe
Regimen2 | | Number
of women treated | 597 | 589 | | Expected
number of pregnancies | 35 | 34 | | Observed
number of pregnancies | 0 | 9 |
| | 1–
a single dose of 600mg | 2–100µg
ethinylestradiol +1mg dl-norgestrel twice, 12hours apart |
Despite the high dose of mifepristone, women in that group reported significantly
fewer side-effects, such as vomiting and nausea, than women in the Yuzpe group
(Table-2). Table-2 : Incidence of
Side-Effects after emergency contraception | | Mifepristone
(600 mg) | Yuzpe Regimen | p
value | | Number of
women treated | n=347 | n=346 | |
| | No
symptoms | 132 (38%) | 45 (13%) | <0.001 | | Nausea
on day of treatment | 137 (40%) | 207
(60%) | <0.002 | | Nausea
after day of treatment | 98 (28%) | 184
(53%) | <0.001 | | Vomiting
on day of treatment | 9 (3%) | 59
(17%) | <0.001 | | Headache at
any time | 170 (49%) | 242 (70%) | <0.001 | | Breast
tenderness at any time | 94 (27%) | 158
(46%) | <0.001 |
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However,
almost half of the women in the mifepristone group experienced a delay of more
than three days in the onset of menstruation compared to about 10% in the
Yuzpe group. This delay was presumably related to mifepristone’s inhibitory effect
on follicular development and ovulation when taken in the follicular phase of
the cycle. Regimen for inducing abortion use
a 600 mg dose. As it was known that lower doses than 600 mg could block ovulation
and cause abnormal secretory maturation of the endometrium, we launched a multinational
study to compare the efficacy and side-effects of three single doses - 600 mg,
50 mg and 10 mg - given within 120 hours of unprotected coitus. This study was
carried out in eleven centres in six countries, and it included a total of 1717
women (Fig.). The results indicate that lowering the dose of mifepristone sixty-fold
did not decrease its effectiveness as an emergency contraceptive. Pregnancy rates
were 1.1%-1.3% in all dose groups and the treatment prevented some 85% of pregnancies
(Table-3). There were no significant differences in any other side-effects (Table-4)
but for the delay in menses, which was significantly (p<0.01) related to the
mifepristone dose. Table-3
:Pregnancy rates and prevented fractions by treatment group
| | Observed
pregnancies total | Proportion pregnant
(%)
| Relative
risk
(95% CI) | No. of
Pregnancies
expected | Prevented fraction
(%) | | Group | | | | | | | 600
mg | 7/559 | 1.3
| 1.00 | 45 | 84 | | 50
mg | 6/560 | 1.1 | 0.85
(0.29-2.51) | 43 | 86 | | 10
mg | 7/565 | 1.2 | 0.99
(0.35 - 2.80)# | 48 | 85 |
| | All
participants | 20/1684 | 1.2 | 136 | 85 | 85 |
| | #
1.2 (0.4-3.4) when 50mg is reference category. |
Table-4
: Side-effects* of three doses of mifepristone in emergency contraception | Side
Effect | 10 mg
(n = 561)
total | 50
mg
(n = 558)
(%) | 600 mg
(n
= 558) | p value** | | Nausea | 17.5 | 14.9 | 19.7
| 0.324 | | Vomiting | 1.8
| 1.3 | 2.0
| 0.819 | | Headache | 12.7 | 13.8 | 11.3 |
0.522 | | Dizziness | 12.3 | 10.4
| 15.2 | 0.145 | | Fatigue | 19.6 | 20.6 | 24.2 | 0.055 | | Bleeding
disturbances | 15.7 | 31.0 | 35.8 | 0.001 |
| *
Percentage rates (recorded for 7 days after treatment)
** Non-zero correlation
between mifepristone dose and occurrence of side-effects. |
In fact, 36% of the women in the 600 mg group had a delay of menses of more than
7 days. When we investigated in more detail, the pregnancies [n=7] that occurred
in the 600 mg group, we found that four women conceived more than two weeks after
treatment suggesting that they may have conceived after further acts of intercourse
due to delayed ovulation in the treatment cycle.
The results of this study have several practical implications. A lower dose of
mifepristone would not only be substantially less expensive, but would also be
safer as women are less likely to have a delay in the onset of the next menses
. Such a delay not only adds to anxiety that treatment may have failed, but
the delay in ovulation exposes the women to the risk of pregnancy should she have
further acts of unprotected intercourse during the treatment cycle.
The efficacy of the 10 mg dose has been tested further in China in a large double-blind
study. A total of 3052 women were included in this trial at ten centres. Women
were randomized to receive either a single dose of 10 mg or 25 mg of Chinese mifepristone.
The results of this study (unpublished) confirm the findings of the WHO multicentre
study. In addition, in the Chinese study, the efficacy of the treatment appeared
to be higher the sooner mifepristone was used after intercourse. Following this
trial, mifepristone was registered for Emergency Contraception in China, as the
first country in the world. To answer the
question whether low-dose mifepristone is more effective than levonorgestrel,
we are carrying out a large multinational, randomized, double-blind study to compare
the efficacy and side-effects of 10 mg of the antiprogestogen and two treatments
of the progestogen in emergency contraception up to 120 hours after unprotected
intercourse. The two levonorgestrel treatment groups will receive either two doses
of 0.75 mg administered at an interval of 12 hours or a single dose of 1.5 mg.
The clinical part of the study was recently completed and the results are being
analysed. The study was carried out in 15 centres in nine countries, including
India, and over 4100 women participated in it. It is anticipated that the results
of this comparative study will be available during the second half of 2001.
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