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Advances in Methods of Emergency Contraception

Emergency Contraception : Research on Mifepristone

- Dr Helena von Hertzen, Geneva

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

 Mifepristone1Yuzpe Regimen2
Number of women treated597589
Expected number of pregnancies 3534
Observed number of pregnancies09

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 treatedn=347n=346

No symptoms132 (38%)45 (13%)<0.001
Nausea on day of treatment137 (40%)207 (60%)<0.002
Nausea after day of treatment98 (28%)184 (53%)<0.001
Vomiting on day of treatment 9 (3%) 59 (17%) <0.001
Headache at any time170 (49%)242 (70%)<0.001
Breast tenderness at any time94 (27%) 158 (46%) <0.001

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 totalProportion pregnant
Relative risk
(95% CI)
No. of
Pregnancies expected
Prevented fraction
600 mg7/5591.3 1.004584
50 mg6/5601.10.85 (0.29-2.51) 4386
10 mg7/5651.20.99 (0.35 - 2.80)#4885

All participants20/16841.21368585

# 1.2 (0.4-3.4) when 50mg is reference category.

Table-4 : Side-effects* of three doses of mifepristone in emergency contraception

Side Effect10 mg
(n = 561)
50 mg
(n = 558)
600 mg
(n = 558)
p value**
Nausea17.514.919.7 0.324
Vomiting1.8 1.3 2.0 0.819
Dizziness12.310.4 15.20.145
Bleeding disturbances15.7

* 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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