8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Efficacy of Emergency Contraception Regimens

C. Enciulescu
Romania

Tutor
E. Ezcurra
HRP - UNDP/UNFPA/WHO/World Bank Special Programme

Introduction

What is emergency contraception

Emergency contraception prevents pregnancy after unprotected sexual intercourse. By definition, contraception is used to prevent pregnancy. Thus, emergency contraception would include any method used after intercourse and before implantation; any method used after implantation would be an abortifacient.

Which methods are most commonly used and how are they utilized

The most commonly used method (Yuzpe-regimen) involves taking two pills each containing 50 µg of ethinylestradiol and 0.50 mg of dl-norgestrel within the first 72 hours of unprotected intercourse. This treatment is repeated 12 hours later. Because norgestrel contains two isomers with only one (levonorgestrel) being bioactive, the total amount of active progestin is 1.0 mg. Some authors have suggested that emergency oral contraception can be effective for up to 120 hours after unprotected coitus⁹. An alternative emergency contraception methode, also based on steroids is levonorgestrel 1.5 mg in two doses 12 h apart.

A recent development is the use of antiprogestagens (mifepristone). The dose is 600 mg (3 tablets of 200 mg), also within the first 72 hours of unprotected intercourse. Mifepristone, when given in the luteal phase, induces uterine bleeding similar to menstruation after approximately 2 days.

Once the 72-hour limit has been exceeded, the insertion of an IUD within five to seven days after unprotected intercourse is occasionally used.

Brief definition/description of efficacy of contraceptive methods

Overall, emergency contraceptive pills are less effective than regular contraceptive methods. Because the emergency contraception pregnancy rate is based on a one-time use, it cannot be directly compared to failure rates of regular contraceptives, which represent the risk of failure during prolonged periods of use in women having regular intercourse. If emergency contraceptive pills were to be used frequently, the failure rate during a full year of use would be higher than that of regular hormonal contraceptives. This is just one reason why emergency contraceptive pills are inappropriate for regular use. The apparent effectiveness of emergency contraception can be attributed both to the action of the treatment regimen and to the limited time during the menstrual cycle when pregnancy is possible. Because menstrual regularity can never be guaranteed during any given cycle (and, therefore, neither can ovulation), the contribution of the medical treatment in preventing pregnancy can only be estimated.

Initial studies of emergency contraception simply reported outcome by stating the number of pregnancies in the treated population. This failure rate was important information for clinicians and patients but vastly overrated the true efficacy of the treatment method. This way of reporting effectiveness assumes that 100 of women would have become pregnant without using emergency contraception: obviously, this is not true.

Thus, for a study to show efficacy, cycle length and day of intercourse during the cycle must be incorporated. If these are known then the expected pregnancy rate for the study population can be calculated and compared to the resulting pregnancy rate after emergency contraceptive treatment. Estimates of conception rates for various days of the menstrual cycle have been published by Dixon (1980)⁵ and are most commonly used in calculations of emergency contraception efficacy in more recently reported studies.

The effectiveness of emergency contraception has been estimated by comparing the observed number of pregnancies with the number of pregnancies expected in the absence of treatment. The expected number of pregnancies is estimated by multiplying the number of treated women who had unprotected intercourse on each cycle day relative to the expected day of ovulation by external estimates of the probability of conception resulting from unprotected intercourse on that cycle day. Only women with regular cycles can be used to estimate the expected number of pregnancies, and hence effectiveness. The expected day of ovulation is estimated as the usual cycle length minus 14 days.

The earlier after unprotected intercourse emergency contraceptive treatment was given, the greater the efficacy, with a downward gradient in efficacy from treatment within 24 h to treatment within 49-72 h²⁴.

Silvester¹⁵ also argued that the true failure rate should take into account the timing of unprotected intercourse and therefore the probability that a pregnancy will occur. Contrary to these studies, an analysis of nine studies found no difference in failure rates when treatment was started within 24, 48, or 72 hours¹.

Review of relevant articles

Efficacy of Yuzpe regimen

After a single act of unprotected sexual intercourse, the Yuzpe regimen fails in about 2 of women who use it correctly (the chances of pregnancy are approximately four times higher when the regimen is not used)²².

The crude failure rate is 1-5 per 100 woman-months while the true reduction in pregnancy risk is over 75. Efficacy is not influenced by the exposure-to-treatment interval within the 72-h window¹³.

It is important to inform the woman that 75 reduction in risk of pregnancy does not translate into a pregnancy rate of 25. Rather, if 100 women have intercourse in the mid 2 weeks of their cycle, approximately 8 will become pregnant. Use of emergency contraceptive pills would reduce this number to 2 women (a 75 reduction)¹. True effectiveness is likely to be at least 75 because treatment failures (observed pregnancies) include women who were already pregnant when treated and women who became pregnant after being treated¹⁶.

A study of Sanchez-Borrego¹⁴ compares the efficacy between dl-norgestrel (2 mg) and levonorgestrel (1 mg) associated with ethinylestradiol (200 µg) given in two doses 12 h apart for emergency contraception. A total of 117 women were consecutively given dl-norgestrel in combination with estrogen (dl-norgestrel group) while 423 consecutive subjects received the combination ethinylestradiol/ levonorgestrel (levonorgestrel group). Overall, four (0.8) pregnancies occurred in the 540 treated women, one (0.9) in the dl-norgestrel group and three (0.7) in the levonorgestrel group.

Table 1. Efficacy of Yuzpe regimen in clinical trials

*Meta-analysis

Efficacy of levonorgestrel

Levonorgestrel-only is significantly more effective in preventing pregnancy after a single act of unprotected intercourse than the combined hormonal method¹⁰.

Levonorgestrel is marketed in several countries for emergency contraception in packs containing 0.75 mg tablets. When the levonorgestrel-only method was initiated within 24 h of coitus its failure rate was only 0.4% (in contrast to the 2.0% for the combined hormonal method)²⁴.

Table 2. Efficacy of levonorgestrel-only regimen in clinical trials

A further advantage of the levonorgestrel-only is the absence of ethinylestradiol, therefore arterial or venous thrombosis in the past or a current attack of migraine with focal aura are not contraindications¹⁰.

Efficacy of mifepristone (RU-486)

Mifepristone (RU 486) is a synthetic steroid with potent antiprogestational activity. When given in combination with a prostaglandin it has proved to be a safe, convenient alternative to surgical termination of early pregnancy. The only apparent disadvantage of mifepristone was that more of the women who took it had a delay in the onset of the next menstrual period - an occurrence that would undoubtedly be stressful to a woman who was worried that she might be pregnant⁷.

Fertility regulation using antiprogestins is therefore at the demarcation line that separates interception by means of postcoital steroids or insertion of postcoital IUD and the use of abortifacients¹¹.

Table 3. Efficacy of mifepristone in clinical trials

Authors	No of women	Pregnancies	Failure rate %
Glasier 1992	402	0	0
Webb 1992	195	0	0

Efficacy of IUDs for Emergency Contraception

A copper-T IUD can be inserted up to 7 days after unprotected intercourse to prevent pregnancy. Copper-T IUD insertion is extremely effective, reducing the risk of pregnancy following unprotected intercourse by more than 99%. Moreover, a copper-T IUD can be left in place to provide continuous, effective contraception for up to 10 years. Women at risk of sexually transmitted infections may not be good candidates for IUDs; insertion of IUD can lead to pelvic infection, which can cause infertility if untreated. Women not at risk of sexually transmitted infections have little risk of pelvic infection following IUD insertion¹⁸.

Table 4. Efficacy of IUD in clinical trials

*Meta-analysis

This method is highly effective. After unprotected sexual intercourse, less than 1% of women are reported to become pregnant if they use a copper-releasing IUD as an emergency contraceptive²².

Studies comparing efficacy of two or more of these methods

In a randomized controlled trial, Webb (19) compared the Yuzpe regimen (ethinyl estradiol 100 ug + levonorgestrel 500 μg repeated after 12 hours) with danazol (two doses of 600 mg) and RU 486 (one dose of 600 mg) in 616 women. The net failure rates are 2,6%, 4,6% and 0%, respectively. A total of 14 pregnancies was observed whereas the predictions carried out according to the method of Dixon gave a number of 34,7.

The study of Glasier⁷ compared the efficacy and side effects of 600 mg mifepristone with those of the standard regimen of estrogen and progestogen as emergency contraceptive agents in a randomized trial in 800 women. A total of 402 women received mifepristone and 398 women received the standard regimen of ethinylestradiol and norgestrel. Only 4 pregnancies were observed, all in the group randomized to the Yuzpe regimen (net failure rate of 1%). Although no pregnancy was observed with RU 486 the difference is not significant between the two methods because of the small sample size.

Von Hertzen²⁴ compared the levonorgestrel regimen (two 0.75 mg tablets taken in 12 h interval) with the Yuzpe regimen in a randomized controlled trial including 1998 women who requested emergency contraception within 72 h of unprotected coitus. The outcome was unknown for 43 women (25 levonorgestrel group, 18 Yuzpe regimen). Among the remaining 1955 women, the crude pregnancy rate was 1.1% (11/976) in the levonorgestrel group compared with 3.2% (31/979) in the Yuzpe regimen group. The proportion of pregnancies prevented (compared with the expected number without treatment) was 85% (95% up to 24h, 85% for 25-48h, and 58% for 49-72h) with the levonorgestrel regimen and 57% (77% up to 24h, 36% for 25-48h, and 31% for 49-72h) with the Yuzpe regimen. Levonorgestrel was slightly, but not significantly more effective than the Yuzpe regimen in preventing pregnancy. The levonorgestrel regimen also was better tolerated.

A prospective randomized study of Haspels¹¹ compared the Yuzpe regimen and levonorgestrel 0.75 mg for two doses, 12 hours apart. 424 subjects were recruited in the Yuzpe group and 410 subjects in the levonorgestrel group. The failure rates were 2.6% and 2.4%, respectively. Side effects were significantly lower in the levonorgestrel group¹¹.

Table 5. Summary table of observed pregnancy and rate of failure according to various methods of emergency contraception.

*Meta-analysis

Overall critical assessment of information retrieved

Emergency contraception is an important method for pregnancy prevention. Various steroid regimens are available throughout the world which are significantly effective in reducing expected pregnancy rates when used after unprotected intercourse.

Emergency contraception is not universally available. It is not licensed, for example, in France or the United States. However, some brands of combined oral contraceptives contain the same hormones as preparations commonly used for emergency contraception, and although not licensed for such use, these contraceptives can be used as a substitute.

The Yuzpe regimen is an effective method for postcoital contraception. In the Yuzpe regimen the risk of pregnancy is less than four times the predicted pregnancy.

Mifepristone is more effective and has fewer side effects but leads to greater disturbance of the cycle and to difficulty in predicting the risk of possible pregnancy until the following cycle. Mifepristone has been a center of controversy since the report of the initial clinical study demonstrated its efficacy as an abortifacient agent. A dose of 600 mg is probably higher than necessary, but no studies have yet been done to determine the optimal dose. (7)

A major disadvantage of postcoital IUD use is that it can produce serious complications if a women has sexually transmitted infection, asymptomatic cervicitis or pelvic inflammatory disease (PID). In nulliparous women, the potential risk of future infertility due to IUD should be considered, since PID rates in these women are up to seven times higher than in non-users. The risk of septic abortion exists if IUD insertion takes place after implantation¹¹.

Conclusions

• The available methods for emergency contraception are: Yuzpe regimen, high dose levonorgestrel, copper IUD.
• The treatment must begin within the first 72 h after unprotected intercourse (for hormonal regimens)
• The Yuzpe regimen fails in about 2% of women who use it correctly. Levonorgestrel was slightly, but not significantly more effective than the Yuzpe regimen in preventing pregnancy.
• The earlier emergency contraceptive treatment is started the more effective it is
• Mifepristone (RU 486) and copper-releasing IUD are highly effective but it need to be administered and followed-up by highly qualified health care providers.

References

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