ARTICLES History and Efficacy of Emergency Contraception: Beyond Coca-Cola By Charlotte Ellertson s affirmed at the 1994 International the Netherlands applied the veterinary take a tablet as soon as possible within three Conference on Population and practice of postcoital estrogen adminis- hours after intercourse and could use the Development in Cairo, women tration to a 13-year-old girl who had been method as often as necessary; some con- A 3 6 have the right to control the number and raped at midcycle. tinued to use this method for two years. timing of their pregnancies. To realize this At around the same time, U.S. re- The results showed that the lower doses right, women throughout the world need searchers were investigating the efficacy were not efficacious and caused some men- access to a broad range of contraceptives, of high-dose estrogens, and toward the strual disruption, chiefly a shortening of the as well as to safe abortion services. While end of the decade, these preparations be- cycle. This experiment marked the first most contraceptives are intended for use came the standard. Women typically re- major venture into ongoing postcoital con- before or during intercourse, some meth- ceived either conjugated estrogens, the traception and laid the groundwork for the ods can be used within a short time after steroidal estrogen ethinyl estradiol or the levonorgestrel methods that have become unprotected intercourse. Rumored folk nonsteroidal estrogen diethylstilbestrol available in many developing countries methods such as postcoital douching with (DES). Today, in places where high-dose and in Eastern Europe. Coca-Cola are of dubious efficacy, but for- estrogens are still used, they are adminis- The late 1970s were to offer the chief tunately are not a woman’s only alterna- tered in the so-called 5x5 regimen: 5 mg nonhormonal method available today, the tive. Within the last 30 years, a number of of ethinyl estradiol per day for five days.4 copper-releasing IUD. This device caus- approaches, which seem safe and effica- In the early 1970s, the high-dose estro- es endometrial changes that inhibit im- cious, have been developed. gen regimens gave way to a combined es- plantation; in addition, the copper ions re- These options, predominantly varia- trogen-progestin standard. Canadian leased appear to be directly embryotoxic.7 tions on oral contraceptive regimens, are physician Albert Yuzpe and his colleagues More recently, two other methods have often called “morning-after pills.” A more began studies in 1972 on this combined been investigated: danazol and mifepris- appropriate name for them, however, is regimen, guided by their observation that tone. Danazol, a synthetic progestin and “emergency contraception,” which would a single dose of 100 mcg of estrogen cou- antigonadotropin, was first used as an dispel the idea that the user must wait pled with 1.0 mg of the progestin dl- emergency contraceptive in the early until the morning after unprotected in- norgestrel induces endometrial changes 1980s.8 Mifepristone, more commonly tercourse to start treatment—or that she that are incompatible with implantation.5 known as RU-486, is a potent antiproges- will be too late if she cannot obtain treat- The “Yuzpe method,” as it came to be terone registered in four countries as an ment until the afternoon or night after. The known, replaced high-dose estrogen for- abortifacient. Relatively little research is name “emergency contraception” also mulations, chiefly because it offered a available on these newer methods, al- stresses that the regimens are not intend- lower incidence of side effects, but also be- though mifepristone in particular appears ed for ongoing use. cause the commonly used DES was linked extremely promising as an emergency The roots of modern emergency con- to vaginal cancer in the daughters of contraceptive. traception date back to the 1920s, when re- women who had taken it to prevent mis- searchers initially demonstrated that es- carriages. The regimen now begins with- Yuzpe Method trogenic ovarian extracts interfere with in 72 hours after unprotected intercourse The Yuzpe method is the best-studied pregnancy in mammals.1 Veterinarians and typically consists of 200 mcg of ethinyl method of oral postcoital contraception.9 were the first to apply this finding, ad- estradiol and 1.0 mg of levonorgestrel. (In addition, trials of vaginal administra- ministering estrogens to dogs and to hors- Research on regimens that omitted es- tion of the Yuzpe method are under way es that had mated when their owner had trogen also began in the early 1970s, pre- in Mexico.10) Although the exact treatment not wanted them to. Despite scattered re- dominantly in Latin America. A 1973 re- varies widely in developing countries,11 ports of clinical use of postcoital estrogens port described the results of a large-scale the regimen typically used in North in humans as early as the 1940s,2 the first trial investigating five doses of levo- America and Europe consists of 200 mcg documented cases were not published norgestrel: 150 mcg, 250 mcg, 300 mcg, 350 of ethinyl estradiol and 1.0 mg of levo- until the mid-1960s, when physicians in mcg and 400 mcg per tablet. The regimen norgestrel. Half the dose is taken within was tested as an ongoing postcoital meth- 72 hours after unprotected intercourse, Charlotte Ellertson is program associate at The Popula- od, rather than an emergency formulation. and the other half is taken 12 hours later. tion Council, New York. Participants in the trial were instructed to One reason for the popularity of the 44 Family Planning Perspectives Yuzpe method is that the hormones it uses ly at times when the probability of preg- renders it less effective remains to be in- are the active ingredients found in sever- nancy is highest, such as following mid- vestigated. Some clinicians also routine- al brands of ordinary combined oral con- cycle intercourse. Therefore, better stud- ly give an antiemetic or antinausea med- traceptives. The brand marketed as Ovral ies of the method limit their scrutiny to ication such as dimenhydrinate or in the United States and Canada, for ex- women with regular cycles. For such cyclizine hydrochloride.18 ample, contains 50 mcg of ethinyl estra- women, an expected number of preg- diol and 0.25 mg of levonorgestrel per nancies can be estimated using published Levonorgestrel tablet; therefore, four Ovral tablets (the fertility tables if investigators record the The levonorgestrel emergency contracep- dosage Yuzpe and his colleagues used cycle day of unprotected intercourse (or tive regimen consists of two doses of 0.75 after their original pilot study) constitute details about a woman’s cycle, such as its mg of levonorgestrel taken 12 hours apart, the complete regimen.* usual length and the first day of the last starting within 48 hours after unprotected Several other brands of combined oral menstrual period). From the 10 available intercourse. Although progestins were contraceptives contain the same hormones studies that approached this optimal de- among the first drugs used in postcoital needed for the Yuzpe method, but in sign,14 it is possible to calculate a propor- contraception, few studies of the emergency lower doses.12 Women using these brands tionate reduction in pregnancy associat- levonorgestrel regimen have controlled for therefore have to take a greater number of ed with the use of the Yuzpe method. By cycle day of unprotected intercourse. pills; for example, women in the United comparing observed and expected preg- The best and most recent of the levo- States can use the brands Nordette, Levlen nancies, investigators have demonstrat- norgestrel emergency contraceptive trials, and Lo/Ovral for the Yuzpe method if ed that the Yuzpe method reduces the conducted in Hong Kong,19 indicates a they simply double the number of tablets chances of pregnancy by about 75%.15 failure rate of 2% and a proportionate re- of these lower dose oral contraceptives. (In Because the regimen consists of the same duction in pregnancy of 60%. The inves- other words, they would take four pills for active ingredients as certain combined oral tigators randomly assigned women re- each half of the regimen.) A number of contraceptives, and because it has never porting for treatment within 48 hours after triphasic oral contraceptive formulations been specifically regulated by the U.S. Food unprotected intercourse to receive either also contain the hormones needed for the and Drug Administration, the contraindi- the Yuzpe or the levonorgestrel regimen. Yuzpe method. For example, eight of the cations for its use sometimes have simply During the trial, 410 women used the lat- yellow tablets (corresponding to cycle been adopted wholesale from those stated ter. Investigators did not detect a statisti- days 12–21) of Triphasil or Tri-Levlen con- for combined pills: current or past throm- cally significant difference between the stitute the complete regimen. boembolic disorders, cerebrovascular dis- methods. This trial is being replicated in In the United States, no contraceptives ease or coronary artery disease, known or a multinational study sponsored by the are specifically marketed and packaged suspected carcinoma of the breast or en- World Health Organization.20 for emergency use. As a result, many clin- dometrium, jaundice, and hepatic adeno- As noted previously, the levonorgestrel icians simply cut up packages of oral con- mas or carcinomas. Women older than 35 regimen has been studied as an ongoing traceptives that contain the appropriate who smoke heavily have also been con- or primary method of postcoital contra- hormones. In several European countries, sidered ineligible for the regimen. Gener- ception. The Hungarian company Gedeon tablets equivalent to Ovral are available al medical consensus, however, is that the Richter once marketed a strip of 10 pills in four-pill strips labeled explicitly for regimen has no contraindications.16 containing 0.75 mg each for this use.