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® ©2005 UpToDate

Emergency contraception

Mimi Zieman, MD Robert L Barbieri, MD

UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 13.2 is current through April 2005; this topic was last changed on April 25, 2005. The next version of UpToDate (13.3) will be released in October 2005.

INTRODUCTION — Emergency contraception (also known as postcoital contraception) typically refers to the administration of drugs to prevent pregnancy in women who have had recent unprotected intercourse (including sexual assault), or to those who have had a failure of another method of contraception (eg, broken condom) (show table 1).

Advisory committees to the United States Food and Drug Administration (FDA) have recommended that emergency contraception (Plan B, levonorgestrel only) be made available without prescription, as in many other countries [1]. Arguments for this approach are that women will have easier access to treatment; thus, they will be more likely to use it and can begin treatment sooner when it is most effective [2,3]. This should reduce the number of unplanned pregnancies and pregnancy terminations (see "Advance planning" below). The major argument against over-the-counter status is that the opportunity for evaluation and counseling by a health care provider is lost. An office encounter could be used to determine whether nonconsensual sex occurred and discuss risk and prevention of sexually transmitted infections, use of regular contraception, and prepregnancy issues. However, studies have shown that most women are able to use emergency contraception appropriately without formal evaluation and counseling by a health care provider [4].

After considering both sides of the argument, both the American Medical Association and the American College of Obstetricians and Gynecologists supported over-the-counter availability of emergency contraception. In May 2004 the FDA considered this issue but did not give approval; instead they requested increased safety information for girls under 16 or restriction of nonprescription availability for girls in this age group [5]. Limited available data suggest adolescents use emergency contraception appropriately and tolerate the drug about as well as adults [6-9].

The available methods for and efficacy of emergency contraception are reviewed here. Long- term methods of contraception are discussed separately. (See "Overview of contraception" and see "Overview of the use of oral contraceptives").

BACKGROUND RISK OF PREGNANCY — There are many factors which affect a woman's fertility. In general, the risk of pregnancy after an episode of coitus without effective contraception is shown in Table 1A (show table 1A). These data represent the rate of pregnancy in a population of young couples in their mid-20's. Given the uncertainty in timing of ovulation, emergency contraception is offered, when indicated, without regard to timing of the menstrual cycle.

MECHANISM — The mechanism of action is uncertain. Emergency contraceptives may act by inhibiting ovulation, interfering with tubal transport, preventing implantation, or possibly causing regression of the corpus luteum. Since these drugs are administered within hours of UpToDate®: 'Emergency contraception' Página 2 de 8

intercourse and implantation does not occur until approximately seven days after ovulation, use of emergency contraception cannot interrupt a pregnancy. a woman is considered pregnant once a conceptus has implanted [10]. The only FDA approved drug that interrupts pregnancy once implantation has occurred is the antiprogestin mifepristone. (See "Mifepristone for the medical termination of pregnancy").

PREPARATIONS — Several options are available for emergency contraception (show table 2) [11,12].

Ethinyl estradiol plus levonorgestrel — A regimen of ethinyl estradiol (100 mcg) and levonorgestrel (0.5 mg) taken twice, 12 hours apart (the Yuzpe regimen), reduces the number of anticipated pregnancies by 75 to 80 percent [13]. Stated differently, if 100 women have unprotected intercourse during the second or third week of their menstrual cycle, it is likely that eight will become pregnant; approximately two will become pregnant with proper use of the Yuzpe regimen and six of the eight pregnancies (75 percent) will be prevented [14].

In 1998, the United States Food and Drug Administration (FDA) approved marketing (by prescription) of the Preven Emergency Contraceptive Kit, which includes four combination tablets, each containing 50 mcg of ethinyl estradiol and 0.25 mg of levonorgestrel, and a pregnancy test to rule out pregnancy before taking the tablets. Instructions are to take two of the tablets as soon as possible within 72 hours of intercourse, and the other two tablets twelve hours later. However, recent research suggests that emergency contraception is still effective up to 120 hours after intercourse, therefore the 120 hour limit is used by many providers, such as Planned Parenthood. The manufacturer of Preven stopped production in 2004 in order to focus marketing on Plan B, a levonorgestrel-only product for emergency contraception, which is more effective and better tolerated than the combined preparation (see below).

Where licensed regimens are not available, an oral contraceptive such as Ovral (two tablets twelve hours apart) or Lo/Ovral (4 tablets twelve hours apart) can be used (show table 3).

Nausea and vomiting are the major side effects of the Yuzpe regimen. Meclizine 50 mg, taken one hour before the first dose, reduces nausea and vomiting but can cause some sedation [15]. A randomized study comparing metoclopramide (10 mg) and placebo taken one hour before each dose found metoclopramide significantly reduced the frequency of nausea from 56 to 28 percent; the reduction in vomiting was of borderline significance, 22 versus 11 percent [16]. There are no absolute contraindications to use of this regimen and, while not specifically studied, there does not appear to be harm to the fetus if the drugs are taken and the pregnancy continues.

If the estrogen-progestin pills are vomited within one hour of ingestion and an antiemetic was not given prophylactically, then an antiemetic can be given and the estrogen-progestin dose repeated. Alternatively, levonorgestrel can be administered for emergency contraception (see below).

Modified Yuzpe regimen — The Yuzpe regimen was not derived from systematic studies evaluating the optimum dose, timing, or type of progestin for emergency contraception. The only trial of modified Yuzpe regimens found that they were slightly less effective, although promising. This multicenter study enrolled 2041 women within 72 hours of unprotected intercourse and randomly assigned them to receive the standard Yuzpe regimen (100 mcg ethinyl estradiol plus 0.5 mg levonorgestrel for two doses 12 hours apart), a variant that substituted 2.0 mg norethindrone for the levonorgestrel, or only the first dose of Yuzpe (norgestrel was substituted for levonorgestrel and placebo pills were given in place of the second dose at 12 hours) [17]. Among 1973 women who had complete follow-up, 58 pregnancies occurred; 43 were considered method failures and 15 user failures. Failure rates were lowest with the standard Yuzpe regimen, although not significantly (show table 4). Nausea and vomiting were lowest with single dose therapy. Further investigation is needed before modified regimens can be recommended; however, this may not be possible since over 12,000 women would have to be enrolled for a study to have enough power to determine whether the small differences detected in this trial were significant. UpToDate®: 'Emergency contraception' Página 3 de 8

Levonorgestrel — Levonorgestrel, 0.75 mg given twice 12 hours apart, may be more effective and better tolerated than an estrogen-progestin regimen [18,19]. This was illustrated in a controlled trial in which 2000 women with regular menses who requested emergency contraception after unprotected coitus were randomly assigned to either levonorgestrel or the Yuzpe regimen [19]. The crude pregnancy rates were 1.1 and 3.2 percent, respectively. The proportion of pregnancies prevented (compared with the expected number) was 85 percent with the levonorgestrel regimen and 57 percent with the Yuzpe regimen. Nausea and vomiting were significantly less common with the levonorgestrel. The reduction in side effects and improved efficacy are significant benefits of the progestin-only regimen. In addition, it is an effective alternative for women with a history of thrombosis or who are otherwise unable to take estrogen preparations.

If the levonorgestrel is vomited within one hour of administration, consider giving an antiemetic agent and then repeating the emergency contraception dose.

The United States FDA has approved marketing of Plan B (by prescription), a pill pack that contains two 0.75 mg tablets of levonorgestrel to be taken twelve hours apart. The cost is comparable to the Preven kit (approximately $20) [20]. An advisory committee to the FDA recommended Plan B be made available without a prescription, but the FDA rejected this recommendation and requested increased safety information for girls under 16 or restriction of nonprescription availability for girls in this age group [5].

Other regimens also appeared to be effective in preliminary studies. Further trials confirming efficacy need to be performed before these regimens can be recommended. They have not been approved for emergency contraception by the FDA.

Levonorgestrel has been given as a single dose of 1.5 mg instead of two smaller doses. In a randomized trial of 4136 women receiving emergency contraception within 120 hours of intercourse, three regimens were equally effective: a single dose of 1.5 mg of levonorgestrel, two doses of 0.75 mg of levonorgestrel given 12 hours apart, and 10 mg of mifepristone (pregnancy rates of 1.5, 1.8, and 1.5 percent, respectively) [21]. A single high dose of levonorgestrel was not associated with more side effects. Nausea occurred in 15 percent and vomiting in 1 percent of women; the rates were equivalent for each regimen.

The interval between the two doses of levonorgestrel has been lengthened to 24 hours apart, instead of the standard interval of 12 hours apart, without significantly changing efficacy. A multicenter trial in China randomly assigned 2071 women requesting emergency contraception within 120 hours of unprotected intercourse to two doses of 0.75 mg levonorgestrel given either 12 or 24 hours apart [22]. The crude pregnancy rate was similar in both groups, 2.0 and 1.9 percent, respectively. The proportion of pregnancies prevented was also similar, estimated to be 75 and 72 percent, respectively. Side effects were mild in both groups. The efficacy of the 12-hour regimen declined significantly when there were further acts of intercourse after treatment (failure rate 1 versus 5 percent, respectively); however, this was not observed in the 24 hour group.

Mifepristone — The antiprogestin mifepristone (RU-486), 600 mg in one dose, was 100 percent effective at preventing pregnancy in two randomized studies when given within 72 hours after intercourse [23,24]. In a subsequent study of 1700 women, a dose of mifepristone as low as 10 mg was as effective as the 600 mg dose and was associated with less disturbance of the subsequent menstrual cycle [25]. Treatment delay up to 120 hours after unprotected intercourse did not diminish efficacy, although emergency contraception should still be given as early as possible. Overall, data from multiple studies shows that mifepristone (10 mg) is as effective as levonorgestrel (given as a single 1.5 mg dose or two doses of 0.75 mg given 12 hours apart) and is 99 percent effective in preventing pregnancy [21,26].

The high efficacy of mifepristone compared with the regimens discussed above is probably due to its ability to inhibit implantation as well as ovulation [10]. In most series, it is also associated with a lower incidence of side effects. (See "Progesterone antagonists and progesterone receptor modulators", and see "Mifepristone for the medical termination of pregnancy"). UpToDate®: 'Emergency contraception' Página 4 de 8

Because mifepristone delays but does not prevent ovulation, contraception should be used if there are further coital episodes during the cycle as with hormonal emergency contraception.

Copper intrauterine device — A copper intrauterine device placed within 120 hours of unprotected intercourse can also be used as a form of emergency contraception [27]. An advantage of this method is that it provides continuing contraception after the initial event. (See "The intrauterine contraceptive device").

ADMINISTRATION OF EMERGENCY CONTRACEPTION — When prescribing emergency contraception, the physician should inquire whether the act of intercourse for which the contraception is being requested was consensual. If not, the physical and psychological assessment for rape victims should be initiated. (See "Evaluation and management of rape victims").

Recommended regimen — Levonorgestrel is preferred over estrogen-progestin regimens because of higher efficacy and fewer side effects. If an estrogen-progestin regimen is prescribed, an antiemetic drug should be taken one hour before the first dose.

Timing — Both the levonorgestrel and Yuzpe regimens are most effective when given soon after unprotected intercourse. There appears to be a linear relationship between efficacy and the time from intercourse to treatment; in one study, pregnancy rates increased from 0.5 percent (2 of 386) to 4 percent (6 of 146) when treatment was administered within 12 hours and 61 to 72 hours after intercourse, respectively [19,28]. Therefore, it is preferable to administer these regimens as soon as possible after intercourse. However, subsequent studies have shown that emergency oral contraception has efficacy up to 120 hours after intercourse and may be started up to that time if necessary [21,29,30], although patients should be informed that efficacy may be reduced. Efficacy after 120 hours has not been proven. Insertion of a copper intrauterine device is considered the best way to prevent pregnancy in women who seek emergency contraception more than 120 hours after unprotected intercourse [31].

Side effects — Nausea and vomiting are the most common side effects. Antiemetics can be given, prophylactically with the Yuzpe regimen (see "Ethinyl estradiol plus levonorgestrel" above) or as needed (see "Levonorgestrel" above). Uncommon side effects include irregular bleeding, dizziness, fatigue, headache, breast tenderness, and lower abdominal pain. These may be treated symptomatically.

Additional contraception — Women using emergency contraception pills should be advised that a risk of pregnancy still exists if they have intercourse after emergency contraception pills have been taken. Therefore, they should use a method of contraception for the rest of the cycle. They may start barrier or hormonal methods the day after the last EC pill.

The duration of effectiveness of emergency contraception has not been determined. There is no contraindication to giving a second dose of emergency contraception if a second episode of unprotected intercourse occurs anytime after the first dose was administered [32].

Follow-up — Menstrual bleeding after emergency contraception typically occurs within one week of the expected time. Exceptions are with the intrauterine device and mifepristone; in one report, 42 percent of women receiving this drug had a delay in onset of the next menstrual period compared to 13 percent of those receiving ethinyl estradiol and norgestrel[23]. Nevertheless, with any form of emergency contraception, a pregnancy test should be performed if bleeding has not occurred within three to four weeks [12,14].

Advance planning — Giving women a home supply of emergency contraceptives (or an advance prescription for emergency contraception) in addition to their primary mode of contraception may reduce the number of unwanted pregnancies. This was illustrated in a study of over 1000 women that compared those who were given a supply of emergency contraceptive pills to take home (treatment group) with those who could only get them by visiting a physician (control group) [33]. Emergency contraception was used at least once by 47 percent of the UpToDate®: 'Emergency contraception' Página 5 de 8

treatment group, but only 27 percent of the control group. Women in the treatment group were not more likely to use emergency contraception repeatedly. Unintended pregnancies were less frequent in the treatment group, but this difference did not reach statistical significance (18 versus 25, relative risk 0.7, 95% CI 0.4-1.2).

Similar results were obtained in another study of over 2000 women randomly assigned to one of three groups: (1) access to a pharmacy where they could obtain emergency contraception without a prescription, (2) advance provision of emergency contraception, or (3) access to a clinic where they would have to make an appointment to be seen but would be able to receive free emergency contraception [34]. The major findings from this study were:

Only 47 percent of women who had unprotected intercourse during the study used emergency contraception.

Women who had advance provision of emergency contraception were more likely to use these drugs than women who had to go to a pharmacy or clinic to obtain them (37, 24, and 21 percent utilization, respectively). However, the advance provision group did not have a significantly lower pregnancy rate compared to the other groups (8 percent versus 7.1 and 8.7 percent in the pharmacy and clinic groups) because of the high rate of unprotected intercourse and relative underutilization of emergency contraception.

In this study, as in the one discussed above, easier access to treatment led to higher utilization but did not result in a significant drop in the pregnancy rate of the population. Some limitations of the study may account for these null findings. A significant observation, however, is that the these data do not show any harm from making emergency contraception readily available or any increase in risky sexual behaviors (eg, unprotected intercourse) or acquisition of sexually transmitted disease. Furthermore, given the proven efficacy of the method, we can assume that some unplanned pregnancies were prevented in women who used emergency contraception, thus benefiting these individuals.

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