Emergency Contraception



Emergency Contraception


Nora Doty, MD, MSCR

Alison Edelman, MD, MPH



Emergency contraception (EC) is a method to prevent pregnancy after intercourse in which a primary contraceptive method was not used or failed.1 Although this approach is commonly referred to as the “morning-after pill,” this nomenclature fails to recognize that a copper intrauterine device (IUD) can also be used for EC, that methods are effective for many days after the “morning after,” and that all EC methods should be initiated as soon as possible, not necessarily the “morning after.” Numerous methods have been evaluated and vary in their ability to act as EC, but only three EC methods are primarily available worldwide: the copper IUD, ulipristal acetate (UPA), and levonorgestrel (Table 12.1). EC is considered an essential treatment option for women wanting to avoid pregnancy following unplanned intercourse, barrier method failure, misuse of other contraceptive methods, or sexual assault. However, many women also report using EC simply due to fear of contraceptive method failure.2

The use of large doses of estrogen to provide EC was pioneered in the 1960s but was associated with significant gastrointestinal side effects.3 Albert Yuzpe then developed a method utilizing a combination oral contraceptive or the “Yuzpe” method (ethinyl estradiol 100 mcg and norgestrel 1 mg given twice, 12 hours apart), resulting in a significant reduction in estrogen dose.4,5 During the 1970s, a number of studies were undertaken, mostly in South America, to test the efficacy of various progestins given without estrogen for the potential use of progestins as on-demand contraceptives (i.e., after each act of intercourse). A WHO-sponsored multicenter trial found that levonorgestrel 0.75 mg had a failure rate of 0.8% per treated cycle without any serious side effects; however, this treatment regimen caused a high incidence of cycle disturbances.6 These studies led to a large WHO-sponsored randomized trial comparing the Yuzpe and levonorgestrel regimens for EC.7 The progestin-only EC containing levonorgestrel 0.75 mg given 12 hours apart not only had fewer side effects but was more effective than the Yuzpe method. Importantly, as a randomized comparative trial, this study was the first to prove that EC works, given the superiority of one regimen over the other; previously, studies only evaluated outcomes (pregnancy) compared to expected rates. This initially marketed two-dose progestin-only EC was replaced with a single-dose product based on studies demonstrating that taking both doses together

provided similar effectiveness and no increase in side effects—leading us to the levonorgestrel regimen that is available today.8,9 Subsequently, selective progesterone receptor modulators (like UPA) and the copper IUD were developed and implemented for EC.








Table 12.1 Characteristics of Emergency Contraception Methods































































EC Method


Dose


Effectiveness*


Timing


Approved


Accessibility


Notes


Intrauterine


Copper IUD


380 mm2


99%


Within 120 h


No


Requires office visit



Oral antiprogestin


Ulipristal acetate


30 mg


67%


Within 120 h


In most developed countries


Requires prescription in the United States, OTC in Europe



Mifepristone


200 mg



Within 120 h


No


Limited access



Oral progestin


Levonorgestrel


1.5 mg


50%


Within 120 h


In most countries


OTC


FDA-approved in the United States for use within 72 h


Combined estrogen-progestin


Ethinylestradiol/norgestrel


100 mcg/1.0 mg



Within 72 h for the first dose; repeat dose in 12 h


No


Requires prescription


Not recommended for routine use due to low efficacy


IUD, intrauterine device; OTC, over the counter.


* Calculated reduction in pregnancy risk.

Norgestrel 1.0 mg is equivalent to levonorgestrel 0.5 mg.



Measuring Efficacy

EC pills are effective at delaying and/or inhibiting ovulation when taken during the correct window of time,9,10,11,12 but determining EC effectiveness for a specific individual also depends on her actual risk of pregnancy. This risk is difficult to determine as it depends on an individual’s inherent fecundability and on which cycle day unprotected intercourse occurred. The average woman’s menstrual cycle has approximately 6 days when intercourse can result in pregnancy: the 5 days prior to ovulation and the day of ovulation itself.13 This window is limited because sperm only have the capacity to fertilize an ovum for up to 5 days in the reproductive tract.14 The risk of pregnancy is highest on the day prior to ovulation and negligible on the first few days of the cycle (Figure 12.1).13 However, the day of ovulation is difficult to predict in each cycle due to lack of regularity even in women who report “regular” cycles; almost half of women will have a cycle range of 7 days or more over the course of four or more cycles.15 Accordingly, 1% to 6% of women with reported regular cycles can be in their fertile window on the day that their next menses is expected to start.13

In EC trials, the number of pregnancies prevented by EC is typically obtained through subject recall as to the cycle day of unprotected intercourse. The likelihood of conception on that cycle day is based on
pregnancy probability data from studies of women who were trying to conceive, which may not be same as the pregnancy probability in women who are not trying to conceive.16 Thus, it is possible that the overall effectiveness of EC may be overestimated in trials.






Figure 12.1 Probability of pregnancy relative to ovulation after intercourse on a given day of the cycle in women of different ages (years). (From Dunson DB, Colombo B, Baird DD, Changes with age in the level and duration of fertility in the menstrual cycle, Hum Reprod 17(5):1399-1403, 2002. Reproduced by permission of European Society of Human Reproduction and Embryology.)

At the individual level, EC effectiveness can be potentially influenced by factors like high BMI, weight over 75 to 80 kg, as well as further unprotected intercourse in the same cycle.17,18 It can be difficult to determine the exact benefit an individual may get from EC, but because of its safety, it is recommended that women use EC at any point in the cycle even if it is outside the suspected fertile window because the benefits of use outweigh the risks.

In the United States, EC was initially touted as the answer to the high rate of unplanned pregnancies and projected to have the ability to reduce abortion rates by 40%.19 Although many women report “ever having” used EC pills (3 in 10 women), population-level effects on unintended pregnancy rates have not been demonstrated.19,20,21 This lack of a population-level effect is likely due to various factors including the incorrect and nonuse of EC, repeat acts of unprotected intercourse in the same month, and other patient-specific issues.17,22,23 Advance prescription or provision does not appear to be a solution; a study of advanced provision of EC pills in Scotland did not demonstrate a change in abortion rates despite 45% of women using EC pills at least once.24


Types of EC


Copper IUD

The copper T380A IUD is the most effective form of EC and can prevent pregnancy for at least 120 hours after unprotected intercourse.25 Some evidence exists that the copper IUD may be effective even if placed up to 14 days after unprotected intercourse as long as a urine pregnancy test is negative prior to placement.26,27

Copper ions impair sperm motility, viability, and the acrosomal reaction when used as a continuous contraceptive; these actions are unlikely to have any benefit when the IUD is inserted postcoitally.28 The copper IUD is the only EC that may have a contragestive effect meaning that it may prevent implantation, but this action is entirely dependent on the timing of IUD placement in relationship to ovulation and intercourse.29 Advantages of the copper IUD over oral EC methods include its cost-effectiveness,30 its ability to be used as an ongoing contraceptive method for 10 or more years, and that weight or other patient characteristics are unlikely to impair its efficacy. In copper IUD EC studies, 1-year continuation rates range from 60% in a U.S. sample to 94% in a large Chinese sample.25,31 Disadvantages of the copper IUD include initial upfront cost, discomfort with placement, and need for a time-sensitive office visit. Side effects of using the copper IUD as EC are the same as those associated with using the copper IUD for contraception and include an initial increase in menstrual bleeding and dysmenorrhea, which typically decrease with time.25


The copper IUD as EC is an excellent choice for women with access to an expedient office visit for placement and who desire to use it as their ongoing method of contraception. One project that investigated increasing copper IUD access found that 11% of women who were seeking EC but not necessarily IUD placement had same-day IUDs placed after a counseling intervention.32 A copper IUD as EC has almost no contraindications for use. According to the U.S. Center for Disease Control’s Medical Eligibility Criteria for Contraceptive Use (MEC), the copper IUD for EC is a category 4 for women who are currently pregnant and a category 3 for women who have undergone solid organ transplant and are having complications.33 If placing a copper IUD for EC, patients should be counseled about the risk of failure and, if this occurs, the risk of having an IUD in place with an ongoing pregnancy. After insertion of copper IUD for EC, no additional or backup method of contraception is needed because the IUD is immediately effective.


Ulipristal Acetate

UPA is the most effective oral EC agent available. UPA is a selective progesterone receptor modulator that works by delaying ovulation.34 Different from other oral EC methods, UPA appears to be able to delay ovulation even at the time of a rising LH surge. A pooled analysis from clinical trials demonstrated that rupture of follicles ≥18 mm in size is delayed by at least 5 days in 59% of cycles exposed to UPA compared to only 15% of levonorgestrel EC-exposed cycles.34 The enhanced activity of UPA relative to levonorgestrel is due to its tissue-specific functions as a selective progesterone receptor modulator. When given prior to the luteinizing hormone (LH) surge, UPA acts at the hypothalamus as a progesterone receptor agonist (like levonorgestrel) and blocks or attenuates the LH surge. However, once the LH surge has initiated, many LH-triggered events in the follicle are mediated by progesterone receptor binding. As a result, UPA acts as an antagonist, blocking the pathways required for follicle rupture and extending the effective dosing window to the time of the LH peak. As a pure agonist, levonorgestrel cannot block these downstream progesterone receptor-mediated pathways (see Chapter 2).35

The efficacy of UPA compared to levonorgestrel has been established in clinical trials. UPA prevented more pregnancies than levonorgestrel both 0 to 72 hours and 72 to 120 hours after unprotected intercourse in a noninferiority trial; however, the 97- to 120-hour subgroup constituted only 3% of the study population, which limits this finding.23 As sperm can be viable in the reproductive tract for up to 5 days,16 UPA can effectively prevent ovulation during a woman’s entire fertile window. UPA’s consistency and duration of effect as well as its longer window of effectiveness are likely what make it a more effective method of EC compared to levonorgestrel.

Risk factors for failure of UPA include subsequent acts of unprotected intercourse during the same menstrual cycle without repeating the use of UPA. UPA delays follicle rupture for at least 5 days; thus, women
are at risk for conception if they have unprotected intercourse again as ovulation just occurs later in that same cycle.36 UPA efficacy may be impaired by obesity. A meta-analysis of two randomized controlled trials found an increased odds of pregnancy after taking UPA in women with a BMI ≥ 30 kg/m2 compared to women with a BMI of less than 25 kg/m2. However, this study was not sufficiently powered to definitively determine this outcome (OR 2.62, 95% CI 0.89 to 7.0).17 Subsequent studies of UPA pharmacokinetics or drug levels demonstrate similar levels in normal and obese BMI subjects,37 but as obesity can impact all aspects of drug function and transport, further pharmacodynamics and/or sufficiently powered pregnancy trials are needed to ultimately answer this question.

Side effects of UPA are mild and include headaches (10%) and nausea (10%).36 UPA is a good choice of EC for almost all patients; according to the MEC, UPA has no contraindications to use.33 UPA EC users can expect onset of their next menses to occur slightly later than expected (average 2.1 days)23 because UPA delays ovulation by 5 to 7 days, which in turn prolongs the follicular phase and lengthens the cycle.

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Mar 1, 2020 | Posted by in OBSTETRICS | Comments Off on Emergency Contraception
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