Katarina Ilic1
(1)
Drug Safety, Exelixis, South San Francisco, CA, USA
Katarina Ilic
Email: katarina.v.ilic@gmail.com
Introduction
Unintended pregnancy and particularly teenage pregnancy is a huge global problem. Of the estimated 210 million pregnancies a year, 38 % are unplanned and 22 % are terminated by an abortion (http://www.guttmacher.org/media/nr/abortww_nr.html, Kost and Henshaw 2014). In the US, about one million teenage girls, 11 % of all girls aged 15–19 (112 per 1,000) and 20 % of those who have had sexual intercourse (204 per 1,000) become pregnant each year. Teenage pregnancy rates are much higher in the United States (US) than many other developed countries – twice as high as in England and Wales, France and Canada; and nine times higher than in the Netherlands or Japan (http://kff.org/womens-health-policy/emergency-contraception/).
Emergency contraception (EC) is the use of hormonal emergency contraceptive pills (ECPs) or an intrauterine device after unprotected sexual intercourse (UPSI) to prevent an unintended pregnancy (Daniels et al. 2013). Emergency contraception (EC) has been studied and used for over 40 years. Although the abortion rate is high in many countries and despite the serious consequences of unintended pregnancy, the percentage of women who use EC has been reported as low. For example, in the US in the early 2000s, only 1.3 % of women who had an abortion reported taking EC to prevent pregnancy; and although 43 % of women knew EC was available, only 6 % of women had ever used EC (Kaiser 2003; Jones et al. 2002). In a survey conducted by the US Center for Disease Control and Prevention (CDC 2006–2008) (Daniels et al. 2013), 9.7 % of women aged 15–44 reported ever having used EC. Older women used emergency contraception less than younger women, with 5.0 % of women aged 30–44 having ever used it. Nearly 1 in 4 (23 %) sexually experienced women aged 20–24 never used emergency contraception, compared to 16 % of women aged 25–29 and 14 % of women aged 15–19. A larger proportion of never-married women (19 %; almost 1 in 5) had never used emergency contraception compared to women who were cohabiting (14 %; 1 in 7 cohabiting women) or were currently or formerly married (5.7 %; 1 in 20 women). The percentage of women who had ever used emergency contraception at least once increased from 4 % in 2002 to 10 % in 2006–2008 (Mosher and Jones 2010).
Indications for Use of Emergency Contraception
Emergency contraception or post-coital contraception is a ‘backup’ method for contraceptive emergencies and is designed to prevent pregnancy after unplanned sexual intercourse or when a regular method of contraception fails. EC may be administered in the following situations: when contraception was not used; during exposure to suspected teratogens (cytotoxic drugs, viruses, live vaccines); after forced intercourse or rape, or in the event of contraception failure. Contraception failure may include the following situations (Katzman et al. 2010):
· Condom breakage, slippage, or incorrect use;
· Missed combined oral contraceptive pills (see Chap. 5);
· Taking the progestogen-only pill more than 3 h late (see Chap. 5);
· The start of combined hormonal contraception is delayed;
· The progestogen-only injection is given more than 2 weeks late;
· The transdermal contraceptive patch is detached for 24 h or longer during week 1, or detachment of the transdermal contraceptive patch for 72 h or longer during week 2 or 3;
· The vaginal contraceptive ring is expelled or removed for 3 h or longer during week 1, or removed for 72 h or longer during week 2 or 3;
· The vaginal ring is left in for more than 5 weeks in a row;
· When hormonal contraceptives are used with inducers of microsomal liver enzymes concomitantly or in the last month.
Types of Emergency Contraception
There are three types of emergency contraceptive pills: (i) combined, which contain estrogen and progestogen (Yuzpe method), (ii) progestogen-only emergency contraceptive pills (contain only levonorgestrel) and (iii) anti-progestin ECPs i.e. a progesterone receptor modulator (ulipristal-acetate) or mifepristone. Nowadays the Yuzpe method (combined contraceptive pills) has been mostly replaced by more effective and safer progestogen-only ECPs. Besides ECPs, a copper intrauterine contraceptive device – (IUD) may also be used for emergency contraception. Each of these methods will be described in this section.
Yuzpe Method
The Yuzpe method (a combination of estrogen and progestogen started within 72 h of sexual intercourse) has now been superseded by the progestogen-only hormonal regimen. This method was named after Dr. Albert Yuzpe from Canada who published the first studies demonstrating the method’s safety and efficacy (Yuzpe et al. 1974). The levels of estrogen and progesterone in combined pills used for the Yuzpe method are higher than those included in daily combined oral contraceptive pills (see Chap. 5). The pills are administered in two doses with a 12 h interval, and are effective if the first dose is administered up to 72 h after unprotected intercourse (Westhoff 2003).
When ECP products are not available, combined progestogen and estrogen pills for regular contraception can be used as emergency contraception in two doses with a 12 h interval, with each dose consisting of 4–5 tablets depending on the brand. For example, for regular oral contraceptives containing ethinyl estradiol 120 μg and LNG 0.60 mg, four pills per dose would be required for emergency post-coital use, whilst for pills containing 100 μg/0.50 mg ethinyl estradiol/LNG, five pills per dose would be needed for emergency contraception (FDA 1997).
Levonorgestrel (LNG) Methods
Levonorgestrel (LNG) is a safer, more effective method of EC (see Effectiveness section below) and less frequently causes nausea and vomiting than the combined ECP (Rodriguez et al. 2013). In the US, the LNG ECP product Plan B®, was approved by the Food and Drug Administration (FDA) in 1999 and in other markets products such as Postinor® and Levonelle® were approved. These products are administered as two 0.75 mg LNG pills to be taken 12 h apart: the first dose should be administered as soon as possible after unprotected intercourse, (72 h at the latest) and the second dose 12 h after the first. A single 1.5 mg dose of levonorgestrel has been shown to be equally effective as the two dose regimen, while the adverse effects are similar (von Hertzen et al. 2002; Ngai et al. 2004; Johansson et al. 2002). Both the two-dose and single dose LNG ECP products are more effective when taken as early as possible after unprotected intercourse. Due to the benefits shown in studies, better compliance and simpler usage, levonorgestrel is increasingly dominating the market as a single-dose formulation of 1.5 mg.
Ulipristal Acetate
Ulipristal acetate (UPA) is a selective progesterone receptor modulator. It has been marketed for EC in Europe since 2009 and in the USA since 2010. UPA was shown in two large randomized controlled trials (RCTs) (Creinin et al. 2006; Glasier et al. 2010) to be as effective as LNG for EC when administered within 72 h of unprotected sexual intercourse. Meta-analysis on the combined data from results of these two RCTs indicated significantly lower failure rate of UPA compared to LNG (1.36 % (22/1,617) vs. 2.15 % (35/1,625), p = 0.046). It has also been shown that the efficacy of UPA does not decrease if the time of administration after UPSI increases up to 120 h (Glasier et al. 2010; Moreau and Trussell 2012). UPA is approved in the US as a single dose of 30 mg, under the trade name Ella® or EllaOne®, which can be administered within 120 h of UPSI.
Mifepristone
Mifepristone is a progesterone receptor antagonist approved as a 600 mg dose for use in many countries for early first-trimester medical abortion and a 200 mg dose which has proven to be equally effective as an abortifacient (Schaff et al. 1999; Raymond et al. 2013). For emergency contraception, a WHO study confirmed that lower doses of mifepristone (50 and 10 mg) had similar efficacy to a 600 mg dose of mifepristone (WHO Task Force et al. 2000). However, because mifepristone is also used to induce medical abortion, and due to various social and political reasons thus far in some countries, it has only been approved for emergency contraception in China, Vietnam, Russia and Armenia in a dose 10–25 mg (Trussell and Raymond 2014; http://www.cecinfo.org/country-by-country-information).
Copper Intrauterine Contraceptive Device
IUDs are usually used as a primary contraceptive method and are considered appropriate for the majority of women, including nulliparous women and adolescents (see Chap. 8). However, an IUD may also be used as emergency contraception when hormonal contraception is contraindicated, when more than 5 days after sexual intercourse are passed, or when a women is taking medicines that interact with emergency contraceptive pills. The copper intrauterine contraceptive device (IUD) is the most effective form of emergency contraception (Wu et al. 2010). In the UK the Faculty of Sexual and Reproductive Health (FSRH) recommend it is offered to all women (FSRH Guidance 2012).
If the time of ovulation is estimated, an IUD can be inserted within 7 days following unprotected intercourse (FSRH Guidance 2012). WHO guidance states that an IUD may be inserted up to the 12th day of the menstrual cycle with no restrictions, or at any other time in the cycle if it is certain that the woman is not pregnant (WHO et al. 2011). Women may keep a copper IUD (ParaGard®) as a long-term contraceptive method for up to 10 years after placement.
Side effects of the copper-containing IUD when used for EC are uncommon and may include menstrual cramping or increased menstrual flow (Milsom et al. 1990; Larsson et al. 1993). In women with sexually transmitted infections, IUD insertion can cause pelvic infection in the first 3 weeks after insertion and infertility if left untreated (Farley et al. 1992). However, in healthy nulligravid women, use of an IUD is not associated with an increased risk of infertility (Hubacher et al. 2001) (see Chap. 8).
The availability of the copper IUD (Harper et al. 2008) for EC may be limited as it involves placement in a clinical setting by a trained healthcare professional. Interestingly, a survey among clinicians (n = 1,246; response rate 65 %) in a California State family planning program showed that although over 93 % of obstetrician–gynecologists were skilled in inserting the copper IUD, they were no more likely to have recommended it for emergency contraception than other physicians or advance practice clinicians (Harper et al. 2012).
Mechanism of Action of Emergency Contraceptives
Emergency contraceptive pills prevent pregnancy through various mechanisms (Gemzell-Danielsson and Marions 2004; Gemzell-Danielsson et al. 2014). Depending on the time they are taken, ECPs may inhibit or delay ovulation and/or block the migration of the sperm and fertilized egg. Several clinical studies showed that combined ECPs inhibit or delay ovulation, which is their most likely mechanism of action (Swahn et al. 1996; Rowlands et al. 1986; Croxatto et al. 2002).
Levonorgestrel emergency contraception has also been shown to inhibit or delay ovulation (Durand et al. 2001). The LNG ECP inhibits ovulation for 5–7 days, by which time any sperm in the reproductive tract will become non-viable (Croxatto et al. 2004). Administration of LNG ECPs immediately after unprotected intercourse and prior to ovulation has an effect on the ovulation process and the function of corpus luteum, the latter of which is required for retaining pregnancy (Müller et al. 2003; FSRH Guidance 2012). It has been shown that the administration of a two-dose regimen of levonorgestrel ECPs, during the medial luteal phase at the expected implantation time has no effect on morphology and development of the endometrium (Gemzell-Danielsson and Marions 2004). It has been demonstrated that LNG ECPs interfere with sperm motility by thickening cervical mucus (Kesseru et al. 1974, 1975). However, in vitro studies found that LNG in doses used for ECPs does not have direct effect on sperm function (Brito et al. 2005; Yeung et al. 2002).
Two studies estimating the effectiveness of LNG-ECPs provided evidence that this method of EC is unable to prevent ovulation (Novikova et al. 2007; Noé et al. 2011). In these studies the day of ovulation was calculated based on the blood level of hormones. In a pilot study (Novikova et al. 2007) 99 women received LNG 1.5 mg. Three women who had unprotected intercourse between one day before ovulation (‘day 1’) and ovulation day (‘day 0’) and took the ECP on day 2 after ovulation became pregnant despite taking the ECP (pregnancy rate, 3.0 %). However, in women who had unprotected intercourse on days −5 to −2 of the fertile period, and took ECP (LNG) before or on the day of ovulation, no pregnancies were occurred, although four pregnancies could have been expected (Novikova et al. 2007).
In another study, among 103 women who took LNG-ECP before ovulation (days −5 to −1), 16 pregnancies were expected and no pregnancy occurred (p < 0.0001) and among 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p = 1.00) (Noé et al. 2011).
Analysis of pooled data from three randomized trials of emergency contraception regimens has shown that ulipristal acetate prevents ovulation more effectively than LNG (Brache et al. 2013). When taken immediately before ovulation is to occur, UPA postpones follicular rupture. The likely mechanism of UPA for EC is inhibition or delay of ovulation. In addition, alterations to endometrium that may affect implantation, may also contribute to efficacy (ELLA Prescribing Information 6/2014).
If mifepristone is used in the follicular phase of the menstrual cycle, it can inhibit ovulation and significantly delay the onset of menstrual bleeding. If mifepristone is administered in the first half of the luteal phase, it inhibits progesterone receptors in the endometrium. In that way, mifepristone interferes with the secretory function of the endometrium, thus impairing implantation (Ashok et al. 2001). In the medial or late luteal phase of the menstrual cycle, it causes the regression of the corpus luteum in 50 % of women (Glasier 1997).
There is more than one mechanism of action for IUDs as post-coital contraceptives. IUDs change the cervical mucus, which can block the passage of sperm. In addition, IUDs cause an inflammatory reaction in the endometrium, and thus exhibit an anti-implantation effect after fertilization (FSRH Guidance 2012). IUDS may also prevent implantation of a fertilized egg (Leung et al. 2010).
Effectiveness of Emergency Contraceptives
The results of a RCT which compared combined ECP and LNG EC indicated that the pregnancy rate was 3.2 % (95 % CI 2.2–4.5) among women assigned the Yuzpe regimen and 1.1 % (0.6–2.0) among those assigned LNG. The crude relative risk of pregnancy for LNG compared with the Yuzpe regimen was 0.46 (0.16–1.32). The fraction of prevented pregnancies was 76 % in the Yuzpe group and 89 % in the LNG group (WHO 1998).
The efficacy and safety of a single 1.5 mg LNG dose and two doses of LNG 0.75 mg administered 12-h apart for emergency contraception was compared in a double-blind, randomized, multicenter, multinational study (WHO Study 97902). In total 2,381 healthy women with a mean age of 27 years, who needed emergency contraception within 72 h of unprotected intercourse were randomly allocated to receive either a single 1.5 mg LNG dose (Plan B One-Step®) or two doses of 0.75 mg LNG 12-h apart (Plan B®). In the Plan B One-Step® group, 16 pregnancies occurred in 1,198 women and in the Plan B® group 20 pregnancies occurred in 1,183 women. Among women receiving Plan B One-Step®, 84 % of 100 expected pregnancies were prevented while 79 % of 95 expected pregnancies were prevented among those women taking Plan B®. The expected pregnancy rate of 8 % (with no contraceptive use) was reduced to approximately 1 % with Plan B One-Step®. The relative risk (RR) of pregnancy for LNG 1.5 mg compared with LNG 2 × 0.75 mg taken 12 h apart was 0.83 (CI: 0.46–1.50) in the full intention to treat (ITT) population and it was concluded that both LNG regimens are similarly effective (CDER Application number 21–998).
UPA (taken as a single 30 mg dose) is the most efficient oral emergency contraceptive with an estimated effectiveness of 62–85 % and can be used up to 5 days after unprotected sexual intercourse. In a randomized, multicenter, non-inferiority trial, 2,221 women were randomly assigned to receive a single oral dose of 30 mg UPA (n = 1,104) or 1.5 mg LNG (n = 1,117). After administering ECP (UPA, n = 844; LNG, n = 852) within 72 h of sexual intercourse, there were 15 pregnancies in the ulipristal acetate group (1.8 %, 95 % CI 1.0–3.0) and 22 in the levonorgestrel group (2.6 %, 1.7–3.9) giving an odds ratio (OR) of 0.68 (95 % CI 0.35–1.31). In 203 women who received emergency contraception between 72 and 120 h after sexual intercourse, there were three pregnancies, all of which were in the levonorgestrel group (Glasier et al. 2010).
The effectiveness of mifepristone administered 72 h to 5 days after unprotected intercourse was studied in women for whom an IUD was not an option. The results of the study showed that the risk of pregnancy was 0.65 % with this method. By using probability of conception it was concluded that 85 % of expected pregnancies were prevented (Ashok et al. 2001). Randomized clinical studies have led to the conclusion that a single 10 mg dose of mifepristone is equally effective as the EC regimen consisting of levonorgestrel alone while the incidence of nausea and vomiting is lower (Westhoff 2003).
In a Cochrane review on interventions for emergency contraception, a meta-analysis was performed which included 55,666 women participating in controlled clinical trials (86/100 trials were conducted in China) and requesting EC following a single act of UPSI (Cheng et al. 2012). This indicated that low-dose mifepristone (<25 mg) was less effective than mid-dose mifepristone (25–50 mg) (25 trials; RR 0.73; 95 % CI 0.55 –0.97). However, both mid and low-dose mifepristone were significantly more effective than LNG. If only high-quality trials were included in this meta-analysis, there were no statistically significant differences in effectiveness between mid and low dose mifepristone (6 trials; RR 0.75; 95 % CI 0.50–1.10), while difference in effectiveness between mifepristone (mid and low dose) and LNG was marginal (4 trials; RR 0.70; 95 % CI 0.49–1.01) (Cheng et al. 2012). When compared with the Yuzpe regimen, the use of mifepristone is associated with a lower incidence of nausea and vomiting, but some users may experience delay of subsequent menstruation secondary to delayed follicular development and ovulation, which may sometimes be a cause for concern (Glasier et al. 1992).
Copper Intrauterine Contraceptive Device
When inserted within 5 days of unprotected sexual intercourse, a copper IUD reduces a woman’s risk of pregnancy to 1 in 1,000 (Wu et al. 2010). To compare this figure with data for other methods of emergency contraception, for every 1,000 women who used an ECP after UPSI, at least 20 users of LNG or 14 users of UPA would face an unintended pregnancy (von Hertzen et al. 2002; Cheng et al. 2008).
Factors Affecting the Effectiveness of Emergency Contraception Pills
The efficacy and effectiveness of ECPs may be reduced due to delay in starting treatment, drug interactions, vomiting, and further acts of intercourse. There has also been discussion about the effect of body mass index (BMI) and weight on effectiveness of ECPs, but in July 2014 the European Medicine Agency (EMA) announced that the available data do not support reduced effectiveness of emergency contraceptives with increased body weight (EMA/440549/2014). All these issues will be discussed further in this section.
Time to Administration/Treatment Delay
The frequently used term ‘morning after pill’ is misleading, because combined ECPs and LNG are effective if taken up to 72 h after unprotected sexual intercourse (Piaggio et al. 1999) while UPA is effective if taken up to 120 h after unprotected sexual intercourse (Davis and Dun 2000). However, ECPs is appropriate term as there is some evidence that earlier administration of ECP increases efficacy. A early RCT which included 1998 women at 21 centers worldwide, of whom 997 were assigned the Yuzpe regimen and 1001 the LNG regimen, showed that the efficacy of both the Yuzpe and LNG method declined significantly (p = 0.01) after 49–72 h, compared to administration in the 0–24 h interval since unprotected coitus. Within each of these strata, the Yuzpe regimen was associated with a higher pregnancy rate than the levonorgestrel regimen (Task Force on Postovulatory Methods of Fertility Regulation 1998).
Data from an extensive randomized clinical study showed that the risk of pregnancy is lower than 1 % if a combined ECP or a LNG regimen is used within 12 h, compared to 3 % if the same regimen is used 61–72 h after unprotected intercourse (Westhoff 2003). This lead to the conclusion that both these methods of emergency contraception are more effective if administered as early as possible after unprotected intercourse. Combined ECPs and LNG remain moderately effective after 72–120 h, but the efficacy decreases as the time interval increases. While LNG can be administered between 72 and 120 h, it is less effective, and is not currently labeled for use after 72 h.
A pooled analysis of four WHO trials examined the effect on pregnancy rates when the LNG ECP was delayed (Piaggio et al. 2011). In this analysis no reduction in effectiveness was shown with delayed administration up to 96 h, but there were limitations which must be considered when interpreting this finding. For example, in some studies it was unclear what the level of risk of pregnancy was for each woman and her partner for each episode of unprotected intercourse. Thus no observed drop in effectiveness could have been due to other factors. Given the evidence which is now available on mechanism of action of the LNG ECP (see section above) it seems likely that efficacy is reduced with time and guidance documents on the ECP support early administration (FSRH Guidance 2012).
Drug Interactions
Interactions may decrease the efficacy of hormonal contraceptives, by accelerating the metabolism of ethinyl estradiol and progesterone. An IUD is regarded as a good option for emergency contraception for women who take other medications that can cause interactions and decrease the efficacy of ECPs.
No specific drug-drug interaction studies for the Yuzpe regimen or LNG method alone have been conducted. Most information available concerning drug-drug interactions with the Yuzpe regimen or LNG method is extrapolated from the oral contraceptive literature. Ethinyl estradiol is metabolized by the cytochrome P450 (CYP) 3A4 enzyme pathway. Drugs known to induce CYP3A4 (e.g. phenytoin, primidone, barbiturates, carbamazepine, ethosuximide, topiramate, methosuximide, rifampin, griseofulvin, protease inhibitors and non-nucleoside reverse transcription inhibitors) can lead to decreased plasma ethinyl estradiol levels and may cause failure of emergency contraception (FSRH Guidance 2012). Use of St. John’s Wort (Hypericum perforatum) may lead to interactions with oral contraceptives as this also induces CYP 3A4 (Hall et al. 2003). Women on liver enzyme-inducing drugs or who have stopped using them (≤28 days ago) who require EC should be offered a copper IUD as efficacy is not affected by drugs.
Levonorgestrel also undergoes hepatic metabolism and is subject to increased clearance by microsomal liver enzyme induction. The label of Plan B One-step® (1.5 mg levonorgestrel) states potential changes in the progestin level in the plasma if the drug is used together with HIV protease inhibitors, or with non-nucleoside inhibitors of reverse transcriptase (FDA 2009). It is recommended that women taking liver enzyme inducing medicines take an increased dose of LNG. For example, if LNG 0.75 mg pills are used, a 2.25 mg dose (three tablets) should be taken up to 72 h after unprotected intercourse. This 50 % dosage increase is based on clinical practice and is not stated on the registration label. If single 1.5 mg doses of LNG are used, it is recommended that women taking liver enzyme inducing drugs who are ineligible or who do not wish an intrauterine method should take a single 3 mg dose (100 % dose increase; i.e. two Levonelle® tablets) (outside product license) up to 72 h after unprotected intercourse. There are no published studies on any possible adverse effects of increased ECPs doses (FSRH Guidance 2012).
In June 2014, the FDA Center for Drug Evaluation and Research (CDER) approved Safety Labeling Changes for Ella® (30 mg ulipristal acetate) to state that as a CYP3A4 inducer, rifampin decreases the plasma concentration of Ella significantly. Coadministration of Ella should be avoided with drugs or herbal products that induce CYP3A4 (rifampin, phenytoin, carbamazepine, oxcarbamazepine, griseofulvin, barbiturates, bosentan, felbamate, topiramate, St. John’s wort) as that may decrease effectiveness of Ella (ELLA Prescribing Information 6/2014).
Furthermore, CYP3A4 inhibitors (e.g. itraconazole, erythromycin, HIV protease inhibitors and grapefruit juice) may increase plasma levels of UPA (FSRH Guidance 2012). The Ella® (30 mg ulipristal acetate) product label states that inhibitors of CYP3A4, such as itraconasol and ketonasol, can cause the increase of UPA concentration in the plasma. Medications which increase gastrointestinal pH (proton pump inhibitors, H2 antagonists, antacids) may reduce the plasma levels of ulipristal acetate and thus are not recommended for simultaneous use (FDA 2010).
Body Mass Index
Data from a meta-analysis of two RCTs comparing the efficacy of UPA with LNG (Glasier et al. 2010) indicated that the risk of pregnancy was greater for overweight (BMI = 25–29.9 kg/m2) and obese women (BMI ≥30 kg/m2) compared with normal or underweight women (BMI < 25 kg/m2) whichever ECP was taken. However, for obese women, the risk was lower for UPA users (OR, 2.62; 95 % CI, 0.89–7.00; ns) than for those taking LNG (OR, 4.41; 95 % CI, 2.05–9.44, p = .0002). For both ECs in these studies, pregnancy risk was related to the cycle day of intercourse. Women who had intercourse the day before the estimated day of ovulation had a fourfold increased risk of pregnancy (OR, 4.42; 95 % CI, 2.33–8.20; p < .0001) compared with women having sex outside the fertile window.
However, the EMA recently concluded that the available data on BMI are limited and not robust enough (EMA/440549/2014). For emergency contraceptives containing LNG, the EMA considered the results from a meta-analysis of three WHO studies which primarily included African and Asian women and data from a meta-analysis of two published studies which primarily included Caucasian women (EMA/440549/2014). The conclusion was that these studies did not show a trend for reduced efficacy with increasing body weight and therefore emergency contraceptives can be used to prevent an unintended pregnancy in women of any weight or body mass index.
Vomiting
Vomiting may reduce the efficacy of ECPs due to decreased absorption. If vomiting occurs within 3 h after the administration of ELLA (ELLA Prescribing Information 6/2014) or within 2 h after the administration of Plan B One Step (Plan B One Step, Prescribing Information 7/2009) it is recommended that the dose should be repeated.
Further Acts of Intercourse
Women who had further acts of intercourse after taking an ECP had higher pregnancy rates than women without further intercourse (Yuzpe regimen 5.3 % [19/360] vs. 1.9 % [12/619]; LNG 1.6 % [6/372] vs. 0.8 % [5/602]) (WHO 1998). Data from a meta-analysis of two randomized controlled trials comparing the efficacy of ulipristal acetate (which may delay ovulation for some days) with levonorgestrel have shown that women who had further intercourse after they took ECPs had significantly higher likelihood to get pregnant compared to women who did not have further intercourse (OR, 95 % CI: LNG 7.3 [3.4–15.1]; UPA 5.6 [2.4–12.5]). For both methods, women who had unprotected intercourse after using EC were more likely to get pregnant than those who did not (Glasier et al. 2011).
Safety of Emergency Contraception
Contraindications for Emergency Contraception
The only absolute contraindication for the use of any emergency contraceptive is established or suspected pregnancy. In addition, for LNG/UPA prescribing information also states that contraindications to use include hypersensitivity to LNG/UPA or any of the other components (Plan B One Step, Prescribing Information 7/2009; ELLA Prescribing Information 6/2014).
Although there has been limited inclusion of under-18 s in the clinical trials of UPA, young age is not listed as a contraindication. Use of a copper IUD for emergency contraception (EC) carries the same contraindications as routine IUD insertion (see Chap. 8). Risk of sexually transmitted infections (STIs), previous ectopic pregnancy, young age and nulliparity are not contraindications to use.
Adverse Effects
The most frequent side effects of Yuzpe method and LNG are nausea and vomiting, abdominal pain, headache, dizziness, breast tenderness and fatigue. Nausea (23.1 vs. 50.5 %) and vomiting (5.6 vs. 18.8 %) as well as dizziness (16.7 vs. 11.2) and fatigue (28.5 vs. 16.9) are significantly less frequent with the levonorgestrel regimen than with the Yuzpe regimen (p < 0.01) (WHO 1998). If these effects occur, it is usually soon after the administration of ECPs and may last for 24 h.
The levonorgestrel ECP can cause changes in the menstrual cycle; however the changes experienced are transient and resolve in the next cycle (Gainer et al. 2006). In a study conducted by the WHO, 16 % of women had bleeding unrelated to expected menstruation within 7 days of ECP treatment. Menstrual bleeding occurred several days before or after the expected menstruation in 50 % of women (FSRH Guidance 2012). From post-marketing surveillance, skin and subcutaneous tissue disorders like rash, urticaria, and pruritus or face oedema have been reported but were very rare (Levonelle SPC 2014).
After use of UPA the most commonly (>10 %) reported adverse effects were headache (18 % overall), nausea (12 % overall), abdominal pain and upper abdominal pain (12 % overall) (ELLA Prescribing Information 6/2014). In addition, UPA delayed onset of menstruation by a mean of 2.1–2.8 days (Richardson and Maltz 2012).
Table 7.1 summarises data from worldwide spontaneous reports to Vigibase™, (the WHO global database) for emergency contraceptive pills (Ilic 2013):
Table 7.1
The most frequently reported adverse reactions of emergency contraceptive pills. Reports to VigiBase™ until Dec 31, 2011 (Ilic 2013)
|
Ethinylestradiol/LNG (14,515) a |
Levonorgestrel (4,578) a |
Ulipristal EC (36) a |
|
Unintended pregnancy (1,369) |
Menstruation irregular (1,952) |
Unintended pregnancy (29) |
|
Menometrorrhagia (1,179) |
Unintended pregnancy (548) |
Abortion induced (12) |
|
Metrorrhagia (1,103) |
Nausea (407) |
Drug ineffective (8) |
|
Nausea (998) |
Pelvic pain (394) |
Pregnancy after post coital contraception (4) |
|
Headache (887) |
Vomiting (286) |
Maternal exposure during pregnancy (2) |
|
DVT (801) |
Drug ineffective (273) |
Therapeutic response decreased (2) |
|
Pulmonary embolism (742) |
Menstruation delayed (240) |
Abdominal pain (1) |
|
Abdominal pain (491) |
Abdominal pain (221) |
Cardiovascular disorder (1) |
|
Vomiting (350) |
Dizziness (193) |
Dizziness (1) |
|
Amenorrhoea (296) |
Headache (193) |
Hypotension (1) |
|
Total No. 23,441 |
Total No. (8,139) |
Total No. (66) |
aNumbers in the brackets represent total number of the reports in descending order of frequency
DVT-Deep Venous Thrombosis
The data in Table 7.1 indicate that the most frequently reported adverse events (besides unintended pregnancy) for ECPs were: menometrorrhagia, metrorrhagia and nausea (combined ECPs), irregular menstruation and nausea (LNG and UPA). VigiBase™ was established in 1968 and includes more than eight million reports at the present time (August 2014) from more than 100 countries and is the largest collection of spontaneous reporting drug safety information (http://www.umc-products.com/DynPage.aspx?id=73471&mn1=1108). The total number of reports for ethinylestradiol/ LNG, LNG and UPA reflects the time these ECPs have been on the market around the world. Thus UPA may be expected to have significantly fewer reports as it has only been approved since August 2010. Because of under reporting and lack of data on patients exposure (denominator is not known) in VigiBase™ the incidence of Adverse Drug Reactions (ADR) cannot be calculated (Ilic 2013).
Mifepristone causes similar side effects to other emergency contraceptives, including changes in menstrual bleeding patterns (Ashok et al. 2001). A disruption in the timing of the next menstrual period was the most frequently reported adverse effect for mifepristone (39 % and 42 %) in two studies (Webb et al. 1992; Glasier et al. 1992). The authors of one study reported a lower frequency of nausea (37 % vs. 70 %) and vomiting (3 % vs. 22 %) with mifepristone compared with the Yuzpe regimen. Breast tenderness occurred in a similar percentage of women in both groups (18 %) (Webb et al. 1992). In another study (Glasier et al. 1992) a similar pattern of adverse effects were identified.
The use of post-coital intrauterine devices may be associated with potential complications such as cramps, bleeding, infections and uterine perforation, although perforation is a rare event (see Chap. 8).
Risk in Pregnancy and Breastfeeding
The available evidence suggests that pregnancies occurring after LNG ECP failure were not associated with any major congenital malformations, pregnancy complications or other adverse pregnancy outcomes. A urine pregnancy test is generally not required before use of LNG EC. There is no evidence that LNG is teratogenic (Plan B Step One, Prescribing Information 7/2009).
Although there are no adequate and well controlled studies in pregnant women, Ella® belongs to FDA Pregnancy Category X (see Chap. 4) based on the results from animal data. The product information for Ella® states that pregnancy should be excluded before prescribing and if pregnancy cannot be excluded on the basis of history/physical examination, pregnancy testing should be performed (Ella Prescribing Information 2014).
Congenital malformations, perinatal complications and delivery circumstances were investigated in a prospective comparative cohort study including 332 pregnant women who had used LNG-EC during the conception cycle, matched to a group of 332 pregnant women without exposure to LNG. In the LNG EC group there were 31 pregnant women who miscarried within 14 weeks of gestation compared with 28 women in the comparison group and four malformations were found in each group. Between the two groups there were no statistically significant differences in the incidence of miscarriage or malformation or in the neonatal outcome. In the study group, both birth weight (3,416 vs. 3,345 g, p = 0.040) and the sex ratio of birth (boys/girls, 1.14 vs. 0.90, p = 0.153) were higher than in the comparison group (Zhang et al. 2009).
There are no restrictions on the use of LNG pills by breastfeeding women according to the WHO Medical Eligibility Criteria. Ulipristal acetate and its active metabolite were detected in breast milk of lactating women 5 days after administration of Ella® but the effect of this exposure on newborn infants has not been studied; thus risk to the breast-fed child cannot be excluded (Ella Prescribing Information 2014). Breastfeeding should be avoided for 1 week after use of EllaOne® (ELLA Prescribing Information 6/2014). To stimulate lactation during this time, it is advised that women express and discard the breast milk (FSRHC 2013).
Overall Risk Benefit of Emergency Contraception Pills
Reducing abortion rates is a priority worldwide. Given the consequences of unintended pregnancy, including the risks of medical and surgical abortion, there are no situations where the risks outweigh the benefits of being able to prevent inadvertent pregnancy. Levonorgestrel ECPs have been used for more than a decade, their safety profile is well characterized and they are safe for use by all women including adolescents. Even if they are accidentally taken by a woman who is already pregnant, there is no evidence that the fetus is harmed or that the course of pregnancy is disturbed (WHO 2010a, b). Although no serious risks have been reported in women who used LNG ECP repeatedly, repeated use of post-coital hormonal contraception is not recommended (Halpern et al. 2010). In a study of 332 pregnant women who used progesterone ECPs, no congenital malformations or any perinatal/delivery complications were found (Zhang et al. 2009).
Use of the LNG EC does not increase the risk of ectopic pregnancy (Plan B One Step Prescribing Information 2009; Kozinszky et al. 2011) but if pregnancy does occur an ectopic pregnancy should be considered. Women with a history of ectopic pregnancy, cardiovascular disease, migraine and liver disease can use the LNG ECP. Women who are allergic to levonorgestrel or any other tablet component should use emergency contraceptives with caution (FSRH Guidance 2012).
There are no data on the minimum time interval between two successive uses of the LNG ECP, but it is known that no additional treatment is needed 12 h after the administration of emergency contraception (FSRH Guidance 2012). Prescribing information for LNG EC recommends caution for women with impaired liver function, hereditary galactose intolerance, or glucose and galactose malabsorption (as the product contains lactose as excipient) (Plan B One-Step, Prescribing Information 2009). In women with serious malabsorption syndromes such as Crohn’s disease, the efficacy of oral emergency contraceptives may be decreased.
Ulipristal acetate is not recommended in women with severe hepatic impairment or with asthma poorly controlled by oral glucocorticoids (Ella Prescribing Information 6/2014). The label for ulipristal acetate (30 mg) states that repeated use of UPA within the same menstrual cycle is not recommended as the safety and efficacy of repeated use has not been evaluated. In a clinical study, single doses equivalent to up to four times the dose of UPA in Ella® were administered to a limited number of subjects without any adverse reactions (Ella Prescribing Information 6/2014; Trussell and Raymond 2014).
Use of EC pills does not contraindicate the continued use of regular contraception (Prescribing Information for Plan B One Step and ELLA) although additional precautions may be required when starting or continuing regular contraception following use of EC pills (CEU Guidance Quick Starting Contraception 2010). LNG can be used more than once in a cycle or for recent indication even if there has been another episode of UPSI outside the treatment window (>120 h). Use of UPA more than once per cycle or if there has been another episode of UPSI outside the treatment window (>120 h) is currently not supported (CEU Guidance 2010).
Availability of Emergency Contraception
In 148 countries at least one ECP brand is registered; in 58 countries ECP are included in their Essential Medicines Lists; but 46 countries have no ECP brands registered. In 73 countries access to EC is without prescription (in 17 countries ECP are available over the counter (OTC) and in 56 ECP are behind the counter – i.e. available from a pharmacist without a prescription) (http://www.cecinfo.org/country-by-country-information). In the US, LNG ECPs remains prescription only for those under age 17, despite recommendations to eliminate age restrictions from FDA experts (Wood et al. 2012).
Levonorgestrel’s long history of safe and effective use and low incidence of side effects has allowed reclassification of LNG by regulatory agencies in many countries as a non-prescription emergency contraceptive. In the US, LNG EC met the criteria to be available OTC, which include: no potential for overdose or addiction, very low toxicity, uniform dosage, no major drug interactions or contraindications, poses no danger to an existing pregnancy, and the user can determine her own need for the product (www.cecinfo.org). However, even with increased availability, EC users still require timely and adequate information and a toll free number and a website could provide information to potential users 24 h a day. Other risk minimization measures proposed for OTC availability of EC include a phone number and website included on outside package and interior labeling, and ECPs dispensed by pharmacists certified every year on emergency contraception use (Ilic 2013).
Although over-the-counter (OTC) availability of LNG EC is more convenient for women and provides rapid access to EC when necessary, a systematic review of 23 published articles which included data from RCTs, cohort studies, and community interventions failed to demonstrate a reduction in unintended pregnancy or abortion rates with increased access (Raymond et al. 2007). The quality of the studies included in this systematic review varied. In only one study, increased access to ECPs was associated with greater use (Raymond et al. 2006). Six studies suggested that intervention increased promptness of emergency contraceptive pill use, though this effect was not seen in one large RCT (n = 1,948) (Raymond et al. 2007).
A meta-analysis performed by Polis et al. in 2007 included eight RCTs representing 6,389 patients in the United States, China and India. Advance provision (in which women receive a supply of emergency contraception before unprotected sex) “did not decrease pregnancy rates compared to standard access (OR 1.0; 95 % CI: 0.78–1.29) in studies for which 12 month follow-up data were included; OR 0.91; 95 % CI: 0.69–1.19 in studies for which 6 month follow-up data were included; OR 0.49; 95 % CI: 0.09–2.74 in a study with 3 month follow up data), despite increased EC use (single use: OR 2.52; 95 % CI 1.72–3.70; multiple use: OR 4.13; 95 % CI 1.77–9.63) and faster use (weighted mean difference (WMD) −14.6 h; 95 % CI −16.77–12.4 h)”. Advance provision did not lead to increased rates of sexually transmitted infections (OR 0.99, 95 % CI 0.73–1.34), unprotected intercourse, nor changes in contraceptive methods (Polis et al. 2007).
Women who must wait for physician appointments could have significant delays in access to the EC, which in turn may compromise the efficacy of the ECP. Because pharmacies are available in rural areas and open on weekends and for more hours than physicians’ offices, pharmacies present unique access points for ECPs. In many countries pharmacists are allowed to dispense LNG to women; the age restriction varies from 15 or older years (Finland), 16 years or older (Bulgaria) 17 years of older (US, Serbia), but in some countries there is no age restriction (Austria, Belgium, Netherland, Ireland, Slovenia, Denmark, France, India).
Although pharmacists have front-line contact with EC users and it is expected that they are familiar with the guidelines for EC use, one study conducted in the UK found that they did not provide sufficient counselling to women in need for ECP for various reasons – for example, the pharmacy does not have private space for conversation, workload in pharmacies, pharmacists’ religious beliefs (Cooper et al. 2008) or lack of knowledge (Van Riper and Hellerstedt 2005). Pharmacists may also miss the opportunity for counseling and to refer women to test for sexually transmitted infections (STI) (Habel and Leichliter 2012). In addition, healthcare providers should educate women who are not in stable relationships to use condoms in order to reduce the risk of STIs.
Levonorgestrel is safe and effective if it used within 72 h of unprotected intercourse and should be available as behind the counter contraceptive in all the countries. Pharmacists must improve their knowledge about ECPs through continuous education and pharmacies must have private space for consulting users of EC.
Legal, Ethical and Regulatory Aspects of Access to Emergency Contraception
Different legal, political, and other factors caused by the interpretation of abortion laws and lack of knowledge may cause obstacles to the introduction of EC into some countries. Additionally, access to EC may be influenced by religious factors (Tadiar and Robinson 1996). Catholic bishops around the world have opposed access to emergency contraception, stating EC is an abortifacient, encourages promiscuity and may even cause ectopic pregnancy (http://www.catholicsforchoice.org/documents/EmergencyContraceptionCatholicsinFavor.pdf). At times, the bishops have been successful, however more often, policymakers armed with medical information, have supported access and increased availability of EC in many countries. The issues surrounding availability of EC in the USA are discussed in some detail in Chap. 16 – “Political and Religious Perspectives on Prescribing Women’s Medicines”.
In 2002, a Judicial Review in the English High Court ruled that pregnancy begins at implantation not with fertilization. As emergency contraception is a method of contraception not abortion, emergency contraception can continue to be lawfully supplied (Judicial Review of Emergency Contraception 2002). In countries where it is considered that pregnancy begins with implantation – such as the UK, Germany and New Zealand (Tadiar and Robinson 1996) – emergency contraception is lawfully supplied as a method of contraception (not abortion). This includes dispensation of ECPs over the counter in pharmacies. However, pharmacists with religious, moral or conscientious objections to EC could also limit the wider use of EC, by either refusing to dispense it, or by giving biased advice (Cooper et al. 2008).
Conclusions
Emergency contraception provides women a last chance to prevent pregnancy after unprotected intercourse and in most countries current options for EC include a copper IUD or hormonal emergency contraception pills (ECPs) containing either levonorgestrel (LNG) or ulipristate acetate (UPA). However, although both unplanned pregnancy rates and abortion rates are high in many countries, the use of emergency contraception is low.
In this chapter the mechanism of action, effectiveness and safety of all methods of currently available EC is reviewed. An IUD is the most effective form of EC and may be inserted within 5 days of unprotected intercourse. The LNG ECP is approved for use up to 72 h after unprotected intercourse and UPA is approved in many countries for up to 5 days after unprotected intercourse. Women should be advised to take the LNG ECP as soon as possible after unprotected intercourse or contraceptive failure. If more than 72 h has elapsed after sexual intercourse, UPA or a copper IUD are the preferred method of EC.
LNG has been used for several decades and it is safe for use by all women including adolescents. Thus it is available in many countries as an OTC or BTC emergency contraceptive. UPA has been used only in recent years and its safety profile is not as well characterized. To date, it is available only with a prescription in some countries and is not yet available in other countries.
Take Home Messages
· The decision which method of EC to use depends on several factors, such as the number and timing of episodes of UPSI, drug interactions and individual choice.
· LNG ECPs greatly decrease the chances of pregnancy if taken within 72 h of UPSI.
· If more than 72 h have elapsed after sexual intercourse, UPA or a copper IUD are preferred methods of EC.
· Mechanism of action studies show that ECPs do not cause abortion.
· In countries where it is considered that pregnancy begins with implantation emergency contraception is lawfully supplied as a method of contraception.
· The LNG ECP is a safe and well tolerated treatment with very few contraindications for use.
· EC users should be told to perform a pregnancy test if the menstrual period does not begin within 3 weeks of taking ECP, or if it is delayed by a week or more, as well as before taking UPA if pregnancy cannot be excluded on the basis of history/physical examination.
· ECP use may be repeated if needed, but women should be advised to use a regular method of contraception.
· Healthcare providers must provide information about adequate use of EC and regular contraception.
Acknowledgment
I am grateful to Ivana Macenovski–Colic Pharm D, former student of mine, for her help with preparation of this manuscript.
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