There are different forms of EC. Emergency contraceptive pills (ECPs), sometimes simply referred to as emergency contraceptives (ECs), or the morning-after pill, are medications intended to disrupt or delay ovulation or fertilization, which are necessary for pregnancy.[3][4][5]
Intrauterine devices (IUDs) – usually used as a primary contraceptive method – are sometimes used as the most effective form of emergency contraception.[4][6] However, the use of IUDs for emergency contraception is relatively rare.[1]
Definition
Emergency contraception is a birth control measure taken to reduce the risk of pregnancy following unprotected sexual intercourse or when other regular contraceptive measures have not worked properly or have not been used correctly.[7] It is intended to be used occasionally and is not the same as medical abortion.[7][8] Emergency contraception is offered to women who do not wish to conceive but have had unprotected sex on any day of the menstrual cycle, from day 21 after giving birth, or from day five after abortion or miscarriage.[7] Emergency contraception measures include tablets taken by mouth or the insertion of a copper intrauterine device.[7][8]
Emergency contraception is not related to medical abortion, which is a drug regimen administered to terminate pregnancies into the second and even third trimester.
Emergency contraceptive pills
Emergency contraceptive pills (ECPs) are sometimes referred to as emergency hormonal contraception (EHC). They are taken after unprotected sexual intercourse or the breakage of a condom.[9]
Types
A variety of emergency contraceptive pills are available, including combined estrogen and progestin pills; progestin-only (levonorgestrel, LNG) pills; and antiprogestin (ulipristal acetate or mifepristone) pills.[10] Progestin-only and anti-progestin pills are available as specifically packaged pills for use as emergency contraceptive pills.[10][11] Emergency contraceptive pills originally contained higher doses of the same hormones (estrogens, progestins, or both) found in regular combined oral contraceptive pills. Combined estrogen and progestin pills are no longer recommended as dedicated emergency contraceptive pills (because this regimen is less effective and caused more nausea), but certain regular combined oral contraceptive pills (taken 2–5 at a time in what was called "the Yuzpe regimen") have also been shown to be effective as emergency contraceptive pills.[10]
Progestin-only emergency contraceptive pills contain levonorgestrel, either as a single tablet (or historically, as a split dose of two tablets taken 12 hours apart), effective up to 72 hours after intercourse.[10] Progestin-only ECPs are sold under many different brand names.[12][13][14] Progestin-only ECPs are available over-the-counter (OTC) in many countries (e.g. Australia, Bangladesh, Bulgaria, Canada, Cyprus, Czech Republic, Denmark, Estonia, India, Malta, Netherlands, Norway, Portugal, Romania, Slovakia, South Africa, Sweden, United States), from a pharmacist without a prescription, and available with a prescription in some other countries.[12][13][14]
The antiprogestin ulipristal acetate is available as a micronized emergency contraceptive tablet, effective up to 120 hours after intercourse.[10][11] Ulipristal acetate ECPs developed by HRA Pharma are available over the counter in Europe[15] and by prescription in over 50 countries under the brand names ellaOne, ella (marketed by Watson Pharmaceuticals in the United States), Duprisal 30, Ulipristal 30, and UPRIS.[12][13][14][16]
The antiprogestin mifepristone (also known as RU-486) is available in five countries as a low-dose or mid-dose emergency contraceptive tablet, effective up to 120 hours after intercourse.[10][11] Low-dose mifepristone ECPs are available by prescription in Armenia, Russia, Ukraine, and Vietnam and from a pharmacist without a prescription in China.[12][13] Mid-dose mifepristone ECPs are available by prescription in China and Vietnam.[12][13]
Combined estrogen (ethinylestradiol) and progestin (levonorgestrel or norgestrel) pills used to be available as dedicated emergency contraceptive pills under several brand names: Schering PC4, Tetragynon, Neoprimavlar, and Preven (in the United States) but were withdrawn after more effective dedicated progestin-only (levonorgestrel) emergency contraceptive pills with fewer side effects became available.[10] If other more effective dedicated emergency contraceptive pills (levonorgestrel, ulipristal acetate, or mifepristone) are not available, specific combinations of regular combined oral contraceptive pills can be taken in split doses 12 hours apart (the Yuzpe regimen), effective up to 72 hours after intercourse.[10]
The U.S. Food and Drug Administration (FDA) approved this off-label use of certain brands of regular combined oral contraceptive pills in 1997.[9] As of 2014, there are 26 brands of regular combined oral contraceptive pills containing levonorgestrel or norgestrel available in the United States that can be used in the emergency contraceptive Yuzpe regimen,[10] when none of the more effective and better-tolerated options are available.
Effectiveness
Ulipristal acetate, and mid-dose mifepristone are both more effective than levonorgestrel, which is more effective than the Yuzpe method.[17]
The effectiveness of emergency contraception is expressed as a percentage reduction in pregnancy rate for a single use of EC. Using an example of "75% effective", the effectiveness calculation thus:
... these numbers do not translate into a pregnancy rate of 25 percent. Rather, they mean that if 1,000 women have unprotected intercourse in the middle two weeks of their menstrual cycles, approximately 80 will become pregnant. Use of emergency contraceptive pills would reduce this number by 75 percent, to 20 women.[18]
The progestin-only regimen (using levonorgestrel) has an 89% effectiveness. As of 2006[update], the labeling on the U.S. brand Plan B explained this effectiveness rate by stating, "Seven out of every eight women who would have gotten pregnant will not become pregnant."[19]
In 1999, a meta-analysis of eight studies of the combined (Yuzpe) regimen concluded that the best point estimate of effectiveness was 74%.[20] A 2003 analysis of two of the largest combined (Yuzpe) regimen studies, using a different calculation method, found effectiveness estimates of 47% and 53%.[21]
For both the progestin-only and Yuzpe regimens, the effectiveness of emergency contraception is highest when taken within 12 hours of intercourse and declines over time.[22][23][24]
The World Health Organization (WHO) suggested that reasonable effectiveness may continue for up to 120 hours (5 days) after intercourse.[25]
For 10 mg of mifepristone taken up to 120 hours (5 days) after intercourse, the combined estimate from three trials was an effectiveness of 83%.[26] A review found that a moderate dose of mifepristone is better than LNG or Yuzpe, with delayed return of menstruation being the main adverse effect of most regimes.[17]
HRA Pharma changed its packaging information for Norlevo (levonorgestrel 1.5 mg, which is identical to many other EHCs) in November 2013 warning that according to studies the drug loses effectiveness in women who weigh more than 75 kg (165 lb) and is completely ineffective for women who weigh over 80 kg (176 lb).[27][28] After a review by European Medicines Agency, the statement was deleted from the leaflet. The agency communicated that levonorgestrel is safe and effective method of emergency contraception, regardless of body weight.[29]
The most common side effect reported by users of emergency contraceptive pills was nausea 14 to 23% of levonorgestrel-only users and 50.5% of Yuzpe regimen users; vomiting is much less common and unusual with levonorgestrel-only ECPs (5.6% of levonorgestrel-only users vs 18.8% of 979 Yuzpe regimen users in 1998 WHO trial; 1.4% of 2,720 levonorgestrel-only users in the 2002 WHO trial).[22][25][30]Anti-emetics are not routinely recommended with levonorgestrel-only ECPs.[30][31] If a woman vomits within 2 hours of taking a levonorgestrel-only ECP, she should take a further dose as soon as possible.[30][32]
Other common side effects (each reported by less than 20% of levonorgestrel-only users in both the 1998 and 2002 WHO trials) were abdominal pain, fatigue, headache, dizziness, and breast tenderness.[22][25][30][33] Side effects generally resolve within 24 hours,[10] although temporary disruption of the menstrual cycle is commonly experienced. If taken before ovulation, the high doses of progestogen in levonorgestrel treatments may induce progestogen withdrawal bleeding a few days after the pills are taken.
One study found that about half of women who used levonorgestrel ECPs experienced bleeding within 7 days of taking the pills.[34] If levonorgestrel is taken after ovulation, it may increase the length of the luteal phase, thus delaying menstruation by a few days.[35] Mifepristone, if taken before ovulation, may delay ovulation by 3–4 days[36] (delayed ovulation may result in a delayed menstruation). These disruptions only occur in the cycle in which ECPs were taken; subsequent cycle length is not significantly affected.[34] If a woman's menstrual period is delayed by two weeks or more, it is advised that she take a pregnancy test.[37] (Earlier testing may not give accurate results.)
Existing pregnancy is not a contraindication in terms of safety, as there is no known harm to the woman, the course of her pregnancy, or the fetus if progestin-only or combined emergency contraception pills are accidentally used, but EC is not indicated for a woman with a known or suspected pregnancy because it is not effective in women who are already pregnant.[10][38][39][37][40][41][42][43][44]
The World Health Organization (WHO) lists no medical condition for which the risks of emergency contraceptive pills outweigh the benefits.[41] The American Academy of Pediatrics (AAP) and experts on emergency contraception have concluded that progestin-only ECPs are preferable to combined ECPs containing estrogen for all women, and particularly those with a history of blood clots, stroke, or migraine.[10][38][39]
ECPs, like all other contraceptives, reduce the absolute risk of ectopic pregnancy by preventing pregnancies and there is no increase in the relative risk of ectopic pregnancy in women who become pregnant after using progestin-only ECPs.[10][45][46]
An effective emergency contraception measure is the copper-T intrauterine device (IUD) which is generally recommended up to 5 days after unprotected intercourse or up to 5 days after probable ovulation.[2][7] Some studies have found it to be effective up to 10 days after unprotected intercourse to prevent pregnancy.[2] A 2021 study found that the hormonal IUD was as effective at emergency contraception as the copper IUD, though it is not offered by clinicians at the moment due to the lack of research done into the subject.[48][49]
Insertion of an IUD is more effective than the use of emergency contraceptive pills – pregnancy rates when used as emergency contraception are the same as with normal IUD use. Unlike emergency contraceptive pills, which work by delaying ovulation, the copper-T IUD works by interfering with sperm motility. Therefore, the copper IUD is equally effective as emergency contraception at all weight ranges.[50] IUDs may be left in place following the subsequent menstruation to provide ongoing contraception for as long as desired (12+ years).[51][52][50]
As regular contraception
One brand of levonorgestrel pills was marketed as an ongoing method of postcoital contraception.[53] However, with typical use, failure rates are expected to be higher than with the use of other birth control methods.[6]
Like all hormonal methods, postcoital high-dose progestin-only oral contraceptive pills do not protect against sexually transmitted infections.[54]
ECPs are generally recommended for backup or "emergency" use – for example, if a woman has forgotten to take a birth control pill or when a condom is torn during sex.[55] However, for women facing reproductive coercion, who are not able to use regular birth control, repeated use of EC pills may be the most viable option available.[6]
High-risk sex and abortion
Making ECPs more widely available does not increase sexual risk-taking.[6] While they are effective for individuals who use them in a timely fashion, the availability of EC pills does not appear to decrease abortion rates at the population level.[1]
In 2012 the American Academy of Pediatrics (AAP) stated: "Despite multiple studies showing no increased risk behaviour and evidence that hormonal emergency contraception will not disrupt an established pregnancy, public and medical discourse reflects that personal values of physicians and pharmacists continue to affect emergency-contraception access, particularly for adolescents."[56]
EC and sexual assault
Beginning in the 1960s, women who had been sexually assaulted were offered diethylstilbestrol (DES).[57][58] Currently, the standard of care is to offer ulipristal or prompt placement of a copper IUD which is the most effective form of EC. However, adherence to these best practices varies by the emergency department.[59] Before these EC options were available (in 1996), pregnancy rates among females of child-bearing age who had been raped were around 5%.[60] Although EC is recommended following sexual assault, room for improvement in clinical practice remains.[61]
Mechanism of action
The primary mechanism of action of progestogen-only emergency contraceptive pills is to prevent fertilization by inhibition of ovulation.[4][30][45][62][63][64] The best available evidence is that they do not have any post-fertilization effects such as the prevention of implantation.[4][30][45][62][63][64] The U.S. FDA-approved labels and European EMA-approved labels (except for HRA Pharma's NorLevo) levonorgestrel emergency contraceptive pills (based on labels for regular oral contraceptive pills) say they may cause endometrial changes that discourage implantation.[65][66][67] Daily use of regular oral contraceptive pills can alter the endometrium (although this has not been proven to interfere with implantation), but the isolated use of a levonorgestrel emergency contraceptive pill does not have time to alter the endometrium.[65]
In March 2011, the International Federation of Gynecology and Obstetrics (FIGO) issued a statement that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling."[65][68] In June 2012, a New York Times editorial called on the FDA to remove from the label the unsupported suggestion that levonorgestrel emergency contraceptive pills inhibit implantation.[69] In November 2013, the European Medicines Agency (EMA) approved a change to the label for HRA Pharma's NorLevo saying it cannot prevent implantation of a fertilized egg.[70]
Progestogen-only emergency contraceptive does not appear to affect the function of the fallopian tubes or increase the rate of ectopic pregnancies.[44]
The primary mechanism of action of progesterone receptor modulator emergency contraceptive pills like low-dose and mid-dose mifepristone and ulipristal acetate is to prevent fertilization by inhibition or delay of ovulation.[4][30][62][63][64] One clinical study found that post-ovulatory administration of ulipristal acetate altered the endometrium, but whether the changes would inhibit implantation is unknown.[4][71] The European EMA-approved labels for ulipristal acetate emergency contraceptive pills do not mention an effect on implantation, but the U.S. FDA-approved label says: "alterations to the endometrium that may affect implantation may also contribute to efficacy."[65][72][73]
The primary mechanism of action of copper-releasing intrauterine devices (IUDs) as emergency contraceptives is to prevent fertilization because of copper toxicity to sperm and ova.[4][30] The very high effectiveness of copper-releasing IUDs as emergency contraceptives implies that they must also prevent some pregnancies by post-fertilization effects such as prevention of implantation.[4][30][62]
History
In 1966, gynecologist John McLean Morris and biologist Gertrude Van Wagenen at the Yale School of Medicine, reported the successful use of oral high-dose estrogen pills as post-coital contraceptives in women and rhesus macaque monkeys, respectively.[74][75] A few different drugs were studied, with a focus on high-dose estrogens, and it was originally hoped that postcoital contraception would prove viable as an ongoing contraceptive method.[76]
The first widely used methods were five-day treatments with high-dose estrogens, using diethylstilbestrol (DES) in the US and ethinylestradiol in the Netherlands by Haspels.[77][78]
In the early 1970s, the Yuzpe regimen was developed by A. Albert Yuzpe in 1974;[79] progestin-only postcoital contraception was investigated (1975);[80] and the copper IUD was first studied for use as emergency contraception (1975).[81]Danazol was tested in the early 1980s in the hopes that it would have fewer side effects than Yuzpe, but was found to be ineffective.[82]
The Yuzpe regimen became the standard course of treatment for postcoital contraception in many countries in the 1980s. The first prescription-only combined estrogen-progestin dedicated product, Schering PC4 (ethinylestradiol and norgestrel), was approved in the UK in January 1984 and first marketed in October 1984.[83] Schering introduced a second prescription-only combined product, Tetragynon (ethinylestradiol and levonorgestrel) in Germany in 1985.[84] By 1997, Schering AG dedicated prescription-only combined products had been approved in only 9 countries: the UK (Schering PC4), New Zealand (Schering PC4), South Africa (E-Gen-C), Germany (Tetragynon), Switzerland (Tetragynon), Denmark (Tetragynon), Norway (Tetragynon), Sweden (Tetragynon) and Finland (Neoprimavlar); and had been withdrawn from marketing in New Zealand in 1997 to prevent it being sold over-the-counter.[85][86] Regular combined oral contraceptive pills (which were less expensive and more widely available) were more commonly used for the Yuzpe regimen even in countries where dedicated products were available.[87]
Over time, interest in progestin-only treatments increased. The Special Program on Human Reproduction (HRP), an international organization whose members include the World Bank and World Health Organization, "played a pioneering role in emergency contraception" by "confirming the effectiveness of levonorgestrel."[88] After the WHO conducted a large trial comparing Yuzpe and levonorgestrel in 1998,[22][89] combined estrogen-progestin products were gradually withdrawn from some markets (Preven in the United States discontinued May 2004, Schering PC4 in the UK discontinued October 2001, and Tetragynon in France) in favor of progestin-only EC, although prescription-only dedicated Yuzpe regimen products are still available in some countries.
In 2002, China became the first country in which mifepristone was registered for use as EC.
In 2020, Japan announced it would consider easing regulations on the sale of emergency contraceptive pills without a prescription.[90] Non-profit groups submitted a petition to the health ministry calling for prescription-free access to the pill. They had collected more than 100,000 signatures.[91]
Calculating effectiveness
Early studies of emergency contraceptives did not attempt to calculate a failure rate; they simply reported the number of women who became pregnant after using an emergency contraceptive. Since 1980, clinical trials of emergency contraception have first calculated probable pregnancies in the study group if no treatment were given. The effectiveness is calculated by dividing observed pregnancies by the estimated number of pregnancies without treatment.[92]
Placebo-controlled trials that could give a precise measure of the pregnancy rate without treatment would be unethical, so the effectiveness percentage is based on estimated pregnancy rates. These are currently estimated using variants of the calendar method.[93]
Women with irregular cycles for any reason (including recent hormone use such as oral contraceptives and breastfeeding) must be excluded from such calculations. Even for women included in the calculation, the limitations of calendar methods of fertility determination have long been recognized. In their February 2014 emergency review article, Trussell and Raymond note:
Calculation of effectiveness, and particularly the denominator of the fraction, involves many assumptions that are difficult to validate. The risk of pregnancy for women requesting ECPs appears to be lower than assumed in the estimates of ECP efficacy, which are consequently likely to be overestimates. Yet, precise estimates of efficacy may not be highly relevant to many women who have had unprotected intercourse, since ECPs are often the only available treatment.[10]
In 1999, hormonal assay was suggested as a more accurate method of estimating fertility for EC studies.[94]
United States
DES
In 1971, a New England Journal of Medicine editorial calling attention to previously published studies on the use of DES as a postcoital contraceptive at Yale University, and a large study published in JAMA on the use of DES as a postcoital contraceptive at the University of Michigan, led to off-label use of DES as a postcoital contraceptive becoming prevalent at many university health services.[76][95]
In May 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive to emergency situations such as rape, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES.[96] (In February 1975, the FDA Commissioner testified that the only error in the May 1973 FDA Drug Bulletin was that the FDA had not approved postcoital contraceptive use of DES).[97]
In September 1973, the FDA published a proposed rule specifying patient labeling and special packaging requirements for any manufacturer seeking FDA approval to market DES as a postcoital contraceptive, inviting manufacturers to submit abbreviated new drug applications (ANDAs) for that indication, and notifying manufacturers that the FDA intended to order the withdrawal of DES 25 mg tablets (which were being used off-label as postcoital contraceptives).[98][99][100]
In late 1973, Eli Lilly, the largest U.S. manufacturer of DES, discontinued its DES 25 mg tablets and in March 1974 sent a letter to all U.S. physicians and pharmacists telling them it did not recommend use of DES as a postcoital contraceptive.[97]
Only one pharmaceutical company, Tablicaps, Inc., a small manufacturer of generic drugs, ever submitted (in January 1974) an ANDA for use of DES as an emergency postcoital contraceptive, and the FDA never approved it.[97][101]
In February 1975, the FDA said it had not yet approved DES as a postcoital contraceptive, but would after March 8, 1975, permit marketing of DES for that indication in emergency situations such as rape or incest if a manufacturer obtained an approved ANDA that provided patient labeling and special packaging as set out in a FDA final rule published in February 1975.[102] To discourage off-label use of DES as a postcoital contraceptive, in February 1975 the FDA ordered DES 25 mg (and higher) tablets removed from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications be changed to state: "THIS DRUG PRODUCT SHOULD not BE USED AS A POSTCOITAL CONTRACEPTIVE" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.[99][103]
In March 1978, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists which said: "FDA has not yet given approval for any manufacturer to market DES as a postcoital contraceptive. The Agency, however, will approve this indication for emergency situations such as rape or incest if a manufacturer provides patient labeling and special packaging. To discourage 'morning after' use of DES without patient labeling, FDA has removed from the market the 25 mg tablets of DES, formerly used for this purpose."[104]
In the 1980s, off-label use of the Yuzpe regimen superseded off-label use of DES for postcoital contraception.[101][105][106]
DES is no longer commercially available in the U.S.; Eli Lilly, the last U.S. manufacturer, ceased production in spring 1997.[107]
Preven
On February 25, 1997, the FDA posted a notice in the Federal Register saying it had concluded that the Yuzpe regimen was safe and effective for off-label use as postcoital EC, was prepared to accept NDAs for COCPs labeled as ECPs, and listed 6 then available COCPs (there are now 22) that could be used as ECPs.[9]
On September 1, 1998, the FDA approved the prescription Yuzpe regimen Preven Emergency Contraception Kit (which contained a urine pregnancy test and 4 COCPs).[108] Preven was discontinued in May 2004.[109]
Plan B
On July 28, 1999, the FDA approved the prescription progestin-only Plan B (two 750 µg levonorgestrel pills) emergency contraceptive.[110]
On August 24, 2006, the FDA approved nonprescription behind-the-counter access to Plan B from pharmacies staffed by a licensed pharmacist for women 18 or older; a prescription-only form of Plan B was made available for younger females aged 17 and younger.[111]
On November 6, 2006, Barr Pharmaceuticals announced that its subsidiary, Duramed Pharmaceuticals, had initiated shipment of dual-label Plan B OTC/Rx and it would be available in pharmacies across the U.S. by mid-November 2006.[112]
On March 23, 2009, a US judge ordered the FDA to allow 17-year-olds to acquire Plan B without a prescription.[113] This now changes the August 24, 2006, ruling and Plan B is now available "behind the counter" for men and women. There is a prescription method available for girls under 17.
On April 30, 2013, the FDA approved (with three-year marketing exclusivity) Teva Pharmaceutical Industries' Plan B One-Step for sale without a prescription to anyone age 15 or over who can show proof of age such as a driver's license, birth certificate, or passport to a drug store retail clerk.[114]Generic one-pill levonorgestrel emergency contraceptives and all two-pill levonorgestrel emergency contraceptives will remain restricted to sale from a pharmacist—without a prescription to anyone age 17 or over who can show proof of age.[114]
On June 10, 2013, the Obama administration ceased trying to block over-the-counter availability of the pill. With this reversal it means that any person will be able to purchase the Plan B One-Step without a prescription.[115]
After Roe v. Wade and Doe v. Bolton resulted in the U.S. Supreme Court's 1973 ruling to legalize abortion, both Federal and State laws were created to allow medical professionals and institutions the right to deny reproductive health services without financial, professional, or legal penalty. Roe v. Wade caused a historical survey to be conducted and concluded that right to privacy cases such as Griswold v. Connecticut allowed women to have parental control over childrearing, including the use of contraception for reproductive autonomy. After this, women became more informed about contraceptives and began requesting them more often.
Almost all 50 states have implemented policies on sterilization, contraceptives, and abortion services.[117] Since the late 1990s, due to rights given by specific policies, the dispensation of emergency contraceptives on issues of religious and moral objections of providing care has extended from doctors, nurses, and hospitals to pharmacies and individual pharmacists. Furthermore, many states have insurance policies that cover contraceptives alongside all other prescription drugs, but may have exemptions for employers or private insurers on religious grounds.[117] Different state legislatures have taken different routes in broadening access to emergency contraceptives.[118] In some states, if a woman has been sexually assaulted, it is mandatory to provide her access to EC. In other states, women have been allowed various amounts of access, including the ability to access EC without a prescription from a physician, creation of policies limiting the ability of pharmacists to deny EC on religious and moral grounds, and creation of policies discouraging pharmacists from denying to fill contraceptive prescriptions.[118] One state even requires all pharmacies to stock and fill every method of contraception.[118] However, other states have restricted access of emergency contraception from state Medicaid family planning eligibility expansions or contraceptive coverage mandates, or by allowing the refusal of providing contraceptive services by healthcare professionals.[118]
Under federal law, a provision of the Affordable Care Act of 2010 has guaranteed coverage of contraceptives, applying to most private health plans nationwide. The provision has also specifically required coverage for 18 methods of contraception used by women, related counselling and services, and requires the coverage provided not to be an out-of-pocket cost to the people.[119] In October 2017, however, the Trump administration made it easier for employers that offer health care plans to exclude contraceptive coverage.[119] The two regulations that allow employers to reject contraceptive coverage are religious and moral objection, but the courts have blocked the enforcement of these regulations.[119] As of today, 29 states require that if insurance covers prescription drugs, it has to provide FDA-approved prescription contraceptive drugs and devices. 10 states prohibit the restriction and delay by insurers or medical management techniques to access contraceptives, and 8 states do not permit refusal on religious or moral grounds by any employers or insurerers. However, 21 states do allow the refusal to comply with the contraceptive coverage mandates, and 14 states prohibit cost sharing for contraceptives.[119]
Emergency contraceptives are the most common prescription drug denied due to of religious or moral beliefs. There have been cases where hormones, drugs and devices used to treat human immunodeficiency virus and diabetic medication have also been denied. This topic continues to be fought upon on different levels; for example, Stormans, Inc v Wiesman challenged Washington state regulations on providing all lawfully prescribed pharmaceuticals, including EC.[120] They were challenging Washington state regulations on providing all lawfully prescribed pharmaceuticals.[120] Courts have been warned that if pharmacists are allowed to deny EC prescriptions on religious or moral beliefs, it can affect public health and set a dangerous precedent with respect to "critical, life-saving preventative care".[121] The court denied the claim, stating that all pharmacies, even if the owner has a religious objection, must provide all prescribed medication, including EC. The pharmacy in question tried to appeal the case to the Supreme Court, but the appeal was rejected, leaving the lower court's ruling in place.[120] Wal-Mart, the third largest U.S. pharmacy chain, refused to carry EC from 1997 to 2006, which shows that accessibility may still be an issue in areas dependent on single pharmacies with no alternatives.[122]
^ abcdefghTrussell J, Schwarz EB (2011). "Emergency contraception". In Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 113–145. ISBN978-1-59708-004-0. ISSN0091-9721. OCLC781956734. p. 121:
Mechanism of action Copper-releasing IUCs When used as a regular or emergency method of contraception, copper-releasing IUCs act primarily to prevent fertilization. Emergency insertion of a copper IUC is significantly more effective than the use of ECPs, reducing the risk of pregnancy following unprotected intercourse by more than 99%.2,3 This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization. Emergency contraceptive pills To make an informed choice, women must know that ECPs—like the birth control pill, patch, ring, shot, and implant,76 and even like breastfeeding77—prevent pregnancy primarily by delaying or inhibiting ovulation and inhibiting fertilization, but may at times inhibit implantation of a fertilized egg in the endometrium. However, women should also be informed that the best available evidence indicates that ECPs prevent pregnancy by mechanisms that do not involve interference with post-fertilization events. ECPs do not cause abortion78 or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health79 and the American College of Obstetricians and Gynecologists (ACOG).80 Ulipristal acetate (UPA). One study has demonstrated that UP can delay ovulation.81... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown.82 p. 122: Progestin-only emergency contraceptive pills. Early treatment with ECPs containing only the progestin levonorgestrel has been shown to impair the ovulatory process and luteal function.83–87 p. 123: Combined emergency contraceptive pills. Several clinical studies have shown that combined ECPs containing ethinylestradiol and levonorgestrel can inhibit or delay ovulation.107–110
^ abcde"7. Genito-urinary System". BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. pp. 838–839. ISBN978-0-85711-369-6.
^ abcdeTrussell, James; Cleland, Kelly (February 13, 2013). "Dedicated emergency contraceptive pills worldwide"(PDF). Princeton: Office of Population Research at Princeton University, Association of Reproductive Health Professionals. Archived from the original(PDF) on March 4, 2016. Retrieved March 25, 2014.
^Trussell J, Rodríguez G, Ellertson C (March 1999). "Updated estimates of the effectiveness of the Yuzpe regimen of emergency contraception". Contraception. 59 (3): 147–151. doi:10.1016/S0010-7824(99)00018-9. PMID10382076.
^Trussell J, Ellertson C, von Hertzen H, Bigrigg A, Webb A, Evans M, et al. (April 2003). "Estimating the effectiveness of emergency contraceptive pills". Contraception. 67 (4): 259–265. doi:10.1016/S0010-7824(02)00535-8. PMID12684144.
^ abcdWHO Task Force on Postovulatory Methods of Fertility Regulation (August 1998). "Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation". Lancet. 352 (9126): 428–433. doi:10.1016/S0140-6736(98)05145-9. PMID9708750. S2CID54419012.
^"Counsel women to take ECPs as soon as possible". Contraceptive Technology Update. 20 (7): 75–77. July 1999. PMID12295381.
^"Emergency contraceptives". European Medicines Agency. 17 September 2018. Archived from the original on 4 October 2018. Retrieved 16 May 2022.
^ abcdefghijRCOG Faculty of Sexual; Reproductive Healthcare; Clinical Effectiveness Unit (January 2012). "Clinical guidance: emergency contraception"(PDF). Clinical Guidance. London: Royal College of Obstetricians and Gynaecologists. ISSN1755-103X. Retrieved 2012-04-30. p.3:
How does EC work? In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation.8 The possible mechanisms of action should be explained to the patient as some methods may not be acceptable, depending on individual beliefs about the onset of pregnancy and abortion. Copper-bearing intrauterine device (Cu-IUD). Copper is toxic to the ovum and sperm and thus the copper-bearing intrauterine device (Cu-IUD) is effective immediately after insertion and works primarily by inhibiting fertilisation.9–11 A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy.11 If fertilisation has already occurred, it is accepted that there is an anti-implantation effect,12,13 Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation.16,17 Ulipristal acetate (UPA). UPA's primary mechanism of action is thought to be inhibition or delay of ovulation.2
^ abRaymond EG, Goldberg A, Trussell J, Hays M, Roach E, Taylor D (April 2006). "Bleeding patterns after use of levonorgestrel emergency contraceptive pills". Contraception. 73 (4): 376–381. doi:10.1016/j.contraception.2005.10.006. PMID16531171.
^ abFDA Center for Drug Evaluation and Research (August 22, 2006). "Plan B Rx to OTC switch Medical Reviews"(PDF). Beltsville, Md.: Food and Drug Administration. pp. 32–7, 133–77. Retrieved 2006-12-13.
Can LNG ECPs cause an abortion? LNG ECPs do not interrupt an established pregnancy or harm a developing embryo.15 The evidence available to date shows that LNG ECP use does not prevent a fertilized egg from attaching to the uterine lining. The primary mechanism of action is to stop or disrupt ovulation; LNG ECP use may also prevent the sperm and egg from meeting.16
^Dean G, Schwarz EB (2019). Contraceptive technology—Chapter 5—Intrauterine Devices (IUDs) (21st ed.). New York, NY. p. 159. ISBN978-1732055605. OCLC1048947218.((cite book)): CS1 maint: location missing publisher (link)
^Gottardi G, Spreafico A, de Orchi L (December 1986). "The postcoital IUD as an effective continuing contraceptive method". Contraception. 34 (6): 549–558. doi:10.1016/S0010-7824(86)80011-7. PMID3549140.
^Holmes MM, Resnick HS, Kilpatrick DG, Best CL (August 1996). "Rape-related pregnancy: estimates and descriptive characteristics from a national sample of women". American Journal of Obstetrics and Gynecology. 175 (2): 320–4. doi:10.1016/S0002-9378(96)70141-2. PMID8765248.
^Stewart FH, Trussell J (November 2000). "Prevention of pregnancy resulting from rape: a neglected preventive health measure". American Journal of Preventive Medicine. 19 (4): 228–229. doi:10.1016/S0749-3797(00)00243-9. PMID11064225.
^ abcdSperoff L, Darney P (2011). "Special uses of oral contraception: emergency contraception, the progestin-only minipill". A clinical guide for contraception (5th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 153–166. ISBN978-1-60831-610-6. p. 155:
Emergency postcoital contraception Levonorgestrel Mechanism and efficacy There is strong evidence that treatment with emergency contraception acts primarily by preventing or delaying ovulation and by preventing fertilization.22–26 Studies have indicated that emergency contraception does not prevent implantation.27–29 Experiments in monkeys and rats could detect no effect of a high dose of levonorgesterel administered postcoitally once fertilization had occurred.30,31 The evidence indicates that a postfertilization effect does not contribute to the efficacy of emergency contraception.25,30–33 Clinicians, pharmacists, and patients can be reassured that treatment with emergency contraception is not an abortifacient. p. 157: The use of progesterone receptor modulators for emergency contraception Mifepristone. In randomized trials, 10 mg mifepristone was as effective as 25, 50, or 600 mg. preventing about 80–85% of expected pregnancies (the same efficacy and side effects as with the levonorgestrel method), with a slight decrease in efficacy when treatment was delayed to 5 days after intercourse.16,52–54 Ulipristal Acetate. Ulipristal acetate (ellaOne) has similar biologic effects as mifepristone and is approved for emergency contraception in Europe and is expected to become available in the U.S.in a single oral dose of 30 mg. Randomized trials demonstrated that ulipristal acetate is slightly more effective than the single 1.5 mg dose of levonorgestrel when used within 72 hours after sexual intercourse and even between 72 h and 120h.55,56 ... Progesterone receptor modulators like ulipristal acetate and mifepristone suppress ovarian follicular growth and also delay endometrial maturation, manifested in a delay in menstruation after treatment. Ovulation can be temporarily postponed. Other methods Another method of emergency contraception is the insertion of a copper IUD, anytime during the preovulatory phase of the menstrual cycle and up to 5 days after ovulation. The failure rate (in a small number of studies) is very low, 0.1%.34,35 This method definitely prevents implantation, but it is not suitable for women who are not candidates for intrauterine contraception, e.g., multiple sexual partners or a rape victim. The use of a copper IUD for emergency contraception is expensive, but not if it is retained as an ongoing method of contraception.
^ abcJensen JT, Mishell Jr DR (2012). "Family planning: contraception, sterilization, and pregnancy termination". In Lentz GM, Lobo RA, Gershenson DM, Katz VL (eds.). Comprehensive gynecology (6th ed.). Philadelphia: Mosby Elsevier. pp. 215–272. ISBN978-0-323-06986-1. p. 257:
Emergency contraception It is believed that the main mechanism of action of high-dose progestin emergency contraception is inhibition of ovulation, but other mechanisms may be involved... Taken together, these data are highly supportive of the concept that levonorgestrel emergency contraception has little or no effect on postovulation events but is highly effective when taken before ovulation. Levonorgestrel emergency contraception does not affect implantation and is not abortifacient. Intrauterine insertion of a copper IUD within 5 to 10 days of midcycle coitus is a very effective method of preventing continuation of the pregnancy... The LNG-IUS should not be used for emergency contraception. A study by the WHO reported that use of a single tablet of 10 mg of mifepristone was an effective emergency contraceptive with a pregnancy rate of 1.2%. Ulipristal, also known as CDB-2914, has been studied as an emergency contraceptive pill... In 2009, European regulatory approval was granted for a 30-mg tablet of ulipristal (under the brand name of EllaOne) as an emergency contraceptive pill for use up to 5 days after unprotected intercourse. An application for approval in the United States is under review.
^Bayer (March 22, 2010). "Summary of Product Characteristics: Levonelle One Step 1500 mcg; 5.1 Pharmacodynamic properties". London: electronic Medicines Compendium (eMC), Datapharm. The precise mode of action of Levonelle One Step is not known. At the recommended regimen, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase when the likelihood of fertilisation is the highest. It may also cause endometrial changes that discourage implantation. Levonelle One Step is not effective once the process of implantation has begun. HRA Pharma (July 19, 2011). "Summary of Product Characteristics: NorLevo 1.5 mg; 5.1 Pharmacodynamic properties". Dublin: Irish Pharmaceutical Healthcare Association. Archived from the original on June 15, 2012. Retrieved August 21, 2012. The precise mode of action of Norlevo 1.5 mg is not known. At the used regimen, levonorgestrel is believed to suppress ovulation thus preventing fertilization if the intercourse has taken place in the preovulatory phase when the likelihood of fertilization is the highest. It could also prevent implantation. It is not effective once the process of implantation has begun.
^Duramed Pharmaceuticals/Barr Pharmaceuticals (now Teva Women's Health) (July 9, 2010). "Prescribing information: Plan B One-Step; 12.1 Mechanism of action"(PDF). Silver Spring, Md.: FDA Center for Drug Evaluation and Research (CDER). p. 4. Emergency contraceptive pills are not effective if a woman is already pregnant. Plan B One-Step is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.
Levonorgestrel-only emergency contraceptive pills: • Interfere with the process of ovulation; • May possibly prevent the sperm and the egg from meeting. Implications of the research: • Inhibition or delay of ovulation is LNG ECPs principal and possibly the only mechanism of action. • Review of the evidence suggests that LNG ECPs cannot prevent the implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling. • The fact that LNG ECPs have no demonstrated effect on implantation explains why they are not 100% effective in preventing pregnancy and are less effective the later they are taken. Women should be given a clear message that LNG ECPs are more effective the sooner they are taken. • LNG ECPs do not interrupt a pregnancy (by any definition of the beginning of pregnancy). However, LNG ECPs can prevent abortions by reducing unwanted pregnancies.
^editorial (June 9, 2012). "How morning-after pills really work". The New York Times. p. A20. The F.D.A. now acknowledges that the emerging data suggest the morning-after pill, often called Plan B, does not inhibit implantation. It should remove that unsupported suggestion from the label.
^Stratton P, Levens ED, Hartog B, Piquion J, Wei Q, Merino M, Nieman LK (April 2010). "Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914". Fertility and Sterility. 93 (6): 2035–2041. doi:10.1016/j.fertnstert.2008.12.057. PMC2911236. PMID19200989. Post-ovulatory early luteal phase administration of 10–100 mg of ulipristal acetate resulted in a statistically significant dose-dependent 0.6 ± 2.2 mm decrease in endometrial thickness from a baseline of 10.3 ± 2.3 mm to 9.7 ± 1.8 mm (vs. a 1.3 ± 2.3 mm increase in endometrial thickness from a baseline of 10.2 ± 3.2 mm to 11.5 ± 4.1 mm with placebo administration) which the authors hypothesized could hamper implantation.
^HRA Pharma (March 15, 2012). "Summary of Product Characteristics: ellaOne 30 mg; 5.1 Pharmacodynamic properties"(PDF). London: European Medicines Agency. p. 7. Archived from the original(PDF) on May 3, 2012. Retrieved August 21, 2012. Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator which acts via high-affinity binding to the human progesterone receptor. The primary mechanism of action is inhibition or delay of ovulation. Pharmacodynamic data show that even when taken immediately before ovulation is scheduled to occur, ulipristal acetate is able to postpone follicular rupture in some women.
^Watson Pharma (under license from HRA Pharma) (May 2, 2012). "Prescribing information: Ella; 12.1 Mechanism of action"(PDF). Silver Spring, Md.: FDA Center for Drug Evaluation and Research (CDER). pp. 4–5. When taken immediately before ovulation is to occur, ella postpones follicular rupture. The likely primary mechanism of action of ulipristal acetate for emergency contraception is therefore inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy... The pharmacodynamics of ulipristal acetate depends on the timing of administration in the menstrual cycle. Administration in the mid-follicular phase causes inhibition of folliculogenesis and reduction of estradiol concentration. Administration at the time of the luteinizing hormone peak delays follicular rupture by 5 to 9 days. Dosing in the early luteal phase does not significantly delay endometrial maturation but decreases endometrial thickness by 0.6 ± 2.2 mm (mean ± SD).
^Yuzpe AA, Thurlow HJ, Ramzy I, Leyshon JI (August 1974). "Post coital contraception--A pilot study". The Journal of Reproductive Medicine. 13 (2): 53–58. PMID4844513.
^Valle G (1975). "[The problem of postcoital contraception using oral progestins]". Aggiornamenti in Ostetricia e Ginecologia. 8 (3): 127–128. PMID12334868.
^"Copper IUD, inserted after coitus averts pregnancy and provides continuing contraceptive protection". International Family Planning Digest. 1 (3): 11–12. September 1975. doi:10.2307/2948217. JSTOR2948217. PMID12307393.
^FDA (February 25, 1997). "Certain combined oral contraceptives for use as postcoital emergency contraception". Fed Regist. 62 (37): 8610. "Since the United Kingdom approved emergency contraceptive pills in 1984, more than 4 million prescriptions have been recorded. However, the actual use is much greater because providers have found it less expensive to provide tablets of identical drugs taken from products packaged as combined oral contraceptives."
^Dixon GW, Schlesselman JJ, Ory HW, Blye RP (September 1980). "Ethinyl estradiol and conjugated estrogens as postcoital contraceptives". JAMA. 244 (12): 1336–1339. doi:10.1001/jama.244.12.1336. PMID6251288.
^Trussell J, Ellertson C, Stewart F (1996). "The effectiveness of the Yuzpe regimen of emergency contraception". Family Planning Perspectives. 28 (2): 58–64, 87. doi:10.2307/2136125. JSTOR2136125. PMID8777940.
^Espinós JJ, Rodríguez-Espinosa J, Senosiain R, Aura M, Vanrell C, Gispert M, et al. (October 1999). "The role of matching menstrual data with hormonal measurements in evaluating effectiveness of postcoital contraception". Contraception. 60 (4): 243–247. doi:10.1016/S0010-7824(99)00090-6. PMID10640171.
^ abcU.S. Senate (1975). Regulation of diethylstilbestrol (DES), 1975: Joint Hearing before the Subcommittee on Health and the Subcommittee on Administrative Practice and Procedure, 94th Congress, 1st Session on S. 963, February 27, 1975. Washington: U.S. Govt. Print. Off.
^FDA (September 26, 1973). "Diethylstilbestrol. Use as postcoital contraceptive; patient labeling". Fed Regist. 38 (186): 26809–11.
^ abFDA (February 26, 1975). "Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice". Fed Regist. 40 (39): 8242.
^FDA (September 26, 1973). "Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications". Fed Regist. 38 (186): 26824–6.
^FDA (February 5, 1975). "Certain estrogens for oral use or parenteral use. Drugs for human use; drug efficacy study implementation; follow-up notice". Fed Regist. 40 (25): 5384.
^FDA (March–April 1978). "DES and Breast Cancer". FDA Drug Bull. 8 (2): 10.
^Hatcher, Robert A.; Stewart, Gary K.; Stewart, Felicia; Guest, Felicia; Schwartz, David W.; Jones, Stephanie A. (1980). Contraceptive Technology 1980–1981 (10th ed.). New York: Irvington Publishers. pp. 128–33. ISBN978-0-8290-0084-9.
^Ibarreta, Dolores; Swain, Shanna H. (2001). "The DES story: long-term consequences of prenatal use"(PDF). In in Harremoës, Poul; Gee, David; Vaz, Sofia Guedes (eds.). Late lessons from early warnings: the precautionary principle 1896–2000. Copenhagen: European Environmental Agency. pp. 84–92. ISBN978-92-9167-323-0. Archived from the original(PDF) on 2006-11-21. Retrieved 2006-12-07.
^Brief of American Academy of Pediatrics in Support of Respondents, Zubik v Burwell (Nos. 14–1418, 14–1453, 14–1505, 15–35, 15–105, 15–119, and 15-191) 2016.
