Contraception is defined as any method that aims to prevent pregnancy. There are as many as 15 contraceptive methods available for men and women to choose, providing autonomy for couples to have sexual intercourse at any mutually desired time with diminished risk of pregnancy. Despite this, the rate of unintended pregnancy is still high and relatively unchanged over several years. It was estimated that 45% percent of pregnancies in the United States in the year 2011 were unintended, and around 40% of those ended in abortion.[1] Among adolescents, studies quote that 75% to 82% of pregnancies were unintended.[2][3][4]

Inconsistent or improper use of contraception, the use of methods known to have a high failure rate, and failure to use any contraception are the common reasons for unintended pregnancy.[4] Sexual assault survivors are at risk of pregnancy, and studies have quoted the pregnancy rate of 5%.[5] Emergency contraception (EC) or postcoital contraception is the intervention that allows women to avoid unintended pregnancy after unprotected intercourse or inadequately protected sexual intercourse described in these scenarios.[6] 

The risk of pregnancy after unprotected intercourse is 5.6% without emergency contraceptive treatment. Women with unintended pregnancy are found to have delayed or inadequate prenatal care, continue smoking and alcohol use, and have an increased rate of premature births and fetal growth restriction. These have serious public health consequences and adverse impacts on the physical and mental health of growing adolescents and young women. Hence, there remains a social justification to reduce unintended pregnancy.[1]

Methods Available

Based on the available literature, EC has been in use since 1960 and originally consisted of a high dose of oral estrogen, which soon was phased out due to increased side effects.[7] Copper intrauterine devices (IUD) and Yuzpe methods became popular in the 1970s. The first dedicated U.S Food and Drug Administration (FDA) approval for the product for EC was in 1998.[6] Several products have been introduced since that time. Oral hormonal method and the non-hormonal copper intrauterine device (Cu-IUD) are the two available groups for emergency contraception for women to avoid unintended pregnancy. Levonorgestrel (LNG), ulipristal acetate (UPA), and Yuzpe method using combined estrogen-progestin pills are the 3 currently approved oral hormonal methods in the United States. Mifepristone, which acts by inhibiting progesterone, is available for use as an emergency contraceptive in other countries.[2] 

Mechanism of Action

Copper IUD releases copper ion that is toxic to sperm and oocytes and thereby inhibits fertilization. In addition, the inflammatory response in endometrium due to Cu-IUD is hostile for the fertilized zygote and potentially inhibits implantation. It is the most effective of all the methods and has additional ongoing contraceptive benefits for up to 10 years after insertion.[8][9] All oral emergency contraceptives work principally either by inhibiting or delaying ovulation. Sperm survives and remains fertile for up to 5 days in the female reproductive tract, and oocyte stays fertile for 24 hrs. When ovulation is delayed by 5 days, the contact between sperm and oocyte is avoided, and fertilization does not happen.  Levonorgestrel (LNG) EC inhibits ovulation by blocking the luteinizing hormone (LH) surge, which in turn prevents follicular development and rupture. Hence, it has no effect once the LH surge has begun or after ovulation. Ulipristal acetate (UPA) exerts similar effects and was found to be effective even after the onset of LH surge but before the peak. This explains the increase in the window of efficacy for UPA as EC for up to 120 hours (5 days) compared to a 72 hrs window for LNG only EC. Some post-ovulatory effects, including decreased endometrial receptivity, altered tubal function, and modulation in sperm activation, were noted in in-vitro studies for UPA with uncertain clinical relevance in the context of emergency contraception.[7][9] Mifepristone is an oral anti-progestogen and used at a lower dose of 10 mg as EC and at higher doses as an abortifacient. It prevents or delays ovulation and affects endometrial development and implantation, explaining its efficacy even when administered in the post-ovulatory period. The Yuzpe method is the least effective method with a mechanism of action similar to the LNG only method.[2] 

Indications, Contraindications, and Side Effects

Emergency contraception is used in the following situations:

• As a backup method in case of contraceptive misuse or failure (such as a break in condoms, missed pill, delay in depot shot, or expired implant).
• For prevention of pregnancy in the absence of any form of contraception usage. 
• In sexual assault, victims to avoid potential pregnancy.

Following single unprotected sexual intercourse at any point in the menstrual cycle, the risk of pregnancy is around 4 to 6 percent. This increases to 30 percent during the fertile period, which is approximately 5 days before and a day after ovulation. Adolescents and perimenopausal women have unpredictable ovulation. For these reasons, it is recommended that EC use should be encouraged and offered to women with unprotected sexual intercourse (UPSI) at any point throughout the menstrual cycle.[2]

As per American College of Obstetricians and Gynecology(ACOG) Practice Bulletin on EC, both oral hormonal ECs using UPA, combined estrogen and progestin pills and Cu IUD should be made available to women for up to 5 days after UPSI when requested. To increase the effectiveness, treatment should be initiated as soon as possible. LNG has decreasing efficacy with time and labeled for use within 72 hours. Cu-IUD and ulipristal acetate do not have a change in efficacy with time and should be considered as the first line if the patient presents late after UPSI. Some studies have used Cu-IUD up to 10 days after UPSI without any failure.[6]

No exams or pregnancy tests are required for providing emergency contraception with oral methods. Bimanual exam and pregnancy tests are needed only prior to inserting Cu IUD.[3] There is reassuring data showing the safety and efficacy of available EC methods. The side effects are mild, and essentially, no serious adverse events have been reported so far.[10] Since 2013, LNG is made available over the counter (OTC) without age restriction in the United States. In many European countries and in Australia, even UPA is available without prescription due to available safety data.[7] Copper IUD requires the patient to schedule an urgent office visit to be inserted within the window and has a risk of perforation(1: 1000), uterine cramping, and heavy menstrual flow in some women. Short term effects that are commonly reported with hormonal methods are headaches (19 percent), nausea and vomiting (12 percent), while drowsiness, spotting, pelvic cramping, and breast tenderness were reported by some patients.[6] No increase in fetal malformation, ectopic pregnancy, or miscarriage was reported with any oral EC methods. Copper IUD is contraindicated in pregnancy, women with menorrhagia, pelvic infection, and Wilson disease. For obese women with body mass index (BMI), more than 30 European guidelines suggest the use of UPA or a higher dose of LNG (3 mg).[2] UPA may not be safe in a patient with uncontrolled asthma requiring oral steroids. Both LNG and UPA may have decreased efficacy among patients on enzyme-inducing drugs (e.g., rifabutin, rifampicin, phenytoin, phenobarbitone, carbamazepine, and St John wort) and Cu-IUD should be considered in those patients.[8]

Regimens

Progestin-only Method: Levonorgestrel is available as 2 doses of 0.75 mg tablet given 12 hours apart, a single dose of 1.5 mg, and as two 0.75 mg tablets taken at once. Its efficacy decreases with time and is licensed for use up to 72 hours by the FDA. The risk of pregnancy varies from 0.6% to 3.1%, depending on when it was started. It does not require a prescription and is available over-the-counter (OTC) without age or gender restriction.[2]

Selective Progesterone Receptor Modulator: Ulipristal acetate is a synthetic hormone with a predominant antiprogestin effect that acts by delaying ovulation. A single dose of 30 mg of ulipristal acetate is effective for up to 5 days after UPSI. It requires the prescription from the physician, and its efficacy, which is measured by the risk of pregnancy is 2% and does not change with time from day one to five. Current United Kingdom guidelines recommend UPA among obese women. This is based on limited evidence showing increased pregnancy among obese women with the use of LNG as EC and altered pharmacokinetics that showed a longer time in achieving steady-state drug levels by LNG. UPA can be used more than once in the same cycle, but women should be counseled about other contraception for regular use as they are at increased risk for unintended pregnancy.[5] Evidence is limited for possible anti progestin effect of UPA with Progestin-only contraceptive use. Until clear evidence becomes available, it is recommended to avoid UPA if progestin is used within the last 1 week and for 5 days after using UPA as EC and if the patient is considering a quick start method of contraception with Progestin-only method.[3]

Yuzpe Method: Consists of combined estrogen and progestin pills given as 2 doses taken 12 hours apart. Each dose should contain the dose equivalent of a minimum of 100 micrograms of ethinylestradiol and 0.5 mg of LNG using various available combined oral contraceptive (OCP) drugs, as no dedicated combination EC pill is available. This method has lower efficacy than other methods with a pregnancy rate of 2% to 3% and is associated with higher rates of nausea, vomiting, and dizziness. This warrants the need for antiemetics to be given at least 30 minutes before each dose. Used when other methods are not available, is off label for EC, with a prescription for up to 5 days after UPSI. As with LNG, the efficacy is better when taken earlier within the first 24 hours compared to later after 72 hours.[2]

Anti-progestin: Consists of oral mifepristone used in low doses of 10 mg, 25 mg, and 50 mg as EC in few countries outside the United States. Its efficacy at EC dosage is comparable to UPA and probably effective even in the post-ovulation phase, similar to Cu-IUD. At higher doses, it acts as an abortifacient, which was the initial indication for this medication. It is important that the provider explains this distinction about doses when prescribed to patients.[2]

Copper Intrauterine Device: It is the most effective but least utilized method for emergency contraception due to a misconception among patients and providers. It prevents pregnancy in 99 percent of the cases as compared to 75 percent with combined pills, 70 percent with LNG, and 85 percent with UPA. Major stumble to use it as EC is a lack of access to providers within the window of 5 days and fear of dislodging existing pregnancy that might be missed by pregnancy tests done earlier than 2 weeks after implantation occurred. The World Health Organization (WHO) encourages its use up to 12 days, provided pregnancy test is negative at the time of insertion. Otherwise, it would be an excellent choice in adolescents and couples desiring long term contraception for up to 10 years.[9]

Effects on Pregnancy

EC is considered generally safe in pregnancy. This resulted in the change that no prescription is required for LNG in the US and for UPA in some European countries. Reassuring data is now available from a meta-analysis of 12 prospective studies on the Yuzpe regimen, including 6000 women, which concluded no increase in fetal malformations. Due to limited pregnancy after UPA and LNG use and voluntary termination of these unintended pregnancies, data are limited to analyze their effects on pregnancy. Postmarketing surveillance data on UPA from over one million women showed no increased risk of miscarriage, ectopic pregnancy, or anomalies among babies exposed to UPA.[6][7]

Effects on Breastfeeding

Women taking oral contraceptives are encouraged to continue breastfeeding due to its safety and the same applied to the LNG only method. UPA is relatively new and lipophylic, with theoretical concerns on its excretion in breast milk. The manufacturer recommends discarding breast milk for 7 days after UPA use, which is endorsed by WHO and United Kingdome (UK) guidelines. In the US, guidelines advise on breastfeeding is to discard milk for 24 hours after taking UPA.[7]

Safety on Repeated Use 

Enough data are not available on safety on repeated use. Since EC pills prevent pregnancy by delaying ovulation, pregnancy will eventually happen in case of further UPSI.  Hence the recommendation is to repeat EC in case of UPSI beyond 24 hrs after last use as LNG and UPA have a half-life range of 24 to 32 hrs. A study on LNG-EC as the only method of contraception reported the pregnancy rate of 11 per 100 women-years with tolerable side effects. Another study with weekly use of UPA at 30 mg dose for 8 weeks showed that ovulation was delayed but eventually happened in most women. Women are at risk of exposure to higher levels of total hormones than they would with regular methods and would have more adverse effects, including irregular bleeding and abdominal cramps.[6][7]

Follow-up

As per the ACOG practice bulletin on EC, no scheduled follow up is required. Women using EC should be provided with information about effective ongoing contraception and appropriate STI testing if indicated. As some delay in the expected periods is inevitable due to delay in ovulation with hormonal methods, it is important to counsel women to return for medical review and exclude pregnancy in case of delay in the cycle for more than 7 days. Consider clinical evaluation if women reports lower abdominal pain or persistent irregular bleeding as these may be due to ectopic pregnancy or a spontaneous pregnancy loss.[6]

Several factors influence the choice of EC. Most important is the timing of the presentation after UPSI. As mentioned earlier, the effectiveness of EC declines with time with Yuzpe and LNG only method, and they are recommended up to 3 days after UPSI. UPA is most effective for up to 5 days, provided ovulation has not already occurred. Cu- IUD may be the only effective method if ovulation has already occurred. Hormonal methods may have decreased efficacy in obese patients, and women on enzyme-inducing drugs and Cu-IUD should be recommended in those patients. Current UK guidelines recommend doubling the dose of LNG (3 mg) or use UPA instead among obese patients. ACOG recommends the use of Cu-IUD as the first-line in obese women and not to withheld oral EC for overweight or obese women because of a lack of adequately powered studies evaluating the threshold weight at which oral EC would be ineffective. Cost, need for a prescription, and the clinical appointment does influence the choice. LNG is cheaper and available OTC without prescription and age restriction in the US. UPA is more expensive and needs a prescription in the US while available OTC in European countries and Australia. Cu- IUD is the most effective method, unaffected by body weight or timing of the cycle, but it requires a trained provider and clinic appointment and costs more than oral methods.[6][7][8]

Women who remain sexually active would require effective contraception to prevent pregnancy. As per guidelines, quick start hormonal contraception can be used immediately after LNG or combined estrogen-progestin EC, but women should follow abstinence or use a barrier method for 7 days. Based on limited evidence from pharmacodynamic studies on UPA, FDA labeling recommends delaying initiation of hormonal contraception to 5 days after taking UPA for EC. If women meet the criteria for IUD and desire long term contraception, Cu-IUD would be the best option. LNG-IUD can be used immediately with LNG-EC and has a similar recommendation to use a barrier method for 14 days or abstinence until the patient's menses when UPA is used for EC.[6][7]

Barriers to Use EC

ACOG Committee Opinion 707, published in 2017, examined the barriers to EC use and made their recommendations to improve the access and use of EC in the US. The main barriers are due to:

• Confusion of EC with medication-induced abortion
• The misconception that ready availability of EC increases risky sexual behavior
• Lack of knowledge among providers about safety, efficacy, and choice of EC to recommend for the women in need
• The financial barriers limiting access to EC

Surveys in the US and many countries have clearly documented that there is no increased risk of sexual behavior or unintended pregnancy. One survey reported that one in five providers were reluctant to discuss EC with adolescents. Only 21% to 50% of sexual assault victims treated in emergency departments received EC, while only 17 states have laws enforcing the provision of EC to sexual assault victims irrespective of religious or restrictive affiliation. One study noted that up to one-third of newly arrested women are eligible for EC, but very few jails screen and offer the EC method, missing the opportunity to avoid unintended pregnancy in incarcerated women. Both clinicians and women are unaware that they could ask and get a prescription for EC in advance. In many underserved communities, there are few facilities or clinicians who could provide EC, and some are even unwilling to provide the method due to religious affiliation. Pharmacies may fail to stock due to low demand and provide inaccurate information to poor and young adolescents who lack awareness, have concerns on confidentiality, and lack access to healthcare.[5]