Advertisement

Society of Family Planning Clinical Recommendations: Emergency contraception

      Abstract

      Emergency contraception refers to several contraceptive options that can be used within a few days after unprotected or underprotected intercourse or sexual assault to reduce the risk of pregnancy. Current emergency contraception options available in the United States include the copper intrauterine device (IUD), levonorgestrel (LNG) 52mg IUD, oral levonorgestrel (such as Plan B One-Step®, My Way®, Take Action®), and oral ulipristal acetate (UPA) (ella®). These clinical recommendations review the indications, effectiveness, safety, and side effects of emergency contraceptive methods; considerations for the use of emergency contraception by specific patient populations and in specific clinical circumstances, and current barriers to emergency contraceptive access. Further research is needed to evaluate the effectiveness of levonorgestrel IUDs for emergency contraceptive use; address the effects of repeated use of ulipristal acetate at different times in the same menstrual cycle; assess the impact on ovulation of initiating or reinitiating different regimens of regular hormonal contraception following ulipristal acetate use; and elucidate effective emergency contraceptive pill options by body mass indices or weight.

      Keywords

      1. Background

      Emergency contraception (EC) refers to contraceptive options that can be used within a few days after an episode of unprotected or under protected intercourse or sexual assault to reduce the risk of pregnancy. Current emergency contraception options available in the United States include the copper intrauterine device (IUD), levonorgestrel (LNG) 52mg IUD, oral levonorgestrel (such as Plan B One-Step®, My Way®, Take Action®), and oral ulipristal acetate (UPA) (ella®). All emergency contraception options are effective, safe, and generally well tolerated. Oral methods are accessible without a clinic visit [
      • Trussell J
      • Ellertson C
      • von Hertzen H
      • Bigrigg A
      • Webb A
      • Evans M
      • et al.
      Estimating the effectiveness of emergency contraceptive pills.
      ,
      • von Hertzen H
      • Piaggio G
      • Ding J
      • Chen J
      • Song S
      • Barfai G
      • et al.
      Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
      ,
      • Glasier A.
      The rationale for use of Ulipristal Acetate as first line in emergency contraception: biological and clinical evidence.
      ,
      • Cleland K
      • Raymond EG
      • Westley E
      • Trussell J
      Emergency contraception review: Evidence-based recommendations for clinicians.
      ]. Emergency contraception differs from medication abortion which is used to end an established pregnancy.
      Unprotected or under protected intercourse and sexual assault are common. Of patients who specifically seek out EC, approximately 40% report multiple episodes of unprotected intercourse in the cycle prior to presentation and 14% report at least one episode of unprotected intercourse six or more days prior to seeking EC [
      • BakenRa A
      • Gero A
      • Sanders J
      • Simmons R
      • Fay K
      • Turok DK.
      Pregnancy Risk by Frequency and Timing of Unprotected Intercourse Before Intrauterine Device Placement for Emergency Contraception.
      ,
      • Sanders JN
      • Howell L
      • Saltzman HM
      • Schwarz EB
      • Thompson IS
      • Turok DK.
      Unprotected intercourse in the 2 weeks prior to requesting emergency intrauterine contraception.
      ]. Additionally, approximately 19% of women in the United States report a history of rape or attempted rape in their lifetime, with ethnic minority women, individuals with a history of military service, and sexual minority and transgender individuals reporting higher rates [
      ACOG Committee Opinion No. 777: Sexual Assault.
      ,
      • Rothman EF
      • Exner D
      • Baughman AL.
      The prevalence of sexual assault against people who identify as gay, lesbian, or bisexual in the United States: a systematic review.
      ,
      • Norris AL
      • Orchowski LM.
      Peer Victimization of Sexual Minority and Transgender Youth: A Cross-Sectional Study of High School Students.
      ].
      Patients present to various settings to inquire about or access EC, including emergency departments, clinics, urgent care centers, and pharmacies. Healthcare providers working in such settings should be knowledgeable about EC options and facilitate provision of these methods in a time-sensitive manner. Many patients face geographic, logistical, financial, and sociocultural barriers to safe abortion care, making EC a critical resource to help patients avoid unintended pregnancies.

      2. Clinical Questions

      2.1 What options are available for emergency contraception?

      2.1.1 Emergency contraceptive pills (ECPS)

      Dedicated oral emergency contraceptive pills (ECPs) containing ulipristal acetate (UPA) 30 mg or levonorgestrel (LNG) 1.5 mg, both as a single dose, are available in the United States and Europe. UPA can be effectively used up to 120 hours after unprotected intercourse while oral LNG can be effectively used up to 96 hours (and possibly up to 120 hours) after unprotected intercourse [
      • Piaggio G
      • Kapp N
      • von Hertzen H.
      Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials.
      ]. In a few countries, oral mifepristone in doses of 10-25 mg is available commercially as EC [

      International Consortium for Emergency Contraception. EC pill types and countries of availability, by brand, https://toolkits.knowledgesuccess.org/toolkits/emergency-contraception/emergency-contraceptive-pills-registration-status-country; 2022 [accessed 29 December 2022].

      ]. The Yuzpe method is a form of EC that comprises two doses of combined oral contraceptive pills containing 100-120 mcg ethinyl estradiol (EE) and 0.5 - 0.6 mg levonorgestrel per dose [
      • Jatlaoui TC
      • Riley H
      • Curtis KM.
      Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception.
      ]. Given the resulting nausea from this high dose of EE, as well as the availability of other more convenient products marketed specifically for EC, the Yuzpe method is likely used infrequently in current clinical practice.

      2.1.2 Mechanism

      ECPs work by preventing or delaying ovulation and are ineffective after ovulation has occurred. Two studies demonstrated that when LNG ECPs are taken on or before the day of ovulation, no pregnancies occurred. However, when taken after the day of ovulation, the number of pregnancies expected without EC occurred (based on the cycle timing of the individuals in the study) [
      • Novikova N
      • Weisberg E
      • Stanczyk FZ
      • Croxatto HB
      • Fraser IS.
      Effectiveness of levonorgestrel emergency contraception given before or after ovulation - a pilot study.
      ,
      • Noé G
      • Croxatto HB
      • Salvatierra AM
      • Reyes V
      • Villarroel C
      • Muñoz C
      • et al.
      Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.
      ]. In a crossover pharmacodynamic study, 34 women were treated with UPA ECPs or placebo when the leading follicle was at least 18 mm. Follicular rupture failed to occur among all women treated with UPA ECPs before the luteinizing hormone surge began, in 79% after the surge began but before the peak, and in eight percent of women treated after the luteinizing hormone peak [
      • Brache V
      • Cochon L
      • Jesam C
      • Maldonado R
      • Salvatierra AM
      • Levy DP
      • et al.
      Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.
      ]. In another study, researchers measured pregnancy rates among women who took UPA ECPs within 120 hours of unprotected intercourse and were classified as pre-ovulatory or post-ovulatory. The observed pregnancy rate in the pre-ovulatory group was significantly lower than expected with 77.6% of expected pregnancies prevented (p<0.0001), while the rate in the post-ovulatory group was as expected with 36.4% of expected pregnancies prevented (p=0.281)[
      • Li HWR
      • Lo SST
      • Ng EHY
      • Ho PC.
      Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.
      ]. Although the United States Food and Drug Administration (FDA) recently addressed the labeling of LNG ECPs, approved labeling for UPA ECPs states that these products can interfere with implantation [

      Duramed Pharmaceuticals Inc. Plan B One-Step (levonorgestrel) tablet, 1.5 mg, for oral use [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021998lbl.pdf; 2009 [accessed 29 December 2022].

      ,

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ]. Two newer systematic reviews do not support this assertion [
      • Endler M
      • Li RHW
      Gemzell Danielsson K. Effect of levonorgestrel emergency contraception on implantation and fertility: A review.
      ,
      • Li HWR
      • Resche-Rigon M
      • Bagchi IC
      • Gemzell-Danielsson K
      • Glasier A.
      Does ulipristal acetate emergency contraception (ella®) interfere with implantation?.
      ,
      • Li D
      • Wilcox AJ
      • Dunson DB.
      Benchmark pregnancy rates and the assessment of post-coital contraceptives: an update.
      ].

      2.1.3 Efficacy

      In clinical trials, pregnancy rates following UPA ECP use within 120 hours of intercourse range from 0.9% - 1.8% [
      • Creinin MD
      • Schlaff W
      • Archer DF
      • Wan L
      • Frezieres R
      • Thomas M
      • et al.
      Progesterone Receptor Modulator for Emergency Contraception: a randomized controlled trial.
      ,
      • Fine P
      • Mathé H
      • Ginde S
      • Cullins V
      • Morfesis J
      • Gainer E.
      Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception.
      ,
      • Glasier AF
      • Cameron ST
      • Fine PM
      • Logan SJS
      • Casale W
      • van Horn J
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      ,
      • Hamoda H
      • Ashok PW
      • Stalder G
      • Flett GMM
      • Kennedy E
      • Templeton A.
      A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception.
      ,
      • Dada OA
      • Godfrey EM
      • Piaggio G
      • von Hertzen H
      Nigerian Network for Reproductive Health Research and Training. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria.
      ]. Similar effectiveness is seen when LNG ECPs are taken up to 96 hours following unprotected intercourse. It is unclear whether protection against unintended pregnancy is provided when LNG ECPs are taken 96-120 hours after unprotected intercourse [
      • Piaggio G
      • Kapp N
      • von Hertzen H.
      Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials.
      ]. In comparative trials, UPA is more effective than LNG. In a combined analysis of two randomized trials comparing the effectiveness of UPA to LNG ECPs, the odds of pregnancy following UPA were 65% lower when taken in the first 24 hours following unprotected intercourse, and 42% lower up to 72 hours after unprotected intercourse, compared to LNG [
      • von Hertzen H
      • Piaggio G
      • Ding J
      • Chen J
      • Song S
      • Barfai G
      • et al.
      Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
      ,
      • Li HWR
      • Lo SST
      • Ng EHY
      • Ho PC.
      Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.
      ,
      • Creinin MD
      • Schlaff W
      • Archer DF
      • Wan L
      • Frezieres R
      • Thomas M
      • et al.
      Progesterone Receptor Modulator for Emergency Contraception: a randomized controlled trial.
      ,
      • Glasier AF
      • Cameron ST
      • Fine PM
      • Logan SJS
      • Casale W
      • van Horn J
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      ,
      • Dada OA
      • Godfrey EM
      • Piaggio G
      • von Hertzen H
      Nigerian Network for Reproductive Health Research and Training. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria.
      ]. This difference in efficacy is best explained by UPA's ability to delay ovulation after the luteinizing hormone surge has begun (at which point LNG ECPs are no longer effective) before the luteinizing hormone peak [
      • Gemzell-Danielsson K
      • Berger C
      • Lalitkumar PGL.
      Emergency contraception - mechanisms of action.
      ].

      2.1.4 Intrauterine devices (IUDs)

      2.1.4.1 Types

      The copper intrauterine device (IUD) and the levonorgestrel (LNG) 52mg IUD can be effectively initiated up to 120 hours after unprotected intercourse as EC. Copper IUDs have been used for decades as EC, while the levonorgestrel 52 mg IUD has recently demonstrated effectiveness as EC [
      • Cleland K
      • Raymond EG
      • Westley E
      • Trussell J
      Emergency contraception review: Evidence-based recommendations for clinicians.
      ,
      • Turok DK
      • Gero A
      • Simmons RG
      • Kaiser JE
      • Stoddard GJ
      • Sexsmith CD
      • et al.
      Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
      ].

      2.1.4.2 Mechanism

      The primary mechanism of the copper IUD is interference with sperm maturation and motility [
      • Ortiz ME
      • Croxatto HB.
      Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action.
      ]. However, the near one hundred percent efficacy of the emergency copper IUD indicates that if fertilization does occur, post-fertilization effects (such as induction of a foreign-body reaction in the uterus through alteration of cytokines in the endometrial lining which can inhibit implantation) may also contribute to its mechanism of action [
      • Gemzell-Danielsson K
      • Berger C
      • Lalitkumar PGL.
      Emergency contraception - mechanisms of action.
      ]. LNG IUDs may work as EC by similarly inducing a foreign-body reaction or through known effects of LNG, such as thickening of cervical mucus, interference with sperm maturation and function, and alterations to oviduct transport [
      • Ortiz ME
      • Croxatto HB.
      Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action.
      ,
      • Black T
      • Goldstuck N
      • Spence A.
      Post-coital intrauterine device insertion - a further evaluation.
      ,
      • Guillebaud J
      • Kubba A
      • Rowlands S
      • White J
      • Elder M.
      Post-coital contraception with danazol, compared with an ethinyloestradiol-norgestrel combination or insertion of an intra-uterine device.
      , -
      • Tamburrino L
      • Marchiani S
      • Minetti F
      • Forti G
      • Muratori M
      • Baldi E.
      The CatSper calcium channel in human sperm: Relation with motility and involvement in progesterone-induced acrosome reaction.
      ].

      2.1.4.3 Efficacy

      The copper IUD used as EC is significantly more effective than ECPs, with a pregnancy rate of 0.09% [
      • Cleland K
      • Zhu H
      • Goldstuck N
      • Cheng L
      • Trussell J.
      The efficacy of intrauterine devices for emergency contraception: a systematic review of 35 years of experience.
      ,
      • Goldstuck ND
      • Cheung TS.
      The efficacy of intrauterine devices for emergency contraception and beyond: a systematic review update.
      ]. A randomized, non-inferiority trial of 638 patients investigated the efficacy of the LNG 52mg IUD for EC compared to the copper IUD within five days of unprotected intercourse. The trial demonstrated a 0.5% (95% CI 0.01 – 1.7%) failure rate for the LNG 52mg IUD as compared to a zero percent (95% CI 0 – 1.1%) failure rate for the copper IUD. The LNG 52mg IUD was found to be non-inferior to the copper IUD for EC [
      • Turok DK
      • Gero A
      • Simmons RG
      • Kaiser JE
      • Stoddard GJ
      • Sexsmith CD
      • et al.
      Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
      ]. The investigators did not estimate anticipated pregnancy rates based on cycle timing of unprotected intercourse in the study. Additional studies investigating the LNG IUD for EC may further strengthen the external validity of these findings [
      • Turok DK
      • Sanders JN
      • Thompson IS
      • Royer PA
      • Eggebroten J
      • Gawron LM.
      Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study.
      ]. We recommend that the LNG 52mg IUD be offered as a first-line EC option (GRADE 1B). IUD for EC patients should be counseled regarding the risk of ectopic pregnancy should an IUD fail, as well as the risks of pregnancy in the setting of an IUD, such as miscarriage and intrauterine infection [
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ].
      We recommend that clinicians counsel individuals considering emergency contraception on the following:
      • The copper IUD is more effective than ECPs (GRADE 1A).
      • UPA ECPs are more effective than LNG ECPs (GRADE 1A).
      • LNG and UPA ECPs prevent pregnancy through pre-ovulatory effects (GRADE 1A).
      • The LNG 52 mg IUD is non-inferior to the copper IUD for EC within five days of unprotected intercourse (GRADE 1B).

      2.2 What are the indications for EC?

      Patients seek EC to reduce their risk of pregnancy after unprotected or underprotected intercourse and sexual assault. Such situations include, but are not limited to: intercourse during which no contraception was used; intercourse surrounding contraception failure (such as a broken condom) or incorrect use (such as recently missed oral contraceptive pills); intercourse during which the contraception used is viewed to have suboptimal effectiveness (such as a barrier method); sexual assault; suspected contraceptive sabotage; and intercourse during fertile days in one's cycle, as tracked by calendars or period tracking applications.
      The World Health Organization (WHO) identifies several specific clinical situations for which EC can be recommended. These clinical scenarios are listed in Table 1 [
      Selected Rractice Recommendations for Contraceptive Use.
      ]. As detailed in this document, the risks of EC use are low. If a patient requests EC outside of the listed criteria for use, we recommend engaging in a shared decision-making process to assist the patient in choosing an option that best meets their goals.
      Table 1World Health Organization indications for emergency contraception use
      Sexual intercourse when no contraceptive has been used

      Sexual assault when the person was not protected by an effective contraceptive method

      Sexual intercourse where there is concern for contraceptive failure or misuse, including:
      CondomsBreakage, slippage, or incorrect use
      Combined hormonal contraceptive pills3 or more consecutively missed pills or

      3 days late during the first week of the cycle
      Progesterone-only contraceptive pills3 or more hours late from usual pill use time or

      more than 27 hours after the previous pill
      Desogestrel-only contraceptive pills12 or more hours from usual pill use time or

      more than 36 hours after the previous pill
      Norethisterone enanthate injection2 or more weeks late for injection
      Depot-medroxyprogesterone acetate injection4 or more weeks late for injection
      Combined injectable contraceptive7 or more days late for injection
      Cervical cap or diaphragmDislodgement, breakage, tearing, or early removal
      WithdrawalFailed withdrawal
      SpermicideFailure to melt prior to intercourse
      Fertility awareness methodsMiscalculation of abstinence period, or failure to abstain or use a barrier on the fertile days
      Intrauterine device or implantDevice expulsion
      Data from Selected Practice Recommendations for Contraceptive Use. 3rd ed. Geneva: World Health Organization; 2016.

      2.3 What clinical considerations may impact the use of emergency contraception?

      2.3.1 Medical conditions

      Given the potential for EC to decrease morbidities associated with mistimed or unwanted pregnancy, the risk of all currently available EC methods should be compared to the risks of pregnancy in the setting of medical conditions. For patients with hypercoagulable conditions or a history of VTE, the estrogen-containing Yuzpe method has not been found to significantly change Factor VII or antithrombin levels, unlike longitudinal combined oral contraceptive use. No cases of venous thromboembolism secondary to estrogen-containing EC use have been reported [
      • Webb A
      • Taberner D.
      Clotting factors after emergency contraception.
      ].
      Acute or chronic illnesses associated with significant vomiting or malabsorption may result in decreased effectiveness of ECPs. The UPA prescribing information and the Centers for Disease Control and Prevention Selected Practice Recommendations for Contraceptive Use (CDC SPR) recommend repeat ECP dosing when vomiting occurs within three hours of pill intake, the maximum amount of time required to achieve peak plasma concentrations in the setting of recent high-fat food intake [

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ,
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ].
      Immunosuppressed patients should be considered appropriate candidates for IUDs for EC, given current understanding of IUD mechanisms of action, absence of evidence for systemic inflammation following LNG IUD placement, and evidence for sterile intrauterine inflammatory response after IUD insertion in solid organ transplant and patients with other immunosuppressive conditions. Additionally, while there are concerns for increased upper genital tract infection risk with the IUD insertion process, such infections are rare, and risk of infection is not increased in immunosuppressed patients [
      • Farley TM
      • Rosenberg MJ
      • Rowe PJ
      • Chen JH
      • Meirik O.
      Intrauterine devices and pelvic inflammatory disease: an international perspective.
      ]. Although the CDC US Medical Eligibility for Contraceptive Use (US MEC) states that IUD insertion is not recommended unless other methods are not available or acceptable in patients with complicated solid organ transplant, such as graft failure, rejection, or cardiac allograft vasculopathy, this recommendation is based on theoretical concern with no published evidence of increased infectious morbidity with IUD placement in such patients. Clinicians should pursue a shared decision-making approach with patients in these circumstances [
      • Gordon C
      • Harken T.
      Controversies in family planning: intrauterine device placement in solid organ transplant patients.
      ,
      • Juliato CRT
      • Stahlschmidt P
      • Fernandes A
      • Monteiro I
      • Bahamondes L.
      A case series on the use of levonorgestrel 52 mg intrauterine system after organ transplant.
      ,
      • Morrison CS
      • Sekadde-Kigondu C
      • Sinei SK
      • Weiner DH
      • Kwok C
      • Kokonya D.
      Is the intrauterine device appropriate contraception for HIV-1-infected women?.
      ,
      • Huguelet PS
      • Sheehan C
      • Spitzer RF
      • Scott S.
      Use of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients: a case series.
      ,
      • Kim CR
      • Martinez-Maza O
      • Magpantay L
      • Magyar C
      • Gornbein J
      • Rible R
      • et al.
      Immunologic evaluation of the endometrium with a levonorgestrel intrauterine device in solid organ transplant women and healthy controls.
      ].

      2.3.2 Weight and BMI

      Multiple studies demonstrate no changes in the failure rate for the copper IUD or the LNG 52mg IUD for EC based on body weight or BMI [
      • Turok DK
      • Gero A
      • Simmons RG
      • Kaiser JE
      • Stoddard GJ
      • Sexsmith CD
      • et al.
      Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
      ,
      • Turok DK
      • Sanders JN
      • Thompson IS
      • Royer PA
      • Eggebroten J
      • Gawron LM.
      Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study.
      ,
      • Boraas CM
      • Sanders JN
      • Schwarz EB
      • Thompson I
      • Turok DK.
      Risk of Pregnancy With Levonorgestrel-Releasing Intrauterine System Placement 6-14 Days After Unprotected Sexual Intercourse.
      ,
      • Thompson I
      • Sanders JN
      • Schwarz EB
      • Boraas C
      • Turok DK.
      Copper intrauterine device placement 6–14 days after unprotected sex.
      ]. However, patient BMI and weight appear to impact the effectiveness of ECPs, with LNG ECPs being negatively affected to a greater extent than UPA ECPs. A meta-analysis of oral EC studies demonstrated that the risk of pregnancy is one and one-half times greater in users with an overweight BMI (25 – 29.9 kg/m2) and more than three times greater in users with an obese BMI (>30 kg/m2), compared to non-overweight users [
      • Glasier A
      • Cameron ST
      • Blithe D
      • Scherrer B
      • Mathe H
      • Levy D
      • et al.
      Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.
      ]. A meta-analysis by Festin et al. pooled data from four oral EC studies and examined data from 6873 EC users. When compared to participants with BMI < 25 kg/m2, participants with BMI ε 30 kg/m2 were eight times more likely to experience pregnancy after EC use [
      • Festin MPR
      • Peregoudov A
      • Seuc A
      • Kiarie J
      • Temmerman M.
      Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies.
      ]. Despite the demonstrated increased risk of pregnancy, the overall pregnancy rate in the obese group was low, at only 2.03% [
      • Festin MPR
      • Peregoudov A
      • Seuc A
      • Kiarie J
      • Temmerman M.
      Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies.
      ]. A study of 1731 oral LNG EC users demonstrated pregnancy rates of 1.4% or less for participants weighing 75kg or less compared to pregnancy rates of 6.4% and 5.7% among users weighing 75 – 85kg and >85 kg, respectively [
      • Kapp N
      • Abitbol JL
      • Mathé H
      • Scherrer B
      • Guillard H
      • Gainer E
      • et al.
      Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception.
      ].
      While doubling the dose of LNG ECPs increases the maximum concentration of serum LNG in individuals with obesity to levels seen in individuals with normal BMI, it was not shown to decrease levels of follicular rupture within five days to levels seen in individuals with BMI δ 25 kg/m2 [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: Single and double dosing.
      ,
      • Edelman AB
      • Hennebold JD
      • Bond K
      • Lim JY
      • Cherala G
      • Archer DF
      • et al.
      Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.
      ]. Although the Edelman 2022 study was not designed to evaluate oral LNG EC efficacy, the failure to decrease levels of follicular rupture in individuals with obesity to levels seen in individuals with overweight or normal BMI suggests lower efficacy of oral LNG EC in individuals with obesity, even with a higher dose of three milligrams LNG [
      • Edelman AB
      • Hennebold JD
      • Bond K
      • Lim JY
      • Cherala G
      • Archer DF
      • et al.
      Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.
      ].
      UPA ECPs are more effective than LNG ECPs in all users, including those with overweight and obese BMIs [
      • von Hertzen H
      • Piaggio G
      • Ding J
      • Chen J
      • Song S
      • Barfai G
      • et al.
      Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
      ,
      • Li HWR
      • Lo SST
      • Ng EHY
      • Ho PC.
      Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.
      ,
      • Creinin MD
      • Schlaff W
      • Archer DF
      • Wan L
      • Frezieres R
      • Thomas M
      • et al.
      Progesterone Receptor Modulator for Emergency Contraception: a randomized controlled trial.
      ,
      • Glasier AF
      • Cameron ST
      • Fine PM
      • Logan SJS
      • Casale W
      • van Horn J
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      ,
      • Dada OA
      • Godfrey EM
      • Piaggio G
      • von Hertzen H
      Nigerian Network for Reproductive Health Research and Training. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria.
      ]. Patients with an overweight BMI have the same failure rate as patients with normal BMI with correct use of UPA for EC [
      • Glasier A
      • Cameron ST
      • Blithe D
      • Scherrer B
      • Mathe H
      • Levy D
      • et al.
      Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.
      ]. However, UPA ECP users with obesity are twice as likely to experience pregnancy compared to users with a normal BMI. It appears the upper limit of efficacy for LNG ECPs occurs at a bodyweight of 70kg and the upper limit of efficacy for UPA ECPs occurs at bodyweight of 85 kg, though it is unclear how the data from prior studies translates from patient weight to BMI [
      • Glasier A
      • Cameron ST
      • Blithe D
      • Scherrer B
      • Mathe H
      • Levy D
      • et al.
      Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.
      ]. Based on this data, we recommend that clinicians counsel individuals that UPA ECPs, if available, are more effective than LNG ECPs in overweight and obese persons and those with body weight 70 kg or greater (GRADE 1C).

      2.3.3 Medications

      As LNG and UPA are substrates of cytochrome P450 3A4 (and LNG also of P450 3A5), concurrent use with enzyme inducers, such as efavirenz, carbamazepine, oxcarbazepine, and phenytoin, is expected to lower the dose of the ECPs, which may decrease their effectiveness [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ]. In women taking the former EC regimen of oral LNG 0.75mg (two doses 12 hours apart) concurrent with efavirenz (a reverse transcriptase inhibitor commonly used in the treatment of HIV), the AUC12, Cmax, and Cmin of LNG were decreased by 56%, 41%, and 67%, respectively [
      • Carten ML
      • Kiser JJ
      • Kwara A
      • Mawhinney S
      • Cu-Uvin S.
      Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz.
      ]. Similar reductions have been noted with carbamazepine, phenytoin, oxcarbazepine, and eslicarbazepine [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ]. While the clinical significance of these reductions is unclear, in 2016 the European Medicines Agency (EMA) recommended to double the dose of LNG ECPs for patients taking CYP3A4 inducers in the preceding four weeks [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ]. However, the effectiveness of double dosing LNG ECPs in this setting has not been evaluated, and it may be inadequate to address the effects of medications that induce CYP3A4 more strongly than efavirenz, such as rifampin and phenytoin [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ]. Lamotrigine, a glucuronidation enzyme inducer, also reduces levels of LNG taken orally [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ,
      • Carten ML
      • Kiser JJ
      • Kwara A
      • Mawhinney S
      • Cu-Uvin S.
      Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz.
      ]. In contrast, coadministration of oral LNG with vigabatrin, levetiracetam, ticagrelor, solifanacin, and vortioxetine does not decrease LNG levels [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ].
      Only three studies evaluating medication interactions with oral UPA are available. While erythromycin and ketoconazole do not lower levels of UPA taken orally, rifampicin, an enzyme inducer, decreases mean UPA exposure more than 10-fold [
      • Pohl O
      • Osterloh I
      • Gotteland JP.
      Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.
      ,
      • Pohl O
      • Zobrist RH
      • Gotteland JP.
      The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids.
      ]. Similar but more modest interactions are predicted for carbamazepine, rifabutin, dabrafenib, and phenobarbital, while stronger interactions are predicted for phenytoin, enzalutamide, and mitotane [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ,
      • Pohl O
      • Osterloh I
      • Gotteland JP.
      Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.
      ,
      • Pohl O
      • Zobrist RH
      • Gotteland JP.
      The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids.
      ]. Using modeling, predicted required dose increases for oral UPA when co-administered with a CYP3A enzyme inducer vary from 1.3-fold for the weakest inducer to 14.3-fold for the most potent inducers, rifampicin and mitotane [
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ]. While current UPA ECP labeling recommends avoiding use in patients who have taken CYP3A4 inducers in the past four weeks, this interval may be insufficient for such medications with long half-lives, such as enzalutamide, phenobarbital, and mitotane [

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ,
      • le Corvaisier C
      • Capelle A
      • France M
      • Bourguignon L
      • Tod M
      • Goutelle S.
      Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
      ].
      While neither UPA nor oral LNG inhibit CYP450 enzyme activity, both may inhibit P-glycoprotein (P-gp) at emergency contraceptive doses, thereby elevating levels of P-gp substrates, such as digoxin, colchicine, and fexofenadine, resulting in potential morbidity related to supratherapeutic levels of such medications [

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ,
      • Matyanga CMJ
      • Dzingirai B.
      Clinical Pharmacology of Hormonal Emergency Contraceptive Pills.
      ]. A case report of a supratherapeutic international normalized ratio (INR) not associated with hemorrhage, noted in a patient on warfarin taking two doses of 0.75 mg levonorgestrel for emergency contraception, may be illustrative of such interaction [
      • Ellison J
      • Thompson AJ
      • Greer I.
      Apparent interaction between warfarin and levonorgestrel used for emergency contraception.
      ].
      We recommend advising patients currently or recently taking cytochrome P450-3A4 and P450-3A5 inducers or glucuronidation enzyme inducers that emergency contraceptive pills may be less effective and that IUD placement for EC should be considered (GRADE 1C).

      2.4 What are counseling considerations regarding repeated use of EC, use by an unknowingly pregnant individual, and use with other hormonal contraceptives?

      2.4.1 Repeated use of emergency contraception in the same cycle

      There are no specific safety concerns regarding repeated or frequent use of LNG ECPs [
      • Jatlaoui TC
      • Riley H
      • Curtis KM.
      Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception.
      ]. Additionally, there is no evidence for increased incidence of ectopic pregnancy (relative to intrauterine pregnancy) with repeated LNG ECP use [
      • Zhang J
      • Li C
      • Zhao WH
      • Xi X
      • Cao SJ
      • Ping H
      • et al.
      Association between levonorgestrel emergency contraception and the risk of ectopic pregnancy: A multicenter case-control study.
      ]. Further, weekly dosing of UPA has not been associated with serious side effects, although headache and nausea were reported in almost 70% of participants in one study [
      • Jesam C
      • Cochon L
      • Salvatierra AM
      • Williams A
      • Kapp N
      • Levy-Gompel D
      • et al.
      A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate.
      ]. While no reports of serious adverse events have been noted with use of UPA ECPs, recent reports of rare but serious liver injury in women using lower daily dosing for the treatment of uterine fibroids calls for additional study of the safety of frequent UPA dosing [

      Medicines and Healthcare products Regulatory Agency UK. Esmya (ulipristal acetate): suspension of the licence due to risk of serious liver injury, https://www.gov.uk/drug-safety-update/esmya-ulipristal-acetate-suspension-of-the-licence-due-to-risk-of-serious-liver-injury; 2021 [accessed 29 December 2022].

      ]. In September 2020, the European Medicines Agency (EMA) concluded that UPA use for the treatment of uterine fibroids should no longer be marketed in the European Union due to eight case reports of serious liver injuries (four requiring transplantation) out of more than 765,000 patients included in post-marketing surveillance [
      • Donnez J
      • Arriagada P
      • Marciniak M
      • Larrey D.
      Liver safety parameters of ulipristal acetate for the treatment of uterine fibroids: a comprehensive review of the clinical development program. Vol. 17.
      ]. In such cases the hepatotoxicity is thought to be an idiosyncratic drug-induced liver injury (DILI) potentially also impacted by UPA's high lipophilicity and long half-life, inhibition of breast cancer resistance protein (BCRP) in liver cells, and bile salt export pump inhibition [
      • Gatti M
      • Poluzzi E
      • de Ponti F
      • Raschi E.
      Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis.
      ]. Such reactions are related more to host factors than to toxic properties of the medication itself, and are thus less dose-dependent and more varied in latency, presentation, and course than intrinsic DILI (such as acetaminophen-associated DILI) [
      • Donnez J.
      Liver injury and ulipristal acetate: an overstated tragedy? Vol. 110.
      ]. In contrast, Yoon et al. compared more than 20,000 patients taking UPA for fibroids to those taking gonadotropin releasing hormone agonists and did not find a difference in the incidence of severe or toxic liver disease between the groups. In that study the rate of severe liver disease and hepatic failure in patients using UPA was 0.04% and no liver transplantations were performed [
      • Yoon EL
      • Yuk JS.
      Use of Ulipristal Acetate and Risk of Liver Disease: A Nationwide Cohort Study.
      ].
      Daily dosing of five to ten milligrams UPA is associated with complete ovulation inhibition in approximately 80% of individuals, as observed with use of a contraceptive vaginal ring releasing 1.5-2.5 mg of UPA daily (unavailable in the United States)[
      • Jesam C
      • Cochon L
      • Salvatierra AM
      • Williams A
      • Kapp N
      • Levy-Gompel D
      • et al.
      A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate.
      ]. However, in a contraceptive study of women administered UPA 30 mg orally every five to seven days, ovulation was observed in more than 70% of cycles, likely explained by the half-life of UPA being only 32 hours [
      • Jesam C
      • Cochon L
      • Salvatierra AM
      • Williams A
      • Kapp N
      • Levy-Gompel D
      • et al.
      A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate.
      ]. Repeat dosing of UPA ECPs in the same cycle is not recommended by the manufacturer [

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ]. Given the potential morbidity of mistimed or unwanted pregnancy, and the fact that individuals may take ECPs at times in the cycle when they are not at significant risk of pregnancy, repeated dosing should not be withheld. Patients should be counseled that repeat dosing of UPA appears safe but the contraceptive effectiveness of multiple UPA doses within the same cycle remains unclear.

      2.4.2 Emergency contraception use by an unknowingly pregnant patient

      For patients who take LNG ECPs while unknowingly pregnant, or who conceive as a result of LNG ECP failure, there is no concern for associated pregnancy-related morbidity. Meta-analyses have not demonstrated an association between embryonic exposure to contraceptive hormones and fetal malformations generally, or genital malformations specifically [
      • Bracken MB.
      Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies.
      ,
      • Raman-Wilms L
      • in Tseng AL
      • Wighardt S
      • Einarson TR
      • Koren G
      Fetal genital effects of first-trimester sex hormone exposure: A meta-analysis.
      ]. More limited but similarly reassuring data are available regarding inadvertent exposure to UPA in pregnancy. One case of optic nerve atrophy has been documented in a pregnancy with UPA exposure, a condition which was determined by an independent Data Safety Monitoring Board not to be attributable to UPA in utero exposure [

      Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: Postmarketing experience after use by more than 1 million women. Contraception. 2014 May;89(5):431–3.

      ]. No other pregnancy or delivery complications have been reported in association with UPA ECP use. The miscarriage rate associated with UPA exposed pregnancies (13.8%) is not higher than the 20% reported in the general population [

      Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: Postmarketing experience after use by more than 1 million women. Contraception. 2014 May;89(5):431–3.

      ,
      • Zinaman MJ
      • Clegg ED
      • Brown CC
      • O'connor J
      • Selevan SG.
      Estimates of human fertility and pregnancy loss.
      ] . Similarly, the incidence of ectopic pregnancy (1.1%) is similar to that in the general population of pregnant individuals of 0.8-2% [

      Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: Postmarketing experience after use by more than 1 million women. Contraception. 2014 May;89(5):431–3.

      ,
      • Cleland K
      • Raymond E
      • Trussell J
      • Cheng L
      • Zhu H.
      Ectopic pregnancy and emergency contraceptive pills: a systematic review.
      ,
      • Barnhart KT
      Ectopic Pregnancy.
      ]. More pregnancies following ECP exposure end in abortion than in the general population, consistent with differences in pregnancy intention between the two populations [

      Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: Postmarketing experience after use by more than 1 million women. Contraception. 2014 May;89(5):431–3.

      ]. Given such findings, pregnancy testing is unnecessary prior to ECP use, unless a patient is concerned about their pregnancy status for other reasons.
      For patients seeking copper or LNG IUDs for EC who also report episodes of unprotected intercourse in the current cycle more than five days before planned IUD insertion, the potential presence of a preimplantation fertilized ovum should be considered. Several studies demonstrate that pregnancy is uncommon in such situations following IUD placement. In a study of same-day LNG IUD placement for routine contraception, 0.4% of patients who did not meet checklist criteria supported by the CDC for reasonable certainty of not being pregnant received a diagnosis of pregnancy in the weeks following IUD insertion [
      • Castaño PM
      • Westhoff CL.
      Experience with same-day placement of the 52 mg levonorgestrel-releasing intrauterine system.
      ]. In another study, one out of 40 patients (2.5%) who presented for EC and reported additional unprotected intercourse six to fourteen days prior to IUD insertion had a positive pregnancy test within the subsequent two weeks [
      • Sanders JN
      • Howell L
      • Saltzman HM
      • Schwarz EB
      • Thompson IS
      • Turok DK.
      Unprotected intercourse in the 2 weeks prior to requesting emergency intrauterine contraception.
      ]. A study of 134 patients who had a copper IUD placed six to fourteen days after unprotected demonstrated zero pregnancies two to four weeks after IUD placement [
      • Thompson I
      • Sanders JN
      • Schwarz EB
      • Boraas C
      • Turok DK.
      Copper intrauterine device placement 6–14 days after unprotected sex.
      ].
      Although uncommon, pregnancies in patients with an IUD have elevated risks of adverse pregnancy outcomes compared to patients who conceive without an IUD. Such elevated risks include miscarriage, preterm delivery, and septic abortion. These risks are decreased in patients who undergo IUD removal during the pregnancy, but remain elevated relative to baseline risks without an IUD [
      • Brahmi D
      • Steenland MW
      • Renner RM
      • Gaffield ME
      • Curtis KM.
      Pregnancy outcomes with an IUD in situ: a systematic review.
      ]. There is currently insufficient data to reach conclusions about any specific risks of an LNG IUD on a developing fetus [
      • Brahmi D
      • Steenland MW
      • Renner RM
      • Gaffield ME
      • Curtis KM.
      Pregnancy outcomes with an IUD in situ: a systematic review.
      ]. Similar considerations pertain to patients who receive an IUD for EC with unprotected intercourse limited to the previous five days in whom the IUD fails, resulting in pregnancy. Given the risks of pregnancy in the setting of IUD, pregnancy testing should be performed prior to IUD insertion for EC and patients counseled regarding the risks of pregnancy in the case a preimplantation fertilized ovum is present at the time of IUD placement for EC or in the case of IUD EC failure.

      2.4.3 Use with other hormonal contraceptives

      Initiating regular contraceptive use immediately following ECPs increases uptake and continuation of the regular contraceptive method [
      • Westhoff C
      • Kerns J
      • Morroni C
      • Cushman LF
      • Tiezzi L
      • Murphy PA.
      Quick Start: novel oral contraceptive initiation method.
      ,

      Nelson AL, Katz T. Initiation and continuation rates seen in 2-year experience with Same Day injections of DMPA. Contraception. 2007 Feb;75(2):84–7.

      ] . There is no mechanism by which LNG, a progestin, would decrease the effectiveness of subsequently initiated hormonal contraception. Similarly, initiation of regular hormonal contraception immediately following LNG ECP use will not decrease the effectiveness of LNG as an ECP. We recommend routine hormonal contraception be initiated as soon as desired following LNG ECP use, with abstinence or a non-hormonal contraceptive method used as back-up for seven days or until the next menstrual period/withdrawal bleed, whichever occurs first (GRADE 1A).
      UPA does not appear to decrease subsequent oral contraceptive pill efficacy. UPA had no significant effect on the contraceptive onset of a 75 mg desogestrel progestin-only pill, with regard to desogestrel's impact on cervical mucus or ovulation inhibition [
      • Brache V
      • Cochon L
      • Duijkers IJM
      • Levy DP
      • Kapp N
      • Monteil C
      • et al.
      A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
      ]. Administration of UPA mid-cycle, followed the next day by initiation of a daily 30 mcg ethinyl estradiol/150 mcg LNG-containing combined hormonal contraceptive pill was associated with ovarian quiescence in most women by seven days, with a minority of women taking additional days (up to 14) to reach quiescence [
      • Cameron ST
      • Berger C
      • Michie L
      • Klipping C
      • Gemzell-Danielsson K.
      The effects on ovarian activity of ulipristal acetate when ‘quickstarting’ a combined oral contraceptive pill: A prospective, randomized, double-blind parallel-arm, placebo-controlled study.
      ]. All women who ovulated did so after 11 days of combined oral contraceptive pill use [
      • Cameron ST
      • Berger C
      • Michie L
      • Klipping C
      • Gemzell-Danielsson K.
      The effects on ovarian activity of ulipristal acetate when ‘quickstarting’ a combined oral contraceptive pill: A prospective, randomized, double-blind parallel-arm, placebo-controlled study.
      ]. No studies to date have investigated the potential for delayed effectiveness of routine contraceptive effects when UPA is closely followed by use of non-oral hormonal contraceptives. After resuming or initiating regular contraception following ECP use, the CDC SPR recommends abstinence or barrier method use for seven days, or until the next menses, whichever occurs first [
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ].
      In contrast, the effectiveness of UPA in delaying ovulation for EC use is reduced by subsequent administration of hormonal contraceptive pills. When a combined oral contraceptive pill containing 30 mcg of ethinyl estradiol and 150 mcg of LNG was administered two days following UPA, more subjects demonstrated evidence of ovulation (follicular rupture) within five days (27% versus three percent) [
      • Edelman AB
      • Jensen JT
      • McCrimmon S
      • Messerle-Forbes M
      • O'Donnell A
      • Hennebold JD
      Combined oral contraceptive interference with the ability of ulipristal acetate to delay ovulation: A prospective cohort study.
      ]. Similarly, administration of 75 mg desogestrel the day following UPA is associated with evidence of ovulation within five days in 45% of subjects, compared to three percent of subjects who took only UPA [
      • Brache V
      • Cochon L
      • Duijkers IJM
      • Levy DP
      • Kapp N
      • Monteil C
      • et al.
      A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
      ]. The mean time to ovulation was eight days in the UPA only group, compared to four days in the group taking UPA followed by desogestrel [
      • Brache V
      • Cochon L
      • Duijkers IJM
      • Levy DP
      • Kapp N
      • Monteil C
      • et al.
      A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
      ]. Consequently, extrapolation of decreased UPA effectiveness to coadministration with other progestin-only pills and non-oral routes of progestin administration should be done with caution [
      • Brache V
      • Cochon L
      • Duijkers IJM
      • Levy DP
      • Kapp N
      • Monteil C
      • et al.
      A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
      ].
      Whether the effectiveness of UPA is similarly decreased when used following missed doses of routine short-term hormonal contraception followed by resumption of the routine contraception is unclear. Additionally, individuals who delay reinitiating their routine hormonal contraception following UPA use may be at elevated risk of ovulation and consequent pregnancy compared to those who resume hormonal contraception immediately following UPA use. In a study of women who missed combined oral contraceptive pill doses (as part of a 21/7 regimen of 30 mcg EE/ 150 mcg LNG) on days five, six, and seven, and took UPA the morning of day eight, those who resumed their combined oral contraceptive pill the same evening demonstrated decreased evidence of subsequent ovulation during that pill pack compared to those who waited five days to restart contraceptive pills [
      • Banh C
      • Rautenberg T
      • Duijkers I
      • Borenzstein P
      • Monteil C
      • Levy-Gompel D
      • et al.
      The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
      ]. No women who completed the study ovulated in the five days after taking UPA, regardless of when the contraceptive pill was restarted [
      • Orchowski LM
      • Yusufov M
      • Oesterle D
      • Bogen KW
      • Zlotnick C.
      Intimate Partner Violence and Coerced Unprotected Sex Among Young Women Attending Community College.
      ]. Given that ovarian activity is suppressed during combined oral contraceptive pill use and that time is required after missed pills for recovery of ovarian activity, restarting contraceptive pills soon after missing pills and taking UPA would be unlikely to result in ovulation [
      • Banh C
      • Rautenberg T
      • Duijkers I
      • Borenzstein P
      • Monteil C
      • Levy-Gompel D
      • et al.
      The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
      ,
      • Zapata LB
      • Steenland MW
      • Brahmi D
      • Marchbanks PA
      • Curtis KM.
      Effect of missed combined hormonal contraceptives on contraceptive effectiveness: a systematic review.
      ]. Some may argue that individuals who miss only a few contraceptive pills are not indicated to use EC at all. However, given that an individual may intermittently miss doses throughout a cycle, providing a patient with a specific risk assessment for conception after missed doses is challenging [
      • Banh C
      • Rautenberg T
      • Duijkers I
      • Borenzstein P
      • Monteil C
      • Levy-Gompel D
      • et al.
      The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
      ].
      Concerns that initiating routine hormonal contraception in the days following UPA use may decrease UPA's effectiveness must be weighed against the risk of subsequent pregnancy if routine contraception is not established or reestablished. This risk benefit ratio is expected to vary by individual and situation based on the risk of pregnancy from the index exposure, risk of subsequent pregnancy in the short-term, contraceptive access, and individual preferences. Following UPA ECPs, we recommend generally delaying initiation of routine hormonal contraception for five days and abstinence or a non-hormonal contraceptive method used as back-up for an additional seven days or until the next menstrual period/withdrawal bleed. However, the specific timing of routine hormonal contraceptive initiation should be individualized through shared decision-making (GRADE 1B).

      2.5 What follow-up and additional services should be offered to individuals seeking emergency contraception?

      2.5.1 Urine pregnancy testing (at time of provision and at follow up)

      EC reduces the risk of pregnancy after unprotected intercourse but does not completely resolve this risk. EC is associated with pregnancy rates ranging from 0.09 – 2.6% [
      • Glasier AF
      • Cameron ST
      • Fine PM
      • Logan SJS
      • Casale W
      • van Horn J
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      ,
      • Turok DK
      • Gero A
      • Simmons RG
      • Kaiser JE
      • Stoddard GJ
      • Sexsmith CD
      • et al.
      Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
      ,
      • Cleland K
      • Zhu H
      • Goldstuck N
      • Cheng L
      • Trussell J.
      The efficacy of intrauterine devices for emergency contraception: a systematic review of 35 years of experience.
      ]. If an EC user experiences menses within two weeks of EC use, they can be reassured of their non-pregnant status. If this does not occur, a pregnancy test is recommended three weeks after EC use. Additionally, pregnancy testing should be considered one month following LNG IUD placement for EC given the potential for menstrual changes with this method [
      • Turok DK
      • Gero A
      • Simmons RG
      • Kaiser JE
      • Stoddard GJ
      • Sexsmith CD
      • et al.
      Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
      ]. If a pregnancy is detected, the patient should present for pregnancy localization and pregnancy options discussion. While pregnancy testing should be performed prior to IUD insertion for EC, ECPs should not be withheld or delayed for pregnancy testing. We recommend against withholding or delaying ECPs for pregnancy testing (GRADE 1B). We recommend offering urine pregnancy testing for post-EC pregnancy assessment as needed (GRADE 1C).

      2.5.2 Sexually transmitted infection screening and treatment

      In 2018, one in five adults in the United States had a sexually transmitted infection (STI) [
      • Tuddenham S
      • Hamill MM
      • Ghanem KG.
      Diagnosis and Treatment of Sexually Transmitted Infections: A Review.
      ]. Given the prevalence of STIs, people who report unprotected or underprotected intercourse should be offered screening for STIs [
      • Workowski K
      • Bachmann L
      • Chan P
      • Johnston CM
      • Muzny CA
      • Park I
      • et al.
      Sexually Transmitted Infections Treatment Guidelines, 2021.
      ] . Active mucopurulent discharge and current chlamydia or gonorrhea infections are contraindications to IUD placement [
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ]. However, asymptomatic individuals with chlamydia or gonorrhea infection at the time of IUD placement may not be at elevated risk of pelvic inflammatory disease (PID) when such infections are recognized and appropriately treated compared to individuals undergoing IUD insertion in the absence of such infections [
      • Jatlaoui TC
      • Simmons KB
      • Curtis KM.
      The safety of intrauterine contraception initiation among women with current asymptomatic cervical infections or at increased risk of sexually transmitted infections.
      ]. Patients with incidentally positive tests noted following IUD insertion should be treated according to current CDC guidelines and the IUD may remain in place if desired [
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ]. The placement of an IUD for EC should not be withheld or delayed for STI screening in the absence of active mucopurulent discharge, regardless of the patient's STI risk. Empiric treatment for gonorrhea, chlamydia, and trichomoniasis should be given to persons reporting sexual assault. Such individuals should be offered Hepatitis B and HPV vaccinations based on their vaccination status [
      • Workowski K
      • Bachmann L
      • Chan P
      • Johnston CM
      • Muzny CA
      • Park I
      • et al.
      Sexually Transmitted Infections Treatment Guidelines, 2021.
      ]. HIV post-exposure and pre-exposure prophylaxis should be considered within a framework of shared decision making [
      • Workowski K
      • Bachmann L
      • Chan P
      • Johnston CM
      • Muzny CA
      • Park I
      • et al.
      Sexually Transmitted Infections Treatment Guidelines, 2021.
      ]. We recommend offering or referring persons requesting EC for sexually transmitted infection screening, post-exposure prophylaxis, pre-exposure prophylaxis, and treatment as indicated (GRADE 1C).

      2.5.3 Intimate partner violence and human trafficking screening

      People who experience intimate partner violence or who are being human trafficked are likely to experience unprotected or underprotected intercourse [
      • Decker MR
      • Mack KP
      • Barrows JJ
      • Silverman JG.
      Sex trafficking, violence victimization, and condom use among prostituted women in Nicaragua.
      ,
      • Orchowski LM
      • Yusufov M
      • Oesterle D
      • Bogen KW
      • Zlotnick C.
      Intimate Partner Violence and Coerced Unprotected Sex Among Young Women Attending Community College.
      ]. People who present for EC should be screened for intimate partner violence and sex trafficking and provided local resources and referrals as desired. We recommend screening persons who use EC for intimate partner violence and human trafficking as indicated (GRADE 1C).

      2.5.4 Ongoing contraception

      Unprotected intercourse is common and EC users frequently have more than one episode of unprotected intercourse prior to presenting for EC [
      • BakenRa A
      • Gero A
      • Sanders J
      • Simmons R
      • Fay K
      • Turok DK.
      Pregnancy Risk by Frequency and Timing of Unprotected Intercourse Before Intrauterine Device Placement for Emergency Contraception.
      ,
      • Sanders JN
      • Howell L
      • Saltzman HM
      • Schwarz EB
      • Thompson IS
      • Turok DK.
      Unprotected intercourse in the 2 weeks prior to requesting emergency intrauterine contraception.
      ]. Discussing or initiating ongoing contraception at the time of presentation for EC may help EC users meet their fertility goals. It is important to recognize that people are fluid in their reproductive intentions [
      • Wolgemuth T
      • Judge-Golden C
      • Callegari L
      • Zhao X
      • Mor M
      • Borrero S.
      Associations between Pregnancy Intention, Attitudes, and Contraceptive Use among Women Veterans in the ECUUN Study.
      ]. Acceptance of EC does not commit a person to avoiding pregnancy for any duration outside of the initial EC use. At EC encounters, healthcare providers should assess users for interest in ongoing contraception and provide contraception management or referrals as desired by the patient. We recommend offering or referring persons who use EC for ongoing contraception as desired (GRADE 1C).

      2.6 How can clinicians support emergency contraception use in special populations?

      2.6.1 Use by gender diverse individuals (particularly those taking testosterone)

      Clinicians should educate all patients at risk for pregnancy, including gender diverse individuals, regarding EC and provide advance prescription of ECPs if desired. Although gender diverse patients may experience amenorrhea secondary to gonadotropin releasing hormone agonist or testosterone use, they remain at risk for pregnancy if having receptive intercourse with a sperm-producing partner. Such patients may be unaware of their pregnancy risk. In addition to the general risks of unintended pregnancy, in gender diverse individuals unintended pregnancy may also be associated with gender dysphoria and with fetal risks associated with in utero testosterone exposure. While there are no published studies regarding EC use in gender diverse populations, expert consensus based on other hormonal contraceptives does not prompt concern about loss of efficacy of EC or testosterone when used concurrently [

      American Society for Emergency Contraception. Emergency Contraception for Transgender and Nonbinary patients, https://www.americansocietyforec.org/reports-and-factsheets; 2021 [accessed 29 December 2022].

      ]. As with all patients, clinicians should use a trauma-informed approach when counseling gender diverse individuals interested in an IUD [
      • Bonnington A
      • Dianat S
      • Kerns J
      • Hastings J
      • Hawkins M
      • de Haan G
      • et al.
      Society of Family Planning clinical recommendations: Contraceptive counseling for transgender and gender diverse people who were female sex assigned at birth.
      ].

      2.6.2 Use while breastfeeding, lactating, or chest feeding

      ECPs are an effective complement for individuals relying on the lactational amenorrhea method (LAM) for contraception. In a study of Egyptian women comparing standard LAM education to LAM and EC education with advanced provision of one pack of LNG ECPs, 44% of women in the EC group used the LNG ECPs, of which 88% did so correctly (when at least one requirement of LAM had expired and intercourse occurred before initiating a regular contraceptive method) [
      • Shaaban OM
      • Hassen SG
      • Nour SA
      • Kames MA
      • Yones EM.
      Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
      ]. Significantly more women in the EC group initiated regular contraception within or shortly after the first six months postpartum (30% vs. 7.3%) and fewer pregnancies occurred in the EC group (0.8% vs. 7.3%)[
      • Shaaban OM
      • Hassen SG
      • Nour SA
      • Kames MA
      • Yones EM.
      Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
      ]. There were no significant differences between groups in duration of lactation, pattern of breastfeeding, or resumption of menstruation [
      • Shaaban OM
      • Hassen SG
      • Nour SA
      • Kames MA
      • Yones EM.
      Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
      ]. The most common LNG side effect was nausea without vomiting, which occurred in approximately 30% of women [
      • Shaaban OM
      • Hassen SG
      • Nour SA
      • Kames MA
      • Yones EM.
      Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
      ]. We recommend clinicians provide EC counseling and advanced prescription of ECPs to individuals relying on the lactational amenorrhea method (GRADE 1B).
      Similar to progestin-only regular contraceptives, LNG ECPs have not been shown to objectively affect the health or development of nursing infants or to subjectively impact the volume of breast milk produced [
      • Shaaban OM
      • Hassen SG
      • Nour SA
      • Kames MA
      • Yones EM.
      Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
      ,
      • Shaaban OM
      • Abbas AM
      • Mahmoud HR
      • Yones EM
      • Mahmoud A
      • Zakherah MS.
      Levonorgestrel emergency contraceptive pills use during breastfeeding; effect on infants’ health and development.
      ]. After a single 1.5mg dose of LNG, levels peak in breast milk after approximately four hours and reach a maximum concentration of approximately 4.1-10.7 ng/mL, with a mean terminal half-life of 26 hours [
      • Gainer E
      • Massai R
      • Lillo S
      • Reyes V
      • Forcelledo ML
      • Caviedes R
      • et al.
      Levonorgestrel pharmacokinetics in plasma and milk of lactating women who take 1.5 mg for emergency contraception.
      ]. The amount of LNG excreted in milk over the first 24 hours is 0.09% of the dose and decreases rapidly over time, with only 0.01% of the dose recovered in breast milk over the 49-72 hour interval [
      • Gainer E
      • Massai R
      • Lillo S
      • Reyes V
      • Forcelledo ML
      • Caviedes R
      • et al.
      Levonorgestrel pharmacokinetics in plasma and milk of lactating women who take 1.5 mg for emergency contraception.
      ]. The estimated mean amount of progestin absorbed by a nursing infant intaking 800 mL/day of breast milk is 1.6 mcg in the first 24 hours, 0.3 mcg in the second 24 hours, and 0.2 mcg in the third 24-hour interval [
      • Gainer E
      • Massai R
      • Lillo S
      • Reyes V
      • Forcelledo ML
      • Caviedes R
      • et al.
      Levonorgestrel pharmacokinetics in plasma and milk of lactating women who take 1.5 mg for emergency contraception.
      ]. We recommend that clinicians counsel individuals that breastfeeding does not need to be disrupted because of LNG ECP use (GRADE 1A).
      The copper IUD does not pose concerns for breastfed infants. Insertion of a copper IUD does not impact lactation performance and does not result in elevated levels of copper in breast milk compared to individuals who did not receive a copper IUD [

      National Library of Medicine (US). Intrauterine Copper Contraceptive [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/

      ,
      • Berry-Bibee EN
      • Tepper NK
      • Jatlaoui TC
      • Whiteman MK
      • Jamieson DJ
      • Curtis KM.
      The safety of intrauterine devices in breastfeeding women: a systematic review.
      ]. Healthcare providers should be attentive to the overall small but increased risk of uterine perforation associated with IUD insertion in breastfeeding individuals compared to individuals who are not breastfeeding [
      • Berry-Bibee EN
      • Tepper NK
      • Jatlaoui TC
      • Whiteman MK
      • Jamieson DJ
      • Curtis KM.
      The safety of intrauterine devices in breastfeeding women: a systematic review.
      ].
      Little information is available on the use of UPA ECPs while breastfeeding. Currently, package labeling recommends avoiding use while breastfeeding, while the CDC Medical Eligibility Criteria for Contraceptive Use recommends expressing and discarding breast milk for 24 hours after dosing [

      Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

      ,
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ]. It is estimated that following a 30 mg dose, a fully breastfed infant would receive approximately 4.1 mc/kg of UPA and its active metabolite over the first 24 hours and a total of 5.2 mcg/kg over five days. This exposure would result in an approximate adjusted dosage of 0.8% of the medication and active metabolite on the first day and a total of one percent of the maternal dose over a five-day period [

      Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Ulipristal. 2022 Jul 18.

      ]. No studies have addressed infant outcomes in the setting of UPA ECP use and there are no published reports of associated harm. Given the established benefits of breastfeeding, the low level of infant exposure, and no evidence of harm, it is reasonable for individuals to continue breastfeeding without interruption if desired in the setting of shared decision-making.

      2.7 What are the barriers to emergency contraception use?

      2.7.1 Intrauterine devices (IUDs)

      IUD insertions require an in-person visit with a trained provider. While many clinicians in obstetrics and gynecology are well-trained and comfortable with long-acting reversible contraception (LARC) provision, many other healthcare professionals are uncomfortable placing an IUD [
      • Davis SA
      • Braykov NP
      • Lathrop E
      • Haddad LB.
      Familiarity with Long-acting Reversible Contraceptives among Obstetrics and Gynecology, Family Medicine, and Pediatrics Residents: Results of a 2015 National Survey and Implications for Contraceptive Provision for Adolescents.
      ]. There is limited awareness of the copper IUD as an EC option and very few obstetrics and gynecology and primary care clinics offer the copper IUD as EC [
      • Schubert FD
      • Bishop ES
      • Gold M.
      Access to the copper IUD as post-coital contraception: results from a mystery caller study.
      ] . Additional efforts should be made to increase healthcare provider and office staff knowledge and training in IUD provision for EC.
      To effectively place IUDs upon patient request, a clinic or institution must stock devices for same-day placement. Unfortunately, many clinics do not have a readily available stock of IUD devices and instead employ a two-visit IUD insertion approach modeled after outdated STI screening and pregnancy testing protocols or based on difficulties with device reimbursement [
      • Castleberry NM
      • Stark L
      • Schulkin J
      • Grossman D.
      Implementing best practices for the provision of long-acting reversible contraception: a survey of obstetrician-gynecologists.
      ] . Approximately half of patients who must return for a subsequent visit for IUD placement do not return [
      • Bergin A
      • Tristan S
      • Terplan M
      • Gilliam ML
      • Whitaker AK.
      A missed opportunity for care: two-visit IUD insertion protocols inhibit placement.
      ]. Additionally, IUD devices can cost upwards of $800-$900 for self-funded patients, with additional charges associated with insertion and removal [
      • Bellows BK
      • Tak CR
      • Sanders JN
      • Turok DK
      • Schwarz EB.
      Cost-effectiveness of emergency contraception options over 1 year.
      ,
      • Amico JR
      • Heintz C
      • Bennett AH
      • Gold M.
      Access to IUD removal: Data from a mystery-caller study.
      ]. While the Affordable Care Act has resulted in many insurers covering the cost of IUD placement without co-pay for patients, cost may still be a barrier for uninsured and underinsured patients [
      • Tschann M
      • Soon R.
      Contraceptive Coverage and the Affordable Care Act.
      ]. Same-day copper and LNG 52mg IUD insertions for patients with a negative urine pregnancy test are safe and associated with low pregnancy rates [
      • Boraas CM
      • Sanders JN
      • Schwarz EB
      • Thompson I
      • Turok DK.
      Risk of Pregnancy With Levonorgestrel-Releasing Intrauterine System Placement 6-14 Days After Unprotected Sexual Intercourse.
      ,
      • Thompson I
      • Sanders JN
      • Schwarz EB
      • Boraas C
      • Turok DK.
      Copper intrauterine device placement 6–14 days after unprotected sex.
      ]. Clinics should develop same-day IUD insertion protocols that balance their ability to meet patient needs and clinic financial responsibilities. Professional organizations should continue to advocate for private and public funding of IUDs for EC and routine use.

      2.7.2 Emergency contraceptive pills (ECPs)

      LNG ECPs have been approved for sale over-the-counter without age or gender restrictions since 2013. However, individuals trying to purchase the product in pharmacies can encounter lack of availability, additional security measures (locked cabinets, locked exterior packaging), unnecessary requests for identification to enforce outdated age restrictions, and unaffordable cost ($40-50 at most pharmacies) [
      • Cleland K
      • Bass J
      • Doci F
      • Foster AM.
      Access to Emergency Contraception in the Over-the-Counter Era.
      ,
      • Vega A
      • Choi YJ
      • Tschann M
      • Salcedo J.
      Over-the-counter access to levonorgestrel emergency contraception in South Texas: Does Over-the-counter mean ready to buy?.
      ]. Individuals seeking UPA ECPs encounter additional challenges due to the requirement for a prescription. Clinicians and pharmacists are frequently unfamiliar with UPA [
      • Batur P
      • Cleland K
      • McNamara M
      • Wu J
      • Pickle S
      Emergency contraception: A multispecialty survey of clinician knowledge and practices.
      ,
      • Castleberry NM
      • Stark L
      • Schulkin J
      • Grossman D.
      Oral and IUD emergency contraception provision among a national sample of obstetrician–gynecologists.
      ]. Additionally, many pharmacies do not routinely stock UPA and may provide inaccurate information regarding its mechanism of action or differences from LNG ECPs [
      • Shigesato M
      • Elia J
      • Tschann M
      • Bullock H
      • Hurwitz E
      • Wu YY
      • et al.
      Pharmacy access to Ulipristal acetate in major cities throughout the United States.
      ,
      • Bullock H
      • Salcedo J.
      Emergency Contraception: Do Your Patients Have a Plan B?.
      ]. Further, the nuanced clinical guidance related to initiation of routine hormonal contraception following UPA use may deter providers from offering it instead of LNG ECPs [
      • Curtis K
      • Jatlaoui T
      • Tepper N
      • Zapata L
      • Horton L
      • Jamieson D
      • et al.
      U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
      ]. In addition to these barriers, nine states have policies that restrict access to ECPs by excluding ECPs from contraceptive coverage mandates or allowing pharmacists to refuse to provide it [

      Guttmacher Institute. Emergency Contraception, https://www.guttmacher.org/state-policy/explore/emergency-contraception; 2022 [accessed 29 December 2022].

      ].
      Pharmacists play a key role in timely EC access. Pharmacists are positioned to advocate for stocking UPA ECPs, ensuring that LNG ECPs are stocked and available over the counter without additional security measures, and educating pharmacy staff members about EC. An informational guide for pharmacy staff is available from the American Society for Emergency Contraception [

      American Society for Emergency Contraception. Emergency contraception: a guide for pharmacies and retailers, https://www.americansocietyforec.org/_files/ugd/7f2e0b_fc23debfbd29451685a17bec4cb8518f.pdf; 2020 [accessed 29 December 2022].

      ]. Several states currently allow pharmacists to dispense ECPs without a prescription, either through a collaborative practice agreement with a physician or through a state-approved protocol [
      • Rafie S
      • Stone RH
      • Wilkinson TA
      • Borgelt L
      • El-Ibiary SY
      • Ragland D.
      Role of the community pharmacist in emergency contraception counseling and delivery in the United States: current trends and future prospects.
      ]. Telemedicine visits for the provision of EC counseling, prescription of ECPs, and facilitation of in-person visits for EC IUD placement may also decrease barriers to EC access for care in which clinician contact is required or helpful [
      • Stifani BM
      • Madden T
      • Micks E
      • Moayedi G
      • Tarleton J
      • Benson LS.
      Society of Family Planning Clinical Recommendations: Contraceptive Care in the Context of Pandemic Response.
      ].

      2.7.3 Populations most negatively impacted by barriers to emergency contraception access

      Barriers to accessing EC may be amplified for individuals from marginalized communities, those living in rural areas, and young people. In parts of the country that are more geographically dispersed, individuals who need EC may be far from a pharmacy. Additionally, individuals from rural or isolated areas may experience confidentiality or privacy concerns related to familiarity with pharmacy staff and lack of alternatives if ECPs are not in stock or difficult to obtain where initially sought. According to the National Survey of Family Growth, from 2006 to 2017, women of reproductive age living in rural areas were significantly less likely to have used emergency contraception than those living in urban areas, with reported ever use of ECPs increased from six percent to 15% in rural areas compared with 11% to 27% in urban areas during this time period [
      • Milkowski C
      • Ziller E
      • Ahrens K.
      Rural-urban residence and emergency contraception use, access, and counseling in the United States, 2006-2017.
      ]. While EC should be routinely offered following sexual assault involving a risk of pregnancy, this is often not the case in emergency departments, particularly for individuals seeking care within religiously affiliated hospital systems [
      • Workowski K
      • Bachmann L
      • Chan P
      • Johnston CM
      • Muzny CA
      • Park I
      • et al.
      Sexually Transmitted Infections Treatment Guidelines, 2021.
      ,
      • Chandramani A
      • Dussault N
      • Parameswaran R
      • Rodriguez J
      • Novack J
      • Ahn J
      • et al.
      A Needs Assessment and Educational Intervention Addressing the Care of Sexual Assault Patients in the Emergency Department.
      ].
      Young people also face unique challenges in accessing EC. The complicated regulatory history of LNG ECPs in the United States involved several different age restrictions over the years. Although these restrictions have not been in place since 2013 (2014 for generics), pharmacy staff may still ask for identification [
      • Cleland K
      • Bass J
      • Doci F
      • Foster AM.
      Access to Emergency Contraception in the Over-the-Counter Era.
      ]. Additionally, young people may have confidentiality concerns when accessing EC through parents’ health insurance and may lack transportation to a healthcare provider or pharmacy. Young people and others with limited financial resources may find EC cost prohibitive, and only 11 states currently have laws that require insurance plans to cover over-the-counter EC without a prescription [
      • Coursolle A
      • McCaman Taylor L
      Coverage of Over-the-Counter Drugs in Medicaid.
      ].
      Gender diverse individuals face additional barriers when seeking reproductive healthcare generally and EC specifically [
      • Krempasky C
      • Harris M
      • Abern L
      • Grimstad F.
      Contraception across the transmasculine spectrum.
      ]. Clinicians may not recognize that transgender and gender nonbinary patients are at risk of pregnancy or may be reluctant to offer EC to patients on testosterone due to concerns about interactions. Additionally, clinicians may be uncomfortable offering IUD placement. Gender diverse individuals may also anticipate and experience unwanted questions, judgment, and stigma when attempting to purchase ECPs at a pharmacy [

      American Society for Emergency Contraception. Emergency Contraception for Transgender and Nonbinary patients, https://www.americansocietyforec.org/reports-and-factsheets; 2021 [accessed 29 December 2022].

      ].

      2.8 Is there a role for ECPs as a primary contraceptive method?

      In one study, almost 70% of abortion clients and 50% of family planning clients would definitely or probably be interested in a post-coital contraceptive pill as routine contraception [
      • Foster DG
      • Biggs MA
      • Grossman D
      • Schwarz EB.
      Interest in a pericoital pill among women in family planning and abortion clinics.
      ]. Patients who reported recently engaging in unprotected intercourse, those reporting that obtaining a prescription for contraception in the past was “not very easy,” and African American women (compared to non-Hispanic white women) expressing higher levels of interest [
      • Foster DG
      • Biggs MA
      • Grossman D
      • Schwarz EB.
      Interest in a pericoital pill among women in family planning and abortion clinics.
      ]. Top reasons for interest included not needing to remember to take a daily pill, liking the idea of only taking hormones when needed, and infrequent intercourse. In contrast, top reasons for lack of interest included desiring a more effective method, not wanting to remember to use a method pericoitally, and dislike of altered menstrual cycles [
      • Foster DG
      • Biggs MA
      • Grossman D
      • Schwarz EB.
      Interest in a pericoital pill among women in family planning and abortion clinics.
      ]. Additional reasons for interest in a routine post-coital contraceptive pill include ability to conceal use and lack of coital interruption (as compared to use of a coitally-dependent non-hormonal method) [
      • Raymond EG
      • Shochet T
      • Drake JK
      • Westley E
      What some women want? On-demand oral contraception.
      ].
      Use of LNG ECPs as a solitary primary contraceptive method is associated with effectiveness that compares reasonably with coitally-dependent methods, such as barrier methods, withdrawal, and periodic abstinence, that have typical use failure rates on the order of 14-40% [

      Hatcher R. Contraceptive Technology. 21st ed. 2018.

      ]. However, given that individuals in studies of LNG ECPs as a primary contraceptive method are usually selected based on relatively low intercourse frequency, direct comparison of method effectiveness is challenging [
      Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.
      ]. Additionally, use of emergency contraceptive pills as a supplement to non-hormonal methods, planned periodic abstinence, and withdrawal may increase overall contraceptive effectiveness [
      • Shelton JD.
      Repeat emergency contraception: facing our fears.
      ]. No studies have specifically evaluated routine post-coital use of UPA ECPs and concerns about delaying ovulation to later in the cycle may limit its effectiveness for this purpose.
      A 2014 Cochrane review calculated a pooled Pearl Index of 5.4 per 100 person-years (95% CI 4.1-7) for the post-coital use of 0.75mg LNG [
      • Halpern V
      • Raymond EG
      • Lopez LM.
      Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.
      ]. A study that specifically included US individuals taking 0.75 mg LNG within 24 hours of intercourse who expected to have intercourse one to four days per month noted a higher Pearl Index of 22.4 (95% CI 4.6-65.4) [
      • Taylor DJ
      • Lendvay A
      • Halpern V
      • Bahamondes LG
      • Fine PM
      • Ginde SY
      • et al.
      A single-arm study to evaluate the efficacy, safety and acceptability of pericoital oral contraception with levonorgestrel.
      ]. In a more recent study evaluating use of LNG 1.5 mg within 24 hours of intercourse, the Pearl Index was noted to be 7.5 for solitary use in all users, and 11.0 for solitary use in women under 35 years old [
      • Festin MPR
      • Bahamondes L
      • Nguyen TMH
      • Habib N
      • Thamkhantho M
      • Singh K
      • et al.
      A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.
      ]. Oral LNG use pre-coitally may be more effective than post-coital use, as it may concurrently affect both cervical mucus and ovulation [
      • Halpern V
      • Raymond EG
      • Lopez LM.
      Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.
      ].
      The main side effect reported in oral LNG emergency contraception studies is bleeding abnormalities, which have been associated with high discontinuation rates in some studies. Other common side effects include nausea, breast tenderness, weakness, dizziness, headache, abdominal bloating or pain, pelvic pain, decreased libido, depression, and vomiting [
      Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.
      ,
      • Festin MPR
      • Bahamondes L
      • Nguyen TMH
      • Habib N
      • Thamkhantho M
      • Singh K
      • et al.
      A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.
      ]. There is no consistent evidence of a relationship between bleeding abnormalities and frequency of pill intake or total dose of LNG [
      • Halpern V
      • Raymond EG
      • Lopez LM.
      Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.
      ]. The side effect of irregular bleeding may be problematic for individuals who wish to use ECPs in conjunction with natural family planning methods that rely on cycle regularity [
      • Cahill EP
      • Blumenthal PD.
      Pericoital contraception.
      ]. Despite high rates of reported bleeding abnormalities and other side effects, a significant majority of study participants express favorable views of the method [
      Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.
      ,
      • Festin MPR
      • Bahamondes L
      • Nguyen TMH
      • Habib N
      • Thamkhantho M
      • Singh K
      • et al.
      A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.
      ]. Current cost, access, and packaging of LNG ECPs in the United States may make routine ECP use challenging or prohibitive.
      We recommend offering regular pericoital use of LNG ECPs for individuals who desire this method either alone or as a supplement to non-hormonal coitus-dependent methods, such as periodic abstinence, barrier methods, or withdrawal (GRADE 1B).

      3. Clinical Recommendations

      • Please see Appendix 1 for a key to interpreting GRADE.
      • We recommend that the LNG 52mg IUD be offered as a first-line EC option (GRADE 1B).
      • We recommend that clinicians counsel individuals considering emergency contraception on the following:
        • The copper IUD is more effective than ECPs (GRADE 1A).
        • UPA ECPs are more effective than LNG ECPs (GRADE 1A).
        • LNG and UPA ECPs prevent pregnancy through pre-ovulatory effects (GRADE 1A).
        • The LNG 52 mg IUD is non-inferior to the copper IUD for EC within five days of unprotected intercourse (GRADE 1B).
      • Based on this data, we recommend that clinicians counsel individuals that UPA ECPs, if available, are more effective than LNG ECPs in overweight and obese persons and those with body weight 70 kg or greater (GRADE 1C).
      • We recommend advising patients currently or recently taking cytochrome P450-3A4 and P450-3A5 inducers or glucuronidation enzyme inducers that emergency contraceptive pills may be less effective and that IUD placement for EC should be considered (GRADE 1C).
      • We recommend routine hormonal contraception be initiated as soon as desired following LNG ECP use, with abstinence or a non-hormonal contraceptive method used as back-up for seven days or until the next menstrual period/withdrawal bleed, whichever occurs first (GRADE 1A).
      • Following UPA ECPs, we recommend generally delaying initiation of routine hormonal contraception for five days and abstinence or a non-hormonal contraceptive method used as back-up for an additional seven days or until the next menstrual period/withdrawal bleed. However, the specific timing of routine hormonal contraceptive initiation should be individualized through shared decision-making (GRADE 1B).
      • We recommend against withholding or delaying ECPs for pregnancy testing (GRADE 1B). We recommend offering urine pregnancy testing for post-EC pregnancy assessment as needed (GRADE 1C).
      • We recommend offering or referring persons requesting EC for sexually transmitted infection screening, post-exposure prophylaxis, pre-exposure prophylaxis, and treatment as indicated (GRADE 1C).
      • We recommend screening persons who use EC for intimate partner violence and human trafficking as indicated (GRADE 1C).
      • We recommend offering or referring persons who use EC for ongoing contraception as desired (GRADE 1C).
      • We recommend clinicians provide EC counseling and advanced prescription of ECPs to individuals relying on the lactational amenorrhea method (GRADE 1B).
      • We recommend that clinicians counsel individuals that breastfeeding does not need to be disrupted because of LNG ECP use (GRADE 1A).
      • We recommend offering regular pericoital use of LNG ECPs for individuals who desire this method either alone or as a supplement to non-hormonal coitus-dependent methods, such as periodic abstinence, barrier methods, or withdrawal

      4. Recommendations for Future Research

      • Effectiveness of the copper IUD compared to the 52 mg LNG IUS for EC.
      • Effective dosing of LNG and UPA ECPs for individuals with elevated BMI or body weight.
      • Effective dosing of LNG ECPs for individuals concurrently or recently using CYP3A4 inducers.
      • Clinically relevant medication interactions with UPA ECPs.
      • Effects of initiation or reinitiation of various methods of regular hormonal contraception on the effectiveness of UPA ECPs.
      • Effects on ovulation of repeat dosing of UPA ECPs at different times during the same menstrual cycle.
      • Effects of UPA on lactation and breastfeeding infants.
      • Acceptability of EC methods to gender diverse individuals.

      4.1 Sources

      A series of clinical questions was developed by the authors and reviewed by the Society of Family Planning Clinical Affairs Committee. A search of the medical literature was performed using the PubMed program of the National Library of Medicine and the Cochrane Library of Clinical Trials from the beginning of the databases through April 9, 2022. Search terms included, but were not limited to: levonorgestrel, ulipristal acetate, copper intrauterine device, levonorgestrel intrauterine device, sexually transmitted infection, breastfeeding, mechanism of action, safety, effectiveness, transgender, and gender diverse, in combination with emergency contraception, emergency contraceptive pills, postcoital contraception, and pericoital contraception. We then hand searched the references of these manuscripts for additional relevant publications. We reviewed relevant product labels and statements from the American College of Obstetricians and Gynecologists and United States Centers for Disease Control and Prevention. A comprehensive systematic review was not performed.

      Intended Audience

      This Clinical Recommendation is intended for Society of Family planning members, reproductive health service clinicians, reproductive health researchers, and policy makers.

      Authorship

      This Clinical Recommendation was prepared by Jennifer Salcedo, MD, MPH, MPP; Kelly Cleland, MPA, MPH; Ivana Thompson, MD, MSCI, and Deborah Bartz, MD, MPH and was reviewed and approved by the Clinical Affairs Committee on behalf of the Board of Directors of the Society of Family Planning.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Disclaimer

      This publication is designed as a resource to assist clinicians in providing family planning care. It should not be considered inclusive of all proper treatments or serve as the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations, taking into account individual circumstances, may be appropriate. This publication reflects the best-available evidence at the time of publication, recognizing that continued research or major changes in the practice environment may impact future recommendations and should be evaluated for incorporation into care. Any updates to this document can be found on https://www.societyfp.org/clinical-guidance/. The Society and its contributors provide the information contained in this publication "as is" and without any representations or warranties, express or implied, of any kind, whether of accuracy, reliability, or otherwise.

      Data Availability

      • The authors are unable or have chosen not to specify which data has been used.

      Conflict of Interest

      The authors have no conflicts of interest to report. The Society of Family Planning receives no direct support from pharmaceutical companies or other industries for the production of clinical recommendations.

      Appendix A. Key for GRADE recommendationsa

      Tabled 1
      SymbolMeaning
      1Strong recommendation
      2Weaker recommendation
      AHigh quality evidence
      BModerate quality evidence
      CLow quality evidence, clinical experience, or expert consensus
      aSociety of Family Planning clinical recommendations use a modified GRADE system. The GRADE system is described in several publications, with a comprehensive set of articles in the Journal of Clinical Epidemiology (J Clin Epidemiology, (2011) 64:383-394, 64:395-400, 64:401-406, 64:407-415, 64:1277-1282, 64:1283-1293, 64:1294-1302, 64:1303-1312, 64:1311-1316, (2013) 66:140-150, 66: 151-157, 66:158-172, 66:173-183, 66:719-725, 66:726-735).

      References

        • Trussell J
        • Ellertson C
        • von Hertzen H
        • Bigrigg A
        • Webb A
        • Evans M
        • et al.
        Estimating the effectiveness of emergency contraceptive pills.
        Contraception. 2003 Apr; 67: 259-265
        • von Hertzen H
        • Piaggio G
        • Ding J
        • Chen J
        • Song S
        • Barfai G
        • et al.
        Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
        Lancet. 2002 Dec 7; 360: 1803-1810
        • Glasier A.
        The rationale for use of Ulipristal Acetate as first line in emergency contraception: biological and clinical evidence.
        Gynecol Endocrinol. 2014 Oct; 30: 688-690
        • Cleland K
        • Raymond EG
        • Westley E
        • Trussell J
        Emergency contraception review: Evidence-based recommendations for clinicians.
        Clin Obstet Gynecol. 2014 Dec; 57: 741-750
        • BakenRa A
        • Gero A
        • Sanders J
        • Simmons R
        • Fay K
        • Turok DK.
        Pregnancy Risk by Frequency and Timing of Unprotected Intercourse Before Intrauterine Device Placement for Emergency Contraception.
        Obstet Gynecol. 2021 Jul 1; 138: 79-84
        • Sanders JN
        • Howell L
        • Saltzman HM
        • Schwarz EB
        • Thompson IS
        • Turok DK.
        Unprotected intercourse in the 2 weeks prior to requesting emergency intrauterine contraception.
        Am J Obstet Gynecol. 2016 Nov; 215 (592.e1-592.e5)
      1. ACOG Committee Opinion No. 777: Sexual Assault.
        ObstetGynecol. 2019; 133: e296-e302
        • Rothman EF
        • Exner D
        • Baughman AL.
        The prevalence of sexual assault against people who identify as gay, lesbian, or bisexual in the United States: a systematic review.
        Trauma Violence Abuse. 2011; 12 (Apr): 55-66
        • Norris AL
        • Orchowski LM.
        Peer Victimization of Sexual Minority and Transgender Youth: A Cross-Sectional Study of High School Students.
        Psychol Violence. 2020; 10: 201-211
        • Piaggio G
        • Kapp N
        • von Hertzen H.
        Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials.
        Contraception. 2011 Jul; 84: 35-39
      2. International Consortium for Emergency Contraception. EC pill types and countries of availability, by brand, https://toolkits.knowledgesuccess.org/toolkits/emergency-contraception/emergency-contraceptive-pills-registration-status-country; 2022 [accessed 29 December 2022].

        • Jatlaoui TC
        • Riley H
        • Curtis KM.
        Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception.
        Contraception. 2016 Feb 1; 93: 93-112
        • Novikova N
        • Weisberg E
        • Stanczyk FZ
        • Croxatto HB
        • Fraser IS.
        Effectiveness of levonorgestrel emergency contraception given before or after ovulation - a pilot study.
        Contraception. 2007 Feb; 75: 112-118
        • Noé G
        • Croxatto HB
        • Salvatierra AM
        • Reyes V
        • Villarroel C
        • Muñoz C
        • et al.
        Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.
        Contraception. 2011 Nov; 84: 486-492
        • Brache V
        • Cochon L
        • Jesam C
        • Maldonado R
        • Salvatierra AM
        • Levy DP
        • et al.
        Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.
        Hum Reprod. 2010; 25: 2256-2263
        • Li HWR
        • Lo SST
        • Ng EHY
        • Ho PC.
        Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.
        Hum Reprod. 2016 Jun 15; 31: 1200-1207
      3. Duramed Pharmaceuticals Inc. Plan B One-Step (levonorgestrel) tablet, 1.5 mg, for oral use [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021998lbl.pdf; 2009 [accessed 29 December 2022].

      4. Watson Pharma Inc. Ella (ulipristal acetate) tablet [package insert], https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2010 [accessed 29 December 2022].

        • Endler M
        • Li RHW
        Gemzell Danielsson K. Effect of levonorgestrel emergency contraception on implantation and fertility: A review.
        Contraception. 2022 May; 109: 8-18
        • Li HWR
        • Resche-Rigon M
        • Bagchi IC
        • Gemzell-Danielsson K
        • Glasier A.
        Does ulipristal acetate emergency contraception (ella®) interfere with implantation?.
        Contraception. 2019 Nov 1; 100: 386-390
        • Li D
        • Wilcox AJ
        • Dunson DB.
        Benchmark pregnancy rates and the assessment of post-coital contraceptives: an update.
        Contraception. 2015 Apr; 91: 344-349
        • Creinin MD
        • Schlaff W
        • Archer DF
        • Wan L
        • Frezieres R
        • Thomas M
        • et al.
        Progesterone Receptor Modulator for Emergency Contraception: a randomized controlled trial.
        Obstet Gynecol. 2006 Nov; 108: 1089-1097
        • Fine P
        • Mathé H
        • Ginde S
        • Cullins V
        • Morfesis J
        • Gainer E.
        Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception.
        ObstetGynecol. 2010 Feb; 115: 257-263
        • Glasier AF
        • Cameron ST
        • Fine PM
        • Logan SJS
        • Casale W
        • van Horn J
        • et al.
        Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
        Lancet. 2010 Feb 13; 375: 555-562
        • Hamoda H
        • Ashok PW
        • Stalder G
        • Flett GMM
        • Kennedy E
        • Templeton A.
        A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception.
        Obstet Gynecol. 2004 Dec; 104: 1307-1313
        • Dada OA
        • Godfrey EM
        • Piaggio G
        • von Hertzen H
        Nigerian Network for Reproductive Health Research and Training. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria.
        Contraception. 2010 Oct; 82: 373-378
        • Gemzell-Danielsson K
        • Berger C
        • Lalitkumar PGL.
        Emergency contraception - mechanisms of action.
        Contraception. 2013 Mar; 87: 300-308
        • Turok DK
        • Gero A
        • Simmons RG
        • Kaiser JE
        • Stoddard GJ
        • Sexsmith CD
        • et al.
        Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.
        N Engl J Med. 2021 Jan 28; 384: 335-344
        • Ortiz ME
        • Croxatto HB.
        Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action.
        Contraception. 2007 Jun; 75: S16-S30
        • Black T
        • Goldstuck N
        • Spence A.
        Post-coital intrauterine device insertion - a further evaluation.
        Contraception. 1980 Dec; 22: 653-658
        • Guillebaud J
        • Kubba A
        • Rowlands S
        • White J
        • Elder M.
        Post-coital contraception with danazol, compared with an ethinyloestradiol-norgestrel combination or insertion of an intra-uterine device.
        J Obstet Gynaecol. 1983; 3: S64-S68
        • Tamburrino L
        • Marchiani S
        • Minetti F
        • Forti G
        • Muratori M
        • Baldi E.
        The CatSper calcium channel in human sperm: Relation with motility and involvement in progesterone-induced acrosome reaction.
        Hum Reprod. 2014 Mar; 29: 418-428
        • Cleland K
        • Zhu H
        • Goldstuck N
        • Cheng L
        • Trussell J.
        The efficacy of intrauterine devices for emergency contraception: a systematic review of 35 years of experience.
        Hum Reprod. 2012 Jul; 27: 1994-2000
        • Goldstuck ND
        • Cheung TS.
        The efficacy of intrauterine devices for emergency contraception and beyond: a systematic review update.
        Int J Womens Health. 2019 Aug; 11: 471-479
        • Turok DK
        • Sanders JN
        • Thompson IS
        • Royer PA
        • Eggebroten J
        • Gawron LM.
        Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study.
        Contraception. 2016 Jun 1; 93: 526-532
        • Curtis K
        • Jatlaoui T
        • Tepper N
        • Zapata L
        • Horton L
        • Jamieson D
        • et al.
        U.S. Selected Practice Recommendations for Contraceptive Use, 2016.
        MMWR Recomm Rep. 2016 Jul 29; 65: 1-66
      5. Selected Rractice Recommendations for Contraceptive Use.
        3rd ed. World Health Organization, Geneva2016
        • Webb A
        • Taberner D.
        Clotting factors after emergency contraception.
        Adv Contracept. 1993 Mar; 9: 75-82
        • Farley TM
        • Rosenberg MJ
        • Rowe PJ
        • Chen JH
        • Meirik O.
        Intrauterine devices and pelvic inflammatory disease: an international perspective.
        Lancet. 1992 Mar 28; 339: 785-788
        • Gordon C
        • Harken T.
        Controversies in family planning: intrauterine device placement in solid organ transplant patients.
        Contraception. 2019 Sep 1; 100: 250-252
        • Juliato CRT
        • Stahlschmidt P
        • Fernandes A
        • Monteiro I
        • Bahamondes L.
        A case series on the use of levonorgestrel 52 mg intrauterine system after organ transplant.
        Contraception. 2018 Sep 1; 98: 252-254
        • Morrison CS
        • Sekadde-Kigondu C
        • Sinei SK
        • Weiner DH
        • Kwok C
        • Kokonya D.
        Is the intrauterine device appropriate contraception for HIV-1-infected women?.
        BJOG. 2001 Aug; 108: 784-790
        • Huguelet PS
        • Sheehan C
        • Spitzer RF
        • Scott S.
        Use of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients: a case series.
        Contraception. 2017 Apr 1; 95: 378-381
        • Kim CR
        • Martinez-Maza O
        • Magpantay L
        • Magyar C
        • Gornbein J
        • Rible R
        • et al.
        Immunologic evaluation of the endometrium with a levonorgestrel intrauterine device in solid organ transplant women and healthy controls.
        Contraception. 2016 Nov 1; 94: 534-540
        • Boraas CM
        • Sanders JN
        • Schwarz EB
        • Thompson I
        • Turok DK.
        Risk of Pregnancy With Levonorgestrel-Releasing Intrauterine System Placement 6-14 Days After Unprotected Sexual Intercourse.
        Obstet Gynecol. 2021 Apr 1; 137: 623-625
        • Thompson I
        • Sanders JN
        • Schwarz EB
        • Boraas C
        • Turok DK.
        Copper intrauterine device placement 6–14 days after unprotected sex.
        Contraception. 2019 Sep 1; 100: 219-221
        • Glasier A
        • Cameron ST
        • Blithe D
        • Scherrer B
        • Mathe H
        • Levy D
        • et al.
        Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.
        Contraception. 2011 Oct; 84: 363-367
        • Festin MPR
        • Peregoudov A
        • Seuc A
        • Kiarie J
        • Temmerman M.
        Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies.
        Contraception. 2017 Jan 1; 95: 50-54
        • Kapp N
        • Abitbol JL
        • Mathé H
        • Scherrer B
        • Guillard H
        • Gainer E
        • et al.
        Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception.
        Contraception. 2015 Feb 1; 91: 97-104
        • Edelman AB
        • Cherala G
        • Blue SW
        • Erikson DW
        • Jensen JT.
        Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: Single and double dosing.
        Contraception. 2016 Jul 1; 94: 52-57
        • Edelman AB
        • Hennebold JD
        • Bond K
        • Lim JY
        • Cherala G
        • Archer DF
        • et al.
        Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.
        Obstet Gynecol. 2022 Jul 1; 140: 48-54
        • le Corvaisier C
        • Capelle A
        • France M
        • Bourguignon L
        • Tod M
        • Goutelle S.
        Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.
        Fundam Clin Pharmacol. 2021 Apr 1; 35: 208-216
        • Carten ML
        • Kiser JJ
        • Kwara A
        • Mawhinney S
        • Cu-Uvin S.
        Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz.
        Infect Dis Obstet Gynecol. 2012; 2012137192
        • Pohl O
        • Osterloh I
        • Gotteland JP.
        Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.
        J Clin Pharm Ther. 2013 Dec; 38: 512-517
        • Pohl O
        • Zobrist RH
        • Gotteland JP.
        The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids.
        ReprodSci. 2015 Apr 15; 22: 476-483
        • Matyanga CMJ
        • Dzingirai B.
        Clinical Pharmacology of Hormonal Emergency Contraceptive Pills.
        Int J Reprod Med. 2018 Oct 4; 20182785839
        • Ellison J
        • Thompson AJ
        • Greer I.
        Apparent interaction between warfarin and levonorgestrel used for emergency contraception.
        BMJ. 2000 Dec 2; 321: 1382
        • Zhang J
        • Li C
        • Zhao WH
        • Xi X
        • Cao SJ
        • Ping H
        • et al.
        Association between levonorgestrel emergency contraception and the risk of ectopic pregnancy: A multicenter case-control study.
        Sci Rep. 2015 Feb 12; 5: 8487
        • Jesam C
        • Cochon L
        • Salvatierra AM
        • Williams A
        • Kapp N
        • Levy-Gompel D
        • et al.
        A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate.
        Contraception. 2016 Apr 1; 93: 310-316
      6. Medicines and Healthcare products Regulatory Agency UK. Esmya (ulipristal acetate): suspension of the licence due to risk of serious liver injury, https://www.gov.uk/drug-safety-update/esmya-ulipristal-acetate-suspension-of-the-licence-due-to-risk-of-serious-liver-injury; 2021 [accessed 29 December 2022].

        • Donnez J
        • Arriagada P
        • Marciniak M
        • Larrey D.
        Liver safety parameters of ulipristal acetate for the treatment of uterine fibroids: a comprehensive review of the clinical development program. Vol. 17.
        Expert Opin Drug Saf. 2018 Dec; 17: 1225-1232
        • Gatti M
        • Poluzzi E
        • de Ponti F
        • Raschi E.
        Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis.
        Drug Saf. 2020 Dec 1; 43: 1277-1285
        • Donnez J.
        Liver injury and ulipristal acetate: an overstated tragedy? Vol. 110.
        Fertil Steril. 2018 Sep; 110: 593-595
        • Yoon EL
        • Yuk JS.
        Use of Ulipristal Acetate and Risk of Liver Disease: A Nationwide Cohort Study.
        Journal of Clinical Endocrinology and Metabolism. 2021 May 13; 106: 1773-1782
        • Bracken MB.
        Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies.
        Obstet Gynecol. 1990 Sep; 76: 552-557
        • Raman-Wilms L
        • in Tseng AL
        • Wighardt S
        • Einarson TR
        • Koren G
        Fetal genital effects of first-trimester sex hormone exposure: A meta-analysis.
        Obstet Gynecol. 1995 Jan; 85: 141-149
      7. Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: Postmarketing experience after use by more than 1 million women. Contraception. 2014 May;89(5):431–3.

        • Zinaman MJ
        • Clegg ED
        • Brown CC
        • O'connor J
        • Selevan SG.
        Estimates of human fertility and pregnancy loss.
        Fertil Steril. 1996 Mar; 65: 503-509
        • Cleland K
        • Raymond E
        • Trussell J
        • Cheng L
        • Zhu H.
        Ectopic pregnancy and emergency contraceptive pills: a systematic review.
        Obstet Gynecol. 2010 Jun; 115: 1263-1266
        • Barnhart KT
        Ectopic Pregnancy.
        N Eng J Med. 2009 Jul 23; 361: 379-387
        • Castaño PM
        • Westhoff CL.
        Experience with same-day placement of the 52 mg levonorgestrel-releasing intrauterine system.
        Am J Obstet Gynecol. 2020 Apr 1; 222 (S883.e1-S883.e6)
        • Brahmi D
        • Steenland MW
        • Renner RM
        • Gaffield ME
        • Curtis KM.
        Pregnancy outcomes with an IUD in situ: a systematic review.
        Contraception. 2012 Feb; 85: 131-139
        • Westhoff C
        • Kerns J
        • Morroni C
        • Cushman LF
        • Tiezzi L
        • Murphy PA.
        Quick Start: novel oral contraceptive initiation method.
        Contraception. 2002 Sep; 66: 141-145
      8. Nelson AL, Katz T. Initiation and continuation rates seen in 2-year experience with Same Day injections of DMPA. Contraception. 2007 Feb;75(2):84–7.

        • Brache V
        • Cochon L
        • Duijkers IJM
        • Levy DP
        • Kapp N
        • Monteil C
        • et al.
        A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
        Hum Reprod. 2015 Dec; 30: 2785-2793
        • Cameron ST
        • Berger C
        • Michie L
        • Klipping C
        • Gemzell-Danielsson K.
        The effects on ovarian activity of ulipristal acetate when ‘quickstarting’ a combined oral contraceptive pill: A prospective, randomized, double-blind parallel-arm, placebo-controlled study.
        Hum Reprod. 2015 Jul; 30: 1566-1572
        • Edelman AB
        • Jensen JT
        • McCrimmon S
        • Messerle-Forbes M
        • O'Donnell A
        • Hennebold JD
        Combined oral contraceptive interference with the ability of ulipristal acetate to delay ovulation: A prospective cohort study.
        Contraception. 2018 Dec 1; 98: 463-466
        • Banh C
        • Rautenberg T
        • Duijkers I
        • Borenzstein P
        • Monteil C
        • Levy-Gompel D
        • et al.
        The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
        Contraception. 2020 Sep 1; 102: 145-151
        • Zapata LB
        • Steenland MW
        • Brahmi D
        • Marchbanks PA
        • Curtis KM.
        Effect of missed combined hormonal contraceptives on contraceptive effectiveness: a systematic review.
        Contraception. 2013 May; 87: 685-700
        • Tuddenham S
        • Hamill MM
        • Ghanem KG.
        Diagnosis and Treatment of Sexually Transmitted Infections: A Review.
        JAMA. 2022 Jan 11; 327: 161-172
        • Workowski K
        • Bachmann L
        • Chan P
        • Johnston CM
        • Muzny CA
        • Park I
        • et al.
        Sexually Transmitted Infections Treatment Guidelines, 2021.
        MMWR Recomm Rep. 2021 Jul 23; 70: 1-187
        • Jatlaoui TC
        • Simmons KB
        • Curtis KM.
        The safety of intrauterine contraception initiation among women with current asymptomatic cervical infections or at increased risk of sexually transmitted infections.
        Contraception. 2016 Dec 1; 94: 701-712
        • Decker MR
        • Mack KP
        • Barrows JJ
        • Silverman JG.
        Sex trafficking, violence victimization, and condom use among prostituted women in Nicaragua.
        Int J Gynaecol Obstet. 2009 Nov; 107: 151-152
        • Orchowski LM
        • Yusufov M
        • Oesterle D
        • Bogen KW
        • Zlotnick C.
        Intimate Partner Violence and Coerced Unprotected Sex Among Young Women Attending Community College.
        Arch Sex Behav. 2020 Apr 1; 49: 871-882
        • Wolgemuth T
        • Judge-Golden C
        • Callegari L
        • Zhao X
        • Mor M
        • Borrero S.
        Associations between Pregnancy Intention, Attitudes, and Contraceptive Use among Women Veterans in the ECUUN Study.
        Womens Health Issues. 2018 Nov-Dec; 28: 480-487
      9. American Society for Emergency Contraception. Emergency Contraception for Transgender and Nonbinary patients, https://www.americansocietyforec.org/reports-and-factsheets; 2021 [accessed 29 December 2022].

        • Bonnington A
        • Dianat S
        • Kerns J
        • Hastings J
        • Hawkins M
        • de Haan G
        • et al.
        Society of Family Planning clinical recommendations: Contraceptive counseling for transgender and gender diverse people who were female sex assigned at birth.
        Contraception. 2020 Aug 1; 102: 70-82
        • Shaaban OM
        • Hassen SG
        • Nour SA
        • Kames MA
        • Yones EM.
        Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial.
        Contraception. 2013 Mar; 87: 363-369
        • Shaaban OM
        • Abbas AM
        • Mahmoud HR
        • Yones EM
        • Mahmoud A
        • Zakherah MS.
        Levonorgestrel emergency contraceptive pills use during breastfeeding; effect on infants’ health and development.
        J Matern Fetal Neonatal Med. 2019 Aug 3; 32: 2524-2528
        • Gainer E
        • Massai R
        • Lillo S
        • Reyes V
        • Forcelledo ML
        • Caviedes R
        • et al.
        Levonorgestrel pharmacokinetics in plasma and milk of lactating women who take 1.5 mg for emergency contraception.
        Hum Reprod. 2007 Jun; 22: 1578-1584
      10. National Library of Medicine (US). Intrauterine Copper Contraceptive [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/

        • Berry-Bibee EN
        • Tepper NK
        • Jatlaoui TC
        • Whiteman MK
        • Jamieson DJ
        • Curtis KM.
        The safety of intrauterine devices in breastfeeding women: a systematic review.
        Contraception. 2016 Dec 1; 94: 725-738
      11. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Ulipristal. 2022 Jul 18.

        • Davis SA
        • Braykov NP
        • Lathrop E
        • Haddad LB.
        Familiarity with Long-acting Reversible Contraceptives among Obstetrics and Gynecology, Family Medicine, and Pediatrics Residents: Results of a 2015 National Survey and Implications for Contraceptive Provision for Adolescents.
        J Pediatr Adolesc Gynecol. 2018 Feb 1; 31: 40-44
        • Schubert FD
        • Bishop ES
        • Gold M.
        Access to the copper IUD as post-coital contraception: results from a mystery caller study.
        Contraception. 2016 Nov 1; 94: 561-566
        • Castleberry NM
        • Stark L
        • Schulkin J
        • Grossman D.
        Implementing best practices for the provision of long-acting reversible contraception: a survey of obstetrician-gynecologists.
        Contraception. 2019 Aug 1; 100: 123-127
        • Bergin A
        • Tristan S
        • Terplan M
        • Gilliam ML
        • Whitaker AK.
        A missed opportunity for care: two-visit IUD insertion protocols inhibit placement.
        Contraception. 2012 Dec; 86: 694-697
        • Bellows BK
        • Tak CR
        • Sanders JN
        • Turok DK
        • Schwarz EB.
        Cost-effectiveness of emergency contraception options over 1 year.
        Am J Obstet Gynecol. 2018 May 1; 218 (508.e1-508.e9)
        • Amico JR
        • Heintz C
        • Bennett AH
        • Gold M.
        Access to IUD removal: Data from a mystery-caller study.
        Contraception. 2020 Feb 1; 101: 122-129
        • Tschann M
        • Soon R.
        Contraceptive Coverage and the Affordable Care Act.
        Obstet Gynecol Clin North Am. 2015 Dec; 42: 605-617
        • Cleland K
        • Bass J
        • Doci F
        • Foster AM.
        Access to Emergency Contraception in the Over-the-Counter Era.
        Womens Health Issues. 2016 Nov-Dec; 26: 622-627
        • Vega A
        • Choi YJ
        • Tschann M
        • Salcedo J.
        Over-the-counter access to levonorgestrel emergency contraception in South Texas: Does Over-the-counter mean ready to buy?.
        Contraception. 2021 Sep 1; 104: 271-274
        • Batur P
        • Cleland K
        • McNamara M
        • Wu J
        • Pickle S
        Emergency contraception: A multispecialty survey of clinician knowledge and practices.
        Contraception. 2016 Feb 1; 93: 145-152
        • Castleberry NM
        • Stark L
        • Schulkin J
        • Grossman D.
        Oral and IUD emergency contraception provision among a national sample of obstetrician–gynecologists.
        Contraception. 2020 Dec 1; 102: 406-408
        • Shigesato M
        • Elia J
        • Tschann M
        • Bullock H
        • Hurwitz E
        • Wu YY
        • et al.
        Pharmacy access to Ulipristal acetate in major cities throughout the United States.
        Contraception. 2018 Mar 1; 97: 264-269
        • Bullock H
        • Salcedo J.
        Emergency Contraception: Do Your Patients Have a Plan B?.
        Obstetd Gynecol Clin North Am. 2015 Dec; 42: 699-712
      12. Guttmacher Institute. Emergency Contraception, https://www.guttmacher.org/state-policy/explore/emergency-contraception; 2022 [accessed 29 December 2022].

      13. American Society for Emergency Contraception. Emergency contraception: a guide for pharmacies and retailers, https://www.americansocietyforec.org/_files/ugd/7f2e0b_fc23debfbd29451685a17bec4cb8518f.pdf; 2020 [accessed 29 December 2022].

        • Rafie S
        • Stone RH
        • Wilkinson TA
        • Borgelt L
        • El-Ibiary SY
        • Ragland D.
        Role of the community pharmacist in emergency contraception counseling and delivery in the United States: current trends and future prospects.
        Integr Pharm Res Pract. 2017 Mar; 6: 99-108
        • Stifani BM
        • Madden T
        • Micks E
        • Moayedi G
        • Tarleton J
        • Benson LS.
        Society of Family Planning Clinical Recommendations: Contraceptive Care in the Context of Pandemic Response.
        Contraception. 2022 Sep 1; 113: 1-12
        • Milkowski C
        • Ziller E
        • Ahrens K.
        Rural-urban residence and emergency contraception use, access, and counseling in the United States, 2006-2017.
        Contracept X. 2021 Feb 8; 3100061
        • Chandramani A
        • Dussault N
        • Parameswaran R
        • Rodriguez J
        • Novack J
        • Ahn J
        • et al.
        A Needs Assessment and Educational Intervention Addressing the Care of Sexual Assault Patients in the Emergency Department.
        J Forensic Nurs. 2020 Apr 1; 16: 73-82
        • Coursolle A
        • McCaman Taylor L
        Coverage of Over-the-Counter Drugs in Medicaid.
        National Health Law Program. 2022; ([accessed 29 December])
        • Krempasky C
        • Harris M
        • Abern L
        • Grimstad F.
        Contraception across the transmasculine spectrum.
        Am J Obstet Gynecol. 2020 Feb 1; 222: 134-143
        • Foster DG
        • Biggs MA
        • Grossman D
        • Schwarz EB.
        Interest in a pericoital pill among women in family planning and abortion clinics.
        Contraception. 2013 Jul; 88: 141-146
        • Raymond EG
        • Shochet T
        • Drake JK
        • Westley E
        What some women want? On-demand oral contraception.
        Contraception. 2014; 90: 105-110
      14. Hatcher R. Contraceptive Technology. 21st ed. 2018.

      15. Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.
        Task Force on on Post=Ovulatory Methods of Fertility Regulation. Contraception. 2000 May; 61: 303-308
        • Shelton JD.
        Repeat emergency contraception: facing our fears.
        Contraception. 2002 Jul; 66: 15-17
        • Halpern V
        • Raymond EG
        • Lopez LM.
        Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.
        Cochrane Database of Syst Revi. 2014 Sep 26; 2014CD007595
        • Taylor DJ
        • Lendvay A
        • Halpern V
        • Bahamondes LG
        • Fine PM
        • Ginde SY
        • et al.
        A single-arm study to evaluate the efficacy, safety and acceptability of pericoital oral contraception with levonorgestrel.
        Contraception. 2014 Mar; 89: 215-221
        • Festin MPR
        • Bahamondes L
        • Nguyen TMH
        • Habib N
        • Thamkhantho M
        • Singh K
        • et al.
        A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.
        Hum Reprod. 2016 Mar 1; 31: 530-540
        • Cahill EP
        • Blumenthal PD.
        Pericoital contraception.
        Curr Opin Obstet Gynecol. 2018 Dec 1; 30: 400-406