Emergency contraception

Dr. Alka Pandey

1. Dr. Alka Pandey Associate Prof. PMCH, Deptt . o f OBS & GYN, Patna Emergency Contraception

2. What is Emergency Contraception ?? Emergency contraception (EC) - Contraception used as an emergency step taken before menstruation is missed It prevents pregnancy following unprotected sexual intercourse(UPSI) or expected failure of contraception It is popularly called as ‘Morning after pill’ or “ Postcoital oral contraceptive.” https://www.acog.org/patient-resources/faqs/contraception/emergency-contraception

3. Unintended pregnancy Each year, approximately 85 million women (41 %) in the world face an unintended pregnancy . More than one in seven of these cases occur in India 46 million unwanted pregnancies end in abortion each year, 20 million of which are unsafe. Singh V et al. Int J Adv Med. 2014 Aug;1(2):105-112

4. Demographics India’s population currently is 1.31 billion. Even though a wide variety of contraceptive choices are available in India, contraceptive prevalence in the country is only 56% as per the WHO global health statistics 2012 *WHO global health statistics 2012

5. Indian Scenario: data by Health Facilities Survey 2015 25·8 million pregnancies (54%) resulted in births 33% of pregnancies ended in induced abortions, and 14% of pregnancies ended in a miscarriage The rate of unintended pregnancy was estimated at 70 pregnancies per 1000 women aged 15–49 years Distribution of pregnancies by outcome, India, 2015

6. National abortion incidence Abortion rate by type and source in India, 2015 It is estimated that 15·6 million abortions took place in India in 2015 , giving an abortion rate of 47 per 1000 women aged 15 –49 years Singh A. Matern Child Health J.2013.

7. Response to the problem With the use of effective contraception, 90% of abortion-related and 20% of pregnancy-related morbidity and mortality can be prevented Emergency contraceptive Pills are largely underutilized in India. Munakampe, M.N, BMC Health Serv Res (2018)

8. Effectiveness OF Emergency CONTRACEPTIVE PILLS

9. In what Situations can emergency contraception be used When no contraceptive has been used. Sexual assault when the woman was not protected by an effective contraceptive method. When there is concern of possible contraceptive failure, from improper or incorrect use, such as : Emergency contraception can be used in a number of situations following sexual intercourse. These include.

10. Condom breakage, slippage, or incorrect use; 3 or more consecutively missed combined oral contraceptive pills; More than 3 hours late from the usual time of intake of the progestogen -only pill ( minipill ), or more than 27 hours after the previous pill. In what Situations can emergency contraception be used

11. More than 12 hours late from the usual time of intake of the desogestrel -containing pill (0.75mg) or more than 36hours after the previous pill. More than 4 weeks late for the depot- medroxyprogesterone acetate (DMPA) progestogen only injection. In what Situations can emergency contraception be used

12. Dislodgment, breakage, tearing, or early removal of a diaphragm or cervical cap. Failed withdrawal , ejaculation in the vagina or on external genitalia). In what Situations can emergency contraception be used

13. Failure of a spermicide tablet or film to melt before intercourse. Miscalculation of the abstinence period, failure to abstain or use a barrier method on the fertile days of the cycle when using fertility awareness based methods . Expulsion of an intrauterine contraceptive device (IUD) or hormonal contraceptive implant. In what Situations can emergency contraception be used

14. Clinical Considerations Recommendations as to which ECP to use depends on a number of factors : Timing of presentation after unprotected sexual intercourse. Patient factors (such as obesity, allergies, and concurrent medications). Availability

15. Timing of unprotected sexual intercourse All methods are highly effective within 72 hours of unprotected sexual intercourse. The Copper IUD and Ulipristal acetate are effective over 120 hours.

16. Patient factor - Weight While BMI 30 kg/m2 is not considered a contraindication to ECPs Selection of a method may vary

17. LNG is metabolized by the CYP3A4 microsomal system. Medications which induce the CYP3A4 eg . Antifungals and Antiepileptic drugs may decrease levels of LNG Patient factor - Concomitant medications

18. The story of Emergency Contraceptive Pills 1967 First used five-day treatments with high-dose estrogens, using diethylstilbestrol (DES) 2002 China was the first country were mifepristone was registered for use as EC 1998 WHO trial Yuzpe regimen was gradually withdrawn and levonorgestel widely used 1975 Copper IUD was first studied for use as EC 1975 Progestin only postcoital pill was investigated 1980 Yuzpe regimen became the standard treatment for EC Rosato E, Farris M and Bastianelli C (2016) Mechanism of Action of Ulipristal Acetate for Emergency Contraception: A Systematic Review 1974 Yuzpe regimen (Combined preparation containing both ethinyl estradiol & levonorgestrel

19. Indian Scenario In India, ECP was introduced in 2002 by the Ministry of Health and Family Welfare (MoHFW) and was made an over the counter (OTC) drug in 2005 Less than one-third women are aware of ECP and less than one percent have ever used it Data from 8 states covered in the Annual Health Survey shows a continued very low (less than 0.2 percent) use of ECP *Indian J Community Med. 2015 Jan-Mar; 40(1): 49–55

20. Yuzpe Method Oldest form of post-coital emergency contraception This method involves taking two pills each containing 50 µg of ethinylestradiol and 0.50 mg of dl- norgestrel or 1 .5 mg levonorgestrel within the first 72 hours . This treatment is repeated 12 hours later The Yuzpe method works by delaying or inhibiting ovulation, when utilized during the first half of the menstrual cycle It is only effective if follicles are not already well developed

21. AUTHORS NO OF WOMEN PREGNANCIES FAILURE RATE % Yuzpe 1982 647 11 1.7 Van Santen1985 461 6 1.3 Wright 1986 184 6 3.3 Percival Smith 1987 774 18 2.3 Fasoli 1989* 3802 69 1.8 Zuliani 1990 407 9 2.2 Webb 1992 191 5 2.6 Glasier 1992 398 4 1 Ho 1993 341 9 2.6 Sanchez-Borrego 1996 117 1 0.9 Sanchez-Borrego 1996 423 3 0.7 Creinin 1997 2871 54 1.9 Trussell 1998* 2858 49 1.7 Von Hertzen 1998 979 31 3.2 Efficacy of Yuzpe regimen in clinical trials (Meta Analysis)

22. Efficacy of Yuzpe regimen After a single act of unprotected sexual intercourse, the Yuzpe regimen fails in about 2 of women who use it correctly (1.9%, 95 CI 1.4–2.4 %) Kubba AA. Eur. J Contracept. Reprod. Health Care 1997

23. Side effects with Yuzpe method The Yuzpe method has more pronounced side effects . 50% of women develop nausea, and 20% develop vomiting ( Yuzpe et al., 1982; Percival - Smith and Abercrombie, 1987; Ho and Kwan, 1993) Antiemetic medications are recommended if the Yuzpe method is used Changes in menstrual bleeding, mastalgia and increased risk of venous thromboembolism are observed

24. Levonorgestrel (LNG) Levonorgestrel (LNG) is a progestin-only pill licensed in many countries around the world Single dose oral tablet of LNG (1.5 mg) or two doses (0.75 mg each – 12 hours apart) to be taken within 72 hours of unprotected intercourse LNG suppresses luteinizing hormone, which delays or inhibits ovulation In order to be effective, it must be administered before the LH surge begins. Thus it is reasonable to infer that LNG is less effective when given closer to the time of ovulation Haeger et al. Contraception and Reproductive Medicine (2018) 3:20

25. A randomized trial with 1998 women at 21 centers worldwide was undertaken by WHO This trial found that the crude pregnancy rate was 1.1% in the LNG group and 3.2% in the Yuzpe method group, yielding a relative risk of 0.36 (95% CI = 0.18–0.70) The estimated efficacy, when used within 72 hours of intercourse was 85% for LNG, compared with 57% in the Yuzpe method group The efficacy (based on estimates of conception probabilities) of LNG decreased with time: from 95% at 24 hours to 58% when taken between 49–72 hours

26. Efficacy of LNG Efficacy of 1.5 mg of LNG may decrease among patients weighing more than 70 kg or with a BMI greater than 26 kg/m2, with a four-fold risk of pregnancy in obese women compared to women with a normal BMI Such cases need doubling the dose to 3.0 mg, but effect is not well documented A further advantage of the levonorgestrel -only is the absence of ethinylestradiol which may cause VTE.

27. Side effects of Levonorgestrel The most common side effects with LNG are nausea (23%) and vomiting (5.6%) Less common effects include fatigue, dizziness, headache, and mastalgia Disruption in the menstrual cycle pattern may also occur When LNG is taken in the preovulatory stage of menses, the length of the cycle may be abbreviated; in the peri - and postovulatory phases, cycle length is unaffected, but the duration of bleeding is elongated in the subsequent cycle

28. Copper IUD The most effective form of emergency contraception.It is inserted within 5 day of UPSI without change in efficacy Has advantage of providing ongoing contraception for up to 10 years The main mechanism of action of copper IUDs is inhibition of fertilization as the copper ions released from the device have a toxic effect on sperm and ova, which affects their motility and viability Where fertilization does occur, implantation is prevented because of the inflammatory response in the endometrium Both PRE-FERTILISATION and POST-FERTILISATION action Australian family physician. 2017 Oct;46(10):722.

29. Efficacy of Copper IUD in clinical trials Authors No of women Pregnancies Failure rate % Comments Lippes 1979 202 Cu7 Insertion < 7 days Black 1980 176 1 0.57 CuT Insertion < 10 days Gottardi 1986 98 Insertion < 7 days Fasoli 1989* 879 1 0.1 Insertion 1-10 days

30. In a systematic review, 42 studies analyzed patients that had copper IUDs inserted 2–10 days after unprotected intercourse From a total of 7,034 patients who had post-coital IUD insertions, there were only 10 pregnancies, with a failure rate of only 0.14% (95% CI = 0.08%–0.25%) Study concluded, IUDs are a highly effective method of contraception after unprotected intercourse Cleland K et al. Human reproduction. 2012

31. Side effects with the copper IUD The most common side effects with the copper IUD are pain during insertion, and increased menstrual bleeding. Absolute contraindications to copper IUD placement are the same as with routine insertion Pregnancy, Undiagnosed vaginal bleeding, Malignancy of the genital tract Congenital abnormalities of the uterus Copper allergy

32. Limitations Despite the long-term contraceptive benefits of the copper IUDs, this method remains underutilized The necessity of IUD placement by a trained health care provider Lack of provider and patient knowledge regarding the IUD’s effectiveness and use as a form of EC, contribute to the relatively low use of the copper IUD as a form of EC

33. Ulipristal Acetate (UPA) 30 mg Ulipristal acetate is a derivative of 19-norprogesterone It is a selective progesterone- receptor modulator (SPRM)

34. Drug Approval Use of this SPRM – Ulipristal Acetate 30 mg for EC was authorized by : 2009 In Europe by The European Medicines (EMEA) 2010 In USA by US Food and Drug Administration (FDA) 2016 In Australia, approved by the Therapeutic Goods Administration (TGA) 2020 In India, approved by DCGI

35. Mechanism of Action UPA has an inhibitory effect on ovulation when administered during the follicular phase

36. One tablet should be taken orally as soon as possible, but no later than 120 hours (5 days) after UPSI or contraceptive failure If vomiting occurs within 3 hours of the tablet intake, another tablet should be taken Pregnancy should be excluded before the tablet is administered

37. Pharmacokinetics - Ulipristal Acetate 30 mg Metabolism occurs in the liver UPA is metabolized to mono- demethylated and di-demethylated metabolites predominantly mediated by CYP3A4 The mono- demethylated metabolite is pharmacologically active The active terminal half-life after 30 mg single dose is estimated to be 32.4 ± 6.3 hours 90% of the excretion is with feces Ferrero S. Expert opinion on drug metabolism & toxicology. 2018

38. DRUG INTERACTIONS - Ulipristal Acetate 30 mg UPA’s efficacy may be reduced when it is taken concomitantly with drugs like -Barbiturates, carbamazepine , phenytoin , griseofulvin , and rifampin . In contrast , CYP3A4 inhibitors such as itraconazole and ketaconazole may increase plasma concentrations of UPA Alterations in gastric pH may also reduce absorption and plasma levels of ulipristal acetate Thus, concomitant use of acid-suppressive drugs, such as PPI, H2 Blocker, and antacids to be avoided

39. Hormonal contraception use after administration of ulipristal acetate Ulipristal acetate: an update for Australian GPs. Australian family physician. 2017 May;46(5):301.

40. Side Effects Headache Abdominal pain Nausea Dysmenorrhea Fatigue Dizziness Delayed menses by 2.1 days *https://www.medscape.com/viewarticle/926833

41. https://www.medscape.com/viewarticle/926833

42. EMA (European Medicines Agency's ) states that the single-dose ulipristal acetate  30 mg emergency contraceptive does not have concerns of liver injury* https://www.medscape.com/viewarticle/926833

43. Safety No teratogenic effects or birth defects have been associated with UPA. There are no adverse outcomes associated with breastfeeding after taking UPA. American guideline discourages mothers from giving breast milk in the 24 h following consumption of UPA. European guidelines suggest a 7-day window before resuming breast feeding following the ingestion of UPA Haeger KO. Contracept Reprod Med. 2018

44. CONTRAINDICATIONS - Ulipristal Acetate 30 mg Hypersensitivity to UPA Severe liver disease, owing to its metabolism in liver Known or suspected pregnancy

45. Effects on Ovulation With a follicle’s diameter of 14 –16mm The lead follicle stops growing and was replaced by a new lead follicle With leading follicle’s diameter ≥18 mm Follicular rupture is delayed for at least 5-6 days, until sperm from the UPSI for which EC was taken are no longer viable Brache et al., 2010

46. Aim : This study was designed to determine the capacity of ulipristal acetate (UPA) 30mg, a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of ≥18 mm.

47. A single dose of 30 mg UPA administered immediately before ovulation (either before the LH surge or when the LH surge has already begun) significantly delays or inhibits subsequent follicular rupture in comparison to placebo-treated cycles Authors concluded…

48. Raw data from three pharmacokinetic studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG + meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of ≥18 mm

49. Three Pharmacodynamics Studies Study 1: LNG 1.5 mg Vs Placebo Study 2 : LNG 1.5 mg Vs LNG 1.5 mg + Meloxicam 15 mg Study 3 : UPA 30 mg Vs Placebo

50. Survival analysis of time to follicular rupture from treatment intake to the fifth day after treatment Dominant Follicle Persisting for at least 5 days after Treatment (%) UPA : 58.8 % LNG : 14.6% LNG + Melox : 38.7% Placebo : 4% The median time from treatment to rupture was 6 days during the UPA cycles versus 2 days in the LNG cycles Brache V. Contraception. 2013

51. Efficacy Difference between Levonorgestrel and Ulipristal Acetate : Proportion of unruptured dominant follicles at 5 days after treatment according to LH status at time of intake Brache V. Contraception. 2013

52. Ulipristal acetate prevents ovulation more effectively than levonorgestrel UPA Contraception. 2013 Nov 1;88(5):611-8. Physiological LH Surge UPA works on the most fertile days, i.e. just before ovulation, during the LH surge (pre-peak), when levonorgestrel is no more effective

53. Effects on the fallopian tube The fallopian tube plays an important role in human conception Some studies have suggested that progesterone may suppress ciliary beating frequency (CBF) and muscular contraction in the fallopian tube UPA in contrast to this enhances CBF in Fallopian tube Alters tubal environment, there is minimal risk of ectopic pregnancy . Li et al., 2010

54. Ulipristal Acetate Taken 48–120 Hours After Intercourse for Emergency Contraception Pregnancy rate of 2.1% (95% confidence interval 1.4 – 3.1%). 1,241 women were evaluated, 26 were pregnant ADRs were mild or moderate (headache, nausea, and abdominal pain) Cycle length increased a mean of 2.8 days, whereas the duration of menstrual bleeding did not change P Fine et al. Obstetrics & Gynecology. 2010 Ulipristal acetate is effective and well tolerated for emergency contraception 48–120 hours after unprotected intercourse

55. How Effective is Ulipristal Acetate (upa) compared to Levonorgestrel (LNG) 55 with no intervention  23 with LNG 9 with UPA UPA is 2.5 times more effective than LNG Glasier A et al. Lancet 2010 Pregnancy rates per 1000 women in the first 24 hours after unprotected sex

56. Levonorgestrel Ulipristal Acetate Fig.1 Fig.2

57. Conclusion: After a single dose of EC, obese-BMI women are exposed to lower concentrations of LNG and similar concentrations of UPA, when compared to normal-BMI women

58. Faculty of Sexual and Reproductive Healthcare (FSRH) guidance 2017 Ulipristal acetate has been demonstrated to be more effective than levonorgestrel and  should be considered as the first-line oral emergency contraception option Ulipristal acetate remains an effective EC option regardless of a woman’s weight or BMI FSRH Guideline (March 2017)

59. Need of hour.. The United Nations Population Fund, The World Health Organization, and The International Federation of Gynecology and Obstetrics, advocate for easy access to emergency contraceptive pills. ECPs are safe. Patient preference, provider capability, and local availability will influence which options are most preferable.

60. Conclusions on current therapies The available methods for emergency contraception in INDIA are: Yuzpe regimen, high dose levonorgestrel , copper IUD, UPA. The treatment must begin within the first 72 h after unprotected intercourse (for hormonal regimens) The Yuzpe regimen fails in about 2% of women who use it correctly. Levonorgestrel is slightly, but not significantly more effective than the Yuzpe regimen in preventing pregnancy The earlier emergency contraceptive treatment is started the more effective it is Mifepristone in low dose (unavailable in India) and copper-releasing IUD and UPA are highly effective.

61. Summary Ulipristal Acetate (UPA) is a selective progesterone- receptor modulator (SPRM). UPA is the  only   EC to work up to the point of ovulation.  It is 2.5 times  more effective than levonorgestrel . FSRH recommends UPA as first-line oral emergency contraceptive and effective regardless of a woman’s BMI.

62. Thank you