1. Clinical Issues in Emergency Contraception James Trussell, PhD

2. Clinical Issues New Plan B regimen Progestins other than LNg Safety Reducing nausea How long after the morning after? Mechanism of action Does EC promote risk taking? Are ECPs effective? Beginning contraception after ECPs When to expect menses Special situations

3. New Plan B Regimen Two studies have shown that both doses of Plan B (both Plan B pills) can be taken at the same time –With no reduction in effectiveness –With no increase in side effects One study has shown that two doses of Plan B taken 24 hours apart are just as effective as two doses taken 12 hours apart Two studies have shown that Plan B is effective up to 120 hours after intercourse Sources: Arowojolu et al. 2002; von Hertzen et al. 2002; Ngai et al. 2004

4. Population Council Trial Design Treatment within 72 hours, with random assignment to: –2 doses of.50mg LNg + 100μg EE –2 doses of 2.0mg norethindrone + 100μg EE –1 dose of.50mg LNg + 100μg EE Source: Ellertson et al. 2003

5. Effectiveness of ECP Regimens % Dark – Typical use Light – Perfect use N=675 N=648 N=650 Source: Ellertson et al. 2003

6. The Achilles Heel: Power The power to detect small differences is small. To detect with 80% power a difference between pregnancy rates of 2.0% –and 4%: 1,000 in each arm –and 3%: 3,200 in each arm –and 2.5%: 11,500 in each arm Do we consider a 2% failure rate and a 2.5% failure rate to be clinically equivalent? What about 2% and 3%? What about 2% and 4%?

7. Safety No evidence-based contraindications for either combined or progestin-only ECPs

8. Contraindications: Combined and Progestin-only ECPs World Health Organization –Confirmed pregnancy Planned Parenthood Federation of America –Suspicion or evidence of an established pregnancy Source: WHO 2004; PPFA 2004

9. Contraindications: Plan B Known or suspected pregnancy Hypersensitivity to any component of the product Undiagnosed abnormal genital bleeding Source: Duramed 2004

10. Side Effects: ECPs nauseavomiting Progestin-only 23.1% 5.6% Combined 50.5% 18.8% RR.46.28 Source: WHO 1998

11. Reducing the Risk of Nausea Taking combined ECPs with food? –Common clinical recommendation based mostly on anecdote and analogy with starting OC use –Evidence from two studies suggests this strategy is not effective Taking anti-nausea medication? –Anti-nausea medications labeled for motion sickness –FHI randomized clinical trial Source: Raymond et al. 2000; Ellertson et al. 2003

12. Reducing the Risk of Nausea Random assignment to one of three arms: –Yuzpe alone –Yuzpe + placebo –Yuzpe + meclizine (2 meclizine hydrochloride [Dramamine II, Bonine] 25-mg tablets 1 hour before the first ECP dose) Outcome measures –Nausea (N) –Vomiting (V) –Drowsiness (D) Source: Raymond et al. 2000

13. Results: Relative Risk of Nausea (N), Vomiting (V), or Drowsiness (D) # N V D Yuzpe alone109 1.001.00 1.00 Yuzpe + placebo107 1.001.39.84 Yuzpe + meclizine108.74.36 1.96 Source: Raymond et al. 2000

14. Reducing the Risk of Nausea Meclizine significantly reduces the risk of nausea and vomiting associated with the Yuzpe regimen of emergency contraception. But meclizine significantly increases the risk of drowsiness. There is no placebo effect. Source: Raymond et al. 2000

15. How Long After the Morning After? Meta-Analysis of 9 Yuzpe Trials Source: Trussell, Ellertson and Rodriguez 1996 p=.25

16. How Long After the Morning After? WHO Pooled Data (Yuzpe and LNg) Source: Piaggio, von Hertzen, Grimes and Van Look 1999 p<.01

17. How Long After the Morning After? Quebec (Yuzpe) p=.75 Source: Rodrigues et al. 2001 8792

18. How Long After the Morning After? Population Council (Yuzpe) Pregnancy Rate p=.52 and.99 Source: Ellertson et al. 2003 111 104 675 589

19. How Long After the Morning After? Latest WHO Trial (LNg) p=.16 Source: von Hertzen et al. 2002 314 2381

20. How Long After the Morning After? Chinese Trial (LNg) p=.26 Source: Ngai et al. 2004 139 1932

21. How MIGHT EC Work? Inhibit ovulation Trap sperm in thickened cervical mucus Inhibit tubal transport of egg or sperm Interfere with fertilization, early cell division, or transport of embryo Prevent implantation by disrupting the uterine lining

22. Mechanism of Action Evidence: Combined ECPs Clinical evidence about the effect of combined ECPs on ovulation, on uterine lining characteristics, and on timing of the next menstrual period Statistical evidence based on combined ECP effectiveness

23. Clinical Evidence: Combined ECPs Combined ECPs can inhibit ovulation but do not always do so. Inhibiting ovulation is probably the primary mechanism of action. Combined ECPs altered uterine lining in early studies but not in more recent studies; whether these changes are sufficient to prevent implantation is not known. Source: Trussell and Raymond 1999

24. The combined ECP regimen could not be as effective as it has proven to be if it worked only when taken before ovulation It must sometimes work by mechanisms other than prevention of ovulation Statistical Evidence: Combined ECPs Source: Trussell and Raymond 1999

25. Mechanism of Action Evidence: Progestin-only ECPs Clinical evidence about the effect of progestin-only ECPs on ovulation, on uterine lining characteristics, and on timing of the next menstrual period One published study of effect of small doses of LNg on sperm motility Source: Kesseru et al. 1974; Durand et al. 2001; Croxatto et al. 2001; Hapangama et al. 2001; Marions et al. 2002; Croxatto et al. 2003; Marions et al. 2004; Croxotto et al. 2004; Durand et al. 2005

26. Clinical Evidence: Progestin-only ECPs Progestin-only ECPs can inhibit ovulation but do not always do so. Inhibiting ovulation may be the primary mechanism of action. Progestin-only ECPs may immobilize sperm by altering uterine pH. Progestin-only ECPs can alter glycodelin in serum and endometrium and can shorten the luteal phase. Source: Kesseru et al. 1974; Durand et al. 2001; Croxatto et al. 2001; Hapangama et al. 2001; Marions et al. 2002; Croxatto et al. 2003; Marions et al. 2004; Croxotto et al. 2004; Durand et al. 2005

27. Animal Evidence: Levonorgestrel Studies in the rat and in the new-world monkey Cebus apella Levonorgestrel administered in doses that inhibit ovulation has no postfertilization effect that impairs fertility Source: Müller et al. 2003; Ortiz et al. 2004

28. Mechanism of Action of Hormonal Contraceptives and IUDs About the same amount of evidence for each of the following statements: –ECPs, –OCs, implants, patches, rings, injectables, –IUDs, –The contraceptive effect of breastfeeding… MAY work by inhibiting implantation of a fertilized egg Source: ACOG 1998; Díaz et al. 1992

29. Does Providing ECPs Increase Risk Taking? Empirical evidence from 1 study in Scotland, 3 in San Francisco, 1 in Pittsburgh, 1 in Hong Kong, 1 in China, 2 in Los Angeles, and 1 in Nevada & North Carolina where women were randomized to receive counseling and ECPs on demand or to receive ECPs in advance for later use should the need arise. Source: Glasier and Baird 1998; Raine et al. 2000; Jackson et al. 2003; Gold et al. 2004; Lo et al. 2004; Raine et al. 2005; Hu et al. 2005; Belzer et al. 2005; Trussell et al. 2006; Raymond et al. 2006; Walsh et al. 2006

30. Results Scotland: Women who received ECPs in advance Were more likely to use ECPs: 47% vs 27% of women who received only counseling (p<.001) Were not more likely to use ECPs repeatedly Used other methods of contraception equally well Had fewer unintended pregnancies: 3.3% vs 4.8 % for women who received only counseling (p=0.14) Source: Glasier and Baird 1998

31. Results San Francisco 1: Women who received ECPs in advance Were more likely to use ECPs: 22% vs 7% of women who received only counseling (p=.006) Were not more likely to have unprotected sex Were not less likely to use condoms consistently Were less likely to use oral contraceptives consistently: 32% vs 58% of women who received only counseling (p=.03) Source: Raine et al. 2000

32. Results San Francisco 2: Women who received ECPs in advance Were more likely to use ECPs: 17% vs 4% of women who received only counseling (p=.006) Were not more likely to change to a less effective method of contraception Were not more likely to have unprotected sex Were not more likely to use contraception less consistently Had fewer unintended pregnancies: 7% vs 10% for women who received only counseling (p=0.16) Source: Jackson et al. 2003

33. Results Pittsburgh: Women who received ECPs in advance Were more likely to use ECPs: 15% vs 8% of women who received only counseling (p=.05) Took ECPs sooner after sex (11 vs 22 hours) Were more likely to use condoms Were not less likely to use hormonal contraception Source: Gold et al. 2004

34. Results Hong Kong: Women who received ECPs in advance Were more likely to use ECPs: 30% vs 13% of women who received only counseling (p<.001) Were not less likely to use contraception consistently Were not less likely to use condoms Took ECPs sooner after sex (14 vs 29 hours) Were not less likely to become pregnant Source: Lo et al. 2004

35. Results San Francisco 3: Women who received ECPs in advance Were more likely to use ECPs: 37% vs 21% of women who received only counseling (p<.001)) Were not more likely to have unprotected sex Were not less likely to use condoms or pills consistently Were not more likely to acquire an STI Were not less likely to become pregnant Source: Raine et al. 2005

36. Results San Francisco 3: Women who received ECPs from a pharmacist Were no more likely to use ECPs: 24% vs 21% of women who received only counseling (p=.25) Were not more likely to have unprotected sex Were not less likely to use condoms or pills consistently Were not more likely to acquire an STI Were not less likely to become pregnant Source: Raine et al. 2005

37. Results China: Women who received ECPs in advance Were twice as likely to use ECPs Were not less likely to use contraception Were not less likely to use condoms Were not less likely to become pregnant Source: Hu et al. 2005

38. Results Los Angeles 1: Women who received ECPs in advance Were more likely to use ECPs: 83% vs 11% of women at 6 months and 64% vs 17% of women at 12 months who received only counseling (p<.01) Were not more likely to have unprotected sex Were not less likely to use condoms Were not less likely to become pregnant Source: Belzer et al. 2005; Trussell et al. 2006

39. Results Los Angeles 2: Women who received ECPs in advance Were more likely to use ECPs: 19% vs 12% of women who received only counseling (p<0.05) Were not more likely to have unprotected sex Were not less likely to use barrier methods or pills Were not less likely to become pregnant Source: Walsh and Frezieres 2006

40. Results Nevada & North Carolina: Women who received ECPs in advance Were more likely to use ECPs: 71% vs 32% of women who received only counseling (p<0.001) Were not more likely to have unprotected sex Were not less likely to use condoms or pills Were not more likely to acquire an STI Were not less likely to become pregnant Source: Raymond et al. 2006

41. Are ECPs Effective? Eight of the ten studies conducted to test whether easy assess to ECPs increased risk taking also measured pregnancies In none of the eight did advance provision of ECPs reduce pregnancy rates Only three studies powered to detect a decrease in pregnancy rates

42. Why No Reduction in Pregnancies? In San Francisco almost half of the women in the advance provision group who had unprotected intercourse did not use ECPs In China, 30 of the 38 pregnancies in the advance provision group occurred to women who did not use ECPs in that cycle In Nevada/NC, 57 of the 74 pregnancies in the advance provision group occurred to women who did not use ECPs in that cycle Lesson: ECPs are not used frequently enough! Source: Raine et al. 2005; Hu et al. 2005; Raymond et al. 2006

43. Advance Provision of ECPs Did Not Reduce Abortions Rates in Lothian Community intervention study in Scotland About 1 in 5 women aged 16-29 got ECPs in advance to take home About half of these used ECPs at least once No effect on abortion rates was observed Women most at risk probably did not get ECPs 78% of women with advance supplies who got pregnant did not use ECPs. Source: Glasier et al. 2004

44. Excellent Evidence that Plan B Works Two trials in which women were randomly assigned to Plan B or Yuzpe regimen. Pregnancy rate in Plan B arm was 51% of the rate in the Yuzpe arm. Plan B is 49% effective if Yuzpe regimen is completely ineffective. If, for example, Yuzpe regimen is 60% effective, then Plan B is 79% effective. Source: Raymond et al. 2004

45. Lesson Learned ECPs are not used nearly frequently enough! Women underestimate their risk of pregnancy More education is needed OTC switch is necessary―but not sufficient―for solving this problem

46. Beginning Contraception after EC Oral contraceptives, patches, and vaginal rings, and monthly injectables –Regular start: use backup until next period, then begin new method according to regular patient instructions –Jump start: take 2 ECP doses. Start new method the next day (use backup for first seven days)

47. Beginning Contraception after EC Depo-Provera –Regular start: use backup until next period, then start Depo-Provera according to regular patient instructions –Jump start: take 2 ECP doses. Start Depo- Provera the next day or the same day (use backup for first seven days) –Modified jump start: take 2 ECP doses. Start OCs the next day (use backup for first seven days); start Depo-Provera after next period (use backup for first seven days)

48. Initiating Ongoing Method: Condomsimmediately Spermicidesimmediately Diaphragmimmediately Implantwithin 7 days after next menses * Mirenaafter next menses * * backup until menses

49. Bleeding Patterns After Plan B Two studies specifically designed to assess the effects of ECPs containing 1.5 mg levonorgestrel taken in a single dose on bleeding patterns Source: Raymond et al. 2006; Gainer et al. 2006

50. Bleeding Patterns After Plan B―1 The first study found that when taken in the first three weeks of the menstrual cycle, ECPs significantly shortened that cycle compared both to the usual cycle length and to the cycle duration in a comparison group of similar women who had not taken ECPs. The magnitude of this effect was greater the earlier the pills were taken. Source: Raymond et al. 2006

52. Bleeding Patterns After Plan B―1 This regimen taken later in the cycle had no effect on cycle length, but it did cause prolongation of the next menstrual period The ECPs had no effect on the duration of the post-treatment menstrual cycle, but the second period was prolonged Intermenstrual bleeding was uncommon after ECP use, although more common than among women who had not taken ECPs Source: Raymond et al. 2006

53. Bleeding Patterns After Plan B―2 The second study compared the baseline cycle with the treatment and post-treatment cycles. Cycle length was significantly shortened by one day when ECPs were taken in the preovulatory phase of the cycle and was significantly lengthened by two days when ECPs were taken in the postovulatory phase. No difference in cycle length was observed for women who took ECPs during the periovulatory phase of the cycle (from two days before to two days after the expected day of ovulation). Source: Gainer et al. 2006

54. Bleeding Patterns After Plan B―2 Menstrual period duration increased significantly when ECPs were taken in the periovulatory or postovulatory phase in both the treatment and post-treatment cycles. The duration of the post-treatment menstrual cycle remained significantly longer when ECPs were taken in the postovulatory phase. During the treatment cycle, 15% of women experienced intermenstrual bleeding; this was significantly more common when ECPs were taken in the preovulatory phase Source: Gainer et al. 2006

55. Special Cases  Missed pills  Late for Depo  Previous ectopic  Breastfeeding  Hx CV/stroke/thrombosis  Drug interactions  Little risk of pregnancy  Post AB  Later than 120 hours  Multiple acts in cycle  Repeated ECP use

56. Special Cases Would emergency treatment make the situation worse? What counts is timing, not frequency of intercourse Remember the IUD option The woman’s feelings and wishes are more important than medical logic

57. Professional Liability Issues EC is the accepted standard of care (ACOG Practice Pattern and ACOG Practice Bulletin) EC is the only treatment available to prevent unintended pregnancy after unprotected intercourse Consider liability for failure to provide EC Source: ACOG 1996, 2001, 2005; CRR 2002

58. Probability of Pregnancy by Cycle Day Source: Wilcox et al. 2001

59. Probability of Pregnancy by Cycle Day Source: Wilcox et al. 2001