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Clinical Issues in Emergency Contraception

Clinical Issues in Emergency Contraception. James Trussell, PhD. 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

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Clinical Issues in Emergency Contraception

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  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: Arowojoluet 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 N=650 N=648 Dark – Typical use Light – Perfectuse N=675 % 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 nausea vomiting 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 alone 109 1.00 1.00 1.00 Yuzpe + placebo 107 1.00 1.39 .84 Yuzpe + meclizine 108 .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 p=.25 Source: Trussell, Ellertson and Rodriguez 1996

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

  17. How Long After the Morning After?Quebec (Yuzpe) p=.75 87 92 Source: Rodrigues et al. 2001

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

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

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

  21. How MIGHT EC Work? • Inhibitovulation • Trap sperm in thickened cervical mucus • Inhibit tubal transport of egg or sperm • Interfere with fertilization, early cell division, or transport of embryo • Preventimplantationby 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. Statistical Evidence: Combined ECPs • 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 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 • Weremore likely to use ECPs: 47% vs 27% of women who received only counseling (p<.001) • Werenotmore likely to use ECPsrepeatedly • 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 • Weremore likely to use ECPs: 22% vs 7% of women who received only counseling (p=.006) • Werenotmore likely to haveunprotected 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 • Weremore likely to use ECPs: 17% vs 4% of women who received only counseling (p=.006) • Werenotmore 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 • Weremore 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 • Weremore likely to use ECPs: 30% vs 13% of women who received only counseling (p<.001) • Werenotless likely to use contraception consistently • Were notless 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 • Weremore likely to use ECPs: 37% vs 21% of women who received only counseling (p<.001)) • Werenotmore likely to haveunprotected sex • Were notless 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 • Wereno more likely to use ECPs: 24% vs 21% of women who received only counseling (p=.25) • Werenotmore likely to haveunprotected sex • Were notless 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 • Weretwice as likely to use ECPs Werenotless likely to use contraception • Were notless 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 • Weremore 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 • Weremore likely to use ECPs: 19% vs 12% of women who received only counseling (p<0.05) • Werenotmore likely to haveunprotected sex • Were notless 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 • Weremore likely to use ECPs: 71% vs 32% of women who received only counseling (p<0.001) • Werenotmore likely to haveunprotected sex • Were notless 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: • Condoms immediately • Spermicides immediately • Diaphragm immediately • Implant within 7 days after next menses * • Mirena after 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

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