1. Issues in Early Medical Abortion Mitchell Creinin, MD Professor Director of Gynecologic Specialties Director of Family Planning University of Pittsburgh Pittsburgh, PA USA

2. Objectives Very early surgical abortion Home use of misoprostol Shortening the interval between mifepristone and misoprostol Follow-up intervals shorter than two weeks

3. Medical Abortion Early pregnancy termination (usually before 9 weeks gestation) performed without primary surgical intervention and resulting from the use of abortion-inducing medications

4. Early surgical abortion Manual vacuum aspirator with locking valve Portable and reusable Generates vacuum equivalent to electric pump Efficacy same as electric vacuum (98–99%) Semi-flexible plastic cannula MVA

5. Early Abortion with Vacuum Aspiration AuthorDateNGestational Age Efficacy Paul et al.20021,132 (MVA+EVA) <698% Creinin & Edwards 19972,399 MVA<699% Hemlin & Möller 200191 MVA<898% Laufe197712,888“About 6”98% Paul ME, et al. Am J Obstet Gynecol 2002;187:407-11. Creinin MD, Edwards J. Curr Prob Obstet Gynecol Fertil 1997;20:6-32. Hemlin J, Möller B. Acta Obstet Gynecol Scand 2001;80:563-7. Laufe LE. Stud Fam Plann 1977;8:253-6.

6. Early Abortion with MVA Methods 2,399 MVA procedures <6 weeks LMP, high sens UCG, vaginal sono Meticulous inspection of products of conception immediately after MVA Results 99.2% effective in terminating pregnancy 6 repeat aspirations (0.25%) 14 ectopic pregnancies (0.6%) diagnosed & treated Creinin MD, Edwards J. Curr Prob Obstet Gynecol Fertil 1997;20:6-32.

7. Mifepristone abortion Can we provide this regimen in an easier fashion and with less cost? Variations: mifepristone dose non-oral misoprostol gestational age limits timing of misoprostol easier follow-up go together - dependent on route

8. Objectives Very early surgical abortion Home use of misoprostol Shortening the interval between mifepristone and misoprostol Follow-up intervals shorter than two weeks

9. Home use of misoprostol Majority of trials in North America High acceptability High efficacy Allowed in the regulatory labeling for mifepristone in the U.S. Standard of care in North America

10. Home use of misoprostol Early studies of mifepristone and vaginal misoprostol in U.S. Women allowed choice of returning Only 3 (1.9%) of 158 women asked the clinician to place the misoprostol. Initial follow-up studies in the U.S. >4300 women with home use of vaginal misoprostol 90% home use acceptable; no difference by prior abortion experience gestational age time between MIF and MIS (1, 2 or 3 days) Schaff et al. Contraception 1999;59:1-6. Schaff et al. Contraception 2000;61:41-6. Schaff et al. JAMA 2000;284:1948-53.

11. Home use of misoprostol Adverse events in the hours after MIS 4/4365 women (0.1%) had emergencies: Two emergent aspiration for heavy bleeding neither required a blood transfusion. One vasovagal reaction to cramping treated with intravenous fluids. One syncopal episode while bleeding fell and broke her nose. Schaff et al. Contraception 1999;59:1-6. Schaff et al. Contraception 2000;61:41-6. Schaff et al. JAMA 2000;284:1948-53.

12. Home use in Europe U.K. 49 women up to 56 days Lived within 12 miles of facility Sublingual MIS at home Contacted at 4 hour intervals by RN 98% -- no trouble with the regimen (1 woman came to hospital after MIS) 93% -- would use it at home again Hamoda et al. J Fam Plann Reprod Health Care 2005;31:189-92.

13. Home use in Europe Sweden and France 130 women up to 49 days oral MIS at home 98% -- no trouble with the regimen 98% -- would use it at home again In 2004, Sweden changed its regulatory guidelines to allow medical abortion at home up to 63 days gestation. Fiala et al. Contraception 2004;70:387-92. Clark et al. Eur J Contracept Reprod Health Care 2005;10:184-91.

14. Objectives Very early surgical abortion Home use of misoprostol Shortening the interval between mifepristone and misoprostol Follow-up intervals shorter than two weeks

15. Mifepristone Actions Rhythmic Uterine Contractions Progesterone Blockade Decidual Necrosis Cervical Softening DetachmentExpulsion Abortion >18 hours for mifepristone effects

16. Shortened interval overview Oral misoprostol 24-36 hours  effective with 800 mcg dose 6-8 hours  doesn’t work Vaginal misoprostol 24 hours 6-8 hours <15 minutes Buccal misoprostol 24 hours

17. Timing of Misoprostol Dosing 2,255 women <56 days gestation Mifepristone 200 mg PO, misoprostol 800 mcg PV Interval randomized  24, 48 or 72 hours Complete medical abortion 98% (95% CI 97, 99%) in the 24 hour group; 98% (95% CI 97, 99%) in the 48 hour group; 96% (95% CI 95, 97%) in the 72 hour group. Time waiting for expulsion acceptable 86% in the 24 hour group; 79% in the 48 hour group; 76% in the 72 hour group (p=0.0001). Schaff EA et al. JAMA 2000;284:1948-53.

18. M edical abortion in O ne D ay 1,080 women enrolled at 4 centers (4/02 - 6/03) Women received mifepristone 200 mg followed 6 to 8 hours later OR 23 to 25 hours later by misoprostol 800 mcg vaginally Follow-up 7 (+ 1) days and 14 (+ 2) days after mifepristone Repeat misoprostol dose at first follow-up if no expulsion Follow-up phone call 5 weeks after mifepristone Creinin MD, et al. Obstet Gynecol 2004;103:851-9.

19. Abortion outcome (%) 23-25 hours6-8 hours (n=531)(n=525) Complete abortion TOTAL98 (97, 99)96 (94, 97) with 1 dose misoprostol 97 (95, 98)95 (93, 97) <49 days gestation98 (96, 100)97 (94, 99) 50-56 days gestation98 (94, 99)94 (89, 98) 57-63 days gestation98 (94, 100)95 (90, 98) Creinin MD, et al. Obstet Gynecol 2004;103:851-9.

20. Side effects (%) after mifepristone 23-25 hours6-8 hours* (n=523)(n=518) Nausea3920 Vomiting145 Diarrhea71 Warmth/chills199 Headache2010 Dizziness2012 Cramping2616 Spotting94 Bleeding50.2 *p<0.05 Creinin MD, et al. Obstet Gynecol 2004;103:851-9.

21. Side effects (%) after misoprostol* 23-25 hours 6-8 hours (n=523)(n=518) Nausea5244 p=0.01 Vomiting3023 p=0.01 Diarrhea2527 Warmth/chills5356 Headache3738 Dizziness3735 (n=377)(n=395) Bleeding soaking >2 pads/hour2517p=0.01 *first dose misoprostol only Creinin MD, et al. Obstet Gynecol 2004;103:851-9.

22. M edical A bortion at the S ame T ime 1,128 women enrolled at 4 centers (4/04 – 5/06) Women received mifepristone 200 mg followed within 15 minutes OR 23 to 25 hours later by misoprostol 800 mcg vaginally Follow-up 7 (+ 1) days and 14 (+ 2) days after mifepristone Repeat misoprostol dose at first follow-up if no expulsion Follow-up phone call 5 weeks after mifepristone Creinin MD, et al. Obstet Gynecol 2007;109:885-94.

23. Abortion outcome (%) 23-25 hourswitihin 15 min (n=546)(n=554) Complete abortion TOTAL97 (95, 98)95 (93, 97) with 1 dose misoprostol 94 (92, 96)91 (88, 93) <49 days gestation98 (96, 99)96 (92, 98) 50-56 days gestation95 (91, 98)94 (90, 97) 57-63 days gestation97 (92, 99)95 (90, 98) Creinin MD, et al. Obstet Gynecol 2007;109:885-94.

24. Questioning results UK study Randomized trial 450 women up to 63 days gestation 6 hour interval (n=225)  stayed in clinic 36-48 hours (n=225)  went home and returned for misoprostol Complete abortion rates 89% in 6 hour group 96% in 36-48 hour group Guest J et al. BJOG 2007;114:207-15.

25. Why a difference? Smaller study (450 vs. 1056) Ultrasound use U.S. study Sonography at 7 days Assess if sac present If present, repeat dose of misoprostol and return in one week. U.K. study Sonography at 2-7 days Assess for a gestational sac and also for evidence of “nonviable products of conception.” If present, could have a suction aspiration or more misoprostol; however, women who wanted another dose of misoprostol were required to remain under observation for 4-6 hours with a follow- up in one week. Creinin MD et al. Obstet Gynecol 2004;103:851-9. Guest J et al. BJOG 2007;114:207-15.

26. Why a difference? Protocol biases results success rate with a single dose of MIS in 6-8 h group U.S. study = 95% U.K. study = 79% Incomplete abortion rates U.S. study = 2% U.K. study = 4% Aspiration for persistent sac U.S. study = 0.6% U.K. study = 4% Increased interventions in U.K. women b/o management schema Creinin MD et al. Obstet Gynecol 2004;103:851-9. Guest J et al. BJOG 2007;114:207-15.

27. Differences in continuing (viable) pregnancy rate intervalrateintervalrate Schaff et al (2000) < 49 d48h0.2% 50-56 d0.4% 57-63 d1.0% Creinin et al (2004) < 49 d6-8h024h0 50-56 d0 0.6% 57-63 d0.8%0 Creinin et al (2007) < 49 d<15 min0.4%24h0.4% 50-56 d1.3%0 57-63 d0.8%0 Schaff EA, et al. Contraception 2000, 61:41-6. Creinin MD, et al. Obstet Gynecol 2004;103:851-9 Creinin MD, et al. Obstet Gynecol 2007;109:885-94.

28. Mifepristone Actions Rhythmic Uterine Contractions Progesterone Blockade Decidual Necrosis Cervical Softening DetachmentExpulsion Abortion WHAT REALLY IS IMPORTANT?

29. Objectives Very early surgical abortion Home use of misoprostol Shortening the interval between mifepristone and misoprostol Follow-up intervals shorter than two weeks

30. Shorter Follow-up Intervals Most studies include follow-up at 1-7 days following treatment Earlier follow-up with transvaginal ultrasound  compare to standard regimen

31. Follow-up No studies validate this practice Does earlier evaluation result in high rates of later intervention? What is the best way to use ultrasound?

32. Follow-up 2 U.S. trials followed subjects who had not had a suction aspiration for 5 weeks after treatment Study#1#2 Women for 5 week follow-up1,0601,103 (no known aspiration) Women contacted829 (88%)974 (78%) Aspiration since last visit14 (1.7%)13 (1.3%) (includes aspiration at 5 week follow-up) Creinin MD, et al. Obstet Gynecol 2004;103:851-9. Creinin MD, et al. Obstet Gynecol 2007;109:885-94.

33. Post-abortion uterus transverselongitudinal

34. Is follow-up exam necessary? Is the ultrasound examination necessary to evaluate for expulsion? Is a clinical examination necessary to evaluate for expulsion? Clinician and patient both feel pregnancy is expelled: Happens in 95% of treatments They are right 99% of time Rossi et al. Contraception 2004;70:313-7.

35. Mifepristone regimens Acceptable alternatives to the Standard Regimen Mifepristone 200 mg mifepristone Home administration of misoprostol Misoprostol 800 mcg vaginally through 63 days gestation 0-72 hours after the mifepristone Misoprostol 800 mcg buccally through 63 days gestation 24-48 hours after the mifepristone Follow-up within 1 week using ultrasound

36. Etienne-Emile Baulieu "Choice is freedom, science cannot and must not dictate our beliefs. But science can provide choices.” 1991

37. Mifepristone and Buccal Misoprostol Mifepristone 200 mg Misoprostol 800 mcg buccally or orally 1-2 days later Follow-up 7-14 days after misoprostol If no expulsion, aspiration or additional misoprostol 966 women up to 63 days gestation Dzuba et al (submitted for publication)

38. Mifepristone and buccal misoprostol oralbuccal (n=546)(n=554) Complete abortion TOTAL*91 (88, 94)96 (94, 98) <42 days gestation98 (92,100)99 (93, 100) 42-49 days gestation95 (89, 98)97 (92, 99) 50-56 days gestation*89 (81, 94)96 (89, 99) 57-63 days gestation*85 (77, 91)95 (89, 98) Dzuba et al (submitted for publication) *p<.05

39. Mifepristone and buccal misoprostol Dzuba et al (submitted for publication)

40. Buccal misoprostol at same time Mifepristone 200 mg and misoprostol 800 mcg buccally gestationalNexpulsion atabortion age (days)24 hours afterrate at misoprostol*2 weeks <49402939 73% (56, 85%)98% (87, 100%) 50-564027/3937/37 69% (52, 83%) 100% (91, 100%) 57-63402937/39 73% (56, 85%)95% (83, 99%) *1, 1, and 2 subjects, respectively, had an aspiration for incomplete abortion. Lohr PA, et al. Contraception 2007;76:215-20.

41. Buccal misoprostol at same time 115 subjects (96%) completed the post-treatment questionnaire. Would choose medical abortion again91% Recommend medical abortion to a friend97% Disliked some part of the buccal misoprostol72% taste objectionable43% buccal retention uncomfortable30% oral irritation, numbness, or oral ulcers10% did not work6% Lohr PA, et al. Contraception 2007;76:215-20.