Miscarriage Management Training Initiative

1. Miscarriage Management Training Initiative Management of Early Pregnancy Loss Sarah Prager, MD Department of Obstetrics and GynecologyUniversity of Washington

2. MM-TI Goals: • Move miscarriage management from the operating room to the outpatient setting • Train primary care clinicians and support staff in miscarriage management

3. Purpose • Expand patient access to prompt, appropriate care • Improve patient safety • Improve patient satisfaction • Decrease costs

4. Challenges and Solutions • Difficult to influence physician practice patterns • Target training during residency • Use a systems approach (include faculty, residents, key administrative personnel and support staff)

5. Clarification • We are not talking about elective abortion • We are teaching and promoting miscarriage management

6. MVA Safety and Efficacy: Summary • MVA is simple • Easily incorporated into office setting • Expanded pain management options • Ultrasound as needed • Patient-provider interaction

7. Management of Early Pregnancy Loss Objectives • Review etiologies of EPL • Review the three methods of EPL management:— Expectant— Medical— Surgical • Discuss benefits of outpatient EPL management

8. NomenclatureManagement of Early Pregnancy Loss Early Pregnancy Loss (EPL) Spontaneous Abortion (SAb) Miscarriage These all mean exactly the same thing!

9. BackgroundManagement of Early Pregnancy Loss • Spontaneous Abortion (SAb) most common complication of early pregnancy— 8–20% clinically recognized pregnancies— 13–26% all pregnancies — ~ 800,000 SABs each year in the US • 80% of SAbs occur in 1st trimester

10. Samantha • 26 yo G2P1 presents to your office for a new ob visit. An ultrasound sows a CRL of 7mm but no cardiac activity. • She wants to know why this happened.

11. Age Prior SAb Smoking Alcohol Caffeine (controversial) Maternal BMI <18.5 or >25 Celiac disease (untreated) Cocaine NSAIDs High gravidity Fever Low folate levels Risk FactorsManagement of Early Pregnancy Loss

12. EtiologyManagement of Early Pregnancy Loss • 33% anembryonic • 50% due to chromosomal abnormalities— Autosomal trisomies 52%— Monosomy X 19%— Polyploidies 22%— Other 7% • Host factors— Structural abnormalities— Maternal infection/endocrinopathy/coagulopathy • Unexplained

13. Normal Implantation & DevelopmentManagement of Early Pregnancy Loss • Implantation: — 5-7 days after fertilization— Takes ~72 hours— Invasion of trophoblast into decidua • Embryonic disc: — 1 wk post-implantation — If no embryonic disc, trophoblast still grows, but no embryo (anembryonic pregnancy) • Embryonic disc embryonic/fetal pole

14. U/S Dating in Normal PregnancyManagement of Early Pregnancy Loss Gestational Age (days) • Mean Sac Diameter(mm) + 30 • OR • Crown-Rump Length(mm) + 42 =

15. Clinical Presentation of EPLManagement of Early Pregnancy Loss • Bleeding • Pain/cramping • Falling or abnormally rising ßhCG • Decreased symptoms of pregnancy • No symptoms at all!

16. Ultrasound Findings of EPLManagement of Early Pregnancy Loss • Anembryonic Pregnancy — No fetal pole with mean sac diam >25 mm (transabdominal) OR >18 mm (transvaginal) — <4 mm growth in 7 days(No yolk sac, with mean sac diameter >10 mm) • Embryonic Demise— No cardiac activity with CRL ≥5 mm Mishell DR, Comprehensive Gynecology 2007

17. Samantha Samantha and her partner request information on all the treatment options. You confirm the rest of her history. PMH: wisdom teeth removed Ob Hx: term SVD without complication All: NKDA

18. Management OptionsEarly Pregnancy Loss Do Nothing:Expectant management Do Something:Medical management Do Surgery:Surgical management Sotiriadis A, Obstet Gynecol 2005Nanda K, Cochrane Database Syst Rev 2006

19. Do NothingExpectant Management • Requirements for therapy:— <13 weeks gestation— Stable vital signs— No evidence infection • What to expect:— Most expel within 1st 2 wks after diagnosis — Prolonged follow-up may be needed— Acceptable and safe to wait up to 4 wks post-diagnosis

20. OutcomesDo Nothing: Expectant Management • Overall success rate 81% • Success rates vary by type of miscarriage(helpful to tailor counseling)— Incomplete/inevitable abortion 91%— Embryonic demise 76%— Anembryonic pregnancies 66% Luise C, Ultrasound Obstet Gynecol 2002

21. What is Success?Definitions Used in Studies • ≤15 mm endometrial thickness (ET)3 days to 6 weeks after diagnosis • No vaginal bleeding • Negative urine hCG

22. Problems with ET Cut-off • No clear rationale for this cut-off • Study of 80 women with successful medical abortion— Mean ET at 24 hours 17.5 mm (7.6–29 mm)— At one week 15% with ET >16 mm • Study of medical management after miscarriage— 86% success rate if use absence of gestational sac— 51% success rate if use ET ≤15 mm Harwood B, Contraception 2001Reynolds A, Eur. J Obstet Gynecol Reproduct. Biol 2005

23. When to intervenefor Expectant Management? • Continued gestational sac • Clinical symptoms • Patient preference • Time (?) • Vaginal bleeding and positive UPT are possible for 2–4 weeks— Poor measures of success

24. Samantha • Samantha appears anxious about waiting and shares with you that she really needs to do something.

25. Do SomethingMedical Management • Misoprostol • Misoprostol + Mifepristone • Misoprostol + Methotrexate No medical regimen for managementof EPL is FDA approved

26. Medical ManagementRequirement for Therapy • <13 weeks gestation • Stable vital signs • No evidence of infection • No allergies to medications used • Adequate counseling and patient acceptance of side effects

27. Misoprostol • Prostoglandin E1 analogue • FDA approved for prevention of gastric ulcers • Used off-label for many Ob/Gyn indications:— Labor induction— Cervical ripening— Medical abortion (with mifepristone)— Prevention/treatment of postpartum hemorrhage • Can be administered by oral, buccal, sublingual, vaginal and rectal routes Chen B, Clin Obstet Gynecol 2007

28. Why Misoprostol? • Do something while still avoiding surgery • Cost effective • Stable at room temperature • Readily available

29. Misoprostol Dosing RegimensEmbryonic Demise & Anembryonic Pregnancy StudyDoseEfficacy Creinin 400 mcg po vs 800 pv 25% vs. 88% Ngoc 800 mcg po vs 800 pv 89% vs. 93% (NS) Tang 600 mcg SL vs 600 pv 87.5%q 3 hrs x 3 doses(SL had more side effects— diarrhea, 70% vs 27.5%) Phupong 600 mcg po x 1 vs. 82% vs 92% (NS)q 4 hrs x 2 doses(Repeat dosing increased diarrhea, 40% vs 18%) Gilles 800 mcg pv saline- 83% vs 87% (NS)moistened vs. dry Creinin MD, Obstet Gynecol 1997; Ngoc NTN, Int.J Gynaecol Obstet 2004; Tang OS, Hum Reproduct 2003; Phupong V, Contraception 2005; Gilles JM, Am J Obstet Gynecol 2004

30. Pooled OutcomesMedical Management Success Rates Placebo 16–60% Single dose misoprostol 25–88% 400–800 mcg Repeat dose x 1 if incomplete 80–88% at 24 hours • Success rate depends on type of miscarriage — 100% with incomplete abortion — 87% for all others Wood SL, Obstet Gynecol 2002; Bagratee JS, Hum Reproduct 2004; Blohm F, BJOG: Int J Obstet Gynecol 2005

31. Serum Level ComparisonMisoprostol by Route of Administration

32. Uterine Tone Over 5 HoursMisoprostol by Route of Administration Rectal p = .006 Meckstroth, not yet published

33. Uterine Activity Over 5 HoursMisoprostol by Route of Administration Meckstroth, not yet published

34. Side Effects and ComplicationsMisoprostol vs. Placebo • N/V, Diarrhea: No difference • Pain: More pain and analgesics in one study • Hemoglobin Conc: No difference • Infection: 0% for placebo vs. .2–4.7% for misoprostol • No benefit with repeat dosing within 3–4 hours • Improved outcome with 1 repeat dose at 24 hours, if incomplete • 90% found medical management acceptable and would elect same treatment again Wood SL, Obstet Gynecol 2002; Bagratee JS, Hum Reproduct 2004; Blohm F, BJOG: Int J Obstet Gynecol 2005

35. Misoprostol Bottom LineMedical Management • 800 mcg pv (or buccal) • Repeat x 1 at 12–24 hours, if incomplete— Occasionally repeat more than once • Measure success as with expectant management • Intervene with surgical management if— Continued gestational sac— Clinical symptoms— Patient preference— Time (?)

36. Mifepristone and MisoprostolMedical Management Mifepristone: Progestin antagonist that binds to progestin receptor— Used with elective medical abortion to “destabilize” implantation site— Current evidence-based regimen: 200 mg mifepristone + 800 mcg misoprostol Success rates for mifepristone & misoprostol in EPL: — 52–84% (observational trials, non-standard dose)— 90–93% (standard dose) No direct comparison between misoprostol alone and mifepristone/misoprostol with standard dosing Mifepristone may help (data still pending) Gronlund A, Acta Obstet Gynaecol 1998; Nielsen S, Br J Obstet Gynaecol 1997; Niinimaki M, Fertility Sterility 2006; Schreiber CA, Contraception 2006

37. Methotrexate and MisoprostolMedical Management • Methotrexate: — Folic acid antagonist — Cytotoxic to trophoblast • Used in medical management for ectopic pregnancy • Introduced in 1993 in combination with misoprostol to treat elective abortion medically — Success rates up to 98% (misoprostol administered 7 days after methotrexate) • No data for use in early pregnancy loss Creinin MD, Contraception 1993

38. Samantha • Samantha opts to try misoprostol and returns to the office 7 days later for follow up. How do you assess whether or not her treatment is complete?

39. Samantha At her follow-up appointment, Samantha says that she had a period of heavy bleeding and is now spotting. Her cramping has resolved. She has noted a marked decrease in breast tenderness and nausea. Her ultrasound shows a uniform endometrial stripe measuring 30mm in its greatest width. Is she complete?

40. Samantha

41. Rebecca • 32 yo G3P2 at 8 weeks by LMP was diagnosed with a fetal demise on her ultrasound and presents to your office after 2 weeks of expectant management stating that she “wants to be done”. She declines medical management and requests a D&C.

42. Rebecca • What questions would you ask to see if she was a good candidate?

43. Surgical ManagementEarly Pregnancy Loss • Suction dilation and curettage (D&C) • Who should have surgical management?— Unstable— Significant medical morbidity— Infected— Very heavy bleeding— Anyone who WANTS immediate therapy

44. Surgical ManagementEarly Pregnancy Loss Convenient timing Observed therapy High success rates (almost 100%) BENEFITS RISKS • Infection (1/200) • Perforation (1/2000) • Cervical trauma • Uterine synechiae(very rare)

45. Infection ProphylaxisSurgical Management • Periabortal antibiotics  infection risk 42% • No strong evidence on what to use • Doxycycline (2–14 doses) • Metronidazole: — Bacterial vaginosis — Trichomoniasis — Suspicious discharge Sawaya GF, Obstet Gynecol 1996; Prieto JA, Obstet Gynecol 1995

46. Comparison of Outcome by MethodManagement of Early Pregnancy Loss FactorComparison of Methods Success rate Surgical > Medical Medical ≥ Expectant Resolution Surgical > Medical > Expectant within 48 hrs Infection risk Expectant = Medical = Surgical.2–3% Number differed by highly variable success rates reported for expectant management Nanda K, Cochrane Database Syst Rev 2006; Nielsen S, Br J Obstet Gynaecol 1999; Shelly JM, Aust. NZ J Obstet Gynaecol 2005; Sotiriadis A, Obstet Gynecol 2005; Tinder J, (MIST) BMJ, 2006

47. Patient SatisfactionManagement of Early Pregnancy Loss • Meta-analysis shows studies report high satisfaction with medical management • Caution: Few studies looked at satisfaction • Satisfaction depended on choice:— If women randomized 55-74% satisfied— If women chose 84-88% satisfied— Both were independent of method • Unsuccessful expectant resulting in surgical showed most profound anxiety and depression Sotiriadis 2005

48. Zhang, NEJM 2005

49. Cost AnalysisManagement of Early Pregnancy Loss Medical management most cost effective— 2 studies— Misoprostol vs. expectant vs. surgical: $1000 vs. $1172 vs. $2007 Expectantmanagement most cost effective— MIST trial— Expectant vs. medical vs. surgical: £1086 vs. £1410 vs. £1585 Doyle NM, Obstet. Gynecol 2004; You JH, Hum Reprod 2005; Petrou S, BJOG 2006

50. Rebecca Refer to OR? Manage with MVA? The clinic schedule is packed…does this have to be done today?