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Management of Early Pregnancy Loss (EPL) Sarah Prager, MD, MAS Department of ob/gyn University of Washington Outline Background information Expectant management Medical management Methotrexate Misoprostol (+/- mifepristone) Surgical management Background Miscarriage is the most common complication of early pregnancy. 8-20% clinically recognized pregnancies 13-26% all pregnancies 80% of miscarriages occur in the first trimester Risk factors Age Prior SAb Smoking Alcohol Caffeine (high intake) Maternal weight BMI < 18.5 or > 25 Celiac disease (untreated) Alcohol Cocaine NSAIDs High gravidity Fever Low folate levels Etiology 33% anembryonic 50% due to chromosomal abnormalities Host factors Autosomal trisomies 52% Monosomy X 19% Polyploidies 22% Other 7% Structural abnormalities Maternal infection/endocrinopathy/coagulopathy Unexplained Clinical presentation Bleeding Pain/cramping Falling or abnormally rising BhCG Ultrasound findings: Absent fetal cardiac activity with CRL > 5 mm Absent fetal pole if mean sac diameter > 25 mm (TA) or 18 mm (TV) No/abnormal yolk sac (95% PPV) No/abnormal fetal heart rate Small sac size Subchorionic hematoma Management options Expectant management Medical management Surgical management Sotiriadis A, Obstet Gynecol 2005; Nanda K, Cochrane Database Syst Rev 2006 Expectant management Requirements for therapy: Less than 13 weeks gestation Stable vital signs No evidence of infection What to expect: Most expulsions occur in the first 2 weeks after diagnosis Prolonged follow-up may be needed Acceptable and safe to wait up to 4 weeks post-diagnosis Outcomes Overall success rate of 81% Success rates vary by type of miscarriage 91% for incomplete/inevitable abortion 76% with missed abortion 66% with anembryonic pregnancies Luise C, Ultrasound Obstet Gynecol 2002 What is success? ≤15 mm endometrial thickness (ET) 3 days to 6 weeks after diagnosis No vaginal bleeding Negative urine hCG Problems with ET measurements No clear rationale for this cut off In a 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 2001; Reynolds A, Eur. J Obstet Gynecol Reproduct. Biol 2005 When to intervene Vaginal bleeding and pos. UPT can continue for 2-4 weeks, so not good measures of success Continued gestational sac Clinical symptoms Patient preference Time (?) Medical management Misoprostol Mifepristone plus Misoprostol Methotrexate plus Misoprostol There is no medical regimen for management of early pregnancy loss that is FDA approved. Medical management Requirements for therapy: Less than 13 weeks gestation Stable vital signs No evidence of infection *No allergies to medications used 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 post-partum hemorrhage Can be administered by oral, buccal, sublingual, vaginal and rectal routes Chen B, Clin Obstet Gynecol 2007 Why misoprostol? Do something while still avoiding surgery Cost effective Few side effects (especially with vaginal) Stable at room temperature Readily available Dosing Regimens 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 q 3 hrs x 3 doses: 87.5% Phupong: 600 mcg po x 1 vs. q 4 hrs x 2 doses: 82% vs 92% (NS) SL had more side effects (diarrhea 70% vs 27.5%) Repeat dosing increased diarrhea (40% vs 18%) Gilles: 800 mcg pv saline-moistened vs. dry: 83% vs 87% (NS) 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 Outcomes Single dose 400 – 800 mcg misoprostol Repeat dose x 1 if incomplete at 24 hours 80 – 88% success rate Placebo success rates: 25 – 88% success rate 16 – 60% 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 Side effects and complications Misoprostol vs. placebo: Nausea, vomiting and diarrhea: no difference Pain: more pain and analgesics in one study Hemoglobin concentration: no difference Infection: 0 for placebo vs. 2 - 4.7% for misoprostol No benefit with repeat dosing within 3-4 hrs. Improved outcome with one repeat dose at 24 hrs. 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 Misoprostol bottom line 800 mcg. per vagina (or buccal) Repeat x 1 at 12-24 hours if incomplete Measure success as with expectant management Intervene with surgical management if: Continued gestational sac Clinical symptoms Patient preference Time (?) Mifepristone and misoprostol Mifepristone: progestin antagonist that binds to progestin receptor Success rates for mifepristone and misoprostol in EPL: Used with elective medical abortion to “destabilize” the implantation site Current evidence-based regimen: 200 mg Mifepristone and 800 mcg misoprostol 52 – 84% (observational trials using non-standard dosing) 90 – 93% ( with standard dosing) No direct comparison b/w 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 Methotrexate and misoprostol Methotrexate: folic acid antagonist Used in medical management for ectopic pregnancy Introduced in 1993 in combination with misoprostol to treat elective abortion medically. Cytotoxic to the trophoblast Success rates up to 98% (misoprostol administered 7 days after methotrexate) No data for use in early pregnancy loss Creinin MD, Contraception 1993 Surgical management Suction dilation and curettage (D&C) Who should have surgical management? Unstable Significant medical morbidity Infected Very heavy bleeding Anyone who wants immediate therapy Surgical Management Benefits: Convenient timing Observed therapy High success rates: (93 – 100%) Risks: Infection (1/200) Perforation (1/2000) Cervical trauma Uterine synechiae (very rare) Infection prophylaxis Periabortal antibiotics reduce 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 Where to perform? Canada: 92.5% women with SAb presenting to hospital have D&C 51% women with SAb presenting to family physician have D&C Manual vacuum aspiration (MVA) in outpatient setting can decrease hospital costs by 41% Weibe E, Fam Med 1998; Finer LB, Perspect Sexu Reproduct Health 2003; Blumenthal PD, Int J Gynaecol Obstet 1994 Outcome comparison Risk of incomplete abortion: Expectant > surgical Expectant ≥ medical Resolution within 48 hours: surgical>medical>expectant management Risk of Infection: 2-3% Expectant = Medical = Surgical 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 Cost analysis Medical management most cost effective 2 studies Misoprostol vs. expectant vs. surgical: 1000 vs. 1172 vs. 2007 dollars Expectant management most cost effective MIST trial Expectant vs. medical vs. surgical: 1086 vs. 1410 vs. 1585 pounds Doyle NM, Obstet. Gynecol 2004; You JH, Hum Reprod 2005; Petrou S, BJOG 2006 Postmiscarriage care Rhogam at time of diagnosis or surgery Pelvic rest for 2 weeks No evidence for delaying conception Initiate contraception upon completion of procedure (even IUDs!) Expect light-moderate bleeding for 2 weeks Menses return after 6 weeks Negative BhCG values after 2-4 weeks Appropriate grief counseling Goldstein R, Am J Obstet. Gynecol 2002; Wyss P, J Perinat Med 1994; Grimes D, Cochrane Database Syst Rev 2000 Future miscarriage risk Increased risk of miscarriage in future pregnancy 20% after 1 miscarriage. 28% after 2 miscarriages 43% after 3+ miscarriages Thank You! Questions? [email protected] O: (206) 731-6292 P: (206) 540-6077