1. Management of Early Pregnancy Loss (EPL)
Sarah Prager, MD, MAS
Department of ob/gyn
University of Washington

2. Outline Background information Expectant management Medical management
Methotrexate
Misoprostol (+/- mifepristone)
Surgical management

3. 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
Studies show substantial percentage of pregnancies are lost prior to being clinically recognized.

4. 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
NSAIDs taken at time of conception
Fever in calendar month of conception
Folate low only in cases with aneuploid fetuses/embryos

5. Etiology 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

6. 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

7. Management options Expectant management Medical management
Surgical management
Sotiriadis A, Obstet Gynecol 2005; Nanda K, Cochrane Database Syst Rev 2006

8. Expectant management Requirements for therapy: What to expect:
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

9. 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

10. What is success? ≤15 mm endometrial thickness (ET) No vaginal bleeding
3 days to 6 weeks after diagnosis
No vaginal bleeding
Negative urine hCG
Many studies define failure as an endometrial thickness of 15 mm at some defined point in time

11. 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

12. 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 (?)

13. Medical management Misoprostol Mifepristone plus Misoprostol
Methotrexate plus Misoprostol
There is no medical regimen for management of early pregnancy loss that is FDA approved.

14. Medical management Requirements for therapy:
Less than 13 weeks gestation
Stable vital signs
No evidence of infection
*No allergies to medications used

15. 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

16. Why misoprostol? Do something while still avoiding surgery
Cost effective
Few side effects (especially with vaginal)
Stable at room temperature
Readily available
It’s a great option for women who want to do something, but avoid surgery

17. 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%
SL had more side effects (diarrhea 70% vs 27.5%)
Phupong: 600 mcg po x 1 vs. q 4 hrs x 2 doses: 82% vs 92% (NS)
Repeat dosing increased diarrhea (40% vs 18%)
Gilles: 800 mcg pv saline-moistened vs. dry: 83% vs 87% (NS)
Multiple different doses and routes of administration have been studied, as well as single versus multiple dose regimens.
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

18. Outcomes Single dose 400 – 800 mcg misoprostol
25 – 88% success rate
Repeat dose x 1 if incomplete at 24 hours
80 – 88% success rate
Placebo success rates:
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

19. 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 % 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

20. Misoprostol bottom line
800 mcg. per vagina (or buccal)
Repeat x 1 at hours if incomplete
Measure success as with expectant management
Intervene with surgical management if:
Continued gestational sac
Clinical symptoms
Patient preference
Time (?)

21. Mifepristone and misoprostol
Mifepristone: progestin antagonist that binds to progestin receptor
Used with elective medical abortion to “destabilize” the implantation site
Current evidence-based regimen: 200 mg Mifepristone and 800 mcg misoprostol
Success rates for mifepristone and misoprostol in EPL:
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
Why not just add mife? Expensive, less available.
Gronlund A, Acta Obstet Gynaecol 1998; Nielsen S, Br J Obstet Gynaecol 1997;
Niinimaki M, Fertility Sterility 2006; Schreiber CA, Contraception 2006

22. Methotrexate and misoprostol
Methotrexate: folic acid antagonist
Cytotoxic to the 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

23. 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

24. Surgical Management Benefits: Risks: Convenient timing
Observed therapy
High success rates: (93 – 100%)
Risks:
Infection (1/200)
Perforation (1/2000)
Cervical trauma
Uterine synechiae (very rare)

25. 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

26. 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

27. 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

28. Cost analysis Medical management most cost effective
2 studies
Misoprostol vs. expectant vs. surgical:
1000 vs vs dollars
Expectant management most cost effective
MIST trial
Expectant vs. medical vs. surgical:
1086 vs vs pounds
Doyle NM, Obstet. Gynecol 2004; You JH, Hum Reprod 2005; Petrou S, BJOG 2006

29. 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

30. Future miscarriage risk
Increased risk of miscarriage in future pregnancy
20% after 1 miscarriage.
28% after 2 miscarriages
43% after 3+ miscarriages

31. Thank You!
Questions?
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