Management of Management of Early Pregnancy Early Pregnancy

Loss (EPL)Loss (EPL)Sarah Prager, MD, MASSarah Prager, MD, MAS

Department of ob/gynDepartment of ob/gyn

University of WashingtonUniversity of Washington

OutlineOutline

Background informationBackground information Expectant managementExpectant management Medical managementMedical management

MethotrexateMethotrexate Misoprostol (+/- mifepristone)Misoprostol (+/- mifepristone)

Surgical managementSurgical management

BackgroundBackground

Miscarriage is the most common Miscarriage is the most common complication of early pregnancy.complication of early pregnancy. 8-20% clinically recognized pregnancies8-20% clinically recognized pregnancies 13-26% all pregnancies13-26% all pregnancies

80% of miscarriages occur in the 80% of miscarriages occur in the first trimesterfirst trimester

Risk factorsRisk factors

AgeAge Prior SAbPrior SAb SmokingSmoking AlcoholAlcohol Caffeine (high Caffeine (high

intake)intake) Maternal weightMaternal weight

BMI < 18.5 or > 25 BMI < 18.5 or > 25 Celiac disease Celiac disease

(untreated)(untreated)

AlcoholAlcohol CocaineCocaine NSAIDsNSAIDs High gravidityHigh gravidity FeverFever Low folate levelsLow folate levels

EtiologyEtiology 33% anembryonic33% anembryonic 50% due to chromosomal abnormalities50% due to chromosomal abnormalities

Autosomal trisomies 52%Autosomal trisomies 52% Monosomy X 19%Monosomy X 19% Polyploidies 22%Polyploidies 22% Other 7%Other 7%

Host factorsHost factors Structural abnormalitiesStructural abnormalities Maternal Maternal

infection/endocrinopathy/coagulopathyinfection/endocrinopathy/coagulopathy UnexplainedUnexplained

Clinical presentationClinical presentation BleedingBleeding Pain/crampingPain/cramping Falling or abnormally rising BhCGFalling or abnormally rising BhCG Ultrasound findings:Ultrasound findings:

Absent fetal cardiac activity with CRL > 5 mmAbsent fetal cardiac activity with CRL > 5 mm Absent fetal pole if mean sac diameter > 25 Absent fetal pole if mean sac diameter > 25

mm (TA) or 18 mm (TV)mm (TA) or 18 mm (TV) No/abnormal yolk sac (95% PPV)No/abnormal yolk sac (95% PPV) No/abnormal fetal heart rateNo/abnormal fetal heart rate Small sac sizeSmall sac size Subchorionic hematomaSubchorionic hematoma

Management optionsManagement options

Expectant managementExpectant management Medical managementMedical management Surgical managementSurgical management

Sotiriadis A, Obstet Gynecol 2005; Nanda K, Cochrane Database Syst Rev 2006

Expectant managementExpectant management

Requirements for therapy:Requirements for therapy: Less than 13 weeks gestationLess than 13 weeks gestation Stable vital signsStable vital signs No evidence of infectionNo evidence of infection

What to expect:What to expect: Most expulsions occur in the first 2 weeks Most expulsions occur in the first 2 weeks

after diagnosis after diagnosis Prolonged follow-up may be neededProlonged follow-up may be needed Acceptable and safe to wait up to 4 weeks Acceptable and safe to wait up to 4 weeks

post-diagnosispost-diagnosis

OutcomesOutcomes

Overall success rate of 81%Overall success rate of 81% Success rates vary by type of Success rates vary by type of

miscarriagemiscarriage 91% for incomplete/inevitable abortion91% for incomplete/inevitable abortion 76% with missed abortion76% with missed abortion 66% with anembryonic pregnancies66% with anembryonic pregnancies

Luise C, Ultrasound Obstet Gynecol 2002

What is success?What is success?

≤≤15 mm endometrial thickness (ET)15 mm endometrial thickness (ET) 3 days to 6 weeks after diagnosis3 days to 6 weeks after diagnosis

No vaginal bleedingNo vaginal bleeding Negative urine hCGNegative urine hCG

Problems with ET Problems with ET measurementsmeasurements

No clear rationale for this cut offNo clear rationale for this cut off In a study of 80 women with successful In a study of 80 women with successful

medical abortion:medical abortion: Mean ET at 24 hours 17.5 mm (7.6 – 29 mm)Mean ET at 24 hours 17.5 mm (7.6 – 29 mm) At one week: 15% with ET > 16 mmAt one week: 15% with ET > 16 mm

Study of medical management after Study of medical management after miscarriage:miscarriage: 86% success rate if use absence of 86% success rate if use absence of

gestational sacgestational sac 51% success rate if use ET ≤15 mm51% success rate if use ET ≤15 mm

Harwood B, Contraception 2001; Reynolds A, Eur. J Obstet Gynecol Reproduct. Biol 2005

When to interveneWhen to intervene

Vaginal bleeding and pos. UPT can Vaginal bleeding and pos. UPT can continue for 2-4 weeks, so not good continue for 2-4 weeks, so not good measures of successmeasures of success

Continued gestational sacContinued gestational sac Clinical symptomsClinical symptoms Patient preferencePatient preference Time (?)Time (?)

Medical managementMedical management

MisoprostolMisoprostol Mifepristone plus MisoprostolMifepristone plus Misoprostol Methotrexate plus MisoprostolMethotrexate plus Misoprostol

There is no medical regimen for There is no medical regimen for management of early pregnancy loss management of early pregnancy loss that is FDA approved. that is FDA approved.

Medical managementMedical management

Requirements for therapy:Requirements for therapy: Less than 13 weeks gestationLess than 13 weeks gestation Stable vital signsStable vital signs No evidence of infectionNo evidence of infection *No allergies to medications used*No allergies to medications used

MisoprostolMisoprostol Prostoglandin E1 analogueProstoglandin E1 analogue FDA approved for prevention of gastric FDA approved for prevention of gastric

ulcersulcers Used off-label for many ob/gyn indicationsUsed off-label for many ob/gyn indications

Labor inductionLabor induction Cervical ripeningCervical ripening Medical abortion (with mifepristone)Medical abortion (with mifepristone) Prevention/treatment of post-partum Prevention/treatment of post-partum

hemorrhagehemorrhage Can be administered by oral, buccal, Can be administered by oral, buccal,

sublingual, vaginal and rectal routessublingual, vaginal and rectal routesChen B, Clin Obstet Gynecol 2007

Why misoprostol? Why misoprostol?

Do something while still avoiding Do something while still avoiding surgerysurgery

Cost effectiveCost effective Few side effects (especially with Few side effects (especially with

vaginal)vaginal) Stable at room temperatureStable at room temperature Readily availableReadily available

Dosing RegimensDosing Regimens

Creinin: 400 mcg po vs 800 pv 25% vs. 88%Creinin: 400 mcg po vs 800 pv 25% vs. 88% Ngoc: 800 mcg po vs 800 pv: 89% vs. 93% Ngoc: 800 mcg po vs 800 pv: 89% vs. 93%

(NS)(NS) Tang: 600 mcg SL vs 600 pv q 3 hrs x 3 doses: Tang: 600 mcg SL vs 600 pv q 3 hrs x 3 doses:

87.5%87.5% SL had more side effects (diarrhea 70% vs 27.5%)SL had more side effects (diarrhea 70% vs 27.5%)

Phupong: 600 mcg po x 1 vs. q 4 hrs x 2 doses: Phupong: 600 mcg po x 1 vs. q 4 hrs x 2 doses: 82% vs 92% (NS)82% vs 92% (NS) Repeat dosing increased diarrhea (40% vs 18%)Repeat dosing increased diarrhea (40% vs 18%)

Gilles: 800 mcg pv saline-moistened vs. dry: Gilles: 800 mcg pv saline-moistened vs. dry: 83% vs 87% (NS)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

OutcomesOutcomes Single dose 400 – 800 mcg misoprostolSingle dose 400 – 800 mcg misoprostol

25 – 88% success rate25 – 88% success rate Repeat dose x 1 if incomplete at 24 hoursRepeat dose x 1 if incomplete at 24 hours

80 – 88% success rate80 – 88% success rate Placebo success rates:Placebo success rates:

16 – 60%16 – 60% Success rate depends on type of Success rate depends on type of

miscarriage:miscarriage: 100% with incomplete abortion100% with incomplete abortion 87% for all others87% for all others

Wood SL, Obstet Gynecol 2002; Bagratee JS, Hum Reproduct 2004; Blohm F, BJOG: Int J Obstet Gynecol 2005

Side effects and Side effects and complicationscomplications

Misoprostol vs. placebo: Misoprostol vs. placebo: Nausea, vomiting and diarrhea: no differenceNausea, vomiting and diarrhea: no difference Pain: more pain and analgesics in one studyPain: more pain and analgesics in one study Hemoglobin concentration: no differenceHemoglobin concentration: no difference Infection: 0 for placebo vs. 2 - 4.7% for misoprostolInfection: 0 for placebo vs. 2 - 4.7% for misoprostol

No benefit with repeat dosing within 3-4 hrs.No benefit with repeat dosing within 3-4 hrs. Improved outcome with one repeat dose at 24 Improved outcome with one repeat dose at 24

hrs. if incompletehrs. if incomplete 90% found medical management acceptable 90% found medical management acceptable

and would elect same treatment againand 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 lineMisoprostol bottom line

800 mcg. per vagina (or buccal)800 mcg. per vagina (or buccal) Repeat x 1 at 12-24 hours if incompleteRepeat x 1 at 12-24 hours if incomplete Measure success as with expectant Measure success as with expectant

managementmanagement Intervene with surgical management if:Intervene with surgical management if:

Continued gestational sacContinued gestational sac Clinical symptomsClinical symptoms Patient preferencePatient preference Time (?)Time (?)

Mifepristone and Mifepristone and misoprostolmisoprostol

Mifepristone: progestin antagonist that binds to Mifepristone: progestin antagonist that binds to progestin receptorprogestin receptor Used with elective medical abortion to “destabilize” Used with elective medical abortion to “destabilize”

the implantation sitethe implantation site Current evidence-based regimen: 200 mg Current evidence-based regimen: 200 mg

Mifepristone and 800 mcg misoprostolMifepristone and 800 mcg misoprostol Success rates for mifepristone and misoprostol Success rates for mifepristone and misoprostol

in EPL: in EPL: 52 – 84% (observational trials using non-standard 52 – 84% (observational trials using non-standard

dosing)dosing) 90 – 93% ( with standard dosing)90 – 93% ( with standard dosing)

No direct comparison b/w misoprostol alone and No direct comparison b/w misoprostol alone and mifepristone/misoprostol with standard dosing mifepristone/misoprostol with standard dosing

Mifepristone may help, data still pendingMifepristone may help, data still pendingGronlund A, Acta Obstet Gynaecol 1998; Nielsen S, Br J Obstet Gynaecol 1997; Niinimaki M, Fertility Sterility 2006; Schreiber CA, Contraception 2006

Methotrexate and Methotrexate and misoprostolmisoprostol

Methotrexate: folic acid antagonistMethotrexate: folic acid antagonist Cytotoxic to the trophoblastCytotoxic to the trophoblast

Used in medical management for Used in medical management for ectopic pregnancyectopic pregnancy

Introduced in 1993 in combination Introduced in 1993 in combination with misoprostol to treat elective with misoprostol to treat elective abortion medically. abortion medically. Success rates up to 98% (misoprostol Success rates up to 98% (misoprostol

administered 7 days after methotrexate)administered 7 days after methotrexate) No data for use in early pregnancy lossNo data for use in early pregnancy loss

Creinin MD, Contraception 1993

Surgical managementSurgical management

Suction dilation and curettage (D&C)Suction dilation and curettage (D&C)

Who should have surgical Who should have surgical management?management? UnstableUnstable Significant medical morbiditySignificant medical morbidity InfectedInfected Very heavy bleedingVery heavy bleeding Anyone who wants immediate therapyAnyone who wants immediate therapy

Surgical ManagementSurgical Management

Benefits: Benefits: Convenient timingConvenient timing Observed therapyObserved therapy High success rates: (93 – 100%)High success rates: (93 – 100%)

Risks: Risks: Infection (1/200)Infection (1/200) Perforation (1/2000)Perforation (1/2000) Cervical trauma Cervical trauma Uterine synechiae (very rare)Uterine synechiae (very rare)

Infection prophylaxisInfection prophylaxis

Periabortal antibiotics reduce Periabortal antibiotics reduce infection risk 42%infection risk 42%

No strong evidence on what to useNo strong evidence on what to use Doxycycline Doxycycline

2 -14 doses2 -14 doses MetronidazoleMetronidazole

Bacterial vaginosisBacterial vaginosis TrichomoniasisTrichomoniasis Suspicious dischargeSuspicious discharge

Sawaya GF, Obstet Gynecol 1996; Prieto JA, Obstet Gynecol 1995

Where to perform?Where to perform?

Canada:Canada: 92.5% women with SAb presenting to 92.5% women with SAb presenting to

hospital have D&Chospital have D&C 51% women with SAb presenting to 51% women with SAb presenting to

family physician have D&Cfamily physician have D&C

Manual vacuum aspiration (MVA) in Manual vacuum aspiration (MVA) in outpatient setting can decrease outpatient setting can decrease hospital costs by 41%hospital costs by 41%

Weibe E, Fam Med 1998; Finer LB, Perspect Sexu Reproduct Health 2003; Blumenthal PD, Int J Gynaecol Obstet 1994

Outcome comparisonOutcome comparison

Risk of incomplete abortion: Risk of incomplete abortion: Expectant > surgicalExpectant > surgical Expectant ≥ medicalExpectant ≥ medical

Resolution within 48 hours: Resolution within 48 hours: surgical>medical>expectant surgical>medical>expectant managementmanagement

Risk of Infection: 2-3%Risk of Infection: 2-3% Expectant = Medical = SurgicalExpectant = 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 analysisCost analysis

Medical management most cost effectiveMedical management most cost effective 2 studies2 studies Misoprostol vs. expectant vs. surgical: Misoprostol vs. expectant vs. surgical: 1000 vs. 1172 vs. 2007 dollars1000 vs. 1172 vs. 2007 dollars

Expectant management most cost Expectant management most cost effectiveeffective MIST trialMIST trial Expectant vs. medical vs. surgical: Expectant vs. medical vs. surgical: 1086 vs. 1410 vs. 1585 pounds1086 vs. 1410 vs. 1585 pounds

Doyle NM, Obstet. Gynecol 2004; You JH, Hum Reprod 2005; Petrou S, BJOG 2006

Postmiscarriage carePostmiscarriage care Rhogam at time of diagnosis or surgeryRhogam at time of diagnosis or surgery Pelvic rest for 2 weeks Pelvic rest for 2 weeks No evidence for delaying conceptionNo evidence for delaying conception Initiate contraception upon completion of Initiate contraception upon completion of

procedure (even IUDs!)procedure (even IUDs!) Expect light-moderate bleeding for 2 Expect light-moderate bleeding for 2

weeks weeks Menses return after 6 weeksMenses return after 6 weeks Negative BhCG values after 2-4 weeksNegative BhCG values after 2-4 weeks Appropriate grief counselingAppropriate grief counseling

Goldstein R, Am J Obstet. Gynecol 2002; Wyss P, J Perinat Med 1994; Grimes D, Cochrane Database Syst Rev 2000

Future miscarriage riskFuture miscarriage risk

Increased risk of miscarriage in Increased risk of miscarriage in future pregnancyfuture pregnancy 20% after 1 miscarriage.20% after 1 miscarriage. 28% after 2 miscarriages28% after 2 miscarriages 43% after 3+ miscarriages43% after 3+ miscarriages

Thank You!Thank You!

Questions?Questions?

pragers@u.washington.edu O: (206) 731-6292O: (206) 731-6292 P: (206) 540-6077P: (206) 540-6077