Why am I Bleeding? Management of 1st Trimester Bleeding

Alison Jacoby, MD

Dept. of Obstetrics, Gynecology & Reproductive Sciences

University of California, San Francisco

Disclosures

• I have no relevant financial disclosures.

• I will discuss off-label use of misoprostol.

Acknowledgements

• Robin Wallace, Carolyn Sufrin, Jody

Steinauer and Meg Autry

Julie is a 23 year-old G1P0 at 6+5 by LMP

with spotting x 1 day, no pain, β-HCG = 2672.

MSD = 25mm, no fetal pole

Objectives

1. Review early pregnancy loss

2. Review clinical, serum, and

ultrasonographic diagnostic features

3. Compare management options

– Discuss role of patient preferences

– Expectant, medical, surgical (office vs. OR)

Early Pregnancy Loss (EPL)

• 15-20% of clinically-recognized pregnancies

• 1 in 4 women experience EPL

Spontaneous abortion Vaginal bleeding + IUP, <20 wks

threatened, inevitable, incomplete,

complete

Embryonic demise >7 mm embryo

with no cardiac activity

Anembryonic gestation Trophoblast development without

development of an embryo

Clinical diagnosis:

Ultrasound diagnosis:

Stages of SAB: VB, + IUP, <20 wks

Threatened

Inevitable

Incomplete

Complete

Closed No tissue passed

IUP on U/S

Open No tissue passed

IUP on U/S

Tissue passed

+/- IUP on U/S

Tissue passed

No IUP on U/S

Open

Closed

STAGE: Os: Tissue & U/S:

Normal Implantation

Implantation: •5-7 days after fertilization

•Takes ~72 hours

•Invasion of trophoblast into

decidua production of

HCG

Embryonic disk: 1 wk after implantation

Diagnosis of EPL

1. Clinical presentation

2. β-HCG

3. Ultrasound

Bleeding, pain, LMP,

examination

Isolated value, trend

Sac, pole, pseudosac

Beta Curves, Redefined

• Rate of increase depends on gestational age1

• 49 normal intrauterine pregnancies

• Doubling time varies by gestational age

<5 wks: 1.5 d

5-6 wks: 2 d

>7 wks: 3d

1. Pittaway 1985 Fertil Steril & Am J Ob Gyn

Letting go of the “double in 48 hours” rule

Beta Curves, Redefined

• Early studies used 85% CI as lower limit1

– Retrospective study of 20 women

– Mean doubling time 2 days

– 66% increase in 48 hrs

• Poor sensitivity and specificity in cohort:

– Of 12 ectopics – 17% normal rise

– Of 16 normal pregnancies - 18% abnormal rise

• Newer data - different median and mean 2

2. Barnhart 2004 Obstet Gynecol

1. Kadar 1981 Obstet Gynecol

Letting go of the “double in 48 hours” rule

• 287 women with pain or bleeding and +UPT

– No IUP on U/S but eventually had normal IUP

– Initial β-HCG < 5000

• Ave GA by LMP = 38 days (range, 0-107)

• At least 2 β-HCG’s within 7 days

Barnhart 2004 Obstet Gynecol

Beta Curves, Redefined Letting go of the “double in 48 hours” rule

β HCG Trends in Normal IUP

Barnhart 2004 Obstet Gynecol

99% of nl IUPs

1 day rise ≥ 24%

2 day rise ≥ 53%

Median rise:

1 day= 50%

2 day =124%

Slowest expected increase for normal pregnancy = 53%

Ultrasound & Early Pregnancy:

Key Findings

Gestational

sac

Yolk Sac

Embryonic

Pole

Cardiac

Activity

Double decidual sign

Grows ~ 1mm/day

Early circulatory system

Grows ~ 1mm/day

100bpm140 bpm

Ultrasound Milestones

When should

you see it?

Abnormality

Gestational Sac Discriminatory Level

β = 1500-2000

Ectopic v. abnl IUP

Multiple gestation

Complete SAB

Yolk sac MSD>13-16mm (wait for fetal pole)

Fetal pole MSD >20mm Anembryonic

gestation

Cardiac activity Fetal pole ≥ 5.3mm Embryonic demise

5mm cut off = 8.3% false +

5.3mm cut off = 0 false + (Abdallah et al 2011 [Oct] Ultrasound Obstet Gynecol)

Ultrasound Diagnosis of EPL:

Anembryonic Gestation

Mean sac diameter >=21mm

(20 mm = 0.5% false positive)

AND no fetal pole

Growth?

Cut off 0.6mm/day 90% spec

Cut off 0.2mm/day 99% spec

1.4mm/week

Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol

ACR Appropriateness Criteria

for First Trimester Bleeding Failed pregnancy can be

diagnosed by:

Mean sac diameter

>= 25mm AND no embryo

Absence of cardiac activity in

an embryo > 7mm in CRL

Barton et al 2013 (Jun) Ultrasound Quarterly

Ultrasound: Poor Prognostic Signs

• Yolk sac > 7 mm

• Abnl Sac size / Embryo size

– Sac too small (MSD-CRL < 6mm)

– Sac too big

• Slow embryonic heart rate (<80)

• Subchorionic hematoma

• Thin decidual reaction (<3 mm)

• Irregular sac contour

• Low position in uterus

Not diagnostic, but may help with counseling

Summary: Diagnosis of EPL

• Be cautious of only one point of information (Lab and ultrasound errors occur)

• Clinical history varies

• HCG rise in 48 hours: Minimum 53%

Average 124%

• Ultrasound: – No growth of small sac (IUP not confirmed)

– No cardiac motion of embryo > 7 mm CRL

– Anembryonic MSD > 25 mm

Julie is a 23 year-old G1P0 at 6+5 by

LMP with spotting x 1 day, no pain.

β-HCG = 2672

MSD = 25mm, no fetal pole

Anembryonic Gestation

EPL Management

Medical Surgical Expectant

Depends on:

1. Hemodynamic stability

2. Patient preference and follow-up

3. Stage in miscarriage process

4. Local resources

Women’s Preferences

There is no “one best way.”

Expectant management is preferred

over aspiration by 70% of women.

When uterine aspiration is indicated

or preferred, the majority of women

will choose an office-based procedure

over one in the OR.

Smith 2006; Wieringa-de Waard 2002; Dalton 2006

Women’s Preferences

• Patients report higher quality-of-life and satisfaction when treated according to preference

• Surgery – Quick resolution – Want and value support from hospital staff1

• Expectant – Desire a natural solution1 – Fear of operation1 – More preferred with higher level information & support2 – 71% with success would opt for same in future3

• Misoprostol – Faster resolution – More natural solution without surgery

1. Ogden & Marker Brit J ObGyn 2004; 2. Molnar J Am Board of Fam Pract;

3. Wieringa-DeWaard et al. J of Clin Epi, 2004

Women’s Preferences

• Up to 89% express a preference

– Challenges in recruitment for RCTs

– Expectant mgt. increasingly preferred (38% in 1997 to

70% in 2002), increased if good counseling and support

– Increasing interest in medical

• Physician recommendation is influential

1. Molnar et al. Am Brd of Fam Pract 2000; O’Connor Health Aff 2007; Dalton ObGyn 2006;

Petrou Value Health 2008; Smith BJGP 2006; Wieringa-de Waard Hum Reprod 2002

Patient Priorities

Pain Time Complications

Safety Bleeding Privacy

Anesthesia Past

experience Finality

Adapted from Wallace et al 2010 Patient Educ Couns

©Robin Wallace, 2011

Personal Priorities

o Treatment by your own provider

o Recommendation of treatment from friend

or family member

o Provider recommendation of treatment

o Experience symptoms of bleeding and

cramping in private

o Family responsibilities/needs

Physical Priorities

o Least amount of pain possible

o Fewest days of bleeding after treatment

o Lowest risk of complications

o Lowest risk of need for other steps

o Avoid invasive procedure

o Avoid medications with side effects

o Avoid seeing blood

o Avoid going to sleep in case of a surgical

procedure

o Want to be asleep in case of a surgical

procedure Emotional Priorities

o Most natural process

o Avoid seeing the pregnancy tissue

Time and Cost Priorities

o Shortest time before miscarriage is complete

o Shortest time in the clinic or hospital

o Fastest return to fertility or normalcy

o Fewest number of clinic visits

o Lowest cost of treatment to you

Previous Miscarriage or Abortion

(if applicable)

o Different treatment from previous

o Similar treatment to previous

Adapted from Wallace et al 2010 Patient Educ Couns

©Robin Wallace, 2011

0

5

10

15

20

25

30

35

40

45

50

Expectant Misoprostol Office aspiration OR

Perc

en

t o

f E

PF

pro

vid

ers

Ob/Gyn CNM FP

EPL Management Practices in the U.S.

Adapted from Dalton AJOG 2010

n=976 ob-gyn, family medicine, CNMs

Provider Issues

Training Safety

Concerns

Efficacy System

Resources

Time Assumptions

of patients

Expectant (14 days)

Overall

Anembryonic

Embryonic Demise

Incomplete

60%-70%

50%

35%-60%

75% - 85%

Misoprostol (7 days)

800 mcg PV

Anembryonic

Embryonic Demise

Incomplete

70% - 96%

81%

88%

93%

Aspiration 97% - 100%

Overall success rates

Expectant Management:

Completion Rates

Day 7

(%)

Day 14

(%)

Day 46

(%)

Incomplete Ab (n=221) 53 71*-84 91

Anembryonic gestation

(n=92)

25 53*/52 66

Embryonic demise (n=138) 30 35*-59 76

Total (n=451) 40 61*-70 81

Luise 2002 BMJ

*Casikar 2010 Ultrasound Obstet Gynecol

* n=203 - Casikar

Expectant Management:

MIST Trial

• MIST – RCT of 1200 women

– Expectant, medical, surgical

• Infection:

– No difference - expectant, medical, surgical (3%, 2%, 3%, p=NS)

• Unscheduled D&C

– 44% (expectant)

– Higher efficacy with incomplete

• Transfusion:

– Expectant > surgical (2% vs. 0% of embryonic demise)

Trinder 2006 BMJ

Expectant Management:

Contraindications

• Uncertain diagnosis

• Severe hemorrhage or pain

• Infection

• Suspected gestational trophoplastic disease

• Indicated karyotyping

Same contraindications for medical management

Expectant Limitations

• Size: Studies generally include gestations up to 9 weeks

• Time: Safety established up to 6 weeks of observation

• Maternal conditions: inappropriate for bleeding at home

• Social: inability to obtain prompt emergency care, understand precautions

Medical Management of EPL

Advantages: • Avoidance of

anesthesia and surgery

• Faster completion of miscarriage compared to expectant

• Reduced emergency visits and D&C’S

Disadvantages

• Pain and increased analgesic requirements

• Increased duration of bleeding vs. surgical

• Gastrointestinal and systemic side effects

• Surgical management may still be necessary

Misoprostol

• PGE1 analogue

• Tabs 100 mcg unscored, 200 mcg scored

• Inexpensive

• Rapidly absorbed PO, PV, PR, SL, buccal

• Common obstetrical uses: labor induction,

medical abortion, PPH, cervical ripening

Misoprostol: Off-label Use

• FDA approved for prevention/tx of gastric ulcers

• Once licensed, FDA does not regulate how used1

• Commonly practiced, often standard of care1

• Not experimental if based on sound scientific evidence2

1. Friedman, FDA Deputy Commissioner speech to U.S. House of Representatives 1996

2. Rayburn, Obstet Gynecol 1993

Physiologic Effects of Misoprostol

Uterine:

Cervical:

Gastrointestinal:

Systemic:

• Stimulates contractions

• Softens and primes cervix

• Prevents/treats ulcers

• Nausea & vomiting

• Diarrhea

• Fever, chills

Medical Management:

Misoprostol for EPL

• Small studies with wide range of doses, follow-up and definition of success – 800 mcg vaginally, repeated in 24h PRN1,2

– ↑ Side effects with PO, buccal, SL

– 400-600 mcg buccal or sublingual3

• Success (avoid surgical intervention) 70-96%4

– Incomplete: higher success

• More acceptable than surgical5,6

• 90% would choose again 4. Sur et al. Best Pract ObG 2009

5. Wood et al, Ob Gyn 2002

6. Demetroulis et al, Hum Reprod 2001

1. .Zhang et al, NEJM, 2005

2. Weeks et al, Obstet Gynecol 2005

3. Gemzell-Danielsson, Int J Obstet Gynecol 2007

Misoprostol vs. Surgical:

MEPF Study • 652 ♀ w/ EPL or incomplete Ab Miso or D&C

• D1: Miso 800 mcg PV – D3: Repeat miso if not complete

– D8: Uterine aspiration if still not complete

– D15: follow-up (all)

• Success (no need for additional D&C) by D 8 – Miso: 84% (CI, 81-87) vs. D&C: 97% (CI, 94-100)

– Lowest for embryonic demise (81%)

– 70% success after 1 dose; 60% after 2nd dose

• Complications: No difference

• Satisfaction: No difference (78% vs. 83%)

Zhang et al 2005 NEJM

Example of Misoprostol Algorithm

Miso 800 mcg PV

Cramping w/ clot/tissue

in 24-48 hrs

2nd Dose Miso on D3

7 Days

Clinical f/u

U/S if indicated

Clinical signs

of passage

DONE!

Sac present or

(Endometrium >30 mm) No Sac &

(endometrium<=30mm)

DONE!

If still sac (or endo>30mm) after 2 doses:

Recommend suction

If wants expectant mgmt, f/u 2-4 wks

Suction if signs of infection or HD instability

Follow up precautions

Bleeding should stop in 2-3 wks

Menses should resume in 6-8 weeks

No clinical passage

in 24-48 hrs (Rhogam for Rh- women)

Adapted from Goldberg 2009 in Mgmt of unintended & abnl pregnancy

Medical Management:

Mifepristone and Misoprostol

• Does not appear to increase efficacy

– Mife 600 + Miso 400 PV vs. Miso alone1

• 74% vs. 71% success at 1 week

– Mife 200 + Miso 800 PV

• 84%2-90%3 success at 3 days or 1 week2,3

1. Gronlund 2002 Acta Obstet Gynecol Scand

2. Wagaarachchi 2001 Human Reproduction

3. Schreiber 2006 Contraception

Surgical Management:

Suction Curettage

• Safe, high efficacy (>95%)

• No need to do in Operating Room

– Outpatient or ED setting – cost-effective

– Manual Uterine Aspiration / Manual Vacuum Aspiration

Used with 5-12 mm cannulae

Capacity 60 cc

Surgical Management:

MUA/MVA

• Manual v. electric: no difference - complication

(2.5% vs. 2.1%)1, pain, provider or pt. satisfaction2,3

• MUA in ER compared to EVA in OR:4

EVA in OR MUA in ER

Wait time (↓52%) 7.14 hrs 3.45 hrs

Procedure time 33 min 19 min

Total cost (↓ 41%) $1404 $827

1.Goldberg 2004 Ob Gyn; 2.Dean, Contraception 2003; 3.

Edelman A. Ob Gyn 2001;184:1564; 4. Blumenthal 1992

IJOG; 5. Raush Fertil Steril 2012.

2012 study supports cost-effectiveness of outpatient MUA to OR-based UA5

Moving MUA out of OR

• Process described by U Michigan

– Medical evidence review

– Review of hospital policy for office procedures

– Trained physicians, nurses, and MAs

• Hands-on workshops

– Institution of privileging program

– Review experience of patients

– Review cost – gyn reimbursement same,

lower institutional cost - $1965 v. $968

90% uterine aspirations are done in OR

Harris, AJOG, 2007.

Overall Success Rates

D&C: 97%-100%

Misoprostol (800 mcg pv) up to

81-96% success in 1 week

Expectant up to 70-85% in 2 wks

Follow-up for Miscarriage

Confirm pregnancy passed:

• Surgical: done at time of aspiration

• Expectant & Medical

– Symptoms, ultrasound or pregnancy test

– Phone call is an option

Other benefits of an office visit:

– Emotional support

– Preconception counseling or contraception

– Recurrence risk – 2% after first SAB

The Patient – provider Interaction

•Affects patient choice and satisfaction

•One half of women would change their

decision based on our recommendation

Molnar 2000

Support women in identifying their

values in and priorities for management.

Be prepared to offer all options, including

misoprostol and office-based uterine aspiration.

• Threatened Abortion

– Keep the patient informed

• Provide reassurance, but avoid guarantees that

“everything will be all right”

• Provide support through process

• What does the bleeding mean?

– 50% ongoing pregnancy with closed os

– 85% ongoing pregnancy with viable IUP on u/s

– Up to 30% of normal pregnancies have VB

The Patient – provider Interaction

• Remain silent after initial results or information

• Follow-up with open-ended questions & active listening

• Use neutral responses

• Determine how the woman feels about the pregnancy

• Normalize emotions

• Validate feelings rather than trying to change them

• Avoid opinions about what patient ‘‘should’’ do

• Encourage seeking emotional support from others

• Assure that you will be available to her through the

process, and answer questions as they arise

Wallace, Patient Educ Couns, 2010.

The Patient – provider Interaction

Key Points: Management

• Offer all 3 management options if stable

– Know success rates when counseling patients

– Patient preference plays a major role

– Minimal difference in risk

• Need for surgical intervention should be based on clinical judgment

• Outpatient MUA is acceptable to women and cost-effective