Management of Early Pregnancy Loss I have no disclosures. & - - PowerPoint PPT Presentation

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Management of Early Pregnancy Loss & Pregnancy of Unknown Location

Jody Steinauer, MD, PhD

• Dept. Ob/Gyn & Reproductive Sciences

Disclosures- October, 2019

I have no disclosures.

Objectives

• 1. Review the workup of bleeding in the first trimester
• 2. Apply evidence-based principles to management of

Pregnancy of Unknown Location

• 3. Apply evidence-based counseling and treatment for

EPL – focus on ultrasound dx, evidence for mifepristone as medical management

Patient Case: H&P

• Maya is a 26 yo G1P0 at 9 weeks’ gestation by LMP

presenting with bleeding. 1 2 3 4

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Evaluation

• History

– Risk factors for ectopic pregnancy – Symptoms, pregnancy course

• Physical exam

– Vital signs – Abdominal and pelvic exam

• Ultrasound

– Transvaginal may be necessary

• Lab

– Rh factor – Hemoglobin or hematocrit may be helpful – β-hCG when indicated Is the pregnancy desired?

Patient Case: H&P

• Maya is a 26 yo G1P0 presenting with bleeding.

– Desired pregnancy – Positive UPT 2 weeks ago, confirmed today in ER – Bleeding like a “light period” for the past 3 days – No risk factors for ectopic pregnancy – On exam, VSS, nontender abdomen, closed cervical os, small uterus – Rh positive

Symptomatic Early Pregnancy Evaluation

Bleeding in Early Pregnancy

• Ectopic pregnancy must be ruled out, and we must be

careful to not diagnose a desired, normal IUP as abnormal

• Management includes preference-sensitive decisions

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Bleeding in Early Pregnancy

• Keep the patient informed

– Provide reassurance but avoid guaranteeing that “everything will be all right” – Assure that you are available

• What does the bleeding mean?

– Up to 20% chance of ectopic pregnancy – Up to 20% chance of early pregnancy loss (EPL) – 30% of normal pregnancies have vaginal bleeding

Ectopic Pregnancy

• 1-2% of all pregnancies
• ½ of ectopic patients have no risk factors
• Mortality has dramatically declined: 0.5/100,000

– 6% of pregnancy-related deaths – 21 deaths per year in US

• Early diagnosis important

Early Pregnancy Loss (EPL)

• Generally defined as up to

12 6/7 weeks’ gestation

• 15-20% of clinically

recognized pregnancies

• 1 in 4 will experience EPL

Pregnancy of Unknown Location

• Pregnancy test +, but no pregnancy on u/s

– Try to follow until a diagnosis is made – Be aware of risk of ectopic pregnancy (EP) – Sometimes never have diagnosis as both EPL and EP may resolve spontaneously

• More commonly encountered in symptomatic early

pregnancy, but can also be encountered when asymptomatic, especially when u/s early 9 10 11 12

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Positive pregnancy test, vaginal bleeding and/or abdominal pain 61% Ongoing IUP 61% Ongoing IUP 28% Spontaneous Abortion 9% Ectopic Pregnancy

Dx upon presentation (80%) Dx upon presentation (80%) 77% Ongoing IUP 77% Ongoing IUP 16% Spontaneous Abortion 6% Ectopic Pregnancy 49% of all with Ectopic Dx at presentation Dx with additional testing (20%) Dx with additional testing (20%) 11% Ongoing IUP 11% Ongoing IUP 77% Spontaneous Abortion 17% Ectopic Pregnancy 51% of all with Ectopic Dx after outpatient follow-up

Barnhart 2004 Obstet Gynecol

Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

4. Once pregnancy clearly abnormal, if undesired or if patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

4. Once pregnancy clearly abnormal, if undesired or if patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

Simplified Workup of Bleeding

3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

– If Bhcg above threshold and no IUP = Abnormal – If Bhcg below threshold - serial beta HCGs

• If Bhcg drops > 50% in 48 hours = Abnormal
• If Bhcg rises > 50% in 48 hours = Most likely normal –

Follow & repeat u/s

• If between = Most likely abnormal – Follow & repeat

u/s

IUP=Intrauterine pregnancy

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Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

– Above threshold - abnormal – Below threshold - serial

4. Once pregnancy clearly abnormal, if undesired or if patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

– Above threshold - abnormal – Below threshold - serial

4. Once pregnancy clearly abnormal, if undesired or if patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

β-hCG Utility in Symptomatic Early Pregnancy Diagnosis

Wide ranges of values

• β-hCG median serum concentration:

– 4 weeks: 100 mIU/ml (5-450) – 10 weeks: 60,000 (5,000 – 150,000)

Discriminatory Level

• Serum β-hCG at which a normal intrauterine

pregnancy should be visualized on ultrasound

• Once above, limited role for “following betas”

Discriminatory & Threshold level

• N=366 with VB/pain nl IUP

Old value of 2000= 91% prob.

• f seeing GS in viable IUP

99% Predicted Probability of Detection Discriminatory Threshold Gestational sac Yolk sac Fetal pole 3510 17,716 47,685 390 1094 1394

Highest seen in the study with no sac: 2,300

Connolly, Obstet Gynecol, 2013.

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• HCG 2000 - 3000

– 2% chance of viable pregnancy – Non-viable intrauterine pregnancy most likely, 2X ectopic – Ectopic is 19 x more likely than viable pregnancy – For each viable pregnancy:

• 19 ectopic pregnancies
• 38 nonviable pregnancies
• HCG > 3000

– 0.5% chance viable IUP – Non-viable IUP still most common – Ectopic 70 x more likely than viable pregnancy

Society of Radiologists in Ultrasound: No Gestational Sac

Doubilet, NEJM, 2013.

Balance of Diagnostic Tests

• Maximize sensitivity at the cost of diagnosing some

IUPs as Ectopic Pregnancies

– Decrease false negatives – try to never miss an ectopic – Error – interrupt desired IUP

• Maximize specificity at the cost of diagnosing some

Ectopic Pregnancies as IUPs

– Decrease false positives – try to never misdiagnose IUP – Error – delay diagnosis resulting in rupture

• Use cut-off of 3,000 v. repeat beta hcg or u/s

Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal

• r abnormal?  quantitative Beta-HCG(s)

– Above threshold - abnormal – Below threshold - serial

4. Once pregnancy clearly abnormal, if undesired or if patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

β HCG trends in normal IUP

Barnhart 2004

99% of nl IUPs 1 day rise ≥ 24% 2 day rise ≥ 53% Median rise: 1 day= 50% 2 day =124% Median rise: 1 day= 50% 2 day =124%

Slowest expected 48-hour increase for normal pregnancy = 53% (20% of ectopics increase)

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β HCG trends : Other Key Points

• Two hcg values may not be enough
• If close to the thresholds – check another
• Repeat ultrasound

Barnhart 2002

Discriminatory Threshold Gestational sac Yolk sac Fetal pole 3510 17,716 47,685 390 1094 1394

Simplified Workup of Bleeding

1. Where is the pregnancy?  U/S 2. If the pregnancy undesired?  uterine aspiration 3. If desired and we can’t tell where it is: Is it normal or abnormal?  quantitative Beta-HCG(s)

– If Bhcg above threshold and no IUP = Abnormal – If Bhcg below threshold - serial beta HCGs

• If drops > 50% in 48 hours = Abnormal
• If rises > 50% in 48 hrs = Most likely NL – Follow & rpt u/s
• If between = Most likely abnormal – Follow & repeat u/s
• 4. Once pregnancy clearly abnormal, if undesired or if

patient desires definitive dx  uterine aspiration

IUP=Intrauterine pregnancy

If Diagnose as Abnormal…

• Do not presume an ectopic pregnancy – uterine

aspiration before MTX

– High HCG & nothing in the uterus (50% failed IUP) – Very low HCG with decrease or abnormal rise (25% failed IUP)

Role of Ultrasound in Ectopic Diagnosis

• Only 2% of u/s are diagnostic for EP

– “Diagnostic” = Gestational Sac with yolk sac or fetal pole visualized outside uterus

• Normal adnexal exam does not exclude ectopic
• Suggestive of ectopic
• Empty uterus + hCG above discriminatory zone
• Complex mass + fluid in cul-de-sac (94% are EP)
• Should still follow them if desired pregnancy

Main role of U/S is to rule in IUP

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Ultrasound Findings to R/o EP

• Remember that an EP has not been ruled out until

there is an intrauterine pregnancy

– Gestational sac with a yolk sac and/or embryo

EPL Diagnosis, Counseling, and Management

EPL – Making the diagnosis

Spontaneous abortion

Vaginal bleeding + IUP, <20 wks threatened, inevitable, incomplete, complete

Embryonic demise

Embryo with no cardiac activity

Anembryonic gestation

Gestational sac without embryonic pole

Clinical diagnosis: Ultrasound diagnosis:

Ultrasound Diagnosis of EPL: Anembryonic Gestation

Mean sac diameter >=21mm (20 mm = 0.5% false positive) AND no fetal pole (n>1000, 100% specificity)

Abdallah 2011

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Ultrasound Diagnosis of EPL: Embryonic Demise

Fetal pole >= 5.3 AND no cardiac activity

Abdallah 2011

Fetal pole – 7 mm

MSD – 25 mm

Radiologists in Ultrasound: Account for Margin of Error

Doubilet, NEJM, 2013.

Patient Case: Counseling

• Maya was diagnosed with an embryonic demise.
• How do we counsel her about management options?

EPL Management

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EPL Management: A Preference-Sensitive Decision

• Best choice for management reflects the woman’s

values and preferences

• Patients have strong and widely divergent preferences

– Higher satisfaction when treated according to patient’s preference

Wieringa-de Waard 2002; Dalton 2006; Smith 2006

Expectant Medication Office-based aspiration Operating room aspiration

EPL Management: Patient Preferences

No ‘one best way’ to treat miscarriage that suits all individuals. Expectant management is preferred over aspiration by 40-70% of patients. When aspiration is indicated or preferred, the majority will choose an office-based procedure.

Smith 2006; Wieringa-de Waard 2002; Dalton 2006

Research on EPL Counseling

• Patients want unbiased and comprehensive counseling about
• ptions for this preference-sensitive decision.
• Patients perceive communication during EPL diagnosis as a

critical time to initiate discussions of management.

• Patients are often weighing personal priorities to make

decisions about EPL management.

• Use of a decision aid may offer a systematic counseling

approach for a patient-centered decision-making process.

Early Pregnancy Failure: Counseling

• Women blame themselves (“was it the stress?”)
• Wonder if will happen again

Patient counseling should include:

• How common it is (encourage to talk to friends)
• Reassurance that it is beyond her control and unlikely to

recur (“Nothing could have been done to prevent it.”)

• Acknowledge/validate grieving
• No need to wait to attempt another pregnancy- ok to try

after resumption of menses (when emotionally ready)

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Early Pregnancy Loss (EPL) Management

• Four options for the clinically stable patient
• 1. Aspiration w/ general/deep sedation (operating room)
• 2. Aspiration w/ local/moderate sedation (office-based)
• 3. Medication (misoprostol +/- mifepristone)
• 4. Expectant
• All methods are effective, with equivalent safety and

patient acceptability = clinical equipoise

NSFG 2004; Chen 2007; Wieringa-de Waard, 2002; Zhang 2005; Trinder 2006

Reference: Helping your patient to choose treatment for EPF

Medical Management: Misoprostol alone: 800mcg pv, rpt if needed: 8-d success: 75% Mife (200 mg po)+Miso @ 24 hrs (800 pv): 8-d success: 90% Uterine Aspiration: Success: ~100% Expectant: Success: 66% at 2wks.

Expectant Management

• “Watchful waiting”
• Proven safety up to 8 weeks
• Type of EPL affects expected efficacy

(incomplete>anembryonic gestation>embryonic demise)

• Acceptable to patients with realistic expectations

about:

Duration, Discomfort, and potential D&C

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Expectant Management

Advantages

• Non-invasive
• Body naturally expels non-

viable pregnancy

• Avoids anesthesia and

surgery risks

• Allows for patient privacy

and continuity of care

Disadvantages

• Unpredictable outcome

and timescale

• Process can last days to

weeks

• Can have prolonged

bleeding and cramping

• Despite waiting, may still

need uterine aspiration

Expectant Management

Contraindications

• Uncertain diagnosis
• Suspected gestational

trophoblastic disease

• Indicated karyotyping
• Severe hemorrhage or pain
• Infection
• IUD in place

Same contraindications for medication management

Medication Management

• Use of medications for active management of EPL
• Misoprostol

– Stimulates uterine contractions & softens cervix – Inexpensive, easy storage

• Mifepristone

– Anti-progestin used for pregnancy termination – New study supports use

Medication Management

Advantages

• Highly cost-effective
• Non-invasive
• Safe
• Can be highly effective
• Avoids anesthesia and

surgery risks

• Allows for patient privacy

and continuity of care

Disadvantages

• Increased need for

analgesics and pain control

• May cause heavier or longer

bleeding

• May cause short-term

gastrointestinal and other side effects

• May still need uterine

aspiration

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Misoprostol for EPL

Recommended in ACOG Practice Bulletin 800 mcg vaginally (PV) with

• ptional repeat dose >3 hours

later if no initial response

Schreiber New England Journal of Medicine 2018

Mifepristone before Misoprostol for EPL

New study in NEJM 200 mg Mifepristone + 800 mcg Miso (PV) 24 hours later

Schreiber New England Journal of Medicine 2018

Mifepristone Pretreatment

• RCT of 300 women
• 200 mg po Mifepristone followed by Misoprostol

800mcg pv 24 hours later

• Followed up in 1-4 days
• If persistent sac offered repeat misoprostol v.

expectant v. aspiration

Mifepristone Pretreatment

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Mifepristone

• Not available at retail pharmacies in the US
• Risk Evaluation and Mitigation Strategy criteria

– Intended for drugs known to cause severe adverse effects that can not be mitigated by labeling instructions

• ACOG has determined no longer necessary

Medications for Symptoms and Side Effects

Cramping

Ibuprofen 600 mg Q6 hrs or 800 mg Q8 hrs (or other NSAID)

Severe cramping pain not relieved by ibuprofen

Hydrocodone/APAP 5/500 or 5/325 Q 4-6 hrs prn

Nausea/vomiting

Promethazine 25 mg Q 4-6 hrs prn or

• ther anti-emetic

Typical Follow-Up

Phone contact

Call patient 1-2 days after first misoprostol dose to assess need for second dose.

In-person visit

1-2 weeks after choosing expectant or medication management to assess:

• 1. If miscarriage is not complete – Is patient

interested in alternate treatments?

• 2. Confirm completion (see below)

Confirming completion

• 1. Clinical history consistent with complete

miscarriage plus β-hCG decline of >50% or negative urine pregnancy test

• 2. Clinical history plus disappearance of intrauterine

pregnancy on transvaginal ultrasound

EPL Expectant/Medical Management

• Clinical checklist for care options:

– Clear diagnosis – Patient is stable – Access to phone & emergency care – Pain control options available – Anticipatory guidance for bleeding, s/sx infection – Rh status – Reliable follow-up

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Aspiration for EPL

• Historically done in operating room under general

anesthesia

• Terminology:

– Surgical “D&C” – Suction curettage with manual or electric vacuum aspiration

Operating Room Aspiration

Advantages

• Predictable
• Offers fastest resolution of

miscarriage

• Reduced duration of bleeding
• Low risk (<5%) of needing

further treatment

• Can be asleep

Disadvantages

• Rare risks associated with

aspiration and general anesthesia

• More cost than office-based

procedures

• More time and physical exams

than office-based procedures

• May be more bleeding

complications under general anesthesia than in office-based procedures

Office-based Aspiration

Advantages

• Predictable
• Offers fastest resolution of

miscarriage

• Reduced duration of

bleeding

• Low risk (<5%) of needing

further treatment

• Pain control with local plus
• ral or IV meds

Disadvantages

• Rare risks of aspiration
• Less pain control options in

some settings

Compared to OR management:

• May allow improved patient

access and continuity of care

• Improved privacy
• Less patient and staff time
• Resource and cost savings

Patient Case: Management

• How do we manage Maya?
• Chance of success for embryonic demise:

– Expectant  1 week (30%) 2 weeks (60%) 6 weeks (75%) – Medical  1 week with mifepristone/misoprostol (90%) – Aspiration  In office or OR (97-100%)

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EPL: Patient-Centered Care

• 1. Keep her informed throughout the diagnostic work-

up

• 2. Use clear but compassionate language
• 3. Be prepared to discuss management options at dx
• 4. Present advantages and disadvantages of each
• 5. Facilitate recognition of patient’s priorities
• 6. Ensure follow-up and allow opportunity to change

management decision

Patient Case: Management

• Maya chose to use mifepristone followed by

misoprostol at home 24 hours later

• She placed the misoprostol pills vaginally and began

having cramping and bleeding 2 hours later

• Her heavy bleeding lasted 4 hours, and she noticed
• ne particularly large clot
• She still has some light bleeding at her follow-up

appointment, 7 days later You confirm that it is complete.

EPL Management: Follow-up

• Use both history and exam to confirm completion

– β-HCG drop >50% in 48 hours or negative UPT @ 2-4 wks – Or ultrasound to confirm no sac/fetal pole

• Address fertility desires

– Contraception vs prenatal vitamins/preconception care

• Offer grief counseling follow-up or referrals

Vaginal Ultrasound

*Thickness of endometrium NOT associated with need for future intervention 65 66 67 68

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ACOG Practice Bulletin Early Pregnancy Loss (May 2015)

Level A

• 800 mcg misoprostol for medical management
• Use of anticoagulants doesn’t reduce risk

Level B

• US preferred modality to verify nonviable IUP
• D&C not required for thick stripe after treatment if

asymptomatic

• Rh- patients should receive Rh(D) immune globulin

Level C

• Can safely accommodate preferences
• Doxycyline before surgical management

Explore the resource page and link to the learning module: www.earlypregnancylossresources.org Innovating Education in Reproductive Health www.innovating-education.org

Conclusion

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Conclusions

• Bleeding in early pregnancy is common
• Pregnancy of unknown location takes patience

– Higher discriminatory zone balancing risk of ectopic – U/S measurement cutoffs – If abnormal – do uterine aspiration before giving MTX

• Patient preference is important
• If medical management, use mifepristone

Thanks to Robin Wallace, Carolyn Sufrin, Meg Autry, Rebecca Jackson

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