Nothing to disclose. Lori Strachowski, MD Clinical Professor of - - PowerPoint PPT Presentation

10/22/2014 1 New Recommendations for Diagnosing Failed Intrauterine Pregnancy

Lori Strachowski, MD Clinical Professor of Radiology, UCSF Chief of Ultrasound, SFGH lori.strachowski@ucsf.edu

Nothing to disclose. The Article

N Engl J Med October 2013;369:1443-51

Lecture Goals

• Detailed overview of update on diagnostic criteria for

nonviable pregnancy early in the first trimester – Panelists – Issue – Objective – Plan – Recommended criteria – Reasoning

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The Panelists

• Society of Radiologists in Ultrasound (SRU) Multispecialty

Panel on Early First Trimester Miscarriage and Exclusion of a Viable Intrauterine Pregnancy

• 3 Specialties:

– Radiologists (7) – Obstetrician-Gynecologists (5) – Emergency Medicine (3)

The Rads

• Peter M. Doubilet, M.D., Ph.D., Brigham and Women’s and

Harvard Medical School*

• Carol B. Benson, M.D., Brigham and Women’s/Harvard*
• Beryl R. Benacerraf, M.D., Brigham and Women’s/Harvard
• Douglas L. Brown, M.D., Mayo Clinic, Rochester
• Roy A. Filly, M.D., UCSF
• Edward A. Lyons, M.D., Univ of Manitoba, Winnipeg, MB
• Dolores H. Pretorius, M.D., UCSD

* primary authors

The OB/Gyn’s

• Tom Bourne, M.B., B.S., Ph.D., Imperial College, London*
• Steven R. Goldstein, M.D., NYU School of Medicine
• Ilan E. Timor-Tritsch, M.D., NYU School of Medicine
• Kurt T. Barnhart, M.D., M.S.C.E., University of Pennsylvania
• Misty Blanchette Porter, M.D., Dartmouth

* primary authors

The ER Docs

• Michael Blaivas, M.D., University of South Carolina*
• J. Christian Fox, M.D., University of California, Irvine
• John L. Kendall, M.D., Denver Health Medical Center

* primary authors

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The Issue

www.facebook.com

Pain +/- Bleeding in Early Pregnancy

Misuse and misinterpretation of US and β-hCG Methotrexate inadvertently administered Miscarriage and malformations MALPRACTICE

_ _ _ _ _ _ _ _ _ _ _

Medical Liability Action

• 2009 Survey on Professional Liability conducted by ACOG

– 90.5%: ≥ 1 professional liability claim – Avg: 2.69 claims per obstetrician - gynecologist

• 62% - OB care
• 38% - Gyne care

– Delayed dx of breast cancer – Inadvertent Tx of IUPs with MTX

Obstetrics and Gynecology 2010 ;116:8-15

Inadvertent Tx of IUPs with MTX

• 3 diagnostic error patterns

– Perception and interpretation of findings on US – Improper correlation of β-hCG levels and US findings – Treatment based on a single hCG level without a definitive US diagnosis of ectopic pregnancy

Obstetrics and Gynecology 2010 ;116:8-15

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US Error Types

• Perception:

– Finding seen in retrospect but initially missed

• i.e. an early intrauterine GS or YS
• Interpretation:

– Findings perceived but incorrectly diagnosed

• i.e. CL interpreted as EP or early GS as a pseudo-sac
• Confounding factors:

– Poor quality images, noncritical image evaluation, incomplete clinical info

Obstetrics and Gynecology 2010 ;116:8-15

The Objective

First, DO NO HARM “or the least possible”

The Plan

• Set quality standards for diagnostic tests
• Standardize terminology
• Establish diagnostic criteria

– Widely applicable and reproducible – Minimize risk

• Based on consequences of false positive and negative

results

The Diagnostic Tests: hCG

• Human chorionic gonadotropin

– Serum measured with use of WHO 3rd or 4th International Standard – Positive serum pregnancy test is defined by > 5 mIU/ml NOTE: low levels of hCG can occur in health non-pregnant patients.

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The Diagnostic Tests: US

• Minimum quality criteria:

– TVS of uterus and adnexa – TAS for FF and mass high in the pelvis – Oversight by an appropriately trained physician – Performed by providers and interpreted by physicians, all

• f whom meet at least minimum training or certification

standards – Scanning equipment permitting adequate visualization of structures early in the first trimester

The Terminology

• Viable
• Nonviable

Definition: Viable (vī-ə-bəl)

1: capable of living; especially: having attained such form and development as to be normally capable of surviving outside the mother's womb <a viable fetus>

www.Merriam-Webster.com

Definition: Viable (vī-ə-bəl)

1: capable of living; especially: having attained such form and development as to be normally capable of surviving outside the mother's womb <a viable fetus>

www.Merriam-Webster.com

10/22/2014 6

Definition: Viable (vī-ə-bəl)

1: capable of living; especially: having attained such form and development as to be normally capable of surviving outside the mother's womb <a viable fetus> 2: capable of growing or developing <viable seeds> <viable eggs> 3 a : capable of working, functioning, or developing adequately <viable alternatives> b : capable of existence and development as an independent unit <the colony is now a viable state> c (1) : having a reasonable chance of succeeding <a viable candidate> (2) : financially sustainable <a viable enterprise>

www.Merriam-Webster.com

Definition: Viable (vī-ə-bəl)

1: capable of living; especially: having attained such form and development as to be normally capable of surviving outside the mother's womb <a viable fetus> 2: capable of growing or developing <viable seeds> <viable eggs> 3 a : capable of working, functioning, or developing adequately <viable alternatives> b : capable of existence and development as an independent unit <the colony is now a viable state> c (1) : having a reasonable chance of succeeding <a viable candidate> (2) : financially sustainable <a viable enterprise>

www.Merriam-Webster.com

The Terminology

• Viable:

– A pregnancy is viable if it can potentially result in a liveborn baby.

• Nonviable:

– A pregnancy is nonviable if it cannot possibly result in a liveborn baby.

• Examples: ectopic pregnancies and failed intrauterine

pregnancies Manual uterine aspiration

The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

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Currently Viable IUP The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

Ectopic Pregnancy

Ov

The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

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Spontaneous AB in Progress

Cervix

The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

What is the best diagnosis for this 1st trimester pregnancy?

A. B. C. D.

20% 71% 1% 7%

• A. Currently viable IUP
• B. Failed/failing IUP
• C. Ectopic Pregnancy
• D. I don’t like any of these

answers

It ain’t always that easy!

10/22/2014 9

FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

FP: Viable IUP

Short delay in dx

FN: Failure

FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA Short delay in dx Likely non-life- threatening!

FN: EP

FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA Short delay in dx Likely non-life- threatening!

FN: EP FN: Failure

FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA

FP: Failure FP: EP

Short delay in dx Likely non-life- threatening!

FN: Viable IUP FN: Viable IUP

10/22/2014 10

To “DO NO HARM”

• 1. Criteria for non-viability require

– 100% Specificity – 100% PPV

• 2. Need more buckets!!!

“or as close as possible”

The Expanded Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA IUP of Uncertain Viability Pregnancy

• f

Unknown Location

The Expanded Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA IUP of Uncertain Viability Pregnancy

• f

Unknown Location Expectant management Expectant management

The Terminology

• Intrauterine pregnancy of uncertain viability:

– Transvaginal ultrasonography shows an intrauterine gestational sac with no embryonic heartbeat and no findings of definite pregnancy failure.

• Pregnancy of unknown location:

– Positive pregnancy test and no intrauterine or ectopic pregnancy on transvaginal US.

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The Pivotal Question

Is there a chance of a viable pregnancy?

The Expanded Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA IUP of Uncertain Viability Pregnancy

• f

Unknown Location Expectant management Expectant management

Viable IUP Failure

Short delay in dx

EP

Likely non-life threatening Short delay in dx

Viable IUP Failure

Likely non-life threatening

EP

The Expanded Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA +/- MTX +/or surgery MUA IUP of Uncertain Viability Pregnancy

• f

Unknown Location Expectant management Expectant management

The Expanded Differential

Failed/ Failing IUP IUP of Uncertain Viability Pregnancy

• f

Unknown Location

Specific criteria and management algorithms

10/22/2014 12

Literature on Nonviable IUP Criteria

• Serum beta level

– Largely unreliable given range of normal

• US findings

– Size-based criteria

• Embryo without heart motion
• GS without an embryo

– Time-based criteria

• Appearance of interval findings

What is the correct order of appearance?

A. B. C. D.

12% 52% 34% 2%

• A. Yolk sac – Gestational sac – Embryo – Amnion
• B. Yolk sac – Amnion – Embryo – Gestational Sac
• C. Gestational sac – Yolk sac – Embryo – Amnion
• D. Gestational sac – Yolk sac – Amnion – Embryo

Let’s review normal.

v v

US of Early Pregnancy

• In order of appearance:

– Intradecidual sign – Double decidual sac sign – Yolk sac – Embryo – Amnion (+ heart motion)

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US of Early Pregnancy

• In order of appearance:

– Intradecidual sign – Double decidual sac sign – Yolk sac – Embryo – Amnion (+ heart motion)

“White Lines” of the Endometrium

Post menses B Basalis (2 layers)

“White Lines” of the Endometrium

Early Proliferative Phase Basalis (2 layers) Functionalis = Spongiosum and Compactum B B C S S

“White Lines” of the Endometrium

B B C S S Basalis (2 layers) Functionalis = Spongiosum and Compactum Late Proliferative Phase Aka: “Triple line sign”

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“White Lines” of the Endometrium

Secretory Phase Basalis (2 layers) Functionalis = Spongiosum and Compactum

“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum Early Secretory Phase

“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum Late Secretory Phase

“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum Decidua In Pregnancy

10/22/2014 15

“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum

Blastocyst

Decidua In Pregnancy

“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum In Pregnancy = Decidua Decidua In Pregnancy

Intradecidual Sign

Basalis (2 layers) Functionalis = Spongiosum and Compactum In Pregnancy = Decidua Decidua In Pregnancy

Intradecidual Sign

• ~ 3-4 weeks
• US:

– ≥ 2 mm cyst – Thin echogenic rim – Eccentric to central echogenic line – “Color flash”

• Occasionally helpful

Yeh, et.al., Radiology. 1986 Nov;161(2)

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Intradecidual Sign: Mimics

• DDx:

– Intracavitary fluid – Decidual cysts

• IUP
• EP

– Endometrial pathology

• Polyps
• Cystic hyperplasia
• Malignancy

Intradecidual Sign

Grows ~ 1mm/day and becomes….

Double Decidual Sac Sign Double Decidual Sac Sign

• ~ 5 weeks
• US:

– Round/oval fluid collection – 2 echogenic rims

• Inner: chorion
• Outer: decidua

Bradley, Filly, et.al., Radiology.1982 Apr;143(1)

10/22/2014 17

Double Decidual Sac Sign: Mimic

• Pseudo-gestational sac
• DDx:

– Decidual reaction – Implantation bleed – EP (10-20%)

• US:

– Fluid collection

• 1 echogenic rim
• Acute ‘s, “tear -

drop” shaped

How reliable are these signs?

• Intradecidual sac sign

– Specificity: 66 - 97% – Sensitivity: 48 - 92 %

• Double decidual sac sign

– Specificity: 85 - 98% – Sensitivity: 64 - 95% Absent in at least 35% of gestational sacs

Any round/oval fluid collection = GS

“ Therefore, any round or oval fluid collection in a woman with a positive pregnancy test most likely represents an intrauterine gestational sac and should be reported as such.”

N Engl J Med October 2013;369:1445

Mean Sac Diameter Measurement

• Add dimensions of anechoic sac

(excluding echogenic rim) – Length + height + width

• Divide by 3

+ +

LONG TRANS

Report: “If this represents a GS, the MSD measures # mm”

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Mean Sac Diameter Measurement

• Add dimensions of anechoic sac

(excluding echogenic rim) – Length + height + width

• Divide by 3

+ +

LONG TRANS

Report: “If this represents a GS, the MSD measures # mm”

Yolk Sac

• ~ 5 ½ weeks
• US:

– Thin round ring-like structure – 3-5 mm

• Typically not

> 6 mm

IUP MSD IUP MSD

10/22/2014 19

What do you do/say in your report/notes?

A. B. C. D.

60% 33% 7% 0%

• A. Too early to calculate gestational age and EDC
• B. Have your partner figure out interval growth when she

returns for her 18 – 20 week scan

• C. Measure yolk sac and add to MSD
• D. Use the formula MSD (mm) + 30 = GA (days) and wheel out

the EDC

IUP MSD

MSD (mm) + 30 = GA (days) i.e. 10 + 30 = 40 days (5 wks, 5 days)

Embryo

• ~ 6 weeks
• US:

– Flickering heart motion adjacent to yolk sac – Grows ~ 1mm/day – Reniform, tadpole appearance Crown-rump length (CRL) = avg of 2-3 end-to-end measurements

Amnion

• ~ 8 weeks
• US:

– Very thin echogenic membrane surrounding embryo – Between YS and embryo – “Fuses” with chorion: 12-16 weeks “2nd skin” YS

10/22/2014 20

US of Early Pregnancy

• In order of appearance:

– Intradecidual sign – Double decidual sac sign – Yolk sac – Embryo – Amnion (+ heart motion) 4 criteria definitive for failure 2 size based 2 time based

Discriminatory CRL

• Defined as CRL size, above which, the absence of cardiac

motion is unequivocal for failure

• Historically: 5 mm

– However:

• Sensitivity: 50%
• More recent data: 5-6 mm
• Inter-observer variability: + 15%
• Most conservative scenario:

Upper nl CRL (6 mm) + 15% (0.9) = 6.9 mm 7.0 mm

Criteria Definitive for Failure

• 1. CRL ≥ 7 mm without

cardiac activity – PPV for failure: 100% “Embryonic demise”

Discriminatory MSD

• Defined as MSD size, above which, the absence of an embryo

is unequivocal for failure

• Historically: 16 – 18 mm

– However:

• Sensitivity: 50%
• More recent data = 17-21 mm
• Inter-observer variability: + 19%
• Most conservative scenario:

Upper nl MSD (21 mm) + 19% (4) = 25 mm

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Criteria Definitive for Failure

• 2. MSD ≥ 25 mm and no visible

embryo – PPV for failure: 100% “1st trimester pregnancy failure”

Time-Based Criteria for Failure

• Needed as discriminatory sac or embryo sizes may never be

achieved

• Based on timing of interval appearance:

– GS - 5 weeks – YS - 5 ½ weeks – Embryo with heart motion - 6 weeks

• Most conservative scenario:

– Lower nl GS (4 ½ wks) - upper nl embryo (6 ½ wks) = 2 wks – Lower nl YS (5 wks) - upper nl embryo (6 ½ wks) = 1 ½ wks +/- ½ week 11 days 14 days

Criteria Definitive for Failure

• 3. Absence of embryo with heartbeat ≥ 14 days after a scan that

showed a GS without a YS

• 4. Absence of embryo with heartbeat ≥ 11 days after a scan that

showed a GS with a YS

8 criteria suggestive for failure

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Criteria Suggestive for Failure

• 1. CRL <7 mm and no heartbeat
• 2. MSD of 16 - 24 mm and no embryo
• 3. Absence of embryo +HM 7–13 days after a GS without a YS
• 4. Absence of embryo +HM 7–10 days after a GS with a YS

“When there are findings suspicious for pregnancy failure, follow-up US at 7 to 10 days is generally appropriate.”

Do we really need to wait to call this?

Normal GS and embryo grow ~1 mm/day

Criteria Suggestive for Failure

• 5. Empty amnion
• Amnion adjacent to YS, with

no visible embryo

Criteria Suggestive for Failure

• 5. Empty amnion
• Amnion adjacent to YS, with

no visible embryo

• 6. Enlarged yolk sac (>7 mm)

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Criteria Suggestive for Failure

• 5. Empty amnion
• Amnion adjacent to YS, with

no visible embryo

• 6. Enlarged yolk sac (>7 mm)
• 7. Small GS in relation to size of

embryo

• MSD – CRL = <5

Criteria Suggestive for Failure

• 8. Absence of embryo ≥ 6 wk

after last menstrual period CAUTION!!!

• Would only consider if:

– Reliable historian with very regular cycles OR – IVF patient

Pregnancy of Unknown Location

• Defined as:

– Pregnant (serum beta hCG > 5 mIU/ml) – US findings:

• No intrauterine fluid collection
• Normal (or near normal) adnexa

corpus luteum of pregnancy

Pregnancy of Unknown Location

10/22/2014 24

Pregnancy of Unknown Location

• NOTE: Serum beta levels

– A single measurement of hCG, regardless of its value, does not reliably distinguish between EP and IUP (viable or nonviable) – Discriminatory level of 2000 (to dx IUP) may not be high enough

• Looked at likelihood ratios of different outcomes based
• n range of serum beta hCG

Beta vs. Likely Outcome

Serum beta Likely outcome < 2000 mIU/ml Viable IUP

Beta vs. Likely Outcome

Serum beta Likely outcome < 2000 mIU/ml Viable IUP 2000 – 3000 mIU/ml Nonviable IUP - 38:1 EP - 19:1 Viable IUP: 2%

Beta vs. Likely Outcome

Serum beta Likely outcome < 2000 mIU/ml Viable IUP 2000 – 3000 mIU/ml Nonviable IUP - 38:1 EP - 19:1 Viable IUP: 2% > 3000 mIU/ml Nonviable IUP - 140:1 EP - 70: 1 Viable IUP: 0.5%

10/22/2014 25

Pregnancy of Unknown Location

• Management recommendations:

– Beta hCG <3000 and stable:

• Presumptive tx for EP with MTX or other pharmacologic
• r surgical means should not be undertaken, in order to

avoid the risk of interrupting a viable IUP. – Beta hCG ≥3000 and stable:

• A viable IUP is possible but unlikely. However, as the

most likely diagnosis is a nonviable IUP, it is generally appropriate to obtain at least one follow-up hCG and follow-up US before undertaking treatment for EP.

Pregnancy of Unknown Location

• Management recommendations:

– Beta hCG <3000 and stable:

• Presumptive tx for EP with MTX or other pharmacologic
• r surgical means should not be undertaken, in order to

avoid the risk of interrupting a viable IUP. – Beta hCG ≥3000 and stable:

• A viable IUP is possible but unlikely. However, as the

most likely diagnosis is a nonviable IUP, it is generally appropriate to obtain at least one follow-up hCG and follow-up US before undertaking treatment for EP.

Pregnancy of Unknown Location

• NOTE:

– When US not yet performed:

• No single serum beta level predicts the likelihood of EP

rupture.

• When clinical findings are suspicious for EP, transvaginal

ultrasonography is indicated, even when the hCG level is low. There isn’t a beta low enough to exclude EP. You gotta do the US!

The Basic Assumption

• Pregnancy is desired.

UCSF: Meredith Warden, M.D., M.P.H. Jody Steinauer, M.D., Univ of Penn: Courtney A. Schreiber, M.D., M.P.H.

10/22/2014 26

In Conclusion

• First, DO NO HARM to a potentially viable pregnancy
• Consider adding “IUP of Uncertain Viability” and “Pregnancy
• f Unknown Location” to your lexicon and manage

expectantly

• In setting of PUL, stable pt. and desired pregnancy

– Always get an US – Beta < 3000, f/u serial betas and US as indicated – Beta ≥ 3000, though viable IUP highly, may consider f/u beta and desired Upper beta limit not addressed.

In Conclusion

• Definitive criteria for early IUP failure:

– CRL ≥ 7 mm + no heart motion – MSD ≥ 25 mm and no embryo – No embryo ≥ 14 days after a GS without a YS – No embryo ≥ 11 days after a GS with a YS

• Suggestive for failure:

– No embryonic heart motion – Empty amnion sign – YS too big, GS too small, others – Consider repeat US at 7-10 days highly suggestive, in my opinion sooner sometimes OK too , in my opinion Role of beta?

Thank you for your attention.