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6/6/2014 1 Sonographic Criteria for Nonviable Pregnancy in the 1st Trimester

Lori Strachowski, MD Clinical Professor of Radiology, UCSF Chief of Ultrasound, SFGH

I have no disclosures. 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 gestational sac or yolk sac
• Interpretation:

– Findings perceived but incorrectly diagnosed

• i.e. CL of pregnancy interpreted as an EP or an early GS

as a pseudo-sac

• Confounding factors for both:

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

Obstetrics and Gynecology 2010 ;116:8-15

The Objective

First, DO NO HARM

• r the least possible

The Plan

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

– Widely applicable and reproducible – Minimize risk

• Based (in part) on downstream consequences of false

positive and false 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

6/6/2014 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.

• Ectopic pregnancies and failed intrauterine pregnancies

are nonviable.

The Differential

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

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Currently Viable IUP The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA, MTX, surgery MUA

Ectopic Pregnancy

Ov

The Differential

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA, MTX, 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, surgery MUA

It ain’t always that easy! FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA, MTX, surgery MUA

FP

Short delay in dx

FN: Failure

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FP + FN Consequences

Currently Viable IUP Failed/ Failing IUP Ectopic pregnancy Expectant management MUA, MTX, 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, 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, surgery MUA

FP FP

Short delay in dx Likely non-life- threatening!

FN: Viable IUP FN: Viable IUP

To “DO NO HARM”

• 1. Criteria for non-viability require

– 100% Specificity – 100% PPV

• 2. Need more buckets!
• r as close as possible

6/6/2014 10

The Expanded Differential

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

• f

Unknown Location

The Terminology

• Intrauterine pregnancy of uncertain viability:

– If 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 is seen on transvaginal US. Is there a chance of a viable pregnancy?

The Expanded Differential

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

• f

Unknown Location Expectant management Expectant management

The Expanded Differential

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

• f

Unknown Location Expectant management Expectant management

Viable IUP Failure

Short delay in dx

EP IUP

Short delay in dx Likely non-life- threatening

6/6/2014 11

The Expanded Differential

Failed/ Failing IUP IUP of Uncertain Viability Pregnancy

• f

Unknown Location

Specific criteria and management algorithms

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

Let’s review normal.

v v

US of Early Pregnancy

• In order of appearance:

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

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US of Early Pregnancy

• In order of appearance:

– Intradecidual sign – Double decidual sac sign – Yolk sac – Embryo – Amnion Gestational sac (+ 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

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

“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 In Pregnancy = Decidua

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“White Lines” of the Endometrium

Basalis (2 layers) Functionalis = Spongiosum and Compactum

Blastocyst

In Pregnancy = Decidua

“White Lines” of the Endometrium

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

Intradecidual Sign

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

Intradecidual Sign

• ~ 3-4 weeks
• US:

– ≥ 2 mm cyst – Thin echogenic rim – Eccentric to central echogenic line of endometrium – Occasional “color flash”

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

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Intradecidual Sign: Mimics

• Intracavitary fluid
• Decidual cysts

– IUP – EP

• Endometrial pathology

– Polyps – Cystic hyperplasia – Cancer

Intradecidual Sign

Grows ~ 1mm/day and becomes….

Double Decidual Sac Sign Double Decidual Sac Sign

• ~ 5 weeks
• US:

– Round/oval fluid collection with 2 echogenic rims

• Inner: chorion
• Outer: decidua

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

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Double Decidual Sac Sign: Mimic

• Pseudogestational sac

– Fluid/blood in endometrial cavity

• US:

– Round/oval fluid collection with 1 echogenic rim = decidua – Acute angle margins

• Associations:

– Implantation bleed – EP (10-20%)

How reliable are these signs?

• Intradecidual sac sign

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

• Double decidual sac sign

– Sensitivity: 64 - 95% – Specificity: 85 - 98% Absent in at least 35% of gestational sacs If you see an oval/round intrauterine fluid collection……

It’s a GS until proven otherwise!

“ 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

• Diameter of anechoic sac

(excluding echogenic rim)

• Measure:

– Greatest length – Perpendicular – Orthogonal greatest length

• Divide by 3

LONG TRANS

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

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Yolk Sac

• ~ 5 ½ weeks
• US:

– 3-5 mm round, thin echogenic ring NOTE: Never > 6mm OR thick/solid appearing at this gestational age

IUP MSD

Never to early to date!

IUP MSD

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

Embryo

• ~ 6 weeks
• US:

– Adjacent to yolk sac – Present as flickering heart motion – Grows ~ 1mm/day – Reniform, tadpole appearance Crown-rump length (CRL) avg

• f 2-4 measurements

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Amnion

• ~ 8 weeks
• US:

– Very thin echogenic ring surrounding embryo between yolk sac and chorion of GS – Fuses with chorion: 12- 16 weeks “2nd skin” YS

US of Early Pregnancy

• In order of appearance:

– Intradecidual sign – Double decidual sac sign – Yolk sac – Embryo – Amnion Gestational sac (+ heart motion) 4 criteria definitive for failure

Size-based Criteria for Failure: CRL

• Discriminatory CRL = size above which, the absence of cardiac

motion is unequivocal for failure

• Historically: 5 mm

– Sensitivity: 50% – Specificity: 100% (95% CI: 90-100%)

• More recent data reports CRL 5-6 mm without heart motion

and subsequent viable pregnancy

• Interobserver variability (measurement technique): + 15%
• Worst case scenario:

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

#1 Criteria Definitive for Failure

• CRL ≥ 7 mm without cardiac

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

6/6/2014 19

Size-based Criteria for Failure: MSD

• Discriminatory MSD = size above which, the absence of an

embryo is unequivocal for failure

• Historically: 16 – 18 mm

– Sensitivity: 50% – Specificity: 100% (95% CI: 88-100%)

• More recent data reports MSD = 17-21 mm without an

embryo and subsequent viable pregnancy

• Interobserver variability (measurement technique): + 19%
• Worst case scenario:

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

#2 Criteria Definitive for Failure

• MSD ≥ 25 mm and no visible

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

Time-Based Criteria for Failure

• Needed as in the setting of failure, discriminatory sac or

embryo sizes may never be achieved

• Based on known timing of interval appearance of:

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

• Worse case scenario:

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

#3 + #4 Criteria Definitive for Failure

• Absence of embryo with heartbeat ≥ 2 wks after a scan that

showed a GS without a YS

• 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 of Failure

• CRL <7 mm and no heartbeat
• MSD of 16 - 24 mm and no embryo
• Absence of embryo with heartbeat 7–13 days after a GS (-YS)
• Absence of embryo with heartbeat 7–10 days after a GS (+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 of Failure

• Empty amnion (amnion seen

adjacent to yolk sac, with no visible embryo)

Criteria Suggestive of Failure

• Empty amnion (amnion seen

adjacent to yolk sac, with no visible embryo)

• Enlarged yolk sac (>7 mm)

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Criteria Suggestive of Failure

• Empty amnion (amnion seen

adjacent to yolk sac, with no visible embryo)

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

embryo (MSD – CRL= <5 )

Criteria Suggestive of Failure

• Absence of embryo ≥ 6 wk after

last menstrual period CAUTION!!! – Unless:

• Really reliable historian

with regular cycles OR

• IVF

Pregnancy of Unknown Location

• US findings:

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

Pregnancy of Unknown Location

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Pregnancy of Unknown Location

• US findings:

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

• Serum beta level:

– 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

Likelihood Ratio vs. Viable IUP

Serum beta Likely outcome < 2000 mIU/ml Viable IUP

Likelihood Ratio vs. Viable IUP

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

Likelihood Ratio vs. Viable IUP

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%

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PUL: Management Recommendations

• Beta hCG <3000 and stable:

– Presumptive tx for EP with MTX or other pharmacologic or 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

• When US not yet performed:

– Serum beta level:

• No single level predicts the likelihood of ectopic

pregnancy rupture. Thus, when clinical findings are suspicious for ectopic pregnancy, transvaginal ultrasonography is indicated even when the hCG level is low.

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.

In Conclusion

• First, DO NO HARM to a potentially viable pregnancy
• Add “IUP of Uncertain Viability” and “Pregnancy of Unknown

Location” to your lexicon and manage expectantly

• In setting of PUL, hemodynamically stable and desired

– Always get an US – If normal US and beta ≥ 3000, though highly unlikely to be a viable IUP, may consider f/u and desired

6/6/2014 24

In Conclusion

• Definitive failed IUP:

– CRL ≥ 7 mm + no heart motion – MSD ≥ 25 mm and no embryo – No embryo ≥ 2 wks after a GS (- YS) or 11 days (+ 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 OK too , in my opinion

Thank you for your attention.