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10/22/2014
1
New Recommendations for Diagnosing Failed Intrauterine Pregnancy
Lori Strachowski, MDClinical Professor of Radiology, UCSF
Chief of Ultrasound, SFGH
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 PregnancyMisuse 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
of 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
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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 viablecandidate> (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 viablecandidate> (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
pregnanciesManual uterine
aspiration
The Differential
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
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Currently Viable IUP The Differential
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
Ectopic Pregnancy
Ov
The Differential
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
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Spontaneous AB in ProgressCervix
The Differential
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
What is the best diagnosis for this1st trimester pregnancy?
A. B. C. D.
20%
71%
1%7%
A. Currently viable IUPB. Failed/failing IUPC. Ectopic PregnancyD. I don’t like any of these
answers
It ain’t always that easy!
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FP + FN Consequences
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
FP: Viable IUP
Short delay in dx
FN: Failure
FP + FN Consequences
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUAShort delay in dxLikely non-life-
threatening!
FN: EP
FP + FN Consequences
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUAShort delay in dxLikely non-life-
threatening!
FN: EP FN: Failure
FP + FN Consequences
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
FP: Failure FP: EP
Short delay in dxLikely non-life-
threatening!
FN: Viable IUP FN: Viable IUP
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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
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
IUP of Uncertain Viability
Pregnancyof
UnknownLocation
The Expanded Differential
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
IUP of Uncertain Viability
Pregnancyof
UnknownLocation
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
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
IUP of Uncertain Viability
Pregnancyof
UnknownLocation
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
CurrentlyViable
IUPFailed/Failing
IUP
Ectopic pregnancy
Expectant management
MUA +/- MTX +/or surgery
MUA
IUP of Uncertain Viability
Pregnancyof
UnknownLocation
Expectant management
Expectant management
The Expanded Differential
Failed/Failing
IUPIUP of Uncertain Viability
Pregnancyof
UnknownLocation
Specific criteria and management algorithms
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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 SacC. Gestational sac – Yolk sac – Embryo – Amnion D. Gestational sac – Yolk sac – Amnion – Embryo
Let’s review normal.
vv
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 EndometriumPost menses
B
Basalis (2 layers)
“White Lines” of the EndometriumEarly Proliferative Phase
Basalis (2 layers) Functionalis = Spongiosum and Compactum
B
BC S
S
“White Lines” of the Endometrium
B
B
C SS
Basalis (2 layers) Functionalis = Spongiosum and Compactum
Late Proliferative Phase
Aka: “Triple line sign”
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“White Lines” of the EndometriumSecretory 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
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“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 = DeciduaDecidua
In Pregnancy
Intradecidual Sign
Basalis (2 layers) Functionalis = Spongiosum and Compactum
In Pregnancy = DeciduaDecidua
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)
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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
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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 EDCB. Have your partner figure out interval growth when she
returns for her 18 – 20 week scanC. Measure yolk sac and add to MSDD. 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
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US of Early Pregnancy• In order of appearance:
– Intradecidual sign– Double decidual sac sign– Yolk sac– Embryo– Amnion
(+ heart motion)
4 criteria definitive for failure2 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 mm7.0 mm
Criteria Definitive for Failure1. 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 Failure2. 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 days14 days
Criteria Definitive for Failure3. 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 Failure1. 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 Failure5. Empty amnion
- Amnion adjacent to YS, with no visible embryo
Criteria Suggestive for Failure5. Empty amnion
- Amnion adjacent to YS, with no visible embryo
6. Enlarged yolk sac (>7 mm)
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Criteria Suggestive for Failure5. 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 Failure8. 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
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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
on 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/mlNonviable 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/mlNonviable IUP - 38:1
EP - 19:1 Viable IUP: 2%
> 3000 mIU/mlNonviable IUP - 140:1
EP - 70: 1Viable IUP: 0.5%
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Pregnancy of Unknown Location• 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• 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• 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
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In Conclusion• First, DO NO HARM to a potentially viable pregnancy
• Consider adding “IUP of Uncertain Viability” and “Pregnancy of 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.