diagnosis and management of early pregnancy loss · 2014-09-30 · diagnosis and management of...

Diagnosis and Management of

Early Pregnancy Loss

Kurt Barnhart MD, MSCE

William Shippen Jr, Professor of Obstetrics and

Gynecology

Penn Fertility Care

Perlman School of Medicine at the University of

Pennsylvania

Objectives

How does one distinguish and ongoing IUP from

a miscarriage and an ectopic pregnancy?

What is a pregnancy of unknown location, and

what do I do about it?

What is the final diagnosis?

Once I make a diagnosis is it better to treat

surgically, medically or use expectant

management

NO Disclosures

Ectopic Pregnancy

This ultrasound image shows an empty endometrial cavity and a

5-mm gestational sac in the right adnexa.

Utility of Ultrasound Above and

Below the Discriminatory Zone

Intrauterine pregnancy 198 (59.0%) 200 (60.0%)

Miscarriage 57 (17.0%) 82 (24.6%)

Ectopic pregnancy 19 (6.0%) 27 (8.0%)

Non-diagnostic 59 (18.0%) ____

Lost to follow-up _____ 22 (6.6%)

Other _____ 2 (0.6%)

Total 333 (100%) 333 (100%)



Patients with bhCG level ABOVE 1500 mIU/mL at

presentation

Ultrasound Diagnosis Sensitivity Specificity +PV -PV

Intrauterine pregnancy 98%* 90% 96% 96%

Miscarriage 73%* 93% 65% 65%

Ectopic pregnancy 80%* 99% 86% 99%



Patients with bhCG level BELOW 1500 mIU/mL at

presentation

Ultrasound Diagnosis Sensitivity Specificity +PV -PV

Intrauterine pregnancy 33%* 98% 80% 86%

Miscarriage 28%* 100% 100% 47%

Ectopic pregnancy 25%* 96% 60% 85%

Classification scheme for women with a

positive pregnancy test at first TVS

Extrauterine gestational

sac with yolk sac and/or

embryo (with or without

cardiac activity)

Definite Ectopic

Pregnancy

Inhomogeneous adnexal

mass or extrauterine

sac-like structure

Probable Ectopic

Pregnancy

No signs of intrauterine

or extrauterine gestation

on transvaginal

sonography

Pregnancy of

Unknown Location

Intrauterine gestational

sac with yolk sac and/or

embryo (with or without

cardiac activity)

Definite Intrauterine

Pregnancy

Intrauterine echogenic

sac-like structure

Probable Intrauterine

Pregnancy

First Trimester ultrasound accuracy

depends more on serum hCG values, than

patient symptoms (2004 – 2007)

Women at High Risk

1 in 14 women who present to

the emergency department

complaining of vaginal bleeding

and/or abdominal pain, who have

a positive pregnancy test, have

an ectopic pregnancy

Incidence

Center for Disease Control and Prevention

1970 1 in 200 (4.5 per 1000 pregnancies)

1990 1 in 60 (16.8 per 1000 pregnancies)

1970 35.5 per 1000 pregnancies

1990 3.8 per 1000 pregnancies

IUP Ectopic Pregnancy Abnormal IUP

Nonviable intrauterine

pregnancy

+ chorionic villi

Ectopic pregnancy

- chorionic villi

D+C

hCG>discriminatory zone

transvaginal ultrasound

when > discrim zone

Normal rise

Nonviable IUP

+ chorionic villi

Ectopic pregnancy

- chorionic villi

D+C

Plateau

Follow to hCG=0

Normal fall

Serial quantitative hCG

hCG<discriminatory zone

Nondiagnostic

Transvaginal Ultrasound

Figure 1. Algorithm for the diagnosis of ectopic pregnancy in

a hemodynamically stable patient

Barnhart et al Obstet Gynecol 1994; 84:1010-5 Gracia C, Barnhart KT. Obstet Gynecol, 97(3):464-470, 2001.

Case Presentation

Your beeper goes Friday afternoon, before

your planned trip to ACOG

Your nurse calls you: Ms Smith called

your nurse.

Ms. Smith has a home pregnancy test is

positive, and she THINKS she is about 2 weeks

late for her period.

She has moderate pain in her left side and has

been spotting for 4 days

She is a G4 P0, with three miscarriages

in the first trimester

Case Presentation

Ms. Smith’s HCG level is 1000

She is clinically stable

This is a desired pregnancy

Normal Rise in hCG

Fit the curve of women who presented to

ED at risk for EP who were definitively

diagnosed with a viable IUP

293 subjects, 873 observations

Average age 24

Average G 2.4 P 0.8

Average hCG value 1000

Fit a number of models:

Linear, Spline, Exponential.

Normal Rise in hCG

2

4

6

8

10

12

loghcg/9

9%

CI/F

itte

d v

alu

es

20 30 40 50gestational age (days)

loghcg 99% CI Fitted values

Number Of Days Since Presentation

hC

G (

mIU

/mL

)

0 2 4 6 8 10 12

05

00

01

00

00

15

00

0

Estimated Curve15 % Lower Bound5 % Lower Bound1 % Lower Bound

Barnhart KT. Symptomatic Patients with an Early Viable Intrauterine Pregnancy; hCG

Curves Redefined. Obstet Gynecol 2004;104:50-5.

Increase in hCG value at different days

(as a percent of initial value)

quartile slope 1 day 2 day 3 days 4 days

99 1.23 1.23 1.53 1.84 2.26

95 1.30 1.30 1.69 2.19 2.84

85 1.37 1.36 1.87 2.55 3.48

50 1.50 1.50 2.22 3.31 4.94

10 1.66 1.66 2.76 4.58 7.60

1 1.81 1.81 3.29 5.96 10.80

Barnhart KT. Symptomatic Patients with an Early Viable Intrauterine

Pregnancy; hCG Curves Redefined. Obstet Gynecol 2004;104:50-5.

hCG Rise After IVF 2

46

81

01

2

sin

gle

ton

/tw

ins/t

rip

lets

20 30 40 50gestational age (days)

singleton twins

triplets

23

The slopes by race

Black

White

Case Presentation

Ms. Smith’s HCG level is 1000

She is clinically stable

This is a desired pregnancy

Repeat hCG in two days is 500

Normal Fall in hCG

Fit the curve of women who presented to ED at risk

for EP who were definitively diagnosed with a

complete SAB

719 subjects, 2914 observations

Serum hCG confirmed to be > 5

Fit a number of models:

Linear, quadratic, cuboidal, change point with

random intercept and random effect

Final model was random linear effect dependant on

initial hCG value

Curve of Complete SAB

# of days after presentation

dro

p o

f hC

G

0 10 20 30 40

0500

1000

1500

2000

Barnhart, K. Decline of serum human chorionic gonadotropin and spontaneous

complete abortion: Defining the normal curve. Ob Gyn 2004:104(5):975-981.

Normal Fall of hCG for Complete SAB

Intial hCG

value

hCG value

at 2 days

hCG value

at 7 days

hCG value

at 21 days

Time to

neg hCG

500 256

447 (21%)

48

337 (60%)

0

76

19

1000 513

894

96

675

0

308

21

2000 1027

1788

193

1351

0

616

23

5000 2567

4470 (35%)

484

3378 (84%)

5

1541

26

Barnhart, K. Decline of serum human chorionic gonadotropin and spontaneous

complete abortion: Defining the normal curve. Ob Gyn 2004:104(5):975-981.

hCG Curve for an Ectopic

1543 patients

(no apparent dx at presentation, + ß-hCG)

366 with EP

166 dx 1st ß-hCG 200 dx serial ß-hCG

121

rising ß-hCG

(60%)

Group A

79

declining ß-hCG

(40%)

Group B

Results Group A

(Rising ß-

hCG)

Group B

(Declining

ß-hCG)

p

N. Visits 3.53 3.51 < 0.93

Days to Dx 5.34 5.29 < 0.72

ß-hCG

presentation

700.36

1287.68 < 0.006

ß-hCG dx 1391.55 991.61 < 0.21

EGA presentation 38.96 42.72 < 0.19

EGA dx 44.30 48.13 < 0. 36

Number of days since presentation

log

(hC

G)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

02

46

81

0

1st percentile of IUP

90th percentile of SAB

Ris ing EP, 75%

Ris ing EP, 90%


log

(hC

G)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

02

46

81

0



34%


log

(hC

G)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

02

46

81

0



Dropping EP, 10%


log

(hC

G)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

02

46

81

0



20%

When to intervene in suspected IUP

Minimal Rise of β-hCG in IUP

Days since presentation

hC

G (

mIU

/mL

)

min hCG

Pt 1

When to intervene in suspected SAB

Minimal Fall of β-hCG in SAB

Days since presentation

hC

G (

mIU

/mL

)

min hCG

Pt 2

Confidence interval

bounds used for

curves (percentile) Sensitivity for EP (%) Sensitivity for IUP (%)

Mean number of days

saved (range)*

Mean number of visits

saved (range)*

Validation Original Validation Original Validation Original Validation Original

IUP (0.999), SM (0.90) 83 83 92 95 2.87 (0-35) 2.64 (0-34) 0.92 (0-7) 1.22 (0-9)

IUP (0.99), SM (0.90) 91 88 83 90 3.27 (0-35) 2.85 (0-34) 1.07 (0-7) 1.30 (0-9)

IUP (0.95), SM (0.90) 92 91 73 78 3.44 (0-37) 2.94 (0-34) 1.12 (0-7) 1.35 (0-9)

IUP (0.999), SM (0.95) 78 79 92 94 2.68 (0-35) 2.36 (0-34) 0.86 (0-7) 1.12 (0-9)

IUP (0.99), SM (0.95) 86 84 83 90 3.08 (0-35) 2.60 (0-34) 1.02 (0-7) 1.21 (0-9)

hCG, human chorionic gonadotropin; EP, ectopic pregnancy; IUP, intrauterine pregnancy; SM, spontaneous

miscarriage.

*For patients with outcome of ectopic pregnancy. #Seeber et al. Fertil Steril 2006 Aug;86(2):454-9.

Confidence interval bound was defined as the minimal expected rise for an intrauterine pregnancy or fall for a

spontaneous miscarriage.

Performance for Various hCG Cutoffs to Predict the Outcome in PUL

Confidence interval

bounds used for curves

(percentile)

Number of

misclassified EPs

(%)

Number of

misclassified

IUPs(%)

Number of

misclassified miscarriages

(%)

Validation Original# Validation Original Validation Original

IUP (0.999), SM (0.90) 30 (16.8) 34 (17.3) 20 (7.7) 12 (4.6) 221 (39.0) 222 (28.0)

IUP (0.99), SM (0.90) 16 (8.9) 24 (12.2) 45 (17.4) 26 (10.0) 231 (40.7) 224 (28.2)

IUP (0.95), SM (0.90) 14 (7.8) 18 (9.2) 71 (27.4) 58 (22.2) 236 (41.6) 225 (28.4)

IUP (0.999), SM (0.95) 39 (21.8) 41 (20.9) 20 (7.7) 15 (5.7) 163 (28.8) 158 (19.9)

IUP (0.99), SM (0.95) 25 (14.0) 31 (15.8) 45 (17.4) 26 (10.0) 173 (30.5) 160 (20.2)

Performance for Various hCG Cutoffs to Predict the Outcome in PUL

#Seeber et al. Fertil Steril 2006 Aug;86(2):454-9.

Confidence interval bound was defined as the minimal expected rise for an intrauterine pregnancy or fall for a spontaneous

miscarriage.

Case Presentation


your vacation to the South of France

Your nurse calls you: Ms Jones is pregnant

and is 2 weeks late for her period

She has moderate pain in her left side and an

ultrasound that says she as a:

4 cm cystic adnexal mass

No evidence of a gestational sac in the uterus

Case Presentation


your vacation to the South of France

Your nurse calls you: Ms Jones is pregnant

and is 2 weeks late for her period

She has moderate pain in her left side and an

ultrasound that says she as a:

4 cm complex adnexal mass with increase

vascularity noted by Doppler (with a possible

“ring of fire”.

No evidence of a gestational sac in the uterus

Case Presentation

This time you are in your office.

Your resident consults you: Ms Johnson

has 6.5 weeks of amenorrhea, pain, and

bleeding.

Ultrasound: No evidence of a gestational sac

in the uterus

hCG 6830

Your resident wants to treat with MTX

YOUR THOUGHTS???

Role of D&C

Can you “presume the diagnosis of

and EP?

Two cases of presumed EP

hCG is high and no sac in the uterus

hCG is low (below the DZ) and there

is a abnormal rise (or fall).

How often does it happen

Role of D&C

Can I skip the D&C to save time?

Pipelle Biopsy?

What if I am wrong???

Inflates success of MTX

I do not miss an EP

At worst I am treating an SAB, Correct?

Legal Implications

Presumed Ectopic Pregnancy?

Overall EP SAB

111 70 (63%) 41 (37%)

Below DZ

76 53 (70%) 23 (30%)

Above DZ

35 17 (49%) 18 (51%)

Age 28.8

Parity 1.4

hCG 2460 + 4800

Two year study:

Barnhart KT, Obstet Gynecol 2002;100(3):505-510.

Miscarriage

N = 66 (38.2%)

Ectopic

N = 107 (61.8%) p

Rise >10% 14 (25.5) 41 (75.5) 0.09

Plateau (+/- 10%) 27 (42.2) 37 (57.8)

Fall > 10% 16 (44.4) 20 (55.6)

hCG < 2000 40 (30.1) 93 (69.9) 0.01

hCG ≥ 2000 26 (65.0) 14 (35.0)

Pain 0.84

hCG < 2000 22 (31.9) 47 (68.1)

hCG ≥ 2000 12 (52.2) 11 (47.8)

Bleedinge 0.52

hCG < 2000 23 (28.1) 59 (71.9)

hCG ≥ 2000 20 (69.0) 9 (31.0)

2004 -2007

USC Experience (2005 -08)

EP

(n = 235)

SAB

(n = 86)

OR for EP p

All patients 235 (73.2%) 86 (26.8%)

hCG< 2000 163 (69.4%) 32 (37.2%) 3.82

(2.28 - 6.41)

<0.001

hCG > 2000 72 (30.6%) 54 (62.8%)

Evidence of intrauterine

pregnancy on TVS

Should be classified as viable,

viability uncertain or

nonviable

Histological

Intrauterine Pregnancy

Chorionic villi identified in

contents of uterine evacuation

Resolved

Persistent PUL

Spontaneous resolution of hCG

levels with expectant

management or after uterine

evacuation without evidence

of chorionic villi on pathology

Persisting PUL

Visualized

Ectopic Pregnancy

Spontaneously

Resolved PUL

Visualized


Evidence of ectopic pregnancy on

transvaginal sonography (TVS)

or via laparoscopy

Spontaneous resolution

of

hCG levels

Pregnancy of Unknown

Location (PUL)

Non-Visualized

Ectopic Pregnancy

Persistent or rising hCG levels

after uterine evacuation

Treated

Persistent PUL

Medical management of PUL

without confirmation of

the location of the gestation


Visualized Intrauterine Pregnancy

Evidence of intrauterine

pregnancy on TVS

Should be classified as viable,

viability uncertain or nonviable

Histological Intrauterine Pregnancy

Chorionic villi identified in contents

of uterine evacuation

Treated PUL

Treated Persistent PUL

Medical management of PUL without

confirmation of the location

of the gestation

Resolved PUL

Spontaneously Resolved PUL

Spontaneous resolution of

hCG levels

Resolved Persistent PUL

Spontaneous resolution of hCG

levels with expectant

management or after uterine

evacuation without evidence

of chorionic villi on pathology

Ectopic Pregnancy

Visualized Ectopic Pregnancy

Evidence of ectopic pregnancy on

transvaginal sonography (TVS)

or via laparoscopy

Non-visualized Ectopic Pregnancy

Persistent or rising hCG levels

after uterine evacuation

Pregnancy of Unknown

Location (PUL)

Single Dose vs. Multiple Dose

26 Articles Published

Single Dose Multiple Dose

Success 88% (940/1067) 93% (241/260)

Range 86% - 90% 86% - 96%

40% of 862 subjects met inclusion criteria

Barnhart KT, Ashby RK, Gosman GG, Sammel M Obstet Gynecol, 2003;101(4):778-84

Odds ratio of failure of "Single dose" Vs

"Multiple dose" OR 95% CI p

Analysis of all data 1.71 1.04 -

2.82

0.03

Analysis controlled for actual

hCG value**

2.34 1.05 -

5.23

0.04

Analysis controlled for estimated

hCG value and EHT

4.74 1.77 –

12.62

0.02

“Single-dose” is more commonly used •Ease of use

•Fewer visits

•Fewer injections

Two Dose Management of EP

Clinical study under FDA IND

UPenn, USC, Univ Miami

Same Inclusion criteria for MTX

Screening labs: CBC, LFTS, CR

CXR if any history of Pulmonary disease

Need DEFINTIVE diagnosis

Repeat screening labs weekly

Two Dose Management of EP

Single dose 50 mg/m2 MTX (nomogram)

Baseline, day 4, day 7

Multiple dose 1 mg/kg MTX, 0.1 mg/kg LUE

“Daily” until 15% decline from previous day

TWO DOSE 50 mg/ m2

Same number of visits as “single dose”

BUT GIVE SECOND DOSE ON DAY 4

Repeat dose(s) based on hCG on day 4 – 7 (or

7-11)

Treatment Success

Successful treatment-no surgery for

EP (N=101)

88 (87%)

Successful treatment-no rupture of

EP (N=101)*

98 (97%)

Success with 1 course (2 doses)

(N=88)

73 (83%)

Needed more than 2 doses (n=88) 12 (14%)

Treated for persistent EP (n=88)** 3 (3%)

*4 women and 2 MDs elected surgery

**4 cases of persistent EP treated with surgery

Cost, Efficacy and Incremental Cost Effectiveness

Ratios (ICER) for Surgical versus Medical Treatment,

Strategy Cost

(USD)

Incremental

Cost

Efficacy Incremental

Efficacy

ICER

All surgery

Medication

$563.4 - 0.844 -

Surgery $899.4 $335.9 0.968 0.124 $2,707

EVA alone

Medication

$563.4 - 0.844 -

Surgery $1,308.8 $745.4 0.977 0.134 $5,580

MVA alone

Surgery $361.0 - 0.955 -

Medication $563.4 $202.4 0.844 -0.112 Dominated

Cost, Efficacy and Incremental Cost Effectiveness Ratios for Surgical

versus Medical Treatment, by Miscarriage Type

Strategy Cost

(USD)

Incremental

Cost

Efficacy Incremental

Efficacy

ICER

Fetal demise

group

Medication $511.9 - 0.878 -

Surgery $957.8 $445.9 0.979 0.101 $4,415

Anembryonic

gestation

Medication $617.6 - 0.807 -

Surgery $842.1

$224.4 0.962 $875 $1,445

Incomplete

gestation

Medication $523.1 - 0.933 -

Surgery $718.8

$195.7 0.876 -0.0582 Dominated

One-way sensitivity analysis

Two-way sensitivity analysis

Rational Diagnosis of Ectopic

Pregnancy

Systematic evaluation of women at risk can assist in

the prompt and accurate diagnosis of ectopic

pregnancy

Use of algorithm should never replace clinical

acumen

New clinical rules are “user friendly”

Min 1 day rise 23%, min 2 day rise is 50%

Chart for expected abnormal fall of complete miscarriage

Ectopic Pregnancy can masquerade as IUP or SAB

Rational Diagnosis of Ectopic

Pregnancy

As clinician you decide optimal trade off

Sensitivity ( do not want to miss an EP)

Specificity (do not want interrupt a growing IUP)

Beware of pitfalls

Ultrasound is less accurate with a low hCG

Presumed EP, without D and E, can be wrong in

up to 50% of case

Mistakes increase medical liability

diagnosis and management of early pregnancy loss · 2014-09-30 · diagnosis and management of...

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