diagnosis and management of early pregnancy loss · 2014-09-30 · diagnosis and management of...
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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%)
Utility of Ultrasound Above and
Below the Discriminatory Zone
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%
Utility of Ultrasound Above and
Below the Discriminatory Zone
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%
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
34%
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
Dropping EP, 10%
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
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 beeper goes Friday afternoon, before
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 beeper goes Friday afternoon, before
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
Intrauterine Pregnancy
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
Intrauterine Pregnancy
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)
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
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