Diagnosis and Management of Early Pregnancy Loss Kurt Barnhart MD, - - PowerPoint PPT Presentation

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

• r extrauterine gestation
• n 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/99% CI/Fitted values 20 30 40 50 gestational age (days) loghcg 99% CI Fitted values

Number Of Days Since Presentation hCG (mIU/mL) 2 4 6 8 10 12 5000 10000 15000

Estimated Curve 15 % Lower Bound 5 % Lower Bound 1 % 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 4 6 8 10 12 20 30 40 50 gestational 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 drop of hCG 10 20 30 40 500 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%) 76 19 1000 513 894 96 675 308 21 2000 1027 1788 193 1351 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(hCG) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 2 4 6 8 10

1st percentile of IUP 90th percentile of SAB

Rising EP, 75% Rising EP, 90%

Number of days since presentation log(hCG) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 2 4 6 8 10

1st percentile of IUP 90th percentile of SAB

34%

Number of days since presentation log(hCG) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 2 4 6 8 10

1st percentile of IUP 90th percentile of SAB

Dropping EP, 10%

Number of days since presentation log(hCG) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 2 4 6 8 10

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 hCG (mIU/mL)

min hCG Pt 1

When to intervene in suspected SAB

Minimal Fall of β-hCG in SAB

Days since presentation hCG (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

• f chorionic villi on pathology

Persisting PUL

Visualized Ectopic Pregnancy Spontaneously Resolved PUL Visualized Intrauterine Pregnancy

Evidence of ectopic pregnancy on transvaginal sonography (TVS)

• r via laparoscopy

Spontaneous resolution

• f

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

• f uterine evacuation

Treated PUL

Treated Persistent PUL Medical management of PUL without confirmation of the location

• f 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

• f chorionic villi on pathology

Ectopic Pregnancy

Visualized Ectopic Pregnancy Evidence of ectopic pregnancy on transvaginal sonography (TVS)

• r 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