KEYNOTE What to Do with a Pregnancy of Unknown Location. Kurt Barnhart, MD, MSCE

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1 KEYNOTE What to Do with a Pregnancy of Unknown Location Kurt Barnhart, MD, MSCE Full Disclosure of Faculty Financial Interests or Relationships I agree to follow the UIC and ACCME policies and declare that I do not have a financial interest or other relationship with any manufacturers of any commercial products that may be discussed during this presentation. 1

2 LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: Discuss poten2al pi5alls in the diagnosis of women with a pregnancy of unknown loca2on. Integrate new nomenclature for the defini2ve ul2mate diagnosis of women with a pregnancy of unknown loca2on. Assess the data suppor2ng the use of medical or surgical management of an ectopic pregnancy or miscarriage. 2

3 Women at High Risk 1 in 14 women who present to the emergency department (ED) complaining of vaginal bleeding and/or abdominal pain and who have a posi2ve pregnancy test have an ectopic pregnancy. Transvaginal Ultrasound IUP Ectopic Pregnancy Abnormal IUP Nondiagnostic hcg>discriminatory zone hcg<discriminatory zone D+C Serial quantitative hcg + chorionic villi - chorionic villi Normal rise Plateau Normal fall Nonviable intrauterine pregnancy Ectopic pregnancy transvaginal ultrasound when > discrim zone D+C Follow to hcg=0 + chorionic villi - chorionic villi Nonviable IUP Ectopic pregnancy Figure 1. Algorithm for the diagnosis of ectopic pregnancy in a hemodynamically stable patient University of Pennsylvania School of Medicine Barnhart et al Obstet Gynecol 1994; 84: Gracia C, Barnhart KT. Obstet Gynecol, 97(3): ,

4 Modern Management! EP is still 1-2% of all pregnancies! Mortality has dramatically declined: 0.5/100,000! Ø Still 6% of pregnancies related deaths/ most common in first trimester! Ø 21 deaths per year in USA! Ø Few catastrophic ruptures! Ø Most now diagnosed with US and hcg algorithms! Modern management has resulted in new problems and iatrogenic error! University of Pennsylvania School of Medicine Modern Management! Ultrasound needs clinical context! hcg surveillance can result in error! The Discriminatory Zone is too low! Premature surveillance can lead to error! Pregnancy of unknown location (PUL)! Ø In particular the management of a persistent PUL is a clinical conundrum! University of Pennsylvania School of Medicine 4

5 Group 1! 80% of all women! Diagnosed upon presentation to ED! Presentation to Emergency Department with: Positive pregnancy test, vaginal bleeding and/or Abdominal pain! Total Population! 61% Viable Ongoing Intrauterine Pregnancy! 28% Spontaneous Abortion! 9% Ectopic Pregnancy! Group 2! 20% of all women! Diagnosed with additional outpatient testing" 77% Viable Ongoing Intrauterine Pregnancy! 16% Spontaneous Abortion! 6% Ectopic Pregnancy! 49% of all women with Ectopic Pregnancy diagnosed at presentation" 11% Viable Ongoing Intrauterine Pregnancy! 77% Spontaneous Abortion! 17% Ectopic Pregnancy! 51% of all women with Ectopic Pregnancy diagnosed after outpatient follow-up! University of Pennsylvania School of Medicine Outcome of all women with EP! All ectopic " pregnancies" 1 in 5 " ruptured" 75% never reach" an βhcg of DZ" " 35% diagnosed" as βhcg is declining" 50% diagnosed " on day of " presentation" University of Pennsylvania School of Medicine 5

6 Ectopic Pregnancy This ultrasound image shows an empty endometrial cavity and a 5-mm gestational sac in the right adnexa. U7lity of Ultrasound Above and Below the Discriminatory Zone Intrauterine pregnancy! diagnosis at presentation donfirmed diagnosis after follow up 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%)! 6

7 U7lity of Ultrasound Above and Below the Discriminatory Zone Patients with βhcg level ABOVE! Ultrasound Diagnosis! Intrauterine pregnancy! 1500 miu/ml at presentation! Sensitivity! Specificity! +PV! -PV! 98%*! 90%! 96%! 96%! Miscarriage! 73%*! 93%! 65%! 65%! Ectopic pregnancy! 80%*! 99%! 86%! 99%! βhcg = β human chorionic gonadotropin; PV = predictive value U7lity of Ultrasound Above and Below the Discriminatory Zone (DZ) Patients with βhcg level BELOW! Ultrasound Diagnosis! Intrauterine pregnancy! 1500 miu/ml at presentation! Sensitivity! Specificity! +PV! -PV! 33%*! 98%! 80%! 86%! Miscarriage! 28%*! 100%! 100%! 47%! Ectopic pregnancy! 25%*! 96%! 60%! 85%! 7

8 Classification scheme for women with a positive pregnancy test at first transvaginal sonography (TVS) Definite Ectopic Pregnancy Extrauterine gestational sac with yolk sac and/or embryo (with or without cardiac activity) Probable Ectopic Pregnancy Inhomogeneous adnexal mass or extrauterine sac-like structure Pregnancy of Unknown Location No signs of intrauterine or extrauterine gestation on transvaginal sonography Probable Intrauterine Pregnancy Intrauterine echogenic sac-like structure Definite Intrauterine Pregnancy Intrauterine gestational sac with yolk sac and/or embryo (with or without cardiac activity) 8

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10 First trimester ultrasound accuracy depends more on serum hcg values than pa7ent symptoms ( ) EP = ectopic pregnancy; PPV = positive predictive value; NPV = negative predictive value American College of Radiology Royal College of Obstetricians and Gynaecologists Crown Rump Length >5 mm with no heartbeat 7 mm with no heartbeat Mean Sac Diameter >8 mm with no yolk sac or >16 mm with no embryo 25 mm with no yolk sac or embryo Based on large prospective studies, assessing: Range of CRL without FH, and MSD, that can go on to normal IUP Variability in measurements in CRL and MSD 10

11 n n Setting: Intrauterine Pregnancy of Unknown Viability Parameter: Crown-Rump Length (CRL) Ultrasound Finding Embryo with no heartbeat Definite failed pregnancy if: CRL 7 mm Suspicious for failed pregnancy if: CRL <7 mm n n Setting: Intrauterine Pregnancy of Unknown Viability Parameter: Mean Sac Diameter (MSD) Ultrasound Finding Gestational sac with no embryo Definite failed pregnancy* if: MSD 25 mm Suspicious for failed pregnancy if: MSD mm 11

12 n n Setting: Intrauterine Pregnancy of Unknown Viability Parameter: Time since LMP (non-art patients) Current U/S Finding Gest l sac with no embryo (+/- YS) Definite failed pregnancy if: -- (cannot definitively diagnose failure via time since LMP) Suspicious for failed pregnancy if: >6 wks since LMP n n Setting: Intrauterine Pregnancy of Unknown Viability Parameter: Time since prior ultrasound Current U/S Finding Gest l sac with no YS or embryo Gest l sac with no embryo Gest l sac with no embryo Definite failed pregnancy if: >2 wks since GS without YS >2 wks since GS without YS >10 days since GS with YS Suspicious for failed pregnancy if: 1-2 wks since GS without YS 1-2 wks since GS without YS 7 10 days since GS with YS GS = gestational sac; YS = yolk sac 12

13 n n Setting: Intrauterine Pregnancy of Unknown Viability Parameter: Miscellaneous findings n Suspicious findings n Abnormal amnion: to be defined (e.g., empty, or larger than embryo when CRL is 8 mm) n Large YS (> 7 mm) n Sustained bradycardia (< 80 bpm) n Small sac size (MSD CRL < 5mm) n Setting: Pregnancy of Unknown Location Ultrasound Finding Intrauterine sac-like structure with no yolk sac or embryo. Normal adnexa*. Interpretation Pregnancy of unknown location that is most likely intrauterine. Ectopic pregnancy, while not excluded, is much less likely. * Normal or near-normal adnexal findings: -- corpus luteum -- trace-small amount of free pelvic fluid -- paratubal cyst 13

14 Ultrasound Finding No intrauterine fluid collection No intrauterine fluid collection & normal adnexa Ultrasound not yet performed Setting: Pregnancy of Unknown Location Key Points If a single hcg is >3000 miu/ml, a normal IUP is very unlikely However, a single hcg (in combination with an empty uterus on ultrasound) should not be used as a criterion for definitive exclusion of a potentially normal IUP A single hcg, regardless of its level, does not reliably distinguish between ectopic and intrauterine pregnancy Thus, a single hcg, regardless of its level, does not justify presumptive treatment for ectopic pregnancy using methotrexate or other medical/surgical means The hcg level with ectopic pregnancies is highly variable, often <1000 miu/ml Thus, in a woman at clinical suspicion for ectopic pregnancy, transvaginal ultrasound is indicated even when the hcg is low What is the Discriminatory Zone?! Surrogate for gestation age! Ø Level at which normal milestones should be identified (gestational sac): the level does not discriminate location! Ø The best DZ is gestational age! 5 5/7 weeks ( 40 days) regardless of number of gestations! Ø Very wide variation in hcg in first trimester! Not all women know their LMP! Ø Maybe off by days, or at times off by 4 weeks! University of Pennsylvania School of Medicine 14

15 What is the Discriminatory Zone?! Value should be based on your own experience and institution.! Barnhart KT, et al: Obstet Gynecol 1994; 84: " University of Pennsylvania School of Medicine Discriminatory Zone! What has changed?! Ø IRP has changed so now 1500 first IU is about rth IU! Ø Most women get US in first trimester (even without symptoms)! Ø Ruptured EP uncommon, clinician very aware of risk! Effort has shifted to avoid interruption of a desired IUP! Methotrexate is common and easy to administer! More scans = more false positives (false negatives)! University of Pennsylvania School of Medicine 15

16 Evidence against a DZ! Metha et al, Radiology 1997;205: ! Ø 17/51 (33%) with hcg > 2000 had an normal IUP! 6 had a fluid collection?! One subject 2150 (san next day showed sac)! One had triples (IVF): hcg 7827 (had possible sac)! One scan was a resident: hcg 11,500; poor quality! In the other 8 subjects, quality was good hcg ,420 (but had fluid in the endometrium )! Can some of this be a due to definition?! University of Pennsylvania School of Medicine More Recent Data! Duobliet P, Benson C. J ultrasound med 2011;30: ! Ø Time period ! Ø 202 subjects with no intrauterine fluid collection and a subsequent IUP diagnosed.! Ø 9 (4.5%) above 2000 (Highest 6567, highest live born 4336)! Ø One was a twin (2217)! Ø What is the denominator?! University of Pennsylvania School of Medicine 16

17 Balance of Diagnostic Tests! Trade off between sensitivity and specificity! Maximize sensitivity at the cost of diagnosing some IUP as EP! Ø Error may be interrupting desired IUP! Maximize specificity at the cost of diagnosing some EP as IUP! Ø Error may be delay diagnosis resulting in rupture! Importance to clinician and patient is predictive value! Numerator driven, or denominator driven?! How high should the bar be? 99, 99.9, 100%! University of Pennsylvania School of Medicine Case Presenta7on Your beeper goes off Friday apernoon, before your planned trip to ASRM. Your nurse calls you: Ms. Smith called your nurse. Ms. Smith has a home pregnancy test is posi2ve, and she THINKS she is about 2 weeks late for her period. She has moderate pain in her lep side and has been spowng for 4 days. She is a G4 P0, with three miscarriages in the first trimester. ASRM = American Society for Reproductive Medicine 17

18 Case Presenta7on Ms. Smith s hcg level is 1000 miu/ml. 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 defini2vely diagnosed with a viable IUP 293 subjects, 873 observa2ons Average age 24 years Average G 2.4; P 0.8 Average hcg value 1000 miu/ml Fit a number of models: Linear, spline, exponen2al G = gravida; P = para 18

19 Normal Rise in hcg loghcg 99% CI Fitted values 12 loghcg/99% CI/Fitted values gestational age (days) 2 hcg (miu/ml) Estimated Curve 15 % Lower Bound 5 % Lower Bound 1 % Lower Bound Number Of Days Since Presentation Barnhart KT. Symptomatic Patients with an Early Viable Intrauterine Pregnancy; hcg Curves Redefined. Obstet Gynecol 2004;104:

20 Increase in hcg value at different days (as a percent of ini7al value) quar2le slope 1 day 2 day 3 days 4 days Barnhart KT. Symptomatic Patients with an Early Viable Intrauterine Pregnancy; hcg Curves Redefined. Obstet Gynecol 2004;104:50-5. hcg Rise APer IVF gestational age (days) singleton triplets twins 20

21 The slopes by race Black White Case Presenta7on Ms. Smith s hcg level is 1000 miu/ml. She is clinically stable. This is a desired pregnancy. Repeat hcg in two days is 500 miu/ml. 21

22 Normal Fall in hcg Fit the curve of women who presented to ED at risk for EP who were defini2vely diagnosed with a complete SAB 719 subjects, 2914 observa2ons Serum hcg confirmed to be > 5 Fit a number of models: Linear, quadra2c, cuboidal, change point with random intercept and random effect Final model was random linear effect dependent on ini2al hcg value Curve of Complete Spontaneous Abor7on (SAB) drop of hcg # of days after presentation Barnhart, K. Decline of serum human chorionic gonadotropin and spontaneous complete abortion: Defining the normal curve. Ob Gyn 2004:104(5):

23 Normal Fall of hcg for Complete SAB Intial hcg value (miu/ml)! 500! 256! hcg value at 2 days (miu/ml)! hcg value at 7 days (miu/ml)! 48! hcg value at 21days (miu/ml)! 0! Days to negative hcg! 19! 1000! 513! 447 (21%)! 337 (60%)! 96! 76! 0! 21! 894! 2000! 1027! 675! 193! 308! 0! 23! 1788! 5000! 2567! 1351! 484! 616! 5! 26! 4470 (35%)! 3378 (84%)! 1541! Barnhart, K. Decline of serum human chorionic gonadotropin and spontaneous complete abortion: Defining the normal curve. Ob Gyn 2004:104(5): Rising EP, 90% log(hcg) Rising EP, 75% 1st percentile of IUP 90th percentile of SAB Number of days since presentation 23

24 log(hcg) % 1st percentile of IUP 90th percentile of SAB Number of days since presentation log(hcg) st percentile of IUP 90th percentile of SAB Dropping EP, 10% Number of days since presentation 24

25 log(hcg) % 1st percentile of IUP 90th percentile of SAB Number of days since presentation Performance in Validation Cohort versus Original Cohort Expected Two-Day Rise for an IUP Sensitivity for EP (%) Sensitivity for IUP (%) Mean number of days saved (range) # Validation Original* Validation Original Validation Original 35% Rise in hcg % Rise in hcg % Rise in hcg (0-35) 3.27 (0-35) 3.44 (0-37) 2.64 (0-34) 2.85 (0-34) 2.94 (0-34) 25

26 Performance in Validation Cohort versus Original Cohort Number of Number of Expected Two-Day Number of misclassified IUPs misclassified Rise for an IUP misclassified EPs (%) (%) miscarriages (%) Validation Original Validation Original Validation Original 35% Rise in hcg 30 (16.8) 34 (17.3) 20 (7.7) 12 (4.6) 221 (39.0) 222 (28.0) 53% Rise in hcg 16 (8.9) 24 (12.2) 45 (17.4) 26 (10.0) 231 (40.7) 224 (28.2) 71% Rise in hcg 14 (7.8) 18 (9.2) 71 (27.4) 58 (22.2) 236 (41.6) 225 (28.4) Results Of 30 (17%) patients with missed EP (classified as IUP or SAB): 24 has NL rise and 6 had NL fall 6 were diagnosed due to pain (3 ruptured) Rupture was 0.03% of cohort or 1.7% of EP Of 22 (8%) patients with missed IUP (classified as EP or SAB): 18 had rise less than 35% 2 had change in direction 26

27 Results How did hcg mislead us into an error? Such that we missed the IUP? 13/20 has findings on US suggesting an IUP Many of abnormal hcg values were the first 2 values and where below 500 If one considered a third hcg; 6 were reclassified (correctly) as an IUP BUT 9 EP and 2 SAB were reclassified (incorrectly) as an IUP Two hcg values may not be enough Day 2 vs Day 4 9.3* * (1.8, 16.7) (-1.7, 10.4) (0.5, 9.2) Day 2 vs Day 7 6.7* (0.6, 12.7) (-1.1, 8.3) (-0.8, 6.9) Day 4 vs Day (-4.3, 6.9) (-5.8, 2.7) (-0.8, 6.5) Net Reclassification Index (NRI) is the total net reclassification improvement in EP prediction, calculated as the sum of NRI E, the net reclassification improvement in EP prediction among those with an ultimate EP diagnosis, and NRI N, the net reclassification improvement in EP prediction among those with an ultimate IUP or SAB diagnosis. J. Zee, KT Barnhart Et al, 2012 ARSM 27

28 Case Presenta7on This 2me you are in your office. Your resident consults you: Ms. Johnson has 6.5 weeks of amenorrhea, pain, and bleeding. o Ultrasound: No evidence of a gesta2onal sac in the uterus o hcg 6830 miu/ml Your resident wants to treat with methotrexate (MTX). YOUR THOUGHTS??? Role of D&C Can you presume the diagnosis of an 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). o How open does it happen? 28

29 Role of D&C Can I skip the D and C to save 2me? Pipelle biopsy? What if I am wrong??? Inflates success of MTX I do not miss an EP At worst, I am trea2ng an SAB, correct? Legal implica2ons D and C = dilation and curettage Presumed Ectopic Pregnancy? Two year study: Overall EP SAB (63%) 41 (37%) Below DZ (70%) 23 (30%) Above DZ (49%) 18 (51%) Age 28.8 years Parity 1.4 hcg miu/ml Barnhart KT, Obstet Gynecol 2002;100(3):

30 Miscarriage Ectopic N = 66 (38.2%) 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 < (30.1) 93 (69.9) 0.01 hcg (65.0) 14 (35.0) Pain 0.84 hcg < (31.9) 47 (68.1) hcg (52.2) 11 (47.8) Bleeding e 0.52 hcg < (28.1) 59 (71.9) hcg (69.0) 9 (31.0) USC Experience ( ) EP SAB OR for EP p (n = 235) (n = 86) All patients 235 (73.2%) 86 (26.8%) hcg< 2000 (miu/ml) 163 (69.4%) 32 (37.2%) 3.82 <0.001 hcg > 2000 (miu/ml) 72 (30.6%) 54 (62.8%) ( ) USC = University of Southern California; OR = odds ratio 30

31 Pregnancy of Unknown Location (PUL) Visualized Ectopic Pregnancy Evidence of ectopic pregnancy on transvaginal sonography (TVS) or via laparoscopy Spontaneously Resolved PUL Spontaneous resolution of hcg levels Visualized Intrauterine Pregnancy Evidence of intrauterine pregnancy on TVS Should be classified as viable, viability uncertain or nonviable Persisting PUL Non-Visualized Ectopic Pregnancy Treated Persistent PUL Resolved Persistent PUL Histological Intrauterine Pregnancy Persistent or rising hcg levels after uterine evacuation Medical management of PUL without confirmation of the location of the gestation Spontaneous resolution of hcg levels with expectant management or after uterine evacuation without evidence of chorionic villi on pathology Chorionic villi identified in contents of uterine evacuation Pregnancy of Unknown Location (PUL) Ectopic Pregnancy Resolved PUL Treated PUL Intrauterine 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 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 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 31

32 Single Dose vs. Mul7ple 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): Odds ra7o of failure of single dose" vs. mul7ple dose" OR! 95% CI! p! Analysis of all data! 1.71! ! Analysis controlled for actual hcg value**! Analysis controlled for estimated hcg value and EHA! 2.34! ! 4.74! ! 0.03! 0.04! 0.02! Single-dose is more commonly used: Ease of use Fewer visits Fewer injections CI = confidence interval; EHA = Embryonic heart activity 32

33 Two- Dose Management of EP Single dose 50 mg/m 2 MTX (nomogram) Baseline, day 4, day 7 Mul2ple dose 1 mg/kg MTX, 0.1 mg/kg Leucovorin Daily un2l 15% decline from previous day TWO DOSE 50 mg/m 2 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)! Successful treatment no rupture of EP (N=101)*! Success with 1 course (2 doses) (N=88)! 88 (87%)! 98 (97%)! 73 (83%)! Needed more than 2 doses (n=88)! 12 (14%)! Treated for persistent EP (n=88)**! 3 (3%)! *4 women and 2 M.D.s elected surgery **4 cases of persistent EP treated with surgery 33

34 Management of PUL! The Case for uterine evacuation! Ø Why does it matter?! The consequences of inappropriate use of methotrexate are very serious! Prognosis matters? ART VS recurrent SAB?! Patients want to know what happened! No time saved for patient (only the clinician)! University of Pennsylvania School of Medicine University of Pennsylvania School of Medicine 34

35 Enrollment - April 2007 to January women randomised 41 women allocated to MTX 32 women allocated to expectant 39 women treated with MTX 41 women included in intentionto-treat analysis 2 women declined MTX after randomisation 32 treated expectant 32 women included in intentionto-treat analysis Results primary outcome Uneventful decline hcg by the initial treatment Single dose MTX n = 41 (%) Expectant management n = 32 (%) RR (95%CI) 31 (76) 19 (59) 1.3 ( ) Per protocol analysis 29 (74) 21 (62) 1.2 ( ) 35

36 Results serum hcg clearance time Serum hcg clearance time in days (median) Single dose MTX Expectant management Log rank test 34 (27-40) 38 (28-48) P = 0.5 Methotrexate Expectant management Ra7onal Diagnosis of Ectopic Pregnancy Systema2c evalua2on 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 : Minimum 1- day rise in hcg, 23%; minimum 2- day rise is 50% Chart for expected abnormal fall of complete miscarriage Ectopic pregnancy can masquerade as IUP or SAB 36

37 Conclusion Solely using serial hcg values can result in misclassification 7% IUP, 16% EP Clinical judgment should trump prediction rules and continued surveillance with a third hcg may be prudent especially when initial values are low or when values are near suggested thresholds. Ra7onal Diagnosis of Ectopic Pregnancy As clinician you decide op2mal trade- off: Sensi2vity (do not want to miss an EP) Specificity (do not want interrupt a growing IUP) Beware of pi5alls: 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. D and E = dilation and evacuation 37

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