ACR Appropriateness Criteria® First Trimester EVIDENCE TABLE

Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 1. Hasan R, Baird DD, Herring AH, Olshan Review/Other 4,539 To characterize the patterns and predictors of Approximately one-fourth of participants 4 AF, Jonsson Funk ML, Hartmann KE. -Dx patients early bleeding, setting aside (n=1,207) reported bleeding (n=1,656 Patterns and predictors of vaginal bleeding episodes that occur at the time of episodes), but only 8% of women with bleeding in the first trimester of . bleeding, reported heavy bleeding. Of the pregnancy. Ann Epidemiol 2010; spotting and light bleeding episodes 20(7):524-531. (n=1,555), 28% were associated with pain. Among heavy episodes (n=100), 54% were associated with pain. Most episodes lasted less than 3 days, and most occurred between gestational weeks 5–8. 12% of women with bleeding and 13% of those without experienced miscarriage. Maternal characteristics associated with bleeding included fibroids and prior miscarriage. Consistent with the hypothesis that bleeding is a marker for placental dysfunction, bleeding is most likely to be seen around the time of the luteal-placental shift. 2. Bree RL, Edwards M, Bohm-Velez M, Review/Other 53 patients; Compare TVUS with -hCG level in the -hCG level of 1000 mIU/ml - gestational sac 4 Beyler S, Roberts J, Mendelson EB. -Dx 75 TVUS evaluation of in early pregnancy. was seen sonographically in each patient. - Transvaginal sonography in the evaluation examinations hCG level of 7200 mIU/ml - yolk sac was of normal early pregnancy: correlation seen in every patient. 10/22 patients with - with HCG level. AJR 1989; 153(1):75-79. hCG between 1000 and 7200 mIU/ml had a visible yolk sac. Every patient with -hCG level >10,800 mIU/ml had a visible embryo with a heartbeat. Results support other studies that TVUS can define pregnancy as early as 32 days and at -hCG levels as low as 1000 mIU/ml. 3. Bradley WG, Fiske CE, Filly RA. The Review/Other 50 suspected Retrospective review of pelvic sonograms to Double sac appearance is a useful indicator 4 double sac sign of early intrauterine -Dx ectopic determine the usefulness of double sac sign in for differentiating an from pregnancy: use in exclusion of ectopic pregnancy differentiating ectopic pregnancy from early an early normal IUP. pregnancy. Radiology 1982; 143(1):223- patients; 17 IUP. 226. proved ectopic cases 4. Parvey HR, Dubinsky TJ, Johnston DA, Observational 169 with Review sonograms to determine whether 126/238 patients had Doppler examination. 3 Maklad NF. The chorionic rim and low- -Dx early IUP; 69 sonographic imaging of an intrauterine Chorionic rim and double decidual sac had impedance intrauterine arterial flow in the with ectopic chorionic rim or arterial flow can help sensitivities of 80% and 64%, respectively, diagnosis of early intrauterine pregnancy: diagnose an early IUP. and specificities of 97% and 100%, evaluation of efficacy. AJR 1996; respectively. Intrauterine arterial flow with 167(6):1479-1485. either peak systolic velocity ≥15 cm/sec or resistive index ≤0.55 had a sensitivity of 70% and a specificity of 95%. * See Last Page for Key 2012 Review Lane/Wong Page 1 ACR Appropriateness Criteria® First Trimester Bleeding EVIDENCE TABLE

Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 5. Laing FC, Brown DL, Price JF, Teeger S, Observational 102 patients Retrospective study to determine if the Sensitivity for diagnosis of an IUP was 34%- 2 Wong ML. Intradecidual sign: is it -Dx 4 observers intradecidual sign at sonography is effective 66%, specificity was 55%-73%, accuracy was effective in diagnosis of an early in the diagnosis of early IUP. 38%-65%, PPV was 91%-93%, and NPV was intrauterine pregnancy? Radiology 1997; 12%-16%. 204(3):655-660. 6. Yeh HC, Goodman JD, Carr L, Observational 36 patients To determine the accuracy of the intradecidual Intradecidual sign was more sensitive (91.7% 4 Rabinowitz JG. Intradecidual sign: a US -Dx with IUP; 5 sign (a feature on sonograms) in the detection vs 63.9%) and specific (100% vs 60%) than criterion of early intrauterine pregnancy. patients with of early IUP. the double decidual sac sign in the detection Radiology 1986; 161(2):463-467. ectopic of early IUP. 7. Chiang G, Levine D, Swire M, McNamara Observational 153 patients Retrospective study to determine if Patients with IUP had sensitivity of 70%. 2 A, Mehta T. The intradecidual sign: is it -Dx with IUP; 34 intradecidual sign is accurate for the diagnosis Ectopic had specificity of 100% reliable for diagnosis of early intrauterine patients with of IUP and the exclusion of ectopic for the intradecidual sign; the accuracy rate pregnancy? AJR 2004; 183(3):725-731. ectopic; 3 pregnancy. was 75%, PPV 100%, and NPV 43%. observers Sensitivity for diagnosis of an IUP increases when -hCG levels are ≥2,000 mIU/ml or the mean sac diameter ≥3 mm. 8. Mehta TS, Levine D, Beckwith B. Review/Other 676 patients Review medical records and US scans to 548 patients had evidence of a normal or 4 Treatment of ectopic pregnancy: is a -Dx determine whether hCG level of 2,000 abnormal IUP. 51 (40%) of the 128 patients human chorionic gonadotropin level of mIU/ml is a reasonable threshold for without evidence of an IUP had an hCG level 2,000 mIU/mL a reasonable threshold? diagnosing ectopic pregnancy in the absence >2,000 mIU/ml. Of 51 patients, 15 (29%) Radiology 1997; 205(2):569-573. of US findings of IUP in order to prevent were treated for ectopic pregnancy; 17 (33%) inappropriate treatment. were not immediately treated for ectopic pregnancy and had a normal IUP at follow-up US. hCG level of 2,000 mIU/ml without US findings of IUP is not diagnostic. 9. Nyberg DA, Filly RA, Mahony BS, Review/Other 49 patients Compare hCG levels with US findings in A gestational sac was always visible when the 4 Monroe S, Laing FC, Jeffrey RB, Jr. Early -Dx patients with normal early IUP to determine hCG level was 1800 mIU/ml in 36 cases and gestation: correlation of HCG levels and the discriminatory level of β-hCG. 357 mlU/ml in one case. Comparison of sonographic identification. AJR 1985; serum hCG levels with US detection is useful 144(5):951-954 for evaluating early pregnancy.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 10. Doubilet PM, Benson CB. Further Observational 202 patients To determine whether a woman with a β-hCG 162 (80.2%) women had β-hCG levels below 3 evidence against the reliability of the -Dx above 2000 mIU/mL and no intrauterine fluid 1000 mIU/mL on the day of the initial scan human chorionic gonadotropin collection on TVUS can subsequently be showing no intrauterine fluid collection, 19 discriminatory level. J Ultrasound Med found to have a live intrauterine gestation and, (9.4%) with levels of 1000 to 1499, 12 (5.9%) 2011; 30(12):1637-1642. if so, what the prognosis is for the pregnancy. 1500 to 1999, and 9 (4.5%) above 2000 mIU/mL. There was no significant relationship between initial β-hCG level and either first-trimester outcome or final pregnancy outcome (P>.05, logistic regression analysis and Fisher exact test). The highest β- hCG was 6567 mIU/mL, and the highest value that preceded a liveborn term baby was 4336 mIU/mL. The hCG discriminatory level should not be used to determine the management of a hemodynamically stable patient with suspected ectopic pregnancy, if sonography demonstrates no findings of intrauterine or ectopic pregnancy. 11. Levi CS, Lyons EA, Lindsay DJ. Early Observational 62 patients Retrospective analysis of prospectively 59 patients with gestation sacs ≥8 mm; 4 diagnosis of nonviable pregnancy with -Dx accumulated data to determine first trimester absence of a yolk sac predicted a nonviable endovaginal US. Radiology 1988; nonviability at endovaginal US on the basis of pregnancy with sensitivity of 67%, specificity 167(2):383-385. gestational sac size and the presence or of 100%. 35 patients with gestation sacs ≥16 absence of a yolk sac or embryo. mm; absence of embryo predicted a nonviable pregnancy with sensitivity of 50% and specificity of 100%. Combining gestation sac size; demonstration of yolk sac, embryo and/or cardiac pulsations) helped in the diagnosis of a nonviable pregnancy with endovaginal US.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 12. Abdallah Y, Daemen A, Kirk E, et al. Observational 1,060 Observational cross-sectional study to define Of the 1,060 women with a diagnosis of IUP 3 Limitations of current definitions of -Dx consecutive the false-positive rate for the diagnosis of of uncertain viability, 473 remained viable miscarriage using mean gestational sac women miscarriage associated with different CRL and and 587 were non-viable by the time of the diameter and crown-rump length MSD measurements with or without a yolk 11-14-week scan. In the absence of both measurements: a multicenter sac in a large study population of patients embryo and yolk sac, the false-positive rate observational study. Ultrasound Obstet attending early pregnancy clinics. The authors for miscarriage was 4.4% when an MSD cut- Gynecol 2011; 38(5):497-502. also aimed to define cut-off values for CRL off of 16 mm was used and 0.5% for a cut-off and MSD that, on the basis of a single of 20 mm. There were no false-positive test measurement, can definitively diagnose a results for miscarriage when a cut-off of MSD miscarriage and so exclude possible ≥21 mm was used. If a yolk sac was present inadvertent termination of pregnancy. but an embryo was not, the false-positive rate for miscarriage was 2.6% for an MSD cut-off of 16 mm and 0.4% for a cut-off of 20 mm, with no false-positive results when a cut-off of MSD ≥21 mm was used. When an embryo was visible with an absent heartbeat, using a CRL cut-off of 4 mm the false-positive rate for miscarriage was 8.3%, and for a CRL cut- off of 5 mm it was also 8.3%. There were no false-positive results using a CRL cut-off of ≥5.3 mm. These data show that some current definitions used to diagnose miscarriage are potentially unsafe. An MSD cut-off of >25 mm and a CRL cut-off of >7 mm could be introduced to minimize the risk of a false- positive diagnosis of miscarriage.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 13. Rowling SE, Coleman BG, Langer JE, Review/Other 2,655 first- Retrospective review of US scans to test the 30 (22%) of 135 patients without yolk sacs 4 Arger PH, Nisenbaum HL, Horii SC. -Dx trimester US reliability of established US parameters in and with an 8 mm mean sac diameter First-trimester US parameters of failed scans in predicting the outcome of first-trimester developed live : 24 had normal pregnancy. Radiology 1997; 203(1):211- 2,285 pregnancy. follow-up or delivery; six were lost to follow- 217. patients up. 5(8%) of 59 patients with no depiction of embryos and with a 16 mm mean sac diameter developed live embryos: Two delivered, one spontaneously aborted, one had death of one twin embryo before being lost to follow-up, and one was lost to follow-up. 17 (0.74%) of 2,285 patients had early oligohydramnios: 6 (35%) had normal follow-up scans or delivery, two (12%) spontaneously aborted, and nine (53%) were lost to follow-up. Established parameters predictive of early pregnancy failure potentially result in misdiagnosis of nonviability or poor prognosis when applied to a large, unselected patient population. Close follow-up is necessary in cases with borderline abnormal findings.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 14. Pexsters A, Luts J, Van Schoubroeck D, et Observational 54 patients To assess intra- and interobserver agreement 54 patients were included in the study, with 3 al. Clinical implications of intra- and -Dx of routinely performed measurements CRL measurements obtained by both observers in interobserver reproducibility of and MSD for assessing the likelihood of 44 of these. Intra- and interobserver intraclass transvaginal sonographic measurement of miscarriage in the first trimester of pregnancy correlation coefficient were high for CRL gestational sac and crown-rump length at using TVUS. measurements, with values of 0.992 and 0.993 6-9 weeks' gestation. Ultrasound Obstet for intraobserver agreement and 0.993 for Gynecol 2011; 38(5):510-515. interobserver agreement. For the MSD, the interobserver intraclass correlation coefficient was 0.952. Limits of agreement were ± 8.91 and ± 11.37% for intraobserver agreement of CRL and ± 14.64% for interobserver agreement of CRL. For MSD, the interobserver limits of agreement were ± 18.78%. For an MSD measurement of 20 mm by the first observer, the prediction interval for the second observer was 16.8-24.5 mm. For a CRL measurement of 6 mm, the prediction interval for the second observer was 5.4-6.7 mm. For dating purposes, there is reasonable reproducibility of CRL measurements using TVUS at 6-9 weeks' gestation. When diagnosing miscarriage based on measurements of CRL care must be taken for values close to any decision boundary. The higher interobserver variability that was observed for MSD has implications for the diagnosis of miscarriage based on this measurement in the absence of a visible embryo or yolk sac.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 15. Abdallah Y, Daemen A, Guha S, et al. Observational 1,060 To establish cut-off values for MSD and CRL The study included 359 pregnancies in which 3 Gestational sac and embryonic growth are -Dx consecutive growth that could be definitively associated a gestational sac with or without embryo was not useful as criteria to define intrauterine with either viability or miscarriage, and to identified at the follow-up scan 7-14 days miscarriage: a multicenter observational pregnancies establish the relationship between growth in later. Of these, 192 were viable and 167 non- study. Ultrasound Obstet Gynecol 2011; of uncertain MSD and appearance of embryonic structures viable at the 11-14-week scan. MSD growth 38(5):503-509. viability in the gestational sac. was significantly higher in viable than non- viable pregnancies (mean 1.003 vs 0.503 mm/day; P<0.001, 95% CI of difference 0.403-0.596). A difference in CRL growth was found between the two groups (mean 0.673 vs 0.148 mm/day; P<0.001, 95% CI of difference 0.345-0.703). MSD growth of 0.6 mm/day was associated with specificity for diagnosing miscarriage of 90.1%, a sensitivity of 61.7% and 19 false-positive test results. A cut-off of CRL growth rate of 0.2 mm/day gave a sensitivity of 76.3% and there were no false-positive test results for miscarriage. On repeat scan the failure of either a yolk sac or embryo to be visualized was always associated with miscarriage. There is an overlap in MSD growth rates between viable and non-viable intrauterine pregnancies of uncertain viability. No cut-off exists for MSD growth below which a viable pregnancy could be safely excluded. A cut-off value for CRL growth of 0.2 mm/day was always associated with miscarriage. These data suggest that criteria to diagnose miscarriage based on growth in MSD and CRL are potentially unsafe. However, finding an empty gestational sac on two scans more than 7 days apart is highly likely to indicate miscarriage, irrespective of growth. 16. Doubilet PM, Benson CB. Embryonic Review/Other 1,185 first Evaluate sonograms to determine prognosis of Lower limit of normal is 100 beats per minute 4 heart rate in the early first trimester: what -Dx trimester first trimester pregnancy as a function of heart (bpm) up to 6.2 weeks’ gestation and 120 bpm rate is normal? J Ultrasound Med 1995; sonograms rate, and to establish normal heart rate of at 6.3-7.0 weeks. 14(6):431-434. .

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 17. Hertzberg BS, Mahony BS, Bowie JD. Review/Other 124 first Determine heart rates of fetuses with real-time Mean embryonic heart rate increased from 4 First trimester fetal cardiac activity. -Dx trimester sonography and analyze with regard to 101 bpm at 5-5.95 menstrual weeks to 143 Sonographic documentation of a fetuses gestational age. bpm at 8-8.95 weeks. After nine weeks, the progressive early rise in heart rate. J rate reached a plateau, ranging from 137-144 Ultrasound Med 1988; 7(10):573-575. bpm. Slower heart rates are normal early in the first trimester. 18. Benson CB, Doubilet PM. Slow Review/Other 37 patients Examine US scans to determine the outcome An embryonic heart rate ≤90 bpm in the first 4 embryonic heart rate in early first -Dx of early first-trimester pregnancies with slow trimester has a high likelihood of fetal loss trimester: indicator of poor pregnancy embryonic heart rates. before the end of the first trimester. Loss outcome. Radiology 1994; 192(2):343- occurred in all embryos with heart rates <70 344. bpm. 19. Doubilet PM, Benson CB. Outcome of Observational 2,937 Retrospective study to determine the outcome When a slow embryonic heart rate is detected 4 first-trimester pregnancies with slow -Dx patients first of pregnancies with slow embryonic heart rate at 6.0-7.0 weeks, likelihood of subsequent embryonic heart rate at 6-7 weeks trimester at 6-7 weeks gestation and normal heart rate first-trimester loss is high although heart rate gestation and normal heart rate by 8 outcome by 8 weeks at US. is normal at follow-up. Follow-up scan in late weeks at US. Radiology 2005; known; 567 first trimester is needed in these pregnancies. 236(2):643-646. patients met all criteria 20. Bromley B, Harlow BL, Laboda LA, Observational 16 patients Prospective study to determine the predictive 15/16 patients (94%) with first-trimester small 3 Benacerraf BR. Small sac size in the first -Dx 52 controls value of a small gestational sac (mean sac sacs had spontaneous abortions. 4/52 control trimester: a predictor of poor fetal size) minus CRL <5 mm in patients 5.5-9 patients (8%) with normal sac sizes had outcome. Radiology 1991; 178(2):375- weeks gestation, and to compare with a group spontaneous abortions. 377. of control patients with normal sac size. 21. Acharya G, Morgan H. First-trimester, Observational 111 patients Cross-sectional observational study to 3D US volumetry of intrauterine contents in 4 three-dimensional transvaginal ultrasound -Dx correlate 3D US volumetry of intrauterine normal and failed pregnancies correlates well volumetry in normal pregnancies and contents in normal and failed pregnancies with conventional 2D measurements. spontaneous . Ultrasound with conventional 2D measurements. Volumetric assessment does not improve Obstet Gynecol 2002; 19(6):575-579. diagnosis of miscarriage. Further research is needed. 22. Horrow MM. Enlarged amniotic cavity: a Observational 25 normal Compare the size of the amniotic cavity with Amniotic cavity that is enlarged relative to the 4 new sonographic sign of early embryonic -Dx gestations; 10 the CRL and the size of the chorionic cavity CRL and the size of the chorionic cavity is a death. AJR 1992; 158(2):359-362. cases of to determine if enlarged amniotic cavity proof of embryonic death. embryonic correlated with embryonic death. death 23. McKenna KM, Feldstein VA, Goldstein Review/Other 15 patients Retrospective review to determine whether “Empty amnion” sign is useful in confirming 4 RB, Filly RA. The empty amnion: a sign -Dx the “empty amnion” (visualization of an early pregnancy failure. of early pregnancy failure. J Ultrasound amnion but no identifiable embryonic pole) is Med 1995; 14(2):117-121. a sign of early pregnancy failure.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 24. Yegul NT, Filly RA. The expanded Observational 806 patients Retrospective study was performed to assess Among the cohort of 806 cases, 520 (64.5%) 4 amnion sign: evidence of early embryonic -Dx the PPV for confirming early embryonic death had an identifiable embryo, and 255 of those death. J Ultrasound Med 2009; in the clinical scenario wherein an embryo is with an identifiable embryo had a visible 28(10):1331-1335. identified without a visible heartbeat, but the amnion (49.0%). 116/255 with a visible embryonic CRL is ≤5 mm. amnion and an identifiable embryo without a heartbeat had a CRL that measured ≤5 mm (45.5%). The CRL of these embryos ranged from 1.7 to 5.4 mm (ie, when rounded to the nearest millimeter, these embryos would be 5 mm) with the breakdown as follows: those measuring ≤3.4 mm (n=28), those measuring 3.5 to 4.4 mm (n=45), and those measuring 4.5 to 5.4 mm (n=43). Eight of these 116 patients did not have any documented follow- up. In the remaining 108 patients, pregnancy failure was confirmed. Authors conclude that any embryo that is surrounded by an amnion and that also lacks a heartbeat has unfortunately but definitively died. This is equally true for embryos measuring <5 mm in CRL. 25. Lindsay DJ, Lovett IS, Lyons EA, et al. Observational 486 women Evaluate women who had endovaginal Yolk sac diameter >2 standard deviations 3 Yolk sac diameter and shape at -Dx sonography with fetuses <10 weeks menstrual above the mean when compared with the endovaginal US: predictors of pregnancy age to establish the normal size and shape of MSD allowed prediction of an abnormal outcome in the first trimester. Radiology the secondary yolk sac and to assess the value pregnancy outcome with sensitivity of 15.6%, 1992; 183(1):115-118. of yolk sac measurement in predicting a specificity of 97.4%, and PPV of 60.0%. pregnancy outcome in the first trimester. Yolk sac diameter >2 standard deviations below the mean allowed prediction of an abnormal outcome with a sensitivity of 15.6%, specificity of 95.3%, and PPV of 44.4%.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 26. Odeh M, Tendler R, Kais M, Grinin V, Observational 141 normal To compare gestational sac volume between Gestational sac volume was significantly 3 Ophir E, Bornstein J. Gestational sac -Dx pregnancies normal pregnancies and missed abortions and larger in normal pregnancies than in missed or volume in missed abortion and and 82 anembryonic pregnancies and to determine at anembryonic abortion: 27.51 +/- 25.25 cm(3) anembryonic pregnancy compared to anembryonic what gestational age differences in gestational and 8.04 +/- 10.54 cm(3), respectively normal pregnancy. J Clin Ultrasound abortions sac volume become evident. (P<0.001). When stratified by weeks, 2010; 38(7):367-371. statistically significant differences were found beginning at 7 weeks, while gestational sac volume measurements were not significantly different between the normal and abnormal pregnancies from 6 to 6(+6) weeks. Gestational sac volume in missed abortion and anembryonic pregnancies is significantly smaller than in normal pregnancies, starting at 7 weeks of gestational age. This finding may be helpful in the diagnosis of missed abortion or anembryonic pregnancies in selected cases. 27. Bennett GL, Bromley B, Lieberman E, Observational 516 patients Retrospective review of US images to assess Spontaneous abortion rate was higher in large 4 Benacerraf BR. Subchorionic hemorrhage -Dx risk of spontaneous abortion relative to size of hemorrhages, older women (over 35 years) in first-trimester pregnancies: prediction subchorionic hemorrhage, age of patient, and and earlier pregnancies (<8 weeks). of pregnancy outcome with sonography. time of presentation. Radiology 1996; 200(3):803-806. 28. Mbugua Gitau G, Liversedge H, Goffey Review/Other 138 women To assess the effect of maternal age on the Outcome measures were pregnancy loss, fetal 4 D, Hawton A, Liversedge N, Taylor M. -Dx outcome of pregnancies complicated by abnormalities, preterm delivery, low birth The influence of maternal age on the bleeding at <12 weeks. weight and cesarean delivery. Age over 35 outcomes of pregnancies complicated by years was significantly associated with bleeding at less than 12 weeks. Acta reduced live-birth and increased miscarriage Obstet Gynecol Scand 2009; 88(1):116- rates. Women over 35 years of age had higher 118. cesarean section and pregnancy loss rates than the younger women. The combination of bleeding in early pregnancy and advanced age increases risk of pregnancy loss even after US has confirmed fetal heart pulsation. 29. Levine D. Ectopic pregnancy. Radiology Review/Other N/A To review and illustrate the sonographic Sonography is useful is making the right 4 2007; 245(2):385-397. -Dx findings of ectopic pregnancy. diagnosis is ectopic pregnancies. 30. Lin EP, Bhatt S, Dogra VS. Diagnostic Review/Other N/A Review diagnosis of ectopic pregnancy. Hormonal assays and pelvic US are used for 4 clues to ectopic pregnancy. Radiographics -Dx the initial evaluation of ectopic pregnancy. 2008; 28(6):1661-1671. 31. Frates MC, Visweswaran A, Laing FC. Observational 26 patients To compare the echogenicity of the tubal ring Tubal ring is usually more echogenic than 4 Comparison of tubal ring and corpus -Dx with tubal of an ectopic pregnancy and the corpus ovarian parenchyma, and the corpus luteum is luteum echogenicities: a useful rings; 45 luteum with that of the ovary for improved usually equal to or less echogenic than the differentiating characteristic. J Ultrasound control detection of early ectopic pregnancy. ovary. Echogenicity of an adnexal mass may Med 2001; 20(1):27-31; quiz 33. patients with help differentiate tubal ring from a corpus IUP luteum. * See Last Page for Key 2012 Review Lane/Wong Page 10 ACR Appropriateness Criteria® First Trimester Bleeding EVIDENCE TABLE

Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 32. Stein MW, Ricci ZJ, Novak L, Roberts Observational 79 women Retrospective review of TVUS to compare the Sonographic features for distinguishing tubal 3 JH, Koenigsberg M. Sonographic -Dx value of different sonographic features in ring from corpus luteum include decreased comparison of the tubal ring of ectopic distinguishing tubal ring from corpus luteum. wall echogenicity compared with the pregnancy with the corpus luteum. J endometrium and an anechoic texture, which Ultrasound Med 2004; 23(1):57-62. suggests a corpus luteum. 33. Dart R, McLean SA, Dart L. Isolated fluid Observational 1ST Group - Retrospective cohort study to examine the risk Ectopic pregnancy was diagnosed in 16/38: 3 in the cul-de-sac: how well does it predict -Dx 38 patients of ectopic pregnancy among patients with 42% (95% CI: 26%-59%) of patients with ectopic pregnancy? Am J Emerg Med with cul-de- isolated abnormal cul-de-sac fluid at TVUS. isolated cul-de-sac fluid, 5/23: 22% (95%. CI: 2002; 20(1):1-4. sac fluid; 2nd Moderate volume of anechoic fluid was 7%-42%) of patients with moderate amount of Group - 523 compared with either a large volume of anechoic fluid, and 11/15: 73% (95%, CI: patients with anechoic fluid or any echogenic fluid. 45%-92%) of patients with a large volume of indeterminate fluid or any echogenic fluid. Patients with US isolated abnormal cul-de-sac fluid are at moderate risk for ectopic pregnancy. The risk increases if the fluid is echogenic or the volume is large. 34. Nyberg DA, Hughes MP, Mack LA, Review/Other 232 patients: Prospective study of TVUS studies to Intraperitoneal fluid was detected in 43 (63%) 4 Wang KY. Extrauterine findings of -Dx Group 1 – 68 determine the significance of different group 1 patients and in 81 (31%) group 3 ectopic pregnancy of transvaginal US: patients with extrauterine findings, including echogenic patients. Echogenic fluid was the only importance of echogenic fluid. Radiology proved fluid in the cul-de-sac in patients with positive abnormal finding at US in 10 (15%) group 1 1991; 178(3):823-826. ectopic serum pregnancy tests considered to be at risk patients and added confidence to the diagnosis gestation; for ectopic pregnancy. of ectopic pregnancy in many others. Group 2 – 83 Echogenic fluid correlated with patients with hemoperitoneum at the time of surgery. reliable Presence of echogenic fluid shows a high risk evidence of for ectopic pregnancy. IUP; Group 3 – 81 patients with no evidence of pregnancy at initial US 35. Wachsberg RH, Levine CD. Echogenic Observational 12 Retrospective study of patients with positive Small-to-moderate amount of echogenic fluid 4 peritoneal fluid as an isolated sonographic -Dx consecutive pregnancy test in whom sonography revealed noted as an isolated finding may not be highly finding: significance in patients at risk of symptomatic echogenic fluid as an isolated finding without predictive of ectopic pregnancy. ectopic pregnancy. Clin Radiol 1998; patients evidence of IUP. 53(7):520-522. 36. Frates MC, Brown DL, Doubilet PM, Observational 132 Retrospective review of US scans and medical Findings at TVUS cannot reliably determine 3 Hornstein MD. Tubal rupture in patients -Dx consecutive records to determine whether sonography can whether tubal rupture is present. with ectopic pregnancy: diagnosis with patients help diagnose tubal rupture in patients with transvaginal US. Radiology 1994; ectopic pregnancy. 191(3):769-772.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 37. Ackerman TE, Levi CS, Dashefsky SM, Observational 12 patients Retrospective study to evaluate the Interstitial line had better sensitivity (80%) 4 Holt SC, Lindsay DJ. Interstitial line: -Dx with relationship of the endometrial canal and and specificity (98%) than eccentric sonographic finding in interstitial interstitial vera to the interstitial gestational sac gestational sac location (sensitivity 40%; (cornual) ectopic pregnancy. Radiology ectopic and to determine if this relationship can be specificity 88%) and myometrial thinning 1993; 189(1):83-87. pregnancy; used to increase the predictive value of US in (sensitivity, 40%; specificity, 93%) for the 40 patients the diagnosis of interstitial ectopic pregnancy. diagnosis of interstitial ectopic pregnancy. with different Ierstitial line sign is a useful diagnostic sign of diagnoses interstitial ectopic pregnancy. 38. Jafri SZ, Loginsky SJ, Bouffard JA, Selis Review/Other 11 patients Review sonographic findings in 11 cases of An ectopic pregnancy was diagnosed in all 4 JE. Sonographic detection of interstitial -Dx proven interstitial pregnancy and compare cases, and an interstitial location was pregnancy. J Clin Ultrasound 1987; with previous 12 cases. suspected in 5 cases preoperatively. Most 15(4):253-257. common findings were eccentrically located gestational sac surrounded by an asymmetric myometrial mantle and a separate empty uterine cavity with endometrial echoes. Laparoscopy is recommended when interstitial pregnancy is suspected by sonography. 39. Jurkovic D, Hillaby K, Woelfer B, Review/Other 18 diagnosed Describe first-trimester US diagnosis and Surgical treatment was successful in all 8 4 Lawrence A, Salim R, Elson CJ. First- -Dx cesarean management of pregnancies implanted into cases. The respective success rates of medical trimester diagnosis and management of section scar uterine cesarean section scars. treatment and expectant management were 5/7 pregnancies implanted into the lower pregnancies (71%) and 1/3 (33%). 5 (28%) required uterine segment Cesarean section scar. transfusion and one woman (6%) had a Ultrasound Obstet Gynecol 2003; hysterectomy. Cesarean section scar 21(3):220-227. pregnancies are common. If diagnosis is made in the first trimester the prognosis is good and the risk of hysterectomy is relatively low. 40. Ushakov FB, Elchalal U, Aceman PJ, Review/Other 117 cases Review cases of cervical pregnancy in English Sonography improved pretreatment diagnosis 4 Schenker JG. Cervical pregnancy: past -Dx from literature from 1978 and cases performed in up to 81.8%. Early diagnosis of cervical and future. Obstet Gynecol Surv 1997; literature the authors department. pregnancy allowed for treatment by 52(1):45-59. 3 cases from chemotherapy in 32 cases, with an 81.3 % authors success rate. Serial -hCG levels and TVUS department with color Doppler are used to monitor therapy.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 41. Malinowski A, Bates SK. Semantics and Review/Other 1 patient To clarify the respective definitions of cornual Correct diagnosis and eventual termination of 4 pitfalls in the diagnosis of -Dx and interstitial pregnancy and to explore the cornual pregnancy and identification of a cornual/interstitial pregnancy. Fertil Steril difficulties in diagnosing these entities, uterine anomaly were achieved. The process 2006; 86(6):1764 e1711-1764. particularly in the context of Müllerian fusion led to the development of an enhanced defects. understanding of diagnostic modalities and their limitations with regard to the entities under discussion. Accurate diagnosis of an interstitial pregnancy requires that those reading and reporting US use consistent, precise nomenclature. Clinicians must remain cognizant of the limitations of US in distinguishing cornual (intrauterine) from interstitial (ectopic) pregnancies and the influence of uterine anomalies on this distinction. 42. Talbot K, Simpson R, Price N, Jackson Review/Other N/A Review diagnosis and management of In the majority (71%) of cases reviewed, risk 4 SR. Heterotopic pregnancy. J Obstet -Dx heterotopic pregnancy. factors for a heterotopic pregnancy were Gynaecol 2011; 31(1):7-12. present. However, in several instances (33%), previous sonographic reports of a normal IUP gave false reassurance. These results highlight the complexity of diagnosis. In addition, the findings were compared with two previous reviews covering cases from 1971 to 2004. This comparison highlighted two important trends: first, the increasing role of US in the definitive diagnosis of a heterotopic pregnancy, and second, the development of conservative approaches to management. 43. Filhastre M, Dechaud H, Lesnik A, Review/Other 2 patients Case report to examine role of MRI in MRI was able to localize the ectopic 4 Taourel P. Interstitial pregnancy: role of -Dx interstitial pregnancy. pregnancy by showing a gestational structure MRI. Eur Radiol 2005; 15(1):93-95. surrounded by a thick wall in the upper part of the uterine wall separated from the endometrium by an uninterrupted junctional zone in both cases. 44. Jung SE, Byun JY, Lee JM, Choi BG, Review/Other 12 patients To assess characteristic MR findings of Typical MR finding for cervical pregnancy is 4 Hahn ST. Characteristic MR findings of -Dx cervical pregnancy. heterogeneous hemorrhagic mass with densely cervical pregnancy. J Magn Reson enhancing papillary solid components. Imaging 2001; 13(6):918-922.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 45. Coulier B, Malbecq S, Brinon PE, Review/Other 1 patient Present a case report on diagnosis of ruptured Diagnosis was made using contrast-enhanced 4 Ramboux A. MDCT diagnosis of ruptured -Dx tubal pregnancy with MDCT. MDCT. The radiologist must be aware of the tubal pregnancy with massive key signs (massive hemoperitoneum with hemoperitoneum. Emerg Radiol 2008; fresh blood clots in the hypogastric area, 15(3):179-182. active free peritoneal extravasation of intravascular contrast material and dramatic peripheral enhancement). 46. Pham H, Lin EC. Adnexal ring of ectopic Review/Other 1 patient Case report to examine role of contrast- Contrast-enhanced CT showed ring enhancing 4 pregnancy detected by contrast-enhanced -Dx enhanced CT in a woman with acute right cystic structure in the right adnexa CT. Abdom Imaging 2007; 32(1):56-58. lower quadrant abdominal pain. corresponding to tubal ring sign of ectopic pregnancy seen on subsequent pelvic US. Right tubal ectopic pregnancy was confirmed at surgery. 47. Barnhart K, van Mello NM, Bourne T, et Review/Other N/A To improve the interpretation of future studies Careful definition of populations and 4 al. Pregnancy of unknown location: a -Dx in women who are initially diagnosed with a classification of outcomes should optimize consensus statement of nomenclature, pregnancy of unknown location, the authors objective interpretation of research, allow definitions, and outcome. Fertil Steril proposed a consensus statement with objective assessment of future reproductive 2011; 95(3):857-866. definitions of population, target disease, and prognosis, and hopefully lead to improved final outcome. clinical care of women initially identified to have a pregnancy of unknown location. 48. Condous G, Timmerman D, Goldstein S, Review/Other N/A Panel of gynecologists with expertise in early Consensus can be achieved in both the 4 Valentin L, Jurkovic D, Bourne T. -Dx pregnancy and US was convened by the diagnostic approach and management of Pregnancies of unknown location: International Society of Ultrasound in women with pregnancy of unknown location. consensus statement. Ultrasound Obstet and Gynecology to discuss the role The panel agreed that because most pregnancy Gynecol 2006; 28(2):121-122. of US and biochemistry in the diagnosis and of unknown location are at low risk of being management of women with a pregnancy of an ectopic pregnancy, provided that the US unknown location. examiner is sufficiently skilled and uses an US system with acceptable image quality, future efforts should concentrate on minimizing follow-up. 49. Green CL, Angtuaco TL, Shah HR, Review/Other N/A Review diagnosis of GTD with emphasis on Although US is recommended for initial 4 Parmley TH. Gestational trophoblastic -Dx the unique information provided by different diagnosis, radiography, angiography, CT, and disease: a spectrum of radiologic diagnostic tools. MRI all play a role in determining the diagnosis. Radiographics 1996; presence of GTD and the extent of its 16(6):1371-1384. complications. US shows molar gestations as alternating cystic and solid tissue that fills the entire . CT and MRI are useful in detecting myometrial invasion, parametrial extension, and metastasis.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 50. Zhou Q, Lei XY, Xie Q, Cardoza JD. Review/Other 355patients Retrospective analysis of cases of GTD in two 106/355 cases had hydatidiform mole, 33 had 4 Sonographic and Doppler imaging in the -Dx hospitals to evaluate the clinical utility of a partial hydatidiform mole, 184 had an diagnosis and treatment of gestational sonography with Doppler examination in the invasive hydatidiform mole, and 32 had trophoblastic disease: a 12-year diagnosis and treatment of GTD. choriocarcinoma. US showed abnormal molar experience. J Ultrasound Med 2005; tissue confined to the endometrial cavity in all 24(1):15-24. cases of hydatidiform mole. Doppler waveforms showed resistive indices of 0.55 for hydatidiform mole, 0.56 for partial hydatidiform mole, 0.28 for invasive hydatidiform mole, 0.25 for choriocarcinoma, and 0.66 for normal pregnancies. Sonography and Doppler imaging were helpful in diagnosing GTD, in determining whether invasive disease was present, in detecting recurrence of disease, and in following the effectiveness of chemotherapy. 51. Hou JL, Wan XR, Xiang Y, Qi QW, Yang Observational 113 cases of Retrospective study to investigate the changes Vaginal bleeding remains the most common 4 XY. Changes of clinical features in -Dx hydatidiform of the clinical features of hydatidiform mole. presenting symptom, occurring in 94/113 hydatidiform mole: analysis of 113 cases. mole cases (83.2%). Of 113 cases, 52 (46%) J Reprod Med 2008; 53(8):629-633. presented with excessive uterine size. Preeclampsia, hyperemesis, hemoptysis and theca lutein cysts occurred in 4/113 (3.5%), 12/113 (10.6%), 4/113 (3.5%) and 19/113 cases (16.8%), respectively. The incidence of postmolar trophoblastic neoplasia was 21% (24/113). Compared to historic data, the incidence of vaginal bleeding and preeclampsia were statistically lower (P<0.005). The incidence of postmolar gestational trophoblastic neoplasia was increased moderately without statistical significance compared to historic data. Because of the wide use of US and serum hCG test, current patients with hydatidiform mole have been diagnosed earlier in gestation and the clinical features have changed. Patterns of medical practice should be changed as well.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 52. Barton JW, McCarthy SM, Kohorn EI, Observational 39 patients To determine whether findings at MRI are Among the three groups (persistent GTD, 4 Scoutt LM, Lange RC. Pelvic MR -Dx specific for primary molar disease, persistent incomplete abortion, or ectopic pregnancy) imaging findings in gestational GTD, incomplete abortion, or ectopic the only significant differences were a higher trophoblastic disease, incomplete pregnancy. prevalence of endometrial distention in the abortion, and ectopic pregnancy: are they group with incomplete abortion (P<.0035) and specific? Radiology 1993; 186(1):163- the absence of junctional zone disruption in 168. the group with ectopic pregnancy (P<.05). In the group with primary molar disease, total intrauterine volume was significantly increased (P<.001), and endometrial distention and presence of an endometrial mass had a significantly higher prevalence than that in the persistent GTD groups with (P<.04) or without (P<.001) metastases. Myometrial or extrauterine disease was identified in 65% of the patients with persistent disease and a -hCG level greater than 500 mIU/mL (500 IU/L). Thus, although MRI findings in persistent GTD, incomplete abortion, and ectopic pregnancy are relatively nonspecific, MRI can depict invasive disease that may alter therapeutic management in patients with documented GTD.

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Patients/ Study Objective Study Reference Study Type Study Results Events (Purpose of Study) Quality 53. Rufener SL, Adusumilli S, Weadock WJ, Observational 29 patients To identify misleading imaging features that Interobserver agreement was as follows: the 4 Caoili E. Sonography of uterine -Dx leads to inclusion of a uterine AVM in the presence of a uterine mass, 90%; myometrial abnormalities in postpartum and differential diagnosis of a uterine abnormality involvement, 83%; the presence of an postabortion patients: a potential pitfall of because consideration of this diagnosis can associated vascular abnormality, 72%; and interpretation. J Ultrasound Med 2008; potentially alter patient treatment. inclusion of a uterine AVM in the differential 27(3):343-348. diagnosis, 86%. Myometrial involvement showed a statistically significant relationship to inclusion of a uterine AVM in the differential diagnosis (P<.05). Final pathologic diagnoses included retained (n=26), an endometrial polyp (n=1), chronic endometritis (n=1), and an exogenous progestational effect (n=1). No uterine AVMs were found. Despite high interobserver agreement in characterizing uterine abnormalities on sonography, readers still include uterine AVMs in the differential diagnosis of uterine masses that are ultimately proven to be retained products of conception. A myometrial location of a uterine mass is a particularly misleading imaging feature of retained products of conception. 54. Kwon JH, Kim GS. Obstetric iatrogenic Review/Other 24 patients Retrospective review to determine value of Color and duplex Doppler US is 4 arterial injuries of the uterus: diagnosis -Dx US in detection and diagnosis of uterine recommended for detection and diagnosis and with US and treatment with transcatheter vascular abnormalities and the value of follow-up of patients after embolization. arterial embolization. Radiographics transcatheter arterial embolization in treating Transcatheter arterial embolization is a safe 2002; 22(1):35-46. these conditions. and effective method. 55. Degani S, Leibovitz Z, Shapiro I, Ohel G. Review/Other 12 patients To assess sonographic and clinical outcome in 9 asymptomatic patients were managed 4 Expectant management of pregnancy- -Dx women with pregnancy-related uterine AVMs expectantly for 4 to 10 weeks without further related high-velocity uterine arteriovenous diagnosed after abortion. complications. None of the 12 required shunt diagnosed after abortion. Int J aggressive interventions such as transcatheter Gynaecol Obstet 2009; 106(1):46-49. arterial embolization, and 6 had uncomplicated pregnancies after resolution of the lesions. Expectant management is an option in many women with pregnancy- related uterine AVMs.

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Study Quality Category Definitions AVM = Arteriovenous malformation  Category 1 The study is well-designed and accounts for common biases. -hCG = Beta human chorionic gonadotropin  Category 2 The study is moderately well-designed and accounts for most CI = Confidence interval common biases. CRL = Crown-rump length  Category 3 There are important study design limitations. CT = Computed tomography  Category 4 The study is not useful as primary evidence. The article may not be GTD = Gestational trophoblastic disease a clinical study or the study design is invalid, or conclusions are based on expert consensus. For example: IUP = Intrauterine pregnancy a) the study does not meet the criteria for or is not a hypothesis-based clinical MDCT = Multidetector computed tomography study (e.g., a book chapter or case report or case series description); MRI = Magnetic resonance imaging b) the study may synthesize and draw conclusions about several studies such as a literature review article or book chapter but is not primary evidence; MSD = Mean gestational sac diameter c) the study is an expert opinion or consensus document. NPV = Negative predictive value

PPV = Positive predictive value Dx = Diagnostic TVUS = Transvaginal ultrasound Tx = Treatment US = Ultrasound

ACR Appropriateness Criteria® Evidence Table Key