Ultrasound in Early Pregnancy: Diagnosis and Dating | Free from Bias

1. Beeldvorming en beleid bij PUL Dirk Timmerman Tom Bourne Emma Kirk Anne Pexsters Caroline Van Holsbeke Dominique Van Schoubroeck Ben Van Calster VVOG Genk, 10 Oktober 2013 CME: Thispresentation is free fromany commercial bias and /orpromotionalintent

2. Positive Pregnancy Test TVS 88% 2% 10% Intra-uterine Pregnancy (IUP) Ectopic Pregnancy (EP) PUL hCG & Prog 0 & 48 hrs TVS Failed PUL EP IUP 10% 90%

3. Ultrasound in early pregnancy 1. Reliable dating of pregnancy 2. Reliable diagnosis of miscarriage 3. Pregnancy of unknown location

4. 1. Reliable Dating US Features – Week 4 • Thickened endometrium also found in: • late luteal phase of menstrual cycle • decidual reaction with an ectopic pregnancy • Corpus luteum

5. US Features - Week 4 IPUV: Intrauterinepregnancy withunknownviability Gestational sac Fluid in cavity 32-34 days Echogenic or trophoblastic ring

6. US Features - Week 6 6 weeks (42 days) Embryo grows rapidly Amniotic cavity expands CRL 4-9mm Mean sac diameter 16-40mm FH clearly visible

7. Fetal Cardiac Activity • Earliest proof of a viable IUP • Should be evident when CRL > 2mm • 5-10% embryos 2-4 mm have no demonstrable FH • Between 5-9 weeks there is a rapid increase in mean heart rate from 110 – 175 bpm

8. US Features - Week 7 • Amniotic membrane and cavity more distinct • CRL 10-15mm • Fetal head visible • Upper limb buds 8w +1 (16mm)

9. Robinson curve Sonar measurement of fetal crown-rump length as means of assessing maturity in first trimester pregnancy Robinson H. British Medical Journal 1973 4, 28-31 • 80 patients with certain dates • 214 transabd US measurements • 6-14 weeks

10.  Background: Robinson curve Dating not possible in very early pregnancy CRL is often too small for gestational age

11. Robinson CRL curve

12. New CRL curve based on more than 3500 pregnancies (Leuven) with known amenorrhoea (Pexsters et al. UOG 2010)

14. Conclusion (CRL curve) • The largest difference between both curves is around 6 weeks. Our new curve is probably more reliable because of large number of patients and the use of transvaginal ultrasound. • The first trimester growth curve was extended to 5 weeks GA, which allows for a correct dating of very early pregnancies

15. Ectopic pregnancy • 90% of Ectopic Pregnancies (EP) should now be visualised on TVS prior to treatment • Diagnosis should be based on the positive visualization of an adnexal mass rather than the inability to visualise an intrauterine pregnancy

16. Ectopic pregnancy • Tubal • Interstitial • Cervical • Caesarean section scar • Ovarian

17. Tubal ectopic pregnancy Uterus Ovary Ectopic Ovary Ectopic Empty sac Inhomogeneous mass “Bagel sign” 20% “Blob sign” 60%

18. Tubal Ectopic Pregnancy Gestational sac and embryo Visible cardiac activity Ectopic Ovary Ovary Ectopic Ovary Ectopic GS, yolk sac and embryo 13% Heart actitvity 7%

19. 2. Diagnosis of miscarriage

22. In the absence of both embryo and yolk sac, the FPR for miscarriage was 4.4% when an MSD cut-off of 16 mm was used and 0.5% for a cut-off of 20 mm.

23. Interobserver reproducibility 8w +2

24. Interobserver variability of measurements CRL MSD PI = prediction interval. Scans by two experienced consultants with an interest in early pregnancy ultrasound

25. Addendum to GTG No 25 (Oct 2006): The Management of Early Pregnancy Loss Recent research suggests that given inter-observer variability in ultrasound measurements and the greater variation in early embryonic growth than has hitherto been assumed, a more conservative approach to the diagnosis of early pregnancy loss is warranted. The studies from Imperial College London, Queen Mary, University of London and the KU Leuven, Belgium published in the November 2011 issue of Ultrasound Obstet Gynaecol concluded that current definitions used to diagnose miscarriage could lead to an incorrect diagnosis and they call for clearer evidence based guidance on detecting miscarriage. Having carefully considered these papers, we recommend adoption of the following interim guidancewith immediate effect:

26. Addendum to GTG No 25 (Oct 2006): The Management of Early Pregnancy Loss We would add: no embryonic structure seen for an empty sac on repeat scan > 7 days later • Ultrasound diagnosis of miscarriage should only be considered with a mean gestation sac diameter >/= 25mm (with no obvious yolk sac), or with a fetal pole with crown rump length >/=7mm (without evidence of fetal heart activity) • A TVS should be performed in all cases where there is any doubt about the diagnosis and/or a woman requests a repeat scan, this should be performed at an interval of at least one week from the initial scan before medical or surgical measures are undertaken for uterine evacuation. No growth in gestation sac size or CRL is strongly suggestive of a non-viable pregnancy in the absence of embryonic structures.

27. Diagnosis of miscarriage (DOM) study Prospective: observational - consecutive cases Multicentre (8): St Thomas’s, Chelsea and Westminster, Northwick Park, Queen Charlottes and Chelsea, St Mary’s, Princess Anne Southampton, Genk Definitions: intrauterine pregnancies of unknown viability (PUV): Empty gestation sac, or gestation sac with a yolk sac but no embryo seen with MSD of < 30 mm. Embryo with an absent heartbeat and CRL < 8 mm Recruitment: 2925 consecutive women Reference standard: viable pregnancy at the time of first trimester screening ultrasonography at 11-14 weeks (@ 99% reach term) Outcome measures: sensitivity, specificity, PPV and NPV with CI’s for specificity. Risk of miscarriage

28. Empty Gestation Sacs Diagnostic performance of MSD to predict miscarriage in pregnancies with an empty GS USA (Spec 96 CI 94-98 ROM 83) Old UK/AUS/NZ (Spec 99,5 CI 98-99.9 ROM 93) New UK/AUS/NZ/USA (Spec 100, CI 99-100 ROM 98)

29. Empty Gestation Sacs Sensitivity and specificity by MSD cut-off for pregnancies with empty GS. 95% CIs 96% at 16 99.5% at 20 100% at 25 Specificity Sensitivity

30. Sensitivity and specificity by CRL cut-off for pregnancies with embryo, but no FH (95% CIs) 95% at 5 97% at 6 99% at 7 Specificity Sensitivity

31. 3. Pregnancy of Unknown Location (PUL) Positive pregnancy test (hCG > 5 IU/L) No sign of intrauterine or extrauterine pregnancy at TVS No products of conception visualised at TVS

32. PUL: London – Leuven studies George Condous (now Sydney), Emma Kirk, Cecilia Bottomley, Yazan Abdallah, Jessica Preisler, Tom Bourne Ben Van Calster, Sabine Van Huffel, Kirsten Van Hoorde, Anne Pexsters, Dominique Van Schoubroeck, Caroline Van Holsbeke, Jan Deprest, Dirk Timmerman

33. PUL clinical issues • Ideal rate of PULs? • Role of single measurements of hCG and progesterone? • Can we manage PULs on single visit? • Change in serum hCG over time better than single measurements of hCG and progesterone? • Can we develop mathematical models to be used in clinical setting to manage PULs?

34. Rate of PULs • Quality of scanning is key - Detection of early IUPs & ectopic pregnancy using TVS increases with experience - PUL rates should be < 15%

36. Classification of final outcomes of PUL

37. PULs: low risk of ectopic pregnancy • Expectant management safe • Outpatient basis • Reduce need for unnecessary intervention

38. ‘PUL and HCG 1000 IU/L, then laparoscopy’ Progesterone nmol/L + Miscarriage +Intrauterine pregnancy +Ectopic pregnancy hCG

39. Single hormonal markers Condous et al, Hum Reprod 2004; Ultrasound Obstet Gynecol 2005

40. Single visit strategy Condouset al, Int’l J Gynaecol Obstet 2004 Condous et al, Human Reproduction 2005 Single measurements of progesterone can predict viability, but neither hCG nor progesterone can locate the pregnancy A ‘single visit strategy’ can eliminate 85% of non-ectopic pregnancies out the system 67% of the ectopic pregnancies are not adequately followed

41. hCG ratio hCG 48 hr hCG 0 hr

42. hCG ratio vs. probability of PUL outcome hCG 0 h 1000 IU/L hCG 48 h 2000 IU/L hCG ratio = 2 hCG 0 h 1000 IU/L hCG 48 h 500 IU/L hCG ratio = 0.5 hCG 0 h 1000 IU/L hCG 48 h 1100 IU/L hCG ratio = 1.1

43. Rules for hCG ratio in PUL • If hCG ratio 0.8, then a miscarriage is likely • If 0.8 < hCG ratio  1.66, there is a high risk of ectopic pregnancy • If hCG ratio > 1.66, then an ongoing intrauterine pregnancy is likely

44. Mathematical Models Condous et al, Hum Reprod 2004 Condous et al, UOG 2007 Van Calster et al, AIM 2009 Model M1 hCGratio (hCG 48 hr/hCG 0 hr) Model M2 log progesterone average Model M3 Age log progesterone average hCG ratio Model M4 hCG ratio log average of the two hCG levels

45. Detection rate of ectopic pregnancy in PUL • Single hCG measurement: 30 % • Single hCG and progesterone: 50 % • HCG ratio: 75 % • Subjective assessment : 25 – 60 % • Logistic regression model M4: 88 %

46. astraia Gyn ultrasound Chris Harris

47. NIUP IPUVI PUL Miscarriage Ectopic

48. 5 wks 7 wks Chance of diagnostic scan

49. Can we accurately define a group of low-risk PUL in order to safely reduce follow-up for these pregnancies and allocate resources to PUL at increased risk? • Select a group of PUL as being at low risk  avoid ectopics in this group: high NPV, high sensitivity for EP • Externally validate the PUL prediction model M4

50. Study design and setting • Multi-centre, observational, diagnostic accuracy study • 5 London university hospitals • Retrospective internal validation on data from St. George’s (SGH) • Prospective external validation on data from • Queen Charlotte’s and Chelsea Hospital (QCH) • Chelsea and Westminster Hospital (CWH) • West Middlesex Hospital (WMH) • St. Mary’s Hospital (SMH) • Aim: avoid giving reduced follow-up to ectopics