3-D Ultrasound and Dopplers in Reproductive Medicine

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1 3-D Ultrasound and Dopplers in Reproductive Medicine Laurel Stadtmauer,M.D. PhD Professor, Department of OB/GYN EVMS Director of REI Division and REI Fellowship Jones institute Norfolk VA, U.S.A.

2 Dr Howard Jones

3 Nothing to disclose Ultrasound In Reproductive Medicine Springer Publisher 2 nd Edition Editors Dr Laurel Stadtmauer Dr Ilan Tur-Kaspa

4 What is the Role of Dopplers in Reproductive Medicine? For the time being 3-D Doppler has no role in routine IVF success. Successful implantation depends on the interaction between the uterine cavity and the blastocysts Uterine pathology such as malformations, myomas, and carcinomas can significantly impair the outcome of IVF Endometrial vasculature, volume and morphology affects implantation Abnormalities in the adnexa such as hydrosalpinx and ovarian cysts and also affect IVF outcomes

5 3-D ultrasound techniques Multiplanar view: The display presents the three orthogonal planes simultaneously: the longitudinal, transverse and coronal planes. The dataset can then be rotated or sliced in order to view the region of interest (ROI). The multi-planar view displays the exact spatial relationships between the 3 planes.

Use Z knob and rotate until horizontal. 3.

6 Z-Technique for the uterus in evaluation of the uterine cavity 1. Put track dot in A in the middle of the endometrium. 2. Use Z knob and rotate until horizontal. 3. Then go to B and rotate Z knob until horizontal. 4. Then look at C, and there should be the coronal view; use Z to rotate until upright.

7 Uterine anomalies congenital

8 Intrauterine synechiae: 3D hydrosonogram

9 Reconstruction and visualization of 3-D images The tomographic ultrasound imaging (TUI) or multi-slice technique: TUI allows for a comprehensive sequential analysis of the desired organ. The same imaging principle is employed in CT and MRI. Dietz HP, Shek KL. Tomographic ultrasound imaging of the pelvic floor: which levels matter most? Ultrasound Obstet Gynecol. 2009;33:

10 Saline sonogram and VCI mode with TUI uterine fibroids

11 Ultrasound evaluation of the fallopian tube -hydrosalpinx

12 Inversion mode hydrosalpinx

13 Volume contrast Rendering - hydrosalpinx

14 The electronic scalpel allows for the removal of pre-located obscuring structures (i) rotation of the rendered image into a position where the obscuring structures can be cut; (ii) creation of the outline for the cut and activation of the cutting mode. Merz E, Miric-Tesanic D, Welter C. Value of the electronic scalpel (cut mode) in the evaluation of the fetal face. Ultrasound Obstet Gynecol. 2000;16:

15 Fallopian tube

16 OmniView: OmniView (GE Medical Systems, Kretztechnik, Zipf, Austria) is a display technology for 3D and 4D US that allows integration of volume datasets and the simultaneous display of up to three independent (non-orthogonal) planes by manually drawing straight or curved lines from any direction or angle. Yeo L, Romero R, Jodicke C, Oggè G, Lee W, Kusanovic JP, Vaisbuch E, Hassan S. Four-chamber view and 'swing technique' (FAST) echo: a novel and simple algorithm to visualize standard fetal echocardiographic planes. Ultrasound Obstet Gynecol. 2011;37:

17 3cm submucosal fibroid in cavity (omniview)

18 3D/4D ET Randomized trial of 227 patients in each group 2-D vs 3-D ultrasound for embryo transfer in women undergoing ART treatment Sarvelos et al. Hum Reprod. 2016;31(10): doi: /humrep/dew206.

19 No difference in IVF outcomes of 2-D vs 3-D ultrasound during transfer

20 Doppler Formula Fd = 2(fc x V x cos α) c Christian J. Doppler described the Doppler effect in 1842

21 Doppler Effect: Application to Ob-Gyn fd = 2(fc x V x cos α) c Us beam fd = Doppler frequency shift V = velocity of blood flow c = propagation speed of sound fd

22 Doppler Ultrasound Types (4) Color flow Doppler Color-coded blood flow patterns superimposed on gray scale B-mode images. The Doppler information is based on mean frequency shift, and color denotes the flow direction. Power Doppler Similar to the color flow images except the flow patterns are based on the amplitude or power of the Doppler shift signals.

23 Doppler Ultrasound Types (4) Spectral Doppler. The magnitude of the Doppler frequency shift over time with the power or the amplitude displayed as brightness. There are 2 types of spectral Doppler: continuous wave and pulsed wave.

24 SLA2 Color and Spectral Doppler Ultrasound Umbilical artery Doppler waveform Cursor line indicates beam path red is flow toward transducer, blue is away SLA1

25 Slide 24 SLA1 flow in a restricted area Stadtmauer, Laurel A., 13/05/2018 SLA2 Stadtmauer, Laurel A., 13/05/2018

Velocity)/Mean Velocity Indication of the pulse strength S/D Ratio = Systolic Velocity/Diastole Velocity An

26 Resistance Index (RI)= Systolic Velocity/(Systolic Velocity +Diastole Velocity) Resistance to blood flow caused by microvascular bed distal to the site of measurement Pulse Index (PI) =(Systolic Velocity Diastolic Velocity)/Mean Velocity Indication of the pulse strength S/D Ratio = Systolic Velocity/Diastole Velocity An index of peripheral resistance Doppler high pulsatility wave forms and high PI and RI are signs of high resistance and benign

28 Neovascularization

29 Angiogenesis plays a role in Neovascularization Conditions Malignancy Pregnancy and folliculogenesis Corpus luteum

31 PI = 0.71 RI = 0.50

34 Angiogenisis of CL

35 3-D Doppler of dominant follicle and stimulated follicles showing angiogenesis may have prognostic value in oocyte quality (huygue ombelet 2017)

36 Color Doppler Parameters Benign PI > 1.0 RI > 0.5 Peripheral flow Diastolic notch Malignant PI < 1.0 RI < 0.5 PSV > 12 cm/s Central flow, unorganized Lakes Changing caliber of vessels Absent diastolic notch PI = Pulsatility Index; RI = Resistance Index; PSV = Peak Systolic Velocity

37 Resistance Index (RI) with Ovarian Masses Tumor type #of patients Mean RI p Benign ovarian tumor < Epithelial ovarian cancer < Malignant germ cell tumors < Metastatic cancer to ovary < Rare malignancies < Wu et al. Cancer 1994;73:

38 CFD and Ovarian Malignancy Doppler study RI < 0.5 Pooled Sensitivity (Range) 0.87 ( ) Pooled specificity (Range) 0.90 ( ) Medeiros et al. Int J Gynecol Cancer 2009;19:

39 43 y.o. G3P3003 s/btl for IVF

41 RI = PI =

43 Mass Resolved Corpus Luteum

44 36 y.o. with ovarian cyst

45 RI = 0.36 PI = 0.58

47 Surgical Findings Pappilary serous cystadenoma

48 35 year old HER2 + Breast CA wants to freeze oocytes

49 RI = 0.76 PI = 1.54

50 Cystadenofibroma

51 42 y.o. with AUB and infertility

54 Granulosa cell tumor

55 CFD and Ovarian Malignancy Conclusion: Ultrasonography with Doppler is a useful preoperative test for the prediction of benign or malignant nature of pelvic masses. However it needs to combined with morphology and other factors Medeiros et al. Int J Gynecol Cancer 2009;19:

56 3-D Antral follicle count with Sono- AVC

57 SONO-AVC SONO-AVC is software especially designed for the automatic detection of multifollicular growth. This software allows not only the display of single follicles in 3D but also automatically calculates the number and volume of hypoechoic structures in a 3D echoderived data set; furthermore, it provides estimations regarding the absolute dimensions of follicles.

58 Wertheimeimer et al. J. ultrasound Med Prospective study no difference in pregnancy outcomes with IVF 2-D vs 3-D

59 Fallopian tube patency

60 Color flow

62 Polyps on Fertility Limited data Lass et al., 1999: Polyps <2 cm no effect on IVF PR, but increases miscarriage rate Lass et al., 1999 and Perez Medina 2005 Prospective observational study, hysteroscopic findings in 55 patients undergoing IVF with repeated failures.all patients had a normal uterine cavity on HSG performed within 1 year. Significantly higher pregnancy (50 % versus 20 %) and implantation (19 % versus 6 %) rates were obtained after hysteroscopic surgical correction of the polyps. Abdelmassih VB, Diamond MP, et al. Uterine cavity findings and hysteroscopic interventions in patients undergoing in-vitro fertilization-embryo transfer who repeatedly cannot conceive. Fertil Steril. 2003;80:1371 5

64 SLA3 Color-flow Doppler may demonstrate the single feeding vessel typical of endometrial polyps. Power Doppler increases sensitivity to 91% and 97% with Specificity and NPV may be increased to 95% and 94%, respectively, when color-flow Doppler is added to grayscale TVUS to identify the feeding vessel Jacob et al 2005.

65 Slide 63 SLA3 Stadtmauer, Laurel A., 26/05/2018

66 Three-Dimensional power Doppler images generated using VOCAL software. Endometrial vasculature (endometrial blood flow from radial artery Endometrial. Subendometrial blood flow parameters on the day of transfer

68 Kupesic et al., (18) Wu et al., (27) Dorn et al., (28) 89 cycles Blastocyst transfer 5 days Inclusion criteria -serum FSH<10IU/L Implantation and Endometrial -no fibroid, ovarian cysts and ovarian after TUGOR endometriosis longprotocol 54 cycles; Inclusion criteria ET (hcg +7) Higher subendometrial FI in pregnant cycles receptivity endometrial vasculature hcg 42 cycles using a long protocol -age<38 yr -normal uterine cavity -serum FSH <15 IU/L ->=2 good quality embryos Exclusion criteria -polycystic ovary syndrome -endometrium <6mm -gynaecological surgery OR Subendometrial VFI higher in pregnant cycles No difference in subendometrial VI, FI and VFI between pregnant and non-pregnant cycles Järvelä et al., (29) 35 cycles using a long protocol ET 2 days after TUGOR Exclusion criteria -uterine fibroids -endometriosis -single ovary -previous operation on uterus or salpingectomy After stimulation and OR No difference in endometrial and subendometrial VI between pregnant and non-pregnant cycles on both days Ng et al., (30) 451 cycles using a long protocol; first cycle only Inclusion criteria -normal uterine cavity on scanning OR Endometrial VI and VFI lower in pregnant cycles. Ng et al., (33) 193 cycles Frozen-thawed embryo transfer cycles Inclusion criteria -normal uterine cavity LH+1 No difference in endometrial and subendometrial 3D Doppler flow indices between pregnant and nonpregnant cycles Mercè et al. (35) 80 cycles using a long protocol Inclusion criteria -first cycle -normal uterine cavity -serum FSH <10IU/L regular cycles hcg Higher endometrial VI, FI and VFI in pregnant cycles

69 Merce et al., Fertil Steril 2008;89:111-7 higher VI, FI and VFI in patients who conceived 0-1 grade 1 embryo transferred >1 grade 1 embryos transferred AUC 95% CI P value AUC 95% CI P EM volume VI (%) FI (0-100) VFI (0-100) AUC=area under the curve

70 In artificial cycles, the endometrial volume (3.9 vs. 2.5 ml, p < 0.05), but not endometrial thickness (10.7 vs mm, ns) was significantly higher in pregnant than in non-pregnant women. Zollner U, Specketer MT, Dietl J, Zollner KP. 3D-Endometrial volume and outcome of cryopreserved embryo replacement Endometrial volume < 1 ml, 0%, <3.2 ml 96% chance of neg cycles. Arch Gynecol Obstet.2012.

236 women with Doppler on ET:The pregnant group had a higher VI, PI and VFI than non-pregnant group better endometrial blood flow subendometrial blood flow is the same (Lee

71 236 women with Doppler on ET:The pregnant group had a higher VI, PI and VFI than non-pregnant group better endometrial blood flow subendometrial blood flow is the same (Lee et al.) Taiwanese Journal of Obstetrics and Gynecology , DOI: ( /j.tjog ) 236 women 3-D power Doppler and color Doppler the day of embryo transfer

72 Utero-ovarian blood flow before and after myomectomy Mahesan and Stadtmauer Vienna 2017 Mean (±SD) n=31 Age (years) 35.4 (5.8) Race African-American 23 (74%) Caucasian 6 (19%) Other 2 (7%) BMI 31.8 (6.0) Parity 0.3 (0.9) SAB 0.7 (0.9) Fibroids Removed (n) 3.1 (1.5) Largest Fibroid (cm) 5.7 (1.8) Weight of specimen(g) (150.7) Effect correlated with size and location of fibroid ipsilateral effect Pre-op Mean (±SD) n=31 Post-op Mean (±SD) n=31 P- value Peak Systolic velocity (cm/s) 19.2 (10.2) 14.9 (8.6) 0.14 End diastolic velocity (cm/s) 5.5 (3.6) 3.91 (1.8) S/D Ratio 4.2 (2.0) 6.38 (9.2) 0.28 Pulsatility index 1.9 (1.0) 3.1 (2.0) Resistance index 0.76 (0.20) 0.98 (0.32) Antimullerian Hormone 3.31 (3.34) 2.36 (2.20) 0.11

73 Does Doppler blood flow to the uterus affect implantation /pregnancy rates

74 Conclusions The role of 3-D U/S is clear, but Doppler in reproductive medicine is still controversial and requires consistent settings and training. Studies have correlated Doppler changes in predicting benign vs cancer, endometrial receptivity, but there is overlap and this measurement and has to be combined with other parameters such as grey scale imaging, endometrial thickness and genetic tests such as ERA.

Neil Goodman, MD, FACE

Initial Workup of Infertile Couple: Female Neil Goodman, MD, FACE Professor of Medicine Voluntary Faculty University of Miami Miller School of Medicine Scope of Infertility in the United States Affects