clinical applications of colour doppler energy imaging in the female

Human Reproduction Update 1999, Vol. 5, No.5 p. 515–529 � European Society of Human Reproduction and Embryology

Clinical applications of colour Doppler energyimaging in the female reproductive tract andpregnancy

Stefano Guerriero1, Silvia Ajossa, Maria Paola Lai, Andrea Risalvato, AnnaMaria Paoletti and Gian Benedetto Melis

Department of Obstetrics and Gynaecology of the University of Cagliari, Ospedale San Giovanni di Dio, ViaOspedale 46, 09124, Cagliari, Italy

This review describes the usefulness of colour Doppler energy (CDE) (or power Doppler) imaging to measurevascularization in the female reproductive tract. CDE imaging is characterized by an increased sensitivity to flow, and thusmay be useful in low-flow states and when optimal Doppler angles cannot be obtained. In addition, longer segments ofvessels and more individual vessels can be visualized with CDE imaging. The role of CDE imaging in the evaluation ofstromal vasculature in normal and in polycystic ovaries is described, and the relationship between follicular vascularityand outcome following in-vitro fertilization are discussed, together with the findings obtained from the evaluation of thecalarteriole of corpus luteum in early pregnancy. The fundamental role of CDE imaging in differentiation among ovarianmasses is also reviewed. We summarize the role of CDE imaging in pregnancy, and describe two new applications ofthree-dimensional power Doppler sonography and the use of ultrasound contrast media. In conclusion, CDE imaging canreplace conventional colour Doppler when the information on the direction of flow is not useful. Moreover, the techniqueappears superior to others for describing microvascular architecture and determining the presence or absence of flow.

Keywords: colour Doppler energy (CDE) imaging/echo-contrast agents/ovary/power Doppler/three-dimensional powerDoppler sonography

TABLE OF CONTENTS

Introduction 515Ovary and CDE imaging 516Other applications of CDE imaging in gynaecology 522Three-dimensional power Doppler sonography 523CDE imaging in pregnancy 524Conclusions 525References 525

Introduction

Conventional colour Doppler imaging, which is based on themean frequency shift Doppler, has had a great impact oninvestigations of the female reproductive tract and pregnancy,albeit with some limitations. These limitations includedependence on the angle of insonation (angle dependence) thatreduces sensitivity to flows perpendicular to the sound field(Rubin et al., 1994), and a difficulty in separating background

noise from true flow (Jaffe, 1992). Recently, a variation ofconventional colour Doppler imaging using the amplitude(energy or power) of the Doppler signal has become available(Rubin et al., 1994). This method has been termed colourDoppler energy (CDE) or power Doppler imaging. Thegreatest advantage of CDE imaging over conventional colourDoppler imaging is its enhanced ability to conveyinformation-containing signals relative to noise, therebyenhancing sensitivity (Rubin et al., 1994; Sohn and Weskott,1997). In fact, noise has low energy, and CDE imagingdemonstrates noise by a uniformly coloured background that iseasily distinguishable from the true flow. Thus, CDE imaginghas the ability to image areas of low blood flow that arecurrently undetectable by frequency-based techniques (Rubinet al., 1994; Hamper et al., 1997; Hoskins and McDicken,1997; Sohn and Weskott, 1997).

Other differences of CDE imaging with conventional colourDoppler imaging include the absolute lack of aliasing, and therelative angle independence (Weskott, 1997). Since pelvic

1To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology of the University of Cagliari, Ospedale San Giovanni di Dio,Via Ospedale 46, 09124, Cagliari, Italy. Tel: +39-70-6092467; Fax: +39-70-668575; E-mail:[email protected]

516 S.Guerriero et al.

vessels are characterized by an irregular course, it is expectedthat angle-independent flow analysis will allow thesonographer to detect these typical vascular features moreeasily. Other advantages of power Doppler are: (i) theevaluation of the amount of blood in the pixel associatedcontinuously with a good boundary effect (Meyerowitz et al.,1996); (ii) better three-dimensional depiction of blood vesselanatomy due to the lack of aliasing and directional informationthat makes vessels appear continuous and easy to identify(Ritchie et al., 1996); and (iii) better appearance of contrastagent (Goldberg et al., 1996). The possibility of obtaining acontinuous map of vascularity can be used for an actualquantification of blood flow or perfusion. With the advent ofappropriate image analysis computer software, as suggested byothers (Dubiel et al., 1997a; Cheng et al., 1999), the amount ofperfusion can be quantified accurately and perhaps morereproducibly than by a subjective grading or scoring system.

The disadvantages of power imaging are the absence ofinformation about speed and direction of flow, and the highmotion sensitivity (Kremkau, 1995). Using CDE imaging, it isimpossible to distinguish the arteries and the veins which showflow in different directions, depending on the organs (liver,kidney, spleen). In contrast, these vessels could be recognizedpromptly by modern and sensitive colour Doppler.Nevertheless, the principal aim of colour Doppler is todetermine the position of vessels and the presence or absence offlow; thus, a lack of information regarding velocity anddirection could not interfere with the data obtained by theenergy mode. CDE imaging has been used in the visualizationof the renal microvasculature (Bude et al., 1994), the detectionof hyperaemia in musculoskeletal disease (Newman et al.,1994), and the evaluation of muscle blood flow volume(Newman et al., 1997). In addition, this technique is useful inthe diagnosis of hepatocellular carcinoma (Lencioni et al.,1996), solid breast masses (Raza and Baum, 1997) and otherfields of internal medicine (Hamper et al., 1997). In the pastthree years, CDE imaging has been also used in obstetrics andgynaecology, with interesting results (Table I).

Ovary and CDE imaging

Angiogenesis and neovascularization

New blood vessel growth occurs during several physiologicalconditions in women, such as ovulation and corpus luteumdevelopment (Folkman and Shing, 1992). Angiogenesis isself-limiting in these conditions, but not in tumoralangiogenesis. Experimental studies suggest that thedevelopment of new blood vessels is necessary to sustain thegrowth, invasion and metastasis of tumours (Folkman, 1985;Folkman and Shing, 1992). Induction of angiogenesis ismediated by a number of angiogenic peptides such as vascularendothelial growth factor (VEGF) (Paley et al., 1997; Sowteret al., 1997) and platelet-derived endothelial cell growth factors

(PD-ECGF) which have similar structure and activity tothymidine phosphorylase (TP) (Hata et al., 1998b). These twofactors are associated with an increase in microvessel density(Nakanishi et al., 1997; Hata et al., 1998b). The newly formedvessels are large capillaries, or sinusoids, and do not containsmooth muscle in their walls but only fibrous connective tissue(Brustmann et al., 1997). Their basement membrane ismarkedly reduced, and their permeability is increased (Bloodand Zetter, 1990). For these reasons, the neoangiogeneticvessels have low impedance, as reflected by blood flowparameters.

Table I. Clinical applications of colour Doppler energy imaging inthe female reproductive tract and pregnancy

Ovarian stromal perfusion

Follicular perfusion

Corpus luteum perfusion

Ovarian cysts

Ovarian torsion

Pelvic inflammatory disease

Endometrial perfusion

Endometrial polyps

Tumours of cervix and corpus uteri

Intravillous flow

Placental vascularity

Fetal lung perfusion

Fetal brain vascularity

Three-dimensional power Doppler sonography

Echo-contrast agents

Conventional colour Doppler permits investigation ofvascularity, but detects microvascularization and bizarrevascular architecture and vessel location only poorly in smallstructures such as intratumoral vegetations. The highersensitivity of power Doppler compared with conventionalcolour Doppler has been confirmed (Park et al., 1998), withpower Doppler sonography reported as being statisticallysuperior to conventional colour Doppler sonography indisplaying tumour vascular distribution and microvessels.Furthermore, CDE imaging presents a high detection rate ofarterial flow in benign and malignant masses (Guerriero et al.,1998b,c). This contrasts with the low detection rate in benignmasses using conventional colour Doppler that can reducereproducibility in studies of tumoral perfusion. For the purposeof this review, a total of 33 articles published between 1992 and1998 was analysed (Hata, K. et al., 1992, 1998a; Kawai et al.,1992; Kurjak et al., 1992; Tekay and Jouppila, 1992; Weineret al., 1992; Hamper et al., 1993; Timor-Tritsch et al., 1993;Brown et al., 1994; Chou et al., 1994; Jain, 1994; Locci et al.,1994; Prompeler et al., 1994, 1996; Salem et al., 1994;Valentin et al., 1994; Wu et al., 1994; Carter et al., 1995; Malyet al., 1995; Stein et al., 1995; Tepper et al., 1995; Alcazaret al., 1996, 1997a; Anandakumar et al., 1996; Buy et al.,1996; Caruso et al., 1996; Rehn et al., 1996; Strigini et al.,

CDE imaging in the female reproductive tract 517

Figure 1. Mean (± SD) detection rate of arterial blood flow in benignovarian cysts in 33 articles published between 1992 and 1998 (seethe text for references).

Figure 2. The advantages of colour Doppler energy imaging in theevaluation of the ovarian vascularity.

1996; Emoto et al., 1997; Reles et al., 1997; Tailor et al., 1997;Alcazar and Jurado, 1998; Merce et al., 1998) in which thedetection rate is clearly reported (Figure 1). The mean detectionrate ranges from 54% in 1992 to 87% in 1993, though thestandard deviation was large and the overall mean (± SD)detection rate was 65 ± 21%. For these reasons, conventionalcolour Doppler does not appear to be accurate and reproduciblein detecting flow in the ovary. In contrast, CDE appears to be awell-established method in the evaluation of vessels withirregular course and low flow that characterizes the ovarianvascularity (Figure 2).

Stromal perfusion

Colour Doppler energy imaging is superior to conventionalcolour Doppler in detecting intra-ovarian vasculature. In onestudy (Crvenkovic and Platt, 1996), CDE imagingdemonstrated a diffuse ‘blush’ of almost the entire ovariancortex in 90% of ovaries, and in 36% of ovaries permittedvisualization of more vessels than did conventional Doppler.

The detection rate of the ovarian stromal vascularization hasbeen evaluated by different authors using conventional colourDoppler, and showed wide variability (Table II) (Aleem andPredanic, 1996; Lunenfeld et al., 1996; Agrawal et al., 1998;Vrtacnick-Bokal and Meden-Vrtovec, 1998). Using CDEimaging in a series of 221 ovaries (113 patients), we found ahigher detection rate, especially when the group of patientswith normal menstrual cycle was considered (Table II). Serumconcentrations of oestradiol have been considered to play animportant role as moderator of ovarian vascularity (Aleem andPredanic, 1996); however the increased ovarian vascularity ofpolycystic ovary (PCO) patients is unlikely to be caused onlyby oestradiol as its plasma levels are not raised in the earlyfollicular phase of these women. It was also demonstrated(Agrawal et al., 1998) that VEGF can be considered as animportant factor for the regulation of ovarian stromal bloodflow (Senger et al., 1983; Leung et al., 1989; Phillips et al.,1990; Shweiki et al., 1993; Dvorak et al., 1995; Kamat et al.,1995; Koos, 1995; Neulen et al., 1995; Gordon et al., 1996).VEGF not only mediates angiogenesis, but also inducesconnective tissue stromal growth by increasing microvascularpermeability (Kamat et al., 1995). Higher serum VEGFconcentrations and higher stromal blood flow in PCO patientsthan in women with normal ovaries, in addition to a positivecorrelation between VEGF concentrations and ovarian stromalblood flow velocities, have also been demonstrated (Agrawalet al., 1998).

Follicular perfusion

The development of ovarian follicles is accompanied by highlyactive angiogenesis. Ovarian granulosa cells produce VEGF(Laitinen et al., 1997; Yamamoto et al., 1997; Anasti et al.,1998), and follicular growth is accompanied by elevated levelsof messenger RNA for VEGF during the hours precedingovulation (Neeman et al., 1997). The angiogenic activitymediated by this growth factor is manifested in the peripheralblood vessels surrounding the follicle that show capillarysprouting and increased vascular permeability (Van Blerkomet al., 1997). Using conventional colour Doppler during theperiovulatory period, intrafollicular blood flow was visiblewhen the luteinizing hormone plasma concentration reached apeak (Collins et al., 1991). Peak systolic blood flow velocity ofthe dominant follicle rose significantly during the menstrualcycle, with no significant change in pulsatility index (Campbellet al., 1993; Tan et al., 1996). In addition, during the ovulatoryprocess there are prominent changes in the regional blood flowof the follicle, with a marked increase to the follicle base and aconcomitant decrease of flow to the apex (Brannstrom et al.,1998). In these studies, conventional colour Doppler was usedto assess follicular vascularity (Campbell et al., 1993), butattempts to quantify the vascularity would be limited by the factthat any flow at 90° would not be displayed.


Table II. Detection rate of ovarian stromal blood flow

Reference Method Detection rate (%) Method of ratecalculation

PCO patients Normal patientscalculation

Lunenfeld et al. (1996) CD – 9–30 Not specified

Aleem and Predanic (1996) CD 88 50 For ovary

Agrawal et al. (1998) CD 98.4 88.4 For patient

Vrtacnick-Bokal and CD 85 4.5 For patient

Meden-Vrtovec (1998) Our data CDE 92 85 For ovary

84 70 For patient

100 100 For patient

aThe authors did not specify if the patient was considered positive when blood flow was found in both (or at leastone) ovaries.bThe patient was considered positive when blood flow was found in both ovaries.cThe patient was considered positive when blood flow was found in at least one ovary.CDE = colour Doppler energy imaging; CD = conventional colour Doppler imaging.

The use of CDE imaging overcomes this problem. Afterpreliminary studies to identify a subjective system to scorefollicular vascularity using CDE imaging (Bhal et al., 1996,1997), the group at the University of Cardiff has established amethod to predict the treatment outcome in in-vitro fertilization(IVF) (Chui et al., 1997). The grading system consisted ofassessing the percentage of follicular circumference in whichflow was identified from a single cross-sectional slice. Theresults demonstrated that follicular vascularity grading wasindependent of follicular size and oocyte retrieval rate. Thefertilization rate seems to improve with increased vascularity,but this was not statistically significant. In contrast, poorfollicular blood flow was significantly associated with pooroutcome, and successful pregnancies occurred more frequentlyin those women with good blood flow. One of the possiblemechanisms involved is the activity of the cumulus/corona cellcomplex. Indeed, the failure of these cells to proliferate in vitrois associated with failed implantation (Gregory et al., 1994)and with the production of VEGF which has been implicated inneovascularization of the follicle and implantation site (Dissenet al., 1994). Recently, the same group (Gregory et al., 1998)found a strong relationship between follicular vascularity andthis cumulus activity in vitro. Future applications of thismethod in an IVF programme are, for example, the increase ofpregnancy by selecting for transfer those embryos derived fromfollicles with the highest grade of vascularization. In addition,and as suggested by the same authors (Chui et al., 1997), it maybe appropriate to counsel patients as to the advisability ofproceeding with oocyte collection in cycles where the follicularvascularity is universally poor. The same group proposed theuse of evaluation of follicular vascularity by CDE imaging(Pembridge et al., 1998) in order to aspirate those follicles withless vascularity, and also to retain only the three follicles withthe best vascularity in cycles of intrauterine inseminations withhigh risk of ovarian hyperstimulation and multiplepregnancies. In those cycles with selective follicular drainage,

the authors found a higher pregnancy rate, without risk ofcancellation due to hyperstimulation.

Corpus luteum perfusion

The corpus luteum undergoes profound neoangiogenesisduring its development, is dependent on vascular flow fornormal function, and exhibits degradation of the vascularsupply during regression (Pierson, 1998). A pronounced ringof vascularity (also called ‘ring of fire’) is typically observedupon colour flow Doppler (Figure 3). Indices of blood flowvelocity and impedance do not actually represent themicrovascular network of capillaries in the corpus luteum. Itwas reported (Bourne et al., 1996) that conventional colourDoppler was able to visualize vessels in the vascular bedaround the corpus luteum, but did not detect the small vesselsassociated with angiogenesis. Subsequently, neo-vascularization in the corpus luteum, and whether corpusluteum blood flow reflects luteal function, was alsoinvestigated (Miyazaki et al., 1998). These authors used CDEimaging to identify vascularity within the corpus luteum and toobserve sufficient of the vessel area to evaluatemicrovascularization. The area of vascularity appeared toincrease from the periovulatory stage to the mid-luteal phase,and then appeared to decrease until the start of menstruation(Miyazaki et al., 1998). The peak of flow–area ratio wasobserved 3–8 days before the start of menstruation, while theserum concentration of progesterone peaked 6–8 days beforethe start of menstruation. This discrepancy was also noted innon-human corpus luteum (Zheng et al., 1993; Miyazaki et al.,1998), in which prominent larger microvessels were observedduring the late luteal stage, despite the degeneration ofcapillaries associated with the breakdown of parenchymalluteal cells and consequent reduction in luteal function (Bruceand Moor, 1976; Niswender et al., 1976). While there was nocorrelation between the volume of corpus luteum or the


Figure 3. Typical perfusion of corpora lutea with conventional colour Doppler imaging (left) and with colour Doppler energy imaging (right)that shows a more accurate definition of vascular architecture.

Figure 4. The relationship between the intensity of colour Dopplerenergy signal and the presence of miscarriage.

flow–area ratio and the concentration of progesterone, thepattern of changes in the product of the flow–area ratio and thecorpus luteum volume compared with those in progesteroneconcentration was similar (Miyazaki et al., 1998). Theprogesterone concentration correlated positively with thisproduct which plateaued during the mid- to late luteal phase. Assuggested by the authors (Miyazaki et al., 1998), these findingsinfer that CDE imaging can detect physiological changes in theblood flow of the ovary in the luteal phase, and may be useful inthe evaluation of corpus luteum function.

The corpus luteum vascularization has been also studied inearly pregnancy by our group. Using this evaluation routinely,we found that there are several corpora lutea with poorvascularization in pregnancy. Thus, we investigated if corpusluteum with apparently poor vascularization (only three to fourspots of colour around the corpus luteum) was associated withhigher rate of miscarriage. Using CDE imaging to evaluate theintensity of CDE signal in the corpus luteum of 32 pregnantwomen from the 5th and 12th week, we found no correlationbetween intensity of CDE signal and miscarriage (Figure 4). Inthese vessels, resistance to vascular flow is usually low, but

Figure 5. The different points where the sample gate can be placed toevaluate the vessels of corpus luteum (right) and the proximal thecalarteriole (left).

studies of luteal development have been based on the pulsatilityand resistance indices at random points in the structure, oftenwithout regard for the anatomy of the gland (Parsons, 1996).The characterization of glandular dynamics based on thesemeasurements is difficult to reproduce because of the presenceof vessels with different impedances and variable indices andpeak systolic velocities. It was reported earlier (Zalud et al.,1994) that the flow in the corpus luteum remains unchangeduntil 12th week of pregnancy, while production ofprogesterone by corpus luteum decreases after the 8th week, atthe moment of placental shift. For these reasons, luteal flow isnot correlated with progesterone production. As proposed by apreliminary study (Parsons, 1996), we investigated a vessel asthe proximal thecal arteriole that can be easily identified byCDE imaging and reproducible peak systolic velocity obtainedby pulsed Doppler (Figure 5). This vessel is responsible for


Figure 6. Different types of Doppler waveform at the level of the corpus luteum (right) and proximal thecal arteriole (left).

feeding to the corpus luteum, and is characterized by high flow(Figure 6) with higher peak systolic velocity (PSV). In apopulation of 32 pregnant women from the 5th and 12th week,we investigated the PSV in this artery and plasmaconcentrations of progesterone. Among women with ongoingpregnancies (n = 23), the PSV decreased from the 6th to the8th week, as did progesterone concentrations (Figure 7). Afterthis time, the PSV remained similar, and the progesteroneplasma concentrations increased as a result of placentalproduction. From the 5th to 7th weeks, in women with viablepregnancies, the correlation between PSV of the proximalthecal arteriole and progesterone plasma concentrations,using a second-order polynomial regression, obeyed theequation: –61.217 +7.1[Progesterone plasma concentration]– 0.108 [PSV]2; R = 0.732; P <0.05. During these weeks thePSV in the proximal thecal arteriole was lower in patients withmiscarriage (n = 9) (Figure 8). The proximal thecal arteriolecan be proposed to investigate early pregnancy loss andpremature luteal regression before the 8th week of pregnancy.For these reasons, we suggest further investigations in theevaluation of late luteal phase, and to detect pregnancy before amissed menses. Another field of application of CDE imagingmight be the early diagnosis of adnexal torsion. Several studieshave investigated the role of conventional colour Doppler todetect the viability of adnexal torsion (Chang et al., 1998; Leeet al., 1998). As yet, however, although the higher sensitivity toflow of CDE imaging might be useful (at least potentially), nostudies have been published in this respect.

Endometriotic cysts

In a previous study, we demonstrated that B-mode transvaginalsonography has a sensitivity of 75% and a specificity of 90% inthe diagnosis of endometriomas (Mais et al., 1993). Inaddition, the association with CA125 and CA 19.9 does notseem to improve the accuracy of B-mode (Guerriero et al.,1996a,b), and colour Doppler imaging may be an interesting

Figure 7. The relationship between peak systolic velocity in theproximal thecal arteriole and plasma progesterone concentrations inearly pregnancy. PSV = peak systolic velocity; P = progesterone.

Figure 8. Peak systolic velocity of the proximal thecal arteriole be-fore 8 weeks in ongoing and non-viable pregnancies.

technique to improve the results of B-mode further. Only twostudies have evaluated the specificity and sensitivity oftransvaginal colour Doppler in the differential diagnosis of this


type of cyst from other adnexal masses (Kurjak and Kupesic,1994; Alcazar et al., 1997b), though with controversial results.Otherwise, several authors (Tekay and Jouppila, 1992, 1995;Timor-Tritsch et al., 1993; Chou et al., 1994; Aleem et al.,1995; Anandakumar et al., 1996) have reported a wide range ofdetection rates for arterial blood flow in endometriomas. Forthe purpose of this review, we analysed eight articles in whichthe detection rate was clearly reported, the mean being 71%(range 44–88%). This important bias about the vascularity ofthese benign adnexal masses may interfere with thepreoperative diagnosis, thus reducing the reproducibility of thestudies (Kurjak, 1995).

Our group studied the role of CDE imaging in differentiatingendometriomas from other adnexal masses in premenopausal,non-pregnant women (Guerriero et al., 1998b). In this study,170 consecutive persistent adnexal masses were submitted toB-mode transvaginal ultrasonography associated with CDEimaging evaluation and CA125 plasma concentrationmeasurement before surgery (Guerriero et al., 1998b). Usingthis approach, we found CDE imaging evaluation to have betteraccuracy in the diagnosis of endometriomas when comparedB-mode ultrasonography alone, with a specificity of 97% andsensitivity of 90% (Guerriero et al., 1998b). In addition, thisstudy confirmed the high detection rate (98%) of arterial flowusing CDE imaging, but an extensive overlap of values ofpulsatility index (PI) and resistance index (RI) betweenendometrioma and other benign adnexal masses (Guerrieroet al., 1998b), as shown previously by others (Kurjak andKupesic, 1994; Aleem et al., 1995; Alcazar et al., 1997b).

The CDE imaging study of the localization of vesselsassociated with the evaluation of the intensity of arterial flowpermits the exclusion of hypoechoic masses with ‘richvascularization’ which are frequently associated with thepresence of corpus luteum cysts or mucinous cystadenoma.Otherwise, the use of this method as a secondary test permitsdifferentiation of atypical endometriomas, in which no flow isdetected in the echogenic portion due to the presence of a clot,from an intracystic vegetation. As derived by logisticregression, when CDE imaging evaluation is positive and thevalue of CA 125 is >25 U/ml, the probability of the presence ofan endometrioma is high (95.6%), and medical treatmentsshould be excluded (Guerriero et al., 1998b). In contrast, theabsence of these ultrasonographic and biochemical factorsreduces the possibility of the presence of ovarianendometrioma to 1.4% (Guerriero et al., 1998b). Thesepatients, in the absence of pelvic pain or suspect findings ofovarian cancer and dermoid cysts, can postpone operativelaparoscopy with a longer follow-up in order to reduce furtherthe risk of unnecessary surgery due to functional cysts.

Ovarian cancer

The majority of published studies on ovarian vascularity are inagreement that malignant ovarian tumours—in comparison

with benign ovarian tumours—have a lower impedance, withlow PI and RI values. The considerable overlap between theranges of PI from benign and malignant tumours was firstreported in 1991 (Fleischer et al., 1991), and has since beenconfirmed by others (Buy et al., 1996; Prompeler et al., 1996;Rehn et al., 1996; Strigini et al., 1996; Tekay and Jouppila,1996; Valentin, 1997). With the aim of improving the accuracyof transvaginal colour Doppler in the diagnosis of adnexalmasses, an additional parameter was proposed as vessellocation (Fleischer et al., 1993), whereupon benign tumourswere found to be vascularized more often in the periphery,while malignant tumours had centrally located vessels. A newapproach based on the location of vessels was proposed (Buyet al., 1996). Using this method, the presence of colour flow inan echogenic portion classified as indeterminate or malignantby B-mode indicated malignancy, while the absence of colourflow in this echogenic portion indicated that the tumour waslikely to be benign.

As previously discussed, conflicting reports exist in theliterature regarding the proportion of benign ovarian tumoursthat have arterial blood flow detectable by conventional colourDoppler imaging (Figure 1). Our group used a similar approachto that cited earlier (Buy et al., 1996) but with CDE, the aimbeing to improve the low detection rate of blood flow in benignmasses, and to increase reproducibility (Guerriero et al.,1998c). In this study, intratumoral arterial blood flow wasreadily detected by CDE imaging in all malignant tumours, andin 94% of benign tumours (Guerriero et al., 1998c). Thecombined use of transvaginal ultrasonography and CDEimaging was associated with a significantly higher specificityin comparison with transvaginal ultrasonography alone. Asshown previously by others (Buy et al., 1996; Prompeler et al.,1996; Rehn et al., 1996; Strigini et al., 1996; Tekay andJouppila, 1996; Valentin, 1997), our study confirmed thepresence of an overlap in values of RI and PI between benignand malignant masses, and the limited diagnostic value ofspectral Doppler analysis with whatever cut-off value.

In our opinion, CDE imaging should be considered only as apredictive ‘secondary test’ because the B-mode appearanceshould be considered first. As a matter of fact, many benignlesions such as serous cyst, endometriomas or dermoid cystsare easily identified because of their characteristic B-modefindings (Mais et al., 1993, 1995; Guerriero et al., 1996a,b,1997a–d, 1998a–c) (Figure 9). In contrast, in atypicalcases—or where findings are questioned—the use of CDEimaging to evaluate vessel distribution can increase diagnosticaccuracy (Figure 9). Besides, the diagnostic accuracy of thistest was found to depend on menopausal status. In fact, inpremenopausal women diagnostic accuracy was always lowerthan in postmenopausal ones, probably because of the highernumber of false positives associated with a lower incidence ofmalignancies in the premenopausal population (Guerrieroet al., 1998c).


Figure 9. A proposed flow chart using colour Doppler energy imaging(CDE) for the evaluation of vessel location in the prelaparoscopicmanagement of adnexal masses.

Recently, systematic differences in the analysis of bloodflow velocity waveforms derived by colour Doppler imagingand CDE imaging of corpora lutea and adnexal tumours wereinvestigated (Tailor et al., 1998). These authors found thatCDE has a minimal and not significant tendency to performbetter than colour Doppler imaging for all investigated bloodflow indices such as PI and RI. These findings may beexplained by the better ability of CDE to distinguish betweenthe low impedance blood flow of new blood vessels and that ofnormally formed distal vasculature. These authors concludedthat examinations with colour Doppler imaging appear to bemore reproducible in terms of flow velocity waveform analysisthan CDE imaging. In our opinion, a bias is present in thisarticle in that CDE imaging was used only for the placement ofsample volumes, as this was the aim of the study (Tailor et al.,1998). In contrast, the best potential of CDE imaging is theability to describe the morphology of vascularity, and thepresence or absence of flow with good reliability. Only if usedwith this aim can CDE imaging increase our knowledge on theperfusion of ovarian masses with greater accuracy than mightconventional colour Doppler.

With the morphological approach described previously,CDE imaging may suggest the presence of a Krukenbergtumour when it shows a relatively prominent vascular signalalong the wall of well-demarcated intramural cysts in a solidovarian mass (Cho et al., 1998). In future, improvements in thediagnostic accuracy of CDE imaging will be achieved byquantifying tumour vascularity (Meyerowitz et al., 1996) andby increasing the detection of small vessels, using anecho-enhancing contrast medium (Suren et al., 1994).

Other applications of CDE imaging ingynaecology

The use of CDE imaging has been suggested in many otherfields of gynaecology, including a role in depicting soft-tissuehyperaemia in endometriosis and other pelvic inflammatoryconditions (Papadimitriou et al., 1996). Soft-tissue hyperaemiawas seen in 22 of 33 symptomatic patients, and CDE imagingdemonstrated a diffused ‘blush’ of almost the entire or theentire symptomatic sites, with a specificity of 52% and asensitivity of 47%. CDE imaging seems able to depicthyperperfusion in many cases associated with pelvicinflammatory disease. Recently, two studies (Jakab et al.,1998; Yap et al., 1998) were performed on normal andabnormal endometrium. Unfortunately, one study (Yap et al.,1998) on endometrial perfusion and IVF and embryo transferdid not find any correlation between CDE imaging of theendometrium and pregnancy outcome. These authors did notevaluate the perfusion with quantitative or semi-quantitativemethods, but only with pulsatility indices of theendometrial/myometrial junction. In this study, CDE imagingwas used only for placement of sample volume, as previousauthors (Tailor et al., 1998) and in our opinion this explains theabsence of any correlation. The power of CDE imaging lies inthe possibility of describing perfusion in a qualitative,quantitative or semi-quantitative manner. Using the evaluationof vessel architecture, CDE imaging was found to be highlyeffective in detecting focal lesions as endometrial polyps byvisualization of feeding vessels (Jakab et al., 1998). The overalldetection rate of 79 polyps included in the study was 47% usingB-mode, and this increased to 77% with CDE imaging. CDEimaging can be also useful in evaluating the presence oftortuous small vessels, as in cases of adenoma malignum of theuterine cervix (Umesaki et al., 1998), uterine sarcoma (Saseet al., 1996) or cervical cancer (Cheng et al., 1999) (Figure 10).Angiogenesis in 35 cervical cancers was examined usingpower Doppler ultrasound and a quantitative image processingsystem (Cheng et al., 1999); results showed that the assessmentof intratumoral vascularity index by power Doppler showedbetter correlation with tumour stage and size, depth of stromalinvasions and pelvic lymph node metastases than intratumoralRI. Finally, CDE imaging has been suggested for theinvestigation of uterine and ovarian perfusion inpostmenopausal women (Zalud et al., 1996). Intrauterineperfusion was visualized in 85% of patients with the powerDoppler technique, but in only 30% with conventional colourDoppler. Moreover, at the same settings power Dopplershowed more colour flow areas representing intrauterineperfusion when compared with conventional colour Doppler(Zalud et al., 1996). Intra-ovarian perfusion was detected inonly 10% of cases with conventional colour Doppler, but in35% of cases with power Doppler.


Figure 10. A tortuous vessel present in a cervical cancer visualized by conventional colour Doppler imaging (left) and by colour Doppler energyimaging (right) that more accurately defines a longer segment of the vessel.

Figure 11. Pre-injection colour Doppler energy imaging of a normal, poorly vascularized placenta (left). The post-injection image (right) showsthe appearance of vessels not previously visualized before injection of echo-contrast agent.

Three-dimensional power Dopplersonography

Further information on angiogenesis can be obtained bythree-dimensional (3D) views of the vascular architecture. Thecontinual changes in colour with direction and velocity, whethertrue or aliased, make conventional colour Doppler 3D picturesdifficult to obtain and to evaluate (Downey and Fenster, 1995;Ohishi et al., 1998). However, using power mode, longersegments of vessels can be visualized continuously, thus makingvascular anatomy easier to track (Downey and Fenster, 1995;Ohishi et al., 1998). Until now, 3D colour power Doppler hasbeen used not only to investigate the vasculature in the cervix, butalso in endometrial and ovarian carcinomas. An investigation ofthe microvasculature within the cervix was performed in benignand pathological conditions (Suren et al., 1998). In normalcervical tissue, power Doppler revealed some small vessels in the

myometrium, whereas no colour-coded areas appeared in thesubmucosal layer. However, 3D power Doppler displays a totallynew view of vascular architecture in pathological conditions. Inthe case of inflammation, 3D power Doppler reveals the arterialblood supply of the submucosal layer spreading into an arterialspiral of vessels running down to the portio, without alteration ofthe vessel architecture (Suren et al., 1998). By comparison,cervical cancer leads to an alteration of the normal echotexture ofthe cervix, and 3D power Doppler clearly shows a chaoticnetwork with tortuous vessels traversing the tumour mass (Surenet al., 1998).

This new technique was proposed for the staging ofendometrial carcinoma (Kupesic and Kurjak, 1998). In thisstudy, 3D power Doppler demonstrated a sensitivity of 100%and a specificity of 94.4% for deep invasion, with a positivepredictive value of 83.3% and a negative predictive value of


100%. The same authors investigated ovarian tumour vascularityusing 3D colour power Doppler (Kurjak et al., 1998); this modewas able to depict the mesovarium vessels entering the hilumarea, and extending to the stroma, with gradually increasingnumbers and branches of fine vessels during the preovulatoryphase. In the luteal cysts, the vessels are usually fewer in numberand seldom have complicated branching or encircling of the cyst(Kurjak et al., 1998). Chocolate cysts and dermoid cysts werecharacterized by vessels being usually straight, regularlybranching, and deriving from a hilar vessel presenting along thesurface of the tumour. In contrast, the tumour vessels of amalignant neoplasm were usually randomly dispersed within thestroma and periphery, with areas of arteriovenous shunts, stenosisand tumoral ‘lake’ (Kurjak et al., 1998). The 3D display permitsthe physician to visualize the many overlapping vessels easilyand quickly, and to assess their relationship with other vessels orsurrounding tissues, and thus creates a better understanding of the3D architecture of the microcirculation (Kurjak et al., 1998).

Recently, studies have been performed to quantify theperfusion using 3D power Doppler sonography (Pairleitneret al., 1997; Pairleitner and Steiner, 1998). Quantification ofvascularization and estimation of blood flow was done bycreated indices. Preliminary observations suggest that therelationship between flow intensity and vessel density seems tobe higher in malignant than in benign tumours (Pairleitneret al., 1997; Pairleitner and Steiner, 1998). Contrast agents areanother possibility for enhancing the 3D colour power Dopplerexaminations by increasing the detection rate of small vessels.Recently, 3D colour power Doppler has been used to carry outpuncturing procedures of ovarian follicles more accurately.Indeed, this technique has been used to create a pronouncedvisualization of the needle in colour, and may be useful not onlyin oncology and surgery but also in prenatal and fetal medicine(Feichtinger, 1998).

CDE imaging in pregnancy

Because of its great sensitivity, CDE imaging provides theability to improve visualization of blood flow in very smallvessels with slow blood flow velocity, usually a characteristicof placental tissues. In the fetus, low perfusion states exist, andobtaining standard anatomic views or controlling the angle ofthe ultrasonographic beam can be difficult because of theposition of the fetus (Fortunato, 1996; Hartung et al., 1997).For these reasons, CDE imaging should be of particular benefitwhen examining several aspects of pregnancy. Only a fewstudies have been performed in early pregnancy, and only verypreliminary results on intravillous flow have been reported(Cacciatore, 1996; Simpson et al., 1997). In intrauterinepregnancies, a persistent and well-vascularized area was foundwithin the endometrium, even before visualization of thegestation sac (Cacciatore, 1996). A major field of application ofCDE imaging in pregnancy might be evaluation of theplacenta. Many studies have been made of the role of CDE

imaging in placental anomalies such as placenta accreta or vasaprevia (Chou and Ho, 1997; Levine et al., 1997; Sauerbrei andDavies, 1998). The use of CDE imaging was described for theantenatal diagnosis of placenta previa accreta (Chou and Ho,1997). In this case report, CDE imaging appeared to delineatemore abnormal individual vessels over longer lengths, and todisplay a perfused region of extensive anomalous placentalvascular supply, with greater vascular arborization patternsthan conventional colour Doppler imaging. Recently, CDEimaging was used to study the placental vasculature inmonochorionic twins and to predict twin-to-twin transfusionsyndrome (Denbow et al., 1998). These authors found CDEimaging to have a sensitivity of 92% and a specificity of 71% inthis type of diagnosis, and was able to detect with highsensitivity haemodynamically compensatory arterioarterialanastomoses that were found absent in twin-to-twin transfusionsyndrome (Denbow et al., 1998).

CDE imaging appears also to have a role in post-partumevaluation. It was found that, on the 25th post-partum day,CDE imaging could be used to detect placental tissue retainedafter delivery (Kanaoka et al., 1998). A placental polyp wassuspected when an abundant blood supply was visualized bypower Doppler imaging in an intrauterine polypoid mass in apatient with elevated serum human chorionic gonadotrophin.CDE imaging can also be used to evaluate the effects of drugson placental perfusion; for example, enhancement of theplacenta after dehydroepiandrosterone sulphate injection waseasily depicted with power Doppler imaging in pregnancy atterm (Hata et al., 1998c). This technique may be useful whenattempting to assess fetoplacental function in normal andhigh-risk pregnancies (Hata et al., 1998c), and may improvethe diagnosis of uteroplacental insufficiency, placental infarctsand compromised placental flow in abruption. Moreover, thevasodilative effect of dehydroepiandrosterone sulphate may bebeneficial as a new therapeutic agent in high-risk pregnancywith decreased uteroplacental blood flow.

Another tissue capable of undergoing modification ofperfusion by the administration of drugs is the fetal lung. Tissueblood flow in the fetal lung was evaluated before and afteradministration of betamethasone (Dubiel et al., 1997b). In thisstudy, a computer-analysed CDE signal, used to quantify lungperfusion, indicated an increased tissue blood flow in the fetallung after maternal corticosteroid treatment. This increasedperfusion was associated with lower interleukin-6 andC-reactive protein concentrations as markers of inflammationand tissue insult (Dubiel et al., 1998). CDE imaging may alsobe useful in the prediction of pulmonary hypoplasia in ahigh-risk population. Indeed, visualization of the fetalpulmonary vascularization using CDE imaging permitted theabsence of severe pulmonary hypoplasia to be predicted (Rothet al., 1998).

Because of its properties, CDE imaging might also be useful insome investigations which are difficult to perform byconventional methods, for example transvaginal evaluation of


fetal brain vessels (Pooh and Aono, 1996; Guerriero et al.,1997b; Pilu et al., 1998). The CDE imaging evaluation is able toassess normal vascularization of the brain (Pooh and Aono,1996), and have a specific role in the diagnosis of intracranialhaemorrhage (Guerriero et al., 1997b) and microcephaly (Piluet al., 1998). In case of haemorrhagic lesions, CDE imaging canhelp to confirm correctly the absence of flow within and aroundthe lesion, and also to demonstrate the absence of normalvascularity within the damaged ventricular system (Guerrieroet al., 1997b). In addition, the technique can identify normalperfusion of the contralateral ventricular system which, if present,could improve outcome in less severe cases (Guerriero et al.,1997b). CDE imaging can also be used to investigate very smallvessels that are visualized only by conventional colour Doppler,such as in fetal thyroid vascularity and splenic perfusion (Dubielet al., 1997a; Nores et al., 1997); the latter condition increaseswith gestational age in normal pregnancy and seems to increasein high-risk pregnancies. Other applications of CDE imaging,also performed by conventional colour Doppler with success,include fetal echocardiography (Chua and Twining, 1997;Brocks et al., 1998), detection of renal arteries in pregnanciescomplicated by oligohydramnios (Laifer-Naron et al., 1998), andthe diagnosis of meconium peritonitis (Tseng et al., 1997) andsacrococcygeal teratoma (Fox et al., 1996).

Future applications of 3D power Doppler include imaging inpregnancies with abnormal umbilical arteries and veins (Chaouiet al., 1998), and the assessment of placental vasculature(Pretorious et al., 1998). Additional knowledge can be derivedfrom using echo-enhancing effects of ultrasound contrastmedium in pregnancy (Schmiedl et al., 1998; Simpson et al.,1998). Until now, no reports have been made regarding the use ofecho-enhancing agents in human pregnancy, as the teratogeniceffect of these contrast media has not been evaluated. We injectedan ultrasound contrast agent (Levovist; Schering AG, Berlin,Germany) into a pregnant women who had requested terminationof pregnancy for the presence of a fetus with trisomy 13 andmultiple severe malformations. After informed parentalcounselling, a solution of 12.5 ml of Levovist (200 mg/ml) wasinjected into the brachial vein. Pre-injection CDE imagingshowed a normal, poorly vascularized placenta (Figure 11). Bycontrast, the post-injection image showed a strong increase inDoppler information, with the appearance of vessels that werenot visible before injection (Figure 11). Thus, the use ofultrasound contrast medium may open new frontiers in theinvestigation of very low perfusion states where the presence offlow cannot detected by conventional methods.

Conclusions

CDE imaging has a fundamental role in the evaluation ofstromal vasculature in both normal and polycystic ovaries. Byusing the technique, the quantification of perfusion(Meyerowitz et al., 1996; Dubiel et al., 1997b; Nilsson et al.,1997; Cheng et al., 1999) that will be available routinely in

future should increase our knowledge of polycystic ovaries andbetter explain the relationship with VEGF. In addition, thecorrelation between follicular vascularity and oocyte quality isa reality that should be used in the clinical practice of eachassisted reproductive team to increase pregnancy rates. Studieson corpus luteum neovascularization, and findings on theperfusion of thecal arterioles, require further investigations,notably if visualization of the ‘ring of fire’ is entering into theclinical evaluation of the luteal phase and early pregnancy. Onthe basis of its increased sensitivity in evaluating vesseldistribution when compared with conventional colour Dopplerultrasound, CDE imaging has a crucial role in differentiatingamong ovarian masses. Moreover, CDE imaging has a specificrole in pregnancy in investigating low-flow states, andespecially when optimal Doppler angles cannot be obtained, asin the fetal brain. Three-dimensional power Dopplersonography and the use of ultrasound contrast medium aredeveloping into an exciting field of application of CDEimaging technology.

In future, the evaluation of vascular architecture, combinedwith an objective quantitation of perfusion, represents a newfrontier in monitoring the female reproductive tract andpregnancy. In addition, the absence of aliasing, the increasedsensitivity, and the angle-independence of CDE imagingrequire less operator experience and training, as well as areduction in examination time. Indeed, CDE imaging picturesare more descriptive and more easily understood by traineesbecause a better continuity of tortuous vessels, as well as moreindividual vessels, can be visualized than with conventionalcolour Doppler imaging. In our opinion, when information onflow direction is not critical, conventional colour Doppler canbe replaced by CDE imaging, which appears to be the besttechnique not only for describing microvascular architecture,but also for determining the presence or absence of flow.

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Received on January 14, 1999; accepted on May 13, 1999

clinical applications of colour doppler energy imaging in the female

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