Semiquantitative classification of ductus venosus blood flow patterns

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1 Ultrsound Obstet Gynecol 2014; 43: Published online in Wiley Online Librry (wileyonlinelibrry.com). DOI: /uog emiquntittive clssifiction of ductus venosus blood flow ptterns O. M. TURAN,. TURAN, L. ANAPO, J. I. ROENBLOOM nd A. A. BACHAT Deprtment of Obstetrics, Gynecology nd Reproductive ciences, University of Mrylnd, Bltimore, MD, UA KEYWORD: tril systole; crdic cycle; velocity rtio; ventriculr relxtion; wveform ABTRACT Objectives To identify the rnge of wveform bnormlities in the ductus venosus (DV) chrcterized by their timing in the crdic cycle nd to evlute if they cn be ctegorized into distinct ptterns. Methods DV velocity rtios were clculted from pek velocities during ventriculr systole (), endsystolic ventriculr relxtion (v), erly distole (D) nd tril systole () (/v, /D, v/d, /, v/ nd D/ rtios). The rtios were converted to their Z- scores nd elevtion > 2 D ws ssigned s bnorml. Combintions of rtio bnormlities were grouped to define distinct wveform ptterns nd their distribution ws relted to the clinicl presenttion. Results Five-hundred nd forty-two bnorml DV wveforms fell into three principl ptterns. In Pttern 1 only the -wve-relted rtios were bnorml (180, 33.2%), in Pttern 2 the v/d rtio ws bnorml (143, 26.3%) nd in Pttern 3 combintions of -wve bnormlities in the presence of norml v/d rtio were norml (94, 17.3%). Conclusions Interprettion of venous wveform ptterns is complex becuse the multiphsic wveforms reflect events in the crdic cycle tht my be differentilly ffected by clinicl pthology. We sought to present clssifiction for the DV flow profile tht chrcterizes bnorml flow confined to tril systole nd occurs during ventriculr relxtion or during holodistole. Further reserch is wrrnted to determine the significnce of these ptterns in specific fetl conditions. Copyright 2013 IUOG. Published by John Wiley & ons Ltd. INTRODUCTION The chnges in pressure nd volume sttus in the hert chmbers during the crdic cycle re responsible for the fluctutions in venous ntegrde blood flow. Typiclly, forwrd flow ccelertes during ventriculr systole nd erly distole (- nd D-wves, respectively) nd shows reltive decelertion during end-systolic ventriculr relxtion nd tril systole (v- nd -wves, respectively, Figure 1). The potentil reltionship between chnges in these velocities nd crdic sttus provides the bsis for using venous Doppler indices in fetl crdiovsculr ssessment 1. However, semiquntittive ductus venosus (DV) Doppler indices, such s the pulstility index for veins (PIV), give n incomplete reflection of crdic function becuse reltive chnges in v- nd D-wve velocities re not well reflected 2,3. Accordingly, bnorml venous wveform ptterns tht originte in phses of the crdic cycle other thn tril systole, which is well recognized in dult medicine, hve not been fully chrcterized in fetl medicine when the PIV is used for wveform nlysis 4,5. In ddition, n bnorml DV flow pttern not only reflects crdic dysfunction but lso gives informtion on prelod nd fterlod resistnce. The recognition of distinct venous wveform ptterns could open new possibilities for qulittive wveform nlysis nd potentilly provide better understnding of fetl crdiovsculr physiology 6. We hve recently derived reference rnges for DV phsic velocity rtios in lrge cohort of norml fetuses 7.We generted nomogrms for /v, /D, v/d, /, v/ nd D/ rtios from 11 to 17 weeks nd from 18 to 38 weeks. Three of these rtios relte consecutive crdic events: the /v rtio quntifies reltive forwrd flow into the tri s the ventricle relxes prior to the opening of the AV vlves; the v/d rtio reflects the erly distolic filling immeditely therefter; nd the D/ rtio is distolic prmeter tht reltes to the mgnitude of forwrd flow during pssive nd ctive distolic filling. Three rtios relte non-consecutive crdic events: the /D rtio quntifies ventriculr systolic to erly pssive distolic filling 8 ;the Correspondence to: Dr A. A. Bscht, Deprtment of Obstetrics, Gynecology nd Reproductive ciences, University of Mrylnd, Bltimore, 22 outh Greene treet, 6 th floor, Room 6NE12, Bltimore, MD 21201, UA (e-mil: bscht@hotmil.com) Accepted: 2 eptember 2013 Copyright 2013 IUOG. Published by John Wiley & ons Ltd. ORIGINAL PAPER

2 Ductus venosus wveform ptterns 509 () v D Figure 1 Mesurement of velocities on norml ductus venosus velocity wveform. () chemtic description. (b) Doppler ultrsound. The blue shded tringle depicts the reltionship between v- nd D-wves (i.e. the v/d rtio)., tril systole; D, erly distole;, ventriculr systole; v, end-systolic ventriculr relxtion. / rtio quntifies ventriculr systolic to ctive distolic filling 9 ; nd the v/ rtio quntifies lte systolic to lte distolic filling. These rtios llow quntifiction of wveform bnormlities during ll phses of the wveform, therefore providing the possibility to determine if there re different wveform ptterns tht contribute to n bnorml PIV. The im of this study ws to test the hypothesis tht severl ptterns of DV wveform bnormlities exist in fetuses with n elevted PIV. METHOD This ws retrospective study of pregnncies tht hd DV Doppler evlution in the context of clinicl mngement t our Fetl Medicine Unit between 2006 nd This period ws selected becuse ll exmintions were performed ccording to prospectively defined stndrd with low inter- nd introbserver vribility for mesurement of the DV-PIV 2,3,7. All ultrsound exmintions were performed trnsbdominlly by registered medicl dignostic sonogrphers or fetl medicine specilists, using the Voluson 750 nd E8 (GE Helthcre, Wuwtos, WI, UA) or the iemens equoi 512 (iemens Helthcre, Erlngen, Germny) equipped with 4 8-MHz trnsbdominl probes. For the purpose of this study, DV wveforms tht hd n elevted PIV of > 2 D were selected from our fetl medicine dtbse. Imges tht met the criteri of previously mentioned stndrd exmintion rules were used for the nlysis. Pek velocities of -, D-, v- nd -wves, in cm/s, were mesured from good-qulity wveforms tht exhibited high signl-to-noise rtio nd were rounded up or down to the nerest bsolute number. The following mthemticl method ws used to express the impct of bsent nd reversed -wve velocities in sttisticl clcultions: bsent -wve ws expressed s 1 cm/s, which is the nerest bsolute number close to zero. Exmple: = 50 cm/s nd -wve= 0; when ressigned the vlue of 1 cm/s, the / rtio = 50/1 = 50. If the -wve ws negtive, the ctul number of the -wve ws dded to the ctul number of, v, nd D divided by 1. Exmple: = 50 cm/s, v = 30 cm/s, D = 40 cm/s nd -wve = 10 cm/s. The / rtio = ( )/1 = 60, the v/ rtio = ( )/1 = 40 nd the D/ rtio = ( )/1 = 50. This conversion ws necessry becuse pek blood-flow velocities, rther thn velocity integrls, were used. The clcultion negtes the mthemticl impct of negtive velocity, voids division by 0 nd yields continuously incresing number tht is proportionl to the degree of -wve bnormlity. Using the previously estblished velocity reference rtios, the individul components of the DV rtios (/v, /D, v/d, /, v/ nd D/) were converted to their Z-scores to exclude the effect of gesttionl ge 7. /v, /D, /, v/ nd D/ rtios > 2 D of the velocity rtio Z-scores nd v/d < 2 D were ssigned s bnorml. Any bnorml /, v/ or D/ rtio ws clssified s n bnorml -wve-relted rtio. Wveform ptterns were defined by the combintion of velocity rtio bnormlities in one wveform, which corresponds to one crdic cycle. The reltive distribution of individul rtio bnormlities nd the ptterns mong the different fetl conditions were evluted ccording to the stndrdized residuls derived from the chi-squre nlysis. P 21.0 (P Co., Chicgo, IL, UA) nd Excel (Microsoft, 2010; Microsoft Corp., nt Ros, CA, UA) were used for nlysis. Normlity of the continuous vribles ws checked using the hpiro Wilk test. The Mnn Whitney U-test ws used for comprison of continuous vribles. Ctegoricl vribles were nlyzed using chi-squre nd Fisher s exct tests. Adjusted P < ws considered s sttisticlly significnt. The study protocol ws pproved by the Institutionl Review Bord of the University of Mrylnd. REULT A totl of 542 bnorml DV wveforms from 232 fetuses were evluted. The mjority of ptients were evluted for twin twin trnsfusion syndrome (TTT) nd fetl growth restriction (FGR). The clinicl brekdown of the fetl conditions is presented in Tble 1. In 24 (4% of ll exmintions with elevted DV-PIV), the velocity rtios were within the norml rnge. The -wve ws bsent or reversed (DV-RAV) in 172 (32%) exmintions. Individully, /v, /D, v/d nd -wve-relted rtios were bnorml in 288 (53%), 108 (20%), 242 (45%) nd 518 (96%) of the exmintions, respectively. The distribution of individul rtio bnormlities strtified by fetl disese is presented in Tble 2. When the combintion of velocity rtio bnormlities in one crdic cycle ws considered, three principl wveform ptterns were identified. In 180 (33%) exmintions, only the -wve-relted rtios were bnorml, indicting tht the lte distolic events contributed to the bnorml PIV. In 143 (26%), the v/d rtio ws bnorml, thereby identifying ventriculr relxtion s the phse contributing to the bnorml PIV. In 94 (17%), -wve bnormlities were combined with bnormlities of the /v nd /D rtios, but the v/d rtio remined norml, indicting tht reltive forwrd flow during ventriculr relxtion ws unchnged. These ptterns were designted s follows: Pttern 1, isolted Copyright 2013 IUOG. Published by John Wiley & ons Ltd. Ultrsound Obstet Gynecol 2014; 43:

3 510 Turn et l. Tble 1 Chrcteristics of study popultion Fetl condition Fetuses (n) Exmintions (n) Gesttionl ge (weeks) PIV Z-score Absent/reversed -wve Right-sided hert defect ( ) 7.7 ( ) 20 (69) Immune/non-immune hydrops ( ) 3.8 ( ) 7 (35) TTT recipient ( ) 4.4 ( ) 94 (39) tges I & II ( ) 2.6 ( ) 0 tge III ( ) 4.2 ( ) 66 (47) tge IV ( ) 6.6 ( ) 28 (85) TTT donor ( ) 3.4 ( ) 31 (19) tges I & II ( ) 3.0 ( ) 0 tges III & IV ( ) 3.6 ( ) 31 (46) Fetl growth restriction ( ) 3.6 ( ) 20 (22) Vlues re given s n, n (%) or medin (minimum mximum). PIV, pulstility index for veins; TTT, twin twin trnsfusion syndrome. Tble 2 Distribution of velocity rtios ccording to fetl disese Fetl condition Exmintions (n) /v /D v/d -wve-relted Right-sided hert defect (59) 14 (48) 11 (38) 29 (100) Immune/non-immune hydrops (65) 6 (30) 9 (45) 19 (95) TTT recipient (47) 60 (25) 78 (33) 224 (93) tges I & II (23) 11 (17) 9 (14) 57 (86) tge III (55) 36 (26) 55 (39) 135 (96) tge IV (61) 13 (39) 14 (42) 32 (97) TTT donor (70) 11 (7) 95 (59) 142 (89) tges I & II (48) 5 (5) 48 (52) 82 (89) tges III & IV (65) 6 (9) 47 (69) 60 (88) Fetl growth restriction (61) 17 (18) 49 (53) 93 (100) Vlues re given s n or n (%)., tril systole; D, erly distole;, ventriculr systole; TTT, twin twin trnsfusion syndrome; v, end-systolic ventriculr relxtion. Tble 3 Chrcteristics of ductus venosus ptterns ccording to different types of fetl condition Abnorml ventriculr relxtion Preserved ventriculr relxtion Fetl condition Pure LD (n = 180) E & LD (n = 182) E & HD (n = 36) LD E & LD E & HD (n = 46) HD (n = 26) Right-sided hert defect (n = 29) 8 (28) 6 (21) 5 (17) 0 1 (3) 5 (17) 4 (14) Immune/non-immune hydrops (n = 20) 6 (30) 6 (30) 3 (15) 0 2 (10) 2 (10) 1 (5) TTT recipient (n = 227) 93 (41) 58 (26) 14 (6) 6 (3) 10 (4) 31 (14) 15 (7) tges I & II (n = 57) 37 (65) 6 (11) 2 (4) 1 (2) 2 (4) 5 (9) 4 (7) tge III (n = 137) 46 (34) 42 (31) 8 (6) 5 (4) 8 (6) 20 (15) 8 (6) tge IV (n = 33) 10 (30) 10 (30) 4 (12) (18) 3 (9) TTT donor (n = 149) 42 (28) 72 (48) 6 (4) 17 (11) 7 (5) 3 (2) 2 (1) tges I & II (n = 84) 30 (36) 37 (44) 2 (2) 9 (11) 3 (4) 2 (2) 1 (1) tges III & IV (n = 65) 12 (18) 35 (54) 4 (6) 8 (12) 4 (6) 1 (2) 1 (2) Fetl growth restriction (n = 93) 31 (33) 40 (43) 8 (9) 1 (1) 4 (4) 5 (5) 4 (4) Vlues re given s n (%), where n represents number of ultrsound exmintions. E, end-systolic dysfunction; HD, holodistolic dysfunction; LD, lte distolic dysfunction; TTT, twin twin trnsfusion syndrome. lte distolic dysfunction; Pttern 2, bnorml ventriculr relxtion; nd Pttern 3, preserved ventriculr relxtion (Tble 3). Pttern 1 ws observed t medin gesttionl ge of 22.0 (rnge, ) weeks. The medin DV-PIV Z-score ws 2.9 (rnge, ) nd DV-RAV ws identified in 32 (19%) exmintions (Figure 2). This ws the most common pttern in ll clinicl conditions (28 42%). Pttern 2 presented with three subtypes. ubtype 2: bnorml end-systolic nd lte-distolic filling. In ddition to the v/d rtio, /v nd -wve-relted rtios were bnorml nd the /D rtio ws norml (Figure 3,b). This ws observed in 182/518 (35%) exmintions. The medin gesttionl ge for exmintion ws 23.4 (rnge, ) weeks. The medin DV-PIV Z-score ws 4.0 (rnge, ). DV-RAV ws identified in 32 (18%) exmintions. This pttern ws observed in TTT donors nd in FGR. ubtype 2b: bnorml end-systolic nd holodistolic filling. In ddition to the v/d rtio, /v, /D nd -wve-relted rtios were bnorml (Figure 3c,d). This ws observed in 36/518 (7%) exmintions. The medin gesttionl ge for exmintion ws 24.4 (rnge, ) weeks. The Copyright 2013 IUOG. Published by John Wiley & ons Ltd. Ultrsound Obstet Gynecol 2014; 43:

4 Ductus venosus wveform ptterns 511 () 1.2 D 0.9 D 2.8 D Figure 2 chemtic representtion () nd Doppler ultrsound imge (b) of Pttern 1. The fint gry re represents norml ductus venosus (DV) wveform, the solid gry re shows n bnorml DV wveform nd the dotted lines represent difference in velocity rtios with D. The blue tringle shows norml reltionship between v- nd D-wves in this pttern (v/d rtio)., tril systole; D, erly distole;, ventriculr systole; v, end-systolic ventriculr relxtion. medin DV-PIV Z-score ws 7.4 (rnge, ), nd DV-RAV ws identified in 25 (67%) exmintions. This pttern ws minly observed in fetuses with rightsided hert lesions nd hydrops. ubtype 2c: bnorml lte-distolic filling. In ddition to the v/d rtio, - wve-relted rtios were bnorml (Figure 3e,f). The /v nd /D rtios were norml. This ws observed in 24/518 (5%) exmintions. The medin gesttionl ge for exmintion ws 20.2 (rnge, ) weeks. The medin DV-PIV Z-score ws 2.7 (rnge, ). DV- RAV ws identified in four (17%) exmintions. This pttern ws observed in TTT donors. Pttern 3 lso presented with three subtypes. ubtype 3: bnorml end-systolic nd lte-distolic filling. /vnd -wve-relted rtios were bnorml (Figure 4,b). The /D rtio ws norml. This ws observed in 24/518 (5%) exmintions. The medin gesttionl ge for exmintion ws 23.4 (rnge, ) weeks. The medin DV-PIV Z-score ws 4.0 (rnge, ). DV- RAV ws identified in 11 (46%) exmintions. This () 0.5 D 2.9 D 3.3 D () 2.2 D 1.7 D 2.8 D (c) 3.3 D 2.5 D 3.6 D (c) 2.5 D 2.5 D 3.7 D (e) v D 1.2 D 1.8 D 2.7 D (e) 1.4 D 2.3 D 3.4 D Figure 3 chemtic representtions (,c,e) nd Doppler ultrsound imges (b,d,f) of Ptterns 2 (,b), 2b (c,d) nd 2c (e,f). The fint gry res represent norml ductus venosus (DV) wveforms, the solid gry res show bnorml DV wveforms nd the dotted lines represent the differences in velocity rtio with ccompnying Ds. The red tringles show n bnorml reltionship between v- nd D-wves in these ptterns (v/d rtio)., tril systole; D, erly distole;, ventriculr systole; v, end-systolic ventriculr relxtion. Figure 4 chemtic representtions (,c,e) nd Doppler ultrsound imges (b,d,f) of Ptterns 3 (,b), 3b (c,d) nd 3c (e,f). The fint gry res represent norml ductus venosus (DV) wveforms, the solid gry res show bnorml DV wveforms nd the dotted lines represent the differences in velocity rtio with ccompnying Ds. The blue tringles show norml reltionship between v- nd D-wves in these ptterns (v/d rtio)., tril systole; D, erly distole;, ventriculr systole; v, end-systolic ventriculr relxtion. Copyright 2013 IUOG. Published by John Wiley & ons Ltd. Ultrsound Obstet Gynecol 2014; 43:

5 512 Turn et l. pttern ws observed in hydrops fetlis. ubtype 3b: bnorml end-systolic nd holodistolic filling. /v, /D nd -wve-relted rtios were bnorml (Figure 4c,d). This ws observed in 46/518 (9%) exmintions. The medin gesttionl ge for exmintion ws 21.5 (rnge, ) weeks. The medin DV-PIV Z-score ws 7.4 (rnge, ). DV-RAV ws identified in 35 (76%) exmintions. ubtype 3c: bnorml holo-distolic filling. /D nd -wve-relted rtios were bnorml (Figure 4e,f). The /v rtio ws norml. This ws observed in 26/518 (5%) exmintions. The medin gesttionl ge for exmintion ws 25.5 (rnge, ) weeks. The medin DV-PIV Z-score ws 3.8 ( ). DV-RAV ws identified in 13 (54%) exmintions. These two ptterns were observed in right-sided hert defects. The distribution of /v, /D nd v/d rtios differed between Ptterns 1 nd 2 (P < for ll comprisons). All rtios except /v nd v/d were significntly different between Ptterns 1 nd 3 (P < ). Incresed /v nd /D rtios nd reduced v/d distinguished Pttern 2 from Pttern 3 (P < for ll). The PIV Z-score ws highest for Ptterns 2b nd 3b (Tble 4). DICUION In dult medicine, ptterns of venous flow tht correlte with bnormlities of crdic function during specific phses of the crdic cycle hve long been recognized 5 7. We utilized velocity rtios tht quntify reltive forwrd flow during individul phses of the crdic cycle to evlute the presence of distinct bnorml venous wveform ptterns in the fetus. A decrese in reltive forwrd flow during tril systole ws the primry contributor to n bnorml PIV found in 96% of exmintions. A reltive decrese in forwrd flow during ventriculr relxtion immeditely following ventriculr systole (/v rtio bnormlity) nd reltive increse in the subsequent pssive distolic forwrd flow (v/d rtio bnormlity) were the two rtios tht were bnorml in pproximtely 50% of exmintions. In contrst, decresed pssive distolic filling reltive to ventriculr systole (/D rtio bnormlity) ws seen in only one-fifth of exmintions. When the combintions of ll phses of the wveform were considered, we identified three principl wveform ptterns. These were chrcterized by isolted flow bnormlities during tril systole, bnorml forwrd flow during ventriculr relxtion nd bnorml forwrd flow involving combintions of crdic phses with norml flow during ventriculr relxtion. Fetuses with right-sided hert lesions or TTT recipients were more likely to present with bnorml forwrd flow during pssive distolic filling (/D rtio), whilst in TTT donors flow bnormlity lso occurred during the period of ventriculr relxtion (v/d rtio). Previous studies hve predominntly nlyzed the DV wveform using indices tht quntify the entire wveform, or by qulittive methods tht emphsize reltive forwrd flow during tril systole 1,3,5,7. These studies hve been instrumentl in demonstrting tht in fetl conditions Tble 4 Distribution of ductus venosus (DV) velocity rtios ccording to pttern Abnorml ventriculr relxtion Preserved ventriculr relxtion HD (n = 26) E & HD (n = 46) E & LD LD E & HD (n = 36) E & LD (n = 182) Pure LD (n = 180) Rtio PIV Z-score 2.9 (2.1 to 12.9) 4.0 (2.1 to 24.1) 7.4 (2.9 to 44.9) 2.7 (2.1 to 8.7) 3.4 (2.2 to 9.5) 7.4 (2.2 to 20.1) 3.4 (2.2 to 11.4) /v 1.2 ( 2.4 to 1.9) 2.9 (2.0 to 4.4) 3.3 (2.7 to 4.5) 1.8 (1.2 to 1.9) 2.2 (2.1 to 2.4) 2.5 (2.1 to 3.7) 1.4 (0.5 to 1.9) /D 0.9 ( 3.3 to 1.9) 0.5 ( 20.6 to 2.0) 2.5 (2.0 to 3.3) 1.2 ( 4.2 to 0.3) 1.7 (0.9 to 1.9) 2.5 (2.1 to 3.3) 2.3 (2.1 to 2.7) v/d 0.9 ( 1.9 to 1.9) 3.3 ( 5.1 to 2.0) 2.8 ( 5.1 to 2.1) 2.3 ( 2.6to2.0) 1.9 ( 2.0 to 1.4) 1.1 ( 1.9 to 2.1) 0.4 ( 0.9to2.1) / 2.8 (1.9 to 7.8) 3.3 (1.6 to 7.8) 3.6 (2.1 to 8.5) 2.7 (1.6 to 5.9) 2.8 (1.5 to 8.8) 3.7 (2.1 to 8.2) 3.4 (1.7 to 7.7) v/ 2.6 (1.5 to 8.4) 2.7 ( 2.0 to 7.9) 3.1 ( 0.9 to 9.1) 2.4 (1.2 to 5.8) 2.3 (0.3 to 9.1) 3.2 (1.3 to 8.4) 3.1 (0.9 to 8.1) D/ 2.5 (1.7 to 7.6) 2.8 (1.6 to 7.4) 3.0 (1.1 to 7.7) 2.5 (1.8 to 5.7) 2.5 (1.3 to 7.1) 3.2 (1.3 to 7.4) 2.9 (0.7 to 7.0) Dt re presented s medin (rnge)., tril systole; D, erly distole; E, end-systolic dysfunction; HD, holodistolic dysfunction; LD, lte distolic dysfunction;, ventriculr systole; v, end-systolic ventriculr relxtion. Copyright 2013 IUOG. Published by John Wiley & ons Ltd. Ultrsound Obstet Gynecol 2014; 43:

6 Ductus venosus wveform ptterns 513 which re ssocited with dvnced crdiovsculr compromise, the elevted venous Doppler indices nd decrese in forwrd velocity during tril systole typiclly define the most severe disese spectrum. However, more detiled correltion with crdic function in conditions such s TTT, tricuspid regurgittion nd FGR shows tht, while there is certinly overlp between bnorml venous Doppler nd crdic dysfunction, there is no consistent reltionship between the two. Detiled crdiovsculr scoring in TTT identifies crdic dysfunction independent of venous Doppler sttus 10,11. In ptients with tricuspid regurgittion the /D rtio hs been reported to provide better reflection of the distolic filling bnormlities thn the PIV 8.InptientswithFGR sizeble proportion with n bnorml DV-PIV hve norml myocrdil performnce 12,13. Furthermore, it hs been demonstrted tht there re severl non-crdic vribles which determine the degree of forwrd flow during tril systole 14 nd tht use of Doppler index (which plces greter emphsis on ventriculr relxtion) provided better prediction of crdiovsculr compromise thn the PIV 15. These studies support the concept of evluting ll phses of the DV flow velocity wveform for more differentited ppliction of venous Doppler in rnge of fetl conditions. Fluctutions in reltive venous forwrd flow correspond to events in the crdic cycle tht modulte the cpcity of the hert to ccommodte venous return. This cpcity depends on the interply mong venous volume (prelod), crdic function (relxtion, complince nd contrctility) nd downstrem rteril blood-flow resistnce. Accordingly, it is not possible to determine the primry underlying mechnism without mesuring ll of these vribles. Nevertheless, bsed on our understnding of the pthophysiology of the conditions included in this study, severl observtions re plusible. The DV flow pttern in which bnormlity ws confined to lte distole concurrent with the -wve ws most common nd did not predominte in ny of the fetl conditions. This is consistent with the observtion tht incresed fterlod, decresed crdic function, incresed venous volume nd chnges in vessel dimeter cn ll ffect forwrd flow during tril systole, s well s the knowledge tht these vribles my be ffected in TTT, FGR nd crdic defects 1,14. The pttern tht ws ssocited with bnorml forwrd flow during end-systolic relxtion ws predominntly seen in TTT donors nd in FGR. These conditions shre the risk for hypovolemi nd hypoxemi s result of plcentl dysfunction 1,10,11,16. In the fetus, both crdic complince nd ventriculr relxtion re relted to myocrdil oxygention 6,17, nd incresed end-systolic pressure or residul volume with worsening hypoxemi cn impir crdic filling during ventriculr relxtion 6,18. This would explin why growth-restricted fetuses tht hve deep DV v-wves re t higher risk for demise 15. Finlly, bnorml DV forwrd flow throughout the pssive nd ctive phses of distole (but with norml flow during ventriculr relxtion) ws seen in TTT recipients nd in fetuses with right-sided hert defects. The principl crdiovsculr bnormlity in TTT recipients is volume overlod, which leds to ventriculr hypertrophy nd vlvulr dysfunction in the most dvnced stges 19,20. imilrly, in right-sided crdic lesions there is resistnce to forwrd flow throughout the pssive nd ctive phses of distole 6,8,18. Accordingly, Pttern 3 suggests tht distolic resistnce to forwrd flow extends beyond tril systole (Pttern 1) throughout the whole of distole. Becuse there is reltively low risk for hypoxemi, ventriculr relxtion is unffected. One cn therefore speculte tht -wve bnormlities re sensitive mrker of impired venous forwrd flow but less specific of the underlying mechnism. In contrst, v-wve bnormlities my be more specific for myocrdil relxtion nd complince issues, whilst D-wve bnormlities reflect globl distolic venous dysfunction. The limittions of our study include the potentil of scertinment bis for the fetl conditions nd the degrees of crdiovsculr compromise. This limits our bility to provide robust dt on the reltionship between wveform ptterns, specific fetl conditions nd degrees of crdiovsculr compromise. Although we re ble to identify the timing of venous flow bnormlities, we do not hve concurrent mesurements of the underlying crdic vribles tht define these venous bnormlities. Accordingly, our interprettions re extrpolted nd require ongoing reserch for verifiction. Becuse we present reltively lrge number of bnormlities nlyzed ginst robust reference rnges, we re ble to discern three primry wveform bnormlities. Although we present subtypes of these ptterns, we recognize tht these my merely represent different degree of severity rther thn truly distinct ptterns. With these cvets in mind we re ble to confirm our hypothesis tht there re distinct venous wveform bnormlities tht coincide with different phses of the crdic cycle. In conclusion, we present evidence of wveform ptterns tht describe different spects of bnorml venous forwrd flow. Among these, -wve bnormlities re ubiquitous but v- nd D-wve bnormlities point towrd mechnisms tht re specific to ventriculr relxtion nd holodistolic filling. This clssifiction for the DV flow profile reflects pthology independent of trditionl Doppler indices nd my prove vluble in refining our understnding of crdic impcts of fetl disese. 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