the fetal venous system, part ii

Ultrasound Obstet Gynecol 2010; 36: 93–111Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.7622

The fetal venous system, Part II: ultrasound evaluationof the fetus with congenital venous system malformationor developing circulatory compromise

S. YAGEL*#, Z. KIVILEVITCH†#, S. M. COHEN*, D. V. VALSKY*, B. MESSING*, O. SHEN*and R. ACHIRON‡*Obstetrics and Gynecology Ultrasound Center, Hadassah-Hebrew University Medical Centers, Mt Scopus, Jerusalem, †Ultrasound Unit,Negev Medical Center, Macabbi Health Services, Beer Sheba and ‡Ultrasound Unit, Department of Obstetrics and Gynecology, ChaimSheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel

KEYWORDS: 3D/4DUS; fetal physiology; fetal venous system; IUGR; prenatal diagnosis; venous Doppler; venousmalformations

ABSTRACT

The human fetal venous system is well-recognized as atarget for investigation in cases of circulatory compromise,and a broad spectrum of malformations affecting thissystem has been described. In Part I of this review,we described the normal embryology, anatomy andphysiology of this system, essential to the understandingof structural anomalies and the sequential changesencountered in intrauterine growth restriction and otherdevelopmental disorders. In Part II we review the etiologyand sonographic appearance of malformations of thehuman fetal venous system, discuss the pathophysiologyof the system and describe venous Doppler investigationin the fetus with circulatory compromise. Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd.

CONGENITAL ANOMALIESOF THE FETAL VENOUS SYSTEM:ETIOLOGY AND SONOGRAPHICAPPEARANCE

Abnormal development of the fetal venous system canstem from any of its four embryonic systems: theumbilical, vitelline, cardinal and pulmonary systems. Wespeculate that the normal developmental course of thefetal venous system may be disturbed in two ways: (a) byprimary failure of a system or part of a system to form or tocreate critical anastomoses, or (b) by secondary occlusionof an already transformed system. We1,2 have proposed

a classification of fetal venous system anomalies thatexpands on the four major embryonic groups mentionedabove.

Classification system of fetal venous system anomalies

A. Cardinal veinsa. Complex malformations: heterotaxy syndromes.b. Isolated malformations: e.g. persistent left superior

vena cava (PLSVC) or double superior vena cava(SVC), interrupted inferior vena cava, persistentleft inferior vena cava, double inferior vena cava.

B. Umbilical veinsa. Primary failure to create critical anastomoses:

abnormal connection of umbilical vein (UV) withagenesis of ductus venosus (DV) (with intra- orextrahepatic systemic shunt of the UV).

b. Persistent right UV with or without left UVand/or DV.

c. UV varix.C. Vitelline veins

a. Primary failure to create critical anastomosesi. Complete agenesis of portal system (portosys-

temic shunt)ii. Partial agenesis of right or left or both portal

branches (portohepatosystemic shunt)D. Anomalous pulmonary venous connection

a. Total anomalous pulmonary venous connectionb. Partial anomalous pulmonary venous connection

Correspondence to: Prof. S. Yagel, Hadassah University Hospital, Mt Scopus - Obstetrics and Gynecology, PO Box 24035, Jerusalem,Mt. Scopus 91240, Israel (e-mail: [email protected])

#S.Y. and Z.K. contributed equally to this article.

Accepted: 5 February 2010

Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. REVIEW

94 Yagel et al.

Cardinal veins

Heterotaxy syndromes

Heterotaxy syndromes, or incomplete errors of lateral-ization, involve abnormal placement of some organs dueto a failure to establish normal left–right patterning. Itis important to differentiate these anomalies from com-plete situs inversus, in which all organs (visceral andthoracic) are rotated to the opposite side, and which isusually asymptomatic. Therefore, the first step in evaluat-ing venous system malformations is to determine the fetalvisceral and thoracic situs.

The incidence of heterotaxy syndromes in newborns isapproximately 1 : 10003,4, and they constitute 2–4% ofall congenital heart diseases (CHD)5. These syndromespresent in two main forms: asplenia and polyspleniasyndromes. Asplenia is characterized by predominantright-sidedness and right atrial isomerism, resulting ina fetus whose left side is a mirror image of its right side.Congenital heart malformations are frequent (occurringin 50–100% of cases) and severe and represent the mostimportant prognostic factors. The most frequent venoussystem malformations associated with asplenia include:PLSVC, anomalous pulmonary venous return and leftsided inferior vena cava (IVC), resulting in a characteristicjuxtaposition of the abdominal aorta and IVC.

Polysplenia is characterized by predominant left-sidedness and left atrial isomerism, resulting in a fetuswhose right side is a mirror image of its left side.Associated cardiac malformations are rare and less severethan in asplenia, the most common being atrioventricularseptal defect with complete heart block. The characteristicvenous malformation is an interrupted IVC with azygoscontinuation to the SVC. This anomaly arises from afailure to form the right subcardinal–hepatic anastomosis,resulting in absence of the hepatic segment of the IVC.The sonographic landmark is a dilated azygos veinalongside the aorta on the abdominal circumferenceplane and four-chamber view plane, and atrioventricularblock bradycardia. In the sagittal abdominal plane thedescending aorta and azygos vein run side-by-side withopposite directions of flow (Figure 1).

Interrupted IVC has also been reported as an isolatedentity6–10. In such cases it is usually clinically silent.

Persistent left superior vena cava (PLSVC)

PLSVC is a known variant of venous return observedin 0.3% of adults without cardiac malformation and inapproximately 4% of adults with CHD11. Galindo et al.12

found a prevalence of 0.2% in fetuses with normal hearts,and 9% of fetuses with cardiac anomalies, in a populationreferred for echocardiographic examination in a tertiarycenter, calculating an odds ratio for CHD of 49.9 for afetus with PLSVC.

PLSVC is a remnant of the proximal segment of theleft anterior cardinal vein (LACV), resulting from failureof the LACV to atrophy following formation of theoblique anastomosis with the right cardinal vein (the

Figure 1 Interrupted inferior vena cava with azygos continuationimaged in high-definition power flow Doppler (HDPD) (a) and inB-flow (b). Note the dilated azygos vein (Az) draining into thesuperior vena cava (SVC), with flow in the opposite direction to theflow in the aorta (Ao). Compare with insets showing HDPD andB-flow images of the normal heart and great vessels. DV, ductusvenosus; LHV, left hepatic vein. (Insets reproduced with permissionfrom Yagel et al.75).

innominate vein) (Figure 2). The vessel most often drainsinto the coronary sinus13,14. It is diagnosed by fetalechocardiography on observation of a dilated coronarysinus (though this may not always be present) and anextraneous vessel identified to the left of the ductal arch inthe three-vessels and trachea (3VT) view of the fetal heart.In very rare instances, PLSVC may be seen with absentright SVC15; in this case the 3VT view shows three vessels:the LSVC, ductal arch and aortic arch16. Multiplanar

Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 95

Figure 2 Persistent left superior vena cava imaged in gray-scale (a) and with color Doppler (b). In (c) the dilated coronary sinus is visible (CSand arrows), where the persistent left superior vena cava (LSVC) drains into it. Ao, aorta; MPA, main pulmonary artery; RSVC, rightsuperior vena cava; Tr, trachea.

reconstruction mode in 4D ultrasound has been shown tobe useful in diagnosis of the PLSVC anomaly17.

When isolated, PLSVC usually has no clinical sig-nificance; however, it has been reported to occur inisolation in only 9% of cases. It is more often seen inassociation with other anomalies: both cardiac (23% ofPLSVC cases), including atrioventricular septal defect,double-outlet right ventricle, left outflow tract obstructiveanomalies, conotruncal anomalies and ventricular septaldefect, and other extracardiac malformations, includ-ing heterotaxy syndrome (41–45%), esophageal atresia,diaphragmatic hernia, IVC malformations, complex mal-formation syndromes and chromosomal anomalies. Theremay be significant morbidity and mortality, arising fromthe associated anomalies rather than the lesion itself12,18.

Other very rare anomalies of the vena cava havebeen reported in the pediatric literature and extensivelyreviewed19.

Umbilical veins

Anomalies of the umbilical and portal veins constitutethe largest group of congenital venous anomalies detectedin-utero. They include three main entities: agenesis ofthe DV with extrahepatic umbilicosystemic shunt or withintrahepatic umbilicohepatic shunt; persistent right UV(PRUV) with or without intact DV; UV varix.

Agenesis of the ductus venosus

Agenesis of the DV results from failure to form the ‘criti-cal anastomosis’: no connection is established between theUV and DV, and this in turn leads to shunting of umbilicalblood through an aberrant vessel that may flow either intoextrahepatic veins such as the iliac vein, IVC, SVC, rightatrium20–27 or coronary sinus28, or via an intrahepaticvenous network (umbilicohepatic shunt), through the por-tal sinus to the hepatic sinusoid (umbilicoportal–hepaticshunt) or even directly into the right atrium (Figure 3). Theprevalence of the anomaly has been estimated at 6 : 1000fetal examinations29. It is often (in 24–65% of cases)associated with cardiac, extracardiac and chromosomal

anomalies, and syndromes such as Noonan syndrome. Itis associated with agenesis of the portal vein in as many as50% of cases, and may be associated in other cases withpartial or total agenesis of the portal system. Hydropsand generalized edema occur in 33–52% of cases30,31,and may require postnatal device occlusion29. DV agen-esis presents as an isolated finding in only 35–59% ofcases. In such cases, however, 80–100% have normaloutcome30–32. While only sporadic cases were reported inneonates before the advent of ultrasound, prenatal sono-graphic diagnosis of DV agenesis is feasible and many caseseries have appeared in the literature2. Among fetuses withno or minor associated anomalies, location of the umbili-cal drainage site seems to impact on prognosis, with a bet-ter outcome expected in cases without liver bypass22,31–34.

Jaeggi et al.22 reported 12 cases of agenesis of the DVwith extrahepatic shunt and reviewed a further 17 fromthe literature. They reported a mortality rate of 17% fromcongestive heart failure in cases with extrahepatic shunt.Associated malformations were reported in 87% of thecases, single umbilical artery being the most common.

Berg et al.31 reported 23 cases of agenesis of the DV,four with extrahepatic drainage and 19 with drainageof the umbilical vein into the portal sinus. Fifteen ofthe 23 fetuses had associated chromosomal or structuralanomalies that impacted outcome. Among the subgroupof fetuses (8/23) with no or minor associated malfor-mations, outcome was significantly better among thosewithout liver bypass. They reported a total of 19 caseswith intrahepatic drainage and no or minor associatedanomalies, all of which survived, while only 20/29 withextrahepatic drainage and no or minor associated anoma-lies survived. Fetuses with extrahepatic drainage havea higher risk of congestive heart failure, even in theabsence of cardiovascular anomaly. In reviewing their andpublished cases the authors determined that findings ofcardiac malformations, complex non-chromosomal mal-formation syndromes and hydrops were predictive ofin-utero or neonatal demise, whether drainage was intra-or extrahepatic31.

From our observations we suggest that the parameterthat most influences outcome in cases of agenesis of theDV is the development of the portal system. We recently


96 Yagel et al.

presented data that support the notion that if the shuntis a narrower, ductus-like connection, some or all of theportal system will have developed. This in turn impactson prognosis35.

Persistent right umbilical vein (PRUV)

In the course of normal embryonic development, theright UV degenerates and the left UV is left to carryblood from the placenta to the fetus. Failure of right UVinvolution results in the PRUV anomaly1,36–39 (Figure 4).PRUV is the most frequently detected fetal venous systemanomaly. Its prevalence has been estimated to range

from 1 : 250 to 1 : 57037,39–42. It may replace the leftUV, or be found as an intrahepatic supernumeraryvein, connecting to the right portal vein. It may alsobypass the liver, causing aberrant drainage of blood intothe IVC or right atrium40,43,44. It has been suggestedthat primary or secondary occlusion by thromboembolicevents arising from the placenta may lead to earlystreaming of blood through the right UV to cause thisanomaly45. Teratogenic agents such as retinoic acid ordeficient folate induced the PRUV anomaly in rats46.Secondary formation of UV anomalies may result fromthromboembolic events occluding the DV or other veins.

Figure 3 (Continued over).



Figure 3 (Continued) Variations of agenesis of the ductus venosus (DV).(a–c) Case of agenesis of the DV with narrow extrahepatic shunt from theumbilical vein (UV) to the inferior vena cava (IVC), imaged with high-definition power flow Doppler (HDPD) (a,c) and B-flow (b). In (c) theappropriately developed portal system is shown. (Az, azygos vein; LHV,left hepatic vein; LPV, left portal vein; MHV, main hepatic vein; RPVa andp, anterior and posterior branches of right portal vein; St, stomach.) (d–g)Complex case of agenesis of the DV with extrahepatic shunt, complicatedwith interrupted IVC. (d) HDPD image showing the UV draining into theshunt, between the IVC and Az. Note the Az is behind the aorta (red)Int-I, internal iliac vein. (e) B-flow image which helps to demonstrate theinterrupted IVC with Az continuation, and the point of communicationof the UV to the IVC at this connection. Note that there are almost noblood vessels in the area of the liver, which further suggests agenesis ofthe portal system. (f,g) Tomographic ultrasound imaging showingsequential sagittal planes, confirming the agenesis of the DV and inter-rupted IVC. The image in (f) is slightly lateral to the left of that in (g).AoA, aortic arch; dAo, descending aorta; Az, azygos; CT, celiac trunk;

DA, ductus arteriosus; MPA, main pulmonary artery. (h,i) Another case of agenesis of the DV with intrahepatic shunt of the UV to the righthepatic vein (RHV), imaged in HDPD and B-flow. (j) 4D ultrasound B-flow image of absent DV, with UV drainage to the right atrium (RA).Ao, aorta; HV, hepatic veins; UC, umbilical cord. (Reproduced with permission from Yagel et al.134.) (k) Agenesis of the DV with partialagenesis of the portal system. Inversion mode in three-dimensional rendering demonstrating the umbilicoiliac shunt (carets). UA, umbilicalartery. (Reproduced with permission from Achiron et al.55).

Figure 4 Typical appearance of persistent right umbilical vein (UV). (a) The UV is seen passing laterally right of the gall bladder (GB).(b) The portal vein presents a mirror image of its normal anatomical configuration. The left portal vein (LPV) assumes the right portal vein(RPV) bifurcation, and its lateral branches change sides, the right side having the inferior (LPVi) and superior (LPVs) branches, and the leftside having only one lateral branch. The ductus venosus (DV) has its origin to the left of the UV axis. (c) The main portal vein (MPV) isconnected to the RPV in a more inferior plane relative to its normal position. LPVm, left portal vein medial branch; ST, stomach; SP, spine;Ao, aorta.

Echogenic foci situated within the fetal liver suggest thisetiology.

Two of the 74 cases of PRUV reviewed by De Catteet al. had Noonan syndrome, and one had trisomy 18, all

with multiple associated anomalies47. While early reportsseemed to indicate that PRUV was a worrisome findingin prenatal ultrasound43,45, accumulated experience hasshown that in the absence of other anomalies intrahepatic


98 Yagel et al.

PRUV with normal DV connection is usually a normalanatomical variant with no clinical significance37,39,40,42.Ultrasound identification of PRUV is made by visualizingthe aberrant vein passing laterally to the right of the gallbladder in the plane of measurement of the abdominalcircumference (Figure 4a).

Fetal intra-abdominal umbilical vein varix

Umbilical vein varix is a focal dilatation of vein. It is anuncommon finding, with an estimated intrauterine inci-dence of about 1 : 100048. Most reported UV varices are ofthe intra-abdominal UV, but extra-abdominal UV variceshave been reported49. Fetal intra-abdominal UV (FIUV)varix is diagnosed when a sonographically anechoic cysticmass is seen between the abdominal wall and lower liveredge. Color Doppler ultrasonography helps to distinguishthis vascular anomaly from other cystic lesions in this area(Figure 5). The diameter of most varices ranges between 8and 14 mm50 and FIUV varix has been variously definedas an intra-abdominal UV diameter at least 1.5 timesgreater than the diameter of the intrahepatic UV51, or asan intra-abdominal UV diameter exceeding 9 mm52.

In a review of 91 cases, Fung et al.53 reported that68% presented as an isolated finding, and of these 74%had a normal outcome. However, 8.1% (5/62) resultedin intrauterine death in which no specific cause couldbe identified and one (1.6%) case had trisomy 21. Inthe group with associated sonographic findings, only27.6% had normal outcome. Congenital abnormalitiesand syndromes were confirmed after birth in 20.7%(6/29), while 27.6% had chromosomal abnormalities.The overall incidence of aneuploidy was 9.9%, themajority being trisomy 21 or 18. The incidence of suddenintrauterine demise was 5.5%, occurring between 29 and38 weeks of gestation.

The diameter of the UV at first diagnosis and the max-imum diameter of the UV over the course of pregnancywere not found to be related to the occurrence of obstet-ric complications53. Diagnosis of FIUV varix warrants adetailed anatomical search for additional anomalies, kary-otyping, echocardiography, and close monitoring of thefetus for sonographic signs of hemodynamic disturbance.Fetal heart monitoring is advised from 28 weeks of gesta-tion. The optimal timing for delivery remains the subjectof debate. In light of the apparent high risk of unfavor-able outcome, including sudden intrauterine demise evenin isolated FIUV varix, the option of induction of laborwhen lung maturity is ascertained may be considered54.

Vitelline veins

Complete or incomplete agenesis of the portal system

Anomalies of the vitelline veins are extremely rare, andfew cases during fetal life have been reported55–59. Mor-gan and Superina60 proposed classifying portal agenesis

Figure 5 Fetal intra-abdominal umbilical vein (UV) varix: ananechoic cystic mass (calipers) is seen between the abdominal walland the lower liver edge in a longitudinal section (a) and imagedwith high-definition power flow Doppler (b). The varix is shown tobe 1.5 times the diameter of the UV. Bl, bladder.

into two types: Type I, in which there is complete diver-sion of the portal blood into the vena cava (portosystemicshunt); and Type II, in which the portal veins are pre-served but a portion of portal blood is diverted into thesystemic venous circulation through the liver (portohep-atic shunt). Both types were further classified into twosubtypes: Subtype a, in which the splenic vein (SpV) andsuperior mesenteric vein (SMV) do not join to form aconfluence, and thus there is no anatomical portal vein;and Subtype b, in which the SpV and SMV do join toform a confluence that may shunt to the IVC, renal vein,iliac vein, azygos vein or right atrium60.

Complete absence of the portal venous system (CAPVS)is an extreme example of total failure of the vitellineveins to transform into the portal system, i.e. there isprimary failure to form the critical anastomosis with thehepatic sinusoids or UVs (Figures 6 and 7). As a result,the enterohepatic circulation is disturbed and the portalvenous blood is shunted systemically. Liver developmentis supplied by the hepatic arteries. Mesenteric and splenicvenous blood may drain directly into the IVC, renal veinsor hepatic veins, or via the caput medusa to the heart61.Associated anomalies are frequent. Northrup et al.62



Figure 6 (a) Tomographic ultrasound imaging (TUI) of the normalportal system. LPV, left portal vein; MPV, main portal vein; RAPV,right anterior portal vein; RPPV, right posterior portal vein.(b) TUI in a case of complete agenesis of the portal venous system.The arrow indicates the only remnant of the portal system. St,stomach. (c) High-definition power flow Doppler image of thesagittal plane showing that the ductus venosus (DV) is present;thus, the anomaly is not secondary to absent DV in this instance.The circle indicates the umbilical cord. Ao, aorta; CT, celiac trunk;IVC, inferior vena cava; LHV, left hepatic vein, UA, umbilicalartery; UV, umbilical vein.

reported heterotaxy–polysplenia in 25% of their cases,CHD in 30% (most frequently atrial septal defect and/orventricular septal defect) and Goldenhar syndrome in10%. Achiron et al.55 reported associated malformations,including trisomy 21, in four of their five cases.

Incomplete absence of the portal venous system(IAPVS) or partial failure to form critical anastomosesmay represent a more benign form of vitelline veinabnormality, and may result in agenesis of the rightportal system, with a persistent left vitelline vein connecteddirectly to the hepatic vein (portohepatic shunt) and anabsent or preserved DV (Figure 8). Neonatal spontaneousresolution may occur. Achiron et al.55 reported fourcases, none with associated malformations, in three ofwhich the shunts resolved spontaneously postnatally55.Prognosis of IAPVS depends on the presence of associatedmalformations and the development of hemodynamicimbalance with signs of heart failure, cardiomegalyand hydrops. As opposed to CAPVS, IAPVS is rarelyassociated with other malformations, and hemodynamiccompromise depends on the intrahepatic shunt ratio,leading to IUGR63.

Hepatic bypass of the portal circulation is knownto cause the so-called hepatic artery buffer effect,which compensates for the decreased portal supplyby increasing blood flow in the hepatic artery. Thisresults in a prominent Doppler signal55, increased bloodflow velocity, and decreased pulsatility index (PI) inthe hepatic artery64. Long term metabolic sequelaeof portosystemic shunting have been reported in thepostnatal literature and include: hypergalactosemia65,hyperbilirubinemia, hyperammonemia66, liver massesincluding focal nodular hyperplasia, adenoma, hepa-toblastoma and hepatocellular carcinoma, and rarelyencephalopathy67,68.

Anomalous pulmonary venous connection

Anomalous pulmonary venous connection is a groupof rare anomalies that may present in total orpartial form. The combined incidence of anoma-lous pulmonary venous connection (APVC) has beenreported as 6.8 : 100 000 livebirths69 or 4.9% of allCHD70.

Partial anomalous pulmonary venous connection

Partial anomalous pulmonary venous connection(PAPVC) is a group of anomalies involving one or more,but not all, of the pulmonary veins connecting to theright atrium or a tributary (Figure 9)71. An atrial septaldefect is often present. There are several variations of thisanomaly70,72–74.

(1) Right pulmonary veins to SVC (Figure 9a): usuallythe right upper and middle lung lobes drain into theSVC and atrial septal defect is present; occasionallythe atrial septum is intact.


100 Yagel et al.

Figure 7 A case of complete agenesis of the portal venous system. (a) Transverse view of the fetal abdomen showing, beyond the stomach(St), the spleen (Sp), with the splenic vein coursing towards the right side of the body (blue) to form a confluence with the main portal vein.Note absence of the afferent intrahepatic venous system and enlarged IVC when compared with the aorta (red, arrow). (b) Pulsed Dopplerinsonation of the splenic vein–portal system junction depicting triphasic flow compatible with a systemic venous shunt. (c,d) Venographyperformed post-termination. In (c), note the umbilico-IVC shunt (arrow); (d) was taken 1 min later: the splenic vein (long black arrow) isshown to be confluent with the renal vein (short arrow) and with the superior mesenteric vein (double headed arrow), forming a conduit(dotted arrow, c) which became enlarged (white arrow) before shunting into the IVC. (Reproduced with permission from Achiron et al.55).

(2) Right pulmonary veins to right atrium: veins from allright lung lobes drain directly into the right atrium,which can be dilated to as much as twice its normalsize; there is usually an atrial septal defect.

(3) Right pulmonary veins to IVC (Figure 9b): all or someright lung lobes are drained into the IVC; right lung

veins form a characteristic ‘fir-tree’ pattern; the atrialseptum is intact. This variation is often seen with rightlung hypoplasia, bronchial system anomalies, cardiacdextroposition, right pulmonary artery hypoplasia,anomalous arterial connection between the aorta andright lung and other cardiac anomalies.



Figure 8 Incomplete absence of the portal venous system (IAPVS).Two different forms are shown: (a) absent right portal vein andportal sinus, showing X-shaped configuration formed by theumbilical vein (UV), left portal vein (LPV) branches and the ductusvenosus (DV), in the standard transverse plane for abdominalcircumference measurement; (b) dilated aberrant ‘horseshoeshaped’ arrangement of vessels encircling the right hepatic lobe. Ao,aorta; IVC, inferior vena cava; LPVi, left portal vein inferiorbranch; LPVm, left portal vein medial branch; SP, spine;St, stomach.

(4) Left pulmonary veins to left innominate vein(Figure 9c): veins from only the upper left lobe, orall of the left lung, drain into the left innominatevein via an anomalous vertical vein; atrial septaldefect is usually present. Left pulmonary drainagemay alternately be to the coronary sinus, IVC, rightSVC, right atrium or left subclavian vein, and may beassociated with cardiac defects or polysplenia/aspleniaor Turner or Noonan syndromes.

(5) Left pulmonary veins to coronary sinus (Figure 9d),IVC, right SVC, right atrium or left subclavian vein;very rarely, the right pulmonary veins may connect tothe azygos vein or coronary sinus.

Echocardiographic diagnosis of PAPVC is made byvisualizing pulmonary veins connecting to the structureinvolved; Doppler studies are invaluable in identificationand classification of this group of anomalies, and three-dimensional (3D)/4D ultrasound modalities may haveadded value in their diagnosis74–76.

Total anomalous pulmonary venous connection

Total anomalous pulmonary venous connection (TAPVC)involves complete disconnection between the pulmonaryveins and the left atrium (Figure 10)71. All the pulmonaryveins drain into the right atrium or systemic veins. One-third of cases present with an associated anomaly, whiletwo thirds are isolated. TAPVC can be classified into fourtypes71:

Type I: anomalous connection at the supracardiac level;Type II: anomalous connection at the cardiac level;Type III: anomalous connection at the infracardiac level;Type IV: connections at two or more of supracardiac,

cardiac and infracardiac levels.

Alternatively, this anomaly can be classed into twogroups:

(1) supradiaphragmatic type: pulmonary veins are con-nected to: the left innominate vein by the characteristicvertical vein, or the coronary sinus, the right atrium,or the SVC, without pulmonary venous obstruction;

(2) infradiaphragmatic type: pulmonary veins drain intothe portal vein or hepatic veins, with pulmonaryvenous obstruction.

There is usually an atrial septal defect. An obstructionin the pulmonary venous channel will impact theprognosis of TAPVC. One third of patients havean associated major anomaly, including cor bilocular,single ventricle, truncus arteriosus, transposition of thegreat arteries, pulmonary atresia, aortic coarctation,hypoplastic left ventricle, or anomalies of the systemicveins.

TAPVC should be suspected when pulmonary veinscannot be visualized entering the left atrium in thefour-chamber apical view plane, with a wide gapbetween the posterior wall of the left atrium and thedescending aorta. In the supracardiac type, the rightatrium volume overload causes enlargement of theatrium and a bowing leftwards of the interatrial septum.The common pulmonary channel may be visualizedposterior to the left atrium with color Doppler, andthis can be followed to the site of its connection.The ascending vertical vein to the left innominate veincan be seen in the 3VT view as an additional vesselto the left of the pulmonary artery. Doppler studiesshow the direction of blood flow in this vessel iscephalad, opposite to that in the SVC. In the infracardiactype, the descending vertical vein can be diagnosedin a transverse plane of the abdomen as an extravessel in front of the descending aorta. In the sagittal


102 Yagel et al.

L. Inn. V.(a) (b)

(c) (d)

S.V.C.

R.A.

R.P.V.

C.S.

I.V.C.

R.V.

L. Inn.S.V.C.

v.v.

L.P.V.

S.V.C.

R.P.V.

R.A.

C.S.

I.V.C.

R.V. L.V.

L.A.

I.V.C.R.V.

C.S.

R.A.

R.P.V.

S.V.C.

L.A.

L.P.V.

L.V.

L.P.V.

L.A.

R.P.V.

R.A.

C.S.

I.V.C.

R.V.L.V.

V.

L.V.

L.P.V.

L.A.

Figure 9 Common forms of partial anomalous pulmonary venous connection. (a) Anomalous connection of the right pulmonary veins(R.P.V.) to the superior vena cava (S.V.C.). There is usually a high or sinus venous defect. (b) Anomalous connections of the rightpulmonary veins to the inferior vena cava (I.V.C.). The right lung commonly drains by one pulmonary vein without its usual anatomicaldivisions. Parenchymal abnormalities of the right lung are common and the atrial septum is usually intact. (c) Anomalous connection of theleft pulmonary veins (L.P.V.) to the left innominate vein (L. Inn. V.) by way of a vertical vein (v.v.). There may be an additional left-to-rightshunt through the atrial septal defect. (d) Anomalous connection of the L.P.V. to the coronary sinus (C.S.). L.A., left atrium; L.V., leftventricle; R.A., right atrium; R.V., right ventricle. (Reproduced with permission from Krabill and Lucas71 (Krabill KA, Lucas RV. In HeartDisease in Infants, Children, and Adolescents (5th edn), Moss AJ, Adams FH, Emmanouilides GC (eds). Williams and Wilkins: Baltimore,1995; 841–849).)

plane, the vertical vein courses cephalad between theIVC and the descending aorta, crossing the diaphragm(Figure 11).

Doppler evaluation is key to the characteriza-tion of TAPVC to identify the anomalous connec-tion. Turbulent flow will reveal the location of anyobstruction and the degree of obstruction can bequantified70–72.

Prognosis

Prognosis in cases of PAPVC and TAPVC is affected by thepresence of any cardiac or extracardiac malformations,the presence and size of the interatrial connection and anyobstructive lesion in the anomalous connecting vessels,

and the development of the pulmonary vascular bed.Isolated TAPVC, if detected and corrected surgicallyearly in life, has an excellent outcome. Prognosis ispoor when it is associated with other cardiac lesionsand portal vein obstruction. In cases of TAPVC withobstruction in the anomalous venous channel, theneonate usually dies in the first weeks of postnatallife71,77.

THE FETAL VENOUS SYSTEMIN PATHOLOGICAL CONDITIONS

In the physiology section of Part I of this review weemphasized the unique role of the venous system inmaintaining a positive umbilicocaval pressure gradient.



S.V.C.(a) (b)

(c) (d)

L. Inn. V.

v.v.

L.P.V.C.P.V.R.P.V.

R.A.C.S.

I.V.C.

R.V.

S.V.C.

R.P.V.R.A.

C.S.

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R.V. L.V.

R.P. P.V. S.V.S.M.V.

L.P.

L.H.

D.V.

R.H.

I.V.C.

R.V.

I.V.C.

R.A.

S.V.C.

L.P.V.

C.S. L.A.

C.P.V.

L.V.

L.V.

I.V.CR.V.

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Figure 10 Common forms of total anomalous pulmonary venous connection. (a) Anomalous connection of the pulmonary veins to the leftinnominate vein (L. Inn. V.) by way of a vertical vein (V.V.). (b) Anomalous connection to the coronary sinus (C.S.): the pulmonary veinsjoin to form a confluence designated as the common pulmonary vein (C.P.V.), which connects to the C.S. (c) Anomalous connection to theright atrium (R.A.). The left and right pulmonary veins (L.P.V. and R.P.V.) usually enter the R.A. separately. (d) Anomalous connection tothe portal vein (P.V.). The pulmonary veins form a confluence, from which an anomalous channel arises. This connects to the P.V., whichcommunicates with the inferior vena cava (I.V.C.) by way of the ductus venosus (D.V.) or the hepatic sinusoids. L.A., left atrium; L.H., lefthepatic vein; L.P., left portal vein; L.V., left ventricle; R.H., right hepatic vein; R.P., right left portal vein; R.V., right ventricle; S.M.V,superior mesenteric vein; S.V., splenic vein; S.V.C., superior vena cava. (Reproduced with permission from Krabill and Lucas71 (Krabill KA,Lucas RV. In Heart Disease in Infants, Children, and Adolescents (5th edn), Moss AJ, Adams FH, Emmanouilides GC (eds). Williams andWilkins: Baltimore, 1995; 841–849).)

This assures a low preload index, which is essential foroptimal cardiac drainage. Cardiac output progressivelyincreases and resistance of the placental vascular beddecreases while the umbilicocaval pressure gradientis maintained steady during the third trimester ofpregnancy78. Any situation hampering this hemodynamicbalance initiates compensatory mechanisms in the arterialand venous systems. These compensatory mechanisms are

gradual and sequential, in correlation with the severity ofthe hypoxic insult, hence creating an efficient monitoringtool of evolving fetal distress.

The most frequent pathological condition affecting thefetoplacental hemodynamic balance is placental dysfunc-tion. Other etiologies are cardiac (malformations, arrhyth-mias, or increased preload blood volume) and conditionsresulting in elevation of ventricular end-diastolic pressure,


104 Yagel et al.

Figure 11 Total anomalous pulmonary venous connection (infracardiac type) imaged in the sagittal plane. Tomographic ultrasound imagingwas applied in post-processing and clearly shows the vertical vein draining into one of the hepatic veins. Ao, aorta; DV, ductus venosus;LHV, left hepatic vein; VV, vertical vein.

atrial pressure and, consequently, precordial venous pres-sure. We focus here on uteroplacental insufficiency andthe gradual hemodynamic changes that accompany itscompromised vascular function.

Reduced placental supply to the fetus initiates multiplecompensatory vasodilatory mechanisms involving variousarterial and venous systems. In the arterial system, theorgan most widely studied and clinically evaluated isthe brain (brain-sparing effect)79,80. Evaluation of variousparts of the arterial circulation in the fetus with circulatorycompromise has been widely performed and reviewedelsewhere81–84.

The cascade of evolving circulatory compromisein uteroplacental insufficiency is characterized by hemo-dynamic changes in the placenta, heart and brain. Thefetal circulation may be viewed as comprising two com-partments, with the division at the aortic isthmus: the rightventricle/placenta, having high resistance, and the left ven-tricle/brain, having low resistance. The ratio between the

resistance indices (RI) of these two compartments has beenused clinically as a monitoring tool of fetal compensatorymechanisms and the magnitude of hypoxic insult85–87.The implications for the venous system of these changesin resistance in the different compartments are four-fold:reduced blood supply from the placenta to the liver, anincreased proportion (also per unit of weight) of cardiacoutput diverted to the fetal body and consequently tothe IVC, increased blood flow through the SVC resultingfrom the brain-sparing effect, and an increased afterloadon the right ventricle. These hemodynamic changes leadto increased preload indices that hamper the supply ofhigh-quality blood flow from the placenta.

Venous compensatory mechanisms aim to improve theplacental supply to the heart by increasing the proportionof DV shunting from the portal sinus. Human Dopplerstudies have reported variable results. Bellotti et al.88

found that the percentage of UV blood flow shuntedthrough the DV increased from 26.5% in normally



grown fetuses to 90.3% in growth-restricted fetuses, witha consequent increased normalized blood flow volumefrom 30.8 mL/min/kg to 41.3 mL/min/kg. Others showedmore moderate changes. Tchirikov et al.89 reported anincrease from 43% to 62%, and Kiserud et al.90 reportedan increase from 25% in normally grown to a mean of39% in IUGR fetuses. They found that the degree ofshunting in IUGR fetuses is positively correlated with theseverity of placental insufficiency as reflected by the UAdiastolic flow. A significant increase in shunting to the DVwas found only in IUGR fetuses with UA-PI above the97.5th percentile (35% blood shunted) and in those withabsent/reversed diastolic flow (57% shunted)90.

Preferential flow through the DV results from reciprocalhemodynamic changes inside the liver. The presence of asphincter in the isthmic portion of the DV has never beenconfirmed91.

Tchirikov et al.92 showed in vitro that rings derivedfrom portal venous branches developed more forcein reaction to catecholamines than did vascular ringsobtained from the isthmic portion of the DV. In hypoxia,increased plasma catecholamine levels may evoke anincrease in the DV shunting rate through differentialcontraction of the portal venous branches as compared tothe DV. This effect may come into play, in addition to theactive nitric oxide-mediated DV distension, which wasshown experimentally92. This intrahepatic shift of bloodfrom the portal system to the DV during hypoxia wassupported by an in-vivo Doppler study. Kessler et al.93

demonstrated that in IUGR fetuses with UA-PI abovethe 97.5th percentile, total liver perfusion is decreasedequally to the left and right lobes. However, as placentalinsufficiency increased (as measured by the oxygen partialpressure in the UA), the proportion of left portal vein(LPV) contribution to the right lobe decreased, beingreplaced by increased flow from the main portal vein.

In summary, placental vasculopathy leads to reducedumbilical flow to the heart. This initiates an intrahepaticcompensatory mechanism, which consists of shiftingblood from the liver to the DV. The liver plays a centralrole in regulating fetal growth. Reduced liver perfusionmay provide the first clinical evidence of placentalinsufficiency, restricted fetal growth and decreased fetalweight.

DOPPLER STUDIES OF THE FETALVENOUS SYSTEM

Doppler investigation is the only non-invasive in-uteromethod for assessing fetoplacental hemodynamic status.Each component of the fetomaternal circulation hasa different role in placental function and fetal well-being. Doppler evaluation of the venous system aimsto assess fetal cardiac function, which in severe cases maydeteriorate to an acute event of congestive heart failure.

The cardiovascular profile score94–96 combines sono-graphic markers of fetal cardiovascular status basedon parameters found to be correlated with perina-tal mortality. The parameters most strongly predictive

of adverse outcome among growth-restricted fetusesare cardiomegaly, monophasic atrioventricular filling orholosystolic tricuspid regurgitation, and pulsations inthe UV96, while among hydropic fetuses they wereUV and DV Doppler94. This concurs with previ-ous studies showing that in the temporal sequenceof events prior to the appearance of abnormal fetalheart rate pattern, atonia or fetal demise, the arte-rial Doppler changes precede those of the venoussystem97 but are too early a sign to be used totime the decision to deliver. This was particularly evi-dent in cases of early-onset IUGR, before 32 weeks ofgestation84,98.

Adverse perinatal outcome is related to gestationalage at delivery and the degree of placental insufficiency.Decision-making concerning the time of delivery aims tostrike a balance between fetal injury related to prematu-rity, and that related to placental insufficiency99. Resultsof the GRIT study100 indicated no significant differencein terms of stillbirth rate when delivery was immediate.However, this was refuted by findings at the 2-year followup: the rate of cerebral palsy in the immediate deliverygroup was as expected (10%), while in the delayed deliv-ery group it was 0%, suggesting that deferred deliverycould be protective management101. In a prospective mul-ticenter study, Baschat et al.83 found that gestational ageat delivery is the best predictor for intact survival until29 weeks or 800 g estimated fetal weight, with sensitivitiesof 68% and 72%, respectively. Above these thresholds,DV Doppler parameters were shown to be the primary car-diovascular factor in predicting intact survival, and as suchare the only parameters to use as a trigger for delivery.

Doppler parameters

Decreased UVflow volume

IncreasedUA resistance

DecreasedMPV resistance

Increasedvenous pulsation

DV A/RDFUV pulsations

FHR latedecelerations/STV

Reducedfetal tone

Decreasedfetal breathing

movements

Decreasedfetal movement

DecreasedAFI

Decreasedfetal growth

Earlyresponse

Decision point

Lateresponse

Biophysical parameters

Hypoxia

Acidosis

Figure 12 Suggested cascade of fetal circulatory compromise.Changes in Doppler and physiological parameters follow atemporal sequence82. The decision point regards the timing ofdelivery. AFI, amniotic fluid index; A/RDF, absent or reverseddiastolic flow; DV, ductus venosus; FHR, fetal heart rate; MPV,main portal vein; STV, short term variability; UA, umbilical artery;UV, umbilical vein.


106 Yagel et al.

Turan et al.82 found a well-ordered sequence ofDoppler abnormalities in placental insufficiency (Figure12), from early-onset ones, including increased UAresistance and brain-sparing effect, to late-onset ones, suchas absent/reversed UA diastolic velocity, absent/reversedDV A-wave, and UV pulsation. The rate of progressionthrough the sequence correlated significantly withgestational age: when appearing as early as 26–27 weeksof gestation, placental insufficiency was usually severe,progressing from one Doppler abnormality to the next inapproximately 7–10 days. When Doppler abnormalitiesemerged near 30 weeks’ gestation, progression intervalswere longer, up to 14 days, and clinically cases weremilder. Doppler changes were limited to the arterialsystem, and the median age of delivery was 33 weeks.These findings, however, were in contrast with those ofArduini et al.85, who showed that time intervals betweenarterial Doppler changes and delivery for late fetal heartrate decelerations were statistically significantly longerwhen Doppler abnormalities appeared before 29 weeksof gestation, compared with late-onset cases (meaninterval between Doppler changes and delivery, 13.5(range, 3–26) vs. 3 (range, 1–9) days. Other studies84,102

have shown that venous Doppler abnormalities precededthe appearance of late decelerations or reduced short-term variability (< 2.2 ms) by 6–7 days. In conclusion,there is a well-documented sequence of biophysical andDoppler abnormalities that correspond with placentalinsufficiency and fetal growth restriction (Figure 12).Abnormalities in venous system Doppler waveforms aresensitive tools for the assessment of fetal well-beingbefore 32 weeks’ gestation, and may help to fine-tune ourdecision-making concerning time of delivery in affectedfetuses.

Venous Doppler patterns

Venous Doppler patterns in normal and IUGR fetuseshave been established in large longitudinal and cross-sectional studies; normal Doppler patterns were discussedin Part I of this review. Here we describe Dopplerabnormalities seen in the most commonly investigatedvessels (Figure 13).

Umbilical vein

Umbilical vein Doppler patterns are usually evaluatedin the intra-abdominal portion of the vein. The samplevolume should include the whole cross-section of thevessel, with an angle of insonation at or as close as possibleto 0◦. Since the IUGR state includes increased impedancein the fetoplacental circulation, reduced UV flow volumeand velocity result. However, the considerable overlapwith normal ranges precludes the usefulness of UV flowvelocity as a measure of IUGR103.

The appearance of pulsatile flow in the UV is asimple and reliable marker of circulatory compromise,long recognized as a marker of asphyxia in small-for-gestational age fetuses and in cases of non-immune

Figure 13 Abnormal Doppler waveforms in the umbilical vein (UV)(a), ductus venosus (b) and inferior vena cava (IVC) (c).(a) Abnormal UV waveform in hemodynamically compromisedfetuses is characterized by the appearance of pulsations. (b) The DVnormally has forward blood flow throughout the cardiac cycle. Incompromised fetuses a drop in atrial systolic forward velocities isobserved. As central venous pressure increases, blood flow may bereversed during atrial systole. (c) Abnormal IVC waveforms inintrauterine growth restriction show a decrease in forward flowduring the S-wave (S) and D-wave (D) and accentuation of reversedflow in the A-wave (annotated ‘a’). As the condition deterioratesthe D-wave may be reversed.

hydrops104,105. Pulsatility in the UV can result from twomain sources of pressure waves: atrial contraction cancause a sharp deflection (notch) in UV flow, or a wavefrom the neighboring arterial flow, which will be travelingin the same direction, can cause an increment in the UVflow. The resulting pulsatile UV Doppler pattern maybe only an A-wave notch or, in some severe cases, atriphasic waveform that mirrors the whole cardiac cyclemay appear103 (Figure 13a).

Ductus venosus

Changes in DV flow are seen in hypoxia and hypo-volemia in experimental animal models and in humanfetuses106–110. The DV is sampled at its inlet, with a largesample volume in a near-sagittal plane, at a low angle ofinsonation111,112. Alternatively, DV flow can be sampled



in an oblique transverse section of the fetal abdomen.Normally at 20 weeks’ gestation about 30% of blood isshunted through the DV, while at 30 weeks about 20%of blood is shunted103,112–114. In small-for-gestationalage fetuses a much higher proportion of blood is shuntedthrough the DV, and earlier placental compromise willshow a more pronounced shunt and distension of theDV103.

Cardiac events are apparent in the DV waveform.Reversed or zero flow in the A-wave is a simple sign ofdisordered cardiac function. There is reduced velocity inthe A-wave in IUGR, and as the situation worsens it is fur-ther deflected owing to increased afterload and preload,as well as increased end-diastolic pressure, the directeffects of hypoxia and increased adrenergic drive. Takentogether, these effects produce an augmented atrial con-traction and strong deflection during the A-wave in the DVwaveform97,115,116 (Figure 13b). The combination of thisand the DV distension, which lessens wave reflection atthe junction with the UV by lessening the difference in thevessels’ diameters, produces a considerable effect on UVflow, and further deterioration leads to decreased velocitybetween the systolic and diastolic peaks. These waveformchanges are most apparent in the second trimester andusually result from chromosomal aberration as opposedto cardiac decompensation115,117–120. Such changes arerarely observed in the third trimester, when improvedendocrine control operates to attenuate them121–123.

Inferior vena cava

The IVC is usually sampled in the fetal abdomen, caudal tothe hepatic confluence and DV outlet, to avoid interferencefrom neighboring vessels. Reference ranges for normalIVC flow parameters have been established124–126. TheIVC is the preferred vessel for postnatal evaluation ofsmall-for-gestational age neonates and is familiar topediatricians, so it is often sampled in the fetus. It isnormal to observe a negative A-wave in the IVC becauseof the vessel’s normally relatively low velocities124–128.In compromised fetuses, an abnormal IVC flow velocitywaveform will show a decrease in forward flow duringthe S- and D-waves, and an accentuated reversed flow inthe A-wave (Figure 13c). In severe cases the D-wave maybe reversed.

Hepatic and portal veins

The hepatic vein, while easy to sample, is employed onlyinfrequently as a parameter in IUGR studies. The signsof cardiac compromise observed in the hepatic vein aresimilar to those apparent in the DV and IVC129,130.

The left portal vein as the watershed of the fetal venouscirculation. The LPV has been suggested as a simplemarker of circulatory compromise131–133. It is sampledin the left portal branch between the DV inlet and thejunction with the main portal stem. Disturbed blood flowin the UA is indicative of increased resistance to bloodflow in the right heart and right liver lobe. Under these

pressures, flow in the LPV is reduced and may become pul-satile, bidirectional or reversed. If reversed, oxygen-poorblood from the spleen and gut will mix with oxygenatedblood from the UV as it courses to the DV, supplyingoxygen-poor blood to the fetal organs. Ultimately duringreversal, more blood could be flowing through the DVthan through the UV that supplies it, possibly creatingsuction on the LPV132. Kilavuz et al.132 showed, in IUGRfetuses with absent or reversed end-diastolic flow in theUA, that while UV flow remained normal, LPV flow wasnormal in mildly affected fetuses, pulsatile in fetuses withincreased RI or absent flow in the UA, and reversed infetuses with reversed flow in the UA. There was a signif-icant correlation between reversed flow in the LPV andincreased RI in the UA.

The normal distribution of blood flow between theleft and right liver lobes is approximately 60%/40%. Asdescribed above, most UV blood (70–80%) perfuses thefetal liver, while 20–30% is shunted to the DV. Bloodflow in the UV is directed to the left liver lobe and theDV, with only a minority diverted to the LPV and rightliver lobe. Low or reversed flow in the left portal branchis an expression of prioritized umbilical perfusion of theleft liver lobe at the expense of the right114.

CONCLUSION

Congenital malformations of the venous system are acomplex and varied group of lesions. There is much thatwe do not know about this system and its anomalies,but it is clear that knowledge of the embryonic devel-opment of affected vessels is key to understanding thein-utero progress and prognosis of these cases. Wheneveranomalies of the cardinal, vitelline or umbilical system arediagnosed, they should prompt thorough investigation ofthe other segments of the cardiovascular system. It wouldappear that anomalies of the venous system are not asrare as formerly believed, and that more will be diag-nosed if practitioners are cognizant of their sonographicappearance and associated anomalies.

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the fetal venous system, part ii

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