The fetal venous system, Part II

Ultrasound Obstet Gynecol 2010; 36: 93–111 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.7622 The fetal venous system, Part II: ultrasound evaluation of the fetus with congenital venous system malformation or 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, Chaim Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel K E Y W O R D S: 3D/4DUS; fetal physiology; fetal venous system; IUGR; prenatal diagnosis; venous Doppler; venous malformations ABSTRACT a classiﬁcation of fetal venous system anomalies that expands on the four major embryonic groups mentioned The human fetal venous system is well-recognized as a above. target for investigation in cases of circulatory compromise, and a broad spectrum of malformations affecting this system has been described. In Part I of this review, we described the normal embryology, anatomy and Classiﬁcation system of fetal venous system anomalies physiology of this system, essential to the understanding of structural anomalies and the sequential changes A. Cardinal veins encountered in intrauterine growth restriction and other a. Complex malformations: heterotaxy syndromes. developmental disorders. In Part II we review the etiology b. Isolated malformations: e.g. persistent left superior and sonographic appearance of malformations of the vena cava (PLSVC) or double superior vena cava human fetal venous system, discuss the pathophysiology (SVC), interrupted inferior vena cava, persistent of the system and describe venous Doppler investigation left inferior vena cava, double inferior vena cava. in the fetus with circulatory compromise. Copyright  B. Umbilical veins 2010 ISUOG. Published by John Wiley & Sons, Ltd. a. Primary failure to create critical anastomoses: abnormal connection of umbilical vein (UV) with agenesis of ductus venosus (DV) (with intra- or CONGENITAL ANOMALIES extrahepatic systemic shunt of the UV). O F T H E F E T A L V E N O U S S Y S T E M: b. Persistent right UV with or without left UV ETIOLOGY AND SONOGRAPHIC and/or DV. APPEARANCE c. UV varix. C. Vitelline veins Abnormal development of the fetal venous system can a. Primary failure to create critical anastomoses stem from any of its four embryonic systems: the i. Complete agenesis of portal system (portosys- umbilical, vitelline, cardinal and pulmonary systems. We temic shunt) speculate that the normal developmental course of the ii. Partial agenesis of right or left or both portal fetal venous system may be disturbed in two ways: (a) by branches (portohepatosystemic shunt) primary failure of a system or part of a system to form or to D. Anomalous pulmonary venous connection create critical anastomoses, or (b) by secondary occlusion a. Total anomalous pulmonary venous connection of an already transformed system. We1,2 have proposed b. 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: simcha.yagel@gmail.com) #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 due to a failure to establish normal left–right patterning. It is important to differentiate these anomalies from complete situs inversus, in which all organs (visceral and thoracic) are rotated to the opposite side, and which is usually asymptomatic. Therefore, the first step in evaluat- ing venous system malformations is to determine the fetal visceral and thoracic situs. The incidence of heterotaxy syndromes in newborns is approximately 1 : 10003,4 , and they constitute 2–4% of all congenital heart diseases (CHD)5 . These syndromes present in two main forms: asplenia and polysplenia syndromes. Asplenia is characterized by predominant right-sidedness and right atrial isomerism, resulting in a fetus whose left side is a mirror image of its right side. Congenital heart malformations are frequent (occurring in 50–100% of cases) and severe and represent the most important prognostic factors. The most frequent venous system malformations associated with asplenia include: PLSVC, anomalous pulmonary venous return and left sided inferior vena cava (IVC), resulting in a characteristic juxtaposition of the abdominal aorta and IVC. Polysplenia is characterized by predominant left- sidedness and left atrial isomerism, resulting in a fetus whose right side is a mirror image of its left side. Associated cardiac malformations are rare and less severe than in asplenia, the most common being atrioventricular septal defect with complete heart block. The characteristic venous malformation is an interrupted IVC with azygos continuation to the SVC. This anomaly arises from a failure to form the right subcardinal–hepatic anastomosis, resulting in absence of the hepatic segment of the IVC. The sonographic landmark is a dilated azygos vein alongside the aorta on the abdominal circumference plane and four-chamber view plane, and atrioventricular block bradycardia. In the sagittal abdominal plane the descending aorta and azygos vein run side-by-side with opposite directions of flow (Figure 1). Figure 1 Interrupted inferior vena cava with azygos continuation Interrupted IVC has also been reported as an isolated imaged in high-definition power flow Doppler (HDPD) (a) and in entity6 – 10 . In such cases it is usually clinically silent. B-flow (b). Note the dilated azygos vein (Az) draining into the superior vena cava (SVC), with flow in the opposite direction to the flow in the aorta (Ao). Compare with insets showing HDPD and Persistent left superior vena cava (PLSVC) B-flow images of the normal heart and great vessels. DV, ductus venosus; LHV, left hepatic vein. (Insets reproduced with permission PLSVC is a known variant of venous return observed from Yagel et al.75 ). in 0.3% of adults without cardiac malformation and in approximately 4% of adults with CHD11 . Galindo et al.12 found a prevalence of 0.2% in fetuses with normal hearts, innominate vein) (Figure 2). The vessel most often drains and 9% of fetuses with cardiac anomalies, in a population into the coronary sinus13,14 . It is diagnosed by fetal referred for echocardiographic examination in a tertiary echocardiography on observation of a dilated coronary center, calculating an odds ratio for CHD of 49.9 for a sinus (though this may not always be present) and an fetus with PLSVC. extraneous vessel identified to the left of the ductal arch in PLSVC is a remnant of the proximal segment of the the three-vessels and trachea (3VT) view of the fetal heart. left anterior cardinal vein (LACV), resulting from failure In very rare instances, PLSVC may be seen with absent of the LACV to atrophy following formation of the right SVC15 ; in this case the 3VT view shows three vessels: oblique anastomosis with the right cardinal vein (the 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 (CS and arrows), where the persistent left superior vena cava (LSVC) drains into it. Ao, aorta; MPA, main pulmonary artery; RSVC, right superior vena cava; Tr, trachea. reconstruction mode in 4D ultrasound has been shown to anomalies, and syndromes such as Noonan syndrome. It be useful in diagnosis of the PLSVC anomaly17 . is associated with agenesis of the portal vein in as many as When isolated, PLSVC usually has no clinical sig- 50% of cases, and may be associated in other cases with nificance; however, it has been reported to occur in partial or total agenesis of the portal system. Hydrops isolation in only 9% of cases. It is more often seen in and generalized edema occur in 33–52% of cases30,31 , association with other anomalies: both cardiac (23% of and may require postnatal device occlusion29 . DV agen- PLSVC cases), including atrioventricular septal defect, esis presents as an isolated finding in only 35–59% of double-outlet right ventricle, left outflow tract obstructive cases. In such cases, however, 80–100% have normal anomalies, conotruncal anomalies and ventricular septal outcome30 – 32 . While only sporadic cases were reported in defect, and other extracardiac malformations, includ- neonates before the advent of ultrasound, prenatal sono- ing heterotaxy syndrome (41–45%), esophageal atresia, graphic diagnosis of DV agenesis is feasible and many case diaphragmatic hernia, IVC malformations, complex mal- series have appeared in the literature2 . Among fetuses with formation syndromes and chromosomal anomalies. There no or minor associated anomalies, location of the umbili- may be significant morbidity and mortality, arising from cal drainage site seems to impact on prognosis, with a bet- the associated anomalies rather than the lesion itself12,18 . ter outcome expected in cases without liver bypass22,31 – 34 . Other very rare anomalies of the vena cava have Jaeggi et al.22 reported 12 cases of agenesis of the DV been reported in the pediatric literature and extensively with extrahepatic shunt and reviewed a further 17 from reviewed19 . the literature. They reported a mortality rate of 17% from congestive heart failure in cases with extrahepatic shunt. Associated malformations were reported in 87% of the Umbilical veins cases, single umbilical artery being the most common. Berg et al.31 reported 23 cases of agenesis of the DV, Anomalies of the umbilical and portal veins constitute four with extrahepatic drainage and 19 with drainage the largest group of congenital venous anomalies detected of the umbilical vein into the portal sinus. Fifteen of in-utero. They include three main entities: agenesis of the 23 fetuses had associated chromosomal or structural the DV with extrahepatic umbilicosystemic shunt or with anomalies that impacted outcome. Among the subgroup intrahepatic umbilicohepatic shunt; persistent right UV of fetuses (8/23) with no or minor associated malfor- (PRUV) with or without intact DV; UV varix. mations, outcome was significantly better among those without liver bypass. They reported a total of 19 cases Agenesis of the ductus venosus with intrahepatic drainage and no or minor associated anomalies, all of which survived, while only 20/29 with Agenesis of the DV results from failure to form the ‘criti- extrahepatic drainage and no or minor associated anoma- cal anastomosis’: no connection is established between the lies survived. Fetuses with extrahepatic drainage have UV and DV, and this in turn leads to shunting of umbilical a higher risk of congestive heart failure, even in the blood through an aberrant vessel that may flow either into absence of cardiovascular anomaly. In reviewing their and extrahepatic veins such as the iliac vein, IVC, SVC, right published cases the authors determined that findings of atrium20 – 27 or coronary sinus28 , or via an intrahepatic cardiac malformations, complex non-chromosomal mal- venous network (umbilicohepatic shunt), through the por- formation syndromes and hydrops were predictive of tal sinus to the hepatic sinusoid (umbilicoportal–hepatic in-utero or neonatal demise, whether drainage was intra- shunt) or even directly into the right atrium (Figure 3). The or extrahepatic31 . prevalence of the anomaly has been estimated at 6 : 1000 From our observations we suggest that the parameter fetal examinations29 . It is often (in 24–65% of cases) that most influences outcome in cases of agenesis of the associated with cardiac, extracardiac and chromosomal DV is the development of the portal system. We recently Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

96 Yagel et al. presented data that support the notion that if the shunt from 1 : 250 to 1 : 57037,39 – 42 . It may replace the left is a narrower, ductus-like connection, some or all of the UV, or be found as an intrahepatic supernumerary portal system will have developed. This in turn impacts vein, connecting to the right portal vein. It may also on prognosis35 . bypass the liver, causing aberrant drainage of blood into the IVC or right atrium40,43,44 . It has been suggested Persistent right umbilical vein (PRUV) that primary or secondary occlusion by thromboembolic events arising from the placenta may lead to early In the course of normal embryonic development, the right UV degenerates and the left UV is left to carry streaming of blood through the right UV to cause this blood from the placenta to the fetus. Failure of right UV anomaly45 . Teratogenic agents such as retinoic acid or involution results in the PRUV anomaly1,36 – 39 (Figure 4). deﬁcient folate induced the PRUV anomaly in rats46 . PRUV is the most frequently detected fetal venous system Secondary formation of UV anomalies may result from anomaly. Its prevalence has been estimated to range thromboembolic events occluding the DV or other veins. Figure 3 (Continued over). Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 97 Figure 3 (Continued) Variations of agenesis of the ductus venosus (DV). (a–c) Case of agenesis of the DV with narrow extrahepatic shunt from the umbilical vein (UV) to the inferior vena cava (IVC), imaged with high- definition power flow Doppler (HDPD) (a,c) and B-flow (b). In (c) the appropriately developed portal system is shown. (Az, azygos vein; LHV, left hepatic vein; LPV, left portal vein; MHV, main hepatic vein; RPVa and p, anterior and posterior branches of right portal vein; St, stomach.) (d–g) Complex case of agenesis of the DV with extrahepatic shunt, complicated with interrupted IVC. (d) HDPD image showing the UV draining into the shunt, 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 the interrupted IVC with Az continuation, and the point of communication of the UV to the IVC at this connection. Note that there are almost no blood vessels in the area of the liver, which further suggests agenesis of the portal system. (f,g) Tomographic ultrasound imaging showing sequential sagittal planes, confirming the agenesis of the DV and interrupted 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 right hepatic 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 partial agenesis of the portal system. Inversion mode in three-dimensional rendering demonstrating the umbilicoiliac shunt (carets). UA, umbilical artery. (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 left side 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) is connected 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 this with multiple associated anomalies47 . While early reports etiology. seemed to indicate that PRUV was a worrisome ﬁnding Two of the 74 cases of PRUV reviewed by De Catte in prenatal ultrasound43,45 , accumulated experience has et al. had Noonan syndrome, and one had trisomy 18, all shown that in the absence of other anomalies intrahepatic Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

98 Yagel et al. PRUV with normal DV connection is usually a normal anatomical variant with no clinical significance37,39,40,42 . Ultrasound identification of PRUV is made by visualizing the aberrant vein passing laterally to the right of the gall bladder in the plane of measurement of the abdominal circumference (Figure 4a). Fetal intra-abdominal umbilical vein varix Umbilical vein varix is a focal dilatation of vein. It is an uncommon finding, with an estimated intrauterine incidence of about 1 : 100048 . Most reported UV varices are of the intra-abdominal UV, but extra-abdominal UV varices have been reported49 . Fetal intra-abdominal UV (FIUV) varix is diagnosed when a sonographically anechoic cystic mass is seen between the abdominal wall and lower liver edge. Color Doppler ultrasonography helps to distinguish this vascular anomaly from other cystic lesions in this area (Figure 5). The diameter of most varices ranges between 8 and 14 mm50 and FIUV varix has been variously defined as an intra-abdominal UV diameter at least 1.5 times greater than the diameter of the intrahepatic UV51 , or as an intra-abdominal UV diameter exceeding 9 mm52 . In a review of 91 cases, Fung et al.53 reported that 68% presented as an isolated finding, and of these 74% had a normal outcome. However, 8.1% (5/62) resulted in intrauterine death in which no specific cause could be identified and one (1.6%) case had trisomy 21. In the group with associated sonographic findings, only 27.6% had normal outcome. Congenital abnormalities Figure 5 Fetal intra-abdominal umbilical vein (UV) varix: an and syndromes were confirmed after birth in 20.7% anechoic cystic mass (calipers) is seen between the abdominal wall (6/29), while 27.6% had chromosomal abnormalities. and the lower liver edge in a longitudinal section (a) and imaged The overall incidence of aneuploidy was 9.9%, the with high-definition power flow Doppler (b). The varix is shown to majority being trisomy 21 or 18. The incidence of sudden be 1.5 times the diameter of the UV. Bl, bladder. intrauterine demise was 5.5%, occurring between 29 and 38 weeks of gestation. into two types: Type I, in which there is complete diver- The diameter of the UV at first diagnosis and the max- sion of the portal blood into the vena cava (portosystemic imum diameter of the UV over the course of pregnancy shunt); and Type II, in which the portal veins are pre- were not found to be related to the occurrence of obstet- served but a portion of portal blood is diverted into the ric complications53 . Diagnosis of FIUV varix warrants a systemic venous circulation through the liver (portohep- detailed anatomical search for additional anomalies, kary- atic shunt). Both types were further classified into two otyping, echocardiography, and close monitoring of the subtypes: Subtype a, in which the splenic vein (SpV) and fetus for sonographic signs of hemodynamic disturbance. superior mesenteric vein (SMV) do not join to form a Fetal heart monitoring is advised from 28 weeks of gesta- confluence, and thus there is no anatomical portal vein; tion. The optimal timing for delivery remains the subject and Subtype b, in which the SpV and SMV do join to of debate. In light of the apparent high risk of unfavor- form a confluence that may shunt to the IVC, renal vein, able outcome, including sudden intrauterine demise even iliac vein, azygos vein or right atrium60 . in isolated FIUV varix, the option of induction of labor Complete absence of the portal venous system (CAPVS) when lung maturity is ascertained may be considered54 . is an extreme example of total failure of the vitelline veins to transform into the portal system, i.e. there is primary failure to form the critical anastomosis with the Vitelline veins hepatic sinusoids or UVs (Figures 6 and 7). As a result, the enterohepatic circulation is disturbed and the portal Complete or incomplete agenesis of the portal system venous blood is shunted systemically. Liver development is supplied by the hepatic arteries. Mesenteric and splenic Anomalies of the vitelline veins are extremely rare, and venous blood may drain directly into the IVC, renal veins few cases during fetal life have been reported55 – 59 . Mor- or hepatic veins, or via the caput medusa to the heart61 . gan and Superina60 proposed classifying portal agenesis Associated anomalies are frequent. Northrup et al.62 Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 99 reported heterotaxy–polysplenia in 25% of their cases, CHD in 30% (most frequently atrial septal defect and/or ventricular septal defect) and Goldenhar syndrome in 10%. 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 anastomoses may represent a more benign form of vitelline vein abnormality, and may result in agenesis of the right portal system, with a persistent left vitelline vein connected directly to the hepatic vein (portohepatic shunt) and an absent or preserved DV (Figure 8). Neonatal spontaneous resolution may occur. Achiron et al.55 reported four cases, none with associated malformations, in three of which the shunts resolved spontaneously postnatally55 . Prognosis of IAPVS depends on the presence of associated malformations and the development of hemodynamic imbalance with signs of heart failure, cardiomegaly and hydrops. As opposed to CAPVS, IAPVS is rarely associated with other malformations, and hemodynamic compromise depends on the intrahepatic shunt ratio, leading to IUGR63 . Hepatic bypass of the portal circulation is known to cause the so-called hepatic artery buffer effect, which compensates for the decreased portal supply by increasing blood flow in the hepatic artery. This results in a prominent Doppler signal55 , increased blood flow velocity, and decreased pulsatility index (PI) in the hepatic artery64 . Long term metabolic sequelae of portosystemic shunting have been reported in the postnatal literature and include: hypergalactosemia65 , hyperbilirubinemia, hyperammonemia66 , liver masses including focal nodular hyperplasia, adenoma, hepa- toblastoma and hepatocellular carcinoma, and rarely encephalopathy67,68 . Anomalous pulmonary venous connection Anomalous pulmonary venous connection is a group of rare anomalies that may present in total or partial form. The combined incidence of anomalous pulmonary venous connection (APVC) has been reported as 6.8 : 100 000 livebirths69 or 4.9% of all CHD70 . Partial anomalous pulmonary venous connection Partial anomalous pulmonary venous connection (PAPVC) is a group of anomalies involving one or more, Figure 6 (a) Tomographic ultrasound imaging (TUI) of the normal but not all, of the pulmonary veins connecting to the portal system. LPV, left portal vein; MPV, main portal vein; RAPV, right anterior portal vein; RPPV, right posterior portal vein. right atrium or a tributary (Figure 9)71 . An atrial septal (b) TUI in a case of complete agenesis of the portal venous system. defect is often present. There are several variations of this The arrow indicates the only remnant of the portal system. St, anomaly70,72 – 74 . stomach. (c) High-definition power flow Doppler image of the sagittal plane showing that the ductus venosus (DV) is present; (1) Right pulmonary veins to SVC (Figure 9a): usually thus, the anomaly is not secondary to absent DV in this instance. The circle indicates the umbilical cord. Ao, aorta; CT, celiac trunk; the right upper and middle lung lobes drain into the IVC, inferior vena cava; LHV, left hepatic vein, UA, umbilical SVC and atrial septal defect is present; occasionally artery; UV, umbilical vein. the atrial septum is intact. Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

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 Doppler insonation of the splenic vein–portal system junction depicting triphasic flow compatible with a systemic venous shunt. (c,d) Venography performed post-termination. In (c), note the umbilico-IVC shunt (arrow); (d) was taken 1 min later: the splenic vein (long black arrow) is shown 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 all veins form a characteristic ‘fir-tree’ pattern; the atrial right lung lobes drain directly into the right atrium, septum is intact. This variation is often seen with right which can be dilated to as much as twice its normal lung hypoplasia, bronchial system anomalies, cardiac size; there is usually an atrial septal defect. dextroposition, right pulmonary artery hypoplasia, (3) Right pulmonary veins to IVC (Figure 9b): all or some anomalous arterial connection between the aorta and right lung lobes are drained into the IVC; right lung right lung and other cardiac anomalies. Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 101 Echocardiographic diagnosis of PAPVC is made by visualizing pulmonary veins connecting to the structure involved; Doppler studies are invaluable in identification and classification of this group of anomalies, and three- dimensional (3D)/4D ultrasound modalities may have added value in their diagnosis74 – 76 . Total anomalous pulmonary venous connection Total anomalous pulmonary venous connection (TAPVC) involves complete disconnection between the pulmonary veins and the left atrium (Figure 10)71 . All the pulmonary veins drain into the right atrium or systemic veins. One- third of cases present with an associated anomaly, while two thirds are isolated. TAPVC can be classified into four types71 : 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 two groups: (1) supradiaphragmatic type: pulmonary veins are connected to: the left innominate vein by the characteristic vertical vein, or the coronary sinus, the right atrium, or the SVC, without pulmonary venous obstruction; (2) infradiaphragmatic type: pulmonary veins drain into the portal vein or hepatic veins, with pulmonary venous obstruction. There is usually an atrial septal defect. An obstruction in the pulmonary venous channel will impact the prognosis of TAPVC. One third of patients have Figure 8 Incomplete absence of the portal venous system (IAPVS). an associated major anomaly, including cor bilocular, Two different forms are shown: (a) absent right portal vein and single ventricle, truncus arteriosus, transposition of the portal sinus, showing X-shaped configuration formed by the great arteries, pulmonary atresia, aortic coarctation, umbilical vein (UV), left portal vein (LPV) branches and the ductus hypoplastic left ventricle, or anomalies of the systemic venosus (DV), in the standard transverse plane for abdominal circumference measurement; (b) dilated aberrant ‘horseshoe veins. shaped’ arrangement of vessels encircling the right hepatic lobe. Ao, TAPVC should be suspected when pulmonary veins aorta; IVC, inferior vena cava; LPVi, left portal vein inferior cannot be visualized entering the left atrium in the branch; LPVm, left portal vein medial branch; SP, spine; four-chamber apical view plane, with a wide gap St, stomach. between the posterior wall of the left atrium and the descending aorta. In the supracardiac type, the right (4) Left pulmonary veins to left innominate vein atrium volume overload causes enlargement of the (Figure 9c): veins from only the upper left lobe, or atrium and a bowing leftwards of the interatrial septum. all of the left lung, drain into the left innominate The common pulmonary channel may be visualized vein via an anomalous vertical vein; atrial septal posterior to the left atrium with color Doppler, and defect is usually present. Left pulmonary drainage this can be followed to the site of its connection. may alternately be to the coronary sinus, IVC, right The ascending vertical vein to the left innominate vein SVC, right atrium or left subclavian vein, and may be can be seen in the 3VT view as an additional vessel associated with cardiac defects or polysplenia/asplenia to the left of the pulmonary artery. Doppler studies or Turner or Noonan syndromes. show the direction of blood flow in this vessel is (5) Left pulmonary veins to coronary sinus (Figure 9d), cephalad, opposite to that in the SVC. In the infracardiac IVC, right SVC, right atrium or left subclavian vein; type, the descending vertical vein can be diagnosed very rarely, the right pulmonary veins may connect to in a transverse plane of the abdomen as an extra the azygos vein or coronary sinus. vessel in front of the descending aorta. In the sagittal Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

102 Yagel et al. (a) (b) S.V.C. L. Inn. V. S.V.C. R.P.V. L.P.V. L.P.V. R.A. R.A. L.A. L.A. C.S. C.S. I.V.C. L.V. R.P.V. R.V. L.V. R.V. I.V.C. (c) (d) S.V.C. V. S.V.C. L. Inn. R.P.V. v.v. L.P.V. R.A. R.P.V. L.P.V. C.S. L.A. R.A. C.S. L.A. I.V.C. L.V. R.V. I.V.C. L.V. R.V. 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 right pulmonary veins to the inferior vena cava (I.V.C.). The right lung commonly drains by one pulmonary vein without its usual anatomical divisions. Parenchymal abnormalities of the right lung are common and the atrial septum is usually intact. (c) Anomalous connection of the left 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-right shunt 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., left ventricle; R.A., right atrium; R.V., right ventricle. (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 and Wilkins: Baltimore, 1995; 841–849).) plane, the vertical vein courses cephalad between the and the development of the pulmonary vascular bed. IVC and the descending aorta, crossing the diaphragm Isolated TAPVC, if detected and corrected surgically (Figure 11). early in life, has an excellent outcome. Prognosis is Doppler evaluation is key to the characteriza- poor when it is associated with other cardiac lesions tion of TAPVC to identify the anomalous connec- and portal vein obstruction. In cases of TAPVC with tion. Turbulent flow will reveal the location of any obstruction in the anomalous venous channel, the obstruction and the degree of obstruction can be neonate usually dies in the first weeks of postnatal quantified70 – 72 . life71,77 . Prognosis THE FETAL VENOUS SYSTEM IN PATHOLOGICAL CONDITIONS Prognosis in cases of PAPVC and TAPVC is affected by the presence of any cardiac or extracardiac malformations, In the physiology section of Part I of this review we the presence and size of the interatrial connection and any emphasized the unique role of the venous system in obstructive lesion in the anomalous connecting vessels, maintaining a positive umbilicocaval pressure gradient. Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 103 (a) S.V.C. L. Inn. V. (b) S.V.C. v.v. C.P.V. R.P.V. C.P.V. L.P.V. R.A. L.A. R.A. C.S. C.S. L.A. I.V.C L.V. I.V.C. R.V. R.V. L.V. (c) (d) S.V.C. S.V.C. C.P.V. R.A. L.P.V. R.A. R.P.V. C.S. L.A. C.S. I.V.C. I.V.C. L.V. L.V. R.V. R.V. I.V.C. R.H. L.H. D.V. L.P. R.P. P.V. S.V. S.M.V. Figure 10 Common forms of total anomalous pulmonary venous connection. (a) Anomalous connection of the pulmonary veins to the left innominate vein (L. Inn. V.) by way of a vertical vein (V.V.). (b) Anomalous connection to the coronary sinus (C.S.): the pulmonary veins join to form a confluence designated as the common pulmonary vein (C.P.V.), which connects to the C.S. (c) Anomalous connection to the right 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 to the portal vein (P.V.). The pulmonary veins form a confluence, from which an anomalous channel arises. This connects to the P.V., which communicates 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., left hepatic 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 and Wilkins: Baltimore, 1995; 841–849).) This assures a low preload index, which is essential for gradual and sequential, in correlation with the severity of optimal cardiac drainage. Cardiac output progressively the hypoxic insult, hence creating an efficient monitoring increases and resistance of the placental vascular bed tool of evolving fetal distress. decreases while the umbilicocaval pressure gradient The most frequent pathological condition affecting the is maintained steady during the third trimester of fetoplacental hemodynamic balance is placental dysfunc- pregnancy78 . Any situation hampering this hemodynamic tion. Other etiologies are cardiac (malformations, arrhyth- balance initiates compensatory mechanisms in the arterial mias, or increased preload blood volume) and conditions and venous systems. These compensatory mechanisms are resulting in elevation of ventricular end-diastolic pressure, Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

104 Yagel et al. Figure 11 Total anomalous pulmonary venous connection (infracardiac type) imaged in the sagittal plane. Tomographic ultrasound imaging was 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- resistance indices (RI) of these two compartments has been sure. We focus here on uteroplacental insufficiency and used clinically as a monitoring tool of fetal compensatory the gradual hemodynamic changes that accompany its mechanisms and the magnitude of hypoxic insult85 – 87 . compromised vascular function. The implications for the venous system of these changes Reduced placental supply to the fetus initiates multiple in resistance in the different compartments are four-fold: compensatory vasodilatory mechanisms involving various reduced blood supply from the placenta to the liver, an arterial and venous systems. In the arterial system, the increased proportion (also per unit of weight) of cardiac organ most widely studied and clinically evaluated is output diverted to the fetal body and consequently to the brain (brain-sparing effect)79,80 . Evaluation of various the IVC, increased blood flow through the SVC resulting parts of the arterial circulation in the fetus with circulatory from the brain-sparing effect, and an increased afterload compromise has been widely performed and reviewed on the right ventricle. These hemodynamic changes lead elsewhere81 – 84 . to increased preload indices that hamper the supply of The cascade of evolving circulatory compromise high-quality blood flow from the placenta. in uteroplacental insufficiency is characterized by hemo- Venous compensatory mechanisms aim to improve the dynamic changes in the placenta, heart and brain. The placental supply to the heart by increasing the proportion fetal circulation may be viewed as comprising two com- of DV shunting from the portal sinus. Human Doppler partments, with the division at the aortic isthmus: the right studies have reported variable results. Bellotti et al.88 ventricle/placenta, having high resistance, and the left ven- found that the percentage of UV blood flow shunted tricle/brain, having low resistance. The ratio between the through the DV increased from 26.5% in normally Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 105 grown fetuses to 90.3% in growth-restricted fetuses, with of adverse outcome among growth-restricted fetuses a consequent increased normalized blood flow volume are cardiomegaly, monophasic atrioventricular filling or from 30.8 mL/min/kg to 41.3 mL/min/kg. Others showed holosystolic tricuspid regurgitation, and pulsations in more moderate changes. Tchirikov et al.89 reported an the UV96 , while among hydropic fetuses they were increase from 43% to 62%, and Kiserud et al.90 reported UV and DV Doppler94 . This concurs with previ- an increase from 25% in normally grown to a mean of ous studies showing that in the temporal sequence 39% in IUGR fetuses. They found that the degree of of events prior to the appearance of abnormal fetal shunting in IUGR fetuses is positively correlated with the heart rate pattern, atonia or fetal demise, the arte- severity of placental insufficiency as reflected by the UA rial Doppler changes precede those of the venous diastolic flow. A significant increase in shunting to the DV system97 but are too early a sign to be used to was found only in IUGR fetuses with UA-PI above the time the decision to deliver. This was particularly evi- 97.5th percentile (35% blood shunted) and in those with dent in cases of early-onset IUGR, before 32 weeks of absent/reversed diastolic flow (57% shunted)90 . gestation84,98 . Preferential flow through the DV results from reciprocal Adverse perinatal outcome is related to gestational hemodynamic changes inside the liver. The presence of a age at delivery and the degree of placental insufficiency. sphincter in the isthmic portion of the DV has never been Decision-making concerning the time of delivery aims to confirmed91 . strike a balance between fetal injury related to prematu- Tchirikov et al.92 showed in vitro that rings derived rity, and that related to placental insufficiency99 . Results from portal venous branches developed more force of the GRIT study100 indicated no significant difference in reaction to catecholamines than did vascular rings in terms of stillbirth rate when delivery was immediate. obtained from the isthmic portion of the DV. In hypoxia, However, this was refuted by findings at the 2-year follow increased plasma catecholamine levels may evoke an up: the rate of cerebral palsy in the immediate delivery increase in the DV shunting rate through differential group was as expected (10%), while in the delayed deliv- contraction of the portal venous branches as compared to ery group it was 0%, suggesting that deferred delivery the DV. This effect may come into play, in addition to the could be protective management101 . In a prospective mul- active nitric oxide-mediated DV distension, which was ticenter study, Baschat et al.83 found that gestational age shown experimentally92 . This intrahepatic shift of blood at delivery is the best predictor for intact survival until from the portal system to the DV during hypoxia was 29 weeks or 800 g estimated fetal weight, with sensitivities supported by an in-vivo Doppler study. Kessler et al.93 of 68% and 72%, respectively. Above these thresholds, demonstrated that in IUGR fetuses with UA-PI above DV Doppler parameters were shown to be the primary car- the 97.5th percentile, total liver perfusion is decreased diovascular factor in predicting intact survival, and as such equally to the left and right lobes. However, as placental are the only parameters to use as a trigger for delivery. insufficiency increased (as measured by the oxygen partial pressure in the UA), the proportion of left portal vein (LPV) contribution to the right lobe decreased, being Doppler parameters Biophysical parameters replaced by increased flow from the main portal vein. In summary, placental vasculopathy leads to reduced Decreased UV Early umbilical flow to the heart. This initiates an intrahepatic Decreased response flow volume Hypoxia fetal growth compensatory mechanism, which consists of shifting blood from the liver to the DV. The liver plays a central Increased role in regulating fetal growth. Reduced liver perfusion UA resistance Decreased AFI may provide the first clinical evidence of placental insufficiency, restricted fetal growth and decreased fetal Decreased MPV resistance weight. Decreased Decision point fetal movement Increased venous pulsation DOPPLER STUDIES OF THE FETAL Decreased VENOUS SYSTEM fetal breathing DV A/RDF movements Doppler investigation is the only non-invasive in-utero UV pulsations method for assessing fetoplacental hemodynamic status. Late FHR late Reduced Each component of the fetomaternal circulation has response fetal tone decelerations/STV Acidosis a different role in placental function and fetal wellbeing. Doppler evaluation of the venous system aims to assess fetal cardiac function, which in severe cases may Figure 12 Suggested cascade of fetal circulatory compromise. deteriorate to an acute event of congestive heart failure. Changes in Doppler and physiological parameters follow a The cardiovascular profile score94 – 96 combines sono- temporal sequence82 . The decision point regards the timing of delivery. AFI, amniotic fluid index; A/RDF, absent or reversed graphic markers of fetal cardiovascular status based diastolic flow; DV, ductus venosus; FHR, fetal heart rate; MPV, on parameters found to be correlated with perina- main portal vein; STV, short term variability; UA, umbilical artery; tal mortality. The parameters most strongly predictive UV, umbilical vein. Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

106 Yagel et al. Turan et al.82 found a well-ordered sequence of Doppler abnormalities in placental insufficiency (Figure 12), from early-onset ones, including increased UA resistance and brain-sparing effect, to late-onset ones, such as absent/reversed UA diastolic velocity, absent/reversed DV A-wave, and UV pulsation. The rate of progression through the sequence correlated significantly with gestational age: when appearing as early as 26–27 weeks of gestation, placental insufficiency was usually severe, progressing from one Doppler abnormality to the next in approximately 7–10 days. When Doppler abnormalities emerged near 30 weeks’ gestation, progression intervals were longer, up to 14 days, and clinically cases were milder. Doppler changes were limited to the arterial system, and the median age of delivery was 33 weeks. These findings, however, were in contrast with those of Arduini et al.85 , who showed that time intervals between arterial Doppler changes and delivery for late fetal heart rate decelerations were statistically significantly longer when Doppler abnormalities appeared before 29 weeks of gestation, compared with late-onset cases (mean interval 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 preceded the 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 and Doppler abnormalities that correspond with placental insufficiency and fetal growth restriction (Figure 12). Abnormalities in venous system Doppler waveforms are sensitive tools for the assessment of fetal well-being Figure 13 Abnormal Doppler waveforms in the umbilical vein (UV) (a), ductus venosus (b) and inferior vena cava (IVC) (c). before 32 weeks’ gestation, and may help to fine-tune our (a) Abnormal UV waveform in hemodynamically compromised decision-making concerning time of delivery in affected fetuses is characterized by the appearance of pulsations. (b) The DV fetuses. normally has forward blood flow throughout the cardiac cycle. In compromised fetuses a drop in atrial systolic forward velocities is observed. As central venous pressure increases, blood flow may be Venous Doppler patterns reversed during atrial systole. (c) Abnormal IVC waveforms in intrauterine growth restriction show a decrease in forward flow Venous Doppler patterns in normal and IUGR fetuses during the S-wave (S) and D-wave (D) and accentuation of reversed have been established in large longitudinal and cross- flow in the A-wave (annotated ‘a’). As the condition deteriorates sectional studies; normal Doppler patterns were discussed the D-wave may be reversed. in Part I of this review. Here we describe Doppler abnormalities seen in the most commonly investigated hydrops104,105 . Pulsatility in the UV can result from two vessels (Figure 13). main sources of pressure waves: atrial contraction can cause a sharp deflection (notch) in UV flow, or a wave Umbilical vein from the neighboring arterial flow, which will be traveling in the same direction, can cause an increment in the UV Umbilical vein Doppler patterns are usually evaluated flow. The resulting pulsatile UV Doppler pattern may in the intra-abdominal portion of the vein. The sample be only an A-wave notch or, in some severe cases, a volume should include the whole cross-section of the triphasic waveform that mirrors the whole cardiac cycle vessel, with an angle of insonation at or as close as possible may appear103 (Figure 13a). to 0◦ . Since the IUGR state includes increased impedance in the fetoplacental circulation, reduced UV flow volume and velocity result. However, the considerable overlap Ductus venosus with normal ranges precludes the usefulness of UV flow velocity as a measure of IUGR103 . Changes in DV flow are seen in hypoxia and hypo- The appearance of pulsatile flow in the UV is a volemia in experimental animal models and in human simple and reliable marker of circulatory compromise, fetuses106 – 110 . The DV is sampled at its inlet, with a large long recognized as a marker of asphyxia in small-for- sample volume in a near-sagittal plane, at a low angle of gestational age fetuses and in cases of non-immune insonation111,112 . Alternatively, DV flow can be sampled Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 93–111.

The fetal venous system, Part II 107 in an oblique transverse section of the fetal abdomen. pressures, flow in the LPV is reduced and may become pul- Normally at 20 weeks’ gestation about 30% of blood is satile, bidirectional or reversed. If reversed, oxygen-poor shunted through the DV, while at 30 weeks about 20% blood from the spleen and gut will mix with oxygenated of blood is shunted103,112 – 114 . In small-for-gestational blood from the UV as it courses to the DV, supplying age fetuses a much higher proportion of blood is shunted oxygen-poor blood to the fetal organs. Ultimately during through the DV, and earlier placental compromise will reversal, more blood could be flowing through the DV show a more pronounced shunt and distension of the than through the UV that supplies it, possibly creating DV103 . suction on the LPV132 . Kilavuz et al.132 showed, in IUGR Cardiac events are apparent in the DV waveform. fetuses with absent or reversed end-diastolic flow in the Reversed or zero flow in the A-wave is a simple sign of UA, that while UV flow remained normal, LPV flow was disordered cardiac function. There is reduced velocity in normal in mildly affected fetuses, pulsatile in fetuses with the A-wave in IUGR, and as the situation worsens it is fur- increased RI or absent flow in the UA, and reversed in ther deflected owing to increased afterload and preload, fetuses with reversed flow in the UA. There was a signif- as well as increased end-diastolic pressure, the direct icant correlation between reversed flow in the LPV and effects of hypoxia and increased adrenergic drive. Taken increased RI in the UA. together, these effects produce an augmented atrial con- The normal distribution of blood flow between the traction and strong deflection during the A-wave in the DV left and right liver lobes is approximately 60%/40%. As waveform97,115,116 (Figure 13b). The combination of this described above, most UV blood (70–80%) perfuses the and the DV distension, which lessens wave reflection at fetal liver, while 20–30% is shunted to the DV. Blood the junction with the UV by lessening the difference in the flow in the UV is directed to the left liver lobe and the vessels’ diameters, produces a considerable effect on UV DV, with only a minority diverted to the LPV and right flow, and further deterioration leads to decreased velocity liver lobe. Low or reversed flow in the left portal branch between the systolic and diastolic peaks. These waveform is an expression of prioritized umbilical perfusion of the changes are most apparent in the second trimester and left liver lobe at the expense of the right114 . usually result from chromosomal aberration as opposed to cardiac decompensation115,117 – 120. Such changes are rarely observed in the third trimester, when improved CONCLUSION endocrine control operates to attenuate them121 – 123 . Congenital malformations of the venous system are a complex and varied group of lesions. There is much that Inferior vena cava we do not know about this system and its anomalies, but it is clear that knowledge of the embryonic devel- The IVC is usually sampled in the fetal abdomen, caudal to opment of affected vessels is key to understanding the the hepatic confluence and DV outlet, to avoid interference in-utero progress and prognosis of these cases. Whenever from neighboring vessels. Reference ranges for normal anomalies of the cardinal, vitelline or umbilical system are IVC flow parameters have been established124 – 126 . The diagnosed, they should prompt thorough investigation of IVC is the preferred vessel for postnatal evaluation of the other segments of the cardiovascular system. It would small-for-gestational age neonates and is familiar to appear that anomalies of the venous system are not as pediatricians, so it is often sampled in the fetus. It is rare as formerly believed, and that more will be diag- normal to observe a negative A-wave in the IVC because nosed if practitioners are cognizant of their sonographic of the vessel’s normally relatively low velocities124 – 128 . appearance and associated anomalies. In compromised fetuses, an abnormal IVC flow velocity waveform will show a decrease in forward flow during the S- and D-waves, and an accentuated reversed flow in REFERENCES the A-wave (Figure 13c). In severe cases the D-wave may 1. 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The fetal venous system, Part II

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