Prenatal diagnosis of abnormalities of the fetal ... - Wiley Online Library

Ultrasound Obstet Gynecol 2000; 15: 231±241.

Prenatal diagnosis of abnormalities of the fetal venous system C. HOFSTAETTER, H. PLATH and M. HANSMANN Division of Prenatal Diagnosis and Therapy, Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany

KEY W OR DS : Abnormal venous system, Embryology, Absent ductus venosus, Absent portal veins, Absent hepatic veins, Interrupted inferior vena cava, Azygos vein, Atrial isomerism, Congenital heart disease

ABSTRACT

INTRODUCTION

Objective To present our experience in the prenatal diagnosis of anomalies of fetal veins using high-resolution color Doppler ultrasound.

The fetal venous system has been investigated intensively in the past few years. It plays a key role in the fetal circulation by transporting oxygenated blood from the placenta to the fetal heart1,2. Kiserud et al.3 have shown that there are two venous pathways to the heart which cross in the upper inferior vena cava (IVC). The left ductus venosus foramen ovale pathway transports approximately 40±50% of the placental blood from the umbilical vein through the ductus venosus (DV) into the left and dorsal portion of the IVC, through the foramen ovale directly into the left heart and to the upper body, and to the brain, heart and adrenal glands. The remaining 50±60% of the placental blood flows via the left and right portal veins into the liver and joins the right IVC right atrium pathway via the right hepatic vein. This pathway collects the less oxygenated blood from the fetal body and the right lobe of the liver and flows mainly into the right heart and, via the ductus arteriosus, into the descending aorta and back to the placenta. Many studies have shown that the DV plays a major role in the regulation of fetal circulation by changing its volume flow depending on the pressure gradient between the umbilical vein (UV) and the heart4,5. There are few case reports on abnormalities of the venous system in the literature and their intrauterine detection by ultrasonography. Congenital heart defects combined with atrial isomerism have also rarely been reported, and mainly in pediatric literature. The outcome of the pregnancies and of the child's life varied, depending on the abnormality and the association with a cardiac defect6±13. The application of high-resolution and color Doppler ultrasonography has enabled the prenatal detection of congenital anomalies of the fetal veins. In addition a targeted fetal examination of the cardiovascular system is being incorporated into the routine scan with increasing regularity. We report 16 cases with an abnormality of the UV, the DV, portal veins, hepatic veins and/or the IVC and superior vena cava (SVC) detected over the past 5 years, and the majority of which were detected in the last

Design An observational study of 16 fetuses with abnormalities of the umbilical, portal, hepatic and caval venous system being diagnosed at the Division of Prenatal Diagnosis and Therapy (Bonn, Germany) over the past 5 years. The abnormality of the venous system, the underlying embryologic disorder and the outcome of the pregnancy are presented and compared with the literature. Results In group A, eight fetuses had an abnormal course of the umbilical vein with a patent (n 3) or absent (n 5) ductus venosus. No portal veins and absent or abnormal hepatic veins were visualized by color Doppler sonography. Six fetuses (75%) did not have an associated malformation and have survived. Two pregnancies with fetal hydrops due to a small heart and to Turner's syndrome were terminated or ended in fetal demise. In group B, seven of eight fetuses with an abnormal caval system had a situs ambiguus or an atrial isomerism. A cardiac defect was detected in six cases (86%). These six pregnancies ended in four terminations of pregnancy and two infant deaths due to the severity of the congenital cardiac defect. One child with a normal heart and a child with an isolated abnormal course of the lower inferior vena cava are developing well. Conclusions In a targeted fetal scan the course of the umbilical vein, ductus venosus, the portal and hepatic veins and inferior vena cava should be carefully examined using color Doppler. Any suspicious finding should be followed by a detailed assessment of the specificity of this abnormality taking into consideration the embryologic development of the fetal venous system together with the associated malformations.

Correspondence: Dr C. Hofstaetter, Division of Prenatal Diagnosis and Therapy, Department of Obstetrics and Gynecology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany Received 12-2-99, Revised 10-8-99, Accepted 17-1-00

O RIGINAL PAPER

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three years. The pre- and postnatal findings are described and discussed in the literature.

Embryology In order to appreciate the large variation in venous abnormalities a short review of the embryology of the venous system is given. There are three pairs of veins, the vitelline, umbilical and cardinal veins (Figure 1). The two vitelline veins transport blood from the yolk sac to the sinus venosus via the liver sinusoids and are connected to each other via anastomoses around the duodenum. The paired umbilical veins transport oxygenated blood from the chorion villi to the sinus venosus, by-passing the liver and co-joining with the cardial veins. The latter transport blood from the embryonal body to the heart (Figure 1a). With the rapid growth of the liver the umbilical veins connect with the liver sinusoids (Figure 1b). The asymmetric development of the heart, and the rotation of the intestinal tract, cause the major change in the venous system by forming a single venous blood stream from left to right. The complete right UV, the cranial part of the left UV, the left vitelline vein and part of the anastomoses obliterate and a new vessel, the DV, develops between the left UV and the right hepatocardial channel, which later becomes the upper IVC (Figure 1c). The upper two anastomoses of the distal vitelline veins fuse to form an S-shaped vessel, the portal vein, while the distal anastomosis forms the superior mesenteric and splenic veins. The proximal parts of the vitelline veins become the hepatic veins (Figure 1d).

Figure 1 Development of umbilical, portal and hepatic venous systems. Adapted from Langman14.

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Figure 2 Development of inferior and superior vena cavae. Adapted from Langman14.

The major body veins, IVC and SVC (Figure 2) also originate from a paired venous system consisting of the anterior and posterior cardinal veins (Figure 2a). With the development of the primary kidneys a new pair of veins, the subcardinal veins, develop (Figure 2b). In contrast with the venous system described earlier, it is the right-sided veins which mainly develop while the left-sided veins and the posterior cardinal veins degenerate. The blood from the left half of the body flows via the left renal vein to the right subcardinal vein. This vein becomes the main body vein and communicates with the right hepatocardinal channel forming the posthepatic part of the IVC. The anastomosis with the right vitelline vein and liver sinusoids forms the hepatic part, the anastomosis of the right and left subcardinal vein at the level of the primary kidneys forms the renal part, and the union with the right sacrocardinal vein forms the prerenal part of the IVC (Figure 2c). The supracardinal veins develop in the upper body. Anastomoses between these veins and between the anterior cardinal veins then form. With the asymmetric development of the heart, the right-sided venous system gains priority. The right common cardinal vein and the right anterior cardinal vein become the SVC, the right supracardinal vein becomes the azygos vein and the left supracardinal vein and its anastomosis become the hemiazygos vein. The blood from the left arm and left half of the head flows via the brachiocephalic vein into the SVC (Figure 2d). This development of the venous system is completed at the end of the first trimester14,15. The development can be disturbed at any stage, causing a wide range of outcomes due to the non-development of anastomoses and the maintaining of the patency of primitive channels7,16. These abnormalities of the venous system, especially of the caval veins, can be associated with abnormalities of the heart, the intestinal tract and the body symmetry, so-called left and right atrial isomerism.

Ultrasound in Obstetrics and Gynecology

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M AT E R I A L S A N D M E T H O D S Approximately 10 000 ultrasound investigations are performed on 3000 patients on average per year in our Division of Prenatal Diagnosis and Therapy. Over the past 5 years, but mainly in the last 3 years, we have studied 16 fetuses with an abnormal venous system, at a mean gestational age of 25 completed weeks (range 19±37 completed weeks). There were eight fetuses with abnormal development of the umbilical, portal and hepatic veins and the DV (group A) and eight fetuses with an abnormal caval venous system (group B). Anomalies of the pulmonary venous system as the primary abnormality were not considered in our study. The primary reasons for referral were enlarged IVC, fetal hydrops, bradyarrhythmia or suspicion of congenital heart defect (Table 1). The ultrasound investigations were performed using a variety of equipment including Acuson XP 10, Aspen, Sequoia (ACUSON, Mountain View, CA, USA) and Sonoline ELEGRA (Siemen's Medical Systems Inc., Issaquah, WA, USA) with 3.5 MHz and 5.0 MHz vector transducers, and pulsed and color Doppler options. The abnormalities of the venous system were detected primarily by realtime ultrasound. Color and pulsed Doppler were added to confirm a suspected abnormality and to determine whether to include or exclude associated malformations. M-mode ultrasound was used additionally in the cases of congenital heart defect and/or arrhythmias. The patients were seen once or had repeat examinations at 2-day to 4-weekly intervals, depending on the type of malformation and the associated malformations. In five cases the pregnancy was terminated, in six cases delivery took place in our Department of Obstetrics and Gynecology. The remaining five pregnancies delivered elsewhere. Reports of the autopsy or delivery and postnatal course were available in four cases. One case of a healthy girl born at term was lost to postnatal follow-up.

R ES U LT S Eight fetuses in group A demonstrated six variations of an abnormal course of the umbilical vein (Table 2). A Table 1

Reasons for referral

Case

Group A

Group B

1

5

Enlarged inferior vena cava Routine scan Fetal hydrops Pericardial effusion, large IVC Severe fetal hydrops

6

Fetal ascites

7 8

Severe fetal hydrops Fetal hydrops

Abnormal course of inferior vena cava Cardiac defect Bradyarrhythmia Malformation scan at 22 weeks' gestation Cardiac defect, bradyarrhythmia Cardiac defect, double bubble Cardiac defect, asplenia Cardiac defect

2 3 4

IVC inferior vena cava.


persisting right umbilical vein (RUV) was seen twice (cases A1 and A6). In one fetus (case A1) only the distal part of the RUV was present and ran parallel to the right umbilical artery (RUA) into the right iliac vein. Case A6 had a complete persisting right hepatic vein, which ran extra hepatically and directly into the right atrium (RA) (Figure 3). There were no DV, portal or hepatic veins detectable with color Doppler. Case A2 had a persisting whole left umbilical vein (LUV), which ran outside the liver directly into the RA. No portal veins and only one atypically situated hepatic vein were seen with color Doppler. All three fetuses demonstrated normal cardiac anatomy. Signs of cardiac dysfunction such as cardiomegaly, early systolic tricuspid regurgitation or a small amount of ascites were present, caused perhaps by the increased cardiac preload due to the abnormal venous system. A late onset of fetal hydrops was seen in one fetus (case A8) at 35 completed weeks of gestation. Persistence of the cranial parts of the LUV and RUV and of the paired cranial vitelline veins with an absent DV led to a holosystolic tricuspid regurgitation, bilateral hydrothorax, ascites and skin edema (Figure 4). Postnatally the hydrops resolved within 3 days. The abnormal venous system was confirmed by angiography and no associated malformations were found. Cardiomegaly and fetal hydrops, which resolved within a few weeks, were seen in two fetuses with a persisting subhepatic anastomosis between the LUV and the right vitelline vein (cases A3 and A4). Case A3 had severe hydrops caused by a Parvo B19 virus infection, which was treated successfully by two intrauterine blood transfusions. The mild hydrops in case A4 resolved spontaneously. The UV had a straight course to the infrahepatic portion of the IVC while a patent DV was localized just at the entrance into the IVC (Figure 5). The DVs were wide and the intracardiac pressure was transmitted into the UV represented as single pulsations. There were no portal veins in either fetus. Normal hepatic veins in one fetus could be visualized by color Doppler. One atypically located hepatic vein, but several hepatic arteries in case 4 were visualized by color Doppler. The heart was normal in both cases. A similar course of the UV was seen in a fetus with severe hydrops and a small, structurally normal heart of 18± 19 mm (case A5). The DV and one hepatic vein entered the RA separately and a single RUA branched off the aorta at the level of the kidneys. An abnormal course of the UV was also seen in a severely hydropic fetus with Turner's syndrome (case A7). The UV was running more anteriorly and to the left and continued via a hepatic vein into the RA. There were no DV and portal veins visible on color Doppler. Cases A5 and A7 were terminated because of rapidly progressing hydrops due to a small heart (case A5), or ended in demise of a karyotypically abnormal fetus (case A7). The remaining six pregnancies continued until at least 35 completed weeks, showing improvement in cardiac function with increasing gestational age and apparently normal fetal development despite the abnormal portal and hepatic venous systems. Only one fetus (case A4) showed

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Abnormal course of umbilical vein with patent or absent ductus venosus, portal veins and/or hepatic veins in group A Patient's data

GA at US

US appearances

Abnormality of venous system

A1

37 yrs G5 P4

271

Enlarged IVC (9.5 mm), cardiomegaly, no CHD

A2

32 yrs G1 P0

371

A3

32 yrs G5 P4

A4

Diagram of abnormality

Doppler pattern

RHV runs parallel to RUA into R iliac vein 1 IVC, no DV, PVs and HVs were visualized

Persistence of distal R UV, obliteration of LUV

DV pattern in IVC

Vaginal delivery at term, female, 3420 g, Apgar 10/10, uneventful neonatal period, postpartum confirmation

Cardiomegaly, early systolic TR, no CHD

Enlarged UV (13 mm) runs left 1 anterior of liver directly into RA, no DV 1 PVs seen, one abnormal HV

Persistence of whole L UV

Biphasic flow pattern in UV, Vmax: 70 cm/s

C-section at 371 wks, male, 3170 g Apgar 10/10, artpH 7.39 short term ventilation, LV insufficient, no DV 1 PV visible on ultrasound postpartum

241

Fetal hydrops (1 anemia, Parvo B19 infection), cardiomegaly, no CHD, intrauterine IUT

UV runs caudal of liver into intrahepatic part of IVC, wide DV, no PVs 1 normal HVs visible on US

Persistence of subhepatic anastomosis between umbilical 1 right vitelline vein

Single pulsations in UV

Repeat C-section at 37 wks, female, 2910 g Apgar 8/9, short-term ventilation of new born postpartum confirmation

39 yrs G1 P0

201

Cardiomegaly, pericardinal effusion, large IVC, no CHD

UV runs caudal of liver into intrahepatic part of IVC, wide DV, no PVs 1 one abnormal HV seen on U/S

Persistence of subhepatic anatomosis between umbilical 1 right vitelline vein

Single pulsations in UV

Vaginal delivery at 39 wks, female, 2250 g (,5.centile), Apgar 10/10, artpH 7.23; hypoglycemia 1 hyperbilirubinamia

A5

27 yrs G1 P0

231

Severe hydrops, small heart of 18 19 mm, no CHD

UV runs caudal of liver into intrahepatic part of IVC, DV 1 HV enter RA separately, no PV

Persistence of subhepatic anastomosis between umbilical 1 right vitelline vein

Double pulsations in UV

Termination of pregnancy for progressing fetal hydrops, female. Confirmation at autopsy

A6

22 yrs G1 P0

271

Mild hydrops ascites

UV runs right 1 anterior of liver directly into RA, no DV, PVs or HVs

Persistence of whole R UV, obliteration of L UV

Biphasic pattern in UV, Vmax 50 cm/s

C-section at 36 wks for PROM 1 breech, female, 3300 g, Apgar 7/ 8, art.pH 7.38, short-term ventilation of newborn, postpartum confirmation on US

Fetal outcome


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Embryological disorder

Case

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Table 2

UV runs into abdomen then divides into two branches running lateral in liver to atria. No DV 1 PVs, atypical HVs Moderate fetal hydrops, bilateral hydrothorax ascites, edema holosystolic TR 351 A8

32 yrs G2 P1

UV runs more anteriorly 1 via HV directly into RA, no DV 1 PVs, normal IVC Severe fetal hydrops, small heart, VSD 45, XO 191 A7

38 yrs G5 P4

Abnormality of venous system US appearances GA at US Patient's data Case

Table 2. continued


CHD ± congenital heart defect; DV ± ductus venosus; HV ± hepatic vein; IUT ± intrauterine bloodtransfusion; IVC ± inferior vena cava; LUV ± left umbilical vein; PV ± portal vein; RA ± right atrium; RHV ± right hepatic vein; RUA ± right umbilical artery; RUV ± right umbilical vein; s ± sagittal section; t ± transverse section of fetal abdomen; TR ± tricuspid regurgitation; US ± ultrasound.

C-section at 36 wks. Male, 2940 g, Apgar 5/9, pH 7.38, shortterm ventilation, resolving of hydrops, hypoglycemia 1 hyperbilirubinamia, confirmation on angiography Normal pattern Persistence of cranial L 1 R UV and vitelline veins, nondevelopment of DV

Intrauterine fetal death at 21 wks, induction of labor with Cergem, maceration 2nd degree, no autopsy Non-development of DV, anastomosis between L UV 1 L hepatocardinal channel

Pulsations in UV

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Diagram of abnormality

Embryological disorder

Doppler pattern

Fetal outcome

Fetal venous system

Figure 3 Extrahepatic course of the umbilical vein directly into right atrium (sagittal section).

growth restriction and demonstrated hypoglycemia and hyperbilirubinemia as a newborn. Case A8 was delivered by Cesarean section at 36 weeks because of fetal hydrops due to an abnormal venous system. The hydrops resolved within a few days after delivery, paralleling the change of fetal to adult circulation. This newborn needed ventilation for a short period of time and had a prolonged hypoglycemia, hyperbilirubinemia and possibly impaired liver function due to the abnormal venous development. Three other neonates (cases A2, A3 and A6) also required artificial ventilation for a short time, perhaps reflecting a sign of increased pulmonary blood flow. The further development of the six newborns has been uneventful to date. A quite different outcome was seen in the eight cases (cases B2, B3, B4, B5 and B6) with an abnormality of the caval system (Table 3). Five fetuses had a left atrial isomerism with interrupted IVC and azygos continuation, and direct connection of the DV and the hepatic veins to the atrium. An associated complex cardiac defect was also present in four of these fetuses. All heart defects had an atrioventricular septal defect (AVSD) in common. Two

Figure 4 Persistence of proximal left and right umbilical veins and proximal vitelline veins (transverse section).

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Figure 5 Subhepatic course of the umbilical vein into intrahepatic part of the inferior vena cava (sagittal section).

pregnancies (cases B2 and B3) were terminated because of severe cardiac defects. An AVSD was combined with a hypoplastic left ventricle and partially abnormal pulmonary venous draining, confirmed at autopsy in case B2. In case B3 a left-transposition of the great arteries (L-TGA), hypertrophy of the ventricles and a dextrocardia were present in addition to the AVSD. This fetus also showed progressing hydrops and a bradyarrhythmia. Case B5 also had a bradyarrhythmia and an isolated AVSD. A postnatal ultrasonography confirmed the heart defect and the interrupted IVC with azygos vein continuation, together with polysplenia, malrotation of the intestinal tract and atresia of the extrahepatic gallducts indicating a left isomerism. Unfortunately the female infant died at 8 months of age after two operations failed to repair the cardiac defect. In the fourth fetus, case B6 and AVSD was combined with a double outlet right ventricle (DORV) and suspected aortic stenosis. The pregnancy progressed to term and a male infant was born by ventouse delivery. The postnatal echocardiography confirmed the AVSD and DORV, but showed a right-sided, normal-sized aortic arch and a pulmonary stenosis. Complex cardiac surgery was performed on the 19th day of life, but the child died shortly after the operation. Case B4 was referred primarily for nuchal translucency at 12 weeks' gestation. A chorion villous sampling excluded a chromosomal disorder. The ultrasound examination at 22 weeks' gestation showed a normal heart, but a left atrial isomerism with an interrupted IVC with azygos vein continuation, a situs ambiguus with a right-sided stomach, a left-sided liver and a large spleen with a suspicion of polysplenia. The prenatal ultrasound findings were confirmed postnatally. A structurally normal heart was confirmed on echocardiography and the child is progressing well. There were two cases of right atrial isomerism in group B (cases B7 and B8). Both fetuses had a situs ambiguus, no visible spleen or splenic vessels and complex cardiac defects, but a normal connection of the IVC and SVC to the atrium. Case B7 had an aplesia of the atrial septum, DORV with right-sided aorta, left SVC and a left single

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Hofstaetter et al. umbilical artery. Case B8 had an AVSD, single ventricle, atretic aorta and mitral valves and dextrocardia. Both pregnancies were terminated due to the severity of the cardiac defects. These were confirmed at autopsy together with the asplenia. One fetus (case B1) had an abnormal course of the distal IVC on the left side, which turned to the right side in its hepatic part. This pregnancy continued to term and the newborn was well. There were only two survivors in group B (cases B1 and B4). Four of the five fetuses with left isomerism, and both fetuses with right isomerism died, due to the severity of the associated cardiac defects. Four pregnancies were terminated and there were two deaths after heart operations in the neonatal period or in infancy.

D ISC U SS IO N Abnormal developments of the fetal venous system are rare and there is a large variation in these abnormalities. In the majority of cases, an abnormal course of veins due to missing obliteration of primitive veins or non-development of new vessels and anastomoses are found7,16,17. The abnormality can either affect the umbilical, hepatic, portal or caval venous system alone, or there may be a combination of defects of the venous systems. Also, venous defects can be associated with abnormalities of the arterial system. If the abnormality only affects the umbilical, hepatic and portal system, it is usually of minor clinical importance. Abnormalities of the major body veins, the IVC and SVC, however, are often associated with major impairments of the development of the heart, the intestinal tract and body symmetry. These associated malformations are of great clinical importance12,13,17. In our study of eight fetuses of group A demonstrated six variations of an abnormal course of the UV. In three fetuses (cases A3, A4 and A5) the UV was running below the liver and entered the IVC in its hepatic part, either with a wide, patent ductus venosus directly before the entrance into the IVC or with DV entering the atrium directly. We suggest, firstly, that the LUV drains into the persisting subhepatic anastomosis to the right vitelline vein, which itself forms, together with the right subcardial vein, the hepatic part of the IVC (Figures 1c and 2c). Secondly, we suggest that the ductus venosus develops at an atypical location. In two cases (A1 and A6) a persisting RUV was present. In the former case the RUV was only present in its lower part, which entered the right iliac vein. In the latter case the whole RUV persisted and entered the right atrium directly. A persisting whole LUV, which entered the right atrium directly, was seen in case A2. An LUV, which was connected to the right atrium via a hepatic vein and an absent ductus venosus was present in case A5. All these cases represent an early disturbance in embryologic development (see Figure 1a,b). In the last case, A6, a left distal umbilical vein divided into left and right branches in the lower liver and continued through the


Abnormal course of caval veins and atrial isomerism in group B Patient's data

GA at US

US appearances of associated malformations

Abnormality of venous system

B1

33 yrs G2 P1

251

Situs solitus; normal heart

IVC runs in the subrenal 1 renal part on the left side parallel to aorta, turns to the right in the intrahepatic part

Normal IVC flow pattern

Vaginal delivery at term, healthy female, no followup data available

B2

25 yrs G2 P1

251

Situs ambiguus, medial position of stomach, spleen present ?; AVSD, hypoplastic LV, partial APVD*

Interrupted IVC with azygos continuation, DV 1 HV enter atrium directly L-isomerism

IVC flow pattern in azygos vein

TOP for CHD, female, confirmation of CHD, asplenia on autopsy

B3

26 yrs G2 P0

231

Situs ambiguus stomach on right side, bradyarrhythmia dextrocardia, AVSD, L-TGA, hypertrophy of ventricles

Interrupted IVC with azygos continuation, DV 1 HV enter atrium directly L±isomerism

RF in DV, single UV pulsations

TOP for CHD and progressing fetal hydrops, female, confirmation of CHD 1 asplenia on autopsy

B4

22 yrs G1 P0

211

Situs ambiguus, stomach on right side, polyspenia, liver on left side, normal heart


Normal flow pattern

Emergency C-section for fetal distress at 40 wks, female, 3070 g Apgar 9/9, art.pH 7.13, no CHD in postpartum echocardiography

B5

28 yrs G2 P1

211

Situs ambiguus, polysplenia*, bradyarrhythmia, AVSD


B6

28 yrs G2 P1

211

Situs ambiguus, medial position of stomach, gallbladder on left side, spleen visible, AVSD, DORV, aortic stenosis


Case

Diagram of course of IVC and aorta

Doppler pattern

Fetal outcome

Fetal venous system


Table 3

Delivery at term, female, confirmation of CHD, also malrotation of intestinal tract 1 atresia of extrahepatic gallducts,; infant death at 8 months after two heart operations Ventouse at term, male, 3900 g, Apgar 9/9, art.pH 7.29; confirmation of AVSD 1 DORV, rightsided aortic arch 1 PS, death after cardiac surgery

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Normal flow pattern

Normal venous connections R±isomerism Situs ambiguus, medial position of stomach, liver on left side, asplenia, dextrocardia, AVSD, single ventricle, atresia of Aorta 1 MV 36 yrs G3 P2 B8

231

41 yrs G2 P0 B7

231

Asplenia, gallbladder on left side, aplesia of atrial septum, DORV right sided aorta, left SUA

Persisting left SVC, R±isomerism

Diagram of course of IVC and aorta Abnormality of venous system US appearances of associated malformations GA at US Patient's data Case

Table 3. continued

238

1 ± umbilical vein, 2 ± stomach, 3 ± aorta, 4 ± azygos or hemiazygos vein, 5 ± spine, 6 ± IVC. *Findings detected postnatally or at autopsy. APVD ± abnormal pulmonary venous drainage; AVSD ± atrioventricular septal defect; CHD ± congenital heart defect; DORV ± double outlet right ventricle; DV ± ductus venosus; HV ± hepatic vein; IVC ± inferior vena cava; L-TGA ± left transposition of the great arteries; LV ± left ventricle; MV ± mitral valve; RA ± right atrium; RF ± reverse flow; s ± sagittal section; SUA ± single umbilical artery; SVC ± superior vena cava; t ± transverse section; TOP ± termination of pregnancy.

TOP for CHD, female, confirmation of CHD 1 asplenia in autopsy

TOP for CHD, male, 590 g, confirmation of CHD 1 asplenia in autopsy

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Doppler pattern

Fetal outcome

Fetal venous system

liver directly into both atria. Other small veins, visualized with color Doppler, divided into smaller vessels in the lower liver. We suggest these findings represent persistence of the left and right proximal umbilical veins, the distal vitelline veins, which drain into the liver sinusoids and a non-development of the ductus venosus. Embryologic development has therefore stopped at the second stage (Figure 1b,c). The DV was absent in the five cases representing an early disturbance in embryologic development (Figure 1b,c). It was patent in the three cases where the anastomosis to the right vitelline vein persisted (Figure 1c). In no fetuses could the portal veins be visualized with color Doppler ultrasound, even using low sensitivity. Similarily, it was not possible to visualize them at postnatal ultrasonography or at autopsy. We suggest that either the portal veins remain very small, or are absent, with the subsequent blood supply to the liver arising via the hepatic arteries, as detected by color Doppler in case A4, and draining from the liver via the liver sinusoids. The hepatic veins were either not visible or presented in an atypical number or in an abnormal course due to obliteration of all proximal vitelline veins or to the non-development of anastomoses. Six fetuses had no associated malformations and all pregnancies continued until at least 35 completed weeks. The neonatal period was only impaired by the need for artificial ventilation for a short period of time in four newborns. Hypoglycemia and hyperbilirubinemia indicating disturbed liver function in the early neonatal period were present in two cases. It remains to be seen, however, whether liver function in these two cases will be normal later in life. The remaining two pregnancies were terminated because of progressing fetal hydrops and a small heart, or ended in fetal demise of a severely hydropic fetus with Turner's syndrome. Jeanty8 reported six cases with persisting RUV of which three had associated anomalies varying from minor to major degree. The remaining three fetuses were normal, although one fetus was growth-restricted, as described in case A4. One of the two fetuses with an abnormal course of the umbilical vein described by Moore et al.10 also presented with an AVSD resulting in a termination of pregnancy. This fetus had an umbilical vein which entered the right iliac vein and the ductus venosus the portal and hepatic veins were absent. The second fetus had a persisting RUV with a patent DV and no associated malformations. Fetal hydrops was seen in six fetuses. Two cases of progressing hydrops were associated with a small heart and Turner's syndrome (cases A5 and A7). Both ended in fetal demise. Three other fetuses demonstrated mild hydrops in the second trimester, which resolved with advancing gestational age (cases A4 and A6) or due to successful treatment of an associated Parvo B 19 virus infection and severe fetal anemia with two intrauterine blood transfusions (case A3). Late onset fetal hydrops was seen in the fetus (case A8) in which non-development of the DV and persistence of the proximal LUV and RUV were present. In


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Figure 6 Diagram of the position of the inferior vena cava relative to the spine in a normal situs and in right and left atrial isomerism.

this case the hydrops progressed in utero, but resolved within days of delivery. A possible cause for this case of hydrops has been previously postulated by Siven et al.18 who describe hydrops with an absent DV, causing umbilical blood to by-pass the liver completely. The anatomical correlations of the aorta to the IVC and the spine and of the venous connections to the atria are very helpful in the sonographic classification of left and right atrial isomerism as described by Huhta19. In situs solitus the aorta is located to the left of the spine and the IVC to the right of the spine. In a situs inversus the location of these vessels is reversed. In right isomerism the aorta and IVC are on the same side of the spine, either left or right, with the IVC running anterior and lateral to the aorta. In left isomerism the aorta runs medial to the spine, the IVC is missing and the azygos vein runs dorsal and lateral to the aorta, either on the right or on the left side (Figure 6). The normal connection of the IVC with the right atrium and the entering of the right hepatic vein into the IVC are also present in right atrial isomerism, as there are two right atria. In left atrial isomerism by contrast, where two left atria are present, the IVC is interrupted in its intrahepatic part, blood flows via the azygos or hemiazygos vein into the SVC and then into the atrium in the majority of cases (Figure 7). This condition arises embryologically from a failure of the right vitelline vein to anastomose with the right subcardinal vein and with persistence of the supracardial veins. The hepatic veins, especially the right hepatic vein, are connected to the right-sided atrium directly via persisting sinus venosus16. This separate entrance of the right hepatic vein into the right-sided atrium is a finding that is always present in left atrial isomerism, whereas an interrupted IVC is found in about 80% of cases of left isomerism. Huhta et al.19 found a normal IVC in two of 16 cases of otherwise definitive left atrial isomerism. A situs ambiguus is a common finding in both types of isomerism. The stomach can be in a left, right or medial position, and can be mistaken as a `double bubble' on ultrasound, as in case B6 (Figure 8). The position of the liver can also be extremely variable. Aplasia of the spleen should be a sign of right atrial isomerism or Ivemark syndrome13. Both fetuses with right isomerism in group B had an absent spleen. In left atrial isomerism one or multiple spleens are usually present, although cases with


Figure 7 The azygos vein entering the atrium with the superior vena cava (sagittal section).

aplasia of the spleen, as in two of our cases, has also been reported20. It should be noted that the sonographic visualization of the spleen can be difficult. An interrupted IVC with azygos vein continuation is present in 0.6% of individuals with congenital heart defects21. Four of our five cases of left atrial isomerism were associated with a complex cardiac defect. All fetuses had an AVSD which was isolated in one fetus and in the remaining three cases, was associated with a single ventricle, aortic stenosis and abnormal pulmonary venous drainage; with a L-TGA, hypertrophy of the ventricles and aortic stenosis or with a DORV and pulmonary stenosis. Only one fetus had a normal heart. Similar cardiac malformations are mentioned in other reports of left isomerism although these were mainly cases of obstruction of the right outflow tract21±25. None of our fetuses with isomerism had a chromosomal disorder, but cases of 22q11 deletion in left atrial isomerism are described26,27. Two fetuses had a bradyarrhythmia due to the fact that the sinus node is either not present or incompletely developed in cases of two left atria. There is usually an AVSD present. Schmidt et al.28 found 29 fetuses with a congenital heart disease, mostly AVSD, in a group of 55 fetuses with complete AV block. A left atrial isomerism was also present in 17 of these 29 fetuses. In our left atrial isomerism group two pregnancies were terminated because of the severity of the associated cardiac defect (cases B2 and B3). The child with the isolated AVSD (case B5) was born at term, but died at the age of 8 months after two heart operations failed to correct the heart defect. A second child with AVSD, DORV and pulmonary stenosis (case B6) was born at term, but died after complex cardiac surgery in the neonatal period. Only the child (case B4) with a normal heart is doing well postnatally. The two cases with right atrial isomerism (cases B7 and B8) had a severe cardiac malformation, either an AVSD with a single ventricle and aortic and mitral atresia or an aplesia of the atrial septum with a left SVC and a DORV. Both pregnancies were terminated.

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6

7 8 9

10 Figure 8 Situs ambiguus demonstrating the medial position of the stomach.

The review of the literature on atrial isomerism also shows a dominance of left atrial isomerism with a better outcome in such cases. This is because left isomerism is either unassociated with a cardiac defect or is present with a correctable heart defect. Right atrial isomerism has a poorer prognosis due to associated severe and complex cardiac defects such as total anomalous pulmonary venous drainage, AVSD, single ventricle DORV and/or obstruction of the right outflow tract. This results in high perinatal, neonatal and infant mortality rates of 70% to 80%12,13,20,29,30. There are few reports of a successful Fontan operation in Ivemark syndrome and in left atrial isomerism24,30,31.

11

12

13 14 15 16 17 18

CONCLUSIONS Abnormal development of the venous system is rare and anomalies vary greatly. While abnormalities of the umbilical, portal and hepatic venous system are rarely associated with other malformations, an abnormal caval venous system is mainly associated with complex cardiac defects, malrotation of the intestinal tract and atrial isomerism. These associated malformations, the grade of impairment of the venous return and the time of clinical onset are predictive of the fetal outcome.

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