Prenatal diagnosis of persistent left superior vena cava and its associated congenital anomalies

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1 Ultrasound Obstet Gynecol 2006; 27: Published online 2 February 2006 in Wiley InterScience ( DOI: /uog.2704 Prenatal diagnosis of persistent left superior vena cava and its associated congenital anomalies C.BERG*,M.KNÜPPEL*, A. GEIPEL*, T. KOHL*, M. KRAPP, G. KNÖPFLE, U. GERMER, M. HANSMANN* and U. GEMBRUCH* *Department of Prenatal Medicine and Obstetrics, University of Bonn, and Department of Pathology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Division of Prenatal Medicine, Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein, Campus Lübeck and Department of Prenatal Medicine, University of Regensburg, Germany KEYWORDS: diagnosis aneuploidy; cardiac defect; echocardiography; fetus; heterotaxy; persistent left superior vena cava; prenatal ABSTRACT Objective To evaluate the associated conditions and the outcome of persistent left superior vena cava (PLSVC) detected in fetal life. Methods This was a retrospective review of all cases of PLSVC detected prenatally between 1998 and 2004 in two tertiary referral centers in Germany. Patient charts, ultrasound video recordings and still frames of all cases were reviewed for associated conditions and outcome. Results Eighty-two cases of PLSVC were detected in the study period. Thirty-seven cases (45%) were associated with heterotaxy syndromes, 19 (23%) with isolated cardiac malformations, seven (9%) with aneuploidy, six (7%) with complex malformation syndromes and six (7%) with isolated extracardiac malformations. Seven cases (9%) had no associated condition. Eighty-three percent of the fetuses in this series had associated cardiac malformations; the most frequent cardiac malformations in those with heterotaxy syndromes were complete atrioventricular septal defect (75%) and right outflow tract obstruction (58%). After exclusion of cases with heterotaxy, most congenital heart defects were ventricular septal defects (41%) and coarctation (34%). The outcome of PLSVC was determined solely by the associated conditions. After exclusion of terminated cases, heterotaxy syndromes as well as complete atrioventricular septal defects were associated significantly with perinatal and infant death. In contrast, all cases with isolated PLSVC or associated correctable extracardiac malformations survived and were doing well at the time of writing. Conclusions PLSVC detected in fetal life has to be followed by a meticulous inspection of the fetal anatomy as it is frequently associated with heterotaxy syndromes, other cardiac/non-cardiac malformations and aneuploidy that determine the outcome. Isolated PLSVC is a benign vascular anomaly and may not affect the outcome. Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Persistent left superior vena cava (PLSVC) represents the most common form of anomalous systemic venous return in adults. It has been observed in 0.3% of autopsies in the general population and in 4 8% of patients with congenital heart disease 1 4. Yet its true incidence is unknown as it is most often asymptomatic and is difficult to detect during routine echocardiographic studies in postnatal patients. The PLSVC usually drains into the right atrium via the coronary sinus and may lead to a dilatation of the latter in the prenatal period 5. The echocardiographic features of a dilated coronary sinus in fetuses and its associated conditions were evaluated recently in two clinical trials and the presence of a PLSVC was confirmed in 96% of the cases 6,7. Although PLSVC was associated most frequently with cardiac defects in these reports, a significant proportion of fetuses also had extracardiac anomalies or no associated conditions 6,7. However, dilatation of the coronary sinus may not identify all cases of PLSVC. We therefore reviewed the databases of our two centers to identify cases of PLSVC Correspondence to: Dr C. Berg, Abteilung für Geburtshilfe und Pränatale Medizin, Zentrum für Geburtshilfe und Frauenheilkunde, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, Bonn, Germany ( christoph.berg@ukb.uni-bonn.de) Accepted: 19 April 2005 Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Fetal persistent left superior vena cava 275 and to review their outcome and associated congenital anomalies. METHODS Patients with a prenatal diagnosis of PLSVC between 1998 and 2004 were identified in the perinatal databases of two tertiary referral centers for prenatal medicine and fetal echocardiography (Bonn and Lübeck, Germany). Patient charts, ultrasound video recordings and still frames of all cases were reviewed for associated conditions and outcome. During the study period the anatomical survey and fetal echocardiography were performed in a standardized fashion. Fetal echocardiography was carried out by a segmental approach using standardized anatomical planes incorporating pulsed-wave and color Doppler imaging 8,9. All ultrasound examinations were performed using an Acuson Sequoia 512 (Siemens, Erlangen, Germany) or an ATL HDI 5000 (Phillips, Solingen, Germany) ultrasound machine, equipped with a 3.5-MHz, 4-MHz, 5-MHz or 7.5-MHz sector or curved array-probe. The three-vessel view was obtained as previously described 9,10 and was an integral part of all echocardiographic examinations. Over the study period 9793 second- and third-trimester echocardiographic examinations were performed in the two centers. Eighty percent of these examinations were routine scans in high-risk patients, and 20% had been referred for suspected fetal anomalies. PLSVC was diagnosed in the presence of an abnormal three-vessel view showing a supernumerary vessel to the left of the pulmonary trunk 10. The diagnosis was then confirmed in the long-axis view, demonstrating by color Doppler direct or indirect drainage via the coronary sinus into the left or right atrium. In our study, the coronary sinus was defined arbitrarily as being dilated when it appeared unusually prominent in a basal four-chamber view of the heart but this was not routinely quantified during the study period. Left isomerism was diagnosed when at least two of the following markers were observed: viscerocardiac heterotaxy; structural heart disease with or without heart block; azygos continuation of an interrupted inferior vena cava. Right isomerism was diagnosed when at least two of the following markers were observed: juxtaposition of descending aorta and inferior vena cava on the same side of the spine; structural heart disease without heart block; viscerocardiac heterotaxy 11. Viscerocardiac heterotaxy was defined as any situs other than situs solitus (levocardia, stomach left, left descending aorta, gallbladder right and portal sinus right) or situs inversus (dextrocardia, stomach right, right descending aorta, portal sinus left and gallbladder left). Postnatal follow-up for a minimum of 1 year was available for all surviving patients of the study population. The prenatal diagnosis of PLSVC was confirmed in all cases during either cardiac surgery or neonatal imaging, or at autopsy. Statistical analysis was performed using the χ 2 and Fisher s exact test. All values are given as mean ± SD unless otherwise indicated. P < 0.05 was considered significant. RESULTS Over the study period 82 fetuses with PLSVC were identified. The mean gestational age at detection was 27 ± 6.8 weeks. Bilateral superior vena cava was diagnosed in 80 cases (Figures 1 and 2). In the remaining two fetuses the right superior vena cava was absent (in one of these fetuses interrupted inferior vena cava and azygos continuation to the PLSVC were also observed (Figure 3); the other had coarctation and severe growth restriction). A dilated Figure 1 Abnormal three-vessel view at 32 weeks in a fetus with severe growth restriction, coarctation and bilateral superior vena cava, showing the supernumerary fourth vessel (persistent left superior vena cava, PLSVC) to the left of the pulmonary trunk (PT). AA, ascending aorta; RSVC, right superior vena cava. Figure 2 Abnormal three-vessel view at 22 weeks in a fetus with left isomerism, complete atrioventricular septal defect, double-outlet right ventricle, pulmonary atresia and interrupted inferior vena cava with azygos continuation to the right superior vena cava (RSVC). Bilateral superior vena cava and a markedly enlarged aorta as well as the missing pulmonary trunk are visible. AA, ascending aorta; PLSVC, persistent left superior vena cava.

3 276 Berg et al. Figure 3 Abnormal three-vessel view in a 32-week fetus with interrupted inferior vena cava with azygos continuity to the persistent left superior vena cava (PLSVC). The PLSVC is evident to the left of the pulmonary trunk and the right superior vena cava to the right of the aorta is missing. AA, ascending aorta; PT, pulmonary trunk. Figure 5 Longitudinal view of the persistent left superior vena cava (PLSVC) entering the markedly dilated coronary sinus (CS) in the same 32-week as in Figures 3 and 4. Figure 4 Four-chamber view in the same 32-week fetus as in Figure 3. A markedly enlarged coronary sinus (CS) is visible, as is the two-vessel sign with parallel course of azygos vein (AZV) and descending aorta (DAO) behind the heart. coronary sinus was documented in 31 cases (Figures 4 and 5). The associated conditions in our series and their outcome are summarized in Table 1. Thirty-seven fetuses (45%) had heterotaxy syndromes (25 left isomerism, 12 right isomerism), 19 (23%) had isolated cardiac defects, 7 (9%) had chromosomal abnormalities, 6 (7%) had complex non-chromosomal malformation syndromes, 6 (7%) had isolated extracardiac anomalies. Seven fetuses (9%) had PLSVC as an isolated finding. Cardiac anomalies were present in 68 fetuses (83%). Their distribution varied depending on the associated condition (Table 2). Of the 37 fetuses with heterotaxy syndromes only one case with left isomerism had no associated cardiac malformation. All cases with chromosomal and non-chromosomal malformation syndromes (n = 13) were associated with cardiac defects (Table 3). The most frequent vascular anomalies were interruption of the inferior vena cava (n = 23), single umbilical artery (n = 12) and juxtaposition of inferior vena cava and aorta (n = 10). Interruption of the inferior vena cava occurred exclusively in left isomerism, while juxtaposition of the inferior vena cava and aorta was associated mainly with right isomerism. Single umbilical artery was distributed equally among the different associated conditions (three in heterotaxy, two in isolated cardiac malformations, three in aneuploidy, two in isolated extracardiac malfomations, one in a complex non-chromosomal malformation syndrome and one in isolated PLSVC). Two cases with complex malformation syndrome were associated with agenesis of the ductus venosus. The predominant extracardiac anomalies in fetuses with heterotaxy syndromes were anomalies of the spleen and various degrees of bowel malrotation. In 22 cases, the status of the spleen was ascertained in the postnatal period (by radioisotope scan, ultrasound or the presence of Howell-Jolly bodies) or at autopsy. Among the 14 fetuses with left isomerism, 11 had polysplenia, one had a single right-sided spleen and two had a normal left-sided spleen. All eight fetuses with right isomerism had asplenia. Additional extracardiac anomalies other than those associated regularly with heterotaxy included agenesis of the corpus callosum (n = 2), unilateral multicystic kidney (n = 2), aplasia of the pancreas (n = 1), annular pancreas (n = 1), postaxial hexadactyly (n = 1) and spina bifida (n = 1). Fifteen fetuses were growth restricted (seven with isolated cardiac malformations, five with chromosomal

4 Fetal persistent left superior vena cava 277 Table 1 Associated conditions and outcome in 82 fetuses with persistent left superior vena cava Associated condition n (%) TOP IUFD NND CD Survived Heterotaxy 37 (46) Left isomerism 25 (31) Right isomerism 12 (15) Isolated cardiac malformation 19 (23) Aneuploidy 7 (9) 6 1 Trisomy 18 3 (4) 3 Trisomy 21 1 (1) 1 Trisomy 13 1 (1) 1 Interstitial deletion chromosome 6 1 (1) 1 Unbalanced translocation 9;15 1 (1) 1 Complex malformation syndrome 6 (7) Smith-Lemli Opitz syndrome 1 (1) 1 Marden Walker-like syndrome 1 (1) 1 Velocardiofacial syndrome 1 (1) 1 Unclassified 3 (4) 2 1 Isolated extracardiac malformation 6 (7) Giant lymphangioma of the neck 1 (1) 1 Esophageal atresia and tracheoesophageal fistula 1 (1) 1 Bilateral diaphragmatic hernia, omphalocele 1 (1) 1 Bilateral renal agenesis 1 (1) 1 Posterior urethral valve and mild megacystis 1 (1) 1 Interrupted inferior vena cava with azygos continuation to PLSVC 1 (1) 1 No associated condition 7 (9) 7 CD, childhood death; IUFD, intrauterine fetal death; NND, neonatal death; TOP, termination of pregnancy. Table 2 Spectrum of cardiovascular anomalies in 68 fetuses with persistent left superior vena cava and associated cardiac defects Heterotaxy Total (n = 68) Left isomerism (n = 24) Right isomerism (n = 12) Isolated cardiac defect (n = 19) Aneuploidy (n = 7) Malformation syndrome (n = 6) Situs Viscerocardiac heterotaxy Visceral situs solitus and levocardia Visceral situs inversus and dextrocardia Venous anomalies Interrupted inferior vena cava Juxtaposition of aorta and IVC Anomalous pulmonary venous return Partial Total 5 5 Cardiac anomalies Atrioventricular septal defect Outlet VSD (not in DORV or TOF) Muscular septal defect Right outflow tract obstruction Pulmonary stenosis (not in TOF) Pulmonary atresia Left outflow tract obstruction Coarctation Hypoplastic aortic arch Transposition Corrected transposition DORV TOF 2 2 Pulmonary atresia with VSD Double inlet ventricle Tricuspid atresia 3 3 Mitral atresia Heart block Hydrops DORV, double-outlet right ventricle; IVC, inferior vena cava; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

5 278 Berg et al. Table 3 Details of 13 fetuses with persistent left superior vena cava and associated complex chromosomal and non-chromosomal malformation syndromes Syndrome Karyotype Associated sonographic and postnatal findings Outcome Edwards syndrome 47,XX + 18 Outlet VSD, bilateral cleft, retrognathia, TOP, no autopsy clinodactyly, SUA, IUGR Edwards syndrome 47,XX + 18 CoA, malalignment VSD, strawberry sign, TOP, no autopsy retrognathia, horseshoe kidney, rocker bottom feet, clinodactyly, SUA, IUGR Edwards syndrome 47,XY + 18 Mitral stenosis, esophageal atresia, clinodactyly, TOP, no autopsy strawberry sign, SUA, IUGR, polyhydramnios Down syndrome 47,XX + 21 CAVSD Biventricular repair, alive Patau syndrome 46,XY,der(13;14)(q10;q10)+13 CoA, perimembranous VSD, brachycephaly, TOP, no autopsy syndactyly, nuchal edema Complex chromosomal Interstitial deletion Muscular VSD, unilateral hydronephrosis, IUGR TOP, autopsy malformation syndrome chromosome 6 46,XX,del(6)(q21q23.1) Complex chromosomal Unbalanced Unbalanced CAVSD, muscular VSD, TA, HRV, TOP, autopsy malformation syndrome translocation 9;15 hyperechogenic kidneys, arthrogryposis, IUGR 46,XY,der (15)t(9;15)(q32;q26.3) Smith-Lemli Opitz Not performed CoA, muscular VSD, ASD II, hypospadias, Survived syndrome PRUV, agen. DV, anal atresia, hypertelorism Marden Walker-like 46,XY CoA, nuchal edema, hypoplastic nasal bone, TOP, autopsy syndrome syndactyly, rocker bottom feet Velocardiofacial syndrome 46,XY d-tga, retrognathia, hypertelorism, exophthalmos, dysplastic ears, micropenis, polyhydramnios Balloon septostomy, switch operation, survived Unclassified complex malformation syndrome 46,XY Unclassified complex 46,XX malformation syndrome Unclassified complex Not performed malformation syndrome Dextrocardia, perimembranous VSD, DORV, PS, juxtapos. IVC/aorta, aplasia of right lung, monolobar left lung, SUA, female phenotype, gonadal dysgenesis, hydrops CAVSD, agen. DV, microphthalmia, hypoplastic nasal bone, Dandy Walker malformation CoA, HLV, Dandy Walker malformation, polyhydramnios, IUGR TOP, autopsy TOP, autopsy NND, no autopsy agen. DV, agenesis of ductus venosus; ASD, atrial septal defect; CAVSD, complete atrioventricular septal defect; CoA, coarctation; DORV, double-outlet right ventricle; d-tga, d-transpostition of the great arteries; HLV, hypoplastic left ventricle; HRV, hypoplastic right ventricle; IUGR, intrauterine growth restriction; juxtapos. IVC/aorta, juxtaposition of inferior vena cava and aorta, NND, neonatal death; PRUV, persistent right umbilical vein; PS, pulmonary stenosis; SUA, single umbilical artery; TA, tricuspid atresia; TOP, termination of pregnancy; VSD, ventricular septal defect. anomalies, two with isolated PLSVC and one with an unclassified complex malformation syndrome). The highest number of pregnancy terminations was performed in the group of fetuses with aneuploidy (86%), followed by complex malformation syndromes (50%) and left isomerism (48%). In the 25 cases with left isomerism most fetuses died in the prenatal period. Twelve pregnancies were terminated (nine had heart block and eight had hydrops) one died in-utero (with heart block), one died in the neonatal period (with heart block and hydrops) and two died in infancy. There were nine survivors with left isomerism, one of them with heart block. In the 12 cases with right isomerism, most deaths occurred in the neonatal period or in infancy: of the 11 continued pregnancies with right isomerism, four neonates and three infants subsequently died. In contrast, the outcome of the 19 cases with isolated cardiac defects was more favorable. Two pregnancies were terminated and two infants died in the postoperative period following single ventricle palliation. After exclusion of terminated cases, heterotaxy syndromes as well as complete atrioventricular septal defect were associated significantly with non-survival (P < 0.05). All cases with isolated PLSVC or associated correctable extracardiac malformations survived and were doing well at the time of writing. DISCUSSION In early development the cephalic portion of the embryo is drained by bilateral symmetrical right and left anterior cardinal veins. The development of the left innominate vein that bridges the anterior cardinal veins at 8 weeks gestation is followed by atrophy of the left anterior cardinal vein. A small portion remains as the left superior intercostal vein and the distal part gives rise to the coronary sinus 1,3. The factors that normally produce obliteration of the lumen of the left anterior cardinal vein or that favor its persistent patency as a PLSVC are uncertain. PLSVC may develop if there is a primary failure to develop

6 Fetal persistent left superior vena cava 279 the innominate vein with subsequent persistent drainage of the left brachycephalic vein via the left anterior cardinal vein which ultimately becomes the PLSVC 1,12. This mechanism would be a plausible explanation for the isolated cases of PLSVC in our series as well as those associated with isolated extracardiac anomalies. On the other hand, there is a striking association with congenital heart defects in our as well as previous studies 1,2,13.Nsah et al. 3 proposed that the physiological obliteration of the left anterior cardinal vein occurs following compression by the growing lungs and the increasing size of the atria. In their retrospective pathological series, PLSVC was found in 104/1208 fetal hearts with congenital abnormalities. A significantly more frequent association was observed with anomalies that would reduce compression of the developing left superior vena cava, such as atrioventricular canal malformation, mitral atresia and cor triatriatum. In our series, atrioventricular septal defect was indeed the leading cardiac defect; however, the large variety of other associated cardiac malformations does not support this concept. Furthermore, atrioventricular septal defect occurred predominantly in fetuses with heterotaxy syndromes (27/32), in which multiple anomalies of the systemic venous connections are invariably present and are more likely to be associated with the underlying defect of lateralization than they are with mechanical factors Given the great variety of associated conditions in our series, the pathogenesis of PLSVC is most likely multifactorial. The spectrum of cardiac malformations in our study differs significantly from that in previous prenatal series that focused primarily on fetuses with a dilated coronary sinus 6,7, but such studies may only represent this subset of fetuses. Dilatation of the coronary sinus was found in only 31 out of 82 cases in our series and was never present in heterotaxy syndromes. In heterotaxy, PLSVC is a frequent association, occurring in 50 70% of cases 11,14,15,17 ; however, the coronary sinus is unroofed in virtually all cases of right as well as most cases of left isomerism 15 17, and will therefore not appear dilated on prenatal echocardiography in the majority of cases. Accordingly, the high proportion of fetuses with heterotaxy syndromes (45%) and their associated cardiac defects accounts largely for the different spectrum of cardiovascular malformations in our series. The most frequent cardiac malformations in the group of fetuses with heterotaxy syndromes were complete atrioventricular septal defect (75%), right outflow tract obstruction (58%) and doubleoutlet right ventricle (36%). These cardiac defects were distributed equally between left and right isomerism. All five cases of total anomalous pulmonary venous return occurred in right isomerism. All 12 cases of heart block were associated with left isomerism. Nine out of 11 cases of hydrops were associated with heart block in left isomerism. After exclusion of cases with heterotaxy most of the congenital heart defects that we encountered were ventricular septal defects (41%) and coarctation/hypoplastic aortic arch (34%), similar to the spectrum described in previous studies on PLSVC associated with dilatation of the coronary sinus 6,7. The association of aneuploidy and PLSVC has been 6,18 20 reported previously and was confirmed in this study. However, most of the fetuses described previously as well as all cases in our study had associated cardiac defects, suggesting an association with the cardiac defects rather than with the chromosomal aberration itself. It has been proposed that a PLSVC may be considered as a marker of embryopathy requiring more attention during the morphological examination, and an analogy with the presence of a single umbilical artery has been made 6. This has been confirmed by the large spectrum of associated cardiac and extracardiac malformations in our series. However, it must be kept in mind that our series may not represent the full spectrum of associated conditions of PLSVC, as it was biased by our referral base. Most of the cases associated with cardiac or extracardiac malformations were referred for suspected fetal anomalies and all of the isolated cases were detected during routine scans in a high-risk population. In addition, the high incidence of growth restriction and single umbilical artery in our study population is explained insufficiently by the proportion of fetuses with chromosomal aberrations. It seems to suggest that more cases of PLSVC are detected if the attention of the examiner is raised by additional pointers (e.g. fetal cardiac and extracardiac anomalies or growth restriction). Therefore the subset of fetuses with associated malformations in our collective is most likely to be larger than that in the general population. In summary, PLSVC detected in fetal life has to be followed by a meticulous inspection of the fetal anatomy as it is frequently associated with heterotaxy syndromes, other cardiac/non-cardiac malformations and aneuploidy that determine the outcome. Isolated PLSVC is a benign vascular anomaly and may not affect the outcome. REFERENCES 1. Steinberg I, Dubilier W Jr., Lukas DS. Persistence of left superior vena cava. 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