The area behind the heart in the four-chamber view and the quest for congenital heart defects

Ultrasound Obstet Gynecol 2007; 30: 721 727 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5152 The area behind the heart in the four-chamber view and the quest for congenital heart defects C. BERG, M. GEORGIADIS, A. GEIPEL and U. GEMBRUCH Department of Obstetrics and Prenatal Medicine, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany KEYWORDS: cardiac defects; echocardiography; fetus; four-chamber view; heterotaxy; prenatal diagnosis; right aortic arch ABSTRACT Objective To evaluate the spectrum of fetal cardiac defects associated with abnormal sonographic findings in the area behind the heart (ABTH) in the four-chamber view. Methods This study included a retrospective review of 393 fetuses with congenital heart defects (CHD) detected in 2003 2005 at our tertiary referral center and a prospective evaluation of 4666 fetal echocardiograms, including 220 cases of CHD, performed between January 2006 and February 2007. The retrospective and prospective groups did not differ significantly with respect to cardiac anomalies or abnormal findings in the ABTH, allowing us to combine the 613 fetuses with CHD investigated over a 50-month period. Results In the study period, 69 fetuses had abnormalities of the ABTH (75% with major CHD). In 28 fetuses, two equally sized vessels ran behind the heart. Of these, 26 had an interrupted inferior vena cava with azygos continuation and two had total anomalous infracardiac pulmonary venous connection. In 41 fetuses, only one vessel was visualized, but the descending thoracic aorta was positioned contralateral to the cardiac apex. Of these, 29 had levocardia with right descending aorta. All of them had a right aortic arch. The remaining 12 had dextrocardia with left descending aorta. Conclusions The ABTH in the four-chamber view is easy to evaluate and offers important diagnostic markers for fetal CHD. Thus, it might enhance the screening performance of the four-chamber view. Attention must be paid to the number of vessels behind the heart and their laterality. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION In the 1980s, the four-chamber view was proposed as the most important plane for screening the fetal heart. Since then, numerous trials investigating the screening performance of this view have achieved widely divergent results, with detection rates varying from 5% to 92% depending on the training level of the examiner, the sonographic approach and the study population 1. Four potential reasons for poor screening results were offered by Chaoui in an Editorial in this Journal in 2003 1 : 1) inadequate examination; 2) the four chambers are visualized but the anomaly is not detected; 3) the anomaly evolves in utero post-examination; and 4) the heart anomaly is not detectable in the four-chamber view on realtime scanning. As proposed by Chaoui, one of the solutions for the dilemma would be the application of a checklist for normal findings in the four-chamber view. However, one of the most simple characteristics of the four-chamber view is neglected in most checklists published by national and international organizations for prenatal ultrasound 2,3 : under normal conditions, the only major vessel that can be observed behind the heart is the descending aorta, which is positioned on the left side of the spine and on the same side as the cardiac apex. Considering this fact, along with our experience that a considerable proportion of fetuses with cardiac defects have associated right aortic arches 4 and heterotaxy syndromes 5 7 (that may alter both the number of vessels and their position behind the heart), we hypothesized that a significant proportion of fetal cardiac defects might be associated with abnormal findings in the area behind the heart (ABTH) in the four-chamber view on gray-scale realtime imaging. Including the ABTH in a checklist for normal findings in the four-chamber view should therefore enhance the performance of cardiac screening at this level. A number of previous publications have described the possible alterations in the ABTH caused by interrupted Correspondence to: Dr C. Berg, Abteilung für Geburtshilfe und Pränatale Medizin, Zentrum für Geburtshilfe und Frauenheilkunde, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, 53105 Bonn, Germany (e-mail: christoph.berg@ukb.uni-bonn.de) Accepted: 16 May 2007 Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

722 Berg et al. inferior vena cava with azygos continuation 5,8, total anomalous pulmonary venous connection 7,9 and right aortic arch 3,10. In this study, therefore, we evaluated, for abnormal findings in the ABTH, all fetuses with cardiac anomalies detected during a 50-month period in a single tertiary referral center. heart block; viscerocardiac heterotaxy. Viscerocardiac heterotaxy was defined as any situs different from both situs solitus (levocardia, stomach left, left descending aorta, gallbladder right and portal sinus right) and situs inversus (dextrocardia, stomach right, right descending aorta, portal sinus left and gallbladder left). MATERIALS AND METHODS All fetuses with cardiac anomalies detected in the second or third trimester during a 36-month period between 2003 and 2005 were identified in the prenatal database of a tertiary referral center for prenatal medicine and fetal echocardiography (University of Bonn, Germany). Inclusion criteria included cardiac malformations, anomalies of the caval veins and anomalies of the aortic arch. Cases of arrhythmia without cardiac defect, dextroposition secondary to pathological states of the adjoining tissues (e.g. diaphragmatic hernia, congenital cystic adenomatoid malformaion of the lung, sequestration, hydrothorax) and cardiomyopathies were excluded. The video recordings of these 393 cases were reviewed for abnormalities of the ABTH visible in the four-chamber view on realtime gray-scale imaging. In addition, 4666 fetal echocardiograms performed during the 14-month period between January 2006 and February 2007 were evaluated prospectively in the fourchamber view for abnormalities in the ABTH. Eighty percent of the examinations were routine in high-risk patients and 20% of the cases had been referred for suspected fetal anomalies. During this part of the study, 220 cardiac anomalies were detected. The spectrum of detected cardiac anomalies as well as the spectrum and proportion of abnormal findings in the ABTH did not differ significantly between the retrospective and the prospective parts of the trial. Therefore, all 613 cases with cardiac anomalies were included in one combined analysis. 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, color and power Doppler imaging 2,11 ; 5-MHz, 7.5-MHz or 9-MHz sector or curved-array probes were used for all ultrasound examinations (ATL HDI 5000 and IU22 Philips, Hamburg, Germany; Voluson 730 Expert Pro, GE Healthcare, Solingen, Germany). Each examination was performed by one of the three principal investigators (C.B., A.G., U.G.). Left isomerism was diagnosed in the presence of a combination of at least two of the following markers 12 : azygos continuation of an interrupted inferior vena cava; structural heart disease with or without heart block; viscerocardiac heterotaxy. Right isomerism was diagnosed in the presence of a combination of at least two of the following markers: juxtaposition of the descending aorta and inferior vena cava on the same side of the spine; structural heart disease without RESULTS In the study period, 613 fetuses had cardiac anomalies, of which 69 (11.3%) had abnormalities of the ABTH (Table 1). Of the 613 with cardiac anomalies, 533 (87%) had major cardiac defects likely to require intervention in the postnatal period, and 52 (10%) of these had an abnormal ABTH (Figure 1). In 28 fetuses, two vessels approximately equal in size ran behind the heart. Of these, 26 had an interrupted inferior vena cava with azygos continuation (Figure 2) and the other two had total anomalous infracardiac pulmonary venous connection (Figure 3). Four cases had azygos continuation as an isolated finding in situs solitus, while the remaining 24 fetuses in this group were associated with heterotaxy syndromes. The two n 125 100 75 50 25 AVSD CoA VSD DORV TOF TA PA+VSD Isol. RAA TGA DIV TAC Cardiac anomaly ctga Isol. azygos Isol. dextroc Figure 1 Distribution of the cardiac anomalies that were to some extent associated with abnormal findings in the area behind the heart (ABTH). Shaded bars indicate the subset with abnormal findings in the ABTH, while white bars indicate those with normal findings in the ABTH. AVSD, atrioventricular septal defect; CoA, coarctation of the aorta; ctga, atrioventricular and ventriculoarterial discordance; DIV, double inlet ventricle; DORV, double outlet right ventricle; Isol. azygos, isolated aplasia of the hepatic segment of the inferior caval vein with azygos continuation; Isol. dextroc, isolated dextrocardia; Isol. RAA, isolated right aortic arch; PA + VSD, pulmonary atresia with ventricular septal defect; TA, tricuspid atresia; TAC, common arterial trunk; TGA, transposition of the great arteries; TOF, tetralogy of Fallot, VSD, ventricular septal defect.

Area behind the heart 723 Table 1 Principal cardiac anomalies* in 613 fetuses and their association with abnormal findings in the area behind the heart (ABTH) Number of cases Anomaly Total Levocardia, right desc. aorta Double vessel sign Dextrocardia, left desc. aorta Normal ABTH Atrioventricular septal defect 126 6 17 1 102 Coarctation of the aorta 65 0 1 0 64 Ventricular septal defect 57 0 0 2 55 Hypoplastic left heart 54 0 0 0 54 Muscular ventricular septal defect 41 0 0 0 41 Double outlet right ventricle 36 0 1 1 34 Tetralogy of Fallot 31 6 0 0 25 Aortic atresia/stenosis with intact ventricular septum 28 0 0 0 28 Tricuspid atresia 25 1 0 2 22 Pulmonary atresia/stenosis with intact ventricular septum 22 0 0 0 22 Pulmonary atresia with ventricular septal defect 17 8 0 1 8 Tricuspid dysplasia/ebstein s anomaly 16 0 0 0 16 Transposition of the great arteries 14 1 0 0 13 Double inlet ventricle 9 0 1 0 8 Common arterial trunk 8 1 0 0 7 Atrioventricular and ventriculoarterial discordance 7 0 1 1 5 Cardiac tumor 5 0 0 0 5 Interrupted aortic arch 4 0 0 0 4 Mitral atresia with ventricular septal defect 3 0 0 0 3 Others 6 0 0 0 6 Isolated right aortic arch 16 6 0 0 10 Isolated left persistent superior vena cava 9 0 0 0 9 Isolated interrupted inferior vena cava with azygos continuation 7 0 7 0 0 Isolated dextrocardia 4 0 0 4 0 Isolated double aortic arch 3 0 0 0 3 Total 613 29 28 12 544 *Anomalies are grouped according to whether they warrant correction (upper part of table) or do not affect wellbeing (lower part of table). desc., descending. Figure 2 Abnormal four-chamber view displaying two vessels running behind the heart in a fetus with left isomerism, atrioventricular septal defect and aplasia of the hepatic segment of the inferior caval vein with hemiazygos continuation (haz). DAo, descending aorta; Sp, spine. fetuses with anomalous pulmonary venous connection had right isomerism and the 22 fetuses with non-isolated interrupted inferior vena cava with azygos continuation had left isomerism. In the 26 fetuses with azygos Figure 3 Abnormal four-chamber view displaying two vessels running behind the heart in a fetus with right isomerism, unbalanced atrioventricular septal defect and total anomalous infracardiac pulmonary venous return. C, confluence of the pulmonary veins; DAo, descending aorta; Sp, spine. continuation, both vessels were positioned on the left side of the spine in 20 cases and on the right side of the spine in six cases. All 24 fetuses with heterotaxy syndromes had ambiguities of the situs and 21 had complex cardiac

724 Berg et al. malformations. Three fetuses with left isomerism had normal cardiac anatomy. In 41 fetuses, only one vessel was visualized, but the descending thoracic aorta was positioned contralateral to the cardiac apex. Of these, 29 had levocardia with right descending thoracic aorta (Figure 4) and 12 had dextrocardia with left descending thoracic aorta (Figure 5). All 29 fetuses with levocardia and right descending thoracic aorta had a right aortic arch. Six cases had isolated right aortic arch with aberrant left subclavian artery. The remaining 23 had a right aortic arch in combination with cardiac malformations: eight with pulmonary atresia and ventricular septal defect (two of which had microdeletion 22q11), six with atrioventricular septal defect (three of which had right isomerism), six with tetralogy of Fallot (one of which had microdeletion 22q11), one with transposition of the great arteries (right isomerism), one with tricuspid atresia and one with common arterial trunk. Eight of the 12 fetuses with dextrocardia and left descending thoracic aorta had cadiac defects: two with tricuspid atresia, two with perimembranous ventricular septal defect, one with atrioventricular septal defect, one with atrioventricular and ventriculoarterial discordance, one with pulmonary atresia and ventricular septal defect and one with double outlet right ventricle (right isomerism). The remaining four cases had dextrocardia with otherwise normal cardiac anatomy (two of which had extracardiac malformations and two were isolated). The cardiac anomalies among the 613 cases that were to some extent associated with abnormal findings in the ABTH are summarized in Figure 1. 35/613 (6%) cases in our series were associated with heterotaxy syndromes. All 23 cases with left isomerism had an abnormal ABTH (22 with two vessels running behind the heart and one with left descending thoracic aorta in dextrocardia). 5/12 (42%) cases with right isomerism had an abnormal ABTH (three of which had right descending thoracic aorta in levocardia and two had two vessels running behind the heart). 49/613 (8%) cases in our series were associated with a right aortic arch. Of all 45 cases with levocardia and a right aortic arch, 29 (64%) had a right descending thoracic aorta at the level of the four-chamber view. In the remainder, the aorta crossed to the left side above the level of the four-chamber view. 17/613 (3%) cases in our series were associated with dextrocardia (11 in situs solitus, four in heterotaxy syndromes and two in situs inversus). Of these, 12 (71%) had a left descending thoracic aorta. Among the 69 cases with abnormal ABTH, 52 (75%) had major cardiac defects. Nine (17%) of these displayed a normal four-chamber view: four with pulmonary atresia and ventricular septal defect, three with tetralogy of Fallot, one with transposition of the great arteries and one with common arterial trunk. During the prospective part of the trial, four cases had abnormalities in the ABTH without associated cardiac defects: two had isolated dextrocardia with left descending aorta, one had situs solitus with interrupted inferior vena cava with azygos continuation and the remaining case had an isolated right aortic arch. During the prospective part of the trial a transitory dilatation of the esophagus was noted in 10 cases and mimicked a second vessel behind the heart. A repeat scan showing the transitory character of this phenomenon as well as the application of color Doppler showing no signal inside the structure enabled a differentiation Figure 4 Thoracic section in a fetus with tetralogy of Fallot showing normal intracardiac anatomy in the four-chamber view although the area behind the heart is abnormal, with a right descending thoracic aorta (rdao). Sp, spine. Figure 5 Abnormal four-chamber view in a fetus with unbalanced atrioventricular septal defect, dextrocardia and left descending thoracic aorta (LDAo). Sp, spine.

Area behind the heart 725 from a vascular structure to be made in all of these cases. DISCUSSION Fetuses with abnormal findings in the ABTH in our study had three different conditions: heterotaxy syndromes, right aortic arch and dextrocardia; some of the cases those associated with heterotaxy had all three. Heterotaxy is defined as the abnormal arrangement of viscera across the left right axis differing from complete situs solitus and complete situs inversus 13,14.Thereare two recognized variants of heterotaxy: left isomerism and right isomerism. Left isomerism is associated with paired left-sided viscera, while right-sided viscera may be absent; right isomerism features paired right-sided viscera, while left-sided viscera may be absent. Typical findings in left isomerism are bilateral morphological left atrial appendages (left atrial isomerism), multiple cardiac anomalies (with a predominance of atrioventricular septal defect and pulmonary stenosis), congenital heart block, bilateral morphological left (bilobed) lungs with hyparterial bronchi, multiple splenules (polysplenia), intestinal malrotation and interruption of the inferior vena cava with azygous continuation 5,7,12,14 20. The latter represents an excellent marker of left isomerism and the unique appearance of the inferior vena cava as a second major vessel behind the heart has previously been referred to as the double vessel sign 8. The reported incidence of this anomaly among fetuses with left isomerism ranges between 55% in postmortem series and 85% in infants 15,16,18,21. In our previous studies, 93% of fetuses with left isomerism had an interrupted inferior vena cava with azygos continuation 5,6 and in our current series, the incidence was 96%. In contrast, this anomaly is rare under other circumstances. Only few cases of right isomerism with interruption of the inferior vena cava with azygos continuation have been described 21 23. Similarly, interruption of the inferior vena cava with azygos continuation in situs solitus of the chest as a benign vascular malformation, as in the four cases in our present series, is rare 5,24. In right isomerism, typical findings are bilateral morphological right atrial appendages (right atrial isomerism), multiple severe cardiac anomalies (with a predominance of atrioventricular septal defect, pulmonary atresia and anomalies of ventriculoarterial connections), bilateral morphological right (trilobed) lungs with eparterial bronchi, an absent spleen (asplenia) and a malpositioned inferior vena cava, which may be anterior or juxtaposed to the aorta 5,16,17,19,20,25 27. Total anomalous pulmonary venous connection may occur in isolation but is in the majority of cases associated with other cardiac lesions and/or right isomerism 28. In our own previous series of fetuses with right isomerism, 8/22 had anomalous pulmonary venous connection; however, four of them were only diagnosed in the postnatal period 7. In a recent series, 10/16 cases with prenatally diagnosed total anomalous pulmonary venous connection were associated with right isomerism 9. The fetal echocardiographic clues to the diagnosis of total anomalous pulmonary venous connection observed in that study included the inability to demonstrate a direct pulmonary venous connection to the left atrium, the presence of a pulmonary venous confluence behind the atrium, a separation between the posterior wall of the atrium and the descending aorta, and the visualization of an ascending or descending vertical vein 9.These sonographic markers were present in both fetuses with infracardiac pulmonary venous connection, but in none of the four with supracardiac pulmonary venous connection. Although both situations are associated with two vessels running behind the heart in the four-chamber view, azygos continuation and total anomalous pulmonary venous connection have two distinct sonographic appearances: in cases with interrupted inferior vena cava with azygos continuation, the aorta and azygos vein are located in close proximity on the same side of the spine (Figure 2), whereas in total anomalous pulmonary venous connection, the pulmonary venous confluence is situated immediately behind the atrium and a wide gap is apparent between the posterior wall of the atrium and the descending aorta (Figure 3). Dextrocardia is a rare condition. A recent prenatal study found an incidence of 81/36 765 (0.22%) in a highrisk population 29. The situs most frequently associated was situs solitus (47% of cases), followed by situs ambiguous (30%) and situs inversus (23%). Cardiac malformations were present in 74% of cases. In mirrorimage dextrocardia associated with situs inversus of the viscera, the aortic arch is usually right-sided 30 and the ABTH is therefore unchanged. Two of the 17 fetuses with dextrocardia in our present series had this combination and both of them had cardiac defects. In dextrocardia with situs solitus of the viscera, the venous atrium is usually located on the right side, and the aortic arch is, as a rule, situated on the left side, opposite the cardiac apex 30.In our present series, this occurred in 12 of the 17 cases with dextrocardia and seven of these had cardiac defects. Of the remaining four, two were associated with left isomerism and a left aortic arch and therefore had an abnormal ABTH. Two were associated with right isomerism and a right aortic arch and therefore had a normal ABTH. All four had complex cardiac malformations. Right aortic arch in levocardia has two major variants: mirror-image branching and retroesophageal, aberrant, left subclavian artery 30. The risk of concomitant congenital heart disease is over 90% with the mirrorimage branching type and only 10% with the aberrant left subclavian artery type 4,31. In cases of right aortic arch with aberrant subclavian artery, the trachea and esophagus are usually entrapped between the right aortic arch and the left ductus arteriosus. Therefore, a vascular ring is found around the trachea on prenatal ultrasound in the three-vessel view, the so-called U-sign 32,33. This U-sign was found in the 16/45 cases with levocardia and right aortic arch; all were isolated findings and six of them had a right descending thoracic aorta and therefore an abnormal ABTH.

726 Berg et al. In cases with right aortic arch with mirror-image branching, both the aorta and the ductus arteriosus usually lie to the right of the trachea and do not form a vascular ring. The left innominate (brachiocephalic) artery arises first from the aortic arch, followed by the right common carotid and right subclavian artery, in a mirror image of the usual branching pattern 32,34.The most common association is tetralogy of Fallot, in which the incidence of right aortic arch (usually the mirror-image branching pattern) ranges from 13 to 35%. Other frequent associations of right aortic arch are pulmonary atresia with ventricular septal defect and common arterial trunk, in which the incidences of right aortic arch are 31 36% and 15 36%, respectively 30,35. In a fetal autopsy series, Ho et al. found a right aortic arch in 5/20 hearts with left isomerism (only one of these was associated with a rightward orientation of the cardiac apex) and in 5/10 hearts with right isomerism (two of which had the cardiac apex to the right) 18. A similar spectrum of cardiac defects was found in two recent studies on fetal right aortic arches 4,10. These figures were largely confirmed in our present series. All 29 fetuses with levocardia and a right aortic arch that were not associated with a U-sign had cardiac defects, with high incidences of pulmonary atresia with ventricular septal defect (28%), tetralogy of Fallot (28%) and heterotaxy syndromes (17%). Of these 29 cases, 23 (79%) had a right descending thoracic aorta and therefore an abnormal ABTH. An important pitfall in the assessment of the ABTH was encountered during the prospective part of the trial: a dilated esophagus mimicked a second vessel in the ABTH in 10 cases. This phenomenon was always transitory and clear differentiation from vascular origin could be made quickly and easily with color and spectral Doppler assessment. Nevertheless, in fetuses with bowel obstruction or hiatal hernia, this dilation of the esophagus can be persistent and there can be some fluid movement in the esophagus 36. In these cases the dilated esophagus might be difficult to differentiate from a vascular structure. In summary, the ABTH is distorted in a considerable proportion of fetuses with cardiac anomalies, particularly those with heterotaxy syndromes and conotruncal malformations. Abnormal findings in the ABTH may even identify congenital heart disease in the presence of an otherwise unsuspicious four-chamber view. Its inclusion therefore has the potential to enhance the screening performance of the basic cardiac examination in the fourchamber view. 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