Fetal echocardiographic evaluation of atrial morphology and the prediction of laterality in cases of heterotaxy syndromes

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1 Ultrasound Obstet Gynecol 2005; 26: Published online in Wiley InterScience ( DOI: /uog.1934 Fetal echocardiographic evaluation of atrial morphology and the prediction of laterality in cases of heterotaxy syndromes C. BERG*, A. GEIPEL*, T. KOHL*, J. SMRCEK, U. GERMER, A. A. BASCHAT, M. HANSMANN* and U. GEMBRUCH* *Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Division of Prenatal Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Department of Prenatal Medicine, University of Regensburg, Regensburg, Department of Obstetrics and Fetal Medicine, University of Hamburg-Eppendorf, Hamburg, Germany and Center of Advanced Fetal Care, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, MD, USA KEYWORDS: atrial morphology; echocardiography; fetus; heterotaxy; isomerism; prenatal diagnosis ABSTRACT Objective To evaluate whether abnormal atrial morphology, which is well recognized in autopsy series, is detectable by fetal echocardiographic examination of the four-chamber view, and can therefore be utilized to differentiate left from right isomerism in heterotaxy syndromes. Methods This study was a retrospective review of 30 cases with prenatally diagnosed heterotaxy syndromes. Ultrasound video recordings and still images were reviewed with respect to atrial morphology in the fourchamber view. In 25 cases the morphology of both atria was sufficiently well visualized on the recordings to be evaluated and only these were included in the study. Results Two types of atrial morphology were distinguished in our cohort: a sickle-shape with the tip pointing laterally and apically, and a blunt shape resembling the usual atrial appearance in the four-chamber view. Nineteen out of the 25 cases (76%) presented with isomerism of the atria in the four-chamber view. Thirteen had bilateral sickle-shaped atrial morphology, all associated with left isomerism. Six had bilateral blunt-shaped atrial morphology, all associated with right isomerism. The atria of the remaining six cases were not isomeric, the right atrium being sickle-shaped and the left blunt-shaped. Five of the latter cases were associated with left and one with right isomerism. Conclusions The majority of prenatally diagnosed heterotaxy syndromes seem to present with isomeric atrial morphology in the four-chamber view. In these cases a differentiation between left and right isomerism can be based on the two distinct types of atrial morphology. This may further enhance the prenatal differentiation of these syndromes. Copyright 2005 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Heterotaxy is defined as the abnormal arrangement of viscera across the left-right axis differing from complete situs solitus and complete situs inversus 1,2. There are 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. In contrast, right isomerism features paired right-sided viscera, while left-sided viscera may be absent 3,4. 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 azygos continuation 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, anomalies of ventriculoarterial connections and anomalous pulmonary venous return), 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 4,6,7,9 13. Correspondence to: Dr C. Berg, Abteilung für Pränatale Medizin und Geburtshilfe, Zentrum für Geburtshilfe und Frauenheilkunde, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, Bonn, Germany ( Christoph.Berg@ukb.uni-bonn.de) Accepted: 15 February 2005 Copyright 2005 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Atrial morphology in heterotaxy syndromes 539 The outcome of fetuses diagnosed with heterotaxy syndromes depends on the cardiac and visceral anomalies that are differently distributed between left and right isomerism. Therefore, the two variants of heterotaxy syndromes should be accurately discriminated in the prenatal period in order to allow appropriate counseling of parents and to plan delivery and neonatal management. As the cardiac malformations associated with heterotaxy syndromes show a considerable overlap during the prenatal period, and since the postnatal diagnostic criteria include features that are not reliably assessed in utero (e.g. lung lobulation, bronchial branching pattern and spleen status), prenatal diagnosis of left and right isomerism has traditionally relied on the presence of heart block, cardiac defects, interruption of the inferior vena cava and juxtaposition of the inferior vena cava and aorta 4,9 12. Autopsy studies have shown that recognition of the morphology of the isomeric atrial appendages is the best indication of the existence of the two entities in heterotaxy syndromes 8. In normal hearts the right and left atrial appendages have different morphologies. The left atrial appendage is finger-like and has a narrow base, whereas the right atrial appendage is pyramidal in shape and its base is rather broad 3,8. The right atrial appendage is usually larger and more anterior than the left atrial appendage 6. In right isomerism there are two morphologically right atrial appendages, while in left isomerism there are two morphologically left atrial appendages. The appendages can be visualized at fetal echocardiography in a plane slightly cranial to the four-chamber view but they are not identified reliably under many conditions due to their small size and their location outside of the standard planes 3. Assessment of the morphology of the atrial appendages in utero has been performed successfully in few fetuses with heterotaxy syndromes 14. However, its routine use has never been established 3. It has recently been proposed that the morphology of the atria (not necessarily their appendages) assessed in the four-chamber view is significantly different between left and right isomerism and could therefore enhance the diagnosis of laterality in these syndromes (pers. comm. J.-C. Fouron, 14th World Congress on Ultrasound in Obstetrics and Gynecology, Stockholm, 2004). We therefore retrospectively reviewed all ultrasound recordings of fetuses with heterotaxy syndromes diagnosed in our centers for the different types of atrial morphology, and correlated the results with laterality, and systemic venous and cardiac malformations. METHODS Patients with a prenatal diagnosis of heterotaxy syndrome 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). Ultrasound video recordings and still images of these 30 cases were reviewed with respect to atrial morphology in the four-chamber view. In 25 cases the morphology of both atria was sufficiently visualized on still images of the four-chamber view to be evaluated. In five cases none or only one of the atria was sufficiently visualized as the recordings focused mainly on the principal cardiac defects. These five cases were excluded from the analysis leaving 25 cases for study. In 15 out of these 25 cases S-VHS video or digital video recordings of the examinations were available and were additionally reviewed. The morphology of the atrial appendages was not assessed as they are not usually visible on the standard echocardiographic planes and therefore were rarely and only incompletely demonstrated in our recordings. During the study period the anatomical survey and fetal echocardiography was 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 15,16. For all ultrasound examinations, 3.5-MHz, 4-MHz, 5-MHz or 7.5-MHz sector or curved array probes (Acuson Sequoia 512, Siemens, Erlangen, Germany; ATL HDI 5000, Phillips, Solingen, Germany) were used. Left isomerism was diagnosed in the presence of a combination of at least two of the following markers: azygos continuation of an interrupted inferior vena cava; structural heart disease with or without heart block; and viscerocardiac heterotaxy 2,4,10,17,18. Viscerocardiac heterotaxy was defined as any situs different from 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). Right isomerism was diagnosed in the presence of a combination of at least two of the following markers: juxtaposition of descending aorta and inferior vena cava on the same side of the spine; structural heart disease without heart block; and viscerocardiac heterotaxy 2,4,11. Postnatal follow-up was available for all patients of the study population. The prenatal diagnosis was confirmed in all cases either during cardiac surgery, neonatal imaging studies or at autopsy. In cases with termination of pregnancy, autopsy was performed in seven out of nine cases. Two cases (Cases 2 and 4; Table 1) were included in the study despite missing autopsy data, as the combination of abnormal situs, complex cardiac malformation and heart block allowed a diagnosis of left isomerism with high probability. Statistical analysis was performed using the χ 2 or Fisher s exact test. P < 0.05 was considered significant. RESULTS In our study group 18 fetuses had left isomerism and seven had right isomerism. Left isomerism was significantly correlated with an interrupted inferior vena cava (P < 0.01) and heart block (P = 0.04), while right isomerism was significantly correlated with a juxtaposition of inferior vena cava and aorta (P < 0.01) and totally anomalous pulmonary venous return (P = 0.03). Other cardiac anomalies did not correlate with laterality. Details

3 540 Berg et al. Table 1 Laterality, atrial morphology, and prenatal and postnatal findings of 25 fetuses with heterotaxy syndromes Morphology Case Isomerism diagnosis Left atrium Right atrium Sonographic findings Additional postpartum findings Outcome and follow-up 1 Left Sickle Sickle VCH, CAVSD, muscular VSD, interr. IVC, NIHF, CHB, bilateral talipes LPSVC, bilobar right lung, polysplenia, malrotation TOP, autopsy 2 Left Sickle Sickle Situs inv., CAVSD, PS, interr. IVC, NIHF, HB II, echogenic bowel No autopsy TOP 3 Left Sickle Sickle VCH, pericardial effusion, CAVSD, common atrium, PS, interr. IVC, HB II LAI, DORV, PAPVC, LPSVC, polysplenia, malrotation, bilobed right lung TOP, autopsy 4 Left Sickle Sickle Situs inv., pericardial effusion, CAVSD, CHB No autopsy TOP 5 Left Sickle Sickle VCH, d-mga, DORV, outlet-vsd, PS, interr. IVC, LPSVC Polysplenia, bilobar right lung TOP, autopsy 6 Left Sickle Sickle VCH, VSD, MA, CoA, HLV, interr IVC, sinus bradycardia, SUA CAVSD, biliary atresia, hypoplastic left spleen CD 7 Left Sickle Sickle Situs sol., PS, TAPVC, interr. IVC, CHB No additional findings NND 8 Left Sickle Sickle Situs sol., CAVSD, LPSVC, interr. IVC, sinus bradycardia Polysplenia CD 9 Left Sickle Sickle VCH, CAVSD, DORV, MA, PAPVC, HLV, interr. IVC LPSVC, bilobar right lung, polysplenia, malrotation Alive 10 Left Sickle Sickle VCH, interr. IVC, CAVSD, DORV, PS, LPSVC, CHB, NIHF Common atrium, periventricular leukomalacia NND 11 Left Sickle Sickle VCH, interr. IVC, CAVSD, common atrium, VSD, PA, d-tga, HRV, pericardial effusion LPSVC, PAPVC, right aortic arch Alive 12 Left Sickle Sickle Situs inv., CAVSD, interr. IVC, LPSVC, SUA Muscular VSD, polysplenia, common atrium, PAPVC Alive 13 Left Sickle Sickle Situs sol., CAVSD, PS, interr. IVC, CHB, LPSVC Alive 14 Left Blunt Sickle VCH, CAVSD, DORV, PS, LPSVC, interr. IVC, NIHF, CHB Polysplenia TOP, autopsy 15 Left Blunt Sickle VCH, common atrioventricular-valve without CAVSD, interr. IVC, gall bladder left, PRUV, sinus bradycardia Polysplenia Alive 16 Left Blunt Sickle Situs sol., CAVSD, commom atrium, CoA, interr. IVC, postaxial hexadactyly No additional findings Alive 17 Left Blunt Sickle VCH, interr. IVC, hyperechogenic large kidneys, postaxial hexadactyly, sinus Polysplenia, choledochal cyst Alive bradycardia 18 Left Blunt Sickle VCH, CAVSD, interr. IVC, NIHF, sinus bradycardia LPSVC, incompletely trilobed right lung, polysplenia TOP, autopsy 19 Right Blunt Blunt Situs inv., VSD, HLV, MA, hypoplastic aortic arch, juxtapos. IVC/aorta, plexus Asplenia TOP, autopsy cysts 20 Right Blunt Blunt Situs inv., CAVSD, common atrium, d-tga, agenesis of ductus arteriosus, asplenia Trilobed left lung TOP, autopsy 21 Right Blunt Blunt VCH, CAVSD, d-mga, DORV, juxtapos. IVC/aorta RAI, TAPVC, LPSVC NND 22 Right Blunt Blunt VCH, CAVSD, cc-tga, PS, TAPVC, juxtapos. IVC/aorta Trilobed left lung, asplenia NND 23 Right Blunt Blunt VCH, CAVSD, d-mga, DORV, PS, juxtapos. IVC/aorta TAPVC (to the LPSVC), asplenia CD 24 Right Blunt Blunt VCH, pericardial effusion, CAVSD, double inlet single ventricle, PA, PAPVC, juxtapos. IVC/aorta, SUA 25 Right Blunt Sickle VCH, common atrium, double inlet single ventricle, PA, d-mga, right aortic arch, LPSVC, TAPVC (liver veins), juxtapos. IVC/aorta LPSVC, asplenia Alive Asplenia Alive AA, aortic atresia; AF, atrial frequency; ASD, atrial septal defect; CAVSD, complete atrioventricular septal defect; cc-tga, congenitally corrected transposition of great arteries; CD, childhood death; CHB, complete heart block; CoA, coarctation of the aorta; CTCR, cardio-thoracic circumference ratio; d-mga, dextro-malposition of great arteries; d-tga, transposition of great arteries; DORV, double outlet right ventricle; GA, gestational age; HB II, second degree heart block; HLV, hypoplastic left ventricle; HRV, hypoplastic right ventricle; interr. IVC, interrupted inferior vena cava with azygos vein continuation; IUFD, intrauterine fetal demise; juxtapos. IVC/aorta, juxtaposition of inferior vena cava and aorta; LAI, left atrial isomerism; LPSVC, left persistent superior vena cava; NIHF, non-immune hydrops fetalis; NND, neonatal death; NM, no data available; MA, mitral atresia; MI, mitral insufficiency; PA, pulmonary atresia; PAPVC, partial anomalous pulmonary venous connection; PI, pulmonary insufficiency; PRUV, persistent right umbilical vein; PS, pulmonary stenosis; RAI, right atrial isomerism; Situs inv., situs inversus; Situs sol., situs solitus; SUA, single umbilical artery; TAPVC, total anomalous pulmonary venous connection; TI, tricuspid insufficiency; TOP, termination of pregnancy; VCH, viscerocardiac heterotaxy; VF, ventricular frequency; VES, ventricular extrasystoles; VSD, ventricular septal defect.

4 Atrial morphology in heterotaxy syndromes 541 Figure 1 Four-chamber view in (a) left isomerism, (b) right isomerism, and (c) normal cardiac anatomy. The dotted line illustrates the shape of the right atrium. While in left isomerism the atrial morphology has a sickle shape (a), in right isomerism the atrial shape is blunt and pyramidal (b) and resembles the normal atrial shape (c). concerning cardiac and extracardiac anomalies, atrial morphology, outcome and neonatal management are given in Table 1. Two general shapes of the atria in the four-chamber view were distinguished in our collective: a sickle-shaped atrium with its base at the interatrial septum and the tip pointing laterally and apically (Figure 1a), and a blunt-shaped atrium (Figure 1b) resembling the normal appearance of both atria in the four-chamber view (Figure 1c). The review of video recordings added no further information to the diagnosis of the atrial shapes when compared to the examination of still images alone. Only three out of four possible combinations of atrial shapes could be demonstrated in our cohort: bilateral sickle-shaped atrial morphology (Figure 2); bilateral blunt-shaped atrial morphology (Figure 3); and sickleshaped right atrium in combination with a blunt-shaped left atrium (Figure 4). Nineteen out of the 25 studied cases (76%) presented with isomerism of the atria in the four-chamber view. Thirteen had bilateral sickle-shaped atrial morphology, all associated with left isomerism. Six had bilateral blunt-shaped atrial morphology, all associated with right isomerism. The remaining six cases were not isomeric and had a sickle-shaped right atrium and a blunt-shaped left atrium. Five of the latter cases were associated with left isomerism and one with right isomerism. If only right atrial morphology is considered, sickleshaped anatomy was associated with left isomerism in 18 out of 19 cases (P < 0.01), and was present in all 17 cases with an interrupted inferior vena cava (P < 0.01). Blunt-shaped right atrial morphology was associated with right isomerism in all six cases (P < 0.01) and with five out of six cases with juxtaposition of the inferior vena cava and aorta (P < 0.01). Details on the correlation of atrial morphology with laterality, venous anomalies and main cardiac anomalies are given in Table 2. If only left atrial morphology is considered, sickleshaped anatomy was associated with left isomerism in all 13 cases (P = 0.02) and with interrupted inferior vena cava in 12 out of 13 cases (P = 0.01). A blunt-shaped left atrium did not correlate with laterality or specific cardiac anomalies. Bilateral sickle-shaped atria were significantly correlated with the presence of an interrupted inferior vena cava and heart block (P < 0.01 and P = 0.02, respectively).

5 542 Berg et al. Figure 2 Bilateral sickle-shaped atrial morphology in a case of left isomerism (Case 11) showing the right atrium (filled arrow) and left atrium (open arrow). SP, spine. Figure 4 Sickle-shaped right (filled arrow) and blunt-shaped left (open arrow) atrial morphology in case of left isomerism (Case 16). SP, spine. DISCUSSION Figure 3 Bilateral blunt-shaped atrial morphology in a case of right isomerism (Case 23) showing the right atrium (filled arrow) and left atrium (open arrow). SP, spine. Bilateral blunt-shaped right atria were significantly associated with the presence of a juxtaposition of the inferior vena cava and aorta (P < 0.01). Other cardiac anomalies, including complete atrioventricular septal defect, right outflow tract obstruction, left outflow tract obstruction, single ventricle morphology and abnormal pulmonary venous return, were not significantly correlated to atrial morphology. The intrauterine course and postnatal outcome are significantly different for left and right isomerism, and therefore an accurate prenatal differentiation is mandatory in order to allow appropriate counseling of parents and to plan neonatal management. The greatest attrition in left isomerism occurs in the fetal period, mainly due to the association with heart block, leading to intrauterine congestive heart failure and subsequent demise in a significant proportion of fetuses In contrast, neonates with right isomerism face a significantly higher mortality and postoperative morbidity due to the more complex type of cardiac malformations 2,4,7,9,17, Although morbidity and mortality in the neonatal period are mainly determined by the cardinal cardiac defects, the visceral anomalies may also strongly affect the long-term outcome of these patients. Varying degrees of malrotation and malfixation of the bowel, preduodenal portal vein, gastric volvulus, esophageal hiatal hernia and biliary atresia are predominant in left isomerism, while children with right isomerism and asplenia who survive cardiac palliation are at great risk of dying from sepsis 17, With the improvement in long-term outcome for these patients with modern cardiac surgery, the intra-abdominal anomalies have become increasingly significant 28,29. Accurate prenatal diagnosis of these syndromes prompts a thorough evaluation for digestive tract or splenic disorders in the neonatal period, with the use of prophylactic antibiotics and vaccination in preventing possible non-cardiac complications. Considering the overlap of cardiac and visceral anomalies in the two variants of heterotaxy syndromes,

6 Atrial morphology in heterotaxy syndromes 543 Table 2 Correlation of atrial morphology with laterality and cardiac anomalies in 25 cases of heterotaxy syndromes Left atrium Right atrium Both atria Diagnosis (n) Sickle Blunt Sickle Blunt Bilateral sickle Bilateral blunt Right sickle, left blunt Left isomerism (18) 13* 5 18* 0 13* 0 5 Right isomerism (7) * 0 6* 1 Interruption of IVC (17) 12* 5 17* 0 12* 0 5 Juxtaposition of IVC/aorta (6) * 0 5* 1 LPSVC (14) CAVSD (19) TAPVC (6) Single ventricle (4) Right outflow obstruction (12) Left outflow obstruction (4) Heart block (8) * 0 1 *P < CAVSD, complete atrioventricular septal defect; IVC, inferior vena cava with azygos vein continuation; LPSVC, left persistent superior vena cava; TAPVC, total anomalous pulmonary venous connection. prenatal differentiation of left and right isomerism mainly relies on the presence or absence of heart block and the anomalies of the inferior vena cava. However, these sonographic markers are not invariably present and have been described with a wide variety of prevalence in previous series 4,6,8 11,17, leaving a definitive diagnosis in certain cases in doubt. The most reliable tool for the diagnosis of laterality is the morphology of the atria and their appendages as it has been demonstrated in some autopsy series 6,8. However, this feature has not been evaluated by fetal echocardiography in larger prenatal series. In our study we could demonstrate two types of atrial morphology in the four-chamber view of fetuses with heterotaxy syndromes, although the atrial appendages were not visualized entirely. A possible explanation for this finding is the anatomy of the junction between the appendage and the smooth-walled venous component of the atrium. In the morphologically right appendage this junction is wide and marked with an extensive crest with pectinate muscles extending all around the atrioventricular junction; in the morphologically left appendage this junction is narrow, has no crest, and only minimal extension of pectinate muscles around the atrioventricular junction 8,30. This would explain the wide and blunt shape of the atria in right isomerism as well as the narrow and sickle shape in left isomerism in our collective. Another explanation could be the anatomical distortion of the heart in heterotaxy syndromes, leading to visualization of parts of the atrial appendages already in the four-chamber view. This would also explain our experience that the specific atrial morphologies described in our series could so far not be reproduced in fetuses with normal cardiac anatomy where both atria have a similar round shape in the four-chamber view (Figure 1c). Our results suggest that in fetuses with heterotaxy syndromes, a sickle-shaped atrium in the four-chamber view corresponds to left atrial morphology, while a bluntshaped atrium corresponds to right atrial morphology. Therefore, bilateral sickle-shaped atrial morphology would correspond to left atrial isomerism, while bilateral blunt-shaped atria would correspond to right atrial isomerism. These findings were in keeping with the prenatal and postnatal diagnosis of laterality in the majority of the cases in our collective. However, the morphology of the atria at autopsy or cardiac surgery was sufficiently described in only two cases, preventing further analyses concerning the correlation between the sonographic findings and the real atrial anatomy. In our study the morphology of the atria would have correctly predicted laterality in the 19 (76%) cases with isomeric atrial morphology, while the six cases (24%) with distinct atrial shapes were neither compatible with right nor with left isomerism. However, it has to be kept in mind, that all these cases were previously diagnosed with heterotaxy, based on other criteria and that the presented study is purely descriptive and was not performed in a blinded manner. In fetuses without previously diagnosed heterotaxy syndromes the different types of atrial anatomy identified in this study have to be judged with caution. A sickleshaped right atrium would still be a finding suspicious of left atrial isomerism, while a blunt-shaped right atrium would not necessarily identify right atrial isomerism as the normal right atrial anatomy is also blunt. This applies even more to the left atrial morphology that showed less concordance with laterality in our cohort. Furthermore, our knowledge concerning atrial morphology in the fourchamber view in normal hearts as well as in different types of complex cardiac malformations other than heterotaxy syndromes is fragmentary and needs to be prospectively evaluated. So far, we were not able to demonstrate the two distinct types of atrial morphology presented in this study in normal fetal hearts or cardiac malformations other than those related to heterotaxy syndromes. Therefore, a diagnosis of heterotaxy syndrome has to precede the diagnosis of laterality based on the morphology of the atria.

7 544 Berg et al. It has been hypothesized that the shapes of the atrial appendages in heterotaxy syndromes are related to the hemodynamics in utero rather than to a genetically determined isomerism 31. In the normal heart the inferior vena caval blood stream enters the right atrium from below and flows in the right atrial appendage, distending it and forming the triangular and relatively large shape. The bloodstream through the foramen ovale into the left atrium flows behind the left atrial appendage through the mitral valve, not distending it, resulting in the fingerlike and relatively small shape 32. In right isomerism the inferior vena cava is not interrupted and the atrial septum is often defective in association with common atrioventricular canal. Consequently, the entering venous bloodstream coming from below can flow into both atrial appendages, distending both and resulting in a bilateral broad and triangular shape. In left isomerism the blood flow through the inferior vena cava is typically interrupted, therefore reducing the systemic venous return to the right atrium from below, and simultaneously redirecting the inferior vena cava blood flow via the azygos vein and the superior vena cava into the right atrium from above, where it flows behind the atrial appendage through the atrioventricular valve. Consequently, both atrial appendages are not distended, resulting in a bilateral finger-like and relatively small shape 31. In fact, there was a high correlation of interrupted inferior vena cava and a sickle-shaped right atrium as well as a high correlation of a patent inferior vena cava with a bluntshaped right atrium in our collective. However, as there was only one case without an interrupted inferior vena cava among our cases with left isomerism (also with a sickle-shaped right atrium), and no case of interrupted inferior vena cava occurred among fetuses with right isomerism, it remains unclear whether atrial morphology is genetically determined by the type of isomerism or mechanically modulated by the disturbed hemodynamics in these hearts. Furthermore, neither the presence of an atrioventricular septal defect nor other cardiac anomalies were significantly correlated with atrial morphology, suggesting that atrial morphology is independent from the major cardiac malformations in heterotaxy syndromes. Although our results seem promising, there are several limitations that have to be considered. A potential bias of this study is that it included only patients with heterotaxy syndromes. This is particularly relevant when classifying an atrium as having a blunt shape, which is similar to the normal morphology of both atria in the fourchamber view. Thus, differences between normal and blunt-shaped atria may be more subtle than between a normal and a sickle-shaped atrium as demonstrated in Figure 1. A further bias is certainly the retrospective nonblind design, incorporating video recordings focussing on cardiac defects rather than atrial anatomy, as well as stills that were retrieved at various stages of the cardiac cycle. However, the atrial morphology may be better seen during systole, in particular at the end of systole. Standardizing the stage of the cardiac cycle would therefore be of potential benefit. In summary, a significant proportion of fetuses with heterotaxy syndromes present with isomeric atrial morphology in the four-chamber view at fetal echocardiography. 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