Fetal cardiac axis in tetralogy of Fallot: associations with prenatal findings, genetic anomalies and postnatal outcome

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1 Ultrasound Obstet Gynecol 2017; 50: Published online 6 June 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Fetal cardiac axis in tetralogy of Fallot: associations with prenatal findings, genetic anomalies and postnatal outcome Y. ZHAO 1, S. EDINGTON 2,J.FLEENOR 2, E. SINKOVSKAYA 1,L.PORCHE 1 and A. ABUHAMAD 1 1 Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA; 2 Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA KEYWORDS: 22q11 deletion; fetal cardiac axis; fetal echocardiogram; postnatal outcome; pulmonary atresia; right aortic arch; tetralogy of Fallot ABSTRACT Objective To compare prenatal findings, associated genetic anomalies and postnatal outcome in fetuses with tetralogy of Fallot (TOF) with normal cardiac axis (CAx) and those with abnormal CAx. Methods In this retrospective cohort study, 85 cases diagnosed with TOF by prenatal ultrasound at our clinic between 2005 and 2015 were reviewed. Follow-up ultrasound and postnatal outcome were available for 68 cases. One case complicated with absent pulmonary valve syndrome and a further seven cases diagnosed postnatally with anomalies other than TOF were excluded from the study. The remaining 60 cases of postnatally confirmed TOF were divided according to CAx into two groups: those with normal CAx (n = 33) and those with abnormal CAx (n = 27). CAx was defined as the angle between the interventricular septum and midline of the fetal thorax at the level of the four-chamber view. CAx > 65 or < 25 was considered abnormal. Prenatal sonographic findings, associated genetic anomalies and postnatal outcome were compared between the two groups. Results Fetuses with TOF and abnormal CAx were more likely to have pulmonary atresia (40.7% vs 15.2%; P = 0.026) and right-sided aortic arch (48.1% vs 21.2%; P = 0.028) than those with normal CAx. Postnatal death occurred in 30.4% of infants with abnormal CAx vs 6.5% with normal CAx (P = 0.028). Incidence of tested genetic anomalies was similar between the two groups. Conclusion In fetuses with TOF, abnormal CAx is associated with the presence of pulmonary atresia, right-sided aortic arch and a higher risk of postnatal death. Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION Tetralogy of Fallot (TOF) represents a common form of congenital heart defect (CHD), with the following four components: obstructed right-ventricular outflow tract (RVOT), malalignment ventricular septal defect (VSD), overriding aorta and right ventricular hypertrophy. Due to the presence of the fetal shunts, right ventricular pressures are not increased in the fetus; right ventricular hypertrophy develops only postnatally. The reported prenatal detection rate of TOF is % with cardiac screening 1 3. Outflow tract and three-vessels and trachea (3VT) views are important in diagnosis. Typical ultrasound findings of TOF include discrepancy in great vessel size in the 3VT view and the presence of a Y sign in the five-chamber view. Fetuses with TOF can have a deviated cardiac axis (CAx), but otherwise normal appearance in the four-chamber view (4CV). Abnormal CAx is associated with many CHDs, especially conotruncal anomalies, of which TOF is an example 4,5. In a previous study, abnormal CAx was present in about one-quarter of all CHD cases and in one-third of cases with conotruncal anomalies 6. CAx was also found to be more prevalent in cases of fetal conotruncal anomalies with 22q11.2 deletion 7. The etiology of an abnormal CAx is still unclear and its association with prenatal findings, genetic anomalies and postnatal outcome in fetuses with TOF has not been evaluated fully. The aim of this study was to investigate prenatal findings, associated genetic anomalies and postnatal outcome in fetuses with TOF and normal CAx and those with abnormal CAx. METHODS This retrospective cohort study enrolled cases diagnosed with TOF by prenatal ultrasound at Eastern Virginia Correspondence to: Dr Y. Zhao, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 825 Fairfax Avenue, Norfolk, VA 23507, USA ( zhao001@evms.edu) Accepted: 10 June 2016 Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

2 Fetal cardiac axis in tetralogy of Fallot Medical School, Division of Maternal-Fetal Medicine, Fetal Cardiovascular Center, between January 2005 and January Fetuses with absent pulmonary valve syndrome or other cardiac abnormalities were excluded from the study. Sonographic findings, genetic testing results and postnatal outcome data were retrieved retrospectively and reviewed. Prenatal diagnosis of TOF was confirmed by postnatal echocardiography, surgery or autopsy. This study was approved by the Human Investigation Review Board at Eastern Virginia Medical School. Postnatally confirmed cases of TOF were divided into two groups: those with normal CAx and those with abnormal CAx. CAx was defined as the angle between the interventricular septum and the midline of the fetal thorax at the level of the 4CV. CAx > 65 or < 25 was considered abnormal (Figure 1). Measurements were obtained retrospectively at end-systole on stored 4CV images by one author (Y.Z.). Inter- and intraobserver variability of CAx measurements were assessed in a previous study6. Sidedness of the aortic arch and ductus arteriosus were determined in the 3VT view. All genetic testing results were obtained either prenatally or postnatally. Prenatal screening for aneuploidy was performed by first- or second-trimester screening methods and/or by non-invasive prenatal testing. To diagnose chromosomal aneuploidy, prenatal karyotyping on samples obtained by amniocentesis or postnatal karyotyping on peripheral blood samples was performed. Deletion of 22q11.2 was diagnosed by fluorescence in-situ hybridization. Information regarding postnatal outcome was retrieved from postnatal records. 59 Statistical analysis All continuous or ordinal variables were documented as median (interquartile range) and compared between groups using the Mann Whitney U-test. All categorical variables were documented as percentages and compared using the chi-square test or Fisher s exact test, depending on the expected cell frequencies. Odds ratios and 95% CIs were calculated when the difference between groups was found to be significant. All statistical analysis was performed using SPSS Statistics 22.0 (IBM Corp., Armonk, NY, USA). A P-value of < 0.05 was considered significant. RESULTS During the 10-year study period, 85 fetuses were diagnosed with TOF. In 17 cases, diagnosis was not confirmed because patients either delivered elsewhere or were transferred to another facility for a second opinion. Of the 68 cases with postnatally confirmed TOF, one case was complicated by absent pulmonary valve syndrome and was not included in the study. Seven further cases had diagnoses other than TOF (atrioventricular septal defect (n = 1), tricuspid atresia with L-transposition of the great arteries (L-TGA) and coarctation of the aorta (n = 1), polyvalvular abnormality (n = 1), L-TGA with ventricular septal defect (VSD) (n = 1), pulmonary atresia (PA) with intact ventricular septum (n = 1) and perimembranous VSD (n = 2)) confirmed postnatally; these were also excluded from the study. Ultimately, 60 cases with postnatally confirmed TOF, including one case with double-outlet right ventricle (TOF type), were included in the study (Figure 2). Figure 1 Ultrasound images in four-chamber view showing: (a) normal cardiac axis (49 ) in a breech fetus with left aortic arch; and (b) abnormal cardiac axis (89 ) in a breech fetus with right aortic arch. Cardiac axis > 65 was defined as abnormal. Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50:

3 60 Zhao et al. Normal cardiac axis (n = 33) TOF suspected prenatally (n = 85) TOF cases enrolled (n = 60) Lost to follow-up (n = 17) Not TOF (n = 7) TOF with APVS (n = 1) Abnormal cardiac axis (n = 27) Figure 2 Flowchart of inclusion in the study of fetuses with tetralogy of Fallot (TOF). APVS, absent pulmonary valve syndrome. Normal CAx was observed in 33 (55%) fetuses and abnormal CAx (all > 65 ) in 27 (45%) fetuses. There was no significant difference regarding the demographic data between the two groups (Table 1). Prevalence of chromosomal aneuploidy and 22q11.2 deletion were not statistically different between the two groups (Table 2). Both PA (40.7% vs 15.2%; P = 0.026) and right-sided aortic arch (RAA) (48.1% vs 21.2%; P = 0.028) were present more frequently in fetuses with abnormal CAx than in those with normal CAx. After consideration of TOF subtypes, among fetuses with pulmonary stenosis (PS), a significantly higher rate of RAA was observed in those with abnormal CAx (50.0% vs 17.9%, P = 0.040). However, this was not the case for fetuses with PA (Table 2). Gestational age at delivery and neonatal Apgar scores were similar between the two groups. Postnatal mortality was significantly higher in fetuses with abnormal CAx than in those with normal CAx (30.4% vs 6.5%; P = 0.028) (Table 3). There were no significant differences between groups regarding admission to the neonatal Table 1 Maternal characteristics for 60 pregnancies in which tetralogy of Fallot with normal or abnormal cardiac axis (CAx) was confirmed postnatally Characteristic Normal CAx (n = 33) Abnormal CAx (n = 27) P Maternal age (years) 30 (23 35) 28 (24 30) Gestational age at diagnosis (weeks) 22.2 ( ) 23.0 ( ) Gravidity 2 (1 3) 3 (1 4) Parity 0 (0 1) 0 (0 2) Race White 11 (33.3) 13 (48.1) Black 16 (48.5) 10 (37.0) Latino 1 (3.0) 1 (3.7) Asian 2 (6.1) 1 (3.7) Multiracial 3 (9.1) 0 (0) Unknown 0 (0) 2 (7.4) Data are given as median (interquartile range) or n (%). Table 2 Prenatal ultrasound findings and genetic results in 60 fetuses with tetralogy of Fallot with normal or abnormal cardiac axis (CAx) confirmed postnatally Finding Normal CAx (n = 33) Abnormal CAx (n = 27) P Odds ratio (95% CI) Pulmonary atresia 5/33 (15.2) 11/27 (40.7) ( ) MAPCA 1/21 (4.8) 5/21 (23.8) Cardiac axis ( ) 52 (46 58) 71 (69 75) < Sidedness of aortic arch ( ) Left 26/33 (78.8) 14/27 (51.9) Right 7/33 (21.2) 13/27 (48.1) In cases with pulmonary stenosis ( ) Left 23/28 (82.1) 8/16 (50.0) Right 5/28 (17.9) 8/16 (50.0) In cases with pulmonary atresia 1 Left 3/5 (60.0) 6/11 (54.5) Right 2/5 (40.0) 5/11 (45.5) Sidedness of DA in cases with RAA Right 1/4 (25.0) 9/12 (75.0) Left 3/4 (75.0) 3/12 (25.0) Chromosomal aneuploidy* 10/22 (45.5) 9/20 (45.0) 1 22q11.2 deletion 2/16 (12.5) 3/14 (21.4) Data are given as median (interquartile range) or n/n (%). Denominators represent number of cases with data available. *Including 22q11.2 deletion. DA, ductus arteriosus; MAPCA, major aortopulmonary collateral artery; RAA, right-sided aortic arch.

4 Fetal cardiac axis in tetralogy of Fallot 61 Table 3 Postnatal outcome in 60 fetuses with tetralogy of Fallot with normal or abnormal cardiac axis (CAx) confirmed postnatally Outcome Normal CAx (n = 33) Abnormal CAx (n = 27) P Odds ratio (95% CI) Gestational age at delivery (weeks) 38 ( ) 38.6 ( ) Apgar score at 1 min (n = 51) 8 (6 8) 8 (6 8) Apgar score at 5 min (n = 51) 8 (8 9) 8 (8 9) PGE infusion 6/27 (22.2) 5/17 (29.4) Admission to NICU 16/26 (61.5) 15/20 (75.0) Procedure None 3/26 (11.5)* 2/18 (11.1) Palliative surgery 1/26 (3.8) 4/18 (22.2) Multistage repair 4/26 (15.4) 3/18 (16.7) One-stage complete repair 18/26 (69.2) 9/18 (50.0) Postnatal death 2/31 (6.5) 7/23 (30.4) ( ) In cases with pulmonary stenosis 1/26 (3.8) 3/13 (23.1) In cases with pulmonary atresia 1/5 (20.0) 4/10 (40.0) Data are given as median (interquartile range) or n/n (%). Denominators represent number of cases with data available. *One case died before operation. Both cases died before operation. NICU, neonatal intensive care unit; PGE, prostaglandin E. intensive care unit (61.5% vs 75.0%, P = 0.335) or the type of procedure performed after delivery (P = 0.323). In total, 11 infants received prostaglandin E (PGE) infusion after birth. Among those, 10 had PA and one had PS. Of the 39 infants that received postnatal surgical treatment, 1/23 with normal CAx and 4/16 with abnormal CAx had palliative surgery only (P > 0.05). No perioperative mortality was noted in the 34 infants that underwent complete repair. Early complete repair < 3 months after delivery was performed in four infants, all of whom had PA with normal CAx. They required a prolonged hospital stay compared with those who received complete repair 3 months after delivery (median (interquartile range), 31.3 ( ) vs 7 (3 17) days; P = 0.048). DISCUSSION The 4CV is one of the standard planes used in cardiac screening. Normal CAx measured in the 4CV is typically at 45 ± Fetuses with TOF can have either a normal or an abnormal CAx. In this study, we investigated the association of abnormal CAx with prenatal findings, genetic anomalies and pregnancy outcome in fetuses with TOF. Association with prenatal findings CAx represents the orientation of the heart within the chest. Abnormal CAx is usually the consequence of intracardiac and extracardiac anomalies, some of which are well understood, such as a disproportion of cardiac chambers and compression from intrathoracic or abdominal masses 4,5,9,10. Abnormal CAx can be observed in the presence of conotruncal anomalies, with an otherwise normal-appearing 4CV. In this study, 45% of all TOF cases had an abnormal CAx, similar to that reported previously 4,5. Over-rotation of the bulboventricular loop is believed to be the cause of abnormal CAx. Vigneswaran et al. found a negative association between CAx and thymic thoracic ratio in fetuses with 22q11.2 deletion, but not in fetuses with a normal karyotype 7. They speculated that the lack of thymic tissue may allow for greater rotation of the developing heart and increase the CAx. Our study included only five cases with 22q11.2 deletion and thus is not sufficiently powered to confirm this finding. However, not all fetuses with TOF and an abnormal CAx had 22q11.2 deletion or abnormal thymus. This indicates that there may be other mechanisms contributing to abnormal CAx in fetuses with TOF. Based on studies in chick embryos, after initial dextral looping (c-looping) and ventral bending of the heart tube, the c-shaped heart tube continues to bend and rotate (s-looping), causing leftward and caudal displacement of embryonic ventricles. Meanwhile, the distance between the arterial and venous ends of the heart tube is shortened due to the pressure from the splanchnopleure, forcing rotation of the cardiac tube along the cranial caudal axis In a physical simulation model, subtle left- and rightward displacements of the caudal end could determine the direction of cardiac looping. Left displacement usually leads to D-looping 12,14,15. The major momentum of rotation is from the venous end, but it is not unreasonable to presume that changes on the arterial end may also have an impact. Based on our data, RAA is more common in fetuses with abnormal CAx. Sidedness of the aortic arch is determined at the end of cardiac looping, and thus should not impact the direction of looping. However, an anteriorly displaced and enlarged aorta in TOF combined with RAA may cause anterior and rightward displacement on the arterial end and consequently exaggerate the rotation process. However, association between RAA and abnormal CAx was not observed in TOF cases with PA. Association with genetic anomalies Chromosomal anomalies are detected frequently in fetuses with TOF. The reported prenatal incidence is approximately 29% if 22q11.2 deletion is included 16,17.A recent systematic review concluded that 22q11.2 deletion is three times more common in TOF with PA than in TOF

5 62 Zhao et al. with PS, while major trisomies are more often noted in TOF with PS 18. No statistically significant difference was identified between the two groups in our study in terms of prevalence of 22q11.2 deletion. Nevertheless, 22q11.2 deletion is a relatively common finding in fetuses with TOF, and prenatal diagnostic testing should be offered. Association with postnatal outcome Reversed blood flow in the ductus arteriosus is a sign of ductal-dependent circulation and a predictor of adverse postnatal outcome. PGE infusion is required to maintain patency of the ductus arteriosus after birth in those patients. Approximately 90% of all cases that required PGE infusion in this study had PA. Surgical repair of TOF is performed commonly around 6 months after birth. Early operation can also achieve excellent outcome 19. In our cohort, all 34 infants who received complete repair survived the operation. Estimated long-term survival (> 20 years) is more than 90% for patients with corrective surgery 20. However, patients undergoing open heart surgery are at risk of neurodevelopmental deficiencies 16. Complete repair of TOF includes closure of the VSD and widening of the RVOT. Pulmonary valve-sparing surgery (PVSS) and transannular patch (TAP) repair are the two major approaches. PVSS can better preserve the functional pulmonary valve and causes fewer complications. TAP is adopted in cases with a severely stenotic pulmonary valve. Infants with TAP repair are at a higher risk of developing pulmonary regurgitation and a later need for pulmonary valve replacement 17. A pulmonary annulus Z-score of 4 or higher was reported to be a good marker for successful PVSS repair 21. Prenatally, a pulmonary valve Z-score 3.5 in the second trimester and increased pulmonary valve peak systolic velocity 87.5 cm/s were found to be useful in predicting need for TAP repair and earlier intervention 22,23. Outcome prediction should be performed on an individual basis. Our results suggest that fetuses with TOF with an abnormal CAx have higher postnatal mortality. Interestingly, this is different from the findings in cases of diaphragmatic hernia, in which abnormal CAx did not affect survival rate 10,24. One possible explanation is that fetal TOF with abnormal CAx has a higher association with PA, and PA was reported previously as an independent risk factor for death and need for reoperation 19,25. RVOT that fails to grow or actually decreases in size is also associated with a poor prognosis. We acknowledge that our study has some limitations. Its retrospective nature limits the ability to collect more comprehensive data. An important component of consultation with the parents is the long-term physical and mental outcome of fetuses with TOF, which cannot be gained from this study. In addition, the sample size is relatively small. 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