Discussion
The survival of patients with heterotaxy is improving. Our survival rates show figures comparable to other contemporary large centre studies from around the world. Nevertheless, this group of cardiac patients is still felt to be at higher risk than those without heterotaxy syndrome. Patients with complex cardiac lesions and heterotaxy syndrome have frequently been compared to, and do less well than, patients with similar cardiac pathology but no heterotaxy syndrome.8–11 The Society of Thoracic Surgeons' Congenital Heart Surgery Database of North America showed that between 1998 and 2009, the discharge mortality after cardiac surgery for patients with heterotaxy syndrome was higher than that of patients without heterotaxy.8 However, some studies suggest that this discrepancy is starting to narrow. One series showed comparable survival rates between patients with and without heterotaxy who required primary total APVD repair between 1995 and 2005.11 Despite a number of studies now supporting an increasingly comparable long-term survival for patients with heterotaxy, they frequently report increased morbidity in the form of arrhythmias, prolonged pleural effusions and reoperations, especially for atrioventricular valve repair.10 ,12 Lim et al13 described an increased need for intervention in cases where biventricular repair was achieved in patients with heterotaxy. This study reported a low incidence of arrhythmias and a high prevalence of symptom-free survival, with 66% of surviving patients falling into NYHA functional class I or II. However, most of our patients had multiple interventions with 71% having three or more surgical or catheter procedures.
Antenatal diagnosis of complex congenital heart disease and heterotaxy syndrome is increasing. Many studies report antenatal diagnosis of heterotaxy syndrome as achievable, as abnormal viscerocardiac situs can often be identified, along with major intracardiac anomalies and specific markers such as an interrupted inferior vena cava in LAI and juxtaposition of the inferior vena cava and aorta in RAI.14 ,15 Fetal heart block in the first trimester is also indicative of LAI.15 The important question is whether antenatal diagnosis improves patient outcome by reducing morbidity and mortality. One would think that the outcome for antenatally diagnosed patients would be improved, as antenatal diagnosis would facilitate prompt intervention for critical lesions. However, so far studies to demonstrate this have been lacking. Lin et al3 found that half of their patients with RAI died despite antenatal diagnosis and that the mortality rate showed no significant differences when compared to similar postnatally diagnosed patients. Another possible reason why antenatal diagnosis has failed to demonstrate improved outcomes for heterotaxy is that, in LAI, it favourably picks up those fetuses with heart block.14 This group of patients has been described as having a poor outcome as they often suffer fetal demise or early neonatal death secondary to hydrops and heart failure.3 ,15 Escobar-Diaz et al16 found that bradycardia was the only predictor of fetal death in a group of 154 fetuses with heterotaxy from 1995 to 2011. However, the same group also found that the 1-year survival rate of antenatally diagnosed patients with heterotaxy syndrome and atrioventricular block or bradycardia was higher than previously published at 63%.17 Our study failed to show a higher rate of survival for cases that were antenatally diagnosed.
Our analysis did not demonstrate the anatomy of the pulmonary veins or atrioventricular valve dysfunction to be significantly associated with poor outcome. Many large centre studies have demonstrated that the presence of anomalous pulmonary venous connections (especially if obstructed), correctly connected but obstructed/stenosed pulmonary veins, and significant atrioventricular valve regurgitation are risk factors for increased mortality in patients with heterotaxy.9 ,11 ,12 ,18 ,19 Lim et al,13 who studied patients with heterotaxy who had a biventricular repair, found that atrioventricular valve regurgitation and anomalous pulmonary venous connections did not increase mortality in these patients and felt that this should be taken into consideration when contemplating borderline cases for biventricular repair. However, an unbalanced complete atrioventricular septal defect was associated with a higher mortality and pulmonary stenosis, pulmonary atresia and a common atrioventricular valve was significantly associated with increased rates of reoperation.13 Five of our patients (14%) had a biventricular repair and they all have good outcomes (no death or cardiac transplant and NYHA class of I). Two of these patients had a balanced complete atrioventricular septal defect, 1 of whom had severe atrioventricular valve regurgitation requiring surgical repair. The other patient had partial APVD.
There appears to be an emerging consensus among cardiologists and cardiac surgeons that repairing APVD at first operation and repairing a regurgitant atrioventricular valve before the Fontan operation leads to a better outcome.7 ,11 ,18 It is felt that while clinically non-obstructed total APVD remains unrepaired, there may in fact be subtle degrees of obstruction that result in elevated or labile pulmonary vascular resistance.18 It is important to note that in patients with heterotaxy, there is the potential for ongoing occult pulmonary venous obstruction. Many authors have described intrinsically small and abnormal pulmonary veins associated with clinically non-obstructed total APVD, which carry the risk of developing stenosis and increasing risk of death.7 ,20 Our study did not demonstrate that total APVD, with or without obstruction, was statistically associated with poor outcome.
Twenty-two of our patients (63%) were asplenic. Eight patients suffered episodes of sepsis, three of whom were asplenic. Absence of a spleen confers decreased immunity from encapsulated bacteria and increased risk of sepsis. It is very important that asplenic patients receive vaccines against encapsulated bacteria at the earliest possible time and that they comply with lifelong daily penicillin prophylaxis. Interestingly, Chiu et al21 found that patients with heterotaxy syndrome had an increased risk of community-acquired severe bacterial infection and higher mortality compared to other complex cardiac patients, whether a spleen was present or not. Our study did not show absence of a spleen to be associated with poor outcome.
This study has several limitations. It is a retrospective, descriptive study involving 1 centre and only 35 patients. This is a small sample size making statistical analysis of poor outcome challenging. This cohort of patients was not matched to patients with similar cardiac anatomy but without heterotaxy. Any patients who were diagnosed with heterotaxy antenatally and subsequently terminated, or for whom active management was not requested by the parents, were not included in this study.
Survival for patients with heterotaxy syndrome was 83% over a median follow-up of 65 months. Thirty-four per cent of patients had a poor outcome. None of the 16 variables studied were found to be predictors of poor outcome, but this may be a function of the small sample size. Since outcomes for patients with complex congenital heart disease and heterotaxy are comparable to those for patients with similar heart disease and no heterotaxy, this may influence the way in which clinicians counsel patients and their guardians about active management.