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Longitudinal Assessment of Outcome From Prenatal Diagnosis Through Fontan Operation for Over 500 Fetuses With Single Ventricle‐Type Congenital Heart Disease: The Philadelphia Fetus‐to‐Fontan Cohort Study

Background Prenatal diagnosis of single ventricle‐type congenital heart disease is associated with improved clinical courses. Prenatal counseling allows for optimal delivery preparations and opportunity for prenatal intervention. Expectant parents frequently ask what the likelihood of survival through staged palliation is and the factors that influence outcome. Our goal was specifically to quantify peri‐ and postnatal outcomes in this population. Methods and Results We identified all patients with a prenatal diagnosis of single ventricle‐type congenital heart disease presenting between July 2004 and December 2011 at our institution. Maternal data, fetal characteristics, and data from the postnatal clinical course were collected for each patient. Kaplan–Meier curves and multivariate analysis with logistic regression were used to evaluate variables associated with decreased transplant‐free survival. Five hundred two patients were identified, consisting of 381 (76%) right ventricle– and 121 left ventricle–dominant lesions. After prenatal diagnosis, 42 patients did not follow up at our center; 79 (16%) chose termination of pregnancy, and 11 had intrauterine demise with 370 (74%) surviving to birth. Twenty‐two (6%) underwent palliative care at birth. Among 348 surviving to birth with intention to treat, 234 (67%) survived to at least 6 months post‐Fontan palliation. Presence of fetal hydrops, right ventricle dominance, presence of extracardiac anomalies, and low birthweight were significantly associated with decreased transplant‐free survival. Conclusions In patients with a prenatal diagnosis of single ventricle‐type congenital heart disease and intention to treat, 67% survive transplant‐free to at least 6 months beyond Fontan operation. An additional 5% survive to 4 years of age without transplant or Fontan completion. Fetuses with right ventricle–dominant lesions, extracardiac anomalies, hydrops, or low birthweights have decreased transplant‐free survival.

S ingle ventricle-type congenital heart disease (SVCHD) consists of a spectrum of malformations in which there is significant hypoplasia of either the right or left ventricle with no anatomical or functional capacity for viability of a 2-ventricle system. Left to its natural course, the condition is lethal in most circumstances. A surgical strategy has evolved over the past 40 years that allows for survival. Staged palliative surgery culminating in the Fontan operation can be undertaken in which the guiding principle is to assign the task of systemic perfusion to the single ventricle while creating a passive pathway for systemic venous return to the pulmonary circulation. Outcomes of individual aspects of staged palliation for SVCHD are well characterized, and long-term survival has increased following improvements in surgical technique and postoperative management. [1][2][3][4] Despite the tremendous challenge and effort necessary to create good outcomes for these complex and fragile patients, survival rates at 5 years of age are now reported to approach 70% for patients with hypoplastic left heart syndrome (HLHS) and are slightly higher for patients with dominant single left ventricular (LV) morphology. [5][6][7][8] The changing outcome statistics for SVCHD can be best understood within the context of current advances in medicine overall. Today, the most common means of initial detection of SVCHD has shifted from identification of neonatal signs of decompensation to prenatal detection in utero. Improvements in obstetrical ultrasound have enabled increased diagnosis of cardiac anomalies in utero, and SVCHD is known to have among the highest prenatal detection rates within congenital heart disease. [9][10][11][12] Prenatal diagnosis is associated with a number of benefits, including improved preoperative clinical status before initial surgery, shorter postoperative mechanical ventilator support, and improved long-term neurological outcomes when compared with those diagnosed after birth. 11,13,14 Counseling before birth allows for parental education and preparation for delivery at highvolume tertiary care centers that can provide optimal neonatal management. 15 Infants with a prenatal diagnosis of SVCHD demonstrate improved myocardial function and increased survival following initial surgery. 13,16 In contrast, fetal diagnosis may also increase the viability of newborns with extracardiac risk factors, given that these high-risk patients may not have previously survived to neonatal identification before the era of prenatal diagnosis and fetal care. Despite this shift toward prenatal diagnosis and the likely impact of fetal detection on overall outcome, survival outcomes for prenatally diagnosed patients beyond the initial palliative procedures are not well characterized and have only recently become a subject of study. 17 Today, prenatal diagnosis is the most common and desired path of entry into the system of care for patients with SVCHD. At prenatal counseling, expectant parents frequently ask: (1) What is the likelihood that our fetus with SVCHD will be alive after completion of all stages of surgical reconstruction?; and (2) What are the factors that influence the outcome? The purpose of our study is to answer these fundamental questions through longitudinal analysis of a large, singlecenter cohort of patients prenatally diagnosed with SVCHD. We also characterize outcomes from the earliest point of detection in fetal life through completion of anticipated surgical palliation after Fontan operation.

Methods
Data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. The database at the Fetal Heart Program at the Children's Hospital of Philadelphia (CHOP) was searched to identify all patients with a prenatal diagnosis of SVCHD presenting between July 2004 and December 2011. Inclusion diagnosis of SVCHD was determined based on the impression formed by the attending faculty fetal cardiologist who interpreted the fetal echocardiogram and counseled the family. This decision was made because of the fact that some cases may present as borderline between 1-or 2-ventricle-type heart disease, and there are no strict criteria for differentiating these. 18,19 Serial fetal imaging and counseling took place, with multiple assessments performed during the pregnancy in most cases. The fetal cardiologist determined that an SVCHD strategy resulting in a Fontan operation was strongly likely as the postnatal management plan, at the latest, by the final fetal encounter before delivery. The time frame of up to 2011 was chosen in order to provide a contemporary cohort for longitudinal analysis from prenatal diagnosis through potential completion of staged palliation with a Fontan operation, which, in our center, typically occurs at %2 to 3 years of age.
Approval was obtained through the CHOP Institutional Review Board (CHOP IRB # 15-012216 CR1) for this investigation. The requirement of informed consent was waived. SVCHD included both dominant right ventricular (RV) and dominant LV lesions. Examples of dominant single LV lesions include: double-inlet left ventricle, tricuspid atresia with D-looped ventricles, pulmonary atresia with intact ventricular septum, single left ventricle, and unbalanced atrioventricular canal to the left ventricle. Examples of dominant single RV lesions include: HLHS and unbalanced atrioventricular canal to the right ventricle. Patients presenting with heterotaxy syndrome were characterized according to morphology of the ventricle most likely associated with the aorta and thus assigned the task of perfusing the systemic circulation. All patients included in the study underwent at least 1 complete fetal echocardiogram. Fetuses deemed to have mild ventricular size discrepancies or considered

Clinical Perspective
What Is New?
• This study evaluates outcomes of a large single-center cohort of single ventricle-type congenital heart disease, uniquely followed longitudinally from fetal diagnosis through completion of anticipated surgical reconstruction. • Pre-and perinatal risk factors for decreased transplant-free survival include the presence of fetal hydrops, right ventricular dominance, the presence of extracardiac anomalies, and low birthweight.
What Are the Clinical Implications?
• Survival attrition occurs throughout the trajectory of preand postnatal care for the fetus with single ventricle-type congenital heart disease, with only 67% of those delivered with intention to treat surviving 6 months beyond Fontan operation. • This information improves accuracy of prenatal counseling for expectant parents and defines the areas of focus and challenges for reduction in mortality.
promising candidates for biventricular repair were excluded. Patients were also excluded if they presented with a prenatal diagnosis from an outside institution or were diagnosed with SVCHD postnatally without prenatal detection. Maternal variables collected for analysis include maternal age at the time of diagnosis, gravidity and parity, and the presence of singleton pregnancy or multiple gestation. Fetal variables include gestational age at time of initial diagnosis, presence of genetic or chromosomal abnormalities, presence of extracardiac anomalies, heterotaxy syndrome, hydrops, cardiac diagnosis, ventricular systolic dysfunction, atrioventricular valvar regurgitation (based on fetal echocardiogram report), and the presence of fetal arrhythmia. Variables selected as potential risk factors are based on experience and previously reported observations. 20,21 Diagnoses from fetal echocardiography were confirmed by review of postnatal echocardiogram reports. For infants surviving to birth with intention to treat, we collected postnatal variables, including gestational age at birth, birthweight, sex, and type of surgery performed at each stage of palliation. Because not all prenatally diagnosed SVCHD patients went on to have typical staged surgical repair, we broadly defined a "first surgical intervention" or "first operation" to include stage 1 Norwood procedures, aorto-pulmonary shunt only without a Damus-Kaye-Stansel, pulmonary arterial banding, and hybrid procedures. The hybrid procedure was defined by bilateral pulmonary artery band placement and ductal stenting, as an alternative means of providing unobstructed systemic outflow and limited pulmonary blood flow. Second-stage surgical palliations included bidirectional Glenn, bilateral bidirectional Glenn, Kawashima, and hemi-Fontan procedures. 22 Thirdstage surgeries included extracardiac conduit and lateral tunnel-type Fontan operations. Additional variables known to affect survival outcome were also collected. Specifically, use of extracorporeal membrane oxygenation post-operatively at any stage, presence of postoperative ventricular dysfunction or AV valve regurgitation, the need for additional cardiac catheterizations outside of anticipated diagnostic preoperative assessment, and any surgeries outside of anticipated staged palliation were variables included in the multivariate analysis.
Analysis was performed for 2 cohorts: (1) all patients presenting with prenatally diagnosed SVCHD and (2) infants who survived to live birth, with intention to treat. Among the entire cohort of patients presenting with prenatally detected SVCHD, outcomes were defined by 4 categories: elective termination of pregnancy (TOP), intrauterine fetal demise, survival to live birth with nonintervention palliative care in which prostaglandin infusion is not administered, and survival to live birth with intention to treat. For infants who survived with intention to treat, the primary outcome was defined as transplant-free survival. Patients who only had one fetal echocardiogram with no further follow up clinical encounters at CHOP were considered lost to follow-up, which we state as having "no follow-up" in the fetal period. Patients who underwent initial postdelivery care or surgical palliation, but who did not receive further care at our center, were considered to have no follow-up in the postnatal period and were censored in the survival analysis as described below.

Statistical Analysis
Descriptive statistics are reported for demographic data and clinical measures. Survival analysis was performed on only patients who survived to birth with intention to treat (n=348). Kaplan-Meier survival curves and log-rank tests were generated to assess the univariate association between time to death or transplant and each of the categorical variables, which were summarized as n (%). Simple Cox regression tests were used to test the bivariate association between time to death or transplant and each of the continuous variables, summarized as median (range). Patients lost to follow-up in the postnatal period were censored at their last known clinical encounter at our institution. Patients surviving to 6 months post-Fontan were censored at that point, and patients on nontraditional surgical pathways were censored at 4 years of age. The 6-month post-Fontan censorship age was used to (1) ensure any adverse postoperative outcomes were captured and (2) maximize the number of patients included in this study who had reached the generally accepted time of 6 months after surgery, by which point full recovery is anticipated. The censorship age of 4 years of age for the nontraditional pathway patients not leading to Fontan completion was selected because it is the approximate average age at which the SVCHD patients were 6 months post-Fontan operation. The variables that were significant at the P≤0.05 level in univariate analysis were then entered into the final multivariate Cox regression model. Statistical tests were based on a two-tailed test at a 0.05 significance level. All statistical analysis was performed using SAS software (version 9.2; SAS Institute Inc, Cary, NC).

Patient Characteristics
Between July 2004 and December 2011, a total of 502 fetuses with a prenatal diagnosis of SVCHD were evaluated at the Fetal Heart Program at CHOP. HLHS was the most common diagnosis, accounting for 43% of fetuses (Table 1) and 24% were LV dominant lesions, with tricuspid atresia the most common subtype. Median maternal age at fetal diagnosis was 30.1 years, with a range of 15.7 to 46.0 years. Median gestational age at fetal diagnosis was 24.0 weeks, with a range 13.9 to 38.7 weeks. Thirty-six of 502 mothers (7%) had twin gestations; in all cases, only 1 fetus had congenital heart disease. Heterotaxy occurred in 72 patients (14%), with asplenia present 57% of the time. Chromosomal abnormalities were detected in 45 fetuses (9%) and extracardiac abnormalities in 99 cases (20%). Hydrops was noted in 8 fetuses (1.6%). In terms of fetal arrhythmia, third-degree heart block was present in 10 cases, sinus bradycardia in 4, and ventricular tachycardia in 1 case. Incidence of significant fetal ventricular dysfunction or AV valvar regurgitation was relatively low (Table 2); 37 patients (7%) had moderate or severe AV valve regurgitation, and only 6 (1%) had moderate or severe ventricular dysfunction. Among the fetuses with moderate or severe ventricular dysfunction, 3 (50%) had RV dominant lesions. Among those with moderate-to-severe AV valve regurgitation, 33 of 37 patients (89%) had RV dominant lesions. Notably, a total of 8 of the 37 patients also had heterotaxy.

Perinatal Outcomes
Of the 502 initial patients, 42 had no follow-up at our institution. Details of the longitudinal outcomes are illustrated in Figure 1. Of the 460 with follow-up, 11 fetuses (2.4%) had intrauterine fetal demise (clinical features are characterized in Table S1). Of 251 mothers diagnosed before 24 weeks gestation, 79 (31%) opted for TOP. Mean gestational age at birth was 38.1 weeks (median, 38.6; range, 26.0-41.6). Of the 370 fetuses surviving to birth, nonintervention palliative care was elected in 22 cases (6%). Clinical characteristics of the fetuses that received palliative care with no intervention are listed in Table S2. Twelve patients with intention to treat died before initial operation (3.4%). A majority of these 12 patients had high-risk hypoplastic left heart lesions or variants thereof (Table S3). Of the 348 patients delivered with intention to treat, there were 5 patients at birth with balanced circulations and no requirement for neonatal surgical interventions, 3 of which survived and 2 who died (Table S4). Additionally, 2 patients underwent biventricular repair, and 1 patient underwent primary orthotopic heart transplant (OHT).

Operative Outcomes
Distribution of operations for each stage are listed in Table 3. A total of 325 patients survived and underwent a first-stage operation. Of these, 41 (12.6%) did not survive to the second stage, and 4 patients underwent OHT. Of the 41 deaths, 14 of these patients died within 7 days of the first-stage operation from associated complications. Three patients who underwent a first operation subsequently underwent biventricular repair, after initial aorto-pulmonary shunt placement. Five patients had no further follow-up at our institution.
Two hundred seventy-two patients proceeded to a secondstage operation. Death between stage 2 and planned stage 3 operations occurred in 19 patients (7%). Two patients had takedown of their superior cavopulmonary anastomoses and conversion to biventricular circulations. There were 2 cases of heterotaxy syndrome, unbalanced common atrioventricular canal, double outlet right ventricle with pulmonary stenosis, and satisfactory oxygen saturations in the 88% to 90% range and are left with superior cavopulmonary (Glenn) physiology. In 3 cases, the decision was made not to proceed with Fontan operation secondary to significantly elevated pulmonary vascular resistances. Four patients underwent OHT. The clinical course of all patients receiving OHT from birth through stage 3 is characterized in Table S5. Eight further patients had no follow-up. A total of 234 patients underwent Fontan operation; average age at time of operation was 3.6AE0.9 years.
Of 502 fetuses with SVCHD, 348 survived to birth with intention to treat, and of these, 234 patients (67%) were alive  at least 6 months after their Fontan operation. There were 15 other patients who survived to 4 years of age (3 had balanced circulations without any intervention, 7 had biventricular repairs, and 5 were status post superior cavopulmonary anastomosis without plans for Fontan). This indicates a total of 72% overall transplant-free survival for the intention-totreat cohort (Figure 2).

Prenatal Risk Factors
Survival analysis was performed using the cohort of fetuses who survived to live birth with intention to treat (n=348). Upon univariate analysis, several prenatal variables were identified as risk factors (Table S6). Fetal cardiac function was strongly associated with hydrops (P<0.0001). Because only 8 patients had greater than mild ventricular dysfunction, we excluded this variable from multivariate analysis. Likewise, the presence of a genetic syndrome was dropped from multivariate analysis, because it was strongly associated with extracardiac defects (P<0.0001) and birthweight (P=0.005). Multivariate analysis using the significant prenatal variables as well as the aforementioned postnatal variables was performed. Clinical characteristics of the patients who underwent extracorporeal membrane oxygenation at any point and those who had moderate-to-severe ventricular dysfunction or AV valve regurgitation are described in Table S7. This analysis demonstrated that the presence of hydrops, RV dominance, presence of extracardiac anomalies, extracorporeal membrane oxygenation immediately after the first surgical procedure, and low birthweight had a lower rate of transplant-free survival (Table 4). Patients with dominant RV morphology had a lower transplant-free survival rate than those with dominant LV morphology (Figure 3; P=0.002), as did patients with extracardiac anomalies versus those without (Figure 4; P<0.0001). Notably, unanticipated additional surgeries and number of catheterizations from birth to discharge after the first surgery were not associated with increased risk of death or transplant.

Discussion
Care for SVCHD starts in prenatal life at the time of ultrasound diagnosis. The hurdles of surgical reconstruction and the challenges of life with a Fontan circulation lead some families to consider termination. 23 As expectant parents consider their options, a common inquiry at prenatal counseling relates to the likelihood of survival through all stages of anticipated surgical reconstruction and what factors contribute to mortality.
Our study offers the benefits of reporting on a large cohort followed longitudinally through multiple nodes of clinical management from a single center with an experience of focused care for SVCHD, thus with relative minimal practice variability. Our contemporary overall transplant-free survival rate (includes 234 Fontan patients and 15 other transplantfree survivors) of 72% in patients with intention to treat is relatively improved compared with studies published in earlier eras. 2,24,25 In addition, we found the incidence of ventricular dysfunction, hydrops, and intrauterine fetal demise to be low. The likelihood of a fetus diagnosed with SVCHD surviving to a viable gestational age is high; however, a number of factors contribute to the potential for postnatal survival.
Rates for termination of pregnancy in HLHS and, more broadly, SVCHD fetuses are variable and multifactorial throughout the world. 17,26,27 Our institution is a large referral center both for prenatal evaluation of complex heart disease and postnatal intervention, likely contributing to a bias toward intention to treat in our overall cohort. Overall termination of pregnancy occurred in 79 subjects of 460 for which there is follow-up (17%); however, of those presenting before 24 weeks gestation, TOP was chosen in approximately one   third of patients (31%) and nonintervention palliative care in 6%. Fetal diagnosis and transitional care can influence the subsequent course and may offer additional benefits to preoperative survival. All subjects were provided comprehensive fetal care within a single center, with >90% delivering at the Special Delivery Unit at CHOP and the remainder at the adjacent University of Pennsylvania. Thus, our study demonstrates that despite prenatal knowledge of SVCHD, anticipatory planning, optimizing care with little practice variability, and single-team clinical management oversight, a small number (3.4%) will not survive to receive an operation. Mortality occurs early in the course of care around initial surgery and in the interstage period between stage 1 and stage 2. The interstage period accounted for the largest proportion of deaths by time period, with 12% (41 of 348 patients delivered with intention to treat) expiring in this period. When we look at outcomes at 12 months of life, 64 patients (18%) expired or underwent OHT. In the landmark Single Ventricle Reconstruction trial looking at HLHS patients, rate of death or transplantation at 12 months was 25.6% in the Sano group and 37.3% in the Blalock-Taussig shunt group. 28 Although the superior cavopulmonary circulation is known to be a relatively stable physiology with low mortality rates, 19 of our patients died in this time frame. Operative mortality was low, consistent with previous studies. 29 However, we do cite higher long-term mortality after the second stage, which is likely attributable to the high-complexity patient population typical of a quaternary care center. Over half of these patients developed severe ventricular dysfunction and/or AV valve regurgitation.
We sought to determine risk factors for mortality in our cohort population. Fetuses with RV-dominant lesions, hydrops, extracardiac manifestations, and low birthweights are less likely to experience transplant-free survival to 6 months after Fontan operation in patients undergoing single ventricle palliation or to 4 years of age in nontraditional interventional pathways not leading to Fontan completion. The extracardiac manifestations, which were strongly associated with presence of genetic anomaly, often involved lung, central nervous system, or renal defects, which themselves can potentially be life-threatening, or increase the risk of mortality at surgical reconstruction through organ dysfunction. Similarly, patients with low birthweights have lower transplant-free survival rates. Congenital heart surgical outcomes in lowweight newborns is decreased, with increased morbidity including increased neurological complications and prolonged ventilation times secondary to lung immaturity. 30,31 Postnatal severe AV valve regurgitation and poor ventricular function have previously been thought to be independently associated with poor outcomes with the Norwood operation. 32 In our own prenatal HLHS study, fetuses with tricuspid regurgitation and ventricular dysfunction had total survival of 89% and 25%, respectively. 20 Both characteristics are relatively rare in fetal life; in our study, only 37 (7.4%) fetuses had at least moderate AV valve regurgitation and only 6 (1.1%) patients had moderately or severely diminished ventricular function. Of note, AV valve regurgitation was not associated with worse outcomes in univariate analysis. Outcomes of patients who had any degree of AV valve regurgitation (mild or greater) at any time in postnatal life are characterized in Table S8, along with the outcomes of patients with any degree of ventricular dysfunction at any time postnatally.
We found that patients prenatally diagnosed with SVCHD and dominant LV lesions had superior transplant-free survival rates than those with dominant RV lesions. Possible explanations include: (1) dominant RV lesion surgeries are more complex, often requiring a Norwood procedure for impediment to systemic blood flow, whereas dominant LV lesions  often only require augmentation of pulmonary blood flow; (2) the RV myocardium may have inherent differences in contractility and diastolic function in comparison with the LV myocardium in single ventricles, rendering them less suited to provide systemic pressure; and (3) the tricuspid valve may be at greater risk for incompetence than the mitral valve when at systemic pressure. 33,34 Our survival curves certainly imply that much of the mortality difference occurs before superior cavopulmonary anastomosis, often related to surgical complications along with interstage deaths. The influence of ventricular dominance on survival after the Fontan operation remains a subject of debate and is outside the scope of our study. 5,35,36 Continued longitudinal follow-up of our prenatally diagnosed cohort may answer additional questions related to post-Fontan morbidity and mortality. Although neurodevelopmental outcomes were not studied here, it also remains a subject of much interest and importance. 37,38 Our study has a number of limitations. The first is that there are no absolute criteria to define single ventricle anatomy, and, as our findings indicate, some lesions are amenable to biventricular repair later in life (7 patients). We thus relied on the impressions of our fetal cardiologists to predict the presence of SVCHD. Second, not all of our patients were screened for chromosomal abnormalities, given that expectant parents sometimes decline amniocentesis. A number of SVCHD patients without dysmorphism or clinical suspicion did not receive genetic analysis in our cohort, although this is changing in the current era of increasing diagnosis of microdeletions and other genetic abnormalities. Our data are thus likely an underestimation of the incidence of genetic abnormalities, which is often included in prenatal counseling. 39 Our rate of TOP is likely an underestimation of the community-wide rate of termination as well, given that many patients referred to our center for evaluation were referred with intention to treat, creating an element of overall population selection bias. Nevertheless, a relatively low rate of TOP in our cohort allows us the unique opportunity to study and discern outcome factors in a large intention-to-treat population. We lost follow-up on 42 subjects (8%), a sizable number of patients, primarily related to return to referring center with no further information on outcomes. Importantly, quality of life of patients with SVCHD is an essential and common concern of expectant parents. The data collected in this study seek to qualify morbidity, but data regarding specific quality-of-life measures are currently most available in patients who have survived after Fontan operation. 40,41 A family's socioeconomic status may have a significant impact on their decisions surrounding peri-and postnatal management, and these data were not examined in this study. Further longitudinal follow-up of this cohort will allow for such analysis as well as the opportunity to explore prenatal factors that may contribute to quality of life throughout the individual's life span.

Conclusion
This is a retrospective, longitudinal study that characterizes the outcomes of fetuses with SVCHD and identifies potential risk factors for morbidity. In this study of patients with a prenatal diagnosis of SVCHD and intention to treat, 67% survive transplant free to at least 6 months beyond Fontan operation. An additional 5% survive to 4 years of age without transplant or Fontan completion, indicating that not all fetuses with SVCHD will travel the traditional pathway to Fontan completion. Among fetuses surviving to birth with intention to treat, those with RV-dominant lesions, extracardiac anomalies, hydrops, or low birthweights have decreased transplant-free survival. Our findings provide sobering data and improve accuracy of prenatal counseling for expectant parents. Further analysis of this cohort may identify modifiable variables related to the maternal-fetal environment that may improve overall survival outcomes.