Long-term outcomes of atrioventricular septal defect and single ventricle: A multicenter study

Objective: The study objective was to analyze survival and incidence of Fontan completion of patients with single-ventricle and concomitant unbalanced atrioventricular septal defect. Methods: Data from 4 Dutch and 3 Belgian institutional databases were retrospec-tively collected. A total of 151 patients with single-ventricle atrioventricular septal defect were selected; 36 patients underwent an atrioventricular valve procedure (valve surgery group). End points were survival, incidence of Fontan completion, and freedom from atrioventricular valve reoperation. Results: Median follow-up was 13.4 years. Cumulative survival was 71.2 % , 70 % , and 68.5 % at 10, 15, and 20 years, respectively. An atrioventricular valve procedure was not a risk factor for mortality. Patients with moderate-severe or severe atrioventricular valve regurgitation at echocardiographic follow-up had a signi ﬁ cantly worse 15-year survival (58.3 % ) compared with patients with no or mild regurgitation (89.2 % ) and patients with moderate regurgitation (88.6 % ) ( P ¼ .033). Cumulative incidence of Fontan completion was 56.5 % , 71 % , and 77.6 % at 5,


CENTRAL MESSAGE
In patients with single-ventricle AVSD, AVV surgery did not increase mortality, whereas severe valve regurgitation decreased survival at follow-up and therefore should be treated.

PERSPECTIVE
Our bi-national study of 151 patients with singleventricle AVSD showed long-term survival and Fontan completion better than previously reported. AVV surgery did not reduce survival or incidence of Fontan completion, whereas severe AVV regurgitation affected survival. Therefore, severe AVV regurgitation should be treated.

See Commentary on page XXX.
Newborns treated with single-ventricle palliation for unbalanced atrioventricular septal defect (AVSD) represent approximately 10% of patients with single-ventricle physiology and have limited long-term survival. 1 Significant atrioventricular valve (AVV) regurgitation has been shown to be associated with a lower incidence of Fontan completion and overall survival. 1,2 The need for AVV surgery is reported to be associated with substantial mortality. 2 Up to 60% of the reported patients underwent an AVV operation in the course of single-ventricle palliation. [1][2][3][4] Many surgical techniques have been described to repair the AVV in the setting of a single ventricle, and the probability of reoperation varies between 30% and 50%, independent from the technique used at first valve repair intervention. 2,3 Our multicenter retrospective study analyzed the survival and incidence of Fontan completion of patients with single-ventricle physiology and unbalanced AVSD and freedom from AVV reoperation after the first valve surgery.

MATERIAL AND METHODS Study Design
This study was multicenter, retrospective, and bi-national (the "BeNe" experience means the scientific cooperation of Belgium and The Netherlands). University Medical Centers of Groningen, Leiden, Rotterdam, and Utrecht were the participating Dutch Centers. University Hospitals of Gent, Leuven, and Louvain were the participating Belgian Centers. Centers are reported in anonymized fashion. All patients with unbalanced AVSD who underwent single-ventricle palliation were selected from each institutional database and follow-up until 2019 was recorded. Unbalanced AVSD was defined as any AVSD with hypoplasia of 1 ventricle that was assessed to be unfeasible for biventricular repair. Preoperative, operative, and postoperative data from all patients were collected retrospectively. Echocardiographic studies at follow-up of 123 patients were collected. The last echocardiogram at follow-up for patients who were alive and the last echocardiogram before death for patients who died were collected.
One patient who underwent a cardiac transplant was included in the study, and transplant was classified as death. Patients who crossed over to a biventricular repair after an initial palliation were excluded. Patients who underwent AVV surgery during their palliation (n ¼ 36) were in the valve surgery group.

End Points
Overall survival at follow-up. Fontan completion at follow-up. Freedom from AVV reoperation after the first AVV surgery.
The Institutional Review Board of the participating centers agreed to waive the need for an informed consent because data were collected as part of routine medical care and patients were not individually identifiable.

Statistical Analysis
Statistical analysis was performed using IBM SPSS Statistics 23 (IBM Corporation, New York, NY) and R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). Values are reported as mean AE standard deviation or as number with percentages.
Survival curves for overall survival and freedom from AVV reoperation with associated point-wise linear 95% confidence intervals (CIs) were estimated using the Kaplan-Meier estimator and compared across groups using the log-rank test. The cumulative incidence curve of Fontan completion with the associated point-wise linear 95% CIs was estimated using the Aalen-Johansen estimator with death before Fontan completion included as a competing risk. Hazard ratios with 95% CIs of potential risk factors were estimated using a Cox proportional hazards regression model for the overall survival end point and a Fine and Gray regression model for the Fontan completion end point. In both models, time zero corresponded to the first surgical procedure performed per patient. Potential risk factors were first tested in an univariable analysis, and all risk factors with a P value .20 or less were entered in a multivariable analysis. In all analyses, study center was included as a stratification variable to account for possible differences in the patient populations across the 7 centers. Because AVV surgery was performed at different timings of the palliative treatment, a sensitivity analysis in which AVV surgery was included as a timedependent covariate was also performed.

RESULTS
A total of 151 patients who underwent operation between 1966 and 2018 were included. Follow-up was complete in all patients. The median follow-up time was 13.4 years (95% CI, 9.7-17.11). Table 1 shows the relevant preoperative characteristics and the surgical steps for all patients. Approximately onethird of the patients had a coexistent syndrome: heterotaxy in 30 patients, Down syndrome in 7 patients, and other chromosomal disorders in 11 patients. Figure 1 shows the flow diagram of all 151 patients, giving an overview of the surgical steps, interstage mortality, and outcome at followup. There was a significant difference in the prevalence of AVV surgery among centers: AVV surgery was performed in only 1 patient at centers E and F, and in approximately half of the patients at center A (chi-square test, P ¼ .03).
In 123 echocardiographic studies at follow-up, 30 patients had undergone an AVV surgery. Median follow-up of last echocardiography was 11.6 years. AVV regurgitation was none or mild in 76 patients, moderate in 37 patients, and moderate-severe or severe in 10 patients. There was a significant difference in overall survival at follow-up comparing patients with increasing degree of AVV regurgitation: 89.2% by none or mild, 88.6% by moderate regurgitation, and 58.3% by moderate-severe or severe regurgitation at 15 years (P ¼ .033), as shown in Figure 2, B.
Univariable and multivariable analyses of mortality are shown in Table 2. In univariable analysis, severe AVV regurgitation at follow-up was associated with worse survival, and a concomitant syndrome was associated with better survival. AVV surgery was not a risk factor for mortality (P ¼ .65). When the time to AVV surgery was taken into The Journal of Thoracic and Cardiovascular Surgery c Volume -, Number -account in a sensitivity analysis including AVV surgery as time-dependent covariate, AVV surgery was not a risk factor for mortality (hazard ratio, 1.35; 95% CI, 0.42-4.37, P ¼ .612). Multivariable analysis identified a severe AVV regurgitation at follow-up as an independent risk factor for mortality (hazard ratio, 5.74, 95% CI, 1.54-21.43, P ¼ .009).

Fontan Completion
The cumulative incidence of Fontan completion is shown in Figure 3: 56.5% at 5 years, 71% at 10 years, and 77.6% at 15 years. In 7 patients, the interval between PCPS and TCPC was longer than 10 years: Three patients had a previous Kawashima operation and then had their Fontan completion through an off-pump hepato-azygos shunt; the reason for delay for the other 4 patients is unknown.
Univariable and multivariable analyses of Fontan completion are shown in Table 3. In univariable analysis isomerism, decades of birth era and a concomitant syndrome were associated with the incidence of Fontan completion: Patients born in the last decade had a higher rate of Fontan completion, and patients with a concomitant syndrome and patients with left isomerism had a lower rate. AVV surgery was not associated with the incidence of Fontan completion (P ¼ .36). In multivariable analysis, none of the factors were associated with incidence of Fontan completion. frequently performed. Mechanical valve replacement was performed in 2 patients. The degree of valve insufficiency at postoperative echocardiography was none or mild in 26 patients, moderate in 4 patients, and moderate-severe or severe in 2 patients after the first repair. Freedom from AVV reoperation at followup was 85.7% at 1 year, 77.9% at 2 years, 52.6% at 5 years, and 47.3% at 10 years ( Figure 4). An AVV reoperation was performed in 13 of 36 patients at a mean interval of 2.5 AE 1.8 months after the first operation. Figure 5 shows the flow diagram of the patients in the valve surgery group. In 24 patients with no or mild postoperative AVV regurgitation after the first AVV operation, an AVV reoperation was performed in 5 patients. One patient had a moderate-severe AVV regurgitation after the AVV reoperation and died at follow-up because of Fontan failure. Fontan circulation was completed in 19 of 24 patients. In 4 patients with moderate AVV regurgitation after the first AVVoperation, an AVV reoperation was performed in 2 patients. All 4 patients completed the Fontan circulation; 1  The Journal of Thoracic and Cardiovascular Surgery c Volume -, Number -patient who underwent an AVV replacement as reoperation died at follow-up, and 1 patient underwent a heart transplant after Fontan completion. All 4 patients with a moderatesevere or severe AVV regurgitation after the first AVVoperation underwent an AVV reoperation. Only 1 patient could complete the Fontan circulation, 1 patient died before the completion and after AVV replacement, 1 patient was considered not eligible because of residual AVV regurgitation, and 1 patient was too young for the completion. Both patients who underwent a valve replacement as first valve surgery died at follow-up. In 2 patients, the degree of AVV regurgitation after the first valve repair was unknown. Freedom from AVV reoperation at 15 years in patients with no or mild AVV regurgitation after the first surgery was 76.5% compared with 33.3% in patients with moderate regurgitation (P ¼ .054) and compared with 0% in patients with moderate-severe or severe regurgitation (P < .001). There was no significant difference in 15-year freedom from AVV reoperation between patients with moderate AVV regurgitation and patients with moderate-severe or severe regurgitation after the first AVV surgery (P ¼ .378). The degree of AVV regurgitation after the first AVV surgery did not influence survival (P ¼ .981) and incidence of Fontan completion (P ¼ .265).

Valve Surgery Group Analysis
A valve replacement was performed in 3 patients by AVV reoperation: Two of the patients died during the hospitalization for valve replacement, which was performed together with TCPC. The degree of AVV regurgitation at postoperative echocardiography after the AVV reoperation was none or mild in 7 patients, moderate in 2 patients, and moderatesevere in 1 patient. In 3 patients, a third AVV reoperation was performed.
AVV surgery was performed before Fontan completion in 22 patients, at the time of TCPC in 14 patients, and after TCPC in 1 patient. There was no difference in survival between patients who underwent an AVV surgery before Fontan completion and patients who underwent AVV surgery at the time of TCPC (at 15 years 59.3% vs 72.2%, respectively, P ¼ .34). The same comparison showed a significant difference in terms of freedom from AVV reoperation: at 15 years 31.5% when AVV surgery was performed before Fontan completion compared with 87.5% when performed at the time of TCPC (P ¼ .03). One patient who underwent AVV surgery after Fontan completion did not undergo an AVV reoperation.

DISCUSSION
Unbalanced AVSD in patients who require singleventricle palliation is associated with poor survival; 60% at 25 years 2 and 50% at 2 years have been reported, although in smaller series. 5 Our study including 151 patients with unbalanced AVSD who underwent singleventricle palliation showed more favorable outcomes: 68.5% survival at 20 years.
Nevertheless, the 20-year survival of all categories of univentricular heart remains remarkably higher, approximately 80%. [6][7][8][9][10] In addition, in our cohort of patients an associated syndrome did not increase the mortality and the survival of our cohort of patients with heterotaxy did not differ from that published in a recent meta-analysis. 11 Our study suggests that the presence of a genetic syndrome in association with single-ventricle AVSD does not preclude an excellent outcome for Fontan palliation.
Severe AVV regurgitation in single-ventricle physiology is known to be a risk factor for mortality, whereas a successful repair of the AVV could improve survival. [12][13][14][15] Our study confirmed this finding because patients with no, mild, or moderate AVV regurgitation at follow-up had a significant better survival than patients with moderate-severe or severe regurgitation, as clearly shown in Figure 6.
Our results merit interpretation in that at the end of Fontan completion the AVV should function satisfactorily and severe AVV regurgitation should be repaired adequately, even if it is at the cost of AVV surgery. Our study showed that AVV regurgitation that exceeds a moderate degree represents a risk factor for mortality in patients with singleventricle AVSD and therefore should be repaired.
Our results in terms of cumulative incidence of Fontan completion (71% at 10 years) compare favorably to the literature, which varied between 40% and 60%. 2,4,5 Multivariable analysis did not identify independent risk factors for incidence of Fontan completion. Freedom from AVV reoperation in our cohort is not different from the range previously reported, which varied between 45% and 56% at 15-year follow-up. 4,12 As expected, all patients with a moderate-severe or severe AVV regurgitation after the first AVV operation required an AVV reoperation and there was a significant difference in freedom from AVV reoperation compared with patients with no or mild AVV regurgitation (5/24 patients required AVV reoperation). However, a moderate-severe or severe degree of AVV regurgitation after the first AVV surgery did not significantly decrease survival or incidence of Fontan completion.
Valve replacement in patients with single ventricle does not have a favorable prognosis, although it could be the last option. [16][17][18][19] In our study, a valve replacement was performed in only 2 patients as a first procedure, and both In regard to the timing of first AVV surgery, one-third of the operations were performed during PCPS, approximately half after PCPS and the majority during TCPC. The anticipated favorable effect of unloading the ventricle on AVV regurgitation may be a reason why the repair was delayed until TCPC in the majority of the patients. In fact, it could be considered that the decrease in ventricular volume described after PCPS operation could result in reduction of atrioventricular annulus dimension, thereby improving the AVV regurgitation. 20,21 Furthermore, in our study freedom from AVV reoperation was significantly lower in patients who underwent AVV surgery at the time of TCPC (87.5% at 15 years) compared with patients who underwent AVV surgery before Fontan completion (31.5% at 15 years, P ¼ .03). However, the degree of AVV regurgitation, the deterioration of ventricular function, or the  patient's clinical picture did not allow us to wait until Fontan completion. AVV surgery performed before PCPS is unusual. In our study, only 7 patients underwent an AVV repair before PCPS, yielding disappointing results in 3 patients who still showed severe regurgitation postoperatively and required a take-down of the repair in 1 patient because the regurgitation was even worse after the AVV repair. However, addressing severe AVV regurgitation at the initial palliative stage is advisable based on the favorable effect of a competent AVVon survival and Fontan completion, bearing in mind that its result might be imperfect and the likelihood of reoperation is high. was independent risk factor for mortality FIGURE 6. Our retrospective multicenter experience showed the results of 151 patients with single-ventricle AVSD of all 7 Dutch and Belgian congenital cardiac centers. AVV surgery was performed in 36 of the patients. Cumulative survival, incidence of Fontan completion, and freedom from AVV reoperation were the end points of the study. AVV surgery did not decrease survival or Fontan completion rate. The results of 123 echocardiographic studies at follow-up (shown in survival graph on the right side) found that patients with moderate-severe or severe AVV regurgitation had a worse survival compared with patients with no/mild or moderate AVV regurgitation. Our results showed that an AVV regurgitation exceeding a moderate degree should be repaired before finalizing Fontan circulation. AVSD, Atrioventricular septal defect; AVV, atrioventricular valve; CI, confidence interval.

Study Limitations
The main limitation of this study is its retrospective and multicenter nature. There was a significant difference in the prevalence of AVV surgery among centers. This difference could be explained by the heterogeneous criteria for concomitant AVV surgery that could have varied over the decades, influencing patient selection among the participating centers. Moreover, the criteria for eligibility for Fontan completion may have varied among centers because of different clinical judgment and patient selection. We did not collect all echocardiograms performed per patient at follow-up to identify the first echocardiography where severe or moderate AVV regurgitation appeared; therefore, we could not analyze the degree of AVV regurgitation as a time-dependent covariate.

CONCLUSIONS
The "BeNe" experience of patients with AVSD Fontan showed 20-year survival of 68.5% and 10-year cumulative incidence of Fontan completion of 71%, both better than previously described (Video 1). A concomitant AVV surgery did not increase the mortality rate or decrease the incidence of Fontan completion, whereas patients with moderate-severe or severe AVV regurgitation at follow-up had a worse survival, reflecting the need for adequate AVV function. Therefore, in patients with single-ventricle AVSD, AVV regurgitation that exceeds a moderate degree should be repaired.