Late Outcome of Survivors of Intervention for Neonatal Aortic Valve Stenosis

Late Outcome of Survivors of Intervention for Neonatal Aortic Valve Stenosis J. William Gaynor, MD, Catherine Bull, MD, Ian D. Sullivan, MD, Brenda E. Armstrong, MD, John E. Deanfield, FRCP, James F. N. Taylor, MD, Philip G. Rees, MD, Ross M. Ungerleider, MD, Marc R. de Leval, MD, Jaroslav Stark, MD, and Martin J. Elliott, FRCS Cardiothoracic Unit, The Hospital for Sick Children, London, England, and Departments of Surgery and Pediatrics, Duke University Medical Center, Durham, North Carolina Background. This study examined the late outcome after intervention for neonatal aortic valve stenosis. Methods. Seventy-three neonates (59 boys and 14 girls) underwent intervention for critical aortic valve stenosis during the first 30 days of life at two institutions, The Hospital for Sick Children, London, and Duke University Medical Center, Durham, North Carolina. Procedures performed include closed valvotomy (n = 12), open valvotomy with inflow occlusion (n = 14), open valvotomy with cardiopulmonary bypass (n = 33), balloon valvotomy (n = 12), and other procedures (n = 2). The mean age at the first intervention was 8 --- 1 days. Results. The hospital mortality was 52.1%. The mean duration of follow-up for the hospital survivors (n = 35) was 8.3-1.1 years. The actuarial survival for the hospital survivors was 93.3% --- 4.7% at 10 years and 83.9% -, 9.8% at 15 years, whereas event-free survival (reintervention, endocarditis, or early death) was 61.8% -+ 9.3% at 5 years, 34.2% _+ 10.8% at 10 years, and 27.4% -, 10.6% at 15 years. Three patients have died and 11 patients have required aortic valve replacement during the follow-up period. The age at the initial intervention, the type of initial intervention, and the year of initial intervention were not predictive of early death or need for reintervention. At last follow-up, 26 of the long-term survivors (n = 32) were in functional class I and 6 were in functional class II. Conclusions. Aortic stenosis in the neonatal period is a difficult problem with a high initial mortality. Late survival and functional class are excellent for patients surviving the initial hospitalization, but most require further intervention within 10 years. (Ann Thorac Surg 1995;60:122-6) I nfants presenting with congenital aortic stenosis in the first month of life are a difficult clinical problem. Neonates with critical aortic stenosis often have severe congestive heart failure that is refractory to therapy and usually require urgent intervention. Advances in anesthesia, critical care, and surgical techniques have reduced operative mortality in recent years, and the introduction of balloon valvuloplasty has provided a new therapeutic option. Although recent studies, including a multiinstitutional trial, have documented improved short-term results, the long-term prognosis for these infants is largely unknown [1-4]. Most previous studies reporting long-term follow-up after intervention for congenital aortic stenosis have focused on older children [5-7]. Several studies have addressed the prognosis of neonates and infants who survive an intervention for aortic stenosis; however, these in general are limited by small numbers of patients, inclusion of patients older than 30 days of age, or short duration of follow-up [2-4, 7-9]. Patients who survive Presented at the Forty-first Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 10-12, 1994. Address reprint requests to Dr Gaynor, Pediatric Cardiothoracic Surgery, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104-4399. intervention for neonatal aortic stenosis remain at risk for recurrent stenosis, aortic regurgitation, subaortic stenosis, bacterial endocarditis, and sudden death. The current study was undertaken to evaluate the late outcome of children who survive an intervention for critical aortic stenosis in the first 30 days of life and to assess the incidence of valve-associated morbidity. Material and Methods Children undergoing intervention in the first 30 days of life for critical aortic stenosis at two institutions (The Hospital for Sick Children, London, and Duke University Medical Center, Durham, North Carolina) were identified by review of operating room records, catheterization records, and the medical records of patients with a diagnosis of congenital aortic stenosis. The medical records of all patients were reviewed and follow-up information was obtained from the medical record, contact with referring physicians, and when possible contact with each patient or his or her family. Data are presented as mean -+ standard error. Variables were compared using the unpaired Student's t test. Actuarial survival and event-free survival were calculated using the Kaplan-Meier method. For the survival analysis, patients were censored at the time of death or 1995 by The Society of Thoracic Surgeons 0003-4975/95/$9.50 0003-4975(95)00384-W

Ann Thorac Surg GAYNOR ET AL 123 1995;60:122-6 NEONATAL AORTIC VALVE STENOSIS 8 ~ 7 ~ e F- ~ 8 3 i2 0 1970 1975 1980 1985 1990 i-:oo::::,::u, vo:- I Fig 1. Distribution of patients by year of initial intervention showing hospital deaths and hospital survivors. withdrawn alive at the time of last follow-up. Adverse events were defined as reintervention, endocarditis, or death. To determine event-free survival, patients were censored at the first occurrence of one of the above events or withdrawn alive at the time of last follow-up. Event-free survival for patients after a second intervention was calculated similarly. Cox's proportional hazards model was used to examine the influence of the age at the time of initial intervention, the type of initial intervention, and the year of initial intervention on time-related freedom from subsequent events in a univariate fashion. Because of the small number of patients, the power to detect a significant difference is limited and a multivariate analysis was not performed. Results From January 1, 1970, to July 31, 1993, 50 consecutive neonates required intervention for critical aortic stenosis at the Hospital for Sick Children. From January 1, 1970, to September 30, 1993, 23 consecutive neonates underwent intervention for critical aortic stenosis at Duke University Medical Center (Fig 1). The type of initial intervention was chosen according to preference of the patient's surgeon and cardiologist and was not assigned by protocol at either institution. Short-term results have been reported previously for some of the patients from The Hospital for Sick Children [10-12]. There were 59 male and 14 female patients. All patients had isolated valvar aortic stenosis except for 6 with associated coarctation, 4 with coarctation and a ventricular septal defect, 2 with a ventricutar septal defect, and 1 with mitral stenosis. The loo ~ t I ~ 80 : --- 6O r ~ 40 0 (3s)... 2~2~)... (13) (s)... (3)........ 0 5 10 15 25 YEARS AFTER INITIAL INTERVENTION Fig 2. Actuarial survival (Kaplan-Meier) of hospital survivors after intervention for neonatal aortic stenosis. The 70% confidence limits also are shown. Numbers in parentheses represent patients remaining at risk. 100 a- 80 tu 60 tu tr u. 40 z i11 2O ~J 0 /3S) (17) (6) (2) (1) 5 10 15 YEARS AFTER INITIAL INTERVENTION Fig 3. Event-free (endocarditis, reintervention, and death) survival (Kaplan-Meier) for hospital survivors of intervention for neonatal aortic stenosis. The 70% confidence limits also are shown. Numbers in parentheses represent patients remaining at risk. mean age at the first intervention was 8 + 1 days with a median age of 5 days. Procedures performed included balloon valvuloplasty (n = 12), closed transventricular valvotomy (n = 12), open valvotomy with inflow occlusion (n = 14), open valvotomy with cardiopulmonary bypass (n = 33), and other procedures (n = 2). Eight patients underwent repair of aortic coarctation at the initial procedure. One patient underwent mitral commissurotomy. Eight patients required a second intervention during the first hospitalization. Thirty-eight of the 73 neonates (52.1%) died before hospital discharge. Only 1 child requiring more than one procedure during the first hospitalization survived to discharge. The mean age at the first intervention was 10 + 2 days for the hospital survivors compared with 6 _+ 1 days for nonsurvivors (p < 0.05). The 35 infants (30 boys and 5 girls) who survived the initial hospitalization form the study group. All of the hospital survivors had isolated valvar aortic stenosis except for 3 infants with coarctation and I with a ventricular septal defect. Seventeen of the hospital survivors underwent open valvotomy on cardiopulmonary bypass, 6 underwent valvotomy with inflow occlusion, 7 underwent closed transventricular valvotomy, and balloon valvotomy was performed on 5 patients. Coarctation repair was performed in 3 of the hospital survivors. A small muscular ventricular septal defect in 1 patient did not require repair. Mean follow-up for the hospital survivors is 8.3 _+ 1.1 years with a median follow-up of 8.8 years. Complete follow-up to death or January 1, 1993, is available on 29 of the 34 hospital survivors who were born before December 31, 1992 (85%). Partial follow-up is available on the remaining patients. Twenty-three children have been followed up for at least 5 years, 13 for at least 10 years, and 5 for 15 years or more. Three children died during the follow-up period. Two children died suddenly at home and 1 died during reintervention. The actuarial survival was 93.3% _+ 4.7% at 5 and 10 years, and 83.9% -+ 9.8% at 15 years (Fig 2). Sixteen patients have required reintervention. Fourteen patients have undergone two interventions and 2 patients have required three or more interventions. The mean interval between the first and second intervention was 5.4 -+ 4.6 years with a median interval of 4.7 years. 25

124 GAYNOR ET AL Ann Thorac Surg NEONATAL AORTIC VALVE STENOSIS 1995;60:122-6.J < rr /) n- Z w loo -~ 80 60 40 0 116) 0 (10) (1) 5 10 15 YEARS AFTER SECOND INTERVENTION Fig 4. Event-free (endocarditis, reintervention, and death) survival (Kaplan-Meier) after second intervention for aortic stenosis. The 70% confidence limits also are shown. Numbers in parentheses represent patients remaining at risk. The interval between the first and second interventions ranged from 1 month to 11 years. The indication for the second intervention was recurrent valvar aortic stenosis in 8 patients, aortic insufficiency in 4, and subaortic stenosis in 4. The second intervention was open valvotomy in 5 patients and balloon valvotomy in 1 patient, whereas aortic valve replacement was necessary in 10 patients, including 4 Konno procedures. One patient who initially underwent closed valvotomy subsequently required open valvotomy followed by balloon valvotomy and eventually a Konno procedure for subaortic stenosis. Overall 11 children have required aortic valve replacement thus far. None of the hospital survivors died during a second intervention. The single death during reintervention in the hospital survivors occurred during a redo aortic valve replacement. Bacterial endocarditis has not occurred in any of the hospital survivors. Freedom from adverse events defined as death, reoperation, and endocarditis was 77.7% _+ 7.5% at 1 year, 61.8% --_ 9.3% at 5 years, 34.2% + 10.8% at 10 years, and only 27.4% + 10.6% at 15 years (Fig 3). By univariate analysis using Cox's proportional hazards model, the age at the initial intervention, the year of the initial intervention, and the type of initial intervention were not predictors of subsequent need for reintervention or early death (p > 0.1). After the second intervention, 2 of the 16 children have required subsequent procedures. The event-free survival after the second intervention was 93.3% _+ 6.4% at 5 years and 83.0% + 11.3% at 10 years (Fig 4). At the time of last follow-up, 26 of the long-term survivors (n 32) were in functional class I and 6 in functional class II. Comment Congenital aortic stenosis is part of a spectrum of leftsided obstructive lesions of which the most extreme manifestation is the hypoplastic left heart syndrome. Infants with congenital aortic stenosis who present in the neonatal period have a worse prognosis than those presenting at an older age [1-4, 8, 9]. Recent reports suggest that initial survival for these patients is dependent more on the size of the left ventricle and its ability to support the systemic circulation than the technique used to relieve the obstruction [13, 14]. Like any retrospective, uncontrolled study, ours has obvious limitations including different patient populations, evolving therapies, lack of randomization, and difficulties with follow-up. Adequate patient numbers were obtained only by acquiring patients from two institutions over many years. As well, long-term follow-up can be obtained only by including patients from an earlier era. However, the patients in this study are a fairly homogenous population. Most had isolated valvar aortic stenosis and all underwent intervention in the first month of life. The results of this study demonstrate that despite the high initial mortality, the long-term prognosis for hospital survivors is good in terms of survival and functional class. The actuarial survival was 93.3% at 10 years and 83.9% at 15 years. All of the long-term survivors (n = 32) were in functional class I or II at the time of last follow-up. Although survival is excellent, most children have required reintervention and 11 children have required aortic valve replacement. The indication for reintervention in the majority of children was either valvar or subvalvar stenosis, and only 4 children in this series have required aortic valve replacement for progressive aortic insufficiency. Many studies of the long-term prognosis for children surviving intervention for neonatal aortic stenosis have mean duration of follow-up of less than 5 years (Table 1). The results of the current study are comparable with previously reported results. There is a high initial mortality but the long-term outlook for survivors of the initial Table 1. Results of Intervention for Neonatal Aortic Stenosis Total Patients ~30 Initial Mean Late Series Patients Days of Life Mortality Follow-up Deaths Reoperations Messina et al [3] 11 11 1/11 2.2 y 0 1 Turley et al [2] 40 40 5/40 29 mo 2 5 Karl et al [4] Isolated AS 9 9 0/9 37 mo 4 2 Associated anomalies 17 17 8/17 Pelech et al [8] Open valvotomy 22 22 14/22 9.4 y 1 1 Closed valvotomy 18 18 9/18 2.5 y 2 6 Ettedgui et al [9] 51 29 /29 10.4 y 2 6 AS = aortic stenosis.

Ann Thorac Surg GAYNOR ET AL 125 1995;60:122-6 NEONATAL AORTIC VALVE STENOSIS hospitalization is good in terms of survival and functional class. However, the need for subsequent reintervention and frequently aortic valve replacement is high. Over time, the incidence of reoperation in this series approaches 100% (see Fig 2). A variety of factors are likely to influence long-term survival and the need for reintervention. The morphology of the subaortic region, aortic valve, and aortic root are likely major determinants for restenosis and the development of subaortic stenosis. The type of valvotomy may affect the long-term outcome, particularly if there is residual stenosis or if aortic regurgitation is created. Interestingly, the most frequent indication for reintervention was recurrent stenosis rather than aortic insufficiency. Although type of initial intervention was not a risk factor for reintervention, the type of valvotomy used and the degree of incision of the commissures might be a determining factor for recurrent stenosis versus insufficiency. In the current study, no particular type of intervention was found to be a risk factor for either late death or need for reintervention; however, the small number of patients undergoing each type of intervention makes statistical analysis difficult. There is a high incidence of aortic valve replacement in this series. The ideal valve prosthesis for use in children has not been developed, so aortic valve replacement introduces the risks of valve dysfunction and thromboembolism, as well as the need for anticoagulation. The prosthesis may require replacement as the child grows. The use of the patient's pulmonary valve to replace the aortic valve is attractive because of the potential for growth and the excellent short-term and mid-term results in older patients [15-17]. However, there is little experience with the pulmonary autograft in neonates and the operative risk is unknown. Performance of a pulmonary autograft in infancy might not reduce the incidence of reoperation because of the necessity for the right ventricular outflow tract conduit replacement as the patient grows. A possible approach would be to perform valvotomy in infancy and then perform a pulmonary autograft when indicated for insufficiency or recurrent stenosis. This study demonstrates that the late outcome for survivors of an intervention for critical aortic stenosis in the neonatal period is excellent in terms of survival and functional status; however, continued follow-up is necessary. The initial hospital mortality is high but short-term results should continue to improve with better patient selection and continued advances in anesthesia, critical care, and surgical techniques. Most children surviving an intervention for neonatal aortic stenosis will require reintervention and many will need aortic valve replacement. New techniques such as the pulmonary autograft may improve the results of valve replacement and decrease the need for serial reintervention. References 1. Gaynor JW, Elliott MJ. Congenital left ventricular outflow tract obstruction. J Heart Valve Dis 1993;2:80-93. 2. Turley K, Bore EL, Amato JJ, et al. Neonatal aortic stenosis. J Thorac Cardiovasc Surg 1990;99:679-84. 3. Messina LM, Turley K, Stanger P, Hoffman JIG Ebert PA. Successful aortic valvotomy for severe congenital valvular aortic stenosis in the newborn infant. J Thorac Cardiovasc Surg 1984;88:92-6. 4. Karl TR, Sano S, Brawn WJ, Mee RBB. Critical aortic stenosis in the first month of life: surgical results in 26 infants. Ann Thorac Surg 1990;50:105-9. 5. Hsieh K, Keane JF, Nadas AS, Bernhard WF, Castaneda AR. Long-term follow-up of valvotomy before 1968 for congenital aortic stenosis. Am J Cardiol 1986;58:338-41. 6. DeBoer DA, Robbins RC, Maron BJ, McIntosh CL, Clark RE. Late results of aortic valvotomy for congenital valvar aortic stenosis. Ann Thorac Surg 1990;50:69-73. 7. Tveter KJ, Foker JE, Moller JH, Ring WS, Lillehei CW, Varco RL. Long-term evaluation of aortic valvotomy for congenital aortic stenosis. Ann Surg 1987;6:496-503. 8. Pelech AN, Dyck JD, Trusler GA, et al. Critical aortic stenosis. J Thorac Cardiovasc Surg 1987;94:510-7. 9. Ettedgui JA, Tallman-Eddy T, Neches WH, et al. Long-term results of survivors of surgical valvotomy for severe aortic stenosis in early infancy. J Thorac Cardiovasc Surg 1992;104: 1714-. 10. Duncan K, Sullivan I, Robinson P, de Leval M, Stark J. Transventricular aortic valvotomy for critical aortic stenosis in infants. J Thorac Cardiovasc Surg 1978;93:546-50. 11. Sink JD, Smallhorn JF, Macartney FJ, Taylor JFN, Stark J, de Leval MR. Management of critical aortic stenosis in infancy. 12. J Thorac Cardiovasc Surg 1984;87:82-6. Wren C, Sullivan I, Bull C, Deanfield J. Percutaneous balloon dilatation of aortic valve stenosis in neonates and infants. Br Heart J 1987;58:608-12. 13. Rhodes LA, Colan SD, Perry SB, Jonas RA, Sanders SP. Predictors of survivors in neonates with critical aortic steno- 14. 15. 16. 17. sis. Circulation 1991;84:2325-35. Parksons MK, Moreau GA, Graham TP, Johns JA, Boucek RJ. Echocardiographic estimation of critical left ventricular size in infants with isolated aortic valve stenosis. J Am Coll Cardiol 1991;18:1049-55. Gerosa G, McKay R, Ross DN. Replacement of the aortic valve or root with a pulmonary autograft in children. Ann Thorac Surg 1991;51:424-9. Elkins RC, Santangelo K, Randolph JD, et al. Pulmonary autograft replacement in children: the ideal solution? Ann Surg 1992;216:363-71. Elkins RC, Knott-Craig CJ, Ward KE, McCue C, Lane MM. Pulmonary autograft in children: realized growth potential. Ann Thorac Surg 1994;57:1387-94. DISCUSSION DR ERIC L. CEITHAML (Jacksonville, FL): I think your study reaffirms that there is a high initial surgical mortality in critical aortic stenosis in the neonate. Because we do know that pulmonary autografts grow, do you think that there might be a place for the Ross procedure in surgical treatment of critical aortic stenosis in the neonate? DR GAYNOR: I think a lot of the initial mortality probably is due to the characteristics of the patient rather than the method used to relieve the obstruction. Particularly in the early years of the study, I imagine many of these children had small left ventricles that were inadequate for a two-ventricle repair. The inclusion of these patients may contribute to the high initial

126 GAYNOR ET AL Ann Thorac Surg NEONATAL AORTIC VALVE STENOSIS 1995;60:122-6 mortality. Although the use of the pulmonary valve to replace the aortic valve is very attractive and the results in older children and adults are very encouraging, there is not a lot of experience with neonatal use of the pulmonary autograft. So I am not sure if the initial survival would be improved by doing a bigger operation in these children. It probably would decrease the need for reintervention on the aortic valve but might not decrease the need for reintervention overall because of the need for conduit changes in the right ventricular outflow tract. I am not sure what the role of the pulmonary autograft is going to be in these patients. Perhaps some of these children should have a valvotomy, and then when they come to reintervention within 4 to 5 years that would be the optimal time for a pulmonary autograft, but I think that is still to be determined. DR DONALD C. WATSON (Memphis, TN): Doctor Gaynor, I congratulate you on an excellent paper. One of the important dimensions of the paper is that the end result is no different for the various modalities that you use. I would like to ask two questions regarding that. On your first intervention do you have a preferred way of intervening in these neonates? Second, one might subscribe to the theory that if there are no differences in the intervention that you used, you might pick the least expensive one to start with. Could you comment on your particular view? DR GAYNOR: Over the course of the study, many of the patients from the 1970s had their initial intervention at The Hospital for Sick Children and a variety of techniques were used. At one time open valvotomy with inflow occlusion commonly was performed, and then at a later time they performed mainly closed valvotomies. Currently the preferred procedure is either balloon valvuloplasty or open valvotomy on cardiopulmonary bypass, and that is similar to our feeling at Duke. I am not sure what the role of balloon valvuloplasty versus an open valvotomy is going to be in these children, but I think one of those two is probably the optimal method for the initial intervention. The Society of Thoracic Surgeons: Thirty-second Annual Meeting Mark your calendars for the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, which will be held at the Walt Disney World Dolphin Hotel in Orlando, Florida, January 29-31, 1996. Members may register for the Scientific Sessions at no charge. There will be a $250 registration fee for nonmember physicians except for Scientific and Poster Session presenters and residents. Registration for the Postgraduate Course is separate from the Annual Meeting. There will be a $70 registration fee for attendees of the Postgraduate Program, which will be held Sunday, January 28. The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. Advance registration forms, hotel reservation forms, and details regarding transportation arrangements, as well as the complete meeting program, will be mailed to Society members this fall (1995). Nonmembers wishing to receive information on attending the meeting should write to the Society's Secretary, Peter C. Pairolero. Peter C. Pairolero, MD Secretary The Society of Thoracic Surgeons 401 N Michigan Ave Chicago, IL 60611-4267 (312) 644-6610