Is Down syndrome a risk for poor outcome in after repair of congenital heart defects?

I

Is Down syndrome a risk factor for poor outcome

after repair of congenital heart defects? Mark D. Reller, MD, and Cynthia D. Morris, PhD, MPH

Down syndrome is commonly associated with significant congenital heart disease with the potential for early development of pulmonary hypertension. As such, children with Down syndrome may be at increased risk for both perioperative and long-term mortality. The purpose of this study, using data collected from a population-based outcomes study, is to analyze the potential role that Down syndrome plays in the outcome of surgically “corrected” congenital heart disease. Data were collected from a registry of all Oregon residents who, in the period 1958 to the present, had a reparative operation for one of 14 congenital cardiac malformations when younger than 18 years (N = 3965 patients). Down syndrome was present in 289 (7%) of the total registry patients. In evaluating the cardiac mortality associated with Down syndrome for each of the repaired cardiac malformations, only complete atrioventricular septal defect was associated with significantly higher perioperative (13% vs 5%) as well as higher overall late cardiac mortality through 20 years after the operation (20% vs 5%; p = 0.04). The survival outcomes for each of the other cardiac malformations were similar for children with and without Down syndrome. (J Pediatr 1998;132:738-41.) Approximately 40% of children with Down syndrome have congenital heart disease, with atrioventricular (AV) septal defects being the most common.1 Other left-to-right shunt lesions are also common and include ventricular septal defect, patent ductus arteriosus, partial AV septal defects (ostium primum atrial septal defects), and secundum ASDs. In addition to these structural cardiac malformations exists the potential for preFrom the Departments of Pediatrics (Cardiology) and Medicine (Cardiology) and the University Congenital Heart Research Center, Oregon Health Sciences University, Portland, Oregon. Supported by National Institutes of Health grants NIH R29 HL39052 and NIH R23 HL36856.

mature development of pulmonary vascular obstructive disease.2 The presence of Down syndrome therefore often influences the decision as to the timing of operation, particularly for those cardiac malformations associated with early development of pulmonary hypertension. In addition, the increased propensity to pulmonary hypertension can affect both the short- (perioperative) and long-term mortality associated with congenital heart disease operations in children with Down syndrome. The purpose of this study is to analyze the role Down syndrome plays in outcome using a population-based outcomes study of congenital heart disease.

Submitted for publication Apr. 2, 1997; revision received July 14, 1997; accepted Sept. 16, 1997. Reprint requests: Mark D. Reller, MD, Division of Pediatric Cardiology, UHN-51, Oregon Health Sciences University, 3181 S. W. Sam Jackson Park Rd., Portland, OR 97201. Copyright © 1998 by Mosby, Inc. 0022-3476/$5.00 + 0

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METHODS As part of such a study of congenital heart disease, we have formed a registry of all Oregon residents who have had a

cardiac operation for one of 14 congenital heart defects when younger than 18 years from 1958 to the present.3 The current registry includes data on 3965 patients. Children who have had palliative operations only are excluded from this cohort. However, children who have had placement of a systemic-to-pulmonary shunt or pulmonary artery banding are included if a subsequent definitive operation was performed. Of the cardiac operations performed, 99.3% were performed at one of five Oregon hospitals, with 70% of the operations performed at the Oregon Health Sciences University. ASD PDA VSD

Atrial septal defect Patent ductus arteriosus Ventricular septal defect

To form the registry, medical records departments in each of the five Oregon hospitals that performed cardiac or thoracic operations were asked to identify cases using both procedure and diagnostic codes of hospital admissions. Computerized records, card files of hospital admission, and surgical logs were searched to identify cases. Since 1982, data have been added to the registry prospectively with yearly ascertainment of operative cases. To obtain long-term follow-up information, subjects were traced through next of kin, physicians, employment records, Department of Motor Vehicles registration, city and telephone directories, and the National Death Index. Follow-up status of all individuals in the registry was determined by a mailed questionnaire every 2 years. Individuals who did not complete the questionnaire were contacted by phone for a formatted interview. All major events noted on the questionnaire or in the interview were

THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 4 verified with medical records. For any subject who died outside of the hospitals included in this study, the death certificate, autopsy record, and pertinent medical records were obtained to ascertain the cause of death. Deaths were coded by two independent observers as cardiac or noncardiac. Cardiac mortality in this report includes death attributed to the operative repair itself (perioperative mortality defined as occurring within 30 days of operation), those that occur at reoperation, those resulting from progressive cardiac failure or pulmonary hypertension, deaths attributed to dysrhythmia, and sudden unexpected deaths. Noncardiac causes include accidental deaths (including motor vehicle deaths), deaths caused by complications from other congenital malformations or disease processes (such as leukemia), infectious causes, including meningitis, and suicidal and homicidal deaths. The cumulative incidence of postoperative deaths for each cohort was estimated by the Kaplan-Meier method. This was defined as the time elapsed from the date of operation to the date of death or the last date of contact with the subject. All statistics were calculated separately for each heart defect cohort. The Mantel-Cox statistic was used to compare survival. For comparison of median values between children with and without Down syndrome, the Mann-Whitney test was used.

RESULTS Of the 3965 registry patients who had a cardiac operation since 1958, 289 (7%) were found to have Down syndrome. The most common cardiac malformation requiring an operation in children with Down syndrome was complete AV septal defect, occurring in 130 of 167 total operations for this cardiac malformation (78%). The presence of Down syndrome was associated with a significantly greater overall mortality (Figure). This difference was seen both as a higher perioperative mortality at 1 month after surgery (13% vs 5%) as well as a greater rate of cardiac mortality through 20 years after surgery (20% vs 5%; p =

RELLER AND MORRIS

Figure. Survival curve demonstrating proportion of children free from cardiac death after operative repair of complete AV septal defect for Down syndrome (dashed line) versus children without Down syndrome (solid line).The difference is statistically significant (p = 0.04).

0.04). An additional 7% cardiac mortality was observed through 20 years of follow-up in perioperative survivors with Down syndrome compared with none in children without Down syndrome. Of the nine late cardiac deaths in children with Down syndrome, pulmonary hypertension was believed to have contributed to the cause of death in 5 children. To date, each of the late deaths has occurred within 5 years of the operation (Figure). The increased risk associated with Down syndrome was found to be independent of the year of the operation. The next most common cardiac malformation requiring operation in children with Down syndrome was VSD, occurring in 76 of 557 total operations for VSD (14%). Children with Down syndrome also comprised 30 of 114 patients with partial AV septal defect (ostium primum ASD) (26%), 21 of 498 of the patients who had operative repair of tetralogy of Fallot (4%), 16 of 623 of patients with PDA (3%), and 16 of 628 of patients with secundum ASD (3%). Importantly, the presence of Down syndrome was not associated with a significantly different risk of cardiac mortality for any of the other cardiac diagnoses. Specifically, operative mortality was

equal in children with and without Down syndrome who had VSD and partial AV septal defect, and was actually somewhat lower in children with Down syndrome who had tetralogy of Fallot (difference not significant). In addition, no differences were noted in late cardiac mortality for any of these other cardiac malformations. The age at reparative operation has remained younger in children with Down syndrome for each of the cardiac malformations (Table), with statistically significant differences for VSD (median age 0.5 vs 1.1 years, p < 0,001), secundum ASD (median age 1.8 vs 3.7 years, p < 0.01), PDA (median age 1.1 vs 2.0 years, p < 0.05), and partial AV septal defect (1.4 versus 2.4 years, p < 0.05). This finding of younger age at operation for children with Down syndrome has persisted even as the overall timing of operative intervention has declined over the years for all cardiac malformations.

DISCUSSION Our data confirm that Down syndrome is commonly seen in patients with cardiac defects necessitating operative 739

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THE JOURNAL OF PEDIATRICS APRIL 1998

Table. Median age of cardiac surgery for operations performed since 1980*

Down syndrome

VSD ASD PDA pAVSD cAVSD TOF

Non–Down syndrome

N

Years (range)

N

Years (range)

p Value

57 14 8 23 116 13

0.5 (0.2-13.8) 1.8 (0.2-11.6) 1.1 (0.3-2.3) 1.4 (0.3-14.2) 0.3 (0.1-11.7) 0.6 (0.2-10.4)

254 327 280 48 28 178

1.1 (0.03-18.2) 3.7 (0.3-18.9) 2.0 (0.3-18.2) 2.4 (0.5-18.8) 0.4 (0.1-8.6) 0.7 (0.03-17.0)

<0.001 <0.01 <0.05 <0.05 0.09 0.20

ASD, Atrial septal defect; cAVSD, complete atrioventricular septal defect; pAVSD, partial atrioventricular septal defect; PDA, patent ductus arteriosus; TOF, tetralogy of Fallot; VSD, ventricular septal defect. *1980 was chosen because the indications for cardiac operation, particularly for children with Down Syndrome, had evolved by this date to be current practice.

repair. The 7% prevalence of Down syndrome in all patients requiring cardiac operation is comparable to the 9% prevalence reported in the Baltimore-Washington Infant Study.4 In addition, the 78% prevalence of Down syndrome in children undergoing an operation for complete AV septal defect is nearly identical to the prevalence reported in previous studies.5,6 Further, the occurrences of Down syndrome with the other cardiac malformations with left-to-right shunting that range from 3% (for ASD and PDA) to 26% (for partial AV septal defect) also are similar to previously reported data.4 Each of these cardiac defects has similar pathophysiologic features in that the defects are associated with the potential for significant left-toright shunts and increased risk for pulmonary hypertension, particularly for the patients with VSD, PDA, and complete AV septal defects. For children with repaired complete AV septal defects, Down syndrome was associated with a significantly higher cardiac mortality. Although no single mechanism explains the higher mortality in children with AV septal defects, our findings suggest that the associated risk of pulmonary hypertension may play some role. It is generally recognized that children with Down syndrome are at risk for the development of pulmonary vascular disease, and it can occur even in the absence of structural heart disease. Noncardiac causes associated with Down syndrome include the risk occurring with chronic upper airway obstruction associated with macroglossia and laryngotra740

cheal obstruction.7,8 In addition, there is evidence that children with Down syndrome are at risk for pulmonary hypertension because of relative lung hypoplasia.9 In a previous analysis of postoperative patients with AV septal defects, we demonstrated that the pulmonary arterial pressure and the pulmonary vascular resistance in patients with Down syndrome decreased less after surgery than in patients without Down syndrome, even though they had similar preoperative hemodynamics.10 Whereas a later age at the time of operative repair of complete AV septal defect is clearly associated with poorer outcome,11 our current data demonstrate a tendency for operations to occur at an earlier age in children with Down syndrome who have complete AV septal defects. However, the difference did not reach statistical significance. For children with Down syndrome who had partial AV septal defect, secundum ASD, isolated VSD, and PDA, the age at operation was significantly lower. Whether the timing was the result of more frequent symptoms preoperatively, larger size of the defect, or an enhanced concern about pulmonary hypertension amongst caretaking physicians in children with Down syndrome is unclear from this study. Although the presumption of an increased risk of pulmonary hypertension exists among clinicians caring for children with Down syndrome, it is also possible that Down syndrome does not substantially increase the risk of pulmonary hypertension associated with these car-

diac malformations, when size of the defect is controlled for. In support of this alternative hypothesis is the other important finding of this study. That is, that the survival data for Down syndrome were comparable for each of the other cardiac anomalies, including patients with VSD and PDA who presumably were at similar risk for pulmonary hypertension. Thus when we exclude the outcome found in children with Down syndrome who have AV septal defects, our data corroborate several previous studies that have shown similar outcomes for children with and without Down syndrome.12,13

REFERENCES 1. Tandon R, Edwards JE. Cardiac malformations associated with Down’s syndrome. Circulation 1973;47:1349-55. 2. Greenwood R, Nadas A. The clinical course of cardiac disease in Down’s syndrome. J Pediatr 1976;58:893-7. 3. Morris CD, Menashe VD. 25-year mortality after surgical repair of congenital heart defect in childhood. JAMA 1991;266:3447-52. 4. Perry LW, Neill CA, Ferencz C, Rubin JD, Loffredo CA. Infants with congenital heart disease: the cases. In: Ferencz C, Rubin JD, Loffredo CA, Magee CA, editors. Epidemiology of congenital heart disease: the Baltimore-Washington Infant Heart Study 1981-1989. Mount Kisco (NY): Futura; 1993. p. 33-61. 5. Chin AJ, Keane JF, Norwood WI, Casteneda A. Repair of complete common atrioventricular canal in infancy. J Thorac Cardiovasc Surg 1982;84:437-45. 6. Sondheimer HM, Byrum CJ, Blackman MS. Unequal cardiac care for children

THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 4 with Down’s syndrome. Am J Dis Child 1985;139:68-70. 7. Levine OR, Simpser M. Alveolar hypoventilation and cor pulmonale associated with chronic airway obstruction in infants with Down syndrome. Clin Pediatr 1982;21:25-9. 8. Southall DP, Stebbens VA, Mirza R. Upper airway obstruction with hypoxemia and sleep disruption in Down syndrome. Dev Med Child Neurol 1987; 29:734-42.

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9. Conney TP, Thurlbeck WM. Pulmonary hypoplasia in Down’s syndrome. N Engl J Med 1982;307:1170-3. 10. Morris CD, Magilke D, Reller MD. Down’s syndrome affects results of surgical correction of complete atrioventricular canal. Pediatr Cardiol 1992; 13:80-4. 11. Kirklin JW, Blackstone EH, Bargeton LM, Pacifico AD, Kirklin JK. The repair of atrioventricular septal defects in infancy. Int J Cardiol 1986;13:333-51.

12. Katie MR, Clark EB, Neill C, Hall JA. Surgical management of congenital heart disease in Down’s syndrome. J Thorac Cardiovasc Surg 1977;74:204-9. 13. Schneider DS, Zahka KG, Clark EB, Neill CA, Baltimore-Washington Infant Study Group. Patterns of cardiac care in infants with Down syndrome. Am J Dis Child 1989;143:363-5.

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