Cardiac malformations occur commonly in Turner syndrome (TS), but the outcomes of cardiac operations and catheter-based procedures are unknown. The Pediatric Cardiac Care Consortium database was queried for individuals with TS and other female subjects without genetic abnormalities or syndromes (non-TS [NTS]). Procedures for left-sided heart lesions represented most TS procedures (95.2%). Three hundred ninety-eight patients with TS who underwent 637 of these procedures of interest were compared with 25,913 female NTS subjects who underwent 56,625 procedures. The numbers of procedures per admission (1.47 vs 1.61, p = 0.01) and per patient (1.85 vs 2.16, p <0.0001) were significantly lower in patients with TS. Procedures for cyanotic heart disease other than hypoplastic left heart (HLH) were performed 4.5-fold less frequently in patients with TS. Patients with TS and NTS subjects had equivalent hospital lengths of stay, except for patients with TS who underwent hypoplastic aortic arch operations, patent ductus arteriosus ligation, pulmonary artery balloon dilation, balloon atrial septostomy, and catheter closure of atrial septal defects. There were 34 deaths among patients with TS and 1,795 among NTS subjects (8.6% vs 7.2%, p = 0.30). When HLH was excluded, mortality was lower in the TS group (3.9% vs 6.5%, p = 0.05). Operations for partial anomalous pulmonary venous connection (14.3% vs 1.9%, p = 0.03) and HLH (90.4% vs 70.5%, p = 0.08) were more likely to result in death in patients with TS. In conclusion, given generally comparable lengths of stay and numbers of procedures as well as uniformly excellent results, these data suggest that the diagnosis of TS does not increase the utilization of limited health care resources. Operations for HLH and partial anomalous pulmonary vein connection carry additional risk for those with TS. These results will permit risk stratification, prognostication, and counseling of individuals with TS and their families.
Turner syndrome (TS) affects many organ systems including renal, genitourinary, musculoskeletal, and lymphatic. The cardiovascular system, however, is most frequently affected and can lead to significant mortality from early in pregnancy. Indeed, nearly 99% of monosomy X (45,X) fetuses die within the first and second trimesters. Furthermore, it is believed that the major cause of midgestational demise in TS is cardiac malformation. Despite this grim prenatal prognosis, approximately 1 in 2,000 live female births are individuals with TS. Of these, approximately 40% have cardiac diseases, primarily left-sided heart malformations or aortic arch obstruction. Accordingly, the burden of congenital heart disease in individuals with TS leads to a disproportionate need for medical intervention. The outcomes of cardiac operations or catheter interventions in the TS population, however, are largely unknown. To address this question, we studied 398 patients with TS who had 637 cardiac procedures registered in the Pediatric Cardiac Care Consortium (PCCC) database.
Methods
The PCCC database was 1 of the first multi-institutional databases for congenital heart disease and remains 1 of only a handful of collaborative efforts for outcomes assessment in the United States and Europe. It currently includes data from 52 pediatric cardiac centers in 19 states and additional centers in Canada. The PCCC reports the results of cardiac catheterizations, cardiac operations, and autopsies representing approximately 20% of the centers providing cardiac care to children. Results are extracted, coded, and entered into the PCCC registry, allowing each center to review and compare outcomes. For our retrospective case-control study, 130,672 patients enrolled from 1982 to 2006 were analyzed to ascertain TS and non-TS (NTS) data. The diagnosis of TS was based on clinical features and karyotype and was determined by coordinators at each site. The University of Minnesota Human Subjects Committee approved the use of deidentified PCCC data for this study. A complete tabulation of all procedures considered is available as supplemental data on-line. Patients with >1 cardiac procedure during an admission were categorized with a “primary procedure” for that admission. This primary procedure was used when considering length of stay and mortality. Length of stay was defined as the duration of hospital stay from the date of the primary procedure to the date of discharge, transfer, or death. Including or excluding those who were transferred or who had died did not significantly change the results.
Descriptive analysis (mean ± SD for continuous variables, frequency and relative frequency for categorical variables) was performed on each outcome of interest to study the distribution of the data. The ages at the time of procedures in patients with TS and NTS subjects were compared using Wilcoxon’s rank-sum test. Poisson regression analysis was applied to compare the differences between TS and NTS regarding the frequency of admissions and procedures. Chi-square or Fisher’s exact tests were applied to identify the differences in commonly occurring procedures between these 2 populations. For length-of-stay analysis, generalized linear mixed effects models with Poisson family were used. A similar analysis was performed that additionally adjusted for age. Generalized linear mixed effects models with Poisson family were used to capture correlations among multiple admissions in each subject. For mortality comparison, univariate analysis with Fisher’s exact or chi-square tests was applied. To further adjust for age at the time of procedures resulting in death, logistic regression was performed. In all cases, the level of significance was set at α = 0.05. A trend of significance was detected if the test had a p value of 0.05 to 0.10. The analysis was performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina) and R version 2.10.1 (R Project for Statistical Computing, Vienna, Austria).
Results
There were a total of 436 patients with TS and 42,442 with NTS. Procedures for left-sided cardiac anomalies represented most of the procedures performed in the TS group (95.2%; Figure 1 ) and are listed in Table 1 . In the NTS group, these “procedures of interest” occurred with significantly less frequency (p <0.0001). Therefore, 9 surgical and 8 catheter-based interventions were analyzed in detail. Three hundred ninety-eight patients with TS with procedures of interest were admitted on 498 occasions and underwent 637 cardiac procedures. Their ages ranged from 0 to 41.5 years (mean 4.1 ± 6.8). There were 527 cardiac operations and 110 cardiac catheterizations. We compared these with 25,913 female patients with NTS admitted 36,526 times with 56,655 procedures of interest. Their ages ranged from 0 to 90.5 years (mean 5.8 ± 10.0). There were 37,770 cardiac operations and 18,885 cardiac catheterizations. In addition, a 10th operative category for cyanotic heart disease other than hypoplastic left heart (HLH) was created to assess TS versus NTS outcomes. The patients in this category (n = 8) had operations for tetralogy of Fallot (n = 4), transposition of the great vessels (n = 2), and truncus arteriosus (n = 2). There were no patients with pulmonary atresia and intact ventricular septum.
| Procedure | TS (% of Patients) | NTS (% of Patients) | Odds | p Value |
|---|---|---|---|---|
| Operations | ||||
| Coarctation of aorta | 54.8 | 6.57 | 17.4 | <0.0001 |
| Hypoplastic aortic arch | 2.75 | 0.33 | 8.55 | <0.0001 |
| Aneurysm/dissection | 1.37 | 0.28 | 4.84 | 0.002 |
| HLH | 7.11 | 2.05 | 3.66 | <0.0001 |
| Aortic valve | 13.07 | 6.93 | 2.01 | <0.001 |
| Interrupted aortic arch type B | 1.2 | 0.62 | 1.85 | 0.2 |
| PAPVC | 4.6 | 2.62 | 1.78 | 0.02 |
| Patent ductus arteriosus ligation | 22.9 | 17.8 | 1.37 | 0.007 |
| Mitral valve | 1.14 | 1.76 | 0.65 | 0.46 |
| Other cyanotic heart diseases (excluding HLH) ⁎ | 1.8 | 8.3 | 0.11 | <0.0001 |
| Interventional catheterization | ||||
| Aortic valve balloon | 8.3 | 1.15 | 7.75 | <0.0001 |
| Coarctation balloon | 9.4 | 1.59 | 6.43 | <0.0001 |
| Mitral valve balloon | 0.23 | 0.045 | 5.13 | 0.51 |
| Aortic arch stent placement | 1.38 | 0.41 | 3.35 | 0.007 |
| Balloon atrial septostomy | 1.37 | 2.64 | 0.51 | 0.13 |
| Occlude patent ductus arteriosus | 1.83 | 7.41 | 0.23 | <0.0001 |
| Catheter closure atrial septal defect | 1.38 | 6.24 | 0.21 | <0.0001 |
| Pulmonary artery balloon | 0.69 | 6.85 | 0.094 | <0.0001 |
⁎ Tetralogy of Fallot (n = 4), transposition of the great arteries (n = 2), and truncus arteriosus (n = 2).
Of the 10 operative categories, several procedures were performed more frequently in patients with TS ( Table 1 , Figure 2 ). Specifically, the TS group was significantly more likely to undergo coarctation repair, hypoplastic aortic arch repair, aortic aneurysm or dissection repair, HLH palliation, aortic valve repair, partial anomalous pulmonary vein connection (PAPVC) repair, and solitary patent ductus arteriosus ligation. In contrast, patients with TS were significantly less likely to have operations for cyanotic heart conditions other than HLH.
Of the 8 catheter-based interventional procedures ( Table 1 , Figure 3 ), those performed significantly more often in patients with TS included aortic valve balloon, coarctation balloon, and aortic arch stent. Catheterization procedures performed significantly less often in the TS population were patent ductus arteriosus occlusion, atrial septal defect catheter closure, and pulmonary artery balloon.
The number of admissions per patient was similar between TS and NTS (1.26 vs 1.34, p = 0.162). However, the number of procedures per admission (1.47 vs 1.61, p = 0.01) and the number of procedures per patient (1.85 vs 2.16, p <0.0001) were significantly smaller in the TS group. When the age at the time of a procedure was compared between patients with TS and those with NTS, several procedures were performed at a significantly younger age in patients with TS. These included coarctation operation (2.1 ± 4.5 vs 2.3 ± 5.6 years, p = 0.035) and patent ductus arteriosus ligation (0.8 ± 2.9 vs 1.6 ± 3.6 years, p <0.0001). HLH operation (0.003 ± 0.02 vs 0.03 ± 0.14 years, p = 0.06) trended toward a younger age in patients with TS but did not reach statistical significance.
Overall, patients with TS had equivalent hospital lengths of stay compared to their NTS counterparts ( Table 2 ). The exceptions were for patients who underwent operations for hypoplastic aortic arch, solitary ligation of patent ductus arteriosus, pulmonary artery balloon dilation, balloon atrial septostomy, and catheter closure of an atrial septal defect. Further analysis demonstrated that for certain procedures, a younger age at the time of the procedure resulted in significantly longer lengths of stay for those with TS compared to those with NTS. These included hypoplastic aortic arch operation (p <0.0001), pulmonary artery balloon dilation (p = 0.007), patent ductus arteriosus ligation (p <0.0001), and balloon atrial septostomy (p = 0.016).
| Procedure | Mean Length of Stay (days) | Mortality | ||||
|---|---|---|---|---|---|---|
| TS | NTS | p Value | TS (%) | NTS (%) | p Value | |
| Operations | ||||||
| Coarctation | 13 | 12.5 | NS | 3/202 (1.5%) | 137/2,040 (6.7%) | 0.001 |
| Hypoplastic aortic arch | 30 | 18.5 | <0.0001 | 1/10 (10%) | 12/60 (20%) | NS |
| Aneurysm/dissection | 6.4 | 9.1 | NS | 0/2 (0%) | 2/37 (5.4%) | NS |
| HLH | 32.1 | 24.5 | NS | 19/21 (90.4%) | 320/454 (70.5%) | 0.08 |
| Aortic valve | 11.1 | 10 | NS | 6/47 (12.8%) | 115/1,663 (6.9%) | NS |
| Interrupted aortic arch type B | 15 | 20.8 | NS | 0/1 (0%) | 60/156 (38.5%) | NS |
| PAPVC | 5.4 | 6.6 | NS | 2/14 (14.3%) | 15/802 (1.9%) | 0.03 |
| Patent ductus arteriosus ligation | 21.5 | 11.2 | <0.0001 | 0/3 (0%) | 26/2,790 (2.5%) | NS |
| Mitral valve | 6.8 | 10.7 | NS | 0/1 (0%) | 40/541 (7.4%) | NS |
| Other cyanotic heart disease (excluding HLH) ⁎ | 10.4 | 13.7 | NS | 0/8 (0%) | 591/3,540 (16.7%) | NS |
| Interventional catheterization | ||||||
| Aortic valve balloon | 5 | 4.1 | NS | 0/21 (0%) | 9/355 (2.5%) | NS |
| Coarctation balloon | 10.7 | 4.2 | 2NS | 0/29 (0%) | 6/397 (1.5%) | NS |
| Mitral valve balloon | 0.5 | 9.2 | NS | 0/1 (0%) | 0/9 (0%) | NS |
| Aortic arch stent | 0.7 | 2.4 | NS | 0/5 (0%) | 1/115 (0.9%) | NS |
| Balloon atrial septostomy | 49.3 | 18.1 | 0.016 | 0/0 (0%) | 48/173 (27.7%) | NS |
| Occlude patent ductus arteriosus | 0.13 | 0.75 | NS | 0/8 (0%) | 2/2,993 (0.1%) | NS |
| Catheter closure atrial septal defect | 14.2 | 1.1 | <0.0001 | 0/5 (0%) | 4/2,531 (0.2%) | NS |
| Pulmonary artery balloon | 24.5 | 3 | 0.004 | 0/0 (0%) | 19/2,222 (0.9%) | NS |
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