The impact of cardiac surgery in patients with trisomy 18 and trisomy 13 in Japan^†

INTRODUCTION

Trisomy 18 (T18) and trisomy 13 (T13) represent common and important chromosomal disorders with multiple congenital anomalies. The incidence of T18 is estimated to 1/3,600–8,500, and that of T13 is estimated to be 1/10,000–20,000 [Carey, 2010]. Congenital heart defects (CHD) are present in about 80% of children with T13 and 90% of children with T18 [Carey, 2010]. Large systemic to pulmonary shunt lesions are common defects, and polyvalvular disease and mitral atresia are characteristic, especially in T18. Progressive pulmonary vascular obstructive change was observed in autopsy cases of T18 as early as 2-month old [Van Praagh et al., 1989].

These trisomies are also associated with multiple extracardiac defects, severe growth failure and developmental delay and only 5–10% survived beyond the first year [Rasmussen et al., 2003; Jones, 2006; Carey, 2010]. In a population-based study from the Northern region of England, the most common mode of death in patients with T18 and T13 was reported to be central apnea [Wyllie et al., 1994; Embleton et al., 1996]. The authors stated that cardiac surgery could not be justified in patients with T18 and those with T13. Even if survival occurs beyond the first year of life, patients with T18 and T13 frequently have marked developmental delay and respiratory and/or feeding problems that require intensive daily care. Therefore, surgical treatment for CHD in these patients has been limited even though their heart defects were expected to be successfully repaired from a view point of hemodynamics.

Recently, Kosho et al. [2006] showed improved survival of patients with T18 under intensive care including respiratory support, cardiac inotropic agents, and gastrointestinal surgery. Although they did not perform cardiac surgery in any of those patients, 25% of patients with T18 survived 1 year. Moreover, Graham et al. [2004] evaluated the outcome of cardiac surgery in 35 patients with T18 and T13, through data from the Pediatric Cardiac Consortium (48 centers in the United States, Canada, and Europe). They showed that 91% discharged alive and the patients without an extended preoperative ventilator requirement did not require prolonged mechanical ventilation after surgery [Graham et al., 2004]. Kaneko et al. [2008] compared outcomes of three distinct periods with different management: the first period, both pharmacological ductal intervention and cardiac surgery withheld; the second period, only pharmacological ductal intervention offered; the third period, both strategies available. The median survival time was significantly longer in the third (243 days), than the first (7 days) and the second (24 days). Kaneko et al. [2009] subsequently reported the outcome of 17 patients with T18 who underwent cardiac surgery including 11 having palliative surgery without cardiopulmonary bypass, 4 having palliative surgery followed by intracardiac repair (ICR), and 3 having primary ICR. Their survival time ranged from 12 to 1,384 days (median, 324 days), and 14 (82%) of them were discharged home with improved symptoms. However, it remains unclear whether cardiac surgery could affect their natural history and improve their lifespan because of lack of the large-scale follow-up study.

In order to accumulate further clinical evidence and determine the operative outcome of CHD in patients with T18 and T13, we performed a nationwide survey and analyzed clinical data, especially cardiac surgery and the outcome in these trisomies.

PATIENTS AND METHODS

Between July, 2005 and March, 2008, questionnaires made by the Committee for Genetics and Epidemiology of Cardiovascular Diseases in the Japanese Society of Pediatric Cardiology and Cardiac Surgery were sent to affiliated hospitals that belonged to this nationwide network. The questionnaires included outcome at survey, genotype, birth weight, gestational age, parental age at birth, family history, cardiac phenotype, coexistence of pulmonary hypertension (PH), type of cardiac surgery, age at surgery, operative outcome, and extracardiac phenotype of patients with T18 and T13 diagnosed and followed at those hospitals. One hundred thirty-four patients with T18 and 27 patients with T13 were registered from 15 of 98 (15%) hospitals with neonatal intensive care units and analyzed in this surveillance. No patient was excluded in spite of incomplete answers.

Group comparison for mean difference was analyzed by Student's t-test or Mann–Whitney U-test. Associations between survival and various anomalies were estimated by Fisher's exact probability test. Logrank test was used to detect the difference of survival rate using Kaplan–Meier method between operated and non-operated patients. A P-value less than 5% was defined as statistically significant. These statistical analyses were performed using Statcel (OMS, Tokorozawa, Saitama).

RESULTS

General information of patients analyzed in this study is shown in Table I. Female patients were predominant in those with T18 (female to male ratio: 1.9) consistent with previous reports [Jones, 2006]. The results of karyotyping were reported in 41 patients with T18 and 12 patients with T13. Extracardiac anomalies were shown in Table II. Cerebellar hypoplasia and gastrointestinal defects including esophageal atresia and hepatoblastoma were characteristic anomalies in patients with T18.

Overall Outcome of Patients With Trisomy 18

Twenty-three patients (17%) of 134 analyzed patients with T18 were alive at this survey (5 males and 18 females). Median age of surviving patients was 2.4 years ranging from 1 month to 19.9 years old. Three (13%) of these 23 patients had mosaicism of T18 and their ages were 3 years and 9 months, 16 years, and 19 years. One hundred five patients (78%) of 134 patients with T18 died at the median age of 3.6 months (40 males and 65 females) and 2 of them (1.9%) who died at 24 days and a year and 11 months old age showed mosaicism of T18. Outcomes of the remaining 6 patients were not reported. The vast majority of patients expired within 12 months as shown in Figure 1A. Although about 25% (survival rate 0.25) of patients with T18 survived the first year, the survival rate remained as high as 0.14 after 1 year, suggesting the relatively better survival in the subsequent years than in the first year (Fig. 1A). The median birth weight of patients who survived was significantly higher than expired patients with T18 (1,923 g in surviving patients vs. 1,701 g in expired patients, P = 0.032). Median gestational age of patients who survived was significantly longer than expired patients (39 weeks in survived patients vs. 37 weeks in expired patients, P < 0.01). The cause of the death was reported in 97 deceased patients (Table III). Thirty-eight patients (39%) of them were reported to die from respiratory failure, including 10 patients diagnosed with central apnea. Twenty-seven (71%) of the 38 patients died during the neonatal period. Cardiac involvement caused death in 25 patients from heart failure (26%) and 12 patients from arrhythmia (12%). Sudden death was also observed in 15 patients (15%). It is a remarkable finding that 6 of 15 patients died suddenly after successful cardiac surgery. Gastrointestinal defects did not significantly affect survival of T18 compared to those without gastrointestinal defects in this survey (P = 0.37).

Table III. Cause of Death in Patients With Trisomy 18 and Trisomy 13

	Trisomy 18 (n = 97)	Trisomy 13 (n = 16)
Respiratory failure	38 (39%)	4 (25%)
Heart failure	25 (26%)	5 (31%)
Arrhythmia	12 (12%)
Sudden death	15 (15%)	3 (19%)
Unknown	7 (7%)	4 (25%)

Congenital Heart Defects in Patients With Trisomy 18

One hundred twenty-six (94%) of 134 patients with T18 had CHD. Details of CHD in T18 were shown in Figure 2A. Ventricular septal defect (VSD) was the most common form of CHD up to 75 patients (59%) with T18 and 68% of those with VSD had other pulmonary-systemic shunts, such as atrial septal defect (ASD) and patent ductus arteriosus (PDA; Fig. 2B). Double outlet right ventricle (DORV) was the second most common CHD found in 14 (11%) of 126 patients and 73% of them did not have pulmonary stenosis resulting in excessive pulmonary flow. Three cases of mitral atresia with DORV (21%) were reported in 14 patients with DORV and T18 (Fig. 2C), which appeared to be characteristic CHD in T18 reported as previous autopsies [Van Praagh et al., 1989].

Sixty-five patients (52%) of 126 patients with CHD in T18 suffered from PH due to pulmonary-systemic shunt lesion. Valvular disease was identified 58 (46%) of 126 patients with T18, including 33 multiple valvular lesions. Fourteen patients showed both atrioventricular and semilunar valvular defects.

Overall Outcome of Patients With Trisomy 13

Five (19%) of 27 patients with T13 were alive at this survey (4 males and 1 female). The complex heart defects such as HLH and PTA were not operated. The median age of surviving patients was 3.5 years of age ranging from 0 day to 5.1 years old. Sixteen (59%) of 27 patients were deceased (3 males, 12 females, and 1 unknown gender) and the median age of death was 1 month. Mosaicism of T13 was reported in 1 surviving patient (20%) and 1 expired patient (6.3%). Congenital anomalies except heart were listed in Table II. Kaplan–Meier survived curve was illustrated in Figure 3 showing that the vast majority of them were dead within the first year. The cause of death of patients with T13 included heart failure (31%), respiratory failure (25%), and sudden death (19%; Table III).

Congenital Heart Defects and Cardiac Surgery in Patients With Trisomy 13

Twenty-three (85%) of 27 patients with T13 had CHD. ASD was the most common CHD found in 5 cases (22%) followed by VSD in 4 cases (17%), and DORV in 3 cases (13%) as shown in Figure 4. Two of 3 patients with DORV were accompanied with pulmonary atresia. Thirteen (57%) of 23 CHD were accompanied by PH.

Six (26%) of 23 patients received cardiac surgery and half of them (50%) were alive at the time of this survey. Age at surgery was distributed between 4 days and 9.5 years. Three (50%) of the 6 operated patients had PH, which improved after surgery. Six surgical procedures included three palliations (50%), along with 2 (67%) surviving and 2 ICR (33%) with 1 (50%) surviving (Table V).

Table V. Details of Congenital Heart Defects and Operative Procedures in Trisomy 13

CHD	Operation	Survival	Procedure
VSD ASD PDA	1	1	PAB + DL (1)
ASD PDA	1	0	UK (1)
AVSD PDA	1	1	ICR (1)
COA VSD PDA	1	1	PAB + DL (1)
IAA APW VSD	1	0	ICR (1)
TOF	1	0	BTS (1)
Total	6	3

• CHD, congenital heart defects; VSD, ventricular septal defect; ASD, atrial septal defect; PDA, patent ductus arteriosus; PAB, pulmonary artery banding; DL, ductus ligation; UK, unknown; AVSD, atrioventricular septal defect; ICR, intracardiac repair; COA, coarctation of aorta; IAA, interruption of aortic arch; APW, aortopulmonary window; TOF, tetralogy of Fallot; BTS, Blalock-Taussig shunt.

DISCUSSION

In order to delineate the current situation of cardiac surgery in patients with T18 and T13, we performed the nationwide survey through the network of Japanese Pediatric Cardiology and Cardiac Surgery. In our study, 94% of T18 and 85% of T13 had CHD. The vast majority of CHD had left to right shunt lesions and excessive pulmonary blood flow, which probably resulted in PH that was observed in 52% of patients with T18 and in 57% of those with T13, respectively. Twenty-six percent of patients with both trisomies received surgery for CHD and only 2 of 32 patients died in perioperative period in T18. It is noteworthy that operated patients survived significantly longer than non-operated patients in patients with T18 (Fig. 1B,C), although it is possible that operated patients had simple CHD and/or less extracardiac problems. As for patients with T13, our data collection was not detailed enough to analyze the surgical impact on their survival. In our limited data, operative survival rate of T13 seemed not inferior to that of T18, suggesting that cardiac surgery may be tolerated in at least some patients with T13. Recently, there is a growing tendency to take cardiac surgery into consideration in both trisomies according to clinical status despite the poor life expectancy [Carey, 2005, 2010; Jones, 2006]. This trend has probably been growing in the background of patients' support groups, general respect for parental autonomy, and accumulation of clinical evidence such as long-term survivors and effectiveness of intensive treatment [Graham et al., 2004; Kosho et al., 2006; Kaneko et al., 2008, 2009]. Our nationwide survey supports this trend providing information from relatively large numbers of patients with T18 and T13.

With regard to surgical procedures in patients with T18 and T13, it is debatable whether an intracardiac repair using cardiopulmonary bypass or a palliative repair should be employed for operative survival. In our study, about 20–30% of patients received ICRs and half of them survived postoperatively in both trisomies, although majority of patients underwent palliative repairs (Tables IV and V). Kaneko et al. [2009] reported better postoperative survival with palliative repairs than primary ICRs among 17 patients with T18 who had life-threatening extracardiac problems. On the other hand, Van Dyke and Allen [1990] reported a T18 patient with VSD and PDA who survived for more than 5 years after ICR. Graham et al. [2004] also reported that 32 (91%) of 35 patients with T18 and T13 who underwent cardiac surgery were discharged from hospitals alive. Their primary surgical procedures included 18 ICRs, 13 palliative repairs as well as 4 PDA ligations, suggesting that palliative surgery such as pulmonary artery banding (PAB) might not be always indicated as a primary repair to alleviate the risk of surgery [Graham et al., 2004]. This series included four patients with VSD who underwent ICRs after PAB. Teraguchi et al. [1998] also described two patients with T18 and large VSD who survived after the ICR following PAB. It should be also noted that all studies described above excluded intracardiac surgery for complex type of CHD, such as HLHS.

Our study was based on questionnaires about CHD and extracardiac anomalies and had limitation for the assessment of clinical severity of each patient. We could not recruit all patients with T18 and T13 because of partial response (15% of affiliated hospitals) to our survey. We might have missed patients who died earlier, resulting in increased survival or surgical success rate. The vast majority of patients died by 26 months in T18 and 8 months in T13, reflecting the short life expectancy. On the other hand, a small number of patients at risk may overestimate the survival rate of both trisomies as no death seemed to occur thereafter (Figs. 1 and 3). Hence, this study may be defined as a multi-institutional observation with some bias rather than as a population-based analysis.

Because no well-defined criteria for cardiac surgery are available for patients with T18/T13, the indication of operation was completely dependent on each physician's decision, and we did not know how physicians struggled and finally decided to operate on patients with T18 and T13. Although our study suggested that operated patients survived longer than non-operated patients with T18, general postoperative survival of simple CHD including VSD, ASD, and PDA should reach more than 99% in nonsyndromic patients, whereas it declined as low as 50% in both trisomies in this study. Even though cardiac surgery successfully corrected abnormal hemodynamics, non-heart-related death could be encountered in T18 and T13 (Table III). Respiratory failure including central apnea may not be avoided in these trisomies regardless of outcomes of cardiac surgery. Unexpected or sudden death was also reported, which might be related to apnea. On the other hand, it was evident that some patients with T18 and T13 could survive and discharge hospital [Carey, 2010]. Technical difficulties in performing surgical treatment of relatively simple CHD in patients with T18/T13 are being overcome and cardiac surgery could be considered in those without severe extracardiac problem.

In this study, although we analyzed the impact of cardiac surgery on survival, we could not evaluate the impact of cardiac surgery on indices concerning quality of life such as hospital discharge rate, rate of home mechanical ventilation, rate of home oxygen therapy, rate of oral feeding without nasal tube. It is important to evaluate how well the patients become after cardiac surgery in future studies.

CONCLUSION

Cardiac surgery for CHD was performed in a quarter of patients with T18 and T13 and resulted in better life outcome, especially in T18, in the nationwide survey in Japan. The indications of cardiac surgery for these patients need to be considered electively from the individual patient's status along with continuous support for decision-making by the parents. It is still not clear whether cardiac surgery improves the long-term prognosis of patients with T18 and T13; however, cardiac surgery may be indicated for patients with relatively simple CHD and/or extracardiac complications. We believe that the opinions of parents of patients should be strongly respected in determining whether such surgery is performed. Physicians should provide information to the family sufficient to enable optimal decision-making. Pediatric cardiologists as well as clinical geneticists need not only to perform counseling and respect parent's decision, but also address the opinions as professionals based on medical experience, knowledge, and ethics.