Association Between Tetralogy of Fallot and Psychiatric Disorders: A Nationwide Cohort Study
Objective: The tetralogy of Fallot (TOF) has been reported to be associated with some neurodevelopmental impairment and psychiatric disorders. Nevertheless, a nationwide study to clarify the risk between TOF and comorbid psychiatric disorders is lacking. Using a nationwide database in Taiwan, this study aimed to explore the role of TOF in various psychiatric disorders and analyze whether there are patient-related risk factors.
Methods: A total of 16,824 enrolled patients, including 4,206 study subjects who were diagnosed with TOF and 12,618 controls with TOF matched (1:3) for sex, age, hospital visits, and index year, were randomly selected from the Taiwanese National Health Insurance Research Database (NHIRD) between 2000 and 2015. Patients’ diagnoses in the NHIRD were encoded using International Classification of Diseases, 9th Revision, Clinical Modification codes.
Results: Of patients with TOF, 256 (6.09%) developed psychiatric disorders compared to 394 (3.12%) in the control group. After adjusting for covariates, the adjusted hazard ratio of psychiatric disorders for patients with TOF was 3.192 (95% CI, 2.683–3.798; P < .001). After exclusion of psychiatric diagnoses within the first 5 years, TOF was associated with an increased risk of anxiety (P < .001), depression (P < .001), bipolar disorder (P < .001), and sleep disorders (P = .005).
Conclusions: This study revealed that TOF patients have a nearly 3-fold higher risk of psychiatric disorders, including anxiety, depressive, bipolar, and sleep disorders, than the general population. Therefore, continued mental health screening and surveillance are warranted in TOF patients.
J Clin Psychiatry 2021;82(2):19m13126
To cite: Hsu WF, Chien WC, Chung CH, et al. Association between tetralogy of Fallot and psychiatric disorders: a nationwide cohort study. J Clin Psychiatry. 2021;82(2):19m13126.
To share: https://doi.org/10.4088/JCP.19m1312
© Copyright 2021 Physicians Postgraduate Press, Inc
aDepartment of Pediatrics, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
bDepartment of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
cGraduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
dSchool of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
eTaiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
fDivision of Pediatric Cardiology, Children’s Medical Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
gSchool of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
hGraduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan, ROC
iDepartment of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
jStudent Counseling Center, National Defense Medical Center, Taipei, Taiwan, ROC
kDepartment of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan, ROC
lDivision of Nephrology, Department of Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
mGraduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
*Corresponding author: Nian-Sheng Tzeng, MD, Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Cheng-Kung Rd, Nei-Hu District, Taipei City 11490, Taiwan, ROC (firstname.lastname@example.org).
Tetralogy of Fallot (TOF), characterized by a ventricular septal defect, overriding of the aorta, right ventricular outflow stenosis, and right ventricular hypertrophy, is the most common form of cyanotic congenital heart disease (CHD).1 The reported incidence is from 0.28 to 0.63 per 1,000 live births.1,2 With advancements in surgical procedures, almost all newborns with TOF can expect to survive surgical correction and reach adulthood.1,3 Hence, clinicians should pay more attention to factors that may decrease the quality of life in TOF survivors.
Patients with TOF were reported to be at an increased risk of neurodevelopmental impairment with diminished performance in general intelligence, academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition as well as having abnormal findings on magnetic resonance imaging.4 In addition, there are also case reports5–7 and one single-center study8 that have documented the association between TOF and psychiatric disorders. Therefore, a nationwide, population-based, matched-cohort study is necessary to clarify the association between TOF and psychiatric disorders. Moreover, no study has investigated psychiatric disorders in Asian TOF patients, even though the incidence of TOF appears to be higher in Asian people.2
In Taiwan, the National Health Insurance (NHI) program, a single-payer mandatory enrollment program, was launched in 1995. Up to 99.99% of the population is enrolled in this program.9 The details of the program have been documented in previous studies.10–13 This medical care system has been widely reported as efficient, and the medical histories of patients with CHDs are easily accessible, including patients with TOF.3 Therefore, we have used a database released from the NHI to conduct a nationwide cohort study to investigate the long-term outcomes of the associated risk of psychiatric disorders in TOF patients.
The National Health Insurance Research Database (NHIRD), derived from the claims data of NHI beneficiaries, uses the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to record diagnoses. The accuracy of several diagnoses in the NHIRD has been verified.14–16 Therefore, the NHIRD can illuminate the disease burden and health care process of the entire population. The NHIRD is established and maintained by the National Health Research Institutes, Taiwan, and provided to scientists for public research purposes. Only researchers who are Taiwanese nationals and fulfill the requirements of conducting research projects can directly access the data.9 Restrictions on the use of the NHIRD can be found at https://nhird.nhri.org.tw/en/Data_Protection.html. A subset of the NHIRD, the Longitudinal Health Insurance Database (LHID), had a randomized sampled population of two million from 2000 to 2015 that was used to study the association between TOF and the risk of psychiatric disorders.
Study Design and Sampled Participants
This study has a population-based, matched-cohort design. According to the ICD-9-CM codes, patients diagnosed with TOF (745.2) between 2000 and 2015 were selected from the LHID. Patients with TOF before 2000 were excluded. In addition, patients diagnosed with anxiety, depression, bipolar disorder, sleep disorders, posttraumatic stress disorder/acute stress disorder (PTSD/ASD), eating disorders, substance-related disorders (SRDs), psychotic disorders, and organic mental disorders before 2000 or before their first visit for TOF were also excluded. Each enrolled patient must have made at least 3 outpatient visits for TOF according to the ICD-9-CM codes to avoid a tentative diagnosis. All enrolled TOF patients were followed from the date of diagnosis instead of surgical intervention because patients with TOF may not have undergone surgical intervention during the study period. For each TOF patient, 3 sex-, age-, hospital visit–, and index year–matched participants without TOF or psychiatric disorders were randomly identified from the same database to form the non-TOF control group. A total of 16,824 patients, including 4,206 subjects with TOF and 12,618 controls, were enrolled.
The covariates included sex, age groups (0−15, 16−30, 31−45, 46−60, and > 60 years), monthly income (< 18,000, 18,000–34,999, and > 35,000 New Taiwan dollars [NT$]), comorbidities, types of hospital visits and stay (length of hospitalization and with/without intensive care unit (ICU) stay), season (spring, summer, autumn, and winter), geographical area of residence (in the north, center, south, and east of Taiwan), urbanization level of residence (levels 1–4, with 1 being the highest), and levels of care (hospital center, regional hospital, and local hospital). Comorbidities were assessed by the Charlson Comorbidity Index, which classifies the comorbidities with ICD-9-CM codes, scores each category, and combines all scores to calculate a single comorbidity score.17 Higher scores indicate higher comorbidity burdens. Some childhood-onset neurodevelopmental and neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) disability, autistic disorder/pervasive disorder (AD/PDD), conduct disorder/oppositional defiant disorder (CD/ODD), other developmental disorders, childhood emotional disorder, Tourette syndrome/tic disorders, enuresis, and encopresis, were also included in comorbidities. The urbanization level of residence was defined according to the population and various indicators of level of development.18
All study participants were followed from the index year until the onset of psychiatric disorders, such as anxiety (ICD-9-CM 300), depression (ICD-9-CM 296.2–296.3, 300.4, and 311), bipolar disorder (ICD-9-CM 296.0, and 296.4–296.8), sleep disorders (ICD-9-CM 307.4, and 780.5), PTSD/ASD (ICD-9-CM 308 and 309.81), eating disorders (ICD-9-CM 307.1 and 307.5), SRD (ICD-9-CM 291–292, 303.3, 303.9, and 304–305), psychotic disorders (ICD-9-CM 295 and 297–298), and organic mental disorders (ICD-9-CM 290, 293–294); withdrawal from the NHI program; or the end of 2015.
All statistical analyses were measured using SPSS for Windows, version 22.0 (IBM Corp; Armonk, New York). χ2 and t tests were performed to evaluate the distributions on categorical and continuous variables, respectively, with a Fisher exact test. The Fine and Gray competing risk analysis was performed to determine the risk of psychiatric disorders, since death can be a competing risk factor for psychiatric disorders.19 The results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). The cumulative incidence of psychiatric disorders between the study and control groups was evaluated by the Kaplan-Meier analysis with a log rank test. A 2-tailed P value of less than .05 was considered to indicate statistical significance.
This study was conducted following the Code of Ethics of the World Medical Association (Declaration of Helsinki). The Institutional Review Board of the Tri-Service General Hospital approved this study and waived the need for individual written informed consent (IRB No. 2–107-05-026).
The study included 4,206 patients with TOF and 12,618 patients in the control cohort between 2000 and 2015. There were no differences in the distribution of sex, age, hospital visits, and insurance premiums between these two groups (Table 1). The mean ± SD follow-up time was 11.66 ± 14.00 years in the TOF cohort and 12.10 ± 15.15 years in the control cohort.
By the end of follow-up, 650 (3.86%) of all enrolled participants developed psychiatric disorders, including 256 participants in the TOF cohort (6.09%) and 394 participants in the control cohort (3.12%), or 521.96 versus 258.03 per 100,000 person-years. There was a trend of TOF patients’ having a higher rate of psychiatric disorders at the end of follow-up than the control group (P < .001). Among the psychiatric disorders, anxiety, depression, bipolar disorder, sleep disorders, PTSD/ASD, and organic mental disorders were higher in the patient group than the control group (P < .05 each).
Association Between TOF and Risk of Psychiatric Disorders
The Kaplan-Meier analysis indicated that in the first year, the incidence of psychiatric disorders was higher in the TOF cohort than in the control cohort (P = .037), and this finding continued until the end of the follow-up (P < .001; Figure 1).
Patients with TOF had a higher risk of psychiatric disorders when compared with the control cohort. In the competing analysis model, the adjusted HR in the study group of developing psychiatric disorders was 3.192 (95% CI, 2.683–3.798; P < .001; Table 2) in comparison to the control group after adjustment for the covariates.
Patients with TOF were associated with having an increased risk of psychiatric disorders in all age groups older than 15 years, with the age group of 0–15 years as the reference. In addition, more days of hospital stay and higher levels of medical care were associated with a higher risk of having a psychiatric disorder. The numbers of visits to the outpatient department/emergency department and inpatient department and the length of stay in the ICU were of multicollinearity with the length of hospital stay.
The risk of developing psychiatric disorders was increased in TOF patients regardless of the operation methods (P < .001; Table 3). The adjusted HRs of the subgroup who received total repair only and Blalock-Taussig (B-T) shunt plus total repair were 3.207 (95% CI, 2.704–3.815; P < .001) and 3.199 (95% CI, 2.690–3.809; P < .001), respectively.
Sensitivity Analysis for Psychiatric Disorders in TOF Patients
Table 4 demonstrates that the overall risk of developing a psychiatric disorder in patients with TOF was increased without exception of the first year or the first 5 years (adjusted HR = 3.192, P < .001) as well as with exclusion of psychiatric diagnoses in the first year (adjusted HR = 2.407, P < .001) and within the first 5 years (adjusted HR = 1.955, P < .001). After exclusion of the psychiatric diagnoses in the first year, the having TOF was still associated with a risk of having anxiety, depression, bipolar disorder, sleep disorders, PTSD/ASD, and organic mental disorders, with adjusted HRs of 2.778 (P < .001), 2.885 (P < .001), 2.991 (P < .001), 2.050 (P < .001), 19.803 (P < .001), and 3.160 (P < .001), respectively. After exclusion of the psychiatric diagnoses in the first 5 years, the associated risk of developing anxiety, depression, bipolar disorder, and sleep disorders was still increased, with adjusted HRs of 2.395 (P < .001), 2.167 (P < .001), 2.559 (P < .001), and 1.802 (P = .005).
To the best of our knowledge, this nationwide and population-based cohort study is the first to explore the risk of psychiatric disorders in patients with TOF. After adjusting for covariates, the overall adjusted HR was 3.192 (95% CI, 2.683–3.798; P < .001), meaning that the risk of developing psychiatric disorders in TOF patients was nearly 3-fold compared to that of the general population. The Kaplan-Meier analysis revealed that the TOF cohort had a significantly higher cumulative risk of psychiatric disorders than controls. Furthermore, the risk was not affected by the method of operation. Both total repair only and B-T shunt plus total repair for TOF patients were associated with psychiatric disorders, with adjusted HRs of 3.207 (P < .001) and 3.199 (P < .001), respectively, which were both close to the overall adjusted HR. The sensitivity analysis found an increased risk of overall psychiatric disorders after excluding psychiatric diagnoses within 1 or 5 years of diagnosis in the TOF cohort. Additionally, after exclusion of psychiatric diagnoses within 5 years, TOF patients were still associated with a nearly 2-fold risk of developing anxiety, depression, bipolar disorder, and sleep disorders.
The study aimed to evaluate the risk of developing psychiatric disorders in patients with TOF using the NHIRD; the non-TOF control group included sex-, age-, hospital visit–, and index year–matched (1:3) subjects that were randomly selected from the same dataset to represent the general population. Therefore, it was reasonable that the length of hospital stay and level of care were different between the two groups (P < .001). The prevalence of psychiatric disorders at the endpoint for both groups was lower than those in a previously published study.20 This difference may be explained by the fact that, in our study, both TOF and non-TOF groups comprised mainly pediatric patients. Wu et al3 demonstrated that the prevalence of TOF in pediatric populations (< 20 years) was around 10 times more than that in adult populations (≥ 20 years), which may explain why more than 60% of participants were younger than 15 years of age in the present study.
Holland et al8 investigated the association between TOF and the risk of psychiatric disorders. They conducted a cross-sectional study that enrolled patients from 2004−2008 at a single medical center. In their study subjects, 23 of the adolescents with TOF had a known genetic diagnosis. The authors found an increased rate of developing psychiatric disorders in adolescents with TOF and a known genetic diagnosis; the most observed disorders were anxiety and ADHD. However, among adolescents without a known genetic diagnosis, the rates of psychiatric disorders did not differ significantly from those of the healthy reference group. Our research did not further evaluate whether there was a known genetic diagnosis or not; however, in comparison to the study by Holland et al,8 the present cohort study was conducted using a nationwide, population-based database with a larger number of participants and 15 years of follow-up instead of a single-center cross-sectional design with a relatively small sample size.
The possible reasons to explain the increased prevalence of psychiatric disorders in patients with TOF are multifactorial. First, in individuals with CHDs, deficits in neurologic and behavioral development have been reported.21–25 Since the blood flow or oxygen content of the circulation system may be reduced in these individuals, maturation of the brain may be impeded, and damage to the brain may occur, such as decreased brain volume, delayed brain maturation, and white matter injuries; as a result, the risk of psychiatric disorders might increase.21,25,26 Besides, patients with TOF may experience acute events, such as hypercyanotic spells and arrhythmia,1,3 which may lead to further damage to the brain due to inadequate perfusion. It is noteworthy that an increased prevalence of psychiatric disorders in individuals with CD/ODD and IQ disability has been documented.27–30 In the present study, we also found that the enrolled patients with comorbid IQ disability and CD/ODD had an increased risk of developing psychiatric disorders, with adjusted HRs of 2.350 (P = .005) and 20.701 (P = .003), respectively. These findings were compatible with those of the previous studies.
Second, in some patients, TOF is part of a genetic syndrome: the genes causing abnormal cardiac development may also cause abnormal brain development. Some known genetic syndromes, such as Alagille, CHARGE, Down, and 22q11 deletion syndromes, have been reported to show an association between developmental disorders, psychiatric disorders, and TOF.21,31–33 However, in reports5–8 regarding patients with TOF and psychiatric disorders, some genetic anomalies, most commonly 22q11 deletion and VACTERL syndromes, were also identified. Although the present study did not further attempt an investigation of the genetic background due to the study design, the relationship of TOF and genetic factors is not well known, and there may be other genetic anomalies not identified. This relationship may be a study topic for further investigation when the genetic backgrounds of TOF are clearer.
Third, apart from CHDs and genetic factors, environmental factors may also contribute to the risk of developing psychiatric disorders in TOF patients, such as early exposure to physical pain or frequently submitting to stressful medical procedures that may correlate with anxiety and fear.34 In addition, Spijkerboer et al35 found long-term distress of parents was positively correlated to the parent-reported behavioral and emotional problems in children with CHDs.
The present study has several limitations to be considered. First, as was the case in previous studies using the NHIRD for TOF,3 data for some variables such as clinical severity, image findings, and laboratory parameters were not available in the NHIRD. Therefore, patients with extreme TOF could not be stratified for further analysis. Second, data on other factors such as occupation, stressful events, and environmental factors were not available in the database. Third, coding errors or misclassification could occur. To minimize this bias, patients with TOF who made outpatient clinic visits < 3 times were excluded, as we believed doing so could increase the accuracy of diagnosis. In addition, because more than 99% of the population are part of the NHI program, and the NHIRD covers all of Taiwan’s hospitals, our data would be valid and representative. Fourth, because almost 75% of the study population were below the age of 16 years, along with standardized interviews, additional input from caregivers was also an important approach to collecting psychiatric data in pediatric patients. Their data may be different from those of adult patients. Fifth, the study eliminates patients whose psychiatric vulnerabilities may be exacerbated by TOF because patients with premorbid psychiatric disorders before the study period were excluded. Therefore, the inclusion criteria may underestimate the emotional and functional impact of TOF.
In conclusion, based on our national cohort from 2000 to 2015, this study has shown that patients with TOF have a nearly 3-fold risk of developing psychiatric disorders. Moreover, after exclusion of psychiatric diagnoses within the first 5 years, the associated risk of developing anxiety, depression, bipolar disorder, and sleep disorders is nearly 2-fold compared to that of the general population. Further studies are necessary to investigate the pathophysiologic connection between psychiatric disorders and TOF. By helping clinicians realize the psychosocial burden of patients with TOF and minimize the impact, these findings should serve as a reminder that, in addition to repair of the anatomic heart, careful follow-up, and timely intervention of the psychological “heart” of TOF survivors may improve their quality of life.
Submitted: October 17, 2019; accepted October 15, 2020.
Published online: February 23, 2021.
Potential conflicts of interest: None.
Funding/support: This work was supported by the Tri-Service General Hospital Research Foundation (TSGH-C108-003, TSGH-C108-151, TSGH-B-109-010, TSGH-E-110240, and TSGH-B-110-012), the Medical Affairs Bureau, Ministry of Defense of Taiwan (MND-MAB-107-084 and MND-MAB-110-087), and the Taoyuan Armed Forces General Hospital (TYAFGH-A-110020).
Role of the sponsor: The providers of support had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgments: We appreciate Taiwan’s Health and Welfare Data Science Center and Ministry of Health and Welfare (HWDC, MOHW) for providing the National Health Insurance Research Database.
- The tetralogy of Fallot (TOF) has been reported to be associated with psychiatric disorders. However, the risk of comorbid psychiatric disorders and TOF has not been well documented.
- This study found that patients with TOF had a nearly 3-fold higher risk of developing psychiatric disorders.
- Continued mental health screening and evaluation in patients with TOF are warranted.
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