Cardiovascular causes of sudden unexpected death in children and adolescents (0–17 years)

In 42/56 cases (75%) of the autopsied cases a probable cause of death was found, with in 13/56 (23%) a cardiovascular cause of death (all causes of death are presented in the online supplementary Tables I and II). These cardiovascular causes of death were more frequently observed in the older age categories. A gender difference was not found.

Below the age of 1 a cardiovascular cause of death was found in 6/29 cases (21%; Fig. 2). These were mainly congenital abnormalities (n = 3) and fulminant myocarditis (n = 2). The congenital abnormalities were congenital aortic stenosis due to dysplastic aortic valve leaflets (Fig. 3), complete unbalanced atrioventricular septal defect, and an anomaly of the coronary arteries. The other cardiovascular cause of death was acute decompensated heart failure (with extensive ascites, pleural effusions and pulmonary siderophages) with unknown underlying cause.

In cases aged 1–9 years old, no cardiovascular causes of death were found.

In cases aged 10–14 years old, 3/7 cases (43%) suffered from a cardiovascular cause of death (Fig. 2). In two cases a congenital abnormality was found (67%). These were both anomalous origins of a coronary artery with histological features of myocardial ischaemia in the perfusion area of the affected artery (Fig. 3). In a 12-year-old male evident fibrofatty replacement was observed in the right ventricle wall, which fitted the diagnostic criteria of arrhythmogenic right ventricular cardiomyopathy (ARVC).

In cases aged 15–17 year, a cardiovascular death was found in 4/8 cases (50%; Fig. 2). These causes were a hypertrophic cardiomyopathy with myocardial disarray (Fig. 4), an infectious endocarditis in a 15-year-old female with an artificial pulmonic valve, a ruptured aneurysm of the ascending aorta (due to severe medial degeneration) which resulted in hemopericardium, and a myocardial infarction due to unknown cause (no coronary artery pathology).

In 14/56 cases (25%) no structural abnormalities were found during autopsy and a cause of death could not be determined. A sudden death without anatomical substrate was mainly seen in patients <1 year of age (11/29 cases in this age group; 38%; Tab. 1). The cases were classified as sudden unexpected death in epilepsy (SUDEP, n = 2), sudden infant death syndrome (SIDS, n = 11) or sudden unexpected death syndrome (SUDS, n = 1) according to age and medical history.

Additionally, we found cardiovascular abnormalities of which the association with the death was uncertain [8]. These cardiovascular abnormalities of uncertain significance were present in 14/56 cases (25%). A more detailed description of these findings is available in the online supplement.

Congenital anomalies were found in 5/56 (9%) of autopsied cases, representing 39% (5/13) of all cases with a cardiovascular cause of death. Congenital anomalies were found to be the cause of death in the very young (<1 year) and between 10 and 14 years of age. The prevalence of 39% is comparable with the 41% congenital anomalies as a cardiovascular cause of death found in a recent large database study in the US [14]. In this study, also more deaths related to congenital heart disease were found in the younger patients and deaths associated with coronary artery anomalies occurred more often in the older categories (>10 years). Our observation that coronary anomalies are related to sudden death in the 10–15 year olds confirm the results of a study from Virmani et al. [15].

Cardiomyopathies were found in 2/56 cases (4%). Paediatric cardiomyopathy is a rare disease with a reported annual incidence of 1,13 cases per 100.000 children in the US [16]. The finding of two cardiomyopathies in 13 cases of cardiovascular death (15%) is more or less comparable to the 12% found in the earlier described database study in the US, and to the 14% found in patients aged 1–20 years included in an Australian study regarding sudden cardiac death [14, 17].

In 2/56 cases (4%; 15% (2/13) of all cases with a cardiovascular cause of death), fulminant myocarditis was considered the cause of death. Both patients were <1 year old. In the earlier described database study in the US, myocarditis was found to be the cause of death in 5% of patients, most often aged 3–10 years old. In this study, an autopsy was only performed in 40% of cases [14]. In a study among young competitive athletes, myocarditis was found to be the cause of cardiovascular death in 6%. However, these patients were, although young, significantly older than our population [18]. A previous study in sudden unexpected deaths in children and adolescents (1–20 years) found myocarditis to be the cause of cardiovascular death in 16/53 (30%) cases [17].

In 14/56 cases (25%) no structural abnormalities were found, despite thorough investigation. The finding of no structural abnormalities can guide further (genetic) investigations in both the deceased and his relatives. Previous studies have shown that 27% of the sudden deaths with negative autopsy in young patients (1–35 years) are likely caused by hereditary arrhythmogenic disorders [17]. Furthermore, cardiogenetic screening of the relatives of young sudden death victims (1–18 years) without structural abnormalities during autopsy revealed a diagnosis in 11/22 cases [19]. The finding of inherited causes of sudden death can prevent future events in these families.

In our study, most (11/14) cases without structural abnormalities were sudden infant deaths (<1 year old). In a previous study in a sudden infant death cohort, genetic variants with likely functional effects in genes associated with channelopathies and cardiomyopathies were found in 34% of patients [20]. Based on these findings, it is likely that at least a number of our cases without major structural disease at autopsy suffered an arrhythmic death due to an inherited disease. Therefore, we suppose that the 23% of cases with a definite cardiovascular cause of death likely reflects an underestimation of the real burden of cardiovascular disease, and especially of inherited cardiovascular disease. Genetic testing in the different age categories in sudden death in children and adolescents is an interesting topic for future studies. Regrettably, genetic analysis was not available in most cases in our study cohort, since it was not included in the procedure and requires specific permission of relatives.

Because unexpected and unexplained death in children is a rare event, only a relatively low number of cases could be included in this study. Since we depended on registered cases, some cases could have been missed. Missing completely at random is expected in these cases and therefore these missing cases will not influence our results of relative frequencies of cardiovascular causes of death. In two cases a forensic autopsy was performed, of which the results are confidential and could not be included in the study. By excluding these cases with theoretically a lower risk on cardiovascular causes of death (due to the suspicion of a non-natural cause of death), there might be a slight selection bias.

During the NODO procedure, investigation into the cause of death of minors was regulated by law in the Netherlands and this period has now ended. Although in the follow-up of this procedure finance for further investigation of causes of death in children became available for a limited time period of three years, death cause investigation has not yet been structurally organised in the Netherlands. Health insurance stops after death, therefore structural finance for autopsies is lacking. In addition, the logistics of arranging an autopsy can be quite laborious for general practitioners and forensic physicians involved in sudden death cases. Therefore, the possibility and importance of a medical autopsy is not discussed with the family members in all cases in busy daily practice. In other countries, such as the UK, in sudden unexpected death cases autopsy is mandatory, which might be an instrument to increase autopsy rate. We think the NODO procedure, a procedure that elucidated the cause of sudden unexpected death in 75% of cases, has proven that this more mandatory approach indeed leads to a very high percentage of explained causes of sudden death.

In conclusion, this national cohort with high autopsy rate reveals a high incidence of macroscopically and/or microscopically visible cardiovascular diseases contributing to sudden unexpected death in children. In another high percentage of victims with only minor or no structural abnormalities a substantial number of genetic arrhythmias as cause of death may be expected. These findings underline the importance of a systematic autopsy in sudden death in the young with implications for cardiogenetic screening of relatives.