Sudden unexpected death in infancy in Denmark

Abstract

Background. Incidence of sudden unexpected death in infancy (SUDI) and sudden infant death syndrome (SIDS) differs among studies and non-autopsied cases are difficult to assess. Objectives. To investigate causes of sudden death in infancy in a nationwide setting. Validate the use of the ICD-10 code for SIDS (R95) in the Danish Cause of Death registry. Design. A retrospective analysis of all infant deaths (< 1 year of age) in Denmark in 2000–2006. All death certificates and autopsy reports were read. Results. We identified 192 SUDI cases (10% of total deaths, 0.42 per 1000 births) with autopsy performed in 87% of cases. In total, 49% of autopsied SUDI cases were defined as SIDS (5% of all deaths, 0.22 per 1000 births); Cardiac cause of death was denoted in 24% of cases. The Danish Cause of Death Registry misclassified 30% of SIDS cases. Conclusions. A large proportion of infant deaths are SUDI, and the majority of these are caused by cardiac disease or SIDS. Autopsy is not always performed and valuable information is subsequently lost. Cause of Death registry data is not accurate in describing SIDS.

Key words::

• Sudden infant death syndrome
• SIDS
• sudden unexpected death in infancy
• SUDI
• SUID
• autopsy
• forensic
• registry
• death certificates
• epidemiology
• sudden death

Sudden unexpected death in infancy (SUDI), defined as the sudden unexpected death of an infant below the age of one year, is always a tragic event, often happening with no or only vague symptoms prior to death.

SUDI often occur during sleep, with post-mortem investigations showing a high prevalence of infections and cardiac disorders (1). However, in the majority of cases no certain or likely cause of death can be established and they are hence termed sudden infant death syndrome (SIDS) (2).

A diagnosis of definite SIDS is generally accepted to require a complete post mortem examination including negative autopsy (3). To acknowledge the problems regarding classification of non-autopsied cases of presumed SIDS cases a new classification system was suggested in 2004 which includes the “unclassified sudden infant deaths” (USID) (4).

The number of autopsied versus non-autopsied SUDI cases (autopsy ratio), is not well established and most data are from the 1990s (5,6). A recent study from USA, however, reported an autopsy ratio of 88% in deaths assigned the ICD-10 code for SIDS (R95) in the cause of death registry (7).

Even though SIDS is the most common cause of death in infants between age one month and one year (2), the aetiology of SIDS at large is still unknown. However, epidemiological research has revealed several risk factors for SIDS, the greatest risk factor being prone sleeping (8,9). SIDS due to prone sleeping is incompletely understood, but the overwhelming epidemiological findings resulted in the “back to sleep” campaign being launched in many parts of the world, including Denmark, in the early 1990s (10,11). Subsequently, SIDS rate decreased between 40% and 83% through the 1990s (8,12). Today, reported prevalence's are diverse ranging between 0.1 and 0.8 SIDS cases per 1000 newborns (2).

The inherited cardiac arrhythmia Long QT Syndrome was proposed to be causative in a fraction of SIDS cases more than three decades ago (13,14). Today there is strong evidence linking 10 to 15% of SIDS cases to mutations in the cardiac ion channel proteins, giving rise to diseases like Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), and Brugada Syndrome (BrS) (15). These diseases are known to cause cardiac arrhythmias and sudden death at any age, including infancy.

The differences in the prevalence of SIDS amongst otherwise in many aspects comparable countries, probably in part reflect the difficulties and heterogeneity in the definition of SIDS, discrepancies in what is defined as a thorough investigation, how to deal with non-autopsied SUDI, the different ways of registering the deaths in official statistics and the lack of a way of grading SIDS in the ICD-10 coding system.

In Denmark the incidence of SUDI is not known and it is not clear whether the Cause of Death Registry correctly classifies all SIDS cases. Danish death certificates are well suited as a primary screening tool for identifying sudden and unexpected deaths, due to a detailed description of the circumstances of the death including a summary of the death scene investigation on the certificate.

Due to the unique National Person Registry ID given to all persons born or living permanently in Denmark, registration of health care related services (which are bound up to the ID) are very thorough. Furthermore, when a person dies, a death certificate is always issued if the death occurred within Danish borders.

The purpose of this study was to provide precise nationwide data of SUDI and SIDS thereby describe the incidence of and causes of death in SUDI and give an accurate estimate of the proportion of these deaths being SIDS without the use of registries with their potential inherent weaknesses. Furthermore we wanted to validate the use of the ICD-10 code for SIDS (R95) in the Danish Cause of Death registry thereby establishing to what extent a registry can be used to describe the incidence of SIDS and how well a registry detects individual SIDS cases.

Methods

Study design

The study was a nationwide retrospective study. All infant deaths (< 1 year of age) in Denmark in 2000–2006 were included. Death certificates were read independently by two physicians, and presumed SUDI and/or SIDS were recorded for each death. If disagreement was noted, the two investigators re-read the death certificate for consensus. Information on previous medical history was retrieved both from the death certificate and from the National Patient Registry, which contains information on all in- and outpatient activity at Danish hospitals.

The number of cases autopsied was ascertained, and all autopsy reports were collected and read. Cause of death was revised based on autopsy findings.

Medico-legal examinations and autopsies in Denmark

The medico-legal examination is the investigation of the death up until the autopsy. In Denmark, a medico-legal examination is carried out by the police and a medical officer of health (a certified physician) if: 1) a criminal act is suspected, 2) in all accidents and suicides, 3) if a person is found dead, and/or 4) the death is sudden and unexpected. The medical-legal examination includes a death scene investigation with particular focus on surroundings regarding the death, supplemented with data from hospital records and interviews with relatives and witnesses. The medical officer of public health always have access to: 1) first responder (emergency medical service, EMS) records, 2) the medical files related to the death (if any), 3) the entire police record including all witness statements, and 4) the body. Furthermore, additional data from, i.e. medical files from previous admissions are retrieved in cases where this is deemed necessary. Whenever a medico-legal examination is carried out, the supplemental information field on the Danish death certificate provides at a minimum: 1) a summary of existing diseases and the physical condition prior to death as described by relatives, 2) a description of the events immediately preceding the death as described by witnesses, 3) a summary of the actions taken by the EMS on the scene, and 4) what actions was taken at hospital (if any).

Forensic autopsy is performed if: 1) a criminal act is suspected, 2) mode of death is not well established (natural death, accident, suicide or homicide), or if 3) cause of death is not well established and the police find it warranted from their own investigative perspective. Hence it is ultimately a police decision if autopsy is performed. In Denmark there are three Departments of Forensic Medicine conducting together approximately 1500 autopsies/year. In the setting of infant and child deaths, autopsies are almost exclusively being conducted by a small number of forensic pathologists, usually one or two at each department, and all autopsies are being supervised by another forensic pathologist.

The observed incidence rate of SIDS was compared with the official statistics in Denmark as provided in the Cause of Death registry. The differences were tested with the χ² test or Fisher's exact test for categorical data, and for continuous data with Student's t-test or Wilcoxon rank-sum test.

The study was approved by the local ethics committee (KF 01 272484), The Danish Data Protection Agency (2005-41-5237) and the Danish National Board of Health (7-505-29-58/1-5).

Definitions

We defined SUDI as the sudden unexpected death of an infant below age of one year. The infant may or may not have been awake at time of death. We defined SIDS as the sudden unexpected death of an infant below the age of one year that remained unexplained after autopsy. If autopsy was not performed and the infant was healthy prior to death with no known disease, the death was termed unclassified sudden infant death (USID). SIDS and USID cases were pooled to provide the highest possible incidence rate of SIDS.

Results

During the seven-year study period (2000–2006) there were a total of 455 091 births (average 65 013 births/year) in Denmark (population size 5.4 million). A flowchart of the review of death certificates is provided in Figure 1.

Figure 1. Flowchart of the review of death certificates in Denmark during a seven-year period (2000–2006) in infants below age one year.

SUDI population

We identified 192 SUDI cases equaling 10% of total deaths. The combined review of death certificates, data from autopsy reports and from the National Patient Registry revealed a previous medical history in 17 (9%) cases (Table I); in 15 cases congenital heart disease had been diagnosed before death and in two cases other diseases were known. Twenty five cases (13%) were not autopsied. In the remaining 167 cases autopsy was conducted and the report was retrieved. Autopsy ratio was 87%.

Table I. Characteristics of the 192 Danish SUDI cases and comparisons between the 167 autopsied and 25 non-autopsied cases during 2000–2006.

SUDI	Total (n = 192)	Autopsied (n = 167)	Non autopsied (n = 25)	p-value
Previous medical history, n (%)	17 (9%)	9 (5%)	8 (32%)	<0.0001
Gender, male/female (% male)	116/76 (60%)	106/61 (63%)	10/15 (40%)	0.025
Median age at death	64 days	59 days	72 days	ns
SUDI autopsies
Forensic autopsy	147 (77%)
Hospital autopsy	20 (10%)
No autopsy	25 (13%)
Autopsy ratio overall	87%
Incidence rate, SUDI	0.42/1000 births

Abbreviation: SUDI = sudden unexpected death in infancy.

Table II provides details on the causes of death in the autopsied SUDI cases; 40 cases (24%) died of congenital heart diseases and 45 cases (27%) died of non-cardiac causes. The annual number of SUDI deaths was stable throughout the study period.

Table II. Causes of death after autopsy in the 167 autopsied SUDI cases in Denmark 2000–2006, categorized in major groups.

Cause of death, autopsied SUDI cases (n = 167)	n	Cardiac disease diagnosed prior to death, n
SIDS	82
Congenital heart malformations	29
Coarctation of the aorta	6
Transposition of the great arteries	5	1
Malformation of cardiac chambers, unclassified	4	1
Truncus arterious communis	3
Hypoplastic left ventricle	3	2
Single ventricle	3
Ebsteins anomaly	1
Valvular disease	2	1
Malformation of coronary artery	1
Aneurysm of pulmonal artery	1
Other heart diseases	11
HCM	2
Endocardial Fibroelastosis	2
Left ventricular hypertrophy	2
Endocarditis	1
Myocarditis	1
Benign tumor, heart	1	1
ARVC	1
Other cardiomyopathy	1
Infectious disease	28
Pneumonia	13
Sepsis	9
Meningitis	4
Epiglottitis	1
Encephalitis	1
Cerebral disease	4
Intestinal volvolus	2
Asphyxia	2
Metabolic disease	1
Other causes	8
Conclusion after autopsy
SUDI, cardiac cause	40 (24%)
SUDI, non cardiac cause	45 (27%)
SIDS	82 (49%)

Abbreviations: HCM = Hypertrophic Cardiomyopathy, ARVC = Arrhythmogenic Right Ventricular Cardiomyopathy, SUDI = sudden unexpected death in infancy, SIDS = sudden infant death syndrome.

Autopsied vs. non-autopsied cases of SUDI

Comparing the autopsied vs. the non-autopsied cases of SUDI, we found a significant difference in gender distribution with a male predominance in the autopsied group but a female predominance in the non-autopsied group (p=0.025). We also found a higher proportion of known (congenital heart) disease in the non-autopsied group (p<0.0001).

SIDS and USID populations

Of the 192 SUDI cases we identified a total of 82 SIDS cases and 16 USID cases (total 98 cases, 14 cases/year, 5% of all deaths, Table III). Median age was 70 days, range 0–325 days. In 10 of the 98 cases (10%) the infant was awake at time of death. Of these, none had any prior disease and eight were autopsied. The conclusion by the pathologist was definite SIDS in seven of the eight cases. In the last case, an infection of the middle ear, that was not deemed causative, was found. Of the ten cases that were awake at time of death, four were eating at time of death (three of which breastfeeding) and six were in a relaxed state – two of which were postprandial and one of which were in a febrile state. In the majority of SIDS and USID cases (62%) the infant was found within four hours after last seen alive with the vast majority found dead in the morning (39% were found between 6 am and 9 am; 81% were found before noon). There was no change in the annual number of deaths throughout the study period.

Table III. Death circumstances in the 98 Danish SIDS cases and comparisons between the 82 autopsied and the 16 non-autopsied cases during 2000–2006.

SIDS and USID	Total (n = 98)	SIDS (n = 82)	USID (n = 16)	p-value
Median age at death	70 days	69 days	72 days	ns
Gender, male/female (% male)	55/43 (56%)	49/33 (60%)	6/10 (38%)	ns
Sleep status
Awake	10 (10%)	8 (10%)	2 (13%)	ns
Sleeping alone	46 (47%)	34 (41%)	12 (75%)	0.026
Sleeping with parents/siblings	42 (43%)	40 (49%)	2 (13%)	0.011
Event place (found)
Home, inside	88 (90%)	75 (91%)	13 (81%)	ns
Other family, inside	3 (3%)	3 (4%)	0 (0%)	ns
Outside, babycarriage	3 (3%)	0 (0%)	3 (19%)	0.004
Hospital	4 (4%)	4 (5%)	0 (0%)	ns
Position found (sleep)
Back	26 (30%)	20 (27%)	6 (43%)	ns
Prone	19 (22%)	17 (23%)	2 (14%)	ns
Side	9 (10%)	9 (12%)	0 (0%)	ns
Not stated	34 (39%)	28 (38%)	6 (43%)	ns
Time of day found (intervals of 3 hours)				0.024
00:01–03:00	13 (13%)	12 (15%)	1 (6%)
03:01–06:00	12 (12%)	12 (15%)	0 (0%)
06:01–09:00	38 (39%)	33 (40%)	5 (31%)
09:01–12:00	16 (16%)	13 (16%)	3 (19%)
12:01–15:00	6 (6%)	5 (6%)	1 (6%)
15:01–18:00	3 (3%)	1 (1%)	2 (13%)
18:01–21:00	8 (8%)	4 (5%)	4 (25%)
21:01–00:00	2 (2%)	2 (2%)	0 (0%)
Incidence rates
Incidence rate SIDS (autopsy negative, death during sleep)	0.16/1000 births
Incidence rate SIDS (autopsy negative)	0.18/1000 births
Incidence rate SIDS (including USID cases)	0.22/1000 births

Abbreviations: SUDI = sudden unexpected death in infancy, USID = unclassified sudden infant death.

SIDS vs. USID

Compared to the USID group, the SIDS cases slept alone less frequent (41% vs. 75%, p=0.026) and more frequently with parents and/or siblings (49% vs. 13%, p=0.011). In three cases (19%) in the USID group the infant slept outside in a baby carriage at time of death. None of the SIDS cases slept outside at time of death (p=0.004). USID victims were generally found later in the day compared to SIDS victims (p=0.024). The incidence rate of SIDS cases was 0.18 per 1000 births. If we include the USID cases with no previous medical history, the incidence rate would increase to 0.22 per 1000 births.

Validation of the Cause of Death Registry

We validated the Cause of Death Registry by comparing the cause of death after reading the autopsy report and the official ICD-10 diagnosis denoting SIDS (R95) in the registry. The Cause of Death Registry correctly categorized 81 of the 98 (83%) SIDS and USID cases. In 17 cases (17%) the ICD-10 SIDS classification was not used. In addition, ten cases (10%) were incorrectly classified as SIDS in the Cause of Death registry. Thus, of the 91 SIDS cases identified by the Cause of Death Registry, 27 (30%) were misclassified.

Discussion

In our study, 49% of autopsied SUDI cases were categorized as SIDS and 24% were found with structural cardiac disease.

Of the 40 cases of structural heart disease only six of them were diagnosed prior to death. It is speculative that at least some of these deaths could have been avoided. It should, however, also be pointed out, that the 34 overlooked fatal cases equals only five deaths per year, which should be put in context to the estimated 500 newborns per year in Denmark with a congenital heart disease.

SIDS is a diagnosis of exclusion with a negative autopsy traditionally considered mandatory. The prevalence of “true” SIDS, though, is potentially underestimated because of a proportion of SUDI cases not being autopsied. To what extent this is a problem, however, has not been well established because the identification of SUDI cases from registries is difficult. By evaluating the summaries provided on the death certificates, we were able to extract detailed information on the circumstances of the deaths, thereby being certain as to which deaths were SUDI. To supplement data from the death certificates we also used data from the registries in Denmark on all prior in- and outpatient hospital contacts, as well as all autopsy reports on deaths suspicious of SUDI. Using this approach, we circumvented the inaccuracies in the official statistics from The National Board of Health regarding SIDS incidences (derived from The Cause of Death registry). Furthermore the data were not affected by the lack of registration of SUDI cases in the official registries. Thus, the methodology used, avoided many biases encountered by some registry studies relying solely on the ICD-10 coding of deaths.

In attempt to give the highest possible estimate of SIDS incidence we also included infants dying while awake (n=10, 10%). These deaths are not included in most definitions of SIDS, as death during sleep is considered a key factor in the syndrome – mainly because the cause of death while awake is usually considered to be due to underlying congenital heart disease (16), but since no cause of death could be found, we categorized them as SIDS/USID.

The incidence rate of SIDS cases in the present study (0.18–0.22/1000 births) is in the lower range compared to previous studies (2). This might in part be because we at autopsy found a higher rate of explained SUDI cases compared with a previous report (17).

Today, 10 to 15% of SIDS cases can be attributable to cardiac channelopathies (15,18–22). An autopsy therefore is essential before considering a genetic testing for cardiac ion channelopathies – both for obtaining material suitable for DNA retrieval and for establishing who to screen for genetic mutations (unexplained deaths, SIDS).

In the SUDI population previous disease was more frequent in the non-autopsied group, which probably explains why some cases where not autopsied. We did, however, also observe that female infants were being less frequent autopsied. We have no explanation for this finding.

From the validation of the Cause of Death Registry in cases of SIDS, we conclude that the registry is not accurate in describing the SIDS population. Almost one-third of cases in the registry were misclassified, and had we retrieved death certificates and autopsy reports only from those with the R95 code, we would have missed more than one in six SIDS cases in the subsequent analysis. Caution, therefore, should be taken in studies relying solely on data deriving from Cause of Death registries. Having only one option for categorizing unexplained infant deaths in the ICD-10 registry (R95) is probably one of the reasons why the registry fails to be accurate as has also been addressed before (7). Having more options to sub-classify SIDS would probably increase the validity. Another problem might be the two-step recording of cause of death into the Danish registry. The two-step recording is due to the delay of the results of i.e. histopathology and toxicology reported to the Danish National Board of Health. Because these additional analyses are neither mandatory by law, nor necessary for the death to be recorded into the registry, inaccuracies can arise if the reporting of these subsequent analyses fails to be registered.

Because our study was retrospective, it has some limitations. First of all, the death scene investigation plays a very important part in the diagnosis of SIDS. Significantly better data was available in the last half of the study period, probably because of the increasing awareness of risk factors of SIDS during our time span of seven years covered in this study. On the other hand, since the annual number of SIDS deaths did not decline during the period, the lack of information in the early years is primarily a problem when interpreting risk factors. We also used data provided on the death certificates for the identification of SUDI cases. The officers of public health who issues the death certificates, however, are highly skilled within their field. We therefore rely on these data being as accurate as if we had read the EMS records, the hospital files and the police records ourselves.

Conclusions

In Denmark we found the incidence of SUDI to be 0.42 per 1000 births corresponding to 10% of all deaths. In total, 1 in 11 previously healthy infants dying sudden and unexpectedly, had no autopsy performed. Incidence rate of SIDS was 0.22 per 1000 births including USID cases. Autopsy was more frequently performed in male infants and in infants with no previous medical history. In total, 49% of autopsied SUDI cases was SIDS, 24% was due to structural cardiac diseases. Data from The Danish Cause of Death Registry is not valid in regards to the SIDS diagnosis and should be used with caution. Modifications of the R95 diagnosis in the ICD-10 coding system with more options to categorize, i.e. non-autopsied and other probable SIDS cases would potentially increase the validity of the registry. We recommend a mandatory autopsy in all cases of SUDI, as autopsy is essential, both in establishing the cause of death and in the subsequent counseling of the bereaved parents in regards to any potential inherited diseases.

Acknowledgements

The study was funded by The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Danish Heart Foundation (07-10-R60-A1751-B743-22412), The Research Foundation at the Heart Centre, Rigshospitalet, The John and Birthe Meyer Foundation, and Bønnelykkefonden. There is no conflict of interest to be declared. BGW conceived of the study, designed it, read all death certificates and autopsy reports, analyzed data and drafted the manuscript. AGH, JT and JTH participated in reading death certificates, analysis of data, study design, and helped to draft the manuscript. IBK, JLT and SHH participated in reading autopsy reports, analysis of data, and helped to draft the manuscript. JHS and SH participated in the conception and design of the study and helped to draft the study. All authors read and approved the final manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.