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Autism spectrum disorder (ASD) is a chronic childhood-onset
neurodevelopmental condition with detrimental effects on adaptive
functions throughout life.
1–3
The number of people with ASD
diagnoses has increased during the last decades although the
underlying reasons for this increase are not fully understood.
4
Both clinical
5,6
and population-based studies
1,7
have reported
poor long-term outcomes
8
regarding education, employment,
independent living and peer relations. A poor long-term outcome
has been observed in both low-functioning ASD (i.e. individuals
with ASD and a co-existing intellectual disability) and high-
functioning ASD (i.e. individuals with ASD and intellectual ability
in the average or above range). Psychiatric comorbidity is common
in individuals with ASD,
9–13
and especially low-functioning ASD
may be part of a known genetic syndrome (‘syndromic’ autism),
such as fragile X syndrome, Down syndrome or tuberous sclerosis.
14
Risk of premature mortality has been reported to be elevated
among individuals with ASD, compared with the general
population,
15–19
as well as compared with healthy cousin or
sibling controls.
20
To date, studies on mortality in ASD with
long-term follow-ups comprise two clinical cohorts
16–19
and two
population-based cohorts,
15,20
diagnosed with ASD as children.
Compared with mortality statistics from the general population
or general population controls, the risk of premature mortality
has been estimated to be twofold to 10-fold higher in the ASD
population. Characteristics of the previous studies on the outcome
of mortality in ASD are summarised in Table 1.
Based on the well-known association between ASD and medical
conditions (e.g. epilepsy),
21
and especially in individuals with low-
functioning ASD, it has been suggested that the excess mortality
in ASD may be related to the presence of comorbid medical
conditions and intellectual disability, rather than ASD per se.
20
However, the only study to date analysing differences in mortality
between individuals with low-functioning ASD and high-
functioning ASD did not identify significant between-group
differences in overall mortality.
17
In addition, in most previous
studies sample sizes have been too small to compare mortalities in
low-functioning and high-functioning ASD reliably. Thus, the
potentially moderating effect of intellectual disability in mortality
and causes of death in ASD remain unclear, and it has not been
possible to determine whether ASD per se carries an increased
mortality.
15
Gender is another possible moderator of excess mortality in
ASD. Relative to males, females with ASD have been reported to
have an elevated mortality risk.
15–20
However, there has been
considerable variation in the reported risk ratios ranging from
3.6 to 20.7 for females, whereas the risk ratios for males have
ranged between 1.6 and 7.9.
15–20
Large confidence intervals
(CIs) in some of the studies indicate imprecise estimations.
Large-scale studies are needed to explore the predictive role
of risk factors (such as comorbid intellectual disability or the
potential role of gender) for mortality in ASD. Moreover, access
to data from a large sample including a broad age range and a
substantial follow-up period is needed to study different causes
of death. On this point, most studies did not have adequate
statistical power to examine less frequent causes of death.
The population-based studies conducted to date have identified
such causes of death as associated medical conditions (including
epilepsy), as well as cardiovascular and respiratory deaths.
15,20
In a clinical cohort, a pattern of causes of death resembling that
of the background population was observed, with exception for
a very strong association for deaths associated with epilepsy.
16,17
The largest study on causes of death in ASD was based on a
clinical cohort including ambulatory Californians with autism.
18,19
Nevertheless, on excluding concomitant conditions such as cerebral
palsy, tuberous sclerosis and Down syndrome, the results showed
an elevated risk for several causes of death.
The aim of the current study was to analyse all-cause
and cause-specific mortality in ASD using nationwide Swedish
population-based registers. A further aim was to address the role
of intellectual disability and gender as possible moderators of
mortality and causes of death in ASD.
Method
Study design
We conducted a matched case cohort study.
1
Premature mortality in autism spectrum disorder
Tatja Hirvikoski, Ellenor Mittendorfer-Rutz, Marcus Boman, Henrik Larsson,
Paul Lichtenstein and Sven Bo
¨lte
Background
Mortality has been suggested to be increased in autism
spectrum disorder (ASD).
Aims
To examine both all-cause and cause-specific mortality in
ASD, as well as investigate moderating role of gender and
intellectual ability.
Method
Odds ratios (ORs) were calculated for a population-based
cohort of ASD probands (n= 27 122, diagnosed between 1987
and 2009) compared with gender-, age- and county of
residence-matched controls (n= 2 672 185).
Results
During the observed period, 24 358 (0.91%) individuals in the
general population died, whereas the corresponding figure
for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI
2.38–2.76). Cause-specific analyses showed elevated mortality
in ASD for almost all analysed diagnostic categories. Mortality
and patterns for cause-specific mortality were partly
moderated by gender and general intellectual ability.
Conclusions
Premature mortality was markedly increased in ASD owing to
a multitude of medical conditions.
Declaration of interest
None.
Copyright and usage
BThe Royal College of Psychiatrists 2015.
The British Journal of Psychiatry
1–7. doi: 10.1192/bjp.bp.114.160192
Study setting
Two nationwide population-based Swedish registers were linked:
the National Patient Register and the Cause of Death Register,
both held by the National Board of Health and Welfare. The data
were linked using the unique 10-digit personal identification
number used in registers for all Swedish residents, including
migrants with a residence permit. The National Patient Register
includes diagnoses for all in-patient treatment episodes for
psychiatric disorders in Sweden since 1973, as well as for
out-patients (including diagnostic assessments with no further
contact with psychiatric services) since 2001. The diagnoses are
coded according to the Swedish versions of the ICD by the World
Health Organization (WHO).
Study population
Individuals with ICD diagnosis codes for any ASD were identified
from the National Patient Register. The validity or diagnostic
accuracy of ASD diagnoses in Swedish health registries has been
shown to be good.
22
We first identified all individuals with an
ASD diagnosis in the National Patient Register between 1987
and 2009. The ICD-9
23
ASD diagnoses (1987–1996; 299xx) were
converted to corresponding ICD-10
24
diagnoses (1997 onwards)
using a conversion instrument provided by the Swedish National
Board of Health and Welfare. In the final cohort, the included
diagnoses were autism (F84.0), Asperger syndrome (F84.5),
atypical autism (F84.1) and pervasive developmental disorder –
not otherwise specified (F84.9), other childhood disintegrative
disorder (F84.3) and other pervasive developmental disorders
(F84.8). Diagnoses of Rett syndrome (F84.2) and overactive
disorder associated with mental retardation and stereotyped
movements (F84.4) were excluded, as these are no longer
considered core ASD diagnoses in current psychiatry (e.g. no
longer classified in DSM-5).
25
In Swedish clinical practice,
diagnostic assessment of ASD was rare before 1990 (less than
2% of the final study cohort) and a majority of the study cohort
(88.2%) was diagnosed after 2001, i.e. after inclusion of out-patient
data in the National Patient Register. The dichotomisation into
low-functioning ASD and high-functioning ASD groups was
based on the registered ICD codes for mental retardation. The
ICD-9 codes 317–319 were converted to the corresponding
ICD-10 diagnoses mild (F70), moderate (F71), severe (F72),
profound (F73), other (F78) and unspecified (F79) intellectual
disability. Thus, individuals with a co-existing intellectual disability
were classified as low-functioning ASD regardless of which ASD
diagnosis they had. The same type of classification strategy has
been applied in previous studies
26,27
based on high-functioning
ASD v. low-functioning ASD as two key categories for the
specification of ASD in DSM-5.
For each proband identified with ASD from the National
Patient Register, up to 100 controls were randomly selected from
the Total Population Register. The controls were alive at the time-
point of inclusion (when the case with ASD was registered the first
time) and were not diagnosed with ASD during the study period.
Controls were matched with cases by birth year, gender and
county of residence in the year when the matched cases received
their first ASD diagnosis.
Classification of the specific causes of death
ICD-9 codes for specific causes of death (for deaths during
1987–1996) were converted into corresponding ICD-10 diagnoses
(1997–2009) using the conversion instrument provided by the
National Board of Health and Welfare. The main causes of death
were grouped into the following categories (ICD-10 chapters and
codes are specified in the Appendix):
(a) Infections
(b) Neoplasms
(c) Endocrine
2
Hirvikoski et al
Table 1 A summary of study cohorts and main results from previous studies on mortality in ASD
Study Country
Total n
ASD
Diagnosis,
% of total
n
Mean age at
diagnosis
(range),
years
Mean
(years)
follow-up
[time period]
Observed
deaths
n
Expected
deaths in
general
population, n
Reported
risk ratio
(95% CI)
Separate
analyses for
HFASD/
LFASD
Risk ratio separately
for females/males
(CIs if given in the
original article)
Isager et al
16
Denmark 341 ASD
a
low-
functioning:
41.8%
9.5
(2–17)
23.7
[1960–1993]
12 6.2 SMR 1.9
(1.0–3.4)
Not
analysed
F: 3.61 (0.75–10.56)
M: 1.67 (0.76–3.18)
Mouridsen et al
17
Update of the cohort reported
in Isager et al
16
35.5
[1960–2006]
26: low-
functioning
12/143; high-
functioning
14/196
13.5 SMR 1.9
(1.3–2.8)
N
significant
differences
F: 4.01 (1.73–7.90)
M: 1.57 (0.93–2.48)
Shavelle et al
19
USA 13 111 ASD low-
functioning:
48.1%
8.5
(2–15)
14
[1983–1997]
202 84.2 SMR 2.4 Not
analysed
F: 5.5, M: 1.7
Pickett et al
18
Update of the cohort reported in
Shavelle et al
19
19
[1998–2002]
280 114.2 SMR 2.5 Not
analysed
F: 5.2, M: 2.3
Gillberg et al
15
Sweden 120 ASD low-
functioning:
80%
11 (4–18) 22.5
[1962–2008]
9 1.6 SMR 5.6
(2.5–10.5)
Not
analysed
F: 20.7, M:2.3
Bilder et al
20
USA 305 ASD low-
functioning:
64%
10.8 (1.4–
29.2)
25
[1982–2011]
29 Comparison
with
matched
population
controls
HRR 9.9
(5.7–17.2)
Not
analysed
F: 20.7 (6.2–69.2)
M: 7.9 (4.2–15.0)
ASD, autism spectrum disorder; SMR, standardised mortality ratio; HRR, hazard rate ratio; CI, confidence interval; F, female; M, male.
a. The previous Scandinavian diagnosis Borderline childhood psychosis was included as a proxy for Asperger syndrome.
IQ was tested in 60% of cases and in the rest of the cases was based on clinical assessments.
Mortality in autism spectrum disorders
(d) Mental and behavioural disorders
(e) Diseases of the nervous system
(f) Diseases of the circulatory system
(g) Diseases of the respiratory system
(h) Diseases of the digestive system
(i) Diseases of the genitourinary system
(j) Congenital malformations
(k) Symptoms, signs and abnormal findings not elsewhere classified
(l) External causes of morbidity and mortality: intentional self-
harm/suicide was analysed separately from other external
causes of death. X60-X84 in ICD-10 was combined with
undetermined suicide Y10-Y34 in ICD-10 and corresponding
codes from ICD-9. These codes were combined to limit the
temporal and geographic variation in the ascertainment. This
practice is common in research and reporting concerning
public health statistics.
28,29
A sensitivity analysis proved the
comparability of the two diagnostic groups. The combined
measure is referred to hereafter as suicide. In Other external
causes we included remaining X and Y diagnoses and V
diagnoses, as well as W diagnoses.
(m) Other causes of death: in this category we included chapters
with only a few cases (in total, 247 cases; 15 of these with
ASD) (for information on ICD chapters and codes, see
Appendix).
Statistical analyses
Conditional logistic regression analyses were performed and odds
ratios (ORs) with 95% CIs were calculated for all-cause and cause-
specific mortality in cases of an ASD diagnosis in the National
Patient Register (1987–2009). In the first step, the ORs were
calculated for the total ASD group, as well as separately for the
genders. In the second step, the ORs were calculated separately
for the low- and the high-functioning ASD groups (compared
with the matched controls). Analyses were performed stratified
for gender if the difference between the entire ASD group and
controls was significant (all other categories except Infections).
For the analysis of interaction (ASD6gender), an interaction
term was added as a covariate in the conditional logistic regression
analyses and significant interaction was tested with the partial
likelihood ratio test. If any cell included fewer than five cases at
any level of the analysis, that level was dropped and the data were
thus not shown. In the analyses of Mental and behavioural
disorders, ASD diagnoses as primary causes of death (n= 2) were
regarded as ill-defined causes of death and excluded. A partial
likelihood ratio test was also used to compare the fit of the null
model of diagnostic status (ASD or control) with the alternative
model (low-functioning ASD, high-functioning ASD or control).
Thus, if the data fitted the alternative model significantly better,
an interaction effect between low-functioning ASD and high-
functioning ASD was assumed and the null model was rejected.
The alpha level was set at P50.05. All statistical analyses were
planned a priori.
Ethical approval
The Regional Ethics Committee in Stockholm approved the study
(0229/939-31/5).
Results
Characteristics of the study sample are described in Table 2.
All-cause mortality
At the time of the follow-up, 24 358 persons (0.91%) in the
general population group had died, whereas the corresponding
figure in the ASD group was 706 (2.60%; Table 3).
Individuals with ASD had a 2.56-fold increased odds of
mortality compared with matched general population controls
(Table 3). Mortality was significantly elevated in both genders
relative to the general population (males: OR = 2.87; females
OR = 2.24), whereas the significant interaction effect indicated
higher mortality among males (Table 3). Moreover, all-cause
mortality was increased in both the low-functioning ASD
3
Table 2 Characteristics of the study groups
Control ASD in total Low-functioning ASD High-functioning ASD
ntotal (%) 2 672 185 27 122 6240 (23.01) 20 882 (76.99)
Females n(%) 840 962 (31.47) 8429 (31.08) 2032 (32.56) 6397 (30.63)
Males n(%) 1 831 223 (68.53) 18 693 (68.92) 4208 (67.44) 14 485 (69.37)
Age at first registered diagnosis, years:
mean (s.d.) median
N/A 19.83 (14.54) 16.49 (13.83)
12
20.83 (14.59)
17
ASD, autism spectrum disorder.
Table 3 Risk for all-cause mortality for the entire autism spectrum disorder (ASD) group, as well as separately for females and males,
and low-functioning ASD and high-functioning ASD groups
Controls
Number of deaths (%)
ASD OR (95% CI)
Number of deaths (%)
Low-functioning ASD OR (95% CI)
Number of deaths (%)
High-functioning ASD OR (95% CI)
Number of deaths (%)
Total 2.56 (2.38–2.76) 5.78** (4.94–6.75) 2.18 (2.00–2.38)
24 358 (0.91) 706 (2.60) 169 (2.71) 537 (2.57)
Females 2.24 (1.99–2.51) 8.52 (6.55–11.08) 1.88 (1.65–2.14)
11 693 (1.39) 296 (3.51) 61 (3.00) 235 (3.67)
Males 2.87* (2.60–3.16) 4.88 (4.02–5.93) 2.49 (2.22–2.80)
12 665 (0.69) 410 (2.19) 108 (2.57) 302 (2.08)
ASD, autism spectrum disorder; OR, odds ratio; CI, confidence interval.
*Partial likelihood ratio test for interaction effect ASD6gender, P= 0.001.
**Partial likelihood ratio test for model selection (low-functioning ASD/high-functioning ASD), P50.001.
Hirvikoski et al
(OR = 5.78) and the high-functioning ASD (OR = 2.18) groups,
compared with the general population. The excess mortality was
significantly higher in the low-functioning ASD group, as
indicated by the significance of the partial likelihood ratio test
(Table 3). Mortality was increased in both females (OR = 8.52)
and males (OR = 4.88) with low-functioning ASD, as well as in both
females (OR = 1.88) and males (OR = 2.49) with high-functioning
ASD, compared with controls of the same gender.
Individuals in the control group died at a mean age of 70.20
years (s.d. = 24.16, median = 80), whereas the corresponding
figure for the entire ASD group was 53.87 years (s.d. = 24.78,
median = 55), for low-functioning ASD 39.50 years (s.d. = 21.55,
median = 40) and high-functioning ASD 58.39 years
(s.d. = 24.01, median = 63) respectively. The time period between
registered ASD diagnosis and death (regardless of cause of death)
was on average 5.30 years (s.d. = 4.85) for low-functioning ASD
and 3.79 years (s.d. = 4.17) for the high-functioning ASD group.
Cause-specific mortality
Specific causes of death in the whole ASD group
Significantly elevated mortality was noted among individuals with
ASD in all analysed categories of specific causes of death except for
infections (Table 4). The ICD diagnoses including only a few
cases were combined and, also in this category, an excess mortality
of the ASD group was observed. The mortality was 1.5-fold to
eightfold increased compared with the general population (with
exception for congenital malformations (OR = 19.10); however,
the broad CIs indicate an imprecise estimation). ORs were highest
in cases of mortality because of diseases of the nervous system
(OR = 7.49) and because of suicide (OR = 7.55), in comparison
with matched general population controls.
Specific causes of death in low-functioning
v.
high-functioning ASD
In most of the specific causes of death (Mental and behavioural
disorders; Nervous system; Circulatory system; Respiratory
system; Digestive system; and Congenital malformations), the
low-functioning ASD group had higher mortality relative to the
high-functioning ASD group, although both groups had
significantly elevated mortality compared with the general
population controls (Table 4). The most common cause of death
in the low-functioning ASD group was epilepsy. In contrast, the
high-functioning ASD group had a significantly more elevated
suicide risk than the low-functioning ASD group, whereas, again,
both groups had an increased risk compared with controls. The
time period between registered ASD diagnosis and suicide was on
average 2.86 years (s.d. = 2.41) in the low-functioning ASD group
and 2.53 years (s.d. = 2.65) in the high-functioning ASD group.
Online Table DS1 specifies the most common subcategories of
the main causes of death for controls, the entire ASD group,
and low-functioning and high-functioning ASD groups.
Gender differences in specific causes of death
For most diagnostic categories, the pattern of mortality risk was
comparable in females and males with ASD. Nevertheless, males
with ASD had a higher relative risk than females of mortality
4
Table 4 Cause-specific mortality in relation to ASD and separately for low-functioning ASD and high-functioning ASD
a
Controls, n
of deaths (%)
ASD OR (95% CI)
nof deaths (%)
Low-functioning ASD
OR (95% CI), nof deaths (%)
High-functioning ASD
OR (95% CI), nof deaths (%)
Infections 1.83 (0.75–4.30) N/A N/A
245 (0.01) 5 (0.02)
Neoplasms 1.80 (1.46–2.23) 2.12 (1.25–3.61) 1.75 (1.39–2.21)
4493 (0.17) 88 (0.32) 14 (0.22) 74 (0.35)
Endocrine 3.70 (2.34–5.87) 8.89 (3.52–22.41) 3.07 (1.80–5.23)
474 (0.02) 19 (0.07) 5 (0.08) 14 (0.07)
Mental and behavioural
disorders
2.80 (1.94–4.03) 21.81** (12.20–39.00) 1.58 (0.96–2.59)
925 (0.03) 30 (0.11) 14 (0.22) 16 (0.08)
Nervous system 7.49 (5.78–9.72) 40.56** (26.82–61.33) 3.98 (2.76–5.74)
737 (0.03) 62 (0.23) 32 (0.51) 30 (0.14)
Circulatory system 1.49 (1.27–1.75) 4.61** (3.06–6.95) 1.33 (1.12–1.58)
8820 (0.33) 157 (0.58) 24 (0.38) 133 (0.64)
Respiratory system 2.68 (1.99–3.62) 13.92** (7.04–27.50) 2.17 (1.55–3.05)
1351 (0.05) 45 (0.17) 10 (0.16) 35 (0.17)
Digestive system 3.31 (2.25–4.87) 9.13* (4.42–18.87) 2.61 (1.65–4.12)
733 (0.03) 27 (0.10) 8 (0.13) 19 (0.09)
Genitourinary system 3.82 (2.13–6.84) N/A N/A
253 (0.01) 12 (0.04)
Congenital malformations 19.10 (11.94–30.55) 38.75* (20.39–73.64) 10.38 (4.98–21.61)
106 (<0.01) 21 (0.08) 13 (0.21) 8 (0.04)
Symptoms, signs and
abnormal findings, other 618 (0.02)
1.81 (1.06–3.08)
14 (0.05)
N/A N/A
Suicide 7.55 (6.04–9.44) 2.41 (1.14–5.11) 9.40** (7.43–11.90)
1094 (0.04) 83 (0.31) 7 (0.11) 76 (0.36)
External causes, other 1.67 (1.16–2.40) 1.53 (0.69–3.44) 1.71 (1.14–2.56)
1696 (0.06) 30 (0.11) 6 (0.10) 24 (0.11)
Other 5.84 (3.46–9.86) N/A N/A
232 (0.01) 15 (0.06)
ASD, autism spectrum disorder; OR, odds ratio; CI, confidence interval.
a. Missing data on primary cause of death (n= 2677, 50.5% in both groups) are not included in the analyses; N/A analyses were not performed owing to the low number of cases in
certain cells; partial likelihood ratio test for model selection (low-functioning ASD/high-functioning ASD).
*P50.01 (Digestive P= 0.009; Congenital malformations P= 0.007); **P50.001.
Mortality in autism spectrum disorders
owing to diseases of the nervous and circulatory systems. On the
other hand, females with ASD had higher relative mortality risk
than males in diseases owing to endocrine diseases, congenital
malformations and suicide (Table 5).
Discussion
In this large population-based study, we observed increased
mortality in individuals with ASD. Mortality was increased in
both low-functioning and high-functioning ASD, as well as in
both genders. However, the risk was particularly high for females
with low-functioning ASD. Patterns of specific causes of death
were somewhat different for low-functioning ASD compared with
high-functioning ASD.
The observed OR of 2.56 for ASD in relation to all-cause
mortality is in line with most of the previous clinical and
population-based mortality studies.
15–20
We found that increased
mortality in ASD was not limited to certain causes of death, such
as diseases of nervous system, but was elevated for all analysed
categories according to the ICD, apart from infectious diseases.
In most previous studies, the samples have been too small
and/or selected to adequately analyse the role of intellectual
disability regarding mortality in ASD. Therefore, we performed all
analyses comparing low-functioning ASD and high-functioning
ASD groups. Based on the well-known association of low-
functioning ASD with several medical conditions, the higher
mortality in low-functioning ASD than in high-functioning ASD
was expected.
21
In approximately 10% of cases, ASD
(predominantly low-functioning ASD) is part of a known genetic
syndrome,
14
which may be associated with both intellectual
disability and many of the comorbid diseases. Opposing results
from the only previous study focusing on differences in mortality
between low-functioning ASD and high-functioning ASD,
17
the
current study showed increased mortality in mental and
behavioural disorders, diseases of nervous, circulatory,
respiratory and digestive systems, as well as congenital
malformations in the low-functioning ASD group compared with
the high-functioning ASD group. However, our results clearly
indicated that mortality was elevated across a multiplicity of
causes of death in ASD as a whole, including high-functioning
ASD. Thus, our results add to the accumulating evidence
indicating that ASD accounts for substantial health loss across
the lifespan.
30
Suicide was the only specific cause of death showing a higher
risk in high-functioning ASD compared with low-functioning
ASD. High-functioning ASD often presents with co-existing
psychiatric disorders.
9–13
In a recent study,
31
high prevalence of
suicidal ideation and suicide attempts was reported among
individuals with Asperger syndrome. Suicidality was increased
5
Table 5 Cause-specific mortality analysed separately for females and males
a
Control females
nof deaths (%)
ASD females OR (95% CI)
nof deaths (%)
Control males
nof deaths (%)
ASD males OR (95% CI)
nof deaths (%)
Neoplasms 1.83 (1.33–2.50) 1.79 (1.34–2.38)
2047 40 2446 48
(0.24) (0.47) (0.13) (0.26)
Endocrine 5.70* (3.25–9.99) 2.11 (0.94–4.73)
214 13 260 6
(0.03) (0.15) (0.01) (0.03)
Mental and behavioural disorders 2.53 (1.58–4.05) 3.31 (1.85–5.92)
614 18 311 12
(0.07) (0.21) (0.02) (0.06)
Nervous system 5.29 (3.50–7.99) 10.19* (7.27–14.29)
405 24 332 38
(0.05) (0.28) (0.02) (0.20)
Circulatory system 1.10 (0.86–1.40) 2.02*** (1.64–2.49)
5071 66 3749 91
(0.60) (0.78) (0.21) (0.49)
Respiratory system 3.24 (2.18–4.79) 2.16 (1.36–3.42)
692 26 659 19
(0.08) (0.31) (0.04) (0.10)
Digestive system 2.78 (1.52–5.07) 3.81 (2.31–6.29)
352 11 381 16
(0.04) (0.13) (0.02) (0.09)
Congenital malformations 33.86* (18.04–63.56) 11.07 (5.30–23.13)
38 13 68 8
(50.01) (0.15) (<0.01) (0.04)
Suicide 13.05** (8.73–19.50) 6.28 (4.79–8.23)
213 27 881 56
(0.03) (0.32) (0.05) (0.30)
External causes, other 2.32 (1.27–4.22) 1.44 (0.91–2.26)
445 11 1251 19
(0.05) (0.13) (0.07) (0.10)
Other 4.89 (2.39–9.99) 7.49 (3.46–16.21)
145 8 87 7
(0.02) (0.09) (<0.01) (0.04)
ASD, autism spectrum disorder; OR, odds ratio; CI, confidence interval.
a. Missing data on primary cause of (n= 2677, 50.5% in both groups) are not included in the analyses; partial likelihood ratio test for interaction effect (ASD gender).
*P50.05 (Endocrine P= 0.039; Nervous system P= 0.014; Congenital malformations P= 0.021); **P50.01 (Suicide P= 0.004); ***P50.001.
Hirvikoski et al
in, but not limited to, individuals with Asperger syndrome and a
history of depression.
31
In addition to psychiatric comorbidity,
individuals with high-functioning ASD may have psychological
vulnerability, such as social disengagement, which may increase
the risk of suicide.
32
Analysis of moderators and mediators of
suicidal behaviours in individuals with ASD is an important area
of future research, and should not only focus on risk factors but
also resilience. Individuals with ASD may lack many of the
protective factors that could decrease the risk of suicide, such as
a supportive social network,
32
good coping skills
33
and overall life
satisfaction.
34
The risk of suicide may also be reduced by
therapeutic and supportive contacts.
32
However, in individuals
with ASD, difficulties in social interaction and communication
(i.e. core symptoms of ASD) may seriously reduce the ability to
seek and receive help and treatment. This may not only apply to
help regarding psychological well-being but also somatic illness.
A large Swedish nationwide register-based study
35
has
indicated lower levels of somatic healthcare quality for psychiatric
patients than for the general population. Thus, higher avoidable
mortality
36
in psychiatric patients suggests that the medical care
for physical disorders provided to psychiatric patients is less
effective than in the general population. A recent systematic
review
30
stressed the public health and policy implications of
the substantial burden of ASD across the lifespan. Given that most
individuals living with ASD today are adults, the support and
interventions need to extend beyond paediatric and early
education. Similarly, our findings may indicate a continuous need
for improvement in public health and medical care for individuals
with ASD. For instance, on average, age at initial diagnosis in the
current sample was rather high in both low-functioning ASD and
high-functioning ASD groups, and the time interval between ASD
diagnosis and death was relatively short (3–5 years for overall
mortality, but under 3 years regarding suicide as cause of death).
However, the present study is unable to differentiate whether
increased mortality in ASD is because of shortcomings in care
provision, increased general biological vulnerability, or both.
Previous studies have reported higher mortality in females
with ASD than males with ASD.
15–20
Our results were in line with
the previous studies in the low-functioning ASD group. However,
we also observed opposite gender-specific mortality risk patterns
among individuals with low-functioning ASD compared with
high-functioning ASD. Among individuals with high-functioning
ASD, females had a somewhat lower mortality risk than males.
However, in the low-functioning ASD group, females had a higher
risk than males. Thus, in the entire ASD group, females with low-
functioning ASD seemed to be an especially vulnerable group in
which the mortality risk was nine times higher than in the general
population control group.
Strengths and limitations
The strengths of this population-based register study include
the large study population with high statistical power and the
good validity of Swedish registers.
22
Consequently, we had the
opportunity to analyse mortality even in less frequent causes of
death for both low-functioning ASD and high-functioning ASD,
as well as in both genders. Weaknesses of the present study include
exclusive reliance on the National Patient Register for case
ascertainment, leading to a selected and perhaps severely affected
sample by only including individuals with ASD who had been in
contact with clinical psychiatry services. This selection bias may be
particularly relevant for individuals diagnosed before the year
2001 (i.e. before contact with out-patient psychiatric care services
was included in the National Patient Register). However, after the
year 2001 (88.2% in current data) all individuals having received
an ASD diagnosis are registered in the National Patient Register
because of the diagnostic assessment per se, i.e. also in cases with
no further contact with psychiatric services. Another limitation is
that this study did not in detail examine comorbidity for other
ICD diagnoses than developmental intellectual disability.
Future studies may highlight the likely possibility of psychiatric
comorbidity moderating or mediating mortality in ASD. Finally,
the generalisability of the present study is limited by the fact that
healthcare is organised differently in different countries. Our
results may not be fully generalisable for countries with very
different healthcare systems.
Clinical implications
Our observation of excess cause-specific mortality in individuals
with ASD may signify a generally increased biological vulnerability
in ASD, as well as insufficient awareness, diagnoses and treatment
of comorbid diseases within the healthcare system. As the
mortality risk was increased for a number of different causes of
death, a better knowledge of ASD appears to be desirable in all
medical specialties. Health- and lifestyle-related issues may be a
future focus for interventions directed at individuals with ASD
and their significant others. Moreover, individuals with ASD
may need support in communicating their symptoms and
developing their skills in seeking help and treatment for problems
involving psychological well-being or somatic health.
In summary, we observed markedly increased premature
mortality in ASD owing to a multitude of medical conditions.
The risk was particularly high for females with low-functioning
ASD. However, individuals with high-functioning ASD had a high
risk for suicide. Adequate and coordinated medical care for
individuals with ASD and research into the phenomenon should
be a target for a considerably broader audience of medical
specialties than psychiatry and neurology.
Tatja Hirvikoski, PhD, Department of Women’s and Children’s Health, Pediatric
Neuropsychiatry Unit, Center for Neurodevelopmental Disorders at Karolinska
Institutet (KIND), Karolinska Institutet, Stockholm, Sweden and Habilitation and
Health, Stockholm County Council, Sweden; Ellenor Mittendorfer-Rutz, PhD,
Department of Clinical Neuroscience, Division of Insurance Medicine, Karolinska
Institutet, Stockholm, Sweden; Marcus Boman, BSc, Henrik Larsson, PhD,
Paul Lichtenstein, PhD, Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Stockholm, Sweden; Sven Bo
¨lte, PhD, Department of Women’s
and Children’s Health, Pediatric Neuropsychiatry Unit, Center for Neurodevelopmental
Disorders at Karolinska Institutet (KIND), Karolinska Institutet, Stockholm and Division
of Child and Adolescent Psychiatry, Stockholm County Council, Sweden
Correspondence: Tatja Hirvikoski, PhD/Neuropsychologist, Center for
Neurodevelopmental Disorders at Karolinska Institutet (KIND), CAP Research
Center, Ga
¨vlegatan 22B, SE-11330 Stockholm, Sweden. Email:
Tatja.Hirvikoski@ki.se
First received 9 Nov 2014, final revision 22 Dec 2014, accepted 15 Jan 2015
Funding
The study was funded by the regional agreement on medical training and clinical research
(ALF) between Stockholm County Council and Karolinska Institutet (grants no. 20120419 and
20130630, Tatja Hirvikoski), Karolinska Institutet in cooperation with the Stockholm County
Council (KI/SLL, 2008:9, Sven Bo
¨lte), the Swedish Research Council (grant no. 523-2009-7054,
Sven Bo
¨lte) and the Swedish Research Council in cooperation with the Swedish Research
Council for Health, Working Life and Welfare, Vinnova and FORMAS (cross-disciplinary
research programme concerning children’s and youth’s mental health, grant no.
259-2012-24, Sven Bo
¨lte).
Acknowledgements
We express our gratitude to psychiatrist Berit Lagerheim for providing us with an overview
of Swedish clinical practice from 1980s onwards in diagnostic assessment of ASD and
other neurodevelopmental disorders. We would also thank MD/Professor in psychiatry Jussi
Jokinen for information on clinical aspects of ICD causes of death codes registration.
6
Mortality in autism spectrum disorders
Appendix
ICD-10 chapters and codes used as a basis for
categorisation of causes of death in current study
Chapter I: Infections (ICD codes A00-B99)
Chapter II: Neoplasms (C00-D48)
Chapter IV: Endocrine, nutritional and metabolic diseases (E00-E99)
Chapter V: Mental and behavioural disorders (F00-F99)
Chapter VI: Diseases of the nervous system (G00-G99)
Chapter IX: Diseases of the circulatory system (I00-I99)
Chapter X: Diseases of the respiratory system (J00-J99)
Chapter XI: Diseases of the digestive system (K00-K99)
Chapter XIV: Diseases of the genitourinary system (N00-N99)
Chapter XVII: Congenital malformations (Q00-Q99)
Chapter XVIII: Symptoms, signs, and abnormal findings not elsewhere
classified (R00-R99)
Chapter XX: External causes of morbidity and mortality (V01-Y98)
Other causes of death
: In this category, we included chapters with only a
few cases chapter III (D50-D89, diseases of the blood and blood-forming
organs and certain disorders involving the immune mechanism); chapter
VII (H00-H59, diseases of the eye and adnexa); chapter VIII (H60-H95,
diseases of the ear and mastoid process); chapter XII (L00-L99, diseases
of the skin and subcutaneous tissue); chapter XIII (M00-M99, diseases of
the musculoskeletal system and connective tissue); chapter XV (O00-O99,
pregnancy, childbirth and/or obstetric causes); chapter XVI (P00-P96, certain
conditions originating in the perinatal period).
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Hirvikoski et al. Premature mortality in autism spectrum disorder. Br J Psychiatry (doi:
10.1192/bjp.bp.114.160192)
Table DS1.Three most common subcategories of specific causes of death(not specified if <5
individuals in the ASD groups).
Controls
ASD
LF ASD
HF ASD
Neoplasms
(C00-D48)
Neoplasm of
bronchus and
lung
; prostate;
breast
Neoplasm of breast
Neoplasm of
pancreas
Mesothelioma
N/A
Neoplasm of
pancreas
Mesothelioma
Nervous
system (G00-
G99)
Stroke
Alzheimer's
disease
Systemic
atrophies
Epilepsy
Epilepsy
Epilepsy
Stroke
Circulatory
(I00-I99)
Ischemic
heart diseases
Heart failure
Atrial
fibrillation
and flutter
Ischemic heart
diseases
Ischemic heart
diseases
Ischemic heart
diseases
Respiratory
(J00-J99)
Pneumonia
Chronic
obstructive
pulmonary
disease
Emphysema
Pneumonia
Chronic obstructive
pulmonary disease
N/A
Pneumonia
Chronic
obstructive
pulmonary
disease
10.1192/bjp.bp.114.160192
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