GASTROENTEROLOGY 1981;80:307-12
Mortality in Crohn’s Disease
P. PRIOR, S. GYDE, W. T. COOKE,
and R. N. ALLAN
The General Hospital, Birmingham, England, and the Cancer
Unit, University of Birmingham, Birmingham, England
A series of 523 patients with Crohn’s disease, who
were followed for 1 to more than 35 yr by one unit,
experienced a twofold increased risk of dying com-
pared with a matched group drawn from the general
population (102 observed; 51.8 expected; p < 0.002).
The overall risk was similar for men and women
and was greatest in the younger patients within a
few years of diagnosis. The relative risk of dying de-
creased as the age at diagnosis of their Crohn’s dis-
ease increased and also fell as the period of time
from diagnosis increased. There was q small but sig-
nificpnt excess of death from tumors of the digestive
orgqns (9 observed; 4 expected; p < 0.05). There was
also a significant excess of deaths from suicide in
women (3 observed; 0.4 expected; p < O.Ol]. The ma-
jor burden of mortality lay in causes directly attrib-
utable to Crohn’s disease or to associqted complica-
tions within the digestive systeg (46 observed; 2.41
expected; p < 0.001).
Despite the use of more sophisticated methods of
analysis the mortality risk in Crohn’s disease is still
debated. Comparisons between series (l-5) are con-
fouade4 because of differences in the selection of
patients which may be based on age (Z-4), sex (Z-4),
site of disease at onset (2,3,5), or the point in the life
cycle of the disease when the analysis is initiated. It
is now clear that crude rates without correction for
age or period of observation are an inadequate and
even misleading measurement of mortality.
In a previous paper from this unit (4) the number
of deaths observed among 298 patients with Crohn’s
disease under review for an average’of 13.8 yr was
compared with the number that might be expected
Received April 18, 1980. Accepted August 22, 1980.
gddress requests for reprints to: Dr. R. N. Allan, Gastroenterol-
ogy Unit, The General Hospital, Steelhouse Lane, Birmingham B4
8Nh, England.
We are grateful for financial support from the West Midlands
Regional Health Authority Research Committee and the Cancer
Research Campaign.
0 1981 by the American Gastroenterological Association
0018-5085/81/020307-08$02.50
J. A. H. WATERHOUSE,
Epidemiology Research
to occur in the general population during the same
period of time after appropriate corrections for age
and survival had been applied. The mortality rate
was 2.36 times that of the general population. The
report included an analysis of the effect of age and
site of disease at diagnosis, but not the pattern of
risk with time. In a separate analysis from this unit
of patients with Crohn’s disease involving the colon
(5), the mortality rate was 2.1 times that of a
matched population while the relative risk of dying
decreased as the period of time from diagnosis in-
creased.
This paper presents a fresh analysis of the pattern
of mortality in a large series of patients with Crohn’s
disease. The criterion for entry was the date at
which a definitive diagposis of Crohn’s disease was
established. The patients were unselected in respect
of age, sex, site or severity of disease. The methods
of analysis have been described previously (4), but
the factors of age at diagnosis and the interval from
diagnosis have been examined in greater detail to
determine their interrelationship. The pattern of
specific causes of death compared with the rates in
the general population has also been considered.
Clinical Materials and Methods
The series comprised all patients seen in the unit in
whom the diagnosis of Crohn’s disease had been made.
Five hundred and thirteen patients (243 men and 270
women) under the care of one physician (W. T. Cooke)
have been included in this prospective study of the life
history of Crohn’s disease initiated more than 35 yr ago.
The date of diagnosis was taken as the starting point for
all analyses apart from 6 patients for whom the outcome
was not known. Each patient was followed to death or to
the close of study (December 31st, 1976), and the length of
survival was computed. A tabulation of patient-years at
risk was constructed in terms of age at diagnosis and the
interval from diagnosis. Each year survived contributes on
pafient-year at a specific age to the tabulation. The ob-
served numbers were ascertained from copies of the death
certificate in al! but 2 cases. The cause of death was coded
308 PRIOR ET AL. GASTROENTEROLOGY Vol. 60, No. 2

Table 1. Crohn’s Disease: Mortality from All Causes by Sex and Year from Diagnosis
Interval
from Males Females Total Patient-
diagnosis years
(Yr) E 0 O/E p E 0 O/E p E 0 O/E p at risk
o- 5.89 26 4.6 -= 2.88 9 3.1 -b 8.57 35 4.1 -= 2303.2
5- 6.06 12 2.0 -a 3.13 7 2.2 --a 9.19 19 2.1 -b 1762.3
lo- 6.61 12 1.8 -0 3.68 8 2.2 -0 10.29 20 1.9 -a 1330.6
15- 6.33 6 1.0 - 4.16 8 1.9 - 9.49 14 1.5 - 969.3
20- 3.88 3 1.0 - 2.64 5 1.9 - 6.52 8 1.2 - 550.2
25+ 4.66 4 1.0 - 3.72 2 0.5 - 7.78 8 0.8 - 517.2
Total 31.63 83 2.0 -c 20.21 39 1.9 _= 51.84 102 2.0 -= 7423.8
E = expected number of death; 0 = observed number of deaths. a p = 0.05. b p = 0.01. = p = O.qol.

according to the International Classification of Disease
(ICD) (6). Age- and sex-specific mortality rates were com-
puted from the Registrar General’s mortality and popu-
lation figures for i961(7) for all causes of deaths and for 11
main-group causes. The numbers pf deaths that might be
expected to occur during the period of review were com-
puted by multiplying each cell of the table of person-years
by the appropriate “age- and sex-specific rate. Statistical
significance of the difference between observed and ex-
pected numbers was assessed using the Poisson distribu-
tion. Analyses were performed in respect of age at diagno-
sis and the interval from diagnosis. An age-specific
mortality curve was constructed from the results, which
were also transformed into actuarial survival curves for
comparison with other surveys.
The observed age-specific mortality rates were com-
puted as the number of deaths occurring between the ages
of x and x + 5 years divided by the patient-years experi-
enced between x and x + 5 years, multiplied by 1ClOO.The
curve for expected rates was obtained in a similar way
from the expected numbers and patient-years at risk. The
rates are plotted as a z-point moving average in order to
smooth fluctuations caused by small numbers at each
point.
The probability of dying (q-J in each yearly interval
from diagnosis was computed from the number of deaths
and the patient-years at risk in each interval to obtain the
annual probability of surviving (pX = 1 - qX).The actuarial
curve of survival was obtained by successive multiplica-
tion of the annual probabilities of survival.
The cumulative excess mortality which was used by
Truelove and Pena (3) is calculated fron) the difference be-
tween the observed and expected mortality at each point
in time.
The cumulative relative risk is calculated from the stan-
dardized mortality ratio at each point in time which is the
observed mortality divided by the expected mortality.
Results
Mortality from A11 Causes
The patient-years at risk by year from diagno-
sis of Crohn’s disease are shoyvn in Table 1. One
hundred and two deaths were recorded during the
period of review (mean followup, 14.5 yr), compared
with an expected number of 51.84 (p < 0.001, Table
1). The overall relative risk was similar in men and
women though men were at greater risk in the first 5
yr after diagnosis, whereas the risk in women was
more evenly spread throughout the review period.
When the results for men and women were com-

5
40 -0 < ,#//------ 4

“..., 3
CUMULATIVE , ***...... CUMULATIVE
20.0 ***............
NUMBER OF ,’ 2 RELATIVE
Figure 1. Cumulative observed (-) and expected DEATHS RISK
/
(---) numbers of deaths and cumulative
10.0 ’
relative risk (0 ?? ?? 0) for all patients. 00 t 8’
6.0
t

10 15 20 25 30 35

YEARS FROM DIAGNOSIS

February 1981 MORTALITY IN CROHN’S DISEASE 309

Table 2. Crohn’s Disease: Mortality from All Causes by Sex and Age at Diagnosis

Age at Males Females Total

diagnosis
(yr) E 0 O/E P E 0 O/E P E 0 O/E P

5-29 5.15 21 4.1 -= 2.97 15 5.1 _c 8.12 36 4.4 _=

30-44 4.85 18 3.7 _c 4.64 10 2.2 -0 9.49 28 3.0 -c
45+ 21.63 24 1.1 12.60 14 1.1 - 34.23 38 1.1 -
Total 31.63 63 2.0 _c 20.21 39 1.9 _c 51.84 102 2.0 -c

bined, the cumulative relative risk of dying de-
creased with time (Figure 1). The relative risk of
dying was particularly high in the younger age group
(Table 2). There was a highly significant excess of
deaths (p < 0.001) in men under 45 yr of age and in
women under 30 yr of age. In women aged 30-44 yr
the excess was significant only at the 5% level. The
risk of dying was not increased in men or women
diagnosed as having Crohn’s disease after the age of
45 yr.
Whatever the age of diagnosis, the relative risk of
dying decreases as the duration of disease increases
(Table 3).
The observed and expected age-specific mortality
rates are shown in Figure 2. The relative risk of
dying is high in younger patients and declines with
increasing age. The observed rates fluctuates about
the expected rate after 60 yr of age.
The actuarial curve of survival (Figure 3) confirms
that men fare worse in the early period of observa-
tion, whereas the risk for women in more evenly
spread. The mortality in women with Crohn’s dis-
ease is only marginally worse than that of men in
the general population. After 30 yr the excess mor-
tality in men (11%) and women (12%) is similar.
Deaths from Specific Causes
The pattern of deaths from specific causes is
summarized in Table 4 for 11 main-group causes of
the International Classification of Diseases (7th Re-
vision) (6). Deaths from diseases of the digestive
tract (group IX) accounted for most of the excess
mortality. No other group showed a statistically sig-
nificant excess of deaths.
Group IX (digestive system). Twenty-nine of
the 46 deaths in this group were attributed on the
death certificate to Crohn’s disease. Of the other 17
deaths, 11 were attributed to some form of enteritis
but were not specified as Crohn’s disease, while the
remaining six deaths were certified as intestinal ob-
struction [2], fistula [3], and hemorrhage from gastric
ulcer [l].
Group I (infective and parasitic dis-
eases). Both deaths in this group were attributed to
tuberculous enteritis, but this was not confirmed by
subsequent histologic examination, though pulmo-
nary tuberculosis was cited as a contributory cause
in one of them. Despite the high rate of postmortem
examinations (70% of all deaths) and the substantial
numbers of patients entered during the early part of
the survey, tuberculosis (inactive) appeared on only
one other death certificate.
Group II (malignant neoplasms). No excess of
deaths from malignant neoplasms was found overall
in contrast with the analysis of cancer morbidity (8).
However, 9 deaths (60% of all cancer deaths) were
attributed to tumors of the digestive system when
only 4.0 would be expected (p < O.O5), the relative
risk in men was 2.2 and in women 2.4, leaving a defi-

Table 3. Crohn’s Disease: Mortality from AI1 Causes by Sex, Age, and Interval from Diagnosis

Age at Interval Males Females Total

diagnosis from -

(Yr) diagnosis E 0 O/E p E 0 O/E p E 0 O/E p

o-4 0.64 10 15.6 -= 0.37 5 13.5 -= 1.01 15 14.9 -1

5-29 5-14 1.17 6 5.1 -b 0.86 5 5.8 -'J 2.03 11 5.4 -_I
15+ 3.34 5 1.5 - 1.74 5 2.9 -" 5.10 10 2.0 -._a
o-4 0.61 5 8.2 -= 0.51 1 2.0 - 1.12 6 5.4 -b
30-44 ( 5-14 1.64 10 6.1 -c 1.40 5 3.6 -O 3.04 15 4.9 _L‘
15+ 2.60 3 1.2 - 2.73 4 1.5 - 5.33 7 1.3 -
o-4 4.44 11 2.5 -b 2.00 3 1.5 - 6.44 14 2.2 -1)
45+ i 5-14 9.86 8 0.8 - 4.55 5 1.1 - 14.41 13 0.9 -
15+ 7.33 5 0.7 - 6.05 6 1.0 - 13.38 11 0.8 -
o-4 5.69 26 4.6 _c 2.88 9 3.1 -b 8.57 35 4.1 _=
Total 5-14 12.67 24 1.9 -b 6.81 15 2.2 -b 19.48 39 2.0 -_c
15+ 13.27 13 1.0 - 10.52 15 1.5 - 23.79 28 1.2 -
310 PRIOR ET AL. GASTROENTEROLOGY Vol. 80, No. 2

MORTALITY RATE
(No. of deaths per

Figure 2. Observed (-) and expected (---)

age-specific mortality rates and rei RELATIVE
RISK
ative risk of mortality (0 ?? ?? 0)

AGE AT DEATH (YEARS)

tit of 2 tumors at the remaining sites (Table 5). Based
on expected numbers for individual sites, one death
from cancer of the male reproductive system (ex-
pected 0.8) and one from breast cancer in women
(expected 1.2) might have been anticipated. The defi-
cits at these and remaining sites were not statisti-
cally significant.
Group 111 (allergic and metabolic dis-
orders). The one death in the group did not repre-
sent a significant excess though it was attributed to
amyloidosis, a known complication of Crohn’s dis-
ease. Amyloidosis appeared in part II of one other
certificate.
Group Vi, VII, VIII (nervous, circulatory, and
respiratory systems). These conditions were consid-
ered together because of the frequency of multiple
“EARS FROM DIAGNOSIS
SURVIVAL
(%)
coding on the death certificate, especially in the el-
derly. Thirty deaths were observed for a total of 31.8
expected; the separate values for men and women
were equally close. There was a small excess of
deaths for the nervous system and a small deficit of
deaths in the circulatory system. The underlying
cause for the six deaths in women (group VI) was
cited as cerebrovascular disease, but in three of
them arteriosclerosis or myocardial infarction ap-
peared elsewhere on the death certificate.
Group X (urinary system disease). Three pa-
tients were certified as dying from renal disease.
While the excess of deaths in this group is not statis-
tically significant, renal complications-uremia,
renal failure, and nephrolithiasis-appeared on
seven other certificates.
Group EXVll (accidents, violence, and poi-
sonings). Although the observed and expected num-
bers were close in this group, the three deaths in
women were due to self-administered drugs or poi-
son. When set against the relevant rubrics (E970-
979), these deaths represent a significant excess (3
observed, 0.4 expected, p = O.Ol), leaving a deficit of
two deaths for the remaining rubrics.
Remainder. There were two deaths in this
group: One was from unknown cause, and the sec-
ond was attributed to ankylosing spondylitis which
also appeared in part II of one other certificate.

Discussion
Selecting the date of diagnosis as the starting
point for the analysis can introduce a small error
Figure 3. Cumulative survival rates by sex: Crohn’s series-
males (-), females (-0-o-o); general population-males among those patients referred from elsewhere, for
(---), females p ?? ?? ??
). they are selected by virtue of their having survived
February 1983 MORTALITY IN CROHN’S DISEASE 311

Table 4. Crohn’s Disease: Mortality from Specific Table 5. Crohn’s Disease: Mortality from Malignant
Causes Neoplasms
Cause ICD Sex E 0 O/E p Cause ICD Sex E 0 p

M 31.6 63 2.0 -= Group II M 6.6 9 -

All causes OOl-E999 F 20.2 39 1.9 -= (Malignant neoplasms) 140-205 F 5.3 6 -
T 51.8 102 2.0 -= T 11.9 15 -
Group I M 0.5 1 2.0 - M 2.3 5 0.08
Infective and 001-138 F 0.3 1 3.3 - Neoplasms of digestive 150-159 F 1.7 4 0.09
parasitic T 0.8 2 2.5 - organs T 4.0 9 0.020
Group II M 6.6 9 1.4 - M 4.4 4 -
Malignant 142-20s F 5.3 6 1.1 - Remainder - F 3.6 2 -
neoplasms T 11.9 15 1.3 - T 8.0 6 -
Group III M 0.3 1 3.3 -
Allergic and 240-289 F 0.4 0 - -
metabolic T 0.7 1 1.4 -
The cumulative excess mortality is still increasing in
Group IV M 0.1 0 - -
Blood disorders 290-299 F 0.1 0 - - women although the cumulative relative risk looks
T 0.2 0 - - more constant over time.
Group V M 0.0 0 - - This contrasts with the findings of the Oxford
Mental and 300-324 F 0.0 0 - - group (3) which (based on the cumulative excess
psychotic T 0.0 0 - -
mortality) suggests that the risk of dying increased
Group VI M 3.7 3 0.8 -
Nervous 330-398 F 3.3 6 1.8 - with time. However, this conclusion was based on
system T 7.0 9 1.3 - calculations of the cumulative excess mortality
Group VII M 11.7 11 0.9 - which is not an accepted statistical method for as-
Circulatory 400-468 F 6.4 4 0.6 - sessing the risk over time and has produced mis-
system T 18.1 15 0.8 -
5 1.1 -
leading results. This is best illustrated with a simple
Group VIII M 4.6
Respiratory 470-527 F 1.9 1 0.5 - example. Table 6 shows the observed and expected
system T 6.5 6 0.9 - mortality at two points in time. The differences be-
Group IX M 0.9 29 32.2 -’ tween the observed and expected numbers (the basis
Digestive 530-587 F 0.6 17 28.3 -’
for calculating the cumulative excess mortality) are
system T 1.5 46 30.7 -’
M 0.7 2 2.9 -
apparently identical, whereas the clear difference
Group X
Urinary 590-637 F 0.4 1 2.5 - between the two points is brought out using the ratio
system T 1.1 3 2.7 - (the basis for calculating the cumulative relative
Group EXVII M 2.1 0 - - risk) which demonstrates the striking difference.
Accidents, E800-E999 F 1.0 3 3.0 -
The ratio of the observed to the expected mortality
violence, T 3.1 3 1.0 -
and poisoning
can readily be used to test the significances of differ-
M 0.4 2 (5.0) - ences between the observed and expected numbers
Remainder - F 0.5 0 - - at different points in time.
T 0.9 2 (2.2) - If the cumulative relative risk (an accepted statis-
tical method) is applied to the Oxford data, then the
relative risk of dying does not increase with time as
from the time of diagnosis to their first referral to the they suggest but stays relatively constant (Table 7).
unit. Because the disease usually occurs in young A similarly misleading pattern emerges if the cu-
patients, the error in computing the expected num- mulative excess mortality is calculated for our own
bers will be small. The date at “onset of symptoms” data (Table 8).
which is commonly taken as a starting point was not The relative risk of dying in the Oxford series was
used because the error ascribed to referred patients a constant twofold risk at 5, 10, and 15 yr of follow-
would apply to all members of the series. The use of
“date first seen” was also discarded since patients
are liable to be compared at different stages of their Table 6. Hypothetical Example to Show the Calculation
disorder. At the end of 1976 the relative risk of dying of Cumulative Excess Mortality (0 - E) and
Cumulative Relative Risk (O/E)
among patients in the series was 1.96, a decrease
from 2.36 reported at the end of 1966 (4) and 2.1 at Mortality experience
the end of 1974 for patients with Crohn’s disease in- Expected
Observed
volving the colon (5). (0) (E) (0 - E) O/E P
Our analysis (based on cumulative relative risk)
25 20.0 5 1.25 -
shows that overall and in men the relative risk of
6 1.0 5 6.0 0.0006
dying falls the longer the interval from diagnosis.
312 PRIOR ET AL. GASTROENTEROLOGY Vol. 80, No. 2

Table 7. The Relative Risk of Dying-Calculated from the general population. After 15 yr of follow-up,
TrueJove and Pena there was no excess of deaths in either men or
5 Yr 10 yr 15 yr
women. These figures differ from the Oxford data
(3), where the relative risks after 5 yr of follow-up
Cumulative excess
were 1.2 for men and 2.2 for women compared with
mortality 3.5 a.4 13.0
Cumulative relative the present series of 4.6, and 3.1, respectively. It has
risk 2.03 2.68 2.55 also been suggested that the mortality in first attacks
may be higher in women (9).
The expected number of deaths in the series were
up, whereas in the present series the relative risk of
computed from the National Rates which are de-
dying fell steadily over the same period. Although
rived from the underlying causes of death as they
the figures are not explicitly quoted, de Dombal et al.
appear on death certificates. The deaths observed
(1) found a fourfold increased relative risk at 20 yrs
were therefore coded strictly to the wording on the
as compared with a 2%fold risk at the same time in
certificate according to the rules laid down in the In-
the present series.
ternational Classification of Diseases (6). Thus, dis-
The important effect of age was clearly shown in
eases of the digestive system accounted for nearly
this series. The greatest risk was in patients ~45 yr
half of the deaths, and in two-thirds of these the un-
of age at the time of diagnosis. The 11.9-fold in-
derlying cause was specified as Crohn’s disease.
creased risk in those diagnosed aged 19 yr or less, is
Among the remainder the majority could be attrib-
similar to the la-fold increase at 20 yr reported by
uted to Crohn’s disease insofar as the underlying
Weedon et al. (2). The effect of age has been denied
cause was given either as ulcerative colitis, divertic-
(3); but, if the relative risks are calculated on that
ulitis, or unspecified enterocolitis or with Crohn’s
data (3), it is clear that 5 yr after diagnosis there is a
disease appearing in part II of the certificate when
6.4-fold increased risk in patients under 40 yr of age
compared with a 1.4-fold risk in those over 40 yr of more correctly it should have been given as the un-
age. The comparable figures in the present series at 5 derlying cause. In group EXVII three deaths from
yr from diagnosis are 12.6 and 1.4. The possibility suicide are not outstanding, but they do constitute a
significant excess when set against the expected
has also been suggested (3), on the basis of crude
mortality rates, that the risks might be worse in the numbers for women. There had been a number of
unsuccessful attempted suicides among patients in
older patients.
the series, and two further suicides have been re-
There was no evidence that sex influenced the
corded since the close of the survey, which suggest
eventual prognosis. In men and women, the relative
that these deaths do represent an area of risk.
risks are greater up to 45 yr of age, while above this
Finally, in the absence of any deficit from cancers
the risks are not significantly different from those of
at other sites, the excess of deaths from cancer of
Table 8. Crohn’s Disease: Cumulative Survival and
the digestive organs support the hypothesis that
Cumulative Relative Risk of Mortality by Sex there is an etiological link between cancer and
and Year from Diagnosis Crohn’s disease.
Cumulative Cumulative
excess relative
mortality risk of
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