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American Journal of Gastroenterology ISSN 0002-9270C 2007 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2006.01000.x

Published by Blackwell Publishing

Overall and Cause-Specific Mortality in Ulcerative Colitis:Meta-analysis of Population-Based Inception

Cohort StudiesTine Jess, M.D.,1 Michael Gamborg, M.S.,2 Pia Munkholm, M.D.,1 and Thorkild I. A. Srensen, M.D.2

1Department of Medical Gastroenterology C, Herlev University Hospital, Copenhagen, Denmark; and2Danish

Epidemiology Science Center at the Institute of Preventive Medicine, Copenhagen University Hospital, Centre

for Health and Society, Copenhagen, Denmark

OBJECTIVES: It remains debated whether patients with ulcerative colitis (UC) are at greater risk of dying and

whether a possible alteration in mortality can be attributed to specific causes of death. We aimed to

clarify this issue by conducting a meta-analysis of population-based inception cohort studies on

overall and cause-specific mortality in patients with UC.

METHODS: The MEDLINE search engine and abstracts from international conferences were searched for relevant

literature by use of explicit search criteria. STATA meta-analysis software was used to calculate

pooled risk estimates (SMR, standardized mortality ratio, observed/expected deaths) of overall

mortality and specific causes of death and to conduct metaregression analyses of the influence of

specific variables on SMR.

RESULTS: Ten papers fulfilled the inclusion criteria, reporting SMRs varying from 0.7 to 1.4. The overall pooled

estimate was 1.1 (95% confidence interval [CI] 0.91.2, P = 0.42). However, greater risk of dying

was observed during the first years of follow-up, in patients with extensive colitis, and in patients

from Scandinavia. Metaregression analysis showed an increase in SMR by increasing cohort size.

UC-related mortality accounted for 17% of all deaths. Mortality from gastrointestinal diseases,

nonalcoholic liver diseases, pulmonary embolisms, and respiratory diseases was increased whereas

mortality from pulmonary cancer was reduced.

CONCLUSIONS: The overall risk of dying in patients with UC did not differ from that of the background population,

although subgroups of patients were at greater risk of dying. The cause-of-death distribution seemed

to differ from that of the background population.

(Am J Gastroenterol 2007;102:609617)

INTRODUCTION

It remains debated whether patients with ulcerative colitis

(UC) are at a greater risk of dying compared with the general

population. A number of prognostic studies are available, but

results differ markedly. Older studies tend to report a reducedoverall survival in UC patients (1, 2) whereas an improvement

in survival in patients diagnosed after year 1980 has been

observed (3).

It is also uncertain if patients with UC are at a greater

risk of dying from specific causes, in particular the disease

itself. Studies on this issue are often founded on small pa-

tient populations and even smaller numbers of deaths (35),

which makes it difficult to reveal differences in cause-specific

mortality between UC patients and the general population.

However, the greatest hindrance in determining the true

prognosis of UC is the difference in study designs repre-

sented in the available literature on the subject. Studies from

referral centers, based on selected and presumably more ill

patient populations, tend to report a worse prognosis (2)

than do population-based studies (6). However, population-

based studies also differ in design and may consequently re-

port conflicting results. Studies including both incident and

prevalent cases are not always representative for the general

UC populationif patients, for instance, move to specificareas for medical carewhereas studies based on incident

cases onlyinception cohort studiestend to give a more

valid picture of the long-term prognosis in UC. Such knowl-

edge is of great importance for proper information of pa-

tients, for access to reasonably priced health and life insur-

ance, foreducation of physicians, and foraccurate health-care

planning.

Hence, the aim of the present study was to conduct a meta-

analysisof overall and cause-specific mortality in population-

based inception cohorts of patients with UC, to describe UC-

related mortality, and to determine whether specific study or

patient population characteristics influenced mortality esti-mates.

609

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610 Jess et al.

MATERIAL AND METHODS

Literature Search

In order to identify papers in English concerning overall and

cause-specific mortality in patients with UC deriving from

well-defined population-based inception cohorts, we con-

ducted a systematic MEDLINE search from January 1965throughMarch 2006 using theMESHheadings inflammatory

bowel disease (IBD)/epidemiology and UC/epidemiology

combined with a free text search on the words: survival OR

mortality, with the following limitations: only items with ab-

stracts and studies of humans. In addition, recent abstracts

available on CD-ROM from the American Digestive Dis-

ease Weeks (20022005) and the United European Gastroen-

terology Weeks (20022005) were searched forulcerative

colitis, and lastly, reference lists of included papers were

scrutinized to disclose additional literature on the topic in a

multiphase process.

Inclusion and Exclusion Criteria

To be included in the meta-analysis, papers should be based

on population-based inception cohorts (i.e., including all pe-

diatric and adult incident cases in a given geographic area in

a given time period) of patientswith UC diagnosed according

to well-defined criteria. In addition, papers should be gener-

ally available, contain information on total number of patients

followed, exact number of deaths occurring in the cohort

during follow-up, expected number of deaths in a matched

background population, and/or rates of observed to expected

deaths with 95% confidence intervals (CI). Studies which

only contained information on cumulative survival, studies

representing subpopulations or selected populations (e.g.,

general practitioner databases, health insurance databases,

hospitalization-based patient populations, pediatric cohorts,

and referral center populations), studies reporting combined

Crohns disease (CD)UC outcome, and reviews were ex-

cluded. In case of duplicate publications, the paper providing

the longest follow-up of patients was used.

Data Collection

A total of 295 papers was identified and 10 papers were ulti-

mately included in the meta-analysis. Of these, eight papers

(3, 4, 611) met the inclusion criteria completely, whereas

two papers (5, 12) were close to fulfilling the criteria. The

latter two were an inception cohort study from Auckland,

New Zealand based on information from in- and outpatient

registries at all public hospitals, which apparently provided

almost allmedicalcare in thearea(thus beingclose to popula-

tionbased) (12), and a population-based study from Florence,

Italy assessing mortality in a regional cohort of IBD patients

aged>15 yr at diagnosis, with the majority of cases being

incident cases (N = 593) and a minor part being prevalent

cases (N = 96) (5, 13). The 10 studies are presented in Table

1. The papers from Copenhagen (6), Florence (5), Olmsted

(3), and Stockholm (7) were all extensions of former stud-

ies (1420). Six (38) of the 10 papers (60%) reported on

cause-specific mortality. In addition to the 10 included stud-

ies, a paper from Spain reported on mortality among 251 UC

patients diagnosed in Gijon during 19541997 (21). How-

ever, it was unclear if only hospitalized patients in the region

had been studied, and the standardized mortality ratio (SMR)

from this paper was therefore only used in a separate pooled

estimate of SMR and not in subanalyses.The included papers were reviewed in detail in order to

record data on number of patients studied, female to male

ratio, age distribution at diagnosis, prevalence of patients

with proctitis only at diagnosis, calendar year of publica-

tion, calendar period of inclusion and observation, duration

of follow-up, number of deaths observed during follow-up

of the cohort, expected numbers in a matched background

population, and/or observed to expected mortality rates with

95% CIs (overall and stratified for clinical characteristics),

mortality rates by cause of death (if available), and classifi-

cation of these (International Classification of Diseases [ICD]

number) (7, 8, 9, or 10).

Statistical Analysis

If SMRs (observed/expected number of deaths) or identical

estimates of survival were reported without 95% CIs, the

interval was calculated using observed and expected number

of deaths and assuming a Poisson distribution of observed

cases (Table 1).

Pooled SMRs with 95% CIs for overall mortality and

cause-specific mortality were calculated using the STATA

meta-analysis program (Stata Corporation, College Station

Texas; www.stata.com). According to the heterogeneity test

(significance at a 5% level) either afixed or a random effectsmodel was applied.

In addition, metaregression analyses were performed in

order to evaluate whether the overall SMR was influenced

by cohort size, mean or median observation time, middle

year in the inclusion and observation period, calendar year of

publication, percentage of patients being men, percentage of

patients aged

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Meta-analysis of Mortality in Ulcerative Colitis 611

Table 1. Standardized Mortality Ratios (SMRs) and Patient Population Characteristics: A Meta-analysis of Population-Based InceptionCohort Studies of Patients With Ulcerative Colitis

Calendar Mean

or Patients With Patients Aged ObservedAuthor, Period (Publication No. of Median Proctitis at

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612 Jess et al.

Figure 1. Individual and combined standardized mortality ratioswith 95% confidence intervals in ulcerative colitis: A meta-analysisof population-based inception cohort studies. The size of the boxesis proportional to the weight (1/SE) of each study.

difference was not statistically significant (2 = 1.3, NS)

(9).

Metaregression Analyses

Metaregressionanalysisrevealedthat cohort size had a signif-

icant impact on the observed risk of dying, as SMR increased

by 2.2% (95% CI 0.44.1%,P= 0.02) per additional 100 pa-

tients observed (Fig. 2). Middle year in the patient inclusion

period, middle year in the observation period, and calendar

year of publication had no significant impact on SMR. The in-

cluded studies reported similar proportions of patients being

men, patients aged

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Meta-analysis of Mortality in Ulcerative Colitis 613

Table 2. Pooled Estimates of Mortality in Patients with Ulcerative Colitis: A Meta-analysis of Population-Based Inception Cohort Studies

No. of Lowest 95% CI Highest 95% CI Pooled 95% CIStudies SMR SMR SMR

Overall survival 10 0.7 0.60.9 1.4 1.21.5 1.1 0.91.2Excluding the lowest and highest SMRs 8 0.8 0.41.4 1.4 1.21.5 1.1 0.91.2Excluding the two borderline studies (5, 12) 8 0.8 0.61.0 1.4 1.21.5 1.1 1.01.3

Nationality 9Scandinavian studies 5 1.1 0.91.2 1.4 1.21.5 1.2 1.11.4

Non-Scandinavian studies 4 0.7 0.60.9 0.9 0.81.1 0.8 0.70.9

Gender 4Female 4 0.7 0.51.1 1.4 1.01.9 1.0 0.91.2Male 4 0.8 0.61.2 1.1 0.91.3 1.0 0.91.1

Calendar year at diagnosis 2

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614 Jess et al.

Figure 2. Impact of cohort size on standardized mortality ratio (SMR) in patients with ulcerative colitis: A meta-analysis of population-basedinception cohort studies. The size of the circles is proportional to the weight (1% SE) of each study.

period on SMR both failed to show a reduction in mortality

over time.

Another explanation for the observed heterogeneity be-

tween studies may be differences in cohort compositions re-

garding gender, age, and calendar periods of inclusion. The

estimation of SMRs from calculation of expected numbers

of deaths on the basis of age- and gender-matched mortal-ity rates from the background populations in the same time

periods has the implicit assumption that the ratio between

observed and expected number of deaths is the same across

the entire joint distribution of sex, age, and time period,

which may not be true. However, the age and gender distribu-

tion seemed fairly similar in the included studies, and meta-

regression revealed no impact of calendar period of inclusion

or observation on the observed SMR.

A third explanation for the observed country-specific dif-

ference in mortality from UC may be differences in treat-

ment regimens between countries. Unfortunately, only a few

studies reported on treatment of UC and mainly in a descrip-

tive way, which did not leave us the opportunity to perform

Table 3. Ulcerative Colitis-Related Mortality: A Meta-analysis of Population-Based Inception Cohort Studies

Deaths Because ofDeaths Related Surgical/Postoperative Deaths Because of Deaths Because

Author, No. of Observed to UC Complications Colorectal Cancer of PSC No. (% of Country Patients Deaths No. (% of All) No. (% of UC Related) No. (% of UC Related) UC Related)

Jesset al., United States (3) 378 62 12 (19%) 2 (17%) 5 (42%) 1 (8%)Stewenius et al., Sweden (4) 471 103 13 (13%) 3 (23%)Wintheret al., Denmark (6) 1,160 261 33 (13%) 19 (58%) 8 (24%)Easonet al., New Zealand (12) 342 10 3 (30%) 3 (100%)Masalaet al., Italy (5) 689 81 9 (11%) 2 (22%) 4 (44%)

direct comparison of data or perform additional metaregres-

sion analyses. Typically, patients had received maintenance

therapy with 5-aminosalicylates, corticosteroids in case of

disease flare, and had undergone proctocolecomy in lack

of response to medical treatment (3, 6, 12). Surgery rates

were either reported as crude rates (9, 12) or as cumula-

tive probabilities (3, 12) and it was not always clear whetherthey included all kinds of surgery or total colectomy only.

Comparable data were available to show that the cumula-

tive probability of proctocolectomy after 15 yr was higher

among Danish (30%) (24) than American (19%) (25) pa-

tients with UC. Although surgery could be expected to reduce

mortality by curing UC and removing the target for CRC, it is

more likely that surgery increases mortality because of post-

operative complicationswhich explained 44% of UC-

related deaths in the present study. Accordingly, an excess

mortality was observed in newly diagnosed patients and in

patients with extensive disease, in whom surgery rates are

known to be high (24). Probert et al., on the other hand, failed

to show a significant difference in mortality among patients

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Meta-analysis of Mortality in Ulcerative Colitis 615

Table 4. Cause-Specific Mortality in Patients with Ulcerative Colitis: A Meta-analysis of Population-Based Inception Cohort Studies

Causes of Deaths No. of Studies Lowest SMR 95% CI Highest SMR 95% CI Pooled SMR 95% CI

Cancer 5 0.7 0.50.9 1.5 1.21.8 1.0 0.71.3Colorectal cancer 4 0.9 0.41.8 4.4 3.25.9 1.9 1.03.8Pulmonary cancer 2 0.3 0.11.0 0.4 0.11.3 0.3 0.10.9

Leukemia 1 2.9 0.410.3 2.9 0.410.3

Non-Hodgkins lymphoma 1 2.4 0.38.7 2.4 0.38.7Cardiovascular diseases 5 0.6 0.40.9 1.1 0.91.4 0.9 0.71.1

Ischemic heart disease 2 0.9 0.81.1 1.0 0.81.3 0.9 0.81.1Pulmonary embolism 1 4.0 1.58.7 4.0 1.58.7

Respiratory diseases 5 0.9 0.32.0 2.0 1.13.5 1.6 1.32.0

COPD 4 0.6 0.12.3 3.4 1.75.9 1.6 0.73.7Pneumonia 2 1.3 0.33.7 3.4 2.15.0 3.1 2.04.6

Gastrointestinal and liver diseases 4 1.6 0.82.8 4.0 1.97.3 2.5 1.93.2

All exclusive ulcerative colitis 3 0.5 0.21.1 2.8 1.74.4 1.7 0.83.6Non-alcoholic liver diseases 3 0.9 0.14.9 4.8 2.19.5 4.0 2.56.5

Genitourinary tract diseases 4 1.0 0.42.3 1.6 0.44.1 1.2 0.72.2Suicide 4 0.8 0.31.8 2.1 1.03.9 1.3 0.82.0Accidents/injuries 5 0.5 0.21.2 0.8 0.31.9 0.7 0.51.0

95% confidence interval excluding 1.0 (P< 0.05). COPD = chronic obstructive pulmonary disease (bronchitis, emphysema, and asthma).

who had undergone surgery versus those who had not, but

CIs were fairly broad (9).

Medical treatment may also be expected to affect survival,

especially the increasing usage of immunosuppressive drugs,

which may either reduce mortality by controlling the intesti-

nal inflammation or increase mortality by causing severe ad-

verse events, such as opportunistic infections and lymphoma

(26). American patients who had never received immuno-

suppressive drugs were found to have a significantly reduced

mortality (3), probably because this subgroup of patients had

less severe disease and still had been followed closely by

physicians.

A fourth theoretical explanation for the observed hetero-

geneity between studies is that SMRs from different geo-

graphic areas may not be directly comparable. SMRs (i.e.,

observations in the clinical material divided by observations

in the background population) are calculated under the as-

sumption that characteristics of the latter are reflected in the

patient material. However, one could hypothesize that the ab-

solute mortality rate among patients with UC was the same

in different regions, whereas SMRs differed because of dif-

ferent background mortality rates, i.e., if the prevalence of

smokers (smoking being a determinant for death) differed

between regions but was fairly identical among UC patients,this would consequently result in the observed heterogeneity

in SMRs. Likewise, if all UC patients were followed closely

by physicians and received early treatment for other disor-

ders, such as cardiovascular disease, whereas the frequency

of physician visits and early detection and treatment varied

in the background population according to geography, then

SMRs might differ despite similar absolute mortality rates

among patients with UC.

Metaregression analysis revealed an increase in mortality

by increasing cohort size, contradicting the more expected

finding of greater mortality in smaller and potentially more

selected cohorts. However, if the above mentioned factors

(differences in cohort age, cohort compositions, and/or treat-

ment policies) explained the higher mortality observed in

Scandinavian studies, then the metaregression result could

also be secondary to the fact that the Scandinavian studies

were based on the largest cohorts. On the basis of available

data, we were not able to determine whether cohort size,

geography, and/or treatment regimens influenced SMR inde-

pendently. However, the fair homogeneity in cohort charac-

teristics, such as gender, age, and disease extent, somehow

decreased the likelihood that SMR was influenced by cohort

size (with the inborn risk of selection bias) or by geography

(expecting variations in environmental or genetic factors to

influence phenotypes). The most likely explanation remains

that patients have been treated differentlydespite similar

descriptions of treatment policies.

Concerning cause-specific mortality, pooled estimates re-

vealed a greater risk of dying from gastrointestinal causes

including the disease itself and from nonalcoholic liver dis-

eases and a borderline-significant risk of death from CRC.

This was in accordance with ourfinding of a 17% UC-related

mortality, covering death from severe disease, surgical inter-

ventions because of severe disease, end-stage liver disease

because of primary sclerosing cholangitis, and CRC. It is,

however, questionable whether it is correct to categorizedeathfrom CRC as an UC-related complication if the overall

risk of this malignancy is not increased in population-based

settings of UC patients (25, 27). Furthermore, the varying

results on CRC mortality may be a result of population-

based differences in access to colonoscopy or other puta-

tive cancer preventive factors on which information was not

available.

We also observed a greater risk of dying from pulmonary

embolisms and respiratory diseases. UC patients are known

to be at a greater risk of thromboembolic events such as deep

vein thrombosis and pulmonary embolism (28). The excess

mortality from respiratory diseases was mainly a result of

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616 Jess et al.

pneumoniaan expected complication in both chronically

ill patients and postoperative patients. However, we also ob-

served a slightly greater mortality from COPD, which stands

in contrast both to the reduced mortality from pulmonary

cancer observed in the present study and to the fact that UC

patients often are nonsmokers. Furthermore, the difference

in smoking habits between UC patients and the backgroundpopulation may per se confound the reported SMRs, as dis-

cussed above. Because the primary papers did not adjust for

smoking habits, we could not determine whether UC diagno-

sis was independently associated with a greater risk of death

from pulmonary embolisms and respiratory diseases.

It would have been of clinical interest to clarify whether

UC patients are at greater risk of dying from lymphoma, but

only a single risk estimate was available and CIs were too

wide to draw any reliable conclusions.

Considering the nonincreased overall mortality among UC

patients, one would intuitively expect the above mentioned

findings to be counterbalanced by a reduced mortality fromother causes. As mentioned before, it is likely that patients

followed closely by physicians carry a reduced risk of death

from certain causes because of early detection and treat-

ment. The reduced risk of death from pulmonary cancer may

have counterweighted the risk of death from CRC, but not

the greater risk of dying from nonmalignant causes, as the

overall risk of death from cancer was close to unity. Some

studies have suggested that UC patients are at reduced risk

of dying from cardiovascular diseases (2, 3, 5) because of

the low prevalence of cigarette smokers among UC patients

and the low blood pressure in patients with extensive disease

second to sodium and water depletion (29). In our pooledanalysis we failed to confirm this association. Another possi-

ble explanation for themissingreduced mortality could be

the use of varying ICD codes in the included studies, which

limited our analysis to main categories of diseases, and the

fact that most studies used incomparable categories, such as

other causesorremaining causes,which may have hid-

den interesting information.

In conclusion, the present meta-analysis of population-

based inception cohort studies revealed an overall nonin-

creased mortality in patients with UC, although a subgroup

of patients with newly diagnosed and extensive disease car-

ried a greater risk of dying from the disease itself and from

surgical complications to the disease. This excess mortality

seemed to be counterbalanced by a reduced mortality from

pulmonary cancer, possibly from cardiovascular diseases, or

from other yet unidentified causes.

STUDY HIGHLIGHTS

What Is Current Knowledge

Long-term prognosis in ulcerative colitis remains de-

bated. Results are often based on selected patient populations.

What Is New Here

Overall mortality is not increased among patients with

ulcerative colitis derived from population-based incep-

tion cohorts. Subgroups of patients with newly diagnosed and ex-

tensive disease are at a greater risk of dying. The cause-of-death distribution differs significantly

from that of the background population.

Reprint requests and correspondence: Tine Jess, M.D., Depart-ment of Medical Gastroenterology C, Herlev Hospital, Universityof Copenhagen, 75 Herlev Ringvej, DK-2730 Herlev, Denmark.

Received July 28, 2006; accepted September 18, 2006.

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CONFLICT OF INTEREST

The authors declare no potential conflicts of interest.