Concurrent Conditions in Patients with Chronic
Constipation: A Population–Based Study
Gaurav Arora1, Ajitha Mannalithara2, Alka Mithal3, George Triadafilopoulos2, Gurkirpal Singh2,3*
1Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 2Division of Gastroenterology and
Hepatology, Stanford University School of Medicine, Stanford, California, United States of America, 3Division of Epidemiology, Institute of Clinical Outcomes Research and
Education, Palo Alto, California, United States of America
Background: Chronic constipation (CC) is a common condition but its concurrent conditions are not well characterized. We
measured the prevalence and risk of developing 15 pre–specified concurrent conditions in patients with CC.
Methods: Retrospective cohort study using the Medicaid database of California, utilizing ICD-9 codes for detection of cases
(CC), controls (patients with GERD) and concurrent conditions. Study period was 01/01/1995 to 06/30/2005. Index date was
the date 3 months before the first physician visit for CC. Pre-index time (12 months) was compared to post-index time (12
months) to assess the association of every concurrent condition within each cohort. To account for ascertainment bias, an
adjusted odds ratio was calculated by comparing the odds ratio for every concurrent condition in the CC cohort to that in
the GERD cohort.
Results: 147,595 patients with CC (mean age 54.2 years; 69.7% women; 36.2% white) and 142,086 patients with GERD (mean
age 56.3 years; 65.3% women; 41.6% white) were evaluated. The most prevalent concurrent conditions with CC were
hemorrhoids (7.6%), diverticular disease (5.9%), ano–rectal hemorrhage (4.7%), irritable bowel syndrome (3.5%) and fecal
impaction (2%). When adjusted for ascertainment bias, the most notable associations with CC were Hirschsprung’s disease,
fecal impaction and ano-rectal conditions such as fissure, fistula, hemorrhage and ulcers.
Conclusion: Chronic constipation is associated with several concurrent conditions of variable risk and prevalence. To reduce
the overall burden of CC, these concurrent conditions need to be addressed.
Citation: Arora G, Mannalithara A, Mithal A, Triadafilopoulos G, Singh G (2012) Concurrent Conditions in Patients with Chronic Constipation: A Population–Based
Study. PLoS ONE 7(10): e42910. doi:10.1371/journal.pone.0042910
Editor: Jan-Hendrik Niess, Ulm University, Germany
Received February 18, 2011; Accepted July 15, 2012; Published October 12, 2012
Copyright: ? 2012 Arora et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was funded in part by a research grant from Takeda Pharmaceuticals America, Deerfield, Illinois. The funders had no role in data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: This research was supported in part by a research grant from Takeda Pharmaceuticals America, Deerfield, Illinois. The authors have
delared no other competing interests exist. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
Constipation is one of the most common digestive problems in
North America, with an estimated prevalence between 2% and
27%.  For many patients, constipation-associated symptoms are
chronic and last for several weeks to several years.  The cost of
evaluating and treating constipation is significant. Each year in the
United States alone, approximately 2.5 million people consult a
physician for constipation , and approximately 92,000 are
hospitalized.  Based on an analysis of 3 national surveys in
2001, the annual costs associated with medical care for constipa-
tion total $235 million.  In a previous study, we evaluated total
costs of care of constipation in the California Medicaid program
(Medi–Cal).  Patients with constipation often experience co-
morbid conditions. In our previous study, the most common co-
morbidity (amongst the 105,130 patients who saw a physician at
least once for constipation) was hemorrhoids, which occurred in
5,657 (5.4%) patients within 1 year of the first visit for
constipation. This was followed in frequency by irritable bowel
syndrome (3,597 [3.42%] patients) and fecal impaction or
intestinal obstruction (2,288 [2.2%] patients). These additional
illnesses can further increase the cost of caring for this patient
population. We could not establish a relationship between
constipation and any of these concurrent conditions, as our study
was not designed for that purpose; it is possible that the association
between constipation and its concurrent conditions could simply
reflect a ‘‘detection’’ or ‘‘ascertainment’’ bias. A concurrent
condition could have been identified simply because a patient was
examined by a physician, even if that condition was not related to
the reason for physician visit. With that in mind, we designed the
present study with a control group and compared the ‘‘before-
after’’ risk for every concurrent condition in the constipation
group, to that in the control group.
We used the research database of Medi-Cal, the Medicaid
program for the state of California.  Medi–Cal provides health
care coverage for low-income and disabled individuals who lack
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health insurance; it covers more than 7 million persons and is the
largest state Medicaid program in the United States. Its claims and
administrative database are a key source of information for a
variety of research efforts related to health care costs, resource
utilization, quality, and effectiveness. The Medi–Cal Research
Database has information on an estimated 100 million patient-
years from 1995–2005 and allows linkage of records to medical
and pharmacy claims. Medical claims or encounter records flow
into the database from all health care sites (inpatient hospital,
outpatient hospital, emergency room, physician’s office, outpatient
surgery center, etc.) for virtually all types of services provided to
enrolees, including specialty, preventive and office-based treat-
ments. Each facility service record contains information on
diagnoses, recorded with the International Classification of
Diseases, Ninth Revision (ICD-9) diagnosis codes, and procedures
recorded with ICD-9 procedure codes, Current Procedural
Terminology (CPT) or Health Care Financing Agency (HCFA)
Common Procedure Coding System (HCPCS) codes. The data in
these databases undergo regular audits to ensure quality control. A
recently published audit of Medi-Cal claims found that 96.4%
were medically necessary, billed appropriately, and were in
concordance with the data in the claims files. 
Study Design, Period and Outcomes
A retrospective cohort design was used. This study covered the
time period from January 1st, 1995 to June 30th, 2005. Each
person’s observation period began on the day he or she joined
Medi–Cal or January 1st, 1995, whichever occurred later.
Observation continued until the earliest of the termination of
Medi–Cal eligibility or June 30th, 2005. The primary objective of
this study was to measure the prevalence of and ascertain the risk
of developing 15 pre-specified concurrent conditions (Table 1) in
patients with chronic constipation. The conditions were chosen
based on a review of the existing literature and also on the basis of
experience of one of the investigators (G.T.) in treating patients
with CC. We did not factor in our analysis any treatments that
might have been given for the treatment of CC.
The study cohort included subjects $18 years of age with a
diagnosis of chronic constipation (defined by an ICD–9 code of
564.06). Index date was defined as the date 3 months before the
first physician visit for chronic constipation. The subjects were
required to have at least 12 months enrollment in Medi–Cal prior
to the index date and at least 12 months subsequent. The ‘‘pre–
index’’ time was 12 months before and ‘‘post–index’’ time was 12
months after the index date. It was assumed that a patient may
have had constipation for a period of 3 months before seeking
The control cohort was comprised of individuals diagnosed with
an unrelated illness–gastro-esophageal reflux disease (GERD).
Using the Montreal definition for GERD, constipation is not an
associated condition (like laryngitis, chronic cough, etc).  There
may be some overlap but it is not pathophysiologically related. We
chose GERD because of its chronicity, similar to constipation.
They had to be $18 years of age with a diagnosis of GERD (ICD-
9 codes 787.1, 530.1, 530.2 or 530.3) made at the first physician
visit. The enrollment criteria were the same as the study cohort.
The ‘‘pre–index’’ and ‘‘post–index’’ time periods were also defined
in the same fashion as for the study cohort. Similarly, it was
assumed that a patient could have had GERD for a period of 3
months before seeking medical attention.
Rationale for selection of GERD as the reference group
The necessity of a control group has already been discussed. A
control group is needed to document whether an increased odds
ratio of ‘‘post–index’’ vs. ‘‘pre–index’’ time periods for a particular
concurrent condition is simply a result of an increased chance of
detection because of a physician visit. An appropriate control
group would have similar clinical care patterns as the study group
so that this detection bias can be controlled. There are several
similarities in the medical management of GERD and constipa-
tion. Patients with both conditions are often symptomatic for
several months before seeking medical attention. Both conditions
are related to the gastrointestinal tract, but are often managed by
primary care physicians before being referred to a gastroenterol-
The association of every concurrent condition with constipation
(or GERD) was assessed by calculating an odds ratio from the
probability of occurrence of the condition after the diagnosis of
constipation (or GERD) compared to the probability of occur-
rence of the concurrent condition in the study period before the
diagnosis of constipation (or GERD). Three separate pre-specified
statistical analyses were performed for each condition: comparison
of ‘‘post–index’’ proportion to ‘‘pre–index’’ proportion as an odds
ratio in the GERD cohort; comparison of ‘‘post–index’’ propor-
tion to ‘‘pre–index’’ proportion as an odds ratio in the constipation
cohort; and comparison of the odds ratios of ‘‘post–index vs. pre–
index constipation’’ to ‘‘post–index vs. pre–index GERD’’ as
another odds ratio, termed ‘‘adjusted–odds ratio’’; this last
comparison was done to control for the effect of detection bias.
To compare the odds ratios in order to derive the ‘‘adjusted–odds
ratio’’ and calculate its confidence interval, we used a method
recently described by Friedrich et al.  For all odds ratios, 95%
confidence intervals are reported. All analyses were done using
SAS 9.1 (Cary, North Carolina, USA).
Table 1. List of primary study outcomes.
Concurrent Condition of ConstipationICD-9 Codes
Fecal incontinence 787.6
Irritable bowel syndrome564.1
Malignant neoplasm of colon153.0–153.9, V1006
Rectal prolapse 569.1
Ulcerative colitis 556.0–556.6, 556.8,556.9
Concurrent Conditions in Chronic Constipation
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A total of 147,595 patients with constipation (mean age 54.2
years; 69.7% women; 36.2% white) and 142,086 patients with
GERD (mean age 56.3 years; 65.3% women; 41.6% white)
formed the study and control cohorts, respectively (Table 2).
Results are presented as ‘‘pre–index’’ and ‘‘post–index’’ (counts
and percentages) as well as odds ratios (comparing ‘‘pre–index’’
and ‘‘post–index’’ time–periods) for the association of every
concurrent condition with GERD and constipation (Table 3). The
adjusted–ratio is the association of every concurrent condition with
constipation when adjusted for the association with GERD.
Overall, there were significant differences in the odds ratios of
most concurrent conditions between the GERD and constipation
The most prevalent concurrent conditions associated with
constipation (during ‘‘post–index’’ time period) were hemorrhoids
(7.6%), diverticular disease (5.9%), ano–rectal hemorrhage (4.7%),
irritable bowel syndrome (3.5%) and fecal impaction (2%). The
remaining concurrent conditions had less than 1% prevalence.
Colon cancer was present in 0.9% of the patients. When adjusted
for detection bias as described in the methods section, the strongest
association (4.4–fold) with constipation was seen for Hirsch-
sprung’s disease, followed by fecal impaction (OR 3.2). Other
notable associations include anal conditions such as fissure (OR
2.5) and fistula (OR 1.7), as well as ano–rectal hemorrhage (OR
1.4) and ulcers (OR 2.1). Other concurrent conditions found to be
significantly associated with constipation included hemorrhoids
(OR 1.2), irritable bowel syndrome (OR 1.1), rectal prolapse (OR
1.6) and volvulus (OR 1.4). The odds of colon cancer rose by 16%
in patients after the onset of constipation. Ulcerative colitis (OR
0.9) was less likely to be associated with constipation. No
statistically significant association with constipation was seen for
Crohn’s disease, diverticular disease and fecal incontinence.
Our results suggest that chronic constipation is associated with
several concurrent conditions of variable risk and prevalence and
serve to eliminate the paucity of current literature on this topic, as
highlighted by Talley et al. . While a causal relationship may
already exist for some of these concurrent conditions, for others,
such association may provide the impetus for further research.
We note that generally the ORs were higher in the constipation
cohort compared to those in the GERD cohort, although several
ORs were significant in the latter as well and this may relate to
increased screening and recognition prompted by the medical care
received for the index condition (constipation or GERD). We
found that hemorrhoids were the most prevalent concurrent
condition in patients who were diagnosed with constipation and
this prevalence increased by about 5% after the latter were
diagnosed. Delco and Sonnenberg, in their retrospective case-
control study of 96,314 veterans found that constipation was a
significant co-morbidity of hemorrhoids (OR 1.48 [95% CI 1.43–
1.54]) ; their results are very similar to ours (OR 1.24 [95% CI
1.20–1.30]). Brook et al., in a study of 1,215 subjects with
constipation and 29,160 propensity score-matched controls,
reported the prevalence of hemorrhoids to be 15.2% in the
constipation group as compared to 1.5% in the control group (OR
11.8, p,0.001).  Our study’s duration was 1 year, starting 3
months before the diagnosis of constipation and in a study design
very similar to ours, Mitra et al., compared 48,585 subjects with
97,170 controls  and found the odds ratio of the association
between hemorrhoids and constipation to be 4.2; this much
stronger association compared to our results is likely secondary to
detection bias in their study.
Ano–rectal complications such as fissures, fistulas or ulcers were
rare (prevalence less than 1% each) in patients with constipation
but were significantly associated with it. Brook et al., reported 5.8%
prevalence of ‘ano–rectal conditions’ ; this likely includes a
combined prevalence of the ano–rectal concurrent conditions that
we reported separately and thus probably reflects similar
prevalence. Mitra reported significant association of constipation
and anal fissures (OR 5.0) and rectal ulcers (OR 4.8) without
specifying their prevalence.  Ano–rectal hemorrhage had a
relatively high prevalence in both the constipation as well as the
control groups in our study, likely reflecting the similarly high
prevalence of hemorrhoids and/or diverticular disease in general.
Even then, the risk of ano–rectal hemorrhage was 36% higher in
patients with constipation.
Diverticular disease has been proposed to be secondary to small
stool volume, longer transit time as well as abnormal colonic
motility and thus has been felt to be associated with constipation.
[15,16] Indeed, in our previous study , we reported -in the
same group of patients as the current study- an odds ratio of 2.8
for this association. However, in the current study, when we
accounted for possible detection bias, this association was rendered
non–significant (OR 1.04 [95% CI 1.00–1.08]). Chronic consti-
pation may be related to rectal neurological dysfunction  and
lead to fecal impaction. Mitra demonstrated a 6.6–fold increased
odds of fecal impaction in constipated patients,  which is
similar to what we found (OR 5.6); however, the adjusted odds
ratio was less, 3.2, and still significantly high. Hirschsprung’s
disease is a known cause of chronic constipation in adults; [19,20]
such cases are believed to be either less severe or zonal forms of
colonic aganglionosis. In our study, even though it was very rare in
patients with constipation (0.04%), it was the concurrent condition
with the strongest association (OR 4.4 [95% CI 2.5–7.9]).
A small study involving 55 elderly patients with fecal impaction
revealed impaired ano–rectal sensation in the subjects as
compared to controls, preventing conscious contraction of the
external anal sphincter when the internal sphincter was relaxed,
thereby causing fecal incontinence.  This was subsequently
confirmed in a much larger study of 16,331 nursing home
residents with fecal incontinence and it was shown that chronic
Table 2. Demographic characteristics of the control and
No. of subjects142,086 147,595
Age (mean [SD])56.3 (17.6)54.2 (20.2)
Gender (n [%])
Women92844 (65.3) 102940 (69.7)
Men 49242 (34.7)44655 (30.3)
Race/Ethnicity (n [%])
Caucasian59147 (41.6) 53483 (36.2)
Black14171 (10.0) 15826 (10.7)
Hispanic 28057 (19.7)36835 (25.0)
Asian20474 (14.4) 21544 (14.6)
Other 5408 (3.8)5790 (3.9)
Missing 14829 (10.4)14117 (9.6)
Concurrent Conditions in Chronic Constipation
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Table 3. Association of concurrent conditions with GERD and chronic constipation and the adjusted–ratio.
Pre–index n (%)
Post–index n (%) Odds Ratio (95% CI)
Pre–index n (%)
Post–index n (%) Odds Ratio (95% CI)
Adjusted-ratio* (95% CI)
Irritable bowel syndrome
Malignant neoplasm of colon
Legend for Table 3:
*denotes OR of constipation and concurrent condition adjusted for detection bias by dividing by the OR of concurrent condition and GERD (control group) using the method described by Friedrich. 
Concurrent Conditions in Chronic Constipation
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constipation increased the odds of fecal incontinence by 30–40% Download full-text
(2–year cross-sectional survey).  However, both of these studies
were done in selected populations, with resulting strong possibility
of selection bias. A population–based study using the Rome ll
criteria for diagnosis and involving an age–stratified random
sample of 507 women in Olmstead county concluded that
constipation did not increase the odds of fecal incontinence (OR
1.1 [95% CI 0.8–1.5]).  The result from our population–based
study concurs with that of this last study (OR 1.16 [95% CI 0.99–
1.35]). It also follows from our results that, since constipation is
associated with increased odds of fecal impaction but not fecal
incontinence, constipation is not a confounder of the association
between fecal impaction and incontinence. We found increased
odds (63% higher) of rectal prolapse in patients with chronic
constipation, consistent with prior studies  and likely resulting
from long–term straining..  Volvulus, similarly, was signifi-
cantly associated with constipation in our study (36% higher odds),
although not to the extent reported by Mitra (OR 10.3). 
Constipation has been linked with colon cancer in previous
studies. A case–control study of 424 incident cases from Seattle
found that constipation present for 10 years before the index date
(2 years before diagnosis of colon cancer) resulted in an adjusted
relative risk of 2.0 (95% CI 1.2–3.6) for colon cancer; the risk
associated with the use of commercial laxatives was nullified after
adjustment for constipation.  In a population–based case–
control study of 643 cases from North Carolina, the adjusted odds
ratio of colon cancer and constipation was 2.36 (95% CI 1.41–
3.93).  The Miyagi cohort study of 41,670 individuals from
Japan noted the multivariate relative risk of colon cancer in those
with constipation to be 1.35 (95% CI 0.99–1.84).  These
studies support our finding that the odds of colon cancer in
constipated patients were higher than those without (OR 1.16
[95% CI 1.05–1.30]).
There are several strengths of our study. It involves a very large
sample size, is population–based and, importantly, controls for
detection bias (described in Methods section). In addition, usage of
the Medi–Cal population for conducting this study has several
advantages of its own: the drop-out rate (loss of eligibility) is
significantly less than private payer plans; patients do not drop-out
when they qualify for Medicare (since Medi–Cal pays for
Medicare deductibles); there is a high representation of minority
populations; and records from Medicare are obtained on all
patients who have dual-eligibility and merged within the Medi–
Cal datasets. Several limitations also apply to our study and its
results. Given a different study population and design, our results
may not be comparable to those reported in previous studies. We
cannot establish causality based only on the strength of the
associations that we observed. As is true for research conducted
using an administrative database, the identification of cases and
controls as well as the associated concurrent conditions are
dependent on the accuracy of the claims submitted for them.
However, this may not be a significant problem in our study as an
audit of Medi-Cal claims found that 96.4% were medically
necessary, billed appropriately and were in concordance with the
data in the claims files.  Furthermore, as our study sample was
derived from a Medicaid population, it represents data from
people who are typically sicker and less affluent, thus potentially
limiting the generalizability of our findings to the Medicaid
population only. It is possible that diet, lifestyle-changes or
treatment for CC might affect the association of the comorbidities
with CC. Finally, we cannot rule out the possibility of detection
bias persisting in our study; however, this is unlikely to affect the
adjusted odds–ratio, thus our results are likely to remain valid.
In summary, we have reported the prevalence and strength of
association of various concurrent conditions of constipation. Our
findings would hopefully help direct future research in patients
with chronic constipation and eventually improve patient care.
Conceived and designed the experiments: GA A. Mannalithara A. Mithal
GT GS. Performed the experiments: GA A. Mannalithara A. Mithal GT
GS. Analyzed the data: GA A. Mannalithara GT GS. Contributed
reagents/materials/analysis tools: GA A. Mannalithara A. Mithal GT GS.
Wrote the paper: GA A. Mannalithara A. Mithal GT GS.
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