Abstract
Objective
To examine the association between sleep pattern, which integrates sleep duration, chronotype and quality, with risk of bowel resection and all-cause mortality in patients with inflammatory bowel disease (IBD) based on a long-term prospective cohort.
Design
Prevalent patients with IBD were categorised into poor (0–2 score), intermediate (3 score) and healthy (4–5 score) based on sleep score. The score assigned 1 point for each of five low-risk sleep behaviours: sleep 7–8 hours per day, early chronotype, no snoring, never/rarely insomnia symptoms and no frequent daytime sleepiness. The primary outcome was all-cause death, with bowel resection as a secondary outcome. Multivariable Cox proportional hazards models were used to explore the association.
Setting
This study used the data from the UK Biobank with participants recruited in 2006–2010.
Participants
Among 502 411 participants recruited in UK biobank, 4262 cancer-free patients with IBD at baseline were finally included.
Results
During a median of 14.6-year follow-up, 793 received bowel resection and 498 deaths developed. Compared with poor sleep pattern, both healthy (HR=0.75, 95% CI 0.59 to 0.94) and intermediate (HR=0.77, 95% CI 0.66 to 0.95) sleep groups had reduced mortality risk, with a dose-response relationship across sleep scores (HR=0.89, 95% CI 0.82 to 0.98). Specifically, appropriate sleep duration (HR=0.79, 95% CI 0.66 to 0.95) and early chronotype (HR=0.82, 95% CI 0.68 to 0.98) were associated with 21% and 18% lower mortality risk, respectively. Marginally significant lower risk of bowel resection was observed with healthy (HR=0.86, 95% CI 0.72 to 1.04) and intermediate (HR=0.87, 95% CI 0.73 to 1.03) sleep pattern, with 22% lower risk associated with never/rarely insomnia symptoms (HR=0.78, 95% CI 0.65 to 0.94).
Conclusions
A healthy sleep pattern, particularly sleep duration and early chronotype, is associated with reduced all-cause mortality risk in patients with IBD, with probably beneficial effect on lowering risk of bowel resection, highlighting the importance of maintaining healthy sleep behaviours for long-term prognosis in IBD.
Keywords: Epidemiology, Healthy Lifestyle, Health Promotion, Clinical Medicine
WHAT IS ALREADY KNOWN ON THIS TOPIC
Considering growing prevalence of sleep disorders and potential link with systemic inflammation, previous epidemiology studies showed that patients with inflammatory bowel disease (IBD) may be more vulnerable to sleep disorders and worse outcome.
WHAT THIS STUDY ADDS
Based on the nearly 15 years’ follow-up, patients with IBD with healthy sleep patterns had a 25% reduced risk of all-cause mortality versus poor sleep patterns, with a dose-response relationship across sleep scores; as well as a potential lower risk of future bowel resection, with a 22% risk reduction associated with never/rarely insomnia symptoms.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The findings demonstrate the importance of early identification and intervention in sleep disorders among patients with IBD for the better management and long-term prognosis of patients with IBD.
Introduction
Sleep is important for physical, psychological and behavioural health. However, approximately 20% of adults are impacted by health issues associated with substandard sleep quality or insufficient sleep durations,1 2 and 30%–40% of the general population experiences insomnia, while millions of these individuals go undiagnosed and untreated.3 Sleep disorders have been linked to impaired physiological functions, chronic metabolic diseases, the development of cardiovascular disease (CVD) and cancers,4 5 and even to all-cause mortality.5 6 Insomnia, difficulty in falling/maintaining sleep and early awakening are associated with all-cause mortality, which is probably by increasing the incidence of cardiovascular events.5 In addition, sleep regularity may be a simple, effective target for improving general health and survival.6
Compared with the general population, patients with inflammatory bowel disease (IBD), a common systemic inflammatory disease including ulcerative colitis (UC) and Crohn’s disease (CD), may be more vulnerable to sleep disorders and worse outcomes.7,13 The relationship between sleep disturbance and inflammation seems bidirectional. Disturbances of sleep, such as insomnia complaints and extremes of sleep duration, adversely influence risk of inflammatory disease and contribute to all-cause mortality.14 Short sleep duration aggravates inflammatory burden which is featured by increased levels of C reactive protein (CRP) and inflammatory cytokines.15 16 Sleep disorder exerts a negative impact on patients with IBD, such as increasing the risk of relapse,11 decreasing quality of life12 and fatigue.9 17 Short sleep duration could also destroy immunity, which might cause cancer in the long term or severe infections in patients with IBD, contributing to the risk of bowel resection and death.
However, cohort studies examining the effect of sleep pattern integrating sleep duration, sleep chronotype, sleep apnea and sleep quality (including insomnia and daytime sleepiness) on risk of bowel resection and all-cause mortality in patients with IBD are lacking. Therefore, we prospectively assessed the associations between sleep patterns, evaluated by a healthy sleep score,18 and the risk of bowel resection and all-cause mortality in patients with IBD based on a long-term prospective cohort.
Methods
Study population
This study used the data from the UK Biobank, a large-scale prospective study with more than 502 411 participants recruited in 2006–2010.19 All participants signed informed consent, completed baseline questionnaires and underwent physical assessment. We enrolled 5806 prevalent patients with IBD identified by using the International Classification of Disease-10 codes (K51 for UC and K50 for CD) at recruitment. Participants who were diagnosed as both UC and CD were defined as IBD unclassified (IBD-U). Finally, a total of 4262 prevalent patients with IBD were included, with 2702 UC, 1209 CD and 351 IBD-U (figure 1, table 1).
Figure 1. Flow chart of the study population. Note: Participants were categorised into poor (0–2 score), intermediate (3 score), healthy (4–5 score) sleep patterns according to the sleep score by assigning 1 point for each low-risk sleep behaviour (including sleep 7–8 hours per day, early chronotype (‘morning’ or ‘morning than evening’), no snoring, never or rarely insomnia symptoms, and no frequent daytime sleepiness (‘sometimes’ or ‘never/rarely’). IBD, inflammatory bowel disease; UKB, UK Biobank.
Table 1. Baseline characteristics according to sleep pattern in patients with IBD.
| Characteristics | Total (N=4262) | Sleep pattern | P value | ||
|---|---|---|---|---|---|
| Poor (N=1120) | Intermediate (N=1659) | Healthy (N=1483) | |||
| Age (years)* | 56.9 (8.0) | 57.3 (7.6) | 57.1 (8.0) | 56.6 (8.2) | 0.052 |
| Sex | <0.001 | ||||
| Male | 2056 (48.2) | 582 (52.0) | 824 (49.7) | 650 (43.8) | |
| Female | 2206 (51.8) | 538 (48.0) | 835 (50.3) | 833 (56.2) | |
| Ethnicity | 0.010 | ||||
| Non-White | 150 (3.5) | 37 (3.3) | 77 (4.6) | 36 (2.4) | |
| White | 4104 (96.3) | 1080 (96.4) | 1578 (95.1) | 1446 (97.5) | |
| Unknown | 8 (0.2) | 3 (0.3) | 4 (0.2) | 1 (0.1) | |
| Education level | <0.001 | ||||
| Non-university | 2979 (69.9) | 830 (74.1) | 1164 (70.2) | 985 (66.4) | |
| University | 1227 (28.8) | 273 (24.4) | 474 (28.6) | 480 (32.4) | |
| Unknown | 56 (1.3) | 17 (1.5) | 21 (1.3) | 18 (1.2) | |
| Townsend deprivation index | |||||
| Mean (SD) | −1.4 (3.0) | −1.0 (3.2) | −1.3 (3.0) | −1.6 (2.9) | <0.001 |
| Q1 (≤−3.65) | 1065 (25.0) | 267 (23.8) | 399 (24.1) | 399 (26.9) | 0.001 |
| Q2 (−3.65 to −2.16) | 1064 (25.0) | 252 (22.5) | 418 (25.2) | 394 (26.6) | |
| Q3 (−2.16 to 0.50) | 1064 (25.0) | 268 (23.9) | 426 (25.7) | 370 (24.9) | |
| Q4 (>0.50) | 1065 (25.0) | 333 (29.7) | 414 (25.0) | 318 (21.4) | |
| Unknown | 4 (0.1) | 0 (0.0) | 2 (0.1) | 2 (0.1) | |
| Smoking status | <0.001 | ||||
| Never | 2001 (46.9) | 453 (40.4) | 752 (45.3) | 796 (53.7) | |
| Previous | 1834 (43.0) | 520 (46.4) | 726 (43.8) | 588 (39.6) | |
| Current | 418 (9.8) | 147 (13.1) | 177 (10.7) | 94 (6.3) | |
| Unknown | 9 (0.2) | 0 (0.0) | 4 (0.2) | 5 (0.3) | |
| Alcohol drinking status | 0.409 | ||||
| Never | 209 (4.9) | 49 (4.4) | 78 (4.7) | 82 (5.5) | |
| Previous | 206 (4.8) | 59 (5.3) | 83 (5.0) | 64 (4.3) | |
| Current | 3846 (90.2) | 1011 (90.3) | 1498 (90.3) | 1337 (90.2) | |
| Unknown | 1 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) | |
| IPAQ | <0.001 | ||||
| Low | 695 (16.3) | 217 (19.4) | 272 (16.4) | 206 (13.9) | |
| Moderate | 1327 (31.1) | 345 (30.8) | 513 (30.9) | 469 (31.6) | |
| High | 1274 (29.9) | 278 (24.8) | 518 (31.2) | 478 (32.2) | |
| Unknown | 966 (22.7) | 280 (25.0) | 356 (21.5) | 330 (22.3) | |
| BMI (kg/m2) | |||||
| Mean (SD) | 27.1 (4.7) | 28.3 (5.0) | 27.2 (4.6) | 26.2 (4.3) | <0.001 |
| <18.5 | 31 (0.7) | 5 (0.4) | 10 (0.6) | 16 (1.1) | <0.001 |
| 18.5–24.9 | 1404 (33.1) | 289 (26.0) | 520 (31.6) | 595 (40.2) | |
| 25.0–29.9 | 1851 (43.6) | 469 (42.1) | 751 (45.6) | 631 (42.6) | |
| ≥30.0 | 955 (22.5) | 350 (31.4) | 367 (22.3) | 238 (16.1) | |
| Diabetes (n, %) | 175 (4.1) | 68 (6.1) | 68 (4.1) | 39 (2.6) | <0.001 |
| Depression (n, %) | 441 (10.3) | 173 (15.4) | 146 (8.8) | 122 (8.2) | <0.001 |
| Anxiety (n, %) | 178 (4.2) | 53 (4.7) | 79 (4.8) | 46 (3.1) | 0.038 |
| Having low-risk sleep factors | <0.001 | ||||
| Early chronotype | 2829 (66.4) | 335 (29.9) | 1089 (65.6) | 1405 (94.7) | <0.001 |
| Sleep 7–8 hours/day | 2619 (61.5) | 286 (25.5) | 1008 (60.8) | 1325 (89.3) | <0.001 |
| Never/rarely insomnia | 2750 (64.5) | 376 (33.6) | 1043 (62.9) | 1331 (89.8) | <0.001 |
| No self-reported snoring | 893 (21.0) | 31 (2.8) | 206 (12.4) | 656 (44.2) | <0.001 |
| No frequent daytime sleepiness | 4109 (96.4) | 1002 (89.5) | 1631 (98.3) | 1476 (99.5) | <0.001 |
| IBD treatment (n, %) | 368 (8.6) | 93 (8.3) | 150 (9.0) | 125 (8.4) | 0.747 |
| Duration of IBD (year) | |||||
| Mean±SD | 17.3 (12.9) | 17.2 (12.8) | 17.4 (12.8) | 17.4 (13.1) | 0.923 |
| Median (IQR) | 14.6 (6.7, 26.0) | 14.4 (6.6, 26.3) | 14.8 (6.8, 25.9) | 14.5 (6.9, 26.0) | 0.875 |
| IBD (n, %) | 0.438 | ||||
| CD | 2702 (63.4) | 729 (65.1) | 1059 (63.8) | 914 (61.6) | |
| UC | 1209 (28.4) | 304 (27.1) | 461 (27.8) | 444 (29.9) | |
| IBD-U | 351 (8.2) | 87 (7.8) | 139 (8.4) | 125 (8.4) | |
| CRP (mg/L) | |||||
| Median (IQR) | 1.9 (0.9, 3.8) | 2.3 (1.0, 4.4) | 1.9 (0.9, 3.9) | 1.6 (0.8, 3.3) | <0.001 |
Notes: Categorical variables are presented as frequencies and percentages.
Data are presented as the mean ± SD.
BMI, body mass index; CD, Crohn’s disease; CRP, C reactive protein; IBD, inflammatory bowel disease; IBD-U, IBD-unclassified; IPAQ, International Physical Activity Questionnaire; UC, ulcerative colitis.
Assessment of sleep behaviours, healthy sleep score and sleep patterns
Baseline sleep behaviours, including sleep duration, sleep chronotype, snoring, insomnia symptoms and daytime sleepiness, were collected at recruitment via self-administered touch-screen questionnaire and nurse-led interview. The sleep duration was recorded as number of reported hours by asking ‘About how many hours sleep do you get in every 24 hours? (include naps)’ and was categorised as short (<7 hours/day), normal (7–8 hours/day) and long (≥9 hours/day).18 Sleep chronotype was assessed by asking ‘Do you consider yourself to be definitely a ‘morning’ person, more a ‘morning’ than ‘evening’ person, more an ‘evening’ than ‘morning’ person, or definitely an ‘evening’ person?’”. Snoring was obtained by asking ‘Does your partner or a close relative or friend complain about your snoring?’ with responses of yes or no. Those who were not having partners or who did not complain were considered as missing data (n=304). Insomnia symptoms were assessed using the question ‘Do you have trouble falling asleep at night or do you wake up in the middle of the night?’ with responses of never/rarely, sometimes or usually. Daytime sleepiness was collected by asking ‘How likely are you to doze off or fall asleep during the daytime when you don’t mean to? (eg, when working, reading or driving)’ with responses of never/rarely, sometimes, often or all of the time.
Thus, low-risk sleep factors were defined as follows: sleep 7–8 hours per day, early chronotype (‘morning’ or ‘morning than evening’), no snoring, never or rarely insomnia symptoms, and no frequent daytime sleepiness (‘sometimes’ or ‘never/rarely’).18 Participants were assigned 1 point for each low-risk sleep behaviour, with higher sleep score indicating adherence to healthy sleep pattern (range from 0 to 5 scores). Meanwhile, all participants were categorised into poor (0–2 score), intermediate (3 score), healthy (4–5 score) sleep patterns.
Assessment of outcomes
The primary outcome of interest was all-cause mortality during the follow-up period. Mortality information was obtained from death certificates held by the National Health Service (NHS) Information Centre (England and Wales) and the NHS Central Register (Scotland). Participants were followed from baseline until the date of death, lost to follow-up or end of follow-up (30 September 2023), whichever came first.
The secondary outcome was bowel resection, which was identified through operation records from hospital admission data of the NHS available in the UK Biobank. Bowel resection was defined via the Offices of Population Censuses and Surveys Classification of Interventions and Procedures codes (online supplemental table S1). Participants were followed from baseline to the date of bowel resection, lost to follow-up or end of follow-up (30 October 2022), whichever came first.
Assessment of potential confounders
We adjusted for baseline confounders which could have a potential effect on the behaviour of sleep and the risk of death,4 20 21 including sociodemographic, lifestyle and clinical factors, including age (continuous), sex (male, female), ethnicity (white, non-white), education level (university degree or higher, no university degree), socioeconomic status (Townsend Deprivation Index (TDI), quartiles), smoking status (never, previous, current), alcohol drinking status (never, previous, current), physical activity (International Physical Activity Questionnaire (IPAQ), quartiles), body mass index (BMI, categorised into <18.5, 18.5–24.9, 25.0–29.9, ≥30.0), history of comorbidities (yes, no; including diabetes, depression and anxiety), duration of IBD (continuous), CRP and treatment status of IBD (Yes/No). The duration of IBD at enrolment was calculated as the interval between the diagnosis date (defined as the first recorded date of a K51 or K50 code) and the recruitment date (defined as the date of attendance at the UK Biobank assessment centre). As for IBD treatment, the included patients were predominantly treated with 5-aminosalicylates (ie, mesalazine, sulfasalazine, olsalazine sodium) or corticosteroids (ie, budesonide, prednisolone, hydrocortisone). Thus, the treatment status was identified as any recorded use of these two agents.
Statistical analysis
Baseline characteristics
Baseline characteristics in each category of sleep patterns were described as frequencies and proportions for categorical variables, and means with SDs for continuous variables with normal distribution or medians with IQRs for data with abnormal distribution. Categorical variables were compared using the χ2 test, and continuous variables were compared using the one-way analysis of variance (normal distribution) or Kruskal-Wallis test for continuous variables (abnormal distribution). Poisson regression was conducted to calculate the cumulative incidence of bowel resection and all-cause mortality per 100 000 person-years.
Cox regression model
Univariable and multivariable Cox Proportional Hazard Regression was used to determine the risk of bowel resection and all-cause mortality associated with sleep scores, sleep patterns and each healthy sleep behaviour at baseline in patients with IBD, summarised with HRs and their 95% CIs. The models were adjusted for age and sex in model 1; BMI, TDI, education level, ethnicity, smoking status, alcohol drinking and IPAQ additionally adjusted in model 2; and diabetes, IBD duration and treatment of IBD additionally adjusted in model 3.
Subgroup analysis
Age was stratified into <60 and ≥60 years subgroups given the cohort’s average age of 56.9 years (table 1). IBD duration was stratified into <10 and ≥10 years based on the cohort data (mean 14.6 years) and existing evidence, which identified the first decade post-diagnosis as the period of peak surgical risk.22,24 Subgroup analyses according to sex (male or female), BMI (<25 kg/m2 or ≥25 kg/m2), smoking status (never or current/ever) and alcohol drinking status (never/ever or current) were also performed to examine the risk of bowel resection and mortality. Interaction effect of each stratified variable (ie, age, sex, BMI, smoking status, alcohol drinking status and IBD duration) and sleep patterns was added to assess the effect modification.
Sensitivity analysis
Several sensitivity analyses were further conducted to examine the robustness of our findings. First, to rule out the possibility of reverse causation, we reanalysed the association by excluding patients who died within 1 and 2 years after baseline enrolment. Second, we additionally adjusted depression and anxiety which may affect sleep quality. Third, age-scaled Cox regressions with left truncation and stratified by 5 years birth cohort were analysed to further evaluate the robustness of the results. Fourth, we considered the potential effect of CVD on the risk of death by additionally adjusting for history of CVD or by excluding those who had a history of CVD. Finally, we additionally adjusted CRP, which is a commonly used indicator of systemic inflammation and available in the UK Biobank database.
All these statistical analyses were performed using R statistical software, V.4.1.2 and SAS software V.9.4, with a two-sided p<0.05 as statistically significant. This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology statement (online supplemental method).25
Results
Baseline characteristics
Among the 4262 patients with IBD (aged 56.9±8.0 years old, 48.2% males), 1120 (26.3%) had poor sleep patterns, 1659 (38.9%) intermediate and 1483 (34.8%) healthy at baseline. Compared with the poor sleep group, the healthy sleep group had more females, white individuals, higher education, lower TDI, more never-smokers, higher IPAQ, lower BMI, lower CRP level and a lower prevalence of diabetes, depression and anxiety (all p<0.05). The detailed baseline characteristics are shown in table 1.
Sleep pattern, healthy sleep score with risk of all-cause mortality
During a total follow-up of 59 821 person-years (median 14.6 years), 498 deaths were identified (table 2), including 167, 187 and 144 deaths in poor, intermediate and healthy sleep pattern groups, respectively. Compared with the poor sleep group, both healthy (HR=0.75, 95% CI 0.59 to 0.94, p=0.013) and intermediate (HR=0.77, 95% CI 0.66 to 0.95, p=0.018) sleep groups had a reduced risk of mortality. A significant inverse dose-response relationship was observed when sleep score was treated as a continuous variable (HR=0.89, 95% CI 0.82 to 0.98, p=0.019) (table 2), further supporting the association.
Table 2. Risk of bowel resection and all-cause mortality in patients with IBD according to sleep pattern and healthy sleep score.
| Sleep pattern | Per 1 score (N=4262) |
|||
|---|---|---|---|---|
| Poor (N=1120) |
Intermediate (N=1659) |
Healthy (N=1483) |
||
| Bowel resection | ||||
| Follow-up, person-years | 12 101 | 18 754 | 16 876 | 47 731 |
| Follow-up, years median (IQR) | 13.2 (8.70–14.2) | 13.4 (12.4–14.2) | 13.3 (12.4–14.2) | 13.3 (11.8–14.2) |
| No. of receiving bowel resection | 238 | 298 | 257 | 793 |
| HR for bowel resection (95% CI, p value) | ||||
| Crude | Reference | 0.82 (0.69 to 0.98, 0.025) | 0.79 (0.66 to 0.94, 0.009) | 0.91 (0.85 to 0.98, 0.010) |
| Adjusted model 1 | Reference | 0.82 (0.70 to 0.98, 0.027) | 0.80 (0.67 to 0.95, 0.013) | 0.91 (0.85 to 0.98, 0.014) |
| Adjusted model 2 | Reference | 0.86 (0.73 to 1.03, 0.097) | 0.86 (0.71 to 1.03, 0.099) | 0.94 (0.88 to 1.01, 0.107) |
| Adjusted model 3 | Reference | 0.87 (0.73 to 1.03, 0.106) | 0.86 (0.72 to 1.04, 0.115) | 0.94 (0.88 to 1.02, 0.122) |
| All-cause mortality | ||||
| Follow-up, person-years | 15 479 | 23 366 | 20 976 | 59 821 |
| Follow-up, years, median (IQR) | 14.5 (13.6–15.3) | 14.6 (13.8–15.3) | 14.6 (13.8–15.4) | 14.6 (13.7–15.3) |
| No. of deaths | 167 | 187 | 144 | 498 |
| HR for all-cause death (95% CI, p value) | ||||
| Crude | Reference | 0.74 (0.60 to 0.91, 0.005) | 0.63 (0.51 to 0.79, <0.001) | 0.83 (0.76 to 0.91, <0.001) |
| Adjusted model 1 | Reference | 0.74 (0.60 to 0.91, 0.004) | 0.66 (0.53 to 0.83, <0.001) | 0.85 (0.77 to 0.93, <0.001) |
| Adjusted model 2 | Reference | 0.75 (0.61 to 0.93, 0.009) | 0.73 (0.58 to 0.92, 0.007) | 0.89 (0.81 to 0.97, 0.010) |
| Adjusted model 3 | Reference | 0.77 (0.63 to 0.96, 0.018) | 0.75 (0.59 to 0.94, 0.013) | 0.89 (0.82 to 0.98, 0.019) |
Adjusted model 1: Age and sex were adjusted; Adjusted model 2: BMI, Townsend deprivation index, education level, ethnicity, smoking status, alcohol drinking and IPAQ were additionally adjusted; Adjusted model 3: Diabetes, IBD duration and treatment of IBD were additionally adjusted.
BMI, body mass index; IBD, inflammatory bowel disease; IPAQ, International Physical Activity Questionnaire.
Subgroup analysis indicated (figure 2a,b) a significant interaction was observed between sex and healthy sleep pattern (Pinteraction=0.038, figure 2a) and per-1 healthy sleep score (Pinteraction=0.032, figure 2b) with mortality, while no significant interactions across age, BMI, smoking status, drinking status or duration of IBD were detected (all Pinteraction>0.05).
Figure 2. Subgroup analysis between sleep pattern and sleep scores with risk of bowel resection and all-cause mortality. Note: (a) Risk of bowel resection and all-cause mortality associated with sleep pattern, considering poor sleep pattern as reference. (b) Risk of bowel resection and all-cause mortality associated with sleep score. *21 participants with missing BMI data were excluded. **9 participants with missing smoking data were excluded. #1 Participants with missing drinking data were excluded. All HRs were calculated by adjusting the following covariates: Age, sex, BMI, Townsend deprivation index, education level, ethnicity, smoking status, alcohol drinking, IPAQ, diabetes, IBD duration and treatment of IBD. BMI, body mass index; IBD, inflammatory bowel disease; IPAQ, International Physical Activity Questionnaire.
Healthy sleep behaviours with risk of all-cause mortality
As shown in table 3, a lower risk of mortality was observed among those sleeping 7–8 hours/day (HR=0.79, 95% CI 0.66 to 0.95, p=0.011) and those with an early chronotype (HR=0.82, 95% CI 0.68 to 0.98, p=0.031). However, no significant associations were detected between self-reported snoring, insomnia or daytime sleepiness and the risk of mortality (table 3).
Table 3. Risk of bowel resection and all-cause mortality in patients with IBD by each healthy sleep behaviour.
| Healthy sleep behaviours | |||||
|---|---|---|---|---|---|
| Sleep 7–8 hours/day | Early chronotype | No self-reported snoring | Never/rarely insomnia | No frequent daytime sleepiness | |
| No. of participants (%) | 2829 (66.4) | 2619 (61.5) | 2750 (64.5) | 893 (21.0) | 4109 (96.4) |
| Bowel resection | |||||
| Follow-up, person-years | 32 205 | 29 373 | 30 628 | 10 382 | 46 172 |
| No. of receiving bowel resection | 499 | 480 | 519 | 140 | 757 |
| HR for bowel resection (95% CI, p value) | |||||
| Crude | 0.83 (0.72 to 0.96, 0.014) | 0.96 (0.83 to 1.11, 0.595) | 1.05 (0.91 to 1.22, 0.484) | 0.79 (0.65 to 0.94, 0.010) | 0.73 (0.52 to 1.02, 0.064) |
| Adjusted model 1 | 0.83 (0.72 to 0.96, 0.010) | 0.98 (0.85 to 1.13, 0.774) | 1.10 (0.95 to 1.28, 0.211) | 0.75 (0.62 to 0.90, 0.002) | 0.73 (0.52 to 1.01, 0.060) |
| Adjusted model 2 | 0.88 (0.76 to 1.02, 0.084) | 1.01 (0.88 to 1.17, 0.871) | 1.08 (0.93 to 1.26, 0.307) | 0.78 (0.65 to 0.94, 0.008) | 0.84 (0.59 to 1.18, 0.310) |
| Adjusted model 3 | 0.88 (0.76 to 1.02, 0.094) | 1.01 (0.88 to 1.17, 0.866) | 1.09 (0.93 to 1.27, 0.289) | 0.78 (0.65 to 0.94, 0.008) | 0.84 (0.59 to 1.19, 0.332) |
| All-cause mortality | |||||
| No. of deaths | 295 | 288 | 321 | 89 | 468 |
| Follow-up, person-years | 39 946 | 36 844 | 38 595 | 12 627 | 57 791 |
| HR for all-cause death (95% CI, p value)* | |||||
| Crude | 0.72 (0.60 to 0.86, <0.001) | 0.85 (0.71 to 1.02, 0.080) | 1.00 (0.83 to 1.20, 0.992) | 0.81 (0.64 to 1.02, 0.073) | 0.54 (0.38 to 0.79, 0.001) |
| Adjusted model 1 | 0.75 (0.63 to 0.90, 0.002) | 0.77 (0.65 to 0.92, 0.004) | 1.13 (0.94 to 1.36, 0.199) | 0.82 (0.65 to 1.04, 0.100) | 0.62 (0.43 to 0.89, 0.010) |
| Adjusted model 2 | 0.79 (0.66 to 0.94, 0.010) | 0.81 (0.68 to 0.98, 0.026) | 1.14 (0.94 to 1.37, 0.187) | 0.87 (0.69 to 1.09, 0.229) | 0.77 (0.52 to 1.14, 0.194) |
| Adjusted model 3 | 0.79 (0.66 to 0.95, 0.011) | 0.82 (0.68 to 0.98, 0.031) | 1.15 (0.95 to 1.39, 0.149) | 0.88 (0.70 to 1.11, 0.282) | 0.81 (0.54 to 1.20, 0.290) |
Compared with all other participants not in this low-risk group. Adjusted model 1: Age and sex were adjusted; Adjusted model 2: BMI, Townsend deprivation index, education level, ethnicity, smoking status, alcohol drinking and IPAQ were additionally adjusted; Adjusted model 3: Diabetes, IBD duration and treatment of IBD were additionally adjusted.
BMI, body mass index; IBD, inflammatory bowel disease; IPAQ, International Physical Activity Questionnaire.
Consistently, subgroup analysis showed no significant interactions across age, BMI, smoking status or drinking status in different healthy sleep behaviours (all Pinteraction>0.05) (online supplemental tables S2–S6), except for the lower risk of mortality associated with sleeping 7–8 hours/day and early chronotype in males compared with females (Pinteraction=0.022, Pinteraction=0.032, respectively) (online supplemental table S3).
Sleep pattern, healthy sleep score and healthy sleep behaviours with risk of bowel resection
During a total follow-up of 47 731 person-years, 793 patients received bowel resection (table 2). A marginally significant lower risk of bowel resection was observed with healthy (HR=0.86, 95% CI 0.72 to 1.04, p=0.115) and intermediate (HR=0.87, 95% CI 0.73 to 1.03, p=0.106) sleep pattern (table 2). As for healthy sleep behaviours, a 22% lower risk of bowel resection was observed with never/rarely insomnia symptoms (HR=0.78, 95% CI 0.65 to 0.94, p=0.008), with null associations of sleep duration, early chronotype, self-reported snoring or frequent daytime sleepiness (table 3).
A similar marginally significant beneficial effect on receiving bowel resection was detected in those with BMI ≥25 kg/m2, current/ever smokers, current drinkers and IBD duration ≥10 years, with no significant interactions across age, BMI, smoking status, drinking status or duration of IBD detected (all P interaction>0.05, figure 2a,b). As for healthy sleep behaviours, the lower risk associated with never/rarely insomnia symptoms was generally indicated in those <60 years, male, BMI <25 kg/m2, current/ever smokers and current drinkers (online supplemental tables S7–S11).
Sensitivity analyses
Sensitivity analyses consistently showed a decreased risk of death associated with healthy sleep pattern, per 1 increase of sleep score, or healthy sleep behaviours after excluding those who died within 1 year and 2 years, additionally adjusting for depression and anxiety, conducting age-scaled Cox regression with left truncation and stratified by 5 years birth cohort, additionally adjusting for CVD, excluding those with history of CVD or additionally adjusting for CRP (table 4, online supplemental table S12). Similar findings were also observed for risk of bowel resection, indicating the robustness of the results (table 4, online supplemental table S12).
Table 4. Sensitivity analysis regarding risk of bowel resection and all-cause mortality associated with sleep scores and patterns.
| Sleep scores and patterns | No. of participants | Bowel resection | All-cause mortality | ||
|---|---|---|---|---|---|
| No. of bowel resection | HR (95% CI, p value) | No. of deaths | HR (95% CI, p value) | ||
| Sensitivity analysis 1: excluding participants who died within 1 year after baseline | |||||
| Per 1 score increase | 4251 | 520 | 0.94 (0.86 to 1.03, 0.178) | 488 | 0.90 (0.82 to 0.98, 0.022) |
| Poor | 1115 | 151 | Reference | 163 | Reference |
| Intermediate | 1656 | 200 | 0.88 (0.71 to 1.09, 0.254) | 184 | 0.78 (0.63 to 0.97, 0.024) |
| Healthy | 1480 | 169 | 0.85 (0.68 to 1.07, 0.159) | 141 | 0.75 (0.60 to 0.95, 0.016) |
| Sensitivity analysis 2: excluding participants who died within 2 years after baseline | |||||
| Per 1 score increase | 4237 | 356 | 0.99 (0.89 to 1.10, 0.836) | 475 | 0.88 (0.80 to 0.97, 0.007) |
| Poor | 1112 | 96 | Reference | 160 | Reference |
| Intermediate | 1654 | 136 | 0.95 (0.73 to 1.24, 0.701) | 183 | 0.79 (0.64 to 0.98, 0.032) |
| Healthy | 1471 | 124 | 0.98 (0.74 to 1.29, 0.876) | 132 | 0.71 (0.56 to 0.91, 0.006) |
| Sensitivity analysis 3: additionally adjusting depression and anxiety | |||||
| Per 1 score increase | 4262 | 793 | 0.94 (0.87 to 1.01, 0.098) | 498 | 0.90 (0.82 to 0.98, 0.022) |
| Poor | 1120 | 238 | Reference | 167 | Reference |
| Intermediate | 1659 | 298 | 0.86 (0.72 to 1.02, 0.090) | 187 | 0.78 (0.63 to 0.96, 0.020) |
| Healthy | 1483 | 257 | 0.85 (0.71 to 1.03, 0.091) | 144 | 0.75 (0.60 to 0.95, 0.015) |
| Sensitivity analysis 4: age-scaled Cox regression with left truncation | |||||
| Per 1 score increase | 4262 | 793 | 0.94 (0.87 to 1.01, 0.090) | 498 | 0.89 (0.82 to 0.98, 0.019) |
| Poor | 1120 | 238 | Reference | 167 | Reference |
| Intermediate | 1659 | 298 | 0.86 (0.73 to 1.02, 0.092) | 187 | 0.77 (0.63 to 0.96, 0.017) |
| Healthy | 1483 | 257 | 0.86 (0.72 to 1.03, 0.101) | 144 | 0.75 (0.60 to 0.94, 0.013) |
| Sensitivity analysis 5: age-scaled Cox regression stratified by 5 years birth cohort | |||||
| Per 1 score increase | 4262 | 793 | 0.95 (0.88 to 1.02, 0.141) | 498 | 0.89 (0.81 to 0.98, 0.017) |
| Poor | 1120 | 238 | Reference | 167 | Reference |
| Intermediate | 1659 | 298 | 0.87 (0.73 to 1.03, 0.103) | 187 | 0.77 (0.62 to 0.95, 0.016) |
| Healthy | 1483 | 257 | 0.87 (0.73 to 1.04, 0.136) | 144 | 0.75 (0.59 to 0.94, 0.012) |
| Sensitivity analysis 6: additionally adjusting cardiovascular disease | |||||
| Per 1 score increase | 4262 | 793 | 0.94 (0.88 to 1.02, 0.123) | 498 | 0.90 (0.82 to 0.99, 0.027) |
| Poor | 1120 | 238 | Reference | 167 | Reference |
| Intermediate | 1659 | 298 | 0.87 (0.73 to 1.03, 0.106) | 187 | 0.78 (0.63 to 0.97, 0.023) |
| Healthy | 1483 | 257 | 0.86 (0.72 to 1.04, 0.116) | 144 | 0.76 (0.61 to 0.96, 0.021) |
| Sensitivity analysis 7: additionally excluding cardiovascular disease | |||||
| Per 1 score increase | 3882 | 719 | 0.92 (0.85 to 1.00, 0.037) | 395 | 0.89 (0.80 to 0.98, 0.024) |
| Poor | 984 | 214 | Reference | 129 | Reference |
| Intermediate | 1513 | 269 | 0.83 (0.69 to 1.00, 0.050) | 149 | 0.76 (0.60 to 0.97, 0.025) |
| Healthy | 1385 | 236 | 0.82 (0.68 to 0.99, 0.041) | 117 | 0.72 (0.55 to 0.93, 0.011) |
| Sensitivity analysis 8: additionally adjusting CRP | |||||
| Per 1 score increase | 4262 | 793 | 0.93 (0.87 to 1.01, 0.084) | 498 | 0.91 (0.83 to 1.01, 0.066) |
| Poor | 1120 | 238 | Reference | 167 | Reference |
| Intermediate | 1659 | 298 | 0.88 (0.73 to 1.05, 0.160) | 187 | 0.80 (0.64 to 0.99, 0.044) |
| Healthy | 1483 | 257 | 0.84 (0.69 to 1.01, 0.065) | 144 | 0.78 (0.62 to 0.99, 0.045) |
All HRs were calculated by adjusting the following covariates: Age, sex, BMI, Townsend deprivation index, education level, ethnicity, smoking status, alcohol drinking, IPAQ, diabetes, IBD duration and treatment of IBD.
BMI, body mass index; CRP, C reactive protein; IBD, inflammatory bowel disease; IPAQ, International Physical Activity Questionnaire.
Discussion
In this prospective cohort study using UK Biobank data with a median follow-up of 14.6 years, our study revealed several significant findings: (1) patients with IBD with healthier sleep patterns experienced a notable reduction of 25% in the risk of death, with a clear dose-response relationship, particularly linked to adequate sleep duration and an early sleep chronotype. (2) The protective association was more pronounced in those ≥60 years, males, higher BMI, current/ever smokers and current drinkers. (3) Patients with IBD with healthier sleep patterns might have a lower risk of future bowel resection, with a 22% risk reduction associated with never/rarely insomnia symptoms.
The possible reasons for the 25% lower mortality risk in patients with IBD, rather than 6% reduced risk in the general population, might be as follows.26 First, UC patients may have approximately 2–3 fold higher risk of colorectal cancer,27 28 contributing to the cancer-cause mortality. Short sleep was associated with impaired immunity,16 which might increase the risk of cancer in the long term. Second, patients with IBD were more likely to develop sleep disorders29 than health controls due to the mediation of inflammation. Animal models proved that peripheral tumour necrosis factor alpha (TNF-α) could enhance other pro-inflammatory cytokines in sleep-related brain areas, therefore influencing non-rapid eye movement sleep.30 31 Hence, worse sleep quality and sleep disorders may aggravate symptom manifestation by increasing systemic and histological inflammatory activity,32 33 thus creating a vicious cycle of sleep disturbance and inflammation.34 35 Additionally, short sleep duration had chronic unfavourable effects of dietary habits,36 which could lead to metabolic disorders37 and CVD. All of these factors might be associated with an increased risk of mortality in patients with IBD.
Our results further suggested the reduced mortality risk associated with appropriate sleep duration and early sleep chronotype. Previous studies indicated the importance of appropriate sleep length by revealing a U-shaped association on sleep duration and mortality38 and a higher incidence of UC among individuals with subjective sleep durations <6 hour or >9 hour.39 Besides, a later chronotype was associated with IBD-specific complications and lower quality of life.40 Given the later chronotype and greater sleep deprivation in patients with IBD owing to night-time diarrhoea and abdominal pain during disease flares,41 it is more important to suggest patients with IBD follow a regular circadian rhythm. The alteration on circadian alignment upregulates circulating cytokines, which in turn triggers sleep disruption and results in increases of circulating cytokine concentrations,42 thus creating a vicious circle that contributes directly to disease flares.34 The defined healthy sleep score in our study makes it easier to provide comprehensive measures of sleep factors and facilitate the application in clinical and public health practice.26
In addition, the protective association of healthy sleep patterns was evidently among patients older than 60 years, higher BMI and current smoking and drinking, all of which were well-established risk factors of all-cause mortality20 by increasing the risk of CVD and metabolic disorders. Thus, modifying sleep behaviour and these risk factors may be easier and more effective strategies to reduce the risk of mortality.
Our findings have important implications for clinical practice in patients with IBD. As sleep duration, chronotype and apnoea are potentially modifiable behaviours, clinicians need to encourage adequate sleep duration, advocate early sleep pattern and figure out strategies to reduce apnoea in patients with IBD, especially in those with risk factors. Corticosteroid therapy should also be considered during IBD disease flares which may cause the side effect of sleep disturbances.43 As a result, it is crucial to early screen poor sleep pattern and take good control of IBD activity to promote sleep quality in patients with IBD possibly by proposing bedtime medication to reduce night-time diarrhoea or by corticosteroid-replacement therapy. Furthermore, sleep quality problems should also be monitored in the remission stage of IBD with available interventions44 given the evidence that sleep problems may persist over time even when IBD is successfully treated44 or in the remission stage.45 It is also worth noting that longitudinal studies and experimental studies are still needed to disentangle the sleep-inflammation interaction.44
There are strengths of this study, including a large-scale prospective cohort, a long follow-up time and a large number of incident cases. We computed sleep pattern as grouped and sleep score as continuous variables and conducted subgroup analysis with comprehensive sensitivity analysis to better understand the association between the overall sleep pattern and mortality, raising concern in the management of sleep disorder in patients with IBD.
We acknowledged some limitations in our study. First, lifestyle and clinical covariates, along with sleep behaviours, were not re-assessed during follow-up, preventing us from ruling out the impact of changes in these covariates on our findings. Second, despite adjustment for well-known confounding factors, unmeasured or residual confounding factors may still exist. Third, selection bias due to voluntary participation and loss to follow-up may exist. Fourth, sleep measurement in our study did not include the Pittsburgh Sleep Quality Index, a common tool used for sleep quality measure such as pain-related sleep disturbances. Hence, future studies should consider such features on the long-term prognosis of patients with IBD. Fifth, participants included in this study were mainly White, while studies showed that patients with IBD in Western Europe had a higher mortality rate,46 indicating the need for studies on other ethnicities and regions. Sixth, the limited count for mortality and surgery cases precluded a stratified analysis of the impact of sleep parameters on these endpoints within IBD subgroups. Further studies with extended follow-up and larger outcome events are required to disentangle the distinct effects of sleep in different IBD subtypes. Seventh, sedative prescriptions could independently affect sleep, but prescription data were not available. Thus, our sensitivity analysis was restricted to adjusting for anxiety and depression diagnoses, with the main findings remaining consistent in this analysis. Finally, the UK Biobank cohort (recruited 2006–2010) was established before the widespread use of biologic therapies in IBD. This precludes adjustment for immunomodulator and biologic therapies, which are significant confounders for surgical and mortality outcomes—a key direction for future research.
Conclusions
In conclusion, healthy sleep pattern, particularly sleep duration and early chronotype, is associated with reduced all-cause mortality risk in patients with IBD, with probably beneficial effect on lowering risk of bowel resection. Future clinical practice should consider prioritising sleep management in patients with IBD, including early detection and management of sleep disorders, promoting adequate sleep and addressing sleep apnoea, especially in high-risk individuals. Further studies are needed to confirm these findings and clarify the mechanisms behind the sleep-inflammation interaction.
Supplementary material
Acknowledgements
This research has been conducted using the UK Biobank Resource under application number 74444.
None of the funding organisations had any role in the design and conduct of the study; in the collection, analysis and interpretation of the data; in the preparation, review and approval of the manuscript.
Footnotes
Funding: This work was supported by the Beijing Nova Program (No. 20230484349) and Beijing High-Level Innovation and Entrepreneurship Talent Support Program Young Backbone Talent Projects (G202533237).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Data availability free text: All data relevant to the study were using the UK Biobank Resource under application number 74444. No additional data available.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval: The UK Biobank study was approved by the North West Multicenter Research Ethical Committee (21/NW/0157), and all participants or their proxy respondents provided written informed consent.
Data availability statement
No data are available.
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Supplementary Materials
Data Availability Statement
No data are available.