Associations between prior healthcare use, time to diagnosis, and clinical outcomes in inflammatory bowel disease: a nationally representative population-based cohort study.

BACKGROUND: Timely diagnosis and treatment of inflammatory bowel disease (IBD) may improve clinical outcomes. OBJECTIVE: Examine associations between time to diagnosis, patterns of prior healthcare use, and clinical outcomes in IBD. DESIGN: Using the Clinical Practice Research Datalink we identified incident cases of Crohn's disease (CD) and ulcerative colitis (UC), diagnosed between January 2003 and May 2016, with a first primary care gastrointestinal consultation during the 3-year period prior to IBD diagnosis. We used multivariable Cox regression to examine the association of primary care consultation frequency (n=1, 2, >2), annual consultation intensity, hospitalisations for gastrointestinal symptoms, and time to diagnosis with a range of key clinical outcomes following diagnosis. RESULTS: We identified 2645 incident IBD cases (CD: 782; UC: 1863). For CD, >2 consultations were associated with intestinal surgery (adjusted HR (aHR)=2.22, 95% CI 1.45 to 3.39) and subsequent CD-related hospitalisation (aHR=1.80, 95% CI 1.29 to 2.50). For UC, >2 consultations were associated with corticosteroid dependency (aHR=1.76, 95% CI 1.28 to 2.41), immunomodulator use (aHR=1.68, 95% CI 1.24 to 2.26), UC-related hospitalisation (aHR=1.43, 95% CI 1.05 to 1.95) and colectomy (aHR=2.01, 95% CI 1.22 to 3.27). For CD, hospitalisation prior to diagnosis was associated with CD-related hospitalisation (aHR=1.30, 95% CI 1.01 to 1.68) and intestinal surgery (aHR=1.71, 95% CI 1.13 to 2.58); for UC, it was associated with immunomodulator use (aHR=1.42, 95% CI 1.11 to 1.81), UC-related hospitalisation (aHR=1.36, 95% CI 1.06 to 1.95) and colectomy (aHR=1.54, 95% CI 1.01 to 2.34). For CD, consultation intensity in the year before diagnosis was associated with CD-related hospitalisation (aHR=1.19, 95% CI 1.12 to 1.28) and intestinal surgery (aHR=1.13, 95% CI 1.03 to 1.23); for UC, it was associated with corticosteroid use (aHR=1.08, 95% CI 1.04 to 1.13), corticosteroid dependency (aHR=1.05, 95% CI 1.00 to 1.11), and UC-related hospitalisation (aHR=1.12, 95% CI 1.03 to 1.21). For CD, time to diagnosis was associated with risk of CD-related hospitalisation (aHR=1.03, 95% CI 1.01 to 1.68); for UC, it was associated with reduced risk of UC-related hospitalisation (aHR=0.83, 95% CI 0.70 to 0.98) and colectomy (aHR=0.59, 95% CI 0.43 to 0.80). CONCLUSION: Electronic records contain valuable information about patterns of healthcare use that can be used to expedite timely diagnosis and identify aggressive forms of IBD.

Adherence to 5-aminosalicylic acid maintenance treatment in young people with ulcerative colitis: a retrospective cohort study in primary care.

BACKGROUND: Maintenance treatment with 5-aminosalicylic acid (5-ASA) is recommended in ulcerative colitis (UC), but accurate estimates of discontinuation and adherence in adolescents transitioning to young adulthood are lacking. AIM: To determine rates and risk factors for discontinuation and adherence to oral 5-ASA in adolescents and young adults 1 year following diagnosis of UC. DESIGN AND SETTING: Observational cohort study using the UK Clinical Practice Research Datalink among adolescents and young adults (aged 10-24 years) diagnosed with UC between 1 January 1998 and 1 May 2016. METHOD: Time to oral 5-ASA discontinuation (days) and adherence rates (proportion of days covered) were calculated during the first year of treatment using Kaplan-Meier survival analysis. Cox regression models were built to estimate the impact of sociodemographic and health-related risk factors. RESULTS: Among 607 adolescents and young adults starting oral 5-ASA maintenance treatment, one-quarter (n = 152) discontinued within 1 month and two- thirds (n = 419) within 1 year. Discontinuation was higher among those aged 18-24 years (74%) than younger age groups (61% and 56% in those aged 10-14 and 15-17 years, respectively). Adherence was lower among young adults than adolescents (69% in those aged 18-24 years versus 80% in those aged 10-14 years). Residents in deprived versus affluent postcodes were more likely to discontinue treatment (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] = 1.10 to 1.92). Early corticosteroid use for an acute flare lowered the likelihood of oral 5-ASA discontinuation (aHR 0.68, 95% CI = 0.51 to 0.90). CONCLUSION: The first year of starting long-term therapies in adolescents and young adults diagnosed with UC is a critical window for active follow-up of maintenance treatment, particularly in those aged 18-24 years and those living in deprived postcodes.

Patterns of cigarette and e-cigarette use among UK adolescents: a latent class analysis of the Millennium Cohort Study.

BACKGROUND: Patterning of cigarette and e-cigarette use among young people remains poorly characterized. We aimed to describe these patterns in the UK Millennium Cohort Study at age 14 and 17 years. METHODS: Data on cigarette and e-cigarette use come from 9731 adolescents. Latent class analysis assigned participants to membership of classes of product use and multinomial logistic regression analyses assessed differences in the likelihood of belonging to classes by sociodemographic (age, gender, ethnicity, household income, maternal education and country of residence) and smoking-related social factors (caregiver tobacco use, caregiver e-cigarette use and peer smoking). RESULTS: We identified four classes of use: 45.8% of adolescents 'continued to abstain' from cigarettes or e-cigarettes; 21.3% 'experimented' (used once or in the past but not currently) with cigarettes and/or e-cigarettes by age 17 but were not current users; 19.0% were 'late adopters', characterized by low levels of use at age 14 but high levels of experimentation and current use at age 17; and 13.9% were 'early adopters', characterized by high levels of experimentation and current use at ages 14 and 17. At age 17, 70.4% of 'early adopters' smoked cigarettes regularly plus an additional 27.3% experimented with cigarettes. Corresponding percentages for e-cigarettes were 37.9% and 58.9%. Tobacco and e-cigarette use by caregivers, and cigarette use by peers, were associated with being both 'late adopters' and 'early adopters'. CONCLUSIONS: Approximately one in seven adolescents in the UK are 'early adopters' of nicotine products. This highlights the need to develop and implement effective policies to prevent nicotine use uptake.

The role of dieting, happiness with appearance, self-esteem, and bullying in the relationship between mental health and body-mass index among UK adolescents: a longitudinal analysis of the Millennium Cohort Study.

Background: Mental illness and obesity are among the biggest challenges to population health, they are linked, and may be modifiable during adolescence. We aimed to determine intervening pathways between mental health and BMI z-score symptoms across adolescence. Methods: In this longitudinal cohort study, we used path models to examine self-reported dieting, happiness with appearance, self-esteem and bullying at 14 years as potential mediators of the cross-lagged relationship between mental health (via the Strengths and Difficulties Questionnaire) and Body Mass Index (BMI) z-score at 11 and 17 years by sex in the UK Millennium Cohort Study, a prospective cohort study of 18,818 children born in the UK between September 1st, 2000, and January 31st, 2002. Full, incomplete data on all singleton children still participating in the study by age 11 years were analysed in GSEM via maximum likelihood estimation (N = 12,450). Findings: We found happiness with appearance and self-esteem, but not dieting or bullying, mediated the relationship between BMI age 11 and mental health age 17. Each increase in BMI z-score at 11 years was associated with 0.12 increase for boys and a 0.19 increase for girls in scores of unhappiness with appearance (boys: b 0.12, 95% C.I.; girls b 0.19, C.I. 0.14 to 0.23) and a 16% increase for boys and a 22% increase for girls in odds of low self-esteem (boys OR 1.16, 95% C.I. 1.07 to 1.26; girls: OR 1.22, 95% C.I. 1.15 to 1.30) at 14 years. In turn, for both boys and girls, being unhappy with appearance and low self-esteem at 14 years were associated with a greater likelihood of emotional and externalizing symptoms at 17 years. Interpretation: Early prevention strategies to encourage healthy physical and mental development of children need to focus on the promotion of positive body-mage and self-esteem. Funding: The National Institute for Health and Care Research (NIHR) School for Public Health Research (SPHR).

Systematic review with meta-analysis: Time to diagnosis and the impact of delayed diagnosis on clinical outcomes in inflammatory bowel disease.

BACKGROUND: The impact of diagnostic delay on the clinical course of inflammatory bowel disease (IBD) remains uncertain. AIM: To perform a systematic review of time to diagnosis and the impact of delayed diagnosis on clinical outcomes in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We searched EMBASE and Medline from inception to 30th November 2022 for studies reporting diagnostic interval, from symptom onset to IBD diagnosis. We calculated the median, interquartile range (IQR) and pooled weighted median, of median diagnostic intervals of eligible studies. We defined delayed diagnosis as individuals above the 75th centile of longest time to diagnosis in each study. Using random effects meta-analysis, we pooled odds ratios (ORs) with 95% confidence intervals (CI) for studies reporting clinical outcomes, according to delayed diagnosis. RESULTS: One hundred and one studies representing 112,194 patients with IBD (CD = 59,359; UC = 52,835) met inclusion criteria. The median of median times to diagnosis was 8.0 (IQR: 5.0-15.2) and 3.7 months (IQR: 2.0-6.7) in CD and UC, respectively. In high-income countries, this was 6.2 (IQR: 5.0-12.3) and 3.2 months (IQR: 2.2-5.3), compared with 11.7 (IQR: 8.3-18.0) and 7.8 months (IQR: 5.2-21.8) in low-middle-income, countries, for CD and UC respectively. The pooled weighted median was 7.0 (95% CI: 3.0-26.4) and 4.6 (95% CI: 1.0-96.0) months, for CD and UC respectively. Eleven studies, representing 6164 patients (CD = 4858; UC = 1306), were included in the meta-analysis that examined the impact of diagnostic delay on clinical outcomes. In CD, delayed diagnosis was associated with higher odds of stricturing (OR = 1.88; CI: 1.35-2.62), penetrating disease (OR = 1.64; CI: 1.21-2.20) and intestinal surgery (OR = 2.24; CI: 1.57-3.19). In UC, delayed diagnosis was associated with higher odds of colectomy (OR = 4.13; CI: 1.04-16.40). CONCLUSION: Delayed diagnosis is associated with disease progression in CD, and intestinal surgery in both CD and UC. Strategies are needed to achieve earlier diagnosis of IBD.

Early Risk Factors for Self-Injurious Thoughts and Behaviours: A UK Population-Based Study of 219,581 People.

Mental disorders are a major problem among young people. To identify early risk factors of self-injurious thoughts and behaviours (SITB) among young adults with mental health problems, this case-control study drew data from the Clinical Practice Research Datalink (CPRD), a primary care database covering 8% of the UK population. We explored the role of early factors (presenting at 8-14 years old) for suicidal ideation, suicide attempts, and non-suicidal self-injury (NSSI) in young adulthood (age 18-25 years) by performing logistic regressions. Our sample consisted of 219,581 participants, of which 6.51% had at least one SITB in young adulthood. Early risk factors for SITB included early NSSI, suicidal ideation, sexual abuse, behavioural problems, and mood and psychotic symptoms. Frequency of GP visits had a protective effect. Lack of access to mortality data, ethnicity, and socioeconomic status was a limitation of the current study. In conclusion, early symptoms in late childhood/early adolescence can be the start of long-standing problems going into adult life. The training of primary care providers in suicide risk assessment and proper co-ordination with child and adolescent mental health services are crucial for suicide prevention.

Antidepressant medication use in Inflammatory Bowel Disease: a nationally representative population-based study.

BACKGROUND: Despite high rates of depression and anxiety, little is known about the use of antidepressants amongst individuals diagnosed with inflammatory bowel disease (IBD). AIMS: To evaluate temporal trends in the use of antidepressants; rates of antidepressant initiation and adherence of antidepressant use to international guidelines amongst individuals with IBD. METHODS: This is a study of 14,525 incident IBD cases from 2004 to 2016 compared with 58,027 controls matched 1:4 for age and sex from the Clinical Practice Research Datalink. After excluding tricyclic antidepressants, we performed a Cox regression analysis to determine the risk associated with antidepressant use and logistic regression analysis to determine risk associated with antidepressant undertreatment. RESULTS: Antidepressant use amongst individuals with IBD increased by 51% during the 12-year study period, who were 34% more likely to initiate antidepressants in the year after IBD diagnosis compared with controls (aHR:1.34, 95% CI 1.21-1.49). In those with IBD starting antidepressants, 67% received treatment lasting less than the duration recommended in international guidelines, of which 34% were treated for 1 month or less. 18-24 year olds were twice as likely to discontinue treatment within 1 month compared with those aged 40-60 years (aHR:2.03, 95% CI 1.40-2.95). Socioeconomic deprivation was also associated with early treatment discontinuation (aHR:1.40, 95% CI 1.07-1.83). CONCLUSIONS: In the year following IBD diagnosis individuals are significantly more likely to start antidepressants compared with controls, but treatment duration fell short of recommendations in the majority. Better integration of services may benefit individuals with IBD and psychiatric comorbidity.

Stoma Formation in Crohn's Disease and the Likelihood of Antidepressant Use: A Population-Based Cohort Study.

BACKGROUND & AIMS: The impact of a temporary or permanent stoma on mental health in Crohn's Disease (CD) is unknown. The aim was to examine the association between intestinal surgery and stoma formation and subsequent antidepressant medication (ADM) use. METHODS: Using the Clinical Practice Research Datalink, we identified individuals with CD who underwent intestinal surgery between 1998-2018. We excluded individuals with a prescription for an ADM in the 6 months before surgery. Individuals were stratified into three groups: no stoma, temporary stoma, and permanent stoma. We used Kaplan-Meier curves to examine initiation of ADM after intestinal surgery and Cox regression to identify risk factors for ADM use after intestinal surgery. RESULTS: We identified 1,272 cases of CD undergoing their first intestinal surgery. Of these, 871 (68.5%) had no stoma, 191 (15.0%) had a temporary stoma and 210 (16.5%) had a permanent stoma. The 10-year cumulative incidence of ADM use was 26.4%, 33.4% and 37.3% respectively. Individuals with a permanent stoma were 71% more likely to receive an ADM than those with no stoma (HR 1.71, 95% CI 1.20-2.44). Individuals with a temporary stoma reversed within 12 months had a similar likelihood of ADM use to those without stoma formation (HR 0.99, 95% CI 0.64-1.53) whereas temporary stoma formation with late reversal after 12 months was associated with significantly greater likelihood of ADM use (HR 1.85, 95% CI 1.15-2.96). CONCLUSIONS: Permanent stomas and temporary stomas with late reversal surgery are associated with increased ADM use after intestinal surgery, likely associated with increased anxiety and depression.

Disadvantage in early-life and persistent asthma in adolescents: a UK cohort study.

OBJECTIVE: To determine how early-life risk factors explain socioeconomic inequalities in persistent asthma in adolescence. METHODS: We did a causal mediation analysis using data from 7487 children and young people in the UK Millennium Cohort Study. Persistent asthma was defined as having a diagnosis reported at any two or more time points at 7, 11 or 14 years. The main exposure was maternal education, a measure of early-life socioeconomic circumstances (SECs), used to calculate the relative index of inequality. We assessed how blocks of perinatal (maternal health behaviours, infant characteristics and duration of breastfeeding, measured at 9 months) and environmental risk factors (family housing conditions; potential exposure to infections through childcare type and sibling number, and neighbourhood characteristics, measured at 3 years) mediated the total effect of childhood SECs on persistent asthma risk, calculating the proportion mediated and natural indirect effect (NIE) via blocks of mediators. RESULTS: At age 14 the overall prevalence of persistent asthma was 15%. Children of mothers with lower educational qualifications were more likely to have persistent asthma, with a clear social gradient (degree plus: 12.8% vs no qualifications: 20.3%). The NIE gives the effect of SECs acting only via the mediators and shows a 31% increased odds of persistent asthma when SECs are fixed at the highest level, and mediators at the level which would naturally occur at the lowest SECs versus highest SECs (NIE OR 1.31, 95% CI 1.04 to 1.65). Overall, 58.9% (95% CI 52.9 to 63.7) of the total effect (OR 1.70, 95% CI 1.20 to 2.40) of SECs on risk of persistent asthma in adolescence was mediated by perinatal and environmental characteristics. CONCLUSIONS: Perinatal characteristics and the home environment in early life are more important in explaining socioeconomic inequalities in persistent asthma in British adolescents than more distal environmental exposures outside the home.

Early-life maternal attachment and risky health behaviours in adolescence: findings from the United Kingdom Millennium Cohort Study.

BACKGROUND: Early uptake of multiple risky behaviours during adolescence, such as substance use, antisocial and sexual behaviours, can lead to poor health outcomes without timely interventions. This study investigated how early-life maternal attachment, or emotional bonds between mothers and infants, influenced later risky behaviours in adolescence alongside other potential explanatory pathways using the United Kingdom Millennium Cohort Study. METHODS: Total maternal attachment scores measured at 9 months using the Condon (1998) Maternal Postnatal Attachment Scale compared higher and lower attachment, where mothers in the lowest 10th percentile represented lower attachment. Multiple risky behaviours, defined as two or more risky behaviours (including smoking cigarettes, vaping, alcohol consumption, illegal drug use, antisocial behaviour, criminal engagement, unsafe sex, and gambling), were scored from 0 to 8 at age 17. Five multivariate logistic regression models examined associations between maternal attachment and multiple risky behaviours among Millennium Cohort Study members (n = 7796). Mediation analysis sequentially adjusted for blocks of explanatory mechanisms, including low attachment mechanisms (multiple births, infant prematurity, sex, breastfeeding, unplanned pregnancy and maternal age at birth), maternal depression, and social inequalities (single-parent status, socioeconomic circumstance by maternal education and household income) at 9 months and poor adolescent mental health at 14 years. RESULTS: Children of mothers with lower maternal attachment at 9 months had 23% increased odds of multiple risky behaviours at 17 years (OR: 1.23, 95% CI: 1.00-1.50) in the unadjusted baseline model. All five explanatory blocks attenuated baseline odds. Low attachment mechanisms attenuated 13%, social inequalities 17%, and poor mental health 17%. Maternal depression attenuated the highest proportion (26%) after fully adjusting for all factors (30%). CONCLUSIONS: Lower maternal attachment in early life predicted increased adolescent multiple risky behaviours. Almost a third of the excess risk was attributable to child, maternal and socioeconomic factors, with over a quarter explained by maternal depression. Recognising the influence of early-life risk factors on adolescent health could innovate current policies and interventions addressing multiple risky behaviour uptake affecting health inequalities across the life course.

Association between antidepressant medication use and steroid dependency in patients with ulcerative colitis: a population-based study.

BACKGROUND: Animal studies indicate a potential protective role of antidepressant medication (ADM) in models of colitis but the effect of their use in humans with ulcerative colitis (UC) remains unclear. OBJECTIVE: To study the relationship between ADM use and corticosteroid dependency in UC. DESIGN: Using the Clinical Practice Research Datalink we identified patients diagnosed with UC between 2005 and 2016. We grouped patients according to serotonin selective reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) exposure in the 3 years following diagnosis: 'continuous users', 'intermittent users' and 'non-users'. We used logistic regression to estimate the adjusted risk of corticosteroid dependency between ADM exposure groups. RESULTS: We identified 6373 patients with UC. Five thousand two hundred and thirty (82%) use no ADMs, 627 (10%) were intermittent SSRI users and 282 (4%) were continuous SSRI users, 246 (4%) were intermittent TCA users and 63 (1%) were continuous TCA users.Corticosteroid dependency was more frequent in continuous SSRI and TCA users compared with non-users (19% vs 24% vs 14%, respectively, χ2 p=0.002). Intermittent SSRI and TCA users had similar risks of developing corticosteroid dependency to non-users (SSRI: OR 1.19, 95% CI 0.95 to 1.50, TCA: OR 1.14, 95% CI 0.78 to 1.66). Continuous users of both SSRIs and TCAs had significantly higher risks of corticosteroid dependency compared with non-users (SSRI: OR 1.62, 95% CI 1.15 to 2.27, TCA: OR 2.02, 95% CI 1.07 to 3.81). CONCLUSIONS: Continuous ADM exposure has no protective effect in routine clinical practice in UC and identifies a population of patients requiring more intensive medical therapy. ADM use is a flag for potentially worse clinical outcomes in UC.

Is earlier obesity associated with poorer executive functioning later in childhood? Findings from the Millennium Cohort Study.

BACKGROUND: Children affected with overweight or obesity have been associated with having lower educational achievement compared to peers who are non-overweight/obese. One of the drivers of this association could be a link between obesity and poorer executive function. Evidence is limited to small, cross-sectional studies which lack adjustment for important common causes. OBJECTIVE: We investigate the association between weight status and executive function longitudinally in mid-childhood, accounting for potential common causes. METHODS: Linear regression analyses were conducted to examine associations between weight status between 5 and 7 years and executive functioning at 11 years in members of the Millennium Cohort Study (n = 7739), accounting for a wide range of potential common causes. Age- and sex-specific International Obesity Taskforce cut-points for body mass index (BMI) were used. Executive function, including decision-making, impulsivity and spatial working memory, was assessed using the Cambridge Neuropsychological Test Automated Battery. RESULTS: There were no unadjusted associations between weight status and decision-making or impulsivity. After adjustment for all potential common causes, there was a lack of consistent evidence to support an association between persistent obesity (including overweight) between 5 and 7 years and spatial working memory task at 11 years. CONCLUSIONS: We found little evidence that poorer spatial working memory contributes to the association of children with obesity having lower educational achievement.

Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case-control study.

OBJECTIVE: Depression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD. DESIGN: We conducted a nested case-control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn's disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5-5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status. RESULTS: We identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38). CONCLUSIONS: Depression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD.