Early Ileocecal Resection for Crohn's Disease Is Associated With Improved Long-term Outcomes Compared With Anti-Tumor Necrosis Factor Therapy: A Population-Based Cohort Study.

BACKGROUND & AIMS: Early Crohn's disease (CD) treatment involves anti-tumor necrosis factor (TNF) agents, whereas ileocecal resection (ICR) is reserved for complicated CD or treatment failure. We compared long-term outcomes of primary ICR and anti-TNF therapy for ileocecal CD. METHODS: Using cross-linked nationwide registers, we identified all individuals diagnosed with ileal or ileocecal CD between 2003 and 2018 and treated with ICR or anti-TNF agents within 1 year of diagnosis. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. We conducted adjusted Cox's proportional hazards regression analyses and determined the cumulative risk of different treatments after primary ICR or anti-TNF therapy. RESULTS: Of 16,443 individuals diagnosed with CD, 1279 individuals fulfilled the inclusion criteria. Of these, 45.4% underwent ICR and 54.6% received anti-TNF. The composite outcome occurred in 273 individuals (incidence rate, 110/1000 person-years) in the ICR group and in 318 individuals (incidence rate, 202/1000 person-years) in the anti-TNF group. The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54-0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes. The proportion of individuals on immunomodulator, anti-TNF, who underwent subsequent resection, or were on no therapy 5 years post-ICR was 46.3%, 16.8%, 1.8%, and 49.7%, respectively. CONCLUSION: These data suggest that ICR may have a role as first-line therapy in CD management and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Yet, given inherent biases associated with observational data, our findings should be interpreted and applied cautiously in clinical decision making.

The effectiveness of pollen allergen immunotherapy on allergic rhinitis over 18 years: A national cohort study in Denmark.

BACKGROUND: Because long-term effectiveness of pollen allergen immune therapy (AIT) for allergic rhinitis (AR) is not well-described, we studied effectiveness over 18 years in Denmark. METHODS: A register-based cohort study using data on filled prescriptions, 1995-2016, Denmark. In a cohort of 1.1 million intranasal corticosteroid inhaler users (proxy for AR), we matched users treated with grass, birch or mugwort AIT 1:2 with non-treated users on baseline year and 24 characteristics in the 3 years prior to baseline. The primary outcome was the odds ratio (OR) of using anti-allergic nasal inhaler during the pollen season in the treated versus non-treated group by years since baseline. RESULTS: Among 7760 AR patients treated with pollen AIT, the OR of using nasal inhaler 0-5 years after baseline was reduced when compared with 15,520 non-treated AR individuals (0-2 years, OR 0.84 (0.81-0.88); 3-5 years, OR 0.88 (0.84-0.92)), but was close to unity or higher thereafter (6-9 years, OR 1.03 (0.97-1.08); 10-18 years, OR 1.18 (1.11-1.26)). In post hoc analyses, results were more consistent for those who already had 3 of 3 baseline years of use, and in patients using nasal inhaler in the latest pollen season (0-2 years, OR 0.76 (0.72-0.79); 3-5 years OR 0.86 (0.81-0.93); 6-9 years, OR 0.94 (0.87-1.02); 10-18 years, OR 0.94 (0.86-1.04)) as opposed to no such use. CONCLUSIONS: Patients treated with pollen AIT in routine care to a higher degree stopped using anti-allergic nasal inhaler 0-5 years after starting the standard 3 years of therapy, and not beyond 5 years. Post hoc analyses suggested effectiveness was more consistent among patients with persistent AR.

Medication-Wide Study: Exploring Medication Use 10 Years Before a Diagnosis of Inflammatory Bowel Disease.

INTRODUCTION: There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis. METHODS: Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching. RESULTS: The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication ( P -value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis ( P -value < 0.0001). DISCUSSION: Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD.

Endocrine disease history and the risk of postpartum depression.

BACKGROUND: Previous research has suggested that some women are at increased risk of postpartum depression (PPD) because of an extra sensitivity to fluctuating hormones before and after parturition. This may particularly apply to women with endocrine disease, characterised by a less than optimal capability to self-regulate the hormonal feedback system. AIMS: To investigate if women with endocrine disease history are at increased risk of developing PPD. METHOD: Based on information from Danish national registers, this nationwide cohort study included 888 989 deliveries (1995-2018). Endocrine disease history was defined as thyroid disease, pre-pregnancy diabetes, polycystic ovary syndrome and/or previous gestational diabetes within 10 years before pregnancy start. PPD was defined as use of antidepressants and/or hospital contact for depression within 6 months after childbirth. RESULTS: Among 888 989 deliveries, 4.1% had a history of endocrine disease and 0.5% had a PPD episode. Overall, women with an endocrine disease history had a 42% (risk ratio 1.42, 95% CI 1.24-1.62) higher risk of PPD when compared with women with no endocrine disease. However, we also found the reverse association, whereby women with a PPD history had a 50% (hazard ratio 1.5, 95% CI 1.4-1.6) higher risk of endocrine disease when compared with women with no PPD history. CONCLUSIONS: Women with endocrine disease history had a 40% higher risk of PPD compared with women with no endocrine disease. More attention should be given to pregnant women with endocrine disease history to increase awareness of early signs of PPD. The bi-directionality of the association points to a common underlying factor.

Familial risk of postpartum depression.

OBJECTIVE: Many psychiatric diseases have a strong familial aggregation, but it is unknown whether postpartum depression (PPD) without prior psychiatric history aggregates in families. METHODS: Based on Danish national registers, we constructed a cohort with information on 848,544 singleton deliveries (1996-2017). Women with an episode of PPD were defined as having used antidepressant medication and/or had a hospital contact for depression within 6 months after delivery. Those with psychiatric history prior to the delivery were excluded. We estimated relative risk (RR) of PPD, comparing women with female relatives with and without PPD history, respectively. RESULTS: Overall, women with a PPD history in female blood relatives had themselves a higher risk of PPD (RR = 1.64, 95% CI 1.16-2.34). Having the first-degree female relative with PPD history was associated with a more than 2.5 times (RR = 2.65, 95% CI 1.79-3.91) increased risk of PPD. However, having the second/third-degree female relative and/or a female non-blood relative with PPD history did not increase the woman's own risk of PPD (RR = 0.58, 95% CI 0.26-1.28, RR = 1.09, 95% CI 0.83-1.44). CONCLUSION: Postpartum depression aggregates in families with no other psychiatric history, but the findings do not support a strong genetic trait as a major cause. Other possible mechanisms are shared environment and/or health-seeking behavior in close relationships.

Does smoking during pregnancy mediate educational disparities in preterm delivery? Findings from three large birth cohorts.

BACKGROUND: Socio-economic disparities in preterm delivery have often been attributed to socially patterned smoking habits. However, most existing studies have used methods that potentially give biased estimates of the mediating effect of smoking. We used a contemporary mediation approach to study to which extent smoking during pregnancy mediates educational disparities in preterm delivery. METHODS: We performed a comparative analysis of data from three large birth cohort studies: the Danish National Birth Cohort (DNBC), the Dutch Generation R Study, and the Norwegian Mother and Child Cohort Study (MoBa). Risk of preterm delivery by maternal education is reported as risk differences and decomposed into a part explained by smoking and a part explained by other pathways. RESULTS: Proportions of preterm singleton deliveries were 4.8%-4.9% in all three cohorts. Total effects of maternal education were 2.0 (95% confidence interval [CI] 1.4, 2.5), 3.2 (95% CI 0.8, 5.2) and 2.0 (95% CI 0.9, 3.0) excess preterm deliveries per 100 singleton deliveries in DNBC, Generation R and MoBa when comparing primary/lower secondary education to an academic degree or equivalent. Smoking mediated, respectively, 22%, 10% and 19% of the excess risk in the DNBC, Generation R and MoBa cohorts. Adjustment for potential misclassification of smoking only increased mediated proportions slightly. CONCLUSIONS: Smoking during pregnancy explains part of educational disparities in preterm delivery, but the mediated proportion depends on the educational gradient in smoking, emphasising that educational disparities in preterm birth may be mediated by different risk factors in different countries.

Educational Attainment and Pregnancy Outcomes: A Danish Register-Based Study of the Influence of Childhood Social Disadvantage on Later Socioeconomic Disparities in Induced Abortion, Spontaneous Abortion, Stillbirth and Preterm Delivery.

Objectives Socioeconomic disparities in pregnancy outcomes have been found across times and places, but there is a lack of studies investigating the underlying causes. The present study investigated the influence of child protective services in the pregnant woman's family of origin as a proxy of childhood social disadvantage. Methods The study population comprised all registered pregnancies in Denmark during the period from 2000 to 2009 that resulted in an induced abortion, spontaneous abortion, stillbirth or live birth (N = 786,054). Linear regression was used to analyze the associations between educational attainment and pregnancy outcomes in models with and without adjustment for age, parental educational attainment and child protective services in the family of origin. Further, it was tested whether child protective services in the pregnant woman's family of origin modified the associations between educational attainment and pregnancy outcomes. Results Women with low educational attainment had a higher risk of induced abortion, stillbirth and preterm delivery and a lower risk of spontaneous abortion. These associations were to some extent explained by child protective services in the family of origin. Further, child protective services in the pregnant woman's family of origin modified the association between educational attainment and risk of preterm delivery. Thus, women with high educational attainment were not found to differ in risk of preterm delivery according to child protective services in the family of origin Conclusions for Practice Information on childhood social disadvantage may enrich our understanding of the socioeconomic disparities in pregnancy outcomes.

Association of light-to-moderate alcohol drinking in pregnancy with preterm birth and birth weight: elucidating bias by pooling data from nine European cohorts.

Women who drink light-to-moderately during pregnancy have been observed to have lower risk of unfavourable pregnancy outcomes than abstainers. This has been suggested to be a result of bias. In a pooled sample, including 193 747 live-born singletons from nine European cohorts, we examined the associations between light-to-moderate drinking and preterm birth, birth weight, and small-for-gestational age in term born children (term SGA). To address potential sources of bias, we compared the associations from the total sample with a sub-sample restricted to first-time pregnant women who conceived within six months of trying, and examined whether the associations varied across calendar time. In the total sample, drinking up to around six drinks per week as compared to abstaining was associated with lower risk of preterm birth, whereas no significant associations were found for birth weight or term SGA. Drinking six or more drinks per week was associated with lower birth weight and higher risk of term SGA, but no increased risk of preterm birth. The analyses restricted to women without reproductive experience revealed similar results. Before 2000 approximately half of pregnant women drank alcohol. This decreased to 39% in 2000-2004, and 14% in 2005-2011. Before 2000, every additional drink was associated with reduced mean birth weight, whereas in 2005-2011, the mean birth weight increased with increasing intake. The period-specific associations between low-to-moderate drinking and birth weight, which also were observed for term SGA, are indicative of bias. It is impossible to distinguish if the bias is attributable to unmeasured confounding, which change over time or cohort heterogeneity.

Exploring educational disparities in risk of preterm delivery: a comparative study of 12 European birth cohorts.

BACKGROUND: An association between education and preterm delivery has been observed in populations across Europe, but differences in methodology limit comparability. We performed a direct cross-cohort comparison of educational disparities in preterm delivery based on individual-level birth cohort data. METHODS: The study included data from 12 European cohorts from Denmark, England, France, Lithuania, the Netherlands, Norway, Italy, Portugal, and Spain. The cohorts included between 2434 and 99 655 pregnancies. The association between maternal education and preterm delivery (22-36 completed weeks of gestation) was reported as risk ratios, risk differences, and slope indexes of inequality with 95% confidence intervals (CIs). RESULTS: Singleton preterm live delivery proportion varied between 3.7% and 7.5%. There were large variations between the cohorts in the distribution of education and maternal characteristics. Nevertheless, there were similar educational differences in risk of preterm delivery in 8 of the 12 cohorts with slope index of inequality varying between 2.2 [95% CI 1.1, 3.3] and 4.0 [95% CI 1.4, 6.6] excess preterm deliveries per 100 singleton deliveries among the educationally most disadvantaged, and risk ratio between the lowest and highest education category varying from 1.4 [95% CI 1.1, 1.8] to 1.9 [95% CI 1.2, 3.1]. No associations were found in the last four cohorts. CONCLUSIONS: Educational disparities in preterm delivery were found all over Europe. Despite differences in the distributions of education and preterm delivery, the results were remarkably similar across the cohorts. For those few cohorts that did not follow the pattern, study and country characteristics did not explain the differences.

Risk of cancer in patients with bile acid diarrhoea: a Danish nationwide matched cohort study.

OBJECTIVE: Bile acid diarrhoea is a common cause of chronic diarrhoea. Increased levels of potentially carcinogenic bile acids in faeces, theoretically, may increase the risk of colorectal cancer in particular, but the long-term disease course is unknown. We aimed to investigate the overall and site-specific cancer risk in bile acid diarrhoea. DESIGN: Adult patients with bile acid diarrhoea were identified using nationwide Danish registries from 2003 to 2020 by a diagnostic gold-standard 75-selenium tauroselcholic acid procedure followed within 6 months by sequestrant prescription. The risk of overall and site-specific cancers in cases with bile acid diarrhoea was compared with sex, age and comorbidity-adjusted matched controls. A competing risk model estimated cumulative incidence functions and cause-specific HRs. RESULTS: We identified 2260 patients with bile acid diarrhoea with a mean follow-up of 5.5 years (SD 4.2). The overall cancer risk was increased by an HR of 1.32 (95% CI 1.12 to 1.54). The risk of site-specific cancer was increased in 3 of 10 cancer groups: haematological, HR 2.41 (1.36 to 4.02); skin, HR 1.33 (1.01 to 1.71); and male genital cancers, HR 1.85 (1.11 to 2.92). No increased risk of colorectal cancer was detected in patients with bile acid diarrhoea, HR 0.73 (0.34 to 1.63). CONCLUSIONS: Bile acid diarrhoea was associated with an increased overall risk of cancer, especially haematological cancers, but the risk of colorectal cancer was not increased. The lack of a diagnostic code for bile acid diarrhoea and potential residual confounding are limitations, and the findings should be replicated in other cohorts.

Impact of immunosuppressive therapy on SARS-CoV-2 mRNA vaccine effectiveness in patients with immune-mediated inflammatory diseases: a Danish nationwide cohort study.

OBJECTIVE: Patients receiving immunosuppressives have been excluded from trials for SARS-CoV-2 vaccine efficacy. Investigation of immunosuppressants' impact on effectiveness of vaccines, particularly in patients with immune-mediated inflammatory diseases (IMID), is therefore required. DESIGN: We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated patients with IMID exposed to immunosuppressives compared with IMID unexposed to immunosuppressives. Exposure to immunosuppressives in the 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from date of second vaccination and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death associated with a positive SARS-CoV-2 test. Risk of infection by immunosuppressant drug class was also analysed. SETTING: This study used population-representative data from Danish national health registries in the period from 1 January to 30 November 2021. RESULTS: Overall, 152 440 patients were followed over 19 341 person years. Immunosuppressants were associated with a significantly increased risk of infection across IMID (HR: 1.4, 95% CI 1.2 to 1.5), in inflammatory bowel disease (IBD) (HR: 1.6, 95% CI 1.4 to 1.9) and arthropathy (HR: 1.3, 95% CI 1.1 to 1.4) but not psoriasis (HR: 1.1, 95% CI 0.9 to 1.4). Immunosuppressants were also associated with an increased risk of hospitalisation across IMID (HR: 1.4, 95% CI 1.1 to 2.0), particularly in IBD (HR: 2.1, 95% CI 1.0 to 4.1). No significantly increased risk of death in immunosuppressant exposed patients was identified. Analyses by immunosuppressant drug class showed increased COVID-19 infection and hospitalisation with anti-tumour necrosis factor (TNF), systemic corticosteroid, and rituximab and other immunosuppressants in vaccinated patients with IMID. CONCLUSION: Immunosuppressive therapies reduced effectiveness of mRNA SARS-CoV-2 vaccination against infection and hospitalisation in patients with IMID. Anti-TNF, systemic corticosteroids, and rituximab and other immunosuppressants were particularly associated with these risks.

Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Gestational age and cognitive ability in early childhood: a population-based cohort study.

BACKGROUND: Recent studies suggest that children born at late preterm (34-36 weeks gestation) and early term (37-38 weeks) may have poorer developmental outcomes than children born at full term (39-41 weeks). We examined how gestational age is related to cognitive ability in early childhood using the U.K. Millennium Cohort Study. METHODS: Cognitive development was assessed using Bracken School Readiness Assessment at age 3 years, British Ability Scales II at ages 3, 5 and 7 years and Progress in Mathematics at age 7 years. Sample size varied according to outcome between 12,163 and 14,027. Each gestational age group was compared with the full-term group using differences in z-scores and risk ratios for scoring more than -1 SD below the mean. RESULTS: Children born at <32 weeks gestation scored lower (P < 0.05) than the full-term group on all scales with unadjusted z-score differences ranging between -0.8 to -0.2 SD. In all groups, there was an increased risk (P < 0.05) of scoring less than -1 SD below the mean compared with the full-term group for some of the tests: those born at < 32 weeks had a 40-140% increased risk in seven tests, those born at 32-33 weeks had a 60-80% increased risk in three tests, those born at 34-36 weeks had a 30-40% increased risk in three tests, and those born at 37-38 weeks had a 20% increased risk in two tests. CONCLUSIONS: Cognitive ability is related to the entire range of gestational age, including children born at 34-36 and 37-38 weeks gestation.

Pregnancy and birth cohort resources in europe: a large opportunity for aetiological child health research.

BACKGROUND: During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. METHODS: European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. RESULTS: In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. CONCLUSION: This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.

Risk of anxiety, depression, and ADHD in pediatric patients with inflammatory bowel disease: A population-based cohort study.

INTRODUCTION: Inflammatory bowel disease (IBD) is associated with depression and anxiety in adults, but data is scarce on risk of psychiatric diseases in children with IBD. We aimed to estimate the risk of anxiety, depression, or attention-deficit/hyperactivity disorder in patients with pediatric-onset IBD. METHODS: We performed a nationwide, register-based cohort study including all patients with pediatric-onset IBD diagnosed in Denmark in the period 1998-2018, resulting in 3,559 patients matched 1:5 on age, sex, municipality of residence, and time period, resulting in 17,795 reference individuals. We used Cox regression to calculate hazard ratios for each outcome following a diagnosis with IBD. RESULTS: Patients with pediatric-onset IBD had an increased risk of depression (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.26-1.80) and of using antidepressants (HR 1.54, 95% CI 1.39-1.71), and surprisingly a reduced risk of using methylphenidate (HR 0.75, 95% CI 0.58-0.98). Patients with both IBD subtypes (Crohn's diseases [CD] and ulcerative colitis [UC]) had an increased risk of using antidepressants and developing depression, which was particularly high in patients with CD (HR 1.73, 95% CI 1.35-2.22). Patients with UC had reduced risk of using methylphenidate (HR 0.63, 95% CI 0.43-0.93) and a reduced - though not statistically significant - risk of being diagnosed with ADHD compared with the background population. DISCUSSION: Patients with pediatric-onset IBD have a 50% increased risk of developing depression, which is important for health care providers to be aware of and manage. Remarkably, we found a reduced risk of receiving methylphenidate and being diagnosed with ADHD, which merits further investigation.

Longitudinal trajectories of anxiety, depression, and bipolar disorder in inflammatory bowel disease: a population-based cohort study.

Background: Inflammatory bowel disease (IBD) is associated with psychiatric diseases, but it is unclear to what degree patients with IBD are affected over their lifetime. We aimed to longitudinally investigate the risk of anxiety, depression, and bipolar disorder before and after IBD diagnosis to understand the full burden of these diseases in patients with IBD. Methods: In this population based cohort study, we identified 22,103 patients diagnosed with IBD between January 1, 2003 and December 31, 2013 in the Danish National registers and 110,515 matched reference individuals from the general population. We calculated yearly prevalence of hospital contacts for anxiety, depression, and bipolar disorder and dispensed prescriptions for antidepressants from five years before to ten years after IBD diagnosis. We used logistic regression to calculate prevalence odds ratios (OR) for each outcome prior to IBD diagnosis, and Cox regression to calculate hazard ratios (HR) of new outcomes after IBD diagnosis. Findings: During >150,000 person years follow-up, patients with IBD had higher risk of anxiety (OR 1.4; 95% confidence interval (CI) 1.2-1.7) and depression (OR 1.4; 95% CI 1.3-1.6) starting at least five years before and continuing until at least ten years after IBD diagnosis (HR 1.3; 95% CI 1.1-1.5 for anxiety and HR 1.5; 95% CI 1.4-1.7 for depression). The risk was particularly high around IBD diagnosis and in patients diagnosed with IBD after the age of 40 years. We found no association between IBD and bipolar disorder. Interpretation: This population-based study suggests that anxiety and depression are clinically significant comorbidities of IBD both before and after IBD diagnosis, which warrant thorough evaluation and management, particularly around the time of IBD diagnosis. Funding: The Danish National Research Foundation [DNRF148], the Lundbeck Foundation [R313-2019-857], and Aage og Johanne Louis-Hansens Fond [9688-3374 TJS].

Characterizing the pre-clinical phase of inflammatory bowel disease.

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.