В канадском продольном исследовании по проблемам старения было проведено исследование с целью выявления взаимосвязи между неблагоприятным детским опытом и иммунопосредованным воспалительным заболеванием.

STRENGTHS AND LIMITATIONS OF THIS STUDY

We analysed a large (n=12 627) population-based sample of Canadians and adjusted for the sampling design using weights.

We used multiple comparator disease cohorts and adjusted for multiple potential confounders.

We captured several different types of adverse childhood experiences (ACE), including maltreatment and household dysfunction, using a validated questionnaire; however, ACE were self-reported, retrospectively, which could lead to recall bias.

Our study design precludes causal inference, thereby inhibiting evaluation of mechanisms responsible for the associations observed.

Introduction

Chronic immune-mediated inflammatory diseases (IMID) affect over 5% of people worldwide and markedly burden affected individuals and society, but their aetiology remains incompletely understood. 1 Given their high burden, understanding their aetiology and potential prevention strategies is important. Rheumatoid arthritis (RA), multiple sclerosis (MS) and inflammatory bowel disease (IBD) are IMID jointly characterised by acute exacerbations and underlying disease progression that have a high incidence in North America. 2 Risk for IMID reflects a complicated interaction between genetic factors and environmental exposures. 3

Adverse childhood experiences (ACE) include childhood maltreatment such as physical and sexual abuse, physical and emotional neglect, or household dysfunction, including parental divorce and exposure to domestic violence. 4 Prior studies have reported associations between ACE and risk of chronic disease, including IMID. For example, a case-control study found that 234 people with MS reported more childhood maltreatment on the Childhood Trauma Questionnaire than 885 participants from the general population, 5 similar to findings of a case-control study of RA. 6 Although an increasing number of studies have evaluated the relationship between ACE and IMID, some have had important limitations including use of small samples, not being population-based, inappropriate choice of controls and failure to use formal assessment tools for ACE. 7 8 Moreover, a recent meta-analysis suggested that ACE were not associated with IMID in general, but reported that specific types of experiences, including emotional abuse and neglect, might be associated with specific IMID. 7 This indicates that further evaluation of the association between ACE and IMID is needed; the meta-analysis highlighted the importance of using multiple comparison groups to clarify the association between ACE and IMID.

Previously, we found that the prevalence of reporting ≥1 childhood maltreatment was similar across RA, MS and IBD groups, but higher than that reported by healthy controls, although the sample size was small. 9 Prior studies have not addressed whether the association between ACE and IMID was similar in magnitude to the association of ACE and other non-IMID. Due to the association of ACE with altered immune reactivity and inflammatory burden, 10 there may be different relationships between ACE and IMID when compared with diseases that are neither inflammatory nor classically immune-mediated. Similarly, ACE have been associated with differences in brain development, such that there may be different relationships between ACE and disorders involving the central nervous system (CNS) than in those that do not. 11

Prior studies have established a relationship between ACE and chronic diseases, including IMID. 5 , 9 For this analysis, our aim was to build on the existing literature by evaluating whether the association between ACE and chronic diseases differs based on whether the disease is immune-mediated or affects the CNS. Therefore, we evaluated whether the association between ACE and IMID differed from the association of ACE with having no chronic diseases or chronic diseases that contrast with IMID including epilepsy (neither inflammatory nor immune-mediated), asthma (aetiology inflammatory but includes more allergic pathogenesis than the classic IMID) and diabetes (aetiology not immune-mediated but can be complicated by inflammation). Each comparison group serves a different purpose by providing the ability to control for a possible pathophysiological mechanism. We also evaluated whether the association between ACE and IMID differed based on the type of IMID, specifically RA, MS or IBD. We hypothesised that ACE would be associated with an increased risk of an IMID diagnosis compared with no chronic health condition or the diagnosis of epilepsy, diabetes or asthma. We hypothesised that the association between ACE and RA, MS and IBD would not differ. Knowledge of differences in the strengths of association may inform policies and strategies aimed at disease-specific prevention by focusing on the most impactful risk factors for each disease.

Methods

Source population

This is a nested retrospective case-control study conducted using data from the Canadian Longitudinal Study on Aging (CLSA). 12 13 As detailed elsewhere, the CLSA enrolled individuals aged 45–85 years between 2010 and 2015 in two cohorts using a stratified random sampling scheme. The tracking cohort includes 21 241 participants from 10 provinces, and the comprehensive cohort includes 30 097 participants from seven provinces. 12 13 Participants in the CLSA are followed prospectively every 3 years until 2033, death or loss to follow-up. Individuals were included in this analysis if they: (1) were enrolled in the CLSA; (2) completed the Childhood Maltreatment and Health across the Lifespan section of the first follow-up survey; (3) responded yes or no when asked at baseline or the first follow-up visit whether they had been diagnosed with MS, RA, IBD or irritable bowel syndrome (IBS), diabetes, asthma or epilepsy; and (4) reported information for all covariates included in our analyses (described below). Participants were not asked to discriminate between the presence of IBD or IBS. We therefore categorised participants as having IBD if they reported having IBD or IBS and were exposed to immune therapies because immune therapies are used to treat IBD but not IBS. Ethics approval for use of de-identified CLSA data was provided by the University of Manitoba Health Research Ethics Board (HS25371). Participants in the CLSA all consented to their data being made available to researchers.

Patient and public involvement

There was no patient and public involvement in this analysis.

Measures

Adverse childhood experiences

The exposure of interest was ACE. During the first follow-up visit, participants were queried about exposure to eight types of ACE before age 16 years using questions from the Childhood Experiences of Violence Questionnaire-Short Form (CEVQ-SF) or the National Longitudinal Study of Adolescent to Adult Health Wave III questionnaire. 14 , 16 Childhood maltreatment was queried using 12 questions about exposure to: physical abuse (three questions), sexual abuse (two questions), neglect (one question) or emotional abuse (one question). Household dysfunction was queried using questions about exposure to: emotional or physical intimate partner violence (two questions), parental divorce or separation (one question), parental death (one question) or living with a family member with mental health problems (one question). The CEVQ-SF has moderate to good test-retest reliability and high internal consistency reliability and good construct validity. 15 Agreement, as measured by a kappa statistic, between the CEVQ-SF and the Childhood Trauma Questionnaire was 0.69 for physical abuse, and 0.69 for sexual abuse. Agreement between the CEVQ and CEVQ-SF was 0.82 for physical abuse and 0.65 for sexual abuse. 15

Exposure to each type of ACE was dichotomised as exposed or unexposed based on reports of frequency and severity, according to scoring instructions. 14 , 16 Participants were categorised as exposed to physical abuse if they reported being slapped on the face, head, or ears or hit or spanked with something hard three or more times; being pushed, grabbed, or shoved or having something thrown to hurt three or more times; or being kicked, bit, or punched or chocked, burned, or physically attacked in some other way one or more times. Participants were categorised as exposed to sexual abuse if they reported being threatened, touched or forced into unwanted sexual activity one or more times. Participants were exposed to emotional abuse if they reported parents or guardians swearing, saying hurtful or insulting things that made them feel unloved or unwanted three or more times. Participants were categorised as neglected if they reported their parents or guardians not having taken care of their basic needs. Participants were categorised as exposed to intimate partner violence if they reported having seen or heard their parents or guardians say hurtful things to each other six or more times, or seeing or hearing parents or guardians hit each other three or more times. Other types of ACE were assessed dichotomously without a specific threshold. To support dose-response analyses, we summed the number of individual ACE reported to create a cumulative ACE score (0, 1, 2 or ≥3).

Chronic disease (outcome)

Chronic diseases were queried at enrolment and follow-up. Participants were asked whether a doctor had ever told them that they have specific chronic diseases, including MS, RA, asthma, diabetes, epilepsy, or a bowel disorder such as IBD (Crohn’s Disease), ulcerative colitis, or IBS. Individuals meeting the criteria for ≥1 condition were assigned to the condition first conferred or excluded if missing year of diagnosis. Among participants with bowel disorders, we restricted inclusion to participants who were exposed to either disease modifying therapies or corticosteroids (detailed in online supplemental methods appendix ) because we were interested in only those participants with IBD, and IBS is not an indication for either class of medication. Medication data were collected from a subset of participants in the CLSA at baseline and first follow-up, as described previously. 17

Participants also reported diagnoses of anxiety disorder or a mood disorder such as depression (including manic depression), bipolar disorder, mania or dysthymia at enrolment and follow-up. Participants reported symptoms of depression at baseline and follow-up and post-traumatic stress at baseline. Symptoms of depression were reported using the Epidemiologic Studies Short Depression Scale 10, 18 which includes 10 questions scored on a 4-point scale; total scores range from 0 to 30, and scores ≥10 indicate depression. Symptoms of post-traumatic stress disorder mental disorder (PTSD) were reported using the four-item Primary Care Posttraumatic Stress Screen Scale, where endorsing at least three items classifies an individual as having PTSD. 19 20

Participants were categorised as having no chronic health condition if they: (1) did not report having any of the chronic physical or mental conditions queried; 21 (2) did not report having any other long-term physical or mental conditions that were not explicitly queried; and (3) had negative screens for depression and PTSD.

Covariates

At enrolment, participants reported date of birth, height, weight, sex assigned at birth, sexual orientation, country of birth, province of residence, cultural background, education, income and smoking status. Age at enrolment was derived from date of birth. Sex was identified as female or male. Sexual orientation was categorised as heterosexual or not due to small cell sizes among participants who identify as homosexual or bisexual. We classified country of birth as born in Canada or not. Cultural background was captured as a mixture of ethnicities and races, which we classified as White or not to optimise cell sizes. Education level was captured as <secondary, secondary graduate, some postsecondary and postsecondary education and then dichotomised as <secondary or not. Household income was captured as <$20 000, $20 000–$49 999, $50 000–$99 999, $100 000–$149 999 and ≥$150 000. Smoking status was classified as non-smoker or ever smoker, defined as lifetime smoking of more than 100 cigarettes. Body mass index (BMI) was derived using height and weight, which was measured in the comprehensive cohort and self-reported in the tracking cohort. We performed a causal mediation analysis to evaluate whether the association between childhood maltreatment (yes/no) and the diagnosis of chronic disease is mediated by smoking status (yes/no) or BMI (continuous). 22 We used a causal mediation package in Stata that implements a parametric algorithm and calculates the average mediation, direct effects by simulating predicted values of the mediator and outcome variable and then calculating the average causal mediation, direct and total effects and the proportion of the total effect that is mediated. 22 23 Based on the findings of this analysis, smoking status and BMI were ultimately included in the models as confounders rather than mediators.

Data analysis

All analyses were adjusted for the sampling design using weights provided by the CLSA, including inflation weights for descriptive analyses and analytic weights for the regression analyses. 24 We summarised participant characteristics using mean (SD), median (IQR) and frequency (percent). We compared participant characteristics between cohorts using unadjusted multinomial logistic regression.

First, we used multivariable polytomous logistic regression to compare whether the association of childhood maltreatment differed across diagnoses. The outcome of interest was diagnosis of IMID (reference group), diabetes, asthma, epilepsy or no chronic diseases. The exposure of interest was a history of childhood maltreatment (no history of childhood maltreatment as reference group).

Second, we used multivariable polytomous logistic regression to compare whether the association of childhood maltreatment differed across IMID diagnoses. The outcome of interest was IMID diagnosis (RA (reference group, MS or IBD)). The exposure of interest was history of childhood maltreatment (no history of childhood maltreatment as reference group). Only participants with IMID were included in these analyses. We reported risk ratios and 95% CIs.

These multivariable analyses were adjusted for covariates including age at enrolment (years, continuous), sex (male as reference group), cultural background (non-white as reference group), sexual orientation (non-heterosexual as reference group), BMI (continuous), smoking status (non-smoker as reference group, binary), education (no high school/General Educational Development as reference group), income (<$20 000 as reference group), province (Ontario as reference group) and country of birth (outside of Canada as reference group). Model assumptions were tested using standard methods. 25 General multinomial logit models generate relative risk ratios rather than ORs; we report relative risk ratios (95% CIs) for the associations observed. Discrimination was measured using multiclass receiver operating characteristic curves to evaluate the ability of our multinomial models to correctly classify observations into outcome categories (ie, diagnoses). 26 Calibration was measured using a goodness of fit test to evaluate agreement between our models’ estimates and observed outcomes. 27 We controlled the false discovery rate using the Benjamini-Hochberg procedure and a critical value of 0.10. 28

Complementary analyses

For comparability to prior work, we repeated multivariable analyses using no chronic disease as the reference group. As described above, we first analysed maltreatment as our primary exposure. We repeated all multivariable analyses using the following secondary exposures: (i) household dysfunction (binary, yes/no); (ii) count of ACE (ordinal; 0, 1, 2 ≥3); and (iii) individual ACE. We examined childhood maltreatment separate from household dysfunction for comparability to prior ACE work. 9 We examined different forms of ACE (eg, count) because a prior study found that the association between ACE and IMID depended on the type of ACE reported. 9 We also repeated our multivariable analyses of IMID participants stratified by sex because a prior study found sex-specific associations between ACE and having an IMID. 9

Sensitivity analyses were performed that excluded people with >1 condition of interest.

Statistical analyses were conducted using Stata 18.0. 23

Results

Participants

Overall, 12 627 CLSA participants met our inclusion criteria; 11 540 were included in our analysis comparing participants with IMID (n=837), other chronic diseases of interest (diabetes n=5 519; asthma n=3 889; epilepsy n=170) or no chronic diseases (n=1 125). We included 2 102 participants in the analysis limited to those with IMID (258 MS, 1 692 RA, 160 IBD); we retained more people with IMID in this analysis because we excluded fewer people related to missing year of condition diagnosis as there were fewer conditions involved ( figure 1 ). Participants had a median (IQR) age of 62 (54–70) years at enrolment, and approximately half were female (50%) or smokers (57%). The median BMI of participants was within the healthy range (28). Most participants were born in Canada (83%), identified as heterosexual (98%), reported white cultural backgrounds (94%) and achieved more than a secondary school education (80%). More than 60% (66%) of participants reported annual household incomes ≥$50 000.

Participants. Among the 51 338 participants enrolled in the CLSA, 44 815 participated in the first follow-up visit, of whom 42 904 completed the questions about ACE. There were 42 762 participants who responded to questions about the diagnosis of MS, IBD, RA, asthma, diabetes and epilepsy, of whom 39 924 also responded to questions about all of the covariates included in the multivariable analyses. We then created two separate cohorts of participants: (1) participants with RA, MS, IBD, diabetes, asthma, epilepsy or no chronic diseases and (2) participants with RA, MS or IBD. Individuals meeting the criteria for ≥1 condition were assigned to the condition first conferred or excluded if missing year of diagnosis, therefore resulting in fewer participants with IMID included in cohort 1 versus cohort 2. Among the 6 246 CLSA participants who reported a diagnosis of IBD or IBS, 3 754 were queried about medications, and 235 were categorised as having IBD because they reported exposure to immune therapies. ACE, adverse childhood experience; CLSA, Canadian Longitudinal Study on Aging; IBD, inflammatory bowel disease; IMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis.

Adverse childhood experiences

Nearly two-thirds of participants (64%) reported a history of either maltreatment or household dysfunction, and 30% reported both. Physical abuse was the most (28%) frequently reported type of ACE, followed by emotional abuse (24%), emotional or physical intimate partner violence (23%), family member(s) with mental illness (22%), sexual abuse (19%), death of a parent (18%), parental divorce or separation (13%) and neglect (4%). One-quarter of participants reported exposure to ≥3 types of ACE. Female participants were more likely to report each type of ACE, except males were more likely to report physical abuse (p<0.05). Younger age at CLSA enrolment was associated (p<0.05) with each type of abuse, except for parental death, which was associated with older age. Higher BMI and smoking were associated with each type of abuse (p<0.05).

Bivariate analyses

Table 1 shows the characteristics of participants stratified by disease cohort. Participants with IMID were more likely to be female, have lower BMIs and report White cultural backgrounds compared to participants with diabetes. Those with IMID were older than those with asthma. Participants with IMID were older and had lower household incomes than those with epilepsy. Participants with IMID were more likely to be female, smoke, be older at CLSA enrolment, have higher BMIs, report White cultural background, not complete post-secondary education, and have lower incomes than those with no chronic diseases.

Table 1 Characteristics of participants stratified by type of disease or IMID Characteristic Stratification by type of disease Stratification by IMID IMID (reference) Diabetes Asthma Epilepsy No chronic disease RA (reference) MS IBD Female, % 62
44
60 49
34
61 72
53
Smoker, % 61 60 58 53
40
61 73 63 Born in Canada, % 86 83 88 87 87 85 92 85 White cultural background, % 97
93
95 94
94
95 94 91 Heterosexual, % 98 98 98 97 99 99 97 96 Age (years) at enrolment, median (IQR) 62 (55, 70) 64 (57, 72) 59 (53, 67 ) 60 (53, 66 ) 53 (50, 59 ) 64 (57, 73) 57 (52, 64 ) 61 (55, 69) BMI (kg/m 2 ), median (IQR) 27 (24, 30) 30 (27, 33 ) 28 (25, 31) 28 (25, 32) 26 (23, 28 ) 28 (25, 32) 26 (23, 29 ) 27 (24, 31) Province of residence, %  Ontario 51
37

36

16

39
48 32 27  Quebec 15 22 26 31 26 15 25 22  Western provinces 25 32 31 48 29 29 37 45  Atlantic provinces 8 9 7 5 6 8 6 6 ≥Secondary school education, % 78 76 83 88
92
76 85 83 Income, %  <$20 000 6 7 7 20 1 9 10 2  $20 000–$49 000 32 31 24
15
13 33 22 21  $50 000–$99 999 38 35 33
29

39
37 37
32
 $100 000–$149 999 15 15 21 23
22
12 20
15
 ≥$150 000 10 11 15 13
25
9 11
30
We compared participants with diabetes, asthma, epilepsy or no chronic disease to participants with IMID (reference group). We compared participants with MS or IBD to participants with RA (reference group). Bold indicates statistical significance (pp<0.05). Western provinces include British Columbia, Alberta, Saskatchewan, and Manitoba. Atlantic provinces include Nova Scota, New Brunswick, Prince Edward Island, and Newfoundland. We report the percentage of participants in each cohort according to standard practice when using survey data with a particular sampling scheme. BMI, body mass index; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

Characteristics of participants stratified by type of disease or IMID

We compared participants with diabetes, asthma, epilepsy or no chronic disease to participants with IMID (reference group).

We compared participants with MS or IBD to participants with RA (reference group). Bold indicates statistical significance (pp<0.05).

Western provinces include British Columbia, Alberta, Saskatchewan, and Manitoba. Atlantic provinces include Nova Scota, New Brunswick, Prince Edward Island, and Newfoundland.

We report the percentage of participants in each cohort according to standard practice when using survey data with a particular sampling scheme.

BMI, body mass index; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

Participants with IMID reported ACEs less frequently compared with those with other chronic diseases and more frequently reported ACEs compared with those with no chronic diseases. Specifically, fewer participants with IMID reported emotional abuse compared with those with asthma; neglect compared with those with diabetes, asthma or epilepsy; family member(s) with mental illness compared with those with diabetes; and fewer participants with IMID reported parental divorce or separation compared with those with epilepsy. Compared with participants with no chronic diseases, more participants with IMID reported physical, sexual or emotional abuse; history of any household dysfunction; emotional or physical intimate partner violence; and higher counts of ACE types ( table 2 ). A larger proportion (8–12%) of participants with IBD reported maltreatment, physical abuse, emotional abuse and ≥3 ACE when compared with participants with RA or MS; however, we did not observe statistically significant differences between IMID groups possibly due to the small sample size.

Table 2 Frequency of ACE stratified by type of disease or IMID ACE Stratification by type of disease Stratification by IMID IMID (reference) Diabetes Asthma Epilepsy No chronic disease RA (reference) MS IBD History of any maltreatment, % 43 44 47 54
30
46 48 57 Physical abuse, % 27 28 30 37
19
31 22 40 Sexual abuse, % 22 19 22 31
9
23 27 20 Emotional abuse, % 20 24
27
33
14
22 22 34 Neglect, % 2
5

5

16
1 4 3 4 History of any household dysfunction, % 52 49 55 53
36
53 60 60 Emotional or physical intimate partner violence, % 24 22 28 28
13
25 23 29 Parental death, % 15 18 17 18 14 19 20 21 Family member(s) with mental illness, % 20
21
27 33 15 20 32 24 Parental divorce or separation, % 12 14 13
25
9 11 11 12 Count ACE, %  0 36 36 33 31 51 33 34 29  1 25 26 25 20 26 27 19 18  2 15 15 15 16
12
15 20 18  ≥3 23 23 28 32
12
25 27 35 We compared participant characteristics between cohorts using bivariate multinomial logistic regression. We compared participants with diabetes, asthma, epilepsy or no chronic disease to participants with IMID (reference group). We compared participants with MS or IBD to participants with RA (reference group). Bold indicates statistical significance (pp<0.05). We report the percentage of participants in each cohort according to standard practice when using survey data with a particular sampling scheme. ACE, adverse childhood experience; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

Frequency of ACE stratified by type of disease or IMID

We compared participant characteristics between cohorts using bivariate multinomial logistic regression.

We compared participants with diabetes, asthma, epilepsy or no chronic disease to participants with IMID (reference group).

We compared participants with MS or IBD to participants with RA (reference group). Bold indicates statistical significance (pp<0.05).

We report the percentage of participants in each cohort according to standard practice when using survey data with a particular sampling scheme.

ACE, adverse childhood experience; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

Multivariable analyses

History of neglect was associated with increased relative risk (5.99 (2.06–17.40); p=0.001) of epilepsy compared with an IMID diagnosis ( table 3 ). History of any maltreatment, sexual abuse and any household dysfunction all associated with increased relative risk of IMID compared with no chronic disease (p<0.01). Additionally, history of ≥3 types of ACE was associated with increased relative risk (2.70 (1.64–4.55)) of IMID compared with no chronic disease. History of physical abuse, emotional abuse, emotional or physical intimate partner violence, having ≥1 family member(s) with mental illness and having two types of ACE also associated with increased relative risk of IMID compared with no chronic disease; however, these associations were not statistically significant after we controlled for the false discovery rate. History of maltreatment was associated with increased risk of all chronic diseases when compared with no chronic disease (p<0.01; online supplemental table 1 ).

Table 3 Relative risk ratio estimates (95% CIs) for variables associated with different types of ACE, stratified by type of disease, IMID, or IMID and sex Outcome Stratification by type of disease Stratification by IMID IMID (reference) Diabetes Asthma Epilepsy No chronic disease RA (reference) MS IBD History of any maltreatment 1.06 (0.79, 1.43) 1.10 (0.81, 1.50) 1.34 (0.75, 2.40) 0.55 (0.39, 0.79 ) 0.95 (0.58, 1.57) 1.81 (0.97, 3.36)  Physical abuse 1.00 (0.71, 1.40) 1.10 (0.78, 1.55) 1.29 (0.66, 2.52) 0.54 (0.36, 0.81) 0.50 (0.28, 0.90) 1.53 (0.80, 2.91)  Sexual abuse 1.05 (0.70, 1.58) 0.98 (0.65, 1.48) 1.68 (0.85, 3.34) 0.42 (0.25, 0.72 ) 1.06 (0.58, 1.97) 1.16 (0.52, 2.59)  Emotional abuse 1.34 (0.95, 1.91) 1.34 (0.95, 1.89) 1.58 (0.82, 3.02) 0.59 (0.38, 0.90) 0.87 (0.48, 1.57) 2.03 (1.11, 3.71)  Neglect 2.11 (1.13. 3.94) 1.75 (0.94, 3.23) 5.99 (2.06, 17.40 ) 0.59 (0.17, 2.02) 0.69 (0.10, 4.60) 1.42 (0.52, 3.92) History of any household dysfunction 0.96 (0.73, 1.26) 1.12 (0.85, 1.48) 1.01 (0.59, 1.71) 0.55 (0.39, 0.77 ) 1.25 (0.78, 2.00) 1.45 (0.82, 2.55)  Emotional or physical intimate partner violence 1.04 (0.72, 1.50) 1.22 (0.84, 1.76) 1.21 (0.60, 2.44) 0.52 (0.33, 0.81) 0.79 (0.44, 1.42) 1.41 (0.78, 2.57)  Parental death 1.21 (0.74, 1.96) 1.26 (0.77, 2.08) 1.35 (0.63, 2.91) 1.15 (0.67, 1.98) 1.27 (0.69, 2.33) 1.24 0.60, 2.57)  Family member(s) with mental illness 1.13 (0.81, 1.57) 1.31 (0.94, 1.82) 1.78 (0.94, 3.34) 0.58 (0.38, 0.89) 1.46 (0.79, 2.72) 1.14 (0.60, 2.18)  Parental divorce or separation 1.30 (0.84, 2.01) 1.12 (0.71, 1.76) 2.29 (1.01, 5.22) 0.68 (0.39, 1.17) 0.80 (0.33, 1.89) 1.18 (0.50, 2.78) ACE count  1 ACE 1.05 (0.71, 1.55) 1.12 (0.75, 1.67) 0.91 (0.46, 1.82) 0.73 (0.47, 1.13) 0.70 (0.36, 1.37) 0.88 (0.43, 1.83)  2 ACE 1.09 (0.74, 1.59) 1.11 (0.74, 1.68) 1.28 (0.57, 2.88) 0.59 (0.36, 0.95) 1.20 (0.56, 2.61) 1.64 (0.66, 4.08)  ≥3 ACE 1.09 (0.74, 1.62) 1.24 (0.84, 1.84) 1.37 (0.66, 2.85) 0.37 (0.22, 0.61 ) 0.90 (0.48, 1.70) 2.04 (1.00, 4.19) We compared participant characteristics between cohorts using multivariable polytomous logistic regression, adjusting for age at enrollment, sex, cultural background, sexual orientation, BMI, smoking status, education, income, province of residence, and country of birth. Bold indicates statistical significance after controlling for the false discovery rate using the Benjamini-Hochberg procedure. ACE, adverse childhood experience; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

Relative risk ratio estimates (95% CIs) for variables associated with different types of ACE, stratified by type of disease, IMID, or IMID and sex

We compared participant characteristics between cohorts using multivariable polytomous logistic regression, adjusting for age at enrollment, sex, cultural background, sexual orientation, BMI, smoking status, education, income, province of residence, and country of birth. Bold indicates statistical significance after controlling for the false discovery rate using the Benjamini-Hochberg procedure.

ACE, adverse childhood experience; IBD, inflammatory bowel diseaseIMID, immune-mediated inflammatory disease; MS, multiple sclerosis; RA, rheumatoid arthritis

On multivariable analysis, history of ACE did not associate with increased risk of RA compared with either MS or IBD ( table 3 ). History of physical abuse was associated with decreased risk (0.50 (0.28–0.90)) of MS compared with RA, history of emotional abuse was associated with increased risk (2.03 (1.11, 3.71)) of IBD compared with RA, and history of ≥3 types was associated with increased risk (2.04 (1.00–4.19)) of IBD compared with RA; however, these associations were not statistically significant after we controlled for the false discovery rate. After stratification by sex, the risk of MS and IBD did not differ from the relative risk of RA after exposure to maltreatment ( online supplemental table 3 ). Among men, after exposure to physical abuse compared with no abuse, the relative risk of RA was greater than the relative risk of MS (0.37 (0.15, 0.95); p=0.04), and the relative risk of RA was less compared with the relative risk of IBD (2.95 (1.25, 6.93); p=0.01). The other types of ACEs were not associated with any difference in risk of RA versus MS or IBD when stratified by sex. History of maltreatment was associated with increased risk of IMID when compared with no chronic disease (p<0.01; online supplemental table 1 ).

Our findings were similar when we restricted the analyses to participants who reported only one condition of interest (detailed in online supplemental table 2 ). We did not find an association between history of neglect and the risk of epilepsy compared with an IMID diagnosis when we restricted inclusion to participants with one condition of interest, but these findings should be considered in the context of the relatively small number of participants who reported a history of neglect.

We found no difference in the point estimates when we repeated our multivariable analyses excluding BMI and smoking status.

Discussion

In this study, we evaluated the association of ACE with chronic disease, and specifically whether the association of ACE were similar or different between IMID and other chronic diseases and across three IMID including MS, IBD and RA. We found that ACE are quite common among Canadians, affecting approximately two thirds of our participants. Approximately one-quarter experienced at least three ACE. Participants with IMID were more likely to have experienced childhood maltreatment, including sexual abuse, and household dysfunction compared with having no chronic disease. Other than the relative risk of neglect being associated with epilepsy compared with IMID, the relative risk of diabetes, asthma or epilepsy compared with having an IMID after ACE did not differ. When we considered any maltreatment or any household dysfunction, the relative risk of MS or IBD versus RA did not differ. Although we observed differences in absolute risks, they were accompanied by broad confidence intervals, possibly due to small sample sizes.

Our findings share similarities with those of a recent meta-analysis involving 18 studies of ACE and risk of autoimmune disease. 7 In that study, any ACE was not associated with IMID in general, but they were associated with organ-specific autoimmune diseases such as thyroiditis, MS, myasthenia gravis or type 1 diabetes. 7 Only emotional abuse, emotional neglect and witnessing violence were associated with autoimmune disease. Following that meta-analysis, additional studies have reported conflicting findings regarding the association of ACE with risk of MS. In an analysis of the Norwegian Mother, Father and Child cohort study, sexual abuse and emotional abuse were associated with an increased rate of developing MS, and the rate of MS rose with an increased number of types of abuse experienced. 29 In contrast, a case-control study from the USA reported that ACE were not associated with the risk of MS. 30 In a study from Manitoba, Canada, childhood maltreatment, specifically emotional abuse was associated with increased risk of having an IMID (any of MS, IBD and RA) compared with being healthy; the association did not differ across IMID. 9 Sex-specific differences in the association between ACE and IMID development have been reported, including for RA where emotional neglect and abuse were associated with RA in women but not men. 6 The association of ACE with increased risk of epilepsy is consistent with a large population-based study that reported that multiple ACE were individually associated with epilepsy. 31

Several potential mechanisms may underlie the association between ACE and development of chronic disease, including immune-mediated disease. First, adverse experiences in early life may alter stress physiology long term, 32 including brain structure and function, the function of the hypothalamic pituitary axis and the immune system. 33 34 Second, ACE including childhood maltreatment as well as household dysfunction are associated with changes in behaviour, including a higher risk of smoking, overuse of alcohol, and low physical activity in adulthood, and these behaviours partially mediate the association between ACE and chronic disease. 35 Adults with ACE are less likely to obtain recommended preventive care. 36 37 Third, ACE influence mental and emotional development including mechanisms for self-regulation and coping. Evaluation of these issues is complex because the effects may vary depending on the type of ACE and the timing of exposure in childhood. 11 Hence, while statistically ACE is associated with later development of chronic diseases, the effect may be indirect and perhaps secondary to other outcomes triggered by ACE.

Study strengths include use of a large sample representative of the Canadian population, use of multiple comparator cohorts and adjustment for multiple potential confounders. Limitations should also be acknowledged. Residual confounding is possible. The exposure of interest, ACE, was assessed self-reported, retrospectively which could lead to recall bias. However, the questionnaire used was validated, and the literature suggests that participants tend to under-report rather than over-report childhood maltreatment, and thus this would bias our findings toward the null. 38 We had to identify IBD by using medication information, so milder cases of IBD that did not require intervention would have been missing from our cohort, and we could not stratify by IBD phenotype. The study design precludes causal inference, and we were unable to evaluate mechanisms responsible for the associations observed. Further, it is possible that participants with a chronic disease may be more likely to recall adverse life experiences. We report differences in relative risk ratios that were not statistically significant, possibly due to a small sample size, as evidenced by broad CIs. We also controlled for the false discovery rate. Future studies of large cohorts are needed to verify our findings.

Our findings have several implications. An improved understanding of the relationship between ACE and IMID may lead to generation of hypotheses regarding the pathogenesis of IMID. For instance, it is possible that ACE increases the likelihood of developing a mood disorder, and we have previously reported that mood disorders are associated with later diagnosis of IMID. 39 Improved appreciation for the long-term consequences of ACE could support interventions aimed at promoting healthy child development through safe household environments. Once individuals with a history of ACE develop a chronic disease, their responses to the experience of illness, symptom severity, and interactions with and use of the health system may differ. 40 , 42 It is important that clinicians be aware of these issues and ensure appropriate supports are available.

In summary, we found a history of ACE is common in a Canadian population and associated with increased relative risk of an IMID compared with having no chronic disease. We also observed a dose-repose relationship where a history of having ≥3 different types of ACE was associated with increased risk of IMID compared with no chronic disease. We did not, however, find a difference in the association between ACE and individual IMID, such as RA versus MS or IBD. Our findings highlight the importance of addressing ACE and raising clinician awareness about the role of ACE in chronic disease.

supplementary material

Acknowledgements

This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). Funding for the Canadian Longitudinal Study on Aging (CLSA) is provided by the Government of Canada through the Canadian Institutes of Health Research (CIHR) under grant reference: LSA 94473 and the Canada Foundation for Innovation as well as the following provinces, Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta and British Columbia. This research has been conducted using the CLSA dataset CLSA Baseline Comprehensive Dataset Version 7.0, Baseline Tracking Dataset Version 4.0, Follow-up 1 Comprehensive Dataset Version 3.2 and Follow-up 1 Tracking Dataset Version 2.3 under Application Number 2201019. The CLSA is led by Drs. Parminder Raina, Christina Wolfson and Susan Kirkland. The opinions expressed in this manuscript are the authors’ own and do not reflect the views of the Canadian Longitudinal Study on Aging.

Footnotes

Funding: This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). Funding for the Canadian Longitudinal Study on Aging (CLSA) is provided by the Government of Canada through the Canadian Institutes of Health Research (CIHR) under grant reference: LSA 94473 and the Canada Foundation for Innovation as well as the following provinces, Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta and British Columbia.

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online ( https://doi.org/10.1136/bmjopen-2024-087133 ).

Provenance and peer review: Not commissioned; externally peer-reviewed.

Patient consent for publication: Consent obtained directly from patient(s).

Ethics approval: This study involves human participants and was approved by the University of Manitoba Health Research Ethics Board (HS25371). Participants gave informed consent to participate in the study before taking part.

Data availability free text: Data are available from the Canadian Longitudinal Study on Aging (www.clsa-elcv.ca) for researchers who meet the criteria for access to de-identified CLSA data.

Patient and public involvement: Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Data availability statement

Data may be obtained from a third party and are not publicly available.

References