Smoking during pregnancy and risk of multiple sclerosis in offspring and mother: A Danish nationwide register-based cohort study.

BACKGROUND: The association between intra-uterine exposure to maternal smoking and risk of multiple sclerosis (MS) has been little studied and with conflicting results. OBJECTIVE: To examine the risk of MS in offspring exposed intra-uterine to maternal smoking. In addition, to re-examine prior observations of an elevated risk of MS among smokers, assuming that self-reported smoking during pregnancy reflects the woman's general smoking habits. METHODS: The study cohort included all Danish women, pregnant in the period 1991-2018, (n = 789,299) and singletons from these pregnancies (n = 879,135). Nationwide information on maternal smoking during pregnancy and MS cases in the study cohort were obtained from the Medical Birth Register and the National Patient Register. Cox regression analysis was used to estimate hazard ratios (HRs) for the association between smoking and MS risk. RESULTS: Women who smoked during pregnancy had a 42% increased risk of developing MS compared with non-smoking women (HR = 1.42 (1.32-1.52), n = 1,296). The risk of MS among singletons of women who smoked during pregnancy was 38% higher than that among singletons born to non-smoking women (HR = 1.38 (1.08-1.76), n = 110). CONCLUSION: Our observations add further to the evidence implicating smoking in the development of MS and suggest that intra-uterine exposure to tobacco smoke may increase MS risk.

Siblings reduce multiple sclerosis risk by preventing delayed primary Epstein-Barr virus infection.

Epstein-Barr virus infection, and perhaps almost exclusively delayed Epstein-Barr virus infection, seems to be a prerequisite for the development of multiple sclerosis. Siblings provide protection against infectious mononucleosis by occasionally preventing delayed primary Epstein-Barr virus infection, with its associated high risk of infectious mononucleosis. Each additional sibling provides further protection according to the age difference between the index child and the sibling. The closer the siblings are in age, the higher the protection, with younger siblings being more protective against infectious mononucleosis than older siblings. If the hypothesis that delayed Epstein-Barr virus infection is necessary for the development of multiple sclerosis is true, then the relative risk of multiple sclerosis as a function of sibship constellation should mirror the relative risk of infectious mononucleosis as a function of sibship constellation. Such an indirect hypothesis test is necessitated by the fact that age at primary Epstein-Barr virus infection is unknown for practically all people who have not experienced infectious mononucleosis. In this retrospective cohort study using nationwide registers, we followed all Danes born during the period 1971-2018 (n = 2 576 011) from 1977 to 2018 for hospital contacts with an infectious mononucleosis diagnosis (n = 23 905) or a multiple sclerosis diagnosis (n = 4442), defining two different end points. Relative risks (hazard ratios) of each end point as a function of sibship constellation were obtained from stratified Cox regression analyses. The hazard ratios of interest for infectious mononucleosis and multiple sclerosis could be assumed to be identical (test for homogeneity P = 0.19), implying that having siblings, especially of younger age, may protect a person against multiple sclerosis through early exposure to the Epstein-Barr virus. Maximum protection per sibling was obtained by having a 0-2 years younger sibling, corresponding to a hazard ratio of 0.80, with a 95% confidence interval of 0.76-0.85. The corresponding hazard ratio from having an (0-2 years) older sibling was 0.91 (0.86-0.96). Our results suggest that it may be possible essentially to eradicate multiple sclerosis using an Epstein-Barr virus vaccine administered before the teenage years. Getting there would require both successful replication of our study findings and, if so, elucidation of why early Epstein-Barr virus infection does not usually trigger the immune mechanisms responsible for the association between delayed Epstein-Barr virus infection and multiple sclerosis risk.

Post-acute symptoms 4 months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study.

Post-acute symptoms are not uncommon after SARS-CoV-2 infection with pre-Omicron variants. How Omicron and COVID-19 booster vaccination influence the risk of post-acute symptoms is less clear. We analyzed data from the nationwide Danish questionnaire study EFTER-COVID comprising 44,553 individuals ≥15 years old, tested between July 2021 and January 2022, in order to evaluate the association of the Omicron variant and COVID-19 booster vaccination with post-acute symptoms and new-onset general health problems, four months after infection with SARS-CoV-2. Risk differences (RDs) were estimated by comparing Omicron -cases to controls, Omicron to Delta -cases, and Omicron vaccinated cases with three to -two doses, adjusted for age, sex, BMI, self-reported chronic diseases, Charlson comorbidity index, healthcare occupation, and vaccination status. Four months after testing for SARS-CoV-2 during the Omicron period, cases experienced substantial post-acute symptoms and new-onset health problems compared to controls; the largest RD was observed for memory issues (RD=7.2%, 95%CI: 6.4 to 8.1). However, risks were generally lower than in the Delta period, particularly for dysosmia (RD=-15.0%, 95%CI: -17.0 to -13.2) and dysgeusia (RD=-11.2%, 95%CI: -13.2 to -9.5). Booster vaccination was associated with fewer post-acute symptoms and new-onset health problems, four months after Omicron infection, compared to two COVID-19 vaccine doses.

Retinoids are not linked to risk of multiple sclerosis: A Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system with an undetermined etiology. Retinoids may have immunomodulatory effects that favorably influence MS progression. We aimed to explore the yet unknown relationship between exposure to retinoids and the risk of acquiring MS. METHODS: We performed a nationwide cohort study in the Danish population in the period 1998-2016, comparing MS incidence in three groups: users of systemic retinoids; users of topical retinoids (negative control group); and users of non-retinoid acne drugs (control group). We used data from the Danish Multiple Sclerosis Registry (DMSR), the Danish National Prescription Registry and the Danish National Patient Registry. Linkage was obtained through the personal identification number (CPR number). We addressed confounding by three-way propensity score (PS)-matching weights. Additionally, to evaluate a cumulative dose-response effect for systemic retinoids on MS incidence, we conducted a case-control study, nested within the cohort. RESULTS: A total of 257,193 users of non-retinoid acne drugs, 130,560 users of topical retinoids, and 75,610 users of systemic retinoids were included. Systemic retinoid use was not associated with a reduced risk of MS compared to non-retinoid acne drug use in crude (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61 to 1.05]) and weighted analyses (HR 0.89, 95% CI 0.67 to 1.20). There was no evidence of a cumulative dose-response association between systemic retinoids and MS incidence. CONCLUSIONS: Use of systemic retinoids was not associated with a reduced incidence of MS compared to use of non-retinoid acne drugs in this study.

Inflammatory bowel diseases among first-generation and second-generation immigrants in Denmark: a population-based cohort study.

OBJECTIVE: Our objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes. DESIGN: Using national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn's disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark. RESULTS: Among 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants. CONCLUSION: Relative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study.

BACKGROUND: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). OBJECTIVES: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. METHODS: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. RESULTS: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35-3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49-2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78-2.54), n = 11). CONCLUSION: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

Distribution of disease courses in familial vs sporadic multiple sclerosis.

OBJECTIVES: The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course. MATERIALS AND METHODS: This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System, and the Danish National Patient Registry. The main variables are MS diagnosis, MS course, and first-degree relatives with MS The statistical analyses were carried out using logistic regression analysis, Kappa coefficient, and intraclass correlations coefficient. RESULTS: In total, 7402 MS cases were included in the study, of which 531 have an affected first-degree relatives, and 6871 are sporadic. We found that relapsing-remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio = 1.64, 95% CI: 1.20-2.24, P = 0.002). We subsequently analyzed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not. CONCLUSION: Familial MS cases are more likely to have relapsing-remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first-degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age.

Neurological Symptoms in Danes with a History of Poliomyelitis: Lifelong Follow-Up of Late Symptoms, their Association with Initial Symptoms of Polio, and Presence of Postpolio Syndrome.

BACKGROUND: Previous studies suggest that patients with a history of poliomyelitis (PM) later in life experience a variety of symptoms. These studies were carried out in patients who later in life were admitted to hospital or became members of polio societies and may therefore not be representative of all polio patients. Little data have been published concerning patients actually discharged from hospital with a diagnosis of acute paralytic PM. OBJECTIVES: The aim of this study was to compare the prevalence of late symptoms in individuals with a history of paralytic PM with that of controls, and to study whether late symptoms in individuals with a history of PM were associated with symptoms at the acute stage of polio, and finally to compare the prevalence of symptoms in polio patients with postpolio syndrome (PPS) with the prevalence of symptoms in polio patients without PPS. METHODS: A questionnaire concerning various symptoms was sent to a previously established cohort of patients, who during the polio epidemics were discharged from the Department of Infectious Disease at Blegdamshospitalet, Copenhagen, with a diagnosis of paralytic PM, and to age- and gender-matched controls without PM. Information about symptoms at the acute stage of disease was obtained from hospital records. Logistic regression analysis with adjustment for age and gender was applied to compare the occurrence of late symptoms in cases and controls and within the above-mentioned groups of individuals with a history of PM. RESULTS: (i) Compared with controls, individuals with a history of polio significantly more often reported muscle symptoms, pain, neuropathic sensory symptoms, and bulbar symptoms; (ii) the occurrence of symptoms did not seem to be related to symptoms of the initial PM; and (iii) symptom prevalence was significantly higher in individuals with a history of polio who reported PPS as compared with those who did not. CONCLUSION: Our data indicate that individuals with a history of PM late in life experience a variety of symptoms that cannot be attributed to lesions of the anterior horn. Furthermore, late symptoms do not seem to be related to initial symptoms of the acute stage of PM but to reported PPS. The last finding supports the perception that the cause of PPS is not just normal ageing.

Age at Menarche and Risk of Multiple Sclerosis: A Prospective Cohort Study Based on the Danish National Birth Cohort.

Few studies have addressed the possible association between age at menarche and multiple sclerosis (MS), and results are conflicting. We studied this issue in a large prospective cohort study. The study cohort comprised 77,330 women included in the Danish National Birth Cohort (1996-2002). Information on menarcheal age was ascertained at the first interview, which took place in the 16th week of pregnancy. Women were followed for MS from the first interview to December 31, 2011. Associations between age at menarche and risk of MS were evaluated with hazard ratios and 95% confidence intervals using Cox proportional hazards regression models. Overall, 226 women developed MS during an average follow-up period of 11.7 years. Age at menarche among women with MS was generally lower than that among women without MS (Wilcoxon rank-sum test; P = 0.002). We observed an inverse association between age at menarche and MS risk. For each 1-year increase in age at menarche, risk of MS was reduced by 13% (hazard ratio = 0.87, 95% confidence interval: 0.79, 0.96). Early age at menarche appears to be associated with an increased risk of MS. The mechanisms behind this association remain to be established.

Severe Human Parechovirus Infections in Infants and the Role of Older Siblings.

Human parechovirus (HPeV) is a cause of severe morbidity among infants and young children. To evaluate the associations between early environmental risk factors and HPeV infections, we carried out a nationwide cohort study linking registry data on birth and sibship characteristics with a laboratory surveillance database, covering all HPeV infections detected in Denmark during 2009-2012 among children <5 years of age. Incidence rate ratios were calculated in log-linear Poisson regression analyses. Overall, 133 HPeV infections, 85 caused by human parechovirus type 3 (HPeV-3) and 48 by human parechovirus other than type 3 (non-HPeV-3), were detected among 132 children. Neither birth weight, mode of delivery, Apgar score, nor gestational age was associated with the risk of HPeV infections. Compared with firstborn children, secondborn children were at a 9-fold increased risk (incidence rate ratio = 8.68, 95% confidence interval: 3.85, 19.53) of contracting HPeV-3 infections, but at no increased risk of contracting non-HPeV-3 infections. However, the shorter the age gap to the nearest older sibling, the higher the risk of HPeV-3 as well as non-HPeV-3 infections, although the trend was strongest for HPeV-3 infections. Our study is the first to suggest that having a slightly older sibling increases the risk for severe neonatal HPeV infections. This new knowledge might lead to new preventive measures.

Self-rated health in women prior to clinical onset of multiple sclerosis: A study within the Danish National Birth Cohort.

BACKGROUND: It has been suggested that onset of multiple sclerosis (MS) is preceded by a clinically silent period of up to 10 years. OBJECTIVES: Examine whether such a period should be associated with poor self-rated health (SRH). METHODS: Information on SRH before pregnancy was ascertained among 80,848 women participating in the Danish National Birth Cohort (DNBC) 1996-2002. Women were followed for MS from enrolment in DNBC in the 16th week of pregnancy until 31 December 2011. Associations between SRH and MS were evaluated by means of hazard ratios (HR) with 95% confidence intervals (CIs) using Cox proportional hazard models. RESULTS: During on average 11.7 years of follow-up, 239 women were diagnosed with MS. Overall, neither women with fair (HR = 1.09 (95% CI = 0.83-1.41), n = 113) nor poor pre-pregnancy SRH (HR = 0.94 (95% CI = 0.47-1.87), n = 9) were at an increased risk of MS compared with women reporting very good pre-pregnancy SRH. Supplementary analyses showed no significant differences in MS risk in consecutive periods of follow-up. CONCLUSION: In this first prospective cohort study assessing MS risk as a function of SRH, we found no indication of a long period of poor SRH prior to MS. Our findings based on pregnant women may not necessarily apply to all women.

The use of valproic acid and multiple sclerosis.

BACKGROUND: Animal studies have suggested that drugs inhibiting the enzyme histone deacetylase might have a beneficial effect on multiple sclerosis (MS). Valproic acid (VPA), an anti-epileptic drug, is the only widely used human drug with a histone deacetylase inhibitory effect. OBJECTIVE: The objective of this paper is to examine if VPA use is associated with a reduced risk of MS. METHODS: We conducted a propensity score-matched cohort study in the period 1997-2011 linking nationwide register data on filled VPA prescriptions, MS cases, and several covariates. The VPA users were matched on propensity scores in a 1:4 ratio with non-users of VPA. Incidence rates of MS were compared among VPA users and non-users of VPA using Cox regression to estimate hazard ratios (HRs). RESULTS: Among 16 028 ever-users of VPA and 54 172 non-users, 18 and 26 cases of MS were identified, respectively. Neither current VPA users nor recent users of VPA, who had ceased VPA treatment within the last year, were at a reduced risk of MS compared with non-users of VPA (HR = 1.30 (95% confidence interval, 0.44-3.80), n = 4, and HR = 1.22 (0.28-5.32), n = 2, respectively). Similarly, in an intention-to-treat analysis, ever-users of VPA were not at reduced risk of MS (HR = 2.41 (1.32-4.43), n = 18). CONCLUSION: In the first human study addressing a possible beneficial effect of VPA use on the risk of MS, we found no support for a protective effect. However, given the wide confidence intervals, only large effects can be ruled out with sufficient certainty.

Major stressful life events in adulthood and risk of multiple sclerosis.

OBJECTIVE: It is unclear whether psychological stress is associated with increased risk of multiple sclerosis (MS). We studied the association between major stressful life events and MS in a nationwide cohort study using death of a child or a spouse or marital dissolution as indicators of severe stress. METHODS: We created two study cohorts based on all Danish men and women born 1950-1992. One cohort consisted of all persons who became parents between 1968 and 2010, and another cohort consisted of all persons who married between 1968 and 2010. Members of both cohorts were followed for MS between 1982 and 2010 using data from the National Multiple Sclerosis Registry. Associations between major stressful life events and risk of MS were evaluated by means of MS incidence rate ratios (RR) with 95% confidence interval (CI) obtained in Poisson regression analyses. RESULTS: During approximately 30 million person-years of follow-up, bereaved parents experienced no unusual risk of MS compared with parents who did not lose a child (RR=1.12 (95% CI 0.89 to 1.38)). Likewise, neither divorced (RR=0.98 (95% CI 0.89 to 1.06)) nor widowed (RR=0.98 (95% CI 0.71 to 1.32) persons were at any unusual risk of MS compared with married persons of the same sex. CONCLUSIONS: Our national cohort study provides little evidence for a causal association between major stressful life events (as exemplified by divorce or the loss of a child or a spouse) and subsequent MS risk.

Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study.

BACKGROUND: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse. OBJECTIVES: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011. METHODS: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models. RESULTS: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03-1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04-1.23). CONCLUSIONS: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS.

Same-sex marriage, autoimmune thyroid gland dysfunction and other autoimmune diseases in Denmark 1989-2008.

Autoimmune diseases have been little studied in gay men and lesbians. We followed 4.4 million Danes, including 9,615 same-sex married (SSM) persons, for 47 autoimmune diseases in the National Patient Registry between 1989 and 2008. Poisson regression analyses provided first hospitalization rate ratios (RRs) comparing rates between SSM individuals and persons in other marital status categories. SSM individuals experienced no unusual overall risk of autoimmune diseases. However, the risk of autoimmune thyroid dysfunction was increased, notably Hashimoto's thyroiditis (women(SSM), RR = 2.92; 95% confidence interval (CI) 1.74-4.55) and Graves' disease (men(SSM), RR = 1.88; 95% CI 1.08-3.01). There was also an excess of primary biliary cirrhosis (women(SSM), RR = 4.09; 95% CI 1.01-10.7), and of psoriasis (men(SSM), RR = 2.48; 95% CI 1.77-3.36), rheumatic fever (men(SSM), RR = 7.55; 95% CI 1.87-19.8), myasthenia gravis (men(SSM), RR = 5.51; 95% CI 1.36-14.4), localized scleroderma (men(SSM), RR = 7.16; 95% CI 1.18-22.6) and pemphigoid (men(SSM), RR = 6.56; 95% CI 1.08-20.6), while Dupuytren's contracture was reduced (men(SSM), RR = 0.64; 95% CI 0.39-0.99). The excess of psoriasis was restricted to same-sex married men with HIV/AIDS (men(SSM), RR = 10.5; 95% CI 6.44-15.9), whereas Graves' disease occurred in excess only among same-sex married men without HIV/AIDS (men(SSM), RR = 1.99; 95% CI 1.12-3.22). Lesbians and immunologically competent gay men in same-sex marriage face no unusual overall risk of autoimmune diseases. However, the observed increased risk of thyroid dysfunction in these lesbians and gay men deserves further study.

Divorce and risk of hospital-diagnosed infectious diseases.

BACKGROUND: Although, divorce is considered to have a negative impact on morbidity, very little is known concerning exposure to divorce and risk of infectious diseases. We aimed to investigate the association between divorce and subsequent hospital contacts with infectious diseases. METHODS: We performed a nation-wide cohort study, including all Danish men and women (n≈5.6 million) alive on the 1 January 1982 or later, and followed them for infectious disease diagnosed in hospital settings from 1982 to 2010. The association between divorce and risk of infectious diseases was evaluated through rate ratios (RRs) comparing incidence rates of infectious diseases between divorced and married pesons. RESULTS: Compared with married persons, divorced persons were overall at a 1.48 fold (RR=1.48 (95% CI: 1.47-1.50)) increased risk of hospital-diagnosed infectious diseases (RR adjusted for sex, age, period, income and education). The risk of infectious diseases was slightly more pronounced for divorced women (RR=1.54 (1.52-1.56)) than divorced men ((RR=1.42 (1.41-1.44)). The increased risk remained almost unchanged even more than 15 years after the divorce. Young age at divorce, short duration of marriage and number of divorces further increased the risk of infectious diseases, whereas number of children at time of divorce had no impact on risk of hospital-diagnosed infectious diseases following the divorce. CONCLUSIONS: Divorce appears to have a moderate but long lasting impact on the risk of infectious diseases the underlying mechanism is unknown but shared risk factors predicting divorce and infectious diseases could contribute to our findings.

Cohort profile: EFTER-COVID - a Danish nationwide cohort for assessing the long-term health effects of the COVID-19 pandemic.

PURPOSE: To follow SARS-CoV-2-infected persons up to 18 months after a positive test in order to assess the burden and nature of post acute symptoms and health problems. PARTICIPANTS: Persons in Denmark above 15 years of age, who were tested positive for SARS-CoV-2 during 1 September 2020 to 21 February 2023 using a RT-PCR test. As a reference group, three test-negative individuals were selected for every two test-positive individuals by matching on test date. FINDINGS TO DATE: In total, 2 427 913 invitations to baseline questionnaires have been sent out and 839 528 baseline questionnaires (34.5%) have been completed. Females, the age group 50-69 years, Danish-born and persons, who had received at least one SARS-CoV-2 vaccination booster dose were more likely to participate. Follow-up questionnaires were sent at 2, 4, 6, 9, 12 and 18 months after the test, with response rates at 42%-54%. FUTURE PLANS: New participants have been recruited on a daily basis from 1 August 2021 to 23 March 2023. Data collection will continue until the last follow-up questionnaires (at 18 months after test) have been distributed in August 2024.

A register and questionnaire study of long-term general health symptoms following SARS-CoV-2 vaccination in Denmark.

Many individuals who refuse COVID-19 vaccination have concerns about long-term side effects. Here, we report findings on self-reported symptoms from a Danish survey- and register study. The study included 34,868 vaccinated primary course recipients, 95.8% of whom received mRNA vaccines, and 1,568 unvaccinated individuals. Participants had no known history of SARS-CoV-2 infection. Using g-computation on logistic regression, risk differences (RDs) for symptoms between vaccinated and unvaccinated persons were estimated with adjustments for possible confounders. Within six weeks after vaccination, higher risks were observed for physical exhaustion (RD 4.9%, 95% CI 1.1% to 8.4%), fever or chills (RD 4.4%, 95% CI 2.1% to 6.7%), and muscle/joint pain (RD 7.0%, 95% CI 3.1% to 10.7%), compared to unvaccinated individuals. Beyond twenty-six weeks, risks were higher among the vaccinated for sleeping problems (RD 3.0, 95% 0.2 to 5.8), fever or chills (RD 2.0, 95% CI 0.4 to 3.6), reduced/altered taste (RD 1.2, 95% CI 0.2 to 2.3) and shortness of breath (RD 2.6, 95% CI 0.9 to 4.0). However, when examining pre-omicron responses only, the difference for reduced/altered taste was significant. As expected, the risk of experiencing physical exhaustion, fever or chills, and muscle/joint pain was higher among persons who responded within six weeks of completing the primary course. No significant differences were observed for the 7-25-week period after vaccination. Associations for the period beyond 26 weeks must be interpreted with caution and in the context of undetected SARS-CoV-2 infection, wide confidence intervals, and multiple testing. Overall, we observe no concerning signs of long-term self-reported physical, cognitive, or fatigue symptoms after vaccination.

Socioeconomic factors in childhood and the risk of multiple sclerosis.

In a national cohort comprising 1.5 million Danes born from 1966 to 1992, we studied the association between childhood socioeconomic status (SES) and the risk of multiple sclerosis (MS) from 1981 to 2007 using information about household income and parental educational levels at the person's 15th birthday. The association between childhood SES and MS was evaluated using MS incidence rate ratios with 95% confidence intervals obtained in log-linear Poisson regression analyses. We found no strong association between childhood SES and MS but did observe a tendency toward a reduced risk of MS among children from households with more highly educated parents, particularly mothers. Children whose mothers had a secondary (rate ratio = 0.95, 95% confidence interval: 0.86, 1.04) or higher (rate ratio = 0.86, 95% confidence interval: 0.76, 0.97) education had reduced risks of MS (5% and 14%, respectively) compared with children of mothers with a basic education (P for trend = 0.02). Results were practically unchanged in an analysis restricted to persons aged 15-29 years, among whom the possible effect of own SES on MS risk is considered limited. Overall, SES in childhood seems of no major importance for the subsequent risk of MS; however, offspring of well-educated mothers may be at a slightly reduced risk of MS.

Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years.

BACKGROUND & AIMS: The risk for colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) could have changed over time, with changes in treatment options. We studied CRC risk in a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period. METHODS: We determined relative risk (RR) values using Poisson regression-derived incidence rate ratios of CRC from 1 year after IBD diagnosis, adjusted for age, sex, and calendar time. We compared incidence of CRC among patients with IBD vs individuals without IBD. RESULTS: During 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn's disease (CD) developed CRC. The overall risk of CRC among patients with UC was comparable with that of the general population (RR, 1.07; 95% confidence interval [CI], 0.95-1.21). However, patients diagnosed with UC in childhood or as adolescents, those with long duration of disease, and those with concomitant primary sclerosing cholangitis were at increased risk. For patients with UC, the overall RR for CRC decreased from 1.34 (95% CI, 1.13-1.58) in 1979-1988 to 0.57 (95% CI, 0.41-0.80) in 1999-2008. Among patients with CD, the overall RR for CRC was 0.85 (95% CI, 0.67-1.07), which did not change over time. CONCLUSIONS: A diagnosis of UC or CD no longer seems to increase patients' risk of CRC, although subgroups of patients with UC remain at increased risk. The decreasing risk for CRC from 1979 to 2008 might result from improved therapies for patients with IBD.