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.

A hybrid register and questionnaire study of Covid-19 and post-acute sick leave in Denmark.

Post-acute sick leave is an underexplored indicator of the societal burden of SARS-CoV-2. Here,  we report findings about self-reported sick leave and risk factors thereof from a hybrid survey and register study, which include 37,482 RT-PCR confirmed SARS-CoV-2 cases and 51,336 test-negative controls who were tested during the index- and alpha-dominant waves. We observe that an additional 33 individuals per 1000 took substantial sick leave following acute infection compared to persons with no known history of infection, where substantial sick leave is defined as >1 month of sick leave within the period 1-9 months after the RT-PCR test date. Being female, 50-65 years, or having certain pre-existing health conditions such as obesity, chronic lung diseases, and fibromyalgia each increase risk for taking substantial sick leave. Altogether, these results may help motivate improved diagnostic and treatment options for persons living with post-Covid conditions.

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.

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.

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.

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.

Increased risk of inflammatory bowel disease in women with endometriosis: a nationwide Danish cohort study.

BACKGROUND: An association between endometriosis and certain autoimmune diseases has been suggested. However, the impact of endometriosis on risk of inflammatory bowel disease (IBD) remains unknown. OBJECTIVE: To assess the risk of Crohn's disease (CD) and ulcerative colitis (UC) in an unselected nationwide Danish cohort of women with endometriosis. DESIGN: By use of national registers, 37 661 women hospitalised with endometriosis during 1977-2007 were identified. The relative risk of developing IBD after an endometriosis diagnosis was calculated as observed versus expected numbers and presented as standardised incidence ratios (SIRs) with 95% CIs. RESULTS: Women with endometriosis had a increased risk of IBD overall (SIR=1.5; 95% CI 1.4 to 1.7) and of UC (SIR=1.5; 95% CI 1.3 to 1.7) and CD (SIR=1.6; 95% CI 1.3 to 2.0) separately, even 20 years after a diagnosis of endometriosis (UC: SIR=1.5; 95% CI 1.1 to 2.1; CD: SIR=1.8; 95% CI 1.1 to 3.2). Restricting analyses to women with surgically verified endometriosis suggested even stronger associations (UC: SIR=1.8; 95% CI 1.4 to 2.3; CD: SIR=1.7; 95% CI 1.2 to 2.5). CONCLUSION: The risk of IBD in women with endometriosis was increased even in the long term, hence suggesting a genuine association between the diseases, which may either reflect common immunological features or an impact of endometriosis treatment with oral contraceptives on risk of IBD.

Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study.

BACKGROUND: Intestinal bacteria have been implicated in the etiology of the common inflammatory bowel diseases (IBD) ulcerative colitis and Crohn's disease. Because delivery by cesarean section disturbs the normal bacterial colonization of the newborn's intestine, we determined the risk of IBD according to mode of delivery. METHODS: A register-based national cohort study of 2.1 million Danes born 1973-2008. The effect of mode of delivery on IBD incidence in the age-span 0-35 years was estimated by means of confounder-adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) obtained in Poisson regression analysis. Information on mode of delivery was obtained from the Danish Medical Birth Registry and cases of IBD were identified in the Danish National Patient Registry 1977-2008. RESULTS: During 32.6 million person-years of follow-up, a total of 8142 persons were diagnosed with IBD before age 36 years. Cesarean section was associated with moderately, yet significantly, increased risk of IBD at age 0-14 years (IRR 1.29, 95% CI 1.11-1.49), regardless of parental disposition to IBD. Assuming causality, an estimated 3.2% of IBD cases before age 15 years were attributable to cesarean section. CONCLUSIONS: Rates of IBD with onset in childhood are moderately increased after birth by cesarean section but underlying mechanisms remain unclear. Even if the association is causal, the possible impact of increasing cesarean section practices on the overall burden of IBD in childhood is small.

Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease.

OBJECTIVE: Enteric pathogens have been implicated in the aetiology of inflammatory bowel disease (IBD), but increased rates of stool testing of patients with unclear gastrointestinal symptoms might cause detection bias. Hence, the objective of this study was to analyse incidence rates of Crohn's disease and ulcerative colitis among patients with Salmonella- or Campylobacter-positive and negative stool tests and to study the incidence of positive and negative stool tests among patients already diagnosed with IBD. METHODS: The Danish population was followed for 94.3 million person-years during 1992-2008 using national registers to identify persons with positive and negative stool tests and patients with IBD. Using Poisson regression, incidence rate ratios (IRRs) for IBD after positive or negative stool tests and, conversely, IRRs for positive and negative stool tests following IBD, were calculated. RESULTS: IRRs for IBD were significantly high in the first year after Salmonella- or Campylobacter-positive stool tests (IRRs 5.4-9.8), and they remained moderately increased 1-10 years later (IRRs 1.6-2.2), and less so >10 years later (IRRs 0.8-1.8). However, IRRs for IBD <1 year after a negative stool test were several-fold higher (IRRs 53.2-57.5), and a decreasing incidence pattern over time was parallel to that following positive test results. Among patients with IBD, IRRs for subsequent positive and-most notably-negative stool test results were also significantly high. CONCLUSION: Similarities in temporal risk patterns for IBD following positive or negative stool tests indicate that the increased occurrence of Salmonella- or Campylobacter-positive results around the time of first IBD hospitalisation results from detection bias.

Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events.

Determining incidence rates of potential adverse events before and after an immunisation programme is initiated, provides a useful framework for the evaluation of vaccine safety concerns. Human papillomavirus vaccination (HPV) of adolescent girls has recently been introduced in Denmark. Using a nationwide hospitalisation registry we estimated incidence rates of immune-mediated disorders before HPV vaccination in a cohort of 418,289 Danish girls aged 12-15 years. We further estimated the expected number of cases of immune-mediated disorders occurring in temporal relationship to a hypothetical HPV vaccination schedule purely by chance. Our results and analytical approach provides a framework for the evaluation of adverse event reports following immunisation of adolescent girls.

Cancer risk among patients with multiple sclerosis: a population-based register study.

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population-based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population-based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live-born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person-years of follow-up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89-1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94-1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05-1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Familial clustering of Hodgkin lymphoma and multiple sclerosis.

BACKGROUND: Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies. Previous investigations have not supported this hypothesis, but the negative results could have been caused by methodologic problems. We therefore assessed the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and for their families and the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and for their families. METHODS: We identified 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives in Danish population-based registers and followed them for the occurrence of Hodgkin lymphoma. Analogously, we identified 4381 patients with Hodgkin lymphoma and 7388 of their first-degree relatives and followed them for the occurrence of multiple sclerosis. The relative risks (RRs) of Hodgkin lymphoma and multiple sclerosis were expressed as standardized incidence ratios (i.e., the ratio between observed and expected numbers of outcomes based on age, sex, and period-specific incidence rates). All statistical tests were two-sided. RESULTS: Overall, six cases of Hodgkin lymphoma were identified in patients with multiple sclerosis (RR for Hodgkin lymphoma = 1.40, 95% confidence interval [CI] = 0.63 to 3.12), two of which occurred in young adults (RR = 1.59, 95% CI = 0.40 to 6.37). The risk of young-adult-onset Hodgkin lymphoma was statistically significantly increased in the first-degree relatives of patients with multiple sclerosis (RR = 1.93, 95% CI = 1.01 to 3.71; n = 9 such lymphomas). Two cases of multiple sclerosis were identified among young adult patients with Hodgkin lymphoma (RR for multiple sclerosis = 0.82, 95% CI = 0.20 to 3.27), and the risk for multiple sclerosis was statistically significantly increased in their first-degree relatives (RR = 2.76, 95% CI = 1.44 to 5.31; n = 9 such multiple sclerosis cases). CONCLUSION: The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.

Long-term mortality after poliomyelitis.

BACKGROUND: Few studies have described mortality and cause of death among persons with a history of polio. METHODS: We identified a group of patients diagnosed with poliomyelitis in Copenhagen between 1919 and 1954. We obtained information on vital status through May 1997 and on cause of death by linkage with the Danish Civil Registration System and the Danish Cause-of-Death Register. Overall and cause-specific standardized mortality ratios served as the measure of mortality risk relative to that of the general population. RESULTS: We observed 1295 deaths among 5977 polio patients compared with an expected 1141 deaths (standardized mortality ratio = 1.14; 95% confidence interval = 1.07-1.20). Excess mortality was restricted to polio patients with a history of severe paralysis of the extremities (1.69; 1.32-2.15) or patients who had been treated for respiratory failure during the epidemics (2.71; 2.18-3.37). Apart from polio patients with respiratory failure, long-term mortality did not appear to increase until 20 years after discharge. Contracting severe paralytic poliomyelitis at a young age seemed to increase long-term mortality. The most common causes of death were polio sequelae (standardized mortality ratio = 141; 95% confidence interval = 98-203), respiratory tract diseases (1.38; 1.13-1.69), breast cancer (1.40; 1.06-1.85), gastrointestinal diseases (1.44; 1.14-1.82) and suicide (1.53; 1.25-1.86). Except for polio sequelae, causes of death did not differ between paralytic and nonparalytic polio patients. CONCLUSIONS: Survivors of poliomyelitis, especially severely paralyzed polio patients, have an increased long-term mortality.