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.

Associations between recalled childhood gender nonconformity and adult sexual dysfunction in Denmark: baseline assessment in the Project SEXUS cohort study.

BACKGROUND: Sexual dysfunctions may negatively affect an individual's self-perceived womanhood or manhood, but whether gender nonconformity in childhood or adolescence can influence adult sexual functioning has not been examined so far. AIM: To explore the possible link between recalled childhood gender nonconformity and sexual dysfunctions in adulthood in a large sample. METHODS: We analyzed baseline questionnaire data from Project SEXUS, a nationally representative cohort study on sexual health among 15- to 89-year-old Danish citizens. Our sample included sexually active participants aged ≥18 years who were queried about gender nonconformity in childhood or adolescence (N = 21 390). To capture sexual dysfunctions, we assessed (1) difficulties with lubrication, orgasm, vaginal cramps precluding sexual intercourse, and/or genital pain during partnered sexual activity in women and (2) difficulties with erection, premature ejaculation, orgasm, and/or genital pain during partnered sexual activity in men. Furthermore, we assessed whether such difficulties were perceived as problematic. The 6-item Female Sexual Function Index and the 5-item International Index of Erectile Function served as standardized measures. Polytomous logistic regression analyses yielded demographically weighted adjusted odds ratios (aORs) with 95% CIs for associations between childhood gender nonconformity and sexual dysfunctions, controlling for age, sociodemographics, health-related factors, and other potential confounders. OUTCOMES: Sexual difficulties and dysfunctions, as well as scores on the Female Sexual Function Index and International Index of Erectile Function. RESULTS: Age-adjusted odds ratios indicated that sexual dysfunctions were significantly more common among childhood gender-nonconforming than conforming participants. After controlling for additional potential confounders, most sexual dysfunctions-notably, vaginal cramps in women (aOR, 2.12; 95% CI, 1.25-3.60) and genital pain dysfunction in men (aOR, 2.99; 95% CI, 1.79-4.99)-remained significantly increased among childhood gender-nonconforming respondents. CLINICAL IMPLICATIONS: Findings suggest that self-perceived gender nonconformity in childhood or adolescence may negatively affect sexual functioning in adult life. If confirmed by future studies, they may warrant a clinical emphasis on such issues in sexologic treatment and care. STRENGTHS AND LIMITATIONS: Our study is the first to report associations between childhood gender nonconformity and adult sexual dysfunction, building on data from a large-scale, nationally representative cohort study. The retrospective assessment of childhood gender nonconformity via one item might have neglected significant dimensions of this construct. CONCLUSION: The present study is the first to show that individuals who recall being gender nonconforming in childhood or adolescence may be at a greater risk of experiencing sexual dysfunctions, particularly sexual pain disorders, as adults.

Transgender Identity and Suicide Attempts and Mortality in Denmark.

Importance: Prior studies have suggested that transgender individuals may be a high-risk group with respect to suicide attempt and mortality, but large-scale, population-based investigations are lacking. Objective: To examine in a national setting whether transgender individuals have higher rates of suicide attempt and mortality than nontransgender individuals. Design, Setting, and Participants: Nationwide, register-based, retrospective cohort study on all 6 657 456 Danish-born individuals aged 15 years or older who lived in Denmark between January 1, 1980, and December 31, 2021. Exposure: Transgender identity was determined through national hospital records and administrative records of legal change of gender. Main Outcomes and Measures: Suicide attempts, suicide deaths, nonsuicidal deaths, and deaths by any cause during 1980 through 2021 were identified in national hospitalization and causes of death registers. Adjusted incidence rate ratios (aIRRs) with 95% CIs controlling for calendar period, sex assigned at birth, and age were calculated. Results: The 6 657 456 study participants (50.0% assigned male sex at birth) were followed up during 171 023 873 person-years. Overall, 3759 individuals (0.06%; 52.5% assigned male sex at birth) were identified as transgender at a median age of 22 years (IQR, 18-31 years) and followed up during 21 404 person-years, during which 92 suicide attempts, 12 suicides, and 245 suicide-unrelated deaths occurred. Standardized suicide attempt rates per 100 000 person-years were 498 for transgender vs 71 for nontransgender individuals (aIRR, 7.7; 95% CI, 5.9-10.2). Standardized suicide mortality rates per 100 000 person-years were 75 for transgender vs 21 for nontransgender individuals (aIRR, 3.5; 95% CI, 2.0-6.3). Standardized suicide-unrelated mortality rates per 100 000 person-years were 2380 for transgender vs 1310 for nontransgender individuals (aIRR, 1.9; 95% CI, 1.6-2.2), and standardized all-cause mortality rates per 100 000 person-years were 2559 for transgender vs 1331 for nontransgender individuals (aIRR, 2.0; 95% CI, 1.7-2.4). Despite declining rates of suicide attempts and mortality during the 42 years covered, aIRRs remained significantly elevated in recent calendar periods up to and including 2021 for suicide attempts (aIRR, 6.6; 95% CI, 4.5-9.5), suicide mortality (aIRR, 2.8; 95% CI, 1.3-5.9), suicide-unrelated mortality (aIRR, 1.7; 95% CI, 1.5-2.1), and all-cause mortality (aIRR, 1.7; 95% CI, 1.4-2.1). Conclusions and Relevance: In this Danish population-based, retrospective cohort study, results suggest that transgender individuals had significantly higher rates of suicide attempt, suicide mortality, suicide-unrelated mortality, and all-cause mortality compared with the nontransgender population.

Symptoms of anxiety and depression in Denmark during the first year of the COVID-19 pandemic: A two-wave matched-control study.

Subsequent to the restriction measures taken to curb the COVID-19 infection rate, researchers theorized these would have detrimental mental health consequences. This two-wave matched-control study investigates depression and anxiety symptoms during the first 12 months of the pandemic (March 2020-March 2021) in Denmark with data from the I-SHARE and Project SEXUS studies. The I-SHARE study includes 1,302 (Time period 1 only n = 914, Time period 2 only n = 304, both time periods 1 and2 n = 84) Danish participants, and the sex and birth year-matched control participants from the Project SEXUS study comprise 9,980 Danes. During the first year of the pandemic, the study populations' anxiety and depression symptom mean levels did not significantly differ from pre-pandemic matched controls. Younger age, female gender, fewer children in the same household (depression only), lower education level, and not being in a relationship (depression only) were associated with increased anxiety and depression symptom scores. The key COVID-19-related variable linked with significantly higher anxiety and depression symptom scores was COVID-19-related loss of income. Contrary to initial concerns, we did not find a significant effect of the pandemic on anxiety and depression symptom scores. However, the results underscore the importance of structural resources to prevent income loss to safeguard mental health during crises such as a pandemic.

Physical and Mental Health Problems and Their Associations With Inter-Personal Sexual Inactivity and Sexual Dysfunctions in Denmark: Baseline Assessment in a National Cohort Study.

BACKGROUND: Physical and mental health are important to sexual function and wellbeing. Yet, associations of ill-health with sexual inactivity and dysfunctions are scarcely researched at population level. AIM: To explore and document associations of self-rated health and physical and mental health problems with inter-personal sexual inactivity and sexual dysfunctions. METHODS: We used data from a probability-based, nationally representative sample of 60,958 sexually experienced Danes aged 15-89 years who participated in the 2017-18 Project SEXUS cohort study. Logistic regression analyses provided demographically weighted odds ratios for associations between health measures and sexual outcomes adjusted for partner status and other potential confounders. OUTCOMES: Inter-personal sexual inactivity and a range of male and female sexual dysfunctions. RESULTS: Inter-personal sexual inactivity was more common among individuals with bad or very bad self-rated health compared to peers rating their health as good or very good (men: adjusted odds ratio 1.93, 95% confidence interval 1.66-2.25; women: 1.66, 1.42-1.94). Individuals rating their health as bad or very bad were also consistently more likely to report sexual dysfunctions, with associated statistically significant adjusted odds ratios ranging from 1.66 to 6.38 in men and from 2.25 to 3.20 in women. Patient groups at high risk of sexual dysfunctions comprised individuals afflicted by cardiovascular diseases, pain conditions, diabetes, gastrointestinal and liver diseases, cancer, skin diseases, nervous system diseases, gynecological diseases, benign prostatic hyperplasia, other physical health problems, stress, anxiety, affective disorders, self-injury or suicide ideation and attempts, posttraumatic stress disorder, personality disorders, eating disorders, psychoses and other mental health problems. CLINICAL IMPLICATIONS: These findings warrant heightened awareness among healthcare professionals, public health promoters and researchers concerning insufficiently appreciated sexual challenges among individuals with poor health. STRENGTHS & LIMITATIONS: The major strengths of our investigation include the large size of the study cohort, the detailed assessment of health-related variables, potential confounders and sexual outcomes, and the fact that we provide new population-based knowledge about less common and sparsely researched sexual dysfunctions and diseases. Limitations of our study include its cross-sectional nature and its modest response rate (35%). CONCLUSION: Findings from our large and nationally representative cohort study provide evidence that poor self-rated health and a range of specific physical and mental health problems are associated with statistically significantly increased rates of inter-personal sexual inactivity and sexual dysfunctions. Bahnsen MK, Graugaard C, Andersson M, et al. Physical and Mental Health Problems and Their Associations With Inter-Personal Sexual Inactivity and Sexual Dysfunctions in Denmark: Baseline Assessment in a National Cohort Study. J Sex Med 2022;19:1562-1579.

Non-therapeutic male circumcision in infancy or childhood and risk of human immunodeficiency virus and other sexually transmitted infections: national cohort study in Denmark.

Whether male circumcision in infancy or childhood provides protection against the acquisition of human immunodeficiency virus (HIV) or other sexually transmitted infections (STIs) in adulthood remains to be established. In the first national cohort study to address this issue, we identified 810,719 non-Muslim males born in Denmark between 1977 and 2003 and followed them over the age span 0-36 years between 1977 and 2013. We obtained information about cohort members' non-therapeutic circumcisions, HIV diagnoses and other STI outcomes from national health registers and used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status (i.e., circumcised v. genitally intact). During a mean of 22 years of follow-up, amounting to a total observation period of 17.7 million person-years, 3375 cohort members (0.42%) underwent non-therapeutic circumcision, and 8531 (1.05%) received hospital care for HIV or other STIs. Compared with genitally intact males, rates among circumcised males were not statistically significantly reduced for any specific STI. Indeed, circumcised males had a 53% higher rate of STIs overall (HR = 1.53, 95% CI: 1.24-1.89), and rates were statistically significantly increased for anogenital warts (74 cases in circumcised males v. 7151 cases in intact males, HR = 1.51; 95% CI: 1.20-1.90) and syphilis (four cases in circumcised males v. 197 cases in intact males, HR = 3.32; 95% CI: 1.23-8.95). In this national cohort study spanning more than three decades of observation, non-therapeutic circumcision in infancy or childhood did not appear to provide protection against HIV or other STIs in males up to the age of 36 years. Rather, non-therapeutic circumcision was associated with higher STI rates overall, particularly for anogenital warts and syphilis.

Sexual Inactivity and Dysfunction in Denmark: A Project SEXUS Study.

Sexual dysfunctions are common experiences that often impact negatively on the health and well-being of affected individuals. We used baseline questionnaire data from 62,675 Danes aged 15-89 years, who participated in the cohort study Project SEXUS 2017-2018, to yield nationally representative estimates of the prevalence of sexual inactivity and dysfunction and to identify their sociodemographic correlates. Overall, we found that 23.0% of sexually experienced men and 28.8% of sexually experienced women had not been sexually active with another person within the last year. Sexual inactivity with another person was associated with both young and old age, single status, less favorable socioeconomic conditions, underweight and obesity, indicators of poor health, no use of alcohol, and physical inactivity. Among sexually active respondents, 18.0% of men had experienced any dysfunction within the last year, including erectile dysfunction (7.4%), premature ejaculation dysfunction (10.0%), orgasmic dysfunction (4.0%), and/or genital pain dysfunction (0.7%). Among women, 20.4% had experienced any dysfunction within the last year, including lubrication dysfunction (9.1%), orgasmic dysfunction (12.2%), genital pain dysfunction (5.0%), and/or vaginal cramp dysfunction (vaginismus) (0.8%). Additionally, 3.4% of men and 9.9% of women with a spouse/partner had experienced hypoactive sexual desire disorder within the last four weeks. Using the 5-item International Index of Erectile Function (IIEF-5) and the 6-item Female Sexual Function Index (FSFI-6) among respondents with a spouse/partner who had attempted sexual intercourse within the last four weeks, we found that 3.8% of men had experienced moderate or severe erectile dysfunction (IIEF-5 score ≤ 11) and 20.8% of women had experienced any sexual dysfunction (FSFI-6 score ≤ 19) during that period. Single status, difficulties paying bills and, among men, unemployment were positively associated with sexual dysfunction. In conclusion, we document several sociodemographic disparities in the prevalence of sexual inactivity and dysfunction in Denmark. In particular, both sexual inactivity and dysfunction were more common among singles and those reporting financial difficulties.

Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis.

Epidemiologic studies have shown associations between periodontitis and rheumatoid arthritis (RA), but a causal relationship has not been established. Citrullination of gingival proteins by human peptidylarginine deiminases (PADs) or PAD from Porphyromonas gingivalis has been proposed to generate autoantigens in anti-CCP-positive RA. This study investigated whether the association between periodontitis and RA is influenced by single nucleotide polymorphisms (SNPs) in the genes encoding PAD2 and PAD4 that catalyze aberrant citrullination in RA and often are overexpressed in inflamed gingival connective tissue in subjects with periodontitis. The study included 137 RA patients and 161 controls with self-reported periodontitis. Periodontitis onset preceded RA onset by 13 years on average and was not associated with any of the SNPs investigated. In subjects with periodontitis, carriage of the minor alleles of rs2057094 and rs2235912 in PADI2 significantly increased the risk of RA (odds ratios 1.42 [p = 0.03] and 1.48 [p = 0.02], respectively), and this effect was driven by the anti-CCP-negative RA patients. The minor alleles of these SNPs only increased risk of anti-CCP-positive RA in individuals with periodontitis and a history of smoking. These data suggest that individuals with periodontitis carrying the minor alleles of SNPs rs2057094, rs2076616 and rs2235912 in PADI2 may be at increased risk of RA.

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.

Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes.

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

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.

Association between Salmonella infection and colon cancer: a nationwide registry-based cohort study.

Laboratory data increasingly suggest that Salmonella infection may contribute to colon cancer (CC) development. Here, we examined epidemiologically the potential risk of CC associated with salmonellosis in the human population. We conducted a population-based cohort study using four health registries in Denmark. Person-level demographic data of all residents were linked to laboratory-confirmed non-typhoidal salmonellosis and to CC diagnoses in 1994-2016. Hazard ratios (HRs) for CC (overall/proximal/distal) associated with reported salmonellosis were estimated using Cox proportional hazard models. Potential effects of serovar, age, sex, inflammatory bowel disease and follow-up time post-infection were also assessed. We found no increased risk of CC ≥1 year post-infection (HR 0.99; 95% confidence interval (CI) 0.88-1.13). When stratifying by serovar, there was a significantly increased risk of proximal CC ≥1 year post-infection with serovars other than Enteritidis and Typhimurium (HR 1.40; 95% CI 1.03-1.90). CC risk was significantly increased in the first year post-infection (HR 2.08; 95% CI 1.48-2.93). The association between salmonellosis and CC in the first year post-infection can be explained by increased stool testing around the time of CC diagnosis. The association between proximal CC and non-Enteritidis/non-Typhimurium serovars is unclear and warrants further investigation. Overall, this study provides epidemiological evidence that notified Salmonella infections do not contribute significantly to CC risk in the studied population.

Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study.

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.

Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study.

Background: The hypothesized link between the measles, mumps, rubella (MMR) vaccine and autism continues to cause concern and challenge vaccine uptake. Objective: To evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, or time periods after vaccination. Design: Nationwide cohort study. Setting: Denmark. Participants: 657 461 children born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013. Measurements: Danish population registries were used to link information on MMR vaccination, autism diagnoses, other childhood vaccines, sibling history of autism, and autism risk factors to children in the cohort. Survival analysis of the time to autism diagnosis with Cox proportional hazards regression was used to estimate hazard ratios of autism according to MMR vaccination status, with adjustment for age, birth year, sex, other childhood vaccines, sibling history of autism, and autism risk factors (based on a disease risk score). Results: During 5 025 754 person-years of follow-up, 6517 children were diagnosed with autism (incidence rate, 129.7 per 100 000 person-years). Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination. Limitation: No individual medical charts were reviewed. Conclusion: The study strongly supports that MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination. It adds to previous studies through significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases. Primary Funding Source: Novo Nordisk Foundation and Danish Ministry of Health.

Increased Risk of Inflammatory Bowel Disease in Families with Tonsillectomy: A Danish National Cohort Study.

BACKGROUND: The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members. METHODS: A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives. RESULTS: During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 [95% CI = 1.43, 1.61]; ulcerative colitis: RR 1.24 [95% CI = 1.18, 1.29]). RRs for Crohn's disease was 1.22 (95% CI = 1.17, 1.27) after first-degree relatives' tonsillectomy, 1.14 (95% CI = 1.08, 1.19) after second-degree relatives' tonsillectomy, and 1.08 (95% CI = 1.01, 1.15) after third-degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI = 1.07, 1.13), 1.05 (95% CI = 1.01, 1.08), and 1.03 (95% CI = 0.98, 1.09). CONCLUSIONS: Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead toward shared hereditary or environmental factors. See video abstract at, http://links.lww.com/EDE/B464.

Circumcision registry promotes precise research and fosters informed parental decisions.

BACKGROUND: In 2017 Ploug and Holm argued that anonymizing individuals in the Danish circumcision registry was insufficient to protect these individuals from what they regard as the potential harms of being in the registry (overreaching social pressure, stigmatization, medicalization of a religious practice, discrimination and promoting polarized research). DISCUSSION: We argue that Ploug and Holm's fears in each of the areas are misguided, not supported by the evidence, and could interfere with the gathering of accurate data. The extent of the risks and harms associated with ritual circumcision is not well known. The anonymized personal health data supplemented with the circumcision registry will enable more precise research into the medical consequences of ritual circumcision, and allow parents to make more fully informed decisions about circumcision with minimal, if any, adverse consequences.

A cluster analysis of serious adverse event reports after human papillomavirus (HPV) vaccination in Danish girls and young women, September 2009 to August 2017.

BackgroundSuspected adverse events (AE) after human papillomavirus (HPV) vaccines include postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS), complex regional pain syndrome (CRPS) and symptoms including headache and orthostatic intolerance.AimWe aimed to identify phenotypes of AEs after HPV vaccination, defined as patterns of AE terms (signs, symptoms, diagnoses), and to evaluate if identified phenotypes reflected previously suspected symptomatology or heightened public concerns over HPV vaccine safety since 1 January 2015.MethodsWe conducted a retrospective observational study using latent class cluster analysis of all serious AE reports (n = 963) reported by females residing in Denmark between September 2009 and August 2017. Resulting clusters were characterised according to AE terms associated with POTS, CFS and CRPS before (September 2009-December 2014) and during (January 2015-August 2017) a time of heightened media activity regarding HPV vaccines.ResultsFour clusters of AE reports were distinguished. The most common symptoms were fatigue, dizziness and headache but their frequency varied among clusters. The majority of reports in one cluster were submitted during a period of heightened media activity, including an anomalous spike in submissions in December 2015; a high proportion of these reports included the symptoms cognitive disorder (78%), abdominal pain (77%), dysuria (60%) and sleep disorder (60%).ConclusionsNon-specific symptoms including headache, fatigue and dizziness feature prominently in serious AE reports from females in Denmark. Our analysis identified a cluster of reports, likely media stimulated, with a focus on symptoms of CFS and POTS.

Cultural background, non-therapeutic circumcision and the risk of meatal stenosis and other urethral stricture disease: Two nationwide register-based cohort studies in Denmark 1977-2013.

BACKGROUND: Meatal stenosis is markedly more common in circumcised than genitally intact males, affecting 5-20 per cent of circumcised boys. However, no population-based study has estimated the relative risk of meatal stenosis and other urethral stricture diseases (USDs) or the population attributable fraction (AFp) associated with non-therapeutic circumcision. METHODS: In two nationwide cohort studies (comprising 4.0 million males of all ages and 810 719 non-Muslim males aged 0-36 years, respectively), we compared hospital contact rates for USD during 1977-2013 between circumcised and intact Danish males. Hazard ratios (HRs) were obtained using Cox proportional hazards regression, and the AFp estimated the proportion of USD cases in <10 year-old boys that is due to non-therapeutic circumcision. RESULTS: Muslim males had higher rates of meatal stenosis than ethnic Danish males, particularly in <10 year-old boys (HR 3.44, 95 per cent confidence interval 2.42-4.88). HRs linking circumcision to meatal stenosis (10.3, 4.53-23.4) or other USDs (5.14, 3.48-7.60) were high, and attempts to reduce potential misclassification and confounding further strengthened the association, particularly in <10 year-old boys (meatal stenosis: 26.3, 9.37-73.9; other USDs: 14.0, 6.86-28.6). Conservative calculations revealed that at least 18, 41, 78, and 81 per cent of USD cases in <10 year-old boys from countries with circumcision prevalences as in Denmark, the United Kingdom, the United States and Israel, respectively, may be attributable to non-therapeutic circumcision. CONCLUSION: Our study provides population-based epidemiological evidence that circumcision removes the natural protection against meatal stenosis and, possibly, other USDs as well.

Reduced risk of UC in families affected by appendicitis: a Danish national cohort study.

OBJECTIVE: The possible aetiological link between appendicitis and UC remains unclear. In order to investigate the hereditary component of the association, we studied the risk of UC in family members of individuals with appendicitis. DESIGN: A cohort of 7.1 million individuals was established by linkage of national registers in Denmark with data on kinship and diagnoses of appendicitis and UC. Poisson regression models were used to calculate first hospital contact rate ratios (RR) for UC with 95% CIs between individuals with or without relatives with a history of appendicitis. RESULTS: During 174 million person-years of follow-up between 1977 and 2011, a total of 190 004 cohort members developed appendicitis and 45 202 developed UC. Individuals having a first-degree relative with appendicitis before age 20 years had significantly reduced risk of UC (RR 0.90; 95% CI 0.86 to 0.95); this association was stronger in individuals with a family predisposition to UC (RR 0.66; 95% CI 0.51 to 0.83). CONCLUSIONS: Individuals with a first-degree relative diagnosed with appendicitis before age 20 years are at reduced risk of UC, particularly when there is a family predisposition to UC. Our findings question a previously hypothesised direct protective influence of appendicitis on inflammation of the large bowel. Rather, genetic or environmental factors linked to an increased risk of appendicitis while being protective against UC may explain the repeatedly reported reduced relative risk of UC in individuals with a history of appendicitis.