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.

Body Mass Index and Risk of Infections Among Women in the Danish National Birth Cohort.

We investigated the possible association between body mass index (BMI; weight (kg)/height (m)(2)) and hospitalization or treatment for acute infection in a prospective cohort study. We linked 75,001 women enrolled in the Danish National Birth Cohort from 1996 to 2002, who had information on BMI and a broad range of confounders, to data on infectious diseases and use of antimicrobial agents from the National Patient Register and the Danish Prescription Register. Associations were tested using Cox proportional hazards models. During 12 years of follow-up, we observed a U-shaped association between baseline BMI and later hospitalization for 1) any infectious disease and 2) infections of the respiratory tract, whereas a dose-response relationship was seen for skin infections. The most pronounced associations were seen for acute upper respiratory infections at multiple and unspecified sites (underweight (BMI <18.5): hazard ratio (HR) = 4.26, 95% confidence interval (CI): 1.69, 10.7; obesity (BMI ≥30): HR = 3.64, 95% CI: 1.62, 8.18), erysipelas (obesity: HR = 5.19, 95% CI: 3.38, 7.95), and fungal infections (underweight: HR = 3.19, 95% CI: 1.53, 6.66). Slightly greater use of antimicrobials was observed among overweight (BMI 25-<30; HR = 1.08, 95% CI: 1.06, 1.10) and obese (HR = 1.21, 95% CI: 1.17, 1.24) women. Among Danish women, underweight and obesity were associated with increased risk of community-acquired infectious diseases, especially infections of the upper respiratory tract and skin.

Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979-2011.

INTRODUCTION: Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort. METHODS: 48 967 individuals were diagnosed with IBD (Crohn's disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979-2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression. RESULTS: 5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979-1986) to 19.6% in cohort (2003-2011) (p < 0.001) for CD, and from 11.7% in cohort (1979-1986) to 7.5% in cohort (2003-2011) (p < 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995-2002) to cohort (2003-2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use <3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of >1 year. CONCLUSIONS: Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found.

SARS-CoV-2 Infection and Risk of Postacute Psychiatric and Neurologic Diagnoses: A Nationwide Danish Cohort Study.

BACKGROUND AND OBJECTIVES: The extent and burden of postacute psychiatric and neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not yet fully understood. To evaluate the association between SARS-CoV-2 infection and postacute manifestations of psychiatric and neurologic disorders, we conducted a nationwide cohort study including the entire Danish population aged 12 years or older on March 1, 2020. METHODS: Individuals were followed up for SARS-CoV-2 infection and diagnosis of subsequent psychiatric and neurologic disorders from March 1, 2020, to January 31, 2023, using the Danish nationwide coronavirus disease 2019 (COVID-19) test surveillance database and the Danish National Patient Registry. The main period of interest was 1-12 months after infection. Incidence rate ratios (IRRs) of new onset of 11 psychiatric and 30 neurologic disorders were calculated by comparing incidence rates of disorders between SARS-CoV-2-positive individuals and individuals without a positive test (nonpositive individuals). Stratified analyses were conducted according to COVID-19 vaccination status, variant period, age, sex, and severity of infection. RESULTS: Overall, 1,775,639 individuals in the study cohort (n = 3,239,008) were tested SARS-CoV-2 positive during follow-up. SARS-CoV-2-positive individuals compared with nonpositive individuals were at 24% reduced risk of any psychiatric disease (IRR 0.76, 95% CI 0.74-0.78) in the postacute period. The risk of any neurologic disorder was slightly higher among SARS-CoV-2-positive individuals than among those without a positive test (IRR 1.05, 95% CI 1.04-1.07). IRRs for specific disorders varied considerably from a 3.9-fold increased risk of change in sense of smell or taste (IRR 3.91, 95% CI 2.77-5.53) to a 29% reduced risk of dementia (IRR 0.71, 95% CI 0.65-0.78). The severity of infection and vaccination status, more so than age, sex, and variant, were found to significantly influence the stratified IRRs. Compared with nonpositive individuals, hospitalized patients with COVID-19 were at a 2.1-fold (IRR 2.05, 95% CI 1.78-2.37) increased risk of psychiatric disorders and at a 2.4-fold increased risk of neurologic disorders (IRR 2.44, 95% CI 2.29-2.60). DISCUSSION: Our study does not support previous findings of substantial postacute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals, but does corroborate an elevated risk among the most severe cases with COVID-19.

Cesarean section and offspring's risk of multiple sclerosis: a Danish nationwide cohort study.

BACKGROUND: Apart from a recent study reporting a 2- to 3-fold increased risk of multiple sclerosis (MS) among women and men who were delivered by Cesarean section (C-section), little attention has been given to the possible association between mode of delivery and the risk of MS. OBJECTIVES: We studied the association between C-section and risk of MS, in a cohort of 1.7 million Danes born from 1973 to 2005. METHODS: Information on C-section and MS was obtained from the Danish Medical Birth Register and the Danish MS Register, respectively. The association between C-section and MS was evaluated by means of MS incidence rate ratios (RR) with 95% confidence intervals (CI) obtained in log-linear Poisson regression analyses. RESULTS: There were 930 cases of MS in the study cohort, of whom 80 (9%) were delivered by C-section. Overall, we found there was no significant association between C-section and risk of MS (RR = 1.17; 0.92-1.46). Analyses stratified by sex revealed no unusual risk of MS for women (RR = 1.08: 0.80-1.42) nor men (RR = 1.37: 0.91-1.98). A supplementary sibling-matched Cox regression analysis likewise suggested there was no excess risk of MS in persons delivered by C-section (HR = 1.03; 0.63-1.69). CONCLUSIONS: Mode of delivery appears to be unimportant in relation to MS development in the offspring.

Use of calcium channel blockers and Parkinson's disease.

Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinson's disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinson's disease (1998-2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinson's disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinson's disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinson's disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinson's disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinson's disease, particularly in older patients, and with reduced mortality among patients with Parkinson's disease.

Use of amiloride and multiple sclerosis: registry-based cohort studies.

PURPOSE: Amiloride reduces functional neurological deficits and neuronal damage in animal models of multiple sclerosis (MS). We investigated whether amiloride use was associated with reduced risk of incident MS and of MS hospitalization and death in humans. METHODS: We conducted two propensity score-matched cohort studies, linking nationwide registry data on filled drug prescriptions, diagnostic information, and covariates. First, we compared rates of incident MS in new users of amiloride and new users of an active control treatment, thiazide diuretics. Second, rates of hospitalizations for MS and of death were compared between users of amiloride and thiazides in a cohort of MS patients. Treatment groups were matched 1 : 4 on propensity scores that included a wide range of covariates, and Cox regression was used to estimate hazard ratios (HRs). RESULTS: Comparing 36 659 users of amiloride and 177 031 users of thiazides, there were 19 cases of incident MS during 92 548 person-years of follow-up among amiloride users and 81 cases during 567 599 person-years of follow-up among thiazide users. There was no significantly decreased risk of MS associated with amiloride use (HR 1.34, 95%CI 0.81-2.20). In the cohort of MS patients, amiloride use was not associated with significantly decreased risk of MS hospitalization (HR 1.11, 95%CI 0.79-1.59) or death (HR 1.38, 95%CI 0.83-2.28). CONCLUSION: Amiloride use was not associated with significantly decreased risk of incident MS or hospitalizations and death among patients with MS. Because amiloride users were represented by older patients, risks could not be evaluated in younger individuals.

Autoimmune diseases in women with Turner's syndrome.

OBJECTIVE: In terms of number of X chromosomes, women with Turner's syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turner's syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turner's syndrome is characterized by diseases with a female or male predominance. METHODS: Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turner's syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS: The overall risk of autoimmune disease among women with Turner's syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turner's syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]). CONCLUSION: Women with Turner's syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.

Epstein-Barr virus-associated infectious mononucleosis and risk of systemic lupus erythematosus.

OBJECTIVES: Elevated levels of serological markers of EBV infection in patients with SLE and observations that infectious mononucleosis (IM) may precede some cases of SLE suggest a possible role of EBV in the aetiology of SLE. We evaluated the relationship between EBV-associated IM and subsequent risk of SLE in a population-based cohort study. METHODS: We followed cohorts of Danes tested serologically for IM using the Paul-Bunnell (PB) heterophile antibody test between 1939 and 1989, and patients hospitalized with IM between 1977 and 2007 for subsequent first hospitalizations with SLE in the period 1977-2008. Standardized incidence ratios (SIRs) with 95% CI served as measures of relative risk. RESULTS: Risk of SLE was not increased either in individuals with a positive PB test (SIR = 1.1; 95% CI 0.8, 1.6; n = 27) or in individuals hospitalized with IM (SIR = 1.3; 95% CI 0.7, 2.2; n = 12). However, SLE risk in PB-negative individuals was significantly increased (SIR = 2.6; 95% CI 2.1, 3.2; n = 82), a risk that was particularly high 1-4 years after the PB test (SIR = 6.6; 95% CI 3.3, 13.2) and remained significantly elevated for >25 years. CONCLUSIONS: EBV-associated IM does not seem to be a risk factor for SLE. The temporal pattern of increased SLE risk in individuals with a negative PB test suggests that some patients who go on to develop SLE may present with unspecific symptoms, for which they may be tested for IM, long in advance of their SLE diagnosis.

Type 1 diabetes and multiple sclerosis: A Danish population-based cohort study.

BACKGROUND: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported. OBJECTIVE: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil Registration System. MAIN OUTCOME MEASURE: Patients with T1D and first-degree relatives of patients with MS were followed up for occurrence of MS and T1D, respectively, and the relative risks were expressed as standardized incidence ratios, that is, ratios of observed to expected numbers of outcomes based on national age, sex, and period-specific MS and T1D incidence rates. RESULTS: Patients with T1D were at more than 3-fold increased risk for development of MS (relative risk, 3.26; 95% confidence interval, 1.80-5.88; n = 11). First-degree relatives of patients with MS were at 63% increased risk (relative risk, 1.63; 95% confidence interval, 1.26-2.12; n = 56) for development of T1D. However, adjusting for familial relationship to patients with T1D reduced the excess risk to 44% (relative risk, 1.44; 95% confidence interval, 1.11-1.88; n = 56). CONCLUSION: The present nationwide cohort study demonstrates an intraindividual and, to a lesser degree, an intrafamilial co-occurrence of MS and T1D.

Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40.

BACKGROUND: Early poliovirus vaccines were accidentally contaminated with simian virus 40 (SV40). In Denmark, poliovirus vaccine was administered to most children from 1955 through 1961. SV40 DNA sequences have been detected in several human malignancies, including mesothelioma, ependymoma, choroid plexus tumors, and non-Hodgkin's lymphoma. To clarify whether SV40 infection increases risk of these cancers or of cancers arising in children, we examined cancer incidence in three Danish birth cohorts. METHODS: Population-based cancer incidence data from 1943 through 1997 were obtained from the Danish Cancer Registry. The relationship between exposure to SV40-contaminated vaccine and cancer incidence was evaluated by examining incidence in birth cohorts that differed in exposure to SV40-contaminated vaccine. In addition, cancer incidence was examined in children who were 0-4 years of age before, during, and after the period of vaccine contamination. Incidence was compared using Poisson regression, adjusting for age differences. All statistical tests were two-sided. RESULTS: After 69.5 million person-years of follow-up, individuals exposed to SV40-contaminated poliovirus vaccine as infants (i.e., born 1955-1961) or children (i.e., born 1946-1952) had lower overall cancer risk (age-adjusted relative risk [RR] = 0.86, 95% confidence interval [CI] = 0.81 to 0.91 and RR = 0.79, 95% CI = 0.75 to 0.84, respectively; P<.001 for both) than unexposed individuals (i.e., born 1964-1970, after the vaccine was cleared of SV40 contamination). Specifically, SV40 exposure was not associated with increased incidence of mesothelioma, ependymoma, choroid plexus tumor, or non-Hodgkin's lymphoma. After 19.5 million person-years of follow-up, incidence of all cancers combined, of intracranial tumors, and of leukemia among children aged 0-4 years was also not associated with SV40 exposure. Ependymoma incidence was higher during the exposed period than during the unexposed period (RR = 2.59, 95%CI = 1.36 to 4.92; P =.004 versus the period before contamination); however, incidence peaked in 1969, after the vaccine was cleared of SV40. CONCLUSION: Exposure to SV40-contaminated poliovirus vaccine in Denmark was not associated with increased cancer incidence.

Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort.

BACKGROUND: A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m2) and 43 ADs. METHODS: 75,008 women participating in the Danish National Birth Cohort were followed during a median time of 11 years. Diagnoses on ADs were retrieved from the Danish National Patient Register. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated adjusting for potential confounders (smoking, alcohol, parity and socio-occupational status). RESULTS: During follow-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5-≤25 kg/m2). Obese women (BMI≥30 kg/m2) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynaud's phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further associations between BMI and risk of psoriasis, rheumatoid arthritis and Crohn's disease were suggested. CONCLUSIONS: BMI was found to be associated with several Ads. This was most pronounced between obesity and risk of sarcoidosis and and risk of type 1 diabetes mellitus. These novel findings need confirmation and the possible role of adipose tissue-derived immunological changes in the development of autoimmune reactions needs consideration.

Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark.

OBJECTIVE: The female predominance in systemic lupus erythematosus (SLE) suggests the possible involvement of reproductive factors in its etiology. We evaluated the relationship between parity and pregnancy losses and subsequent risk of SLE in a population-based cohort study. METHODS: We followed 4.4 million Danes aged 15-69 years for first inpatient hospitalizations for SLE between 1977 and 2004. As measures of relative risk, we used Poisson regression-derived hospitalization rate ratios (RR) with 95% confidence intervals (CI) for cohort members with different reproductive histories. RESULTS: Overall, 1614 women and 274 men were hospitalized with SLE during 88.9 million person-years of followup. Number of children was unrelated to SLE risk in men, but women with at least one liveborn child were at lower risk than nulliparous women (RR 0.74; 95% CI 0.64-0.86), and women with 2 or more children were at lower risk than 1-child mothers. Recurrent idiopathic pregnancy losses, including spontaneous abortions, missed abortions, and stillbirths, were associated with markedly increased SLE risk (RR 3.50; 95% CI 2.38-4.96, for 2+ vs none; p < 0.001). CONCLUSION: Nulliparous women, 1-child mothers, and women who experience spontaneous abortions, missed abortions, or stillbirths are at increased SLE risk. Theoretically, immunological processes involved in subfertility or idiopathic pregnancy losses might act as initiating or contributing factors in some cases of SLE. However, considering the well established excess of pregnancy complications in women with established SLE, the observed associations more likely reflect the effect of subclinical immunological processes in women destined to develop SLE.

Autoimmune diseases in a Danish cohort of 4,866 carriers of constitutional structural chromosomal rearrangements.

OBJECTIVE: Constitutional structural chromosomal rearrangements (CSCRs) have facilitated the identification of genes associated with early-onset monogenic disorders and, more recently, genes associated with common and late-onset disorders. In an attempt to find genetic clues to their etiologies, we studied the risk of autoimmune diseases in a Danish cohort of CSCR carriers. METHODS: We followed up 4,866 CSCR carriers over 71,230 person-years (1980 through 2004) for autoimmune diseases recorded in the Danish Hospital Discharge Register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) served as measures of the relative risk. To identify possible candidate loci for autoimmune diseases, the reported chromosomal breakpoints and deletions in CSCR carriers who developed autoimmune diseases were compared with previously suggested loci for these diseases. RESULTS: The overall risk of any autoimmune disease among CSCR carriers was inconspicuous (SIR 1.2 [95% CI 0.95-1.5]; n = 74 cases observed versus 61.3 expected), but carriers of rearrangements involving chromosomes 2, 19, and 21 were at significantly increased risk. For the specific autoimmune diseases studied, cohort members were at significantly increased risk of Dupuytren's contracture, pernicious anemia, and juvenile rheumatoid arthritis (JRA). Sixteen carriers who developed an autoimmune disease had a chromosomal breakpoint or deletion coinciding with a previously suggested locus, including deletions 18p11, 18q22, and 22q11 associated with JRA. CONCLUSION: CSCR carriers do not have a generalized predisposition to autoimmune diseases. However, we confirmed a number of reported susceptibility loci for JRA, and we suggest new susceptibility loci on chromosomes 5 and 11 for Dupuytren's contracture, and 19p13 as a possible shared susceptibility locus for a range of autoimmune diseases.