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Background: Data about the clinical benefit from initial low-density lipoprotein cholesterol (LDL-C) reduction with lipid lowering treatment for secondary prevention and risk of major vascular events amongst older as compared with younger individuals treated during routine clinical care are limited. We investigated this in a nationwide cohort., Methods: Individuals aged ≥ 50 years with a first-time hospitalisation for a cardiovascular event (index event, including acute coronary syndrome, non-haemorrhagic stroke, transient ischaemic attack and coronary revascularisation), 1 January 2008 to 31 October 2018, who subsequently used lipid lowering treatment, and had an LDL-C measurement before and after the event were included. Hazard ratios (HRs) for major vascular events per 1 mmol/L reduction in LDL-C were estimated for the included 21,751 older and 22,681 younger individuals (≥/<70 years old) using Cox regression., Results: LDL-C lowering was associated with a 12% lower risk of major vascular events in older individuals per 1 mmol/L reduction in LDL-C (HR 0.88, 95% confidence interval [CI] 0.84-0.93), with no significant difference compared with the risk reduction amongst younger individuals (HR 0.88, 95% CI 0.83-0.93; P-value for difference between age groups: 0.86). The risk reduction was more pronounced when post hoc restricting, as a proxy for compliance, to new users with an LDL-C reduction above the lowest decile for both older (0.81, 95% CI 0.73-0.90) and younger (0.81, 95% CI 0.72-0.91) individuals., Conclusions: This study strongly supports a similar relative clinical benefit of LDL-C reduction with lipid lowering treatment for secondary prevention of major vascular events amongst individuals aged ≥70 and <70 years., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pre-pregnancy diabetes is a strong risk factor for congenital heart defects (CHDs), suggesting a role for glucose in the causal pathway. Oral corticosteroids may cause hyperglycemia and maternal use could affect embryonic heart development. The objective of this study was to determine the association between maternal intake of oral corticosteroids 0-8 weeks after conception and CHDs in offspring., Methods: A register-based nationwide prevalence study including all live singleton births in Denmark, 1996-2016, was conducted. In total, 1 194 687 individuals and their mothers were identified and linked with information on offspring CHDs and the mothers' use of oral corticosteroids in early pregnancy. Corticosteroid use was defined as a filled prescription for maternal use of oral corticosteroid 0-8 weeks after conception. CHDs were identified through International Classification of Diseases codes. The association was estimated by prevalence (odds) ratios using logistic regression and propensity score-matched analyses., Results: Among 1 194 687 live births, 2032 had a mother who had used oral corticosteroids 0-8 weeks from conception. Of these offspring, 32 had a heart defect. Among the offspring of never-users of oral corticosteroids, 10 534 had a heart defect. The adjusted prevalence ratio was 1.29 (95% confidence interval, 0.90-1.84) comparing offspring prevalence of heart defects in oral corticosteroid users with that in oral corticosteroid never-users. Propensity score-matched analysis yielded similar results (prevalence ratio 1.38; 95% confidence interval, 0.95-2.02)., Conclusions: This study supports that there is no association between maternal use of oral corticosteroids in the first 8 weeks after conception and CHDs., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Several studies have reported a high risk of ischemic stroke (IS) during the acute phase of infective endocarditis (IE). The long-term risk of IS after IE, however, is not fully illuminated., Methods: This Danish, nationwide, register-based, propensity score-matched cohort study used Cox regression to estimate hazard ratios (HRs) of IS for persons with vs without a history of left-sided IE, from 1977 to 2015., Results: We followed 9312 patients exposed to a first-time IE and 91 996 nonexposed, matched control persons. Compared to persons without IE, patients with a history of IE had a significantly increased risk of IS; the risk was highest during the first 4 weeks after IE diagnosis (HR 57.20, 95% confidence interval [CI] 45.58-71.78; P < .0001) and a moderately elevated risk persisted until 2 years after IE (4 weeks to 3 months after IE, HR 5.40, 95% CI 4.11-7.19; 3 months to 2 years after IE, HR 1.73, 95% CI 1.48-2.01). Mediation analyses showed that the higher risk of IS the first 2 years after IE could not be explained by atrial fibrillation (AF) or inserted mechanical valves in IE patients. In the period from 4 weeks to 3 months after IE diagnosis, patients treated with anticoagulative therapy had a lower risk of IS (HR 0.30, 95% CI .10-0.96; P = .04)., Conclusions: Patients with a history of IE had an increased risk of IS for up to 2 years after IE diagnosis. The increased risk was unrelated to AF and inserted mechanical valves. During the initial phase after IE, patients taking an anticoagulative medication had a lower risk of IS., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A man's risk of prostate cancer has been linked to his prior reproductive history, with low sperm quality, low ejaculation frequency, and a low number of offspring being associated with increased prostate cancer risk. It is, however, highly controversial whether vasectomy, a common sterilization procedure for men, influences prostate cancer risk., Methods: We established a cohort of all Danish men (born between 1937 and 1996) and linked information on vasectomy, doctor visits, socioeconomic factors, and cancer from nationwide registries using unique personal identification numbers. Incidence risk ratios for prostate cancer by time since vasectomy and age at vasectomy during the follow-up were estimated using log-linear Poisson regression., Results: Overall, 26 238 cases of prostate cancer occurred among 2 150 162 Danish men during 53.4 million person-years of follow-up. Overall, vasectomized men had an increased risk of prostate cancer compared with nonvasectomized men (relative risk = 1.15, 95% confidence interval = 1.10 to 1.20). The increased risk of prostate cancer following vasectomy persisted for at least 30 years after the procedure and was observed regardless of age at vasectomy and cancer stage at diagnosis. Adjustment for the number of visits to the doctor and socioeconomic factors did not explain the association., Conclusions: Vasectomy is associated with a statistically significantly increased long-term risk of prostate cancer. The absolute increased risk following vasectomy is nevertheless small, but our finding supports a relationship between reproductive factors and prostate cancer risk., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Extremely strong associations between male hormone-interfering drugs and meningiomas have been reported in two previous studies, but these findings are limited by small size of the study populations and possibly by surveillance- and selection bias. Thus, such possible and indeed very interesting association must be investigated in a large, unselected cohort. Accordingly, the aim of this study was to determine whether patients exposed to male hormone-interfering drugs had a higher risk of meningioma development in a nationwide cohort study., Methods: A retrospective Danish nationwide cohort study with follow-up from January 1, 1996 to December 31, 2016. Exposure was use of male hormone-interfering drugs (5-α-reductase-inhibitors, luteinizing hormone-releasing hormone agonist, steroidal antiandrogen, and nonsteroidal antiandrogen). Hazard ratio of first-time diagnosis of meningioma according to drug use was estimated using Cox proportional hazards model with adjustment for age and birth year., Results: The cohort included 244,696 men of which 64,047 had used male hormone-interfering drugs. Overall 444 meningiomas occurred during follow-up. No significant association was observed between use of male hormone-interfering drugs and the occurrence of meningioma (hazard ratio 1.02, 95% confidence interval 0.82-1.27). Similar results were observed 0-1, 2-4, and 5+ years after first use. In explorative analyses, no elevated risk association was observed for specific drugs (5-α-reductase-inhibitors, luteinizing hormone-releasing hormone agonist, steroidal antiandrogen, and nonsteroidal antiandrogen)., Conclusion: As opposed to previous studies, we found no evidence of an increased risk of meningioma in men treated with male hormone-interfering drugs., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

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., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The present study aimed to investigate the long-term risk of hemorrhagic stroke (HS) in patients with infective endocarditis (IE)., Methods: Using a register-based nationwide cohort of 9 million Danes, we performed propensity score matching between patients with left-sided IE from 1977 to mid-2015 and IE-free individuals (1:10). Follow-up started 1 year after the IE diagnosis. Hazard ratios (HRs) for HS in patients with IE compared with the matched cohort were estimated using Cox regression., Results: During follow-up of 5735 patients with left-sided IE from 1 year after IE diagnosis and up to 37.5 years (median, 6.3 years), 103 cases of HS were observed. Compared with the matched cohort, patients with IE had a higher long-term risk of HS (HR, 1.47; 95% confidence interval, 1.20-1.80; P < .001). The risk of HS was particularly increased in patients within the lowest propensity score quartile (HR, 2.60; 95% confidence interval, 1.89-3.58). Mediation analyses suggested that the increased HS risk could be explained by an indirect effect of mechanical heart valve insertion, atrial fibrillation, or treatment with anticoagulants. The cumulative risk of HS 30 years after start of follow-up was 3.0% in patients with IE., Conclusions: IE does not directly increase the long-term risk of HS. The apparent excess risk of HS in patients with previous IE was explained by mediating factors, including mechanical heart valve insertion, atrial fibrillation, and anticoagulation medication.

Background: Associations of reproductive history with breast cancer risk differ by oestrogen receptor (ER±) status and possibly by the joint expression of ER and the human epidermal growth factor receptor-2 (ER±/HER2±). However, large sample sizes are needed to establish ER-specific risks by HER2± expression., Methods: We linked a cancer registry covering nearly 95% of the primary breast cancer diagnoses in Denmark with a research parity database to assess associations for parity, number of live births and age at first live birth (AFLB) with receptor-specific risk. Relative risks (RRs) for associations were estimated with Poisson regression models., Results: With nearly 31 million women-years of follow-up, 45 786 Danish women aged 20-84 years developed invasive breast cancer during 1992-2011. ER± expression was available for the entire study period and HER2± after 2006. Of the breast cancers with known ER expression, 79% were ER+. Most breast cancers with known ER and HER2 were HER2- (90% of ER+ cancers and 65% of ER- cancers). RRs differed by ER± expression for all reproductive variables ( p -homogeneity < 0.001). Associations were stronger for ER+ than ER- cancers and for those diagnosed before age 50. Parity and early [not later] AFLB showed a protective association with ER+/HER2- and risk association with ER-/HER2- cancers., Conclusion: Associations of reproductive history with breast cancer risk varied among Danish women by ER± and ER±/HER2± expression and age-at-diagnosis, consistent with receptor-specific and age-related etiological heterogeneity. Further stratification by HER2 status demonstrated dual (or opposite) effects for ER+/HER2- and ER-/HER2- cancers., (Published by Oxford University Press on behalf of the International Epidemiological Association 2016. This work is written by US Government employees and is in the public domain in the US.)

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., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neoplastic transformation of damaged astrocytes has been proposed as a possible pathological mechanism behind malignant astrocytic tumors. This study investigated the association between structural brain injuries causing reactive astrogliosis and long-term risk for malignant astrocytic tumors., Methods: The cohort consisted of all individuals living in Denmark between 1978 and 2011. The personal identification number assigned to all individuals allowed retrieval of diagnoses of traumatic brain injury, cerebral ischemic infarction, and intracerebral hemorrhage from the National Patient Discharge Register. Diagnoses of anaplastic astrocytoma and glioblastoma multiforme (World Health Organization grades III and IV) were retrieved from the Danish Cancer Registry. Rate ratios (RR's) were estimated using log-linear Poisson regression., Results: In a cohort of 8.2 million individuals, 404 812 experienced a structural brain injury and 6152 developed a malignant astrocytic tumor. No significant association was observed 1-4 years after a structural brain injury (RR = 1.14; 95% CI: 0.87-1.46), whereas the long-term (5+ y) risk for malignant astrocytic tumors was significantly reduced (RR = 0.68; 95% CI: 0.49-0.90) compared with no injury. The specific long-term risks by type of injury were: traumatic brain injury RR = 0.32 (95% CI: 0.10-0.75); cerebral ischemic infarction RR = 0.69 (95% CI: 0.47-0.96); and intracerebral hemorrhage RR = 1.39 (95% CI: 0.64-2.60)., Conclusion: We found no evidence for an association between structural brain injury and malignant astrocytic tumors within the first 5 years of follow-up. However, our study indicated a protective effect of astrogliosis-causing injuries 5 or more years after structural brain injury., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Greenland remains a highly endemic area for hepatitis B virus (HBV) infection. This is in sharp contrast to other modern societies, such as Denmark. To address this discrepancy, we investigated the natural history of HBV infection in Greenland by estimating the age-specific incidence of HBV infection, the proportion of chronic carriers, and the rates of hepatitis B surface antigen seroclearance. In total, 8,879 Greenlanders (16% of the population) from population-based surveys conducted in 1987 and 1998 were followed through March 2010. Data on HBV status were supplemented by HBV test results from all available HBV registries in Greenland to determine changes in HBV status over time. Incidence rates of HBV infection and hepatitis B surface antigen seroclearance were estimated after taking into account interval censoring. The incidence of HBV infection in 5-14-year-old subjects was less than 1 per 100 person-years and peaked at 5 per 100 person-years in persons 15-24 years of age. Overall, 17.5% of persons infected in adulthood were estimated to become chronic carriers. HBV is primarily transmitted in adolescence and adulthood in Greenland. In contrast to what is observed in most other populations, HBV-infected adults in Greenland have a high risk of progressing to chronic HBV carriage. This phenomenon might explain how the high rate of infection is maintained in Greenland., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Present understanding of increased risk of Epstein-Barr virus (EBV)-related infectious mononucleosis among children of low birth order or small sibships is mainly based on old and indirect evidence. Societal changes and methodological limitations of previous studies call for new data., Methods: We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study incidence rates of inpatient hospitalizations for infectious mononucleosis before the age of 20 years in a cohort of 2,543,225 Danes born between 1971 and 2008, taking individual sibship structure into account., Results: A total of 12,872 cases of infectious mononucleosis were observed during 35.3 million person-years of follow-up. Statistical modelling showed that increasing sibship size was associated with a reduced risk of infectious mononucleosis and that younger siblings conferred more protection from infectious mononucleosis than older siblings. In addition to this general association with younger and older siblings, children aged less than 4 years transiently increased their siblings’ infectious mononucleosis risk. Our results were confirmed in an independent sample of blood donors followed up retrospectively for self-reported infectious mononucleosis., Conclusions: Younger siblings, and to a lesser degree older siblings, seem to be important in the transmission of EBV within families. Apparently the dogma of low birth order in a sibship as being at the highest risk of infectious mononucleosis is no longer valid.

Aims: To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort., Methods and Results: We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease belonging to the selected subgroups, the risk was particularly high in the first year after DM diagnosis [SIR 15.4 (95% CI: 10.9-21.3)] but remained significantly elevated in subsequent years [SIR 6.07 (95% CI: 5.11-7.16]). The risk was higher in young cohort members [e.g. 20-39 years: SIR 18.1 (95% CI: 12.3-25.8)] compared with older [e.g. 60-79 years: SIR 3.99 (95% CI: 2.98-5.23)] but remained significantly increased in all age categories. Results were similar in separate analyses of the genetically confirmed DM1 patients., Conclusion: Myotonic dystrophy is strongly associated with cardiac disease. The risk is pronounced in the young and remains elevated throughout life, stressing the importance of lifelong cardiac follow-up from time of DM diagnosis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Circumstantial evidence from genome-wide association and family studies of various Epstein-Barr virus-associated diseases suggests a substantial genetic component in infectious mononucleosis (IM) etiology. However, familial aggregation of IM has scarcely been studied., Methods: We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study rate ratios of IM in a cohort of 2 823 583 Danish children born between 1971 and 2011. Specifically, we investigated the risk of IM in twins and in first-, second-, and third-degree relatives of patients with IM. In the analyses, IM was defined as a diagnosis of IM in a hospital contact. Effects of contagion between family members were dealt with by excluding follow-up time the first year after the occurrence of IM in a relative., Results: A total of 16 870 cases of IM were observed during 40.4 million person-years of follow-up from 1977 to 2011. The rate ratios and the associated 95% confidence intervals were 9.3 (3.0-29) in same-sex twins, 3.0 (2.6-3.5) in siblings, 1.9 (1.6-2.2) in children, 1.4 (1.3-1.6) in second-degree relatives, and 1.0 (0.9-1.2) in third-degree relatives of IM patients. The rate ratios were very similar for IM in children (aged 0-6 years) and older children/adolescents (aged 7-19 years)., Conclusions: We found evidence of familial aggregation of IM that warrants genome-wide association studies on IM disease etiology, especially to examine commonalities with causal pathways in other Epstein-Barr virus-related diseases., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Preeclampsia encompasses multiple conditions of varying severity. We examined the recurrence and familial aggregation of preeclampsia by timing of onset, which is a marker for severity. We ascertained personal and family histories of preeclampsia for women who delivered live singletons in Denmark in 1978-2008 (almost 1.4 million pregnancies). Using log-linear binomial regression, we estimated risk ratios for the associations between personal and family histories of preeclampsia and the risk of early-onset (before 34 weeks of gestation, which is typically the most severe), intermediate-onset (at 34-36 weeks of gestation), and late-onset (after 36 weeks of gestation) preeclampsia. Previous early-, intermediate-, or late-onset preeclampsia increased the risk of recurrent preeclampsia with the same timing of onset 25.2 times (95% confidence interval (CI): 21.8, 29.1), 19.7 times (95% CI: 17.0, 22.8), and 10.3 times (95% CI: 9.85, 10.9), respectively, compared with having no such history. Preeclampsia in a woman's family was associated with a 24%-163% increase in preeclampsia risk, with the strongest associations for early- and intermediate-onset preeclampsia in female relatives. Preeclampsia in the man's family did not affect a woman's risk of early-onset preeclampsia and was only weakly associated with her risks of intermediate- and late-onset preeclampsia. Early-onset preeclampsia appears to have the largest genetic component, whereas environmental factors likely contribute most to late-onset preeclampsia. The role of paternal genes in the etiology of preeclampsia appears to be limited.

Background: Because parvovirus B19 infection in pregnancy has been associated with infant morbidity and mortality in case reports and after intrauterine transfusion, we tested the population-based association using serum and hospital data of high quality., Methods: We established a cohort of 113 228 children born to women tested for parvovirus B19 infection during pregnancy in a major diagnostic laboratory in Denmark, from 1994 to 2009. Information on 20 selected morbidity diagnoses and on mortality was obtained from the Danish National Patient Register, the Danish Cancer Register and the Danish Civil Registration System. Incidence rate ratios (IRR) were estimated by log-linear Poisson regression with adjustment for age and sex of the child, maternal age and year of maternal parvovirus B19 test., Results: A total of 1095 (1.0%) children were born to mothers who were infected with parvovirus B19 during pregnancy. During 1 million person-years of follow-up, 10 856 children experienced morbidity and 590 children died. Overall, maternal infection status was neither associated with morbidity during infancy (IRR 0.64; 95% CI: 0.40 to 1.02) or childhood (IRR 0.93; 95% CI: 0.77 to 1.14), nor with infant mortality (IRR 0.98; 95% CI: 0.44 to 2.20). Specifically, there was no association with 19 of 20 morbidities. An excess risk of cancer in the central nervous system was observed (IRR 5.88; 95% CI: 1.41 to 24.6); however, the number of exposed cases was very small (n = 2)., Conclusions: Parvovirus B19 infection during pregnancy was not associated with overall morbidity or mortality in infancy and childhood.

Aims: Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population., Methods and Results: All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively., Conclusion: CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.

Because parvovirus B19 infection during pregnancy has been associated with increased risk of fetal loss in small or selected study populations, the authors evaluated the risk in a population-based study. A nested case-control study was conducted by using a population-based screening for syphilis in 3 regions in Denmark from 1992 to 1994. Cases of women with fetal loss were identified in the National Patient Register (n = 2,918), and control women with live-born children were identified in the Medical Birth Register (n = 8,429) by matching on age and sampling week. First-trimester serum samples were tested for parvovirus B19 immunoglobulin M positivity. Parvovirus B19 immunoglobulin M positivity was associated with a 71% increased risk of fetal loss (odds ratio = 1.71, 95% confidence interval: 1.02, 2.86). Adjustment for number of children or stratifying for gestational age at loss did not change the risk estimate. Assuming causality, only 0.1% of fetal losses were attributable to parvovirus B19 positivity, a proportion which could increase to approximately 1% during epidemic periods. In conclusion, acute parvovirus B19 infection during the first trimester of pregnancy was associated with an increased risk of fetal loss. However, the impact on the overall burden of fetal losses appeared small even during epidemics.

The objective of the study was to investigate familial aggregation of primary congenital hydrocephalus in an unselected, nationwide population. Based on the Danish Central Person Register, we identified all children born in Denmark between 1978 and 2008 and their family members (up to third-degree relatives). Information on primary congenital hydrocephalus was obtained from the National Patient Discharge Register. Using binomial log-linear regression, we estimated recurrence risk ratios of congenital hydrocephalus. An alternative log-linear regression model was applied to quantify the genetic effect and the maternal effect. Of 1 928 683 live-born children, 2194 had a diagnosis of idiopathic congenital hydrocephalus (1.1/1000). Of those, 75 (3.4%) had at least one other family member with primary congenital hydrocephalus. Significantly increased recurrence risk ratios of primary congenital hydrocephalus were observed for same-sex twins, first- and second-degree relatives as follows: 34.8 (95% confidence interval: 16.4-74.0), 6.2 (95% confidence interval 4.3-8.9) and 2.2 (95% confidence interval 1.6-3.1), respectively. Recurrence risk ratio for third-degree relatives was 1.5 (95% confidence interval 0.8-2.7). A maternal component was supported by the facts that recurrence risk ratios for opposite-sex twins (37.3, 95% confidence interval 11.9-116.7) were significantly higher than other first-degree relatives and that recurrence risk ratios for maternal half-siblings (8.4, 95% confidence interval 3.7-18.7) were significantly higher than for paternal half-siblings (3.0, 95% confidence interval 0.8-12.2). This population-based study found strong evidence of familial aggregation of primary congenital hydrocephalus, which supports the existence of a genetic component to the aetiology. In addition, the pattern of association suggests that a strong maternal component contributes to the familial aggregation.

Pyloric stenosis occurs with a nearly 5-fold male predominance. To what extent this is due to environmental factors is unknown. In a cohort of all children born in Denmark, 1977-2008, the authors examined the association between pre- and perinatal exposures and pyloric stenosis and investigated whether these factors modified the male predominance. Information on pre- and perinatal factors and pyloric stenosis was obtained from national registers. Poisson regression models were used to estimate rate ratios. Among 1,925,313 children, 3,174 had surgery for pyloric stenosis. The authors found pyloric stenosis to be significantly associated with male sex, age between 2 and 7 weeks, early study period, being first born, maternal smoking during pregnancy, preterm delivery, small weight for gestational age, cesarean section, and congenital malformations. Among cases, 2,595 were males and 579 were females. Lower male predominance was associated with age at diagnosis outside the peak ages, early study period, no maternal smoking during pregnancy, preterm delivery, and congenital malformations. The authors have previously found a strong familial aggregation of pyloric stenosis indicating a genetic influence. This study shows that environmental factors during and shortly after pregnancy also play a role and that several of these modify the strong male predominance.

Background: In Greenland, the prevalence of hepatitis B surface antigen carriers, reflecting chronic hepatitis B virus (HBV) infection, is 5%-10%. However, the incidence of cirrhosis and hepatocellular carcinoma in this population has been reported to be low. We investigated this discrepancy in a large population-based cohort study., Methods: In total, 8879 Greenlanders (16% of the population) were recruited for population-based surveys performed from May 5 to July 7, 1987, and from November 1 to November 21, 1998, with follow-up until March 31, 2010. HBV status was based on serological testing, supplemented by data from all available HBV registries in Greenland to determine changes in HBV status over time. Information on morbidity and mortality was obtained from the Patient Discharge Registry, the Cancer Registry, and the Central Registration System. Sex, age, ethnicity, and period-adjusted incidence rate ratios (IRRs) were estimated using Poisson regression. World standardized rates were derived from these and World Health Organization data., Results: The 650 chronically HBV-infected persons had higher rates of hepatocellular carcinoma (adjusted IRR = 8.70; 95% CI = 2.06 to 36.7), liver disease (adjusted IRR = 5.73, 95% CI = 3.52 to 9.34), and all-cause mortality (adjusted IRR = 1.47; 95% CI = 1.21 to 1.79) than the 5160 HBV-negative persons. However, the world standardized incidence rates of hepatocellular carcinoma (38.5 cancers per 100 000 person-years) and cirrhosis (24 cases per 100 000 person-years) among chronically HBV-infected persons were low compared with results from population-based studies from countries with low, intermediate, and high rates of endemic HBV infection., Conclusion: The relatively low incidence of hepatocellular carcinoma and other HBV-related morbidity among chronic HBV-infected persons in Greenland suggest a more benign course of HBV among the Greenlandic Inuit than in populations in other parts of the world.

Background: Little is known about the aetiological factors underlying strabismus. We undertook a large cohort study to investigate perinatal risk factors for strabismus, overall and by subtype., Methods: Orthoptists reviewed ophthalmological records for Danish National Birth Cohort (DNBC) children examined for strabismus in hospital ophthalmology departments or by ophthalmologists in private practice. Information on perinatal characteristics was obtained from national registers. We used log-linear binomial regression and polytomous logistic regression to estimate risk ratios for strabismus overall and by strabismus subtype, respectively., Results: Among 96,842 DNBC children born in Denmark between 1996 and 2003, we identified 8783 children who had been evaluated for strabismus. Ophthalmological records were available for 5655 of these children, of whom 1321 were diagnosed with strabismus. In multivariable analysis, low birth weight, prematurity, large head circumference and presence of congenital abnormalities were all associated with increased risk of strabismus. Presence of congenital abnormalities was more strongly associated with exotropia than with esotropia. Of 183 exotropia cases, 40 (22%) had congenital abnormality. Although not associated with esotropia, delivery by Caesarean section was associated with exotropia (relative risk = 1.65; 95% confidence interval 1.16-2.34). After adjustment for birth weight, Apgar score at 5 min, multiple gestation and parental ages were not associated with strabismus overall., Conclusions: Congenital abnormalities, low birth weight, prematurity and large head circumference were independent risk factors for strabismus. Differences in risk factors for esotropia and exotropia suggest that strabismus subtypes may have different underlying aetiologies. The proportion of exotropic children with congenital abnormalities suggests that a large angle constant exotropia in an infant should alert physicians to the possibility of a congenital abnormality.

Background: Merkel cell carcinoma (MCC) is a rare skin cancer that was recently found to be associated with a polyomavirus and with immunosuppression, provoking new interest in its epidemiology. We conducted a nationwide study in Denmark to describe MCC incidence and mortality and the association between MCC and other cancers., Methods: We used data from Danish national health and population registers on MCC diagnoses, deaths, and population counts during the study period (1978-2006) to calculate MCC incidence rates, cumulative risks of MCC at age 100 years, and MCC mortality rates by tumor stage. We used Poisson regression to estimate the excess mortality rate ratio attributable to MCC and examined associations between MCC and other cancers diagnosed before and after the MCC diagnosis using standardized incidence rate ratios (SIRs). All statistical tests were two-sided., Results: Between January 1, 1978, and December 31, 2006, 185 persons were diagnosed with MCC in Denmark. MCC incidence between 1995 and 2006 was 2.2 cases per million person-years. In the first year after MCC diagnosis, 22% of persons with localized disease died compared with 54% of patients with nonlocalized disease; by 5 years after diagnosis, the proportions of MCC patients who had died increased to 55% and 84%, respectively. MCC incidence was statistically significantly increased more than 1 year after a diagnosis of squamous cell carcinoma of the skin (SIR = 14.6, 95% confidence interval [CI] = 8.4 to 25.6), basal cell carcinoma (SIR = 4.3, 95% CI = 2.7 to 6.6), malignant melanoma (SIR = 3.3, 95% CI = 1.1 to 10.3), chronic lymphocytic leukemia (SIR = 12.0, 95% CI = 3.8 to 37.8), Hodgkin lymphoma (SIR = 17.6, 95% CI = 2.5 to 126), and non-Hodgkin lymphoma (SIR = 5.6, 95% CI = 1.4 to 22.4). Squamous cell carcinoma (SIR = 12.1, 95% CI = 5.1 to 29.1) and chronic lymphocytic leukemia (SIR = 14.7, 95% CI = 3.7 to 58.8) occurred in statistically significant excess more than 1 year after MCC diagnosis., Conclusions: These results support the existence of shared risk factors for MCC and other cancers. Heightened awareness of the association between MCC and other cancers, particularly squamous cell carcinoma and chronic lymphocytic leukemia, may facilitate earlier clinical detection and treatment of MCC, thereby improving patient survival.

In a prospective, population-based cohort study, the authors investigated the effect of in-utero exposure to maternal smoking and consumption of alcohol, coffee, and tea on the risk of strabismus. They reviewed medical records for children in the Danish National Birth Cohort identified through national registers as possibly having strabismus. Relative risk estimates were adjusted for year of birth, social class, maternal smoking, maternal age at birth, and maternal coffee and tea consumption. The authors identified 1,321 cases of strabismus in a cohort of 96,842 Danish children born between 1996 and 2003. Maternal smoking was associated with a significantly elevated risk of strabismus in the child, increasing with number of cigarettes smoked per day (<5 cigarettes/day: relative risk (RR) = 0.95, 95% confidence interval (CI): 0.80, 1.14; 5-<10 cigarettes/day: RR = 1.38, 95% CI: 1.12, 1.70; > or =10 cigarettes/day: RR = 1.90, 95% CI: 1.57, 2.30). Nicotine replacement therapy was not associated with strabismus risk (RR = 1.22, 95% CI: 0.92, 1.61). Light maternal alcohol consumption was inversely associated with strabismus risk, whereas maternal coffee and tea drinking were not associated with strabismus risk. In conclusion, smoking during pregnancy is associated with an increased risk of strabismus in the offspring. Conversely, light alcohol consumption is associated with decreased risk.

Background: Cryptorchidism, hypospadias, and testicular germ cell cancer (TGCC) may be symptoms of a testicular dysgenesis syndrome that manifests during fetal life. To address the inheritability of this syndrome, we examined whether family history of cryptorchidism or hypospadias is associated with an increased risk of TGCC., Methods: A total of 2,159,883 men born since 1953, identified through Danish health registers, were followed from April 2, 1968, through May 31, 2008. First-, second-, and third-degree relatives were identified in the Danish Family Relations Database; cryptorchidism and hypospadias patients were identified in the Danish Hospital Discharge Register; and TGCC patients were identified in the Danish Cancer Register. Poisson regression was used to calculate the risk ratio for TGCC by family history of cryptorchidism or hypospadias., Results: A total of 5441 patients developed TGCC. A personal history of cryptorchidism or hypospadias was associated with an increased relative risk (RR) of developing TGCC (RR = 3.71, 95% confidence interval [CI] = 3.29 to 4.19; and RR = 2.13, 95% CI = 1.26 to 3.61, respectively). For example, in men in their thirties, the overall rate per 100 000 is 25.1 in the cohort, but 88.6 and 55.4 in men born with cryptorchidism or hypospadias, respectively. In contrast, relatives of a hypospadias patient did not have a statistically significantly increased risk of TGCC nor did the first- and second-degree relatives of cryptorchidism patients. However, we found a small increased risk of TGCC for third-degree relatives of patients with cryptorchidism., Conclusions: Having hypospadias or cryptorchidism was associated with an increased risk of developing TGCC. However, our finding that family history of hypospadias or cryptorchidism generally was not associated with increased risk of developing TGCC does not support the hypothesis of shared inheritability of cryptorchidism, hypospadias, and TGCC.

Preterm delivery (PTD) is a complex trait with a significant familial component. However, no specific inheritance patterns have been established. The authors examined the contribution of PTDs in both the woman's family and her partner's family to her risk of PTD. The authors linked birth information from Danish national registers with pedigree information from the Danish Family Relations Database for 1,107,124 live singleton deliveries occurring from 1978 to 2004. Risk ratios were estimated comparing women with and without various PTD histories. Women with previous PTDs were at greatly increased risk of recurrent PTD (risk ratio = 5.6, 95% confidence interval: 5.5, 5.8); however, their PTD risk was unaffected by a partner's history of preterm children with other women. PTDs to a woman's mother, full sisters, or maternal half-sisters also increased her PTD risk (risk ratio = 1.6, 95% confidence interval: 1.5, 1.6), whereas PTDs in her paternal half-sisters, the female partners of her male relatives, or members of her partner's family did not affect her PTD risk. Inheritance patterns were similar for all gestational ages from very early through late PTD. The substantial portion of PTD risk explained by effects passed through the female line suggests a role for either imprinting or mitochondrial inheritance.

If birth defects resulting from fusion failure in the midline have a common etiology, as previously hypothesized, persons with a family history of 1 type of midline defect should have an increased risk of dissimilar midline defects. The authors examined this hypothesis by linking information from the National Patient Register, the Causes of Death Register, and the Danish Family Relations Database for all Danish residents registered in the Civil Registration System during 1977-2005. Linkage yielded a cohort of 1.7 million persons with 1 or more relatives, including 9,063 persons with 1 or more midline defects. The authors investigated familial clustering of midline defects by estimating relative risks of similar and dissimilar midline defects according to family history of midline defects. Given a history of similar defects in first-degree relatives, relative risks for neural tube defects, conotruncal defects, oral facial clefts, anal/rectal defects, and diaphragmatic defects were 8.2 (95% confidence interval (CI): 3.1, 21.7), 7.7 (95% CI: 4.3, 13.8), 13.2 (95% CI: 10.8, 16.2), 10.3 (95% CI: 2.6, 41.1), and 11.2 (95% CI: 1.6, 79.7), respectively. However, given a dissimilar defect in a family member, the relative risk for any midline defect was null. Thus, similar defects but not dissimilar defects clustered in families, providing no evidence of a shared etiology for dissimilar midline defects.

Although cryptorchidism is the most common birth defect in boys affecting 4-9 percent of newborns and 1-2 percent of boys 1 year of age, the etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of cryptorchidism. Using Danish health registers, they identified 25,395 boys diagnosed with cryptorchidism in a cohort of 1,022,713 boys born in 1977-2005. Using binomial log-linear regression, they estimated recurrence risk ratios (RRRs) of cryptorchidism for male twin pairs and first-, second-, and third-degree relatives of a cryptorchidism case. The RRR in same-sex twins was 10.1 (95% confidence interval (CI): 7.78, 13.1). The RRR among first-degree relatives was significantly higher among brothers (RRR = 3.52, 95% CI: 3.26, 3.79) than for offspring of a cryptorchidism case (RRR = 2.31, 95% CI: 2.09, 2.54). The RRR was also found to be significantly higher in maternal (RRR = 2.12, 95% CI: 1.74, 2.60) than paternal (RRR = 1.28, 95% CI: 1.01, 1.61) half brothers. In conclusion, inherited factors were found to have a moderate influence on the risk of cryptorchidism. The data are compatible with the hypothesis that maternal factors operating in utero are important for the risk of cryptorchidism.

Severe infections may be influenced by genetic constitution. The authors examined familial aggregation of invasive infections, using invasive pneumococcal disease (IPD) as the index condition to ascertain families at risk. From Danish national registers, they identified relatives of persons with IPD from 1977 through 2005. Risks of IPD, bacterial meningitis, septicemia, and any invasive infection were analyzed for relatives of IPD cases in a prospective cohort study (23 million person-years). In total, 43,134 persons were found to have an IPD case in the family. The authors observed an increased risk of invasive infections in relatives of IPD cases most likely sharing the same household (parents, offspring, siblings, half-siblings), but only regarding those events within 1 year of the index IPD diagnosis (rate ratio = 7.4, 95% confidence interval: 2.4, 23.0). After 1 year, there were no increased risks of severe infections, including IPD, in close relatives. For other relatives, no increased risks of severe infections were observed at any time. No aggregation of invasive infections in IPD relatives was found, other than for close events among relatives who most likely shared the same household. Thus, at the population level, genetic constitution appears of little importance in the development of IPD and other severe infections.

Hypospadias is one of the most common birth defects. However, its etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of hypospadias. Using Danish health registers, they identified 5,380 boys diagnosed with hypospadias in a cohort of 1,201,790 boys born in 1973-2005. Using binomial log-linear regression, they estimated recurrence risk ratios of hypospadias for male twin pairs and first-, second-, and third-degree relatives of a hypospadias case, which were 50.8 (95% confidence interval [CI]: 34.2, 75.5), 11.6 (95% CI: 9.75, 13.7), 3.27 (95% CI: 2.47, 4.34), and 1.33 (95% CI: 0.94, 1.88), respectively. Recurrence risk ratios did not differ for family members of a hypospadias case related to the same degree. In addition, the authors found no difference in the recurrence risk ratio for maternal compared with paternal second- and third-degree relatives of a hypospadias case. In conclusion, hypospadias was found to have a strong familial component and also to aggregate within more-distant relatives. Importantly, hypospadias was equally transmitted through the paternal and maternal sides of a family, and recurrence risk ratios for brothers and sons of a hypospadias case were similar. These findings indicate that genetic rather than intrauterine environmental factors have a principal role in causing familial hypospadias.

Background: Immigrant studies offer insights into the relative importance of environment and genes in disease etiology. There is considerable variation in testicular cancer incidence worldwide. We investigated testicular cancer risk in first- and second-generation immigrants to Denmark, a high-incidence country, to evaluate the relative influence of genes and environment and the potential timing of action of environmental factor(s)., Methods: A cohort of 2.1 million men who were born since 1930 and lived in Denmark between 1968 and 2003 was established based on information in the Danish Civil Registration System, which included their immigration histories. Cancer histories were obtained from the Danish Cancer Registry. Testicular cancer risk was estimated as rate ratios (RRs) with 95% confidence intervals (CIs) based on log-linear Poisson regression., Results: Overall, 4216 testicular cancer cases occurred during 43 million person-years of follow-up in 2.1 million men. These included 166 cases among 344,444 direct immigrants to Denmark and 13 cases among 56,189 men born in Denmark to immigrant parents. These first- and second-generation immigrants had RRs of testicular cancer of 0.37 (95% CI = 0.31 to 0.43) and 0.88 (95% CI = 0.51 to 1.53), respectively, compared with men born in Denmark of parents born in Denmark. The rate in first-generation immigrants was not modified by age at immigration or duration of stay and reflected that in the country of origin., Conclusion: The testicular cancer risk in first-generation immigrants was lower than that in native-born Danes and reflected that in the countries of origin, whereas the risk in second-generation immigrants was similar to that in natives of Denmark. Together these findings argue for a substantial influence of environmental factors limited to the period early in life, most probably to the period in utero.

To evaluate whether previously observed associations between parity and cutaneous malignant melanoma (CMM) risk in women reflected a biologic mechanism or resulted from uncontrolled confounding by lifestyle factors associated with parity (e.g., patterns of sun exposure), the authors investigated the effect of reproductive history (parenthood) on CMM risk in both women and men. Using information from Danish national registers (1968-2003), the authors established a population-based cohort of more than 3,500,000 persons with information on parenthood and CMM. Relative risks were estimated using Poisson regression models. Overall, number of children was significantly associated with a woman's risk of CMM (p = 0.004), with the lowest risk being seen among women with many births. Women aged 25 years or older at their first birth had a 24% (95% confidence interval: 16, 33) higher risk of CMM than younger women. Ten or more years after the birth of her youngest child, a woman had a 15% (95% confidence interval: 5, 27) higher risk of CMM than she did in the first 10 years. Similar results were observed in men. The similarity of effects for men and women suggests that lifestyle factors, rather than exposure to pregnancy hormones, may be responsible for the observed associations between reproductive history and CMM risk in women.

Background: Denmark's systems of registry-based data offer a unique opportunity to examine, on a population basis, risk factors for invasive pneumococcal disease (IPD) relating to perinatal and crowding exposures among children. The main objective of this study was to identify the role of familial and day care factors in the risk of IPD among unvaccinated infants and children., Methods: A total of 1381 children aged 0-5 years old who experienced IPD were identified from a national surveillance program of IPD in Denmark. Risk factors were assessed in a matched, nested, case-control study that assigned 10 population control subjects to every case patient. Exposure information was obtained from several population-based, person-identifiable Danish registries., Results: Preterm birth and low birth weight significantly increased the risk of IPD among infants. In infants 0-5 months of age, the risk of IPD was high among infants who had older siblings, compared with infants of the same age who had no older siblings (adjusted rate ratio [aRR], 3.38; 95% confidence interval, 2.11-5.42), whereas the aRR was low (aRR, 0.56; 95% confidence interval, 0.47-0.65) in children aged 6-23 months. Day care attendance, compared with home care, increased the aRR of IPD 0-2 months after enrollment in a day care program (aRR, 2.28; 95% confidence interval, 1.73-3.00), whereas the aRR was 0.70; (95% confidence interval, 0.46-1.06) > or = 6 months after enrollment in children aged 6-23 months., Conclusions: During infancy (age, 0-6 months), risk of IPD is associated with low birth weight, presumably because of lower levels of passively acquired maternal antibody. During early childhood, exposure to other young children (either siblings or through day care attendance) is clearly associated with IPD, but natural exposure appears to occur rapidly and confer durable immunity.

Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.

In a study of 2,978 Danish children aged 5 years from two suburban counties of Copenhagen, carried out in 1998, the authors compared risk factor profiles for wheeze and recurrent cough without wheeze by using polytomous logistic regression to clarify whether the two conditions are likely to have the same etiology. Data were obtained 1) by a mailed parental questionnaire (International Study of Asthma and Allergies in Childhood questions and supplementary questions on cough, sociodemography, perinatal factors, and environmental exposure); 2) through general practitioners (familial allergic disease); and 3) from the National Medical Birth Register (birth weight). Wheeze (WH) was defined as more than one episode of wheeze within the last 12 months (irrespective of cough status) and recurrent cough without WH (RC) as cough occurring outside colds and usually lasting for periods of more than 1 week in children with no more than one attack of wheeze within the last 12 months. Risk factors for comparison were selected as those that, after repeated stepwise logistic regression, remained significant for children with WH or RC. Significant differences were found for gender (p = 0.003), gestational age (p = 0.0002), maternal history of asthma (p = 0.0008), and standard of housing condition (p = 0.04)-all risk factors for WH but not RC. Results may suggest that the two conditions have different etiologies.

Studying associations between sibship characteristics and allergic diseases in detail may contribute clues to their etiology. The authors studied associations between sibship characteristics and risk of self-reported allergic rhinitis and asthma among 31,145 pregnant women participating in a nationwide study in Denmark during 1997-2000. Increasing sibship size was associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis. The protective effect of having older siblings was stronger than the protective effect of having younger siblings for both allergic rhinitis and asthma with allergic rhinitis. There was no association between interval to closest older or younger sibling and risk of allergic rhinitis or asthma with allergic rhinitis, while the risk of asthma without allergic rhinitis increased with intervals of 2 or more years compared with less than 2 years to the nearest older sibling. The protective effect of having siblings on the risk of asthma with allergic rhinitis could be explained by a protective effect of siblings on the risk of allergic rhinitis alone. In conclusion, our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Furthermore, the findings that allergic rhinitis was associated with the number of younger siblings but not with the age interval to younger siblings support the hypothesis of an influence of postnatal mechanisms and suggest that these mechanisms may not necessarily be operating only in early life.

The role of breastfeeding in allergic diseases remains controversial. The authors studied the association between breastfeeding and development of atopic dermatitis during the first 18 months of life among children with and without a parental history of allergy. A cohort study of 15,430 mother-child pairs enrolled in The Danish National Birth Cohort was carried out between 1998 and 2000. Data on breastfeeding, atopic dermatitis, and potential confounders was obtained from telephone interviews conducted during pregnancy and when the children were 6 and 18 months of age. The cumulative incidence of atopic dermatitis was 11.5% at 18 months of age. Overall, current breastfeeding was not associated with atopic dermatitis (incidence rate ratio (IRR) = 0.91, 95% confidence interval (CI): 0.80, 1.04). Exclusive breastfeeding for at least 4 months was associated with an increased risk of atopic dermatitis in children with no parents with allergies (IRR = 1.29, 95% CI: 1.06, 1.55) but not for children with one (IRR = 1.11, 95% CI: 0.94, 1.31) or two (IRR = 0.88, 95% CI: 0.69, 1.13) parents with allergies (test for homogeneity, p = 0.03). The authors found no overall effects of exclusive or partial breastfeeding on the risk of atopic dermatitis. However, the effect of exclusive breastfeeding for 4 months or more depended on parental history of allergic diseases.

Background: According to the polio model, severity of disease increases with age at infection. Firstborn children and people belonging to small families are generally infected later and should accordingly have a higher risk of severe polio. However, this model does contradict other explanations of severity of childhood infections including the intensive-exposure model., Methods: To evaluate the deductions from the polio model we performed a study based on medical records from 5590 historical polio cases from the county of Copenhagen 1940-1953. The relative risk (RR) of polio according to age, birth order and sibship size was evaluated using census data from 1940 and 1950., Results: Severity of polio measured as frequency of paralysis or mortality did not show a steady increase with age, but a U-shaped curve being highest for the youngest as well as the oldest patients. The incidence of polio and paralytic polio was higher in families with several children compared with single children (RR = 1.13, 95% CI : 1.0-1.3). Furthermore, the incidence was higher in later-born children (P(trend) < 0.0001). However, as predicted from the intensive-exposure model, second-born children aged 1-4 years in two-child families had a higher risk of paralytic polio than first-born children (RR = 1.47, 95% CI : 1.1-2.0), whereas the opposite relationship was found for those aged > or = 5 years (RR = 0.65, 95% CI : 0.5-0.9)., Conclusion: The polio model's prediction about the impact of age, sibship size and birth order on polio incidence and severity found only limited support. A model emphasizing intensity of exposure as a risk factor for severity may account better for the epidemiology of polio infection.