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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.

Gender of offspring is influenced by maternal hormonal level during pregnancy, which is blieved to influence the subsequent maternal breast cancer risk. However, analysing national birth and cancer registrations in a cohort of 998 499 women, we found no association between gender of offspring and subsequent breast cancer risk. © 2000 Cancer Research Campaign

One of the more consistent findings in leukemia research is the association between birth weight and childhood leukemia. Because thyroid hormones are critically involved in growth and differentiation, we speculated that hormone levels could be of significance to the development of leukemia in early life. Specifically, we hypothesized that high levels of thyroid-stimulating hormone (TSH) would be associated with a low risk of leukemia. Accordingly, high TSH (low free thyroid hormone) early after birth most likely reflects low function of the thyroid accompanied by low rate of cell turnover and so lower risk of faulty cell divisions leading to cancer. In a matched case-control study nested from all singleton children born in Denmark between 1986 and 1998, we compared levels of TSH (as measured in a neonatal screening program for congenital hypothyroidism) in 188 cases of acute lymphoblastic leukemia (ALL) and 28 of acute myeloid leukemia (AML) with levels in 1,450 and 216 matched controls, respectively. Data were analyzed using conditional logistic regression and odds ratios (OR) were adjusted for birth weight. As hypothesized, we found a decreased risk of ALL and AML associated with high TSH (ORALL = 0.7 [0.5–1.0]; ORAML = 0.3 [0.1–1.0]). However, both conditions were also associated with low levels of TSH (ORALL = 0.4 [0.2–0.7]; ORAML = 0.3 [0.1–1.4]). In conclusion, extreme TSH levels a few days after birth appears to be associated with a decreased risk of acute childhood leukemia. Int. J. Cancer 88:486–488, 2000. © 2000 Wiley-Liss, Inc.

Background: It has been suggested that cryptorchidism and hypospadias may be the result of a common pathologic pathway that causes testicular dysgenesis during fetal life. To address the potential heritability of this pathway, we specifically examined to what extent a family history of cryptorchidism increases the risk of developing hypospadias and vice versa. Methods: By using Danish health registers, we identified 27,762 boys diagnosed with cryptorchidism and 4832 boys diagnosed with hypospadias in a cohort of 1,018,517 boys born during 1977–2005. Using binomial log-linear regression, we estimated risk ratios of cryptorchidism and hypospadias in male twin pairs and first-, second-, and third-degree relatives with a family history of hypospadias and cryptorchidism, respectively. Results: After adjusting for birth period and personal hypospadias/cryptorchidism status, there was little evidence of increased risk of cryptorchidism given a family history of hypospadias, and vice versa. However, cryptorchidism and hypospadias was associated on an individual level. Conclusion: We found no persuasive evidence that a family history of hypospadias increases the risk of cryptorchidism and vice versa. Thus, we found no support for shared heritability of hypospadias and cryptorchidism.

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.

Objective.To test if Mycobacterium tuberculosis screening results differ among patients with inflammatory disease depending on whether the QuantiFeron TB-Gold test (QFT) or tuberculin skin test (TST) is used; and to evaluate if a possible difference is influenced by the presence of risk factors or immunosuppression.Methods.The interferon-γ response to in vitro stimulation of M. tuberculosis-specific antigens was measured with QFT and results were compared with TST. Associations to bacillus Calmette-Guerin (BCG) vaccination, risk factors, and immunosuppression were analyzed for both tests.Results.QFT and TST results were available for 294/302 and 241/302 patients, respectively; 234 had results from both tests. Twenty-one (7%) tested positive with QFT and 45 (19%) with TST. A positive QFT was associated with risk factors for M. tuberculosis infection: i.e., birth or upbringing in a TB-endemic area [risk ratio (RR) = 7.8, 95% CI 1.5–18.2, p < 0.001], previous TB treatment (RR 4.7, 95% CI 1.6–13.5, p = 0.005), and any latent TB infection risk factor (RR 4.7, 95% CI 2.1–11.0, p = 0.0002). Treatment with corticosteroids increased the risk for an inconclusive QFT result (RR 4.2, 95% CI 1.6–10.7, p = 0.04) and decreased the risk for a positive TST result (RR 0.4, 95% CI 0.1–1.0, p = 0.04). Agreement between the tests was low (kappa 0.2, 95% CI 0.02–0.3, p = 0.002).Conclusion.The study documented a high degree of discordant positive QFT and TST results. A positive QFT was more closely associated with risk factors for M. tuberculosis infection than the TST. The use of corticosteroids affected test outcome by increasing the risk for an inconclusive QFT result and decreasing the risk for a positive TST result.

Based on the intriguing finding of an east-west gradient of testicular cancer risk in the Nordic countries with a low risk in Finland, intermediate in Sweden, and high risk in Denmark, it was suggested that national practices rather than individual behavior may be important in the etiology of this cancer. We investigated the risk of testicular cancer in all men born in Denmark, 1931-1969 according to birthplace. Testicular cancer information was derived from the Danish Cancer Registry and population data from Statistics Denmark. There was a several fold geographical variation in testicular cancer risk within Denmark. Among men born in the early period, 1931-39, the highest risk was primarily observed in the western part of Denmark whereas no such gradient was observed in more recent cohorts. The incidence of testicular cancer increased in all counties from the earliest to the latest birth cohort, but the increase was highest in the eastern parts of Denmark. The heterogeneity in risk according to place of birth within Denmark suggests that individual behavior plays an important role for the risk of testicular cancer. Based on the Danish data, the factor that may have caused the east-west gradient in testicular cancer risk appears to have been more unevenly distributed in the early part of the past century compared to more recent times.

Summary Background Measles persists in Europe despite the incorporation of the measles vaccine into routine childhood vaccination programmes more than 20 years ago. Our aim was therefore to review the epidemiology of measles in relation to the goal of elimination by 2010. Methods National surveillance institutions from 32 European countries submitted data for 2006–07. Data for age-group, diagnosis confirmation, vaccination, hospital treatment, the presence of acute encephalitis as a complication of disease, and death were obtained. 30 countries also supplied data about importation of disease. Clinical, laboratory-confirmed, and epidemiologically linked cases that met the requirements for national surveillance were analysed. Cases were separated by age: younger than 1 year, 1–4 years, 5–9 years, 10–14 years, 15–19 years, and older than 20 years. Countries with indigenous measles incidence per 100 000 inhabitants per year of 0, less than 0·1, 0·1–1, and more than 1 were grouped into categories of zero, low, moderate, and high incidence, respectively. Findings For the 2 years of the study, 12 132 cases of measles were recorded with most cases (n=10 329; 85%) from five countries: Romania, Germany, UK, Switzerland, and Italy. Most cases were unvaccinated or incompletely vaccinated children; however, almost a fifth were aged 20 years or older. For the same 2 years, seven measles-related deaths were recorded. High measles incidence in some European countries revealed suboptimum vaccination coverage. Of the 210 cases that were reported as being imported, 117 (56%) came from another country within Europe and 43 (20%) from Asia. Interpretation The suboptimum vaccination coverage raises serious doubts that the goal of elimination by 2010 can be attained. Achievement and maintenance of optimum vaccination coverage and improved surveillance are the cornerstones of the measles elimination plan for Europe. Funding European Commission and the Statens Serum Institut, Denmark.

Background Time trends in congenital heart defects (CHD) by specific phenotype and with long follow-up time are rarely available for an entire population. We present trends in national CHD prevalences over the past 3 decades. Methods We linked information from the National Patient Register, the Causes of Death Register, and the Danish Cytogenetic Central Register for all persons born in Denmark, 1977 to 2005, and registered in the Civil Registration System, yielding a cohort of 1,763,591 persons—18,207 with CHD. Individuals with CHDs were classified by phenotype (heterotaxia, conotruncal defect, atrioventricular septal defect, anomalous pulmonary venous return, left and right ventricular outflow tract obstructions, septal defects, complex defects, associations, patent ductus arteriosus, unspecified, and other specified) by combining International Classification of Diseases codes using a hierarchical approach. Results From 1977 to 2005, the overall CHD birth prevalence increased from 73 to 113 per 10,000 live births. Generally, prevalence increased for defects diagnosed in infancy, until 1996–1997, and then stabilized. For each 5-year interval, isolated septal defects and severe defects increased by 22% (95% CI, 20%-25%) and 5% (95% CI, 4%-7%), respectively. Among the severe defects, conotruncal defects and atrioventricular septal defect showed the largest prevalence increases. Women had a lower prevalence of severe defects during the 1980s. The CHD prevalence increase was unchanged when persons with extracardiac defects or chromosomal aberrations were excluded. Conclusions CHD birth prevalence increased from the beginning of the 1980s but stabilized in the late 1990s.

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.

The etiology of vulvar and vaginal squamous cell carcinoma (VV-SCC) has received little attention. A total of 182 women with invasive VV-SCC (116 with VV-SCC(vulva), 66 with VV-SCC(vagina)), 164 uterine corpus cancer controls and 518 population controls were interviewed in a population-based case-control study in Denmark, and 87 (48%) of the VV-SCC cases had tissue samples examined for human papillomavirus (HPV) DNA using the GP5+/6+ PCR-EIA assay and subsequent reverse line blotting for HPV typing. Logistic regression-derived odds ratios with 95% confidence intervals served as relative risks. Cervical cancer-associated high-risk HPVs (hrHPVs) were detectable in most (89%) examined cases of VV-SCC(vagina) and in half (50%) of cases of VV-SCC(vulva) (p < 0.001). In site-specific multivariate logistic regression analyses, statistically significant risk factors for both VV-SCC(vulva) and VV-SCC(vagina) included measures of hrHPV exposure (anogenital warts for VV-SCC(vulva); cervical neoplasia and poor genital hygiene for VV-SCC(vagina)), tobacco smoking and alcohol consumption. Furthermore, socioeconomic variables (marital status and years at school) were associated with risk of VV-SCC(vulva). Comparing hrHPV-positive and hrHPV-negative VV-SCCs in polytomous logistic regression analysis revealed that tobacco smoking and cervical neoplasia were significant risk factors only for hrHPV-positive VV-SCCs. Our study shows that VV-SCC(vulva) and VV-SCC(vagina) share measures of prior hrHPV exposure, tobacco smoking and alcohol consumption as statistically significant risk factors. HPV vaccination programs aimed at reducing the burden of cervical cancers are likely to also provide considerable protection against VV-SCCs.

Summary Background Studies of delivery by caesarean section (c-section) and the offspring's risk of allergic diseases are of current interest due to concerns about the increased use of c-section in many countries. However, previous studies have reported inconsistent findings. Objective We investigated whether delivery by c-section is associated with an increased risk of atopy and allergic disease by reviewing the literature, performing a meta-analysis, and assessing publication bias. Methods We used a systematic literature search of MEDLINE (1966 to May 2007). Six common allergic outcomes were included: food allergy/food atopy, inhalant atopy, eczema/atopic dermatitis, allergic rhinitis, asthma, and hospitalization for asthma. For each outcome a meta-analysis was performed, where a summary odds ratio (OR) was calculated taking into account heterogeneity between the study-specific relative risks. Publication bias was assessed using the funnel plot method. Results We identified 26 studies on delivery by c-section and one or more of the six allergic outcomes. C-section was associated with an increased summary OR of food allergy/food atopy (OR 1.32, 95% CI 1.12–1.55; six studies), allergic rhinitis (OR 1.23, 95% CI 1.12–1.35; seven studies), asthma (OR 1.18, 95% CI 1.05–1.32; 13 studies), and hospitalization for asthma (OR 1.21, 95% CI 1.12–1.31; seven studies), whereas there was no association with inhalant atopy (OR 1.06, 95% CI 0.82–1.38; four studies) and eczema/atopic dermatitis (OR 1.03, 95% CI 0.98–1.09; six studies). Funnel plots indicated that the association with food allergy/food atopy could be difficult to interpret due to publication bias. For each significant association with an allergic outcome, only 1–4% of cases were attributable to c-section. Conclusion Delivery by c-section is associated with a moderate risk increase for allergic rhinitis, asthma, hospitalization for asthma, and perhaps food allergy/food atopy, but not with inhalant atopy or atopic dermatitis. The increased use of c-section during the last decades is unlikely to have contributed much to the allergy epidemic observed during the same period.

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.

Background Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. Methods Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. Results Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4–2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7–27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4–0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3–0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn’s disease (RR = 1.4 (CI: 1.04–1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99–1.7), n = 51), Addison’s disease (RR = 3.4 (CI: 1.3–9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4–10.0), n = 4). Conclusion Patients with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

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.

Udgivelsesdato: 2008-Feb-1 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.

Two models provide reliable estimates that can be used to assess vaccine need and effectiveness., In anticipation of licensure and introduction of rotavirus vaccine into the western market, we used modeling of national hospital registry data to determine the incidence and direct medical costs of annual rotavirus-associated admissions over

BACKGROUND. It is well established that prenatal biologic processes are important for the development of some childhood cancers, whereas less is known regarding their influence on adult cancer risk. High birth weight has been associated with risk of breast cancer, whereas studies of other specific cancers and all cancers together have been less conclusive. METHODS. The authors established a cohort of more than 200,000 men and women who were born between 1936 and 1975. Birth weights were obtained from school health records and information concerning cancer from the Danish Cancer Registry. Follow‒up was performed between April 1, 1968 and December 31, 2003. During 6,975,553 person-years of follow‒up, a total of 12,540 primary invasive cancers were diagnosed. RESULTS. Analyses of site‒specific cancers revealed that the majority of cancers had a positive linear association with birth weight. Departures from a positive linear association were found to be statistically significant for cancers of the pancreas and bladder, which demonstrated a V‒shaped association, and testicular cancer, which demonstrated an inverse association with birth weight. Excluding these 3 exceptions, the trends for the individual cancer sites were not heterogeneous, and the overall trend was a relative risk of 1.07 (95% confidence interval, 1.03–1.11) per 1000‒g increase in birth weight. This trend was the same in men and women and in all age groups. CONCLUSIONS. A 7% increase in cancer risk was observed per 1000‒g increase in birth weight. Few cancers demonstrated a nonlinear association with birth weight, and testicular cancer was found to be negatively associated with birth weight. The authors hypothesized that the biologic explanation behind the association between birth weight and cancer at different sites should be sought in a common pathway. Cancer 2007. © 2007 American Cancer Society.

Objective To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs). Methods To address these issues, a nationwide case–control study was conducted in Denmark during 2002–2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex- and age-matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk. Results Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti-CCP–positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8–29.4) but not anti-CCP–negative RA (OR 1.07, 95% CI 0.53–2.18). Strong combined gene–environment effects were observed, with markedly increased risks of anti-CCP–positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0–154), heavy coffee drinkers (OR 53.3, 95% CI 15.5–183), or oral contraceptive users (OR 44.6, 95% CI 15.2–131) compared with SE noncarriers who were not exposed to these environmental risk factors. Conclusion Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti-CCP–positive RA. A distinction between anti-CCP–positive RA and anti-CCP–negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.

Introduction Pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy (HDP) both often exhibit angiogenic imbalances, suggesting that the same underlying processes may play a role in the etiology of heart defects and the pathology associated with HDP. Objectives To determine whether fetal heart defects are associated with an increased risk of maternal HDP, and whether the mechanisms driving the association are primarily maternal or fetal. Methods Using Danish national registers, we constructed a cohort comprising all singleton pregnancies without chromosomal abnormalities continuing to at least 20 completed weeks gestation in Denmark, 1977–2011. We then identified both pregnancies complicated by offspring congenital heart defects and those complicated by HDP (severe preeclampsia [PE]/eclampsia, moderate PE, gestational hypertension [GH]). Using polytomous logistic regression, we estimated odds ratios (ORs) for the association between carrying a fetus with a congenital heart defect and maternal risk of an HDP in the second half of pregnancy, overall and for specific heart defects. We also estimated ORs for the association between (1) an HDP in a previous pregnancy and the risk of carrying a child with a heart defect in subsequent pregnancies, and (2) fetal congenital heart defects in a previous pregnancy and the risk of HDP in subsequent pregnancies. Results Carrying a child with a heart defect was associated with a 3-fold increase in the risk of severe PE later in pregnancy (OR 3.02, 95% confidence interval [CI] 2.71–3.37) and a modest increase in the risk of moderate PE (OR 1.29, 95% CI 1.18–1.41), but not with the risk of GH (OR 1.08, 95% CI 0.93–1.25). These associations did not appear to depend on the type of offspring heart defect. Having a child with a heart defect in a previous pregnancy was also associated with PE (severe PE: OR 1.57, 95% CI 1.24–1.97; moderate PE: OR 1.32, 95% CI 1.16–1.51) but not with GH (OR 1.00, 95% CI 0.82–1.22) in subsequent pregnancies. Similarly, a history of PE in a previous pregnancy, but not of GH alone, was associated with an increased risk of offspring heart defects in later pregnancies (severe PE: OR 1.46, 95% CI 1.21–1.77; moderate PE: OR 1.13, 95% CI 1.01–1.27; GH: OR 1.12, 95% CI 0.91–1.37). Conclusion Our findings suggest that the same pathophysiological mechanisms may be involved in both congenital heart defects and severe PE (but are less important in less severe forms of HDP), and that these processes are most likely maternal, rather than fetal.

Adult height and body-mass index influence the risk of breast cancer in women. Whether these associations reflect growth patterns of the fetus or growth during childhood and adolescence is unknown.We investigated the association between growth during childhood and the risk of breast cancer in a cohort of 117,415 Danish women. Birth weight, age at menarche, and annual measurements of height and weight were obtained from school health records. We used the data to model individual growth curves. Information on vital status, age at first childbirth, parity, and diagnosis of breast cancer was obtained through linkages to national registries.During 3,333,359 person-years of follow-up, 3340 cases of breast cancer were diagnosed. High birth weight, high stature at 14 years of age, low body-mass index (BMI) at 14 years of age, and peak growth at an early age were independent risk factors for breast cancer. Height at 8 years of age and the increase in height during puberty (8 to 14 years of age) were also associated with breast cancer. The attributable risks of birth weight, height at 14 years of age, BMI at 14 years of age, and age at peak growth were 7 percent, 15 percent, 15 percent, and 9 percent, respectively. No effect of adjusting for age at menarche, age at first childbirth, and parity was observed.Birth weight and growth during childhood and adolescence influence the risk of breast cancer.

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.

Udgivelsesdato: 2006-Jul 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.

PURPOSE: To investigate maternal, demographic, and pre- and perinatal risk factors for idiopathic congenital/infantile (ICI) cataract. METHODS: Based on national registries, a cohort of all children born in Denmark and aged 0 to 17 years during 1977 to 2001 was established, and congenital/infantile cataract cases were identified. Cases of unknown/idiopathic cause were included in the study. Associations between maternal, demographic, and pre- and perinatal factors with the development of cataract were investigated. RESULTS: In a cohort of 2.9 million children, 1027 cases of congenital/infantile cataract were identified. Of the children in those cases, 629 were born in Denmark and had ICI. Bilateral isolated cataract cases were male dominated (62%; 95% confidence interval [CI], 56%-69%) but not unilateral isolated cases (40%; 95% CI, 34%-47%). Older age (> or =40 years) of mothers at delivery and caesarean section increased the risk of ICI cataract. Low birth weight (< 2000 g) was associated with a 10.6-fold (95% CI, 6.99-16.10) increased risk of bilateral, but not unilateral, ICI cataract. No significant associations were found with birth order, month/place of birth, or cigarette smoking during pregnancy. CONCLUSIONS: Variables indicative of environmental influence were not associated with ICI cataract. Low-birth-weight children (< 2000 g) had a significantly increased risk of bilateral ICI, whereas no strong risk factors were found for unilateral cataract. Together with the sex difference, this suggests that the etiologies of bilateral and unilateral cataract are different.

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 ¼ 7.1, 95% confidence interval: 5.8, 8.8) (n ¼ 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 firstdegree 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. cohort studies; Denmark; family; multiple sclerosis; risk

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.

Pertussis in young children is severe and relatively prevalent in vaccinated populations. We estimated the impact of pre-school booster vaccination of 4-6-year-old children on pertussis in 0-1-year-old children. We conducted a population-based historical cohort study of all children born in Denmark, 1977-2001 (N=1,536,717) using information on place of residence to identify household members and vaccination history from nationwide registers. We estimated rate ratios (RRs) of pertussis hospitalisation among children in the cohort according to number, age, and vaccination status of their household members. This enabled, through population attributable risks, the estimation of the preventable proportion of hospitalisations among 0-1-year-old children according to age at booster vaccination (4-6 years), booster uptake, and the efficacy of the booster against transmission. The preventable proportion of pertussis hospitalisations among 0-1-year-old children ranged from 7% to 33% (most realistic scenario=18%), varying according to age at booster vaccination, uptake, and efficacy of booster against transmission. This relatively limited impact of a pre-school booster was partly a consequence of the actual number of 0-1-year-old children living with children of pre-school age or older and partly the result of significant exposure from children younger than pre-school age in the household. According to our model the effectiveness of pre-school booster vaccination as an intervention to prevent pertussis hospitalisation of 0-1-year-old children is modest.

Levels of maternal alpha-fetoprotein (AFP) are increased during multiple gestations and preeclampsia but little is known regarding AFP levels in relation to other reproductive factors. Consequently, the objective of this work was to describe the possible relationship between AFP levels during pregnancy and maternal age at birth, maternal age at first birth, parity, time since previous birth and gender of the offspring.Based on national registries we obtained the reproductive history on a population-based cohort of 44 227 women who had serum AFP levels determined in gestational weeks 14-21 and whose present and previous pregnancies resulted in live-born singletons.Many previous births and an interval of less than 2 years since last birth were significantly associated with extremely low levels of AFP in the mother. However, age at first birth and age at present pregnancy did not influence the AFP level. Women who gave birth to a girl had AFP levels that were 5%[95% confidence interval (CI) 4-6%] lower than those of women who had a boy. Adjustment for birthweight did not significantly affect the estimate.Low serum AFP levels in pregnancy are significantly correlated with high parity and with a short interval between births. The significantly lower levels of AFP in women who gave birth to girls could indicate a possible gender-specific regulatory mechanism.

CONTEXT:The rate of febrile seizures increases following measles, mumps, and rubella (MMR) vaccination but it is unknown whether the rate varies according to personal or family history of seizures, perinatal factors, or socioeconomic status. Furthermore, little is known about the long-term outcome of febrile seizures following vaccination.OBJECTIVES:To estimate incidence rate ratios (RRs) and risk differences of febrile seizures following MMR vaccination within subgroups of children and to evaluate the clinical outcome of febrile seizures following vaccination.DESIGN, SETTING, AND PARTICIPANTS:A population-based cohort study of all children born in Denmark between January 1, 1991, and December 31, 1998, who were alive at 3 months; 537,171 children were followed up until December 31, 1999, by using data from the Danish Civil Registration System and 4 other national registries.MAIN OUTCOME MEASURES:Incidence of first febrile seizure, recurrent febrile seizures, and subsequent epilepsy.RESULTS:A total of 439,251 children (82%) received MMR vaccination and 17,986 children developed febrile seizures at least once; 973 of these febrile seizures occurred within 2 weeks of MMR vaccination. The RR of febrile seizures increased during the 2 weeks following MMR vaccination (2.75; 95% confidence interval [CI], 2.55-2.97), and thereafter was close to the observed RR for nonvaccinated children. The RR did not vary significantly in the subgroups of children that had been defined by their family history of seizures, perinatal factors, or socioeconomic status. At 15 to 17 months, the risk difference of febrile seizures within 2 weeks following MMR vaccination was 1.56 per 1000 children overall (95% CI, 1.44-1.68), 3.97 per 1000 (95% CI, 2.90-5.40) for siblings of children with a history of febrile seizures, and 19.47 per 1000 (95% CI, 16.05-23.55) for children with a personal history of febrile seizures. Children with febrile seizures following MMR vaccinations had a slightly increased rate of recurrent febrile seizures (RR, 1.19; 95% CI, 1.01-1.41) but no increased rate of epilepsy (RR, 0.70; 95% CI, 0.33-1.50) compared with children who were nonvaccinated at the time of their first febrile seizure.CONCLUSIONS:MMR vaccination was associated with a transient increased rate of febrile seizures but the risk difference was small even in high-risk children. The long-term rate of epilepsy was not increased in children who had febrile seizures following vaccination compared with children who had febrile seizures of a different etiology.

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.

PURPOSE:To determine the incidence and cumulative risk of childhood cataract in Denmark during 1980 to 2000. METHODS:A cohort of 2,616,439 Danish children born between 1962 and 2000 was followed from 1980 or from the day of birth, whichever occurred later, until their 18th birthday, death, emigration, or diagnosis of cataract, whichever occurred first. Cases were ascertained from the Danish National Register of Patients (NRP) and validated by reviewing the medical records. They were divided into four groups: congenital/infantile (CI) cataract, traumatic cataract, complicated cataract, and "other" types of cataract. RESULTS:After diagnostic validation, 1311 children with cataract (59% with CI cataract) were included in the study. During 1995 to 2000 the overall cumulative risk of childhood cataract was 108.4 per 100,000 children. There was no significant difference in incidence between girls and boys or over time (1980 to 2000) for CI, complicated, and "other" types of cataract. In contrast, the incidence of traumatic cataract was significantly higher among boys. It remained increased during the entire study period despite a 23% decrease per 5 years among boys. Sixty-six percent of the children diagnosed with CI cataract below 2 years of age underwent surgery within 1 year. CONCLUSIONS:The stable incidence during a 20-year period of CI cataract and complicated cataract indicates that risk factors for these conditions have remained unchanged, whereas the marked drop of traumatic cataract among boys most likely reflects changed behavior and an increased focus on preventive measures.

A link between childhood vaccinations and the development of type 1 diabetes has been proposed.We evaluated a cohort comprising all children born in Denmark from January 1, 1990, through December 31, 2000, for whom detailed information on vaccinations and type 1 diabetes was available. Using Poisson regression models, we estimated rate ratios according to vaccination status, including the trend associated with the number of doses, among all children and in a subgroup of children who had siblings with type 1 diabetes. Given recent claims of clustering of cases of diabetes two to four years after vaccination, we also estimated rate ratios during the period after vaccination.Type 1 diabetes was diagnosed in 681 children during 4,720,517 person-years of follow-up. The rate ratio for type 1 diabetes among children who received at least one dose of vaccine, as compared with unvaccinated children, was 0.91 (95 percent confidence interval, 0.74 to 1.12) for Haemophilus influenzae type b vaccine; 1.02 (95 percent confidence interval, 0.75 to 1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine; 0.96 (95 percent confidence interval, 0.71 to 1.30) for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine; 1.06 (95 percent confidence interval, 0.80 to 1.40) for whole-cell pertussis vaccine; 1.14 (95 percent confidence interval, 0.90 to 1.45) for measles, mumps, and rubella vaccine; and 1.08 (95 percent confidence interval, 0.74 to 1.57) for oral poliovirus vaccine. The development of type 1 diabetes in genetically predisposed children (defined as those who had siblings with type 1 diabetes) was not significantly associated with vaccination. Furthermore, there was no evidence of any clustering of cases two to four years after vaccination with any vaccine.These results do not support a causal relation between childhood vaccination and type 1 diabetes.

To study the distribution of congenital/infantile cataract in the entire population of Denmark according to etiological and clinical classifications.Population-based cohort study with retrospective chart review.All children (0 to 17 years old) who were born between 1959 and 2001 and registered with congenital/infantile cataract in Denmark during the period 1977 to 2001. Cases were ascertained from the mandatory Danish National Register of Patients, and all medical records were reviewed.Etiological and clinical classifications of the cataract cases were based on information from the medical records.Classification of congenital/infantile cataract according to presumed etiology; gender; clinical appearance, including laterality and morphology; and the time trends according to etiology and laterality.A total of 1027 children with congenital/infantile cataract, 529 boys and 498 girls, were included, of whom 64% were bilateral. Males predominated with bilateral cataract, whereas females predominated with unilateral cases. Isolated cataract was the most frequent clinical presentation (71% of all cases), followed by an even proportion of cataract associated with additional ocular dysmorphology and cataract associated with systemic anomalies. Almost two thirds of all cases had an unknown etiology (idiopathic). Idiopathic cases showed a higher proportion of unilateral cataract and of additional ocular dysmorphology compared with cases of known etiology. The etiology was unknown in 87% of unilateral cases and in 50% of bilateral cases. The distribution by presumed etiology was stable during the study period, except for cataract caused by maternal infections, which decreased mainly due to the elimination of congenital rubella.With the exception of the decline of congenital rubella, the proportion of congenital/infantile cataract cases of unknown, genetic, and infectious origins has been stable since the late 1970s. The causes of 87% of unilateral cataracts and 50% of bilateral congenital/infantile cataracts remain unknown, making the prevention of the disease a continuing challenge.

In many countries, acellular pertussis vaccines have replaced whole-cell vaccines. We evaluated the impact of a pertussis toxoid vaccine on pertussis in Denmark. We calculated incidence rates for pertussis before and after pertussis toxoid vaccine was introduced, and estimated vaccination effectiveness (VE). We found that routine vaccination with pertussis toxoid vaccine was effective against both hospitalisation with pertussis (VE, 93% for three doses) and non-hospitalised pertussis (VE, 78% for three doses). However, after the introduction we found an increase in pertussis among the youngest infants, a direct result of the new schedule (ages 3, 5 and 12 months) where the youngest infants are unvaccinated for a longer time-period compared with the prior schedule (ages 5, 9 weeks and 10 months).

The possible association between prenatal factors and breast cancer has been discussed for more than a decade. Birth weight has been used commonly as a proxy measure for intrauterine growth. Whereas some previous studies have found support for an association between birth weight and breast cancer, others have been inconclusive or found no association. We investigated the relationship between birth weight and risk of female breast cancer in a cohort of 106,504 Danish women. Birth weights were obtained from school health records on girls born between 1930-1975. Information on breast cancer came from linking the cohort with the Danish Cancer Registry and the Danish Breast Cancer Cooperative Groups Registry. A total of 2,334 cases of primary breast cancer were diagnosed in the cohort during 3,255,549 person-years of follow-up among women with birth weight between 500-6,000 g. Of these, 922 (40%) were diagnosed with primary breast cancer at the age of 50 years or older. A significant association between birth weight and breast cancer was found equivalent to an increase in risk of 9% per 1,000 g increase in birth weight (95% CI 2-17). The increase was observed for all age groups, representing both pre- and post-menopausal women, and irrespective of tumor characteristics. Adjustment for age at first birth and parity did not influence the results. Birth weight is positively associated with risk of breast cancer, indicating that prenatal factors are important in the etiology of breast cancer.

ContextMercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, contains ethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmental disorders such as autism.ObjectiveTo determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism.Design, Setting, and ParticipantsPopulation-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine.Main Outcome MeasuresRate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury.ResultsDuring 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval {CI}, 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 µg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders).ConclusionThe results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.

It has been suggested that the measles-mumps-rubella (MMR) vaccination causes autism.We conducted a retrospective cohort study of all children born in Denmark from January 1991 through December 1998. The cohort was established based on data from the Danish Civil Registration System. A unique person identifiable number given to all subjects enabled linkage with other national registries. MMR vaccination status was obtained from the Danish National Board of Health. Information on the children's autism status was obtained from the Danish Psychiatric Central Register which contains information on all diagnoses received from psychiatric hospitals, psychiatric wards, and outpatient clinics in Denmark. We obtained information on potential confounders from the Danish Medical Birth Registry, the National Hospital Registry, and Statistics Denmark.In the cohort of 537,303 children (2,129,864 person-years), 440,655 children had been MMR vaccinated. We identified 316 children with a diagnosis of autistic disorder and 442 with a diagnosis of other spectrum disorders. After adjusting for potential confounders, the risk for autistic disorder and other spectrum disorders was not increased in vaccinated compared with unvaccinated children (relative risk 0.92; 95 percent confidence interval, 0.68 to 1.24 and relative risk 0.83; 95 percent confidence interval, 0.65 to 1.07). There was no association between age at vaccination, time since vaccination or calendar period at time of vaccination and development of autistic disorder.This study provides strong evidence against the hypothesis that MMR vaccination causes autism.

The increased risk of breast cancer in women with family history of breast cancer (FHBC) might be reduced by early childbirths. However, childbirth induces a transient increase in risk in the first 5-10 years, which coincides with the relatively increased risk of family cases at a young age. The objective was to investigate this short-term change in risk according to FHBC.We used a population-based cohort of 1.5 million Danish women. Between 1968 and 1990, 2770 incident cases of breast cancer below 40 years of age were identified in the Danish Cancer Register, of whom 276 (10%) had a FHBC.The first 5 years after a birth the short-term increase in risk was 30% (3-64%) larger in women with FHBC than without FHBC. After the first 5 years we observed no difference in the effect of a birth between women with and without FHBC.The adverse short-term effect of childbirthis stronger in women with FHBC.

Summary:Summary A population-based study of measles, mumps, and rubella vaccination and autism. Ugeskr Læger 2002; 164: 5741-4. Introduction: It has been suggested that the measles-mumps-rubella (MMR) vaccination causes autism. Material and methods: We conducted a retrospective cohort study of all children born in Denmark from January 1991 through December 1998. The cohort was established based on data from the Danish Civil Registration System. A unique person identifiable number given to all subjects enabled linkage with other national registries. MMR vaccination status was obtained from the Danish National Board of Health. Information on the children's autism status was obtained from the Danish Psychiatric Central Register which contains information on all diagnoses received from psychiatric hospitals, psychiatric wards, and outpatient clinics in Denmark. We obtained information on potential confounders from the Danish Medical Birth Registry, the National Hospital Registry, and Statistics Denmark. Results: In the cohort of 537,303 children (2,129,864 person-years), 440,655 children had been MMR vaccinated. We identified 316 children with a diagnosis of autistic disorder and 442 with a diagnosis of other spectrum disorders. After adjusting for potential confounders, the risk for autistic disorder and other spectrum disorders was not increased in vaccinated compared with unvaccinated children (relative risk 0.92; 95 percent confidence interval, 0.68 to 1.24 and relative risk 0.83; 95 percent confidence interval, 0.65 to 1.07). There was no association between age at vaccination, time since vaccination or calendar period at time of vaccination and development of autistic disorder. Discussion: This study provides strong evidence against the hypothesis that MMR vaccination causes autism.

We thank de Vries for his valuable comments about our study.1 2 He states that the finding of an incidence rate ratio of 29.8 (95% confidence interval 16.4 to 54.1) for exposure from infant macrolide use during the first two weeks after birth is “either a very strong association or too good to be true.” This association …

To determine the long-term risk of retinal detachment following pediatric cataract surgery and to identify risk factors for retinal detachment.We included all children (aged 0 to 17 years) who during the time period of 1977 to 2005 underwent pediatric cataract surgery in Denmark, excluding cataract cases caused by trauma, or acquired systemic or acquired ocular pathology, and cases with ocular anomalies associated with the development of retinal detachment. Cases of cataract were ascertained from the mandatory Danish National Patient Register, and information on retinal detachment was based on medical chart review.Among 1043 eyes of 656 children undergoing surgery for pediatric cataract, 25 eyes (23 children) developed retinal detachment at a median time of 9.1 years after surgery. The overall 20-year risk of retinal detachment was 7% (95% confidence interval [CI]: 3%-11%) among cataract patients. In otherwise normal children having isolated cataract, the risk was 3% (95% CI: 0%-7%). A significantly higher risk of developing retinal detachment was found in children with mental retardation (23% [95% CI: 9%-35%]) or in cataract cases with other ocular or systemic anomalies (16% [95% CI: 6%-24%]).The estimated overall risk of retinal detachment 20 years after pediatric cataract surgery was 7%, but only 3% for isolated cataract. Particularly high risks of retinal detachment after cataract surgery were associated with mental retardation and having other ocular or systemic diseases.

Objective To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS). Design Nationwide register based cohort study. Setting Denmark, 1996-2011. Participants 999 378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30 091; maternal use after birth, n=21 557; use in infants, n=6591), surgery for IHPS, and potential confounders. Main outcome measures Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth. Results 880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and −0.11 (−0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (−0.31 to 0.50) and 0.67 (−0.06 to 2.02). Conclusions Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.

A pregnancy may lead to hormone-induced growth of breast tumors. The authors investigated whether women in the first years after childbirth had a higher incidence of breast cancer and, in particular, a higher incidence of late-stage tumors (i.e., a large tumor, nodal involvement, or histologic grading II + III). The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry. Overall, uniparous and biparous mothers experienced a transient increased risk that did not appear to be attributable to delayed cancer diagnosis. The risk of being diagnosed with a tumor whose diameter was larger than 5 cm was, on average, 53% higher during the first 10 years after birth compared with later. The risk of tumors of less than 2 cm was not significantly associated with time since the latest birth. In conclusion, after a childbirth, mothers experience a transient increased risk of breast cancer and, in particular, a relatively high risk of late-stage disease. This finding suggests that pregnancy-related factors transiently induce a high growth rate in cells that are already malignant and stimulate new tumor growth.

Poliomyelitis has hypothetically been associated with an increased risk of central nervous system (CNS) tumors. The present study was performed to examine not only the risk of CNS tumors but also the overall risk of cancer among a cohort of 5,883 polio patients. Patients diagnosed with acute poliomyelitis in the Danish capital, Copenhagen, between 1919 and 1954 were identified and followed with respect to cancer. Information on vital status and cancer diagnoses was obtained through linkage with the Danish Civil Registration System and the Danish Cancer Registry, respectively. The ratio of observed number of cancers to the number expected from population-based incidence rates, i.e., the standardized incidence ratio (SIR), served as measure of the relative cancer risk. Overall, 717 cases of cancer were observed among 5,883 polio patients during 249,084 person-years of follow-up vs. an expected number of 645 (SIR = 1.11 [95% confidence interval 1.03 to 1.20])). The increased risk was restricted to female polio patients (SIR = 1.18 [1.07 to 1.30]), among whom the risk was particularly high for breast cancer (SIR = 1.35 [1.12 to 1.61]) and for skin cancer (SIR = 1.66 [1.32 to 2.07]). The risk of breast cancer was highest among women with a history of paralytic polio (SIR = 1.62 [1.24 to 2.10]). The observed number of CNS tumors did not exceed the expected (SIR = 1.09 [0.72 to 1.60]). Women diagnosed with poliomyelitis, in particular paralytic polio, may be at increased risk of breast cancer. There was no association between malignancies of the CNS and poliomyelitis.