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Many studies of animals, including primates, indicate that hyperthermia during pregnancy is associated with fetal death and possibly lethal malformations. There are suggestions that in humans, either endogenous (febrile) hyperthermia or external heating may be linked with neural tube defects. This cohort study interviewed 24,040 women in Denmark during the first half of pregnancy to document febrile episodes in the first 16 weeks of gestation. The incidence of miscarriage or stillbirth during the 18-month study period was 4.8%. Nearly one in five women, 18.5%, reported at least one episode of fever, and about 45% of those reporting a peak temperature had had fever of 39°C or higher. Fever had lasted 2 to 3 days in a majority of women and 4 days or longer in nearly one fourth of the study group. Close to 10% of women reported more than one febrile episode. The risk of fetal death in women reporting fever in the first 16 gestational weeks was no higher than in those without fever, and this result was unchanged after adjusting for numerous factors: maternal age, parity, previous miscarriages, and the use of tobacco, alcohol, and coffee during pregnancy. When including pregnancies ending with induced abortion on indication in the fetal death group, the relative risk of fetal death in women reporting fever was 0.99 (95% CI, 0.84-1.16). There were no differences in fetal death in any trimester of pregnancy or for any specified period within the first 16 weeks. Taking the maximum temperature into account also made no difference. Neither the days of fever nor the number of febrile episodes correlated with fetal death. The lack of a relationship between early gestational fever and fetal death held when only women who were interviewed while pregnant and followed up prospectively were considered. This large-scale cohort study failed to show that fever in the first 16 weeks of pregnancy increases the risk of fetal death, and the investigators believe that pregnant women may be reassured on this point.

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 laterborn children (P trend < 0.0001). However, as predicted from the intensive-exposure model, secondborn children aged 1-4 years in two-child families had a higher risk of paralytic polio than firstborn children (RR = 1.47, 95% CI: 1.1-2.0), whereas the opposite relationship was found for those aged ≥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.

Objective: 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. Methods: 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. Results: 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. Conclusions: The adverse short-term effect of childbirth is stronger in women with FHBC.

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time. Design Nationwide register based cohort study. Setting Denmark. Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses). Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression. Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later. Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy.

Background Preeclampsia (PE), a pregnancy disorder often characterized by renal complications, has previously been associated with later end-stage renal disease. We conducted a nationwide register-based cohort study to explore associations between PE and later kidney disease. Methods Using Danish health registers, we identified all women with pregnancies lasting ⩾20 weeks in Denmark, 1978–2015. PE included preeclampsia, eclampsia or HELLP syndrome registered from 30 days before delivery to 7 days postpartum and was classified as early preterm, late preterm or term based on timing of delivery ( Results The study cohort consisted of 1,072,330 women followed for 19,994,470 person-years (average: 18.6 years/woman). During follow-up, 6060 women developed acute kidney disease and 3082 developed chronic kidney disease. Compared with women without PE delivering in the same gestational age interval, women with a history of PE had only modestly increased rates of acute kidney disease, but significantly higher rates of post-pregnancy chronic kidney disease: early preterm PE, HR 3.93, 95% confidence interval [CI] 2.90–5.33; late preterm PE, HR 2.81, 95% CI 2.13–3.71; term PE, HR 2.27, 95% CI 2.02–2.55. Associations for glomerular disease were especially striking (e.g. early preterm PE, HR 5.27, 95% CI 3.32–8.35). Conclusion Our study provides the first population-based evidence that PE, early PE in particular, is associated with several types of kidney disease later in life.

Introduction Women with a history of preeclampsia (PE) have an increased risk of cardiovascular disease (CVD) later in life. To assess whether PE and CVD might share underlying, potentially heritable mechanisms, we examined the familial co-aggregation of PE and CVD. Objectives To determine whether PE in daughters is associated with CVD in parents, by timing of PE onset in the daughters and type of CVD in the parents. Material and methods Using Danish health and civil registers, we identified all women with pregnancies in 1978–2015, along with their parents (656,027 mothers and 581,035 fathers). We followed the parents from the first pregnancy in a daughter until registration of an ischemic event (myocardial infarction [MI], cerebrovascular infarction or ischemic heart disease), death, immigration or the end of follow-up (31 December 2015). Using Cox regression, we estimated hazard ratios (HRs) for ischemic events in parents by history of PE in daughters. Results Parents with one daughter with a history of PE had 1.15 (95% confidence interval [CI] 1.13–1.18) times the rate of ischemic events as parents whose daughters had no history of PE. Having two or more daughters with a history of PE yielded an HR of 1.28 (95% CI 1.13–1.45). The corresponding HRs for MI alone were 1.21 (95% CI 1.17–1.25, 1 daughter with PE) and 1.55 (95% CI 1.29–1.86, ⩾ 2 daughters with PE). Effect magnitudes did not differ for mothers and fathers. Early-onset (delivery Conclusion PE in daughters is associated with an increased risk of ischemic events, MI in particular, in parents. Increasing strength of association with increasing number of affected daughters, similar effect magnitudes for mothers and fathers, and stronger associations with early-onset PE than with term PE, all suggest that the association between PE and CVD can be explained by common heritable mechanisms, rather than shared behavioral risk factors.

Introduction The preeclampsia (PE) syndrome almost certainly encompasses multiple disease entities. Cardiovascular dysfunction is well documented in early-onset (GA Objectives To compare repeated cardiac function measurements (stroke volume, cardiac output, and total vascular resistance) measured in normotensive pregnancies and pregnancies complicated with late-onset PE. Patients and methods The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension) study is an ongoing longitudinal prospective study being conducted at two university hospitals in Copenhagen, Denmark. PEACH recruits women presenting to the obstetrics departments of these hospitals with signs of hypertensive disorders of pregnancy (HDP) and follows them until the end of pregnancy with serial blood tests and repeated cardiac function measurements obtained using the USCOM-1A device. The study also follows normotensive pregnant women frequency matched to the women in the HDP group and assesses their cardiac function in gestational weeks 28, 35, 38 and 40. USCOM data on cardiac function are analyzed using linear mixed models that include a random personal effect (woman-specific effect), a time-dependent gestational age effect (a trend describing how normal cardiac function changes over the course of pregnancy) and a time-dependent PE effect (how PE – overall or by subtypes – affects cardiac function at a given point during pregnancy). Results and conclusion We compare cardiac function measurements and corresponding indexed values from the first 100 women recruited to the PEACH study with late-onset PE and 100 appropriate controls, at given points during pregnancy, adjusting for age, parity, hospital, ethnicity and other potential confounders. The resulting profiles should help to clarify what role cardiac function monitoring can play in prediction, triage, diagnosis and/or management of late-onset PE.

Background Atopic dermatitis (AD) appears to be more common in regions with hard domestic water and in children with a fall/winter birth. However, it is unknown whether a synergistic effect exists. Objective We sought to evaluate the association between domestic water hardness and season of birth, respectively, with onset of AD within the first 18 months of life in a large Danish birth cohort. Methods Of children from the Danish National Birth Cohort, 52,950 were included. History of physician-diagnosed AD and population characteristics were obtained from interviews. Birth data were obtained from the Civil Registration System, and domestic water hardness data were obtained from the Geological Survey of Denmark and Greenland. The relative prevalence (RP) of AD was calculated by using log-linear binomial regression. Results The prevalence of AD was 15.0% (7,942/52,950). The RP of AD was 5% (RP trend , 1.05; 95% CI, 1.03-1.07) higher for each 5° increase in domestic water hardness (range, 6.60-35.90 German degrees of hardness [118-641 mg/L]). Although the RP of AD was higher in children with a fall (RP, 1.24; 95% CI, 1.17-1.31) or winter (RP, 1.18; 95% CI, 1.11-1.25) birth, no significant interaction was observed with domestic water hardness. The population attributable risk of hard domestic water on AD was 2%. Conclusion We observed that early exposure to hard domestic water and a fall/winter birth was associated with an increase in the relative prevalence of AD within the first 18 months of life. Although the 2 exposures did not interact synergistically, a dose-response relationship was observed between domestic water hardness and AD.

Background— Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons ( Methods and Results— By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature ( Conclusions— A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.

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.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.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).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.

Objectives To investigate the associations between isolated congenital hydrocephalus (CHC) and maternal characteristics, maternal medical diseases, and medicine intake during pregnancy as well as birth characteristics of the child in a retrospective, register-based, nationwide cohort study. Furthermore, to identify the risk factors unique for isolated CHC as compared to syndromic CHC. Methods We established a cohort of all children born in Denmark between 1978 and 2008. Information on CHC and maternal medical diseases were obtained from the National Patient Discharge Register, maternal intake of medicine during pregnancy from the National Prescription Drug Register, and birth characteristics of the child from the Danish National Birth Register. Rate ratios (RR) of isolated and syndromic CHC with 95% CI were estimated using log-linear Poisson regression. Results In a cohort of 1 928 666 live-born children, we observed 1193 cases of isolated CHC (0.062/1000) born children. First-borns had an increased risk of isolated CHC compared to later-borns (1.32 95% CI 1.17 to 1.49) (0.72/1000 born children). First trimester exposure to maternal use of antidepressants was associated with a significantly increased risk of isolated CHC compared to unexposed children (RR 2.52, 95% CI 1.47 to 4.29) (1.5/1000 born children). Risk factors also found for syndromic CHC were: Male gender, multiples and maternal diabetes. Conclusions The higher risk for isolated CHC in first-born children as well as behavioural aspects and comorbidities associated with maternal use of antidepressants, should be the targets for future research. Potential biological pathways by which antidepressants may cause hydrocephalus remain to be elucidated.

In response to previous reports of geographical clustering of individuals with psychosis, a study was carried out in Denmark utilizing the national case register. Two-thousand one-hundred and ninety-nine (2199) individuals with schizophrenia were divided by place of birth into 217 geographical areas and analyzed by age, gender, month of birth, genetic relatedness, and degree of urbanization of birthplace. Heterogeneity was ascertained using log-linear Poisson regression. The greatest amount of heterogeneity was associated with degree of urbanization of place of birth. Heterogeneity was also associated with age-gender interaction and calendar period. When adjusted for these factors, there was no remaining heterogeneity, suggesting that all geographical clustering in our study was explained by the above factors.

Objective: To determine the risk of adverse pregnancy outcome by maternal serum alpha-fetoprotein (MSAFP) level. Methods: We followed 77,149 pregnant women and their infants from MSAFP screening in the 15th to 20th week of gestation until 1 year after birth. Information on pregnancy outcome was obtained from national registries. The relative risks (RRs) and 95% confidence intervals (CIs) for adverse pregnancy outcome were estimated according to the level of MSAFP, with adjustment for confounders. Results: A total of 638 pregnancies resulted in spontaneous abortion, 289 in stillbirth, and 437 in infant death. Compared with women with MSAFP levels at 0.75–1.24 multiples of the median (MoM), those with MSAFP levels greater than or equal to 2.5 MoM had an increased risk of spontaneous abortion (RR 12.5; 95% CI 9.7, 16.1), preterm birth (RR 4.8; 95% CI 4.1, 5.5), small for gestational age (RR 2.8; 95% CI 2.4, 3.2), low birth weight (RR 5.8; 95% CI 5.0, 6.6), and infant death (RR 1.9; 95% CI 1.2, 2.8). Women with MSAFP levels below 0.25 MoM had an increased risk of spontaneous abortion (RR 15.1; 95% CI 9.3, 24.8), preterm birth (RR 2.2; 95% CI 1.3, 3.8), and stillbirth (RR 4.0; 95% CI 1.0, 16.0); those with levels less than 0.5 MoM had an increased risk of infant death (RR 1.9; 95% CI 1.2, 3.0). The increased risk of infant death remained after the subtraction of recognized conditions associated with extreme MSAFP values. Conclusion: Pregnant women with extreme MSAFP values in the second trimester have an increased risk of fetal and infant deaths. Obstet Gynecol 2001;97:277–82.

To examine the importance of intensity of exposure for the outcome of the poliomyelitis infection 429 polio cases were identified belonging to families with 2, 3 or 4 polio cases, all hospitalized in Copenhagen from 1919 to 1953. Furthermore, 87 pairs of polio cases living on the same stairway, but not in the same household, were identified. Severity among multiple cases in families analysed according to time of appearance showed a U-shaped curve. Initial cases had a higher risk of developing paralysis [relative risk (RR) = 1.5, 95% confidence interval (CI) 1.2-1.91 and of dying (RR = 2.5, 95% CI 0.9-6.9). Decreased severity was observed among subsequent cases appearing within 11 d after the initial case (RR = 1.0); however, severity increased again, with higher mortality for cases likely to have been infected by the initial case (cases appearing more than 11 d later) (RR = 5.7, 95% CI 1.8-17.8). The pattern described among multiple family cases was not found among cases from the same stairway. Since family cases appearing within 11 d were probably infected simultaneously, a short incubation period is associated with severe disease and a prolonged incubation period with milder infections. Furthermore, intensive exposure from being infected in the household increased severity. These observations therefore suggest that intensity of exposure and dose of infection are important factors in the severity of poliomyelitis.

The period before the first birth is traditionally viewed as particularly critical for a woman's breast cancer risk. Nonetheless, the importance of early timing of a woman's first compared with subsequent births is not well understood. In the present study we examine this question using a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1968 and 1994, 13,049 incident cases of breast cancer were identified in the Danish Cancer Registry. According to our results, a woman's breast cancer risk is related to her age at any of her births. The risk increase per 5 year's increase in maternal age at first, second, third, and fourth birth was 9%, 7%, 5%, and 14%, respectively. For fifth and sixth births it was 5%. We observed a risk reduction after any birth occurring before 30 years of age (in uniparous women before 25 years of age). These effects were strongest more than 10 years after birth. Thus, our study shows that early timing of any additional birth induces an additional long-term reduction in maternal risk of breast cancer; that is, early reproductive years, rather than just the nulliparous years, constitute the critical period.

Objective - To evaluate whether persons with a history of poliomyelitis are at an increased risk of developing multiple sclerosis (MS). Material and methods - All patients diagnosed with acute poliomyelitis in the greater capital area of Copenhagen, Denmark, between 1919 and 1954 were identified and followed with respect to MS. Information on vital status and diagnosis of sclerosis was obtained through linkage with the Danish Civil Registration System and The Danish Multiple Sclerosis Registry, respectively. Follow-up started on the date of the establishment of the Danish Civil Registration System (April 1, 1968) until death, emigration or December 31, 1996, whichever came first. The observed incidence of MS among polio patients was compared with the expected incidence calculated according to national gender, age and period specific rates of MS. Results - During 149,364 years of follow-up, 19 cases of multiple sclerosis were observed among 5652 polio patients compared with 11.0 expected (SIR = 1.73 (1.04-2.74)). The increased risk of MS was most pronounced in polio patients hospitalized during adolescence. Neither gender nor the acute severity of poliomyelitis modified the risk of MS. Conclusion - Our results are based on small numbers of events, however the findings suggest that the polio patients might be at an increased risk of MS.

Objective To investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment influences such an association. Design: Retrospective cohort study based on a population based database of patients with breast cancer containing detailed information on tumour characteristics, treatment regimens, and survival. Setting: Denmark. Subjects: 10 356 women with primary breast cancer who were less than 50 years old at diagnosis. Main outcome measures: Relative risk of dying within the first 10 years after diagnosis according to age at diagnosis after adjustment for known prognostic factors and expected mortality. Results: Overall, young women with low risk disease who did not receive adjuvant treatment had a significantly increased risk of dying; risk increased with decreasing age at diagnosis (adjusted relative risk: 45-49 years (reference): 1; 40-44 years: 1.12 (95% confidence interval 0.89 to 1.40); 35-39 years: 1.40 (1.10 to 1.78); Conclusion The negative prognostic effect of young age is almost exclusively seen in women diagnosed with low risk disease who did not receive adjuvant cytotoxic treatment. These results suggest that young women with breast cancer, on the basis of age alone, should be regarded as high risk patients and be given adjuvant cytotoxic treatment.

Aims: We investigated whether menstrual cycle dependent variations in prognostic factors are detectable in malignant breast tissue. Methods: Since 1977 the Danish Breast Cancer Cooperative Group has collected population-based information about primary clinical data, treatment regimens and follow-up status on Danish women with breast cancer. Information about last menstrual periods prior to surgery was obtained from files recorded at the time of admission for primary surgery. Included in this study were 1060 patients self-reported to be regularly menstruating and with a menstrual period within 6 weeks of surgery and who were operated in a single-step procedure. None of the patients were current users of exogenous hormones at the time of surgery. Variations of prognostic factors throughout the menstrual cycle were evaluated. Results: Overall, no significant correlation between endogenous hormone fluctuations and oestrogen receptor (ER) status and progesterone receptor (PgR) status were found. Furthermore, we observed no cycle-dependent variation for mitotic index, lymph node involvement or tumour size. Conclusions: The classical prognostic factors in breast cancer did not differ significantly throughout the menstrual cycle in the present study.

Competing risks models can be used to compare the effect of risk factors for different causes of death or subtypes of a disease. However, sometimes more than one outcome classification is available and if two such classifications are correlated, one may speculate whether differences in the effect of a risk factor according to one classification simply may be an effect of differences according to the other correlated classification. We introduce in this paper the new concept of multivariate competing risks to test formally such a hypothesis.

To explore the risk of breast cancer in relation to the length of a pregnancy we tested whether a preterm delivery carries a higher risk of breast cancer than does a full-term delivery. Based on information from the Civil Registration System, and the National Birth Registry in Denmark, we established a population-based cohort of 474 156 women born since April 1935, with vital status and detailed parity information, including the gestational age of liveborn children and stillbirths. Information on spontaneous and induced abortions was obtained from the National Hospital Discharge Registry and the National Registry of Induced Abortions. Incident cases of breast cancer in the cohort (n = 1363) were identified through linkage with the Danish Cancer Registry. The period at risk started in 1978 and continued until a breast cancer diagnosis, death, emigration, or 31 December, 1992, whichever occurred first. After adjusting for attained age, parity, age at first birth and calendar period, we observed the following relative risks of breast cancer for different lengths of the pregnancy: < 29 gestational weeks = 2.11 (95% confidence interval 1.00–4.45); 29–31 weeks = 2.08 (1.20–3.60); 32–33 weeks = 1.12 (0.62–2.04); 34–35 weeks = 1.08 (0.71–1.66); 36–37 weeks = 1.04 (0.83–1.32); 38–39 weeks = 1.02 (0.89–1.17); 40 weeks = 1 (reference). Parous women who had a preterm delivery below 32 weeks gestation had a 1.72-fold (1.14–2.59) increased risk of breast cancer compared with other parous women. In conclusion, a preterm delivery of 32+ weeks gestation did not significantly increase a woman's risk of contracting breast cancer. Only for the very small group of women with preterm deliveries of less than 32 weeks gestation did we observe an increased risk. © 1999 Cancer Research Campaign

Background: Human papillomavirus-associated anogenital carcinogenesis depends on poorly defined cofactors. Smoking was recently suggested to increase the risk of anal cancer more in premenopausal women than in postmenopausal women. Thus, we used our population-based anal cancer case-control study in Denmark and Sweden to test this hypothesis. Methods: Our study included 417 patients (324 women and 93 men) who were diagnosed with anal cancer (84% invasive cancer) from 1991 through 1994; it also included five patients diagnosed in 1995. Two control groups were used: 1) 554 population control subjects (349 women and 205 men) and 2) 534 patients with rectal adenocarcinoma (343 women and 191 men). Odds ratios (ORs), calculated from logistic regression analyses, were used as measures of relative risk. All P values are two-sided. Results: Compared with the risk for lifelong nonsmokers, the risk of anal cancer was high among premenopausal women who currently smoked tobacco (multivariate OR = 5.6; 95% confidence interval [CI] = 2.4-12.7) and increased linearly by 6.7% per pack-year smoked (one pack-year is equivalent to one pack of cigarettes smoked per day for 1 year) (P for trend

It is well established that a woman's reproductive history influences her risk of breast cancer. We examined whether the effect of reproductive history was similar for different sub-types of breast cancer. The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978, with individual information on births. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry, including detailed information on receptor status, histology, laterality and location of the tumour. Overall, the incidence of breast cancer was 13% lower in parous compared with nulliparous women. This reduction was significantly stronger for mucinous than for ductal carcinomas and for tumours located centrally than for those non-central in the breast. Overall, the incidence in parous women increased by 10% by each 5-year postponement of their first birth. For the incidence of lobular carcinomas this increase was significantly stronger, and for mucinous carcinomas it tended to be stronger than for ductal carcinomas. For the incidence of centrally located tumours the increase was stronger than for non-centrally located tumours. On average, there was a 10% decrease in breast-cancer risk by each additional birth. This decrease was seen in most sub-types, but not for lobular carcinomas of for centrally located tumours. According to our findings, lobular and mucinous carcinomas and centrally located tumours may have risk-factor profiles that differ from other types of breast cancer.

Introduction Women with preeclampsia often have higher levels of anti-angiogenic factors than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, women with a history of preeclampsia may have a reduced risk of solid cancers. Objectives To investigate the association between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and later risks of solid and non-solid cancers. Methods We applied Cox regression to Danish health register data and estimated hazard ratios (HRs) for solid and non-solid cancers, comparing women with and without a history of HDP. Results In a cohort of 1.08 million women with ⩾ 1 birth in 1978–2011, 68,236 women had ⩾ 1 pregnancy complicated by HDP; during follow-up, 42,236 and 1,899 women developed solid and non-solid cancers, respectively. A history of HDP was not associated with the rate of solid cancer (HR 0.96, 95% confidence interval [CI] 0.92–1.00), regardless of HDP severity, nor was it associated with delayed solid cancer onset. Interestingly, prior HDP were modestly associated with the rate of non-solid cancer (HR 1.21, 95% CI 1.02–1.45). In analyses of specific cancer subtypes, prior HDP were associated with reduced rates of breast (HR 0.89, 95% CI 0.83–0.95) and lung cancer (HR 0.66, 95% CI 0.54–0.79) and increased rates of leukemia (HR 1.43, 95% CI 1.12–1.83), endometrial (HR 1.62, 95% CI 1.33–1.97) and urinary tract cancer (HR 1.42, 95% CI 1.09–1.97). Conclusion Prior HDP were not associated with overall solid cancer risk, suggesting that observed associations with specific cancer subtypes are probably not explained by an angiogenic imbalance.

Objective: To investigate whether time since birth of last child was of prognostic importance in women with primary breast cancer. Design: Retrospective cohort study based on a population based database of breast cancer diagnoses with detailed information on tumour characteristics, treatment regimens, reproductive factors, and vital status. Setting: Denmark. Subjects: 5652 women with primary breast cancer aged 45 years or less at the time of diagnosis. Main outcome measures: 5 and 10 year survival; relative risk of dying. Results: Women diagnosed in the first 2 years after last childbirth had a crude 5 year survival of 58.7% and 10 year survival of 46.1% compared with 78.4% and 66.0% for women whose last childbirth was more than 2 years before their diagnosis. After adjustment for age, reproductive factors, and stage of disease (tumour size, axillary nodal status, and histological grading), a diagnosis sooner than 2 years since last childbirth was significantly associated with a poor survival (relative risk 1.58, 95% confidence interval 1.24 to 2.02) compared with women who gave birth more than 5 years previously. Further analyses showed that the effect was not modified by age at diagnosis, tumour size, and nodal status. Conclusion: A diagnosis of breast cancer less than 2 years after having given birth is associated with a particularly poor survival irrespective of the stage of disease at debut. Therefore, a recent pregnancy should be regarded as a negative prognostic factor and should be considered in counselling these patients and in the decisions regarding adjuvant treatment. Key messages A childbirth close to subsequent diagnosis of breast cancer has a negative effect on the woman9s cancer prognosis The negative effect of recent childbirth is not affected by age at diagnosis, nodal status, and tumour size The negative effect is found both in patients who receive adjuvant treatment and those who do not Childbirth history should be taken into account when counselling young women with breast cancer

Background: The occurrence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) during childhood may be influenced by factors operating in fetal life. Furthermore, childhood ALL has been suggested to be linked to patterns of infection during infancy. Purpose: To explore these hypotheses and other associations, we studied the impact of sibling patterns (e.g., birth order) and birth characteristics (e.g., birth weight) on the risk of childhood ALL and AML. Methods: By linkage of records of population-based registries, a cohort of all children whose mothers were born in Denmark from April 1935 through March 1978 was established. Children who developed ALL or AML during the period from April 1968 through December 1992 were identified by linkage with the Danish Cancer Registry. Birth weights were obtained for children born during the period from January 1973 through December 1992 by linkage with the Medical Birth Registry. Results: The cohort of approximately 2.0 million children was followed for the diagnosis of ALL or AML for 20.9 million person-years. A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively (P for trend = .09). A decreasing trend was not observed among 5-14 year olds. A significant log-linear association between birth weight and the risk of ALL was observed for both age groups. Overall, the RR of ALL increased by a factor of 1.46 (95% CI = 1.18-1.81) (P = .0005) for each kilogram of increase in birth weight. A total of 114 cases of childhood AML were identified. Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. A particularly high risk of AML at ages 2 (RR = 2.53; 95% CI = 1.46-4.40) and 3 years was associated with having siblings compared with being an only child at those ages. Similar to the findings for ALL risk, there was a significant association between birth weight and AML risk. The relative increase in AML risk per 1-kg increase in birth weight was 2.14 (95% CI = 1.19-3.85; P = .009). Conclusion and Implications: The association between birth weight and childhood leukemia suggests the importance of intrauterine factors. A plausible explanation may be that increasing birth weight is associated with a higher rate of cell proliferation and/or a larger number of precursor cells being at risk of malignant transformation. The inverse association between birth order and ALL risk among 0-4 year olds was weak, but it was compatible with the hypothesis that delayed exposure to infection may increase the risk of ALL in this age group. The association of childhood AML with birth order and sibship size at young ages deserves further attention in the search for environmental factors that affect childhood AML risk. [J Natl Cancer Inst 1997; 89:939-47]

It has been hypothesized that an interrupted pregnancy might increase a woman's risk of breast cancer because breast cells could proliferate without the later protective effect of differentiation.We established a population-based cohort with information on parity and vital status consisting of all Danish women born from April 1, 1935, through March 31, 1978. Through linkage with the National Registry of Induced Abortions, information on the number and dates of induced abortions among those women was combined with information on the gestational age of each aborted fetus. All new cases of breast cancer were identified through linkage with the Danish Cancer Registry.In the cohort of 1.5 million women (28.5 million person-years), we identified 370,715 induced abortions among 280,965 women (2.7 million person-years) and 10,246 women with breast cancer. After adjustment for known risk factors, induced abortion was not associated with an increased risk of breast cancer (relative risk, 1.00; 95 percent confidence interval, 0.94 to 1.06). No increases in risk were found in subgroups defined according to age at abortion, parity, time since abortion, or age at diagnosis of breast cancer. The relative risk of breast cancer increased with increasing gestational age of the fetus at the time of the most recent induced abortion:7 weeks, 0.81 (95 percent confidence interval, 0.58 to 1.13); 7 to 8 weeks, 1.01 (0.89 to 1.14); 9 to 10 weeks, 1.0012 weeks, 1.38 (1.00 to 1.90) (reference category, 9 to 10 weeks).Induced abortions have no overall effect on the risk of breast cancer.A full-term pregnancy increases a woman's short-term risk of breast cancer, possibly as a result of the growth-enhancing properties of pregnancy-induced estrogen secretion. On the other hand, pregnancy decreases the long-term risk of breast cancer, possibly by inducing terminal differentiation of the susceptible mammary cells. It has been hypothesized that an interrupted pregnancy may increase a woman's risk of breast cancer because breast cells could proliferate without the later protective effect of differentiation. A population-based cohort study including all 1.5 million Danish women born from April 1, 1935, through March 31, 1978, was conducted to determine whether induced abortion has an effect upon the risk of breast cancer. Through linkage with the National Registry of Induced Abortions, information on the number and dates of induced abortions among those women was combined with information on the gestational age of each aborted fetus. It is mandatory in Denmark to report all induced abortions as well as the week of gestation. All new cases of breast cancer were identified through linkage with the Danish Cancer Registry. 370,715 induced abortions were identified among 280,965 women; 10,246 women had breast cancer. Adjusting for known risk factors, induced abortion was found to have no overall effect upon the risk of breast cancer. A statistically significant increase in risk, however, was found among women with a history of second-trimester abortion.

Background and purpose Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted. Methods DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed). Results In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71–1.12) overall, and in stratified analyses 0.68 (0.37–1.12) before age 50 and 0.96 (0.74–1.23) at age 50 or older. Conclusions The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort.48 967 individuals were diagnosed with IBD (Crohn's disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979-2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression.5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979-1986) to 19.6% in cohort (2003-2011) (p 0.001) for CD, and from 11.7% in cohort (1979-1986) to 7.5% in cohort (2003-2011) (p 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995-2002) to cohort (2003-2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of1 year.Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found.

Background and objectiveVaricella zoster virus (VZV) is known to cause VZV vasculopathy, which may be associated with stroke. A recent study found an increased risk of stroke within one year of herpes zoster. We aimed to investigate the short and long-term effects of herpes zoster on the risk of stroke.MethodsUsing Danish national registers, we constructed a cohort consisting of all Danish adults ≥18 years old between 1995 and 2008 (n = 4.6 million; person-years of follow-up = 52.9 million). Individual-level information on prescriptions for herpes zoster antiviral treatment and diagnoses of stroke was obtained from national registers. We compared the risk of stroke in persons who had received the specific dosage of acyclovir for herpes zoster with persons who had never received antiviral treatment by Poisson regression.ResultsDuring follow-up, 2.5% received treatment for herpes zoster and 5.0% were diagnosed with stroke. Individuals who had received medication had a 127% (95% CI 83-182%) increased risk the first two weeks, 17% (CI 9-24%) between two weeks and one year, and 5% (2-9%) after the first year. The increased risk was greatest in the youngest age group (ConclusionsThis large nationwide cohort study found an increased risk of stroke after treatment for herpes zoster. Although the short-term risk was particularly high, we cannot rule out the possibility of a small but important long-term risk.

Spironolactone, an aldosterone-antagonist, is associated with gynecomastia. Digoxin, which can also cause gynecomastia, has been associated with increased incidence of breast and uterus cancers. We therefore postulated that spironolactone use might also increase these cancer risks. Using a nationwide prescription drug registry between 1995 and 2010, we identified use of spironolactone in a cohort of Danish women (≥20 years old). In users and non-users, incidence rate ratios adjusted by age group and calendar-year examined risk of breast and uterus cancers, both estrogen-sensitive, and ovary and cervix cancers, both relatively estrogen-insensitive. As an added control exposure, risk ratios in women who used another diuretic, furosemide, were examined by the same approach. Among 2.3 million women (28.5 million person-years), risks of breast, uterus, ovary, and cervix cancers were generally increased about 10-30% in both spironolactone and furosemide users. In the first year of drug exposure, incidences were increased, especially for ovary cancers. However, incidence increases in the first year of use were not specific for estrogen-sensitive cancers, occurred with both spironolactone and furosemide, and were driven by exposures immediately prior to diagnosis. For drug exposure ≥1 years before cancer diagnosis, incidences of these cancers were not significantly increased. We conclude that associations observed with first use in the year immediately before cancer diagnosis were driven by reverse causality, i.e., because of treatment for symptoms related to the incipient cancer. With respect to breast, uterus, ovarian and cervical cancer, there is no evidence of increased risk with spironolactone or furosemide use.

Introduction Digoxin use is associated with increased incidence of breast and uterus cancers. We postulated that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer. Methods Incident breast cancer cases in Danish women (n = 49,312; 1995 to 2008) were identified. Analyses were conducted in women 20 to 74 years old. Relapse hazard ratios (HR) were compared in women using and not using digoxin, adjusting for age, calendar period, protocol, tumor size, nodal involvement, histology grade, estrogen-receptor (ER) status, and anti-estrogen therapy in Cox regression models. Results At diagnosis, tumors in digoxin users were more likely ER+ (85.4% vs. 78.6%: P = 0.002) and have grade 1 ductal histology (37.2% vs. 25.7%; P = 0.004), compared to non-users. 45 relapses occurred in women already using digoxin at breast cancer diagnosis (1,487 person-years); 24 relapses occurred in women later starting digoxin (384 person-years). Overall relapse risk HR in digoxin users was 1.13 (95% confidence interval: 0.88, 1.46) compared to non-users. Relapse risk in digoxin users was significantly increased in the first year (2.19; 1.26, 3.78) but not thereafter (0.99; 0.74, 1.32) (P = 0.02 for difference in HRs). First-year relapse hazard was high in digoxin-using women with ER+ tumors (2.51; 1.39, 4.55) but not ER- tumors (0.72; 0.10, 5.27). Recurrence hazard was not significantly changed among digoxin-using women also using tamoxifen. Conclusions Breast cancers arising in digoxin-using women had better prognostic features. After adjustment for markers, overall breast cancer relapse risk in digoxin users was not increased significantly, although recurrence hazards for ER+ tumors were higher in the first year following diagnosis.

Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations

There are several reports of familial testicular cancer in the literature but few systematic attempts have been made to estimate the risk of testicular cancer in first-degree relatives of patients with this neoplasm, and the risk remains to be fully assessed in population-based studies. By means of data from the Danish Cancer Registry, we identified all testicular cancer patients (index cases) born and diagnosed during 1950–1993 in Denmark. Their fathers were identified from national registries, as were the brothers of a subcohort of these patients. Familial cancer occurrence was determined through linkage with the cancer registry and compared with the cancer incidence in the general male population in Denmark. The ratio of observed to expected cancers generated the measure used for the relative risk. Fathers of 2,113 index cases with testicular cancer experienced an almost 2-fold risk of developing testicular cancer themselves (RR = 1.96; 95% CI: 1.01–3.43). Overall, the fathers had a decreased relative cancer risk (RR = 0.84; 95% CI: 0.74–0.95) with a significantly decreased risk of cancers of the lung and digestive organs. Brothers of a subcohort of 702 index cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI: 3.37ndash;31.5). In conclusion, we documented a significantly increased familial risk of testicular cancer which was relatively more pronounced between brothers than between fathers and sons. These findings support the possible involvement of a genetic component in the aetiology of testicular cancer, but also leave room for a hypothesized influence of in-utero exposures, such as specific maternal hormone levels, that might be shared by brothers. © 1996 Wiley-Liss, Inc.

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.

Background The potential non-specific effects of BCG (Bacillus Calmette-Guerin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non-specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children. Methods A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression. Results Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children. Conclusion Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB.

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 ¼ 470), along with their first- and second-degree relatives (n ¼ 3073). We compared the incidence of CVD in those relatives with that in the back- ground 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 (Phomogeneity , 0.0001). For first-degree relatives ,35 years, SIRs for ischaemic heart disease, cardiomy- opathy, 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.

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.

Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort design, based on the unique nationwide Danish registers, to investigate the association between use of antibiotics and the risk of NHL subtypes. On the basis of the Civil Registration System, we established a cohort of the entire adult (≥ 15 years) Danish population. Information on use of antibiotics came from the Danish Drug Prescription Registry and lymphoma diagnosis from the Danish Cancer Registry. Associations were assessed by adjusted rate ratios (RRs). In total, 13,602 patients were diagnosed with one of the NHL subtypes during 51.6 million person-years of follow-up (1995-2008). We observed positive associations between use of antibiotics and plasma cell myeloma [RR = 1.11, 95% confidence intervals (CIs) = 1.00-1.24], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (RR = 1.32, 95% CI = 1.20-1.45), mantle cell lymphoma (MCL) (RR = 1.40, 95% CI = 1.04-1.88) and anaplastic large T-cell lymphoma (ALCL) (RR = 1.83, 95% CI = 1.00-3.36). Among these, the increased risk of CLL/SLL, MCL and ALCL, respectively, did not vary by years since use, and only the risk of CLL/SLL risk differed by number of prescriptions. While causality could not be established in our study, an intriguing positive long-term association between antibiotic use and CLL/SLL risk was observed. To what extent these findings indicate a role for bacteria in lymphoma pathogenesis requires further investigation.

Context Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks that have never been quantified. Objective To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age. Design, Setting, and Participants We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration. Main Outcome Measures Risks of all cancers combined and by anatomic site, stratified by sex and age. Results One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10 000 person-years in MMD vs an expected rate of 36.9 per 10 000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n = 11; observed rate, 16.1/10 000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n = 7; observed rate, 4.9/10 000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n = 7; observed rate, 10.3/10 000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n = 10; observed rate, 7.1/10 000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P = .81 for heterogeneity; observed rates, 64.5 and 47.7 per 10 000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently. Conclusion Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.

Introduction: To present the work previously and presently being carried out based on the nationwide Childcare Database. Research topics: The Childcare Database comprises individually linked Danish register-based data on childcare attendance, childcare facility characteristics, child and family characteristics, and infectious disease hospitalisations. The database includes about 1 million children aged 0–5 years and has, since the creation, been linked with separate disease registers on atopic disease, pneumococcal disease, and childhood cancers. The present paper is a review of epidemiological studies based on the Childcare Database. Studies of childhood infections confirmed that childcare attendance dramatically increases the risk, but emphasised that the increased risk is often transient and confined to subsets of children. Studies of childhood cancers showed that early childhood infections are likely to reduce the risk of childhood leukaemia and that this risk reduction applies to all children. Conclusion: The Childcare Database is a unique data source for studying the association between childcare attendance and health outcomes. Further linkage with Danish registers is possible on an individual level. The studies based on the Childcare Database confirm and extend previous findings of an increased risk of infection associated with childcare attendance, as well as point towards a possible protective role of early infections in childhood cancer.

Purpose Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group. Patients and Methods Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios. Results Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users. Conclusion Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.

Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.

UnlabelledSymptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3(rd) dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤ 14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation.Trial registrationUniversity hospital Medical Information Network trial registry Reg. no. R000001298, Trial ID UMIN000001070.

OBJECTIVE: To examine the risk factors for Mycobacterium tuberculosis infection (MTI) among Greenlandic children for the purpose of identifying those at highest risk of infection. METHODS: Between 2005 and 2007, 1797 Greenlandic schoolchildren in five different areas were tested for MTI with an interferon gamma release assay (IGRA) and a tuberculin skin test (TST). Parents or guardians were surveyed using a standardized self-administered questionnaire to obtain data on crowding in the household, parents' educational level and the child's health status. Demographic data for each child - i.e. parents' place of birth, number of siblings, distance between siblings (next younger and next older), birth order and mother's age when the child was born - were also extracted from a public registry. Logistic regression was used to check for associations between these variables and MTI, and all results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Children were considered to have MTI if they tested positive on both the IGRA assay and the TST. FINDINGS: The overall prevalence of MTI was 8.5% (152/1797). MTI was diagnosed in 26.7% of the children with a known TB contact, as opposed to 6.4% of the children without such contact. Overall, the MTI rate was higher among Inuit children (OR:4.22; 95% CI: 1.55-11.5) and among children born less than one year after the birth of the next older sibling (OR:2.48; 95% CI: 1.33-4.63). Self-reported TB contact modified the profile to include household crowding and low mother's education. Children who had an older MTI-positive sibling were much more likely to test positive for MTI themselves (OR:14.2; 95% CI: 5.75-35.0) than children without an infected older sibling. CONCLUSION: Ethnicity, sibling relations, number of household residents and maternal level of education are factors associated with the risk of TB infection among children in Greenland. The strong household clustering of MTI suggests that family sources of exposure are important.

Thanks to Turner et al for commenting on our article. Turner et al challenge our finding that the Bacillus Calmette-Guerin vaccine (BCG) can prevent Mycobacterium tuberculosis infection (MTI), and propose an alternative explanation: that the absence of a positive interferon gamma release assay (IGRA) could be due to antigenic sin and does not necessarily demonstrate absence of infection. A positive IGRA is the best available surrogate for MTI, but we are fully aware of its limitations. With the IGRA test, MTI is defined by a T-cell-induced interferon gamma response to M tuberculosis antigens …

Background & Aims Parasitic helminth infections can suppress symptoms of allergy, type 1 diabetes, arthritis, and inflammatory bowel disease in animal models. We analyzed data from a large, population-based cohort study to determine whether common childhood enterobiasis protects against these diseases. Methods We collected information on individual prescriptions filled for the drug Mebendazole against Enterobius vermicularis for all children born in Denmark 1995–2008 from the National Register of Medicinal Product Statistics (n = 924,749; age 0–14 years); 132,383 of these children (14%) filled a prescription for Mebendazole, 102,482 of the children (11%) had a household peer who was registered with a filled Mebendazole prescription, and the remaining 689,884 children (75%) comprised the reference group. Children diagnosed with asthma, type 1 diabetes, juvenile arthritis, ulcerative colitis, or Crohn's disease were identified from the National Patient Registry. We used Poisson regression to estimate confounder-adjusted incidence rate ratios for first in- or outpatient hospital diagnosis of chronic inflammatory disease according to history of Mebendazole treatment prescribed to children in the study. Results Chronic inflammatory disease was diagnosed in 10,352 children during 6.4 million person-years of follow-up. The incidence rate ratios was 1.07 for asthma (95% confidence interval [CI]: 1.00–1.13), 1.05 for type 1 diabetes (95% CI: 0.79–1.12), 1.13 for juvenile arthritis (95% CI: 0.94–1.37), 0.77 for ulcerative colitis (95% CI: 0.41–1.46), and 1.44 for Crohn's disease (95% CI: 0.82–2.53). Results were not modified by number of treatments or age at treatment. Conclusions Based on a population-based analysis, enterobiasis does not reduce risk for asthma, type 1 diabetes, arthritis, or inflammatory bowel disease.

Udgivelsesdato: Jun-16 CONTEXT: Pyloric stenosis is the most common condition requiring surgery in the first months of life. Case reports have suggested familial aggregation, but to what extent this is caused by common environment or inheritance is unknown. OBJECTIVES: To investigate familial aggregation of pyloric stenosis from monozygotic twins to fourth-generation relatives according to sex and maternal and paternal contributions and to estimate disease heritability. DESIGN, SETTING, AND PATIENTS: Population-based cohort study of 1,999,738 children born in Denmark between 1977 and 2008 and followed up for the first year of life, during which 3362 children had surgery for pyloric stenosis. MAIN OUTCOME MEASURE: Familial aggregation of pyloric stenosis, evaluated by rate ratios. RESULTS: The incidence rate (per 1000 person-years) of pyloric stenosis in the first year of life was 1.8 for singletons and 3.1 for twins. The rate ratios of pyloric stenosis were 182 (95% confidence interval [CI], 70.7-467) for monozygotic twins, 29.4 (95% CI, 9.45-91.5) for dizygotic twins, 18.5 (95% CI, 13.7-25.1) for siblings, 4.99 (95% CI, 2.59-9.65) for half-siblings, 3.06 (95% CI, 2.10-4.44) for cousins, and 1.60 (95% CI, 0.51-4.99) for half-cousins. We found no difference in rate ratios for maternal and paternal relatives of children with pyloric stenosis and no difference according to sex of cohort member or sex of relative. The heritability of pyloric stenosis was 87%. CONCLUSION: Pyloric stenosis in Danish children shows strong familial aggregation and heritability.

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.