Tine Westergaard

Effects of family history and place and season of birth on the risk of schizophrenia.

BACKGROUND Although a family history of schizophrenia is the best-established risk factor for schizophrenia, environmental factors such as the place and season of birth may also be important. METHODS Using data from the Civil Registration System in Denmark, we established a population-based cohort of 1.75 million persons whose mothers were Danish women born between 1935 and 1978. We linked this cohort to the Danish Psychiatric Central Register and identified 2669 cases of schizophrenia among cohort members and additional cases among their parents. RESULTS The respective relative risks of schizophrenia for persons with a mother, father, or sibling who had schizophrenia were 9.31 (95 percent confidence interval, 7.24 to 11.96), 7.20 (95 percent confidence interval, 5.10 to 10.16), and 6.99 (95 percent confidence interval, 5.38 to 9.09), as compared with persons with no affected parents or siblings. The risk of schizophrenia was associated with the degree of urbanization of the place of birth (relative risk for the capital vs. rural areas, 2.40; 95 percent confidence interval, 2.13 to 2.70). The risk was also significantly associated with the season of birth; it was highest for births in February and March and lowest for births in August and September. The population attributable risk was 5.5 percent for a history of schizophrenia in a parent or sibling, 34.6 percent for urban place of birth, and 10.5 percent for the season of birth. CONCLUSIONS Although a history of schizophrenia in a parent or sibling is associated with the highest relative risk of having the disease, the place and season of birth account for many more cases on a population basis.

Caesarean delivery and risk of atopy and allergic disesase: meta‐analyses

Background Studies of delivery by caesarean section (c‐section) and the offsprings 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.

INDUCED ABORTION AND THE RISK OF BREAST CANCER

BACKGROUND It has been hypothesized that an interrupted pregnancy might increase a womans risk of breast cancer because breast cells could proliferate without the later protective effect of differentiation. METHODS 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. RESULTS 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, 1.00 >12 weeks, 1.38 (1.00 to 1.90) (reference category, 9 to 10 weeks). CONCLUSIONS Induced abortions have no overall effect on the risk of breast cancer.

Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial

BACKGROUND Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease. OBJECTIVE To determine efficacy of helminth therapy for allergic rhinitis. METHODS We conducted a double-blind, placebo-controlled, parallel group trial in which 100 subjects age 18 to 65 years with grass pollen-induced allergic rhinitis were randomly assigned to ingest a total of 8 doses with 2500 live T suis ova or placebo with an interval of 21 days. The primary outcome was a change in mean daily total symptom score for runny, itchy, sneezing nose (maximum change, 9.0) or in percentage of well days during the grass pollen season. RESULTS Treatment with T suis ova (N = 49) compared with placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of participants (placebo, 2%), and increased eosinophil counts (P < .001) and T suis-specific IgE (P < .05), IgG (P < .001), IgG(4) (P < .003), and IgA (P < .001), whereas there was no significant change in symptom scores (0.0; 95% CI, -0.5 to 0.4; P = .87), well days (3%; 95% CI, -9% to 14%; P = .63), total histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction on skin prick testing with grass (P = .85) or 9 other allergens. CONCLUSION Repeated treatment with the helminth T suis induced a substantial clinical and immunologic response as evidence of infection, but had no therapeutic effect on allergic rhinitis.

Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A population-based study

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.

Birth order, sibship size and risk of Hodgkin's disease in children and young adults: a population-based study of 31 million person-years.

It has been proposed that Hodgkins disease (HD) may have an infectious origin and that delayed exposure to infection may increase the risk of HD in young adults. This hypothesis is addressed by studying the family structure among children and young adults. The Civil Registration System was used to establish a population‐based cohort consisting of all persons whose mothers were born in Denmark since 1935. Persons who developed HD were identified by linkage with the Danish Cancer Registry. HD incidence rate ratios were estimated based on a log‐linear Poisson regression model. The cohort of 2.1 million persons (aged 0–42 years) was followed for 31.1 million person years, during which period 378 cases of HD occurred. Among children (<15 years, n = 72), the relative risk (RR) of HD tended to increase with increasing sibship size, the relative increase in risk per increase in sibship size (the trend) being 1.28 [95% confidence interval (CI) 1.00–1.63]. The trend for birth order was 1.26 (95% CI 0.92–1.73). Among young adults (≥15 years, n = 306) the risk of HD, on the contrary, tended to decrease with increasing sibship size [trend = 0.91 (95% CI, 0.81–1.03)] and birth order (trend = 0.85 (95% CI, 0.71–1.01). These trends among young adults were significantly different from the corresponding trends among children (p < 0.05). Siblings of cases were at increased risk of HD (RR = 18; 95% CI, 2.2–65, n = 2). Our findings are compatible with the hypothesis that delayed exposure to infection may be a risk factor for HD in young adults, and that early exposure perhaps to another infectious agent may increase the risk of HD in children. Int. J. Cancer 72:977–981, 1997.

Population based study of rates of multiple pregnancies in Denmark, 1980-94

Abstract Objective: To study trends in multiple pregnancies not explained by changes in maternal age and parity patterns. Design: Trends in population based figures for multiple pregnancies in Denmark studied from complete national records on parity history and vital status. Population: 497 979 Danish women and 803 019 pregnancies, 1980-94. Main outcome measures: National rates of multiple pregnancies, infant mortality, and stillbirths controlled for maternal age and parity. Special emphasis on primiparous women ≥30 years of age, who are most likely to undergo fertility treatment. Results: The national incidence of multiple pregnancies increased 1.7-fold during 1980-94, the increase primarily in1989-94 and almost exclusively in primiparous women aged ≥30 years, for whom the adjusted population based twinning rate increased 2.7-fold and the triplet rate 9.1-fold. During 1989-94, the adjusted yearly increase in multiple pregnancies for these women was 19% (95% confidence interval 16% to 21%) and in dizygotic twin pregnancies 25% (21% to 28%). The proportion of multiple births among infant deaths in primiparous women ≥30 years increased from 11.5% to 26.9% during the study period. The total infant mortality, however, did not increase for these women because of a simultaneous significant decrease in infant mortality among singletons. Conclusions: A relatively small group of women has drastically changed the overall national rates of multiple pregnancies. The introduction of new treatments to enhance fertility has probably caused these changes and has also affected the otherwise decreasing trend in infant mortality. Consequently, the resources, both economical and otherwise, associated with these treatments go well beyond those invested in specific fertility enhancing treatments.

Time since childbirth and prognosis in primary breast cancer: population based study

Abstract 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 womans 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

Autoimmune disease in patients with multiple sclerosis and their first-degree relatives: a nationwide cohort study in Denmark.

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.

Maternal and Gestational Risk Factors for Hypospadias

Background An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown. Objectives Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors. Methods We conducted a case–control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls. Results A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6–13.3]. Boys born to obese [body mass index (BMI) ≥ 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2–5.7) compared with boys born to mothers with a normal weight (BMI = 20–24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy’s risk of hypospadias 2.0-fold (95% CI, 1.1–3.7) and 1.8-fold (95% CI, 1.2–2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1–53). Conclusions A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.