Jan Wohlfahrt

Maternal age and fetal loss: population based register linkage study

Abstract Objective: To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a womans reproductive history. Design: Prospective register linkage study. Subjects: All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes. Main outcome measures: Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions. Results: Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20–24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age. Conclusions: Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.

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.

Sexually Transmitted Infection as a Cause of Anal Cancer

Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.

Growth patterns and the risk of breast cancer in women

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

Factors influencing the effect of age on prognosis in breast cancer: population based study

Abstract 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); <35 years: 2.18 (1.64 to 2.89). However, no similar trend was seen in patients who received adjuvant cytotoxic treatment. The increased risk in younger women who did not receive adjuvant treatment compared with those who did remained when women were grouped according to presence of node negative disease and by tumour size. 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.

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.

Association Between Thimerosal-Containing Vaccine and Autism

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

Recurrence of Congenital Heart Defects in Families

Background— Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse. We estimated an individual’s risk of CHD given a family history of CHD, as well as the contribution of CHD family history to the total number of CHD cases in the population. Methods and Results— In a national cohort study, we linked all Danish residents to the National Patient Register, the Causes of Death Register, the Danish Central Cytogenetic Register, and the Danish Family Relations Database, yielding 1 763 591 persons born in Denmark between 1977 and 2005, of whom 18 708 had CHD. Individuals with CHD were classified by phenotype. We estimated recurrence risk ratios and population-attributable risk. Among first-degree relatives, the recurrence risk ratio was 79.1 (95% confidence interval [CI] 32.9 to 190) for heterotaxia, 11.7 (95% CI, 8.0 to 17.0) for conotruncal defects, 24.3 (95% CI,12.2 to 48.7) for atrioventricular septal defect, 12.9 (95% CI, 7.48 to 22.2) for left ventricular outflow tract obstruction, 48.6 (95% CI, 27.5 to 85.6) for right ventricular outflow tract obstruction, 7.1 (95% CI, 4.5 to 11.1) for isolated atrial septal defect, and 3.4 (95% CI, 2.2 to 5.3) for isolated ventricular septal defect. The overall recurrence risk ratio for the same defect was 8.15 (95% CI, 6.95 to 9.55), whereas it was 2.68 (95% CI, 2.43 to 2.97) for different heart defects. Only 2.2% of heart defect cases in the population (4.2% after the exclusion of chromosomal aberrations) were attributed to CHD family history in first-degree relatives. Conclusions— Specific CHDs showed highly variable but strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared with the population prevalence, whereas the crossover risks between dissimilar cases of CHD were weaker. Family history of any CHD among first-degree relatives accounted for a small proportion of CHD cases in the population.

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.

Measles in Europe: an epidemiological assessment

BACKGROUND Measles persists in Europe despite the incorporation of the measles vaccine into routine childhood vaccination programmes more than 20 years ago. Our aim was therefore to review the epidemiology of measles in relation to the goal of elimination by 2010. METHODS National surveillance institutions from 32 European countries submitted data for 2006-07. Data for age-group, diagnosis confirmation, vaccination, hospital treatment, the presence of acute encephalitis as a complication of disease, and death were obtained. 30 countries also supplied data about importation of disease. Clinical, laboratory-confirmed, and epidemiologically linked cases that met the requirements for national surveillance were analysed. Cases were separated by age: younger than 1 year, 1-4 years, 5-9 years, 10-14 years, 15-19 years, and older than 20 years. Countries with indigenous measles incidence per 100 000 inhabitants per year of 0, less than 0.1, 0.1-1, and more than 1 were grouped into categories of zero, low, moderate, and high incidence, respectively. FINDINGS For the 2 years of the study, 12 132 cases of measles were recorded with most cases (n=10 329; 85%) from five countries: Romania, Germany, UK, Switzerland, and Italy. Most cases were unvaccinated or incompletely vaccinated children; however, almost a fifth were aged 20 years or older. For the same 2 years, seven measles-related deaths were recorded. High measles incidence in some European countries revealed suboptimum vaccination coverage. Of the 210 cases that were reported as being imported, 117 (56%) came from another country within Europe and 43 (20%) from Asia. INTERPRETATION The suboptimum vaccination coverage raises serious doubts that the goal of elimination by 2010 can be attained. Achievement and maintenance of optimum vaccination coverage and improved surveillance are the cornerstones of the measles elimination plan for Europe.