Autoimmune diseases 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). PATIENTS: with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

Caesarean delivery and risk of atopy and allergic disease: meta-analyses.

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

Age at bacille Calmette-Guérin vaccination and risk of allergy and asthma.

BACKGROUND: It has been proposed that early age at bacille Calmette-Guérin (BCG) vaccination protects against the development of allergy. OBJECTIVE: To study whether early age at BCG vaccination was associated with a decreased risk of atopy, allergic rhinitis, and asthma compared to BCG vaccination at later ages in childhood. METHODS: The occurrence of atopy, allergic rhinitis, and asthma was studied in nearly 2000 women participating in the Danish National Birth Cohort study. Detailed information on age at BCG vaccination (age 0-15 years) was available from school health records. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during the period 1997-2001. Information on allergic rhinitis and asthma was available from telephone interviews. RESULTS: Approximately 85% of the women had been BCG-vaccinated. Age at BCG vaccination was not associated with risk of atopy, allergic rhinitis, or asthma. The odds ratio of atopy, allergic rhinitis, and asthma associated with being vaccinated during the first year of life was 1.05 (95% CI 0.71-1.56), 1.42 (95% CI 0.85-2.36), and 1.71 (95% CI 0.91-3.20), respectively, compared with being vaccinated at the age of 7 years. Adjustment for birth cohort, sibship size, age of the woman's mother at birth, and social class in childhood did not affect the results. CONCLUSION: Our findings suggest that age at BCG vaccination in childhood does not influence the development of allergy or asthma.

Reproductive history and allergic rhinitis among 31145 Danish women.

BACKGROUND AND OBJECTIVE: A successful pregnancy is associated with a strong skewing of the immune system towards a Th2-type immune response. Because such a deviation is also the hallmark of allergic disease, it was investigated whether allergic rhinitis in women was associated with an increased likelihood of becoming pregnant and having a successful outcome of pregnancies. MATERIAL AND METHODS: Information on allergic rhinitis and reproductive history was obtained for 31145 pregnant women who participated in a national birth cohort study in Denmark during September 1997 to March 2000, and for whom complete information on siblings and place of residence and birth was available via the Civil Registration System. Data were analysed using logistic regression. RESULTS: Women who had previously been pregnant (OR = 0.91, 95% CI 0.85-0.98) or who had given birth previously (OR = 0.91, 95% CI 0.85-0.98) were less likely to report allergic rhinitis than others. The number of previous spontaneous abortions, gestational week of the first spontaneous abortion and fertility treatment were not associated with allergic rhinitis. Women who had waited less than a year to become pregnant more often had allergic rhinitis (OR = 1.18, 95% CI 1.06-1.32, P = 0.002) than women who had waited for more than a year. Early age at menarche was associated with an increased likelihood of allergic rhinitis (Ptrend = 0.003). CONCLUSIONS: Our findings did not support the hypothesis that an atopic genotype overall should be associated with an increased likelihood of successful outcome of pregnancies, but it might be associated with a decreased waiting time to pregnancy.

Age at childhood infections and risk of atopy.

BACKGROUND: It has been proposed that early age at exposure to common childhood infections is associated with a decreased risk of allergy. Previous studies on the possible association between allergy and infection with measles, mumps, rubella, and varicella have not been conclusive as most did not include information on exact age at exposure. The objective of our study was to investigate whether early age at exposure to these infections was associated with a decreased risk of atopy using information on exact age at infection. METHODS: The study population consisted of 889 pregnant women who participated in a national birth cohort study in Denmark and for whom detailed information on history of measles, rubella, varicella, and mumps before school entry (age 7 years) was available from school health records from Copenhagen. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during pregnancy. RESULTS: Measles in the first year of life was associated with a higher risk of atopy than no measles before age 7 years (OR 3.36, 95% CI 1.47 to 7.68). There was no association between atopy and mumps, rubella, or varicella in the first 7 years of life or with measles acquired after the first year of life. The risk of atopy increased significantly with increasing number of childhood infections in the first 2 years of life (p(trend)=0.01). CONCLUSIONS: These findings do not support the suggestion that childhood exposure to measles, rubella, varicella, or mumps protects against atopy, even if acquired very early in life.

[Sibships characteristics, influenza and risk of schizophrenia. A population-based cohort study]. / Søskendeflokkarakteristika, influenza og skizofrenirisiko. Et populationsbaseret kohortestudie.

INTRODUCTION: To address the hypothesis that infections, perhaps prenatal exposure to influenza virus, might increase the risk of schizophrenia we studied the possible association between schizophrenia risk and birth order, sibship size, interval between siblings, and influenza prevalence. MATERIAL AND METHODS: We established a population-based cohort of 1,746,366 persons born to Danish woman who themselves were born since 1935 using data from the Civil Registration System. Schizophrenia in cohort members (n = 2669) and their parents was identified by linkage with the Danish Psychiatric Case Register. Influenza notifications per month in Denmark were obtained from the National Board of Health and Statens Serum Institut. RESULTS: We found no association between birth order and schizophrenia risk or between schizophrenia risk and influenza prevalence during any month of prenatal life. Coming from a large sibship and having a short interval to the nearest older or younger sibling was associated with an increased risk of schizophrenia. DISCUSSION: Our findings do not add support to the hypothesis that schizophrenia is associated with prenatal exposure to influenza virus or other common infections, but are compatible with the hypothesis that environmental exposure, perhaps to common infections in childhood, may be a risk factor.

Second-trimester maternal serum alpha-fetoprotein and risk of adverse pregnancy outcome(1).

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.

Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence.

BACKGROUND: It has been proposed that infections, perhaps prenatal exposure to the influenza virus, might increase the risk of schizophrenia. To address this hypothesis, we studied the possible influence on schizophrenia risk of sibship characteristics and ecological influenza prevalence data. Birth order and influenza prevalence were used as proxy measures for exposure to prenatal infection, and sibship size and interval to siblings were used as proxy measures for exposure to common childhood infections. METHODS: We established a population-based cohort of 1746366 persons whose mothers were Danish-born women born since 1935 by using data from the Civil Registration System. Schizophrenia in cohort members (n = 2669) and their parents was identified by linkage with the Danish Psychiatric Case Register. Birth order, sibship size, and interval to siblings were calculated for each cohort member based on person-identifiable information on all siblings. The number of notifications of influenza per month in Denmark was obtained from the National Board of Health and Statens Serum Institut. RESULTS: There was no association between birth order and schizophrenia risk or between schizophrenia risk and influenza prevalence during any month of prenatal life. Coming from a large sibship was associated with an increased schizophrenia risk. The relative risks were 1.26 (95% confidence interval [CI], 1.11-1.44) and 1.46 (95% CI, 1.22-1.75) for sibships of 4 and 5 or more, respectively, vs. a sibship of 2. Short interval (<2 years) to the nearest older sibling and nearest younger sibling was associated with a risk of 1.22 (95% CI, 1.05-1.38) and 1.15 (95% CI, 1.03-1.28), respectively, compared with longer intervals. CONCLUSIONS: Our findings do not support the hypothesis that schizophrenia is associated with prenatal exposure to common infections or influenza. However, they are compatible with the hypothesis that environmental exposure, perhaps to common infections in childhood, may be a risk factor, although other explanations are also possible.

Sex ratios, family size, and birth order.

In many countries, the male:female ratio at birth has varied significantly over the past century, but the reasons for these changes have been unclear. The authors observed a close parallel between decreasing family size and declining male:female sex ratio in Denmark from 1960 to 1994. To explain this finding, they examined the sex ratio and birth order of 1,403,021 children born to 700,030 couples. Overall, 51.2% of the first births were male. However, families with boys were significantly more likely than expected to have another boy (biologic heterogeneity). By the fourth birth to families with three prior boys, 52.4% were male. The increase varied directly with the number of prior boys (p for trend = 0.0007). Furthermore, couples with boys were more likely to continue to have children. In summary, the authors found that the declining male:female ratio in Denmark and probably other European populations is mainly attributable to three effects: declining family size, biologic heterogeneity, and child sex preference. Why families with boys are more likely to have additional boys is unknown.

PIP: The relationship between the sex ratio and birth order of 1,403,021 children born to 700,030 couples was examined by analyzing the birth records from 1960 to 1994 in Denmark. The analysis revealed that about 51.2% of the first births were male. However, families with boys were significantly more likely than expected to have another boy (biologic heterogeneity). By the 4th birth to families with 3 prior boys, 52.4% were males. The increase varied directly with the number of prior boys (p for trend = 0.0007). Furthermore, couples with boys were more likely to continue to have children. The researchers found that the declining sex ratio between male and female in Denmark, and perhaps in other European populations, is mainly attributable to 3 factors: 1) declining family size; 2) biologic heterogeneity; and 3) child sex preference. Lastly, it is not known why families with boys are more likely to have additional boys.

Preterm delivery and risk of breast cancer.

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.

Risk factors for parvovirus B19 infection in pregnancy.

CONTEXT: Parvovirus B19 infection during pregnancy has been associated with fetal death. However, the incidence of and risk factors for infection in pregnant women have not been well studied. OBJECTIVES: To estimate a pregnant woman's risk of infection with parvovirus B19 in epidemic and endemic situations and to study risk factors for infection. DESIGN: Population-based cohort study conducted between November 1992 and June 1994. SETTING: Three regions in Denmark. PARTICIPANTS: A total of 30946 pregnant women from a consecutive and population-based screening. MAIN OUTCOME MEASURES: Specific IgG antibodies in serum samples obtained in the first trimester of pregnancy and from the newborn infant to assess past infection and seroconversion. Information on family structure, educational background, socioeconomic status, and pregnancy outcome was obtained from national registers. RESULTS: Based on 30 946 serum samples, 65.0% of pregnant women had evidence of past infection. Annual seroconversion rates among susceptible women during endemic and epidemic periods were 1.5% (95% confidence interval [CI], 0.2%-1.9%) and 13.0% (95% CI, 8.7%-23.1 %), respectively. Baseline seropositivity was significantly correlated with increasing number of siblings, having a sibling of the same age, number of own children, and occupational exposure to children. Risk of acute infection increased with the number of children in the household as follows: 0 children odds ratio (OR), 1 (reference); 1 child OR, 3.17 (95% CI, 2.24-4.49); 2 children OR, 5.47 (95% CI, 3.55-8.45); 3 or more children OR, 7.54 (95% CI, 3.80-14.94). Having children aged 6 to 7 years resulted in the highest rate of seroconversion among mothers (6.8%; OR, 4.07; 95% CI, 1.89-8.73). Compared with other pregnant women, nursery school teachers had a 3-fold increased risk of acute infection (OR, 3.09; 95% CI, 1.62-5.89). Population-attributable risk of seroconversion was 55.4% for number of own children and 6.0% for occupational exposure. CONCLUSIONS: The risk of infection is high for susceptible pregnant women during epidemics and associated with the level of contact with children. Nursery school teachers have the highest occupational risk, but most infections seem to be the result of exposure to the woman's own children.

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.

Parity, age at first childbirth and the prognosis of primary breast cancer.

Reproductive factors are known to be aetiologically important in breast cancer, but less is known regarding their effect on breast cancer prognosis. We have investigated the prognostic effect of age at first birth and total parity using data from the Danish Breast Cancer Cooperative Group that, since 1977, has collected population-based information on tumour characteristics, treatment regimes and follow-up status on Danish women with breast cancer. Details of pregnancy history were added from the Danish Civil Registration System and the National Birth Registry. Included in the study were 10,703 women with primary breast cancer. After adjusting for age and stage of disease (tumour size, axillary nodal status and histological grading), the number of full-term pregnancies was found without prognostic value. However, women with primary childbirth between 20 and 29 years experienced a significantly reduced risk of death compared with women with primary childbirth below the age of 20 years [20-24 years: relative risk (RR) = 0.88, 95% confidence interval (CI) 0.78-0.99; 25-29 years: RR = 0.80, 95% CI 0.70-0.91]. Further adjustment for oestrogen receptor status did not influence these results. The effect was not modified by age at diagnosis, tumour size or nodal status. In conclusion, low age at first childbirth, but not parity, was associated with a poor prognosis of breast cancer. We speculate whether women who develop breast cancer despite an early first full-term pregnancy might represent a selected group with a more malignant disease.

[Multiple pregnancies in Denmark 1980-1994]. / Flerfoldsfødsler i Danmark 1980-1994.

The objective was to study trends in national rates of multiple pregnancies that were not explained by changes in maternal age and parity. Information on childbirths to Danish-born women were obtained from national registers. The national incidence of multiple pregnancies increased 1.7-fold during 1980-1994, the increase primarily in 1989-1994 and almost exclusively in primiparous women > or = 30 years, for whom the adjusted population-based twinning rate increased 2.7-fold and the triplet rate 9.1-fold. The proportion of multiple births among infant deaths in primiparous women > or = 30 years increased from 11.5% to 26.9%. In conclusion, the marked increase in the rate of multiple pregnancies, which in particular was observed during the 1990s and in primiparous women > or = 30 years, could not be explained by changes in maternal age or parity. Fertility-enhancing treatments are believed to have caused this increase.

[Induced abortion and risk of breast cancer]. / Provokeret abort og risiko for brystkraeft.

It has been hypothesized that an interrupted pregnancy might increase the risk of breast cancer, because proliferation of breast cells will take place without the protective effect of subsequent differentiation. In a cohort of 1.5 million women (28.5 million person-years) we identified 370,715 induced abortions in 280,965 women (2.7 million person-years) and 10,246 women with breast cancer. After adjustment for other risk factors, induced abortion was not associated with the risk of breast cancer (relative risk: 1.00; 95 percent confidence interval 0.94 to 1.06). However, the relative risk of breast cancer increased with increasing gestational age of the most recently induced abortion: < 7 weeks: 0.81; 7 to 8 weeks; 1.01; 9 to 10 weeks: 1 (reference); 11 to 12 weeks: 1.12; 13 to 14 weeks: 1.13; 15 to 18 weeks: 1.23; > 18 weeks: 1.89; P(trend) = 0.016. On a population basis, induced abortion was not associated with an increased risk of breast cancer. An increase was only seen for the special group of late second trimester abortions, but this finding was based on small numbers.

Testicular cancer risk and maternal parity: a population-based cohort study.

The aim was to study, in a population-based cohort design, whether first-born sons run a higher risk of testicular cancer than later born sons; to investigate whether this difference in risk was affected by birth cohort, age of the son, maternal age, interval to previous delivery and other reproductive factors; and, finally, to evaluate to what extent changes in women's parity over time might explain the increasing incidence of testicular cancer. By using data from the Civil Registration System, a database was established of all women born in Denmark since 1935 and all their children alive in 1968 or born later. Sons with testicular cancer were identified in the Danish Cancer Registry. Among 1015994 sons followed for 15981 967 person-years, 626 developed testicular cancer (443 non-seminomas, 183 seminomas). Later born sons had a decreased risk of testicular cancer (RR = 0.80, 95% CI = 0.67-0.95) compared with first-born sons. The RR was 0.79 (95% CI = 0.64-0.98) for non-seminomas and 0.81 (95% CI = 0.58-1.13) for seminomas. There was no association between testicular cancer risk and overall parity of the mother, maternal or paternal age at the birth of the son, or maternal age at first birth. The decreased risk of testicular cancer among later born sons was not modified by age, birth cohort, interval to the previous birth, sex of the first-born child, or maternal age at birth of the son or at first birth. The increased proportion of first-borns from birth cohort 1946 to birth cohort 1969 only explained around 3% of an approximated two-fold increase in incidence between the cohorts. Our data document a distinctly higher risk of testicular cancer in first-born compared with later born sons and suggest that the most likely explanation should be sought among exposures in utero. The increase in the proportion of first-borns in the population has only contributed marginally to the increase in testicular cancer incidence.

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

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. CONCLUSIONS: 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.

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 Hodgkin's 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 (> or = 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.

Birth characteristics, sibling patterns, and acute leukemia risk in childhood: a population-based cohort study.

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.