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Background A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of alpha-fetoprotein, an estradiol-binding protein, rise sharply. In culture, alpha-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of alpha-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer. Methods From a population-based cohort of 42057 pregnant women in Denmark, enrolled in an alpha-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998. Results During pregnancy, women with an alpha-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an alpha-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41-0. 85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08-0.56); 30-34 years, RR = 0.61 (95% CI = 0.32-1.14); 35-37 years, RR = 0.96 (95% CI = 0.49-1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29-1. 75) (P for trend =.02). Further analyses suggested that high levels of alpha-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum alpha-fetoprotein, compared with women with low levels of serum alpha-fetoprotein, showed a particularly reduced incidence of large tumors (>2 cm; RR = 0.24 [95% CI = 0.11-0.50]). Conclusion A high level of alpha-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age.

A woman's reproductive history influences her risk of breast cancer. The authors hypothesized that reproductive history also influences stage of disease at the time of diagnosis. The authors analyzed a population-based cohort of 1.5 million Danish women born between 1935 and 1978 for whom individual information on births was available. Between 1978 and 1994, 10,790 incident cases of breast cancer in women under 60 years of age were identified. Nulliparous women compared with parous women and women with a late age at first birth compared with an early age were at significantly increased risk of being diagnosed with a large tumor and with cancer that had spread to regional lymph nodes. However, such an association was not seen for women diagnosed with a small tumor and women with cancer that had not spread to regional lymph nodes. Reproductive history did not appear to influence the time interval from first symptoms to first physician visit ("patient delay") or the time interval from first physician visit to surgery ("doctor delay"). The authors conclude that reproductive history is associated both with incidence of breast cancer and with stage of the disease at diagnosis, indicating possible influences on tumor progression and growth rate. Intensified awareness is warranted to achieve earlier diagnosis among nulliparous women and women with a late age at first childbirth, with the hope of improving their prognosis.

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.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.

We examined the association between birth characteristics of offspring and the subsequent maternal risk of breast cancer in a population-based cohort of 998,499 women, 13 to 48 years of age at entry. There were 9,495 incident cases of breast cancer during 12.8 million person-years of follow-up among these women. Compared with mothers of singleton infants, mothers having a multiple birth had an increased risk of breast cancer in the first 5 years after a birth (relative risk (RR) = 1.8; 95% confidence interval (CI) = 1.1-2.8). The risk for mothers having a heavy-weighted child (3.75 kg), as compared with a child of light weight (or =3 kg), was also slightly increased (RR = 1.2; 95% CI = 0.9-1.5). This latter effect was primarily due to an increased incidence of tumors larger than 2 cm at diagnosis (RR = 1.4; 95% CI = 0.9-1.9). Our findings are compatible with the hypothesis that the hormonal level during pregnancy influences the risk of breast cancer in the early years after delivery.

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.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.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.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.

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.To determine efficacy of helminth therapy for allergic rhinitis.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.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.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.

PURPOSE. To determine the risk of glaucoma after surgery for pediatric cataract and to evaluate risk factors for glaucoma. METHODS. A population-based cohort of all children in Denmark aged 0 to 17 years during the period 1977 to 2001, who underwent surgery for pediatric cataract, was established by retrospective chart review. Glaucoma cases were defined as those in which glaucoma surgery (trabeculectomy and/or diode laser transscleral cyclophotocoagulation) was performed and/or permanent medical therapy prescribed after cataract surgery. RESULTS. Of 946 eyes (595 patients) undergoing pediatric cataract surgery, 72 eyes (48 patients) had subsequent development of glaucoma. Early surgery (

Summary Background Oestrogen is an established growth factor in breast cancer. There has, therefore, been much discussion about whether women should be advised against becoming pregnant after breast-cancer treatment because of a possible negative prognostic effect from the high oestrogen concentrations associated with pregnancy. Methods We studied 5725 women with primary breast cancer. Information on these women was obtained from the Danish Breast Cancer Cooperative Group. Since 1977 this group has collected population-based data on tumour characteristics, treatment regimens, and follow-up status of Danish women with breast cancer. Details of reproductive history were obtained from The Danish Civil Registration System, the National Birth Registry, and the National Induced Abortion registry. We estimated the relative risk of death among women who became pregnant after breast-cancer treatment compared with women who had not become pregnant. Findings 5725 women with primary breast cancer aged 45 years or younger at the time of diagnosis were followed up for 35 067 patient-years. Among these, 173 women became pregnant after treatment of breast cancer. Women who had a full-term pregnancy after breast-cancer treatment had a non-significantly reduced risk of death (relative risk 0·55 [95% CI 0·28–1·06]) compared with women who had had no full-term pregnancy after adjustment for age at diagnosis, stage of disease (tumour size, axillary nodal status, and histological grading), and reproductive history before diagnosis. The effect was also not significantly modified by age at diagnosis, tumour size, nodal status, or reproductive history before diagnosis of breast cancer. Neither miscarriages nor induced abortions after breast-cancer treatment influenced the prognosis. Interpretation We found no evidence that a pregnancy after breast-cancer treatment increased the risk of a poor outcome.

The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis (RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients recently diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and 769 gender- and age-matched population controls. Telephone interviews provided information about non-genetic exposures, and serum samples for patients were tested for anti-CCP-antibodies. Associations between exposure variables and risk of anti-CCP-positive and anti-CCP-negative RA were evaluated using logistic regression. A series of RA subtype-specific risk factors were identified. Tobacco smoking (odds ratio [OR] = 1.65; 95% confidence interval: 1.03–2.64, for >20 versus 0 pack-years) was selectively associated with risk of anti-CCP-positive RA, whereas alcohol consumption exhibited an inverse dose-response association with this RA subtype (OR = 1.98, 1.22–3.19, for 0 versus >0–5 drinks per week). Furthermore, coffee consumption (OR = 2.18; 1.07–4.42, for >10 versus 0 cups per day), ever use of oral contraceptives (OR = 1.65; 1.06–2.57) and having a first-degree relative with schizophrenia (OR = 4.18; 1.54–11.3) appeared more strongly associated with risk of anti-CCP-positive RA. Obesity was selectively associated with risk of anti-CCP-negative RA, with obese individuals being at more than 3-fold increased risk of this subtype compared with normal-weight individuals (OR = 3.45; 1.73–6.87). Age at menarche was the only examined factor that was significantly associated with both serologic subtypes of RA (p-trends = 0.01); women with menarche at age ≥ 15 years had about twice the risk of either RA subtype compared with women with menarche at age ≤ 12 years. Major differences in risk factor profiles suggest distinct etiologies for anti-CCP-positive and anti-CCP-negative RA.

ContextIt has been hypothesized that multiple-antigen vaccines, such as measles-mumps-rubella vaccine, or aggregated vaccine exposure could lead to immune dysfunction, resulting in nontargeted infectious diseases as a result of an “overload” mechanism.ObjectiveTo evaluate the relationship between routinely administered childhood vaccines (Haemophilus influenzae type b; diphtheria-tetanus-inactivated poliovirus; diphtheria-tetanus-acellular pertussis-inactivated poliovirus; whole-cell pertussis; measles-mumps-rubella; oral poliovirus) and hospitalization for nontargeted infectious diseases.Design, Setting, and ParticipantsPopulation-based cohort comprising all children born in Denmark from 1990 through 2001 (N = 805 206). Longitudinal information was collected on type and number of vaccine doses received and hospitalization with infectious diseases, specifically acute upper respiratory tract infection, viral and bacterial pneumonia, septicemia, viral central nervous system infection, bacterial meningitis, and diarrhea.Main Outcome MeasuresRate ratios for each type of infectious disease according to vaccination status.ResultsDuring 2 900 463 person-years of follow-up, 84 317 cases of infectious disease hospitalization were identified. Out of 42 possible associations (6 vaccines and 7 infectious disease categories), the only adverse association was for Haemophilus influenzae type b vaccine and acute upper respiratory tract infection (rate ratio, 1.05; 95% confidence interval, 1.01-1.08 comparing vaccinated participants with unvaccinated participants). This one adverse association of 42 possible outcomes was within the limits of what would be expected by chance alone and the effect was not temporal or dose-response. When considering aggregated vaccine exposure, we found no adverse associations between an increasing number of vaccinations and infectious diseases.ConclusionThese results do not support the hypotheses that multiple-antigen vaccines or aggregated vaccine exposure increase the risk of nontargeted infectious disease hospitalization.

We found increasing sibship size to be associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis (1). However, by use of polytomous logistic regression, we found that the protective effect of having siblings on the risk of asthma with allergic rhinitis could be explained by a protective effect of siblings on the risk of allergic rhinitis alone. Thus, having siblings was found to protect against allergic rhinitis while, in contrast, having siblings (older, younger, or total number of siblings) was not associated with asthma. Our findings suggest that different mechanisms may be involved in the development of allergic rhinitis and asthma with respect to the effect of sibship characteristics. This interpretation of our findings is challenged by Karmaus and Johnson (2) in their invited commentary. They propose that the three studied outcomes (allergic rhinitis and asthma with and without allergic rhinitis) do not necessarily represent different disease entities with different mechanisms, because allergic rhinitis in our study is likely to be based on immunoglobulin E sensitization triggered by pollen and because asthma not leading to allergic rhinitis might also be based on immunoglobulin E. Their speculation, however, does not explain our findings of differential effects. Karmaus and Johnson furthermore speculate that, since our results are based on lifetime prevalence, exposures that took place after the inception of asthma or rhinitis could have confounded our results for older siblings. However, although confounding is always of concern in epidemiologic studies, important potential confounders for older siblings after disease initiation are not obvious. Karmaus and Johnson (2) appear to find a contradiction between our finding that, if there are no older siblings, there is no effect of younger siblings on the risk of allergic rhinitis and our finding that allergic rhinitis is associated with the number of younger siblings. However, this is no contradiction. Overall, as we reported in table 1 of our paper (1), there was a highly significant (ptrend ¼ 0.0008) inverse association between the number of younger siblings and allergic rhinitis. Further, when we studied the association stratified by the number of older siblings (table 2) (1), this association was present primarily in strata where the person had older siblings. However, it should be acknowledged that, when stratifiedanalysesareperformed,thepowertodetectassociations is highly reduced. On the basis of our findings, it would clearly be wrong to conclude that younger siblings are not associated with the risk of allergic rhinitis. Karmaus and Johnson (2) find that it would be interesting if we studied whether the change in risk per increase in number of older siblings (i.e., the trend or gradient) varied by birth cohort. We have already reported that the trend for number of siblings overall did not vary by birth cohort for allergic rhinitis. We can now furthermore report that the trend for number of older siblings or lack of trend did not vary by birth cohort for any of the three studied outcomes. In conclusion, we find our previous conclusions valid and anobviousandlikelywaytointerprettheresultsofourstudy.

ContextIt has been suggested that BCG vaccination may protect against development of allergic diseases, particularly when given just after birth. BCG vaccination was given routinely to all infants in Greenland until 1990, when it was withdrawn from the vaccination program. Whether this resulted in an increased prevalence of atopy in children born after the stop of BCG vaccination is unknown.ObjectiveTo determine whether BCG vaccination and age at BCG vaccination are associated with development of atopy.Design, Setting, and ParticipantsCross-sectional study among schoolchildren aged 8 to 16 years in 4 towns on the northwest coast of Greenland. Participants had a blood sample drawn and information on BCG vaccination was obtained during 2 periods, November 1998 and November 2001. A total of 1686 children (79% of available children) participated, 1575 of whom had complete information on vaccination status. Atopy was defined as a positive test result in an assay that tests for IgE specific against the most common inhalant allergens in serum.Main Outcome MeasuresOdds ratio (OR) of atopy in BCG-vaccinated compared with unvaccinated children and OR according to age at vaccination.ResultsThe risk of atopy was the same in BCG-vaccinated compared with unvaccinated children after adjustment for confounders (OR, 1.03; 95% confidence interval, 0.72-1.48). The risk of atopy in BCG-vaccinated children was not associated with age at vaccination (P = .17).ConclusionsBCG vaccination administered to infants is not associated with reduced risk of development of atopy.

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.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.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.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.

1 reported that stature at age 18 years in Austrian men varied up to 6 mm, according to month of birth. They suggested that this variation resulted from environmental exposure late in uterine life or within the first year of life. We found a circannual variation in length of birth in a population-based cohort of 1 166 206 children born in Denmark. This finding is consistent with Weber and colleagues' hypothesis that birth month may be reflected in adult stature. We obtained from the Danish National Birth Registry birth characteristics, including gestational age, length, and weight for all children born from 1973 to 1994. We found seasonal variation in mean length and weight at birth, whereas the secular trends were different (figure). To analyse the seasonal variation of the length at birth we did linear- regression analysis of the length with month of birth and two adjoining 10-year secular trends as independent variables. Children born in April were a mean of 2·2 (SD 0·1) mm longer than those born in December (figure). The temporal variation in length at birth was observed irrespective of birth order. The circannual variation of 2·2 mm in length at birth is compatible with the 6 mm variation in stature between men aged 18 years born in spring and autumn (roughly 3·5 times the stature of newborn babies). 1

Objective: To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman9s 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.

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 > or = 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 in 1989-94 and almost exclusively in primiparous women aged > or = 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 > or = 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.

The aim of the present study was to evaluate whether births occurring at Christmas are different from births taking place on other days of the year. We specifically wanted to test whether the pressure on the pregnant woman to have everything ready for the most important family feast of the year might increase her risk of premature labour. In Denmark, that feast takes place on the eve of 24 December. For a previous study we obtained, from the Danish civil registration system, details of all births to women born between 1935 and 1978, including information on date of births, sex of children, and multiple births.1 For the present study we added information from the Danish national birth registry on gestational age and whether delivery was by caesarean section. Preterm births were defined as those with a gestational age …