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It has been debated whether the reported increased risk of Hodgkin's lymphoma (HL) after tonsillectomy could be due to some underlying factor rather than the surgery itself. We studied whether not only tonsillectomy but also tonsillitis was associated with HL. This nationwide cohort study included all Danish residents during 1977-2001. Information on a diagnosis of tonsillitis, tonsillectomy, or HL was obtained from national registries. During 124 million person-years we observed 2,988 HL patients of whom 58 were tonsillectomized (most with preceding tonsillitis) and 14 were diagnosed with only tonsillitis at more than 1 year before HL diagnosis. Tonsillectomy was associated with a significantly increased HL risk in persons under 15 years of age as follows: 1-4 years after tonsillectomy, relative risk (RR) = 3.9 [95% CI: 1.4-11; n = 4]; >5 years after tonsillectomy, RR = 3.5 [1.4-8.5; n = 5]. No young cases of HL occurred among persons diagnosed with only tonsillitis. In contrast, 1-4 years after a hospital diagnosis of tonsillitis without subsequent tonsillectomy we found an increased HL risk in persons aged 15 years or above as follows: 15-34 years of age at HL diagnosis, RR = 3.5 [1.6-7.7; n = 6]; 35+ years, RR = 5.9 [2.2-16; n = 4]. Age at tonsillitis or tonsillectomy did not modify HL risk within the 3 age strata. An increased HL risk was found both after tonsillectomy and after an isolated diagnosis of tonsillitis. These results suggest that tonsillitis is a risk factor for HL and not that, as previously reported, only the surgical removal of tonsils is a risk factor.

Background: Intussusception is the most common cause of intestinal obstruction in infancy and early childhood, but its etiology remains unknown. The present study analyzes whether some children with intussusception subsequently have a higher risk of tonsil disease, suggesting an enhanced tendency to lymphoid hyperplasia. Methods: This nationwide cohort study included all Danish children younger than age 15 years, who were born in 1977–2001 and diagnosed with intussusception at a hospital (n = 2018). The cohort was followed-up for tonsil disease in the Danish National Patient Registry and the Danish Health Security System. Results: A total of 172 children were identified with tonsil disease following intussusception. The risk of tonsil disease was 48% higher (95% confidence interval = 27%–72%) after intussusception compared with the general population of the same age. Age, sex, age at intussusception, and time since intussusception did not modify risk of tonsil disease. The risks of acute tonsillitis, chronic disease of the tonsils, and tonsillectomy were equally increased after intussusception. Conclusions: Intussusception was associated with an increased risk of tonsil disease in childhood. Children with a general tendency to lymphoid hyperplasia may be at increased risk of intussusception.

In a study of 2,978 Danish children aged 5 years from two suburban counties of Copenhagen, carried out in 1998, the authors compared risk factor profiles for wheeze and recurrent cough without wheeze by using polytomous logistic regression to clarify whether the two conditions are likely to have the same etiology. Data were obtained 1) by a mailed parental questionnaire (International Study of Asthma and Allergies in Childhood questions and supplementary questions on cough, sociodemography, perinatal factors, and environmental exposure); 2) through general practitioners (familial allergic disease); and 3) from the National Medical Birth Register (birth weight). Wheeze (WH) was defined as more than one episode of wheeze within the last 12 months (irrespective of cough status) and recurrent cough without WH (RC) as cough occurring outside colds and usually lasting for periods of more than 1 week in children with no more than one attack of wheeze within the last 12 months. Risk factors for comparison were selected as those that, after repeated stepwise logistic regression, remained significant for children with WH or RC. Significant differences were found for gender (p = 0.003), gestational age (p = 0.0002), maternal history of asthma (p = 0.0008), and standard of housing condition (p = 0.04)-all risk factors for WH but not RC. Results may suggest that the two conditions have different etiologies.

Background. Levels of maternal alpha-fetoprotein (AFP) are increased during multiple gestations and preeclampsia but little is known regarding AFP levels in relation to other reproductive factors. Consequently, the objective of this work was to describe the possible relationship between AFP levels during pregnancy and maternal age at birth, maternal age at first birth, parity, time since previous birth and gender of the offspring. Methods. Based on national registries we obtained the reproductive history on a population-based cohort of 44 227 women who had serum AFP levels determined in gestational weeks 14-21 and whose present and previous pregnancies resulted in live-born singletons. Results. Many previous births and an interval of less than 2 years since last birth were significantly associated with extremely low levels of AFP in the mother. However, age at first birth and age at present pregnancy did not influence the AFP level. Women who gave birth to a girl had AFP levels that were 5%[95% confidence...

Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

Summary Background It has been proposed that early age at bacille Calmette–Guerin (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.

Background. High parity is associated with reduced risk of ovarian cancer. One hypothesis is that pregnancy is associated with clearance of a fraction of the genetically modified (pre-malignant) cells from the ovaries. Methods. We evaluated this hypothesis using a model that estimates the cell clearance fraction at first and second pregnancy according to age at pregnancy. The model was fitted using reproductive history data from a cohort of 1.5 million Danish women born between 1935 and 1978 and followed for 28.7 million person-years. During this follow-up period, 2,035 developed invasive ovarian cancer. Results. We found the model to have a satisfactory fit despite the very few parameters involved. The model estimated similar cell clearance fractions for the first and second pregnancy and decreasing clearance with later age at pregnancy. Conclusion. The relation of pregnancy history to risk of ovarian cancer can be well described by a cell clearance model that allows the cell clearance fraction to decrease with age at pregnancy.

Summary 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.

Background: It has been hypothesized that cesarean section might increase the risk of developing allergic disease by depriving the fetus and newborn of exposure to maternal microflora. Furthermore, it has been suggested that complicated modes of delivery might be associated with an increased risk of asthma. Objective: The purpose of this investigation was to study whether cesarean section and other complicated modes of delivery are associated with an increased risk of allergic rhinitis or asthma. Methods: Information on self-reported allergic rhinitis, asthma ever, current asthma, and occupation was obtained from 9722 singleton women born in Denmark during the period 1973-1977 who participated in a national cohort study during the period 1997-2001. For these women, information was available on mode of delivery (spontaneous delivery, cesarean section, vacuum extraction, or other complicated mode of delivery, such as rotation/traction or use of forceps), gestational age, birth weight, and length at birth from the Danish Medical Birth Register. Information on parity and maternal age was obtained from the Danish Civil Registration System. Results: The odds ratios (ORs) of allergic rhinitis were 1.16 (95% CI, 0.90-1.49) for cesarean section and 1.06 (95% CI, 0.85-1.32) for other complicated modes of delivery in comparison with spontaneous delivery. The corresponding ORs of asthma ever were 1.33 (95% CI, 1.02-1.74) and 1.18 (95% CI, 0.94-1.49) for cesarean section and other complicated modes of delivery, respectively, and the ORs of current asthma were 1.22 (95% CI, 0.87-1.73) and 1.26 (95% CI, 0.94-1.68), respectively, in comparison with spontaneous delivery. Conclusions: Our findings do not support the hypothesis that cesarean section or other complicated modes of delivery are associated with the development of allergic rhinitis. However, there might be a positive association with development of asthma—in particular, for cesarean section—that was not explained by gestational age, birth weight, ponderal index, smallness for gestational age, parity, maternal age, or occupation. (J Allergy Clin Immunol 2003;111:51-6.)

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

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

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.

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

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

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

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

Summary 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.

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.

BACKGROUND Immigrant studies offer insights into the relative importance of environment and genes in disease etiology. There is considerable variation in testicular cancer incidence worldwide. We investigated testicular cancer risk in first- and second-generation immigrants to Denmark, a high-incidence country, to evaluate the relative influence of genes and environment and the potential timing of action of environmental factor(s). METHODS A cohort of 2.1 million men who were born since 1930 and lived in Denmark between 1968 and 2003 was established based on information in the Danish Civil Registration System, which included their immigration histories. Cancer histories were obtained from the Danish Cancer Registry. Testicular cancer risk was estimated as rate ratios (RRs) with 95% confidence intervals (CIs) based on log-linear Poisson regression. RESULTS Overall, 4216 testicular cancer cases occurred during 43 million person-years of follow-up in 2.1 million men. These included 166 cases among 344,444 direct immigrants to Denmark and 13 cases among 56,189 men born in Denmark to immigrant parents. These first- and second-generation immigrants had RRs of testicular cancer of 0.37 (95% CI = 0.31 to 0.43) and 0.88 (95% CI = 0.51 to 1.53), respectively, compared with men born in Denmark of parents born in Denmark. The rate in first-generation immigrants was not modified by age at immigration or duration of stay and reflected that in the country of origin. CONCLUSION The testicular cancer risk in first-generation immigrants was lower than that in native-born Danes and reflected that in the countries of origin, whereas the risk in second-generation immigrants was similar to that in natives of Denmark. Together these findings argue for a substantial influence of environmental factors limited to the period early in life, most probably to the period in utero.

Udgivelsesdato: 2008-Feb-1 Hypospadias is one of the most common birth defects. However, its etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of hypospadias. Using Danish health registers, they identified 5,380 boys diagnosed with hypospadias in a cohort of 1,201,790 boys born in 1973-2005. Using binomial log-linear regression, they estimated recurrence risk ratios of hypospadias for male twin pairs and first-, second-, and third-degree relatives of a hypospadias case, which were 50.8 (95% confidence interval [CI]: 34.2, 75.5), 11.6 (95% CI: 9.75, 13.7), 3.27 (95% CI: 2.47, 4.34), and 1.33 (95% CI: 0.94, 1.88), respectively. Recurrence risk ratios did not differ for family members of a hypospadias case related to the same degree. In addition, the authors found no difference in the recurrence risk ratio for maternal compared with paternal second- and third-degree relatives of a hypospadias case. In conclusion, hypospadias was found to have a strong familial component and also to aggregate within more-distant relatives. Importantly, hypospadias was equally transmitted through the paternal and maternal sides of a family, and recurrence risk ratios for brothers and sons of a hypospadias case were similar. These findings indicate that genetic rather than intrauterine environmental factors have a principal role in causing familial 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.

Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.

Udgivelsesdato: 2006-Jul BACKGROUND: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported. OBJECTIVE: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil Registration System. MAIN OUTCOME MEASURE: Patients with T1D and first-degree relatives of patients with MS were followed up for occurrence of MS and T1D, respectively, and the relative risks were expressed as standardized incidence ratios, that is, ratios of observed to expected numbers of outcomes based on national age, sex, and period-specific MS and T1D incidence rates. RESULTS: Patients with T1D were at more than 3-fold increased risk for development of MS (relative risk, 3.26; 95% confidence interval, 1.80-5.88; n = 11). First-degree relatives of patients with MS were at 63% increased risk (relative risk, 1.63; 95% confidence interval, 1.26-2.12; n = 56) for development of T1D. However, adjusting for familial relationship to patients with T1D reduced the excess risk to 44% (relative risk, 1.44; 95% confidence interval, 1.11-1.88; n = 56). CONCLUSION: The present nationwide cohort study demonstrates an intraindividual and, to a lesser degree, an intrafamilial co-occurrence of MS and T1D.

Studying associations between sibship characteristics and allergic diseases in detail may contribute clues to their etiology. The authors studied associations between sibship characteristics and risk of self-reported allergic rhinitis and asthma among 31,145 pregnant women participating in a nationwide study in Denmark during 1997-2000. Increasing sibship size was associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis. The protective effect of having older siblings was stronger than the protective effect of having younger siblings for both allergic rhinitis and asthma with allergic rhinitis. There was no association between interval to closest older or younger sibling and risk of allergic rhinitis or asthma with allergic rhinitis, while the risk of asthma without allergic rhinitis increased with intervals of 2 or more years compared with less than 2 years to the nearest older sibling. 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. In conclusion, our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Furthermore, the findings that allergic rhinitis was associated with the number of younger siblings but not with the age interval to younger siblings support the hypothesis of an influence of postnatal mechanisms and suggest that these mechanisms may not necessarily be operating only in early life.

The belief that oestrogens are involved in the pathogenesis both of testicular cancer in young men and of cancers of the endometrium and female breast has become widespread. In a search for possible hormonal links between these cancers, we investigated the cancer pattern in a cohort of women who had given birth to sons who developed testicular cancer. Particular focus was given to oestrogen-related cancers. The present retrospective population-based cohort study is based on data from the Danish Cancer Registry. Mothers of 2,204 testicular-cancer patients were followed for the occurrence of cancer over a total of 70,063 person years. The ratio of observed cancers in the cohort over the expected numbers based on cancer incidence in the underlying female population served as measure of the relative risk (RR). The RR of developing breast cancer among mothers of testicular-cancer patients was 0.8 (95% confidence interval 0.6–1.1), the relative risk of endometrial cancer 0.6 (0.3–1.0) and of ovarian cancer 1.0 (0.6–1.6). Mothers of testicular-cancer patients are not at increased risk of developing oestrogen-related cancers. © 1996 Wiley-Liss, Inc.

Background: Compelling evidence suggests that childhood leukemia often originates in utero. Birth weight is one of the few pregnancy-related risk factors that has been associated with leukemia risk, but the association has remained poorly characterized. We conducted a population-based case-control study in Denmark, Sweden, Norway, and Iceland to investigate the association between birth weight (and other birth characteristics) and the risk of childhood leukemia. Methods: Overall, 1905 children (aged 0-14 years) with acute lymphoblastic leukemia (ALL) and 299 children with acute myeloid leukemia (AML) diagnosed between January 1, 1984, and December 31, 1999, were identified in the Nordic Society of Paediatric Haematology and Oncology acute leukemia database. Each case patient was matched to five population control subjects (n = 10 745) on nationality, age, and sex. All live-born siblings of case patients (n = 3812) and control subjects (n = 17 937) were also identified in population registers. Information on birth weight and gestational age at birth was ascertained from the national Medical Birth Registers. The association between various birth characteristics and leukemia risk was assessed by conditional logistic regression. All statistical tests were two-sided. Results: Risk of ALL overall was statistically significantly associated with birth weight (odds ratio [OR] = 1.26 per 1-kg increase in birth weight, 95% confidence interval [CI] = 1.13 to 1.41). The association was similar for B- and T-lineage ALL and across all diagnostic ages (0-14 years). However, children with ALL did not weigh more at birth than their siblings. Statistically significantly reduced risks of B-precursor ALL were observed with increasing position in the birth order (OR = 0.90 per position increase, 95% CI = 0.84 to 0.96) and increasing gestational age (OR = 0.87 per 2-week increase in gestational age, 95% CI = 0.81 to 0.94). Risk of AML did not vary monotonically with birth weight, and low birth weight (

The role of breastfeeding in allergic diseases remains controversial. The authors studied the association between breastfeeding and development of atopic dermatitis during the first 18 months of life among children with and without a parental history of allergy. A cohort study of 15,430 mother-child pairs enrolled in The Danish National Birth Cohort was carried out between 1998 and 2000. Data on breastfeeding, atopic dermatitis, and potential confounders was obtained from telephone interviews conducted during pregnancy and when the children were 6 and 18 months of age. The cumulative incidence of atopic dermatitis was 11.5% at 18 months of age. Overall, current breastfeeding was not associated with atopic dermatitis (incidence rate ratio (IRR) = 0.91, 95% confidence interval (CI): 0.80, 1.04). Exclusive breastfeeding for at least 4 months was associated with an increased risk of atopic dermatitis in children with no parents with allergies (IRR = 1.29, 95% CI: 1.06, 1.55) but not for children with one (IRR = 1.11, 95% CI: 0.94, 1.31) or two (IRR = 0.88, 95% CI: 0.69, 1.13) parents with allergies (test for homogeneity, p = 0.03). The authors found no overall effects of exclusive or partial breastfeeding on the risk of atopic dermatitis. However, the effect of exclusive breastfeeding for 4 months or more depended on parental history of allergic diseases.

Evidence has emerged that childhood leukemia is initiated in utero. High birth weight is one of the few birth-related factors that has been associated with childhood leukemia, albeit not consistently. The authors conducted a meta-analysis of studies of the association between birth weight and childhood leukemia risk. Study-specific odds ratios for leukemia were calculated, using a cutoff at 4,000 g of birth weight. The authors also evaluated whether the association between birth weight and leukemia followed a log-linear dose-response-like pattern. They calculated summary estimates using weighted averages of study-specific odds ratios from dichotomous and trend analyses. Eighteen studies (published between 1962 and 2002) were included, encompassing 10,282 children with leukemia. Children weighing 4,000 g or more at birth were at higher risk of acute lymphoblastic leukemia than children weighing less (odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.17, 1.37). Furthermore, data were consistent with a dose-response-like effect (OR = 1.14/1,000-g birth weight increase, 95% CI: 1.08, 1.20). Studies of acute myeloid leukemia indicated a similar increase in risk for children weighing 4,000 g or more at birth (OR = 1.27, 95% CI: 0.73, 2.20) and a dose-response-like effect (OR = 1.29/1,000 g, 95% CI: 0.80, 2.06), but results varied across studies. Our findings support a relation between birth weight and childhood acute lymphoblastic leukemia risk and emphasize the need for additional studies of the biologic mechanisms underlying this association.

ContextParvovirus 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.ObjectivesTo estimate a pregnant woman's risk of infection with parvovirus B19 in epidemic and endemic situations and to study risk factors for infection.DesignPopulation-based cohort study conducted between November 1992 and June 1994.SettingThree regions in Denmark.ParticipantsA total of 30,946 pregnant women from a consecutive and population-based screening.Main Outcome MeasuresSpecific 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.ResultsBased 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.ConclusionsThe 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.

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.

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.

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.

The belief that estrogens are centrally involved in the pathogenesis of both testicular cancer in young men and cancers in the endometrium and female breast has become widespread. In order to provide further insight into the possible hormonal links between these cancers, we investigated the cancer pattern in a large cohort of women who had given birth to sons who developed testicular cancer. Particular focus was given to estrogen-related cancers. Material Mothers of 2,204 testicular cancer patients were identified, with a total of 70,063 person years of follow up. Results No increased risk was found with regard to breast, endometrial or ovarian cancers among mothers of testicular cancer patients. Brothers of testicular cancer patients have a significantly increased relative risk of developing testicular cancer( P Conclusion On the basis of this large study no clues of common hormonal etiology of testicular cancer in young men and cancers of the endometrium and breast could be identified. Some kind of hereditary predisposition of testicular cancer seems likely.

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 …

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.