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Background— Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort. Methods and Results— In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51–4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23–10.6, and relative risk, 3.49; 95% confidence interval, 2.91–4.13, respectively; P =0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74–13.8). Conclusions— The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

We thank Ziliang Ye and colleagues for their comments on our article, in which we reported associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy.1 They suggest 3 possible limitations that may have weakened our study. We contend that, although our study undoubtedly had limitations, those mentioned by Ye et al are not among them. First, Ye et al argue that our results may have been confounded by medication use, specifically the use of folic acid and vitamin B12 to prevent neural tube defects, and the use of medications to treat hypertensive …

Background— Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension. Methods and Results— Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1 031 279 women followed for >15 928 900 person-years, we identified 27 98 myocardial infarctions, 40 53 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06–3.50), 1.74 (1.32–2.28), and 2.42 (1.59–3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03–1.24), 1.16 (1.07–1.25), and 1.20 (1.05–1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women ( Conclusions— Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis.

Importance Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown. Objective To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period. Design, Setting, and Participants Nationwide register–based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1 075 763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012. Exposures A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register. Main Outcomes and Measures Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months. Result The women in the primary cohort had 2 067 633 eligible pregnancies during the study period, 76 108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18 211 603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100 000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173 062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100 000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697 447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100 000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213 197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100 000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy. Conclusions and Relevance Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

Background— Variation within a single gene might produce different congenital heart defects (CHDs) within a family, which could explain the previously reported familial aggregation of discordant CHDs. We investigated whether certain groups of discordant CHDs are more common in families than others. Methods and Results— Using Danish national population and health registers, we identified CHDs among all singletons born in Denmark during 1977–2005 and their first-degree relatives. In a cohort of 1 711 641 persons, 16 777 had CHDs, which we classified into 14 phenotypes. We estimated relative risks of discordant CHDs by history of specific CHDs in first-degree relatives. The relative risk of any dissimilar CHD given the specified CHD in first-degree relatives was as follows: heterotaxia, 2.00 (95% CI, 0.96 to 4.17); conotruncal defects, 2.78 (95% CI, 2.12 to 3.66); atrioventricular septal defects, 2.25 (95% CI, 1.39 to 3.66); anomalous pulmonary venous return, 1.76 (95% CI, 0.66 to 4.64); left- and right-ventricular outflow tract obstruction, 2.55 (95% CI, 1.87 to 3.48) and 3.09 (95% CI, 2.03 to 4.71), respectively; isolated atrial septal defects, 2.76 (95% CI, 2.11 to 3.61); isolated ventricular septal defects, 2.27 (95% CI, 1.75 to 2.94); persistent ductus arteriosus, 1.92 (95% CI, 1.32 to 2.79); other specified CHDs, 3.29 (95% CI, 2.51 to 4.32); and unspecified CHDs, 2.30 (95% CI, 1.76 to 3.00). Relative risks for all pairwise combinations of discordant CHD phenotypes gave no indications that certain constellations of CHDs cluster more in families than others. Conclusion— We documented strong familial aggregation of discordant CHD phenotypes. However, we observed no excess clustering of specific CHD phenotypes among the first-degree relatives.

Background: Infant deaths cluster in families, but beyond infancy, little is known about familial aggregation of premature deaths. We hypothesized that an individual's risk of premature death would be influenced by prior premature deaths of any age in family members. Methods: For all Danish residents registered in the Civil Registration System, 1968-2005, information was linked to the Causes of Death Register and the Danish Family Relation Database, yielding a cohort of 4,870,821 persons linked to one or more relatives (93 million persons-years and 73,278 deaths). We used log-linear Poisson regression to estimate mortality rate ratios (relative risks) for premature death (before age 40 years) in persons with a family history of premature death, compared with persons without such a history. Results: Persons with a family history of premature death were 46% more likely themselves to die prematurely than persons without such a family history (relative risk [RR] = 1.46 [95% confidence interval = 1.42-1.50]). Relative risks were higher for concordant age at death, a close kinship relation, and similar causes of death. As expected, certain natural causes clustered among first-degree relatives (RRs ranged from 1.81-618), but unnatural causes of death, such as nonsimultaneous motor vehicle injuries, other injuries, and suicides, also clustered (RRs = 1.80, 3.53, and 4.23, respectively). Previous family history of premature death in a first-degree relative also increased the risk of dying from another cause (overall RR = 2.08 in infancy and 1.33 between ages 1 and 39). Conclusion: Premature deaths cluster in families, for both similar and dissimilar causes.

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

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.

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.

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.

The period before the first birth is traditionally viewed as particularly critical for a woman's breast cancer risk. Nonetheless, the importance of early timing of a woman's first compared with subsequent births is not well understood. In the present study we examine this question using a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1968 and 1994, 13,049 incident cases of breast cancer were identified in the Danish Cancer Registry. According to our results, a woman's breast cancer risk is related to her age at any of her births. The risk increase per 5 year's increase in maternal age at first, second, third, and fourth birth was 9%, 7%, 5%, and 14%, respectively. For fifth and sixth births it was 5%. We observed a risk reduction after any birth occurring before 30 years of age (in uniparous women before 25 years of age). These effects were strongest more than 10 years after birth. Thus, our study shows that early timing of any additional birth induces an additional long-term reduction in maternal risk of breast cancer; that is, early reproductive years, rather than just the nulliparous years, constitute the critical period.

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.