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Preeclampsia and cardiovascular disease (CVD) might share heritable underlying mechanisms. We investigated whether preeclampsia in daughters is associated with CVD in parents. In a register-based cohort study, we used Cox regression to compare rates of CVD (ischemic heart disease, ischemic stroke, myocardial infarction) in parents with ≥ 1 daughters who had preeclampsia and parents whose daughters did not have preeclampsia in Denmark, 1978–2018. Our cohort included 1,299,310 parents, of whom 87,251 had ≥ 1 daughters with preeclampsia and 272,936 developed CVD during 20,252,351 years of follow-up (incidence rate 135/10,000 person-years). Parents with one daughter who had preeclampsia were 1.19 times as likely as parents of daughters without preeclampsia to develop CVD at age Preeclampsia and cardiovascular disease (CVD) might share heritable underlying mechanisms. We investigated whether preeclampsia in daughters is associated with CVD in parents. In a register-based cohort study, we used Cox regression to compare rates of CVD (ischemic heart disease, ischemic stroke, myocardial infarction) in parents with >= 1 daughters who had preeclampsia and parents whose daughters did not have preeclampsia in Denmark, 1978-2018. Our cohort included 1,299,310 parents, of whom 87,251 had >= 1 daughters with preeclampsia and 272,936 developed CVD during 20,252,351 years of follow-up (incidence rate 135/10,000 person-years). Parents with one daughter who had preeclampsia were 1.19 times as likely as parents of daughters without preeclampsia to develop CVD at age < 55 years (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.13-1.25). Having >= 2 daughters who had preeclampsia yielded an HR of 1.88 (95% CI 1.39-2.53). The corresponding HRs for CVD at >= 55 years of age were 1.13 (95% CI 1.12-1.15) and 1.27 (95% CI 1.16-1.38). Patterns of association were similar for all CVD subtypes. Effect magnitudes did not differ for mothers and fathers (p = 0.52). Analyses by timing of preeclampsia onset in daughters suggested a tendency toward stronger associations with earlier preeclampsia onset, particularly in parents < 55 years. Preeclampsia in daughters was associated with increased risks of CVD in parents. Increasing strength of association with increasing number of affected daughters, equally strong associations for mothers and fathers, and stronger associations for CVD occurring before age 55 years suggest that preeclampsia and CVD share common heritable mechanisms.

Aims Pre-eclampsia increases women’s lifetime risk of cardiovascular disease (CVD). Little is known about the trajectory of CVD after pre-eclampsia, limiting the usefulness of this knowledge for informing screening, prevention, and interventions. We investigated when the risk of CVD increases after pre-eclampsia and how the risk changes over time since pregnancy. Methods and results This register-based study included 1 157 666 women with >1 pregnancy between 1978 and 2017. Cumulative incidences of acute myocardial infarction (AMI) and ischaemic stroke were estimated, as well as hazard ratios (HRs) by attained age and time since delivery. Up to 2% [95% confidence interval (CI): 1.46–2.82%] of women with pre-eclampsia in their first pregnancy had an AMI or stroke within two decades of delivery, compared with up to 1.2% (95% CI: 1.08–1.30%) of pre-eclampsia-free women; differences in cumulative incidences were evident 7 years after delivery. Ten years after delivery, women with pre-eclampsia had four- and three-fold higher rates of AMI (HR = 4.16, 95% CI: 3.16–5.49) and stroke (HR = 2.59, 95% CI 2.04–3.28) than women without pre-eclampsia; rates remained doubled >20 years later. Women with pre-eclampsia aged 30–39 years had five-fold and three-fold higher rates of AMI (HR = 4.88, 95% CI 3.55–6.71) and stroke (HR = 2.56, 95% CI 1.95–3.36) than women of similar age without pre-eclampsia. Conclusions Women with a history of pre-eclampsia have high rates of AMI and stroke at early ages and within a decade after delivery. The findings suggest that pre-eclampsia history could be useful in identifying women at increased risk of CVD and that targeted interventions should be initiated soon after delivery.

Background: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide, with implications for maternal and neonatal well-being in the short term and for long-term maternal cardiovascular health. Although the mechanisms behind HDP remain incompletely understood, evidence suggests that preeclampsia in particular is a syndrome with more than one distinct subtype. Objectives: The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction, Hypertension) Study was established to identify new HDP subtyping systems reflecting aetiology and prognosis and to find markers of later cardiovascular disease risk associated with preeclampsia. Population: The PEACH Study recruited pregnant women referred to two Copenhagen-area hospitals with suspected preeclampsia (mean gestational age at enrolment: 36.7 weeks) and a group of frequency-matched pregnant women planning delivery at the same hospitals and healthy when enrolled mid-pregnancy. Design: Prospective, longitudinal pregnancy cohort. Methods: Participants underwent repeated third-trimester blood sample collection, longitudinal cardiac function assessments using the USCOM-1A during the third trimester and at 1 year postpartum and collection of placental samples immediately after delivery. Medical information was abstracted from medical records and hospital databases. Preliminary results: During 2016–2018, we recruited 1149 pregnant women, of whom 1101 were followed to delivery. Among 691 women enrolled with suspected preeclampsia, 310 and 172 developed preeclampsia and gestational hypertension respectively. Among 410 women with healthy pregnancies when enrolled mid-pregnancy, 37 later developed hypertensive disorders of pregnancy. Of 1089 women still in the cohort 1 year postpartum, 578 (53.1%) participated in the follow-up assessment. Conclusions: The PEACH Study's rich data from women with and without HDP will enable us to identify new, clinically useful HDP subtypes to aid in decision-making regarding monitoring and treatment. Continued postpartum follow-up will help us develop algorithms to identify women at risk of persistent postpartum cardiac dysfunction and later cardiovascular disease after pregnancies complicated by HDP.

Background High parity and extremes of age at first birth have been linked with increased dementia risk in women, with exposure to pregnancy-associated physiological changes proposed as an explanation. However, confounding by socioeconomic and lifestyle factors could also produce such associations, whereby men would share similar patterns of association. We investigated whether these associations hold for both sexes. Methods In a cohort study including all women (N = 2,222,638) and men (N = 2,141,002) ≥ 40 years of age in 1994–2017 in Denmark, we used Cox regression to evaluate associations between number of children, age at first birth, and dementia risk separately for women and men. Results During follow-up, 81,413 women and 53,568 men (median age at diagnosis, 83.3 and 80.3 years, respectively) developed dementia. Compared with having one child, having two or more children was associated with modest decreases in overall dementia risk in both sexes (hazard ratio [HR] range 0.82–0.91, Pdifference men vs. women = 0.07). Although the associations between childlessness and overall dementia risk differed statistically for men and women, the association magnitudes differed only slightly (HRmen 1.04, 95% confidence interval [CI] 1.01–1.06; HRwomen 0.99, 95% CI 0.97–1.01; P = 0.002). Associations between age at becoming a parent and overall dementia were also similar for women and men, with the exception of older (≥ 40 years) first-time parents (HRmen 1.00, 95% CI 0.96–1.05; HRwomen 0.92, 95% CI 0.86–0.98; P = 0.01). With few exceptions, sub-analyses by dementia subtype and timing of onset also revealed similar patterns and effect magnitudes for women and men. Conclusions Associations between number of children, age at becoming a parent, and dementia risk were similar for both sexes. Lifestyle and socioeconomic factors are more likely to explain the observed associations than normal pregnancy-related physiological changes.

Background: Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs. Methods: All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression. Results: The RRs for any CHD in offspring were 5.39 (95% CI, 4.88–5.96) for mothers and 3.04 (95% CI, 2.59–3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 ( P Conclusions: Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.

Background: Previous studies have suggested an increased prevalence of congenital heart disease among children born to women aged ≥35 years. In recent decades, the mother’s age at childbirth has increased dramatically in industrialized countries. It has not been investigated if increasing maternal age affects the neonatal cardiac electrical system. Methods: The Copenhagen Baby Heart Study is a prospective general population study that performed cardiac evaluation in newborns. Electrocardiograms were analyzed with a computerized algorithm. Results: We included 16,518 newborns with normal echocardiograms (median age 11 days; range 0–30 days; 52% boys). Median maternal age at delivery was 31 years; 790 newborns were born to mothers aged between 16 and 24 years, 11,403 between 25 and 34 years, 4,279 between 35 and 44 years, and 46 newborns had mothers aged between 45 and 54 years. The QRS axis and maximum R-wave amplitude in V1 (R-V1) differed across the four maternal age groups (both p < 0.01), with absolute differences of 3.5% (114 vs. 110°) and 12% (1,152 vs. 1,015 µV), respectively, between newborns with the youngest and oldest mothers. Associations between maternal age and the QRS axis and R-V1 remained significant after multifactorial adjustment. Heart rate, PR interval, QRS duration, uncorrected QT interval, QTcBazett, and maximum amplitudes of S-V1, R-V6, and S-V6 were not associated with maternal age (all p > 0.05). Conclusion: We observed a significant association between maternal age and the neonatal QRS axis and R-V1. However, the absolute differences were relatively small and maternal age is unlikely to have a clinically significant effect on the neonatal cardiac electrical system.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality., Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Background Ventricular septal defect (VSD) is one of the most common congenital heart defects. Some VSDs close spontaneously while persistence of the VSD may result in heart failure and, at long term, irreversible pulmonary hypertension. Consequently, identification of factors associated with spontaneous closure are important to ensure relevant clinical follow up of those at risk of a persistent VSD. Purpose We aimed to assess the rate of spontaneous closure in a population-based cohort of newborns with VSD and to identify significant predictors for spontaneous closure. Methods The study is part of a large-scale population-based study, focusing on cardiac structure and function, including newborns born from 1st April 2016 to 31st October 2018. Newborns with a VSDs at baseline were followed with echocardiography at 3, 6 and 12 months (+30 days) of age. Cox proportional hazard model was used to determine significant predictors of spontaneous closure Results Based on echocardiographies of 25.750 newborn, 850 newborns (3.3%) with a VSD were identified. The majority of newborns with VSDs were born at term (88.7%) and the mean age at inclusion was 11.7±8.1 days. VSDs were more frequent in females (57.1%, p Conclusion In a population study including more than 25,000 newborns we found that the vast majority, i.e. almost 9/10 of all VSDs, closed spontaneously during the first year of life, ultimately resulting in a prevalence of VSD in one-year old children of 0.5%. The identified factors associated with spontaneous closure – anatomical location, size and presence of multiple VSDs are of use for future management of VSDs in newborns. Funding Acknowledgement Type of funding source: Other. Main funding source(s): The Danish Heart Foundation

Background Prenatal exposure to maternal diabetes has been associated with increased risk of congenital heart defects. Purpose To evaluate whether maternal diabetes is associated with more subtle morphological and functional cardiac changes in neonates without congenital heart defects. Methods We included 17,869 newborns sampled from the Copenhagen Baby Heart Study, all of whom underwent transthoracic echocardiography within 30 days of delivery. We investigated the association between exposure to maternal diabetes (pre-existing diabetes [type 1 or type 2 diabetes] or gestational diabetes [GDM]) and the neonates' echocardiographic indices of left ventricular structure (left posterior wall thickness in end-diastole [LVPWd], interventricular septum thickness in end-diastole [IVSd], left ventricular internal diameter in end-systole [LVIDs] and end-diastole [LVIDd]), systolic function (fractional shortening [FS], stroke volume [SV]) and diastolic function (mitral valve peak early and atrial filling velocities, deceleration time of early filling, and E/A-ratio), using linear and logistic regression. Models were adjusted for maternal age, infant sex, infant birth weight for gestational age and gestational age in days. In additional analyses, we evaluated the relationship between HbA1C levels in first and third trimester and left ventricular structure and function. Results We found that infants exposed to pre-existing maternal diabetes (n=x) had, on average, a thicker LVPWd (mean difference 0.12 mm [95% CI: 0.06–0.19]), a smaller LVIDs (−0.27 mm [95% CI: −0.46, −0.07]) and LVIDd (−0.43 mm [95% CI: −0.66, −0.19]), and decreased SV (−0.50 ml [95% CI: −0.77, −0.23]). We found no significant differences in IVSd, FS, and measures of diastolic function for infants exposed to pre-existing maternal diabetes compared with infants not exposed to diabetes. Infants exposed to GDM (n=) also had thicker LVPWd (0.06 mm [95% CI: −0.28, −0.01]) and smaller LVIDs (−0.15 mm [95% CI: −0.28, −0.01]); however, on average, IVSd, LVIDd, and measures of systolic and diastolic function did not differ for infants born to mothers with and without GDM. We observed no consistent association between HbA1C levels measured early and late in pregnancy in mothers with diabetes and indices of left ventricular structure and function. Conclusion In conclusion, we found that exposure to maternal pre-existing diabetes, and to a lesser degree GDM, was associated with changes in neonatal left ventricular structure and function, including a thicker left ventricular posterior wall, smaller left ventricular internal diameters, and lower stroke volumes. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Rigsbospitalet Research Foundation

Introduction Pregnancy losses may be associated with increased risks of dementia. Methods We conducted a register-based cohort study in 1,243,957 women with ≥1 pregnancy in Denmark in the period 1977–2015. Using Cox regression, we estimated hazard ratios (HRs) comparing risks of dementia in women with and without pregnancy losses. Results During 21,672,433 person-years of follow-up, 261,279 women experienced a pregnancy loss, and 2188 women were diagnosed with dementia. Stillbirth was associated with an 86% increased risk of dementia overall (HR 1.86, 95% confidence interval [CI] 1.28–2.71). By contrast, miscarriage was not associated with later risk of dementia overall (single miscarriage, HR 0.99, 95% CI 0.87–1.12; recurrent miscarriages, HR 1.06, 95% CI 0.84–1.35). Adjustment for cardiovascular disease, hypertension, and diabetes did not meaningfully alter the association magnitudes. Discussion Stillbirth and dementia may share underlying mechanisms, suggesting that a history of stillbirth should be considered when assessing dementia risk in women.

Objective To evaluate the acceptability and feasibility of providing assisted reproductive services as part of routine HIV care and treatment in Ethiopia. Methods The present cross-sectional study using semistructured in-depth interviews was conducted at St. Paul Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia, during July 2014 and July 2015. The interviews assessed the perspectives of healthcare providers (HCPs) regarding the reproductive desires of HIV-affected couples, on assisting them in achieving pregnancy, and on the facilitators and barriers to offering such services as part of routine HIV care. Results There were 40 HCPs from two SPHMMC clinics interviewed. All HCPs asserted that HIV-affected couples should have equal access to assisted reproductive services and most agreed that couples should have this access to reduce the risk of HIV transmission, even in the absence of underlying infertility. However, the HCPs cited systemic and structural barriers to the implementation and delivery of assisted reproductive services. Conclusion The integration of assisted reproductive services into HIV care and treatment programs is acceptable and feasible to HCPs. Formal training of HCPs may improve the implementation of these services for HIV-affected couples in low-resource settings. This article is protected by copyright. All rights reserved.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia., Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Background Maternal preeclampsia (PE) has been associated with an increased risk of a variety of congenital heart defects in the infant. Whether PE also confers an increased risk of subtle structural and functional cardiac deficits is unknown. Purpose We investigated whether left ventricular dimensions and systolic function differed among infants of mothers with PE, compared to infants born after uncomplicated pregnancies. Method Systematic transthoracic echocardiography (TTE) was performed in neonates included in a population-based study in the period 2016–2018 (n=25,000). TTE was preferably performed within 14 days of birth. Left ventricular (LV) posterior wall end-diastolic thickness (LVPWd), interventricular septum end-diastole thickness (IVSd), LV internal diameter in end-diastole and end-systole (LVIDd and LVIDs), LV ejection fraction (LVEF) and fractional shortening (FS) were assessed. Information on maternal PE (ICD-10 codes DO140–142 and DO159) was retrieved from an obstetric database. Using linear regression in a sample of echocardiograms, we compared the LV structure and function adjusted for maternal age; gestational age; sex; weight and length. Results In total, 447 infants were exposed to PE, and 7,178 were born to uncomplicated pregnancies (Table). In infants of PE mothers, we found significantly larger LVPWd and IVSd (0.18 mm, 95% CI [0.14; 0.22], p LV measures in PE and non-PE infants Parameter Infants of PE mothers, Infants of non-PE mothers, p-value Estimate* [95% CI] p-value mean [± SD] (n=447) mean [± SD] (n=7,178) Left Ventricular Posterior Wall in end-Diastole, LVPWd (mm) 2.20 [±0.58] 2.07 [±0.40] Conclusion In the largest population-based group of neonates to date, we showed that infants born to PE mothers compared to infants of non-PE mothers had significantly thicker left ventricular myocardium, and reduced left ventricular volumes. However, PE was not associated with altered systolic function. Our results might reflect an adaption of the fetal heart to the increased resistance in the placental arteries in PE mothers, and a secondary increased left ventricular afterload. Acknowledgement/Funding Danish Heart Association, Danish Children's Heart Foundation, Candy's Found., Toyota Found., Herlev-Gentofte Hospital Research Found., Lundbeck Found.

ObjectiveTo investigate associations between pre-eclampsia and later risk of kidney disease.DesignNationwide register based cohort study.SettingDenmark.PopulationAll women with at least one pregnancy lasting at least 20 weeks between 1978 and 2015.Main outcome measureHazard ratios comparing rates of kidney disease between women with and without a history of pre-eclampsia, stratified by gestational age at delivery and estimated using Cox regression.ResultsThe cohort consisted of 1 072 330 women followed for 19 994 470 person years (average 18.6 years/woman). Compared with women with no previous pre-eclampsia, those with a history of pre-eclampsia were more likely to develop chronic renal conditions: hazard ratio 3.93 (95% confidence interval 2.90 to 5.33, for early preterm pre-eclampsia (delivery Conclusions Pre-eclampsia, particularly early preterm pre-eclampsia, was strongly associated with several chronic renal disorders later in life. More research is needed to determine which women are most likely to develop kidney disease after pre-eclampsia, what mechanisms underlie the association, and what clinical follow-up and interventions (and in what timeframe post-pregnancy) would be most appropriate and effective.

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.

Women with hypertensive disorders of pregnancy (HDP) have higher levels of antiangiogenic growth factors during pregnancy than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, we hypothesized that women with a history of HDP might have a reduced risk of solid cancers (cancers other than lymphomas, hematologic cancers and nonmelanoma skin cancers) later in life. In a register-based cohort study of 1.08 million women giving birth at least once between 1978 and 2011, we used Cox regression to estimate hazard ratios (HRs) comparing solid cancer rates for women with and without a history of HDP. In this cohort, 68,236 women (6.3%) had ≥1 pregnancy complicated by HDP and 42,236 women (3.9%) developed solid tumors during follow-up. A history of HDP was not associated with a clinically meaningful reduction in the overall rate of solid cancer (HR 0.96, 95% confidence interval 0.92-1.00), regardless of HDP severity or time since HDP, nor was there a general tendency toward reduced solid cancer rates across organ sites. A history of HDP was only significantly associated with decreased rates of breast and lung cancers and with increased rates of endometrial and urinary tract cancers. Overall, our results do not support the hypothesis that women with a history of HDP have a reduced overall risk of solid cancer due to a persistent post-HDP antiangiogenic state or an innate tendency toward antiangiogenesis. Observed associations with specific cancers may instead be due to other pregnancy-related mechanisms or to residual/unmeasured confounding.

Background: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. Methods: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (

ObjectiveTo explore associations between pre-eclampsia and later dementia, overall and by dementia subtype and timing of onset.DesignNationwide register based cohort study.SettingDenmark.PopulationAll women with at least one live birth or stillbirth between 1978 and 2015.Main outcome measureHazard ratios comparing dementia rates among women with and without a history of pre-eclampsia, estimated using Cox regression.ResultsThe cohort consisted of 1 178 005 women with 20 352 695 person years of follow-up. Women with a history of pre-eclampsia had more than three times the risk of vascular dementia (hazard ratio 3.46, 95% confidence interval 1.97 to 6.10) later in life, compared with women with no history of pre-eclampsia. The association with vascular dementia seemed to be stronger for late onset disease (hazard ratio 6.53, 2.82 to 15.1) than for early onset disease (2.32, 1.06 to 5.06) (P=0.08). Adjustment for diabetes, hypertension, and cardiovascular disease attenuated the hazard ratios only moderately; sensitivity analyses suggested that body mass index was unlikely to explain the association with vascular dementia. In contrast, only modest associations were observed for Alzheimer’s disease (hazard ratio 1.45, 1.05 to 1.99) and other/unspecified dementia (1.40, 1.08 to 1.83).ConclusionsPre-eclampsia was associated with an increased risk of dementia, particularly vascular dementia. Cardiovascular disease, hypertension, and diabetes were unlikely to mediate the associations substantially, suggesting that pre-eclampsia and vascular dementia may share underlying mechanisms or susceptibility pathways. Asking about a history of pre-eclampsia could help physicians to identify women who might benefit from screening for early signs of disease, allowing for early clinical intervention.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. We conducted a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 was associated with gestational duration; the association was replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,536 mother-child pairs showed that the association was driven by fetal rather than maternal genotype. Functional experiments showed that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18–20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

Peter Bager,Giulia Corn,Jan Wohlfahrt,Heather A Boyd,Bjarke Feenstra,Mads Melbye Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Background: The tonsils are immunological gatekeepers against pathogens. Immunological response to tonsillitis may vary clinically from no enlargement of the tonsils to nearly obstructive conditions. In this investigation, we studied the familial aggregation of tonsillectomy, as an indicator of the extent to which tonsillar immune responses to infections might be genetically controlled. Methods: Data on kinship relations and vital status from the Danish Civil Registration System were used to establish a cohort of Danes with relatives born since 1977. Tonsillectomies in all hospitals and clinics from 1977 to 2013 were identified in national registers together with the indication for tonsillectomy. Rate ratios (RRs) for tonsillectomy >1 year after tonsillectomy in specific types of relatives (first to fourth degree) were estimated in Poisson regression models with adjustment for calendar period, sex, age, and total number of specified relatives. Results: A cohort of 2.4 million persons was followed for 44,100,697 million person-years (mean 18.4 years/person), and included 148,190 tonsillectomies. RRs of tonsillectomy were consistently higher when the relatedness and the number of tonsillectomized relatives were higher. RRs were similar in boys and girls, but were larger in early childhood. Additional analyses suggested that this relatively higher RR at younger ages was due to a larger influence of shared environment at younger ages, whereas the genetic influence was similar at all ages. Results were similar for tonsillectomies performed strictly due to tonsillitis. Conclusions: Genetic factors appear to predispose to severe tonsillitis underlying tonsillectomies, regardless of age and sex. Further studies are needed to understand how genes regulate the tonsils’ immune response against infections. Keywords: tonsillitis, epidemiology, hereditary, risk factors, infection

To determine whether Monterey Botryllus and Woods Hole Botryllus are the same species, comparisons were made of their morphology, biology, and colony specificity. In addition, matings were carried out to ascertain whether fertile [Monterey x Woods Hole] F1 progeny could be obtained. The morphology and biology of Botryllus colonies from Monterey and from Woods Hole are very similar, and fertile F1 progeny were obtained from interpopulation crosses. Therefore, we conclude that Monterey and Woods Hole Botryllus belong to the same species. However, slight differences were observed in the allorecognition reactions (colony specificity) of these two populations. Although there are some inconsistencies among the descriptions of Botryllus schlosseri and further extensive studies of Botryllus taxonomy are needed, our data indicate that Botryllus from Monterey and from Woods Hole may be designated contingently as B. schlosseri.

To our knowledge, there have been few population-based studies of strabismus incidence conducted. Our population-based study provides valuable data for health services planning and identifying research needs.To determine the incidence and age distribution of strabismus, overall and by subtype, among children 7 years or younger.This population-based cohort study was conducted with data from 96 842 children enrolled in the Danish National Birth Cohort.Age-specific incidence and cumulative incidence and median age at the detection of strabismus, overall and by subtype.The study cohort included 96 842 children born between 1996 and 2008 who are predominantly Caucasian and is composed of approximately 30% of births in Denmark, with a boy-girl ratio of 51:49. Overall, 1309 cases of strabismus were identified in the cohort. We found an overall cumulative strabismus incidence of 2.56% (95% CI, 2.42-2.69) at 7 years. The overall incidence was similar among boys and girls. Two hundred sixteen participants (16.5%) (95% CI, 14.5-18.6) had congenital esotropia, 177 (13.5%) (95% CI, 11.7-15.5) had fully accommodative esotropia, 252 (19.3%) (95% CI, 17.1-21.5) had partially accommodative esotropia, and 181 (13.8%) (95% CI, 12.0-15.8) had exotropia. The esotropia:exotropia ratio was 5.4:1 (95% CI, 3.4:1 to 7.5:1). Age-specific incidence curves for congenital esotropia, fully accommodative esotropia, partially accommodative esotropia, and all exotropia revealed interactions between strabismus subtype and age, suggesting that the different subtypes had different age-specific patterns of incidence (P .001 for all comparisons between pairs of curves). The median age at detection for the 4 subtypes was 0, 32.0, 26.1, and 16.6 months, respectively.In a national, population-based cohort study, we found a cumulative incidence of strabismus consistent with those reported in smaller European and American cohorts, but a somewhat higher esotropia:exotropia ratio than those that, to our knowledge, are typically reported by English and American studies. Patterns of incidence by age differed for different strabismus subtypes, indicating differences in age at onset and thereby implying differences in the underlying etiology.

Preeclampsia encompasses multiple conditions of varying severity. We examined the recurrence and familial aggregation of preeclampsia by timing of onset, which is a marker for severity. We ascertained personal and family histories of preeclampsia for women who delivered live singletons in Denmark in 1978-2008 (almost 1.4 million pregnancies). Using log-linear binomial regression, we estimated risk ratios for the associations between personal and family histories of preeclampsia and the risk of early-onset (before 34 weeks of gestation, which is typically the most severe), intermediate-onset (at 34-36 weeks of gestation), and late-onset (after 36 weeks of gestation) preeclampsia. Previous early-, intermediate-, or late-onset preeclampsia increased the risk of recurrent preeclampsia with the same timing of onset 25.2 times (95% confidence interval (CI): 21.8, 29.1), 19.7 times (95% CI: 17.0, 22.8), and 10.3 times (95% CI: 9.85, 10.9), respectively, compared with having no such history. Preeclampsia in a woman's family was associated with a 24%-163% increase in preeclampsia risk, with the strongest associations for early- and intermediate-onset preeclampsia in female relatives. Preeclampsia in the man's family did not affect a woman's risk of early-onset preeclampsia and was only weakly associated with her risks of intermediate- and late-onset preeclampsia. Early-onset preeclampsia appears to have the largest genetic component, whereas environmental factors likely contribute most to late-onset preeclampsia. The role of paternal genes in the etiology of preeclampsia appears to be limited.

Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions.

Retention rates of undergraduates at large urban universities serving minority populations have been problematic, especially among students in science and technology fields. John Jay College of Criminal Justice has designed a cohesive collegiate retention program according to the Tinto model of retention. This article details the strategies utilized as they relate to known factors affecting college persistence. Preliminary outcomes of this work are also explored in terms of student involvement and institutional support.

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.