Vascular health years after a hypertensive disorder of pregnancy: The EPOCH study.

BACKGROUND: Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum. METHODS: Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound. RESULTS: Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses, cases (N = 68) were more likely than controls (N = 71) to have hypertension (18% vs 4%, P = .034), higher calculated ASCVD risk (0.6 vs 0.4, P = .02), higher blood pressures (systolic: 118.5 vs 111.6 mm Hg, P = .0004; diastolic: 75.2 vs 69.8 mm Hg, P = .0004), and higher augmentation index values (7.7 vs 2.3, P = .03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs 0.5, P = .29) or reactive hyperemia index (2.1 vs 2.1, P = .93), nor in pulse wave amplitude (416 vs 326, P = .11), carotid elastic modulus (445 vs 426, P = .36), or carotid beta stiffness (2.8 vs 2.8, P = .86). CONCLUSION: Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

Reference ranges for third-trimester maternal cardiovascular function parameters measured in normotensive pregnant women using a non-invasive cardiac output monitor: A study based on data from the prospective PEACH cohort study.

OBJECTIVE: We defined reference ranges for maternal cardiac output, systemic vascular resistance, and stroke volume measured in the third trimester of pregnancy using the Ultrasound Cardiac Output Monitor 1A. DESIGN: Based on data from the prospective PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension) cohort study. SETTING: Rigshospitalet and Hvidovre Hospital, Denmark. SAMPLE: Normotensive pregnant women aged 18-45 years with singleton pregnancies, enrolled in the PEACH study in 2016-2018. METHODS: We modelled cardiac output, systemic vascular resistance and stroke volume as a function of gestational age using multilevel linear models with fractional polynomials. MAIN OUTCOME MEASURES: Unconditional and conditional reference ranges for cardiovascular parameters measured in gestational weeks 28-40. RESULTS: Our study cohort included 405 healthy pregnant women who contributed 1210 cardiovascular function measurements for analysis. Maximum cardiac output and stroke volume values were measured in gestational weeks 30-32 and decreased over the third trimester, whereas systemic vascular resistance increased during the same period. We created reference ranges for eight combinations of maternal height, age and parity. We also created a simple calculator to allow for implementation of the reference ranges in clinical practice. CONCLUSIONS: Our reference ranges allow the use of a bedside ultrasound device to non-invasively assess cardiac function in pregnancy and identify women at risk of complications. The unconditional ranges allow clinicians to evaluate isolated measurements and identify women needing follow-up. The conditional ranges incorporate information from previous measurements and improve monitoring over time.

Time trends in preeclampsia and gestational diabetes in Denmark and Alberta, Canada, 2005-2018-A population-based cohort study.

INTRODUCTION: Preeclampsia and gestational diabetes mellitus share risk factors such as obesity and increased maternal age, which have become more prevalent in recent decades. We examined changes in the prevalence of preeclampsia and gestational diabetes between 2005 and 2018 in Denmark and Alberta, Canada, and investigated whether the observed trends can be explained by changes in maternal age, parity, multiple pregnancy, comorbidity, and body mass index (BMI) over time. MATERIAL AND METHODS: This study was a register-based cohort study conducted using data from the Danish National Health Registers and the provincial health registers of Alberta, Canada. We included in the study cohort all pregnancies in 2005-2018 resulting in live-born infants and used binomial regression to estimate mean annual increases in the prevalence of preeclampsia and gestational diabetes in the two populations across the study period, adjusted for maternal characteristics. RESULTS: The study cohorts included 846 127 (Denmark) and 706 728 (Alberta) pregnancies. The prevalence of preeclampsia increased over the study period in Denmark (2.5% to 2.9%) and Alberta (1.7% to 2.5%), with mean annual increases of 0.03 (95% confidence interval [CI] 0.02-0.04) and 0.06 (95% CI 0.05-0.07) percentage points, respectively. The prevalence of gestational diabetes also increased in Denmark (1.9% to 4.6%) and Alberta (3.9% to 9.2%), with average annual increases of 0.20 (95% CI 0.19-0.21) and 0.44 (95% CI 0.42-0.45) percentage points. Changes in the distributions of maternal age and BMI contributed to increases in the prevalence of both conditions but could not explain them entirely. CONCLUSIONS: The prevalence of both preeclampsia and gestational diabetes increased significantly from 2005 to 2018, which portends future increases in chronic disease rates among affected women. Increasing demand for long-term follow up and care will amplify the existing pressure on healthcare systems.

Normative Echocardiographic Left Ventricular Parameters and Reference Intervals in Infants.

BACKGROUND: In pediatric echocardiography, reference intervals are required to distinguish normal variation from pathology. Left ventricular (LV) parameters are particularly important predictors of clinical outcome. However, data from healthy newborns are limited, and current reference intervals provide an inadequate approximation of normal reference ranges. OBJECTIVES: Normative reference intervals and z-scores for 2-dimensional echocardiographic measurements of LV structure and function based on a large group of healthy newborns were developed. METHODS: The study population included 13,454 healthy newborns from the Copenhagen Baby Heart Study who were born at term to healthy mothers, had an echocardiogram performed within 30 days of birth, and did not have congenital heart disease. To develop normative reference intervals, this study modeled 10 LV parameters as a function of body surface area through joint modeling of 4 statistical components. RESULTS: Infants in the study population (48.5% were female) had a median body surface area of 0.23 m2 (IQR: 0.22-0.25 m2) and median age of 12.0 days (IQR: 8.0-15.0 days) at examination. All normative reference intervals performed well in both sexes without stratification on infant sex. In contrast, creation of separate reference models for infants examined at <7 days of age and those examined at 7-30 days of age was necessary to optimize the performance of the reference intervals. CONCLUSIONS: This study provides normative reference intervals and z-scores for 10 clinical, widely used echocardiographic measures of LV structure and function based on a large cohort of newborns. These results provide highly needed reference material for clinical application by pediatric cardiologists.

Associations between parenthood and dementia in men and women: biology or confounding?

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.

Association between preeclampsia in daughters and risk of cardiovascular disease in parents.

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.

Risk and trajectory of premature ischaemic cardiovascular disease in women with a history of pre-eclampsia: a nationwide register-based study.

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.

Women with a history of pre-eclampsia constitute a high-risk subgroup of women who would benefit from additional clinical monitoring while still comparatively young. Up to twice as many women with a first pregnancy complicated by pre-eclampsia develop acute myocardial infarction or ischaemic stroke within 20 years of delivery compared with women without pre-eclampsia in their first pregnancy (2 vs. 1.2%).Relative risks of acute myocardial infarction and ischaemic stroke were greatest in women aged 30­39 years and within a decade of pre-eclampsia but remained substantial even <20 years later and in older women.

The Impact of Maternal Age on the Neonatal Electrocardiogram.

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.

Risk of Congenital Heart Defects in Offspring of Affected Mothers and Fathers.

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<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype. 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.

Maternal Hypertensive Disorders of Pregnancy and Cardiac Structure and Function in the Newborn.

Background: Maternal hypertensive disorders of pregnancy (HDPs) are strongly associated with offspring congenital heart defects. Objectives: This study assessed whether infants exposed to maternal HDPs were also more likely to have subtle cardiac structural and functional abnormalities than unexposed infants. Methods: We used regression analyses to compare: 1) left ventricular parameters from conventional echocardiography performed in infants from the Copenhagen Baby Heart Study born to mothers with preeclampsia, gestational hypertension (GH), or no HDP; and 2) advanced echocardiographic parameters for 545 term infants born to mothers with preeclampsia and 545 matched infants not exposed to HDPs. Results: Compared with infants unexposed to HDPs (n = 17,384), infants exposed to preeclampsia (n = 754) had a thicker interventricular septum in end-diastole (adjusted mean difference [± SD] 0.05 [±0.02] mm; P = 0.004), thicker left ventricular posterior wall (0.04 [±0.02] mm; P = 0.009), larger left ventricular internal diameter (0.12 [±0.06] mm; P = 0.04), and larger left ventricular volume (0.21 [±0.10] mL; P = 0.03). Systolic function changes included increased fractional shortening (0.36% [±0.14%]; P = 0.01) and stroke volume (0.18 [±0.07] mL; P = 0.006), whereas diastolic function changes included lower transmitral early peak inflow velocity (-1.76 [±0.49] mL; P = 0.0003), lower mitral annulus lateral wall a' (-0.21 [±0.09] cm/s; P = 0.02), and smaller lateral E/e' (-1.06 [±0.38] cm/s; P = 0.005). Conversely, there was little evidence of any association between maternal GH (n = 469) and offspring left ventricular parameters. Conclusions: Maternal preeclampsia, but not GH, was associated with subtle newborn cardiac morphological and functional alterations, including thickening of the left ventricular myocardium and altered systolic and diastolic function.

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Handedness has been extensively studied 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 the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

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.

Pregnancy loss and risk of later dementia: A nationwide cohort study, Denmark, 1977-2017.

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.

Pre-eclampsia and risk of later kidney disease: nationwide cohort study.

OBJECTIVE: To investigate associations between pre-eclampsia and later risk of kidney disease. DESIGN: Nationwide register based cohort study. SETTING: Denmark. POPULATION: All women with at least one pregnancy lasting at least 20 weeks between 1978 and 2015. MAIN OUTCOME MEASURE: Hazard 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. RESULTS: The 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 <34 weeks); 2.81 (2.13 to 3.71) for late preterm pre-eclampsia (delivery 34-36 weeks); 2.27 (2.02 to 2.55) for term pre-eclampsia (delivery ≥37 weeks). In particular, strong associations were observed for chronic kidney disease, hypertensive kidney disease, and glomerular/proteinuric disease. Adjustment for cardiovascular disease and hypertension only partially attenuated the observed associations. Stratifying the analyses on time since pregnancy showed that associations between pre-eclampsia and chronic kidney disease and glomerular/proteinuric disease were much stronger within five years of the latest pregnancy (hazard ratio 6.11 (3.84 to 9.72) and 4.77 (3.88 to 5.86), respectively) than five years or longer after the latest pregnancy (2.06 (1.69 to 2.50) and 1.50 (1.19 to 1.88). By contrast, associations between pre-eclampsia and acute renal conditions were modest. CONCLUSION: s 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.

Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM. METHODS: Using nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity. RESULTS: In a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0-37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18-16.9; gestational hypertension, RR 5.16, 95% CI 2.11-12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02). CONCLUSIONS: Although 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart's capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy.

Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis.

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.

Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion.

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.