The Prevalence and Spontaneous Closure of Ventricular Septal Defects the First Year of Life.

INTRODUCTION: Ventricular septal defect (VSD) is one of the most common congenital heart defects. We aimed to determine the prevalence of VSD in a population-based cohort of newborns and assess the rate of spontaneous closure during the first 12 months of life. METHODS: The Copenhagen Baby Heart Study (CBHS) is a population-based cohort study, including more than 25,000 newborns born in the greater Copenhagen area. Newborns underwent echocardiography within 60 days of birth. Newborns with VSDs had echocardiographic follow-up after 3, 6, and 12 months. RESULTS: A total of 850 newborns (3.3% of 25.556) with a VSD were identified in the CBHS. Of these, 787 (92.6% [95% CI 90.1-94.2]) were muscular VSDs, 60 (7.0% [95% CI, 5.5-9.0]) were perimembranous, and 3 (0.4% [95% CI, 0.0-1.1]) were subarterial. After 1 year, 83.5% (607 of 727) of all VSDs had closed spontaneously, resulting in a decrease of prevalence from 3.3% at birth to 0.5% in 1-year old children. Muscular VSDs showed significantly higher rate of spontaneous closure compared with perimembranous VSDs (86.9% (582/670) vs. 46.9% (25/54), p < 0.001). Determinants associated with spontaneous closure were smaller size of the VSD (p < 0.001) and the absence of multiple VSDs (p < 0.0025). CONCLUSION: The prevalence of VSDs in unselected newborns was 3.3%. Almost 9/10 of all VSDs identified in newborns, close spontaneously during the first year of life, ultimately resulting in a prevalence of VSD in 1-year-old children of 0.5%. The identified factors associated with spontaneous closure were muscular type, small size, and absence of multiple VSDs.

Factors associated with medico-legal autopsy of decedents with psychiatric disorders.

INTRODUCTION: Autopsy rates are declining worldwide, resulting in increasing selectivity in referral for forensic autopsy and increased uncertainty about the validity of assigned causes of death. Persons with psychiatric disorders have high rates of premature death but not all are referred for forensic autopsies. Knowledge is needed on which decedents with psychiatric disorders are chosen for forensic autopsy to determine whether causes of death are at risk of being misclassified among certain subgroups of decedents. METHODS: We conducted a nationwide register-based case-control study including all decedents with psychiatric disorders in Denmark in the period 1998-2015. Using multivariate logistic regression, we examined associations between demographic and socioeconomic factors, comorbidities, healthcare utilization, and referral for forensic autopsy, overall and stratified by age at death (<45, 45-64, ≥65 years). RESULTS: Of the 152,799 decedents in the study population, 7043 (4.61 %) had a forensic autopsy. Decedents referred for forensic autopsy were more likely to be young, have a history of substance use, and have schizophrenia or an affective disorder (factors listed in diminishing order of strength of association). Increasing severity of comorbidities as measured by the Charlson comorbidity index was associated with decreasing likelihood of being autopsied. Patterns of association with sex, alcohol use, habitation and education did not vary by age at death. Schizophrenia and drug use were most strongly associated with forensic autopsy in decedents < 45 years of age, whereas death early in the study period was more strongly associated with autopsy in the oldest age groups. DISCUSSION: The decision to refer a decedent for forensic autopsy was predominantly based on the decedent's age, history of drug use, and the absence of non-psychiatric comorbidities. Causes of death in decedents with comorbidities or recent contact with the healthcare system and decedents > 65 years may be more likely to be inaccurate, particularly in drug users.

Impact of maternal age and body mass index on the structure and function of the heart in newborns: a Copenhagen Baby Heart Study.

BACKGROUND: Maternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn. METHODS: Infants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2) < 18.5; 18.5-24.9 (reference); 25-29.9; 30-34.9 and ≥ 35 and maternal age (years) < 25; 25-29; 30-34 (reference); 35-39 and ≥ 40. Outcomes were LV parameters ascertained by 2D-echocardiography. Associations between each maternal factor and infant LV parameters were analysed with either a linear model adjusted for the child's weight and length at birth, gestational age, sex, age at TTE, and maternal smoking, or a linear mixed model, further adjusted for random effects of analyst and month of analysis. Analyses investigating impact of maternal BMI were adjusted for maternal age, and vice versa. RESULTS: The study cohort included 24,294 infants. Compared with infants in the BMI reference group, infants born to women with a BMI ≥ 25 kg/m2 generally had smaller measures of LV internal diameters in end-diastole, reaching statistical significance for BMI 30-34.9 kg/m2 [-0.11 ± 0.04 mm, p = 0.01]. All groups of infants born to women with a BMI ≥ 25 kg/m2 had significantly smaller LV internal diameters in end-systole: BMI 25-29.9 kg/m2 [-0.04 ± 0.02 mm, p = 0.04], BMI 30-34.9 kg/m2 [-0.12 ± 0.03 mm, p = 0.001] and BMI ≥ 35 kg/m2 [-0.11 ± 0.05 mm, p = 0.03]. Compared with infants in the age reference group, infants born to women ≥ 40 years had significantly smaller LV internal diameters in end-diastole [-0.15 ± 0.04 mm, p = 0.001] and end-systole [-0.09 ± 0.04 mm, p = 0.009]. CONCLUSIONS: Systematic population-based echocardiography of infants showed that a maternal prepregnancy BMI ≥ 25 kg/m2 and maternal age ≥ 40 years were associated with smaller systolic and diastolic LV diameters. The long-term effects are unknown. CLINICAL TRIAL REGISTRATION: April 2016, Copenhagen Baby Heart, NCT02753348 .

The influence of comorbid disease on premature death due to natural and unnatural causes in persons with schizophrenia.

BACKGROUND: Comorbid disease may increase mortality in persons with schizophrenia, but how specific diseases are associated with natural and unnatural death in different age groups is unclear. AIMS: To investigate the association between eight major comorbid diseases and death from natural and unnatural causes in different age groups in persons with schizophrenia. METHOD: Retrospective register-based cohort study in 77,794 persons with schizophrenia in Denmark, 1977-2015. Using Cox regression in matched cohorts, we estimated hazard ratios for natural and unnatural death in three age groups (<55 years, 55-64 years, ≥65 years). RESULTS: Hypertensive disease, atrial fibrillation, coronary heart disease, cerebrovascular disease, heart failure, type 2 diabetes, liver disease and chronic kidney disease were all strongly associated with natural death, with the strongest associations observed in persons <55 years (hazard ratio [HR] range 1.98-7.19). The strongest associations were observed for heart failure (HR 7.19, 95 % confidence interval [CI] 5.57-9.28; HR 4.56, CI 3.85-5.40; HR 2.83, CI 2.53-3.17), liver disease (HR 4.66, CI 3.59-6.05; HR 4.70, CI 3.55-6.22; HR 2.57, CI 1.98-3.34) and chronic kidney disease (HR 6.59, CI 1.66-26.1; HR 7.37, CI 3.03-17.9; HR 2.86, CI 1.84-4.46) for persons <55 years, 55-64 years and ≥65 years, respectively. Liver disease was strongly associated with unnatural death in persons <55 years (HR 5.42, CI 3.01-9.75); associations with the remaining comorbidities were weaker. CONCLUSIONS: Comorbid disease was strongly associated with natural death, with the strength of the associations decreasing with age. Comorbid disease was also modestly associated with unnatural death, regardless of age.

Cohort profile: The PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension (PEACH) Study.

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.

Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies.

BACKGROUND: Both pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy often exhibit angiogenic imbalances, suggesting that the same mechanisms are involved in the pathogenesis of the former and the pathophysiology of the latter. We conducted a register-based cohort study to determine whether offspring congenital heart defects are associated with an increased risk of hypertensive disorders of pregnancy and whether the mechanisms driving any association are primarily maternal or fetal. METHODS: Among singleton pregnancies without chromosomal abnormalities lasting ≥20 weeks in Denmark from 1978 to 2011 (n= 1 972 857), we identified pregnancies complicated by offspring congenital heart defects or early preterm preeclampsia, late preterm preeclampsia, term preeclampsia, and gestational hypertension. We used polytomous logistic regression to estimate odds ratios (ORs) for associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy overall and for specific heart defects. RESULTS: Offspring congenital heart defects were strongly associated with early preterm preeclampsia (OR, 7.00; 95% confidence interval [CI], 6.11-8.03) and late preterm preeclampsia (OR, 2.82; 95% CI, 2.38-3.34) in the same pregnancy and weakly associated with term preeclampsia (OR, 1.16; 95% CI, 1.06-1.27), but they were not associated with gestational hypertension (OR, 1.07; 95% CI, 0.92-1.25). Association strengths were consistent across heart defect types. Offspring congenital heart defects in a previous pregnancy were also strongly associated with preterm preeclampsia in subsequent pregnancies (early preterm preeclampsia: OR, 2.37; 95% CI, 1.68-3.34; late preterm preeclampsia: OR, 2.04; 95% CI, 1.52-2.75) but were only modestly associated with term preeclampsia and not associated with gestational hypertension. Similarly, preterm preeclampsia in a previous pregnancy, but not term preeclampsia or gestational hypertension, was associated with offspring congenital heart defects in later pregnancies (early preterm preeclampsia: OR, 7.91; 95% CI, 6.06-10.3; late preterm preeclampsia: OR, 2.83; 95% CI, 2.11-3.79; term preeclampsia: OR, 0.98; 95% CI, 0.88-1.10; gestational hypertension: OR, 1.13; 95% CI, 0.92-1.38). CONCLUSIONS: Linked pathophysiological mechanisms may be involved in some congenital heart defects and preterm preeclampsia. The strong associations across pregnancies support a predominantly maternal origin of effect.

Hypertensive disorders of pregnancy and subsequent risk of solid cancer--A nationwide cohort study.

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.

Association between pregnancy losses in women and risk of atherosclerotic disease in their relatives: a nationwide cohort study†.

AIMS: A common underlying mechanism with a genetic component could link pregnancy losses with vascular disease. We examined whether pregnancy losses (miscarriages and stillbirths) and atherosclerotic outcomes co-aggregated in families. METHODS AND RESULTS: Using Danish registers, we identified women with pregnancies in 1977-2008, and their parents (>1 million) and brothers (>435 000). We followed parents for incident ischaemic heart disease (IHD), myocardial infarction (MI), and cerebrovascular infarction (CVI), and brothers for a broader combined atherosclerotic endpoint. Using Cox regression, we estimated hazard ratios (HRs) for each outcome by history of pregnancy loss in daughters/sisters. Overall, parents whose daughters had 1, 2, and ≥3 miscarriages had 1.01 [95% confidence interval (CI) 0.99-1.04], 1.07 (95% CI 1.02-1.11), and 1.10 (95% CI 1.02-1.19) times the rate of MI, respectively, as parents whose daughters had no miscarriages. For parents with ≥3 daughters, the HRs were 1.12 (95% CI 1.02-1.24), 1.29 (95% CI 1.13-1.48), and 1.33 (95% CI 1.12-1.57). Effect magnitudes did not differ for fathers and mothers. We observed similar patterns for IHD and CVI (parents) and the atherosclerotic endpoint (brothers). Parents whose daughters had stillbirths had 1.14 (95% CI 1.05-1.24) and 1.07 (95% CI 0.96-1.18) times the rates of MI and CVI, respectively, as parents whose daughters had no stillbirths. CONCLUSION: Certain pregnancy losses and atherosclerotic diseases in both heart and brain may have a common aetiologic mechanism. Women in families with atherosclerotic disease may be predisposed to pregnancy loss; conversely, pregnancy losses in first-degree relatives may have implications for atherosclerotic disease risk.

[Genome-wide association studies]. / Associationsstudier af hele genomet.

Within the last year, genome-wide association (GWA) studies have identified a large number of robust associations between genetic variants and common diseases. Two key premises underlie this burst of discovery. First, the HapMap project has provided a catalogue of human genetic variation. Second, genotyping microarrays can now assess up to 1 million SNPs, allowing hypothesis-free screening of the entire genome. An important next step will be to elucidate the mechanisms behind genotype-phenotype associations. Ultimately, the goal is improved prevention, diagnosis and therapy.