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Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Summary: Background: Body composition between prepubertal children and adolescents varies, and it is unclear how physical activity and sedentary behaviour affect adolescent body composition. Objectives: This study aimed to examine the associations of physical activity and screen time with overall and specific fat depots in the general adolescent population. Methods: In a population‐based prospective cohort study, among 3258 adolescents aged 13 years, physical activity and screen time were assessed via self‐report questionnaires. Body mass index, dual‐energy X‐ray absorptiometry‐based measures (i.e. fat mass and lean body mass) and magnetic resonance imaging–based measures (i.e. abdominal subcutaneous and visceral fat mass) were obtained. Results: After adjusting for social‐demographic and growth‐related factors, each additional hour of daily physical activity was associated with lower fat mass, abdominal visceral fat mass and higher lean body mass (all p < 0.05). However, these associations were not observed in the longitudinal analyses. Each additional hour of daily screen time was associated with higher body mass index, fat mass, abdominal subcutaneous and visceral fat mass (all p < 0.05), which were consistent with the longitudinal analyses. Conclusion: Adolescents with higher physical activity and lower screen time had lower levels of adiposity both at the general and visceral levels. [ABSTRACT FROM AUTHOR]

Aims Statistical shape models (SSMs) of cardiac anatomy provide a new approach for analysis of cardiac anatomy. In adults, specific cardiac morphologies associate with cardiovascular risk factors and early disease stages. However, the relationships between morphology and risk factors in children remain unknown. We propose an SSM of the paediatric left ventricle to describe its morphological variability, examine its relationship with biometric parameters and identify adverse anatomical remodelling associated with obesity. Methods and results This cohort includes 2631 children (age 10.2 ± 0.6 years), mostly Western European (68.3%) with a balanced sex distribution (51.3% girls) from Generation R study. Cardiac magnetic resonance short-axis cine scans were segmented. Three-dimensional left ventricular (LV) meshes are automatically fitted to the segmentations to reconstruct the anatomies. We analyse the relationships between the LV anatomical features and participants' body surface area (BSA), age, and sex, and search for features uniquely related to obesity based on body mass index (BMI). In the SSM, 19 modes described over 90% of the population's LV shape variability. Main modes of variation were related to cardiac size, sphericity, and apical tilting. BSA, age, and sex were mostly correlated with modes describing LV size and sphericity. The modes correlated uniquely with BMI suggested that obese children present with septo-lateral tilting (R 2 = 4.0%), compression in the antero-posterior direction (R 2 = 3.3%), and decreased eccentricity (R 2 = 2.0%). Conclusions We describe the variability of the paediatric heart morphology and identify anatomical features related to childhood obesity that could aid in risk stratification. Web service is released to provide access to the new shape parameters. [ABSTRACT FROM AUTHOR]

BACKGROUND Exposure to parental tobacco smoking during fetal life and childhood is associated with adverse cardiovascular health outcomes. It is not known whether these adverse parental lifestyle exposures are also associated with changes in the structure and function of the carotid arteries in children aged 10 years. METHODS In a population-based prospective cohort study among 4,639 healthy children, we examined the associations of fetal exposure to maternal (no, first trimester only, continued), paternal (no, yes), and combined parental tobacco smoking (nonsmoking parents, mother only, father only, both parents smoked) with carotid intima-media thickness and distensibility at 10 years. We also assessed the associations of exposure to any parental tobacco smoking at ages 6 and 10 years with these outcomes. RESULTS Compared with no exposure, fetal exposure to continued maternal smoking was not associated with carotid intima-media thickness (−0.04 standard deviation score (SDS); 95% confidence interval (CI): −0.13, 0.05); and distensibility (0 SDS, 95% CI: −0.09, 0.09) at age 10 years. Fetal exposure to two smoking parents was also not associated with carotid intima-media thickness (−0.07 SDS, 95% CI: −0.16, 0.02) and distensibility (0 SDS, 95% CI: −0.09, 0.10) at this age. Exposure to any parental smoking during childhood also was not associated with these outcomes at age 10 years. CONCLUSIONS Exposure to parental tobacco smoking during fetal life and childhood was not associated with markers of arterial health in children aged 10 years. Prevention strategies aiming at minimizing smoke exposure later in life are still relevant regarding arterial health. [ABSTRACT FROM AUTHOR]

Summary: Background: Body mass index is associated with carotid intima‐media thickness and distensibility in adults and children. Objective: To examine whether general and specific fat depots are associated with these markers of arterial health at school age. Methods: This cross‐sectional analysis was embedded in a population‐based prospective cohort study among 4708 children aged 10 years. Body, lean and fat mass index were estimated by dual‐energy X‐ray absorptiometry. Pericardial, visceral and liver fat were estimated by magnetic resonance imaging. Carotid intima‐media thickness and distensibility were measured by ultrasound. Results: A 1‐standard‐deviation‐score (SDS) higher body mass index was associated with higher carotid intima‐media thickness (0.06 SDS, 95% confidence interval [CI]: 0.03–0.08) and lower distensibility (−0.17 SDS, 95% CI: −0.20 to −0.14). These associations tended to be similar for lean mass index. A 1‐SDS higher fat mass index was associated with lower carotid intima‐media thickness (−0.08 SDS, 95% CI: −0.11 to −0.05) and lower distensibility (−0.10 SDS, 95% CI: −0.14 to −0.07). A 1‐SDS higher liver fat fraction was associated with lower carotid intima‐media thickness (−0.04 SDS, 95% CI: −0.08 to −0.00) and lower distensibility (−0.06 SDS, 95% CI: −0.10 to −0.03). We observed similar associations for visceral fat. Conclusions: At school age, lean and fat mass seem to be differentially related to carotid intima‐media thickness but not distensibility. Arterial development might be affected by lean mass, general and specific fat mass. [ABSTRACT FROM AUTHOR]

Background: The relation of physical condition with respiratory outcomes in adolescents is unclear. We examined the hypothesis that adolescents with a lower physical condition represented by a lower cardiorespiratory fitness and physical activity, and a higher screen time have a lower lung function and higher risk of asthma. Methods: In a population‐based prospective cohort study on 4854 children aged 13 years, we assessed cardiorespiratory fitness by using the peak work rate measured by the steep ramp test. Information on physical activity and screen time was obtained by self‐reported questionnaires. Lung function was measured by spirometry and current asthma was assessed by a parental‐reported questionnaire. Results: Taking sociodemographic, lifestyle, and growth‐related confounders and multiple hypothesis testing into account, a 1 SD lower cardiorespiratory fitness was associated with a lower FEV1, FVC, and FEF75 (Z‐score difference (95% CI): −0.31 (−0.35, −0.28), −0.30 (−0.33, −0.26), −0.13 (−0.17, −0.10), respectively), and a higher risk of asthma (Odds Ratio (95% CI) 1.25 (1.06, 1.46)). A 1 SD higher screen time was associated with a lower FVC (Z‐score difference (95% CI): −0.06 (−0.10, −0.03)). Physical activity and screen time were not related to asthma. Results did not materially change after additional adjustment for respiratory outcomes at an earlier age. Conclusion: Adolescents with a lower cardiorespiratory fitness had a lower lung function and a higher risk of asthma. Those with a higher screen time had a lower FVC. Further studies are needed to explore the effect of improvements in physical condition on long‐term respiratory outcomes. [ABSTRACT FROM AUTHOR]

Children are generally considered main drivers of transmission for respiratory viruses, but the emergence of SARS-CoV-2 challenged this paradigm. Human rhinovirus (RV) continued to co-circulate throughout the pandemic, allowing for direct comparison of age-specific infectivity and susceptibility within households between these viruses during a time of low SARS-CoV-2 population immunity. Households with children were prospectively monitored for ≥23 weeks between August 2020 and July 2021. Upon onset of respiratory symptoms in a household, an outbreak study was initiated, including questionnaires and repeated nasal self-sampling in all household members. Swabs were tested by PCR. Age-stratified within-household secondary attack rates (SARs) were compared between SARS-CoV-2 and RV. A total of 307 households participated, including 582 children and 627 adults. Overall, SAR was lower for SARS-CoV-2 than for RV (aOR 0.55) and age distributions differed between both viruses (p < 0.001). Following household exposure, children were significantly less likely to become infected with SARS-CoV-2 compared to RV (aOR 0.16), whereas this was opposite in adults (aOR 1.71). In households, age-specific susceptibility to SARS-CoV-2 and RV differs and drives differences in household transmission between these pathogens. This highlights the importance of characterizing age-specific transmission risks, particularly for emerging infections, to guide appropriate infection control interventions. • SARS-CoV-2 emergence redefined the role of children in respiratory virus transmission • This study directly compares household transmission patterns of SARS-CoV-2 and RV • Children were less susceptible to SARS-CoV-2 than adults, but more susceptible to RV • This study stresses the need for age-specific interventions in novel respiratory outbreaks [ABSTRACT FROM AUTHOR]

Background: Cardio‐metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio‐metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI). Methods: In a population‐based cohort study among 4988 children, cardio‐metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C‐reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician‐diagnosed asthma was assessed by questionnaire. Results: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z‐score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z‐score difference (95% CI) −0.21 (−0.36, −0.06)). No consistent associations of other cardio‐metabolic risk factors with respiratory outcomes were observed. Conclusion: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long‐term effects of these associations require further investigation. [ABSTRACT FROM AUTHOR]

Studies involving large observational datasets commonly face the challenge of dealing with multiple missing values. The most popular approach to overcome this challenge, multiple imputation using chained equations, however, has been shown to be sub-optimal in complex settings, specifically in settings with longitudinal outcomes, which cannot be easily and adequately included in the imputation models. Bayesian methods avoid this difficulty by specification of a joint distribution and thus offer an alternative. A popular choice for that joint distribution is the multivariate normal distribution. In more complicated settings, as in our two motivating examples that involve time-varying covariates, additional issues require consideration: the endo- or exogeneity of the covariate and its functional relation with the outcome. In such situations, the implied assumptions of standard methods may be violated, resulting in bias. In this work, we extend and study a more flexible, Bayesian alternative to the multivariate normal approach, to better handle complex incomplete longitudinal data. We discuss and compare assumptions of the two Bayesian approaches about the endo- or exogeneity of the covariates and the functional form of the association with the outcome, and illustrate and evaluate consequences of violations of those assumptions using simulation studies and two real data examples. [ABSTRACT FROM AUTHOR]

Aims  We examined the associations of pericardial adipose tissue with cardiac structures and cardiovascular risk factors in children. Methods and results  We performed a cross-sectional analysis in a population-based cohort study among 2892 children aged 10 years (2404 normal weight and 488 overweight/obese). Pericardial adipose tissue mass was estimated by magnetic resonance imaging (MRI) and indexed on height 3. Left ventricular mass (LVM) and left ventricular mass-to-volume ratio (LMVR) were estimated by cardiac MRI. Cardiovascular risk factors included android adipose tissue percentage obtained by Dual-energy X-ray absorptiometry, blood pressure and glucose, insulin, cholesterol, and triglycerides concentrations. Adverse outcomes were defined as values above the 75 percentile. Median pericardial adipose tissue index was 3.6 (95% range 1.6–7.1) among normal weight and 4.7 (95% range 2.0–8.9) among overweight children. A one standard deviation (1 SD) higher pericardial adipose tissue index was associated with higher LMVR [0.06 standard deviation scores, 95% confidence interval (CI) 0.02–0.09], increased odds of high android adipose tissue [odd ratio (OR) 2.08, 95% CI 1.89–2.29], high insulin concentrations (OR 1.17, 95% CI 1.06–1.30), an atherogenic lipid profile (OR 1.22, 95% CI 1.11–1.33), and clustering of cardiovascular risk factors (OR 1.56, 95% CI 1.36–1.79). Pericardial adipose tissue index was not associated with LVM, blood pressure, and glucose concentrations. The associations showed largely the same directions but tended to be weaker among normal weight than among overweight children. Conclusion  Pericardial adipose tissue is associated with cardiac adaptations and cardiovascular risk factors already in childhood in both normal weight and overweight children. [ABSTRACT FROM AUTHOR]

Objective: Maternal obesity and metabolic health affect pregnancy outcomes. We examined whether maternal metabolic profiles are associated with placental and fetal hemodynamics.Study Design: In a population-based prospective cohort study among 1175 women we examined the associations of an adverse maternal metabolic profile in early pregnancy with placental, fetal cerebral and cardiac hemodynamic development. We obtained maternal pre-pregnancy BMI by questionnaire and measured blood pressure, cholesterol, triglycerides and glucose concentrations at a median gestational age of 12.6 (95 % range 9.6-17.1) weeks. An adverse maternal metabolic profile was defined as ≥4 risk factors. Placental and fetal hemodynamics were measured by pulsed-wave-Doppler at a median gestational age of 30.3 (95 % range 28.8-32.3) weeks.Results: An adverse maternal metabolic profile was associated with a 0.29 Z-score higher (95 %CI 0.08-0.50) fetal cerebral middle artery pulsatility index (PI), but not with placental or fetal cardiac hemodynamic patterns. When the individual components of an adverse maternal metabolic profile were assessed, we observed that higher maternal total cholesterol and triglyceride concentrations were associated with a higher cerebral middle artery PI (Z-score, 0.09 (95 %CI 0.02-0.15), 0.09 (95 %CI 0.03-0.15) per Z-score increase). Higher total and HDL maternal cholesterol concentrations were also associated with a higher aorta ascendens peak systolic velocity (PSV) Z-score, 0.08 (95 %CI 0.01-0.14)), and a larger left cardiac output (Z-score, 0.08 (95 %CI 0.00-0.15), respectively).Conclusion: An adverse maternal metabolic profile, especially higher cholesterol and triglycerides concentrations, are associated with increased fetal cerebral vascular resistance and larger fetal aorta ascendens diameter, PSV and left cardiac output, but not with placental vascular resistance indices. Further studies are needed to identify long-term consequences of the observed associations. [ABSTRACT FROM AUTHOR]

Background: Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health. Objective: To examine the association of early‐life airway bacterial carriage with respiratory tract infections and vice versa, and of early‐life airway bacterial carriage with wheezing, lung function, and asthma in later childhood. Methods: We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population‐based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross‐lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models. Results: Cross‐lagged modeling showed that early‐life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school‐age lung function or asthma. Conclusion: Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function. [ABSTRACT FROM AUTHOR]

Background: Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T‐helper‐1 and EBV infection a T‐helper‐2 cell response, possibly leading to disbalanced T‐helper cell response, and subsequent risk of asthma or atopy. Objective: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. Methods: This study among 3546 children was embedded in a population‐based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. Results: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z‐score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non‐significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. Conclusions and Clinical Relevance: Associations of EBV and CMV infections in early childhood with school‐age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle‐related factors. [ABSTRACT FROM AUTHOR]

Rationale: Obesity has been implicated as a pathogenic factor in asthma, but the underlying role of general and organ fat is unclear.Objectives: We hypothesized that organ fat, rather than the total fat mass, increases the risk of asthma.Methods: In a population-based prospective cohort study among 5,421 children aged 10 years, we measured general fat including body mass index and fat mass index by dual-energy X-ray absorptiometry, and organ fat including subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging. Lung function was measured by spirometry. Current asthma was assessed by questionnaire.Measurements and Main Results: Higher body mass index and fat mass index were associated with higher FEV1 (z-score difference [95% confidence interval (CI)], 0.16 [0.14 to 0.19] and z-score difference [95% CI], 0.06 [0.03 to 0.09] per SD score increase, respectively), higher FVC (z-score difference [95% CI], 0.19 [0.17 to 0.22] and z-score difference [95% CI], 0.07 [0.04 to 0.10]), and lower FEV1/FVC ratio (z-score difference [95% CI], -0.07 [-0.10 to -0.05] and z-score difference [95% CI], -0.03 [-0.06 to -0.00]) but not with forced expiratory flow after exhaling 75% of FVC or asthma. Higher visceral fat index, independent of fat mass index, was associated with higher FVC (z-score difference [95% CI], 0.07 [0.03 to 0.10]), lower FEV1/FVC (z-score difference [95% CI], -0.05 [-0.09 to -0.01]), and higher risk of asthma (odds ratio, 1.20; 95% CI, 1.01 to 1.43 per SD score increase). No other organ fat measures were independently associated with lung function or asthma.Conclusions: The obesity-asthma link is driven mainly by visceral fat, independent of total fat mass; therefore, abdominal fat might contribute to asthma development. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake Inhibitors (SSRIs) are frequently used during pregnancy. Evidence about the long-term consequences of prenatal SSRI exposure on child neurodevelopment is controversial. We prospectively investigated whether prenatal SSRI exposure was associated with childhood non-verbal cognition in a population-based study, and contrasted it to exposure to depressive symptoms (without SSRIs). We included 71 children prenatally exposed to SSRIs, 385 children prenatally exposed to maternal depressive symptoms and 5427 unexposed children. Child executive functioning was assessed by maternal report at 4 years ( n=4020). Non-verbal intelligence was measured at 5 years ( n=5001) and children were tested with a neuropsychological battery at 7 years ( n=1194). Prenatal SSRI exposure was not related to maternal reported executive function at 4 years, nor was it related with observed non-verbal intelligence at age 5 or neuropsychological function at 7 years. Exposure to untreated maternal depressive symptoms was related to maternal reported shifting problems and emotional control problems at 4 years. No associations between exposure to depressive symptoms and observed non-verbal IQ at 5 years or neuropsychological function at 7 years were found. This population-based study suggests that neither SSRI use nor untreated depressive symptoms during pregnancy had a major impact on child non-verbal cognition. [ABSTRACT FROM AUTHOR]

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that prenatal maternal folate deficiency is associated with reduced prenatal brain growth and psychological problems in offspring. However, little is known about the longer-term impact. The aims of this study were to investigate whether prenatal maternal folate insufficiency, high total homocysteine levels and low vitamin B12 levels are associated with altered brain morphology, cognitive and/or psychological problems in school-aged children. This study was embedded in Generation R, a prospective population-based cohort study. The study sample consisted of 256 Dutch children aged between 6 and 8 years from whom structural brain scans were collected using MRI. The mothers of sixty-two children had insufficient (<8 nmol/l) plasma folate concentrations in early pregnancy. Cognitive development was assessed by the Snijders-Oomen Niet-verbale intelligentietest – Revisie and the NEPSY-II-NL. Psychological problems were assessed at age 6 years using the parent report of the Child Behavior Checklist. Low prenatal folate levels were associated with a smaller total brain volume (B –33·34; 95 % CI –66·7, 0·02; P =050) and predicted poorer performance on the language (B –0·28; 95 % CI –0·52, –0·04; P =0·020) and visuo-spatial domains (B –0·27; 95 % CI –0·50, –0·04; P =0·021). High homocysteine levels (>9·1 µmol/l) predicted poorer performance on the language (B –0·31; 95 % CI –0·56, –0·06; P =0·014) and visuo-spatial domains (B –0·36; 95 % CI –0·60, –0·11; P =0·004). No associations with psychological problems were found. Our findings suggest that folate insufficiency in early pregnancy has a long-lasting, global effect on brain development and is, together with homocysteine levels, associated with poorer cognitive performance. [ABSTRACT FROM AUTHOR]

Purpose: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. Methods: 5931 children (50.1% girls) from a population‐based prospective birth cohort study underwent intra‐uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. Results: Weight and length from mid‐pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9–9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (β 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. Conclusions: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height. [ABSTRACT FROM AUTHOR]

Background: Fetal growth restriction is associated with higher risks of childhood respiratory morbidity. Fetal blood flow adaptations might contribute to these associations. We examined the associations of fetal umbilical, cerebral, and pulmonary blood flow with wheezing patterns, lung function, and asthma in childhood. Methods: In a population‐based prospective cohort study among 903 children, we measured fetal umbilical, cerebral, and pulmonary blood flow by pulsed‐wave Doppler at a median gestational age of 30.3 (95% range 28.8‐32.3) weeks. We obtained information about wheezing patterns until the age of 6 years by questionnaires. Lung function was measured by spirometry and information about current asthma was obtained by questionnaire at the age of 10 years. Results: Results showed a non‐significant relationship between a higher umbilical artery pulsatility index (PI) and umbilical artery PI/cerebral artery PI ratio, indicating fetal blood flow redistribution at the expense of the trunk, with higher risks of early wheezing (OR [95% CI]: 2.07 (0.70‐6.10) and 2.74 (0.60, 12.62) per unit increase, respectively). A higher pulmonary artery time velocity integral, indicating higher pulmonary vascular resistance, was associated with a higher risk of late/persistent wheezing (Z‐score 1.14 [1.01‐1.29]). A higher middle cerebral artery PI was associated with a higher FEV1/FVC (Z‐score [95% CI]: 0.21 [0.01‐0.42]). Results did not materially change after additional adjustment for birth and growth characteristics. Conclusion: Third‐trimester fetal blood flow patterns might be related to childhood respiratory health. These findings should be considered as hypothesis generating and need further replication. [ABSTRACT FROM AUTHOR]

Background: Dietary composition has been associated with sleep indexes. However, most of the evidence is based on cross-sectional data, and studies in young children are lacking.Objective: The aim of this study was to explore the longitudinal associations of macronutrient composition of the diet with sleep duration and consolidation (number of awakenings) in infancy and early childhood.Methods: The study was performed in 3465 children from the Generation R Study, a population-based cohort study in the Netherlands. Mothers reported their child's food intake at 13 mo of age by using a validated food-frequency questionnaire and their child's sleep patterns at 2 and 3 y of age. We used nutrient substitution models to assess the associations of relative macronutrient intakes with sleep indexes and adjusted the models for sociodemographic and lifestyle factors.Results: Isocaloric substitution of fat intake by protein or carbohydrate in infancy was associated with longer total sleep duration at 2 but not 3 y of age. For each 5% increase in energy intake of either protein or carbohydrate at the expense of fat, sleep duration at 2 y of age was longer by 6 min (95% CI: 0.4, 12 min) and 4 min (95% CI: 2, 6 min), respectively. Further exploration of macronutrient subtypes indicated no consistent differences between saturated or unsaturated fat and that intake of plant compared with animal protein or Trp did not explain the association of higher total protein intake with longer sleep duration at 2 y of age. Replacing unsaturated with saturated fat was associated with 7 min (95% CI: -13, -1 min) shorter total sleep duration at 3 y of age. Macronutrient intakes were not associated with sleep consolidation.Conclusions: Our results suggest that the macronutrient composition of the diet is associated with sleep duration in young children. Future research should further study the causality of this association and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Summary Background & aims Cardiometabolic risk has its origins in early life. However, it is unclear whether diet during early childhood is associated with cardiometabolic health, and what the role is of obesity. We aimed to study whether overall diet during early childhood is associated with cardiometabolic health and to examine if difference in body composition explain this association. Methods We examined associations of different types of dietary patterns in infancy with cardiometabolic health at school age among 2026 Dutch children participating in a population-based cohort in the Netherlands. Food intake at the age of 1 year was assessed with a food-frequency questionnaire. Three dietary pattern approaches were used: 1) An a priori- defined diet quality score; 2) dietary patterns based on variation in food intake, derived from principal component analysis (PCA); and 3) dietary patterns based on variations in fat and fat-free mass index, derived with reduced-rank regression (RRR). At the children's age of 6 years, we measured their body composition, systolic and diastolic blood pressure, and serum concentrations of insulin, triglycerides, and HDL-cholesterol, which we combined in a cardiometabolic risk-factor score. Results We observed that, after adjustment for confounders, children with higher adherence to a ‘Health-conscious’ PCA-derived pattern had a lower cardiometabolic risk-factor score (−0.07 SD (95%CI −0.12; −0.02) per SD). This association did not change after adjustment for fat and fat-free mass index. The RRR-derived dietary patterns based on variations in body composition were not associated with the cardiometabolic risk-factor score. Conclusions Our results suggest that diet in early childhood may affect cardiometabolic health independent of differences in body composition. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Recent literature suggested that higher vitamin D concentrations in childhood are associated with a lower prevalence of molar incisor hypomineralization (MIH). As tooth development already starts in utero, we aimed to study whether vitamin D status during foetal, postnatal and childhood periods is associated with the presence of hypomineralized second primary molars (HSPMs) and/or MIH at the age of six. Methods: Our study was embedded in the Generation R Study, a population‐based, prospective cohort from foetal life onwards in Rotterdam, the Netherlands. HSPMs and MIH were scored from intraoral photographs of the children at their age of six. Serum 25(OH)D concentrations were measured at three points in time, which resulted in three different samples; mid‐gestational in mothers’ blood (n = 4750), in umbilical cord blood (n = 3406) and in children's blood at the age of 6 years (n = 3983). Results: The children had a mean (±SD) age of 6.2 (±0.5) years at the moment of taking the intraoral photographs. After adjustment for confounders, no association was found between foetal 25(OH)D concentrations and the presence of HSPMs (OR 1.02 per 10 nmol/L higher 25(OH)D, 95% CI: 0.98‐1.07) or MIH (OR 1.05 per 10 nmol/L increase, 95% CI: 0.98‐1.12) in 6‐year‐olds. A higher 25(OH)D concentration in umbilical cord blood resulted in neither lower odds of having HSPM (OR 1.05, 95% CI: 0.98‐1.13) nor lower odds of having MIH (OR 0.95, 95% CI: 0.84‐1.07) by the age of six. Finally, we did not find higher 25(OH)D concentrations at the age of six to be associated with a significant change in the odds of having HSPM (OR 0.97, 95% CI: 0.92‐1.02) or MIH (OR 1.07, 95% CI: 0.98‐1.16). Conclusions: 25(OH)D concentrations in prenatal, early postnatal and later postnatal life are not associated with the presence of HPSMs or with MIH at the age of six. Future observational research is required to replicate our findings. Furthermore, it is encouraged to focus on identifying other modifiable risk factors, because prevention of hypomineralization is possible only if the causes are known. [ABSTRACT FROM AUTHOR]

Paediatric population neuroimaging is an emerging field that falls at the intersection between developmental neuroscience and epidemiology. A key feature of population neuroimaging studies involves large-scale recruitment that is representative of the general population. One successful approach for population neuroimaging is to embed neuroimaging studies within large epidemiological cohorts. The Generation R Study is a large, prospective population-based birth-cohort in which nearly 10,000 pregnant mothers were recruited between 2002 and 2006 with repeated measurements in the children and their parents over time. Magnetic resonance imaging was included in 2009 with the scanning of 1070 6-to-9-year-old children. The second neuroimaging wave was initiated in April 2013 with a total of 4245 visiting the MRI suite and 4087 9-to-11-year-old children being scanned. The sequences included high-resolution structural MRI, 35-direction diffusion weighted imaging, and a 6 min and 2 s resting-state functional MRI scan. The goal of this paper is to provide an overview of the imaging protocol and the overlap between the neuroimaging data and metadata. We conclude by providing a brief overview of results from our first wave of neuroimaging, which highlights a diverse array of questions that can be addressed by merging the fields of developmental neuroscience and epidemiology. [ABSTRACT FROM AUTHOR]

Summary Background & aims Maternal nutrition during pregnancy might be important in influencing offspring cardiometabolic health. However, research has focused mostly on specific nutrients or total energy, and possible effects of whole diet are unclear. We aimed to assess the associations between different dietary patterns during pregnancy and offspring cardiometabolic health among 2592 mother–child pairs from Generation R, a prospective population-based cohort study from fetal life onwards in Rotterdam, the Netherlands. Methods Maternal diet was assessed in early pregnancy with a food-frequency questionnaire. We identified three a posteriori- dietary patterns, namely a ‘Vegetable, fish and oil’, ‘Nuts, soy and high-fiber cereals’ and ‘Margarine, snacks and sugar’-pattern. An a priori- pattern was created based on the ‘Dutch Healthy Diet Index’. Cardiometabolic health (pulse wave velocity, blood pressure, insulin, HDL-cholesterol and triglycerides) was measured at the child's age of 6 years. Results In the crude models, the ‘Vegetable, fish and oil’, ‘Nuts, soy and high-fiber cereals’ and ‘Dutch Healthy Diet Index’ seemed beneficial, as higher adherence to these patterns was significantly associated with lower blood pressure and lower pulse wave velocity. After adjustment for other socio-demographic and lifestyle factors, most associations disappeared, except for lower pulse wave velocity with the ‘Vegetable, fish and oil’-dietary pattern (−0.19 SD (95% CI −0.33; −0.06), highest quartile of adherence vs. lowest quartile). No associations were found between maternal dietary patterns and offspring blood lipids or insulin levels. Conclusions Our results suggest that there are no consistent independent associations of maternal dietary patterns with offspring cardiometabolic health at 6 years. [ABSTRACT FROM AUTHOR]

Background: High intake of sugar-containing beverages (SCBs) has been linked to increased risk of obesity. However, associations of SCB intake during pregnancy with child body composition have been unclear. Objectives: We explored whether SCB intake during pregnancy was associated with children's body mass index (BMI) and detailed measures of body composition. In addition, we examined different types of SCBs (i.e., fruit juice, soda, and concentrate). Design: We included 3312 mother-child pairs of the Generation R Study, a prospective cohort from fetal life onward in the Netherlands. Energy-adjusted SCB intake was assessed in the first trimester with a food-frequency questionnaire. Anthropometric data of the children were collected repeatedly ≤6 y of age, and BMI was calculated. At 6 y of age, we further measured fat mass index (FMI) and fat-free mass index with dual-energy X-ray absorptiometry. All outcomes were sex- and age-standardized. Associations of SCB intake with children's BMI trajectories and body composition were analyzed with multivariable linear mixed and regression models. Results: Results from linear mixed models showed that, after adjustment for confounders including the SCB intake of the child itself, mothers' total SCB intake was positively associated with children's BMI ≤6 y of age [per serving per day: 0.04 SD score (SDS); 95% CI: 0.00, 0.07 SDS]. In addition, intakes of total SCBs and fruit juice, but not of soda or concentrate, were associated with a higher FMI [total SCBs: 0.05 SDS (95% CI: 0.01, 0.08 SDS); fruit juice: 0.04 SDS (95% CI: 0.01, 0.06 SDS)] of the 6-y-old children. These associations remained significant (P < 0.05) after additional adjustment for gestational weight gain, birth weight, and children's insulin concentrations. Conclusion: Our study suggests that maternal SCB intake during pregnancy is positively associated with children's BMI during early childhood and particularly with higher fat mass. [ABSTRACT FROM AUTHOR]

Background: Creatinine and cystatin C concentrations are commonly used to estimate glomerular filtration rate (eGFR) in clinical practice and epidemiological studies. To estimate the influence of different body composition measures on eGFR from creatinine and cystatin C blood concentrations, we compared the associations of different anthropometric and body composition measures with eGFR derived from creatinine (eGFRcreat) and cystatin C (eGFRcystC) blood concentrations.Methods: In a population-based cohort study among 4,305 children aged 6.0 years (95% range 5.7-8.0), we measured weight and height and calculated body mass index (BMI) and body surface area (BSA), and lean and fat mass using dual-energy X-ray absorptiometry. At the same age, we measured creatinine and cystatin C blood concentrations and estimated the GFR.Results: Correlation between eGFR based on creatinine and cystatin C concentrations was r = 0.40 (p value <0.01). Higher BMI was associated with lower eGFRcystC but not with eGFRcreat. Higher BSA was associated with higher eGFRcreat and lower eGFRcystC (p value <0.05). Lean and fat mass percentages were associated with eGFRcreat but not with eGFRcystC.Conclusion: Our findings suggest that both eGFRcreat and eGFRcystC are influenced by BMI and BSA. eGFRcreat is more strongly influenced by body composition than eGFRcystC. [ABSTRACT FROM AUTHOR]

Aim: Alcohol consumption during pregnancy is sometimes associated with adverse outcomes in offspring, potentially mediated by epigenetic modifications. We aimed to investigate genome-wide DNA methylation in cord blood of newborns exposed to alcohol in utero. Materials & methods: We meta-analyzed information from six population-based birth cohorts within the Pregnancy and Childhood Epigenetics consortium. Results: We found no strong evidence of association at either individual CpGs or across larger regions of the genome. Conclusion: Our findings suggest no association between maternal alcohol consumption and offspring cord blood DNA methylation. This is in stark contrast to the multiple strong associations previous studies have found for maternal smoking, which is similarly socially patterned. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure, exploration of a different tissue and a more global assessment of genomic DNA methylation might show evidence of association.

The aim of this study was to investigate potential differences in caries prevalence of children from ethnic minority groups compared to native Dutch children and the influence of socio-economic status (SES) and parent-reported oral health behaviour on this association. The study had a cross-sectional design, embedded in a population-based prospective multi-ethnic cohort study. 4,306 children with information on caries experience, belonging to 7 different ethnic groups, participated in this study. The decayed, missing, and filled teeth (dmft) index was assessed at the age of 6 and categorized in two ways for analysis: children without caries (dmft = 0) versus any caries experience (dmft >0) and children without caries (dmft = 0) versus children with mild caries (dmft = 1-3) or severe caries (dmft >3). Compared to native Dutch children, children with a Surinamese-Hindustani, Surinamese-Creole, Turkish, Moroccan, and Cape Verdean background had significantly higher odds for dental caries. Especially the Surinamese-Hindustani, Turkish, and Moroccan group had significantly higher odds for severe dental caries. Household income and educational level of the mother explained up to 43% of the association between ethnicity and dental caries, whereas parent-reported oral health behaviour did not mediate the association. Alarming disparities in caries prevalence between different ethnic (minority) groups exist, which cannot be fully explained by social inequalities. Public health strategies can apply this new knowledge and specifically focus on the reduction of ethnic disparities in oral health. More research is needed to explain the high caries prevalence among different ethnic minority groups. [ABSTRACT FROM AUTHOR]