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To examine feasibility and reproducibility and to evaluate the cardiovascular response to an isometric handgrip exercise in low-risk pediatric population using Cardiovascular Magnetic Resonance measurements. In a subgroup of 207 children with a mean age of 16 years participating in a population-based prospective cohort study, children performed an isometric handgrip exercise. During rest and exercise, continuous heart rate and blood pressure were measured. Cardiovascular magnetic resonance (CMR) measurements included left ventricular mass, aortic distensibility and pulse wave velocity at rest and left ventricular end-diastolic and end-systolic volumes, ejection fraction, stroke volume and cardiac output during rest and exercise. 207 children had successful CMR measurements in rest and 184 during exercise. We observed good reproducibility for all cardiac measurements. Heart rate increased with a mean ± standard deviation of 42.6% ± 20.0 and blood pressure with 6.4% ± 7.0, 5.4% ± 6.1 and 11.0% ± 8.3 for systolic, diastolic and mean arterial blood pressure respectively (p-values < 0.05). During exercise, left ventricular end-diastolic and end-systolic volumes and cardiac output increased, whereas left ventricular ejection fraction slightly decreased (p-values < 0.05). Stroke volume did not change significantly. A sustained handgrip exercise of 7 min at 30–40% maximal voluntary contraction is a feasible exercise-test during CMR in a healthy pediatric population, which leads to significant changes in heart rate, blood pressure and functional measurements of the left ventricle in response to exercise. This approach offers great novel opportunities to detect subtle differences in cardiovascular health. [ABSTRACT FROM AUTHOR]

Background: Fetal exposure to bisphenols is associated with altered fetal growth, adverse birth outcomes and childhood cardio-metabolic risk factors. Metabolomics may serve as a tool to identify the mechanisms underlying these associations. We examined the associations of maternal bisphenol urinary concentrations in pregnancy with neonatal metabolite profiles from cord blood. Methods: In a population-based prospective cohort study among 225 mother–child pairs, maternal urinary bisphenol A, S and F concentrations in first, second and third trimester were measured. LC–MS/MS was used to determine neonatal concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL), and carnitines in cord blood. Results: No associations of maternal total bisphenol concentrations with neonatal metabolite profiles were present. Higher maternal average BPA concentrations were associated with higher neonatal mono-unsaturated alkyl-lysophosphatidylcholine concentrations, whereas higher maternal average BPS was associated with lower neonatal overall and saturated alkyl-lysophosphatidylcholine (p-values < 0.05).Trimester-specific analyses showed that higher maternal BPA, BPS and BPF were associated with alterations in neonatal NEFA, diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholine, sphingomyelines and acyl-carnitines, with the strongest effects for third trimester maternal bisphenol and neonatal diacyl-phosphatidylcholine, sphingomyeline and acyl-carnitine metabolites (p-values < 0.05). Associations were not explained by maternal socio-demographic and lifestyle characteristics or birth characteristics. Discussion: Higher maternal bisphenol A, F and S concentrations in pregnancy are associated with alterations in neonatal metabolite profile, mainly in NEFA, PL and carnitines concentrations. These findings provide novel insight into potential mechanisms underlying associations of maternal bisphenol exposure during pregnancy with adverse offspring outcomes but need to be replicated among larger, diverse populations. [ABSTRACT FROM AUTHOR]

Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. We examined the ethnic differences in cardiac structure and function in children using cardiac magnetic resonance imaging in a European migrant population, and whether any difference was explained by early life factors. We used a prospective population-based cohort study among 2317 children in Rotterdam, the Netherlands. We compared children from Dutch (73%), Cape Verdean (3.5%), Dutch Antillean (3.3%), Moroccan (6.1%), Surinamese-Creoles (3.9%), Surinamese-Hindustani (3.4%), and Turkish (6.4%) background. Main outcomes were cMRI-measured cardiac structures and function. Cardiac outcomes were standardized on body surface area. Cape Verdean, Surinamese-Hindustani, and Turkish children had smaller right ventricular end-diastolic volume and left ventricular end-diastolic volume relative to their body size than Dutch children (p < 0.05). These results were not fully explained by fetal and childhood factors. Right ventricular ejection fraction and left ventricular ejection fraction did not differ between ethnicities after adjustment for fetal and childhood factors. Conclusion: Right ventricular end-diastolic volume and left ventricular end-diastolic volume differ between ethnic subgroups in childhood, without affecting ejection fraction. Follow-up studies are needed to investigate whether these differences lead to ethnic differences in cardiac disease in adulthood. What is Known: • Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. • The prevalence of cardiovascular disease differs between ethnic groups. What is New: • We examined ethnic differences in left and right cardiac structure and function in children using cMRI. • Right and left cardiac dimensions differ between ethnic groups in childhood and are only partly explained by fetal and childhood factors. [ABSTRACT FROM AUTHOR]

Brain morphology is altered in both anorexia nervosa and obesity. However, it is yet unclear if the relationship between Body Mass Index-Standard Deviation Score (BMI-SDS) and brain morphology exists across the BMI-SDS spectrum, or is present only in the extremes. The study involved 3160 9-to-11 year-old children (50.3% female) who participate in Generation R, a population-based study. Structural MRI scans were obtained from all children and FreeSurfer was used to quantify both global and surface-based measures of gyrification and cortical thickness. Body length and weight were measured to calculate BMI. Dutch growth curves were used to calculate BMI-SDS. BMI-SDS was analyzed continuously and in two categories (median split). The relationship between BMI-SDS (range − 3.82 to 3.31) and gyrification showed an inverted-U shape curve in children with both lower and higher BMI-SDS values having lower gyrification in widespread areas of the brain. BMI-SDS had a positive linear association with cortical thickness in multiple brain regions. This study provides evidence for an association between BMI-SDS and brain morphology in a large sample of children from the general population and suggests that a normal BMI during childhood is important for brain development. Future studies could determine whether lifestyle modifications optimize BMI-SDS result in return to more typical patterns of brain morphology. [ABSTRACT FROM AUTHOR]

Stress inducement by physical exercise requires major cardiovascular adaptations in both adults and children to maintain an adequate perfusion of the body. As physical exercise causes a stress situation for the cardiovascular system, cardiovascular exercise stress tests are widely used in clinical practice to reveal subtle cardiovascular pathology in adult and childhood populations with cardiac and cardiovascular diseases. Recently, evidence from small studies suggests that the cardiovascular stress response can also be used within research settings to provide novel insights on subtle differences in cardiovascular health in non-diseased adults and children, as even among healthy populations an abnormal response to physical exercise is associated with an increased risk of cardiovascular diseases. This narrative review is specifically focused on the possibilities of using the cardiovascular stress response to exercise combined with advanced imaging techniques in pediatric population-based studies focused on the early origins of cardiovascular diseases. We discuss the physiology of the cardiovascular stress response to exercise, the type of physical exercise used to induce the cardiovascular stress response in combination with advanced imaging techniques, the obtained measurements with advanced imaging techniques during the cardiovascular exercise stress test and their associations with cardiovascular health outcomes. Finally, we discuss the potential for cardiovascular exercise stress tests to use in pediatric population-based studies focused on the early origins of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life. [ABSTRACT FROM AUTHOR]

Introduction: Adverse exposures in early life may predispose children to cardio-metabolic disease in later life. Metabolomics may serve as a valuable tool to disentangle the metabolic adaptations and mechanisms that potentially underlie these associations. Objectives: To describe the acquisition, processing and structure of the metabolomics data available in a population-based prospective cohort from early pregnancy onwards and to examine the relationships between metabolite profiles of pregnant women and their children at birth and in childhood. Methods: In a subset of 994 mothers-child pairs from a prospective population-based cohort study among pregnant women and their children from Rotterdam, the Netherlands, we used LC–MS/MS to determine concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines in blood serum collected in early pregnancy, at birth (cord blood), and at child's age 10 years. Results: Concentrations of diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholines and sphingomyelines were the highest in early pregnancy, concentrations of amino acids and non-esterified fatty acids were the highest at birth and concentrations of alkyl-lysophosphatidylcholines, free carnitine and acyl-carnitines were the highest at age 10 years. Correlations of individual metabolites between pregnant women and their children at birth and at the age of 10 years were low (range between r = − 0.10 and r = 0.35). Conclusion: Our results suggest that unique metabolic profiles are present among pregnant women, newborns and school aged children, with limited intergenerational correlations between metabolite profiles. These data will form a valuable resource to address the early metabolic origins of cardio-metabolic disease. [ABSTRACT FROM AUTHOR]

Background: Psychological distress and inappropriate or excessive weight gain are common in pregnancy and are associated with adverse maternal and offspring outcomes. Psychological well-being and weight status of women during pregnancy might be interrelated. We aimed to examine whether psychological distress during pregnancy is associated with gestational weight gain. Method: In a population-based cohort of 3393 pregnant women, information about psychological distress, depressive and anxiety symptoms was assessed at 20 weeks of gestation using the Brief Symptom Inventory questionnaire. Weight was repeatedly measured during pregnancy and obtained by questionnaire before and after pregnancy. Linear regression and multinomial logistic regression models were used. Weight gain in the second half of pregnancy, total weight gain, and the risks of inadequate and excessive total weight gain were the main outcome measures. Results: In total, 7.0% of all women experienced psychological distress. Overall psychological distress and anxiety were associated with lower weight gain in the second half of pregnancy (differences − 1.00 kg (95% confidence interval (CI) − 1.62, − 0.37) and − 0.68 kg (95% CI - 1.24, -0.11), respectively). These associations fully attenuated into non-significance after taking account for socio-demographic variables. Similar results were observed for total weight gain. Only women with anxiety symptoms had, independently of potential confounders, a lower risk of excessive weight gain (odds ratio (OR) 0.61 (95% CI 0.48, 0.91)). Conclusions: In this large prospective cohort study, the observed associations of psychological distress with weight gain during pregnancy seem to be largely explained by common socio-demographic factors. [ABSTRACT FROM AUTHOR]

The gut microbiota has been shown to play diverse roles in human health and disease although the underlying mechanisms have not yet been fully elucidated. Large cohort studies can provide further understanding into inter-individual differences, with more precise characterization of the pathways by which the gut microbiota influences human physiology and disease processes. Here, we aimed to profile the stool microbiome of children and adults from two population-based cohort studies, comprising 2,111 children in the age-range of 9 to 12 years (the Generation R Study) and 1,427 adult individuals in the range of 46 to 88 years of age (the Rotterdam Study). For the two cohorts, 16S rRNA gene profile datasets derived from the Dutch population were generated. The comparison of the two cohorts showed that children had significantly lower gut microbiome diversity. Furthermore, we observed higher relative abundances of genus Bacteroides in children and higher relative abundances of genus Blautia in adults. Predicted functional metagenome analysis showed an overrepresentation of the glycan degradation pathways, riboflavin (vitamin B2), pyridoxine (vitamin B6) and folate (vitamin B9) biosynthesis pathways in children. In contrast, the gut microbiome of adults showed higher abundances of carbohydrate metabolism pathways, beta-lactam resistance, thiamine (vitamin B1) and pantothenic (vitamin B5) biosynthesis pathways. A predominance of catabolic pathways in children (valine, leucine and isoleucine degradation) as compared to biosynthetic pathways in adults (valine, leucine and isoleucine biosynthesis) suggests a functional microbiome switch to the latter in adult individuals. Overall, we identified compositional and functional differences in gut microbiome between children and adults in a population-based setting. These microbiome profiles can serve as reference for future studies on specific human disease susceptibility in childhood, adulthood and specific diseased populations. [ABSTRACT FROM AUTHOR]

Purpose: Oral health-related quality of life (OHRQoL) is the most important patient-reported outcome measure in oral health research. The purpose of the present research was to study the association of family socioeconomic position (SEP) with children's OHRQoL.Methods: This cross-sectional study was embedded in the Generation R Study, a population-based cohort study conducted in Rotterdam, The Netherlands. For the present study, OHRQoL was assessed of 3871 ten-year old children. Family SEP was assessed with the following indicators: maternal/paternal education level, maternal/paternal employment status, household income, benefit dependency, and family composition. Linear regression analyses were performed to evaluate the (independent) associations of family SEP indicators with OHRQoL.Results: The median (90% range) OHRQoL score of the participating children was relatively high [50.0 (43.0-53.0)]; however, OHRQoL was consistently lower in children with low family SEP. Positive associations were found for all SEP indicators (p-values <0.05) except maternal employment status and family composition. Benefit dependency, paternal employment, and household income were the most strongly associated with OHRQoL. No family SEP indicator was significantly associated with OHRQoL independent of the other indicators.Conclusions: Based on the present findings, interventions and policies promoting good oral health and oral well-being should target children from low socioeconomic position. More research is needed, however, to understand the pathways of social inequalities in children's OHRQoL especially for the effects of material resources on subjective oral health measures. [ABSTRACT FROM AUTHOR]

Developmental patterns of anxiety and depression symptoms in early childhood have previously been related to anxiety and mood disorders in middle childhood. In the current study, trajectories of anxiety and depression symptoms (1.5-10 years) were related to children's broader psychosocial and school-related functioning at 10 years. We included a population-based sample of 7499 children, for whom primary caregivers reported anxiety and depression symptoms on the Child Behavior Checklist, at children's ages of 1.5, 3, 6, and 10. Growth Mixture Modeling identified four distinct, gender-invariant, trajectories of anxiety and depression symptoms: low (82.4%), increasing (7.4%), decreasing (6.0%), and increasing symptoms up to age 6 followed by a decrease to age 10 (preschool-limited, 4.2%). Children with a non-Dutch ethnicity had lower odds to be in the increasing trajectory and higher odds to be in the decreasing and pre-school limited trajectory. Also, low maternal education predicted the decreasing and pre-school limited trajectory. Higher levels of psychopathology during pregnancy for both mothers and fathers predicted the increasing, decreasing, and preschool-limited trajectory, compared to the low trajectory. At age 10, children in the increasing and preschool-limited trajectory had diminished psychosocial outcomes (friendship-quality and self-esteem) and worse school-related outcomes (school performance and school problems). This study adds to current knowledge by demonstrating that developmental patterns of anxiety and depression symptoms in early childhood are related to broader negative outcomes in middle childhood. Child and family factors could guide monitoring of anxiety and depression symptoms in the general population and provide targets for prevention programs. [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]

Aims/hypothesis: The study aimed to assess the associations of maternal early-pregnancy blood glucose levels with fetal growth throughout pregnancy and the risks of adverse birth outcomes. Methods: In a population-based prospective cohort study among 6116 pregnant women, maternal non-fasting glucose levels were measured in blood plasma at a median 13.2 weeks of gestation (95% range 9.6–17.6). We measured fetal growth by ultrasound in each pregnancy period. We obtained information about birth outcomes from medical records and maternal sociodemographic and lifestyle factors from questionnaires. Results: Higher maternal early-pregnancy non-fasting glucose levels were associated with altered fetal growth patterns, characterised by decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, resulting in an increased length and weight at birth (p ≤0.05 for all). A weaker association of maternal early-pregnancy non-fasting glucose levels with fetal head circumference growth rates was present. Higher maternal early-pregnancy non-fasting glucose levels were also associated with an increased risk of delivering a large-for-gestational-age infant, but decreased risk of delivering a small-for-gestational-age infant (OR 1.28 [95% CI 1.16, 1.41], OR 0.88 [95% CI 0.79, 0.98] per mmol/l increase in maternal early-pregnancy non-fasting glucose levels, respectively). These associations were not explained by maternal sociodemographic factors, lifestyle factors or BMI. Maternal early-pregnancy non-fasting glucose levels were not associated with preterm birth or delivery complications. Conclusions/interpretation: Higher maternal early-pregnancy non-fasting glucose levels are associated with decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, and an increased risk of delivering a large-for-gestational-age infant. Future preventive strategies need to focus on screening for an impaired maternal glucose metabolism from preconception and early pregnancy onwards to improve birth outcomes. [ABSTRACT FROM AUTHOR]

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization and physician-diagnosed allergy in Dutch children at age 10 years. This study among 5471 children was performed in a population-based prospective cohort from fetal life onwards. Allergic sensitization was measured by skin prick tests. Physician-diagnosed allergy and parental and child characteristics were collected by questionnaires. In children aged 10 years, inhalant and food allergic sensitization was present in 32.2% and 7.1%, and physician-diagnosed inhalant and food allergy in 12.4% and 2.3%. Maternal and paternal history of allergy, eczema or asthma was associated with increased risks of physician-diagnosed inhalant allergy (aOR (95% CI) 1.44 (1.23-1.70) and 1.59 (1.30-1.94), respectively), but not with food allergy. Asthma and eczema ever at age 10 years were associated with increased risks of physician-diagnosed inhalant allergy (4.60 (3.55-5.96) and 2.42 (1.94-3.03), respectively). Eczema ever at age 10 years was associated with an increased risk of physician-diagnosed food allergy (5.78, 3.04-9.52), with the highest risk of cashew (7.36, 3.20-16.94) and peanut (5.58, 3.08-10.10) food allergy.Conclusions: We found strong effects of parental history of allergy, eczema or asthma on the presence of physician-diagnosed inhalant allergy in children at age 10 years. Eczema ever at age 10 years was a strong risk factor for the development of physician-diagnosed inhalant and food allergy. What is Known: • The prevalence of allergic diseases in children has markedly increased. • Early-life influences are critically important in the development of allergic diseases. What is New: • Maternal and paternal history of allergy, eczema or asthma is associated with increased risks of physician-diagnosed inhalant allergy but not with food allergy. • Eczema ever at age 10 years is associated with an increased risk of physician-diagnosed food allergy, with the highest risk for cashew and peanut food allergy. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate diet quality of 8-year-old children in the Netherlands, to identify sociodemographic and lifestyle correlates of child diet quality, and to examine tracking of diet quality from early to mid-childhood. Methods: For 4733 children participating in a population-based cohort, we assessed dietary intake using a validated food-frequency questionnaire at a median age of 8.1 years (interquartile range 8.0–8.2) (2011–2014). Based on dietary guidelines, we developed and validated a food-based diet quality score for children consisting of ten components (score 0–10): sufficient intake of vegetables; fruit; whole grains; fish; legumes; nuts; dairy; oils and soft fats; and low intake of sugar-containing-beverages; and high-fat and processed meat. Results: We observed a mean (± SD) diet quality score of 4.5 (± 1.2) out of a maximum of 10. On average, intake of legumes, nuts, and oils or soft fats was below recommendations, whereas intake of sugar-containing beverages and high-fat or processed meat was higher than recommended. The main factors associated with higher diet quality were higher maternal educational level (β = 0.29, 95% CI 0.21, 0.37 versus low education), higher household income (β = 0.15, 95% CI 0.05, 0.25 versus low income), no maternal smoking (β = 0.13, 95% CI 0.02, 0.25 versus current smoking), and less screen time (β = 0.31, 95% CI 0.24, 0.38)—all independent of each other. For children with available dietary data at age 1 year (n = 2608), we observed only weak tracking of diet quality from early to mid-childhood (Pearson's r = 0.19, k = 0.11 for extreme quartiles). Conclusion: Overall diet quality of 8-year-old children did not conform to dietary guidelines, especially for children having more screen time, children of lower educated or smoking mothers, or from lower-income households. [ABSTRACT FROM AUTHOR]

This study examined the stability of internalizing and externalizing problems from age 1.5 to 6 years, while taking into account developmental changes in the presentation of problems. The study comprised a population-based cohort of 7,206 children (50.4 % boys). At ages 1.5, 3, and 6 years, mothers reported on problem behavior using the Child Behavior Checklist/1.5-5 (CBCL/1.5-5). At each age we performed latent profile analysis on the CBCL/1.5-5 scales. Latent transition analysis (LTA) was applied to study the stability of problem behavior. Profiles of problem behavior varied across ages. At each age, 82-87 % of the children did not have problems whereas approximately 2 % showed a profile of co-occurring internalizing and externalizing problems. This profile was more severe (with higher scores) at 6 years than at earlier ages. A predominantly internalizing profile only emerged at 6 years, while a profile with externalizing problems and emotional reactivity was present at each age. LTA showed that, based on profiles at 1.5 and 3 years, it was difficult to predict the type of profile at 6 years. Children with a profile of co-occurring internalizing and externalizing problems early in life were most likely to show problem behavior at 6 years. This study shows that the presentation of problem behavior changes across the preschool period and that heterotypic continuity of problems is very common among preschoolers. Children with co-occurring internalizing and externalizing problems were most likely to show persisting problems. The use of evidence-based treatment for these young children may prevent psychiatric problems across the life course. [ABSTRACT FROM AUTHOR]

This study examined multiple determinants of discrepancies between mother and child reports of problem behavior. In 5,414 6-year-olds, child problem behavior was assessed by self-report using the Berkeley Puppet Interview and by maternal report using the Child Behavior Checklist. Patterns in mother-child reports were modeled using latent profile analysis. Four profiles, differing in problem level, and the direction and magnitude of mother-child discrepancies, were identified: one profile representing agreement (46%), another representing slight discrepancies (30%), and two representing higher problem levels and more discrepancies. In the latter two profiles either children (11%) or mothers (13%) reported more problems. Compared to the first profile, the second was predominantly characterized by a positive family environment, the third by child cognitive difficulties, and the fourth by harsh discipline and poor family functioning. Knowledge about specific child/family characteristics that contribute to mother-child discrepancies can help to interpret informants' reports and to make diagnostic decisions. [ABSTRACT FROM AUTHOR]

Family adversity has been associated with children's bullying behaviors. The evidence is, however, dominated by mothers' perceptions of the family environment and a focus on mothers' behaviors. This prospective population-based study examined whether children's bullying behaviors were associated with mother- and father-reported family adversity, assessed before and after child birth. Peer-nominations were used to assess bullying behaviors of 1298 children in elementary school (mean age 7.5 years). The following paternal risk factors were prospectively associated with children's bullying behaviors: (1) father-reported prenatal family distress, (2) fathers' hostility at preschool age, and (3) fathers' harsh disciplinary practices at preschool age, but effect sizes were relatively small. The effect of maternal risk factors was less consistent, only mother-reported family distress in childhood was associated with children's bullying behaviors. The associations were independent of background family risk factors (i.e., life stress, contextual factors, and other background factors such as parental education and risk taking record) and early childhood externalizing problems. Moreover, our results indicated that father-reported family adversity predicted children's bullying behaviors over and above the background family risk factors, early childhood externalizing problems and mother-reported family adversity. We also demonstrated that the association of fathers' prenatal hostility and family distress with subsequent bullying behavior of their child at school was partly mediated by fathers' harsh disciplinary practices at preschool age. Our findings highlight the importance of fathers' behaviors in the development of children's bullying behaviors. [ABSTRACT FROM AUTHOR]

To examine associations between hypertensive pregnancy disorders and maternal cardiovascular disease (CVD) in later life. We examined the associations between blood pressure (BP) in pregnancy, gestational hypertension (GH) and preeclampsia (PE) with cardiovascular measurements 6 years after index pregnancy among 4912 women participating in the Generation R Study, the Netherlands. BP, left ventricular mass (LV mass), aortic root diameter (AOD), left atrial diameter, fractional shortening, and carotid-femoral pulse wave velocity (PWV). Early pregnancy systolic and diastolic BP were associated with more adverse maternal cardiovascular measurements and a higher incidence of chronic hypertension 6 years after pregnancy. GH was associated with a higher BP, a higher PWV, a larger AOD and an increased LV mass 6 years after index pregnancy. Compared to previous normotensive pregnancies these women had a sixfold increased risk to develop chronic hypertension after pregnancy (OR 6.6, 95% CI 4.6-9.5). Compared to women with a normotensive pregnancy, women with PE had a higher BP and a higher risk of chronic hypertension (OR 4.5, 95% CI 2.6-7.8) at follow-up. After adjustment for BMI at follow-up in all the analyses on GH, PE and cardiovascular measurements, effect estimates attenuated up to 65%, but remained significant. Both GH and PE are associated with markers of adverse maternal cardiovascular health after pregnancy with an increased risk of chronic hypertension. Women with GH and PE may be offered long-term cardiovascular follow-up incorporated in CVD risk management guidelines. [ABSTRACT FROM AUTHOR]

Background: The objective of our study was to assess whether TG2A levels in the healthy childhood population can be predictive of subclinical CD.Methods: A total of 4442 children (median age, 6.0 years) participating in a population-based prospective cohort study were screened on serum TG2A. Those with positive TG2A (≥7 U/ml; n = 60, 1.4%) were invited for clinical evaluation (median age, 9.0 years). Medical history, physical examination, serum TG2A, and IgA-endomysium (EMA) were assessed, as well as HLA DQ 2.2/2.5/8 typing. Patients with positive serologies and genetic risk types underwent duodenal biopsies. TG2A levels at the time of biopsy were compared with the degree of enteropathy.Results: Fifty-one TG2A-positive children were included in the follow-up: 31 (60.8%) children had CD, ten (19.6%) did not have CD, and ten (19.6%) were considered potential CD cases because of inconclusive serologies. Duodenal biopsies were performed in 26/31 children. CD with Marsh 3a/b enteropathy was observed in 75% (15/20) of children having TG2A levels ≥10ULN at 6 years of age, as well as in 75% (6/8) of children having a positive TG2A <10 ULN (OR 1.00; 95% CI 0.15-6.64). CD cases had a lower BMI SDS (mean -0.49, SD 0.92) than children without CD (mean 0.47, SD 1.37; p = 0.02). No differences were observed in gastrointestinal symptoms.Conclusions: Serum TG2A screening at 6 years of age in the healthy childhood population has a positive predictive value of 61% to detect subclinical CD. We did not find a positive correlation between serum TG2A levels and the degree of enteropathy. [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]

Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child’s brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6–9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology. [ABSTRACT FROM AUTHOR]

Women who drink light-to-moderately during pregnancy have been observed to have lower risk of unfavourable pregnancy outcomes than abstainers. This has been suggested to be a result of bias. In a pooled sample, including 193 747 live-born singletons from nine European cohorts, we examined the associations between light-to-moderate drinking and preterm birth, birth weight, and small-for-gestational age in term born children (term SGA). To address potential sources of bias, we compared the associations from the total sample with a sub-sample restricted to first-time pregnant women who conceived within six months of trying, and examined whether the associations varied across calendar time. In the total sample, drinking up to around six drinks per week as compared to abstaining was associated with lower risk of preterm birth, whereas no significant associations were found for birth weight or term SGA. Drinking six or more drinks per week was associated with lower birth weight and higher risk of term SGA, but no increased risk of preterm birth. The analyses restricted to women without reproductive experience revealed similar results. Before 2000 approximately half of pregnant women drank alcohol. This decreased to 39% in 2000-2004, and 14% in 2005-2011. Before 2000, every additional drink was associated with reduced mean birth weight, whereas in 2005-2011, the mean birth weight increased with increasing intake. The period-specific associations between low-to-moderate drinking and birth weight, which also were observed for term SGA, are indicative of bias. It is impossible to distinguish if the bias is attributable to unmeasured confounding, which change over time or cohort heterogeneity. [ABSTRACT FROM AUTHOR]

Purpose: Intra-uterine exposure to protein may affect body composition and may increase the prevalence of childhood adiposity. Therefore, we examined whether protein intake during pregnancy is associated with offspring body composition at the age of 6 years and whether associations differ for animal protein and vegetable protein. Methods: We included 2694 Dutch mother-child pairs participating in a prospective population-based cohort in Rotterdam, the Netherlands. Energy-adjusted protein was measured in pregnancy using a food-frequency questionnaire and analyzed in quartiles. At a mean age of 6.1 ± 0.4 years, we measured children's body mass index, and fat-free mass index and fat mass index using dual-energy X-ray absorptiometry. Outcomes were standardized for age and sex. BMI was used to classify children's overweight status. Results: After adjustment for sociodemographic and lifestyle factors, a higher maternal protein intake was associated with a higher children's fat-free mass index [difference 0.14 standard deviation (95 % CI 0.03, 0.25) for highest vs. lowest quartile of protein intake], but not with children's fat mass index or body mass index. Comparable associations were found for animal protein and vegetable protein. Maternal protein intake was not associated with children's overweight. Conclusions and relevance: This study suggests that higher protein intake during pregnancy is associated with a higher fat-free mass in children at the age of 6 years, but not with their fat mass. Our results do not suggest specific recommendations regarding maternal protein intake during pregnancy to prevent overweight in the offspring. [ABSTRACT FROM AUTHOR]

Background: Impaired fetal growth is associated with increased risks of kidney diseases in later life. Because human development rates are highest during the first trimester, this trimester may be a particularly critical period for kidney outcomes. We have therefore examined the association of fetal first trimester growth with kidney outcomes in childhood. Methods: This study was embedded in a prospective population-based cohort study among 1176 pregnant women and their children. We used fetal first trimester crown-length as the growth measure among mothers with a regular menstrual cycle and a known first day of the last menstrual period. At the childhood age of 6 (median 5.7-6.8) years, we measured combined kidney volume, microalbuminuria and estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C concentrations. Results: No consistent associations of fetal first trimester crown-rump length with childhood combined kidney volume, eGFR and microalbuminuria were observed. Compared to children with a fetal first trimester crown-rump length in the highest quintile, those in the lowest quintile had a larger childhood combined kidney volume (difference 5.32 cm, 95 % confidence interval 1.06 to 9.57), but no differences in kidney function. Conclusion: Our results do not support the hypothesis that fetal first trimester growth restriction affects kidney size and function in childhood. Further studies are needed to focus on critical periods in early life for kidney function and disease in later life. [ABSTRACT FROM AUTHOR]

Psychiatric symptoms in childhood are closely related to neurocognitive deficits. However, it is unclear whether internalising and externalising symptoms are associated with general or distinct cognitive problems. We examined the relation between different types of psychiatric symptoms and neurocognitive functioning in a population-based sample of 1177 school-aged children. Internalising and externalising behaviour was studied both continuously and categorically. For continuous, variable-centred analyses, broadband scores of internalising and externalising symptoms were used. However, these measures are strongly correlated, which may prevent identification of distinct cognitive patterns. To distinguish groups of children with relatively homogeneous symptom patterns, a latent profile analysis of symptoms at age 6 yielded four exclusive groups of children: a class of children with predominantly internalising symptoms, a class with externalising symptoms, a class with co-occurring internalising and externalising symptoms, that resembles the CBCL dysregulation profile and a class with no problems. Five domains of neurocognitive ability were tested: attention/executive functioning, language, memory and learning, sensorimotor functioning, and visuospatial processing. Consistently, these two different modelling approaches demonstrated that children with internalising and externalising symptoms show distinct cognitive profiles. Children with more externalising symptoms performed lower in the attention/executive functioning domain, while children with more internalising symptoms showed impairment in verbal fluency and memory. In the most severely affected class of children with internalising and externalising symptoms, we found specific impairment in the sensorimotor domain. This study illustrates the specific interrelation of internalising and externalising symptoms and cognition in young children. [ABSTRACT FROM AUTHOR]

Human chorionic gonadotropin (hCG) is a pregnancy-specific hormone that regulates placental development. hCG concentrations vary widely throughout gestation and differ based on fetal sex. Abnormal hCG concentrations are associated with adverse pregnancy outcomes including fetal growth restriction. We studied the association of hCG concentrations with fetal growth and birth weight. In addition, we investigated effect modification by gestational age of hCG measurement and fetal sex. Total serum hCG (median 14.4 weeks, 95 % range 10.1-26.2), estimated fetal weight (measured by ultrasound during 18-25th weeks and >25th weeks) and birth weight were measured in 7987 mother-child pairs from the Generation R cohort and used to establish fetal growth. Small for gestational age (SGA) was defined as a standardized birth weight lower than the 10th percentile of the study population. There was a non-linear association of hCG with birth weight ( P = 0.009). However, only low hCG concentrations measured during the late first trimester (11th and 12th week) were associated with birth weight and SGA. Low hCG concentrations measured in the late first trimester were also associated with decreased fetal growth ( P = 0.0002). This was the case for both male and female fetuses. In contrast, high hCG concentrations during the late first trimester were associated with increased fetal growth amongst female, but not male fetuses. Low hCG in the late first trimester is associated with lower birth weight due to a decrease in fetal growth. Fetal sex differences exist in the association of hCG concentrations with fetal growth. [ABSTRACT FROM AUTHOR]

Purpose: Folic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring. Methods: Within a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5-17.2) and assessed folic acid supplementation by questionnaire (2001-2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002-2012). Results: In unadjusted models, foetal head growth was 0.006 SD (95 % CI 0.003; 0.009, P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; estimated absolute difference at birth of 2.7 mm). The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth. Conclusions: Our results suggest an independent, modest association between maternal folate concentrations in early pregnancy and foetal head growth. More research is needed to identify whether specific brain regions are affected and whether effects of folate on foetal head growth influence children's long-term functioning. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that children's participation in early childhood education and care (ECEC), especially center-based services, is associated with positive outcomes, particularly for children over one year of age and children of low socioeconomic backgrounds. This signals an important opportunity for reducing socioeconomic disparities in young children's development. Many western countries have adopted policies to encourage maternal employment, facilitate ECEC service use, or both, often focusing on disadvantaged families. Yet few studies to date have tested the impact of these policies for reducing socioeconomic selection into ECEC. This study integrates data from five cohorts of children living in different western, high-income countries (UK, USA, Netherlands, Canada, and Norway; total N = 21,437). We compare participation rates and socioeconomic selection into ECEC across the different policy contexts in infancy (5-9 months) and early childhood (36-41 months). Policy environments where parents had access to at least 6 months of paid maternity/parental leave had lower ECEC participation in infancy but higher participation in early childhood. Higher participation rates were also associated with universal ECEC subsidies (i.e., not targeted to low-income families). In general, low income, low maternal education and having more than one child were associated with reduced use of ECEC. Selection effects related to low income and number of children were reduced in countries with universal ECEC subsidies when out-of-pocket fees were income-adjusted or reduced for subsequent children, respectively. Most socioeconomic selection effects were reduced in Norway, the only country to invest more than 1% of its GDP into early childhood. Nevertheless, low maternal education was consistently associated with reduced use of ECEC services across all countries. Among families using services however, there were few selection effects for the type of ECEC setting (center-based vs. non-center-based), particularly in early childhood. In sum, this comparative study suggests wide variations in ECEC participation that can be linked to the policy context, and highlights key policy elements which may reduce socioeconomic disparities in ECEC use. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to identify critical periods and specific longitudinal growth patterns from fetal life onwards associated with childhood insulin and C-peptide levels. Methods: In a prospective population-based cohort study of 4328 children, we repeatedly measured (femur) length and (estimated fetal) weight from the second trimester of fetal life until 6 years of age. BMI was calculated from 6 months onwards. Insulin and C-peptide levels were measured at 6 years of age. Results: Preterm birth and small or large size for gestational age at birth were not associated with childhood insulin levels. Conditional growth modelling showed that, independent of growth in other time intervals, weight growth in each time interval from birth onwards, length growth from 6 months onwards and BMI growth from 12 months onwards were positively associated with childhood insulin levels. The strongest associations were present for weight and BMI growth between 48 and 72 months of age. Repeated measurement analyses showed that, compared with children in the lowest quartile of childhood insulin, those in the highest quartile had a higher length from birth onwards and a higher weight and BMI from 24 months onwards. These differences increased with age. No associations were observed for fetal growth characteristics. Similar results were observed for C-peptide levels. Conclusions/interpretation: Our results suggest that rapid length, weight and BMI growth from birth onwards, but not during fetal life, is associated with higher insulin levels in childhood. [ABSTRACT FROM AUTHOR]

Purpose: High protein intake in infancy has been linked to obesity. We aimed to examine the associations of protein intake in early childhood with cardiovascular and metabolic outcomes at school age. Methods: This study was performed in 2965 children participating in a population-based prospective cohort study. Protein intake at 1 year was assessed with a food frequency questionnaire and was adjusted for energy intake. At the children's age of 6 years, we measured their body fat percentage (BF%), blood pressure (BP), and insulin, HDL cholesterol, and triglyceride serum levels. These measures were incorporated into a cardiometabolic risk factor score, using age- and sex-specific SD scores. Results: In covariate-adjusted models, higher protein intake was associated with a higher BF%, lower diastolic BP, and lower triglyceride levels. We observed a significant interaction of protein intake with child sex on metabolic outcomes. Stratified analyses showed that protein intake was positively associated with BF% [0.07 SD (95 % CI 0.02; 0.13) per 10 g/day] and insulin levels in girls, but not in boys. In boys, but not in girls, higher protein intake was associated with lower triglyceride levels [−0.12 SD (95 % CI −0.20; −0.04) per 10 g/day] and a lower cardiometabolic risk factor score. Protein intake was not consistently associated with systolic BP or HDL cholesterol levels. Conclusion: Protein intake in early childhood was associated with a higher BF% and higher insulin levels at 6 years in girls and with lower triglyceride levels in boys. Further studies are needed to explore these sex differences and to investigate whether the observed changes persist into adulthood. [ABSTRACT FROM AUTHOR]

Dietary patterns have been linked to obesity in adults, however, not much is known about this association in early childhood. We examined associations of different types of dietary patterns in 1-year-old children with body composition at school age in 2026 children participating in a population-based cohort study. Dietary intake at the age of 1 year was assessed with a food-frequency questionnaire. At the children's age of 6 years we measured their body composition with dual-energy X-ray absorptiometry and we calculated body mass index, fat mass index (FMI), and fat-free mass index (FFMI). 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 FMI and FFMI, derived with reduced-rank-regression (RRR). Both the a priori-defined diet score and a 'Health-conscious' PCA-pattern were characterized by a high intake of fruit, vegetables, grains, and vegetable oils, and, after adjustment for confounders, children with higher adherence to these patterns had a higher FFMI at 6 years [0.19 SD (95 % CI 0.08;0.30) per SD increase in diet score], but had no different FMI. One of the two RRR-patterns was also positively associated with FFMI and was characterized by intake of whole grains, pasta and rice, and vegetable oils. Our results suggest that different a priori- and a posteriori-derived health-conscious dietary patterns in early childhood are associated with a higher fat-free mass, but not with fat mass, in later childhood. [ABSTRACT FROM AUTHOR]

Objectives: In this cross-sectional study, we aimed to investigate the pattern of hypodontia in the Dutch population and determine the association between hypodontia and dental development in children with and without hypodontia, applying three different standards, Dutch, French Canadian, and Belgian, to estimate dental age. Methods: We used dental panoramic radiographs (DPRs) of 1488 children (773 boys and 715 girls), with a mean age of 9.76 years (SD = 0.24) participating in a population-based cohort study in Rotterdam, the Netherlands, born in 2002-2004, and 452 children (219 boys and 233 girls) with a mean age of 9.83 years (SD = 1.09) participating in a mixed-longitudinal, interdisciplinary population-based cohort study in Nijmegen, the Netherlands born in 1960-1968. Results: The prevalence of hypodontia in the Generation R Study was 5.6 % ( N = 84) and 5.1 % ( N = 23) in the Nijmegen Growth Study. Linear regression analysis showed that children with hypodontia had a 0.37 [95 % CI (−0.53,-0.21)] to 0.52 [95 % CI (−0.76,-0.38)] years lower dental age than children without hypodontia. The ordinal regression analysis showed a delay in development of mandibular second premolars [1.68 years; 95 %CI (−1.90,-1.46)], mandibular first premolars [0.57 years; 95 % CI (−0.94,-0.20)], and mandibular second molars [0.47 years; 95 % CI (−0.84,-0.11)]. Conclusion: These findings suggest that children with hypodontia have a delayed dental development. Clinical relevance: The delay of dental development in children with hypodontia should be taken into consideration and therefore orthodontists should recognize that a later start of treatment in these patients may be necessary. [ABSTRACT FROM AUTHOR]

Infants' temperamental anger or frustration reactions are highly stable, but are also influenced by maturation and experience. It is yet unclear why some infants high in anger or frustration reactions develop disruptive behavior problems whereas others do not. We examined family regularity, conceptualized as the consistency of mealtime and bedtime routines, as a protective factor against the development of oppositional and aggressive behavior. This study used prospectively collected data from 3136 families participating in the Generation R Study. Infant anger or frustration reactions and family regularity were reported by mothers when children were ages 6 months and 2-4 years, respectively. Multiple informants (parents, teachers, and children) and methods (questionnaire and interview) were used in the assessment of children's oppositional and aggressive behavior at age 6. Higher levels of family regularity were associated with lower levels of child aggression independent of temperamental anger or frustration reactions ( β = −0.05, p = 0.003). The association between child oppositional behavior and temperamental anger or frustration reactions was moderated by family regularity and child gender ( β = 0.11, p = 0.046): family regularity reduced the risk for oppositional behavior among those boys who showed anger or frustration reactions in infancy. In conclusion, family regularity reduced the risk for child aggression and showed a gender-specific protective effect against child oppositional behavior associated with anger or frustration reactions. Families that ensured regularity of mealtime and bedtime routines buffered their infant sons high in anger or frustration reactions from developing oppositional behavior. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the relationship between serum 25(OH)D levels and axial length (AL) and myopia in 6-year-old children. A total of 2666 children aged 6 years participating in the birth-cohort study Generation R underwent a stepwise eye examination. First, presenting visual acuity (VA) and AL were performed. Second, automated cycloplegic refraction was measured if LogMAR VA > 0.1. Serum 25-hydroxyvitamin D [25(OH)D] was determined from blood using liquid chromatography/tandem mass spectrometry. Vitamin D related SNPs were determined with a SNP array; outdoor exposure was assessed by questionnaire. The relationships between 25(OH)D and AL or myopia were investigated using linear and logistic regression analysis. Average 25(OH)D concentration was 68.8 nmol/L (SD ± 27.5; range 4-211); average AL 22.35 mm (SD ± 0.7; range 19.2-25.3); and prevalence of myopia 2.3 % (n = 62). After adjustment for covariates, 25(OH)D concentration (per 25 nmol/L) was inversely associated with AL (β −0.043; P < 0.01), and after additional adjusting for time spent outdoors (β −0.038; P < 0.01). Associations were not different between European and non-European children (β −0.037 and β −0.039 respectively). Risk of myopia (per 25 nmol/L) was OR 0.65 (95 % CI 0.46-0.92). None of the 25(OH)D related SNPs showed an association with AL or myopia. Lower 25(OH)D concentration in serum was associated with longer AL and a higher risk of myopia in these young children. This effect appeared independent of outdoor exposure and may suggest a more direct role for 25(OH)D in myopia pathogenesis. [ABSTRACT FROM AUTHOR]

Obesity during pregnancy may be correlated with an adverse nutritional status affecting pregnancy and offspring outcomes. We examined the associations of prepregnancy body mass index and gestational weight gain with plasma fatty acid concentrations in mid-pregnancy. This study was embedded in a population-based prospective cohort study among 5636 women. We obtained prepregnancy body mass index and maximum weight gain during pregnancy by questionnaires. We measured concentrations of saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), n-3 polyunsaturated fatty acid (n-3 PUFA) and n-6 polyunsaturated fatty acid (n-6 PUFA) at a median gestational age of 20.5 (95 % range 17.1-24.9) weeks. We used multivariate linear regression models. As compared to normal weight women, obese women had higher total SFA concentrations [difference: 0.10 standard deviation (SD) (95 % Confidence Interval (CI) 0, 0.19)] and lower total n-3 PUFA concentrations [difference: − 0.11 SD (95 % CI − 0.20, − 0.02)]. As compared to women with sufficient gestational weight gain, those with excessive gestational weight gain had higher SFA concentrations [difference: 0.16 SD (95 % CI 0.08, 0.25)], MUFA concentrations [difference: 0.16 SD (95 % CI 0.08, 0.24)] and n-6 PUFA concentrations [difference: 0.12 SD (95 % CI 0.04, 0.21)]. These results were not materially affected by adjustment for maternal characteristics. Our results suggest that obesity and excessive weight gain during pregnancy are associated with an adverse fatty acids profile. Further studies are needed to assess causality and direction of the observed associations. [ABSTRACT FROM AUTHOR]

This study determined the impact of impairment criteria on the prevalence and patterns of comorbidity of child DSM-IV disorders. The validity of these impairment criteria was tested against different measures of mental health care referral and utilization. We interviewed parents of 1,154 children aged 5-8 years in-depth using the Diagnostic Interview Schedule for Children in Rotterdam, the Netherlands, to establish DSM-IV diagnosis. These children were randomly selected or oversampled based on Child Behavior Checklist ratings from a large population-based study ( N = 6,172). Referral data were extracted from the psychiatric interview as well as from a follow-up questionnaire. The results showed an overall prevalence of DSM-IV disorders of 31.1 % when impairment was not considered. This rate declined to 22.9 % when mild impairment was required and declined even further, to 10.3 %, for more severe levels of impairment. Similarly, the overall comorbidity rate declined from 8.5 to 6.7 and 2.7 % when mild and severe impairment were required, respectively. Virtually all children who attained symptom thresholds for a specific disorder, and had been referred to a mental health care professional because of the associated symptoms, also had mild impairment. The requirement of severe impairment criteria significantly increased diagnostic thresholds, but for most disorders, this definition captured only half of the clinically referred cases. In conclusion, prevalence was highly dependent upon the criteria used to define impairment. If severe impairment is made a diagnostic requirement, many children with psychiatric symptoms and mild impairment seeking mental health care will be undiagnosed and possibly untreated. [ABSTRACT FROM AUTHOR]

Background: High protein intake has been linked to kidney growth and function. Whether protein intake is related to kidney outcomes in healthy children is unclear. Methods: We examined the associations between protein intake in infancy and kidney outcomes at age 6 years in 2968 children participating in a population-based cohort study. Protein intake at 1 year was assessed using a food-frequency questionnaire and was adjusted for energy intake. At age 6 years we measured the kidney volume and urinary albumin/creatinine ratio (ACR) of all participating children, and we estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C levels. Results: In models adjusted for age, sex, body surface area, and sociodemographic factors, a higher protein intake was associated with a lower ACR and a higher eGFR but was not consistently associated with kidney volume. However, after further adjustment for additional dietary and lifestyle factors, such as sodium intake, diet quality, and television watching, higher protein intake was no longer associated with kidney function. No differences in associations were observed between animal and vegetable protein intake. Conclusions: Our findings show that protein intake in early childhood is not independently associated with kidney size or function at the age of 6 years. Further study is needed on other early life predictors of kidney size and function in later life. [ABSTRACT FROM AUTHOR]

Objective: Few studies have focused on the neuroanatomy of aggressive behavior in children younger than 10 years. Here, we explored the neuroanatomical correlates of aggression in a population-based sample of 6- to 9-year-old children using a multiple-informant approach. Methods: Magnetic resonance (MR) scans were acquired from 566 children from the Generation R study who participated in the Berkeley Puppet Interview and whose parents had completed the Child Behavior Checklist. Linear regression analyses were used to examine associations between aggression and amygdala and hippocampal volume. We performed surface-based analyses to study the association between aggression and cortical thickness, surface area, and gyrification. Results: Aggressive behavior was associated with smaller amygdala ( p < .05) but not hippocampal volume. Aggression was associated with a thinner cortex in the left precentral cortex ( p < .01) and in a cluster including the right inferior parietal, supramarginal, and postcentral cortex ( p < .001). Gender moderated the association between aggression and cortical thickness in the right medial posterior cortex ( p = .001) and the right prefrontal cortex ( p < .001). Aggression was associated with decreased gyrification in a large cluster including the right precentral, postcentral, frontal, and parietal cortex ( p = .01). Moreover, aggression was associated with decreased gyrification in the right occipital and parietal cortex ( p = .02). Conclusion: We found novel evidence that childhood aggressive behavior is related to decreased amygdala volume, decreased sensorimotor cortical thickness, and decreased global right hemisphere gyrification. Aggression is related to cortical thickness in regions associated with the default mode network, with negative associations in boys and positive associations in girls. [ABSTRACT FROM AUTHOR]

Human chorionic gonadotropin (hCG) is a pregnancy hormone secreted by the placental synctiotrophoblast cell layer that has been linked to fetal growth and various placental, uterine and fetal functions. In order to investigate the effects of hCG on clinical endpoints, knowledge on reference range (RR) methodology and determinants of gestational hCG levels is crucial. Moreover, a better understanding of gestational hCG physiology can improve current screening programs and future clinical management. Serum total hCG levels were determined in 8195 women participating in the Generation R Study. Gestational age specific RRs using 'ultrasound derived gestational age' (US RRs) were calculated and compared with 'last menstrual period derived gestational age' (LMP RRs) and a model-based RR. We also investigated which pregnancy characteristics were associated with hCG levels. Compared to the US RRs, the LMP RRs were lower, most notably for the median and lower limit levels. No considerable differences were found between RRs calculated in the general population or in uncomplicated pregnancies only. Maternal smoking, BMI, parity, ethnicity, fetal gender, placental weight and hyperemesis gravidarum symptoms were associated with total hCG. We provide gestational RRs for total hCG and show that total hCG values and RR cut-offs during pregnancy vary depending on pregnancy dating methodology. This is likely due to the influence of hCG on embryonic growth, suggesting that ultrasound based pregnancy dating might be less reliable in women with high/low hCG levels. Furthermore, we identify different pregnancy characteristics that influence total hCG levels considerably and should therefore be accounted for in clinical studies. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether maternal educational level is associated with gestational diabetes mellitus (GDM), and to what extent risk factors for GDM mediate the effect of educational level. Methods: We examined data of 7,511 pregnant women participating in a population-based cohort study in Rotterdam, the Netherlands. The highest achieved education was categorized into four levels. Diagnosis of GDM was retrieved from delivery records. Odds ratios (OR) of GDM were calculated for levels of education, adjusting for confounders and potential mediators. Mediators were selected according to Baron and Kenny's causal step approach. Results: Adjusted for ethnicity, age, family history of diabetes and parity, women in the lowest educational level were three times more likely to develop GDM than women in the highest level (OR 3.07; 95 % CI 1.37, 6.89). Selected mediators were alcohol use and body mass index (BMI). Additional adjustment for alcohol use attenuated the OR to 2.54 (95 % CI 1.11, 5.78). The individual addition of BMI attenuated the OR to 2.35 (95 % CI 1.03, 5.35). All mediators together explained 51 % (95 % CI −122, −25) of the association between low education and GDM. Conclusions: Low maternal educational level is associated with GDM, which is mainly due to higher rates of overweight and obesity. In order to reduce the higher rates of GDM, and consequently type 2 diabetes among women in low socioeconomic subgroups, prevention and intervention strategies need to be focused on reducing the rates of overweight and obesity before pregnancy. [ABSTRACT FROM AUTHOR]

The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18-25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiological studies. [ABSTRACT FROM AUTHOR]

Higher placental weight relative to birthweight has been described as an adaptive mechanism to fetal hypoxia in small for gestational age (SGA) infants. However, placental weight alone may not be a good marker reflecting intrauterine growth restriction. We hypothesized that fetoplacental ratio (FPR)-the ratio between birthweight and placental weight-may serve as a good marker of SGA after adjustment for surrogates of fetal hypoxemia (maternal iron deficiency anemia, smoking and choriodecidual necrosis). We conducted a within-sibling analysis using data from the US National Collaborative Perinatal Project (1959-1966) of 1,803 women who delivered their first two (or more) consecutive infants at term (n = 3,494). We used variance-component fixed-effect linear regression models to explore the effect of observed time-varying factors on placental weight and conditional logistic regression to estimate the effects of the tertiles of FPRs (1st small, 2nd normal and 3rd large) on the odds of SGA infants. We found placental weights to be 15 g [95 % confidence interval (CI) 8, 23] higher and −7 g (95 % CI −13, −2) lower among women that had anemia and choriodecidual necrosis, respectively. After multivariable adjustment, newborns with a small FPR (1st-tertile ≤7) had twofold higher odds of being SGA (OR 2.0, 95 % CI 1.2, 3.5) than their siblings with a large FPR (3nd-tertile ≥9). A small FPR was associated with higher odds of SGA, suggesting that small FPR may serve as an indicator suggestive of adverse intrauterine environment. This observation may help to distinguish pathological from constitutional SGA. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have been successful in identifying loci associated with a wide range of complex human traits and diseases. Up to now, the majority of GWAS have focused on European populations. However, the inclusion of other ethnic groups as well as admixed populations in GWAS studies is rapidly rising following the pressing need to extrapolate findings to non-European populations and to increase statistical power. In this paper, we describe the methodological steps surrounding genetic data generation, quality control, study design and analytical procedures needed to run GWAS in the multiethnic and highly admixed Generation R Study, a large prospective birth cohort in Rotterdam, the Netherlands. Furthermore, we highlight a number of practical considerations and alternatives pertinent to the quality control and analysis of admixed GWAS data. [ABSTRACT FROM AUTHOR]

This study aims to explore the relationship between currently recommended ambulatory blood pressure (ABP) measures used to classify pediatric hypertension and left ventricular mass index (LVMI) in children with true ambulatory hypertension. We performed a cross-sectional survey among 94 children who were consecutively referred for suspected hypertension. The calculated ABP measures were average 24-h systolic blood pressure (24-h aSBP) and 24-h SBP load. The LVMI was estimated by M-mode echocardiography using Devereux's formula and indexed by height. A total of 35 children fulfilled the criteria for true ambulatory hypertension (elevated office blood pressure, 24-h SBP load >25 %, and 24-h aSBP >95th percentile). Compared with children not fulfilling these criteria, those with true ambulatory hypertension had significantly higher values of 24-h aSBP, 24-h SBP load, and LVMI, as well as body mass index (BMI; P < 0.0001). In a separate analysis of both groups, none of the examined ABP measures adjusted for age, sex, and BMI correlated with LVMI. In those with true hypertension, only BMI was significantly associated with increased LVMI ( F = 9.651; P = 0.004; adjusted R = 0.203). The results of our study suggest that pediatric hypertension, as determined by currently recommended ABP (SBP) measures, is not associated with subclinical end-organ damage as defined by the increased left ventricular mass. Therefore, additional factors associated with BMI increase must be considered as risk factors for the development of end-organ damage in hypertensive children. [ABSTRACT FROM AUTHOR]

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. In total, 9,778 mothers were enrolled in the study. Data collection in children and their parents include questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, Magnetic Resonance Imaging and biological samples. Efforts have been conducted for collecting biological samples including blood, hair, faeces, nasal swabs, saliva and urine samples and generating genomics data on DNA, RNA and microbiome. In this paper, we give an update of the collection, processing and storage of these biological samples and available measures. Together with detailed phenotype measurements, these biological samples provide a unique resource for epidemiological studies focused on environmental exposures, genetic and genomic determinants and their interactions in relation to growth, health and development from fetal life onwards. [ABSTRACT FROM AUTHOR]