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Background & Aims: Dysregulation of iron homeostasis is associated with cardiac alterations in a sex-dependent manner in adults. It is unknown whether iron status during pregnancy has long-term impact on cardiovascular health, and if this association is influenced by sex. Therefore, this study aimed to evaluate sex-specific association between maternal iron status during early pregnancy and cardiac outcomes in children aged 10 years., Methods: In a population-based cohort study among 1972 mother-child pairs, hemoglobin and ferritin were measured in early pregnancy (<18 weeks) and categorized into anemia (hemoglobin<11 g/dL), elevated hemoglobin (hemoglobin≥13.2 g/dL), iron deficiency (ferritin<15 μg/L), and iron overload (ferritin>150 μg/L). At 10 years of age, cardiac MRI was performed to measure right and left cardiac outcomes of function (ventricular end-diastolic volume (RVEDV and LVEDV) and ejection fraction (RVEF and LVEF)), and structure (left ventricular mass (LVM), and left ventricular mass-to-volume ratio (LMVR)). Results are presented for boys and girls separately and models were adjusted for confounders and multiple testing., Results: In boys, one standard deviation score (SDS) increase in maternal hemoglobin was associated with lower RVEDV and LVEDV (difference (95%CI) -0.10 (-0.17, -0.03) SDS and -0.09 (-0.16, -0.03) SDS, respectively). In boys, maternal anemia, as compared to normal hemoglobin levels, was associated with higher LVEDV (difference 0.34 (0.10, 0.59) SDS). No associations were observed for other cardiac outcomes and for ferritin in boys. No associations were observed in girls., Conclusion: In boys, dysregulated iron status during early pregnancy might permanently alter cardiovascular RVEDV and LVEDV function. Underlying mechanisms need further study., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Early-life stress (ELS) has been robustly associated with a range of poor mental and physical health outcomes. Recent studies implicate the gut microbiome in stress-related mental, cardio-metabolic and immune health problems, but research on humans is scarce and thus far often based on small, selected samples, often using retrospective reports of ELS. We examined associations between ELS and the human gut microbiome in a large, population-based study of children. ELS was measured prospectively from birth to 10 years of age in 2,004 children from the Generation R Study. We studied overall ELS, as well as unique effects of five different ELS domains, including life events, contextual risk, parental risk, interpersonal risk, and direct victimization. Stool microbiome was assessed using 16S rRNA sequencing at age 10 years and data were analyzed at multiple levels (i.e. α- and β-diversity indices, individual genera and predicted functional pathways). In addition, we explored potential mediators of ELS-microbiome associations, including diet at age 8 and body mass index at 10 years. While no associations were observed between overall ELS (composite score of five domains) and the microbiome after multiple testing correction, contextual risk - a specific ELS domain related to socio-economic stress, including risk factors such as financial difficulties and low maternal education - was significantly associated with microbiome variability. This ELS domain was associated with lower α-diversity, with β-diversity, and with predicted functional pathways involved, amongst others, in tryptophan biosynthesis. These associations were in part mediated by overall diet quality, a pro-inflammatory diet, fiber intake, and body mass index (BMI). These results suggest that stress related to socio-economic adversity - but not overall early life stress - is associated with a less diverse microbiome in the general population, and that this association may in part be explained by poorer diet and higher BMI. Future research is needed to test causality and to establish whether modifiable factors such as diet could be used to mitigate the negative effects of socio-economic adversity on the microbiome and related health consequences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions., Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity., Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity., Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Exposure to infections during pregnancy may be a potential risk factor for later psychopathology, but large-scale epidemiological studies investigating associations between prenatal infection and long-term offspring behavioral problems in the general population are scarce. In our study, we aimed to investigate the following: (1) the association between prenatal infection and adolescent behavior, (2) putative underlying pathways (mediation), and (3) "second hits" interacting with prenatal infection to increase the risk of adolescent behavior problems (moderation)., Method: Our study was embedded in a prospective Dutch pregnancy cohort (Generation R; n = 2,213 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. At age 13 to 16 years, we assessed total, internalizing, and externalizing problems, and autistic traits using the Child Behavioral Checklist and the Social Responsiveness Scale, respectively. We investigated maternal lifestyle and nutrition, perinatal factors (placental health and delivery outcomes), and child health (lifestyle, traumatic events, infections) as mediators and moderators., Results: We observed associations of prenatal infection with adolescent total behavioral, internalizing, and externalizing problems. The association between prenatal infection and internalizing problems was moderated by higher levels of maternal psychopathology, alcohol and tobacco use, and a higher number of traumatic childhood events. We found no association between prenatal infection and autistic traits. Yet, children exposed to prenatal infections and maternal substance use, and/or traumatic childhood events, had a higher risk of autistic traits in adolescence., Conclusion: Prenatal infection may be a risk factor for later psychiatric problems as well as a disease primer making individuals susceptible to other hits later in life., Study Preregistration Information: Prenatal maternal infection and adverse neurodevelopment: a structural equation modelling approach to downstream environmental hits; https://osf.io/cp85a; cp85a., Diversity & Inclusion Statement: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The link between the gut microbiome and the brain has gained increasing scientific and public interest for its potential to explain psychiatric risk. While differences in gut microbiome composition have been associated with several mental health problems, evidence to date has been largely based on animal models and human studies with modest sample sizes. In this cross-sectional study in 1,784 ten-year-old children from the multi-ethnic, population-based Generation R Study, we aimed to characterize associations of the gut microbiome with child mental health problems. Gut microbiome was assessed from stool samples using 16S rRNA sequencing. We focused on overall psychiatric symptoms as well as with specific domains of emotional and behavioral problems, assessed via the maternally rated Child Behavior Checklist. While we observed lower gut microbiome diversity in relation to higher overall and specific mental health problems, associations were not significant. Likewise, we did not identify any taxonomic feature associated with mental health problems after multiple testing correction, although suggestive findings indicated depletion of genera previously associated with psychiatric disorders, including Hungatella, Anaerotruncus and Oscillospiraceae. The identified compositional abundance differences were found to be similar across all mental health problems. Finally, we did not find significant enrichment for specific microbial functions in relation to mental health problems. In conclusion, based on the largest sample examined to date, we do not find clear evidence of associations between gut microbiome diversity, taxonomies or functions and mental health problems in the general pediatric population. In future, the use of longitudinal designs with repeated measurements of microbiome and psychiatric outcomes will be critical to identify whether and when associations between the gut microbiome and mental health emerge across development and into adulthood., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Whether maternal iron status during pregnancy is associated with cardiometabolic health in the offspring is poorly known., Objectives: We aimed to assess the associations of maternal iron status during early pregnancy with body fat measures and cardiometabolic risk factors in children aged 10 y., Methods: In a population-based cohort study among 3718 mother-child pairs, we measured ferritin, transferrin, and transferrin saturation during early pregnancy. We obtained child BMI, fat mass index, and android/gynoid fat mass ratio by DXA, subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging and assessed systolic and diastolic blood pressure, serum lipids, glucose, insulin, and CRP at 10 y., Results: A one-standard deviation score (SDS) higher maternal ferritin was associated with lower fat mass index [difference -0.05 (95% CI: -0.08, -0.02) SDS] and subcutaneous fat index [difference -0.06 (95% CI: -0.10, -0.02) SDS] in children. One-SDS higher maternal transferrin was associated with higher fat mass index [difference 0.04 (95% CI: 0.01, 0.07) SDS], android/gynoid fat mass ratio [difference 0.05 (95% CI: 0.02, 0.08) SDS], and subcutaneous fat index [difference 0.06 (95% CI: 0.02, 0.10) SDS] in children. Iron status during pregnancy was not consistently associated with organ fat and cardiometabolic risk factors at 10 y., Conclusions: Maternal lower ferritin and higher transferrin in early pregnancy are associated with body fat accumulation and distribution but are not associated with cardiometabolic risk factors in childhood. Underlying mechanisms and long-term consequences warrant further study., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Importance: Animal studies show that Maternal Immune Activation (MIA) may have detrimental effects on fetal brain development. Clinical studies provide evidence for structural brain abnormalities in human neonates following MIA, but no study has investigated the long-term effects of MIA (as measured with biomarkers) on human brain morphology ten years after the exposure., Objective: Our aim was to evaluate the long-term impact of MIA on brain morphology in 10-year-old children, including the possible mediating role of gestational age at birth., Design: We leveraged data from Generation R, a large-scale prospective pregnancy cohort study. Pregnant women were included between 2002 and 2006, and their children were invited to participate in the MRI study between 2013 and 2015. To be included, mother-child dyads had to have data on maternal C-reactive protein levels during gestation and a good quality MRI-scan of the child's brain at age 10 years. Of the 3,992 children scanned, a total of 2,053 10-year-old children were included in this study., Exposure: Maternal C-reactive protein was measured in the first 18 weeks of gestation. For the analyses we used both a continuous approach as well as a categorical approach based on clinical cut-offs to determine if there was a dose-response relationship., Main Outcomes and Measures: High-resolution MRI brain morphology measures were used as the primary outcome. Gestational age at birth, established using ultrasound, was included as a mediator using a causal mediation analysis. Corrections were made for relevant confounders and multiple comparisons. Biological sex was investigated as moderator., Results: We found a direct association between continuous MIA and lower cerebellar volume. In girls, we demonstrated a negative indirect association between continuous MIA and total brain volume, through the mediator gestational age at birth. We observed no associations with categorical MIA after multiple testing correction., Conclusion and Relevance: Our results suggest sex-specific long-term effects in brain morphology after MIA. Categorical analyses suggest that this association might be driven by acute infections or other sources of severe inflammation, which is of clinical relevance given that the COVID-19 pandemic is currently affecting millions of pregnant women worldwide., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Maternal polyunsaturated fatty acids (PUFA) concentrations in pregnancy are essential for fetal lipid metabolism and adipocyte differentiation. Whether suboptimal maternal gestational PUFA concentrations adversely affect offspring liver fat development is unknown. We aimed to examine the associations of maternal n-3 and n-6 PUFA concentrations in pregnancy with childhood liver fat accumulation., Methods: In a population-based prospective cohort study among 2424 mother-child pairs, we measured maternal total and individual n-3 and n-6 PUFA plasma concentrations at mean gestational age of 20.6 ± 1.1 weeks. Childhood liver fat fraction was obtained by MRI at 10 years. Non-alcoholic fatty liver disease was a liver fat fraction ≥5.0%., Results: We observed that 1-Standard deviation (SD) higher maternal n-3 PUFA concentrations, especially DHA, was associated with a lower childhood liver fat fraction [-0.07 SD-score (95% CI -0.11 to -0.02, p-value = 0.001) for both total n-3 PUFA and DHA concentrations]. Of n-6 PUFAs, 1-SD higher maternal dihomo-gamma-linolenic acid concentrations was associated with a higher childhood liver fat fraction [0.06 SD-score (95% CI 0.02-0.10, p-value = 0.004)]. Associations were not explained by maternal or childhood socio-demographic and lifestyle characteristics. Associations were stronger among boys and less consistent among girls. Among boys, higher maternal total n-3 PUFA concentrations were associated with a lower risk of childhood non-alcohol fatty liver disease [odds ratio 0.42 (95% CI 0.25-0.70, p-value = 0.001)]., Conclusions: Maternal lower n-3 PUFA and higher n-6 PUFA concentrations in pregnancy are associated with offspring liver fat accumulation in childhood. Optimizing maternal PUFA concentrations during pregnancy may be a target for preventing liver fat accumulation in their offspring., Competing Interests: Conflict of interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Reduced maternal placental growth factor (PlGF) and higher soluble fms-like tyrosine kinase (sFlt-1) concentrations in pregnancy may have persistent effects on offspring vasculature. We hypothesized that suboptimal maternal angiogenic factors in pregnancy may adversely affect fetal vascular development, leading to an increased risk of adverse atheriosclerotic adaptations and higher blood pressure in offspring., Methods: In a population-based prospective cohort among 4565 women and their offspring, we examined the associations of maternal serum PlGF and sFlt-1 concentrations in the first half of pregnancy with offspring vascular development. We measured childhood blood pressure and obtained childhood carotid intima media thickness and carotid distensibility through ultrasonography at 9 years., Results: After adjustment for maternal sociodemographic and lifestyle characteristics, no associations were present of maternal first and second trimester angiogenic factors with childhood blood pressure, carotid intima media thickness (IMT) or distensibility in the total population. In preterm born children only, higher maternal second trimester PlGF concentrations, but not sFlt-1 concentrations, were associated with a lower childhood diastolic blood pressure (difference: -0.16 SDS (95% CI -0.30, -0.03) per SDS increase in maternal second trimester PlGF concentration). No associations among children born small-for-gestational age were present., Conclusions: In a low-risk population, maternal angiogenic factors in the first half of pregnancy are not associated with childhood blood pressure, carotid IMT or carotid distensibility after considering maternal socio-demographic and lifestyle factors. Only in children born preterm, lower maternal second trimester PlGF concentrations are associated with higher childhood diastolic blood pressure, but not with other vascular outcomes., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Suboptimal circulating vitamin B12, folate and homocysteine concentrations during fetal life seem to be associated with cardiometabolic health at school-age. We examined whether fetal exposure to lower circulating vitamin B12 and folate concentrations and higher circulating homocysteine concentrations is also associated with early signs of atherosclerosis at school-age., Methods: This study among 3826 school-age children and their mothers was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We examined the associations of early-pregnancy and cord blood serum total and active B12 and plasma folate and homocysteine concentrations with common carotid artery intima-media thickness and distensibility in the children aged ten years., Results: As compared to normal early-pregnancy serum total B12 concentrations (≥145 pmol/L), low serum total B12 concentrations (<145 pmol/L) were associated with higher carotid intima-media thickness in the children at school-age (difference 0.09 standard deviations score (SDS); 95% confidence interval (CI): 0.01, 0.16). As compared to normal early-pregnancy plasma folate concentrations (≥8 nmol/L), low plasma folate concentrations (<8 nmol/L) were associated with lower carotid distensibility in the children at school-age (difference -0.16 SDS; 95% CI: -0.28, -0.04). Early-pregnancy circulating total and active B12, folate and homocysteine concentrations measured continuously were not associated with carotid intima-media thickness or carotid distensibility in the children at school-age. One SDS higher plasma homocysteine concentrations measured in cord blood at birth was associated with a -0.05 SDS (95% CI: -0.09, -0.02) lower carotid distensibility at school-age. Cord blood total and active B12 and folate concentrations were not associated with carotid intima-media thickness or carotid distensibility at school-age., Conclusions: Circulating total B12, folate and homocysteine concentrations during fetal life seem to be associated with markers of subclinical atherosclerosis at school-age. Further studies need to examine the causality and mechanisms underlying these associations., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning., Method: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis., Results: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations., Conclusions: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Higher maternal cow-milk intake during pregnancy is associated with higher fetal growth measures and higher birth weight., Objective: The aim of this study was to assess the associations of maternal milk intake during pregnancy with body fat measures and cardiometabolic risk factors at the age of 10 y., Methods: In a population-based cohort of Dutch mothers and their children (n = 2466) followed from early pregnancy onwards, we assessed maternal first-trimester milk intake (milk and milk drinks) by food-frequency questionnaire. Maternal milk intake was categorized into 0-0.9, 1-1.9, 2-2.9, 3-3.9, 4-4.9, and ≥5 glasses/d, with 1 glass equivalent to 150 mL milk. For children at the age of 10 y, we calculated BMI and obtained detailed measures of body and organ fat by DXA and MRI. We also measured blood pressure and lipid, insulin, and glucose concentrations. Data were analyzed using linear and logistic regression models., Results: Compared with children whose mothers consumed 0-0.9 glass of milk/d during their pregnancy, those whose mothers consumed ≥5 glasses of milk/d had a 0.29 SD (95% CI: 0.10, 0.48) higher BMI, 0.27 SD (95% CI: 0.08, 0.47) higher fat mass, 0.26 SD (95% CI: 0.07, 0.46) higher lean mass, 0.30 SD (95% CI: 0.09, 0.50) higher android-to-gynoid fat mass ratio and 0.38 SD (95% CI: 0.09, 0.67) higher abdominal visceral fat mass. After correction for multiple comparisons, groups of maternal milk intake were not associated with pericardial fat mass index, liver fat fraction, blood pressure, or lipid, insulin, or glucose concentrations (P values >0.0125)., Conclusions: Our results suggest that maternal first-trimester milk intake is positively associated with childhood general and abdominal visceral fat mass and lean mass, but not with other cardiometabolic risk factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Higher circulating folate and vitamin B-12 concentrations and lower circulating homocysteine concentrations during pregnancy seem to be associated with fetal development. These micronutrients may also be associated with cardiometabolic health., Objective: We examined the associations of circulating folate, vitamin B-12, and homocysteine concentrations during pregnancy and in neonates with childhood cardiometabolic outcomes., Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onward. We sampled blood in early pregnancy and cord blood. We measured cardiometabolic outcomes in the children at school age. Among 4449 children aged 10 y (median: 9.7; 95% range: 9.3, 10.7), we examined associations of plasma folate, serum vitamin B-12, and plasma homocysteine concentrations in early pregnancy and at birth with BMI, body fat distribution, heart rate, blood pressure, and insulin, glucose, and lipid concentrations, using linear regression models. Using logistic models, we examined the associations of these micronutrients with risks of overweight/obesity and clustering of cardiovascular risk factors., Results: One standard deviation score (SDS) higher maternal plasma folate concentration was associated with lower BMI (-0.04 SDS; 95% CI: -0.08, -0.01), android-to-gynoid fat ratio (-0.04 SDS; 95% CI: -0.07, -0.01), systolic blood pressure (-0.06 SDS; 95% CI: -0.10, -0.03), risk of overweight (OR: 0.87; 95% CI: 0.78, 0.96), and clustering of cardiovascular risk factors (OR: 0.79; 95% CI: 0.68, 0.91). One SDS higher maternal serum total B-12 concentration was associated with lower glucose (-0.06 SDS; 95% CI: -0.10, -0.02) and higher HDL cholesterol concentrations (0.04 SDS; 95% CI: 0.00, 0.08). Cord blood folate, vitamin B-12, and homocysteine concentrations were not consistently associated with cardiometabolic outcomes., Conclusions: Subtle differences in circulating folate and vitamin B-12 concentrations in early pregnancy may be associated with child cardiometabolic health at age 10 y. The causality and mechanisms underlying these associations need further study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Cumulative evidence shows that low maternal folate levels during pregnancy are associated with offspring neuropsychiatric disorders even in the absence of neural tube defects. However, the relationship between prenatal exposure to folate and brain development in late childhood has been rarely investigated., Methods: In 2095 children from a prospective population-based cohort in Rotterdam, the Netherlands, we examined the association of maternal folate levels during pregnancy with downstream brain development in offspring. Maternal folate concentrations were measured from venous blood in early gestation. Child structural neuroimaging data were measured at age 9-11 years. In addition, measures of child head circumference using fetal ultrasound in the third trimester and total brain volume using magnetic resonance imaging at age 6-8 years were used for analyses with repeated assessments of brain development., Results: Maternal folate deficiency (i.e., <7 nmol/L) during pregnancy was associated with smaller total brain volume (B = -18.7 cm 3 , 95% CI -37.2 to -0.2) and smaller cerebral white matter (B = -7.2 cm 3 , 95% CI -11.8 to -2.6) in children aged 9-11 years. No differences in cortical thickness or surface area were observed. Analysis of the repeated brain assessments showed that children exposed to deficient folate concentrations in utero had persistently smaller brains compared to controls from the third trimester to childhood (β = -0.4, 95% CI -0.6 to -0.1)., Conclusions: Low maternal folate levels during pregnancy are associated with altered offspring brain development in childhood, suggesting the importance of essential folate concentrations in early pregnancy., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background & Aims: Maternal hyperglycemia during pregnancy is an important risk factor for childhood adiposity. Maternal dietary glycemic index during pregnancy directly influences maternal and fetal glucose concentrations. We examined the associations of maternal early-pregnancy dietary glycemic index with offspring general, abdominal and ectopic fat accumulation among normal weight and overweight or obese pregnant women and their offspring., Methods: In a population-based cohort study among 2488 Dutch pregnant women and their children, we assessed maternal dietary glycemic index by food frequency questionnaire at median 13.4 (95% range 10.7; 21.1) weeks gestation. Dietary glycemic index was used continuously and categorized into low (≤55), normal (56-69) and high (≥70) glycemic index diet. We measured offspring BMI, total fat mass and android/gynoid fat mass ratio by DXA, and visceral fat mass and liver fat fraction by MRI at 10 years., Results: No associations of maternal early-pregnancy dietary glycemic index with offspring adiposity were present among normal weight women and their children. Among overweight and obese women and their children, 1-Standard Deviation Score (SDS) increase in maternal early-pregnancy dietary glycemic index was associated with higher childhood BMI (0.10 SDS, 95% Confidence Interval (CI) 0.01; 0.19), total fat mass index (0.13 SDS, 95% CI 0.05; 0.22), visceral fat mass index (0.19 SDS, 95% CI 0.07; 0.32) and tended to be associated with a higher android/gynoid fat mass ratio (0.09 SDS, 95% CI -0.01; 0.19) and higher risk of childhood overweight (Odds Ratio (OR) 1.20, 95% CI 0.97; 1.48). Overweight and obese women consuming an early-pregnancy low-glycemic index diet, as compared to an early-pregnancy normal-glycemic index diet, had children with lower BMI, total fat mass index, visceral fat mass index and android/gynoid fat mass ratio at 10 years (p-values<0.05). No women consumed a high-glycemic index diet. No associations were explained by maternal socio-economic, lifestyle and dietary characteristics, birth or childhood characteristics. No associations with liver fat fraction were present., Conclusions: In overweight or obese women and their children, a higher maternal early-pregnancy dietary glycemic index is associated with childhood general, abdominal and visceral fat accumulation, but not with liver fat. Intervention studies among overweight and obese pregnant women may need to target the dietary glycemic index to prevent childhood adiposity., Competing Interests: Conflicts of interest All authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Co-occurrence of behavioral and emotional problems in childhood is widespread, and previous studies have suggested that this reflects vulnerability to experience a range of psychiatric problems, often termed a general psychopathology factor. However, the neurobiological substrate of this general factor is not well understood. We tested the hypothesis that lower overall white matter microstructure is associated with higher levels of the general psychopathology factor in children and less with specific factors., Method: Global white matter microstructure at age 10 years was related to general and specific psychopathology factors. These factors were estimated using a latent bifactor model with multiple informants and instruments between ages 6 and 10 years in 3,030 children from the population-based birth cohort Generation R. The association of global white matter microstructure and the psychopathology factors was examined with a structural equation model adjusted for sex, age at scan, age at psychopathology assessment, parental education/income, and genetic ancestry., Results: A 1-SD increase of the global white matter factor was associated with a β = -0.07SD (standard error [SE] = 0.02, p < .01) decrease in general psychopathology. In contrast, a 1-SD increase of white matter microstructure predicted an increase of β = +0.07 SD (SE = 0.03, p < .01) specific externalizing factor levels. No association was found with the specific internalizing and specific attention factor., Conclusion: The results suggest that general psychopathology in childhood is related to white matter structure across the brain and not only to specific tracts. Taking into account general psychopathology may also help reveal neurobiological mechanisms behind specific symptoms that are otherwise obscured by comorbidity., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to bisphenols and phthalates might influence bone health. We hypothesized that exposure to bisphenols and phthalates during fetal life has persistent effects on bone development., Objectives: To analyze the associations of fetal exposure to bisphenols and phthalates with bone health in school-aged children., Methods: Among 1,362 mother-child pairs participating in a population-based cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at first, second and third trimester with high performance liquid chromatography electrospray ionization-tandem mass spectrometry. Total body bone mineral density (BMD) and bone area (BA) were measured using dual-energy X-ray absorptiometry (DXA) at 6 and 10 years, and were both used to calculate bone mineral content (BMC) and area-adjusted BMC (aBMC, a measure of volumetric BMD)., Results: Maternal bisphenol concentrations were not associated with childhood bone measures at 6 years. After adjustment for covariates and multiple testing correction, an interquartile range increase in maternal first trimester bisphenol S (BPS) concentrations was associated with lower BMD and aBMC at 10 years (-6.08 (95% confidence interval (CI), -9.97 to -2.19) mg/cm 2 and -0.12 (95% CI, -0.20 to -0.04) g). Maternal third trimester low molecular weight (LMW) phthalate concentrations were associated with higher aBMC at 6 years whereas, maternal third trimester di-n-octylphthalate (DNOP) concentrations were associated with lower aBMC at 10 years. However, these associations did not remain statistically significant after multiple testing correction., Discussion: Maternal first trimester BPS concentrations are associated with lower BMD and aBMC in school-aged children. These findings should be considered as hypothesis generating and need further replication and exploration of potential underlying mechanisms., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Many studies have investigated the impact of orthodontic treatment need (OTN) on children's oral health-related quality of life (OHRQOL). However, few studies have explored the impact of deviant occlusal traits on OHRQOL regarding the severity of OTN. This cross-sectional study aims to address this gap in the literature., Methods: This study was conducted within the Generation R Study, a population-based prospective cohort study. We assessed OTN with the Index of Orthodontic Treatment Need and OHRQOL with a parental short-form of the Child Oral Health Impact Profile in 3048 children at a median age of 9.74 years (9.5-10.0). We also further assessed individual malocclusion traits in a subsample of 2714 children. We investigated the association between OTN, malocclusion traits, and OHRQOL using multiple regression analysis with weighted least squares., Results: Children with definite (adjusted effect estimate = -0.81; 95% confidence interval -1.12 to -0.50) or borderline (adjusted effect estimate = -0.34; 95% confidence interval -0.61 to -0.08) OTN experienced significant decreases in their OHRQOL than those with no need. An impacted tooth, increased overjet, or crowding had significant negative impacts on children's OHRQOL. Children with an overjet experienced negative impacts on OHRQOL even when orthodontic treatment was not necessary., Conclusions: Progressively greater OTN has increasingly negative impacts on parent's perception of children's OHRQOL. In particular, children presenting with large overjets and impacted teeth have lower OHRQOL. These perspectives add to better patient-clinician communication and understanding of patient expectations around OTN, which may potentially lead to improvements in quality of care from the patient perspective., (Copyright © 2020 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background: A balanced diet in childhood is important for growth and development. We aimed to examine associations of overall diet quality in both early and mid-childhood with trajectories of growth and body composition until age 10 years., Methods: We included 3991 children from the Generation R Study, a population-based, prospective cohort in Rotterdam, the Netherlands. At child's ages of 1 and 8 years, dietary intake was assessed using food-frequency questionnaires to calculate diet quality scores (0-10), which measure adherence to age-specific dietary guidelines. Height and weight were measured repeatedly between ages 1 and 10 years. Body composition was assessed using dual-energy X-ray absorptiometry at ages 6 and 10 years. We calculated sex- and age-specific SD-scores for body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and body fat percentage (BF%)., Results: After adjustment for socioeconomic and lifestyle factors, results from linear mixed models showed that higher diet quality at 1 year was associated with higher height, weight, and BMI up to age 10 years. Using linear regression analyses, similar associations were observed for diet quality at 8 years. For diet quality at both time points, positive associations with BMI were fully driven by a higher FFMI (β = 0.07 SDS, 95%CI: 0.05, 0.10 for diet quality at 8 years), and not FMI or BF%. Most of the observed associations were independent of diet quality at the other time point., Conclusion: We observed that better diet quality in both early and mid-childhood was associated with higher height, weight, and FFMI, but not with body fatness up to age 10 years. This was independent of diet quality at an earlier or later time point. Our findings suggest that dietary intake according to dietary guidelines may have a beneficial impact on growth and body composition throughout childhood., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: The growth of the craniofacial complex is important for establishing a balanced relationship among the teeth, jaws, and other facial structures. However, there is still a lack of information about craniofacial parameters that are affected by the rate of dental development. The aim of this study was to investigate the association between dental development and craniofacial morphology in school-age children., Methods: This study was embedded in the Generation R Study, Rotterdam, The Netherlands. In 3,896 children aged 8 to 11 years, dental development was assessed from panoramic radiographs and craniofacial morphology was assessed by combining cephalometric parameters into 9 uncorrelated principal components, each representing a distinct skeletal or dental craniofacial pattern. The statistical analysis was performed using linear and nonlinear regression model., Results: Dental development was positively associated with the bimaxillary growth (β = 0.04; 95% CI 0.01 to 0.08). Children with above-average dental development had a tendency toward Class II jaw relationship (β = -0.08; 95% CI -0.13 to -0.04). Regarding dental parameters, the proclination increased for incisors and lips with advanced dental development (β = 0.15 [95% CI 0.10 to 0.19] and β = 0.13 [95% CI 0.09 to 0.17], respectively), but the incisor proclination remained more pronounced in children that had above-average dental development., Conclusions: The findings of this large population-based study show that dental development is associated with specific dental and skeletal cephalometric characteristics in school-age children. Further longitudinal studies are necessary to confirm the observed effects over time., (Copyright © 2019 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Protein intake in infancy promotes growth, but excessive intake may lead to adiposity in children. However, whether this increased adiposity persists throughout childhood and is independent of diet in later life remains unclear. Therefore, we studied the associations of total protein intake and protein from different sources at age 1 year with repeatedly measured growth and body composition up to age 10 years. Additionally, we examined whether these associations are independent of protein intake and overall diet quality at age 8 years., Methods: We included 3573 children from the Generation R study, a population-based prospective cohort in the Netherlands. Dietary intakes were assessed with food-frequency questionnaires at ages 1 and 8 years and macronutrient intakes were expressed as energy percentages (E%). Height and weight were measured at eight time points between ages 1 and 10 years. Fat and fat-free masses were measured at ages 6 and 10 years with dual-energy X-ray-absorptiometry. We calculated body mass index (BMI), fat mass index (FMI) and fat-free mass index (FFMI). Outcomes were standardized for sex and age and expressed as standard deviation scores (SDS). Associations of protein intake with growth and body composition trajectories were examined with multivariable linear mixed models., Results: After adjustment for confounders, 5E% additional protein intake at age 1 year was associated with a 0.10 SDS higher weight (95% CI 0.04, 0.16), 0.10 SDS higher BMI (95% CI 0.04, 0.16), and 0.07 SDS higher FMI (95% CI 0.01, 0.13) up to age 10 years. These associations were explained by protein from animal sources and not plant sources. Associations were independent of protein intake and overall diet quality at age 8 years, and were independent of whether higher protein was consumed at the expense of carbohydrates or fat in the diet., Conclusions: Our study suggests that high protein intake in infancy, particularly from animal food sources, is persistently associated with adiposity up to age 10 years. Restricting protein intake in this critical period of development may aid in the early prevention of adiposity in childhood., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: This study examined the relation between polygenic scores (PGSs) for 5 major psychiatric disorders and 2 cognitive traits with brain magnetic resonance imaging morphologic measurements in a large population-based sample of children. In addition, this study tested for differences in brain morphology-mediated associations between PGSs for psychiatric disorders and PGSs for related behavioral phenotypes., Method: Participants included 1,139 children from the Generation R Study assessed at 10 years of age with genotype and neuroimaging data available. PGSs were calculated for schizophrenia, bipolar disorder, major depression disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intelligence, and educational attainment using results from the most recent genome-wide association studies. Image processing was performed using FreeSurfer to extract cortical and subcortical brain volumes., Results: Greater genetic susceptibility for ADHD was associated with smaller caudate volume (strongest prior = 0.01: β = -0.07, p = .006). In boys, mediation analysis estimates showed that 11% of the association between the PGS for ADHD and the PGS attention problems was mediated by differences in caudate volume (n = 535), whereas mediation was not significant in girls or the entire sample. PGSs for educational attainment and intelligence showed positive associations with total brain volume (strongest prior = 0.5: β = 0.14, p = 7.12 × 10 -8 ; and β = 0.12, p = 6.87 × 10 -7 , respectively)., Conclusion: The present findings indicate that the neurobiological manifestation of polygenic susceptibility for ADHD, educational attainment, and intelligence involve early morphologic differences in caudate and total brain volumes in childhood. Furthermore, the genetic risk for ADHD might influence attention problems through the caudate nucleus in boys., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Feeding practices have been implicated in childhood overweight, but the long-term effects of using food to comfort a distressed child remain unknown., Objective: This study examined whether the use of food to soothe in infancy was associated with later body composition, and whether children's eating behaviors mediate this relation., Methods: Participants were 3960 children of Generation R, a population-based birth cohort in the Netherlands. Parents reported on the use of food to soothe when infants were 6 mo old and on child eating behavior (food responsiveness, emotional eating) at ages 4 and 10 y. Body mass index (BMI), fat mass, and fat-free mass were measured at ages 6 and 10 y. Linear regression and mediation analyses were conducted, accounting for various potential confounding factors., Results: The use of food to soothe when infants were 6 mo old predicted a higher BMI from age 6 y onwards, independently of infant weight, maternal BMI, and other confounders. Specifically, frequent use was associated with a BMI z score 0.13 higher at age 10 y (95% CI: 0.03, 0.22) as compared with never use. Children's emotional eating mediated this association (indirect effect B = 0.04; 95% CI: 0.02, 0.06). The feeding-body composition association was most evident for fat mass (P for trend = 0.014) and somewhat less for fat-free mass (P for trend = 0.079)., Conclusions: The use of food to comfort a distressed infant was consistently associated with obesogenic eating behaviors and an unhealthy body composition throughout middle and late childhood. As our design precludes conclusions on causal associations, we recommend further studies with precise, repeated assessments of infant feeding practices. Such research can help ascertain the direction of effect, which is needed for establishing evidence-based guidelines for parents regarding the use of food to soothe early in life., (Copyright © American Society for Nutrition 2019.)

Background: Studies of white matter connectivity in children with disruptive behavior have yielded inconsistent results, possibly owing to the trait's heterogeneity, which comprises diverse symptoms like physical aggression, irritability, and delinquency. This study examined associations of global and specific white matter connectivity with childhood disruptive behavior problems, while accounting for their complex multidimensionality., Methods: In a large cross-sectional population-based study of 10-year-old preadolescents (n = 2567), we assessed four previously described empirically derived dimensions of disruptive behavior problems using the Child Behavior Checklist: physical aggression, irritability, disobedient behavior, and delinquent behavior. Global and specific white matter microstructure was assessed by diffusion tensor imaging., Results: Global fractional anisotropy and mean diffusivity were not associated with broad measures of disruptive behavior, e.g., Child Behavior Checklist externalizing problems scale. Global fractional anisotropy was negatively associated with delinquent behavior (β = -.123, p false discovery rate adjusted  = .028) and global mean diffusivity was positively associated with delinquent behavior (β = .205, p false discovery rate adjusted < 0.001), suggesting reduced white matter microstructure in preadolescents with higher levels of delinquent behavior. Lower white matter microstructure in the inferior longitudinal fasciculus, superior longitudinal fasciculus, cingulum, and uncinate underlie these associations. Global white matter microstructure was not associated with physical aggression, irritability, or disobedient behavior., Conclusions: Delinquent behavior, a severe manifestation of childhood disruptive behavior, was associated with lower white matter microstructure in tracts connecting frontal and temporal lobes. These brain regions are involved in decision making, reward processing, and emotion regulation. This study demonstrated that incorporating the multidimensional nature of childhood disruptive behavior traits shows promise in advancing the search for elucidating neurobiological correlates of disruptive behavior., (Published by Elsevier Inc.)

Purpose: To identify risk factors for axial length (AL) elongation and incident school myopia., Design: Population-based prospective birth-cohort study., Participants: Four thousand seven hundred thirty-four children examined at 6 and 9 years of age from the Generation R Study in Rotterdam, The Netherlands., Methods: Axial length and corneal radius (CR) were measured with an IOLMaster 500 and daily life activities and demographic characteristics were obtained by questionnaire. Three thousand three hundred sixty-two children (71%) were eligible for cycloplegic refractive error measurements. Linear regression models on AL elongation were used to create a risk score based on the regression coefficients resulting from environmental and ocular factors. The predictive value of the prediction score for myopia (≤-0.5 diopter) was estimated using receiver operating characteristic curves. To test if regression coefficients differed for baseline AL-to-CR ratio, interaction terms were calculated with baseline AL-to-CR ratio and environmental factors., Main Outcome Measures: Axial length elongation and incident myopia., Results: From 6 to 9 years of age, average AL elongation was 0.21±0.009 mm/year and myopia developed in 223 of 2136 children (10.4%), leading to a myopia prevalence at 9 years of age of 12.0%. Seven parameters were associated independently (P < 0.05) with faster AL elongation: parental myopia, 1 or more books read per week, time spent reading, no participation in sports, non-European ethnicity, less time spent outdoors, and baseline AL-to-CR ratio. The discriminative accuracy for incident myopia based on these risk factors was 0.78. Axial length-to-CR ratio at baseline showed statistically significant interaction with number of books read per week (P < 0.01) and parental myopia (P < 0.01). Almost all predictors showed the highest association with AL elongation in the highest quartile of AL-to-CR ratio; incidental myopia in this group was 24% (124/513)., Conclusions: Determination of a risk score can help to identify school children at high risk of myopia. Our results suggest that behavioral changes can offer protection particularly in these children., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Although a longer duration of breastfeeding has been associated with a lower risk of childhood obesity, the impact on specific organ fat depots is largely unknown., Objective: We examined the associations of any breastfeeding, duration and exclusiveness of breastfeeding, and of age at introduction of solid foods with measures of general, visceral, and organ adiposity at 10 y., Design: In a population-based prospective cohort study in 4444 children, we obtained information on infant feeding by questionnaires. At the mean age of 9.8 y, we estimated body mass index from height and weight; fat mass index and fat-free mass index by dual-energy X-ray absorptiometry; and visceral fat index, pericardial fat index, and liver fat fraction by MRI. MRI scans were performed in a subgroup of 2646 children., Results: After adjustment for age and sex, we observed associations of infant feeding with all general, visceral, and organ fat outcomes, except for pericardial fat index, at the age of 10 y. After further adjustment for family-based sociodemographic, maternal lifestyle-related, and childhood factors, only the associations of shorter breastfeeding duration and nonexclusive breastfeeding with a lower fat-free mass index remained significant (P < 0.05). The associations of infant feeding with visceral fat index and liver fat fraction were attenuated to nonsignificant. Maternal education was found to be the strongest confounder., Conclusion: Our results suggest that the assoiations of any breastfeeding, duration and exclusiveness of breastfeeding, and age at the introduction of solid foods with general, visceral, and organ fat measures at the age of 10 y are largely explained by family-based sociodemographic factors.

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., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Air pollution exposure during fetal life has been related to impaired child neurodevelopment, but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children., Methods: We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002-2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at 6 to 10 years of age (n = 783). Models were adjusted for several socioeconomic and lifestyle characteristics., Results: Mean fine particle levels were 20.2 μg/m 3 (range, 16.8-28.1 μg/m 3 ). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g., cerebral cortex of the precuneus region in the right hemisphere was 0.045 mm thinner (95% confidence interval, 0.028-0.062) for each 5-μg/m 3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes., Conclusions: Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex, and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Maternal fatty acids are essential for fetal growth and development. Here, we examine associations between maternal mid-pregnancy plasma n-3 and n-6 polyunsaturated fatty acids (PUFAs) and fetal health determined by fetal growth velocity, birth weight and duration of pregnancy., Methods: Participants were 6974 pregnant women and their infants from a population-based birth cohort, the Generation R Study. Maternal plasma n-3:n-6 PUFA ratio and n-3 and n-6 PUFA percentage in glycerophospholipids in mid-pregnancy were related to fetal growth velocity calculated from repeatedly measured weight, length and head circumference, birth weight, and duration of pregnancy., Results: A higher maternal mid-pregnancy n-3:n-6 PUFA ratio was associated with a higher growth velocity of the fetal weight (β = 0.082 SD-score/week, 95% CI 0.055; 0.108, P < 0.001), length (β = 0.085 SD-score/week, 95% CI 0.052; 0.119, P < 0.001); and head (β = 0.055 SD-score/week, 95% CI 0.019; 0.091, P = 0.003). We also observed positive associations between n-3:n-6 PUFA ratio and birth weight (β = 0.76 SD-score, 95% CI 0.22; 1.29, P = 0.006), and duration of pregnancy (β = 1.32 weeks, 95% CI 0.24; 2.40, P = 0.02)., Conclusions: These results are consistent with the hypothesis that a higher n-3:n-6 PUFA ratio is important for fetal health., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Sex-specific body mass index (BMI) and waist circumference (WC) cut-off values have been validated for a limited number of ethnic groups. We aimed to derive these cut-off values for Amerindians, Creoles, Hindustani, Javanese, Maroons and Mixed living in Suriname., Methods: Data from individuals aged 20-65, in the Suriname Health Study was used to derive optimal cut-off values for BMI and WC for the prediction of hypertension (n=4910) and cardio-metabolic risk (n=2924). Results from the analysis with Receiver Operating Curves were calculated and compared these with recommended values., Results: The area under the ROC curve was consistently higher for WC compared to BMI among Creoles, Hindustani, Maroons and Mixed. The BMI cut-off values ranged from 24.8kg/m 2 for Creole men and 26.9kg/m 2 for Maroon women to 28.4kg/m 2 and 30.2kg/m 2 for Amerindian men and women, respectively. The WC cut-off values ranged from 80.7cm for Maroon men, 86.7cm for Javanese women to 90.8cm for Hindustani men and 95.7cm for Amerindian women. Optimal BMI cut-off values approximated Asian cut-off values from the World Health Organization whilst those of WC for men approximated and for women exceeded cut-off values from the International Diabetes Federation., Conclusion: In most ethnic groups, we found better discriminatory power for WC compared to BMI in the relation with cardiovascular risk factors. The estimated BMI and WC cut-off values differed between ethnic groups. Further studies are needed to identify cut-off values related to the future risk of cardiovascular disease and mortality., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: Exposure to different concentrations of fatty acids during fetal life may affect growth and metabolism. However, most studies examined individual fatty acids, whereas concentrations highly correlate and may interact with each other. We aimed to evaluate patterns of plasma fatty acids during pregnancy and their associations with growth, body composition, and cardiometabolic health of the 6-year-old offspring., Methods: This study was performed in 4830 mother-child pairs participating in a population-based cohort in the Netherlands. Around 20 weeks of gestation, we measured plasma phospholipid concentrations of 22 fatty acids, in which we identified three fatty acid patterns using principal component analysis: a 'high n-6 polyunsaturated fatty acid (PUFA)' pattern, a 'monounsaturated and saturated fatty acid (MUFA and SFA)' pattern, and a 'high n-3 PUFA' pattern. When the children were 6 years old, we measured their anthropometrics and detailed body composition (using dual-energy X-ray absorptiometry), and we calculated their body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI). At the same age, children's blood pressure, and serum insulin, HDL-cholesterol, and triacylglycerol were measured., Results: After adjustment for confounders and the other patterns, a higher score for the 'high n-6 PUFA' pattern during pregnancy was associated with a higher height, BMI, and FFMI in the offspring at 6 years, but not independently with cardiometabolic outcomes. The 'MUFA and SFA' pattern was not consistently associated with child body composition or cardiometabolic health. A higher score for the 'high n-3 PUFA' pattern was associated with a lower FMI, higher FFMI, higher HDL-cholesterol, and lower triacylglycerol., Conclusions: Our results suggest that plasma fatty acid patterns during pregnancy may affect offspring's body composition and cardiometabolic health. Specifically, a pattern characterized by high n-3 PUFA levels was associated with a more favorable body composition and blood lipid profile., (Copyright © 2017. Published by Elsevier Ltd.)

Background & Aims: Dietary intake could induce a mild maternal metabolic acidosis that might lead to a higher level of blood pressure. Because studies in pregnancy are scarce, we evaluated the association between maternal dietary acid load and changes in blood pressure during pregnancy, pregnancy-induced hypertension and pre-eclampsia., Methods: We included 3411 pregnant women of Dutch ancestry from a prospective population-based cohort (Rotterdam, The Netherlands). Dietary data was self-reported via a food-frequency questionnaire in early pregnancy. Four dietary acid load measurements were calculated: dietary potential renal acid load (dPRAL), net endogenous acid production (NEAP), animal protein/potassium ratio, and vegetable protein/potassium ratio. Diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured three times during pregnancy. Information on pregnancy-induced hypertension and pre-eclampsia was obtained from medical records. Linear mixed models and logistic regression were used and adjusted for sociodemographic and lifestyle factors., Results: The results indicated that dPRAL, NEAP and animal protein/potassium ratio were not associated with DBP or SBP in pregnancy. One standard deviation higher vegetable protein/potassium ratio was associated with lower DBP (-0.30 mmHg [95% CI -0.54; -0.06]) but not with SBP (-0.29 mmHg [95% CI -0.60; 0.01]). Dietary acid load measurement was neither associated with the prevalence of pregnancy-induced hypertension nor with pre-eclampsia., Conclusions: Dietary acid load was not associated with changes in DBP or SBP during pregnancy, although women with a higher vegetable protein/potassium ratio had a slightly lower DBP. Dietary acid load was not associated with pregnancy-induced hypertension or pre-eclampsia., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Gestational hypertensive disorders (GHDs), including gestational hypertension and preeclampsia, are associated with an increased risk of cardiovascular disease in later life, possibly through an atherogenic lipid profile., Objective: The objective of this study is to assess if women with a previous GHD have a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy., Methods: In a population-based prospective cohort study, we included 4933 women during pregnancy, including 302 women with a GHD. Six years after pregnancy, we determined maternal lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein[a], and apolipoprotein B) and glucose levels., Results: Women with a previous GHD had a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. These atherogenic lipid profiles were a result of higher levels of triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B and lower levels of high-density lipoprotein cholesterol. Differences in lipid profile between women with a previous GHD and women with a previous normotensive pregnancy were attenuated after adjustment for prepregnancy body mass index. Between women from both groups, no differences were observed in total cholesterol, lipoprotein[a], and glucose levels., Conclusion: Women with a previous GHD show a more atherogenic lipid profile 6 years after pregnancy than women with a previous normotensive pregnancy. The increased risk of cardiovascular disease after a GHD might result from an atherogenic lipid profile after pregnancy, primarily driven by prepregnancy body mass index., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background & Aims: A role of vitamin D in the development of respiratory and allergic disease in children remains unclear. It may be likely that vitamin D has an effect on airway inflammation, but only few studies examined the effect in children. We aimed to examine whether serum 25-hydroxyvitamin D (25(OH) vitamin D) concentrations are associated with the fraction of exhaled nitric oxide (FeNO), airway interrupter resistance (Rint), physician diagnosed asthma ever, wheezing and eczema in a population-based cohort study in 6 year old children., Methods: Serum 25(OH) vitamin D concentration was assessed in 3815 children. 25(OH) vitamin D concentrations ≥75 nmol/L were considered as sufficient, between 50 and 75 nmol/L as insufficient, and <50 nmol/L as deficient. FeNO and Rint were measured at the research center. Data on physician diagnosed asthma, wheezing, and eczema were obtained by parent-reported questionnaires., Results: In comparison with sufficient 25(OH) vitamin D concentration, deficient concentrations were associated with elevated FeNO of ≥25 ppb (OR: 2.54; 95% CI: 1.34-4.80). In addition, deficient and insufficient 25(OH) vitamin D concentrations were associated with a lower Rint (Z-score: -1.26; 95% CI: -1.66 to -0.85) (ß: -0.75; 95% CI: -1.08 to -0.42), and increased risks of eczema (OR: 1.65; 95% CI: 1.13-2.41) (OR: 1.44; 95% CI: 1.06-1.95). Insufficient 25(OH) vitamin D concentration were associated with a decreased risk of physician diagnosed asthma ever (OR: 0.59; 95% CI: 0.38-0.94)., Conclusions: Our results indicate that lower 25(OH) vitamin D levels are associated with elevated FeNO levels, but lower Rint values. Lower 25(OH) vitamin D levels are also associated with a decreased risk for asthma diagnoses but an increased risk for eczema., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Exposure to bisphenols and phthalates in pregnancy may lead to adverse health effects in women themselves and their offspring., Objective: To describe first trimester bisphenol and phthalate urine concentrations, including bisphenol and phthalate replacements, and determine nutritional, socio-demographic and lifestyle related determinants., Methods: In a population-based prospective cohort of 1396 mothers, we measured first trimester bisphenol, phthalate and creatinine urine concentrations (samples collected in 2004-2005, median gestational age 12.9 weeks [inter-quartile range (IQR) 12.1-14.4]). We examined associations of potential determinants with log-transformed bisphenol and phthalate concentrations. Outcomes were back-transformed. Nutritional analyses were performed in a subgroup of 642 Dutch participants only, as the Food Frequency Questionnaire was aimed at Dutch food patterns., Results: Bisphenol A, bisphenol S, and bisphenol F were detected in 79.2%, 67.8% and 40.2% of the population, respectively. Mono-n-butylphthalate, mono-(2-ethyl-5-hydroxyhexyl)phthalate and monobenzylphthalate were detected in > 90% of the population. Nutritional intake was not associated with bisphenol and phthalate concentrations after correction for multiple testing was applied. Obesity was associated with higher high-molecular-weight phthalate concentrations and the lack of folic acid supplement use with higher di-n-octylphthalate concentrations (respective mean differences were 46.73nmol/l [95% CI 14.56-93.72] and 1.03nmol/l [0.31-2.06])., Conclusion: Bisphenol S and F exposure was highly prevalent in pregnant women in the Netherlands as early as 2004-5. Although associations of dietary and other key factors with bisphenol and phthalate concentrations were limited, adverse lifestyle factors including obesity and the lack of folic acid supplement use seem to be associated with higher phthalate concentrations in pregnant women. The major limitation was the availability of only one urine sample per participant. However, since phthalates are reported to be quite stable over time, results concerning determinants of phthalate concentrations are expected to be robust., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Parental restrictive feeding (i.e., limiting food intake of children) has been linked to childhood overweight. However, the directionality of the causal pathway remains unknown. Objective: The objectives of this study were to examine the bidirectional association of maternal restrictive feeding with children's weight and body composition across childhood and to explore a possible mediating role of maternal concern about child weight. Design: Data were available for 4689 mother-child dyads participating in Generation R, a prospective birth cohort in the Netherlands. At ages 4 and 10 y, restrictive feeding was assessed with the parent-reported Child Feeding Questionnaire, and children's body mass index (BMI) was measured. At age 6 y, fat mass index (FMI) and fat-free mass index (FFMI) were measured with dual-energy X-ray absorptiometry. Both directions of the relation between restriction and child body composition were examined with multivariable linear regression analyses and cross-lagged modeling. Mediation analyses were performed to examine concern about child weight (mother reported at child age of 10 y) as a potential mediator. Results: Higher child sex- and age-adjusted BMI SD scores ( z BMI) at age 4 y predicted more restrictive feeding at age 10 y (B = 0.15; 95% CI: 0.11, 0.18). Both sex- and age-adjusted FMI SD scores ( z FMI) and sex-and age-adjusted FFMI SD scores ( z FFMI) at 6 y were also positively associated with restrictive feeding at 10 y. Maternal concern about child weight partially mediated these associations from child body composition to restrictive feeding (e.g., for zBMI at 4 y: B indirect = 0.10; 95% CI: 0.07, 0.13). There was no temporal association from restrictive feeding at age 4 y to child z BMI at age 10 y after adjustment for baseline z BMI. Conclusions: The continued use of restrictive feeding practices at age 10 y appeared to be primarily a response of mothers to an unhealthy weight of their child rather than a cause of children's overweight. Guidelines discouraging restrictive feeding for preventing childhood overweight should therefore be reconsidered., (© 2017 American Society for Nutrition.)

Objective: Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions., Method: Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n = 6,209) and 10 (n = 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n = 4,402, and Swedish Twin Study of Child and Adolescent Development, n = 1,089) and a clinical sample (n = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist., Results: Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16)., Conclusion: This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuroimaging and genetic measures., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of our study was to investigate the association of different socioeconomic and sociodemographic factors with dental caries in six-year-old children. Furthermore, we applied a district based approach to explore the distribution of dental caries among districts of low and high socioeconomic position (SEP)., Methods: In our cross-sectional study 5189 six-year-olds were included. This study was embedded in a prospective population-based birth cohort study in Rotterdam, the Netherlands, the Generation R Study. Parental education level, parental employment status, net household income, single parenting, and teenage pregnancy were considered as indicators for SEP. Dental caries was scored on intraoral photographs by using the decayed, missing, and filled teeth (dmft) index. We compared children without caries (dmft=0) to children with mild caries (dmft=1-3) or severe caries (dmft >3). Multinomial logistic regression analyses and binary logistic regression analyses were performed to study the association between SEP and caries, and between district and caries, respectively., Results: Only maternal education level remained significantly associated with mild caries after adjusting for all other SEP-indicators. Paternal educational level, parental employment status, and household income additionally served as independent indicators of SEP in children with severe caries. Furthermore, living in more disadvantaged districts was significantly associated with higher odds of dental caries., Conclusion: Dental caries is more prevalent among six-year-old children with a low SEP, which is also visible at the district level. Maternal educational level is the most important indicator of SEP in the association with caries., Clinical Significance: Our results should raise concerns about the existing social inequalities in dental caries and should encourage development of dental caries prevention strategies. New knowledge about the distribution of oral health inequalities between districts should be used to target the right audience for these strategies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Autism spectrum disorder (ASD) is thought to arise from aberrant development of connections in the brain. Previous studies have identified differences in white matter microstructure in children with ASD, offering support to such hypotheses. While ASD is thought to represent the severe end of a spectrum of traits, there are no studies evaluating white matter microstructure in relation to autistic traits in children from the general population. In a population-based sample of 604 6-to-10 year-old children, we assessed the relation between a continuous measure of autistic traits and white matter microstructure, using both probabilistic tractography and Tract-Based Spatial Statistics (TBSS). Using the TBSS approach, a cluster in the left superior longitudinal fasciculus (SLF) was identified where autistic traits negatively associated with fractional anisotropy (FA). In addition, two clusters of lower axial diffusion were identified; one in the corpus callosum and another in the corticospinal tract. Part of the findings remained when excluding children with ASD and were paralleled with similar, trend-level differences in 19 children with ASD, compared to matched controls. This study showed localized associations between autistic traits on a continuum and white matter microstructure, which could indicate a continuum of the neurobiology along the spectrum of autistic symptoms., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Nausea and occasional vomiting in early pregnancy is common. Why some women experience severe nausea and occasional vomiting in early pregnancy is unknown. Causes are multifactorial and only symptomatic treatment options are available, although adverse birth outcomes have been described. Helicobacter pylori infection has been implicated in the cause of nausea and occasional vomiting in early pregnancy., Objective: The purpose of this study was to investigate the association of H pylori with vomiting severity in pregnancy and its effect on birth outcome., Study Design: We assembled a population-based prospective cohort of pregnant women in The Netherlands. Enrolment took place between 2002 and 2006. H pylori serology was determined in mid gestation. Women reported whether they experienced vomiting in early, mid, and late gestation. Maternal weight was measured in the same time periods. Birth outcomes were obtained from medical records. Main outcome measures were vomiting frequency (no, occasional, daily) and duration (early, mid, late gestation), maternal weight gain, birthweight, small for gestational age, and prematurity. Data were analyzed with the use of multivariate regression., Results: We included 5549 Women, of whom 1932 (34.8%) reported occasional vomiting and 601 (10.8%) reported daily vomiting. Women who were H pylori-positive (n=2363) were more likely to report daily vomiting (adjusted odds ratio, 1.44; 95% confidence interval, 1.16-1.78). H pylori-positivity was associated with a reduction of total weight gain in women with daily vomiting (adjusted difference, -2.1 kg; 95% confidence interval, -2.7 to -1.5); infants born to women with H pylori and daily vomiting had slightly reduced birthweight (addjusted difference -60g; 95% confidence interval, -109 - -12) and an increased risk of being small for gestational age (adjusted odds ratio, 1.49; 95% confidence interval, 1.04-2.14). H pylori and daily vomiting did not significantly affect prematurity rate., Conclusion: This study suggests that H pylori is an independent risk factor for vomiting in pregnancy. In women with daily vomiting, H pylori is also associated with low maternal weight gain, reduced birth weight, and small for gestational age. Because effective treatments for severe nausea and occasional vomiting in early pregnancy are currently lacking, the effect of H pylori eradication therapy on nausea and occasional vomiting in early pregnancy symptom severity should be the target of future studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Not much is known about the associations of maternal obesity and excessive gestational weight gain with body fat in infancy., Objective: To examine the associations of maternal pre-pregnancy body mass index and gestational weight gain with infant subcutaneous fat., Methods: In a population-based prospective cohort study among 845 mothers and their infants, we obtained maternal pre-pregnancy body mass index and measured maternal weight during pregnancy. At 1.5, 6 and 24months, we estimated infant total subcutaneous fat (sum of biceps, triceps, suprailiacal and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat)., Results: Maternal body mass index was positively associated with higher infant body mass index from 6months onwards. Maternal body mass index was not associated with infant subcutaneous fat measures at 1.5 or 6months. A 1-standard deviation scores (SDS) higher maternal body mass index was associated with a 0.09 (95% Confidence Interval 0.01, 0.17) SDS higher infant total subcutaneous fat at 24months, but not with central-to-total subcutaneous fat ratio. No associations were present for maternal total or period-specific gestational weight gain with infant fat., Conclusion: Maternal body mass index was positively associated with infant body mass index and total subcutaneous fat in late infancy. Maternal total and period-specific gestational weight gain were not associated with infant body fat mass measures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016. Published by Elsevier Ltd.)

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., (© 2017 American Society for Nutrition.)

Background: Evidence is plentiful that trans fatty acids (TFAs) induce vascular inflammation with adverse metabolic consequences. However, it is not clear whether TFAs increase the risk of vascular pregnancy complications such as preeclampsia. Objective: We investigated associations between midpregnancy maternal plasma trans 18:1 fatty acid (t18:1) concentrations and pregnancy course and outcomes. Methods: Participants were 6695 pregnant women and newborns from the Generation R Study, Rotterdam, Netherlands (enrollment in 2001-2005). Maternal midpregnancy (mean ± SD gestational age: 20.7 ± 1.2 wk) t18:1 plasma concentrations were determined and related to gestational age and sex-adjusted birth weight SD scores, placental weight, and the risk of preeclampsia. In addition, we explored potential time trends by testing the association of maternal plasma t18:1 concentrations with birth weight in birth cohorts given the Dutch industry-initiative to lower food TFA contents during the inclusion period. Multiple logistic and linear regression analyses were performed, taking various socioeconomic and biological covariates into account. Results: A higher midpregnancy maternal plasma t18:1 concentration was associated with lower birth weight (SD score, adjusted β: -0.10; 95% CI: -0.15, -0.04; P < 0.001) and placental weight (kilograms, adjusted β: -10,65; 95% CI: -20.23, -1.07; P = 0.03) and with a higher risk of preeclampsia (adjusted OR: 1.65; 95% CI: 1.10, 2.49; P = 0.02). We observed a 31% decrease in the median plasma t18:1 concentration in our population over time, but the association between the plasma t18:1 concentration standardized per birth year and birth weight was comparable between birth-year cohorts (years 2001-2005). Conclusions: A higher maternal midpregnancy plasma t18:1 concentration was associated with lower birth weight and placental weight and with a higher risk of preeclampsia. Although the intake of TFAs in our population decreased during the inclusion period, the association with adverse pregnancy outcomes was unchanged even at lower maternal plasma t18:1 concentrations., (© 2017 American Society for Nutrition.)

Background: Studies in adults indicate that a lower saturated and higher unsaturated fat intake is associated with a lower risk of metabolic syndrome and cardiovascular diseases. However, studies on fat intake in relation to cardiometabolic health during childhood are scarce. Objective: We examined associations between dietary intake of fatty acids (FAs) at age 1 y and measures of growth, adiposity, and cardiometabolic health up to age 6 y. Methods: This study was conducted in 2927 children participating in the Generation R Study, a multiethnic, prospective, population-based cohort in the Netherlands. We measured children's total fat intake and intakes of saturated FAs (SFAs), monounsaturated FAs (MUFAs), and polyunsaturated FAs (PUFAs) at a median age of 12.9 mo (95% range: 12.2, 18.9 mo) with a food-frequency questionnaire. We repeatedly measured their height and weight up to age 6 y. At 6 y of age, we measured body fat percentage, diastolic and systolic blood pressure, and serum insulin, triacylglycerol, and HDL cholesterol. These outcomes were combined into a cardiometabolic risk factor score. We examined associations of FA intake with repeated measures of height, weight, and body mass index by using linear mixed models and with cardiometabolic outcomes by using linear regression models, adjusting for sociodemographic and lifestyle factors and taking into account macronutrient substitution effects. Results: In multivariable models, we observed no associations of a higher intake of total fat or SFAs, MUFAs, or PUFAs with growth, adiposity, or cardiometabolic health when fat was consumed at the expense of carbohydrates. In subsequent models, there were also no associations observed for higher MUFA or PUFA intakes at the expense of SFAs with any of the outcomes. Results did not differ by sex, ethnicity, age, or birth weight. Conclusion: The results of this study did not support our hypothesis that intake of different types of FAs was associated with adiposity or cardiometabolic health among children., (© 2017 American Society for Nutrition.)

Lipid concentrations are heritable traits. Recently, the number of known genetic loci associated with lipid levels in adults increased from 95 to 157. The effects of these 157 loci have not been tested in children. Considering that lipid levels track from childhood to adulthood, we studied to determine whether these variants already affected lipid concentrations in a large group of 2,645 children with a median age of 6.0 years (95% range 5.7-7.3 years) from the population-based Generation R Study. Twenty-eight SNPs associated with TGs, 39 SNPs associated with total cholesterol (TC), 28 SNPs associated with LDL cholesterol (LDL-C), and 56 SNPs associated with HDL cholesterol (HDL-C) were analyzed individually and combined into genetic risk scores (GRSs). All risk scores were associated with their specific outcomes. The differences in mean absolute lipid and lipoprotein values between the 10% of children with the highest lipid or lipoprotein GRS versus the 10% with the lowest score were 0.28, 0.25, 0.32, and 0.30 mmol/l for TGs, TC, LDL-C, and HDL-C, respectively. In conclusion, we show for the first time that GRSs based on 157 SNPs associated with adult lipid concentrations are associated with lipid levels in children. The genetic background of these phenotypes at least partly overlaps between children and adults., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Co-occurrence of mental disorders is commonly observed, but the etiology underlying this observation is poorly understood. Studies in adolescents and adults have identified a general psychopathology factor associated with a high risk for different psychiatric disorders. We defined a multi-informant general psychopathology factor in school-aged children and estimated its single nucleotide polymorphism (SNP) heritability. The goal was to test the hypothesis that child behavioral and emotional problems are under the influence of highly pleiotropic common autosomal genetic variants that nonspecifically increase the risk for different dimensions of psychopathology., Method: Children from the Generation R cohort were repeatedly assessed between ages 6 to 8 years. Child behavior problems were reported by parents, teachers, and children. Confirmatory factor analysis estimated a general psychopathology factor across informants using various psychiatric problem scales. Validation of the general psychopathology factor was based on IQ and temperamental measures. Genome-wide complex trait analysis (GCTA) was used to estimate the SNP heritability (N = 2,115)., Results: The general psychopathology factor was associated with lower IQ, higher negative affectivity, and lower effortful control, but not with surgency. Importantly, the general psychopathology factor showed a significant SNP heritability of 38% (SE = 0.16, p = .008)., Conclusion: Common autosomal SNPs are pleiotropically associated with internalizing, externalizing, and other child behavior problems, and underlie a general psychopathology factor in childhood., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)