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Knowledge on determinants of children’s psychosocial care use is important to improve their access to care. This study examined the independent contributions of need and predisposing factors to psychosocial care use in 9-year-old children, guided by the Gateway Provider Model. Data of the Generation R Study, a prospective cohort of children born in Rotterdam, the Netherlands, were analysed using multivariable logistic regression (n = 4714). Need (quality of life, presence and type of emotional/behavioural problems) and predisposing factors (sex, ethnic background and maternal educational level) were measured using parent questionnaires at multiple time points between ages 1.5 and 9 years. Psychosocial care use was parent-reported at 9 years old (9.6% among children with Western background, 7.3% among children with non-Western background). Having emotional/behavioural problems at 5 and 9 years old was associated with more care use, while having a higher quality of life, being a girl and having a Moroccan/Turkish or other non-Western background were associated with less care use. Externalising and internalising problems, as well as several types of problems, at 5 and 9 years old were associated with psychosocial care use. Stratified analyses revealed that, in children with non-Western backgrounds, only a poorer psychosocial quality of life was associated with psychosocial care use. To conclude, girls with a Western background and children with a non-Western background were less likely to receive care compared to their peers. Children with parent-reported emotional/behavioural problems at 5 and 9 years old and decreased quality of life at 5 years old were more likely to receive psychosocial care use at 9 years old. Our findings hold relevance for preventive policies.

Background and aims: Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors. Design: First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner's substance use). The results were meta-analysed across the cohorts. Secondly, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. Setting: We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. Participants: Phenotype data available for children were: N ALSPAC = 5455–7751; N GENR = 1537–3119; N MOBA = 28 053–42 206. Genotype data available for mothers was: N ALSPAC = 7074; N MOBA = 14 583. Measurements: A measure of offspring ADHD symptoms at age 7–8 years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. Findings: The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms [odds ratio (OR) SMOKING = 1.11, 95% confidence interval (CI) = 1.00–1.23; OR ALCOHOL = 1.27, 95% CI = 1.08–1.49; OR CAFFEINE = 1.05, 95% CI = 1.00–1.11], while not for fathers (OR SMOKING = 1.03, 95% CI = 0.95–1.13; OR ALCOHOL = 0.83, 95% CI = 0.47–1.48; OR CAFFEINE = 1.02, 95% CI = 0.97–1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa. Conclusions: There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms.

Purpose To investigate the spinopelvic alignment and vertebral shape in children, and associations with body composition and structural spinal abnormalities on magnetic resonance imaging (MRI). Methods We performed a cross-sectional study embedded in the Generation R Study, a prospective population-based birth cohort. Pelvic incidence and vertebral concavity ratios for each lumbar level were determined on sagittal MRI images in 9-year-old children, and structural spinal abnormalities were scored semi-quantitatively. The BMI-SD score was calculated, and body composition was assessed using DXA scans. Associations of pelvic incidence and vertebral concavity ratios with structural abnormalities and body composition measures were assessed using (multilevel) regression analyses. Results This study included 522 participants (47.7% boys), aged 9.9 years (IQR 9.7–10.0). The mean pelvic incidence was 36.6° (SD 8.0). Vertebral concavity ratios ranged from 0.87 to 0.90, with significantly lower ratios for boys compared to girls. Associations were found for a larger pelvic incidence with decreased disc height [OR 1.03 (95% CI 1.02–1.05)], and a pelvic incidence in the lowest tertile with less disc bulging [OR 0.73 (95% CI 0.56–0.95)]. Increased vertebral concavity ratio was associated with decreased disc height [OR 14.16 (95% CI 1.28–157.13)]. Finally, increased fat-free mass index was associated with a smaller pelvic incidence [adjusted OR 0.85 (95% CI 0.07–1.63)]. Conclusion The mean pelvic incidence of 9-year-old children is 36.6° on supine MRI images, and a slightly concave shape of the lumbar vertebrae is seen. Spinopelvic alignment is associated with structural spinal abnormalities, and might itself be influenced by the children’s body composition.

Objective Pediatric obsessive-compulsive disorder (OCD) and clinically relevant obsessive-compulsive symptoms in the general population are associated with increased thalamic volume. It is unknown whether this enlargement is explained by specific thalamic subregions. The relation between obsessive-compulsive symptoms and volume of thalamic subregions was investigated in a population-based sample of children. Method Obsessive-compulsive symptoms were measured in children (9–12 years of age) from the Generation R Study using the Short Obsessive-Compulsive Disorder Screener (SOCS). Thalamic nuclei volumes were extracted from structural 3T magnetic resonance imaging scans using the ThalamicNuclei pipeline and regrouped into anterior, ventral, intralaminar/medial, lateral, and pulvinar subregions. Volumes were compared between children with symptoms above clinical cutoff (probable OCD cases, SOCS ≥ 6, n = 156) and matched children without symptoms (n = 156). Linear regression models were fitted to investigate the association between continuous SOCS score and subregional volume in the whole sample (N = 2500). Results Children with probable OCD had larger ventral nuclei compared with children without symptoms (d = 0.25, p = .025, false discovery rate adjusted p = .126). SOCS score showed a negative association with pulvinar volume when accounting for overall thalamic volume (β = −0.057, p = .009, false discovery rate adjusted p = .09). However, these associations did not survive multiple testing correction. Conclusion The results suggest that individual nuclei groups contribute in varying degrees to overall thalamic volume in children with probable OCD, although this did not survive multiple comparisons correction. Understanding the role of thalamic nuclei and their associated circuits in pediatric OCD could lead toward treatment strategies targeting these circuits.

Context Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. Objective First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. Design, Setting, and Participants Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. Main Outcome Measures Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. Results A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values Conclusions A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Supplemental digital content is available in the text., SIGNIFICANCE Our findings show that non-Dutch background, lower maternal education, and lower net household income level may be new risk factors for myopia development in the Netherlands. Newly introduced physical activity spaces may not be effective enough in increasing outdoor exposure in children to reduce eye growth. PURPOSE The aims of this study were to evaluate socioeconomic inequalities in myopia incidence, eye growth, outdoor exposure, and computer use and to investigate if newly introduced physical activity spaces can reduce eye growth in school-aged children. METHODS Participants (N = 2643) from the Dutch population–based birth cohort Generation R were examined at ages 6 and 9 years. Socioeconomic inequalities in myopia incidence, eye growth, and lifestyle were determined using regression analyses. Information on physical activity spaces located in Rotterdam was obtained. Differences in eye growth between those who became exposed to new physical activity spaces (n = 230) and those nonexposed (n = 1866) were evaluated with individual-level fixed-effects models. RESULTS Myopia prevalence was 2.2% at age 6 years and 12.2% at age 9 years. Outdoor exposure was 11.4 h/wk at age 6 years and 7.4 h/wk at age 9 years. Computer use was 2.1 h/wk at age 6 years and 5.2 h/wk at age 9 years. Myopia incidence was higher in children with non-Dutch background, and families with lower household income and lower maternal education (odds ratio [OR], 1.081 [95% confidence interval, 1.052 to 1.112]; OR, 1.035 [95% confidence interval, 1.008 to 1.063]; OR, 1.028 [95% confidence interval, 1.001 to 1.055], respectively). Children living

Purpose To investigate the association between smartphone use and refractive error in teenagers using the Myopia app. Design Cross-sectional population-based study. Participants A total of 525 teenagers 12 to 16 years of age from 6 secondary schools and from the birth cohort study Generation R participated. Methods A smartphone application (Myopia app; Innovattic) was designed to measure smartphone use and face-to-screen distance objectively and to pose questions about outdoor exposure. Participants underwent cycloplegic refractive error and ocular biometry measurements. Mean daily smartphone use was calculated in hours per day and continuous use as the number of episodes of 20 minutes on screen without breaks. Linear mixed models were conducted with smartphone use, continuous use, and face-to-screen distance as determinants and spherical equivalent of refraction (SER) and axial length-to-corneal radius (AL:CR) ratio as outcome measures stratified by median outdoor exposure. Main Outcome Measures Spherical equivalent of refraction in diopters and AL:CR ratio. Results The teenagers on average were 13.7 ± 0.85 years of age, and myopia prevalence was 18.9%. During school days, total smartphone use on average was 3.71 ± 1.70 hours/day and was associated only borderline significantly with AL:CR ratio (β = 0.008; 95% confidence interval [CI], –0.001 to 0.017) and not with SER. Continuous use on average was 6.42 ± 4.36 episodes of 20-minute use without breaks per day and was associated significantly with SER and AL:CR ratio (β = –0.07 [95% CI, –0.13 to –0.01] and β = 0.004 [95% CI, 0.001–0.008], respectively). When stratifying for outdoor exposure, continuous use remained significant only for teenagers with low exposure (β = –0.10 [95% CI, –0.20 to –0.01] and β = 0.007 [95% CI, 0.001–0.013] for SER and AL:CR ratio, respectively). Smartphone use during weekends was not associated significantly with SER and AL:CR ratio, nor was face-to-screen distance. Conclusions Dutch teenagers spent almost 4 hours per day on their smartphones. Episodes of 20 minutes of continuous use were associated with more myopic refractive errors, particularly in those with low outdoor exposure. This study suggested that frequent breaks should become a recommendation for smartphone use in teenagers. Future large longitudinal studies will allow more detailed information on safe screen use in youth.

Background There is limited evidence regarding socioeconomic inequalities of exposure to the food environment and its contribution to childhood obesity. Methods We used data from 4235 children from the Generation R Study, a large birth-cohort conducted in the city of Rotterdam, The Netherlands. We included 11,277 person-observations of body mass index (BMI) and 6240 person-observations of DXA-derived fat mass index (FMI) and fat-free mass index (FFMI) when children were between 4 and 14 years. We applied linear regression models to evaluate changes in the relative and absolute exposure of fast-food outlets, and the healthiness of the food environment within 400 m from home by maternal education. Furthermore, we used individual-level fixed-effects models to study changes in the food environment to changes in BMI, FMI and FFMI. Results Children from lower educated mothers were exposed to more fast-food outlets at any time-point between the age of 4 and 14 years. Over a median period of 7.1 years, the absolute (0.6 fast-food outlet (95% CI: 0.4–0.8)) and relative (2.0%-point (95% CI: 0.7–3.4)) amount of fast-food outlets increased more for children from lower as compared to higher educated mothers. The food environment became more unhealthy over time, but no differences in trends were seen by maternal education level. Changes in the food environment were not associated with subsequent changes in BMI, FMI and FFMI. For children from lower educated mothers not exposed to fast-food at first, we found some evidence that the introduction of fast-food was associated with small increases in BMI. Conclusions Our findings provide evidence of widening inequalities in exposure to fast-food in an already poor food environment. Access to more fast-food outlets does not seem to have an additional impact on BMI in contemporary contexts with ubiquitous fast-food outlets.

PurposeUrinary iodine-to-creatinine ratio (UI/Creat) reflects recent iodine intake but has limitations for assessing habitual intake. Thyroglobulin (Tg) concentration, which increases with thyroid size, appears to be an indicator of longer-term iodine status in children and adults, however, less is known in pregnancy. This study investigated the determinants of serum-Tg in pregnancy and its use as an iodine-status biomarker in settings of iodine-sufficiency and mild-to-moderate deficiency.MethodsStored blood samples and existing data from pregnant women from the Netherlands-based Generation R (iodine-sufficient) and the Spain-based INMA (mildly-to-moderately iodine-deficient) cohorts were used. Serum-Tg and iodine status (as spot-urine UI/Creat) were measured at median 13 gestational weeks. Using regression models, maternal socio-demographics, diet and iodine-supplement use were investigated as determinants of serum-Tg, as well as the association between UI/Creat and serum-Tg.ResultsMedian serum-Tg was 11.1 ng/ml in Generation R (n = 3548) and 11.5 ng/ml in INMA (n = 1168). When using 150 mu g/g threshold for iodine deficiency, serum-Tg was higher in women with UI/Creat < 150 vs >= 150 mu g/g (Generation R, 12.0 vs 10.4 ng/ml, P = 0.010; INMA, 12.8 vs 10.4 ng/ml, P < 0.001); after confounder adjustment, serum-Tg was still higher when UI/Creat < 150 mu g/g (regression coefficients: Generation R, B = 0.111, P = 0.050; INMA, B = 0.157, P = 0.010). Iodine-supplement use and milk intake were negatively associated with serum-Tg, whereas smoking was positively associated.ConclusionThe association between iodine status and serum-Tg was stronger in the iodine-deficient cohort, than in the iodine-sufficient cohort. Serum-Tg might be a complementary (to UI/Creat) biomarker of iodine status in pregnancy but further evidence is needed., European Journal of Nutrition, ISSN:1436-6207, ISSN:1436-6215

Autism spectrum disorders (ASD) are associated with widespread brain alterations. Previous research in our group linked autistic traits with altered gyrification, but without pronounced differences in cortical thickness. Herein, we aim to replicate and extend these findings using a larger and older sample. Additionally, we examined whether (a) brain correlates of autistic traits were associated with polygenic risk scores (PRS) for ASD, and (b) autistic traits are related with brain morphological changes over time in a subset of children with longitudinal data available. The sample included 2400 children from the Generation R cohort. Autistic traits were measured using the Social Responsiveness Scale (SRS) at age 6 years. Gyrification, cortical thickness, surface area, and global morphological measures were obtained from high-resolution structural MRI scans at ages 9-to-12 years. We performed multiple linear regression analyses on a vertex-wise level. Corresponding regions of interest were tested for association with PRS. Results showed that autistic traits were related to (a) lower gyrification in the lateral occipital and the superior and inferior parietal lobes, (b) lower cortical thickness in the superior frontal region, and (c) lower surface area in inferior temporal and rostral middle frontal regions. PRS for ASD and longitudinal analyses showed significant associations that did not survive correction for multiple testing. Our findings support stability in the relationship between higher autistic symptoms and lower gyrification and smaller surface areas in school-aged children. These relationships remained when excluding ASD cases, providing neurobiological evidence for the extension of autistic traits into the general population. Lay Summary: We found that school-aged children with higher levels of autistic traits had smaller total brain volume, cerebellum, cortical thickness, and surface area. Further, we also found differences in the folding patterns of the brain (gyrification). Overall, genetic susceptibility for autism spectrum disorders was not related to these brain regions suggesting that other factors could be involved in their origin. These results remained significant when excluding children with a diagnosis of ASD, providing support for the extension of the relationship between autistic traits and brain findings into the general population.

Background We aimed to investigate the associations between sociodemographic factors and instant messaging and social network site exposure among 9-year-old children. Methods Data of 4568 children from the Generation R study, a population-based cohort study performed in Rotterdam, the Netherlands, were analyzed. Instant messaging exposure was defined as using online chat applications such as MSN, chat boxes, WhatsApp, and Ping. Social network site exposure was defined as using Hyves or Facebook. A series of multiple logistic regression analyses were performed, adjusting for covariates. Results Children of low educated mothers had a higher odds ratio (OR) for instant messaging (OR: 1.44, 95% CI: 1.12, 1.86) and social network site exposure (OR: 1.73, 95% CI: 1.13, 2.66) than their counterparts. Being a child from a single-parent family was associated with instant messaging (OR: 1.48, 95% CI: 1.16, 1.88) and social network site exposure (OR: 1.34, 95% CI: 1.01, 1.78) more often than their counterparts. Children of low educated fathers (OR: 1.48, 95% CI: 1.12, 1.95) or from families with financial difficulties (OR: 1.28, 95% CI: 1.04, 1.59) were associated with a higher OR of social network site exposure than their counterparts. Conclusion The findings suggest that several indicators of lower social position are associated with higher social network site and instant messaging exposure among 9-year-old children. More research is needed in younger children to understand the determinants and impact of social media use.

Background To understand determinants of oral health inequalities, multilevel modelling is a useful manner to study contextual factors in relation to individual oral health. Several studies outside Europe have been performed so far, however, contextual variables used are diverse and results conflicting. Therefore, this study investigated whether neighbourhood level differences in oral health exist, and whether any of the neighbourhood characteristics used were associated with oral health. Methods This study is embedded in The Generation R Study, a prospective cohort study conducted in The Netherlands. In total, 5 960 6-year-old children, representing 158 neighbourhoods in the area of Rotterdam, were included. Data on individual and neighbourhood characteristics were derived from questionnaires, and via open data resources. Caries was assessed via intraoral photographs, and defined as decayed, missing and filled teeth (dmft). Results Differences between neighbourhoods explained 13.3% of the risk of getting severe caries, and 2% of the chance of visiting the dentist yearly. After adjustments for neighbourhood and individual characteristics, neighbourhood deprivation was significantly associated with severe dental caries (OR: 1.48, 95% CI: 1.02–2.15), and suggestive of a low odds of visiting the dentist yearly (OR: 0.81, 95% CI: 0.56–1.18). Conclusions Childhood caries and use of dental services differs between neighbourhoods and living in a deprived neighbourhood is associated with increased dental caries and decreased yearly use of dental services. This highlights the importance of neighbourhoods for understanding differences in children’s oral health, and for targeted policies and interventions to improve the oral health of children living in deprived neighbourhoods.

Background: Previous studies have suggested that insufficient concentrations of vitamin D are associated with dental caries in primary teeth, but evidence remains inconclusive. Objectives: We assessed the longitudinal associations between prenatal, perinatal, and early childhood serum 25-hydroxyvitamin D concentrations [25(OH)D] and the risk of dental caries in 6-year-old children. Methods: This research was conducted within the Generation R Study, a large, multi-ethnic, prospective cohort study located in Rotterdam, the Netherlands. Dental caries were assessed in children using the decayed-missing-filled-primary teeth index at a mean age of 6.1 years (90% range, 4.8-9.1). We measured serum total 25(OH)D concentrations at 3 time points: prenatally (at 18-24 weeks of gestation), perinatally (at birth), and during early childhood (at age 6 years). We performed logistic regression analyses to determine the longitudinal association of serum 25(OH)D concentrations with caries risks in 5257 children. Additionally, we constructed a Genetic Risk Score (GRS) for the genetic predispositions to serum total 25(OH)D concentrations based on 6 vitamin D-related single nucleotide polymorphisms in a subsample of 3385 children. Results: Children with severe prenatal and early childhood serum 25(OH)D deficiencies (

Chronic pain and internalizing problems are characterized by concurrent associations but the directionality of this relationship in early childhood remains unclear. This prospective study aimed to investigate the bidirectional effect of chronic pain and internalizing problems and test the persistence of pain over time in a population-based sample of preschoolers. The study was embedded in Generation R, a large population-based cohort. Mothers of 3,996 children assessed their child’s experienced pain and internalizing problems at 3 and 6 years. At 3 years, paternal reports were available too. Reports of family functioning, discipline practices and parental psychopathology were also collected. The prevalence of chronic pain was 2.7% (106) and 8.0% (294) at baseline and follow-up, respectively. The presence of internalizing problems at child age 3 years predicted chronic pain at 6 years, for both maternal (OR 1.05, 95% CI 1.02,1.07, p < 0.001) and paternal (OR 1.03, 95%CI 1.00, 1.06, p < 0.05) internalizing problem reports, when adjusted for potential confounding factors. In contrast, chronic pain did not increase the likelihood of internalizing problems. The temporal relationship between chronic pain and internalizing problems appears to follow a largely unidirectional trend in early childhood, with internalizing problems increasing the likelihood of concurrent physical symptoms. Current understanding of the directionality of this relationship, highlights the importance for comprehensive assessment of psychiatric problems contributing to the manifestation of chronic pain.

Background: Being born small for gestational age (SGA

Objectives: Behavioural and lifestyle factors, as oral hygiene and diet, are well-established risk factors in the pathogenesis of dental caries, though displaying large differences in susceptibility across individuals. Since enamel formation already starts in utero, pregnancy course and outcome may eventually play a role in enamel strength and caries susceptibility. Therefore, we studied the association between history of pregnancy complications and the caries experience in their six-year-old children. The pregnancy complications included small for gestational age (SGA), spontaneous preterm birth (sPTB), gestational hypertension (GH), pre-eclampsia (PE), individually, and a combination of those, designated as placental syndrome. Methods: This study was embedded in Generation R, a prospective longitudinal Dutch multiethnic pregnancy cohort study. Information about pregnancy complications was obtained from questionnaires completed by midwives and obstetricians with cross-validation in medical records. These included SGA, sPTB, GH and PE. Caries experience was assessed with the decayed, missing and filled teeth (dmft) index at a mean age of six years. The association between dental caries experience and a history of pregnancy complications was studied by using hurdle negative binomial (HNB) models. Results: We were able to assess the dmft index in 5323 six-year-old children (mean age 6.2 years, SD 0.5). We did not find an association between the different pregnancy complications and dental caries experience in childhood, whether for SGA, sPTB, GH, PE, or for the combined outcome placental syndrome (HNB estimates: OR 1.02, 95%CI 0.87 - 1.19; RR 0.90, 95%CI 0.78 - 1.04). Further adjustment of the models with different confounders did not alter the outcome. Conclusions: Although it is expected that prenatal stress can be a risk factor for caries development later in life, our findings do not support this hypothesis. Therefore, we believe disparities in caries experience between children are probably not explained by early life events during a critical intrauterine period of development.

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, serumvitamin 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.

Weeland et al.1 discuss the relationship between subregional thalamic volumes and obsessive-compulsive symptoms (OCS) in children from the general population. The thalamus is the last relay node of the so-called corticostriatal-thalamocortical (CSTC) circuits before information reenters the cortex. There are different CSTC circuits involved in motor, cognitive, and affective/motivational processes whose information is conveyed in parallel through different thalamic nuclei.2 Studies have shown that patients with obsessive-compulsive disorder (OCD) show pervasive alterations in these circuits.3 Indeed, such alterations are central to prevailing neurobiological models of OCD, which are largely based on the results from neuroimaging research conducted with clinical OCD samples over the last 3 decades.3 This research includes magnetic resonance imaging studies identifying a range of structural changes in relay nodes within CSTC circuits. In one of the earliest reports, Gilbert et al.4 identified enlarged thalamic volumes in a small sample of treatment-naive children with OCD, which normalized after treatment with paroxetine. Although treatment effects have not been replicated, recent research with larger datasets from the ENIGMA international consortium confirmed these initial findings in unmedicated children with OCD.5 Likewise, in a previous study conducted with children from the population-based birth cohort Generation R, the same sample used in the study by Weeland et al.,1 total thalamic volume was also associated with OCS.6.

Objective Obsessive-compulsive (OC) symptoms are common in the general population, but it is unclear whether subclinical OC symptoms and obsessive-compulsive disorder (OCD) are part of a neuroanatomical continuum. The goal of this study was to investigate the relation between OC symptoms and subcortical and cortical morphology in a population-based sample of children. Method The study included 2,551 participants, aged 9–12 years, from the population-based Generation R Study. OC symptoms were measured using the 7-item caregiver-rated Short Obsessive-Compulsive Disorder Screener (SOCS). Structural (3T) magnetic resonance imaging scans were processed using FreeSurfer to study the thalamus and other subcortical volumes, intracranial volume, vertexwise cortical thickness, and surface area. We used linear regression models to investigate the association between OC symptoms and brain morphology. Emulating case-control studies from the literature, we compared children scoring above the clinical cutoff of the SOCS (probable OCD cases, n = 164) with matched children without symptoms. Results Children with probable OCD had larger thalami compared with the control group (d 0.16, p = .044). Vertexwise analysis showed a positive association between OC symptoms and thickness of the right inferior parietal cortex, which disappeared after adjusting for total behavioral problems. SOCS scores correlated negatively with intracranial volume (B = −2444, p = .038). Conclusion Children with probable OCD showed thalamus alterations similar to those previously reported in unmedicated children with OCD. OC symptoms showed a stronger association with total intracranial volume than regional brain measures. Longitudinal studies are needed to further elucidate similarities and distinctions between neural correlates of subclinical and clinical OC symptoms.

OBJECTIVE: Poor mental health in childhood is associated with a greater risk of cardiometabolic disease in adulthood, but less is known about when these associations begin to emerge. This study tests whether poor mental health (indexed by emotional and behavioral problems) in early childhood predicts increases in cardiometabolic dysregulation over 4 years of follow-up. METHODS: Data are from 4327 participants in the Generation R Study. Problem behaviors were reported by mothers using the Child Behavior Checklist at age 6 years. Repeated measurements of six cardiometabolic parameters were collected at ages 6 and 10 years: high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, systolic and diastolic blood pressures, C-reactive protein, and body mass index. Standardized measures were used to create continuous cardiometabolic dysregulation scores at ages 6 and 10 years. Change in dysregulation was defined as the difference in dysregulation scores over time. Cross-sectional and prospective associations were tested using linear regression, sequentially adjusting for relevant confounders. Additional analyses examined whether prospective relationships were robust to adjustment for baseline levels of dysregulation. RESULTS: There was no association between child problem behaviors and cardiometabolic dysregulation at age 6 years. However, higher levels of problem behaviors predicted increases in cardiometabolic dysregulation (β = 0.12, 95% confidence interval = 0.00-0.23) from ages 6 to 10 years. CONCLUSIONS: Worse child mental health may be associated with increases in cardiometabolic dysregulation by preadolescence. To our knowledge, this is the first study to demonstrate that adverse physiologic effects of psychological distress identified in adult populations may be observed as early as childhood.

Previous studies showed that prolonged breastfeeding increases the risk of caries. However, the observed associations were mainly based on non-European populations, and important confounding and mediating factors like socioeconomic position (SEP) and diet were often neglected. The aim of this study was to investigate the role of breastfeeding and bottle-feeding practices on dental caries during childhood while accounting for SEP, ethnic background, and sugar intake. This study was part of the Generation R Study, a prospective multiethnic cohort study conducted in Rotterdam, The Netherlands. In total, 4,146 children were included in the analyses. Information about feeding practices was derived from delivery reports and questionnaires during infancy. Caries was measured via intraoral photographs at the age of 6 years and defined as decayed, missing, and filled teeth (dmft). Negative binomial hurdle regression analyses were used to study the associations between several infant feeding practices and childhood caries. The prevalence of dental caries at the age of 6 years was 27.9% (n = 1,158). Prolonged breastfeeding (for >12 months) was associated with dental caries (OR 1.35, 95% CI 1.04–1.74) and the number of teeth affected by dental caries (RR 1.27, 95% CI 1.03–1.56). Furthermore, nocturnal bottle-feeding was associated with dental caries (OR 1.52, 95% CI 1.20–1.93). All associations were independent of family SEP, ethnic background, and sugar intake. Results from this Dutch cohort study confirmed the previously observed associations between prolonged breastfeeding and nocturnal bottle-feeding and the increased risk of childhood dental caries, even after proper adjustments for indicators of SEP, ethnic background, and sugar intake. Future studies are encouraged to elaborate further on possible explanations for the observed relationships. Healthcare professionals should be aware and advise caregivers about the potential risk of prolonged breastfeeding on caries development by applying the current recommendations on breastfeeding, oral hygiene, and feeding frequency.

Background: Iron deficiency during early life could affect the developing lung and immune system, and influence child's respiratory or allergy outcomes in later life. Objective: To examine the associations of maternal iron status during early pregnancy with child's lung function, asthma, inhalant allergic sensitization, and physician-diagnosed inhalant allergy at school-age. Methods: In a population-based cohort study, among 3825 mother–child pairs, ferritin, transferrin concentrations, and transferrin saturation were measured from maternal venous blood samples during early pregnancy. In children at the age of 10 years, spirometry was used to determine child's lung function, current asthma and physician-diagnosed inhalant allergy were assessed by questionnaires, and inhalant allergic sensitization was measured by skin prick tests. We used multivariable regression models to examine the associations. Results: After adjustment for gestational age at maternal iron status measurement and sociodemographic or lifestyle-related confounders, a higher maternal transferrin concentration was associated with a higher risk of physician-diagnosed inhalant allergy (odds ratio [95% confidence interval]: 1.13 [1.01 to1.26]), but not with lung function, asthma, or inhalant allergic sensitization. This association did not attenuate after further adjustment for maternal hemoglobin levels or early growth factors. We observed no consistent association of maternal ferritin concentrations or transferrin saturation with child's respiratory or allergy outcomes. Conclusion: Higher maternal transferrin concentrations during pregnancy, reflecting lower serum iron levels, were associated with an increased risk of child's physician-diagnosed inhalant allergy but not lung outcomes. Underlying mechanisms and clinical implications need to be explored.

Preregistration of a research article on bidirectional longitudinal associations of brain structural connectivity (Diffusion tensor imaging) and psychiatric symptoms (internalising and externalising problems) in adolescents from two large paediatric cohorts (ABCD and Generation R). Importantly, all information on the preregistration is available in the attached PDF. Key information was also copied to the preregistration online template.

While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8–17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.

OBJECTIVE: This study examines the association between child autistic traits and constipation symptoms, and explores whether this association is mediated by food selectivity.METHOD: The sample included participants (N = 2,818) from the population-based birth cohort, Generation R (Rotterdam, the Netherlands). Parents reported their child's autistic traits at 6 years (using the Social Responsiveness Scale), food selectivity at 10 years (using the Stanford Feeding Questionnaire) and the frequency and severity of constipation symptoms they experienced at 10 years (using the ROME III functional constipation diagnostic criteria). Mediation analyses tested mediation through food selectivity in the association of autistic traits and the number of constipation symptoms, adjusting for covariates.RESULTS: There was a positive association between parent-reported child autistic traits and constipation symptoms (r = 0.08, p DISCUSSION: This study provides empirical support for the mediating role of food selectivity in the association between autistic traits and constipation. Behavioral interventions aimed to target food selectivity and support families of children with autistic traits may bolster conventional medical and nutritional treatments to alleviate gastrointestinal symptoms like constipation.

Individual differences in subcortical brain volumes are highly heritable. Previous studies have identified genetic variants that underlie variation in subcortical volumes in adults. We tested whether those previously identified variants also affect subcortical regions during infancy and early childhood. The study was performed within the Generation R study, a prospective birth cohort. We calculated polygenic scores based on reported GWAS for volumes of the accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus. Participants underwent cranial ultrasound around 7 weeks of age (range: 3–20), and we obtained metrics for the gangliothalamic ovoid, a predecessor of the basal ganglia. Furthermore, the children participated in a magnetic resonance imaging (MRI) study around the age of 10 years (range: 9–12). A total of 340 children had complete data at both examinations. Polygenic scores primarily associated with their corresponding volumes at 10 years of age. The scores also moderately related to the diameter of the gangliothalamic ovoid on cranial ultrasound. Mediation analysis showed that the genetic influence on subcortical volumes at 10 years was only mediated for 16.5–17.6% of the total effect through the gangliothalamic ovoid diameter at 7 weeks of age. Combined, these findings suggest that previously identified genetic variants in adults are relevant for subcortical volumes during early life, and that they affect both prenatal and postnatal development of the subcortical regions., We show that polygenic scores for adult subcortical volumes relate to subcortical volume during infancy and childhood. Furthermore, the polygenic scores seemed to associate partly independent with infant and childhood subcortical volumes, suggesting that the polygenic scores capture specific stages of postnatal development.

Brain morphology is altered in both anorexia nervosa and obesity. However, it is yet unclear if the relationship between Body Mass Index-Standard Deviation Score (BMI-SDS) and brain morphology exists across the BMI-SDS spectrum, or is present only in the extremes. The study involved 3160 9-to-11 year-old children (50.3% female) who participate in Generation R, a population-based study. Structural MRI scans were obtained from all children and FreeSurfer was used to quantify both global and surface-based measures of gyrification and cortical thickness. Body length and weight were measured to calculate BMI. Dutch growth curves were used to calculate BMI-SDS. BMI-SDS was analyzed continuously and in two categories (median split). The relationship between BMI-SDS (range − 3.82 to 3.31) and gyrification showed an inverted-U shape curve in children with both lower and higher BMI-SDS values having lower gyrification in widespread areas of the brain. BMI-SDS had a positive linear association with cortical thickness in multiple brain regions. This study provides evidence for an association between BMI-SDS and brain morphology in a large sample of children from the general population and suggests that a normal BMI during childhood is important for brain development. Future studies could determine whether lifestyle modifications optimize BMI-SDS result in return to more typical patterns of brain morphology. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-020-02209-0.

Contains fulltext : 238932.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Low folic acid, folate and vitamin B12 might affect tooth formation and mineralization. The conversion of folic acid into folate is catalysed by the methylenetetrahydrofolate (MTHFR) enzyme which is encoded by the MTHFR gene. Among 3728 mothers and their 10-year-old children from the Generation R Study, we investigated associations of maternal folic acid supplementation and prenatal folate and vitamin B12 concentrations with child dental development. Secondly, we checked the modifying effect of MTHFR-C677T polymorphism. METHODS: Information on folic acid supplementation was obtained by questionnaires. Concentrations of folate and vitamin B12 were measured from venous samples taken in early pregnancy. Developmental stages of teeth were defined by the Demirjian method at the age-10 assessment. In addition, dental age of the children was calculated using the Dutch standard. GLM and multivariate linear regression models were built to study the associations. RESULTS: Folic acid supplementation started when pregnancy was known (β = -0.09; 95% CI: -0.17, -0.01) and folic acid supplementation started prior to known pregnancy (β = -0.12; 95% CI: -0.20, -0.04) were both associated with decelerated dental development by 1-2 months lower dental age of 10-year-old children. Folate (β = -0.02, 95% CI: -0.05, 0.02) and vitamin B12 (β = 0.03, 95% CI: -0.00, 0.06) were not associated with dental age. MTHFR-C677T did not modify the associations. CONCLUSIONS: Maternal folic acid supplementation delays dental development of children by 1-2 months dental age, whereas maternal folate and vitamin B12 concentrations in early pregnancy do not affect the timing of child dental development.

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer’s Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children’s parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.

BACKGROUND: Childhood obesity is a global epidemic, and its prevalence differs by ethnicity. The objective of this study was to estimate the change in ethnic inequalities in child adiposity at age 10 resulting from interventions on diet at age 8 and screen time and sports participation at age 9. METHODS: We conducted a population-based cohort study, the Generation R Study, from 9,749 births in Rotterdam (2002-2006), of which 9,506 children remained in the analysis. We measured ethnicity, diet, screen time, and sports participation through questionnaires; we measured weight, body mass index (BMI), fat mass index, and fat-free mass index directly. We used sequential G-estimation to estimate the reduction in inequality that would result from the interventions. RESULTS: We observed that sociodemographic characteristics, diet, screen time, sports participation, and all adiposity measurements were more favorable in children from Western versus non-Western ethnic backgrounds: weight = -1.2 kg (95% confidence interval [CI] = -1.7, -0.8), BMI = -1.0 kg/m (CI = -1.2, -0.9), and fat mass index = -0.8 kg/m (CI = -0.9, -0.7). We estimated that extreme intervention (maximum diet score of 10, no screen time, and >4 hours/week of sports) reduced ethnic inequalities by 21% (CI = 8%, 35%) for weight, 9% (CI = 4%, 14%) for BMI, and 9% (CI = 6%, 13%) for fat mass index. A diet score ≥5 points, screen time ≤2 hours/day, and sports participation >2 hours/week reduced ethnic inequalities by 17% (CI = 6%, 28%) for weight, 7% (CI = 3%, 11%) for BMI, and 7% (CI = 4%, 10%) for fat mass index. CONCLUSIONS: Our results are consistent with the hypothesis that interventions integrating diet, screen time, and sports participation have a moderate impact on reducing ethnic inequalities in child adiposity.

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a time-dependent Cox regression analysis. Subsequently, we stratified by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16–0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015–0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10–4.77) or secondary (adjusted HR 1.71, 95%CI 1.16–2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms. Electronic supplementary material The online version of this article (10.1007/s10578-020-01016-2) contains supplementary material, which is available to authorized users.

BACKGROUND: Psychotic experiences are common in childhood and an important risk indicator of adverse mental health outcomes. However, little is known about the association of psychotic experiences with functional outcomes in childhood, particularly regarding school performance. The aim of the present study was to examine whether psychotic experiences were prospectively related to school performance in childhood.METHODS: This study was embedded in the population-based Generation R Study (N = 2,362). Psychotic experiences were assessed using self-reports on hallucinations at age 10 years. School performance was assessed using a standardized national school performance test at age 12 years. We considered the total school performance score, as well as language and mathematics subscales. Analyses were adjusted for sociodemographic characteristics, maternal nonverbal IQ, nonverbal IQ at age 6 years and co-occurring psychopathology at age 10 years.RESULTS: Psychotic experiences were prospectively associated with poorer school performance scores (B = -0.61, 95% CI [-0.98;-0.25], p = .001), as well as poorer language (Bpercentile rank score = -2.00, 95% CI [-3.20;-0.79], p = .001) and mathematical ability (Bpercentile rank score = -1.75, 95% CI [-2.99;-0.51], p = .006). These associations remained after additional adjustment for nonverbal IQ at age 6 years (B = -0.51, 95% CI [-0.86;-0.16], p = .005), and co-occurring internalizing (B = -0.40, 95% CI [-0.77;-0.03], p = .036) and externalizing problems (B = -0.40, 95% CI [-0.75;-0.04], p = .029), but not attention problems (B = -0.10, 95% CI [-0.47;0.26], p = .57).CONCLUSIONS: Children with psychotic experiences had lower school performance scores than their nonaffected peers. The finding was independent of sociodemographic characteristics, intelligence and co-occurring internalizing and externalizing problems, but not attention problems. This study suggests that psychotic experiences are associated with childhood functional impairments, although the relatively small effects and the role of attention problems warrant further exploration.

BackgroundDNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate ofR2Methylationwould provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and GenerationR(n = 1382).ResultsUsing information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SDCV = 0.06) of gestational age variance and 5% (SDCV = 0.02) of birth weight variance. TheR2Methylationestimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations.ConclusionsThe results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the trueR2Methylationfor these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.