Laura M. E. Blanken

Maternal vitamin D concentrations during pregnancy, fetal growth patterns, and risks of adverse birth outcomes

BACKGROUND Maternal vitamin D deficiency during pregnancy may affect fetal outcomes. OBJECTIVE The objective of this study was to examine whether maternal 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy affect fetal growth patterns and birth outcomes. DESIGN This was a population-based prospective cohort in Rotterdam, Netherlands in 7098 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.3 wk (range: 18.5-23.3 wk). Vitamin D concentrations were analyzed continuously and in quartiles. Fetal head circumference and body length and weight were estimated by repeated ultrasounds, and preterm birth (gestational age <37 wk) and small size for gestational age (less than the fifth percentile) were determined. RESULTS Adjusted multivariate regression analyses showed that, compared with mothers with second-trimester 25(OH)D concentrations in the highest quartile, those with 25(OH)D concentrations in the lower quartiles had offspring with third-trimester fetal growth restriction, leading to a smaller head circumference, shorter body length, and lower body weight at birth (all P < 0.05). Mothers who had 25(OH)D concentrations in the lowest quartile had an increased risk of preterm delivery (OR: 1.72; 95% CI: 1.14, 2.60) and children who were small for gestational age (OR: 2.07; 95% CI: 1.33, 3.22). The estimated population attributable risk of 25(OH)D concentrations <50 nmol/L for preterm birth or small size for gestational age were 17.3% and 22.6%, respectively. The observed associations were not based on extreme 25(OH)D deficiency, but presented within the common ranges. CONCLUSIONS Low maternal 25(OH)D concentrations are associated with proportional fetal growth restriction and with an increased risk of preterm birth and small size for gestational age at birth. Further studies are needed to investigate the causality of these associations and the potential for public health interventions.

Prevalence and predictors of vitamin D deficiency based on maternal mid-gestation and neonatal cord bloods: The Generation R Study

BACKGROUND Population-based studies have confirmed that the prevalence of vitamin D deficiency is substantial in many societies, and is of particular concern in pregnant women. Vitamin D deficiency during pregnancy is associated with a wide range of adverse maternal and offspring health outcomes. To date, studies of vitamin D deficiency during pregnancy have focused on measurements at one or two time points in isolation. We examined both midgestation and cord blood 25 hydroxyvitamin D (25OHD) concentration and explored the prevalence and correlates of vitamin D deficiency in a large ethnically diverse cohort of pregnant women and their infants in the Netherlands. METHODS This study was embedded in the Generation R Study, a population-based prospective cohort from fetal life onwards in Rotterdam, The Netherlands. Using a highly sensitive tandem mass spectroscopy-based assay, we measured 25OHD in 7256 midgestation samples (mean gestation 20.6 weeks) and 5023 neonatal cord blood samples (mean gestation 40.0 weeks). Using a conservative threshold of less than 25nmol/L to define vitamin D deficiency, we examined the prevalence and socio-demographic correlates of vitamin D deficiency in mothers and infants. We also derived a measure of vitamin D deficiency based on the two time points in order to explore persistent vitamin D deficiency in mother-infant pairs. RESULTS The prevalence of vitamin D deficiency at midgestation was 26%, while in neonates 46% were deficient. 21% of the mother-infant pairs had persistent vitamin D deficiency (i.e., deficient in maternal and cord samples) and an additional 29% were vitamin D deficient in one of the two samples only. Persistent vitamin D deficiency was strongly associated with non-European ancestry and spring birth. CONCLUSIONS A sizeable proportion of women and their neonatal offspring in the Generation R cohort were vitamin D deficient. In light of the large body of evidence linking vitamin D deficiency with adverse health outcomes for pregnant women and their offspring, our findings indicate a large unmet need in this population. In particular, women and infants from non-European ethnic background are at high risk of vitamin D deficiency.

Cortical Morphology in 6- to 10-Year Old Children With Autistic Traits : A Population-Based Neuroimaging Study

OBJECTIVE Recent evidence suggests that symptoms of social impairment in autism spectrum disorder (ASD) form a spectrum that extends into the general population. However, it is unclear whether the neuroanatomy of ASD also shows a similar continuum in the general population. Therefore, the goal of the present study was to investigate the relationship between cortical morphology and autistic traits along a continuum in a large population-based sample of young children. METHOD The study included 717 children, aged 6-10 years, who are participants in the Generation R Study, a large population-based cohort. Autistic traits were measured using the Social Responsiveness Scale when the children were approximately 6 years old. High-resolution MRI was obtained, and morphological measures of the cortex, including cortical thickness and gyrification, were quantified brain-wide. RESULTS Children with more autistic traits showed widespread areas of decreased gyrification. After excluding children with the highest autistic traits and confirmed ASD, the association remained present in a large cluster involving the left hemisphere temporal and precuneus regions. Comparable, but nonsignificant, effects when comparing a small sample of confirmed ASD case subjects with age- and gender-matched control subjects were observed. CONCLUSIONS Differences in cortical morphology related to autistic traits along a continuum in a large population-based sample of school-aged children were found. Part of these differences remained after excluding the most severely affected children. These findings lend support to an extension of the neurobiology of autistic traits to the general population.

Enhancing studies of the connectome in autism using the autism brain imaging data exchange II

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

Gestational vitamin D deficiency and autism-related traits: the Generation R Study

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l−1. Compared with the 25OHD sufficient group (25OHD>50 nmol l−1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, β=0.06, P<0.001; cord blood n=1712, β=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

White matter integrity and cognitive performance in school-age children: A population-based neuroimaging study.

Child and adolescent brain development are typically accompanied by marked improvements in a wide range of cognitive abilities. However, limited information is available surrounding the role of white matter in shaping cognitive abilities in children. The current study examined associations between white matter microstructure and cognitive performance in a large sample (n=778) of 6- to 10-year-old children. Results show white matter microstructure is related to non-verbal intelligence and to visuospatial ability, independent of age. Specificity was demonstrated, as white matter associations with visuospatial ability were independent of general intellectual ability. Associations between white matter integrity and cognition were similar in boys and girls. In summary, results demonstrate white matter structure-function associations are present in children, independent of age and broader cognitive abilities. The presence of such associations in the general population is informative for studies examining child psychopathology.

Resting-state networks in 6-to-10 year old children

Resting‐state functional magnetic resonance imaging provides a non‐invasive approach to the study of intrinsic functional brain networks. When applied to the study of brain development, most studies consist of relatively small samples that are not always representative of the general population. Descriptions of these networks in the general population offer important insight for clinical studies examining, for instance, psychopathology or neurological conditions. Thus our goal was to characterize resting‐state networks in a large sample of children using independent component analysis (ICA). The study further aimed to describe the robustness of these networks by examining which networks occur frequently after repeated ICA. Resting‐state networks were obtained from a sample of 536 6‐to‐10 year old children. Distributions of networks were built from repeated subsampling and group ICA analyses, and meta‐ICA was used to construct a representative set of components. Within‐ and between‐network properties were tested for age‐related developmental associations using spatio‐temporal regression. After repeated ICA, many networks were present over 95% of the time suggesting the components are highly reproducible. Some networks were less robust, and were observed less than 70% of the time. Age‐related associations were also observed in a selection of networks, including the default‐mode network, offering further evidence of development in these networks at an early age. ICA‐derived resting‐state networks appear to be robust, although some networks should further scrutinized if subjected to group‐level statistical analyses, such as spatiotemporal regression. The final set of ICA‐derived networks and an age‐appropriate T1‐weighted template are made available to the neuroimaging community, https://www.nitrc.org/projects/genr. Hum Brain Mapp 37:4286–4300, 2016.

The association of gender, age, and intelligence with neuropsychological functioning in young typically developing children: The Generation R study

ABSTRACT Although early childhood is a period of rapid neurocognitive development, few studies have assessed neuropsychological functioning in various cognitive domains in young typically developing children. Also, results regarding its association with gender and intelligence are mixed. In 853 typically developing children aged 6 to 10 years old, the association of gender, age, and intelligence with neuropsychological functioning in the domains of attention, executive functioning, language, memory, sensorimotor functioning, and visuospatial processing was explored. Clear positive associations with age were observed. In addition, gender differences were found and showed that girls generally outperformed boys, with the exception of visuospatial tasks. Furthermore, IQ was positively associated with neuropsychological functioning, which was strongest in visuospatial tasks. Performance in different neuropsychological domains was associated with age, gender, and intelligence in young typically developing children, and these factors should be taken into account when assessing neuropsychological functioning in clinical or research settings.

The influence of valence and decision difficulty on self-referential processing

Self-referential processing is defined as the process by which a person becomes aware that specific contents are related to his or her own self. Cortical midline structures (CMS), such as dorsal and medial prefrontal cortex, and regions such as inferior frontal cortex, insula, and temporal pole have been implicated in self-referential processing. However, the specific contribution of each of these areas is still largely unknown. More particularly, not many studies have examined the influence of valence and decision making difficulty on regions involved in self-referential processing. In this study, participants evaluated how well personality traits, differing in valence and decision difficulty, described themselves or the current US President. In line with predictions, ventral, rostral, and dorsal parts of medial prefrontal cortex showed greater activity when participants judged traits about themselves relative to judging traits about the current US President. However, none of these regions showed significant modulation by trait valence. Increasing trait decision difficulty was associated with increased activity within dorsal medial prefrontal cortex and bilateral anterior insula. However, there was very minimal overlap (6/119 voxels, i.e., 5%) of the regions of dorsal medial prefrontal cortex implicated in self-referential processing and those implicated in trait decision difficulty. The results are interpreted within current accounts of self-referential processing.

Incidental Findings on Brain Imaging in the General Pediatric Population

Brain MRI in 3966 children from the population-based Generation R Study (mean age, 10.1 years) revealed incidental findings in 25.6%. Most findings did not require neurosurgical intervention, but 7 children (0.18%) had suspected primary brain tumors.