Adolescent substance use initiation and long-term neurobiological outcomes: insights, challenges and opportunities.

The increased frequency of risk taking behavior combined with marked neuromaturation has positioned adolescence as a focal point of research into the neural causes and consequences of substance use. However, little work has provided a summary of the links between adolescent initiated substance use and longer-term brain outcomes. Here we review studies exploring the long-term effects of adolescent-initiated substance use with structural and microstructural neuroimaging. A quarter of all studies reviewed conducted repeated neuroimaging assessments. Long-term alcohol use, as well as tobacco use were consistently associated with smaller frontal cortices and altered white matter microstructure. This association was mostly observed in the ACC, insula and subcortical regions in alcohol users, and for the OFC in tobacco users. Long-term cannabis use was mostly related to altered frontal cortices and hippocampal volumes. Interestingly, cannabis users scanned more years after use initiation tended to show smaller measures of these regions, whereas those with fewer years since initiation showed larger measures. Long-term stimulant use tended to show a similar trend as cannabis in terms of years since initiation in measures of the putamen, insula and frontal cortex. Long-term opioid use was mostly associated with smaller subcortical and insular volumes. Of note, null findings were reported in all substance use categories, most often in cannabis use studies. In the context of the large variety in study designs, substance use assessment, methods, and sample characteristics, we provide recommendations on how to interpret these findings, and considerations for future studies.

Alcohol exposure before and during pregnancy is associated with reduced fetal growth: the Safe Passage Study.

BACKGROUND: Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort. METHODS: The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes. RESULTS: This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED30; - 0.13 (95% CI; - 0.22; - 0.04), ED36; - 0.14 (95% CI; - 0.25; - 0.04)) and a smaller abdominal circumference (ED36; - 0.09 (95% CI; - 0.18; - 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.14 (95% CI; - 0.25; - 0.02), ED36; - 0.22 (95% CI; - 0.37; - 0.06)) and a smaller estimated fetal weight (ED36; - 0.22 (95% CI; - 0.38; - 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.49 (95% CI; - 0.86; - 0.12), ED36; - 0.70 (95% CI; - 1.22; - 0.17)) and estimated fetal weight (ED30; - 0.54 (95% CI; - 0.94; - 0.14), ED36; - 0.69 (95% CI; - 1.25; - 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth. CONCLUSIONS: This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy.

Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood.

BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms. METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years. RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms. CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.

Measures of Early-life Behavior and Later Psychopathology in the LifeCycle Project - EU Child Cohort Network: A Cohort Description.

BACKGROUND: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. METHODS: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. RESULTS: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. CONCLUSION: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Timing and type of adverse life events: Impact on substance use among high-risk adolescents.

A robust association has been reported between childhood adverse life events (ALEs) and risky substance use in adolescence. It remains unclear, however, what the impact of type and timing of these ALEs is. We investigated the association between ALEs and substance use in adolescents. ALEs were operationalized as broad (e.g., moving, parental divorce, family sickness) or physically threatening (physical and/or sexual abuse). First, we examined lifetime ALEs, followed by an investigation into their timing. The sample consisted of 909 adolescents (aged 12-18 years) from a cohort oversampled on high levels of emotional and behavioral problems. The primary caregiver indicated which ALEs each adolescent experienced across their lifetime. Adolescents self-reported on number and frequency of substances used. Poisson and ordinal regression models were used to model the associations. The associations between lifetime ALEs and a substance used were observed only for physical ALEs (incidence rate ratio 1.18 [1.03, 1.35], p = 0.02). When investigating timing, physical ALEs after the age of 12 predicted number of substances used (IRR 1.36 [1.13, 1.63], p < .001). Recent ALEs (occurring after age 12) seem to have considerable impact on substance use. Alcohol and drugs as a coping mechanism were considered a plausible explanation for the results.

Prenatal maternal and cord blood vitamin D concentrations and negative affectivity in infancy.

Higher maternal vitamin D concentration during pregnancy is associated with better child mental health. Negative affectivity, an early-emerging temperamental trait, indicates an increased risk of psychopathology. We investigated if maternal early/mid-pregnancy 25-hydroxyvitamin D (25(OH)D) and neonatal cord blood 25(OH)D concentrations are associated with Negative affectivity in infancy. We studied term-born infants from the vitamin D Intervention in Infants study (VIDI, n = 777, follow-up rate 80%, Finland), and the Generation R Study (n = 1505, follow-up rate 40%, Netherlands). We measured maternal serum 25(OH)D at 6-27 weeks (VIDI) or 18-25 weeks (Generation R) of pregnancy, and cord blood 25(OH)D at birth (both cohorts). Caregivers rated infant Negative affectivity at 11.7 months (VIDI) or 6.5 months (Generation R) using the Revised Infant Behavior Questionnaire. Using linear regression, we tested associations between 25(OH)D and Negative affectivity adjusted for infant age, sex, season of 25(OH)D measurement, maternal age, education, smoking, and body-mass-index. Per 10 nmol/l increase in maternal early/mid-pregnancy 25(OH)D, infant Negative affectivity decreased by 0.02 standard deviations (95% confidence interval [CI] - 0.06, - 0.004) in VIDI, and 0.03 standard deviations (95% CI - 0.03, - 0.01) in Generation R. Cord blood 25(OH)D was associated with Negative affectivity in Generation R (- 0.03, 95% CI - 0.05, - 0.01), but not VIDI (0.00, 95% CI - 0.02, 0.02). Lower maternal 25(OH)D concentrations were consistently associated with higher infant Negative affectivity, while associations between cord blood 25(OH)D concentrations and Negative affectivity were less clear. Maternal vitamin D status during early- and mid-pregnancy may be linked with early-emerging differences in offspring behavior.

The association of sociodemographic factors and risk behavior with unsafe use of personal listening devices in adolescents.

Many young people are potentially at risk of noise-induced hearing loss due to unsafe use of personal listening devices. The aim of this cross-sectional study was to examine the association of sociodemographic factors and risk behavior with unsafe use of personal listening devices in adolescents to identify a target group for prevention. A smartphone application was developed to objectively measure music listening habits among 314 adolescents with a mean age of 13 years and 7 months (SD ±5 months). Listening habits were characterized as safe or unsafe based on the weekly noise dose. Data on sociodemographic factors and traditional health risk behaviors were obtained by questionnaires. Within the study group, 10.5% of the participants exceeded the 50%, and 4.8% the 100% recommended weekly noise dose. Adolescents with a lower socioeconomic status were more likely to engage in unsafe listening habits as compared to adolescents with a higher socioeconomic status. Additionally, risk behavior was associated with higher odds of having unsafe listening habits as compared to no risk behavior. Age, sex and educational levels were not significantly associated with unsafe listening habits. The findings of the present study indicate that interventions to promote safe listening habits should target adolescents with a lower socioeconomic status and higher risk behavior. Future research is needed to investigate how these adolescents can be motivated to adopt safe listening habits.

Maternal early-pregnancy ferritin and offspring neurodevelopment: A prospective cohort study from gestation to school age.

BACKGROUND: Iron plays a role in many key processes in the developing brain. During pregnancy, iron supplementation is widely recommended to prevent and treat iron deficiency; however, the prevalence of iron deficiency and the risk of iron overload vary greatly between populations. Evidence on the role of high levels of maternal ferritin, a storage iron marker during pregnancy in relation to offspring neurodevelopment is lacking. OBJECTIVE: Our main objective was to examine if maternal ferritin levels during pregnancy are associated with child cognitive and motor abilities. METHODS: We included Dutch mother-child dyads from the prospective population-based Generation R Study, born in 2002-2006. We compared children whose mothers had high (standard deviation score >+1) or low (standard deviation score <-1) early-pregnancy ferritin to children whose mothers had intermediate ferritin (reference group) using linear regression. Children underwent non-verbal intelligence and language tests at 4-9 years (cognitive abilities), finger-tapping and balancing tests at 8-12 years (motor abilities), and structural magnetic resonance imaging at 8-12 years (brain morphology). Covariates were child age, sex, maternal intelligence quotient estimate, age, body-mass-index, education, parity, smoking and alcohol use. RESULTS: Of the 2479 mother-child dyads with data on maternal ferritin and at least one child neurodevelopmental outcome, 387 mothers had low (mean = 20.6 µg/L), 1700 intermediate (mean = 64.6 µg/L) and 392 high (mean = 170.3 µg/L) early-pregnancy ferritin. High maternal ferritin was associated with 2.54 points (95% confidence interval -4.16, -0.92) lower child intelligence quotient and 16.02 cm3 (95% confidence interval -30.57, -1.48) smaller brain volume. Results remained similar after excluding mothers with high C-reactive protein. Low maternal ferritin was not associated with child cognitive abilities. Maternal ferritin was unrelated to child motor outcomes. CONCLUSION: High maternal ferritin during pregnancy was associated with poorer child cognitive abilities and smaller brain volume. Maternal iron status during pregnancy may be associated with offspring neurodevelopment.

Prenatal exposure to trans fatty acids and head growth in fetal life and childhood: triangulating confounder-adjustment and instrumental variable approaches.

Dietary trans fatty acids (TFAs) are primarily industrially produced and remain abundant in processed food, particularly in low- and middle-income countries. Although TFAs are a cause of adverse cardiometabolic outcomes, little is known about exposure to TFAs in relation to brain development. We aimed to investigate the effect of maternal TFA concentration during pregnancy on offspring head growth in utero and during childhood. In a prospective population-based study in Rotterdam, the Netherlands, with 6900 mother-child dyads, maternal plasma TFA concentration was assessed using gas chromatography in mid-gestation. Offspring head circumference (HC) was measured in the second and third trimesters using ultrasonography; childhood brain morphology was assessed using magnetic resonance imaging at age 10 years. We performed regression analyses adjusting for sociodemographic and lifestyle confounders and instrumental variable (IV) analyses. Our IV analysis leveraged a national policy change that led to a substantial reduction in TFA and occurred mid-recruitment. After adjusting for covariates, maternal TFA concentration during pregnancy was inversely related to fetal HC in the third trimester (mean difference per 1% wt:wt increase: - 0.33, 95% CI - 0.51, - 0.15, cm) and to fetal HC growth from the second to the third trimester (- 0.04, 95% CI - 0.06, - 0.02, cm/week). Consistent findings were obtained with IV analyses, strengthening a causal interpretation. Association between prenatal TFA exposure and HC in the second trimester or global brain volume at age 10 years was inconclusive. Our findings are of important public health relevance as TFA levels in food remain high in many countries.

Clustering of characteristics associated with unplanned pregnancies: the generation R study.

BACKGROUND: Unplanned or unintended pregnancies form a major public health concern because they are associated with unfavorable birth outcomes as well as social adversity, stress and depression among parents-to-be. Several risk factors for unplanned pregnancies in women have previously been identified, but studies usually take a unidimensional approach by focusing on only one or few factors, disregarding the possibility that predictors might cluster. Furthermore, data on predictors in men are largely overlooked. The purpose of this study is to determine predictors of unplanned versus planned pregnancy, to determine predictors of ambivalent feelings regarding pregnancy, and to investigate how characteristics of men and women with an unplanned pregnancy cluster together. METHODS: This study was embedded in Generation R, a multiethnic population-based prospective cohort from fetal life onwards. Pregnancy intention was reported by 7702 women and 5367 partners. Information on demographic, mental, physical, social, and sexual characteristics was obtained. Logistic regression, multinomial regression and cluster analyses were performed to determine characteristics that were associated with an unplanned pregnancy, with ambivalent feelings regarding the unplanned pregnancy and the co-occurrence of characteristics in women and men with unplanned pregnancy. RESULTS: Twenty nine percent of the pregnancies were unplanned. Logistic regression analyses showed that 42 of 44 studied predictors were significantly associated with unplanned pregnancy. The most important predictors were young age, migration background, lower educational level, lower household income, financial difficulties, being single, lower cognitive ability, drug use prior to pregnancy, having multiple sexual partners in the year prior to the pregnancy, younger age of first sexual contact and a history of abortion. Multinomial regression analyses showed that a Turkish or Moroccan background, Islamic religion, little financial opportunities, being married, having ≥3 children, high educational level, more mental health and social problems and older age of first sexual contact were associated with prolonged ambivalent feelings regarding pregnancy. Different combinations of characteristics were observed in the four clusters of women and men with unplanned pregnancy. CONCLUSIONS: Many predictors are related with unplanned pregnancies, ambivalent feelings toward the pregnancy, and we identified very heterogeneous groups of women and men with unplanned pregnancies. This calls for heterogeneous measures to prevent unplanned pregnancies.

Associations of Air Pollution on the Brain in Children: A Brain Imaging Study.

Introduction: Epidemiological studies are highlighting the negative effects of the exposure to air pollution on children's neurodevelopment. However, most studies assessed children's neurodevelopment using neuropsychological tests or questionnaires. Using magnetic resonance imaging (MRI) to precisely measure global and region-specific brain development would provide details of brain morphology and connectivity. This would help us understand the observed cognitive and behavioral changes related to air pollution exposure. Moreover, most studies assessed only a few air pollutants. This project investigates whether air pollution exposure to many pollutants during pregnancy and childhood is associated with the morphology and connectivity of the brain in school-age children and pre-adolescents. Methods: We used data from the Generation R Study, a population-based birth cohort set up in Rotterdam, the Netherlands in 2002-2006 (n = 9,610). We used land-use regression (LUR) models to estimate the levels of 14 air pollutants at participant's homes during pregnancy and childhood: nitrogen oxides (NOx), nitrogen dioxide (NO2), particulate matter with aerodynamic diameter ≤10 µm (PM10) or ≤2.5 µm (PM2.5), PM between 10 µm and 2.5 µm (PMCOARSE), absorbance of the PM2.5 fraction - a measure of soot (PM2.5absorbance), the composition of PM2.5 such as polycyclic aromatic hydrocarbons (PAHs), organic carbon (OC), copper (Cu), iron (Fe), silicon (Si), zinc (Zn), and the oxidative potential of PM2.5 evaluated using two acellular methods: dithiothreitol (OPDTT) and electron spin resonance (OPESR). We performed MRI measurements of structural morphology (i.e., brain volumes, cortical thickness, and cortical surface area) using T1-weighted images in 6- to 10-year-old school-age children and 9- to 12-year-old pre-adolescents, structural connectivity (i.e., white matter microstructure) using diffusion tensor imaging (DTI) in pre-adolescents, and functional connectivity (i.e., connectivity score between brain areas) using resting-state functional MRI (rs-fMRI) in pre-adolescents. We assessed cognitive function using the Developmental Neuropsychological Assessment test (NEPSY-II) in school-age children. For each outcome, we ran regression analysis adjusted for several socioeconomic and lifestyle characteristics. We performed single-pollutant analyses followed by multipollutant analyses using the deletion/substitution/addition (DSA) approach. Results: The project has air pollution and brain MRI data for 783 school-age children and 3,857 pre-adolescents. First, exposure to air pollution during pregnancy or childhood was not associated with global brain volumes (e.g., total brain, cortical gray matter, and cortical white matter) in school-age children or pre-adolescents. However, higher pregnancy or childhood exposure to several air pollutants was associated with a smaller corpus callosum and hippocampus, and a larger amygdala, nucleus accumbens, and cerebellum in pre-adolescents, but not in school-age children. Second, higher exposure to several air pollutants during pregnancy was associated with a thinner cortex in various regions of the brain in both school-age children and pre-adolescents. Higher exposure to air pollution during childhood was also associated with a thinner cortex in a single region in pre-adolescents. A thinner cortex in two regions mediated the association between higher exposure to air pollution during pregnancy and an impaired inhibitory control in school-age children. Third, higher exposure to air pollution during childhood was associated with smaller cortical surface areas in various regions of the brain except in a region where we observed a larger cortical surface area in pre-adolescents. In relation to brain structural connectivity, higher exposure to air pollution during pregnancy and childhood was associated with an alteration in white matter microstructure in pre-adolescents. In relation to brain functional connectivity, a higher exposure to air pollution, mainly during pregnancy and early childhood, was associated with a higher brain functional connectivity among several brain regions in pre-adolescents. Overall, we identified several air pollutants associated with brain structural morphology, structural connectivity, and functional connectivity, such as NOx, NO2, PM of various size fractions (i.e., PM10, PMCOARSE, and PM2.5), PM2.5absorbance, PAHs, OC, three elemental components of PM2.5 (i.e., Cu, Si, Zn), and the oxidative potential of PM2.5. Conclusions: The results of this project suggest that exposure to air pollution during pregnancy and childhood play an adverse role in brain development. We observed this relationship even at levels of exposure that were below the European Union legislations. We acknowledge that identifying the independent effects of specific pollutants was particularly challenging. Most of our conclusions generally refer to traffic-related air pollutants. However, we did identify pollutants specifically originating from brake linings, tire wear, and tailpipe emissions from diesel combustion. The current direction toward innovative solutions for cleaner energy vehicles is a step in the right direction. However, our findings indicate that these measures might not be completely adequate to mitigate health problems attributable to traffic-related air pollution, as we also observed associations with markers of brake linings and tire wear.

Alcohol use and brain morphology in adolescence: A longitudinal study in three different cohorts.

Alcohol consumption is commonly initiated during adolescence, but the effects on human brain development remain unknown. In this multisite study, we investigated the longitudinal associations of adolescent alcohol use and brain morphology. Three longitudinal cohorts in the Netherlands (BrainScale n = 200, BrainTime n = 239 and a subsample of the Generation R study n = 318) of typically developing participants aged between 8 and 29 years were included. Adolescent alcohol use was self-reported. Longitudinal neuroimaging data were collected for at least two time points. Processing pipelines and statistical analyses were harmonized across cohorts. Main outcomes were global and regional brain volumes, which were a priori selected. Linear mixed effect models were used to test main effects of alcohol use and interaction effects of alcohol use with age in each cohort separately. Alcohol use was associated with adolescent's brain morphology showing accelerated decrease in grey matter volumes, in particular in the frontal and cingulate cortex volumes, and decelerated increase in white matter volumes. No dose-response association was observed. The findings were most prominent and consistent in the older cohorts (BrainScale and BrainTime). In summary, this longitudinal study demonstrated differences in neurodevelopmental trajectories of grey and white matter volume in adolescents who consume alcohol compared with non-users. These findings highlight the importance to further understand underlying neurobiological mechanisms when adolescents initiate alcohol consumption. Therefore, further studies need to determine to what extent this reflects the causal nature of this association, as this longitudinal observational study does not allow for causal inference.

Body fat, cardiovascular risk factors and brain structure in school-age children.

BACKGROUND: In adults, cardiovascular risk factors are known to be associated with brain health. We hypothesized that these associations are already present at school-age. We examined the associations of adverse body fat measures and cardiovascular risk factors with brain structure, including volumetric measures and white matter microstructure, in 10-year-old children. METHODS: We performed a cross-sectional analysis in a population-based prospective cohort study in Rotterdam, the Netherlands. Analyses were based on 3098 children aged 10 years with neuroimaging data and at least one measurement of body fat and cardiovascular risk factors. Body fat measures included body mass index (BMI), fat mass index and android fat mass percentage obtained by Dual-energy X-ray absorptiometry. Cardiovascular risk factors included blood pressure, and serum glucose, insulin and lipids blood concentrations. Structural neuroimaging, including global and regional brain volumes, was quantified by magnetic resonance imaging. DTI was used to assess white matter microstructure, including global fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: As compared to children with a normal weight, those with underweight had a smaller total brain and white matter volumes (differences -18.10 (95% Confidence Interval (CI) -30.97,-5.22) cm3, -10.64 (95% CI -16.82,-4.47) cm3, respectively). In contrast, one SDS (Standard Deviation Score) increase in fat mass index was associated with a smaller gray matter volume (differences -3.48 (95% CI -16.82, -4.47) cm3). Also, one SDS increase in android fat mass percentage was associated with lower white matter diffusivity (difference -0.06 (95% CI -0.10, -0.02) SDS). None of the other cardiovascular risk factors were associated with any of the brain outcomes. CONCLUSIONS: Body fat measures, but not other cardiovascular risk factors, were associated with structural neuroimaging outcomes in school-aged children. Prospective studies are needed to assess causality, direction and long-term consequences of the associations.

Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

Air pollution exposure during pregnancy and childhood and brain morphology in preadolescents.

BACKGROUND: Studies investigating the relationship between exposure to air pollution and brain development using magnetic resonance images are emerging. However, most studies have focused only on prenatal exposures, and have included a limited selection of pollutants. Here, we aim to expand the current knowledge by studying pregnancy and childhood exposure to a wide selection of pollutants, and brain morphology in preadolescents. METHODS: We used data from 3133 preadolescents from a birth cohort from Rotterdam, the Netherlands (enrollment: 2002-2006). Concentrations of nitrogen oxides, coarse, fine, and ultrafine particles, and composition of fine particles were estimated for participant's home addresses in pregnancy and childhood, using land use regression models. Structural brain images were obtained at age 9-12 years. We assessed the relationships of air pollution exposure, with brain volumes, and surface-based morphometric data, adjusting for socioeconomic and life-style characteristics, using single as well as multi-pollutant approach. RESULTS: No associations were observed between air pollution exposures and global volumes of total brain, and cortical and subcortical grey matter. However, we found associations between higher pregnancy and childhood air pollution exposures with smaller corpus callosum, smaller hippocampus, larger amygdala, smaller nucleus accumbens, and larger cerebellum (e.g. -69.2mm3 hippocampal volume [95%CI -129.1 to -9.3] per 1ng/m3 increase in pregnancy exposure to polycyclic aromatic hydrocarbons). Higher pregnancy exposure to air pollution was associated with smaller cortical thickness while higher childhood exposure was associated with predominantly larger cortical surface area. CONCLUSION: Higher pregnancy or childhood exposure to several air pollutants was associated with altered volume of several brain structures, as well as with cortical thickness and surface area. Associations showed some similarity to delayed maturation and effects of early-life stress.

Radiofrequency electromagnetic fields from mobile communication: Description of modeled dose in brain regions and the body in European children and adolescents.

BACKGROUND: Little is known about radiofrequency electromagnetic fields (RF) from mobile technology and resulting dose in young people. We describe modeled integrated RF dose in European children and adolescents combining own mobile device use and surrounding sources. METHODS: Using an integrated RF model, we estimated the daily RF dose in the brain (whole-brain, cerebellum, frontal lobe, midbrain, occipital lobe, parietal lobe, temporal lobes) and the whole-body in 8358 children (ages 8-12) and adolescents (ages 14-18) from the Netherlands, Spain, and Switzerland during 2012-2016. The integrated model estimated RF dose from near-field sources (digital enhanced communication technology (DECT) phone, mobile phone, tablet, and laptop) and far-field sources (mobile phone base stations via 3D-radiowave modeling or RF measurements). RESULTS: Adolescents were more frequent mobile phone users and experienced higher modeled RF doses in the whole-brain (median 330.4 mJ/kg/day) compared to children (median 81.8 mJ/kg/day). Children spent more time using tablets or laptops compared to adolescents, resulting in higher RF doses in the whole-body (median whole-body dose of 81.8 mJ/kg/day) compared to adolescents (41.9 mJ/kg/day). Among brain regions, temporal lobes received the highest RF dose (medians of 274.9 and 1786.5 mJ/kg/day in children and adolescents, respectively) followed by the frontal lobe. In most children and adolescents, calling on 2G networks was the main contributor to RF dose in the whole-brain (medians of 31.1 and 273.7 mJ/kg/day, respectively). CONCLUSION: This first large study of RF dose to the brain and body of children and adolescents shows that mobile phone calls on 2G networks are the main determinants of brain dose, especially in temporal and frontal lobes, whereas whole-body doses were mostly determined by tablet and laptop use. The modeling of RF doses provides valuable input to epidemiological research and to potential risk management regarding RF exposure in young people.

A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents.

Low vitamin D level during pregnancy has been associated with adverse neurodevelopmental outcomes such as autism spectrum disorders (ASD) in children. However, the underlying neurobiological mechanism remains largely unknown. This study investigated the association between gestational 25-hydroxyvitamin D [25(OH)D] concentration and brain morphology in 2597 children at the age of 10 years in the population-based Generation R Study. We studied both 25(OH)D in maternal venous blood in mid-gestation and in umbilical cord blood at delivery, in relation to brain volumetric measures and surface-based cortical metrics including cortical thickness, surface area, and gyrification using linear regression. We found exposure to higher maternal 25(OH)D concentrations in mid-gestation was associated with a larger cerebellar volume in children (b â€‹= â€‹0.02, 95%CI 0.001 to 0.04), however this association did not remain after correction for multiple comparisons. In addition, children exposed to persistently deficient (i.e., <25 â€‹nmol/L) 25(OH)D concentration from mid-gestation to delivery showed less cerebral gray matter and white matter volumes, as well as smaller surface area and less gyrification at 10 years than those with persistently sufficient (i.e., ≥50 â€‹nmol/L) 25(OH)D concentration. These results suggest temporal relationships between gestational vitamin D concentration and brain morphological development in children.

Parental psychological distress during pregnancy and the risk of childhood lower lung function and asthma: a population-based prospective cohort study.

BACKGROUND: Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood. OBJECTIVE: To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age. METHODS: This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire. RESULTS: The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference -0.10 (95% CI -0.20 to -0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV1) and FVC (-0.13 (95% CI -0.24 to -0.01) and -0.13 (95% CI -0.24 to -0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity. CONCLUSION: Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory disease.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years. METHOD: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. RESULTS: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. CONCLUSIONS: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Psychological Distress and Weight Gain in Pregnancy: a Population-Based Study.

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