Risk Factors for Term-Born Spastic Diplegic Cerebral Palsy: A Case-Control Study.

BACKGROUND: To identify if a predetermined set of potential risk factors are associated with spastic diplegic cerebral palsy (SDCP) in term-born children. METHODS: This is a case-control study with cases (n = 134) extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls (n = 1950) from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Our primary variable was the SDCP phenotype in term-born children. Possible risk factors were selected a priori and include extreme maternal age (<19 or >35 years), pregnancy complications, maternal disease, substance use, perinatal infection, mode of delivery, perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia), sex, and birth weight. Multivariable analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Multivariable analysis revealed associations between term-born SDCP and pregnancy complications (OR = 4.73; 95% CI = 1.91 to 10.56), maternal disease (OR = 2.52; 95% CI = 1.57 to 3.93), substance use (OR = 3.11; 95% CI = 2.10 to 4.55), perinatal infection (OR = 2.72; 95% CI 1.32 to 5.10), Caesarean section (OR = 2.35; 95% CI = 1.62 to 3.40), and perinatal adversity (OR = 2.91; 95% CI = 1.94 to 4.50). Multiple regression analysis revealed associations between SDCP and pregnancy complications (OR = 3.28; 95% CI 1.20 to 8.15), maternal disease (OR = 2.52; 95% CI 1.50 to 4.12), substance use (OR = 3.59; 95% CI 2.37 to 5.40), perinatal infection (OR = 3.78, 95% CI 1.71 to 7.72), Caesarean section (OR = 2.72; 95% CI 1.82 to 4.03), and perinatal adversity (OR = 4.16; 95% CI 2.67 to 6.70). INTERPRETATION: Antenatal (pregnancy complications, maternal disease, substance use) and perinatal (infections, Caesarean section, and perinatal adversity) risk factors are associated with an increased risk of SDCP in term-born children, suggesting variable interactions between risk factors to provide a clinicopathologic framework that is different from SDCP observed in preterm-born children.

Assessing the Contribution of Measures of Attention and Executive Function to Diagnosis of ADHD or Autism.

Attention and executive function (EF) dysregulation are common in a number of disorders including autism and attention-deficit/hyperactivity disorder (ADHD). Better understanding of the relationship between indirect and direct measures of attention and EF and common neurodevelopmental diagnoses may contribute to more efficient and effective diagnostic assessment in childhood. We obtained cognitive (NIH Toolbox, Little Man Task, Matrix Reasoning Task, and Rey Delayed Recall) and symptom (CBCL, and BPMT) assessment data from the Adolescent Brain and Cognitive Development (ABCD) database for three groups, autistic (N = 110), ADHD (N = 878), and control without autism or ADHD diagnoses (N = 9130) and used ridge regression to determine which attention and EF assessments were most strongly associated with autism or ADHD. More variance was accounted for in the model for the ADHD group (31%) compared to the autism group (2.7%). Finally, we ran odds ratios (using clinical cutoffs where available and 2 standard deviations below the mean when not) for each assessment measure, which generally demonstrated a greater significance within the indirect measures when compared to the direct measures. These results add to the growing literature of symptom variably across diagnostic groups allowing for better understanding of presentations in autism and ADHD and how best to assess diagnosis. It also highlights the increased difficulty in differentiating autism and controls when compared to ADHD and controls and the importance of indirect measures of attention and EF in this differentiation.

Cluster-specific associations between the gut microbiota and behavioral outcomes in preschool-aged children.

BACKGROUND: The gut microbiota is recognized as a regulator of brain development and behavioral outcomes during childhood. Nonetheless, associations between the gut microbiota and behavior are often inconsistent among studies in humans, perhaps because many host-microbe relationships vary widely between individuals. This study aims to stratify children based on their gut microbiota composition (i.e., clusters) and to identify novel gut microbiome cluster-specific associations between the stool metabolomic pathways and child behavioral outcomes. METHODS: Stool samples were collected from a community sample of 248 typically developing children (3-5 years). The gut microbiota was analyzed using 16S sequencing while LC-MS/MS was used for untargeted metabolomics. Parent-reported behavioral outcomes (i.e., Adaptive Skills, Internalizing, Externalizing, Behavioral Symptoms, Developmental Social Disorders) were assessed using the Behavior Assessment System for Children (BASC-2). Children were grouped based on their gut microbiota composition using the Dirichlet multinomial method, after which differences in the metabolome and behavioral outcomes were investigated. RESULTS: Four different gut microbiota clusters were identified, where the cluster enriched in both Bacteroides and Bifidobacterium (Ba2) had the most distinct stool metabolome. The cluster characterized by high Bifidobacterium abundance (Bif), as well as cluster Ba2, were associated with lower Adaptive Skill scores and its subcomponent Social Skills. Cluster Ba2 also had significantly lower stool histidine to urocanate turnover, which in turn was associated with lower Social Skill scores in a cluster-dependent manner. Finally, cluster Ba2 had increased levels of compounds involved in Galactose metabolism (i.e., stachyose, raffinose, alpha-D-glucose), where alpha-D-glucose was associated with the Adaptive Skill subcomponent Daily Living scores (i.e., ability to perform basic everyday tasks) in a cluster-dependent manner. CONCLUSIONS: These data show novel associations between the gut microbiota, its metabolites, and behavioral outcomes in typically developing preschool-aged children. Our results support the concept that cluster-based groupings could be used to develop more personalized interventions to support child behavioral outcomes. Video Abstract.

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections.

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study's objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal-child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath's pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

Maternal pre-pregnancy weight status and gestational weight gain in association with child behavior: The mediating role of prenatal systemic inflammation.

BACKGROUND AND AIMS: Maternal pre-pregnancy obesity and excessive gestational weight gain (EGWG) may predispose children to behavioral problems through increased prenatal inflammation. We investigated the association between maternal body mass index (BMI) and gestational weight gain (GWG), and child behavioral problems (primary aim), and the mediating role of prenatal inflammation (secondary aim). METHODS: We used self-reported pre-pregnancy BMI and estimated-GWG data (N = 1137) from a longitudinal cohort study. Maternal serum C-reactive protein (CRP) was measured in the 3rd-trimester. Parent-reported Child Behavior Checklist (CBCL) was used to assess child internalizing and externalizing behaviors at 3-years-of-age. We used analysis of covariance (ANCOVA), multiple linear regression, and mediation analyses for data analysis. RESULTS: Maternal obesity (F = 21.98, df 3836), EGWG (F = 6.53, df 2764), and their combination (F = 18.51, df 3764) were associated with the 3rd trimester CRP, but not child behavior in the whole sample. Maternal underweight was associated with withdrawal problems in all children (ß = 0.56, 95%CI, 0.11,1.00) and aggressive behaviors in female children (ß = 2.59, 95%CI, 0.28,4.91). Obesity had a significant association with externalizing behaviors in female children after controlling for maternal CRP (ß = 3.72, 95%CI, 0.12,7.32). Both inadequate and EGWG were associated with somatic complaints in male children (ß = 0.50, 95%CI, 0.05,0.95; ß = 0.36, 95%CI, 0.01,0.71, respectively). Combined obesity/EGWG was associated with externalizing (ß = 6.12, 95%CI, 0.53,11.70) and aggressive (ß = 4.23, 95%CI, 0.90,7.56) behaviors in female children. We found no significant effects through CRP. CONCLUSIONS: Maternal pre-pregnancy BMI and GWG showed sex-specific associations with child behavioral problems. Prenatal CRP, although increased in obesity and EGWG, did not mediate these associations.

The Association between Cesarean Section Delivery and Child Behavior: Is It Mediated by Maternal Post-Traumatic Stress Disorder and Maternal Postpartum Depression?

Cesarean sections (C-sections) account for up to 21% of births worldwide. Studies have linked delivery via C-section with an increased risk of child behavior problems, such as internalizing and externalizing behaviors. Maternal postpartum depression (PPD) is also linked to child behavioral problems and may play a mediating role in the association between the mode of delivery and child behavior. Mixed findings between mode of delivery and PPD may be due to a failure to distinguish between C-section types, as unplanned/emergency C-sections are linked to post-traumatic stress disorder (PTSD), which has been linked to PPD. The objectives of this study were to determine whether, (1) compared with spontaneous vaginal delivery (SVD) and planned C-section, unplanned/emergency C-sections are associated with increased child behavior problems at two to three years of age and (2) maternal PTSD and PPD mediate the association between delivery type and child behavior problems. A secondary data analysis was conducted on 938 mother-child dyads enrolled in the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Conditional process modeling was employed. Child behavior was assessed using the Child Behavior Checklist (CBCL) 1.5-5 years, and maternal PPD and PTSD were assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the Psychiatric Diagnostic Screening Questionnaire (PDSQ), respectively. No associations were found between delivery type and child behaviors; however, the indirect effect of emergency C-section on child behaviors was significant via the mediating pathway of maternal PTSD on PPD symptoms.

Structural neural connectivity correlates with pre-reading abilities in preschool children.

Pre-reading abilities are predictive of later reading ability and can be assessed before reading begins. However, the neural correlates of pre-reading abilities in young children are not fully understood. To address this, we examined 246 datasets collected in an accelerated longitudinal design from 81 children aged 2-6 years (age = 4.6 ± 0.98 years, 47 males). Children completed pre-reading assessments (NEPSY-II Phonological Processing and Speeded Naming) and underwent a diffusion magnetic resonance imaging (MRI) scan to assess white matter connectivity. We defined a core neural network of reading and language regions based on prior literature, and structural connections within this network were assessed using graph theory analysis. Linear mixed models accounting for repeated measures were used to test associations between children's pre-reading performance and graph theory measures for the whole bilateral reading network and each hemisphere separately. Phonological Processing scores were positively associated with global efficiency, local efficiency, and clustering coefficient in the bilateral and right hemisphere networks, as well as local efficiency and clustering coefficient in the left hemisphere network. Our findings provide further evidence that structural neural correlates of Phonological Processing emerge in early childhood, before and during early reading instruction.

Maternal Iron and Vitamin D Status during the Second Trimester Is Associated with Third Trimester Depression Symptoms among Pregnant Participants in the APrON Cohort.

BACKGROUND: The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. OBJECTIVES: This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. METHODS: The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. RESULTS: Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (ß: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (ß: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (ß: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 µg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (ß: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 µg/L) and vitamin D (25(OH)D <75 nmol/L) (ß: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. CONCLUSIONS: A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.

Maternal Pre-Pregnancy BMI and Gestational Weight Gain Are Associated with Preschool Children's Neuropsychological Outcomes in the APrON Cohort.

This study examined the associations between maternal pre-pregnancy BMI and gestational weight gain (GWG) and children's neuropsychological outcomes at 3 to 5 years of age. A total of 379 women and their children from the Alberta Pregnancy Outcomes and Nutrition (APrON) study participated. Covariate-adjusted robust regressions examined associations between maternal pre-pregnancy BMI, GWG class, interaction terms, and child outcomes. Each unit increase in maternal BMI was linked to a 0.48-point decrement (95% CI: -0.75 to -0.21) in children's Full Scale IQ. Higher pre-pregnancy BMI was related to poorer performance on the other intelligence indexes (B = -0.35 to -0.47, 95% CIs: -0.75, -0.02) and lower performance on measures of language (B = -0.08 to -0.09, 95% CIs: -0.16, -0.02), motor skills (B = -0.08 to -0.11, 95% CIs: -0.18, -0.01), and executive function (B = -0.09 to -0.16, 95% CIs: -0.26, -0.01). GWG below the recommended range was associated with a 4.04-point decrement (95% CI: 7.89, -0.11) in Full Scale IQ, but better performance on a spatial working memory test (B = 0.27, 95% CI: 0.02, 0.52). GWG above the recommended range was associated with lower language (B = -0.79, 95% CI: -1.52, -0.06) and memory scores (B = -0.93, 95% CI: -1.64, -0.22). Interactions were found between pre-pregnancy BMI and GWG on measures of intelligence and executive function. Maternal pre-pregnancy BMI and GWG are related to children's performance in various neuropsychological domains and may interact to predict outcomes. Optimizing maternal health and weight prior to conception and during pregnancy may enhance children's neuropsychological outcomes.

Antenatal corticosteroid therapy, delivery intervals and perinatal mortality in low-resource settings.

BACKGROUND: Uncertainty exists regarding the ideal interval between the administration of antenatal corticosteroids (ACS) and delivery. The study's objective was to assess the risks of perinatal mortality and respiratory distress syndrome (RDS) among preterm neonates whose mothers gave birth within 48 h of the administration of ACS and those whose mothers gave birth between 48 h and 7 days. METHODS: The study design was a secondary analysis of data from an observational prospective chart review study that was carried out in Tanzania in 2020. Preterm infants born to mothers who got at least one dose of ACS between 28 and 34 weeks of pregnancy were included. RESULTS: A total of 346 preterm neonates (294 singletons and 52 twins) were exposed to ACS. Compared to infants born 48 h following the first dose of ACS, those exposed to the drug between 48 h and 7 days had significantly decreased rates of perinatal mortality and RDS. Multivariable analysis revealed that infants exposed ACS between 48 h and 7 days prior to delivery had lower risk of perinatal mortality (aRR 0.30, 95% CI 0.14-0.66) and RDS (aRR 0.27, 95% CI 0.14-0.52). CONCLUSION: The first dose of ACS given between 48 h and 7 days before delivery was associated with a lower risk of perinatal mortality and RDS than when the first dose was given <48 h before delivery. To improve neonatal outcomes, healthcare providers should consider administering ACS to mothers at the appropriate time.

Preterm infants exposed to antenatal corticosteroids (ACS) have lower rates of perinatal mortality and morbidity. Uncertainty exists regarding the ideal interval between the administration of ACS and delivery. We conducted a secondary analysis of data from a study that included preterm infants born in four hospitals in Tanzania. We investigated whether there were differences in perinatal mortality and respiratory distress syndrome between preterm neonates whose mothers delivered within 48 h of receiving a partial course of ACS and those whose mothers delivered between 48 h and 7 days after a full course of ACS therapy. Participants were the preterm infants of women who received ACS between 28 and 34 weeks of gestation. Neonates exposed to ACS between 48 h and 7 days prior to delivery had significantly lower risks of perinatal mortality and respiratory distress syndrome compared to infants who were delivered <48 h after ACS administration. This finding highlights the importance of optimizing the timing of ACS administration to maximize its potential benefits and minimize risks to preterm neonates. To improve neonatal outcomes, healthcare providers should consider administering ACS to mothers at the appropriate time.

Long-term and trimester-specific effects of prenatal stress on the child gut microbiota.

OBJECTIVE: Stress is common among pregnant individuals and is associated with an altered gut microbiota composition in infants. It is unknown if these compositional changes persist into the preschool years when the gut microbiota reaches an adult-like composition. This study aimed to investigate if indicators of prenatal stress (i.e., psychological distress and stress-related physiology) are associated with children's gut microbiota composition and metabolites at 3-4 years of age. METHODS: Maternal-child pairs (n = 131) were from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. Each trimester, psychological distress was measured as symptoms of anxiety (Symptom Checklist-90-R) and depressed mood (Edinburgh Postnatal Depression Scale), whereas salivary cortisol was quantified as a measure of stress-related physiology. Child stool samples were collected at 3-4 years to evaluate gut microbiota composition using 16S rRNA gene sequencing and fecal metabolome using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Associations between prenatal distress and cortisol with the gut microbiota were determined using Pearson and Spearman correlations and corrected for multiple testing. Associations between prenatal distress and cortisol with the fecal metabolome were assessed using Metaboanalyst. RESULTS: Symptoms of depressed mood during the 2nd and 3rd trimesters and anxiety during the 2nd trimester of pregnancy were associated with increased alpha diversity of the child's gut microbiota. Cortisol levels during the 1st trimester were also associated with increased Faith PD diversity (r = 0.32), whereas cortisol levels during the 2nd trimester were associated with reduced Shannon diversity (r = -0.27). Depression scores during the 2nd and 3rd trimesters were associated with reductions in the relative abundances of Eggerthella, Parasutterella, and increases in Ruminococcaceae (rs = -0.28, rs = -0.32, rs = 0.32, respectively), as well as the fecal metabolome (e.g., branched-chain amino acid metabolism). Cortisol levels during the 2nd trimester correlated with 7 bacterial taxa, whereas 1st-trimester cortisol levels were associated with the child's fecal metabolome. CONCLUSIONS: Prenatal distress and cortisol were associated with both child gut microbiota composition and fecal metabolome at preschool age. Understanding these associations may allow for the identification of microbiota-targeted interventions to support child developmental outcomes affected by prenatal stress.

Associations between the chemical exposome and pregnancy induced hypertension.

Exposure to environmental chemicals has been linked to an increased risk of pregnancy-induced hypertension (PIH). This prospective cohort study examined the associations between PIH and maternal chemical exposure to four classes of chemicals (i.e., phthalates, bisphenols, perfluoroalkyl acids, non-essential metals and trace minerals). Participants included 420 pregnant women from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort who had data available on diagnosed PIH and environmental chemical exposure. Twelve phthalate metabolites, two bisphenols, eight perfluoroalkyl acids and eleven non-essential metals or trace minerals were quantified in maternal urine or blood samples collected in the second trimester of pregnancy. Associations between the urinary and blood concentrations of these chemicals and PIH were assessed using multiple logistic and LASSO regression analyses in single- and multi-chemical exposure models, respectively. Thirty-five (8.3%) participants were diagnosed with PIH. In single chemical exposure models, two phthalate metabolites, mono-methyl phthalate (MMP) and monoethyl phthalate (MEP), three perfluoroalkyl acids, perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), and one metal, manganese, were associated with increased odds of PIH. The metabolites of di (2-ethylhexyl) phthalate (DEHP) and the molar sum of these metabolites, as well as antimony, displayed trend associations (p < 0.10). In multi-chemical exposure models using LASSO penalized regressions and double-LASSO regressions, MEP (AOR: 1.43, 95% CI: 1.09-1.88, p = 0.009) and PFNA (AOR: 2.03, 95% CI: 1.01-4.07, p = 0.04) were selected as the chemicals most highly associated with PIH. These findings suggest that maternal levels of phthalates and perfluoroalkyl acids may be associated with the diagnosis on PIH. Future research should consider both individual and multi-chemical exposures when examining predictors of PIH and other maternal cardiometabolic health disorders, such as preeclampsia, eclampsia, HELLP syndrome, and gestational diabetes.

Sex-specific associations between maternal phthalate exposure and neurodevelopmental outcomes in children at 2 years of age in the APrON cohort.

BACKGROUND: There is inconsistent evidence regarding the sex-specific associations between prenatal phthalate exposure and children's neurodevelopment. This could be due to differences in the phthalate exposures investigated and the neurodevelopmental domains assessed. OBJECTIVE: To evaluate the associations between prenatal phthalate exposure and sex-specific outcomes on measures of cognition, language, motor, executive function, and behaviour in children 2 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. METHODS: We evaluated the associations between prenatal phthalate exposure and sex-specific neurodevelopmental outcomes in children at 2 years of age using data from 448 mothers and their children (222 girls, 226 boys). Nine phthalate metabolites were measured in maternal urine collected in the second trimester of pregnancy. Children's cognitive, language, and motor outcomes were assessed using the Bayley Scales of Infant Development - Third Edition (Bayley-III). Parents completed questionnaires on children's executive function and behavior, the Behavior Rating Inventory of Executive Function- Preschool Version (BRIEF-P) and Child Behavior Checklist (CBCL), respectively. Sex-stratified robust multivariate regressions were performed. RESULTS: Higher maternal concentrations of ΣDEHP and its metabolites were associated with lower scores on the Bayley-III Cognitive (ß's from -11.8 to -0.07 95% CI's from -21.3 to -0.01), Language (ß's from -11.7 to -0. 09, 95% CI's from -22.3 to -0.02) and Motor (ß's from -10.9 to -0.07, 95% CI from -20.4 to -0.01) composites in boys. The patterns of association in girls were in the opposite direction on the Cognitive and Language composites; on the Motor composite they were in the same direction as boys, but of reduced strength. Higher concentrations of ΣDEHP and its metabolites were associated with higher scores (i.e., more difficulties) on all measures of executive function in girls: inhibitory self-control (B's from 0.05 to 0.11, 95% CI s from -0.01 to 0.15), flexibility (B's from 0.04 to 0.11, 95% CI s from 0.01 to 0.21) and emergent metacognition (B's from -0.01 to 0.06, 95% CIs from -0.01 to 0.20). Similar patterns of attenuated associations were seen in boys. Higher concentrations of ΣDEHP and its metabolites were associated with more Externalizing Problems in girls and boys (B's from 0.03 to 6.82, 95% CIs from -0.08 to 12.0). Two phthalates, MMP and MBP, had sex-specific adverse associations on measures of executive function and behaviour, respectively, while MEP was positively associated with boys' cognitive, language, and motor performance. Limited associations were observed between mixtures of maternal phthalates and sex-specific neurodevelopmental outcomes. CONCLUSIONS: Maternal prenatal concentrations of DEHP phthalates were associated with sex specific difference on measures of cognition and language at 2 years of age, specifically, poorer outcomes in boys. Higher exposure to DEHP was associated with poorer motor, executive function, and behavioural outcomes in girls and boys but the strength of these associations differed by sex. Limited associations were noted between phthalate mixtures and child neurodevelopment.

Maternal co-exposure to mercury and perfluoroalkyl acid isomers and their associations with child neurodevelopment in a Canadian birth cohort.

BACKGROUND: Perfluoroalkyl acids (PFAAs) within the broader class of per- and polyfluoroalkyl substances (PFAS) are present in human serum as isomer mixtures, but epidemiological studies have yet to address isomer-specific associations with child development and behavior. OBJECTIVES: To examine associations between prenatal exposure to 25 PFAAs, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) isomers, and child neurodevelopment among 490 mother-child pairs in a prospective Canadian birth cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. To consider the influence of a classic neurotoxicant, total mercury (THg), based on its likelihood of co-exposure with PFAAs from common dietary sources. METHODS: Maternal blood samples were collected in the second trimester and child neurodevelopment was assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Linear or curvilinear multiple regression models were used to examine associations between exposures and neurodevelopment outcomes. RESULTS: Select PFAAs were associated with lower Cognitive composite scores, including perfluoroheptanoate (PFHpA) (ß = -0.88, 95% confidence interval (CI): -1.7, -0.06) and perfluorododecanoate (PFDoA) (ß = -2.0, 95% CI: -3.9, -0.01). Non-linear relationships revealed associations of total PFOS (ß = -4.4, 95% CI: -8.3, -0.43), and linear-PFOS (ß = -4.0, 95% CI: -7.5, -0.57) and 1m-PFOS (ß = -1.8, 95% CI: -3.3, -0.24) isomers with lower Language composite scores. Although there was no effect modification, including THg interaction terms in PFAA models revealed negative associations between perfluorononanoate (PFNA) and Motor (ß = -3.3, 95% CI: -6.2, -0.33) and Social-Emotional (ß = -3.0, 95% CI: -5.6, -0.40) composite scores. DISCUSSION: These findings reinforce previous reports of adverse effects of maternal PFAA exposure during pregnancy on child neurodevelopment. The unique hazards posed from isomers of PFOS justify isomer-specific analysis in future studies. To control for possible confounding, mercury co-exposure may be considered in studies of PFAAs.

Long-Term Effects of Preterm Birth on Children's Brain Structure: An Analysis of the Adolescent Brain Cognitive Development (ABCD) Study.

Approximately 10% of births are preterm [PTB; <37 weeks gestational age (GA)], which confers risk for cognitive, behavioral, and mental health challenges. Using the large and relatively diverse (i.e., designed to reflect sociodemographic variation in the United States population) Adolescent Brain Cognitive Development Study (ABCD Study), we characterized the impact of PTB on brain structure in middle-late childhood (9-10 years). The ABCD sample covers the GA spectrum, and the large sample size (∼11,500) permits consideration of how associations between PTB and brain structure are impacted by GA, sex, birthweight, and analytic choices such as controlling for total brain size. We found a pattern of relative cortical thinning in temporoparietal and dorsal prefrontal regions and thickening of medial prefrontal and occipital regions in PTB compared with children born full term (≥37 weeks GA). This pattern was apparent when controlling for mean thickness and when considering moderate (>32 and <37 weeks GA) and very PTB (≤32 weeks GA) separately, relative to full term birth. Surface area (SA) and subcortical volumes showed reductions in PTB children that were largely attenuated when controlling for brain size. Effects on cortical thickness (CT) and surface area were partially mediated by birthweight. Although boys are at increased risk for adverse outcomes following PTB, there was limited evidence of sex differences of PTB effects. Finally, cortical thickness effects estimated in a "discovery" sample (N = 7528) predicted GA in a holdout "replication" sample (N = 2139). Our findings help to clarify the effects of PTB on brain structure into late childhood across the GA spectrum.

Arcuate fasciculus and pre-reading language development in children with prenatal alcohol exposure.

Introduction: Prenatal alcohol exposure (PAE) contributes to widespread neurodevelopmental challenges, including reading, and has been associated with altered white matter. Here, we aimed to investigate whether arcuate fasciculus (AF) development is associated with pre-reading language skills in young children with PAE. Methods: A total of 51 children with confirmed PAE (25 males; 5.6 ± 1.1 years) and 116 unexposed controls (57 males; 4.6 ± 1.2 years) underwent longitudinal diffusion tensor imaging (DTI), for a total of 111 scans from participants with PAE and 381 scans in the unexposed control group. We delineated the left and right AF and extracted mean fractional anisotropy (FA) and mean diffusivity (MD). Pre-reading language ability was assessed using age-standardized phonological processing (PP) and speeded naming (SN) scores of the NEPSY-II. Linear mixed effects models were run to determine the relationship between diffusion metrics and age, group, sex, and age-by-group interactions, with subject modeled as a random factor. A secondary mixed effect model analysis assessed the influence of white matter microstructure and PAE on pre-reading language ability using diffusion metric-by-age-by-group interactions, with 51 age- and sex-matched unexposed controls. Results: Phonological processing (PP) and SN scores were significantly lower in the PAE group (p < 0.001). In the right AF, there were significant age-by-group interactions for FA (p < 0.001) and MD (p = 0.0173). In the left AF, there was a nominally significant age-by-group interaction for MD that failed to survive correction (p = 0.0418). For the pre-reading analysis, a significant diffusion-by-age-by-group interaction was found for left FA (p = 0.0029) in predicting SN scores, and for the right FA (p = 0.00691) in predicting PP scores. Discussion: Children with PAE showed altered developmental trajectories for the AF, compared with unexposed controls. Children with PAE, regardless of age, showed altered brain-language relationships that resembled those seen in younger typically developing children. Our findings support the contention that altered developmental trajectories in the AF may be associated with functional outcomes in young children with PAE.

Functional MRI responses to naturalistic stimuli are increasingly typical across early childhood.

While findings show that throughout development, there are child- and age-specific patterns of brain functioning, there is also evidence for significantly greater inter-individual response variability in young children relative to adults. It is currently unclear whether this increase in functional "typicality" (i.e., inter-individual similarity) is a developmental process that occurs across early childhood, and what changes in BOLD response may be driving changes in typicality. We collected fMRI data from 81 typically developing 4-8-year-old children during passive viewing of age-appropriate television clips and asked whether there is increasing typicality of brain response across this age range. We found that the "increasing typicality" hypothesis was supported across many regions engaged by passive viewing. Post hoc analyses showed that in a priori ROIs related to language and face processing, the strength of the group-average shared component of activity increased with age, with no concomitant decline in residual signal or change in spatial extent or variability. Together, this suggests that increasing inter-individual similarity of functional responses to audiovisual stimuli is an important feature of early childhood functional brain development.

Exploring associations between the gut microbiota and full-scale intelligence in preschool children.

The relationship between the gut microbiota and neurocognitive outcomes is becoming increasingly recognized; however, findings in humans are inconsistent. In addition, few studies have investigated the gut microbial metabolites that may mediate this relationship. The objective of this study was to investigate associations between full-scale intelligence (FSIQ) and the composition of the gut microbiota and metabolome in preschool children. Stool samples were collected from a community sample of 245 typically developing children (3-5 years) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. The faecal microbiome was assessed using 16S rRNA sequencing and the metabolome using LC-MS/MS. FSIQ and scores on the Verbal Comprehension, Visual Spatial, Working Memory indices of the Wechsler Preschool and Primary Scale of Intelligence-IV were used to assess neurocognition. Associations between the gut microbiota and FSIQ were determined using Pearson and Spearman correlations, which were corrected for multiple testing and relevant covariates. Verbal Comprehension correlated negatively with both Shannon alpha diversity (r = -0.14, p = 0.032) and the caffeine-derived metabolite paraxanthine (r = -0.22, p < 0.001). No other significant correlations were observed. Overall, the weak to modest correlations between Verbal Comprehension with alpha diversity and paraxanthine provide limited evidence of an association between the gut microbiota and neurocognitive outcomes in typically developing preschool children.

The distribution of dietary choline intake and serum choline levels in Australian women during pregnancy and associated early life factors.

BACKGROUND: Maternal dietary choline has a central role in foetal brain development and may be associated with later cognitive function. However, many countries are reporting lower than recommended intake of choline during pregnancy. METHODS: Dietary choline was estimated using food frequency questionnaires in pregnant women participating in population-derived birth cohort, the Barwon Infant Study (BIS). Dietary choline is reported as the sum of all choline-containing moieties. Serum total choline-containing compounds (choline-c), phosphatidylcholine and sphingomyelin were measured using nuclear magnetic resonance metabolomics in the third trimester. The main form of analysis was multivariable linear regression. RESULTS: The mean daily dietary choline during pregnancy was 372 (standard deviation (SD) 104) mg/day. A total of 236 women (23%) had adequate choline intake (440 mg/day) based on the Australian and New Zealand guidelines, and 27 women (2.6%) took supplemental choline ([Formula: see text] 50 mg/dose) daily during pregnancy. The mean serum choline-c in pregnant women was 3.27 (SD 0.44) mmol/l. Ingested choline and serum choline-c were not correlated (R2) = - 0.005, p = 0.880. Maternal age, maternal weight gain in pregnancy, and a pregnancy with more than one infant were associated with higher serum choline-c, whereas gestational diabetes and environmental tobacco smoke during preconception and pregnancy were associated with lower serum choline-c. Nutrients or dietary patterns were not associated with variation in serum choline-c. CONCLUSION: In this cohort, approximately one-quarter of women met daily choline recommendations during pregnancy. Future studies are needed to understand the potential impact of low dietary choline intake during pregnancy on infant cognition and metabolic intermediaries.

Fluoride exposure during pregnancy from a community water supply is associated with executive function in preschool children: A prospective ecological cohort study.

BACKGROUND: On May 19, 2011, Calgary, Canada stopped fluoridating its drinking water. This prospective ecological study examined if maternal exposure to fluoride during pregnancy from drinking water that was fluoridated at the recommended level of 0.7 mg/L was associated with children's intelligence and executive function at 3-5 years of age. METHODS: Participants were 616 maternal-child pairs enrolled in the Calgary cohort of the Alberta Pregnancy Outcomes and Nutrition (APrON) study between 2009 and 2012. Maternal-child pairs were classified as fully exposed to fluoridated drinking water throughout pregnancy (n = 295); exposed to fluoridated drinking water for at least part of the pregnancy plus an additional 90 days (n = 220); or not exposed to fluoridated drinking water during pregnancy plus the 90 days prior to pregnancy (n = 101). Children's Full Scale IQs were assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition: Canadian (WPPSI-IVCDN). Children's executive functions were also assessed: working memory (WPPSI-IVCDN Working Memory Index), inhibitory control (Gift Delay, NEPSY-II Statue subtest), and cognitive flexibility (Boy-Girl Stroop, Dimensional Change Card Sort (DCCS)). RESULTS: No associations were found between exposure group and Full Scale IQ. However, compared to no exposure, full exposure to fluoridated drinking water throughout pregnancy was associated with poorer performance on the Gift Delay (B = 0.53, 95 % CI = 0.31, 0.93). Sex-specific analyses revealed that girls in the fully exposed (AOR = 0.30, 95 % CI = 0.13, 0.74) and partially exposed groups (AOR = 0.42, 95 % CI = 0.17, 1.01) performed more poorly than girls in the not exposed group. Sex effects were also found on the DCCS; girls in the fully exposed (AOR = 0.34, 95 % CI = 0.14, 0.88) and partially exposed groups (AOR = 0.29, 95 % CI = 0.12, 0.73) performed more poorly. CONCLUSION: Maternal exposure to drinking water throughout pregnancy fluoridated at the level of 0.7 mg/L was associated with poorer inhibitory control and cognitive flexibility, particularly in girls, suggesting a possible need to reduce maternal fluoride exposure during pregnancy.