Sex differences in neurodevelopmental trajectories in children with different levels of autistic traits.

AIM: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. METHODS: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups-low, moderate, and high-based on the Social Responsiveness Scale-Second Edition. Cognitive and motor functions were measured at seven time-points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time-points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales-Second Edition. Trajectories were depicted using latent growth curve modeling. RESULTS: Sex-specific trajectories were observed in the high-autistic-trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high-autistic-trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. CONCLUSION: Females and males with higher autistic traits than their same-sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood.

Identification of neurodevelopmental transition patterns from infancy to early childhood and risk factors predicting descending transition.

It is unclear whether neurodevelopmental progress from infancy to early childhood remains stable. Moreover, little is known about the risk factors, if any, affecting neurodevelopmental descending transition patterns and the relationship between these patterns and later childhood adaptive behaviours. We used data of 875 children from the Hamamatsu Birth Cohort Study in Japan. Children's neurodevelopment at 18 and 32 months and adaptive behaviours at 40 months were evaluated. Perinatal factors and infant overweight status at 18 months were investigated to identify descending-transition-associated risk factors. In the latent transition analysis, ultimately, three classes were identified for each time-point, resulting in nine transition patterns; among them, 10.4% of children showed descending class shifts (normal to delayed class). Such decelerated growth was predicted by maternal pre-pregnancy overweight status (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.23, 5.02), low maternal educational history (OR 1.20; 95% CI 1.04, 1.36), and infant overweight status at 18 months (OR 5.89; 95% CI 1.26, 27.45). Children with descending transition showed poor functioning in adaptive behaviours at the age of 40 months. To prevent subsequent poor adaptive functioning, it may be necessary to consider that a certain percentage of children show decelerated growth.

Association Between Genetic Risks for Obesity and Working Memory in Children.

Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated. Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory. Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (ß[SE], -1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (ß[SE], -2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (ß[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (ß[SE], -2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children. Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.

Elevated risk of attention deficit hyperactivity disorder (ADHD) in Japanese children with higher genetic susceptibility to ADHD with a birth weight under 2000 g.

BACKGROUND: Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. METHODS: We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as <2000 g, 2000-2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother's age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father's age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model. RESULTS: Birth weight of 2000-2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07-2.27) and hyperactivity (RR 1.87, 95% CI 1.14-3.06). CONCLUSIONS: Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

Polygenic risk score analysis revealed shared genetic background in attention deficit hyperactivity disorder and narcolepsy.

Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold < 0.05, ß [SE], 5.815 [1.774]; P = 0.002) and inattention domain (e.g., P-value threshold < 0.05, ß [SE], 5.734 [1.761]; P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

Measuring School Climate among Japanese Students-Development of the Japan School Climate Inventory (JaSC).

School climate is a significant determinant of students' behavioral problems and academic achievement. In this study, we developed the Japan School Climate Inventory (JaSC) to see whether it measures school climate properly. To do so, we investigated whether or not the measurement with JaSC varies across sub-groups of varying grade and of gender and examined the relationship between the perception of school climate and the psychological and behavioral traits at individual levels in a sample of Japanese elementary and junior high school students (n = 1399; grade 4-9). The results showed that the measurement was consistent, since single-factor structures, factor loadings and thresholds of the items were found not to vary across sub-groups of the participants. The participants' perception of school climate was associated positively with quality of life, especially in school (ß = 0.152, p < 0.001) and associated negatively with involvement in ijime (bullying) as "victim" and "bully/victim" (ß = -0.098, p = 0.001; ß = -0.188, p = 0.001, respectively) and peer relationship problems (ß = -0.107, p = 0.025). JaSC was found to measure school climate consistently among varying populations of Japanese students, with satisfactory validity.

Association of Genetic Risks With Autism Spectrum Disorder and Early Neurodevelopmental Delays Among Children Without Intellectual Disability.

Importance: Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood. Objective: To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population. Design, Setting, and Participants: In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019. Main Outcomes and Measures: Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months. Results: Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; ß, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; ß, -1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; ß, -1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; ß, -5.28; SE, 1.40; P < .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; ß, -5.30; SE 1.30; P < .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; ß, -6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; ß, -6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; ß, 7.37; SE, 2.15; P = .001); glutamatergic signaling-associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; ß, -5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; ß, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; ß, -5.38; SE, 1.74; P = .002). Conclusions and Relevance: In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.

Neurodevelopmental Trajectory During Infancy and Diagnosis of Autism Spectrum Disorder as an Outcome at 32 Months of Age.

BACKGROUND: Little is known about the extent to which neurodevelopmental trajectories in infancy predict a later diagnosis of autism spectrum disorder (ASD). METHODS: We investigated the association between the neurodevelopmental trajectory classes identified using a latent class growth analysis and the distal clinical outcome. Participants included 952 infants from the Hamamatsu Birth Cohort for Mothers and Children (HBC study). Neurodevelopment was measured using the Mullen Scales of Early Learning, which contains five subscales (gross motor, fine motor, visual reception, receptive language, and expressive language), at seven time points from 1 to 24 months of age. ASD was diagnosed in 3.1% of the children at 32 months of age. The clinical outcome was included in our analysis model. RESULTS: Five neurodevelopmental classes were identified: high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%). The probability of a diagnosis of ASD in the markedly delayed class was highest (32.6%) when compared with the other classes. The probabilities of receiving a diagnosis of ASD in the delayed and low normal classes were 6.4% and 4.0%, respectively, whereas the probabilities in the normal and high normal classes were both 0%. CONCLUSIONS: A diagnosis of ASD may be predicted by the neurodevelopmental trajectories during infancy, which can be evaluated both routinely and objectively in clinical settings. In this representative population, children diagnosed with ASD showed early signs in neurodevelopmental domains during the first 2 years of life.

Reliability and validity of the Japan Ijime Scale and estimated prevalence of bullying among fourth through ninth graders: A large-scale school-based survey.

AIM: The present study aimed at developing a novel scale, the Japan Ijime Scale (JaIS), to measure bullying in Japan with substantial reliability and validity, with which we estimated the prevalence of bullying among children and adolescents of school age. METHODS: The JaIS is a self-report questionnaire and consists of three parts: subscales measuring victimization and witnessing, and an item measuring perpetration. To test the reliability and validity of the two subscales, the authors analyzed responses to the JaIS from 2334 school students (Grades 4-9) in six elementary and three junior high schools in a middle-sized industrial city in central Japan, using exploratory factor analysis, item response theory, and examination of the external validity of the items. The prevalence of bullying victimization, witnessing, and perpetration was estimated. RESULTS: Item response theory models revealed that both the Victimization and Witness subscales have sufficient discrimination power and measurement precision, and the external validity of each scale has been confirmed. Using the JaIS, we found that 35.8% of students had been victims of bullying every 2-3 months (27.6% were solely victims and 8.3% were bully/victims), 32.8% had witnessed some type of bullying act, and 11.8% had perpetrated some type of bullying (3.5% as perpetrators, and 8.3% as bully/victims). CONCLUSION: The JaIS is a reliable and valid measure. Using this scale, we found a high prevalence of bullying victimization in Japanese schools.

Interaction effect of oxytocin receptor (OXTR) rs53576 genotype and maternal postpartum depression on child behavioural problems.

Previous studies have reported interaction effects of oxytocin receptor genotype (rs53576) and environmental factors on mental health in youth. However, the findings are mixed, especially regarding the type of allele (i.e., A vs. G), and it remains unanswered whether such an interaction presents at an early stage of development. Thus, using a unique longitudinal birth cohort sample in Japan (n = 568), we examined whether there was an effect of the interaction between the OXTR rs53576 genotype and maternal postpartum depression, as an environmental risk, on behavioural problems in children. Child behavioural problems (internalising and externalising problems) were ascertained using the Strengths and Difficulties Questionnaire when children were 6 years old. Maternal postpartum depression was measured using the Edinburgh Postnatal Depression Scale when children were at 2 months and 10 months of age. The results revealed a significant effect in the interaction between OXTR rs53576 genotype and maternal postpartum depression on externalising problems in children with AA genotype (ß = 0.136, 95% CI 0.032 to 0.240), but not in those with GG/GA genotype. This indicates that an interaction of vulnerable genotypes (i.e., A allele of OXTR rs53576) with an environmental burden (i.e. maternal postpartum depression) may be one of the potential elements that predisposes the infant to developing behavioural problems early in life. Hence, special attention needs to be paid to children exposed to environmental risks such as maternal postpartum depression, to facilitate the provision of appropriate care.

Association of late-onset postpartum depression of mothers with expressive language development during infancy and early childhood: the HBC study.

BACKGROUND: While it has been implied that an infant's exposure to maternal postpartum depression (PPD) may be associated with delayed development of expressive language, it remains unclear whether such a delay persists into childhood and whether the onset of PPD onset-early (within 4 weeks after childbirth) vs. late (between 5 and 12 weeks postpartum)-is relevant in this context. OBJECTIVE: To examine whether children of mothers with early- or late-onset PPD have reduced expressive language scores during infancy and early childhood (up to 40 months of age). METHODS: This longitudinal, observational study was conducted as a part of the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), a population-representative sample in Japan. A total of 969 neonates and their mothers were included in the analysis. EXPOSURES: Early- and late-onset PPD was measured using the Edinburgh Postnatal Depression Scale. MAIN OUTCOMES AND MEASURES: Expressive language development was measured using the Mullen Scales of Early Learning. Six points over time were monitored (10, 14, 18, 24, 32, and 40 months postpartum). The relationship between the exposure variable and any change in expressive language score was evaluated using multiple linear regression analysis and growth curve analysis, both adjusted for covariates. RESULTS: Results from the adjusted regression analysis showed that children of mothers with late-onset PPD had significantly lower expressive language scores at 18 months of age and beyond, with a score reduction of approximately 0.6 standard deviations from the reference value at 40 months of age (95% CI [-0.888 to -0.265], p < .001). This association was confirmed on growth curve analysis, which revealed a significant, monotonic decline of expressive language development between 10 and 40 months of age among children of mothers with late-onset PPD, but not among children of mothers with early-onset PPD. CONCLUSION: Exposure to late-onset PPD may lead to a persistent decline in the rate of expressive language development in offspring during infancy and early childhood, highlighting the significance of monitoring for late-onset PPD to facilitate early detection and intervention.

Effect of Physical State on Pain Mediated Through Emotional Health in Rheumatoid Arthritis.

OBJECTIVE: Pain is one of the main symptoms of patients with rheumatoid arthritis (RA). Pain in RA is caused by specific physical changes, such as joint destruction, and is therefore used as a disease activity marker. Although pain can also be influenced by emotional factors, neither the effect of emotional health nor the indirect effect of the physical state mediated by emotional health on pain has been quantified. METHODS: A total of 548 patients with RA participated. Emotional health was assessed using the Hospital Anxiety and Depression Scale (HADS). Measures routinely used in practice were used to evaluate the physical state and pain. To quantify the effects of the physical state on emotional health, and the effects of both physical and emotional health on pain, we used structural equation modeling, with emotional health, physical state, and pain as latent variables. RESULTS: The prevalence of anxiety and depression (HADS score ≥8 for each) among patients with RA was 18.7% and 29.4%, respectively. Emotional health was significantly influenced by the physical state (ß = 0.21). Pain was affected by physical (ß = 0.54) and emotional health (ß = 0.29). The effect of the physical state on pain was mediated by emotional health, with this mediation effect (ß = 0.06) accounting for 10.2% of the total effect. CONCLUSION: The magnitude of pain in RA is determined by the mediation effect of emotional health as well as the direct physical state. Our findings suggest that emotional factors should be taken into account when assessing RA disease activity.

Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes.

Epidemiological studies suggest that obstetric complications, particularly those related to hypoxia during labor and delivery, are a risk factor for development of schizophrenia. The impact of perinatal asphyxia on postnatal life has been studied in a rodent model of global hypoxia, which is accompanied by cesarean section birth. This asphyxia model shows several behavioral, pharmacological, neurochemical, and neuroanatomical abnormalities in adulthood that have relevance to schizophrenia. Further, it is suggested that schizophrenia has a strong genetic component, and indeed novel candidate genes were recently identified by a genome-wide association study. Here, we examined alteration in the novel schizophrenia risk genes, CNNM2, CSMD1, and MMP16 in the brains of rats undergoing cesarean section with or without global hypoxia. The brain regions studied were the prefrontal cortex, striatum, and hippocampus, which are all relevant to schizophrenia. Risk gene expression was measured at three time periods: neonatal, adolescence, and adulthood. We also performed an in vitro analysis to determine involvement of these genes in CNS maturation during differentiation of human neuronal and glial cell lines. Cnnm2 expression was altered in the brains of asphyxia model rats. However, Csmd1 and Mmp16 showed altered expression by exposure to cesarean section only. These findings suggest that altered expression of these risk genes via asphyxia and cesarean section may be associated, albeit through distinct pathways, with the pathobiology of schizophrenia.

Maternal postpartum depressive symptoms predict delay in non-verbal communication in 14-month-old infants.

We investigated the potential relationship between maternal depressive symptoms during the postpartum period and non-verbal communication skills of infants at 14 months of age in a birth cohort study of 951 infants and assessed what factors may influence this association. Maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale, and non-verbal communication skills were measured using the MacArthur-Bates Communicative Development Inventories, which include Early Gestures and Later Gestures domains. Infants whose mothers had a high level of depressive symptoms (13+ points) during both the first month postpartum and at 10 weeks were approximately 0.5 standard deviations below normal in Early Gestures scores and 0.5-0.7 standard deviations below normal in Later Gestures scores. These associations were independent of potential explanations, such as maternal depression/anxiety prior to birth, breastfeeding practices, and recent depressive symptoms among mothers. These findings indicate that infants whose mothers have postpartum depressive symptoms may be at increased risk of experiencing delay in non-verbal development.

Season of Birth Predicts Emotional and Behavioral Regulation in 18-Month-Old Infants: Hamamatsu Birth Cohort for Mothers and Children (HBC Study).

BACKGROUND: Previous research has demonstrated that the season of birth may predict development of emotional and behavioral regulation during childhood or adolescence. This study examined whether the season of birth predicts effortful control (i.e., the ability to voluntarily choose course of actions during conflict and to plan for the future) and aggression (i.e., the use of physical force and expression of anger toward others) in 18-month-old infants. METHODS: Participants included 885 infants who were enrolled in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan. Seasons of birth were categorized into winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and autumn (September, October, and November). At 18 months of age, effortful control was assessed using the Early Childhood Behavior Questionnaire, and aggression was measured using the Cardiff Infant Contentiousness Scale. Structural equation modeling analysis with measurement and structural equations was conducted to test our prediction. RESULTS: Effortful control was higher in infants born in spring [B = 0.095, 95% CI (0.014 to 0.175), p = 0.021, ß = 0.146] and summer [B = 0.078, 95% CI (0.001 to 0.156), p = 0.049, ß = 0.118] than in those born in winter. In addition, aggression was lower in those born in spring [B = -0.286, 95% CI (-0.551 to -0.021), p = 0.035, ß = -0.135] than those born in winter, even after controlling for seven covariates. CONCLUSION: The findings suggest that season of birth may determine development of emotional and behavioral regulation skills during early infancy. Future research should pay more attention to the underlying mechanisms of the effects of birth season on development of emotional and behavioral regulation during infancy.

Fetal Environment and Glycosylation Status in Neonatal Cord Blood: A Comprehensive Mass Spectrometry-based Glycosylation Analysis.

Fetal environment is known to be a major predictive factor of type 2 diabetes and cardiovascular disease. However, associations of fetal environment and cord blood glycoforms are uncertain. In this study, we aimed to determine whether glycosylation status in neonatal cord blood is associated with perinatal outcomes reflecting a poor fetal environment.Thirty-six low birth weight (LBW) infants and 120 normal birth weight infants were recruited from a longitudinal birth cohort. We conducted a comprehensive cord blood N-glycan analysis using matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry. Associations of N-glycans with perinatal outcomes, including LBW, small for gestational age, and levels of cord blood leptin and adiponectin, were evaluated using logistic or multiple regression. We also prospectively explored correlations between N-glycans and 6 or 18-month rapid weight gain (>0.67 SD score).A total of 35 N-glycans were detected (m/z value 1362.481-3865.407). Of these, abundance levels of G3414 (m/z value 3414.238) were inversely correlated with LBW and small for gestational age. Abundance levels of G1915 (m/z value 1914.698), G2744 (m/z value 2743.994), G3049 (m/z value 3049.105), and G3719 (m/z value 3719.349) were inversely related to LBW. The total N-glycan abundance levels were strongly positively correlated with levels of leptin and adiponectin in cord blood. In a prospective exploratory analysis, the 5 LBW-related N-glycans (G1915, G2744, G3049, G3414, and G3719) were all inversely associated with 6 or 18-month rapid weight gain. These N-glycans are structurally categorized into 2 different categories: fucosylated bi or tri-antennary N-glycans; and tri or tetra-antennary N-glycans without fucosylation.In conclusion, mass spectrometry-based cord blood glycosylation analysis shows that 5 types of N-glycans are potential predictors of a poor fetal environment.

Identification of neurodevelopmental trajectories in infancy and of risk factors affecting deviant development: a longitudinal birth cohort study.

BACKGROUND: We investigate patterns of neurodevelopmental trajectories in infants, using a representative population, and identify risk factors that predict delayed growth. METHODS: Participating infants (n = 952; 82.8% of the total sample) were assessed by Mullen Scales of Early Learning at seven time points, from 1 month to 24 months of age. Mothers were recruited in early pregnancy and data on demographic characteristics were collected during pregnancy. Trajectory patterns were investigated using latent class growth analysis, and risk factors for the derived trajectory classes were investigated by multinomial logistic regression. RESULTS: Participants were found to be a fairly representative sample with respect to their demographic characteristics. Five classes of high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%) were identified. The markedly delayed class was characterized by overall delay from the early developmental stages; notably, such delay first became salient in motor domains and was then exceeded by language domains, especially receptive language. This class was predicted by male sex (odds ratio 4.0; 95% confidence interval 1.7-9.1), small for gestational age (2.8; 1.0-7.5), low placenta-to-birthweight ratio (2.8; 1.2-6.4) and low maternal education (4.7; 1.2-19.0). The delayed class was characterized by gradual downward deviation after the first birthday, and was predicted by male sex (2.5; 1.5-4.2), preterm birth (4.4; 1.6-12.6) and advanced paternal age (1.9; 1.0-3.5). CONCLUSIONS: Our results demonstrate that about 1 out of 5 infants exhibits delayed neurodevelopment. Infants with distinct patterns of delayed trajectories and varying risk factors are considered to have different pathophysiological mechanisms.