Risk Of Neurodevelopmental Disorders Research Articles

Selective mutism and the risk of mental and neurodevelopmental disorders among siblings.

The siblings of children with mental disorders are more likely to experience mental health issues themselves, but there has been a lack of sibling studies on selective mutism (SM). The aim of this population-based study was to use national registers to examine associations between children with SM and diagnoses of various mental disorder in their siblings. All singleton children born in Finland from 1987 to 2009, and diagnosed with SM from 1998 to 2012, were identified from national health registers and matched with four controls by age and sex. Their biological siblings and parents were identified using national registries and the diagnostic information on the siblings of the subjects and controls was obtained. The final analyses comprised 658 children with SM and their 1661 siblings and 2092 controls with 4120 siblings. The analyses were conducted using generalized estimating equations. Mental disorders were more common among the siblings of the children with SM than among the siblings of the controls. The strongest associations were observed for childhood emotional disorders and autism spectrum disorders after the data were adjusted for covariates and comorbid diagnoses among SM subjects. The final model showed associations between SM and a wide range of disorders in siblings, with strongest associations with disorders that usually have their onset during childhood. Our finding showed that SM clustered with other mental disorders in siblings and this requires further research, especially the association between SM and autism spectrum disorders. Strong associations with childhood onset disorders may indicate shared etiologies.

Prenatal Antidepressant Exposures and Autism Spectrum Disorder or Traits: A Retrospective, Multi-Cohort Study.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Psychometric properties of the Infant Motor Profile (IMP): A scoping review protocol.

The IMP is a novel video-based instrument to assess motor behavior of infants. It evaluates gross and fine motor behavior in five domains: variation, adaptability, symmetry, fluency, and performance. The latter assesses motor milestones, the other four domains assess qualitative aspects of movements. Literature suggests that it is a promising tool for pediatric health care, as its assists early detection of neurodevelopmental disorders and facilitates the design and monitoring of early intervention. This, this scoping review (ScR) aims to evaluate the psychometric properties of the Infant Motor Profile (IMP). A systematic search will be conducted to identify relevant studies up to October 15, 2022. All papers published in English that evaluated or used the IMP in children under two years of age will be included. The search will be performed in Pubmed, Lilacs, PEDro, Scielo, CINAHL, Embase, Web of Science, Ovid PsycINFO, Cochrane Database of Systematic Reviews, as well as in gray literature sources following the University of Toronto library guidelines. Standardized data extraction forms (Excel Tables) will be used to collect information. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for the Scoping Reviews (PRISMA-ScR) Checklist and JBI guidelines will be taken into consideration for results analysis and reporting. This Scoping Review will summarize available knowledge on the psychometric properties of the IMP. By proving that IMP is a reliable tool, a valid predictor of neurodevelopmental outcomes and a responsive instrument to measure change induced by early intervention, this will facilitate the implementation of the IMP in pediatric health care. It will assist the detection of infants at high risk of neurodevelopmental disorders, and it will facilitate the design of the tailor-made early intervention. This scoping review protocol has been registered at Open Science Framework (OSF) (https://doi.org/10.17605/OSF.IO/4HYKZ).

Application of chromosome microarray analysis and karyotyping in diagnostic assessment of abnormal Down syndrome screening results

BackgroundDown syndrome (DS) is the most common congenital cause of intellectual disability and also leads to numerous metabolic and structural problems. This study aims to explore the application value of chromosomal microarray analysis (CMA) and karyotyping in prenatal diagnosis for pregnant women with abnormal DS screening results.MethodsThe study recruited 1452 pregnant women with abnormal DS screening results including 493 with an enlarged nuchal translucency thickness (NT ≥ 2.5 mm) and 959 with an abnormal second-trimester maternal serum biomarker screening results. They underwent amniocentesis to obtain amniotic fluid for CMA and karyotyping.ResultsCMA identified 74/1452 abnormal results, which was more efficient than karyotyping (51/1452, P < 0.05.) CMA is equivalent to traditional karyotyping for identifying aneuploidies. Compared to karyotyping CMA identified 1.90% more copy number variants (CNVs) ranging from 159Kb to 6496Kb. However, 34.4% of them were recurrent pathogenic CNVs associated with risk of neurodevelopmental disorders. CMA identified 13 variants of uncertain significance (VUS) results and 1 maternal uniparental disomy (UPD) of chromosome 7. Karyotyping identified 3 mosaic sex chromosome aneuploidy and 4 balanced translocation which could not be identified by CMA. In enlarged NT group, karyotyping identified 80.9% abnormal results while in serum screening group karyotyping identified 35.7%. However, the incidence of pathogenic/likely pathogenic (P/LP) CNVs was nearly the same in both groups. That was because aneuploidies and gross duplication/deletion were previously screened out by NT scan.ConclusionsCMA and karyotyping have both advantages and disadvantages in prenatal diagnosis of pregnant women with abnormal DS screening results. However, there was not enough evidence to support routine CMA in pregnant women with abnormal DS screening results.

Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence

BackgroundThe knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD).MethodsThe sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately.ResultsA total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes.ConclusionImpulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.

"Not Valproic Acid" Is Not Without Risk: In Utero Exposure to Topiramate Is Associated With an Increased Risk of Neurodevelopmental Disorders.

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The developing brain: Challenges and opportunities to promote school readiness in young children at risk of neurodevelopmental disorders in low- and middle-income countries.

This paper discusses possibilities for early detection and early intervention in infants with or at increased risk of neurodevelopmental disorders in low- and middle-income countries (LMICs). The brain's high rate of developmental activity in the early years post-term challenges early detection. It also offers opportunities for early intervention and facilitation of school readiness. The paper proposes that in the first year post-term two early detection options are feasible for LMICs: (a) caregiver screening questionnaires that carry little costs but predict neurodevelopmental disorders only moderately well; (b) the Hammersmith Infant Neurological Examination and Standardized Infant NeuroDevelopmental Assessment (SINDA) which are easy tools that predict neurodisability well but require assessment by health professionals. The young brain's neuroplasticity offers great opportunities for early intervention. Ample evidence indicates that families play a critical role in early intervention of infants at increased risk of neurodevelopmental disorders. Other interventional key elements are responsive parenting and stimulation of infant development. The intervention's composition and delivery mode depend on the infant's risk profile. For instance, in infants with moderately increased risk (e.g., preterm infants) lay community health workers may provide major parts of intervention, whereas in children with neurodisability (e.g., cerebral palsy) health professionals play a larger role.

AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition.

Despite a prominent risk factor for Neurodevelopmental disorders (NDD), it remains unclear how Autism Susceptibility Candidate 2 (AUTS2) controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, forms a novel protein complex (AWS) specifically in neuronal progenitors and promotes neuronal differentiation through inhibiting BMP signaling. Genomic and biochemical analyses demonstrated that the AWS complex achieves this effect by recruiting the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Furthermore, using primary cortical neurons, we observed aberrant BMP signaling and dysregulated expression of neuronal genes upon manipulating the AWS complex, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Thus, our findings uncover a sophisticated cellular signaling network mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

Increasing maternal age predicts placental protein expression critical for fetal serotonin metabolism: Potential implications for neurodevelopmental research

High fetal exposure to serotonin and increasing maternal age both contribute to the risk for neurodevelopmental disorders. While identifying covariates for a study of placental protein expression, we found a significant negative correlation between maternal age and the expression of monoamine oxidase A (MAOA), and a significant positive correlation between maternal age and the expression of the serotonin transporter SERT. MAOA and SERT play key roles in placental serotonin metabolism relevant to fetal neurodevelopment. These preliminary findings suggest that the effect of increasing maternal age on neurodevelopmental risk may be mediated in part by changes in placental protein expression relevant to fetal serotonin metabolism.

Avis d’experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d’un trouble bipolaire traitées par valproate

IntroductionThe perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. MethodsA panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. ResultsFirst of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. ConclusionAlthough the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children

Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors. To evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children. This cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021. Dispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis. Neurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses. Among the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows. The results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

31.4 DAGSY: A Novel Clinical Framework to Address a Currently Unmet Need in Child and Adolescent Psychiatry

A growing number of genetic variants are identified that confer an increased risk for neurodevelopmental and neuropsychiatric disorders. The detection of these genomic disorders is becoming more prevalent in young children and provides an opportunity for proactive anticipatory psychiatric care, which contrasts to traditional (“reactive”) psychiatric care models indicated primarily by the presence of symptoms or behavioral concerns. This presentation aims to describe the first 3 years of experience with a novel, “genetic-first” child and adolescent psychiatric clinic.

31.5 DAGSY: A Novel Clinical Framework to Address a Currently Unmet Need in Child and Adolescent Psychiatry (second presenter)

A growing number of genetic variants are identified that confer an increased risk for neurodevelopmental and neuropsychiatric disorders. The detection of these genomic disorders is becoming more prevalent in young children and provides an opportunity for proactive anticipatory psychiatric care, which contrasts to traditional (“reactive”) psychiatric care models indicated primarily by the presence of symptoms or behavioral concerns. This presentation aims to describe the first 3 years of experience with a novel, “genetic-first” child and adolescent psychiatric clinic.

Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child.

To provide an updated summary and appraisal of work from 2019 to 2022 examining risks of selective serotonin reuptake inhibitor (SSRI) use in pregnancy. Perinatal SSRI exposure does not increase risk of major malformations or gestational diabetes after accounting for underlying maternal illness. SSRIs are associated with small increase in risk of pre-eclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, and neonatal intensive care unit admissions, though absolute risk of these outcomes is low. While data suggests no increased risk of neurodevelopmental disorders in offspring, mixed evidence indicates increased risk of adverse cognitive outcomes and affective disorders. Recent evidence suggest low absolute risk of clinically relevant negative outcomes with perinatal SSRI exposure when compared to untreated perinatal depression. However, study design and ability to control for confounding remains an ongoing research challenge, highlighting need for ongoing rigorous study design and analysis.

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Intra-amniotic inflammation in the mid-trimester of pregnancy is a risk factor for neuropsychological disorders in childhood.

Intra-amniotic inflammation is a subclinical condition frequently caused by either microbial invasion of the amniotic cavity or sterile inflammatory stimuli, e.g., alarmins. An accumulating body of evidence supports a role for maternal immune activation in the genesis of fetal neuroinflammation and the occurrence of neurodevelopmental disorders such as cerebral palsy, schizophrenia, and autism. The objective of this study was to determine whether fetal exposure to mid-trimester intra-amniotic inflammation is associated with neurodevelopmental disorders in children eight to 12years of age. This is a retrospective case-control study comprising 20 children with evidence of prenatal exposure to intra-amniotic inflammation in the mid-trimester and 20 controls matched for gestational age at amniocentesis and at delivery. Amniotic fluid samples were tested for concentrations of interleukin-6 and C-X-C motif chemokine ligand 10, for bacteria by culture and molecular microbiologic methods as well as by polymerase chain reaction for eight viruses. Neuropsychological testing of children, performed by two experienced psychologists, assessed cognitive and behavioral domains. Neuropsychological dysfunction was defined as the presence of an abnormal score (<2 standard deviations) on at least two cognitive tasks. Neuropsychological dysfunction was present in 45% (9/20) of children exposed to intra-amniotic inflammation but in only 10% (2/20) of those in the control group (p=0.03). The relative risk (RR) of neuropsychological dysfunction conferred by amniotic fluid inflammation remained significant after adjusting for gestational age at delivery [aRR=4.5 (1.07-16.7)]. Of the 11 children diagnosed with neuropsychological dysfunction, nine were delivered at term and eight of them had mothers with intra-amniotic inflammation. Children exposed to intra-amniotic inflammation were found to have abnormalities in neuropsychological tasks evaluating complex skills, e.g., auditory attention, executive functions, and social skills, whereas the domains of reasoning, language, and memory were not affected in the cases and controls. Asymptomatic sterile intra-amniotic inflammation in the mid-trimester of pregnancy, followed by a term birth, can still confer to the offspring a substantial risk for neurodevelopmental disorders in childhood. Early recognition and treatment of maternal immune activation in pregnancy may be a strategy for the prevention of subsequent neurodevelopmental disorders in offspring.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.

Infection of the murine placenta by Listeria monocytogenes induces sex-specific responses in the fetal brain.

Epidemiological data indicate that prenatal infection is associated with an increased risk of several neurodevelopmental disorders in the progeny. These disorders display sex differences in presentation. The role of the placenta in the sex-specificity of infection-induced neurodevelopmental abnormalities is not well-defined. We used an imaging-based animal model of the bacterial pathogen Listeria monocytogenes to identify sex-specific effects of placental infection on neurodevelopment of the fetus. Pregnant CD1 mice were infected with a bioluminescent strain of Listeria on embryonic day 14.5 (E14.5). Excised fetuses were imaged on E18.5 to identify the infected placentas. The associated fetal brains were analyzed for gene expression and altered brain structure due to infection. The behavior of adult offspring affected by prenatal Listeria infection was analyzed. Placental infection induced sex-specific alteration of gene expression patterns in the fetal brain and resulted in abnormal cortical development correlated with placental infection levels. Furthermore, male offspring exhibited abnormal social interaction, whereas females exhibited elevated anxiety. Placental infection by Listeria induced sex-specific abnormalities in neurodevelopment of the fetus. Prenatal infection also affected the behavior of the offspring in a sex-specific manner. Placental infection with Listeria monocytogenes induces sexually dichotomous gene expression patterns in the fetal brains of mice. Abnormal cortical lamination is correlated with placental infection levels. Placental infection results in autism-related behavior in male offspring and heightened anxiety levels in female offspring.

Prevalence of neurodevelopmental disorders in a clinically referred sample of children with CHD.

Youth with CHD are at greater risk for neurodevelopmental disorders compared to healthy controls. The aetiology is multi-factorial but includes medical and demographic factors. We sought to characterise the prevalence of neurodevelopmental disorders in patients with CHD. Our population included 206 patients with CHD, aged 3-21, who were referred for neuropsychological evaluation. Neurodevelopmental diagnoses were determined by a licensed psychologist. Rates of neurodevelopmental diagnoses were compared to national prevalence rates. Exploratory analyses (chi-square) examined which medical factors (i.e., cardiac diagnosis, genetic condition, prematurity, seizures, and stroke) were associated with neurodevelopmental diagnosis. There was higher prevalence of neurodevelopmental disorders in CHD when compared to the general population (44%). Rates of attention-deficit/hyperactivity disorder (27.3%), autism spectrum disorder (9.6%), and intellectual disability (5.9%) were notably higher than those seen in the general population (p<.01). Children with a history of aortic obstruction were more likely to be diagnosed with autism (p<.05), and children with genetic conditions were more likely to be diagnosed with an intellectual disability (p<.05). Neurodevelopmental diagnoses were not significantly associated with any other specific medical variables (e.g., cardiac diagnosis, seizures, stroke, prematurity, and antenatal diagnosis). School-aged children were more likely to be diagnosed with any neurodevelopmental disorder and attention-deficit/hyperactivity disorder (31.7%; p<.01) than preschool-age children. In summary, our results confirm that children and adolescents with CHD are at high risk for neurodevelopmental disorders and require ongoing monitoring, care, and support. Children with genetic disorders and those with aortic obstruction may be more at risk for certain neurodevelopmental disorders.

Interleukin-1β-induced inflammation and acetaminophen during infancy: Distinct and interactive effects on social-emotional and repetitive behavior in C57BL/6J mice

Acetaminophen (APAP) exposure early in life has been associated with increased risk of neurodevelopmental disorders in epidemiological studies. In rodent models, early-life APAP has similarly been shown to produce long-term changes in brain and behavior, including altered activity levels and social behavior. Most rodent studies to date have, nevertheless, attempted to model early-life APAP without considering that most APAP exposure occurs in a context of immune activation and/or fever. To mimic the repeated infections common during infancy, we employed the cytokine interleukin-1β (IL-1β) to induce immune activation three times during early postnatal development (i.e., day 5, 8, and 11). On these days, C57BL/6J pups were administered either IL-1β (0.2 μg/kg) or saline vehicle followed, after 45 min, by either APAP (103.9 mg/kg) or vehicle. Mice were subsequently administered a battery of tests of social-emotional and repetitive behavior. A number of distinct long-term effects of IL-1β and APAP treatments were found, including sex-specific shifts in repetitive behavior and emotional hyperthermia following early-life IL-1β and increased social caution in males following early-life APAP. We also observed significant interaction between IL-1β and APAP: as adults, ‘two-hit’ IL-1β + APAP females displayed greater anxiety-related thigmotaxis across a number of tests, including an open field. ‘Two hit’ males, in turn, showed elevated levels of avoidance of an unfamiliar social partner during a social interaction test. Our results highlight that IL-1β-induced inflammation and APAP have both distinct effects and significant interactions during early life, with enduring sex-specific effects on phenotypes relevant to neurodevelopmental disorders.