Risk Of Neurodevelopmental Disorders Research Articles

Hypertensive disorders in pregnancy and child development at 36 months in the All Our Families prospective cohort study.

Hypertensive disorders in pregnancy (HDP) are associated with increased risk of offspring neurodevelopmental disorders, suggesting long-term adverse impacts on fetal brain development. However, the relationship between HDP and deficits in general child development is unclear. Our objective was to assess the association between HDP and motor and cognitive developmental delay in children at 36 months of age. We analyzed data from the All Our Families community-based cohort study (n = 1554). Diagnosis of HDP–gestational or chronic hypertension, preeclampsia, or eclampsia–was measured through medical records. Child development was measured by maternal-report on five domains of the Ages and Stages Questionnaire (ASQ-3). Standardized cut-off scores were used to operationalize binary variables for any delay, motor delay, and cognitive delay. We calculated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) using logistic regression, sequentially controlling for potential confounders followed by factors suspected to lie on the causal pathway. Overall, 8.0% of women had HDP and hypertension-exposed children had higher prevalence of delay than unexposed children. Hypertension-exposed children had elevated risk for developmental delay, but CIs crossed the null. The aRRs quantifying the fully adjusted effect of HDP on child development were 1.19 (95% CI 0.92, 1.53) for any delay, 1.18 (95% CI 0.86, 1.61) for motor delay, and 1.24 (95% CI 0.83, 1.85) for cognitive delay. We did not find a statistically significant association between HDP and developmental delay. Confidence intervals suggest that children exposed to HDP in utero have either similar or slightly elevated risk of any, motor, and cognitive delay at 36 months after controlling for maternal and obstetric characteristics. The observed direction of association aligns with evidence of biological mechanisms whereby hypertensive pathology can disrupt fetal neurodevelopment; however, more evidence is needed. Findings may have implications for early developmental monitoring and intervention following prenatal hypertension exposure.

Pregnancy-Related Anxiety and Impact of Social Media Among Pregnant Women Attending Primary Health Care.

BackgroundPregnant women go through physiological as well as psychological changes during pregnancy. Antenatal anxiety disorders are common, with proven adverse maternal and fetal outcomes. Anxiety increases the risks for prematurity and neurodevelopmental disorders. This study aimed to estimate the prevalence of pregnancy-related anxiety and the impact of social media among pregnant women in Al-Ahsa, Saudi Arabia.Materials and methodsThis observational cross-sectional study included pregnant women who were attending antenatal care (ANC) in primary healthcare centers between May and October of 2021 in Al-Ahsa, Saudi Arabia. For data collection, a structured self-administered questionnaire was distributed randomly to eligible pregnant women. The presence of pregnancy-related anxiety was assessed by using the 10-item Pregnancy-Related Anxiety Questionnaire-Revised (PRAQ-R), Arabic version. The impact of social media was measured through Social Media Engagement Questionnaire (SMEQ).ResultsOut of 823 pregnant women, 382 were eligible. Their mean age was 26.1 ± 10.9 years. Most of them (70.4%) had adhered to ANC. However, 32.1% had a history of miscarriage, and 6.7% had previous birth with congenital anomalies. The mean scores of pregnancy-related anxiety domains were 10.6 out of 15 for fear of giving birth, 8.7 for concern of own appearance, and 6.4 out of 12 for worries about bearing a handicapped child. More than half of the participants scored 28 out of 50 for pregnancy-related anxiety. The factors that were significantly associated with pregnancy-related anxiety were healthcare workers, first trimester, and unplanned pregnancy (P < 0.05). Social media engagement showed no correlation with anxiety.ConclusionsThe pregnancy-related anxiety level was average among pregnant women in Al-Ahsa, and fear of giving birth was the most common reason. Its predictors included early pregnancy, being a healthcare provider, and unplanned pregnancy. Pregnancy-related anxiety should be diagnosed early during routine ANC for better maternal and fetal outcomes.

Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes.

SUMMARYDeleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs).We profile chromatin accessibility and gene expression in Pogz−/− mice and show that POGZ promotes the active chromatin state and transcription of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with ADNP, another high-confidence ASD risk gene, and provide evidence that POGZ regulates other neurodevelopmental disorder risk genes as well. Our results reveal a neurodevelopmental function of an ASD risk gene and identify molecular targets that may elucidate its function in ASD.

Developmental Vitamin D Deficiency in Pregnant Rats Does Not Induce Preeclampsia.

Preeclampsia is a pregnancy disorder characterized by hypertension. Epidemiological studies have associated preeclampsia with an increased risk of neurodevelopmental disorders in offspring, such as autism and schizophrenia. Preeclampsia has also been linked with maternal vitamin D deficiency, another candidate risk factor also associated with autism. Our laboratory has established a gestational vitamin-D-deficient rat model that shows consistent and robust behavioural phenotypes associated with autism- and schizophrenia-related animal models. Therefore, we explored here whether this model also produces preeclampsia as a possible mediator of behavioural phenotypes in offspring. We showed that gestational vitamin D deficiency was not associated with maternal blood pressure or proteinuria during late gestation. Maternal and placental angiogenic and vasculogenic factors were also not affected by a vitamin-D-deficient diet. We further showed that exposure to low vitamin D levels did not expose the placenta to oxidative stress. Overall, gestational vitamin D deficiency in our rat model was not associated with preeclampsia-related features, suggesting that well-described behavioural phenotypes in offspring born to vitamin-D-deficient rat dams are unlikely to be mediated via a preeclampsia-related mechanism.

Neurodevelopmental Screening in Young Children with Sickle Cell Disease

It is important to prioritize screening and surveillance for neurodevelopmental dysfunction in children with SCD because this vulnerable population is at higher risk for neurological complications including stroke, silent cerebral infarction, and neurodevelopmental disorders (NDD) such as language disorders, attention deficit hyperactivity disorder, and autism spectrum disorder (ASD). The American Society of Hematology (ASH) and American Academy of Pediatrics (AAP) have published guidelines to accomplish this, as well as to improve quality of life for people with SCD and NDDs. Despite the recognition of the increased risk and the clinical guidelines, the co-occurrence rates of SCD and NDD remain lower than expected.We hypothesize that the risk of NDDs is lower than expected in children with SCD due to low rates of neurodevelopmental screening and surveillance among primary care providers and hematologists, particularly in young children. Therefore, we examined the frequency of neurodevelopmental screening and surveillance among young children with SCD and identified clinical characteristics of young children with SCD who did not receive appropriate neurodevelopmental screening and surveillance.We conducted a retrospective chart review using the clinic rosters of two affiliated inner-city hospitals with a pediatric hematology clinic and sickle cell neurodevelopmental clinic. Children under 5 years old with SCD confirmed by their hematologists who were not adopted or in foster care were included in the study. A total of 276 patients were identified and reviewed. NDD and ASD specific screenings were documented at the time of review, although participants may have been diagnosed later in life. Analyses were completed using chi squared test, Fisher exact test, t-test in Stata IC-15.Patients were screened by a variety of providers, most commonly pediatricians and hematologists (see Figure 1). Table 1a shows the characteristics of the SCD patients assessed/not assessed for appropriate neurodevelopment (ND) by their pediatrician and/or hematologist. A total of 214 participants qualified for study inclusion and 148 participants (70%) were assessed for neurodevelopment. Ages and Stages Questionnaire- 3 (32%) and other non-standardized screening tools (85%) were the most common tool used (see Table 2a). Of the ND assessed patients (N=148), 37 (25%) were diagnosed with NDDs (see Table 3a). Among the not assessed ND patients (N=66), 16 (24%) were diagnosed with NDDs. Table 1b shows the characteristics of the SCD patients assessed/not assessed specifically for ASD by their pediatrician and/or hematologist. A total of 207 participants qualified for study inclusion and 39 participants (19%) were assessed for ASD. Modified Checklist for Autism in Toddlers (92%) was the most utilized screening tool (see Table 2b). None of these patients had ASD. Of the ASD assessed patients (N=39), 9 (23%) were diagnosed with NDDs (see Table 3a). Among the not assessed ASD patients (N=168), 41 (24%) were diagnosed with NDDs.Children with SCD are being screened by their healthcare providers at a much lower rate than the general pediatric population. More specifically, many children with SCD were being screened for NDD, but not ASD. Among screened children, a majority were screened with non-standardized (or poorly documented) tools or outside the age guidelines recommended by ASH and AAP (see Figure 2). Children among ND and ASD assessment groups exhibited similar percentages of NDD diagnosis, which may highlight disparities in screening and early detection of these disorders; NDDs may have also been diagnosed later in life these patients. Guidelines regarding developmental screening in pediatric SCD were released in mid-2020; given the short timeline, we did not expect to see changes in practice from this chart review. However, the AAP has guidelines for developmental surveillance and screening since 2004. Due to study design, limitations include lack of access to some data at the time of review, as patient medical records were switched to another electronic system. Additionally, standardized tools may have been used but not documented in patient charts.In conclusion, it is crucial to know the utility of these assessments in this vulnerable population. A future study could examine how the rates of screening and surveillance have changed since the guidelines release, using these data for comparison purposes. [Display omitted] DisclosuresCasella: Mast Pharmaceuticals (previously Adventrx Pharmaceuticals): Consultancy, Honoraria, Patents & Royalties. Lance: Novartis: Other: participated in research advisory board in 2020.

Neurodevelopmental and psychiatric disorders in females with Turner syndrome: a population-based study

BackgroundTurner syndrome is the result of the partial or complete absence of an X chromosome in phenotypic girls. This can cause an array of medical and developmental difficulties. The intelligence quotient in females with Turner syndrome has previously been described as uneven, but considered within normal range. Although their social, intellectual, and psychiatric profile is described, it is unclear to what extent these females meet the clinical criteria for neurodevelopmental or psychiatric diagnoses. The aim of this study was to examine the prevalence of neurodevelopmental and psychiatric disorders in females with Turner syndrome.MethodsA retrospective cohort study was performed with a total of 1392 females with Turner syndrome identified through the Swedish National Patient Register and compared with 1:100 age- and sex-matched controls from the general population. The associations between Turner syndrome and diagnoses of neurodevelopmental and/or psychiatric disorders were calculated using conditional logistic regression and is presented as estimated risk (odds ratio, OR, 95% confidence interval, CI) in females with Turner syndrome compared with matched controls.ResultsFemales with Turner syndrome had a higher risk of neurodevelopmental or psychiatric disorder (OR 1.37, 95% CI 1.20–1.57), an eightfold increased risk of intellectual disability (OR 8.59, 95% CI 6.58–11.20), and a fourfold increased risk of autism spectrum disorder (OR 4.26, 95% CI 2.94‑6.18) compared with the controls. In addition, females with Turner syndrome had twice the risk of a diagnosis of schizophrenia and related disorders (OR 1.98, 95% CI 1.36–2.88), eating disorders (OR 2.03, 95% CI 1.42–2.91), and behavioral and emotional disorders with onset in childhood (OR 2.01, 95% CI 1.35–2.99).ConclusionsFemales with Turner syndrome have an increased risk of receiving a diagnosis of neurodevelopmental or psychiatric disorder. This warrants extensive assessment of intellectual and cognitive functions from early age, and increased psychiatric vigilance should be a part of lifelong healthcare for females with Turner syndrome.

Early manifestations of genetic risk for neurodevelopmental disorders.

Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism) and schizophrenia are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. It is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls. Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a subsample of 15 205 children from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mother-reported traits of repetitive behavior, social communication, language and motor difficulties, hyperactivity and inattention were measured in children at 6 and 18 months, 3, 5 and 8 years. Linear regression models in a multigroup framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, using sex as a grouping variable. Before the age of 2, the ADHD PRS was robustly associated with hyperactivity and inattention, with increasing strength up to 8 years, and with language difficulties at age 5 and 8. The autism PRS was robustly associated with language difficulties at 18 months, motor difficulties at 36 months, and hyperactivity and inattention at 8 years. We did not identify robust associations for the schizophrenia PRS. In general, the PRS associations were similar in boys and girls. The association between ADHD PRS and hyperactivity at 18 months was, however, stronger in boys. Polygenic risk for autism and ADHD in the general population manifests early in childhood and broadly across behavioral measures of neurodevelopmental traits.

Maternal prenatal selenium levels and child risk of neurodevelopmental disorders: A prospective birth cohort study.

Selenium (Se) is an essential trace element involved in various biological processes, including neurodevelopment. Available literature indicates that both Se deficiency and excess may be detrimental to health. It is also known that Se can cross the placenta from maternal to fetal circulation. To date, the role of maternal Se status in child long-term neurodevelopment is largely unexplored. This study investigated the temporal and dose-response associations between maternal Se status and child risk of neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). It consisted of 1550 mother-infant dyads from the Boston Birth Cohort. Maternal red blood cell (RBC) Se levels were measured in samples collected within 72 h of delivery (biomarker of third trimester Se status). Pediatric neurodevelopmental diagnoses were obtained from electronic medical records. Data analyses showed that maternal RBC Se levels were positively associated with child risk of developing ASD, with an adjusted odds ratio of 1.49 for ASD (95% CI: 1.09, 2.02) per IQR increase in Se. There was also a positive association between maternal Se and ADHD (OR: 1.29; 95% CI: 1.04, 1.56, per IQR increase in Se). These associations remained robust even after adjusting for pertinent covariables; and there was no significant interaction between Se and these covariables. Our findings suggest that prenatal exposure to high maternal Se levels may adversely affect child neurodevelopment. Our findings warrant further investigation; if confirmed, optimizing maternal prenatal Se levels may be necessary to maximize its health benefits while preventing undue risk. LAY SUMMARY: Selenium (Se) is an essential nutrient for the health of the pregnant mother and her baby. While Se can readily cross the placenta from maternal to fetal circulation, little is known about maternal Se status on her child's neurodevelopmental outcomes. We studied over 1500 mother-child dyads from birth to school age of the child. We found that babies born from mothers with high blood Se levels may be at increased risk of developing autism spectrum disorder or attention deficit hyperactivity disorder. Given this is the first study of the kind, more study is needed to confirm our findings.

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs.

Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

Developmental milestones in early childhood and genetic liability to neurodevelopmental disorders.

Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia. We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences. We found that ADHD PGS were associated with earlier walking age (β = -0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (β = 0.039, padj = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment. Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.

Fever during pregnancy as a risk factor for neurodevelopmental disorders: results from a systematic review and meta-analysis

BackgroundFever during pregnancy is a relatively common and most often trivial event. However, under specific conditions, it could affect significantly fetal brain development. Few studies, with inconsistent results, investigated whether fever, regardless the pathogen, could represent a risk factor for neurodevelopmental disorders (NDD) in the offspring. We aimed to explore further this question by performing a systematic review and meta-analysis.MethodsPeer-reviewed studies exploring the occurrence of NDD in offspring after a fetal exposure to maternal fever were included. We specifically considered the impact of fever severity and duration, taking into consideration some confounding variables such as the use of antipyretic during pregnancy, the trimester in which the fever arose, the maternal age or smoking at time of gestation. MEDLINE, EMBASE, PsycINFO, Cochrane and Web of Science were searched without language restriction. PRISMA recommendations were followed. Odds ratio (OR) were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using random-effects meta-regression analysis. (PROSPERO CRD42020182801).ResultsWe finally considered ten studies gathering a total of 10,304 children with NDD. Among them, 1394 were exposed to fever during pregnancy. The selected studies were divided into 5 case–control studies and 5 cohort studies. Maternal exposure to fever during pregnancy increased the risk of NDD in offspring with an OR of 1.24 [95% CI: 1.12–1.38]. Secondary analysis revealed an increased risk for NDD when fever occurred during the first trimester of gestation [OR 1.13–95% CI: 1.02–1.26].LimitationsWe excluded studies that considered infections with no evidence of fever. Another potential limitation may be the possible heterogeneity between study designs (cohorts and case–control).ConclusionAdditional evidence supported the association between fever during pregnancy and increased risk for NDD in offspring. Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy (specifically during the first trimester).

Attention deficit hyperactivity and autism spectrum disorders in patients with anorectal malformations.

To assess the risk of neurodevelopmental disorders in patients with anorectal malformations compared to controls. This was a population-based cohort study including all patients born in Sweden 1997-2012 with anorectal malformation in the Swedish National Patient Register and five matched controls per patient. Anorectal malformation was the exposure. All individuals were evaluated for the outcomes, attention deficit hyperactivity disorder or autism spectrum disorder in the National Patient Register. Data on drugs for attention deficit hyperactivity disorder were retrieved from the Swedish Prescribed Drug Register and used as proxy for attention deficit hyperactivity disorder. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Analyses were adjusted for confounders. Five hundred and fifteen patients with anorectal malformations and 2560 controls were included. Patients with anorectal malformation had a higher risk of attention deficit hyperactivity disorder (OR 3.01 (95% CI, 1.83-4.95)) and autism spectrum disorders (OR 3.07 (95% CI, 1.62-5.79)) compared to the controls. Significantly more patients with anorectal malformation had been prescribed medication for attention deficit hyperactivity disorder compared to controls (OR 2.26 (95% CI 1.33-3.85)). Patients with anorectal malformations have a higher risk of attention deficit hyperactivity disorder and autism spectrum disorders than controls.

Association between intracytoplasmic sperm injection and neurodevelopmental outcomes among offspring

PurposeTo compare the risk of neurodevelopmental disorders in children conceived via intracytoplasmic sperm injection (ICSI) and those conceived naturally.Materials and methodsA population-based cohort study using data retrieved from the Taipei Medical University Research Database (TMURD) from January, 2004 to August, 2016. The data included maternal pregnancy history, perinatal history and developmental follow up of their babies up to 5 years of age. The study included 23885 children, of whom 23148 were naturally conceived and 737 were conceived via ICSI. Neurodevelopmental disorders defined by 21 ICD-9-CM codes.ResultsOf the 23885 children enrolled for analysis, 2778 children were included for further subgrouping analysis after propensity matching to reduce bias from maternal factors. The single-birth group included 1752 naturally conceived (NC) children and 438 ICSI children. The multiple-birth group included 294 NC and 294 ICSI children. The risk of neurodevelopmental disorders was not increased for ICSI children in both groups (single birth: adjusted hazard ratio aHR = 0.70, 95% CI = 0.39–1.27, p = 0.243; multiple-birth group aHR = 0.77, 95% CI = 0.43–1.35, p = 0.853). In the single-birth group, multivariate analyses showed that male sex (aHR = 1.81, 95% CI = 1.29–2.54, p < 0.001), and intensive care unit (ICU) admission (aHR = 3.10, 95% CI = 1.64–5.86, p < 0.001) were risk factors for neurodevelopmental disorders. In the multiple-birth group, multivariate analyses demonstrated that ICU admission (aHR = 3.58, 95% CI = 1.82–7.04, p < 0.001), was risk factor for neurodevelopmental disorders.ConclusionOur study indicated that the use of ICSI does not associated with higher risk of neurodevelopmental disorders in the offspring. But male sex, and ICU admission do have increased risk of neurodevelopmental disorders. However, long term follow up of this cohort on health outcomes in adolescence and adulthood will strengthen the conclusions that ICSI is safe regarding offspring long term outcome.

Feeding and Eating Disorder and Risk of Subsequent Neurodevelopmental Disorders: A Population-Based Cohort Study.

Background: There are limited data concerning the long-term mental health of children with feeding and eating disorder (FED). We aimed to investigate whether children with FED are at greater risks of developing emotional/behavioral disorders with onset usually during childhood, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID).Methods: We conducted a population-based cohort study, including all singleton births in Denmark from January 1, 1995, to December 31, 2015. For each child diagnosed with FED, 10 age- and sex-matched controls who did not meet the criteria for FED were randomly selected from the general population. Associations were estimated with Cox regression modes adjusting for other perinatal and maternal factors, and sibling analyses were performed for controlling potential confounding by shared familial (genetic or environmental) factors.Results: Of the 1,256,989 individuals in the cohort, there were 1967 (53.4% girls) children diagnosed with FED. Children with FED had higher risks for clinically diagnosed emotional/behavioral disorders with onset usually in childhood (hazard ratio [HR], 2.78; 95% CI, 2.34–3.31), ADHD (HR, 1.74; 95% CI, 1.33–2.26), ASD (HR, 3.05; 95% CI, 2.36–3.94), and ID (HR, 6.38; 95% CI, 4.48–9.11), compared with matched controls. Girls with FED are at greater risks for emotional/behavioral disorders and ID, but not ADHD and ASD. Alike, in sibling analysis, increased rates are also observed for other neurodevelopmental disorders, but not for ADHD.Conclusion: Children with FED are associated with substantially increased risks of emotional/behavioral disorders, ADHD, ASD, and ID. This study highlights the importance of carefully monitoring neurodevelopmental disorders in children with FED.

Genetic Factors of Non-Obstructive Azoospermia: Consequences on Patients' and Offspring Health.

Non-Obstructive Azoospermia (NOA) affects about 1% of men in the general population and is characterized by clinical heterogeneity implying the involvement of several different acquired and genetic factors. NOA men are at higher risk to be carriers of known genetic anomalies such as karyotype abnormalities and Y-chromosome microdeletions in respect to oligo-normozoospermic men. In recent years, a growing number of novel monogenic causes have been identified through Whole Exome Sequencing (WES). Genetic testing is useful for diagnostic and pre-TESE prognostic purposes as well as for its potential relevance for general health. Several epidemiological observations show a link between azoospermia and higher morbidity and mortality rate, suggesting a common etiology for NOA and some chronic diseases, including cancer. Since on average 50% of NOA patients has a positive TESE outcome, the identification of genetic factors in NOA patients has relevance also to the offspring’s health. Although still debated, the observed increased risk of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profile in children conceived with ICSI from NOA fathers may indicate the involvement of transmissible genetic factors. This review provides an update on the reproductive and general health consequences of known genetic factors causing NOA, including offspring’s health.

A-27 A Pediatric Case Study of Neurodevelopmental Disorder Associated with Complete Agenesis of the Corpus Callosum

Abstract Objective The corpus callosum is a major white matter pathway of the brain that coordinates the transfer of information between both cerebral hemispheres. Children with complete agenesis of the corpus callosum (ACC) are at increased risk for neurodevelopmental disorders, epilepsy, and genetic abnormalities. Method This case study presents the neuropsychological profile of a 6-year-old girl in the 1st grade who was born with complete ACC and presented with a history of attention problems and behavioral-emotional difficulties. Results Neuropsychological testing revealed mild to severe deficits in attention, executive functioning, and self-regulation in the context of average intellectual functioning and broadly average to above-average academic achievement. Conclusions School recommendations included establishing a 504 plan and weekly counseling sessions with the school social worker in order to provide accommodations to support the child’s attention difficulties in the academic setting. Recommendations for genetic testing and ongoing monitoring by the patient’s neurologist were suggested given the higher rates of genetic abnormalities and seizures in children with ACC as these conditions can adversely impact neurodevelopmental outcomes. Medication management, as well as private behavior therapy with a parent-training component, were recommended for interventions to address the child’s deficits with attention and behavioral regulation. This case study demonstrates the need for prompt neuropsychological evaluation for children with ACC in order to more efficiently facilitate access to targeted assessments and treatments that can lead to improved outcomes.

Cerebral cortex and blood transcriptome changes in mouse neonates prenatally exposed to air pollution particulate matter

BackgroundPrenatal exposure to air pollutants is associated with increased risk for neurodevelopmental and neurodegenerative disorders. However, few studies have identified transcriptional changes related to air pollutant exposure.MethodsRNA sequencing was used to examine transcriptomic changes in blood and cerebral cortex of three male and three female mouse neonates prenatally exposed to traffic-related nano-sized particulate matter (nPM) compared to three male and three female mouse neonates prenatally exposed to control filter air.ResultsWe identified 19 nPM-associated differentially expressed genes (nPM-DEGs) in blood and 124 nPM-DEGs in cerebral cortex. The cerebral cortex transcriptional responses to nPM suggested neuroinflammation involvement, including CREB1, BDNF, and IFNγ genes. Both blood and brain tissues showed nPM transcriptional changes related to DNA damage, oxidative stress, and immune responses. Three blood nPM-DEGs showed a canonical correlation of 0.98 with 14 nPM-DEGS in the cerebral cortex, suggesting a convergence of gene expression changes in blood and cerebral cortex. Exploratory sex-stratified analyses suggested a higher number of nPM-DEGs in female cerebral cortex than male cerebral cortex. The sex-stratified analyses identified 2 nPM-DEGs (Rgl2 and Gm37534) shared between blood and cerebral cortex in a sex-dependent manner.ConclusionsOur findings suggest that prenatal nPM exposure induces transcriptional changes in the cerebral cortex, some of which are also observed in blood. Further research is needed to replicate nPM-induced transcriptional changes with additional biologically relevant time points for brain development.

Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review.

It was late 2015 when Northeast Brazil noticed a worrying increase in neonates born with microcephaly and other congenital malformations. These abnormalities, characterized by an abnormally small head and often neurological impairment and later termed Congenital Zika Syndrome, describe the severity of neurodevelopmental and nephrological outcomes in early childhood, and the implication of microcephaly at birth. The purpose of the study was to describe the neurodevelopmental outcomes in children exposed to Zika virus during fetal life, with and without microcephaly at birth. The systematic review included research studies about the neurodevelopmental outcomes with and without microcephaly, as well as nephrological outcomes in early childhood. We searched PubMed, Crossref, PsycINFO, Scopus, and Google Scholar publications and selected 19 research articles published from 2018 to 2021. Most studies have linked the severity of microcephaly in childbirth to the neurodevelopmental and urinary outcomes in early childhood. However, most children without microcephaly at birth develop typically, while others may be at risk for language impairment.

Risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in children associated with gestational levels of toxic metals and essential elements

BACKGROUND AND AIM: Intrauterine exposure to toxic metals and deficient/excess levels of essential elements may adversely affect the uniquely sensitive developing human brain and contribute to risk of neurodevelopmental disorders in children. We investigated prenatal levels of toxic metals and essential elements and risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children. METHODS: We included 705 ADHD case, 397 ASD case and 1034 control children and their mothers from the Norwegian Mother, Father and Child Cohort Study (MoBa). Linkage with the Norwegian Patient Registry was used to identify cases. We measured toxic metals and essential elements in maternal whole blood sampled at week 17 of gestation: cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Associations between individual metals/elements and odds ratio (OR) of ADHD or ASD diagnoses were investigated using multivariable adjusted logistic regressions with exposures categorized by quartiles (Q1-Q4; Q1 as reference). Also, the exposure-response relationships were examined in restricted cubic splines. RESULTS:Several associations were identified, with many overlapping findings for the two diagnoses. Among the main findings were increased risk of ADHD with both low and high maternal levels of arsenic (nonlinear U-shape) and increased odds of ASD in arsenic Q2 [OR = 1.77 (CI: 1.26, 2.49)]. The highest levels of maternal cadmium were associated with increased risk of ADHD [Q4: OR = 1.59 (CI: 1.15, 2.18) and ASD [Q4: OR = 1.57 (CI: 1.07 2.31]. Increased odds of both diagnoses were observed with the essential elements magnesium [ADHD: Q4: OR = 1.42 (CI: 1.06, 1.91), ASD: nonlinear U-shape] and manganese [ADHD: nonlinear U-shape, ASD: Q4: OR = 1.84 (CI: 1.30, 2.59]. CONCLUSIONS:Although more studies are warranted, our findings suggest that even population levels of these compounds may adversely impact fetal neurodevelopment and constitute common risk factors for both ADHD and ASD. KEYWORDS: toxic metals, essential elements, prenatal exposure, neurodevelopmental disorders

The effect of gestational age on major neurodevelopmental disorders in preterm infants.

Preterm infants have an increased risk of neurodevelopmental disorders. We established a direct quantitative comparison of the association between the degree of prematurity and three different neurodevelopmental disorders. In this cohort study, we combined data from 995,498 children in the Danish Medical Birth Register, from birth years 1997-2013, with information on cerebral palsy, epilepsy, and special educational needs. We estimated the gestational week-specific prevalence and risk for each of the disorders. The risk ratio of cerebral palsy at gestational weeks 21-24, compared to term birth, was more than ten times higher than for the two other disorders. The prevalence of epilepsy and special educational needs declined almost parallel, with 9.2% (4.6%-13.5%) and 12.5% (11.2%-13.7%), respectively, per week of gestation toward term birth. Cerebral palsy did not decline similarly: from gestational weeks 21-24 until week 29 the prevalence declined insignificantly by 0.6% (-11.1%-11.0%) per week; whereas from week 29 until term, the prevalence declined markedly by 36.7% (25.9%-45.9%) per week. The prevalence and risk of cerebral palsy are affected differently by the degree of prematurity compared with epilepsy and special educational needs, possibly reflecting important differences in cerebral pathophysiology. For each week of gestation toward term birth, there was a clear log-linear decline in the prevalence of early childhood epilepsy and special educational needs. In contrast, the risk of cerebral palsy was high at the earliest gestational age, and the prevalence did not decline significantly until gestational week 29, from where it declined notably by nearly 40% for each week of gestation until term birth. Our results indicate important differences in the pathophysiological processes that associate preterm birth with these three neurodevelopmental disorders.