Risk Of Neurodevelopmental Disorders Research Articles

P-544 CNV is a genetic factor underlying risk of neurodevelopmental disorder in a child of a woman with miscarriage in anamnesis

Abstract Study question What underlies an increased risk of having children with neurodevelopmental disorders in women with miscarriage? Summary answer Women with miscarriage have a statistically significant increase in the frequency of giving birth to children with intellectual disabilities due to CNV. What is known already A link between woman’s history of miscarriage and neurodevelopmental disorders (NDD) in her children was shown recently (PMID:30058166, PMID:33580539). In women with sporadic and recurrent miscarriage, the risk of having a child with NDD is increased by 13% and 30%, respectively (PMID:33580539). About half of miscarriage cases can be due to genetic causes. Genetic abnormalities also underlie NDD. It is likely that CNV may be a common etiological factor for both pathologies. Our aim was to assess the frequency and characteristics of CNV in groups of mothers having a child with NDD and presence or absence of miscarriages in anamnesis. Study design, size, duration Families with children with NDD and maternal obstetric history were investigated (n = 405). They were divided into groups based on the presence (n = 190) or absence (n = 215) of pathogenic CNV in a child. Further each group was divided into subgroups with the presence (n = 37, n = 21) or absence (n = 153, n = 194) of miscarriage to determine the association of CNV with pregnancy loss and NDD. Genes involved in CNVs were obtained to identify pathogenetically significant molecular pathways. Participants/materials, setting, methods The DNA of patients and their parents was isolated from blood lymphocytes. Probands with NDD were studied using aCGH on SurePrint G3 Human CGH Microarray Kit, 8 × 60K (Agilent Technologies). Validation of CNVs and determination of their origin was carried out using qPCR. Enrichment analysis was performed by the Enrichr resource and the Mammalian Phenotype ontology. The results of the analysis were considered significant at p ≤ 0.05. The chi-squared test was used for statistical analysis. Main results and the role of chance For the first time we showed that pathogenic CNVs were statistically significantly more common in families with miscarriage having a child with NDD (p = 0.006). In the groups with or without miscarriage, respectively, 16 and 66 deletions and 21 and 87 duplications were found. Thus, no predominance of a certain type of CNV was found (p = 0.991). The origin was established for 49 CNVs out of 190 (26%). The group with miscarriage included 8 maternally inherited and 2 de novo CNVs, while the non-miscarriage group included 33 inherited (mat-18, pat-15) and 6 de novo variants (p = 0.899). Enrichment analysis revealed 26 and 36 categories, respectively, in miscarriage and non-miscarriage groups. Common categories between the groups were maternal imprinting, abnormal cochlear innervation pattern, abnormal GABA-mediated receptor currents, increased skeletal muscle fiber size. Separately, the miscarriage group included one category associated with abnormal head morphology. The group without miscarriage included categories associated with development, functioning and anomalies of different organs. Although the enrichment analysis identified categories that may be associated with the pathologies included in this study, at this stage of data collection it was not possible to explain why some CNV can lead to either miscarriage or child with NDD in the same family. Limitations, reasons for caution There is no data on the causes of miscarriage, at least on the presence or absence of maternally inherited CNV in abortions. A small sample size does not allow us to identify differences in the structure of CNVs between groups with and without miscarriage. Wider implications of the findings Accumulating data potentially can be used for predicting the risk of having a child with NDD in families with miscarriage. If one of the parents carries pathogenic CNV with pleiotropic effect prenatal diagnosis or PGT-SR should be recommended. This study was supported by the Russian Science Foundation № 21-65-00017, https://rscf.ru/project/21-65-00017/. Trial registration number not applicable

A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders.

ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

Prediction of Neurodevelopmental Outcome of High-Risk Neonates: A study from a Tertiary Care Centre in Bangladesh

Background: High-risk neonates are most vulnerable to develop neurodevelopmental impairment. Early identification and intervention can modify brain development and improve outcomes in neonates at risk for neurodevelopmental disorders. Objective: To predict the neurodevelopmental impairments (NDIs) in high-risk neonates. Methods: This observational study was conducted in the Department of Neonatology and Department of Paediatric Neurology, Institute of Paediatric Neurodisorder and Autism (IPNA), Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from July 2019 to June 2020. A total of 85 high-risk term neonates were included in this study. A neurodevelopmental evaluation was completed using the rapid neurodevelopmental assessment instrument (RNDA) at neonatal (0 to 28 days) age and again at three months of age after a comprehensive history and clinical examination. Result: Among the enrolled 85 neonates at first assessment, NDI was found in 64.7% cases. Seizure was present in 49.4% cases and affected domains were cognition (48.2%), behavior (47.1%), hearing (45.9%), gross motor (41.2%), vision (42.3%), speech (42.3%), primitive reflexes (36.5 %) and fine motor (32.9%). At the age of 3 months, NDI was found in 47.1% and affected domains were gross motor (47.1%), speech (40.0%), fine motor (37.7%), vision (36.5%), cognition (36.5%), behavior (35.3%) and hearing (30.6%). The seizure was found in 29.4% of cases. A significant difference was found between the first and second assessment. Conclusion: NDI are common sequelae of high-risk neonates. The most frequently affected domains were gross motor, fine motor and speech. Thus, RNDA can be used to predict early NDI in high-risk newborns.

The combined effect between BDNF genetic polymorphisms and exposure to metals on the risk of Chinese dyslexia

BDNF gene has been implicated in the development of cognition and language. Meanwhile, exposure to metals might interact with BDNF gene to increase the risk of neurodevelopmental disorders. The present study aimed to explore the association between BDNF genetic polymorphisms and dyslexic risk and examine whether BDNF polymorphisms would interact with metal exposures, jointly contributing to dyslexia. Among a case-control study composed of 238 children with dyslexia and 228 healthy controls, the BDNF genetic polymorphisms were genotyped by the Sequenom MassARRAY system, and the exposure to eight metals, such as lead (Pb), mercury (Hg) and copper (Cu), were measured using an inductively coupled plasma-mass spectrometer (ICP-MS). Multivariable logistic regression models were used to assess the adjusted odds ratios (ORs) and 95% confidence interval (CI) of dyslexia. After multivariate adjustment, significant associations of dyslexic risk with rs6265 polymorphisms of the BDNF gene were observed (OR = 1.99; 95% CI: 1.15–3.44). Furthermore, exposure to Cu could interact with rs6265 to increase the risk of dyslexia (P interaction = 0.045). High-Cu children with the rs6265 TT genotype were more likely to have dyslexia compared with low-Cu children carrying CC + CT genotypes (OR = 3.19; 95% CI: 1.38–7.39). The findings of this study suggested that the polymorphism of rs6265 in BDNF gene could interact with Cu exposure to increase the occurrence of dyslexia.

Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy

Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021. Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy. Neurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01). This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.

DeepND: Deep multitask learning of gene risk for comorbid neurodevelopmental disorders

SummaryAutism spectrum disorder and intellectual disability are comorbid neurodevelopmental disorders with complex genetic architectures. Despite large-scale sequencing studies, only a fraction of the risk genes was identified for both. We present a network-based gene risk prioritization algorithm, DeepND, that performs cross-disorder analysis to improve prediction by exploiting the comorbidity of autism spectrum disorder (ASD) and intellectual disability (ID) via multitask learning. Our model leverages information from human brain gene co-expression networks using graph convolutional networks, learning which spatiotemporal neurodevelopmental windows are important for disorder etiologies and improving the state-of-the-art prediction in single- and cross-disorder settings. DeepND identifies the prefrontal and motor-somatosensory cortex (PFC-MFC) brain region and periods from early- to mid-fetal and from early childhood to young adulthood as the highest neurodevelopmental risk windows for ASD and ID. We investigate ASD- and ID-associated copy-number variation (CNV) regions and report our findings for several susceptibility gene candidates. DeepND can be generalized to analyze any combinations of comorbid disorders.

Neurodevelopmental continuum and pathogenic CNV detection in adult onset psychiatric disorders: microarray analysis in psychiatric clinical practice

IntroductionStructural variations of DNA, such as copy number variations (CNVs), are important contributors to risk for human diseases. Several CNVs have been associated with an increased risk of early-onset neurodevelopmental disorders (NDD), adult-onset psychiatry disorders and physical comorbidities. While in Pediatrics the microarray is the first-line genetic analysis technique in the study of child onset NDD, its use in psychiatry care of young/adult onset NDD has been limited to research purposes.ObjectivesReview of the diagnostic yield of the use of microarrays analysis in psychiatric clinical practice of severe mental disorder care in adults, according to the concept of a neurodevelopmental continuum.MethodsAn exploratory literature review on the topic in PubMed, including the terms: “copy number variants/CNVs” AND “neurodevelopmental delay/disorders, congenital anomalies/malformations, ADHD, autism/ASD, learning disabilities, epilepsy, Tourette, schizophrenia, bipolar, behaviour”.ResultsThe prevalence of carriers of pathogenic or likely pathogenic CNVs among the different NDD phenotypes investigated by microarray analysis ranged from 3-22.5%. The majority of studies in adult psychiatric populations examined schizophrenia. Intellectual disability, autism spectrum disorders, dysmorphic features and multiple NDD/psychiatric diagnoses were described as predictors of an increased diagnostic yield of microarray testing.ConclusionsWhile CNV testing is frequent in early-onset NDD; microarray analysis has not been established in psychiatric clinical practice despite the evidence of a high prevalence of findings in adult-onset NDD. The potential benefits in the detection of CNV are associated with physical comorbidities detection, understanding of pathogenesis of disease or genetic counseling. High-quality research designs are required before a routine clinical use.DisclosureNo significant relationships.

Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders.

Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and Other Neurodevelopmental Outcomes Associated With Antipsychotic Drug Exposure During Pregnancy.

Between 0.3%-4.6% of women use antipsychotic (AP) drugs during pregnancy. Two large, retrospective, population-based cohort studies, conducted in Nordic countries and in the US, examined the risk of neurodevelopmental disorders (NDDs) following gestational exposure to APs. The Nordic study found that, in unadjusted analyses, exposure to APs during pregnancy was associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring; that the risk all but disappeared after adjusting for covariates; and that the risk appeared to be related to maternal major mental illness rather than to gestational exposure to APs. The US study also found that, in unadjusted analyses, gestational exposure to APs was associated with an increased risk of almost all of the study-specified NDDs in offspring; however, after adjusting for covariates, the risks were no longer meaningfully increased and, importantly, were no longer statistically significant for ADHD and ASD. Thus, these 2 studies suggest that gestational exposure to APs is a marker of NDD risk in offspring rather than a potential cause. Whereas a small but significantly increased risk was identified for aripiprazole in the US study, the signal was inconsistent across analyses, and confounding due to maternal mental illness was not ruled out. Previous studies have suggested that the use of APs during pregnancy is not associated with an increased risk of major congenital malformations and other adverse gestational outcomes. Considering the potential harm and suffering associated with major mental illness and the very low risks associated with AP use during pregnancy, initiation or continuation of APs appears to carry a favorable risk-benefit ratio in pregnant women who need these drugs; however, decision-making should be shared between patients, their caregivers, and the treating team.

Prediction of Neurodevelopmental Disorders Based on De Novo Coding Variation

The early detection of neurodevelopmental disorders (NDDs) can significantly improve patient outcomes. The differential burden of non-synonymous de novo mutation among NDD cases and controls indicates that de novo coding variation can be used to identify a subset of samples that will likely display an NDD phenotype. Thus, we have developed an approach for the accurate prediction of NDDs with very low false positive rate (FPR) using de novo coding variation for a small subset of cases. We use a shallow neural network that integrates de novo likely gene-disruptive and missense variants, measures of gene constraint, and conservation information to predict a small subset of NDD cases at very low FPR and prioritizes NDD risk genes for future clinical study.

Excessive folic acid intake combined with undernutrition during gestation alters offspring behavior and brain monoamine profiles

Dietary folic acid augmentation during gestation reduces neurodevelopmental disorder risk in offspring; however, it is still unclear if excessive maternal folic acid intake can impair brain function in offspring. We examined if excessive folic acid intake throughout gestation altered the behavior of male offspring under poor nutrition during early gestation (E5.5-E11.5). Dams were divided into four groups: control (CON, 2mg folic acid/kg of food), excessive folic acid fortification (FF, 10mg folic acid/kg of food), undernutrition (UN, 40% food reduction from E5.5-E11.5), and excessive folic acid fortification plus undernutrition (UN-FF). Excess maternal folic acid fortification induced hyperactivity in the open-field and lower anxiety-like behavior in the elevated plus maze at 9 weeks of age. These behavioral changes were accompanied by reduced dopamine in the prefrontal cortex (PFC), norepinephrine in the amygdala, and 5-hydroxytryptamine (5-HT) in the dorsal midbrain (DM), PFC, and amygdala where 5-HT neurons project from the DM. Furthermore, canonical discriminant analysis, including dopamine and DOPAC concentrations in the PFC, norepinephrine concentrations in the PFC, amygdala, and pons, and 5-HT and 5-HIAA concentrations in the amygdala and DM, correctly classified 73.5% of the offspring in CON, FF, UN, and UN-FF groups. The first discriminant function mainly classified groups based on nutritional status, whereas the second function mainly classified groups based on folic acid intake. Our study suggests that combined transformations of brain monoamine profiles by maternal undernutrition and excess folic acid intake is involved in the behavioral alteration of offsprings.

Parental Occupational Exposure and Neurodevelopmental Disorders in Offspring: a Systematic Review and Meta-analysis.

Parental occupational exposures might be associated with neurodevelopmental disorders (NDDs) in offspring. We aimed to conduct a systematic review and meta-analysis to summarize and synthesize the current literature and to estimate the pooled magnitude of the underlying association(s) between parental occupational exposures and subsequent risk of NDDs. In the meta-analysis of 20 included studies, significant associations were found between parental occupational exposure to pesticides or solvents and the risk of attention deficit hyperactivity disorder in offspring. Prenatal occupational exposure to pesticides was significantly associated with motor development or cognition disorders in children. Furthermore, some evidence showed that metals might have a role in the development of autism spectrum disorders. Further studies need to identify the level of parental occupational exposures that can be significantly associated with NDDs. Moreover, utilizing standardized outcome and exposure scales is recommended to incorporate paternal, maternal, and parental as well as both prenatal and postnatal exposure in future studies.

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

Rapid assessment of the temporal function and phenotypic reversibility of neurodevelopmental disorder risk genes in Caenorhabditis elegans.

ABSTRACTRecent studies have indicated that some phenotypes caused by decreased function of select neurodevelopmental disorder (NDD) risk genes can be reversed by restoring gene function in adulthood. However, few of the hundreds of risk genes have been assessed for adult phenotypic reversibility. We developed a strategy to rapidly assess the temporal requirements and phenotypic reversibility of NDD risk gene orthologs using a conditional protein degradation system and machine-vision phenotypic profiling in Caenorhabditis elegans. We measured how degrading and re-expressing orthologs of EBF3, BRN3A and DYNC1H1 at multiple periods throughout development affect 30 morphological, locomotor, sensory and learning phenotypes. We found that phenotypic reversibility was possible for each gene studied. However, the temporal requirements of gene function and degree of rescue varied by gene and phenotype. This work highlights the critical need to assess multiple windows of degradation and re-expression and a large number of phenotypes to understand the many roles a gene can have across the lifespan. This work also demonstrates the benefits of using a high-throughput model system to prioritize NDD risk genes for re-expression studies in other organisms.

Influence of Maternal Diabetes on the Risk of Neurodevelopmental Disorders in Offspring in the Prenatal and Postnatal Periods.

This study aimed to evaluate the influence of maternal diabetes in the risk of neurodevelopmental disorders in offspring in the prenatal and postnatal periods. This cohort study included singleton gestational diabetes mellitus (GDM) pregnancies >22 weeks' gestation with live newborns between 1991 and 2008. The control group was randomly selected and matched (1:2) for maternal age, weeks of gestation and birth year. Cox regression models estimated the effect of GDM on the risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and maternal type 2 diabetes mellitus (T2DM). Moreover, interaction between maternal T2DM and GDM-ADHD relationship was evaluated. Children (n=3,123) were included (1,073 GDM; 2,050 control group). The median follow-up was 18.2 years (interquartile range, 14.2 to 22.3) (n=323 with ADHD, n=36 with ASD, and n=275 from women who developed T2DM). GDM exposure was associated with ADHD (hazard ratio [HR]crude, 1.67; 95% confidence interval [CI], 1.33 to 2.07) (HRadjusted, 1.64; 95% CI, 1.31 to 2.05). This association remained significant regardless of the treatment (diet or insulin) and diagnosis after 26 weeks of gestation. Children of mothers who developed T2DM presented higher rates of ADHD (14.2 vs. 10%, P=0.029). However, no interaction was found when T2DM was included in the GDM and ADHD models (P>0.05). GDM was not associated with an increased risk of ASD (HRadjusted, 1.46; 95% CI, 0.74 to 2.84). Prenatal exposure to GDM increases the risk of ADHD in offspring, regardless of GDM treatment complexity. However, postnatal exposure to maternal T2DM was not related to the development of ADHD.

Impact of Preterm Birth on Neurodevelopmental Disorders in South Korea: A Nationwide Population-Based Study.

Neurodevelopmental disorder (NDD) in preterm infants has become of great interest. We aimed to investigate the impact of preterm birth on the proportion of NDD using nationwide data provided by the Korean National Health Insurance Service. We included 4894 extremely preterm or extremely low-birth-weight (EP/ELBW; <28 weeks of gestation or birth weight < 1000 g) infants, 70,583 other preterm or low-birth-weight (OP/LBW; 28–36 weeks of gestation or birth weight < 2500 g) infants, and 264,057 full-term infants born between 2008 and 2015. We observed their neurodevelopment until 6 years of age or until the year 2019, whichever occurred first. Diagnoses of NDDs were based on the World Health Organization’s International Classification of Diseases 10th revision. An association between preterm birth and NDD was assessed using a multivariable logistic regression model. There was a stepwise increase in the risk of overall NDD with increasing degree of prematurity, from OP/LBW (adjusted odds ratio 4.46; 95% confidence interval 4.34–4.58), to EP/ELBW (16.15; 15.21–17.15). The EP/ELBW group was strongly associated with developmental delay (21.47; 20.05–22.99), cerebral palsy (88.11; 79.89–97.19), and autism spectrum disorder (11.64; 10.37–13.06). Preterm birth considerably increased the risk of NDD by the degree of prematurity.

Pre-eclampsia is associated with increased neurodevelopmental disorders in children with congenital heart disease.

AimsOur primary aim was to examine whether exposure to pre-eclampsia increases the risk of neurodevelopmental disorders in children born with congenital heart disease (CHD). Our secondary aim was to evaluate whether CHD and pre-eclampsia may act in synergy and potentiate this risk.Method and resultsUsing population-based registries, we included all Danish children born with CHD between 1994 and 2017. Non-singletons and children born with a syndrome were excluded. Neurodevelopmental disorders including attention-deficit/hyperactivity disorder, autism spectrum disorders, and tic disorders were identified with the use of the 10th edition of International Classification of Disease (ICD-10) codes DF80–DF98. Using Cox proportional hazard regression, we estimated the risk of neurodevelopmental disorders in children with CHD exposed to pre-eclampsia compared with those with CHD not exposed to pre-eclampsia. The population consisted of 11 449 children born with CHD. Children exposed to pre-eclampsia had an increased risk of neurodevelopmental disorders, hazard ratio: 1.84 (95% confidence interval: 1.39–2.42). Furthermore, a comparison cohort of 113 713 children with no CHD diagnoses were included. Using cumulative incidence analyses with death as competing risk, we compared the risk of neurodevelopmental disorders if exposed to pre-eclampsia among children with CHD and children without CHD. Exposure to pre-eclampsia drastically increased the cumulative incidence of neurodevelopmental disorders in children born with CHD.ConclusionExposure to pre-eclampsia is associated with increased risk of neurodevelopmental disorders in children born with CHD. CHD and pre-eclampsia may act in synergy and potentiate this effect. Clinicians should therefore be especially attentive to neurodevelopmental problems in this vulnerable subgroup.

A Diffusion Tensor Imaging Analysis of Frontal Lobe White Matter Microstructure in Trigonocephaly Patients

BackgroundChildren with trigonocephaly are at risk for neurodevelopmental disorders. The aim of this study is to investigate white matter properties of the frontal lobes in young, unoperated patients with metopic synostosis as compared to healthy controls using diffusion tension imaging (DTI). MethodsPreoperative DTI data sets of 46 patients with trigonocephaly with a median age of 0.49 (interquartile range: 0.38) years were compared with 21 controls with a median age of 1.44 (0.98) years. White matter metrics of the tracts in the frontal lobe were calculated using FMRIB Software Library (FSL). The mean value of tract-specific fractional anisotropy (FA) and mean diffusivity (MD) were estimated for each subject and compared to healthy controls. By linear regression, FA and MD values per tract were assessed by trigonocephaly, sex, and age. ResultsThe mean FA and MD values in the frontal lobe tracts of untreated trigonocephaly patients, younger than 3 years, were not significantly different in comparison to controls, where age showed to be a significant associated factor. ConclusionsMicrostructural parameters of white matter tracts of the frontal lobe of patients with trigonocephaly are comparable to those of controls aged 0-3 years.

Maternal vitamin D supplementation and treadmill exercise attenuated vitamin D deficiency-induced anxiety-and depressive-like behaviors in adult male offspring rats

ABSTRACT Background Vitamin D is a vital neuroactive steroid for brain development and function. Vitamin D deficiency is a worldwide health problem, particularly in children and women. Gestational or developmental vitamin D deficiency is associated with an increased risk of neurodevelopmental and neuropsychiatric disorders. This study examined the effect of maternal vitamin D dietary manipulations and treadmill exercise on anxiety-and depressive-related behaviors, pro-inflammatory cytokines, and prefrontal cortex (PFC) protein levels of brain-derived neurotrophic factor (BDNF) and vitamin D receptor (VDR) in adult male offspring born to vitamin D-deficient diet (VDD)-fed dams. Methods and Results Female rats were provided standard diet (SD) or VDD for six weeks and then were treated with SD (started a week before mating throughout gestation and lactation) and treadmill exercise (a week before mating until gestational day 20). Male offspring were separated on postnatal day (PND) 21 and fed SD chow until PND90. Our results demonstrated that maternal vitamin D deficiency increased anxiety and depression-related behaviors, increased levels of TNF-α and IL-1β in serum, and decreased prefrontal protein expressions of BDNF and VDR in adult male offspring. However, maternal vitamin D supplementation and treadmill exercise reversed these changes alone or in combination. Conclusion It seems that developmental vitamin D deficiency disrupts brain development and has a long-lasting effect on VDR and BDNF signaling in the rat brain resulting in neuropsychiatric disorders in offspring. Therefore, vitamin D supplementation and physical exercise are reasonable strategies to prevent these neurobehavioral impairments.