Risk Of Neurodevelopmental Disorders Research Articles

Maternal COVID-19 infection associated with offspring neurodevelopmental disorders.

Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.

Thriving Beyond Adversity: A Prospective Longitudinal Cohort Study Using a Strength-Based Approach Depicts Indigenous Adolescents with Less Adverse Childhood Experiences (ACEs) Had Fewer Neurodevelopmental Disorders (NDDs)

Improving social and emotional well-being (SEWB) among Indigenous adolescents is crucial. Since neurodevelopmental disorders (NDDs) are common in Indigenous people and adverse childhood experiences (ACEs) are important contributors to negative health outcomes throughout the lifespan, we investigated whether limited ACE exposure is associated with reduced risk of NDDs in Australian Indigenous teens using the data from multiple waves (Wave 1 to Wave 9, and Wave 11) of the Longitudinal Study of Indigenous Children (LSIC). We also examined the role of other protective factors, such as Indigenous cultural identity and school connectedness, against NDDs. A strengths-based approach using mixed-effects logistic regression models examined the protective effect of limited ACE exposure (from LSIC waves 1–9) on NDDs (outcome from LSIC wave 11), adjusting for sociodemographic factors. The NDDs included autism, ADHD, intellectual, neurological, and specific learning disabilities. Of the 370 individuals analysed, 73.2% valued Indigenous cultural identity, and 70.5% were strongly connected at school. More than one-fourth (27.8%) reported limited ACE exposure, while the majority was not diagnosed with NDDs (93%). Longitudinal analysis revealed limited ACE exposure was 6.01 times (95% CI: 1.26–28.61; p = 0.024) more likely to be protective against NDDs compared to those exposed to multiple ACEs. Moreover, valuing cultural identity (aOR = 2.81; 95% CI: 1.06–7.39; p = 0.038) and girls (aOR = 13.88; 95% CI: 3.06–62.84; p = 0.001) were protective against NDDs compared to their respective counterparts. Our findings highlight the need to prevent ACE exposure and promote Indigenous cultural identity in preventing negative health outcomes and the exacerbation of health inequities to strengthen the SEWB of Indigenous communities.

Predictive value of the General Movements Assessment and Standardized Infant NeuroDevelopmental Assessment in infants at high risk of neurodevelopmental disorders.

Predictive value of the General Movements Assessment and Standardized Infant NeuroDevelopmental Assessment in infants at high risk of neurodevelopmental disorders.

Development and Validation of the Participation Questionnaire for Preschoolers with Autism Spectrum Disorder: Structural Validity, Internal Consistency, and Construct Validity

Aim This study aimed to develop the Participation Questionnaire for Preschoolers (PQP) and validate its psychometric properties as a disability-specific tool designed to assess participation in preschool-aged children with autism spectrum disorder (ASD). Methods This cross-sectional study recruited caregivers of 412 children, including those diagnosed with ASD and those at risk for neurodevelopmental disorders. Participants were recruited from child development facilities, medical institutions, and developmental support websites across Japan. Data from 287 children diagnosed with ASD were analyzed for item reduction, followed by exploratory factor analysis and the calculation of Cronbach’s alpha to evaluate internal consistency. Five hypotheses were tested to assess construct validity. Results Item reduction resulted in the removal of seven items and the identification of four factors: Friendship and Education, Family Satisfaction, Daily Living and Independence, and Leisure and Community Life. Cronbach’s alpha values for these factors ranged from 0.74 to 0.88, indicating acceptable internal consistency. Three of the five hypotheses related to construct validity were supported, aligning with expectations. Conclusion The PQP exhibited structural validity, internal consistency, and construct validity. However, further longitudinal studies are needed to validate its measurement properties over time.

Risk of neurodevelopmental impairment in Swedish preterm children treated for necrotizing enterocolitis: retrospective cohort study.

As the survival of preterm infants has increased, the management of long-term complications, especially neurodevelopmental impairment, becomes increasingly important. The aim of this study was to investigate the risk of neurodevelopmental disorders in preterm babies receiving medical or surgical treatment for necrotizing enterocolitis, compared with other preterm babies and preterm babies who received abdominal surgery for other indications. In this nationwide Swedish cohort study, including all liveborn preterm babies born between 1998 and 2019, the risk of attention deficit (and hyperactivity) disorder, autism spectrum disorders, cerebral palsy and intellectual disability was assessed by multivariable Cox regression, expressed as hazard ratios and 95% confidence intervals (c.i.). Of the surgically (n = 384) and medically (n = 709) treated preterm infants with necrotizing enterocolitis, neurodevelopmental disorders were present in 32% (HR 2.24, 95% c.i. 1.86 to 2.69) and 22% respectively (HR 1.40, 95% c.i. 1.19 to 1.65), compared with 21% (HR 1.63, 95% c.i. 1.40 to 1.91) in the abdominal surgery group (n = 844) and 13% (reference) among other preterm infants (n = 78 972). The highest relative increases were for intellectual disability (HR 3.60, 95% c.i. 2.65 to 4.89) in the surgical necrotizing enterocolitis group and abdominal surgery group (HR 2.84, 95% c.i. 2.12 to 3.80) compared with the control preterm group, and for cerebral palsy (respectively HR 2.74, 95% c.i. 2.04 to 3.68 and HR 2.54, 95% c.i. 1.87 to 3.44). Medically treated necrotizing enterocolitis was associated with autism (HR 1.67, 95% c.i. 1.34 to 2.08), without significant increases for the other specific outcomes. Both surgically treated groups were also strongly associated with both attention deficit (and hyperactivity) disorder and autism. Surgically treated necrotizing enterocolitis, medically treated necrotizing enterocolitis and abdominal surgery for other indications in preterm infants were all associated with an increased risk of impaired neurodevelopmental outcomes, compared with other preterm infants.

Maternal Human Papillomavirus Infection and Offspring Neurodevelopmental Disorders.

Human papillomavirus (HPV) infection can lead to multiple comorbidities in women, including mental health problems. However, few studies have examined the association between maternal HPV infection and risk of neurodevelopmental disorders in their offspring. We aimed to investigate the association between maternal HPV infection and risk of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) among their offspring. Data from the Taiwan National Health Insurance Research Database were used for analysis. Offspring of mothers with HPV infection were identified as the index group, and a demographic-matched group (offspring of mothers without HPV infection) was selected as the controls. The primary outcome was risk of ADHD or ASD. Cox regression models with multiple adjustments were used to estimate hazard ratios (HRs) with 95% of confidence intervals (CIs). We included 7,762 individuals in the index group and 31,048 in the control group. After adjusting for potential confounding factors, the index group had a higher risk of ADHD (HR: 1.39, 95% CI: 1.15-1.67) than the controls. Importantly, the risk remained significance when HPV infection was diagnosed either before (HR: 1.29, 95% CI: 1.05-1.59) or during pregnancy (HR: 1.79, 95% CI: 1.28-2.51). No increased risk of ASD was identified in the index group compared to the control group. This study highlights the importance of preventing and treating HPV infection during and before pregnancy. Clinicians should be aware of the association between maternal HPV infection and ADHD in their offspring.

Neurodevelopmental outcomes in children prenatally exposed to opioid maintenance treatment: A population-based study.

Opioid maintenance treatment (OMT), with methadone or buprenorphine, is a key approach for managing opioid use disorder (OUD) during pregnancy. Despite buprenorphine's superior short-term outcomes, its long-term effects remain understudied. This study aims to evaluate the effects of prenatal OMT exposure on the incidence of childhood neurodevelopmental disorders (NDDs) considering timing effect. A retrospective cohort study using Rhode Island Medicaid data linked to vital statistics from 2008 to 2018 was conducted. The study included pregnancies having live birth from 2008 to 2016 with continuous Medicaid insurance and OUD diagnosis within 3 months preceding conception until delivery. At least one buprenorphine dispensing or a claim of methadone was required for exposure definition. Exposure was evaluated during early (0-90 days) or late (>90 days) gestation, or at any pregnancy phase. NDDs, including autism, attention-deficit/hyperactivity disorder (ADHD), learning disabilities, speech/language disorders, developmental coordination disorder, intellectual disability, and behavioral disorders, were identified using validated algorithms. Applying Cox proportional-hazard models with propensity score overlap weighting, adjusted hazard ratios (aHR) were calculated, mitigating potential confounders. Children were followed up from birth until NDD diagnosis, disenrollment, or study end. Of 416 mother-child dyads with OUD, 40% used methadone and 20% had buprenorphine exposure during pregnancy. NDDs were observed in 36% of children with early methadone exposure compared to 17% in the early buprenorphine exposed group (aHR: 2.75; 95% confidence interval [CI]: 1.42-5.35). Further comparison to late buprenorphine exposure, late methadone exposure was associated with higher NDD risk (aHR: 2.05; 95% CI: 1.09-3.86). Compared to unexposed group, children exposed to methadone during early and late periods showed higher NDD incidences (aHR: 2.33; 95% CI: 1.51-3.60 and aHR: 2.42; 95% CI: 1.54-3.80, respectively). The study suggests that buprenorphine is a good treatment option for OUD during pregnancy due to minimal long-term neurodevelopmental impacts on children. However, further extensive research is necessary to rule-out potential confounding.

Extra-cerebral recombination activity of Emx1-Cre and nestin-Cre in the kidney.

Individuals with neurodevelopmental disorders (NDDs) are frequently diagnosed with comorbidities in other organs, indicating that NDD risk genes may have extra-cerebral functions. The engineered mouse models are pivotal in understanding the functions of candidate NDD genes. Here, we report that Emx1-Cre and nestin-Cre mouse strains, the popular tools to study brain development, also exhibit recombination activity in the kidney. We find that both Emx1-Cre and nestin-Cre can drive recombination in epithelial cells lining proximal and distal convoluted tubules of the nephron. Additionally, nestin-Cre drives recombination in the glomerulus of the nephron. Furthermore, we use Emx1-Cre and nestin-Cre to knock out Larp7, a gene linked to a human NDD called Alazami syndrome. We find that Larp7 knockout using nestin-Cre, but not Emx1-Cre, results in elevated blood urea nitrogen. This result suggests a compromised kidney function, reminiscent of recently revealed renal anomalies in Alazami syndrome patients. Many genes have been knocked out using Emx1-Cre and nestin-Cre to study their roles during embryonic neurogenesis. It will be of great interest to reinvestigate whether the renal development and function is affected in these existing mouse models.

Prenatal and early childhood infections requiring hospitalization and risk of neurodevelopmental disorders in offspring: a population-based birth cohort study in Taiwan.

In utero and early childhood infections have been associated with an increased risk of neurodevelopmental disorders; however, the observed associations may be confounded by familial predispositions. This study examined the neurodevelopmental disorders attributable to maternal infections during pregnancy and early childhood infections during the first year of life, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), tic disorders, and mental retardation (MR). We performed population and sibling comparison analyses to account for unmeasured familial confounding factors. We conducted a register-based cohort study with 2,885,662 individuals (comprising 1,864,660 full siblings) born in Taiwan between 2001 and 2018 and followed up until 2021. We employed Cox regression analysis to assess the association between in utero and early childhood infections requiring hospitalization and the subsequent risk of neurodevelopmental disorders. In the population analyses, an offspring exposed to maternal infection had an increased risk for ASD (hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.13-1.26), ADHD (HR = 1.14, 95% CI: 1.11-1.18), and MR (HR = 1.21, 95% CI: 1.13-1.30). These associations attenuated toward null in the sibling analyses. Individuals exposed to early childhood infection had an increased risk for ASD (HR = 1.13, 95% CI: 1.10-1.16), ADHD (HR = 1.16, 95% CI: 1.15-1.18), tic disorders (HR = 1.12, 95% CI: 1.09-1.15), and MR (HR = 1.64, 95% CI: 1.60-1.69) in the population analyses; these associations were also significant for ASD (HR = 1.14, 95% CI: 1.07-1.21) and MR (HR = 1.52, 95% CI: 1.44-1.62) in the sibling analyses. The association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors. Conversely, infection in early childhood may be attributable to it being a sensitive period and may play a role in the subsequent risk of ASD and MR.

A Scoping Review: Risk of Autism in Children Born from Assisted Reproductive Technology

Background/Objectives: As the incidence of autism spectrum disorder (ASD) and use of assisted reproductive technologies (ART) continue to rise in tandem, their relationship to one another, as well as the general risks of ART, are increasingly being explored. The purpose of this review is to summarize the literature on ASD risk, as well as the risks for other neurological and neurodevelopmental disorders, in children born following the implementation of ART. Methods: Here we review studies published between 2000−2023 that elucidate relationships between ASD and some of the most common forms of ART, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), using fresh vs. frozen embryo transfer. Articles were identified by searching Google Scholar and PubMed databases. Results: Though some studies report adverse neurodevelopmental outcomes in ART-conceived children, such as ASD, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy, a majority of studies do not show a significant association between ART and neurodevelopmental disorders. Additionally, many confounding factors like multiple and preterm births, underlying infertility, and advanced parental age have been discussed, highlighting the need for studies that effectively control for these confounders. Potential mechanisms implicated in the pathogenesis of ASD, including epigenetic mechanisms of gene expression, that may be related to ART procedures, are also discussed. Conclusion: ART may pose a low additional risk to development of ASD, but confounding factors likely account for most of this risk. Several steps in the process of ART may cause epigenetic changes that are implicated in the development of ASD.

Executive function deficits in congenital heart surgical patients: prevalence and timing of presentation.

Congenital heart patients undergoing congenital heart surgery in the first year of life are at high risk of having a neurodevelopmental disorder. The most common difficulties are related to executive functioning. The following questions were assessed in the current project: Are patients having congenital heart surgery after one year of life at lower risk for neurodevelopmental disorders? At what age do executive function deficits manifest? We evaluated executive function in four groups of congenital heart patients who had undergone congenital heart surgery. These groups were high-risk patients with and without a genetic syndrome associated with a neurodevelopmental disorder and low-risk patients with and without a genetic syndrome associated with a neurodevelopmental disorder. We evaluated executive function using the Behavior Rating Inventory of Executive Function - Preschool Version, Behavior Rating Inventory of Executive Function-2, and Minnesota Executive Function Scale at various ages. We compared the rates of executive function deficits in the high- and low-risk groups as well as compared that to the published norms for age. We also assessed at what age these deficits become apparent. We found that both high- and low-risk groups had higher levels of executive functioning deficits compared to the norms for age. The low-risk group's degree of executive function deficits appeared a little lower than the high-risk group. However, it was difficult to comment on the statistical significance. We also saw that executive function deficits often do not become apparent for many years after surgery. This finding highlights the need for continued evaluation of functioning as these kids mature.

A-310 Neurodevelopmental disorders and hyperlipidemia in HIV-exposed uninfected children in the Bronx, New York

Abstract Background The implementation of combination antiretroviral therapy (cART) for treating human immunodeficiency virus (HIV) has significantly reduced the rates of vertical HIV transmission. With increasing cART coverage, the number of HIV-positive infants has declined, while the number of HIV-exposed uninfected (HEU) infants has risen. This group now comprises a rapidly expanding cohort of HIV-affected individuals, currently totaling 16 million and increasing by 1.6 million annually. However, our understanding of the potential in-utero toxicity of cART remains limited. Numerous studies, primarily from Africa, suggest that HEU children may face heightened risks of adverse health outcomes, including growth restriction, increased susceptibility to infections, and neurobehavioral disorders. It is widely recognized that infants with growth restriction are at a greater risk of developing chronic diseases such as cardiometabolic and neurological disorders later in life, which is accentuated by low socioeconomic status. The objective of this study was to assess the prevalence of neurodevelopmental disorders and hyperlipidemia in HIV-negative children born to HIV-infected mothers in the Bronx, New York, utilizing retrospective medical records information. Methods We conducted a retrospective chart review of HEU and age-matched control (HIV-unexposed and uninfected; HUU) children (age 0-15 years) using clinical data obtained from the electronic medical record (EMR) at the Montefiore Medical Center in the Bronx, New York, between 2015 and 2023. Demographic data and documented diagnostic data were collected. Lipid panel results were also obtained from the EMR and stratified by age and testing date. Neurodevelopmental outcome measures were compared between HEU and HUU children using Chi-square and Student’s t-test was used for continuous variables. Results A total of 127 HEU (46% females, 54% males) children and 157 HUU (46% females, 54% males) children were analyzed. Among the HEU children, 12 (9.5%) were diagnosed with attention-deficit/hyperactivity disorder (ADHD), while only 1 out of 157 (0.6%) HUU children had this diagnosis (p=0.0004). Similarly, a significant number of HEU children were found to have autism spectrum disorder, with 11 (8.7%) affected compared to 2 (1.3%) in the control group (p=0.0036). HEU children also exhibited a higher prevalence of unspecified developmental delay compared to HUU children (14.2% vs 5.1%; p=0.012). However, no significant differences were observed between the two groups regarding speech and language delay or learning difficulties. Abnormal cholesterol levels were detected in 33% of HEU children, while 54.5% had abnormal triglyceride levels. These percentages surpass the prevalence of pediatric hypercholesterolemia (7%) and hypertriglyceridemia (10.2%) in the United States. Conclusions Our findings indicate that HEU children born in areas designated as medically underserved and socioeconomically disadvantaged, such as the Bronx in the United States, face significant risks of neurodevelopmental disorders and hyperlipidemia. Considering the increasing population of HEU children, even minor rises in adverse health effects could lead to significant public health challenges. To support HEU children in achieving their utmost potential, further studies must be encouraged to understand these children's needs. Moreover, it is imperative to enact policies that facilitate equitable distribution of resources, ensuring timely screening and intervention in underprivileged communities.

Neurodevelopmental or behavioural disorders in children conceived after assisted reproductive technologies: A nationwide cohort study

To study differences in risk for drug-treated neurodevelopmental or behavioural disorders in children conceived through assisted reproductive technologies in comparison with children conceived without assisted reproductive technologies and to examine if different treatments alter these risks. Nationwide registry-based cohort study. Liveborn children born in Denmark between 1994 and 2012 after assisted reproductive technologies in comparison to children conceived without assisted reproductive technologies aged 0-7. Conception following assisted reproductive technologies treatment, including in vitro fertilisation, intra-cytoplasmic sperm injection, intrauterine insemination and 'others' comprising frozen embryo transfer, and frozen embryo transfer in both in vitro fertilisation and intra-cytoplasmic sperm injection and testicular sperm aspiration. Prescription of neurodevelopmental or behavioural disorders medication in offspring: Antipsychotics, anxiolytics, antidepressants, antiepileptics, attention deficit hyperactivity disorder medication and hypnotics/sedatives obtained from nationwide registers. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated. The association was examined in different sensitivity analyses, including sibling and mediator analyses. In total, 57,964 (4.7%) children conceived after assisted reproductive technologies and 1,183,070 (95.3%) children not conceived using assisted reproductive technologies were included. The adjusted analysis showed higher odds of prescribing neurodevelopmental or behavioural medication to assisted reproductive technology-conceived children (OR 1.15; 95% Cl 1.09-1.20) compared to other children. Prescription of antipsychotics in assisted reproductive technology-conceived children was the most common association in intrauterine insemination treatments, hypnotics/sedatives with both including in vitro fertilisation and intra-cytoplasmic sperm injection and antiepileptics with 'other' treatments. Birth weight partially mediated the association between assisted reproductive technologies and diminished the odds of neurodevelopmental or behavioural medication use in children conceived using assisted reproductive technologies. Sibling analysis showed no increased risk for the first-born child conceived without assisted reproductive technology vs. the second-born child conceived with assisted reproductive technology and vice-versa. Based on the minor observed effects, a potentially higher increased attentiveness of assisted reproductive technology parents, the demonstrated mediation effect of birth weight and preterm birth on the observed association, and the no effect of the within-mother analysis, we find little evidence for increased risk of neurodevelopmental or behavioural disorders in children conceived using assisted reproductive technologies.

Long-Term Neurodevelopmental, Mental, and Cardiometabolic Health in Individuals Conceived with Assisted Reproductive Technology: A Literature Review

Background: Assisted reproductive technology (ART) has revolutionised fertility treatments since 1978 and, while itsimmediate perinatal outcomes have been extensively studied, its long-term health effects require exploration. Method: PubMed database was searched for studies spanning 2016 to 2023 to conduct this literature review of the long-term neurodevelopmental, mental, and cardiometabolic health of ART-conceived individuals. Results: A total of 49 studies were included in this review. ART-conceived individuals revealed mostly positive neurodevelopmental and mental health impacts. However, children conceived via intracytoplasmic sperm injection (ICSI)demonstrated an increased risk of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and psychological and neurological development delays, while frozen embryo transfer was linked to an increased risk of language delay. Additionally, children born via ART as multiples or prematurely showed an elevated risk of cerebral palsy. While ART generally demonstrated a favourable impact on cardiometabolic health, there were concerns about increased risk of high blood pressure, altered lipid profiles, obesity, insulin resistance, premature vascular aging, and adverse metabolic changes. Specifically, ICSI-conceived individuals were more prone to adiposity and insulin resistance, while frozen embryo transfer was associated with type 1 diabetes. Conclusion: While ART-conceived individuals generally exhibit favourable health, specific subgroups may face elevated risks for certain neurodevelopmental disorders and long-term cardiometabolic issues, warranting further research. ART may be associated with metabolic alterations at a young age, potentially increasing the risk of chronic diseases such as metabolic syndrome, type 2 diabetes, and cardiovascular disease later in life. Continued long-term monitoring and targeted interventions are recommended to mitigate these risks.

A scalable, high-throughput neural development platform identifies shared impact of ASD genes on cell fate and differentiation.

Deleterious mutations in hundreds of genes confer high risk for neurodevelopmental disorders (NDDs), posing significant challenges for therapeutic development. Identifying convergent pathways shared across NDD genes could reveal high-impact therapeutic targets. To identity convergent pathways in NDD genes, we optimized Perturb-seq, a method combining CRISPR perturbation with single-cell RNA sequencing (scRNA-seq), and applied structural topic modeling (STM) to simultaneously assess impact on cell fate and developmental stage. We then studied a subset of autism spectrum disorder (ASD) genes implicated in regulation of gene expression using these improved molecular and analytical approaches. Results from targeting 60 high-confidence ASD risk genes revealed significant effects on neural development. As expected, ASD risk genes impacted both progenitor fate and/or neuronal differentiation. Using STM, we could identify latent topics jointly capturing cell types, cell fate, and differentiation stages. Repression of ASD risk genes led to changes in topic proportions and effects of four genes (DEAF1, KMT2A, MED13L, and MYT1L) were validated in an independent dataset. Our optimized Perturb-seq method, combined with a novel analytical approach, provides a powerful, cost-effective framework for uncovering convergent mechanisms among genes involved in complex neurodevelopmental processes. Application of these methods advanced understanding of the impact of ASD mutations on multiple dimensions of neural development, and provides a framework for a broader examination of the function of NDD risk genes.

Female Infertility and Neurodevelopmental Disorders in Children: associations and evidence for familial confounding in Denmark.

Existing research suggests the impact of infertility on the risk of neurodevelopmental disorders in children, however, studies to date have failed to separate the impact of male and female infertility, often blurring the lines with proxies that encompass all forms of infertility. Moreover, while both health conditions co-occurring with infertility and genetic factors operating upstream have been suggested to influence the association between infertility and child outcomes, their roles and potential impact on observed associations remain unclear. The objectives of this study are to investigate the relationship between female infertility and autism in the child, differentiating it from the effects of male and the couple infertility; consider the role of various maternal and birth factors in the association; and examine the effects of shared familial confounders on the association. Danish population-based cohort study, including all singleton live births in Denmark 1998-2015, their parents and parents' siblings. The cohort was followed up until December 31, 2016. The exposure was a history of female infertility in the mother and the mother's sister. We examined four definitions of female infertility based on the ICD-10 codes derived from the Danish National Patient Register - any female infertility; specified female infertility; female exclusive infertility; and female or male infertility. The outcome was diagnosis of autism spectrum disorder (ASD) in the Danish Psychiatric Central Research Register or the national patient register. A multivariable Cox regression model was used to estimate the associations between female infertility and autism, accounting for child's sex, year of birth, maternal age, education level, chronic comorbidities, and pregnancy and birth complications. The effects of shared familial factors on the association were analyzed using exposure information from the child's maternal aunt. The cohort included 1,131,899 mother-child pairs, among which 18,374 children with ASD diagnosis. History of female infertility in the mother (all definitions) was significantly associated with autism in the child, with the association remaining robust after adjustment for covariates (HRadj=1.14 (95% CI, 1.03-1.26) for specified infertility). The diagnosis of infertility in a child's maternal aunt was also significantly linked to the child's autism risk, even after adjustment for maternal infertility (HRadj=1.10 (95% CI, 1.00-1.20). in This population-based birth cohort study, we found a slightly higher risk of autism in children born to mothers with a history of infertility, with the association remaining consistent across various definitions of female infertility and robust to adjustments for demographic, child, and maternal factors. The study suggests for the first time that shared familial factors, possibly both genetic and non-genetic, could be influencing both female infertility and the risk of autism in children, indicating a need for further investigation into these familial effects.

Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements

CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes. Applying this method to a library of 493 gRNAs targeting candidate cis-regulatory elements in both K562 cells and iPSC-derived excitatory neurons, we identify gRNAs capable of specifically upregulating intended target genes and no other neighboring genes within 1 Mb, including gRNAs yielding upregulation of six autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes in neurons. A consistent pattern is that the responsiveness of individual enhancers to CRISPRa is restricted by cell type, implying a dependency on either chromatin landscape and/or additional trans-acting factors for successful gene activation. The approach outlined here may facilitate large-scale screens for gRNAs that activate genes in a cell type-specific manner.

Socio-medical Factors Associated with Neurodevelopmental Disorders on the Kenyan Coast.

Neurodevelopmental disorders (NDDs) are a group of conditions with their onset during the early developmental period and include conditions such as autism, intellectual disability and attention deficit hyperactivity disorder (ADHD). Occurrence of NDDs is thought to be determined by both genetic and environmental factors, but data on the role of environmental risk factors for NDD in Africa is limited. This study investigates environmental influences on NDDs in children from Kenya. This case-control study compared children with NDDs and typically developing children from two studies on the Kenyan coast that did not overlap. We included 172 of the study participants from the Kilifi Autism Study and 151 from the NeuroDev Study who had a diagnosis of at least one NDD and 112 and 73 with no NDD diagnosis from each study, respectively. Potential risk factors were identified using unadjusted univariable analysis and adjusted multivariable logistic regression analysis. Univariable analysis in the Kilifi Autism Study sample revealed hypoxic-ischaemic encephalopathy conferred the largest odds ratio (OR) 10.52 (95%CI 4.04 - 27.41) for NDDs, followed by medical complications during pregnancy (gestational hypertension & diabetes, eclampsia, and maternal bleeding) OR: 3.17 (95%CI 1.61 - 6.23). In the NeuroDev study sample, labour and birth complications (OR: 7.30 (2.17 - 24.61)), neonatal jaundice (OR: 5.49 (95%CI 1.61 - 18.72)) and infection during pregnancy (OR: 5.31 (1.56 - 18.11)) conferred the largest risk associated with NDDs. In the adjusted analysis, seizures before age 3 years in the Kilifi Autism study and labour and birth complications in the NeuroDev study conferred the largest increased risk. Higher parity, the child being older and delivery at home were associated with a reduced risk for NDDs. Recognition of important risk factors such as labour and birth complications could guide preventative interventions, developmental screening of at-risk children and monitoring progress. Further studies examining the aetiology of NDDs in population-based samples, including investigating the interaction between genetic and environmental factors, are needed.

Valproate use in men increases risk of neurodevelopmental disorders

Valproate use in men increases risk of neurodevelopmental disorders

Association of Parental Prenatal Mental Health on Offspring Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis.

Parental prenatal mood and anxiety disorders (PMAD) are linked to child neurodevelopmental disorders (NDDs), but evaluations of the magnitude and mechanisms of this association are limited. This study estimates the strength of the association and whether it is impacted by genetic and environmental factors. A systematic search of PubMed, CENTRAL, PsycINFO, OVID, and Google Scholar was performed for articles published from January 1988 to January 2024. Of 2,170 articles screened, 64 met the inclusion criteria. Meta-analyses were conducted on 20 studies, and 44 were included in the narrative synthesis. We conducted random-effects meta-analyses, along with tests for heterogeneity (I2) and publication bias (Egger's test). The review followed PRISMA and MOOSE guidelines. Maternal PMADs were associated with a significantly increased risk of ADHD (OR 1.91, 95% CI 1.45-2.52) and ASD (OR 1.57, 95% CI 1.37-1.81) in children. Paternal PMADs were also associated with the risk of NDDs, with combined odds for ASD and ADHD (OR 1.24, 95% CI 1.15-1.34). Several studies suggested that the link between parental PMADs and offspring NDDs might be impacted by both genetic and environmental factors, including the impact of ongoing parental depression on child behavior. Parental PMADs are significantly associated with an increased risk of NDDs in children. These associations may be influenced by both genetic predispositions and environmental factors. Understanding these pathways is important for informing interventions aimed at mitigating mental health risks in families and supporting child development.