Clinical Features of Typically Developing Children With and Without Prenatal Alcohol Exposure.

OBJECTIVE: To determine if prenatal alcohol exposure (PAE) affected physical and cognitive/behavioral outcomes in apparently typically developing, first-grade children. STUDY DESIGN: Three groups were compared: children with fetal alcohol spectrum disorders (FASD); children with PAE without FASD; and children without PAE. RESULTS: The three groups were significantly different on most physical traits and fewer neurodevelopmental traits. Two-group comparisons of exposed and unexposed, non-FASD groups were statistically different on: height, weight, head circumference (OFC), body mass index (BMI), and palpebral fissure length (PFL). Neurobehavioral outcomes were significant in three-group, but not two-group, comparisons. Few sex differences were observed; however, sex ratios indicated fewer male offspring in first grade among women who consumed 6+ drinks per occasion during pregnancy. For weight, OFC, BMI, age, rural residence, and drinking measures, mothers of exposed children without FASD were intermediaries between, and significantly different from, the other maternal groups. Adjusted for socioeconomic covariates, multivariate analysis of covariance (MANCOVA), three-group comparisons were significantly different for cognitive/behavioral variables (p<.001); however, two-group neurobehavior comparisons for children without FASD were not significant (p>.05). Physical trait MANCOVA comparisons of the non-FASD groups were significant only for weight (p<.004) when tested univariately and through stepdown analysis. Socioeconomic-adjusted trend plots were in the expected direction for nonverbal IQ, problem behaviors, attention, height, weight, OFC, vermilion, PFL, and total dysmorphology score. CONCLUSIONS: Even when meeting developmental norms, children with PAE exhibited trends of poorer growth and cognitive/behavioral traits than children without PAE. These findings support the notion that abstinence during pregnancy is best.

Alcohol and brain structure across the lifespan: A systematic review of large-scale neuroimaging studies.

Alcohol exposure affects brain structure, but the extent to which its effects differ across development remains unclear. Several countries are considering changes to recommended guidelines for alcohol consumption, so high-quality evidence is needed. Many studies have been conducted among small samples, but recent efforts have been made to acquire large samples to characterize alcohol's effects on the brain on a population level. Several large-scale consortia have acquired such samples, but this evidence has not been synthesized across the lifespan. We conducted a systematic review of large-scale neuroimaging studies examining effects of alcohol exposure on brain structure at multiple developmental stages. We included studies with an alcohol-exposed sample of at least N = 100 from the following consortia: ABCD, ENIGMA, NCANDA, IMAGEN, Framingham Offspring Study, HCP and UK BioBank. Twenty-seven studies were included, examining prenatal (N = 1), adolescent (N = 9), low-to-moderate-level adult (N = 11) and heavy adult (N = 7) exposure. Prenatal exposure was associated with greater brain volume at ages 9-10, but contemporaneous alcohol consumption during adolescence and adulthood was associated with smaller volume/thickness. Both low-to-moderate consumption and heavy consumption were characterized by smaller volume and thickness in frontal, temporal and parietal regions, and reductions in insula, cingulate and subcortical structures. Adolescent consumption had similar effects, with less consistent evidence for smaller cingulate, insula and subcortical volume. In sum, prenatal exposure was associated with larger volume, while adolescent and adult alcohol exposure was associated with smaller volume and thickness, suggesting that regional patterns of effects of alcohol are similar in adolescence and adulthood.

Properties of the prefrontal tracts and cingulum bundle in children with prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) significantly impacts brain structure and function, including cognition and behavior. The cingulum bundle and frontal lobe mediate social-, emotional- and cognitive-related functioning that are affected by PAE. However, the neurobehavioural development of the cingulum and intra-frontal tracts has not been examined in people with PAE. METHODS: We recruited 29 children and adolescents with PAE and 42 age- and gender-matched unexposed controls. Diffusion magnetic resonance imaging (MRI) data were acquired on a 3 T scanner. The rostral, dorsal and parahippocampal cingulum as well as medio-orbitofrontal, lateral-orbitofrontal, dorsolateral-prefrontal and medial-prefrontal tracts, were delineated and their fractional anisotropy and mean (MD), radial (RD), and axial (AD) diffusivities were calculated using constrained spherical deconvolution and deterministic tractography. We measured behavioural and emotional difficulties using the Behavior Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with diffusion metrics that differed between groups. RESULTS: We found lower MD, RD, and AD in the right parahippocampal cingulum and multiple intra-frontal tracts in youth with PAE compared to controls; however, these differences did not withstand correction for multiple comparisons. While, youth with PAE showed significantly more emotional and behavioural difficulties compared to unexposed controls, these challenges were not associated with differences in diffusion metrics between groups. CONCLUSION: PAE may be weakly associated with restricted diffusion in the right parahippocampal cingulum and multiple intra-frontal tracts. However, diffusivity changes related to PAE might not be the primary contributor to emotional and behavioural challenges in children and adolescents with PAE.

Deep learning for detecting prenatal alcohol exposure in pediatric brain MRI: a transfer learning approach with explainability insights.

Prenatal alcohol exposure (PAE) refers to the exposure of the developing fetus due to alcohol consumption during pregnancy and can have life-long consequences for learning, behavior, and health. Understanding the impact of PAE on the developing brain manifests challenges due to its complex structural and functional attributes, which can be addressed by leveraging machine learning (ML) and deep learning (DL) approaches. While most ML and DL models have been tailored for adult-centric problems, this work focuses on applying DL to detect PAE in the pediatric population. This study integrates the pre-trained simple fully convolutional network (SFCN) as a transfer learning approach for extracting features and a newly trained classifier to distinguish between unexposed and PAE participants based on T1-weighted structural brain magnetic resonance (MR) scans of individuals aged 2-8 years. Among several varying dataset sizes and augmentation strategy during training, the classifier secured the highest sensitivity of 88.47% with 85.04% average accuracy on testing data when considering a balanced dataset with augmentation for both classes. Moreover, we also preliminarily performed explainability analysis using the Grad-CAM method, highlighting various brain regions such as corpus callosum, cerebellum, pons, and white matter as the most important features in the model's decision-making process. Despite the challenges of constructing DL models for pediatric populations due to the brain's rapid development, motion artifacts, and insufficient data, this work highlights the potential of transfer learning in situations where data is limited. Furthermore, this study underscores the importance of preserving a balanced dataset for fair classification and clarifying the rationale behind the model's prediction using explainability analysis.

Life outcomes in adults living with FASD in a rural South African community: A follow-up study.

Background: Even though adults with foetal alcohol spectrum disorder (FASD) are at risk of negative life outcomes, there is no published evidence of this in South Africa, which has the highest estimated FASD prevalence rate globally. Objectives: The purpose of the study was to describe and compare the life outcomes of adults with FASD and adults without FASD in a South African rural community, 16 years after diagnosis. Method: Participants were examined and interviewed regarding their biographical information, knowledge of FASD, information on their family, relationships, home circumstances, education, work and medical history. Results: Adults with FASD were less likely to be in a relationship and more likely to have poor educational outcomes and to be exposed to violence as victim or perpetrator than their peers who did not have FASD. None of the participants with FASD completed secondary school successfully. No differences were found for independent living, employment, health, substance use and legal outcomes, between the foetal alcohol syndrome (FAS) or partial foetal alcohol syndrome (PFAS) and control group. Conclusion: While significant differences existed in certain aspects, differences are not as stark as one would expect between individuals with FASD and controls. Contribution: This study highlights the importance of considering the social context in which a FASD diagnosis is made. The comparative negative impact of an FASD diagnosis and the associated challenges on life outcomes may be less pronounced in rural communities where everyone has fewer opportunities and resources. This can also make the unique needs of persons with disabilities less visible.

Prenatal tobacco and alcohol exposure, white matter microstructure, and early language skills in toddlers from a South African birth cohort.

Introduction: Tobacco and alcohol are the two most common substances used during pregnancy, and both can disrupt neurodevelopment, resulting in cognitive and behavioral deficits including language difficulties. Previous studies show that children with prenatal substance exposure exhibit microstructural alterations in major white matter pathways, though few studies have investigated the impact of prenatal substance exposure on white matter microstructure and language skills during the toddler years. Methods: In this study, 93 children (34 exposed to alcohol and/or tobacco) aged 23 years from the Drakenstein Child Health Study, South Africa, completed Expressive and Receptive Communication assessments from the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and underwent diffusion MRI scans. Diffusion images were preprocessed, and 11 major white matter tracts were isolated. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted for each white matter tract. Linear regression was used to examine differences between the tobacco/alcohol exposed group and unexposed controls for FA, MD, and language scores, as well as relationships between brain metrics and language. There were no significant group differences in language scores or FA. Results: Children with alcohol or tobacco exposure had lower average MD in the splenium of the corpus callosum compared to unexposed controls. Significant interactions between prenatal substance exposure and language scores were seen in 7 tracts but did not survive multiple comparisons correction. Discussion: Our findings show that prenatal alcohol and/or tobacco exposure appear to alter the relationship between white matter microstructure and early language skills in this population of toddlers, potentially laying the basis of language deficits observed later in older children with prenatal substance exposure, which may have implications for learning and interventions.

Integrated service delivery for individuals with fetal alcohol spectrum disorder.

BACKGROUND: Individuals with fetal alcohol spectrum disorder (FASD) experience complex needs that often necessitate support from multiple systems. There is growing evidence that people with FASD may benefit from integrated service delivery (ISD), but little is known about ISD elements and processes for this population. METHOD: Using a multi-method approach involving a literature review, analysis of programme data, and staff interviews, we examined how ISD is enacted at a rural Canadian FASD centre, and identified facilitators, barriers, and potential impacts of ISD at the centre. RESULTS: We describe key elements of integrated FASD programming and identify important contextual factors and themes related to ISD barriers, facilitators, and impacts: (1) connection, (2) freedom and autonomy, (3) client-centred care, (4) learning and growth, (5) and reframing expectations. CONCLUSIONS: This study may help to inform a roadmap for enhancing FASD service delivery and guiding FASD research and policy in Canada and beyond.

Exploring epigenetic modification of the stress-related FKBP5 gene in mice exposed to alcohol during early postnatal development.

Early developmental exposure to alcohol has been implicated in adverse effects on the brain, often associated with the onset of neurodevelopmental disorders. Moreover, maternal alcohol consumption during pregnancy has been linked to the manifestation of mental health disorders, such as depression and anxiety, in subsequent generations. These mood disturbances may be attributed to alterations in protein expressions related to depression and anxiety within the hippocampus. While the precise mechanisms remain elusive, it is likely that pre- and postnatal exposure to alcohol induces changes in hippocampus, potentially through epigenetic modifications. The FKBP5 gene, known to modulate the stress response, is particularly relevant in this context. We postulate that alcohol-induced methylation of the FKBP5 gene disrupts HPA axis function, thereby prompting individuals to anxiety-like and depressive-like behaviors. To investigate this hypothesis, female C57BL/6 pups were subjected to early alcohol exposure via intubation with ethanol mixed in artificial milk from Postnatal Day 3 to Day 20. The intubation control pups were subjected to the same procedures without ethanol or milk, and a non-intubated control group included. Anxiety-like and depressive-like behaviors were assessed using the open field test, plus maze test, forced swim test, and tail suspension test when the pups reached 3 months of age. For epigenetic analysis of the FKBP5 gene, genomic DNA was isolated from hippocampal tissues and subjected to bisulfite conversion to distinguish methylated and unmethylated cytosines. Then, methylation-specific PCR was performed to assess methylation levels. Pups exposed to early postnatal alcohol exhibited increased levels of depression-like behavior and susceptibility to anxiety-like behavior during adolescence, as verified by behavioral assessments. Methylation profiling revealed higher rates of methylation within the stress-associated gene FKBP5 in both the early postnatal alcohol-exposed cohort (13.82%) and the intubation control group (3.93%), in contrast to the control cohort devoid of stress or alcohol exposure. These findings suggest a potential epigenetic mechanism underlying the observed behavioral alterations, implicating FKBP5 methylation as a candidate mediator of the increased vulnerability to mood disorders following early postnatal alcohol exposure.

Analysis of microRNAs and the microRNA-messengerRNA regulatory network in chronic alcohol exposure.

Introduction: Chronic alcoholism is one of the most common neurological diseases in modern society. However, the key mechanisms underlying learning and memory impairments caused by chronic alcohol exposure remain unclear. In this study, a microRNA-messenger RNA (miRNA-mRNA) network was constructed to explore the potential function of key genes in chronic alcohol exposure, their effects on the hippocampus, and their mechanisms which facilitate brain injury in mice. Methods: The Morris water maze test was used to assess the learning ability of mice in each group. Mitochondrial ATPase activity and H2S levels in the hippocampi of mice were determined. Differentially expressed miRNAs and mRNAs in the mouse hippocampus were identified using second-generation sequencing. Using the TargetScan, miRTarBase, and miRDB databases, we predicted miRNA target genes and constructed a miRNA-mRNA regulatory network. Furthermore, using the Gene Ontology and KEGG databases we performed functional enrichment and protein-protein interaction analyses. Real-time quantitative polymerase chain reaction (qPCR) and other methods were employed to verify the mRNA expression of related genes. Results: The Morris water maze test revealed that mice exposed to chronic alcohol exhibited a significantly reduced learning ability compared to the control group (p < 0.05). Compared with the control group, the activity of mitochondrial ATPase in the hippocampal tissue of alcohol-treated mice was significantly decreased (p < 0.01), suggesting brain injury. In the model group, H2S significantly increased in the mice hippocampi (p < 0.01), indicating that chronic alcohol exposure could activate cystathionineß-synthase (CBS) and catalyze the mass formation of H2S, suggesting brain injury. A total of 208 differentially expressed miRNAs and 377 differentially expressed mRNAs were screened through bioinformatic analysis. Enrichment analysis indicated that the main pathways were involved in neurodegeneration and regulation of the Wnt signaling pathway. The PCR detected a significant downregulation in the expressions of FOS and EGR1 genes. Discussion: Consequently, chronic alcohol exposure may regulate the expression of FOS and EGR1 in the hippocampus through miR-222-3p, miR-132-3p, miR-212-3p, and miR-191-5p, reduce the activity of hippocampal mitochondrial ATPase, activate CBS, catalyze the large amount of H2S formation, and destroy the mitochondrial structure, resulting in decreased learning ability. Our findings revealed valuable genes and miRNAs for the study of chronic alcohol exposure.

Using Planned and Unplanned Adaptation to Implement Universal Alcohol Screening and Brief Intervention to Prevent Alcohol-Exposed Pregnancies in Four Primary Care Health Systems.

BACKGROUND: The United States Preventive Services Task Force recommends annual alcohol screening and brief behavioral intervention (alcohol SBI) with general adult and pregnant populations. Implementation of alcohol SBI in primary care has encountered numerous barriers to adapting procedures and infrastructure to support its routine delivery. This collection of case studies describes the implementation strategies used by 4 academic health system teams that were funded by the Centers for Disease Control and Prevention to implement alcohol SBI within healthcare systems to prevent alcohol-exposed pregnancies. METHODS: We used constructs from the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to describe planned and unplanned adaptations to implementation strategies, and the SBIRT (Screening, Brief Intervention, and Referral to Treatment) Program Matrix to identify key questions, challenges, and recommendations for improving alcohol SBI implementation. Participating systems were 2 regional affiliates of a national reproductive healthcare organization, an integrated non-profit healthcare system, and an urban medical center and its affiliated network of community health centers. RESULTS: Planned adaptations included expanding the target population for brief interventions to include patients drinking at low levels who could become pregnant, modifying workflows and systems to support routine screening, and customizing training content and logistics. Unplanned adaptations included varying site recruitment and pre-implementation awareness-building strategies to enhance local receptivity of systems with decentralized management, and pivoting from in-person to virtual training during the COVID-19 pandemic. Fewer unplanned adaptations were observed for health systems with centralized management structures and practice teams that were fully engaged in implementation planning, training, roll-out, and problem-solving. CONCLUSIONS: Unplanned adaptations were observed across the 4 cases and emphasized the importance of flexible, adaptive designs when implementing evidence-based practice in dynamic settings. Participation of the health system in planning, including decisions to modify electronic health records and workflows, supported adapting to unplanned circumstances to achieve implementation goals.

Exploring the intersection of polygenic risk scores and prenatal alcohol exposure: Unraveling the mental health equation.

BACKGROUND: Prenatal alcohol exposure poses significant risks to offspring mental health. However, the interplay between genetic predispositions to mental health disorders and prenatal alcohol exposure remains incompletely understood, limiting our ability to develop effective interventions for these conditions. METHODS: Data from the Adolescent Brain and Cognitive Development (ABCD) Study were analyzed to explore associations between polygenic risk scores (PRS) for mental disorders and maternal alcohol consumption during pregnancy. Logistic regression and structural equation modeling were utilized to assess these relationships. RESULTS: Maternal alcohol consumption after pregnancy awareness was significantly associated with an increased genetic risk for specific mental health disorders, particularly bipolar disorder in offspring. The relationship between maternal alcohol consumption and mental health outcomes was influenced by polygenic risk scores, with both externalizing and internalizing problems being affected. CONCLUSIONS: Our findings highlight the specific interaction between increased genetic risk for bipolar disorder and prenatal alcohol exposure in shaping offspring mental health outcomes. The significant associations we observed underscore the importance of considering both polygenic risk scores and prenatal alcohol exposure when assessing mental health risks in children. These insights emphasize the need for targeted interventions that address both genetic predispositions and environmental exposures to better understand and mitigate the impact on offspring mental health.

Neurodevelopmental outcome at two years of age and predictive value of General Movement Assessment in infants exposed to alcohol and/or drugs during pregnancy: a prospective cohort study.

BACKGROUND: Exposure to alcohol and/or other addictive drugs in pregnancy is a documented risk factor for neurological impairment. We aimed to assess neurodevelopmental outcome at two years of age in infants exposed to prenatal alcohol and/or other addictive drugs and to examine the predictive value of early motor assessment. METHODS: This was a follow-up at two years of age in the prospective cohort study Children Exposed to Alcohol and/or Drugs in Intrauterine Life (CEADIL). The exposed group comprised 73 infants recruited from primary health care and included in a hospital follow-up programme at St. Olavs Hospital, Trondheim University Hospital, Norway. The control group comprised 93 healthy, unexposed infants recruited from the maternity ward at the same hospital. All children had been assessed by physiotherapists using the General Movement Assessment (GMA) at three months of age. Presence of fidgety movements, movement character and the Motor Optimality Score - Revised (MOS-R) were used. At two years of age, the children were assessed by trained examiners using the Bayley Scales of Infant and Toddler Development - Third Edition (BSID-III), Ages & Stages Questionnaires: Social-Emotional (ASQ:SE) and the Hollingshead Two-Factor Index of Social Position (SES). RESULTS: The cognitive, language and motor composite scores of BSID-III were considerably lower in the exposed group than in the control group. Mean differences adjusted for age and parental SES ranged from - 13.3 (95% confidence interval, CI: -18.6 to -8.0) to -17.7 (95% CI: -23.3 to -12.2). Suboptimal fidgety movements and monotonous movement character had high sensitivity (0.94 to 0.74), but low specificity (0.10 to 0.32), while sensitivity and specificity of the MOS-R was around 50 and 60%, respectively. CONCLUSIONS: Neurodevelopmental outcome at two years of age was poorer in a group of children exposed to alcohol and/or drugs in pregnancy compared with a control group of healthy, unexposed children. Sensitivity of suboptimal fidgety movements and monotonous movement character at three months of age for later neurodevelopmental outcome was high to acceptable, but the MOS-R had limited sensitivity.

Sex-specific DNA methylation and gene expression changes in mouse placentas after early preimplantation alcohol exposure.

During pregnancy, exposure to alcohol represents an environmental insult capable of negatively impacting embryonic development. This influence can stem from disruption of molecular profiles, ultimately leading to manifestation of fetal alcohol spectrum disorder. Despite the central role of the placenta in proper embryonic development and successful pregnancy, studies on the placenta in a prenatal alcohol exposure and fetal alcohol spectrum disorder context are markedly lacking. Here, we employed a well-established model for preimplantation alcohol exposure, specifically targeting embryonic day 2.5, corresponding to the 8-cell stage. The exposure was administered to pregnant C57BL/6 female mice through subcutaneous injection, involving two doses of either 2.5 g/kg 50 % ethanol or an equivalent volume of saline at 2-hour intervals. Morphology, DNA methylation and gene expression patterns were assessed in male and female late-gestation (E18.5) placentas. While overall placental morphology was not altered, we found a significant decrease in male ethanol-exposed embryo weights. When looking at molecular profiles, we uncovered numerous differentially methylated regions (DMRs; 991 in males; 1309 in females) and differentially expressed genes (DEGs; 1046 in males; 340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Preimplantation alcohol exposure had a greater impact on imprinted genes expression in male placentas (imprinted DEGs: 18 in males; 1 in females). Finally, by using machine learning model (L1 regularization), we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas in a sex-specific manner. Our findings highlight that the DNA methylation profiles of the placenta could serve as a potent predictive molecular signature for early preimplantation alcohol exposure.

Effects of Chronic Prenatal Alcohol Exposure on Nociceptive Responses to Mechanical and Thermal Stimuli in Rats.

The present study sought to investigate the effects of chronic prenatal alcohol exposure (PAE) on nociceptive responses to mechanical and thermal stimuli in rats. The Von Frey and Hot Plate tests were employed to assess the nociceptive responses of 10 control rats and 7 experimental rats whose mothers had been administered ethanol from day 5 to day 20 of gestation. In healthy animals, a decrease in pain sensitivity was observed between days 28 and 70, which was not observed in the experimental group. The findings also indicated that rats with PAE exhibited diminished sensitivity to nociceptive stimuli during the early postnatal period, as evidenced by a higher threshold response to mechanical stimuli at day 28 than in the control group. However, those observations did not apply to thermal stimuli. It appears that this may be a result of distinctiveness in neural pain pathways for particular stimuli at the receptor or ion channel level, while a disruption in the equilibrium between the sympathetic and parasympathetic nervous systems may be a contributing factor. The results of this study highlight a critical aspect of the harmful systemic effects of alcohol, while also underscoring the need for further research to elucidate the underlying mechanisms, including the role of the hypothalamic-pituitary-adrenal axis and the serotonergic system in modulating pain responses in individuals prenatally exposed to alcohol.

Iron Deficiency and Restless Sleep/Wake Behaviors in Neurodevelopmental Disorders and Mental Health Conditions.

Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a 'suggested clinical immobilization test'. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35-15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37-8.64]), and RLS (OR: 7.00, p = 0.01, [1.49-32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82-12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54-22.1]), RLS (OR: 4.05, p = 0.01, [1.33-12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17-6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors.

Late-term moderate prenatal alcohol exposure impairs tactile, but not spatial, discrimination in a T-maze continuous performance task in juvenile rats.

Existing maze apparatuses used in rodents often exclusively assess spatial discriminability as a means to evaluate learning impairments. Spatial learning in such paradigms is reportedly spared by moderate prenatal alcohol exposure in rats, suggesting that spatial reinforcement alone is insufficient to delineate executive dysfunction, which consistently manifests in humans prenatally-exposed to alcohol. To address this, we designed a single-session continuous performance task in the T-maze apparatus that requires rats to discriminate within and between simultaneously-presented spatial (left or right) and tactile (sandpaper or smooth) stimuli for food reinforcement across four sequential discrimination stages: simple discrimination, intradimensional reversal 1, extradimensional shift, and intradimensional reversal 2. This design incorporates elements of working memory, attention, and goal-seeking behavior which collectively contribute to the executive function construct. Here, we found that rats prenatally-exposed to alcohol performed worse in both the tactile intradimensional reversal and extradimensional shift; alternatively, rats prenatally-exposed to alcohol acquired the extradimensional shift faster when shifting from the tactile to spatial dimension. In line with previous work, moderate prenatal alcohol exposure spared specifically spatial discrimination in this paradigm. However, when tactile stimuli were mapped into the spatial dimension, rats prenatally-exposed to alcohol required more trials to discriminate between the dimensions. We demonstrate that tactile stimuli can be operantly employed in a continuous performance T-maze task to detect discriminatory learning impairments in rats exposed to moderate prenatal alcohol. The current paradigm may be useful for assessing features of executive dysfunction in rodent models of fetal alcohol spectrum disorders.

Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in a South African population.

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations' unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed and has one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts (N=308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGAex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and âˆ¼ 221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51 %; Bantu and San); European (26 %; Northern/Western); South Asian (18 %); and East Asian (5 %; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6 %), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with higher FASD risk, and maternal and child ancestry-by-prenatal alcohol exposure interaction effects were seen on child cognition. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.

A Population-Based Study on Women Who Used Alcohol during Pregnancy and Their Neonates in Ontario, Canada.

BACKGROUND: Data from birth registries can be studied to assess the prevalence of prenatal alcohol use and associated maternal and neonatal outcomes. METHODS: Linked maternal and neonatal data (2015-2018) for alcohol-exposed pregnancies were obtained from the Better Outcomes Registry and Network (BORN) Ontario. Descriptive statistics were generated for maternal demographics, prenatal substance use, mental health/substance use history, and neonatal outcomes. Logistic regression models were performed to assess the odds of prenatal heavy (binge or weekly) alcohol and other substance use based on mental health/substance use history and other maternal demographics, and the impacts of heavy alcohol use and other prenatal substance exposures on neonatal outcomes. RESULTS: A total of 10,172 (2.4%) women reported alcohol use during pregnancy. One-third had pre-existing or current mental health and/or substance use problems, which was associated with significantly higher odds of heavy alcohol use during pregnancy. Prenatal exposure to heavy alcohol use was associated with increased odds of neonatal abstinence syndrome (2.5 times); respiratory distress syndrome (2.3 times); neonatal intensive care unit (NICU) admission (58%); and hyperbilirubinemia (57%). Prenatal exposure to one or more substances in addition to alcohol was associated with significantly higher odds of fetal/maternal/placental pregnancy complications; preterm birth; NICU admission; low APGAR scores; one or more confirmed congenital anomalies at birth; respiratory distress syndrome; and intrauterine growth restriction. CONCLUSIONS: It is crucial to routinely screen childbearing-age and pregnant women for alcohol and other substance use as well as mental health problems in order to prevent adverse maternal and neonatal outcomes.

A Case of Secondary Pulmonary Hypertension in a Patient With Atrial Septal Defect and Fetal Alcohol Syndrome.

We report a case of a 34-year-old man with fetal alcohol syndrome (FAS) presenting with dyspnea, cough, and hoarse voice. The patient was found to have severe pulmonary hypertension secondary to a large atrial septal defect (ASD). In this article, we discuss the challenges patients with FAS and other patients with cognitive impairments face that could explain the first diagnosis of such a large cardiac birth defect being made in the patient's adulthood. Moreover, severe pulmonary hypertension due to ASD also presents a therapeutic dilemma, as shunt closure can lead to a worsening of the condition.

Fetal alcohol spectrum disorders prevention and clinical guidelines research - workshop report.

It is estimated that up to 1 in 20 people in the United States may have a fetal alcohol spectrum disorder (FASD), or the array of physical, cognitive, emotional, and social disorders caused by exposure to alcohol during prenatal development (May et al., JAMA 319:474-82, 2018). While this condition is present in a broad range of individuals and families, it has not previously been examined in the military community, where cultural factors including an increased prevalence of alcohol misuse may pose a unique set of challenges (Health.mil, Alcohol misuse, 2024).The Uniformed Services University of the Health Sciences (USUHS), in conjunction with FASD United, hosted the second annual Workshop on Fetal Alcohol Spectrum Disorders Prevention and Clinical Guidelines Research on 20 September 2023 in Washington, DC. Organized as part of a four-year, federally-funded health services research initiative on FASD in the U.S. Department of Defense (DoD) Military Health System (MHS), the workshop provided a forum for exploring the initiative's focus and progress; examining current knowledge and practice in the research and clinical spheres; and identifying potential strategies to further improve prevention, screening, diagnosis, interventions, and family support. Building off of the 2022 workshop that covered the state of the science surrounding prenatal alcohol exposure and FASD, the 2023 focused primarily on FASD and efforts aimed at identification and management (Koehlmoos et al., BMC Proc 17 Suppl 12:19, 2023). One hundred and thirty attendees from academia, healthcare, federal agencies, and patient advocacy organizations gathered to share research findings; learn from lived experiences; and discuss initiatives to advance research, screening, and services for at-risk pregnant women as well as families and caregivers supporting individuals with FASD.