Alternative splicing events as peripheral biomarkers for motor learning deficit caused by adverse prenatal environments.

Severity of neurobehavioral deficits in children born from adverse pregnancies, such as maternal alcohol consumption and diabetes, does not always correlate with the adversity's duration and intensity. Therefore, biological signatures for accurate prediction of the severity of neurobehavioral deficits, and robust tools for reliable identification of such biomarkers, have an urgent clinical need. Here, we demonstrate that significant changes in the alternative splicing (AS) pattern of offspring lymphocyte RNA can function as accurate peripheral biomarkers for motor learning deficits in mouse models of prenatal alcohol exposure (PAE) and offspring of mother with diabetes (OMD). An aptly trained deep-learning model identified 29 AS events common to PAE and OMD as superior predictors of motor learning deficits than AS events specific to PAE or OMD. Shapley-value analysis, a game-theory algorithm, deciphered the trained deep-learning model's learnt associations between its input, AS events, and output, motor learning performance. Shapley values of the deep-learning model's input identified the relative contribution of the 29 common AS events to the motor learning deficit. Gene ontology and predictive structure-function analyses, using Alphafold2 algorithm, supported existing evidence on the critical roles of these molecules in early brain development and function. The direction of most AS events was opposite in PAE and OMD, potentially from differential expression of RNA binding proteins in PAE and OMD. Altogether, this study posits that AS of lymphocyte RNA is a rich resource, and deep-learning is an effective tool, for discovery of peripheral biomarkers of neurobehavioral deficits in children of diverse adverse pregnancies.

The interaction of genetic sex and prenatal alcohol exposure on health across the lifespan.

Prenatal alcohol exposure (PAE) can reprogram the development of cells and tissues, resulting in a spectrum of physical and neurobehavioral teratology. PAE immediately impacts fetal growth, but its effects carry forward post-parturition, into adolescence and adulthood, and can result in a cluster of disabilities, collectively termed Fetal Alcohol Spectrum Disorders. Emerging preclinical and clinical research investigating neurological and behavioral outcomes in exposed offspring point to genetic sex as an important modifier of the effects of PAE. In this review, we discuss the literature on sex differences following PAE, with studies spanning the fetal period through adulthood, and highlight gaps in research where sex differences are likely, but currently under-investigated. Understanding how sex and PAE interact to affect offspring health outcomes across the lifespan is critical for identifying the full complement of PAE-associated secondary conditions, and for refining targeted interventions to improve the quality of life for individuals with PAE.

Prenatal alcohol exposure and associations with physical size, dysmorphology and neurodevelopment: a systematic review and meta-analysis.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria. METHODS: Six databases were searched (inception-February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size < 10, PAE determined via biological markers only, or no suitable comparison group. Summary data were extracted and associations between outcomes and standardised levels of PAE or FASD diagnosis determined using random-effects meta-analyses. Certainty of the evidence was assessed using GRADE. RESULTS: Of the 306 included studies, 106 reported physical size, 43 dysmorphology, 195 functional neurodevelopment and 110 structural/neurological outcomes, with 292 different outcomes examined. There was a dose-response relationship between PAE and head circumference, as well as measures of physical size, particularly at birth. There was also an association between higher PAE levels and characteristic sentinel facial dysmorphology, as well as many of the current functional neurodevelopmental outcomes considered during diagnosis. However, data were often lacking across the full range of exposures. There was a lack of evidence from studies examining PAE to support inclusion of non-sentinel dysmorphic features, social cognition, speech-sound impairments, neurological conditions, seizures, sensory processing or structural brain abnormalities (via clinical MRI) in diagnostic criteria. GRADE ratings ranged from very low to moderate certainty of evidence. CONCLUSIONS: This comprehensive review provides guidance on which components are most useful to consider in the diagnostic criteria for FASD. It also highlights numerous gaps in the available evidence. Future well-designed pregnancy cohort studies should specifically focus on dose-response relationships between PAE and dysmorphology, neurodevelopment and brain structure/neurological outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021230522.

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 blunts pregnancy-mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes.

Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal-fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose-6-phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol-exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.

Effects of prenatal alcohol exposition on cognitive outcomes in childhood and youth: a longitudinal analysis based on meconium ethyl glucuronide.

BACKGROUND: Prenatal alcohol exposure (PAE) has been linked to severe, adverse child outcomes. However, little is known regarding subclinical outcomes of low/moderate PAE and its longitudinal consequences, especially regarding neurophysiological and neurocognitive development. A newborn biomarker of PAE, meconium ethyl glucuronide (EtG), has been shown to predict cognitive impairments in primary-school-aged children. The current study investigated the ongoing effects of subclinical PAE in adolescence. METHODS: A sample of n = 96 mother-child dyads of the FRAMES/FRANCES cohort were classified into PAE/no PAE using EtG with a 10 ng/g cutoff. Mothers were recruited during pregnancy and children were assessed during primary-school age (M = 7.57, SD = 0.65, range: 6.00-9.92 years) and adolescence (M = 13.26, SD = 0.31, range: 12.79-14.20 years) on three levels: clinical (ADHD rating), neuropsychological (IQ score and performance in a go/nogo task), and neurophysiological (analysis of P3 event-related potentials (ERP) during said go/nogo task). Developmental outcomes and courses following PAE were assessed using rmANCOVAs, controlling for relevant confounders (socioeconomic status (SES), birth weight, and maternal psychopathology). RESULTS: Neurophysiological impairments emerged for exposed children in the form of diminished attentional resource recruiting in childhood and adolescence (reduced go-P3 amplitudes) with no differences in performance. Neuropsychological testing showed a reduced IQ score for both time points with dose-dependent effects in childhood. Clinical ADHD symptoms were not significantly affected. CONCLUSION: Subclinical PAE, as determined by meconium EtG, has negative developmental consequences on cognitive function that persist from childhood to adolescence. These findings suggest that there is no safe limit for alcohol consumption during pregnancy and that more thorough screening of alcohol consumption during pregnancy is necessary for early identification and treatment of at-risk children.

Fetal MRI based brain atlas analysis detects initial in utero effects of prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can change the normal trajectory of human fetal brain development and may lead to long-lasting neurodevelopmental changes in the form of fetal alcohol spectrum disorders. Currently, early prenatal patterns of alcohol-related central nervous system changes are unclear and it is unknown if small amounts of PAE may result in early detectable brain anomalies. This super-resolution fetal magnetic resonance imaging (MRI) study aimed to identify regional effects of PAE on human brain structure. Fetuses were prospectively assessed using atlas-based semi-automated 3-dimensional tissue segmentation based on 1.5 T and 3 T fetal brain MRI examinations. After expectant mothers completed anonymized PRAMS and TACE questionnaires for PAE, fetuses without gross macroscopic brain abnormalities were identified and analyzed. Linear mixed-effects modeling of regional brain volumes was conducted and multiple comparisons were corrected using the Benjamini-Hochberg procedure. In total, 500 pregnant women were recruited with 51 reporting gestational alcohol consumption. After excluding confounding comorbidities, 24 fetuses (26 observations) were identified with PAE and 52 age-matched controls without PAE were analyzed. Patients with PAE showed significantly larger volumes of the corpus callosum (P ≤ 0.001) and smaller volumes of the periventricular zone (P = 0.001). Even minor (1-3 standard drinks per week) PAE changed the neurodevelopmental trajectory.

Investigating the relationship between prenatal alcohol exposure and children's behavioural and emotional development: analysis of the Growing Up in New Zealand study.

AIMS: To examine the relationship between prenatal alcohol exposure (PAE) and children's behavioural and emotional development in a large generalizable sample of women and their children in Aotearoa New Zealand. METHODS: Using data from the Growing Up in New Zealand longitudinal cohort, we investigated the relationship between maternal PAE and behavioural and emotional development in 8-year-old children. We explored secondary outcomes including measures of language, executive function, academic achievement, and adaptive behaviour. RESULTS: We found no significant differences in the measures of behavioural and emotional development in children 8 years old based on alcohol consumption. No significant differences in behavioural and emotional development were found based on amount of PAE and when PAE occurred, despite controlling for a range of potential confounding factors, such as neighbourhood deprivation and maternal health measures. PAE was associated with significantly higher scores for parent-rated oral language indicating better oral language. In Maori mothers, PAE was significantly associated with an increased risk of higher scores on two of the Strengths and Difficulties Questionnaire subscales. CONCLUSIONS: We did not find an association between PAE and behavioural and emotional development in children aged 8 years. PAE and behavioural and emotional development are difficult to measure accurately, and the moderating variables between them are complex. Future analyses will require larger cohorts of mothers and their children using precise measures of PAE and outcomes to enable more precise estimates of association.

Prevention of alcohol exposed pregnancies in Europe: the FAR SEAS guidelines.

INTRODUCTION: Drinking during pregnancy is the leading cause of birth defects and child developmental disorders in Europe. The adverse effects of drinking during pregnancy may include physical, behavioural and cognitive problems, known collectively as fetal alcohol spectrum disorders (FASD). Evidence-based comprehensive recommendations at the European level on how to implement preventive and treatment policies to reduce alcohol-exposed pregnancies are needed. FAR SEAS, a tendered service contract (number 20,187,106) awarded by the European Commission, aimed at developing guidelines to respond to this knowledge gap. METHODS: FAR SEAS recommendations were built on (1) a two-phase review of interventions, (2) an international expert consultation, and (3) a pilot study on prevention of FASD conducted in the Mazovia region of Poland. The review of interventions included nineteen electronic open access databases, several repositories of grey literature and a key informant consultation covering most European Union (EU) countries and an additional guidelines search. After triangulating sources, 94 records were collected. Experts contributed in the design of the research questions, addressing the gaps in the literature and reviewing the recommendations formulated. The Polish pilot added nuances from real world practice to the formulated recommendations, resulting in the final set of guidelines for dissemination. RESULTS: The FAR SEAS Guidelines comprise 23 recommendations grouped into different topics areas of policies, communication strategies, screening, brief intervention and referral to treatment, treatment and social services. The recommendations highlight the need to respect women's autonomy and avoid discrimination and stigmatization; using universal screening for women of childbearing age, including detection of other psychosocial risks (such as domestic violence); and individualized, comprehensive and multidisciplinary supportive interventions for those who require it, such as those with alcohol use disorders, including women's partners. Policies to prevent FASD should be multicomponent, and public health communication should combine information about the risks together with self-efficacy messages to promote changes. CONCLUSIONS: The FAR SEAS guidelines are a tool to support policy-makers and service managers in implementing effective programmes to reduce prenatal alcohol exposure among general and at-risk population groups. FASD prevention has to involve comprehensive and multi-level evidence-based policies and practice, with services and activities tailored to the needs of women at differing levels of risk, and with due attention to reducing stigma.

Exercise reduces physical alterations in a rat model of fetal alcohol spectrum disorders.

BACKGROUND: Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention. RESULTS: Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not. CONCLUSION: PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD.

Benchmark dose profiles for bivariate exposures.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

Moderate Prenatal Alcohol Exposure Increases Toll-like Receptor Activity in Umbilical Cord Blood at Birth: A Pilot Study.

The prevalence of prenatal alcohol exposure (PAE) is increasing, with evidence suggesting that PAE is linked to an increased risk of infections. PAE is hypothesized to affect the innate immune system, which identifies pathogens through pattern recognition receptors, of which toll-like receptors (TLRs) are key components. We hypothesized that light-to-moderate PAE would impair immune responses, as measured by a heightened response in cytokine levels following TLR stimulation. Umbilical cord samples (10 controls and 8 PAE) from a subset of the Ethanol, Neurodevelopment, Infant and Child Health Study-2 cohort were included. Peripheral blood mononuclear cells (PMBCs) were stimulated with one agonist (TLR2, TLR3, TLR4, or TLR9). TLR2 agonist stimulation significantly increased pro-inflammatory interleukin-1-beta in the PAE group after 24 h. Pro- and anti-inflammatory cytokines were increased following stimulation with the TLR2 agonists. Stimulation with TLR3 or TLR9 agonists displayed minimal impact overall, but there were significant increases in the percent change of the control compared to PAE after 24 h. The results of this pilot investigation support further work into the impact on TLR2 and TLR4 response following PAE to delineate if alterations in levels of pro- and anti-inflammatory cytokines have clinical significance that could be used in patient management and/or attention to follow-up.

Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

This study evaluated criteria for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Kable et al. (Child Psychiatry Hum Dev 55:426, 2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17 years) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.

Neuropsychological profiles of adolescents sentenced to detention in Western Australia with and without prenatal alcohol exposure.

BACKGROUND/AIMS: Youth with prenatal alcohol exposure (PAE) are under-recognised in the justice system, warranting improved identification. This study aimed to compare neuropsychological profiles of adolescents, with and without PAE and identify neuropsychological tasks predictive of PAE-group membership. It was hypothesised that participants with PAE would score significantly lower on neuropsychological tests. METHODS: Participants included 85 young people sentenced to detention (mean 15.7 years, 78 males), 46 with PAE. A one-way-multivariate analysis of variance tested differences in neuropsychological functioning between PAE/No-PAE groups, while logistic regression determined tests predictive of PAE. RESULTS: No statistically significant difference in test scores emerged between groups, and regression was not indicative of any models predictive of PAE-group membership. Neuropsychological profiles were characterised by both strengths and weaknesses, with lower verbal and mathematical skills. CONCLUSION(S): While no statistically significant differences were found between the groups, the results provided a unique insight into the neurocognitive profile of Australian youth in detention. Routine screening assessments were recommended for young people sentenced to detention.

Associations between community-level patterns of prenatal alcohol and tobacco exposure on brain structure in a non-clinical sample of 6-year-old children: a South African pilot study.

The current small study utilised prospective data collection of patterns of prenatal alcohol and tobacco exposure (PAE and PTE) to examine associations with structural brain outcomes in 6-year-olds and served as a pilot to determine the value of prospective data describing community-level patterns of PAE and PTE in a non-clinical sample of children. Participants from the Safe Passage Study in pregnancy were approached when their child was ∼6 years old and completed structural brain magnetic resonance imaging to examine with archived PAE and PTE data (n = 51 children-mother dyads). Linear regression was used to conduct whole-brain structural analyses, with false-discovery rate (FDR) correction, to examine: (a) main effects of PAE, PTE and their interaction; and (b) predictive potential of data that reflect patterns of PAE and PTE (e.g. quantity, frequency and timing (QFT)). Associations between PAE, PTE and their interaction with brain structural measures demonstrated unique profiles of cortical and subcortical alterations that were distinct between PAE only, PTE only and their interactive effects. Analyses examining associations between patterns of PAE and PTE (e.g. QFT) were able to significantly detect brain alterations (that survived FDR correction) in this small non-clinical sample of children. These findings support the hypothesis that considering QFT and co-exposures is important for identifying brain alterations following PAE and/or PTE in a small group of young children. Current results demonstrate that teratogenic outcomes on brain structure differ as a function PAE, PTE or their co-exposures, as well as the pattern (QFT) or exposure.

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.

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.

Enhancing fetal alcohol spectrum disorders diagnosis with a classifier based on the intracerebellar gradient of volumetric undersizing.

In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non-syndromic FASD (NS-FASD, i.e., those without specific diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS-FASD) and 126 typically developing controls (6-20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (Vi ) and the total brain or cerebellum volume (Vt ) was fitted (Vi = bVt a ), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (v DTS) learned in the controls. Lastly, we trained and tested two classifiers to discriminate FAS from controls, one based on the total cerebellum v DTS only, the other based on all the cerebellar v DTS, comparing their performance both in the FAS and the NS-FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (v DTS = -10.6%) and revealed an antero-inferior-posterior gradient of volumetric undersizing in the hemispheres (-12.4%, 1.1%, 2.0%, respectively) and the vermis (-16.7%, -9.2%, -8.6%, repectively). The classifier based on the intracerebellar gradient of v DTS performed more efficiently than the one based on total cerebellum v DTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient-based classifier identified 35% of the NS-FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum-only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior-inferior-posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intracerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS-FASD.

Auditory Outcomes in Adolescents with Prenatal Alcohol Exposure.

The aim of the study was to investigate three aspects of auditory function (auditory acuity, cochlear dysfunction, and auditory processing) in adolescents with fetal alcohol exposure without phenotypic changes. Fifty-one adolescents with and without intrauterine exposure to alcohol were selected from a cohort study. The summons, evaluation, and analysis of the results were carried out blindly regarding the respective exposure to alcohol. The auditory tests were pure-tone audiometry, transient otoacoustic emissions, and behavioral assessment of auditory processing (speech-in-noise, dichotic digits, and gap-in-noise). After testing, 45 adolescents were included in the evaluation and were divided into exposed (n = 22) and non-exposed (n = 23) groups. Hearing loss was identified in one subject in the exposed group (4.5%). In the absence of hearing loss, there were no significant differences in tonal thresholds or in the magnitudes of the sensory (cochlear) responses between groups (p > 0.05). There was also no difference between the two groups regarding performance on the processing tests (speech-in-noise p = 0.71, dichotic p = 0.94, and gap-in-noise p = 0.33). However, the exposed group had more cases of hearing disorders (hearing loss plus auditory processing disorders) than the non-exposed group (22.7% vs. 4.3%).

Alcohol exposure before and during pregnancy is associated with reduced fetal growth: the Safe Passage Study.

BACKGROUND: Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort. METHODS: The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes. RESULTS: This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED30; - 0.13 (95% CI; - 0.22; - 0.04), ED36; - 0.14 (95% CI; - 0.25; - 0.04)) and a smaller abdominal circumference (ED36; - 0.09 (95% CI; - 0.18; - 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.14 (95% CI; - 0.25; - 0.02), ED36; - 0.22 (95% CI; - 0.37; - 0.06)) and a smaller estimated fetal weight (ED36; - 0.22 (95% CI; - 0.38; - 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.49 (95% CI; - 0.86; - 0.12), ED36; - 0.70 (95% CI; - 1.22; - 0.17)) and estimated fetal weight (ED30; - 0.54 (95% CI; - 0.94; - 0.14), ED36; - 0.69 (95% CI; - 1.25; - 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth. CONCLUSIONS: This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy.