Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.
Drinking excessive amounts of alcohol during pregnancy can cause foetal alcohol spectrum disorder and other conditions in children that affect their physical and mental development. Many countries advise women who are pregnant or trying to conceive to avoid drinking alcohol entirely. However, surveys of large groups of women in Western countries indicate that most women continue drinking low to moderate amounts of alcohol until they discover they are pregnant and then stop consuming alcohol for the rest of their pregnancy. It remains unclear how this common drinking pattern affects the foetus. The instructions needed to build and maintain a human body are stored within molecules of DNA. Some regions of DNA called genes contain the instructions to make proteins, which perform many tasks in the body. Other so-called ‘non-coding’ regions do not code for any proteins but instead have roles in regulating gene activity. One way cells control which genes are switched on or off is adding or removing tags known as methyl groups to certain locations on DNA. Previous studies indicate that alcohol may affect how children develop by changing the patterns of methyl tags on DNA. To investigate the effect of moderate drinking during the early stages of pregnancy, Bestry et al. exposed pregnant mice to alcohol and examined how this affected the patterns of methyl tags on DNA in their offspring. The experiments found moderate levels of alcohol were sufficient to alter the patterns of methyl tags in the brains and livers of the newborn mice. Most of the changes were observed in non-coding regions of DNA, suggesting alcohol may affect how large groups of genes are regulated. Fewer changes in the patterns of methyl tags were found in mice whose mothers had diets rich in two essential nutrients known as folate and choline. Further experiments found that some of the affected mouse genes were similar to genes linked to foetal alcohol spectrum disorder and other related conditions in humans. These findings highlight the potential risks of consuming even moderate levels of alcohol during pregnancy and suggest that a maternal diet rich in folate and choline may help mitigate some of the harmful effects on the developing foetus.

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.
METHODS: 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.

BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are lifelong conditions that can occur in a person with prenatal alcohol exposure. Although studies using intensive, in-person assessments of children in selected communities have found higher estimates of children with FASDs than studies of healthcare claims data, claims-based studies provide more current information about individuals with recognized FASDs from diverse populations. We estimated the proportion of children with administratively reported FASDs in two large healthcare claims databases.
METHODS: We analyzed Merative™ MarketScan® commercial and Medicaid claims databases, that include nationwide data from employer-sponsored health plans and from Medicaid programs in 8-10 states, respectively. For each database, we estimated the proportion of children aged 0-17 years with administratively reported FASDs, identified by one inpatient or two outpatient codes for prenatal alcohol exposure or fetal alcohol syndrome during the entire seven-year period from 2015 to 2021 and during each year.
RESULTS: During 2015-2021, 1.2 per 10,000 commercially-insured and 6.1 per 10,000 Medicaid-insured children had an administratively reported FASD; estimates varied by sex, geography, and other available demographics. Among commercially-insured children, 0.5 per 10,000 in 2015 and 0.6 per 10,000 children in 2021 had an administratively reported FASD; among Medicaid-insured, 1.2 per 10,000 in 2015 and 2.1 per 10,000 children in 2021 had an administratively reported FASD.
CONCLUSIONS: Although an underestimate of the true population of children with FASDs, patterns in administratively reported FASDs by demographics were consistent with previous studies. Healthcare claims studies can provide timely, ongoing information about children with recognized FASDs to complement in-persons studies.

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.

BACKGROUND: Despite several diagnostic guidelines, Fetal Alcohol Spectrum Disorders (FASDs) remain underdiagnosed or misdiagnosed, delaying the care of these patients and support for families.
OBJECTIVE: This study aims to help professionals caring for these children and their families to suspect this diagnosis earlier and to provide the most appropriate follow-up.
METHODS: A retrospective chart review with monocentric recruitment was performed at the Genetics Unit of the University Hospital of Reunion Island. A total of 147 children and adolescents with FASDs were included.
RESULTS: Prenatal alcohol exposure was associated with paternal alcohol consumption in 42.9%, and a high rate of prematurity (33.3%) was observed. Sixty percent of children or adolescents were placed in foster families. Learning difficulties without cognitive deficits were found in 65.8% of cases (50/76). Postural control and fine motor skills disabilities were described, respectively, in 54.7% (35/64) and 72.5% (50/69) of cases. A systematic genetic assessment was carried out, identifying in these FASD patients an associated Copy Number Variation (CNVs) in 22.6% of cases.
CONCLUSIONS: Children with FASDs combine significant vulnerabilities, associating exposure to alcohol during the preconception and/or the prenatal period, prematurity, complex familial and sociocultural living conditions, and a genetic anomaly in almost a quarter of cases.

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual\'s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6-10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK, PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3, NR1D1, DEC1, DEC2, and DBP, as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

Prenatal alcohol exposure and fetal alcohol spectrum disorders (FASDs) remain critical public health issues. Alcohol use in pregnancy is a leading preventable cause of birth defects, developmental disabilities, and learning disabilities. Alcohol screening and brief intervention (SBI) is effective at reducing excessive alcohol use. However, this clinical preventive service remains critically underutilized in primary care. In 2014, the Centers for Disease Control and Prevention called for the creation of FASD Champion programs to promote clinician education about FASDs. Six professional health organizations and groups providing reproductive and child health services set out to create FASD Champion programs. The American College of Obstetricians and Gynecologists FASDs Prevention Program was created to focus on reducing alcohol-exposed pregnancies. The American Academy of Pediatrics\' Champion program maintains the goal of improving health outcomes for children with FASDs by improving pediatricians\' diagnostic capacity. The American Academy of Family Physicians has prioritized training family physician champions to improve the delivery of alcohol SBI among adult patients. The University of Alaska Anchorage has partnered with the National Association of Nurse Practitioners in Women\'s Health, the American College of Nurse-Midwives, and the Association of Women\'s Health, Obstetric, and Neonatal Nurses to assure advanced practice registered nurses and midwives have the knowledge and skills to prevent alcohol-exposed pregnancies and FASDs. The American Association of Medical Assistants has prioritized expanding the knowledge and skills of medical assistants related to promoting alcohol-free pregnancies. Finally, the Champions program at the University of Texas at Austin was established to train health social workers in alcohol SBI. Through the advocacy, education, and mission of these 6 health sectors in collaboration with national organizations and educational institutions, the evidence-based approach of alcohol SBI is being disseminated throughout the United States to reduce the harmful effects of prenatal alcohol exposure.

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.

BACKGROUND: Prenatal alcohol exposure (PAE) is one of the leading causes of preventable developmental disabilities. A lack of objective screening methods results in an under-recognition of the phenomenon. Phosphatidylethanol (PEth) is a specific ethanol biomarker that reveals alcohol intake up to several weeks after alcohol use. So far, PEth has mostly been a tool for detecting moderate and heavy drinking. With lower PEth cut-offs, revealing even minor prenatal alcohol consumption is possible. We aimed to find out if a sensitive method for PEth analysis would give additional information about PAE and to assess the cut-off value for a positive alcohol result in prenatal screening.
METHODS: The study was an observational study of 3000 anonymous blood samples collected from the Helsinki University Hospital Diagnostic Center between June and September 2023. The Finnish Red Cross Blood Service received the samples originally for blood group typing and antibody screening as part of the prenatal blood screening program. We developed a sensitive PEth 16:0/18:1 analysis method using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) equipment after liquid-liquid extraction of PEth from whole blood. The lower limit of quantification was 1 ng/mL.
RESULTS: PEth was ≥2 ng/mL in 5.2% of the cases, ≥8 ng/mL in 2.0%, and ≥20 ng/mL in 1.0%. The detection time of PEth can be several weeks, especially with low PEth concentrations and after heavy alcohol consumption. It remained unknown whether the positive PEth tests resulted from drinking deliberately during pregnancy or before pregnancy recognition.
CONCLUSIONS: We suggest adding PEth 16:0/18:1 to a routine prenatal blood screening program with a cut-off of 2 ng/mL-and in positive cases, clinical evaluation and retesting in 2-4 weeks. In clinical settings, information on gestational week and alcohol consumption before pregnancy is relevant and needs to be considered when interpreting low PEth concentrations.

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 ∼ 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.