Risk For Fetal Alcohol Spectrum Disorder Research Articles

Maternal and paternal risk factors for fetal alcohol spectrum disorders: Alcohol and other drug use as proximal influences.

To explore and analyze the significance of proximal influences of maternal and paternal traits associated with bearing a child with a fetal alcohol spectrum disorder (FASD). Aggregated, maternal interview-collected data (N = 2515) concerning alcohol, tobacco, and other drug use were examined to determine risk for FASD from seven cross-sectional samples of mothers of first-grade students who were evaluated for a possible diagnosis of FASD. Mothers of children with fetal alcohol syndrome (FAS) reported the highest alcohol use throughout pregnancy, proportion of binge drinking, drinks per drinking day (DDD), drinking days per week, and total drinks per week. Mothers of children with FAS also consumed significantly more alcohol than mothers of children with partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), or typically developing controls. Mothers of children with PFAS and ARND reported similar drinking patterns, which exposed fetuses to 3-4 times more alcohol than mothers of controls, but the PFAS group was more likely than the ARND group to abstain in latter trimesters. Fathers of all children were predominantly drinkers (70%-85%), but more fathers of children with FASD binged heavily on more days than fathers of controls. Compared to the few mothers of controls who used alcohol during pregnancy, the ARND group binge drank more (3+ DDD) throughout pregnancy and drank more DDD before pregnancy and first trimester. Regression analysis, controlling for tobacco use, indicated that mothers who reported drinking <1 DDD were significantly more likely than abstainers to bear a child with FASD (OR = 2.75) as were those reporting higher levels such as 5-5.9 DDD (OR = 32.99). Exclusive, first-trimester maternal drinking increased risk for FASD five times over that of abstinence (p < 0.001, OR = 5.05, 95% CI: 3.88-6.58), first- and second-trimester drinking by 12.4 times, and drinking all trimesters by 16 times (p < 0.001, OR = 15.69, 95% CI: 11.92-20.64). Paternal drinking during and prior to pregnancy, without adjustment, increased the likelihood of FASD significantly (OR = 1.06 and 1.11, respectively), but the significance of both relationships disappeared when maternal alcohol and tobacco use were controlled. Differences in FASD risk emerged from the examination of multiple proximal variables of maternal alcohol and tobacco use, reflecting increased FASD risk at greater levels of maternal alcohol consumption.

Significance of Selected Environmental and Biological Factors on the Risk of FASD in Women Who Drink Alcohol during Pregnancy.

Prenatal alcohol exposure (PAE), which refers to alcohol consumption by pregnant women, is associated with the risk of numerous severe complications during fetal development. The State Agency for Alcohol Problem Solving reports that the incidence of fetal alcohol spectrum disorder (FASD) in Poland's general population is over 1.7%, and the incidence of fetal alcohol syndrome (FAS) is estimated at more than 0.5%. This study aimed to evaluate the significance of alcohol exposure and focused on the pattern of alcohol intoxication exhibited by the mother during pregnancy and other environmental factors of the maternal environment contributing to the development of FASD. The study covered 554 subjects, including 251 mothers and 303 children (213 girls and 90 boys). The mother's drinking problem was determined based on the information obtained from the case history. All children qualified for the study fulfilled the h-PAE (high alcohol exposure) criteria during their fetal life. The clinical diagnosis of FAS and pFAS (occurrence of morphological symptoms of fetal alcohol syndrome) was made using a four-digit diagnostic questionnaire validated in the Polish version of the Washington Questionnaire for the assessment of the spectrum of alcohol-related neurodevelopmental disorders or alcohol-related cognitive impairment (ARND/C). Statistical analysis of the obtained research results was developed using statistical software-STATISTICA PL, version 13.1 (StatSoft, Inc., Szczecin, Poland 2016, STATISTICA-data analysis software system, version 13.1). The most destructive drinking behaviors are compulsive intoxication (BD, binge drinking) during the first 6 weeks of pregnancy and chronic addiction throughout its duration (CHD, chronic drinking). Chronic alcohol intoxication (CHD) leads to a poorer nutritional status in mothers, which is reflected in a lower body mass index (BMI) (<18 kg/m2).

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Screening for fetal alcohol spectrum disorder in infants and young children.

Introduction: With an estimated prevalence of up to five percent in the general population, fetal alcohol spectrum disorders (FASD) are the most common neurodevelopmental disorder and more prevalent than autism. Early identification and subsequent early intervention have the potential to improve developmental trajectory of children with FASD. In addition, new research suggests supplementation with choline may ameliorate the developmental impairments associated with prenatal alcohol exposure. Availability of a screening tool with acceptable epidemiologic performance criteria may be clinical useful in identification of young children at increased risk for FASD. In this paper we describe the Early Fetal Alcohol Spectrum Disorder Screening Test (E-FAST) to identify young children at increased risk for an FASD. Methods: We developed the E-FAST dataset from previously published studies, comprised of 281 children under 5years of age, 180 (64.1%) were diagnosed with FASD and 101 (35.9%) were non-FASD. Analysis: The analysis identified seven useful variables (prenatal alcohol exposure, ADHD (Attention Deficit Hyperactivity Disorder), foster care or adopted, small OFC (occipital frontal circumference), communication impairments, impaired social skills, and cognitive deficits. All variables were categorized as yes/no for ease of use in a screening tool. Risk ratios for each of the seven indicators were estimated using two-way table analyses. Weights for each variable were estimated based on the relative strength of their odds ratios. Results: The average age was 2.7years of age (S.D. 1.29) and ranged from infant (6.4%) to 4years old (35.9%). Maternal alcohol use alone had a sensitivity of 0.97, specificity 0.65, and accuracy 0.86. For the combined seven variables, sensitivity was 0.94, specificity 0.74, and accuracy 0.87. Thus, the seven-item E-FAST screen had acceptable epidemiologic screening characteristics. Discussion: In the United States, up to 547 infants with FASD are born each day which far exceeds the capacity of multidisciplinary diagnostic clinics. During routine clinical management of infants and young children the use of an evidence-based screening tool provides a time efficient means to exclude large numbers of young children from further follow-up for FASD. Conversely, a positive screen identifies a smaller number of children at increased risk for FASD requiring more intensive evaluation and follow-up.

Differential Early Mechanistic Frontal Lobe Responses to Choline Chloride and Soy Isoflavones in an Experimental Model of Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of neurodevelopmental defects, and white matter is a major target of ethanol neurotoxicity. Therapeutic interventions with choline or dietary soy could potentially supplement public health preventive measures. However, since soy contains abundant choline, it would be important to know if its benefits are mediated by choline or isoflavones. We compared early mechanistic responses to choline and the Daidzein+Genistein (D+G) soy isoflavones in an FASD model using frontal lobe tissue to assess oligodendrocyte function and Akt-mTOR signaling. Long Evans rat pups were binge administered 2 g/Kg of ethanol or saline (control) on postnatal days P3 and P5. P7 frontal lobe slice cultures were treated with vehicle (Veh), Choline chloride (Chol; 75 µM), or D+G (1 µM each) for 72 h without further ethanol exposures. The expression levels of myelin oligodendrocyte proteins and stress-related molecules were measured by duplex enzyme-linked immunosorbent assays (ELISAs), and mTOR signaling proteins and phosphoproteins were assessed using 11-plex magnetic bead-based ELISAs. Ethanol's main short-term effects in Veh-treated cultures were to increase GFAP and relative PTEN phosphorylation and reduce Akt phosphorylation. Chol and D+G significantly modulated the expression of oligodendrocyte myelin proteins and mediators of insulin/IGF-1-Akt-mTOR signaling in both control and ethanol-exposed cultures. In general, the responses were more robust with D+G; the main exception was that RPS6 phosphorylation was significantly increased by Chol and not D+G. The findings suggest that dietary soy, with the benefits of providing complete nutrition together with Choline, could be used to help optimize neurodevelopment in humans at risk for FASD.

Psychotropic Medication Usage in Individuals with Fetal Alcohol Spectrum Disorders (FASD) and Psychiatric Co-morbidities in Canada

Background and objective Individuals with Fetal Alcohol Spectrum Disorder (FASD) tend to be prescribed a high number of psycho-tropic medications to treat high rates of comorbid psychiatric disorders. A lack of guidance regarding best practices for prescribing psychotropic medications to individuals with FASD probably accounts for this reliance on polypharmacy. The objective of this study is to describe the types of medications prescribed to individuals with prenatal alcohol exposure, comparing rates between individuals diagnosed with FASD and individuals without FASD as well as how medications are prescribed based on age, sex, and comorbid psychiatric disorders. Material and methods Data were drawn from Canada's national FASD database. This database includes information collected during an FASD assessment related to diagnostic outcomes, secondary challenges, and medical and mental health information. Descriptive statistics were calculated for four diagnostic groups (FASD with sentinel facial features [FASD + SFF], FASD without sentinel facial features [FASD - SFF], at risk for FASD [“at risk”], and no FASD). Group demographics were compared using Chi-Square, Fisher's Exact Test, and ANOVA, as appropriate. Differences in the proportion of individuals between these four diagnostic groups were calculated using each of the following six classes of psychotropic medications—antipsychotics, antidepressants/anxiolytic, anticonvulsants/mood stabilizers, stimulants, melatonin, and others—using ANOVA. Considering just the individuals with FASD by combining the FASD + SFF and FASD - SFF groups, independent sample tests were used to compare differences in the proportion of males and females prescribed different medications. Chi-Square and Fisher's Exact Test were used to compare the proportion of individuals using psychotropic medications, according to category, within the FASD group based on the presence or absence of 13 comorbid psychiatric disorders. Results The overall sample included 2349 participants (mean value = 18.1 years, SD = 10.3). The sample included 1453 participants with an FASD diagnosis (n = 218, FASD + SFF, mean = 23.7 years, SD = 15.8, and n = 1235, FASD - SFF, mean = 19.5 years, SD = 10.0 years) and 896 participants who were assessed but did not receive an FASD diagnosis (n = 653, no FASD, mean = 16.1 years and n = 261, “at risk” for FASD, mean = 12.2 years). The FASD groups had a significantly higher rates of anxiety disorders, depressive disorders, and the presence of at least one comorbid psychiatric disorder compared to the no FASD and the “at risk” groups. Both FASD groups had a higher proportion of individuals taking antipsychotic and antidepressant/anxiolytic medications compared to the no FASD and “at risk” groups. Females with FASD were more often prescribed antidepressants/anxiolytics compared to males with FASD, while males with FASD were more often prescribed stimulants than females with FASD. The prevalence of antidepressants/anxiolytics, stimulants, and melatonin use by individuals with FASD differed across the lifespan. The prevalence of the prescription of six medication categories was found to differ according to psychiatric disorder. Conclusion Compared to individuals assessed as not fulfilling criteria for FASD, those with FASD had higher rates of psychiatric disorders and were prescribed significantly more antidepressants/anxiolytics and antipsychotics. The class and rate of prescriptions may support efforts in devising treatment guidelines for a complex disorder with known high comorbidity such as FASD.

Nutritionists' Practices and Knowledge about the Risks of Alcohol Consumption during Pregnancy: An Israeli Survey.

Fetal alcohol spectrum disorders (FASDs) are lifelong disabilities and the leading preventable cause of developmental disabilities. Antenatal care providers may influence pregnant women’s dietary practices and their awareness of the risks of alcohol consumption during pregnancy. This study aimed to assess nutritionists’ self-reported knowledge about the risks of drinking alcohol during pregnancy, professional practices in this respect, and self-perceived competence to assess and guide women about alcohol consumption during pregnancy in Israel. A sample of 526 professional nutritionists completed an anonymous online questionnaire. Results showed significant differences between the nutritionists’ knowledge and professional practices scores. About 349 (66.3%) of the sample agreed (to any degree) that they did not have enough knowledge to guide pregnant women regarding drinking alcohol. The number of years of experience, combined with self-perceived competence and the mean knowledge score, explained 18% of the variance in professional practices. Nutritionists and other health professionals may have a crucial role in preventing FASD and should prioritize appropriate screening for prenatal alcohol use. Eliminating alcohol consumption at any point in pregnancy would reduce the risk for FASDs.

Review of the questionnaires used to detect alcohol consumption during pregnancy and the Green Page.

Alcohol consumption during pregnancy is a leading cause of fetal alcohol spectrum disorder (FASD). Maternal reporting in childbearing women or pregnant women is the standard for the early detection of alcohol consumption. The Green Page (GP) is a screening questionnaire of environmental health which includes the alcohol intake record during pregnancy and/or lactation period. The aim of this paper is to review the features of the different questionnaires for the detection of alcohol consumption during the gestation period and the GP, as well as to make a comparison between them. Review of the scientific literature published over the last 10 years of indexed articles in Medline. Combined searching strategy with MeSH descriptors: 'pregnancy, alcohol drinking, surveys and/or questionnaires. AUDIT, AUDIT-C and SURP-P are mainly self-administered and do not require training. SURP-P and 4P´s are validated in pregnant women. Others detect quantity and frequency of exposure, need specific training and are administered face to face: TLFB, RD, ACOG antepartum record and the GP. ACOG antepartum record and GP are specific for pregnant population. GP detects alcohol consumption at the beginning of pregnancy in both women and their partner on a holistic and global environmental health approach. A careful face-to-face recording of alcohol exposure with trained staff, with an integrative and global environmental health focus throughout pregnancy, may help improve prevention and screening of pregnancy at risk for FASD.

Maternal psycho-social risk factors associated with maternal alcohol consumption and Fetal Alcohol Spectrum Disorder: a systematic review.

Fetal Alcohol Spectrum Disorder (FASD) is a preventable range of neurocognitive disorders associated with the biological mother's consumption of alcohol during pregnancy. However, on average, 45% of Australian women continue to consume alcohol during pregnancy resulting in a high rate of alcohol-exposed pregnancies and risk of FASD. This level of exposure is higher than the estimated global average of alcohol-exposed pregnancies (9.8%). This systematic literature review aims to identify demographic, health and psycho-social variables associated with alcohol consumption during pregnancy which may lead to FASD. Using PRISMA principles, this systematic literature review reports on psycho-social factors which increase the risk of alcohol consumption during pregnancy thereby increasing the risk of FASD. Fourteen studies were accepted into this review. Studies were conducted across several countries and included a total of 386,067 cases. Seven studies were case-controlled and seven were cross-sectional design. Multiple studies identified the significance of prior mental illness, anxiety, depression, exposure to abuse and/or domestic violence and alcohol consumption behaviours of partners and family members as strong predictors of risky alcohol consumption during pregnancy and therefore associated risk of FASD. Clinical services may be able to use the evidence-based findings from this review to improve assessment and treatment services for vulnerable women to reduce alcohol-exposed pregnancies.

Prevalence of Fetal Alcohol Spectrum Disorders (FASD) among Children Adopted from Eastern European Countries: Russia and Ukraine.

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disorders. Children adopted internationally from countries where alcohol consumption during pregnancy is very high are at greater risk for FASD. Lack of expertise in diagnosing FASD and mixed neurodevelopmental and behavioral signs due to abandonment complicate a timely diagnosis. The aim of this study was to determine the prevalence of FASD in adopted children. Children between the ages of 8 and 24 adopted from Russia and Ukraine were evaluated for clinical and historical features of FASD. Of the 162 children evaluated, 81 (50%) met FASD diagnostic criteria. Thirty-three (20.4%) children had fetal alcohol syndrome (FAS), 28 (17.2%) had partial FAS, 2 (1.2%) had alcohol-related birth defects (ARBD) and 18 (11.1%) had alcohol-related neurodevelopmental disorder (ARND). Of the 81 children in which fetal alcohol exposure could not be confirmed, many had manifestations that would have established a diagnosis of FASD if a history of maternal alcohol consumption was confirmed. In a population of children with a high risk of prenatal alcohol exposure (adoptees from Eastern European countries), at least 50% showed manifestations associated with FASD. The reported prevalence in this study is in line with the results obtained in a previous study as well as in orphanages of origin.

Relationships between Fetal Alcohol Spectrum Disorder, Adverse Childhood Experiences, and Neurodevelopmental Diagnoses

Objective: Children with fetal alcohol spectrum disorder (FASD) are overrepresented in early intervention programs, foster care, special education, juvenile corrections, and mental health services. In this study, we examine relationships between FASD and non-FASD controls for adverse childhood experiences (ACEs), and neurodevelopmental disorders. Methods: A chart review was conducted among patients seen at our clinic from 2010-2017 with data on FASD, ACEs, neurodevelopmental diagnoses, and foster or residential care placement available. Results: Relative risk for FASD was increased in patients with increased ACE scores (RR = 5.08), increased numbers of neurodevelopmental diagnoses (RR = 2.36), and patients who have been in foster or residential care (RR = 9.53). FASD risk increased as ACE scores or the number of neurodevelopmental diagnoses increased. Patients with any ACEs were 3.96 times more likely to have FASD, and those with eight or more ACEs were 6.31 times more likely to have FASD than those with no ACEs. Patients with three or more neurodevelopmental diagnoses were 6.55 times more likely to have FASD than those with two or fewer diagnoses. Nine or more diagnoses increased the risk for FASD ten-fold (RR = 10.91). Conversely, patients diagnosed with FASD were more likely to have at least three ACEs (RR = 3.71), at least five neurodevelopmental diagnoses (RR = 1.61), and high rates of previous foster or residential care placement (RR = 5.39). Conclusion: This study demonstrates that all children being considered for placement in foster care or residential should be screened for FASD.

Profile of Mothers of Children with Fetal Alcohol Spectrum Disorder: A Population-Based Study in Canada.

Objective: To compare the characteristics of mothers of children with Fetal Alcohol Spectrum Disorder (FASD) with mothers of typically developing control children. Methods: The study utilized a cross-sectional, observational design, using active case ascertainment. Biological mothers were interviewed using a standardized retrospective questionnaire to collect data on demographics, living environment, pregnancy history, nutrition, alcohol and other drug use prior to and following pregnancy recognition. Results: A total of 173 mothers were interviewed. Of these, 19 had a child who was diagnosed with FASD, five had a child who had received a deferred FASD diagnosis, and 37 had children who were selected into the control group as typically developing children. The remaining 112 mothers had children who did not meet diagnostic criteria for FASD. The mothers of children with FASD did not differ significantly from mothers of the control group children with respect to age, ethnicity, marital status, and employment status at the time of pregnancy. However, mothers of children with FASD had lower levels of education (p < 0.01) and were more likely to have received financial support (p < 0.05) at the time of pregnancy, to have smoked tobacco (p < 0.001), and to have used marijuana or hashish (p < 0.01) prior to pregnancy recognition, compared with mothers of control children. All mothers of children with FASD reported alcohol consumption prior to pregnancy recognition; however, only 10.5% reported alcohol consumption following pregnancy recognition. None of the mothers interviewed reported any drug use following pregnancy recognition. Conclusions: Population-based preventive interventions, including repeated screening, monitoring, and education regarding the effects of alcohol use, as well as other substances, before and during pregnancy, are needed to eliminate risk for FASD and other negative consequences on child and maternal health.

Phosphatidylethanol Levels in Postpartum Women and Their Newborns in Uruguay and Brazil.

There is increasing interest in the development of newborn screening tests to identify children at riskof fetal alcohol spectrum disorder (FASD) in order to provide these children with early intervention. Phosphatidylethanol (PEth) has emerged as a potentialuniversal newborn screeningcandidate. The aim of this report was to present the results of a study designed to compare PEth levels in 1,140postpartum women and their newborn infants in Montevideo, Uruguay, and Sao Paulo, Brazil. Self-report alcohol use during pregnancy data was collected, along with both maternal and newborn dried blood spot samples for PEth analysis. The average age and parity of the women in the sample were 26years of age and 2.3 pregnancies. For the Uruguay sample (n=611), 45.8% of postpartum women had PEth levels≥8ng/mlwith a mean positive PEth of 43.6ng/ml. In contrast, 86.8% of the newborns hadPEth levels≥8ng/ml,with a meanpositivePEthof 77.4ng/ml. For the Brazil sample (n=529), 33.2% of women hadPEthlevels≥8ng/ml with a mean positivePEthof 31ng/ml. In contrast,76.9% of theBrazilnewborns hadPEthlevels≥8ng/ml and 43.9% withameanpositivePEthof 61.1ng/ml. PEthlevels were significantly higher in newborns compared with their postpartum mothers in both the Uruguay and Brazil samples. Self-reported third-trimester alcohol was 6% in theUruguaysample and 9.1% in the Brazil sample compared with positivematernalPEthlevelsin 45.8% and 33.2%,respectively. Clinicians may want to consider newbornPEthscreening in high-risk populations where prenatal alcohol use is common. The mechanism underlying significantlyhigherPEthlevelsin newborns compared with their mothers is not known.

Fetal Alcohol Spectrum Disorders in a Pacific Southwest City: Maternal and Child Characteristics.

There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States. During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD. A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374). Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting.

Nifedipine Prevents Apoptosis of Alcohol-Exposed First-Trimester Trophoblast Cells.

Maternal alcohol abuse leading to fetal alcohol spectrum disorder (FASD) includes fetal growth restriction (FGR). Ethanol (EtOH) induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD. EtOH facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca2+ . We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca2+ . Therefore, nifedipine, a Ca2+ channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol. Human first-trimester chorionic villous explants and the human trophoblast cell line HTR-8/SVneo (HTR) were pretreated with 12.5 to 50nM of the Ca2+ channel blocker nifedipine for 1hour before exposure to 50mM EtOH for an additional hour. Intracellular Ca2+ concentrations were monitored in real time by epifluorescence microscopy, using fluo-4-AM. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), accumulation of cytoplasmic cytochrome c, and cleavage rates of caspase 3 and caspase 9. The increase in intracellular Ca2+ upon exposure to EtOH in both villous explants and HTR cells was completely blocked (p<0.05) when pretreated with nifedipine, accompanied by inhibition of EtOH-induced release of cytochrome c, caspase activities, and TUNEL. This study indicates that nifedipine can interrupt the apoptotic pathway downstream of EtOH exposure and could provide a novel strategy for future interventions in women with fetuses at risk for FASD.

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N=149) and low or no alcohol-exposed (LNA) (N=92) women were recruited into the study during mid pregnancy (mean of 19.8±5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p=0.020 and p=0.036, respectively) and 12 months (p=0.043 and p=0.029, respectively), and with MDI scores at 12 months (p=0.013 and p=0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1β, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1β and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p=0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

Metabolomics and fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) is a major public health issue that encompass an array of physical, neurological, and behavioral effects due to alcohol consumption during pregnancy. The classical biomarkers of FASD that are currently used lack sensitivity and specificity, and as such there is an opportunity through the use of novel metabolomics analysis to identify new biomarkers to identify those at risk for FASD, which could more effectively aid in early intervention. The focus of this minireview is to identify current work that is being done in the field of metabolomics in FASD in utero, and to highlight promising metabolites that could act as biomarkers in the future. We will conclude with suggestions for further research, as there is a large gap of knowledge in this particular area of metabolomics.

Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs.

Fetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures including volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups - heavy binge alcohol (HBA; 2.5g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5g/kg/treatment ethanol and 10mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ∼280mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4-41; choline was administered on GD 4-148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures.

Alcohol use and binge drinking among women of childbearing age - United States, 2011-2013.

Excessive alcohol use is risk factor for a wide range of health and social problems including liver cirrhosis, certain cancers, depression, motor vehicle crashes, and violence. Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders (FASDs) and other adverse birth outcomes . Community studies estimate that as many as 2% to 5% of first grade students in the United States might have an FASD, which include physical, behavioral, or learning impairments. In 2005, the Surgeon General reissued an advisory urging women who are or might be pregnant to abstain from alcohol consumption to eliminate the risk for FASDs or other negative birth outcomes. To estimate current prevalences of any alcohol use and binge drinking (consuming four or more drinks on an occasion) among pregnant and nonpregnant women aged 18-44 years in the United States, CDC analyzed 2011-2013 Behavioral Risk Factor Surveillance System (BRFSS) data. Among pregnant women, the prevalences of any alcohol use and binge drinking in the past 30 days were 10.2% and 3.1%, respectively. Among nonpregnant women, the prevalences of any alcohol use and binge drinking in the past 30 days were 53.6% and 18.2%, respectively. Among binge drinkers, pregnant women reported a significantly higher frequency of binge drinking than nonpregnant women (4.6 and 3.1 episodes, respectively); the largest amount consumed during binge drinking was also higher among pregnant women than nonpregnant women (7.5 versus 6.0 drinks), although this difference was not statistically significant. Implementation of evidence-based clinical and community-level strategies would be expected to reduce binge drinking among pregnant women and women of childbearing age, and any alcohol consumption among women who are or might be pregnant. Healthcare professionals can support these efforts by implementing alcohol screening and brief interventions in their primary care practices, and informing women that there is no known safe level of alcohol consumption when they are pregnant or might be pregnant.

Incidence of prenatal alcohol exposure in Prince Edward Island: a population-based descriptive study.

Fetal alcohol spectrum disorder (FASD) is a leading preventable cause of neurodevelopmental disability in North America. The stigma associated with alcohol use and abuse during pregnancy makes it difficult to obtain information on prenatal alcohol use through self-reporting. We assessed the incidence of prenatal alcohol exposure in Prince Edward Island to facilitate future public health initiatives addressing FASD. Prenatal alcohol exposure was examined via population-based collection of meconium and analysis of fatty acid ethyl esters (FAEEs). Fatty acid ethyl esters are nonoxidative metabolites of ethanol that are produced in the fetus. Meconium FAEE concentrations of 2.0 nmol/g or greater are indicative of frequent prenatal alcohol exposure during the last 2 trimesters of pregnancy. Samples were collected from 1307 neonates between Nov. 8, 2010, and Nov. 8, 2011, in hospitals in PEI, or from those born to mothers who resided in PEI but gave birth in Halifax, Nova Scotia. Samples were frozen and shipped for analysis. Fatty acid ethyl esters were analyzed by gas chromatography-mass spectrometry and quantified by means of deuterated internal standards. Of the 1307 samples collected, 1271 samples were successfully analyzed. Positive results for FAEEs were obtained in 3.1% (n = 39) of samples collected within the first 24 hours after birth. Not all neonates exposed to heavy prenatal alcohol in utero will exhibit FASD; based on current estimates of predictive value for disease by exposure, our findings suggest that 1.3% of neonates born in PEI during this 1-year period will have FASD. In its application to an entire provincial birth cohort, this study successfully implemented a public health-centred approach for evaluating population-based risk of FASD, with implications for practice across Canada.