Maternal consumption of alcohol during pregnancy is associated with alterations in fetal development that negatively impact the offspring causing neurochemical and neurobehavioural dysfunction termed fetal alcohol spectrum disorders; the most severe outcome is fetal alcohol syndrome. Changes in maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis activation, induction of cytochrome P450 2E1 (CYP2E1) enzyme activity and alterations in micronutrient status, including folate, following chronic ethanol exposure (CEE) are key contributors to the neuroendocrine and neurobehavioural effects observed in offspring. This study tested the following hypotheses: Maternal consumption of ethanol throughout pregnancy can: alter maternal and fetal HPA axis function and induce CYP2E1 enzyme activity in the third-trimester-equivalent; decrease folate status in the maternal-fetal unit, which can be mitigated by folic acid supplementation; and cause neurobehavioural deficits in offspring at low-moderate dose of maternal ethanol consumption. These hypotheses were tested in the guinea pig, a well established model of ethanol neurobehavioural teratogenicity. CEE had no effect on maternal HPA axis function at any gestational day (GD). Fetal cortisol was unaffected by CEE, but did increase with gestational age in both CEE and control. CEE increased maternal and GD 65 fetal liver CYP2E1 enzyme activity. Maternal supplementation with folic acid did not mitigate CEE fetal growth restriction, but did increase maternal red blood cell (RBC) folate at term. At term, maternal supplementation prevented the CEE-induced decrease in fetal liver folate, did not affect fetal RBC folate, and did not mitigate the nutritional-deficit-induced decrease in fetal hippocampal folate. Maternal consumption of 5% (v/v) ethanol decreased offspring birth weight, increased spontaneous locomotor activity, increased preference for ethanol, and delayed learning on day two of Morris water maze testing in young adult offspring. These data indicate that, in the guinea pig: there is a threshold blood ethanol concentration for HPA axis activation; CEE can induce CYP2E1 in the GD 65 fetus; folic acid supplementation is not protective in this model of CEE; and low-moderate CEE can cause neurobehavioural perturbations in offspring. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2012-05-31 14:38:44.391

The parietal lobe has been shown to be one of the regions most affected by prenatal alcohol exposure. Functional domains dependent on intact parietal functioning, including mathematical and visuospatial ability, have been consistently implicated in fetal alcohol spectrum disorders. This thesis examines, in children, using blood oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging, the effect of prenatal alcohol exposure on brain activation during symbolic and nonsymbolic number processing, and place learning in a virtual environment. These functional domains were investigated using tasks of proximity judgment and exact addition to assess neural correlates of symbolic number processing in 65 children (mean age ± SD = 9.45 ± 0.42 years), nonsymbolic number comparison at varying difficulties in 34 children (11.55 ± 1.15 years), and place learning in a virtual reality computer generated (CG) arena in 57 children (9.44 ± 0.42 years; 29 boys). In the symbolic number processing tasks greater prenatal alcohol exposure was related to less activation in the right horizontal intraparietal sulcus known to mediate mental representation and manipulation of quantity. Children with fetal alcohol syndrome and partial fetal alcohol syndrome appeared to compensate for this deficit by increased activation of the left angular gyrus during the proximity judgment task. Syndromal children with fetal alcohol syndrome or partial fetal alcohol syndrome also demonstrated poor recruitment of the right horizontal intraparietal sulcus during nonsymbolic number comparison, indicating that mental representation and manipulation of quantity are impaired in children with heavy prenatal alcohol exposure, irrespective of the representation format used. This impairment was compensated for by the left angular gyrus, with only exposed children needing to recruit the left angular gyrus to a greater extent as number comparison task difficulty increased. Further, reduced activation of the right posterior superior parietal lobule in children with increasing prenatal alcohol exposure suggests that exposed children may be less able to employ the attentional systems associated with number processing. Notably, activation of nonsyndromal heavily exposed children was impaired in the right posterior superior parietal lobule, but spared in the right horizontal intraparietal sulcus. In boys only, prenatal alcohol exposure was associated with poorer place learning and reduced activation during place learning in the precuneus and posterior cingulate, as well as parahippocampal gyrus, frontal and temporal lobes, caudate, insula, claustrum, lentiform nucleus and thalamus. In girls, prenatal alcohol exposure was not associated with place learning performance or activation during place learning in any regions. These results confirm that boys and girls use different navigation strategies that rely on different brain regions and suggest that the regions used by boys are more susceptible to alcohol damage, while the regions used by girls are relatively spared. In conclusion, all the tasks investigated showed prenatal alcohol exposure related alterations in parietal function, with the impairments being widespread throughout the parietal lobe bilaterally. Notably, activation of the bilateral precuneus was affected by prenatal alcohol exposure in both the spatial navigation and nonsymbolic number comparison tasks. It is possible that this is a key region linking the deficits in number processing and visuospatial skills in children with prenatal alcohol exposure.

The goal of this study was to examine differential effects of amount and pattern of prenatal alcohol exposure on child outcome. Alcohol use was assessed at each prenatal visit, and IQ and behavior were measured at age 7 years. After control for confounders, the amount of exposure was unrelated to IQ score and behavior for >500 black 7-year-old children. However, children who were exposed to binge drinking were 1.7 times more likely to have IQ scores in the mentally retarded range and 2.5 times more likely to have clinically significant levels of delinquent behavior. During prenatal care, clinicians should attend not only to amount but also to the pattern of alcohol intake, because of the elevated risk for cognitive deficits and long-term behavioral abnormality.

Objectives Prenatal alcohol exposure can lead to fetal alcohol spectrum disorders (FASD), which include a broad range of cognitive, growth, behavior, and physical abnormalities. Early detection of the teratogenic effects of prenatal alcohol exposure is necessary to identify early interventions. The aim of this study is to identify the effects of prenatal alcohol exposure on growth and infant development, to determine if ultrasound imaging can be used as an early identification tool, and to determine if maternal folate supplementation can mitigate the detrimental effects on growth and infant development. Methods A prospective cohort study and randomized trial from 2008 to 2014 conducted in two sites of Western Ukraine was analyzed. A sample of pregnant women who reported moderate-to-heavy alcohol consumption during pregnancy, and a sample reporting little-to-no alcohol use during pregnancy participated in a comprehensive maternal interview and screening process. Women were further randomized into micronutrient supplementation groups. Standard ultrasound examinations during pregnancy including study specific brain growth measurements, along with blood and urine samples were obtained during follow-up visits. A biometric screening was conducted at birth, along with Bayley Scales of Infant Development-II Mental Development Index (MDI) and Psychomotor Development Index (PDI) assessments at 6 and 12 months of age. Results Estimated fetal weight (EFW), abdominal circumference (AC), biparietal diameter (BPD), transverse cerebellar diameter (TCD), occipitofrontal diameter (OFD), caval-calvarial distance (CCD), and orbital diameter (OD) were significantly reduced by alcohol exposure at third trimester ultrasound (p2(7)=18.044, p=0.012), AC at third trimester (X2(5)=17.955, p=0.003), and birth weight (X2(6)=75.058, p2(11)=63.051, p Conclusions Significant reductions in fetal growth measurements during third trimester ultrasound suggest that the effects of prenatal alcohol exposure may be detectable in late pregnancy. Significant associations between multivitamin supplementation and specific growth measurements suggest that micronutrient supplementation during pregnancy, including high doses of folate, may be an early intervention to reduce the harmful effects of prenatal alcohol exposure. Further studies are needed to identify the specific micronutrients producing these effects, and to assess the appropriate level of these micronutrients necessary to provide the greatest benefit without exceeding the safe limit.

No description available.

Interrogative suggestibility refers to the extent to which an individual internally accepts messages communicated during a formal questioning situation, as indicated by an external response. Research indicates low intelligence, poor memory and weak inhibitory control is associated with heightened suggestibility. Children with fetal alcohol spectrum disorder (FASD) may also display deficits in these key areas, indicating a potential vulnerability to suggestion. The present study compared levels of suggestibility among alcohol exposed and typical children. The findings indicate that children with FASD may be at heightened risk to suggestion following negative feedback or pressure. In addition, a large amount of the suggested material was elicited and internalized as truth by all children, dependent on question format. These findings have important consequences for future interrogative interactions with children with and without FASD, to ensure information is not presented and thus elicited in a suggestive manner. / Graduate

Prenatal alcohol exposure (PAE) is associated with a range of physical, growth, and neurobehavioral deficits characteristic of individuals with fetal alcohol spectrum disorders (FASD). Although declarative memory impairment is a key feature of the neurocognitive profile of FASD, the mechanisms underlying this deficit require further clarification. The aim of this cross-sectional research was to examine, both directly and indirectly (via bottom-up and top-down processes), a critical cognitive mechanism that supports successful declarative memory functioning (viz., memory encoding), in children with FASD. Data were collected from a sample (N = 88) of South African children with and without PAE. In Study I, I used a blocked design functional magnetic resonance imaging (fMRI) paradigm to investigate neural activation during visual perception, a lower-order cognitive process essential to memory encoding. The task elicited bilateral category-specific activation during the visual perception of objects and scenes in all participants. The absence of between-group differences suggests that functional recruitment of brain regions during basic visual perception is less susceptible to the effects of PAE than during higher-order processes supporting memory encoding. In Study II, I used an event-related fMRI paradigm to investigate neural activation during memory encoding itself. All participants demonstrated similar memory performance accuracy and recruited extensive bilateral networks during memory encoding. However, participants with a diagnosis of fetal alcohol syndrome (FAS) or partial FAS (PFAS) activated additional regions associated with attentional function. Within the FAS/PFAS group, higher exposure levels were associated with smaller activation increases in the parahippocampal gyri and greater activation increases in the right hippocampal formation during encoding. Data from this study therefore suggest that children with FAS/PFAS recruited more extensive neural resources to support successful memory encoding during this task. In Study III, I used a behavioral source memory paradigm to investigate higher-order executive processes essential for memory encoding. Despite similar recognition accuracy across all diagnostic groups, participants in the FAS/PFAS group showed impaired memory for source details. This pattern of impairment was only partially mediated by working memory performance. These three studies provide novel clarification of the neural and cognitive mechanisms underlying declarative memory impairments in children with FASD.

Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Externalizing disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have a high prevalence rate in both children of alcoholics and in those with prenatal alcohol exposure (PAE). These disorders are also predictors of alcohol dependence (alcdep), heritable, and share an underlying genetic liability with alcdep. Furthermore, a mother who drinks while pregnant is likely to be alcohol dependent (AD), and vice-versa. This study incorporated these factors into one model, including as well as a measure of broad genetic risk for ADHD and alcdep to test for the contributions of these effects simultaneously. An independent sample was used to confirm the results for PAE and broad genetic risk. The hypothesis is that PAE will increase the risk to ADHD but not to CD or ODD. Methods: Each of these factors was evaluated independently to test if that effect on its own, significantly contributed to each disorder. Another model included several demographic covariates, to determine which of these environmental effects also contributed to the disorder. The final model for each disorder included environmental effects along with the primary effects of interest. Results: PAE resulted in increased risk for the inattentive (INATT) sub-type of ADHD and conduct disorder (CD) in the discovery sample and for the hyperactive-impulsive (HYPIMP), INATT and CD in the replication sample. PAE and the PAE*maternal alcohol dependence interaction increased the risk for ADHD and INATT. A broad genetic risk for ADHD was associated with all disorders except HYPIMP in the replication sample. Conclusion: This study further supports the trending evidence of a unique etiology of ADHD in those with PAE, and more specifically, that INATT and HYPIMP are affected according to two different mechanisms of action, independent of a genetic contribution due to either ADHD or alcohol dependence, both of which also were associated with a risk for INATT. The contribution of PAE to INATT and CD were the only consistent results across all definitions of alcohol exposure and in both datasets, indicating that PAE is a veritable risk for INATT and CD.

Abstract: Background: Fetal Alcohol Syndrome (FAS), located on the severe end of a spectrum of disorders known as Fetal Alcohol Spectrum Disorders (FASDs), is one of the most detrimental, and publicized, teratogenic outcome of alcohol consumption during pregnancy within the United States. During pregnancy, alcohol that is consumed by the mother passes through the placenta and transfers to the baby via the umbilical cord. The same prenatal transference of alcohol that leads to FAS and FASDs might also be contributing to an increased likelihood of hypertension in youth. Additionally, factors such as stress influenced by familial instability, an increased likelihood of developing congenital and conotruncal heart defects, and a reduction in nephron count might be leading to an increased likelihood of hypertension in FAS-affected youth. The purpose of this study is to examine the relationship between prenatal exposure to alcohol, manifested through FAS, and hypertension in children, adolescents, and young adults. Methods: A case-control study design was incorporated to analyze the association between FAS status and hypertensions status; cases (n=165) were collected from a FAS clinical database in Atlanta, Georgia. Controls (n=177) were taken from the National Health and Nutrition Examination Survey (NHANES). Chi-square analyses were used to examine the extent to which FAS status, sex, race/ethnicity, medication use, and obesity status each relate to hypertension status. A logistic regression was performed analyzing the relationship between FAS status (y/n: independent) and hypertension status (y/n: dependent) whilst controlling for sex, race/ethnicity, medication use, and obesity status. Results: The univariate relationships between FAS status and hypertension status (OR=4.491, p<.001) as well as medication use and hypertension status (OR= 2.951, p=.002) proved to be statistically significant (p<.05). Through the regression, FAS status significantly predicted hypertension status (β = 1.646, OR = 5.184, p< .001) after accounting for sex, race/ethnicity, medication use, and obesity status. Those with a race/ethnicity categorized as either Non-Hispanic African American (β =1.259, OR = 3.523, p = .049) or Hispanic (β = 1.192, OR = 3.294, p = .061) were significantly more likely to have hypertensions than those categorized as non-Hispanic Caucasian. Conclusion: The major findings of this study suggest a significant relationship between FAS and hypertension in youth. Race/ethnicity also proved important in predicting hypertensive blood pressure readings independent of FAS diagnosis. The most obvious biological mechanism catalyzing the relationship between FAS and hypertension is prenatal alcohol exposure. Because prenatal alcohol exposure is the primary definitional and diagnostic factor of FAS, associative connectivity may exist independently between prenatal alcohol exposure and blood pressure at various levels of severity along an alcohol exposure dose-response spectrum. Further research is needed to isolate and measure the effect that prenatal alcohol exposure has on blood pressure independently of FAS as well as to assess the extent to which the risk for hypertension in alcohol-affected individuals increases with age and through the life course.

In this thesis I evaluate the impact of an experiment with free sales of strong beer in two Swedish counties that took place in the 1960s. I do this by studying adult earnings of persons in utero during the experiment. My data includes date and place of birth and allows me to evaluate the impact of the experiment using a difference-in differences methodology, comparing earnings across cohorts and counties. Since the availability of alcohol increased most heavily for persons under the age of 21, and male fetuses are less physiologically robust than female fetuses, I choose to study persons born by mothers younger than 21 separately and also estimate the impact of the experiment separately for men and women. I find that persons born by mothers under the age of 21 during the experiment have lower average earnings than persons born before the experiment, and that the impact is larger on men. My results indicate that the experiment has led to adverse effects on adult earnings, probably caused by the prenatal alcohol exposure’s negative impact on fetal development. This means that alcohol consumption have long-term consequences that represent large costs to society. Since these costs are generally disregarded when evaluating the cost of alcohol consumption, society’s cost of alcohol is probably higher than usually estimated.