Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vii, 146 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

Thesis (MA)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: The objective of this thesis is to review and synthesize the scientific literature on cognitive and neuropsychological deficits associated with children who were exposed to alcohol prenatally and to highlight possible areas of future attention. High incidences of Fetal Alcohol Syndrome has been reported especially in patients from low socio-economic areas. The highest reported incidence is found in the Western Cape province in South Africa. The devastating part of FAS is that its affects are entirely preventable. Alcohol is a physical and a behavioural teratogen. Prenatal alcohol exposure causes structural damage to the central nervous system and the brain that is vulnerable throughout the pregnancy. A dose-response association exist as exposure to heavier amounts of alcohol can cause more harm. The timing and pattern of alcohol consumption also plays a role. To date though, no "safe" level of alcohol consumption during pregnancy can be advocated. Various neuropsychological decrements are found in individuals with fetal alcohol syndrome or alcohol related neuro-developmental deficits as evaluated on standardized tests. Mental retardation is commonly found and even individuals with normal IQ's still display other learning disabilities. IQ's remain stable over the life span. Along with impaired intellectual functioning they also struggle with mathematical tasks especially as their complexity increases. Speech and language development is also delayed in individuals with FAS. There is little variation in the pith and display poor language comprehension. Attentional deficits are also noted and especially impact on academic functioning. Clinically, children often present with ADHD but in-depth studies have revealed that neurobiologically there is some differences as children with FAS struggle more with encoding and shifting of attention as opposed to other patients with ADHD. Difficulties with visual-spatial functioning has also been found. Verbal learning and memory are also impaired in individuals with FAS. Their poor verbal learning are influenced by their shallow level of encoding. Problems with fine motor skills are also noted. It also appear that all executive functions are impaired. They demonstrate poor planning skills, initiation, cognitive shifting, slow information processing, their thinking is concrete and they have poor self-regulatory skills. Behavioural problems include impulsivity, hyperactivity, aggressiveness, poor social skills and impaired judgement. Early intervention is thus essential to lessen the impact of neuro-psychological deficits on functional adaptation. A sensitive battery of neuro-psychological tests are also required to identify all the impairments in affected individuals and to plan more focussed intervention strategies. / AFRIKAANSE OPSOMMING: In hierdie tesis word 'n oorsig aangebied van literatuur wat betrekking het op die disfunksie van kinders wie se moeders tydens swangerskap alkohol misbruik het. Leemtes asook moontlike areas van toekomstige navorsing, is bespreek. 'n Hoe voorkoms van fetale alkohol sindroom (FAS) word gerapporteer, pasiente uit die lae SES gebiede. Die hoogste voorkoms word gerapporteer in die Wes- Kaapse provinsie in Suid Afrika. Wat die probleem meer tragies maak, is die feit dat dit heeltemal voorkombaar is. Alkohol is 'n teratogeen wat fisieke, neurologiese en gedragsimplikasies het. Blootstelling aan alkohol voor geboorte veroorsaak strukturele veranderinge in die sentrale senuweestelsel en die brein. Blootstelling tot hoer volumes van alkohol veroorsaak noodwendig meer skade. Die spesifieke stadium van alkohol-inname tydens die swangerskap, en die moeder se drinkpatroon, speel 'n rol in die neurosielkundige uitkomste. Tot op hede kon geen veilige alkoholsvlak tydens swangerskap vasgestel word nie. Verskeie neurosielkundige uitvalle is gevind in kinders met FAS en ook kinders met alkohol-verwante neurologies ontwikkelings probleme, volgens neurosielkundige toetsing. Verstandelike gestremdheid kom algemeen voor in kinders met FAS. Kinders met FAS wat oor normale intellektuele vernoens beskik ervaar leerprobleme. Die intellektuele inkortings bly stabiel oor die lewenspan. Kinders met FAS ondervind erge probleme met wiskunde, veral wanneer die werk moeiliker raak. Die spraak-en taalontwikkeling wat kinders met FAS ervaar sluit in beperkte taalbegrip en intonasie. Hulle kort aandagspan affekteer veral hulle akademiese funksionering. Die aandagsteuring van kinders met FAS en kinders met aandagstekort-hiperaktiwiteit versteuring verskil neuro-biologies. Verdere verskille bestaan ook aangesien kinders met FAS spesifiek sukkel met swak enkoderingsvermoe en om kognitiewe aanpassings te maak. Visueel-ruimtelike verrnoe van kinders met FAS is ook benadeel. Hulle sukkel ook met verbale leer en hulle geheue is ook ingekort. Die inkortings dui op 'n oppervlakkige enkoderingsvermoe. Probleme met fyn-motoriese vaardighede is ook gevind, volgens toetseing. Toetse wat gemik is om uitvoerende funksies te evalueer, het verskeie uitvalle aan die lig gebring. Probleme in abstrakte redenering, beplanning, impulsiwiteit, self-regulering, en die lnlslerlnq en prosessering van informasie. Gedragsprobleme soos swak sosialiseringsvaardighede, aggresiwiteit, swak oordeel en hiperaktiwiteit. Die wye neurosielkundige uitvalle wat voorkom in kinders met FAS noodsaak vroee intervensie om die langtermyn-impak daarvan te verminder. Hiervoor word 'n sensitiewe battery neurosielkundige toetse benodig wat al die kognitiewe uitvalle kan identifiseer.

Alcohol use during pregnancy is common and its consequences often result in a broad range of negative, lifelong developmental outcomes. This study describes the effects of prenatal alcohol exposure and interacting socio-demographic factors on early childhood development. One hundred and twenty one children from the Northern Cape, South Africa, were clinically examined using standard diagnostic procedures and assessed using the Griffiths Mental Development Scales (GMDS/ER) at 7-12 months (Time 1) and 5 years of age (Time 2). Participants were assigned to either: a Fetal Alcohol Syndrome (FAS/Partial Fetal Alcohol Syndrome (PFAS); a Prenatal Alcohol Exposed (PAE); or a Control group based on the diagnosis at 5 years. Mothers/caregivers were interviewed to ascertain socio-demographic information, including prenatal alcohol exposure. During infancy, the FAS/PFAS group showed significantly lower gross motor and language abilities, with delays in higher-order executive functioning becoming more apparent with age. No significant differences were noted during infancy between the PAE and Control groups over any developmental subscales. However, with age, higher-order executive function delays were reported in the PAE group. Performance on the infant and child versions of the GMDS was not significantly correlated, suggesting that the tests may be measuring different developmental constructs. Lower maternal education, unemployment and later recognition of pregnancy were associated with reduced social adaptive functioning, and language and eye hand coordination abilities, irrespective of amount of prenatal alcohol exposure over both time points. Larger anthropometric birth measurements and longer duration of breastfeeding were significantly related to increased performance on the GMDS at 5 years within the groups exposed to prenatal alcohol. Socio–demographic variables are likely to complicate developmental profiles for all three groups, with prenatal and postnatal nutrition emerging as possible protective factors for positive developmental outcomes at 5 years of age.

Fetal alcohol spectrum disorders (FASD), caused by maternal alcohol consumption during pregnancy, has been extensively studied in the human. Animal studies show that alcohol exposure during very early development may result in severe brain damage, often incompatible with a postnatal life. However, for surviving offspring it is unknown whether they suffer long term brain damage. The final assembly of the mature brain results from a controlled balance between proliferation of glial and neuronal precursors and programmed cell death. The overall aim of the current study was to use a physiologically relevant mouse model to assess the acute and long-term effects of binge alcohol exposure on the early embryo, to simulate human pregnancy at the third week of gestation when pregnancy may be undetected. A number of paradigms were used to assess the acute dose-response effect, the blood alcohol concentration (BAC) profile and the extent of cell death following alcohol exposure on gestational day (G) 7.5. The exposure paradigms were single binge IG6.5, IG4.5, IP4.5, or an extended binge IG4.5+, IG3.0+. Two control groups were Con6.5 and Con4.5+. Acute cell death was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), activated caspase-3 staining, and transmission electron microscopy. Cell proliferation was investigated using S-phase immuno-labeling, bromodeoxyuridine (BrdU) birthdating and immuno-detection (BrdU/anti-BrdU). The long-term effects were investigated at G18.5 and postnatal day (PN) 60. Unbiased stereological methods were used to assess the effect of ethanol exposure at G7.5 on neocortical volume, cell number and density of neurons, glial cells, and capillary cells at PN60. The first principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute apoptotic cell death in the ectoderm of the mouse embryo. Cell death was dependent on both peak BAC and the duration of elevated BAC. Significant increased cell death (TUNEL labeling) was observed in groups IG6.5 (9.43 � 2.08%) and IG4.5+ (8.97 � 2.12%) compared with control groups Con6.5 (2.14 � 0.09%) and Con4.5+ (2.81 � 0.36%). There was no significant increased cell death in ethanol exposed groups IG4.5 (3.43 � 0.45%), IP4.5 (3.68 � 0.67%), or IG3.0+ (1.72 � 0.24%). TEM analysis revealed that cell death exhibited characteristics of the apoptotic pathway. The second principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute arrested proliferation in the ectoderm of the mouse embryo. The S-phase proliferation was significantly decreased within the whole ectoderm in the ethanol exposed group IG6.5 (45.58 � 2.34%) compared with control group Con6.5 (62.08 � 3.11%). The third principal finding of the present study was that binge ethanol exposure during gastrulation induced the long term effect of laminate disorganization in the neocortex. The incidence of abnormal lamination was 87.5% in IG6.5 compared with 16.7% in IG3.0+ and 14.3% in Con6.5. Although ethanol exposure increased embryonic reabsorption, decreased litter size, and increased abnormal offspring, neocortical volume, and the total number of neurons, glial cells, and capillary cells was not affected. The total number (10⁶) of neurons, glial cells, and endothelial cells respectively was 12.221 � 0.436, 4.865 � 0.167, and 2.874 � 0.234 in IG6.5; 11.987 � 0.416, 4.942 � 0.133, and 2.922 � 0.130 in IG3.0+; and 11.806 � 0.368, 5.166 � 0.267, and 3.284 � 0.217 in controls, at PN60. These results provide important information pertinent to fetal outcome for those women who drink heavily in early pregnancy. The results also demonstrate the importance of the pattern of ethanol exposure and blood alcohol concentration in determining the magnitude of ethanol�s teratogenic impact. Ethanol exposure on G7.5 that resulted in a high transient BAC, induced disorganized neocortical lamination, indicative of a permanent structural change. This disruption may result in altered neocortical function and requires further investigation.

This study described the hospital morbidity of 194,persons with Fetal Alcohol Syndrome (FAS), born between 1973-1992, who were identified through a major referral center for Saskatchewan children with disabling conditions. Computerized provincial hospital separation data were obtained for 84% of 101 males and 77% of 93 females. Complete hospitalization histories were obtained for 128 patients, and partial histories for 29 patients. This data provided information on 1,556 hospitalizations from January 1, 1973 to November 30, 1992. At least 54% of study group members experienced morbidity as newborns, and 83% of all females and 91% of all males had experienced at least one other hospitalization (excluding the newborn stay) during their life (based on provincial data combined with information from patient follow-up and record reviews). By November 1992 (provincial data only), the mean number of hospitalizations (SD) for males and females age 15-19 years was 8.4 (7.0) and 10.2 (8.1), respectively. For children <5 years the mean (SD) was 6.0 (5.8) for males and 3.1 (4.7) for females. Age and sex-specific hospital separation rates for the FAS group (based only on provincial data pooled from fiscal years 1987-91) were compared to the 1989-90 Saskatchewan rates. The 95% confidence intervals for the rate ratios indicated significantly higher rates for both males and females with FAS <1 year, 1-4 years and 5-14 years of age, relative to children in general. Comparisons were made using Saskatchewan Registered Indian rates, since 88% of the study group was Aboriginal. The 95% confidence intervals indicated significantly higher rate ratios for males with FAS in all age groups, and for females with FAS age 5-14 years, relative to Registered Indians. The rate ratios for females <1 year and 1-4 years may not have achieved significance because of a possible bias toward underestimation, given the higher proportions of missing data in these groups. The results suggest the high rates of hospitalization in children with FAS are not explicable solely by factors associated with racial identity or ethnicity.

This study described the hospital morbidity of 194,persons with Fetal Alcohol Syndrome (FAS), born between 1973-1992, who were identified through a major referral center for Saskatchewan children with disabling conditions. Computerized provincial hospital separation data were obtained for 84% of 101 males and 77% of 93 females. Complete hospitalization histories were obtained for 128 patients, and partial histories for 29 patients. This data provided information on 1,556 hospitalizations from January 1, 1973 to November 30, 1992. At least 54% of study group members experienced morbidity as newborns, and 83% of all females and 91% of all males had experienced at least one other hospitalization (excluding the newborn stay) during their life (based on provincial data combined with information from patient follow-up and record reviews). By November 1992 (provincial data only), the mean number of hospitalizations (SD) for males and females age 15-19 years was 8.4 (7.0) and 10.2 (8.1), respectively. For children <5 years the mean (SD) was 6.0 (5.8) for males and 3.1 (4.7) for females. Age and sex-specific hospital separation rates for the FAS group (based only on provincial data pooled from fiscal years 1987-91) were compared to the 1989-90 Saskatchewan rates. The 95% confidence intervals for the rate ratios indicated significantly higher rates for both males and females with FAS <1 year, 1-4 years and 5-14 years of age, relative to children in general. Comparisons were made using Saskatchewan Registered Indian rates, since 88% of the study group was Aboriginal. The 95% confidence intervals indicated significantly higher rate ratios for males with FAS in all age groups, and for females with FAS age 5-14 years, relative to Registered Indians. The rate ratios for females <1 year and 1-4 years may not have achieved significance because of a possible bias toward underestimation, given the higher proportions of missing data in these groups. The results suggest the high rates of hospitalization in children with FAS are not explicable solely by factors associated with racial identity or ethnicity.

This study investigated the effect of chronic alcohol exposure on the responses of the maternal hypothalamus-pituitary adrenal axis (HPA-axis) and thyroid hormones throughout gestation using an ovine model. Maternal plasma concentrations of ACTH, cortisol and the thyroid hormones T3, free T4 and total T4 were determined in response to infusion of 0.75, 1.25 and 1.75 g/kg alcohol. Maternal endocrine responses to alcohol administration have been investigated before in rodent models. However, this is the first study using a large animal model (sheep), in which all three human trimester equivalents occur in utero. Different concentrations of alcohol were administered intermittently from gestational day 4 to 132 in a pattern that modeled human binge drinking during pregnancy. Maternal blood samples were collected on specific days (GD 6, 40, 90, 132) and at multiple time-points (0, 0.5, 1, 1.5, 2, 6, 24 hours) and were analyzed to determine blood alcohol concentrations (BACs) and ACTH, cortisol, free T4, total T4 and T3 plasma concentrations. Alcohol readily permeates the placenta and can directly affect fetal cells and tissues. Alcohol also causes endocrine imbalances in the mother and interferes with maternal-fetal hormonal interactions and the mother’s ability to maintain a healthy pregnancy, thus also indirectly affecting fetal development. Sheep receiving either 0.75, 1.25 or 1.75 g/kg alcohol achieved peak BAC values of 93 + 5, 126 + 5 and 183 + 5 respectively. Alcohol exposure resulted in increased plasma ACTH and cortisol concentrations peaking at 2 hours after beginning of the infusion and returning to baseline values at 6 hours after beginning of the infusion. There was no effect of alcohol on any of the plasma thyroid hormone concentrations. Thyroid hormone concentrations changed as a result of progressing pregnancy. Plasma concentrations of total T4 and free T4 were higher on gestational days 6 and 40 compared to GDs 90 and 132, and plasma T3 concentrations were highest on GD 6. The results of this study show that alcohol stimulates the HPA-axis in a dose dependent fashion in pregnant sheep. The response of the HPA-axis to repeated alcohol exposure throughout gestation remained unchanged. Alcohol exposure did not affect the release of thyroid hormones. Thyroid hormone concentrations changed during pregnancy in sheep in a manner similar to changes observed in pregnant women.

Alcohol consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), which encompass a range of physical, behavioral, learning, emotional and social disturbances. Many mechanisms for this array of alcohol-derived fetal injuries have been proposed, but none fully accounts for the deficiencies observed. Alcohol is a ubiquitous drug that may affect the brain at any or all stages of development and at multiple sites; regional differences in vulnerability of different brain structures during different periods of exposure have been demonstrated. This study investigates possible mechanisms for the alcohol induced neurodevelopment damage seen as a result of prenatal alcohol exposure, and also includes evaluation of a potential intervention strategy (glutamine). These experiments all utilized the sheep model, which has distinct advantages over the rodent model for third trimester-equivalent studies (a time of increased vulnerability to the effects of alcohol). The fetal hippocampal formation (pyramidal cells in the CA1 and CA2/3 fields and granule cells of the dentate gyrus) and olfactory bulb (mitral cells) have been altered in response to alcohol exposure in rodent model studies. This study examined the effects on the fetal hippocampal formation and olfactory bulb in response to all three trimester-equivalent alcohol exposure in the sheep model, a species in which the third trimester-equivalent occurs in utero (as opposed to post-natal as occurs in the rodent). It is known that both maternal and fetal cortisol levels increase in response to alcohol. The role of cortisol in mediating fetal cerebellar Purkinje cell loss (known to occur with alcohol exposure) was analyzed. Lastly, the availability of circulating amino acids, both maternal and fetal, in response to alcohol are reported. The results of administration of a single acute dose of glutamine to the ewe, concurrent with alcohol, was evaluated for its ability to prevent the amino acid and pH perturbations known to occur in response to alcohol.

Thesis (Ph.D.)--Brown University, 2008. / Vita. Advisor : Suzanne M. de la Monte. Includes bibliographical references.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references (leaves 92-105). / Also available by subscription via World Wide Web / xv, 105 leaves, bound ill. 29 cm