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.

Structural brain changes occur in a complex manner throughout life, and understanding healthy brain development is crucial for the study of brain abnormalities in various conditions. Diffusion tensor imaging (DTI) is an advanced magnetic resonance imaging technique that provides information about tissue microstructure not accessible via conventional imaging methods. In this dissertation, DTI is used to assess typical brain development, brain abnormalities in fetal alcohol spectrum disorder (FASD), and relationships between cognition and brain structure in both populations. Cross-sectional and longitudinal DTI studies were used to measure brain maturation from childhood to adulthood. Significant, nonlinear changes of diffusion parameters were noted across the brain, with regional variation in the timing and magnitude of development. Most regions experienced rapid maturation during childhood and adolescence, reached a developmental peak during adulthood, and then, during senescence, underwent a reversal of structural changes that occurred more gradually than the initial development. The genu and splenium of the corpus callosum had the earliest development, while frontal-temporal connections and the corticospinal tracts showed the most prolonged maturation trajectories. DTI was also used to examine brain abnormalities in children with FASD, an acquired brain disorder associated with numerous cognitive, behavioural, and emotional difficulties. DTI revealed widespread differences in children with FASD when compared to healthy controls, suggesting extensive structural brain damage. Finally, significant relationships between cognitive abilities and brain structure were observed in both populations. Brain lateralization of a frontal-temporal pathway correlated with two specific cognitive abilities in typically-developing children. Additionally, a significant relationship between brain structure and mathematical ability was observed in the left parietal lobe of children with FASD. Preliminary results demonstrating reading-brain structure correlations in both healthy and FASD groups are also presented. In conclusion, DTI has shown significant age-related changes in the typically-developing human brain, abnormalities in children with FASD, and correlations between brain structure and cognition in both populations. Normative DTI studies such as the ones presented here are important to establish healthy milestones of brain development and degradation, which may then be used to understand abnormalities in a variety of conditions, including FASD.

This thesis examines the experiences of parents who are raising their adopted children who have Fetal Alcohol Effects (FAE). Four married couples, and one single mother, who married after she had raised her sons participated in this study. All are white and middle or upper-middle class. Five adoptive mothers and one adoptive father were interviewed, while their spouses contributed to the study by reviewing the interview transcripts, and discussing issues raised within them. Eight children with diagnosed or suspected FAE are discussed. They are Cree or Saulteaux, and are between the ages of nine and 23 . Through multiple in-depth interviews, and the demographic profile form, richly detailed information was recorded on these families' day-to-day lives: the children's school experiences, learning disabilities and behaviour problems, their strengths, their health and interactions with peers; parents' interactions with professionals, treatments and behaviour management strategies they sought or devised, their use of support groups and other forms of social support and encounters with the criminal justice and mental health systems. <p> Grounded theory methodology was used to analyse the data and a conceptual model was constructed to outline the process of redefining parenting which describes the practical and psychological tasks parents perform as the family evolves over time. A central role is taken by the mothers who become advocates for their children as they undertake a quest for the meaning of their children's behaviour, seek a diagnosis, and try to secure services for them. It was found that people with FAE are misunderstood and misdiagnosed because of their anomalous nature, which often leads to stigmatisation. This thesis attempts to dispel these misconceptions, document the parents' and children's struggles, and identify the types of services these families desperately need.

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.

Background: Sleep disorders have been poorly described in children and adolescents diagnosed with FASD. The objective of this study is to describe the sleep and circadian rhythm characteristics of children with FASD using overnight polysomnography, sleep questionnaires, and the Dim Light Melatonin Onset (DLMO) test. To our knowledge, no comprehensive studies of this nature have been conducted. Methods: Children ages 6-18 years diagnosed with Fetal Alcohol Spectrum Disorder (FASD) were recruited from various FASD clinics to the Youthdale Child and Adolescent Sleep Centre in Toronto. After medical consultation, each participant had one night of overnight polysomnography, as well as an additional night of DLMO. Participants completed various sleep and FASD questionnaires. Results: Significant differences were found when comparing the sleep architecture of FASD participants to normative data. There was a high prevalence of sleep disorders in this sample. Most of the melatonin profiles of the FASD participants were found to be abnormal.

Background: Sleep disorders have been poorly described in children and adolescents diagnosed with FASD. The objective of this study is to describe the sleep and circadian rhythm characteristics of children with FASD using overnight polysomnography, sleep questionnaires, and the Dim Light Melatonin Onset (DLMO) test. To our knowledge, no comprehensive studies of this nature have been conducted. Methods: Children ages 6-18 years diagnosed with Fetal Alcohol Spectrum Disorder (FASD) were recruited from various FASD clinics to the Youthdale Child and Adolescent Sleep Centre in Toronto. After medical consultation, each participant had one night of overnight polysomnography, as well as an additional night of DLMO. Participants completed various sleep and FASD questionnaires. Results: Significant differences were found when comparing the sleep architecture of FASD participants to normative data. There was a high prevalence of sleep disorders in this sample. Most of the melatonin profiles of the FASD participants were found to be abnormal.

In this thesis I used Caenorhabitis elegans as a model of Fetal Alcohol Spectrum Disorder (FASD) to study the physical and behavioral effects of ethanol exposure during embryonic development. Davis et al. (2008) found that ethanol exposure during larval development in C. elegans produced physical/developmental and behavioral effects; however, whether exposure during embryonic development might produce similar outcomes remained to be elucidated. Because the type and degree of effects caused by developmental ethanol exposure was dependent on the pattern of ethanol treatment, in the first part of the thesis I investigated the physical/developmental effects of embryonic exposure to various ethanol doses, exposure durations, onsets and frequencies. I found that exposure to >30% ethanol for an hour during embryonic development was necessary to lower hatch rate, delay reproductive onset, and reduce body size in C. elegans. Furthermore, exposure during early embryonic development caused a larger effect than exposure during later stages, and multiple exposures produced a worse outcome than a single exposure for a comparable duration. In the second part of the thesis, I investigated locomotory activities and habituation of adult C. elegans exposed to various patterns of embryonic ethanol treatment. I found that the rate of locomotion was altered differently by chronic and acute embryonic ethanol exposure, but I did not find any effect in short- or long-term habituation. In summary, I have characterized the pattern of embryonic ethanol exposure necessary to produce physical/developmental effects in C. elegans, and identified the types of exposure conditions that would cause worse outcomes than others; in addition, I have found that embryonic ethanol exposure affects the rate of locomotion in C. elegans. In this thesis, I have established a foundation for the future investigation into the physical and motor defects caused by embryonic ethanol exposure in C. elegans.

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 thesis examines the experiences of parents who are raising their adopted children who have Fetal Alcohol Effects (FAE). Four married couples, and one single mother, who married after she had raised her sons participated in this study. All are white and middle or upper-middle class. Five adoptive mothers and one adoptive father were interviewed, while their spouses contributed to the study by reviewing the interview transcripts, and discussing issues raised within them. Eight children with diagnosed or suspected FAE are discussed. They are Cree or Saulteaux, and are between the ages of nine and 23 . Through multiple in-depth interviews, and the demographic profile form, richly detailed information was recorded on these families' day-to-day lives: the children's school experiences, learning disabilities and behaviour problems, their strengths, their health and interactions with peers; parents' interactions with professionals, treatments and behaviour management strategies they sought or devised, their use of support groups and other forms of social support and encounters with the criminal justice and mental health systems. <p> Grounded theory methodology was used to analyse the data and a conceptual model was constructed to outline the process of redefining parenting which describes the practical and psychological tasks parents perform as the family evolves over time. A central role is taken by the mothers who become advocates for their children as they undertake a quest for the meaning of their children's behaviour, seek a diagnosis, and try to secure services for them. It was found that people with FAE are misunderstood and misdiagnosed because of their anomalous nature, which often leads to stigmatisation. This thesis attempts to dispel these misconceptions, document the parents' and children's struggles, and identify the types of services these families desperately need.