Health at birth is considered an important indicator of health outcomes in adulthood. It is also shown to have a strong association with future educational attainment and labor market outcomes. I examine the effects of behavioral and environmental factors on infant health. The factors I focus on include alcohol consumption during pregnancy, extreme weather events associated with climate change, and pollution that may result from unconventional oil and natural gas development. In Chapter II, I examine the effects of point-of-sale alcohol warning signage that alcohol retailers are required to post in some states on alcohol use during pregnancy and on birth outcomes. I find that point-of-sale warning signs discourage alcohol consumption among pregnant women and are associated with a decrease in the odds of newborns having very low birth weight or being very pre-term. The findings of this research inform decision makers about a potentially effective mechanism through which alcohol consumption among pregnant women can be reduced. They also suggest causal evidence for the link between prenatal alcohol exposure and inferior health at birth. Chapter III documents that exposure to heat waves during pregnancy is associated with increased likelihood of the mother experiencing an adverse health condition during pregnancy and the newborn having an abnormal condition at birth. The results provide an assessment of the magnitude and timing of the effects of extreme heat events associated with climate change on infant health which is potentially helpful in enhancing the effectiveness of adaptation efforts. Finally, Chapter IV provides an empirical investigation of the link between unconventional oil and natural gas development and infant health. The results indicate that unconventional drilling activity is associated with a small, but statistically significant, decline in birth outcomes, especially for those living in rural areas. Given that it is estimated that the rapid expansion in unconventional oil and gas extraction will continue for at least a few more decades, the results of this study may contribute to the discussions related to initiation or tightening of regulations and monitoring efforts to control pollution. This dissertation includes previously unpublished co-authored material.

In 1996, the Institute of Medicine made an initial step towards addressing the confusion and controversy regarding the diagnosis of fetal alcohol syndrome (FAS) by proposing a classification scheme and calling for research to evaluate its validity and clinical utility. Previous research evaluated memory, executive functions, and behaviour problems in FAS. Prior to the present study, however, there had not been an empirical evaluation of the existence of a spectrum of diagnostic subgroups or an evaluation of subgroup functioning on neuropsychological components of attention during the pre-teen and adolescent years. Part 1 of this study used categorical data regarding diagnostic domains to determine if an a priori spectrum of four subgroups could be identified. This spectrum included FAS and three fetal alcohol effect (FAE) subgroups, which were defined using teratogenic theory, previous research findings, and logic. The sample consisted of 112 children with a confirmed history of excessive prenatal alcohol exposure. Part 2 evaluated the continuity and comparability of the CNS dysfunction subgroups exhibited by assessing neuropsychological components of attention using models by Mirsky and Conners. The sample consisted of 30 children and subgroups were matched on age, sex, and living situation. Results identified 3 of the 4 potential subgroups. All subgroups exhibited a clinically significant attention deficit. After adjusting for IQ, the FAS and FAE subgroups had comparable levels of functioning on all components of attention with one exception. On the sustain component, the FAE subgroups had more difficulties than the FAS subgroup in maintaining a consistent response-speed in response to changes in the length of time between targets. This study provides empirical and theoretical support for the validity and clinical utility of a spectrum of fetal alcohol subgroups consistent with the IOM's classification. It furthers a theoretical understanding of the dose-response effects of alcohol as a teratogenic agent. It suggests that attention regulation functions are especially vulnerable to the damage caused by prenatal alcohol exposure. The findings emphasize the importance of obtaining a history of prenatal alcohol exposure in individuals presenting with neuropsychological difficulties, and developing treatment programs for pregnant women with an alcohol addiction.

Maternal consumption of alcohol during pregnancy can induce a range of behavioral and cognitive deficits in offspring, which are collectively termed Fetal Alcohol Spectrum Disorders (FASD). There are significant delays in motor development and sensory-motor skills in children with FASD, but the underlying neurobiological mechanisms of these deficits are poorly understood. The goal of this research project is to test the hypothesis that the Kinesiological Instrument for Normal and Altered Reaching Movements (KINARM) will serve as an effective tool for identifying and measuring specific, neurologically-based motor deficits in children with FASD. These deficits were revealed through investigation of multi-joint upper limb movements during the performance of sensory-motor tasks. Children (31 FASD; 83 controls, aged 5 to 18 years, male and female) performed: (1) a visually-guided reaching task with fingertip feedback only; and children (31 FASD; 49 controls, aged 5 to 18 years, male and female) performed: (2) an arm position-matching task in the absence of visual feedback. Children with FASD differed significantly from controls in many reaching task outcome measures, specifically those related to the initial motor response and corrective responses. In particular, large effect sizes were observed for outcome measures related to the first (initial) movement (corresponding to feedforward control; e.g., direction error; distance error), as well as for those measures related to corrective responses (corresponding to feedback control; e.g., difference between minimum and maximum hand speeds; number of speed peaks during movement). In the position-matching task, children with FASD constricted the spatial workspace of the subject-controlled arm relative to the robot-controlled arm, in the horizontal axis. There was also observed a systematic shift between the subject- and robot-controlled arms in the XY end position, resulting in significant error. Additionally, children with FASD exhibited significantly increased trial-to-trial variability for final hand position of the subject-controlled arm, over all targets, and for which large effect sizes were observed. The results suggest that children with FASD have difficulty integrating sensory information into planned motor movements. The KINARM is a promising research tool that may be used to assess motor control deficits in children affected by prenatal exposure to alcohol. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-09-02 15:10:25.653

The cognitive and/or behavioural problems associated with Fetal Alcohol Spectrum Disorder (FASD) place this population at increased risk of involvement in the justice system. Although FASD poses challenges at each stage of the justice system, legal discussion and commentary have pinpointed the sentencing stage as the phase in which the issue of FASD is most commonly raised and considered. The purpose of this study is to examine if (and how) FASD is being taking into consideration at sentencing. To this end, a comparative analysis of 87 sentencing judgments (42 FASD offenders and 45 non-FASD offenders) reported in Quicklaw was conducted. Cases were matched on most serious offence (assault, robbery and sexual assault) and jurisdiction (Yukon, British Columbia and Ontario). Descriptions of FASD and non-FASD offenders as reported by judges were found to differ in a number of significant ways. Similarly, sentencing purposes applied to each offender group emerged as distinct. Despite these distinctions, no differences were found in the type and length of sentence handed down (even after controlling for criminal record and breaches). These findings indicate a need for further research and possible policy changes.

The cognitive and/or behavioural problems associated with Fetal Alcohol Spectrum Disorder (FASD) place this population at increased risk of involvement in the justice system. Although FASD poses challenges at each stage of the justice system, legal discussion and commentary have pinpointed the sentencing stage as the phase in which the issue of FASD is most commonly raised and considered. The purpose of this study is to examine if (and how) FASD is being taking into consideration at sentencing. To this end, a comparative analysis of 87 sentencing judgments (42 FASD offenders and 45 non-FASD offenders) reported in Quicklaw was conducted. Cases were matched on most serious offence (assault, robbery and sexual assault) and jurisdiction (Yukon, British Columbia and Ontario). Descriptions of FASD and non-FASD offenders as reported by judges were found to differ in a number of significant ways. Similarly, sentencing purposes applied to each offender group emerged as distinct. Despite these distinctions, no differences were found in the type and length of sentence handed down (even after controlling for criminal record and breaches). These findings indicate a need for further research and possible policy changes.

Maternal consumption of ethanol during pregnancy contributes to a set of pathologies, grouped together as the fetal alcohol spectrum disorders, affecting as many as 5% of live births in the United States annually. Ethanol acts widely in the developing embryo, affecting many tissues, but causing deficits in neuronal and neural crest populations particularly. These deleterious effects cause archetypical craniofacial expression and neurological deficits, including microcephaly and neuronal dysfunction. Severity of symptoms is linked to frequency of maternal alcohol consumption as well as the maximum blood alcohol concentration reached by the mother. The teratology of ethanol has been widely researched over the last four decades, with the link between the neural crest pathology and the fetal alcohol spectrum phenotype becoming clearer. Animal model studies have managed to replicate many of the symptoms seen in humans afflicted with fetal alcohol spectrum disorders, and have allowed us to elucidate the biochemical mechanisms behind the disease. There is no singular pathway responsible for the fetal alcohol spectrum disorders: over half a dozen models of dysfunction have been identified, and ethanol’s ability to react with a series of targets means that more pathways are likely to be discovered. Current theories regarding the effects of ethanol on the neural crest have implicated apoptosis of the cephalic neural crest, mediated by G-protein coupled receptors, activation of a phospholipase C pathway, and subsequent release of intracellular calcium; perturbations of the actin cytoskeleton leading to migration dysfunction of neural crest cells in the developing neural tube; lack of functional trophic molecules, specifically Shh, likely due to dysfunction of the cholesterol biosynthetic pathway; lack of retinoic acid production; oxidative stress, production of reactive oxygen species, and iron dysregulation; and genetics, which seems to confer greater susceptibility and resistance to ethanol in certain individuals. Ultimately, a global model for ethanol’s actions on the developing fetus eludes researchers, as do any potential treatments, and more research is required to further elucidate ethanol’s teratogenic mechanism.

Background: Fetal alcohol spectrum disorders (FASD), which are caused by prenatal alcohol exposure (PAE), affects people around the world. Certain communities in South Africa have among the highest reported incidences of fetal alcohol syndrome (FAS) in the world. Although PAE-related brain alterations have been widely documented, the mechanisms whereby alcohol affects the brain are not clearly understood. MRI relaxation parameters T1, T2, T2* and proton density (PD), are basic tissue properties that reflect the underlying biology. The present study aims to advance our understanding of how PAE alters the microstructural properties of tissue by examining PAE-related changes in these tissue parameters in adolescents with FASD. Methods: The final sample used in this study consisted of 53 children from a previously studied longitudinal cohort (Jacobson et al., 2008) and 12 additionally recruited subjects. Of the 65 participants, 18 were diagnosed with FAS or partial FAS (PFAS) and made up the FAS/PFAS group, 18 were diagnosed as heavily exposed non-syndromal (HE) and 29 were age matched controls. Subjects were scanned at the Cape Universities Body Imaging Centre (CUBIC) located at Groote Schuur Hospital on a 3T Siemens Skyra MRI. Structural images were obtained using the MEMPRAGE sequence. From these images T1, T2, T2* and PD parameter maps were constructed and segmented into 43 regions of interest (ROI) using Freesurfer, FSL and AFNI. Linear regression analyses were used to analyse group differences as well as correlations between parameter values and the amount of alcohol the mother consumed during pregnancy. Results: Significant T1 differences were found in the caudate, cerebellar cortex, hippocampus, accumbens, putamen, choroid plexus, ventral diencephalon (DC), right vessel and ventricles. Significant T2 differences were found in the caudate, brain stem, corpus callosum (CC), amygdala, cerebral cortex, choroid plexus, vessels and ventricles. Significant T2* differences were found in the cerebellar cortex, optic chiasm and ventricles. Significant PD differences were found in the hippocampus and left lateral ventricle. The exploratory nature of this study resulted in none of the results surviving FDR correction for multiple comparisons. Conclusions: Overall, our findings point to regional PAE-related increases in water content and cellular and molecular changes in underlying tissue of the anatomical structure. Exceptions were the right cerebral cortex, brain stem, hippocampus, amygdala and ventral diencephalon where our findings point to less free water and increased cell density, and cerebellar cortex where simultaneous reductions in T1 and T2* suggest the possibility of increased iron content. In highly myelinated white matter structures, such as the CC and optic chiasm, our results point to PAErelated demyelination, and possibly increased iron. These findings extend previous knowledge of effects of PAE and demonstrate that tissues are affected at a microstructural level.

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Fetal Alcohol Spectrum Disorder (FASD) is a preventable cause of intellectual delay. Highly prevalent in South Africa, it has become a public health concern. Effective screening measures to identify women at risk of producing a FASD child is therefore important. This study postulated that a distinctive maternal profile may exist for mothers with FASD infants compared to a comparison group. Consequently, the study investigated the occurrence of maternal depression and its potential association with maternal risk factors and infant development respectively; differences in the profiles of mothers; as well as developmental differences in FASD and No FASD groups of children. An ex-post facto design was implemented, where the sample comprised of dyads that completed initial (infants 9-18 months) and follow-up (children 18-45 months) assessments. Severity of maternal depression (measured on the Beck Depression Inventory); maternal current mood states (measured on the Profile of Mood States) and infant developmental differences (measured with the Griffiths Mental Developmental Scales) were assessed. The results showed no distinct patterns in maternal depression in the FASD versus the No FASD groups; maternal depression was not significantly correlated with infant development; infants with FASD showed impaired overall development, with especially poor social adjustment; and all infants (FASD and No FASD) performed lower than the expected developmental norms. Maternal alcohol use was the only significant covariate associated with infant development. Identifying the predictors of high risk behaviour during pregnancy is complex, where prenatal alcohol exposure cannot be viewed in isolation from contextual factors, as limited resources, historical factors, cultural/community knowledge, a lack of stimulation and malnutrition prevail in many areas of South Africa. Profiling maternal predisposition to prenatal alcohol use is essential in reducing the incidence of FASD in South Africa and implementing social skills intervention programs could aid the long-term adjustment of FASD infants.

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.

Although the hazards of prenatal exposure to addictive substances have been documented for decades, it continues to be a prevalent social and health concern today. Alcohol and cocaine are two commonly abused substances during pregnancy, often leading to behavioral and cognitive disorders in exposed children. At present, the relationship between teratogenic effects of prenatal alcohol exposure (PAE) and prenatal cocaine exposure (PCE) on the brain and observed behavioral outcomes is still unclear. A primary reason for this incomplete understanding is the lack of information regarding neuronal functioning in these populations. Functional MRI, which measures real-time brain activation in response to certain stimuli, can be utilized to bridge the gap between known structural damage and observed behavioral outcomes. This thesis aims to examine structural and functional alterations in PAE and PCE populations as compared to unexposed, socio-economic status-matched populations. As the PAE population is highly affected by structural dysmorphology, the applicability of a newly developed diffeomorphic image registration method to this population is examined. Additionally, task-positive and task-negative functional connectivity and activity are investigated in the PAE population, and related to underlying structural alterations. Neural correlates of global arousal and emotional regulation are investigated in the PCE population, as these behavioral outcomes are most notable. Similarly, functional connectivity and activation in task-positive and task-negative networks, as well as correlated structural measures, are examined in the PCE population. The diffeomorphic image registration algorithm was found to improve both structural and functional image registration for the PAE population. In the examination of specific deficits in arithmetic processing, poorer performance in the PAE group was attributed to a multi-level effect produced by altered structural and functional connectivity and functional activity in calculation and default mode networks. Baseline arousal levels were found to be higher in adolescents with PCE as compared to healthy controls (by altered default mode network functioning); emotional regulation also appeared to be affected in the PCE group by a prefrontal-amygdala structural and functional disconnect. The findings of this thesis give insights into the relationship between task-positive and task-negative duality and cognitive impairment, and contribute to a more comprehensive understanding of the spectrum of clinical disorders caused by prenatal exposure to alcohol and cocaine.