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.

Diagnosis of fetal alcohol spectrum disorders (FASD) is challenging and typically requires confirmation of in utero alcohol exposure. Due to the poor reliability of maternal self-reports, biomarkers have emerged to address the problem of obtaining exposure history. A relatively novel method for detecting prenatal alcohol exposure is analysis of meconium for fatty acid ethyl esters (FAEEs), which are non-oxidative ethanol metabolites. Screening newborns using meconium FAEEs may facilitate early diagnosis and intervention in alcohol-affected individuals. The overall objective of this thesis is to further investigate, validate, and assess the clinical utility of meconium FAEE analysis as a screening tool for the identification of neonates at-risk for FASD. This objective was addressed in four separate studies. The first study assessed whether meconium FAEE concentrations can be predictive of ethanol-induced organ injury in fetal sheep, and determined that the levels of these esters could be used to identify fetuses at-risk for organ dysfunction that do not display overt physical signs of ethanol teratogenicity. The second study investigated the effect of delayed meconium collection and contamination with postnatal stool on FAEE analysis, and determined it to be a risk factor for false positive test results. In the third study, maternal willingness to partake in an open meconium screening program was assessed and found to be low enough to diminish the utility of meconium FAEE testing for population-based open screening. Lastly, a systematic review examining the capacity for FAEE synthesis and the enzymology of this non-oxidative metabolic pathway in mammalian organs and tissues revealed that FAEE synthesis is mediated by numerous enzymes and isoenzymes, many of which have other primary physiological functions, and that their contribution to overall FAEE-synthesis may be tissue-specific. Overall, the results of this research provide new information on the benefits, limitations, and utility of meconium FAEE testing as a screening tool for identifying prenatal alcohol exposure − a test that may be of great clinical value in the diagnosis and management of FASD.

Diagnosis of fetal alcohol spectrum disorders (FASD) is challenging and typically requires confirmation of in utero alcohol exposure. Due to the poor reliability of maternal self-reports, biomarkers have emerged to address the problem of obtaining exposure history. A relatively novel method for detecting prenatal alcohol exposure is analysis of meconium for fatty acid ethyl esters (FAEEs), which are non-oxidative ethanol metabolites. Screening newborns using meconium FAEEs may facilitate early diagnosis and intervention in alcohol-affected individuals. The overall objective of this thesis is to further investigate, validate, and assess the clinical utility of meconium FAEE analysis as a screening tool for the identification of neonates at-risk for FASD. This objective was addressed in four separate studies. The first study assessed whether meconium FAEE concentrations can be predictive of ethanol-induced organ injury in fetal sheep, and determined that the levels of these esters could be used to identify fetuses at-risk for organ dysfunction that do not display overt physical signs of ethanol teratogenicity. The second study investigated the effect of delayed meconium collection and contamination with postnatal stool on FAEE analysis, and determined it to be a risk factor for false positive test results. In the third study, maternal willingness to partake in an open meconium screening program was assessed and found to be low enough to diminish the utility of meconium FAEE testing for population-based open screening. Lastly, a systematic review examining the capacity for FAEE synthesis and the enzymology of this non-oxidative metabolic pathway in mammalian organs and tissues revealed that FAEE synthesis is mediated by numerous enzymes and isoenzymes, many of which have other primary physiological functions, and that their contribution to overall FAEE-synthesis may be tissue-specific. Overall, the results of this research provide new information on the benefits, limitations, and utility of meconium FAEE testing as a screening tool for identifying prenatal alcohol exposure − a test that may be of great clinical value in the diagnosis and management of FASD.

In addition to fetal alcohol syndrome and fetal alcohol spectrum disorders, prenatal alcohol exposure is associated with many other adverse pregnancy and birth outcomes. Research suggests that alcohol use during pregnancy may increase the risk of miscarriage, stillbirth, preterm delivery, and sudden infant death syndrome. This research has some inherent difficulties, such as the collection of accurate information about alcohol consumption during pregnancy and controlling for comorbid exposures and conditions. Consequently, attributing poor birth outcomes to prenatal alcohol exposure is a complicated and ongoing task, requiring continued attention to validated methodology and to identifying specific biological mechanisms.

The effects from prenatal alcohol exposure have been found to cause a range of congenital physical and cognitive abnormalities (Chasnoff, Wells, Telford, Schmidt, & Messer, 2010; Kable & Coles, 2004a). The neurological impairments associated with the effects from prenatal alcohol exposure often cause learning problems, most notably in mathematics (Kable & Coles, 2004a; Howell et al., 2006). Studies have indicated that when provided instructional interventions in mathematics, children affected by prenatal alcohol exposure made gains in learning. However, the studies did not provide specifics as to how children with FAS construct the understanding of a skill or concept (Kable, Coles, & Taddeo, 2007; Coles, Kable, & Taddeo, 2009). This study contributes to the literature by examining how children affected by prenatal alcohol exposure learn the concept of equivalence through their use of gestures in contrast to their learning outcomes. Previous studies have shown that children’s use of gestures while learning mathematics assist with the integration of verbal and visual stimuli, support concept formation, and facilitate flexible encoding of problems (Goldin-Meadow, Cook, & Mitchell, 2009; McNeil & Alibali, 2004). The results from this study indicated that children in the Alcohol Exposed group showed little to no learning after the intervention as compared to a control group matched by age and IQ. The study showed that children affected by prenatal alcohol exposure used fewer conceptual gestures while learning equivalence as compared to a control group. According to the gesture analysis, the children in the Alcohol Exposed group mentally represented the concept of equivalence as a series of isolated steps or procedures. The procedural representation was not transitioned into a flexible conceptual format and applied to solve different problem types accurately (McNeil & Alibali, 2004). Future studies need to investigate whether teaching children affected by prenatal alcohol exposure to gesture during mathematics instruction would be effective to increase concept formation, accurate encoding, and learning mathematics / Inclusive Education / D. Ed. (Inclusive Education)

A grande prevalência do consumo de álcool por mulheres em idade reprodutiva aliada à gravidez não planejada expõe a gestante a um elevado risco de se alcoolizar em algum momento da gestação, principalmente no início do período gestacional em que a maioria delas ainda não tomou ciência do fato. Assim, torna-se extremamente relevante o desenvolvimento de métodos de detecção precoce de recém-nascidos em risco de desenvolvimento de problemas do espectro dos transtornos relacionados à exposição fetal ao álcool. O objetivo desse estudo foi desenvolver, validar e avaliar a eficácia de um método de quantificação de ésteres etílicos de ácidos graxos (FAEEs) no mecônio de recém-nascidos para avaliação da exposição fetal ao álcool. Os FAEEs avaliados foram: palmitato de etila, estearato de etila, oleato de etila e linoleato de etila.O método consistiu no preparo das amostras pela extração líquido-líquido utilizando água, acetona e hexano, seguida de extração em fase sólida empregando cartuchos de aminopropilsilica. A separação e quantificação dos analitos foi realizada por cromatografia em fase gasosa acoplada à espectrometria de massas. Os limites de quantificação (LQ) variaram entre 50-100ng/g. A curva de calibração foi linear de LQ até 2000ng/g para todos os analitos. A recuperação variou de 69,79% a 106,57%. Os analitos demonstraram estabilidade no ensaio de pós-processamento e em solução. O método foi aplicado em amostras de mecônio de 160 recém-nascidos recrutados em uma maternidade pública de Ribeirão Preto-SP. O consumo de álcool materno foi reportado utilizando questionários de rastreamento validados T-ACE e AUDIT e relatos retrospectivos da quantidade e frequência de álcool consumida ao longo da gestação. A eficácia do método analítico em identificar os casos positivos foi determinada pela curva Receiver Operating Characteristic (ROC). O consumo alcoólico de risco foi identificado pelo T-ACE em 31,3% das participantes e 50% reportaram o uso de álcool durante a gestação. 51,3% dos recém-nascidos apresentaram FAEEs em seu mecônio, sendo que 33,1% apresentaram altas concentrações para a somatória dos FAEEs (maior que 500ng/g), compatível com um consumo abusivo de álcool. O oleato de etila foi o biomarcador mais prevalente e o linoleato de etila foi o biomarcador que apresentou as maiores concentrações. Houve uma variabilidade no perfil de distribuição dos FAEEs entre os indivíduos, e discordâncias entre a presença de FAEEs e o consumo reportado pela mãe. A concentração total dos FAEEs nos mecônio mostrou-se como melhor indicador da exposição fetal ao álcool quando comparado com o uso de um único biomarcador. O ponto de corte para esta população foi de aproximadamente 600ng/g para uso tipo binge (três ou mais doses por ocasião) com sensibilidade de 71,43% e especificidade de 84,37%. Este estudo reforça a importância da utilização de métodos laboratoriais na identificação da exposição fetal ao álcool. / The high prevalence of alcohol consumption by women of reproductive age combined with unplanned pregnancy exposes the mother to a high risk to intoxicate at some time during pregnancy, especially in the early gestational period in which most of them have not yet became aware of the fact. Therefore, the development of methods for early detection it is extremely relevant for the prevention of fetal alcohol exposure as well for the early assessment of neonates at risk for development of problems of the fetal alcohol spectrum. The aim of this study was to develop, validate and evaluate the effectiveness of a method for quantifying fatty acid ethyl esters (FAEEs) in meconium from newborns for evaluation of fetal alcohol exposure. The evaluated FAEEs were: ethyl palmitate, ethyl stearate, ethyl oleate and linoleate etila. The method consists in preparing the samples by liquid-liquid extraction using water, acetone and hexane, followed by solid phase extraction employing aminopropyl silica cartridges. The separation and quantitation of analytes was performed by gas chromatography coupled with mass spectrometer. Limits of quantification (LOQ) ranged between 50 and 100 ng/g. The curves calibration were linear from LQ- 2000ng / g for all analytes. The recovery ranged from 69.79% to 106.57%. The analytes demonstrated stability in post-processing assay and in stability assay for standard solutions. The method was applied in meconium samples from 160 newborns recruited in a public maternity hospital of Ribeirão Preto. The maternal alcohol consumption was assessed by validated screening questionnaires (T-ACE and AUDIT) and by retrospective self-reports about the amount and frequency of alcohol consumption during pregnancy. The effectiveness of the analytical method in identifying positive cases was determined by receiver operating characteristic curve (ROC). The risk drinking was identified by the T-ACE in 31.3% of participants and 50% of them reported alcohol use during pregnancy. 51.3% of newborns tested positive for FAEEs, and 33.1% had high concentrations for sum of FAEEs (greater than 500 ng/g), compatible with alcohol abuse. The ethyl oleate was the most prevalent biomarker and ethyl linoleate was the biomarker that showed the highest concentrations. There was a variability in the distribution profile of FAEEs between individuals, and there were disagreements between the results of FAEEs and consumption reported by the mother. The cumulative sum of FAEEs was better than individual FAEEs for interpretation of positive cases. A positive cutoff of cumulative FAEE at 600 ng/g for binge drinking was stablished with 71,43% sensitivity and 84,37% specificity. This study reinforces the importance of using laboratory methods for identifying fetal alcohol exposure.

Background: Prenatal alcohol consumption is one of the leading preventable causes of birth defects, including fetal alcohol syndrome and learning disabilities. Although there is strong evidence of the benefits of screening and alcohol brief interventions (ABIs) in reducing hazardous and harmful drinking among the primary care population, evidence of its effectiveness with the antenatal care population is limited. Nevertheless, the Scottish Government is incorporating an alcohol screening and ABI programme as part of the routine antenatal care provided to women in a bid to protect the health and safety of the unborn child and improve subsequent health and developmental outcomes. This research therefore seeks to increase understanding of the factors that are likely to influence the effectiveness of this recently implemented programme. It also aims to explore the extent to which contemporary issues such as change in guidelines regarding alcohol consumption during pregnancy influences perceptions and attitudes, and the possible implications of these on the screening and ABI delivery. Methods: The study described in this thesis employed a realistic evaluation methodology. Realistic evaluation is a theory-driven approach to investigating social programmes. It is concerned with hypothesising, testing and refining programme theories by exploring the interaction of contexts, mechanisms and outcomes. To identify the relevant screening and ABI programme theories, two separate systematic reviews, a critical review and four face-to-face interviews were undertaken with health policy implementers. The findings were used to construct context, mechanism and outcomes propositions. The propositions were then tested by conducting individual interviews with seventeen pregnant women and fifteen midwives, a further six midwifery team leaders were involved in a focus group discussion. A thematic approach using a hybrid of inductive and deductive coding and theme development informed the qualitative analysis. Results: In the context of uncertainties regarding the threshold of drinking that causes fetal harm, pregnant women reported that screening assessment helped them to reflect on their drinking behaviour and facilitate behaviour change. For women who drank at hazardous and harmful levels before attending the booking appointment, screening and ABI may be helpful in terms of eliciting behaviour change. However, they may not be very beneficial in terms of reducing harm to the fetus as it has been found that drinking during the first trimester poses the most risk to the fetus. Training and resources provided to midwives as part of the screening and ABI programme were found to be facilitating mechanisms that midwives indicated improved their skills and confidence. However, most of the midwives had not subsequently employed the motivational interviewing skills required for the ABI delivery, as many of the pregnant women reported that they reduced or abstained from alcohol consumption once pregnancy was confirmed. The outcome noted was that midwives confidence decreased leading to missed opportunities to appropriately deliver the ABI to eligible women. The small numbers of women being identified for ABI meant midwives rarely delivered the ABI. This negatively influenced midwives attitudes as they then accorded ABI low priority in their workload. Other disenabling mechanisms noted to be hampering the implementation of the screening and ABI initiative included midwives contending with competing priorities at the booking appointments, and the lack of adequate rapport between midwives and pregnant women at the booking appointment to discuss alcohol issues appropriately, leading to women providing socially desirable responses to screening questions. Conclusions: The findings of this study has generated greater explanations of the working of the screening and ABI programme in antenatal care setting and has provided transferable lessons that can be used by others intending to implement similar programmes in other settings.

No description available.

The effects from prenatal alcohol exposure have been found to cause a range of congenital physical and cognitive abnormalities (Chasnoff, Wells, Telford, Schmidt, & Messer, 2010; Kable & Coles, 2004a). The neurological impairments associated with the effects from prenatal alcohol exposure often cause learning problems, most notably in mathematics (Kable & Coles, 2004a; Howell et al., 2006). Studies have indicated that when provided instructional interventions in mathematics, children affected by prenatal alcohol exposure made gains in learning. However, the studies did not provide specifics as to how children with FAS construct the understanding of a skill or concept (Kable, Coles, & Taddeo, 2007; Coles, Kable, & Taddeo, 2009). This study contributes to the literature by examining how children affected by prenatal alcohol exposure learn the concept of equivalence through their use of gestures in contrast to their learning outcomes. Previous studies have shown that children’s use of gestures while learning mathematics assist with the integration of verbal and visual stimuli, support concept formation, and facilitate flexible encoding of problems (Goldin-Meadow, Cook, & Mitchell, 2009; McNeil & Alibali, 2004). The results from this study indicated that children in the Alcohol Exposed group showed little to no learning after the intervention as compared to a control group matched by age and IQ. The study showed that children affected by prenatal alcohol exposure used fewer conceptual gestures while learning equivalence as compared to a control group. According to the gesture analysis, the children in the Alcohol Exposed group mentally represented the concept of equivalence as a series of isolated steps or procedures. The procedural representation was not transitioned into a flexible conceptual format and applied to solve different problem types accurately (McNeil & Alibali, 2004). Future studies need to investigate whether teaching children affected by prenatal alcohol exposure to gesture during mathematics instruction would be effective to increase concept formation, accurate encoding, and learning mathematics / Inclusive Education / D. Ed. (Inclusive Education)