Abstract: Australian Aboriginal children experience disproportionate levels of health, educational and social disadvantage. Their significant disadvantage stands in stark contrast to the well-being of the majority of Australians. These poor outcomes are magnified in remote communities where Aboriginal children have been shown to have developmental vulnerability beyond the national average. A concerning and poorly understood determinant of development and well-being is the influence of prenatal alcohol exposure (PAE). National surveys show differences in the drinking patterns between Aboriginal and non-Aboriginal Australian women. Aboriginal women are less likely to drink than non-Aboriginal women but when they do consume alcohol, they do so at far more hazardous levels. As alcohol is a teratogen, PAE can have devastating effects on fetal and brain development leading to a spectrum of disorders termed Fetal Alcohol Spectrum Disorders (FASD). FASD are characterised by significant learning, behavioural, cognitive and motor deficits which disrupt education and development trajectories leading to severely limited occupational options and dependent living. These adverse life outcomes place enormous burden on families, their communities and social supports. The Fitzroy Valley in north Western Australia contains a unique, culturally rich population of 4,500 people (81% Australian Aboriginal), living in approximately 45 very remote communities with five distinct language groups. Over the last decade there has been growing anxiety amongst Aboriginal leaders in the Fitzroy Valley, that high-risk maternal drinking within many of their remote communities may be harming the development and future potential of children. This concern led to an invitation from Aboriginal leaders for researchers to collaborate with them on a project to evaluate the impact of in-utero alcohol exposure on child health and development. This project conducted in 2011 was named The Lililwan Project and is Australia’s first population-based study to determine FASD prevalence, using active case ascertainment, in remote Australian Aboriginal communities. Population-based data from this study indicate that high-risk alcohol use is common. Of the 127/134 (95%) eligible mothers and caregivers who participated in this study, it was reported that more than half (55%) of mothers drank. Of mothers who did drink, 52% did so at “risky” or “high risk” levels with 88% drinking in the first trimester and 53% drinking in all three trimesters. FASD diagnoses were determined in 21/108 (194.4 per 1000) children, one of the highest prevalence rates in the world. The FASD diagnostic process includes the assessment of neurodevelopmental functional outcomes in a number of central nervous system (CNS) domains known to be affected by PAE. Motor performance and its subset gross motor performance is one of several CNS domains recommended for assessment by four key international FASD guidelines. Despite this, data on motor function are rarely included in FASD prevalence or observational studies and therefore the association of motor performance and PAE or FASD is poorly understood. In the Fitzroy Valley, physical activity including football, basketball, netball, swimming and cultural activities such as hunting and traditional dance feature highly in recreational pursuits of children. Given concern that the motor skills needed to participate in these activities could be significantly affected by PAE, motor performance was included as a CNS domain for assessment in the Lililwan Project, with the results of this original research being reported in the following chapters. Chapter One provides an introduction to the context of this Thesis and a literature review of the existing evidence. The current Thesis contributes much needed evidence to support the neurodevelopmental needs of children with motor impairment associated with PAE or FASD who live in the Fitzroy Valley. This work is unique as cultural considerations and the very remote geographical location with extreme climate makes this population very difficult to assess. Not surprisingly, there is paucity of data related to motor performance of Aboriginal children living in very remote communities and currently no normative data or observational studies exist. The findings provide a significant evidence base to assist parents, clinicians, the education sector and policy makers, to make optimal decisions for management of children and their families living with FASD. The first aim of this Thesis was to characterize gross motor impairment in children with a diagnosis of fetal alcohol spectrum disorder (FASD) or “moderate” to “heavy” maternal alcohol intake. Chapter Two describes a systematic review where 2881 articles were identified of which 14 met the inclusion criteria. The subjects’ mean age ranged from 3 days to 13 years. Study limitations included failure to report cut-offs for impairment, non-standardised reporting of PAE, and small sample sizes. The meta-analysis pooled results (n=10) revealed a significant association between a diagnosis of FASD or moderate to heavy PAE and gross motor impairment (Odds Ratio: 2.9; 95% Confidence Interval: 2.1–4.0). GM deficits were found in balance, coordination, and ball skills. There were insufficient data to determine the prevalence of gross motor dysfunction in the included cohorts. In conclusion, these results suggest that evaluation of gross motor proficiency should be a standard component of multidisciplinary FASD diagnostic services. The second aim of this Thesis was to identify a suitable standardised instrument to measure motor performance (including fine and gross motor skills) and determine its reliability for use in predominantly Australian Aboriginal children living in very remote communities and with risky levels of PAE. Chapter Three reports on this work. The Bruininks-Oseretsky Test of Motor Proficiency – Second Edition (BOT-2) Complete Form was identified after performing a literature review and consulting with national and international experts. Given the difficult logistical context in which the research was performed, it was decided to use the highly correlated short-form version of the BOT-2 for the reliability testing. A reliability study using the BOT-2 Short Form was then performed with a convenience sample (n=30) of children aged 7-9 years from the Lililwan Project (n=108). The inter-rater reliability for the BOT-2 Short Form score sheet outcomes ranged from 0.88 (95%CI, 0.77 – 0.94) to 0.92 (95%CI, 0.84 – 0.96) indicating excellent reliability. The test-retest reliability (median interval between tests being 45.5 days) for the BOT-2 Short Form score sheet outcomes ranged from 0.62 (95%CI, 0.34 – 0.80) to 0.73 (95%CI, 0.50 – 0.86) indicating fair to good reliability. The raw score Minimal Detectable Change was 6.12. In conclusion, the BOT-2 Short Form has acceptable reliability for use in remote Australian Aboriginal communities and will be useful in determining motor deficits in children prenatally exposed to alcohol. This is the first known study evaluating the reliability of the BOT-2 Short Form, either in the context of assessment for FASD or in Aboriginal children. The third aim of this Thesis was to describe motor performance in predominantly Australian Aboriginal children living in very remote communities (n=108) and to compare motor performance in children with no PAE, PAE or FASD. Chapter Four describes this work. Motor performance of the cohort was assessed using the modified BOT-2 Complete Form, and the relationship between motor skills, PAE, and FASD was explored. FASD diagnoses were assigned using the Canadian guidelines. Motor impairment sufficient to contribute to a CNS domain of impairment was defined according to these guidelines as a score two or more standard deviations (SD) below the mean. A total of 108 children (Aboriginal: 98.1%; male: 53%) with a mean age of 8.7 years were assessed. The cohort’s mean total motor composite score (mean±SD: 47.2±7.6) approached the Bruininks–Oseretsky Test of Motor Proficiency - Second Edition normative mean (50±10) despite high levels of risky PAE, social disadvantage, and poor fine motor skills. There was no difference between children with PAE and those without PAE (mean difference ± standard error: -2.2±1.5; 95% CI: -5.1 to 0.80). Motor performance was lower in children with FASD diagnosis than those children without a diagnosis (Mean Difference±SD: -5.0±1.8; 95% CI:-8.6 to -1.5). The prevalence of motor impairment (≥ 2SD below the mean) was 1.9% in the entire cohort, 9.5% in children with FASD, 3.3% in children with PAE and 0.0% both in children without PAE or FASD. In conclusion, these results show that almost 10% of children with FASD have significant motor impairment. Evaluation of motor function should routinely be included in assessments for FASD, to document impairment and enable targeted early intervention. The fourth aim of this Thesis was to characterise gross motor performance, as distinct from total motor performance as discussed above. In children participating in the Lililwan Project (n=108), a subset of the BOT-2 motor performance data that related to the gross motor performance of the cohort was extracted which enabled exploration of the relationship between gross motor skills, PAE, and FASD. Chapter Five describes this work. A total of 108 children (98.1% Aboriginal; 53% males, mean age: 8.7 years) were assessed. Half (52.2%) were exposed to at least “risky” levels of PAE and 21 (19%) were diagnosed with a FASD. The mean Gross Motor Composite score of the cohort (47.0±8.4) approached the BOT-2 normative mean (50.0±10) despite poor health and development indices, and was similar between children with and without PAE (MD±SD: -1.8±16.5; p=0.27). This mean score however, was significantly lower in children with FASD than those without (MD±SD: -5.5±20.6; p=0.006). Compared to children without FASD, children with FASD had (i) significant impairment in Subtests for Running Speed and Agility (MD±SD:-2.4±8.1; p=0.003) and Strength (MD±SD:-2.8±9.9; p=0.004) and (ii) a higher proportion than expected had overall gross motor impairment (≤2SD:9.5%; ≤1SD:23.8%). In groups with PAE, no PAE, and no FASD, gross motor function approached expected population norms and there were no significant difference in function between these groups. In conclusion, almost 10% of children with FASD had gross motor scores that indicated significant impairment whilst 25% of these children had scores which indicated a need for therapy. Evaluation of gross motor performance should routinely be included in FASD assessment to determine strategies to optimise child development. The fifth aim of this Thesis was to describe the presence of soft neurological signs (SNS) in predominantly Australian Aboriginal children (n=108) living in very remote communities where children had no PAE, PAE and FASD. Chapter Six reports on this work. The presence of SNS in the cohort was assessed using the Quick Neurological Screening Test – Second Edition (QNST -2) and the relationship between SNS, PAE, and FASD was explored. “Severe discrepancy” was defined as scores equal or below the 5th percentile while “moderate discrepancy” represented scores from the 6-24th percentile. FASD diagnoses were assigned using the Canadian guidelines. International expert opinion recommended that a QNST-2 Total Score of equal to or greater than 30 be used to define SNS sufficiently significant to contribute to a CNS domain of impairment. A total of 108 of 134 (80.6%) eligible children (mean age 8y 9mo, SD=6mo, 53% male) were assessed. The median QNST-2 Total Score for all participants was within the normal category (19.0, range 4–66) despite more than half (52.2%) of the cohort being exposed to at least risky levels of PAE. However, the median QNST-2 Total Score was higher in children with PAE than without PAE (r=0.2, p=0.045) and in children with FASD than without FASD (r=0.3, p=0.004). Half (8/16) of children scoring ‘moderate discrepancy’ and all (2/2) children scoring ‘severe discrepancy’ had at least three domains of CNS impairment. In conclusion, SNS were more common in children with PAE or FASD, consistent with the known neurotoxic effect of PAE. The QNST-2 is a useful screen for subtle neurological dysfunction and for indicating the need for more comprehensive assessment in children with PAE or FASD. The final aim of this Thesis was to systematically review the literature to investigate the efficacy of conservative interventions to improve gross motor performance in children with PAE or FASD or a range of similar neurodevelopment conditions. Chapter Seven describes this work. As no clinical trials for children with FASD were found, results from groups of children with similar neurodevelopmental disorders and mild to moderate gross motor impairment were considered. Of 2513 papers, 9 met inclusion criteria including children with cerebral palsy (CP) (n=2) or Developmental Co-ordination Disorder (DCD) 98 (n=7). There were 11 different interventions reported among the 9 included trials. Two of 9 trials showed an effect for treatment, and a meta-analysis was performed to determine the pooled effect of intervention on gross motor function. Using the least conservative trial outcomes a large beneficial effect of intervention was shown (standardised MD:-0.8; 95%CI:-1.1 to -0.5) with “very low quality” Grading of Recommendations, Assessment, Development and Evaluations (GRADE) ratings. Using the most conservative trial outcomes there was no treatment effect (SMD:-0.1; 95%CI:-0.3 to 0.2) with “low quality” GRADE ratings. Study limitations included the small number and poor quality of the available trials. In conclusion, although we found that some interventions such as Taekwondo can improve gross motor outcomes in children with DCD or CP, our confidence is limited by the very low quality of the available evidence. High quality intervention trials are urgently needed. Chapter Eight provides a summary of the principal findings of this Thesis, describes implications of these findings, proposes directions for future research and presents recommendations. In conclusion, the series of studies reported in this Thesis provide the first data on motor performance, gross motor performance and SNS in a population-based cohort of predominantly Aboriginal Australian children with PAE. They represent the only data of this kind. The findings provide new information regarding the motor performance skills of Aboriginal children living in remote communities, and demonstrate the significant impairments that children with a FASD suffer. This work has significant implications for future studies of FASD prevalence emphasising the importance of assessing motor performance as a component of CNS function. The findings also highlight the impact of alcohol on child development particularly motor performance and indicate the critical need for allied health services to ensure the health and well-being of these most vulnerable children.