Global DNA Methylation and Histone Posttranslational Modifications in Human and Nonhuman Primate Brain in Association with Prenatal Alcohol Exposure.

BACKGROUND: Based upon experimental animal studies, the neurodevelopmental abnormalities associated with prenatal alcohol exposure (PNAE)/fetal alcohol spectrum disorder (FASD) have been attributed, at least in part, to epigenetic modifications. However, there are no direct analyses of human brain tissue. METHODS: Immunohistochemical detection of global epigenetic markers was performed on temporal lobe samples of autopsied fetuses and infants with documented PNAE. They were compared to age-, sex-, and postmortem delay-matched control cases (18 pairs; 20 to 70.5 weeks postconception). Temporal lobe tissue from a macaque monkey model of PNAE was also studied (5.7 to 6 months of age). We used antibodies targeting 4 DNA cytosine, 4 histone methylation, and 6 histone acetylation modifications and assigned scores based upon the semiquantitatively graded intensity and proportion of positively labeled nuclei in the ventricular and subventricular zones, ependyma, temporal cortex, temporal white matter, dentate gyrus (DG), and CA1 pyramidal layer. RESULTS: Temporal changes were identified for almost all marks according to the state of maturation in the human brain. In the DG (and 3 other brain regions), a statistically significant increase in H3K9ac was associated with PNAE. Statistically significant decreases were seen among 5mC, H3K4me3, H3K9ac, H3K27ac, H4K12ac, and H4K16ac in select regions. In the macaques, H3K36me3 decreased in the DG, and the ependyma showed decreases in 5fC and H3K36me3. CONCLUSIONS: In human brain, global intranuclear epigenetic modifications are brain region and maturation state-specific. These exploratory results support the general hypothesis that PNAE is associated with a global decrease in DNA methylation, a global decrease in histone methylation, and a global increase in histone acetylation. Although the human and monkey subjects are not directly comparable in terms of brain maturation, considering the rapid temporal changes in global epigenetic modifications during brain development, interspecies comparisons may be extremely difficult.

An investigation of intra-individual variability in children with fetal alcohol spectrum disorder (FASD).

Intra-individual variability (IIV) is defined as systematic within-person variation in performance either across test sessions (e.g., test/retest performance on the same task) or in one session (e.g., variations in performance on multiple trials of a single task). Higher levels of IIV have been noted as a characteristic of neurodevelopmental disorders such as attention deficit/hyperactivity disorder​ (ADHD), but IIV is yet to be investigated in fetal alcohol spectrum disorder (FASD). FASD is a term used to describe a range of conditions resulting from prenatal exposure to alcohol. As part of a comprehensive neuropsychological battery, four study groups (1. fetal alcohol syndrome/partial fetal alcohol syndrome; 2. static encephalopathy/alcohol exposed; 3. neurobehavioral disorder/alcohol exposed as diagnosed using the University of Washington FASD 4-Digit Code; 4. typically-developing (TD) age-matched children with no prenatal alcohol exposure) were administered measures of motor response and inhibitory control, attention, and adaptive behavior. The results indicate increased levels of IIV in those with FASD compared to the TD controls. It was found that IIV uniquely contributes to predicting adaptive behavior above and beyond attention, while attention partially mediates the relationship between IIV and adaptive behavior. This is the first study to the authors' knowledge to show the presence of increased IIV in children with FASD. It additionally provides evidence that IIV measures some inherent variability in performance independent of poor attention in children with FASD.

Comparison of the FASD 4-Digit Code and Hoyme et al. 2016 FASD diagnostic guidelines.

BACKGROUND: As clinicians strive to achieve consensus worldwide on how best to diagnose fetal alcohol spectrum disorders (FASD), the most recent FASD diagnosstic systems exhibit convergence and divergence. Applying these systems to a single clinical population illustrates contrasts between them, but validation studies are ultimately required to identify the best system. Currently, only the 4-Digit Code has published comprehensive validation studies. METHODS: The 4-Digit Code and Hoyme 2016 FASD systems were applied to the records of 1,392 patients evaluated for FASD at the University of Washington to: 1) Compare the diagnostic criteria and tools used by each system, 2) Compare the prevalence and concordance of diagnostic outcomes and assess measures of validity. RESULTS: Only 38% of patients received concordant diagnoses. The Hoyme criteria rendered half as many diagnoses under the umbrella of FASD (n=558) as the 4-Digit Code (n=1,092) and diagnosed a much higher proportion (53%) as fetal alcohol syndrome/partial fetal alcohol syndrome (FAS/PFAS) than the 4-Digit Code (7%). Key Hoyme factors contributing to discordance included relaxation of facial criteria (40% had the Hoyme FAS face, including patients with confirmed absence of alcohol exposure); setting alcohol exposure thresholds prevented 1/3 with confirmed exposure from receiving FAS/FASD diagnoses; and setting minimum age limits for Alcohol-Related Neurodevelopmental Disorder prevented 79% of alcohol-exposed infants with neurodevelopmental impairment a FASD diagnosis. The Hoyme Lip/Philtrum Guides differ substantively from the 4-Digit Lip-Philtrum Guides and thus are not valid for use with the 4-Digit Code. CONCLUSIONS: All FASD diagnostic systems need to publish comprehensive validation studies to identify which is the most accurate, reproducible, and medically valid.

The Essential Role of Growth Deficiency in the Diagnosis of Fetal Alcohol Spectrum Disorder.

BACKGROUND: Laboratory studies confirm prenatal alcohol exposure (PAE) causes growth deficiency (GD). GD has traditionally been a core diagnostic feature of fetal alcohol spectrum disorders (FASD), but was removed from the Canadian and Australian FASD diagnostic guidelines in 2016. This study aimed to empirically assess the clinical role and value of GD in FASD diagnosis. METHODS: Data from 1814 patients with FASD from the University of Washington Fetal Alcohol Syndrome Diagnostic & Prevention dataset were analyzed to answer the following questions: 1) Is there evidence of a causal association between PAE and GD in our clinical population? 2) Is GD sufficiently prevalent among individuals with PAE to warrant its inclusion as a diagnostic criterion? 3) Does GD aid the diagnostic team in identifying and/or predicting which individuals will be most impaired by their PAE? RESULTS: GD significantly correlated with PAE. GD was as prevalent as the other core diagnostic features (facial and CNS abnormalities). GD occurred in all FASD diagnoses and increased in prevalence with increasing severity of diagnosis. The most prevalent form of GD was postnatal short stature. GD was as highly correlated with, and predictive of, severe brain dysfunction as the FAS facial phenotype. Individuals with GD had a two to three-fold increased risk for severe brain dysfunction. Sixty percent of patients with severe GD had severe brain dysfunction. GD accurately predicted which infants presented with severe brain dysfunction later in childhood. CONCLUSIONS: GD is an essential diagnostic criterion for FASD and will remain in the FASD 4-Digit Code.

Palpebral fissure length measurement: accuracy of the FAS facial photographic analysis software and inaccuracy of the ruler.

BACKGROUND: Accurate fetal alcohol spectrum disorder diagnoses require accurate facial measurement. The Fetal Alcohol Syndrome (FAS) Facial Photographic Analysis Software was developed to overcome measurement error known to occur with ruler measurement of the PFL. Recent publications have queried the Software's accuracy. OBJECTIVES: 1) Demonstrate the Software's ability to accurately measure a PFL from a 2-dimensional digital facial photograph. 2) Demonstrate the frequency and magnitude of error when the PFL is measured directly by clinicians using a ruler. METHODS: Objective 1: PFLs of mannequins were measured using the Software and a sliding digital caliper, with the latter serving as the gold-standard accurate measure. Mannequins allowed the caliper prongs to be placed directly on the landmarks that define the PFL. Objective 2: PFLs of 1,027 patients evaluated at the University of Washington FAS Diagnostic & Prevention Network were measured with the Software and directly by one or two clinicians using a ruler. RESULTS: Objective 1: The Software derived PFLs that were identical to or within 0.2 mm of the caliper measures. Objective 2: There was tremendous inter-rater variability in PFLs measured by clinicians using a hand held ruler. Seventy-seven percent of patients had their PFLs measured incorrectly (greater than 1 mm error) by at least one of the two clinicians using a ruler. CONCLUSION: The FAS Facial Photographic Analysis Software measures the PFL with the same accuracy as a sliding digital caliper, as it was programmed to do. Direct measurement of the PFL with a ruler is very prone to error.

Invited commentary on Australian fetal alcohol spectrum disorder diagnostic guidelines.

The publication of Australian fetal alcohol spectrum disorder (FASD) diagnostic guidelines marks an important step forward in Australia's efforts to prevent FASD. But do we need yet another set of FASD guidelines? At the 5th International FASD Conference, the ever growing number of FASD diagnostic guidelines was identified as a core area of concern by leaders in FASD worldwide. All agreed we need to strive to adopt a single set of guidelines. It is essential that FASD diagnosis advance to incorporate new knowledge and technology. But to date, the field of FASD has seen multiple sets of guidelines published that do not address the important question-How is the performance of these new guidelines superior to the performance of existing guidelines to warrant/justify their introduction into the medical literature?The Australian guidelines include FAS, PFAS and Neurodevelopmental Disorder-Alcohol Exposed (ND-AE). This latter group includes individuals with severe CNS abnormalities without the physical features of FAS. This is the group the 4-Digit-Code calls Static-Encephalopathy-Alcohol-Exposed (SE-AE). The criteria for FAS, PFAS, and ND-AE (or what the 4-Digit-Code calls SE-AE) are identical between the Australian and 4-Digit-Code guidelines with the exception of one very small, but very consequential difference in facial criteria for PFAS. The 4-Digit-Code requires a Rank 3 FAS facial phenotype for PFAS (J Popul Ther Clin Pharmacol20(3):e416-e467, 2013); the Australian guidelines relax the criteria to include the Rank 2 FAS facial phenotype. This relaxation of the criteria renders the facial phenotype NOT specific to prenatal alcohol exposure as confirmed in published empirical studies. If the facial phenotype is not specific to (caused only by) prenatal alcohol exposure one can no longer validly call the outcome PFAS. When one makes a diagnosis of FAS (full or partial), one is stating explicitly that the individual has a syndrome caused by prenatal alcohol exposure. One is also stating explicitly that the biological mother drank alcohol during pregnancy and, as a result, harmed her child. These are bold conclusions to draw and are not without medical, ethical, and even legal consequences. So the question remains-Why go against the published empirical evidence and relax the PFAS facial criteria into the normal range?

The value of a FASD diagnosis (2013).

2013 marks the 40th year since the term fetal alcohol syndrome (FAS) was coined at the University of Washington. In 1993, the University of Washington opened the first interdisciplinary FASD diagnostic clinic; expanded to a statewide network of clinics in 1995 (Washington State FAS Diagnostic & Prevention Network (WA FASDPN)), and introduced a new, rigorous diagnostic system, the fetal alcohol spectrum disorder (FASD) 4-Digit Diagnostic Code in 1997. The WA FASDPN mission is FASD primary and secondary prevention. Evidence of successful primary prevention (fewer alcohol-exposed pregnancies and FAS births) was documented in WA in the 1990s. Secondary prevention (reduction of disability among individuals with prenatal alcohol exposure) starts with accurate diagnoses and access to interventions that meet patients' needs.

Validation of the fetal alcohol spectrum disorder (FASD) 4-Digit Diagnostic Code.

BACKGROUND: The fetal alcohol spectrum disorder (FASD) 4-Digit Diagnostic Code has been used by interdisciplinary diagnostic teams worldwide for 17 years. It was created to improve the ease, accuracy, and reproducibility of diagnoses across the full spectrum of FASD. Over the years, a number of FAS/D diagnostic guidelines have been proposed. As the field of FASD moves forward, it will be important to adopt a single set of diagnostic guidelines worldwide. To achieve this, the performance (validity) of current diagnostic guidelines must be rigorously assessed and reported. OBJECTIVE: To summarize the body of evidence that has amassed over 20 years that validates the performance of the FASD 4-Digit Diagnostic Code. METHODS: The evidence validating the 4-Digit Code is documented across 35 studies published between 1992 and 2012, including new information presented in this report. These studies and data sources include the delineation of the FAS facial phenotype; creation of the 4-Digit Code (1997-2004); our 10-year, foster-care FAS screening program; our MRI/fMRI/MRS studies; analysis of 2,550 individuals evaluated for FASD over 20 years in the WA State FASDPN clinics, and analysis of 622 patient satisfaction/follow-up surveys; surveys of 10,000 professionals attending the University of Washington FASD diagnostic clinic trainings; and surveys of over 700 professionals worldwide who completed the 4-Digit Code Online Course. CONCLUSION: The 4-Digit Code is a simple, comprehensive, evidence-based, validated diagnostic system. It has served as the cornerstone of a fully integrated FASD screening, diagnostic, intervention, prevention, and surveillance program in Washington State for the past 20 years.

Sensory control of balance: a comparison of children with fetal alcohol spectrum disorders to children with typical development.

BACKGROUND: Inefficient central processing and integration of visual, vestibular, and somatosensory information may contribute to poor balance and diminished postural control in children with fetal alcohol spectrum disorders (FASD). OBJECTIVES: This pilot study examined sensorimotor performance and the sensory control of balance using a battery of clinical tests in combination with an experimental laboratory assessment that quantifies sensory subsystem use (i.e., sensory weighting) among a systematically diagnosed sample of children with FASD and children with typical development. METHODS: Using a case-control design, 10 children with FASD (8.0-15.9 years; 20% female) were compared to 10 age- and sex-matched controls on standardized clinical measures and on kinematic outcomes from the Multimodal Balance Entrainment Response system (MuMBER), a computerized laboratory assessment whereby visual, vestibular, and somatosensory input is manipulated at different frequencies during standing balance. RESULTS: Children with FASD showed poorer sensorimotor performance across clinical outcomes with significant group differences (p < .05) on parent-reported movement behaviors (Sensory Processing Measure and Movement Assessment Battery for Children-2 Checklist) and performance on the Dynamic Gait Index. Experimental kinematic outcomes yielded statistically significant group differences (p <.10) on a small proportion of somatosensory and vestibular sensory weighting fractions and postural sway velocity in response to the manipulation of sensory input. CONCLUSIONS: Preliminary findings showed small group differences in sensorimotor and sensory weighting behaviors, specifically those that rely on the integration of vestibular sensation. Differences must be examined and replicated with a larger sample of children with FASD to understand the impact on balance control and functional sensorimotor behaviors.

Canadian palpebral fissure length growth charts reflect a good fit for two school and FASD clinic-based U.S. populations.

BACKGROUND: Short palpebral fissure lengths (PFL) are one of three facial features that define the unique facial phenotype of fetal alcohol syndrome (FAS). Published PFL growth charts vary greatly in both rate and magnitude of growth, placing their accuracy and validity in question. New PFL growth charts were recently published to reflect a racial/ethnic cross section of Canadian girls and boys 6-16 years of age. PFLs were measured from digital facial photographs using the FAS Facial Photographic Analysis Software. OBJECTIVES: Assess the goodness of fit of two U.S. populations (healthy children and children with prenatal alcohol exposure) when plotted on the Canadian, Hall, and other published PFL charts. METHODS: The PFLs of 106 healthy children and 822 children with prenatal alcohol exposure from Washington State were measured from digital facial photographs using the FAS Facial Photographic Analysis Software. Goodness of fit was assessed graphically and by computation of the mean PFL z-score. RESULTS: Our predominantly Caucasian, healthy group of children scattered along the mean growth curve on the Canadian charts (mean PFL z-score +0.2), and fell 1.6 SDs below the mean on the Hall chart (mean PFL z-score -1.6). The mean PFL z-score for the children with FAS was 2.4 SDs below the mean on the Canadian charts and 3.9 SDs below the mean on the Hall chart. African Americans were not a good fit. CONCLUSION: The Canadian PFL charts were a good fit for our predominantly Caucasian populations of healthy U.S. school-aged children. Children with FAS continued to present with PFLs 2 or more SDs below the mean when plotted on the Canadian PFL charts, supporting the FAS PFL diagnostic criteria used by the FASD 4-Digit Diagnostic Code. Use of PFL charts normed for African Americans is recommended. Updated PFL charts for 0-6 years of age are vital to prevent an artificial over-estimation of short PFLs in this age group.

Profile of the first 1,400 patients receiving diagnostic evaluations for fetal alcohol spectrum disorder at the Washington State Fetal Alcohol Syndrome Diagnostic & Prevention Network.

BACKGROUND: An interdisciplinary approach to fetal alcohol spectrum disorder (FASD) diagnosis using rigorously defined diagnostic guidelines has been adopted as best practice. Diagnostic clinics are being established worldwide. If these clinics are to successfully compete for limited health care dollars, it is essential to document their value. OBJECTIVE: The primary objectives were to document the value of the largest and longest standing interdisciplinary FASD diagnostic program; the Washington State Fetal Alcohol Syndrome Diagnostic & Prevention Network (WA FAS DPN). Now in its 17th year of operation, the WA FAS DPN is a statewide network of diagnostic clinics all using the 4-Digit Diagnostic Code and contributing to a centralized electronic database. METHODS: The clinical database was used to generate comprehensive profiles of all patients evaluated for FASD from 1993-2005. These profiles were used to answer a multitude of clinical, research, and public health questions including: What is the demand for FASD diagnostic services, who is referred to the clinics, and what are their FASD diagnostic outcomes? Can FAS/D prevalence estimates from this clinical population be used to estimate FAS/D prevalence estimates in the general population? Do FASD diagnostic outcomes vary by race, age or alcohol exposure? Does the presence of other adverse exposures/events lead to more severe outcomes? Does this approach to diagnosis meet the needs of families? RESULTS: Demand for diagnosis remains very high. Of 1,400 patients (newborn to adult) with confirmed prenatal alcohol exposure, 11% were diagnosed with FAS/PFAS, 28% with static encephalopathy, 52% with neurobehavioral disorder, and 9% with no evidence of CNS abnormality. FASD outcomes varied significantly by age, race, gender, alcohol exposure, and presence of other risk factors. Families reported high satisfaction with the diagnostic process, and receipt of information/services they were unable to obtain elsewhere. CONCLUSIONS: This report documents the immense contribution of a statewide FASD diagnostic program, and underscores the extraordinary value of a comprehensive FASD clinical dataset.

Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders.

BACKGROUND: Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. METHODS: A comprehensive neuropsychological/psychiatric battery, coupled with MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessments, were administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The 4 study groups included: (i) fetal alcohol syndrome (FAS)/partial FAS (PFAS); (ii) static encephalopathy/alcohol exposed (SE/AE); (iii) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (iv) healthy peers with no prenatal alcohol exposure. Presented here are the MRI assessments that were used to compare the sizes of brain regions between the 4 groups. The neuropsychological/behavioral, MRS, and fMRI outcomes are reported separately. RESULTS: Progressing across the 4 study groups from Controls to ND/AE to SE/AE to FAS/PFAS, the mean absolute size of the total brain, frontal lobe, caudate, putamen, hippocampus, cerebellar vermis, and corpus callosum length decreased incrementally and significantly. The FAS/PFAS group (the only group with the 4-Digit FAS facial phenotype) had disproportionately smaller frontal lobes relative to all other groups. The FAS/PFAS and SE/AE groups [the 2 groups with the most severe central nervous system (CNS) dysfunction] had disproportionately smaller caudate regions relative to the ND/AE and Control groups. The prevalence of subjects in the FAS/PFAS, SE/AE, and ND/AE groups that had 1 or more brain regions, 2 or more SDs below the mean size observed in the Control group was 78, 58, and 43%, respectively. Significant correlations were observed between size of brain regions and level of prenatal alcohol exposure, magnitude of FAS facial phenotype, and level of CNS dysfunction. CONCLUSIONS: Magnetic resonance imaging provided further validation that ND/AE, SE/AE, and FAS/PFAS as defined by the FASD 4-Digit Code are 3 clinically distinct and increasingly more affected diagnostic subclassifications under the umbrella of FASD. Neurostructural abnormalities are present across the spectrum. MRI could importantly augment diagnosis of conditions under the umbrella of FASD, once population-based norms for structural development of the human brain are established.

Magnetic resonance spectroscopy outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders.

Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. A comprehensive neuropsychological/behavioral, MR imaging (MRI), MR spectroscopy (MRS) and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine whether global and/or focal abnormalities could be identified and to distinguish diagnostic subclassifications across the spectrum. The four study groups included (1) FAS/partial FAS; (2) static encephalopathy/alcohol exposed (SE/AE); (3) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (4) healthy peers with no prenatal alcohol exposure. Results are presented in four separate reports: MRS (reported here) and neuropsychological/behavioral, MRI and fMRI outcomes (reported separately). MRS was used to compare neurometabolite concentrations [choline (Cho), n-acetyl-aspartate (NAA) and creatine (Cre)] in a white matter region and a hippocampal region between the four study groups. Choline concentration in the frontal/parietal white matter region, lateral to the midsection of the corpus callosum, was significantly lower in FAS/PFAS relative to all other study groups. Choline decreased significantly with decreasing frontal white matter volume and corpus callosum length. These outcomes suggest low choline concentrations may reflect white matter deficits among FAS/PFAS. Choline also decreased significantly with increasing severity of the 4-Digit FAS facial phenotype, increasing impairment in psychological performance and increasing alcohol exposure. NAA and Cre concentrations did not vary significantly. This study provides further evidence of the vulnerability of the cholinergic system in FASD.

Neuropyschological and behavioral outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders.

BACKGROUND: Clinical and research advancements in the field of fetal alcohol spectrum disorders (FASD) require accurate and valid identification of FASD clinical subgroups. OBJECTIVES: A comprehensive neuropsychological battery, coupled with magnetic resonance imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) were administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified across the spectrum, and distinguish diagnostic subclassifications within the spectrum. The neuropsychological outcomes of the comprehensive neuroimaging study are presented here. METHODS: The study groups included: 1) FAS/Partial FAS; 2) Static Encephalopathy/Alcohol Exposed (SE/AE); 3) Neurobehavioral Disorder/Alcohol Exposed (ND/AE) as diagnosed by an interdisciplinary team using the FASD 4-Digit Code; and 4) healthy peers with no prenatal alcohol. A standardized neuropsychological battery was administered to each child and their primary caregiver by a psychologist. RESULTS: Use of the 4-Digit Code produced three clinically and statistically distinct FASD clinical subgroups. The three subgroups (ND/AE, SE/AE and FAS/PFAS) reflected a linear continuum of increasing neuropsychological impairment and physical abnormality, representing the full continuum of FASD. Behavioral and psychiatric disorders were comparably prevalent across the three FASD groups, and significantly more prevalent than among the Controls. All three FASD subgroups had comparably high levels of prenatal alcohol exposure. CONCLUSIONS: Although ND/AE, SE/AE, and FAS/PFAS are distinct FASD subgroups, these groups are not distinguishable solely by their neuropsychological profiles. While all children within a group shared the same magnitude of neuropsychological impairment, the patterns of impairment showed considerable individual variability. MRI, MRS and fMRI further distinguished these FASD subgroups.

Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders.

A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N-back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potential research and diagnostic value of this non-invasive MR tool in the field of FASD.

Exploring the utility of narrative analysis in diagnostic decision making: picture-bound reference, elaboration, and fetal alcohol spectrum disorders.

PURPOSE: To evaluate classification accuracy and clinical feasibility of a narrative analysis tool for identifying children with a fetal alcohol spectrum disorder (FASD). METHOD: Picture-elicited narratives generated by 16 age-matched pairs of school-aged children (FASD vs. typical development [TD]) were coded for semantic elaboration and reference strategy by judges who were unaware of age, gender, and group membership of the participants. Receiver operating characteristic (ROC) curves were used to examine the classification accuracy of the resulting set of narrative measures for making 2 classifications: (a) for the 16 children diagnosed with FASD, low performance (n = 7) versus average performance (n = 9) on a standardized expressive language task and (b) FASD (n = 16) versus TD (n = 16). RESULTS: Combining the rates of semantic elaboration and pragmatically inappropriate reference perfectly matched a classification based on performance on the standardized language task. More importantly, the rate of ambiguous nominal reference was highly accurate in classifying children with an FASD regardless of their performance on the standardized language task (area under the ROC curve = .863, confidence interval = .736-.991). CONCLUSION: Results support further study of the diagnostic utility of narrative analysis using discourse level measures of elaboration and children's strategic use of reference.

Comparison of the 4-digit diagnostic code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders.

OBJECTIVE: The 4-Digit Diagnostic Code for fetal alcohol spectrum disorders and the Hoyme fetal alcohol spectrum disorders diagnostic guidelines differ markedly. The performances of the 2 diagnostic systems were compared. METHODS: The fetal alcohol syndrome diagnostic criteria from the 4-Digit Code and Hoyme guidelines were applied to 952 patients who had received an interdisciplinary, fetal alcohol spectrum disorders, diagnostic evaluation at the University of Washington with the 4-Digit Diagnostic Code and 16 children with confirmed absence of prenatal alcohol exposure. RESULTS: The prevalence of fetal alcohol syndrome was 3.7% with the 4-Digit Code and 4.1% with the Hoyme guidelines. Although the prevalences were similar, the patients identified were not. Only 17 individuals met the fetal alcohol syndrome criteria for both systems. An extraordinary number of patients (35%) met the Hoyme criteria for the fetal alcohol syndrome facial phenotype, but only 39 of those 330 patients met the Hoyme criteria for fetal alcohol syndrome. Even some children with no alcohol exposure (25%) had the Hoyme fetal alcohol syndrome face. The specificities of the Hoyme fetal alcohol syndrome face for the Hoyme fetal alcohol syndrome diagnosis and prenatal alcohol exposure were low in these populations. CONCLUSIONS: Without a specific facial phenotype, a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with prenatal alcohol exposure, because a causal link between their outcomes and exposure cannot be established, and a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with unknown alcohol exposure, because the face cannot serve as a valid proxy measure for alcohol exposure. Diagnostic guidelines must confirm the specificity of their fetal alcohol syndrome facial criteria to validate their diagnostic criteria.

Fetal alcohol syndrome prevention in Washington State: evidence of success.

Fetal alcohol syndrome (FAS) is a permanent birth defect syndrome caused by maternal consumption of alcohol during pregnancy. It is characterised by growth deficiency, central nervous system damage/dysfunction, and a unique cluster of minor facial anomalies. To assess the effectiveness of fetal alcohol syndrome prevention efforts, one must be able to estimate accurately the prevalence of fetal alcohol syndrome over time in population-based samples. With the establishment of the Washington State Fetal Alcohol Syndrome Diagnostic and Prevention Network of clinics, the development of the Fetal Alcohol Syndrome Facial Photographic Analysis Software, the creation of the Fetal Alcohol Spectrum Disorders (FASD) 4-Digit Diagnostic Code, the establishment of the Foster Care Fetal Alcohol Syndrome Screening Program, and the collection of Pregnancy Risk Assessment Management System data on maternal use of alcohol during pregnancy, the tools, methods and infrastructure for assessing the effectiveness of fetal alcohol syndrome primary prevention efforts in Washington State are in place. A cross-sectional study was conducted to determine whether the prevalence of fetal alcohol syndrome among children in a foster care population, born between 1993 and 1998, decreased with the documented decrease in prevalence of maternal use of alcohol during pregnancy from 1993 and 1998 in Washington State. The prevalence of maternal drinking during pregnancy in Washington State declined significantly (P < 0.001) from 1993 to 1998 as did the prevalence of fetal alcohol syndrome among foster children born 1993-98 (P < 0.03). These observations support the likelihood that fetal alcohol syndrome prevention efforts in Washington State are working successfully.

Application of the fetal alcohol syndrome facial photographic screening tool in a foster care population.

We determined the prevalence of fetal alcohol syndrome (FAS) in a foster care population and evaluated the performance of the FAS Facial Photographic Screening Tool. All children enrolled in a Washington State Foster Care Passport Program were screened for three conditions: (1) the FAS facial phenotype from a photograph, (2) evidence of brain damage with prenatal alcohol exposure from their Health and Education passport, and/or (3) other syndromes identifiable from a facial photograph. Screen-positives received diagnostic evaluations at a FAS Diagnostic and Prevention Network clinic. The prevalence of FAS in this foster care population was 10 to 15/1000, or 10 to 15 times greater than in the general population. The screening tool performed with 100% sensitivity, 99.8% specificity, 85.7% predictive value positive, and 100% predictive value negative. We conclude that the foster care population is a high-risk population for FAS. The screening tool performed with very high accuracy and could be used to track FAS prevalence over time in foster care to accurately assess the effectiveness of primary prevention efforts.