Fetal Alcohol Syndrome: An International Perspective

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Kenneth R. Warren and Faye J. Calhoun. The presentations were (1) Epidemiological research on fetal alcohol syndrome (FAS) in the United States, by Philip A. May; (2) An overview of fetal alcohol syndrome in the Western Cape Province of South Africa, by Denis L. Viljoen and Ting-Kai Li; (3) Diagnostic perspectives of fetal alcohol and tobacco syndromes, by Harumi Tanaka; (4) FAS among pupils of special boarding schools and orphanages in Moscow, Russia, by Galina S. Marinicheva and Luther K. Robinson; and (5) Research on FAS and FAE in Germany: Update and perspectives, by Goetz Mundle.     

Neuropsychological Deficits in Fetal Alcohol Syndrome and Fetal Alcohol Effects

A clinical sample of 19 school-aged native children diagnosed with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) was compared with age- and sex-matched normal controls. Results on a battery of intellectual and neuropsychological tests indicated large and significant differences between alcohol-affected children and controls. FAS differed significantly from controls on measures of intellectual abilities, while FAE did not; FAS mean scores on these measures were significantly lower than FAE means. For neuropsychological measures, FAS were significantly poorer than controls on most measures, while FAE showed deficits compared with controls only on grip strength. The results suggest that neuropsychological measures would be a valuable supplement to intellectual measures for the purpose of assessing alcohol effects because they are less vulnerable than intellectual measures to the influence of cultural and educational experiences.     

Congenital Heart Defects and Fetal Alcohol Spectrum Disorders

Objective. Review of the prevalence of congenital heart defects (CHD) and fetal alcohol spectrum disorder (FASD). Design. We conducted a search of the Medline and Pubmed databases to identify papers reporting the association. We then searched the reference lists of the papers and reference books for additional sources. Results. We found 29 studies that met our inclusion criteria. In the 12 case series studies of subjects with FASD, the proportion of cases with a CHD (atrial [ASD] and ventricular [VSD] septal defects, other defects, or unspecified CHD) ranged from 33% to 100%. From the 14 retrospective studies, the rate of septal defects was 21%, other structural defects 6% and unspecified defects was 12%. For the 2 case–control studies, the odds of CHD ranged from 1.0 (subjects with fetal alcohol effect) to 18.0 (subjects with fetal alcohol syndrome). In the 1 prospective study of CHD the OR for a child to have CHD and FASD was 1.0. Key Conclusion. Pediatric cardiologists may have frequent contact with children with FASD and increased levels of attention to prenatal alcohol exposure as a potential etiology of CHD is indicated.     

A Fetal Alcohol Syndrome Screening Tool

The purpose of this study was to derive a multivariate, quantitative case definition of the fetal alcohol syndrome (FAS) facial phenotype from a dysmorphologist-derived gold standard and use it to develop an effective screening tool for identification of children at risk for FAS. The facial and physical features of a racially mixed group of children (0.2–10.0 years of age), evaluated by a single dysmorphologist in the University of Washington FAS Clinic, were used to determine which feature or set of features best differentiated between children with and without a diagnosis of FAS. The study population was divided into two groups balanced on gender, age at examination, race, diagnosis, and date of examination. Group 1 was used to identify the most differentiating feature(s), and group 2 was used to validate the differentiating capability of the feature(s). Group 1 included 97 children (20 with FAS and 77 without FAS). Group 2 included 97 children (19 with FAS and 78 without FAS). Discriminant analysis identified smooth philtrum, thin upper lip, and short palpebral fissures as the cluster of features that best differentiated children with and without FAS based on the discriminant function [D = 1.7953086 + 0.8116083 (thin upper lip) + 2.6411562 (smooth philtrum) - 3.4073780 (% predicted right palpebral fissure length)]. Patients with a D-score ± 1.5 were classified as at-risk for FAS (screen positive). Using this cut-off value for the D-score, children in group 1 were classified with 100% sensitivity (20 of 20 true positives) and 90.0% specificity (70 of 77 true negatives). The children in group 2 were classified with 100% sensitivity (19 of 19 true positives) and 87.3% specificity (68 of 78 true negatives). Across all 194 patients, sensitivity was 100% [95% confidence interval (97–100)] and specificity was 89% [95% confidence interval (85 to 93)]. Seventy-one percent (n= 12) of the 17 false-positives had a true classification of possible fetal alcohol effects. Sensitivity and specificity were unaffected by race, gender, and age through 10 years. This screening tool is effective at differentiating children with and without FAS as diagnosed by a single dysmorphologist (S.K.C.) at the University of Washington FAS Clinic. Assessment of diagnostic interrater agreement between trained dysmorphologists and testing in other clinic populations will be needed to assess the tool's external validity.     

Characterization of White Matter Microstructure in Fetal Alcohol Spectrum Disorders

Background:  Exposure to alcohol during gestation is associated with CNS alterations, cognitive deficits, and behavior problems. This study investigated microstructural aspects of putative white matter abnormalities following prenatal alcohol exposure.
Methods:  Diffusion tensor imaging was used to assess white matter microstructure in 27 youth (age range: 8 to 18 years) with ( n  = 15) and without ( n  = 12) histories of heavy prenatal alcohol exposure. Voxelwise analyses, corrected for multiple comparisons, compared fractional anisotropy (FA) and mean diffusivity (MD) between groups, throughout the cerebrum.
Results:  Prenatal alcohol exposure was associated with low FA in multiple cerebral areas, including the body of the corpus callosum and white matter innervating bilateral medial frontal and occipital lobes. Fewer between-group differences in MD were observed.
Conclusions:  These data provide an account of cerebral white matter microstructural integrity in fetal alcohol spectrum disorders and support extant literature showing that white matter is a target of alcohol teratogenesis. The white matter anomalies characterized in this study may relate to the neurobehavioral sequelae associated with gestational alcohol exposure, especially in areas of executive dysfunction and visual processing deficits.     

Toward a Neurobehavioral Profile of Fetal Alcohol Spectrum Disorders

Background: A primary goal of recent research is the development of neurobehavioral profiles that specifically define fetal alcohol spectrum disorders (FASD), which may assist differential diagnosis or improve treatment. In the current study, we define a preliminary profile using neuropsychological data from a multisite study. Methods: Data were collected using a broad neurobehavioral protocol from 2 sites of a multisite study of FASD. Subjects were children with heavy prenatal alcohol exposure and unexposed controls. The alcohol‐exposed group included children with and without fetal alcohol syndrome (FAS). From 547 neuropsychological variables, 22 variables were selected for analysis based on their ability to distinguish children with heavy prenatal alcohol exposure from nonexposed controls. These data were analyzed using latent profile analysis (LPA). Results: The results indicated that a 2‐class model best fit the data. The resulting profile was successful at distinguishing subjects with FAS from nonexposed controls without FAS with 92% overall accuracy; 87.8% of FAS cases and 95.7% of controls were correctly classified. The same analysis was repeated with children with heavy prenatal alcohol exposure but without FAS and nonexposed controls with similar results. The overall accuracy was 84.7%; 68.4% of alcohol‐exposed cases and 95% of controls were correctly classified. In both analyses, the profile based on neuropsychological variables was more successful at distinguishing the groups than was IQ alone. Conclusions: We used data from 2 sites of a multisite study and a broad neuropsychological test battery to determine a profile that could be used to accurately identify children affected by prenatal alcohol exposure. Results indicated that measures of executive function and spatial processing are especially sensitive to prenatal alcohol exposure.     

Perspectives on the Pathophysiology of Fetal Alcohol Syndrome

Fetal alcohol syndrome (FAS) is a major known cause of fetal malformations and mental retardation. Prevention/intervention of FAS can only be achieved with identification of the mechanisms by which alcohol induces birth defects. The purpose of this paper is to discuss the data on possible mechanisms of FAS, and to give a number of suggestions for future research areas.     

Comparison of Social Abilities of Children with Fetal Alcohol Syndrome to Those of Children with Similar IQ Scores and Normal Controls

Children diagnosed with fetal alcohol syndrome (FAS) were assessed with items from the social skills domain of the Vineland Adaptive Behavior Scales (VABS) via interviews with their caregivers. Their scores were compared with scores from children in two control groups. The control groups included children matched for IQ to the FAS group (specifically on verbal IQ, henceforth, the VIQ group) and children with IQ scores in the average to above-average range (normal control group). Forty-five children (age range, 5 years 7 months to 12 years 11 months) were assessed ( n /group = 15). All groups differed with regard to social ability, as measured by the VABS (NC > VIQ > FAS), even when the effects of socioeconomic status were held constant. The three subdomains of the VABS social scale (interpersonal relationship skills, use of play and leisure time, and coping skills) were assessed, and results showed that the children with FAS were most impaired on the subdomain that assessed interpersonal relationship skills. An additional measure was constructed by obtaining an age-equivalent score for the VABS social scale and calculating a difference score by subtracting the child's chronological age from his/her age-equivalent score. There was a significant correlation between chronological age and difference scores for children in the FAS group but not for children in the two control groups. Specifically, in older children with FAS, there was an increased discrepancy between their ages and their age-equivalent scores, a discrepancy that was not present in children in the control groups. These results suggest that social deficits in children with FAS are beyond what can be explained by low IQ scores and indicate that there may be arrested, and not simply delayed, development of social abilities in children with FAS.     

Verbal and Nonverbal Memory in Adults Prenatally Exposed to Alcohol

Background: Neurocognitive effects of prenatal alcohol exposure in adulthood are not well documented. Questions persist regarding the extent to which there are specific, measurable effects beyond those associated with global ability deficits, whether individuals without the full fetal alcohol syndrome (FAS) demonstrate alcohol‐related cognitive impairments, and whether observed memory effects are specific to a particular modality, i.e., verbal vs. visual/spatial domains. Methods: In this study, verbal and nonverbal selective reminding paradigms were used to assess memory function in 234 young adults (M age: 22.78, SD: 1.79). Alcohol exposure was quantified prenatally. Alcohol groups included: Individuals with physical effects of alcohol exposure (Dysmorphic group, n = 47); Exposed individuals without such effects (n = 74). Contrast groups included: Controls (n = 59) matched for ethnicity, socioeconomic status, and hospital of birth; Special Education contrast group (n = 54) included to control for disability status. Memory outcomes entailed total recall, delayed recall, and measures of encoding and retrieval, and learning over trials as indexed by slope. Results: Results indicated that Dysmorphic individuals were significantly less efficient in memory performance than Controls on all of the outcomes measured, but they did not differ from those in the Special Education contrast group. The nondysmorphic, alcohol‐exposed group was intermediate in their performance, suggesting a continuum of effects of prenatal exposure. Evaluation of the encoding and retrieval aspects of memory performance indicated that learning rather than forgetting accounted for the deficits associated with prenatal alcohol exposure. Finally, no interaction was found between modality of presentation (verbal and nonverbal) and effects of alcohol exposure on memory performance. Conclusion: These findings indicate that prenatal alcohol exposure is associated with persistent and specific effects on memory performance, and these problems result from less efficient encoding of information across both verbal and nonverbal modalities. Education and training efforts with this clinical group should take these characteristics into account.     

An fMRI Study of Number Processing in Children With Fetal Alcohol Syndrome

Background: Number processing deficits are frequently seen in children exposed to alcohol in utero. Methods: Functional magnetic resonance imaging was used to examine the neural correlates of number processing in 15 right‐handed, 8‐ to 12‐year‐old children diagnosed with fetal alcohol syndrome (FAS) or partial FAS (PFAS) and 18 right‐handed, age‐ and gender‐matched controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, using Proximity Judgment and Exact Addition tasks. Results: Control children activated the expected fronto‐parietal network during both tasks, including the anterior horizontal intraparietal sulcus (HIPS), left posterior HIPS, left precentral sulcus, and posterior medial frontal cortex. By contrast, on the Proximity Judgment task, the exposed children recruited additional parietal pathways involving the right and left angular gyrus and posterior cingulate/precuneus, which may entail verbally mediated recitation of numbers and/or subtraction to assess relative numerical distances. During Exact Addition, the exposed children exhibited more diffuse and widespread activations, including the cerebellar vermis and cortex, which have been found to be activated in adults engaged in particularly challenging number processing problems. Conclusions: The data suggest that, whereas control children rely primarily on the fronto‐parietal network identified in previous studies to mediate number processing, children with FAS/PFAS recruit a broader range of brain regions to perform these relatively simple number processing tasks. Our results are consistent with structural neuroimaging findings indicating that the parietal lobe is relatively more affected by prenatal alcohol exposure and provide the first evidence for brain activation abnormalities during number processing in children with FAS/PFAS, effects that persist even after controlling statistically for group differences in total intracranial volume and IQ.     

The Effects of Fetal Alcohol Syndrome on Response Execution and Inhibition: An Event-Related Potential Study

Background: Both executive function deficits and slower processing speed are characteristic of children with fetal alcohol exposure, but the temporal dynamics of neural activity underlying cognitive processing deficits in fetal alcohol spectrum disorder have rarely been studied. To this end, event‐related potentials (ERPs) were used to examine the nature of alcohol‐related effects on response inhibition by identifying differences in neural activation during task performance. Methods: We recorded ERPs during a Go/No‐go response inhibition task in 2 groups of children in Cape Town, South Africa (M age = 11.7 years; range = 10 to 13)—one diagnosed with fetal alcohol syndrome (FAS) or partial FAS (FAS/PFAS; n = 7); the other, a control group whose mothers abstained or drank only minimally during pregnancy (n = 6). Children were instructed to press a “Go” response button to all letter stimuli presented except for the letter “X,” the “No‐go” stimulus, which occurred relatively infrequently. Results: Task performance accuracy and reaction time did not differ between groups, but differences emerged for 3 ERP components—P2, N2, and P3. The FAS/PFAS group showed a slower latency to peak P2, suggesting less efficient processing of visual information at a relatively early stage (～200 ms after stimulus onset). Moreover, controls showed a larger P2 amplitude to Go versus No‐go, indicating an early discrimination between conditions that was not seen in the FAS/PFAS group. Consistent with previous literature on tasks related to cognitive control, the control group showed a well‐defined, larger N2 to No‐go versus Go, which was not evident in the FAS/PFAS group. Both groups showed the expected larger P3 amplitude to No‐go versus Go, but this condition difference persisted in a late slow wave for the FAS/PFAS group, suggesting increased cognitive effort. Conclusions: The timing and amplitude differences in the ERP measures suggest that slower, less efficient processing characterizes the FAS/PFAS group during initial stimulus identification. Moreover, the exposed children showed less sharply defined components throughout the stimulus and response evaluation processes involved in successful response inhibition. Although both groups were able to inhibit their responses equally well, the level of neural activation in the children with FAS/PFAS was greater, suggesting more cognitive effort. The specific deficits in response inhibition processing at discrete stages of neural activation may have implications for understanding the nature of alcohol‐related deficits in other cognitive domains as well.