Increased Mortality Risk in Children with Fetal Alcohol Spectrum Disorders: A Scoping Review

Objective: Fetal Alcohol Spectrum Disorders (FASDs) are common, often undiagnosed, lifelong developmental disorders that result from prenatal alcohol exposure. FASD is present at birth and typically identified around seven years of age. The most severe outcome in cases of FASD is mortality. The purpose of this scoping review is to 1) use a systematic review to provide an estimated mortality proportion for children with FASD, and 2) update a study published in 2014 by reviewing published reports of mortality in individuals diagnosed with FASD. Method: A search of PubMed, CINAHL, and Google Scholar for reports published between 2013 and 2023 on mortality in individuals with FASD. Results: Three population-based studies have reported on all-cause mortality rates, finding a combined mortality rate of 10.9%, a 2.63 fold (95% CI: 2.61 to 2.65) increase in mortality risk over the general population. Since 2016, this review identified only eight new cases meeting the study inclusion criteria. The reported causes of death were five cases of pneumonia, and one case each of failure to thrive and dehydration, intestinal dilatation and asphyxiation caused by overeating due to pica, and acute gastric volvulus. Discussion: While current research suggests a diagnosis of FASD is associated with a 2.6-fold increase in mortality risk, this is likely an underestimation, as most cases of FASD-related mortality go unreported. Globally, about 1 new case is reported every 15 months. However, in the United States alone, between 1752 to 4400 FASD related deaths occur annually. Our review suggests that FASD is rarely identified as a causal or contributing factor in deaths of children and adolescents, resulting in a substantial undercount of FASD-related deaths. Increased attention to the role of FASD in infant and child mortality case reviews, child death review committee reports, and mortality reviews is needed.

Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder

Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.

Is a Mini-Screen for Fetal Alcohol Spectrum Disorder Feasible?

Background: Fetal Alcohol Spectrum Disorders (FASDs) are a global public health concern with lifelong consequences for affected individuals. Recent prevalence studies suggest FASD prevalence rates range from 1-5% among school age children. Most people with FASD are not correctly diagnosed and inadequate screening to identify patients with increased risk may contribute to under-diagnosis. This study developed a 10-item screening tool for FASD and examined its feasibility. Methods: The sample consisted of 355 children who had been evaluated at an FASD clinic. Data from the 33-item Alcohol Related Neurodevelopmental Disorder Behavioral Checklist was used to develop a brief FASD screen by comparing the changes in Cronbach’s alpha for different combinations of items. The validity of the brief scale was then further examined using receiving operating characteristic analyses. Results: The 10-item screen demonstrated acceptable sensitivity, specificity, and accuracy to identify children at high risk for FASD. The percentage correctly classified was 91.3 and the area under the receiving operating characteristic curve was 0.971. Conclusions: This feasibility study demonstrated that a screen for FASD consisting of 10 items with yes or no responses can be completed in 3 - 4 minutes. The tool is brief, with a low administration burden and has acceptable epidemiologic performance characteristics including accuracy. Future research should examine the performance of this tool when used in larger, community-based populations where screening for FASD would be appropriate.

Fetal alcohol spectrum disorder: molecular insights into neural damage reduction

Fetal alcohol spectrum disorders（FASD）is a group of entirely preventable,lifelong conditions,which occur upon maternal alcohol use during pregnancy.This can result in severe consequences for the newborn and ultimately the family.It is usually characterized by delays in development and motor function,craniofacial abnormalities,and difficulties with learning,memory,speech,and academic achievement.According to the German guidelines for fetal alcohol syndrome （FAS） diagnosis, the prevalence of FASD ranges between 0.02-0.8% of all annual births and often the disorder is not recognized （Landgraf et al., 2013）. The U.S. National Institutes of Health regard FAS as the most common nonhereditary cause of mental retardation. Thus, preventing programs, like the one undertaken by the Aus- tralian Government, which appointed a National FASD Techni- cal Network （Elliott, 2015）, may seem a very reasonable strategy.

Neurobiology of Neuronal Network Alteration in Intellectual Disability Related to Fetal Alcohol Spectrum Disorders

The molecular and cellular mechanisms by which alcohol produces its deleterious effects on neuronal networks are only now beginning to be understood. This review focused on alcohol-induced neurobiological alterations on neuronal network components underlying information processing, for further understanding of intellectual disability related to FASD. Abnormal neurodevelopmental events related to alcohol-damaged fetal brain included neurogenesis inhibition, aberrant migration, impaired differentiation, exacerbated apoptosis, impaired axon outgrowth and branching altering synaptogenesis and synaptic plasticity, abnormal GABAergic interneurons triggering synaptic inhibitory/excitatory imbalance, reduced myelinogenesis causing injured white matter in prefrontal lobe and atrophied corpus callosum compromising interhemispheric information transfer, the whole compromising neuronal network scaffolding which may lead to biased information processing with deficits in executive function. What added to these abnormalities are smaller gray matter and reduced hippocampus, resulting in cognition and memory failures. As a whole, these developmental disorders may underlie intellectual disability related to FASD. In rodents, these neuronal network components matured mainly during the second and third trimesters equivalents of human gestation. Transferability of results from animal to human was also discussed. It was hoped that the understanding of alcohol-induced neuronal networks failure mechanisms during the developing brain may lay a foundation for prospective new treatments and interventions.

Relationships between Fetal Alcohol Spectrum Disorder, Adverse Childhood Experiences, and Neurodevelopmental Diagnoses

Objective: Children with fetal alcohol spectrum disorder (FASD) are overrepresented in early intervention programs, foster care, special education, juvenile corrections, and mental health services. In this study, we examine relationships between FASD and non-FASD controls for adverse childhood experiences (ACEs), and neurodevelopmental disorders. Methods: A chart review was conducted among patients seen at our clinic from 2010-2017 with data on FASD, ACEs, neurodevelopmental diagnoses, and foster or residential care placement available. Results: Relative risk for FASD was increased in patients with increased ACE scores (RR = 5.08), increased numbers of neurodevelopmental diagnoses (RR = 2.36), and patients who have been in foster or residential care (RR = 9.53). FASD risk increased as ACE scores or the number of neurodevelopmental diagnoses increased. Patients with any ACEs were 3.96 times more likely to have FASD, and those with eight or more ACEs were 6.31 times more likely to have FASD than those with no ACEs. Patients with three or more neurodevelopmental diagnoses were 6.55 times more likely to have FASD than those with two or fewer diagnoses. Nine or more diagnoses increased the risk for FASD ten-fold (RR = 10.91). Conversely, patients diagnosed with FASD were more likely to have at least three ACEs (RR = 3.71), at least five neurodevelopmental diagnoses (RR = 1.61), and high rates of previous foster or residential care placement (RR = 5.39). Conclusion: This study demonstrates that all children being considered for placement in foster care or residential should be screened for FASD.