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.

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.

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.

Mortality in Fetal Alcohol Spectrum Disorders

Objective: Mortality in FASD has not been well studied. In this paper we review published reports of mortality in FASD. Method: We searched using Pub Med for all years in all languages for reports of all-cause mortality associated with any FASD. Results: We located 26 papers reporting on 57 deaths. Cause of death was reported for 49/57 cases (86%). The two most prevalent potential causes of death were malformations of the heart (37 of 49 cases, 75.5%) which varied from atrial septal defect or patent ductus arteriosus to tetralogy of Fallot, hypoplastic left heart, aortic arch interruption, etc. and brain malformations(25 of 49, 51%) including microcephaly, hydrocephalus, porencephaly, agenesis/absence of the corpus callosum and semilobar holoprosencephaly. In several cases potential causal findings overlapped. The three most frequent other causes of death were sepsis (7 cases, 14.3%), kidney malformations (7 cases, 14.3%), and cancer (4 cases, 8.2%). Over half the deaths (30/55, 54.5%) occurred in the first year of life. Discussion: We found that congenital heart disease was the most common cause of death in people with FASD. This may be due to an ascertainment bias since many of the published studies were focused on congenital heart disease in FASD. We conclude that FASD is frequently undetected in mortality events and could be a common finding in infant, child, adolescent and adult mortality.

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.

Neurodevelopmental Timing of Ethanol Exposure May Contribute to Observed Heterogeneity of Behavioral Deficits in a Mouse Model of Fetal Alcohol Spectrum Disorder (FASD)

Maternal drinking during pregnancy can result in a wide spectrum of cognitive and behavioral abnormalities termed fetal alcohol spectrum disorders (FASD). The heterogeneity observed in FASD-related phenotypes can be attributed to a number of environmental and genetic factors;however, ethanol dose and timing of exposure may have significant influences. Here, we report the behavioral effects of acute, binge-like ethanol exposure at three neurodevelopmental times corresponding to the first, second, and third trimester of human development in C57BL/6J mice. Results show that developmental ethanol exposure consistently delays the development of basic motor skill reflexes and coordination as well as impairs spatial learning and memory. Observed changes in activity and anxiety-related behaviors, however, appear to be dependent on timing of alcohol exposure. The variability in behaviors between different treatment models suggests that these may be useful in evaluating the mechanisms disrupted by ethanol at specific neurodevelopmental times. The results provide further evidence that, regardless of developmental stage, the developing brain is acutely sensitive to alcohol exposure.

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.

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.

Drinking during pregnancy: Potential role of endocannabinoid signaling in fetal alcohol effects

Alcohol is a well-recognized teratogen that can causevariable physical and behavioral effects on the fetus.Alcohol use and abuse during pregnancy is one of the major health and societal problems and has been linked to a wide range of birth defects in the offspring collectively termed as fetal alcohol spectrum disorder(FASD). The severity of abnormalities may depend on a number of factors that include the amount, the frequency, the period during gestation and the route of alcohol administration. The current knowledge about the neurobiological basis of FASD is limited. However, recent studies have suggested that the membrane-derived lipids especially bioactive endogenous cannabinoids(eCB)such as arachidonyl ethanolamide and 2-arachidonyl glycerol resulting from alcohol exposure, may play a significant role in modulating neurophysiological and neurobehavioral effects in chronic alcohol exposed adult animals. Based on these findings and on reported studies on the role of eCB signaling in neurodevelopment and behavior, it is speculated that the eC B signaling may play a critical role in fetal alcohol syndrome and FASD-related behavioral effects. The current discussion will touch upon some of the mechanistic explanations about the role of eCB signaling system in FASD and provide further guidance for future direction.

Notch信号通路抑制剂DAPT改善酒精诱导的斑马鱼神经元分化障碍

目的探讨Notch信号通路在胎儿酒精谱系障碍(FASD)斑马鱼模型的神经元分化及及感觉-运动能力中的作用。方法首先,将斑马鱼胚胎分为二甲基亚砜(DMSO)组和50μmol/L氮-[氮-(3,5-二氟苯乙酰基)-L-丙氨酰]-S-苯基甘氨酸丁酯(DAPT,Notch信号通路抑制剂)处理组,检测比较两组斑马鱼的死亡率、孵化率以及畸形率;比较两组斑马鱼的身体长度;利用原位杂交和qRT-PCR技术检测两组神经干/前体细胞标志物sox2、神经前体细胞分化因子neurogenin1、神经元标志物huc的表达;检测两组在无刺激、强光、震动刺激情况下的行为学表现。其次,将斑马鱼胚胎分为DMSO组、1.5%酒精处理组、DAPT处理组、酒精和DAPT联合处理组,利用原位杂交和qRT-PCR技术检测各组sox2、neurogenin1、huc的表达,检测Notch信号通路相关基因(Notch)信号受体notch1a,促进神经发育的靶基因her8a及Notch胞内活性片段(NICD)的mRNA表达水平;检测各组在无刺激、强光、震动刺激情况下的行为学表现。结果50μmol/L DAPT处理斑马鱼胚胎后,受精后1 d(1 dpf)胚胎死亡率(P<0.01)显著增加,2 dpf孵化率显著降低(P<0.01),3 dpf畸形率(P<0.001)显著增加,15 dpf斑马鱼体长显著缩短(P<0.05);斑马鱼胚胎sox2表达水平显著降低(P<0.01),neurogenin1(P<0.05)和huc mRNA(P<0.01)表达水平显著增加;在无刺激、强光、震动刺激情况下,DAPT处理组的斑马鱼运动距离均显著缩短(P<0.001),运动速度均显著降低(P<0.05)。单独使用1.5%酒精处理斑马鱼胚胎后,notch1a、her8a及NICD的mRNA表达水平显著升高(P<0.05);1.5%酒精联合DAPT处理斑马鱼胚胎后,较酒精单独处理组,neurogenin1和huc mRNA表达水平显著增加,sox2 mRNA表达水平显著降低(P<0.01),在强光刺激下的运动距离显著变长,运动速度显著变快(P<0.05)。结论酒精上调斑马鱼胚胎Notch信号、抑制神经元分化并降低感觉-运动能力,而抑制Notch信号通路可改善斑马鱼胚胎神经元分化及感觉-运动能力。

MECP2在认知障碍性疾病中的研究进展

甲基CpG结合蛋白2(methyl-CpG-binding protein 2,MECP2)是大脑中DNA甲基化的主要标志物,是一种核蛋白,是中枢神经系统的重要调控因子。MECP2特异性与二核苷酸5CpG的胞嘧啶甲基化的DNA结合,能够参与突触重塑、神经发育、大脑功能维持、促使行为改变、电位平衡调节等神经系统生理过程。MeCP2在脑内分布有差异性,缺失或过表达均会导致神经系统疾病,改变机体社交行为、精神活动等,受到靶基因、激素等反馈调节。Rett综合征(Rett Syndrome,RTT)、MeCP2重复综合征(MECP2 Duplication Syndrome,MDS)、胎儿酒精谱系障碍(Fetal Alcohol Spectrum Disorders,FASD)、孤独症谱系障碍(Autistic Spectrum Disorder,ASD)等认知障碍性疾病均与MECP2突变有关,本文对以往研究综合分析、系统阐述,深入剖析MECP2在认知障碍性疾病中的作用,为Rett综合征、MDS、ASD、FASD治疗寻找新的靶点,提供临床精准诊治。

6城市3708名孕妇风险性饮酒现况调查

目的:了解6城市孕妇的风险性饮酒现况,为进行干预性研究以及制定相关政策提供依据。方法:采用多阶段分层随机整群抽样方法对北京、上海、广州、济南、成都和哈尔滨等6城市的所有行政区,根据经济发展情况进行分层,分别从各层随机选择1~2个城市,每个城市各选择4~6个城区,在入选城区中,分别随机选择2所三甲医院;对每所医院参加产前孕妇学校课程的门诊孕妇进行自填式匿名问卷调查。结果:通过AUDIT-C、T-ACE和TWEAK三个量表筛查显示调查对象在过去1年中饮酒人数分别为712、729和729人,其中风险性饮酒的人数分别为90人(12.6%)、451人(61.9%)和471人(64.6%)。年龄为16~22岁、做家务、学历较低、农业户口,以及在妊娠前3个月吸过烟的孕妇风险性饮酒率高于其他组(P<0.05)。结论:我国孕妇风险性饮酒行为较为普遍,应针对其人群分布特点制定防治策略和干预措施,进而预防胎儿酒精谱系障碍风险的发生。

The Detection of 1-Palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphoethanol and Ethyl Glucuronide in Human Umbilical Cord

In utero exposure to ethanol continues to be a significant public health issue and neonatal healthcare professionals are in need of objective means to identify exposed newborns. The aim of this study was to fully validate two methods for the detection of two direct alcohol biomarkers, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (POPE) and ethyl glucuronide (EtG), in umbilical cord and apply the assays to a group of authentic specimens. The limits of detections were 2 and 1 ng/g for POPE and ETG and the limits of quantitation were 4 and 3 ng/g, respectively. Inter and intra-day precision and accuracy measurements were within 15%. The assays were applied to 308 authentic specimens where we detected POPE in five (1.6%) specimens and EtG in twelve (3.9%) specimens. The mean concentrations were 11.4 ng/g ± 9.4 ng/g and 127.2 ± 227.7 ng/g for POPE and EtG, respectively. This study suggested that umbilical cord was a suitable specimen type for the identification of newborns exposed to ethanol in the womb and the prevalence of POPE and EtG detected in umbilical cord were consistent with the prevalence of self-reported binge drinking reported by the National Birth Defect Prevention Study (NBDPS) and Behavioral Risk Factor Surveillance System (BRFSS). Further studies are required to fully describe the association between the observed concentrations of POPE and EtG in umbilical cord to the level of maternal consumption of ethanol.

胎儿酒精谱系障碍的筛查工具与诊断标准

胎儿酒精谱系障碍是指母孕期酒精暴露导致的从胎儿轻度损伤到典型的胎儿酒精综合征的一系列障碍谱系,被公认为导致胎儿缺陷与儿童发育迟滞的主要原因之一,其症状包含四大类特征:胎儿宫内发育迟滞和/或出生后发育迟滞;中枢神经系统功能异常;颜面特征畸形(眼睑裂短、人中平以及上唇薄等);母孕期酒精暴露。本文介绍该胎儿酒精谱系障碍的筛查工具和诊断标准。

Protection role of resveratrol against alcohol-induced heart defect in zebrafish embryos

To the Editor:Alcohol-induced heart defect is one of the most important clinical manifestations of fetal alcohol spectrum disorder(FASD),characterized by atrioventricular septal defect and arterial conical deformity.[1]Resveratrol,a polyphenol component of the traditional Chinese herb Polygonum cuspidatum,which is mainly extracted from its rhizome,is known to exhibit beneficial effects on the cardiovascular system.For example,resveratrol has beneficial effects on heart dysfunction,myocardial hypertrophy,and pressure overload.Moreover,resveratrol was found to inhibit platelet aggregation,prevent atherosclerosis,and scavenge free radicals.[2]However,the effect of resveratrol on alcohol-induced heart defect during heart formation is still unknown.The unique characteristics of zebrafish embryos,such as their transparent body,in vitro fertilization,and short reproductive cycle,make them an attractive tool for cardiovascular research.Moreover,the immersion-based alcohol delivery method used with zebrafish embryos is non-invasive unlike most of the alcohol administration protocols applied in rodent models.

广州市孕妇饮酒行为及饮酒风险评估

目的了解广州市孕妇饮酒行为并对其风险进行评估。方法 2013年7月~8月间采用多阶段分层整群抽样的方法,对在医院产科门诊就诊的孕妇进行问卷调查,了解孕妇的基本情况和饮酒现况,并用胎儿酒精谱系障碍（FASD）筛查量表（T-ACE、AUDIT-C和TWEAK量表）进行饮酒风险评估。结果639名孕妇参加调查,收回有效答卷637份。17.58%（112/637）的孕妇报告在非怀孕期有饮酒行为,18名在怀孕后有饮酒行为,和孕前相比差异有统计学意义（P〈0.01）。不同年龄段的孕妇在怀孕期饮酒情况差异均无统计学意义（P〉0.05）,但不同学历的孕妇在怀孕期饮酒情况的差异有统计学意义（P〈0.05）,文化程度为初中及以下的孕妇在怀孕后饮酒率从各组别最低变为最高。T-ACE、AUDIT-C和TWEAK量表的阳性率分别为6.28%、2.35%和6.75%,对于平时有饮酒和孕期有饮酒的孕妇各量表的阳性率均高于没有饮酒的,差异有统计学意义（P〈0.01）。结论广州市孕妇的饮酒率和危险饮酒情况均低于西方国家的水平,但孕妇饮酒年轻化趋势、孕期饮酒风险明显增加,应加强孕妇饮酒预防干预工作,减少对孕妇及胎儿健康危害。

胎儿酒精综合征1例

总结深圳市儿童医院诊断的1例胎儿酒精综合征(FAS)患儿的临床特点。患儿,女,6岁4个月,因"身高增长缓慢6年余"入院。患儿胎儿期存在明确的酒精暴露史,出生时为低体质量儿,出生后身高、体质量增长缓慢,存在典型的FAS面部特征,有小头畸形,记忆及叙述能力低下,可诊断为FAS。孕期酒精暴露对胎儿造成的影响是永久性的,而戒酒则是唯一也是彻底预防FAS的办法。现总结FAS临床特点并复习文献,旨在提高临床对该病的认识。