Background: This study aimed to develop an efficient and easily calculable risk score that can be used to identify an individual's risk of having been exposed to alcohol prenatally. Methods: Data for this study were collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, Phases 2 and 3. Two cohorts (ages 5 to 17 years) completed a comprehensive neurobehavioral battery and a standard dysmorphology exam: a development cohort (DC; n = 325) and a comparative cohort (CC; n = 523). Both cohorts included two groups: those with histories of heavy prenatal alcohol exposure (AE-DC, n = 121; AE-CC, n = 177) and a control group that included subjects with minimal or no prenatal alcohol exposure (CON-DC, n = 204; CON-CC, n = 346). Behavioral assessments and physical exam data were combined using regression techniques to derive a risk score indicating the likelihood of prenatal alcohol exposure. Subjects were then divided into two subgroups: (1) low risk and (2) high risk. Chi-square (χ2) determined classification accuracy and ROC curves were produced to assess the predictive accuracy. Correlations between risk scores and intelligence quotient and executive function scores were calculated. Results: Subjects were accurately classified in the DC (χ2 = 78.61, p < 0.001) and CC (χ2 = 86.63, p < 0.001). The classification model also performed well in the DC (ROC = 0.835 [SE = 0.024, p < 0.001]) and CC (ROC = 0.786 [SE = 0.021, p < 0.001]). In the AE-CC and CON-CC, there were modest but significant associations between the risk score and executive function (AE-CC: r = −0.20, p = 0.034; CON-CC: r = −0.28, p < 0.001) and intelligence quotient (AE-CC: r = −0.20, p = 0.034; CON-CC: r = −0.28, p < 0.001). Conclusion(s): The risk score significantly distinguished alcohol-exposed from control subjects and correlated with important cognitive outcomes. It has significant clinical potential and could be easily deployed in clinical settings.

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.

There are significant barriers in engaging pregnant and postpartum women that are considered high-risk (e.g., those experiencing substance use and/or substance use disorders (SUD)) into longitudinal research studies. To improve recruitment and retention of this population in studies spanning from the prenatal period to middle childhood, it is imperative to determine ways to improve key research engagement factors. The current manuscript uses a qualitative approach to determine important factors related to recruiting, enrolling, and retaining high-risk pregnant and postpartum women. The current sample included 41 high-risk women who participated in focus groups or individual interviews. All interviews were analyzed to identify broad themes related to engaging high-risk pregnant and parenting women in a 10-year longitudinal research project. Themes were organized into key engagement factors related to the following: (1) recruitment strategies, (2) enrollment, and (3) retention of high-risk pregnant and parenting women in longitudinal research studies. Results indicated recruitment strategies related to ideal recruitment locations, material, and who should share research study information with high-risk participants. Related to enrollment, key areas disclosed focused on enrollment decision-making, factors that create interest in joining a research project, and barriers to joining a longitudinal research study. With regard to retention, themes focused on supports needed to stay in research, barriers to staying in research, and best ways to stay in contact with high-risk participants. Overall, the current qualitative data provide preliminary data that enhance the understanding of a continuum of factors that impact engagement of high-risk pregnant and postpartum women in longitudinal research with current results indicating the need to prioritize recruitment, enrollment, and retention strategies in order to effectively engage vulnerable populations in research.

PURPOSE: Early identification of prenatal alcohol exposure (PAE) and of those in need of services resulting from this exposure is an important public health concern. This study reviewed the existing literature on potential biomarkers and screening tools of PAE and its impact. SEARCH METHODS: Electronic databases were searched for articles published between January 1, 1996, and November 30, 2021, using the following search terms: ("fetal alcohol" or "prenatal alcohol" or "FASD" or "alcohol-related neurodevelopmental disorder" or "ARND" or "ND-PAE") and ("screening" or "identification" or "biomarker"). Duplicate articles were electronically eliminated. Titles and abstracts were reviewed for appropriateness, and selected articles were retrieved for further analysis. Additional articles were added that were referenced in the reviewed articles or identified from expert knowledge. Information about the characteristics of the sample, the biomarker or screening tool, and the predictive validity outcome data were abstracted. A narrative analysis of the studies was then performed on the data. SEARCH RESULTS: A total of 3,813 articles were initially identified, and 1,215 were removed as duplicates. Of the remaining articles, 182 were identified as being within the scope of the review based on title and abstract inspection, and 181 articles were successfully retrieved. Of these, additional articles were removed because they were preclinical (3), were descriptive only (13), included only self-report of PAE (42), included only mean group comparison (17), were additional duplicates (2), focused on cost analysis (9), missed predictive validity data (24), or for other reasons (23). The remaining articles (n = 48) were abstracted. An additional 13 manuscripts were identified from these articles, and two more from expert knowledge. A total of 63 articles contributed to the review. DISCUSSION AND CONCLUSIONS: Biomarkers and screening tools of PAE and its impact fall short of ideal predictive validity characteristics. Higher specificity than sensitivity was found for many of the biomarkers and screening tools used to identify PAE and its impact, suggesting that current methods continue to under-identify the full range of individuals impacted by PAE. Exceptions to this were found in recent investigations using microRNAs related to growth and vascular development, proteomic changes associated with PAE, and combinations of markers estimating levels of various cytokines. Replications of these findings are needed across other samples to confirm the limited data available. Future research on biomarkers and screening tools should attend to feasibility and scalability of implementation. This article also recommends a systematic process of evaluation to improve early identification of individuals impacted by PAE so that harm reduction and habilitative care efforts can be implemented.

Objective: To characterize patterns of prenatal alcohol exposure (PAE), and determine whether PAE trajectories were associated with behavior from a community-based sample of first-grade children. Methods: Using data collected as part of the Collaboration of Fetal Alcohol Spectrum Disorders Prevalence study (n = 1663), we performed longitudinal cluster analysis on prenatal alcohol use reported for four time points around conception and pregnancy. From the sample, 638 respondents reported any alcohol use in pregnancy and were included in trajectories for average daily and maximum drinks per drinking day (max DDD). We then estimated the association with behavioral problems measured by the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF) with multivariable linear regression. The reference group had 1025 children with no reported PAE. Results: Five trajectories were selected to describe max DDD patterns: very low/discontinuing (n = 186), low/discontinuing (n = 111), very low/continuing (n = 47), med/high (n = 245), and high (n = 49). Six trajectories best described average daily alcohol use: very low/discontinuing (n = 378), very low/continuing (n = 98), low/continuing (n = 56), low/discontinuing (n = 37), medium/high (n = 35), and high (n = 31). When assessing max DDD trajectories for both the CBCL and TRF, individuals with PAE in the two highest trajectories and the very low/continuing trajectory had more behavioral problems relative to children with no PAE, although confidence intervals for most estimates included the null. PAE modeled as average drinks per day did not predict behavior in any consistent pattern. Conclusions: In this community-based sample, select PAE trajectories were associated with behavior, even at relatively low levels of PAE that continued later in gestation.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) on attentional regulation skills was explored in a randomized clinical trial conducted in Ukraine. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to one of three groups [No study-provided supplements, Multivitamin/Mineral Supplement (MVM), or MVM plus Choline]. Their offspring were seen in the preschool period and a reaction time task was administered. Participants were asked to press a response button as quickly as possible as 30 stimuli from the same category (animals) were presented consecutively and then followed by six stimuli from a novel category (vehicles). Number correct, mean latency of the response over trials, and variability in the latency were analyzed separately by sex. During the initial animal trials, boys whose mothers received MVM during pregnancy had more correct responses and reduced response latency compared to boys whose mothers had no MVM treatment. During vehicle trials, maternal choline supplementation was associated with increased response speed in males without a PAE history. Females receiving supplements did not show the same benefits from micronutrient supplementation and were more adversely impacted by prenatal alcohol exposure. Relationships between maternal levels of choline, betaine, and dimethylglycine (DMG) and task performance were also assessed. Although no effects were found for choline after adjusting for multiple comparisons, lower baseline DMG level was associated with greater accuracy and shorter latency of responses in the initial animal trials and shorter latency in the vehicle trials in female preschoolers. Level of betaine in Trimester 3 was associated with reduced variability in the latency of male responses during the animal trials. Maternal micronutrient supplementation in pregnancy appears to improve preschool reaction time performance, but the effects varied as a function of sex and PAE exposure status.

Background: Although the effects of prenatal alcohol exposure (PAE) have been studied extensively, there is relatively little information available on adult mental health functioning among exposed individuals. The current study compares the self-reported midlife mental health status of individuals who were prenatally exposed to alcohol and diagnosed in childhood with the effects of this exposure with that of unexposed individuals. Methods: Participants (N = 292) were recruited from two longitudinal cohorts in Atlanta and Seattle and asked to complete an Adult Health Questionnaire that surveyed their current health and mental health status. The questionnaire was completed either in-person or remotely and included questions about current symptoms of depression and anxiety and mental health disorder diagnoses. The analysis compared a Nonexposed Contrast group to those in two exposure groups: (1) Alcohol Exposed with Fetal Alcohol Effect but not meeting criteria for Fetal Alcohol Syndrome (FAS) and (2) Alcohol Affected and meeting criteria for FAS. Results: Both alcohol-exposed groups reported higher levels of current depressive symptoms and a higher prevalence of diagnoses of depression, anxiety, bipolar disorder, and/or attention deficit/hyperactivity disorder. No differences were noted for psychotic disorders. PAE was also associated with greater environmental stressors, including higher levels of adverse childhood events and lower current socioeconomic status. Path analyses suggested that PAE was indirectly related to mood disorders with its effects being mediated by other environmental factors. Conclusions: PAE is associated with greater rates of mental health disorders in middle adulthood. These outcomes appear to result from multiple stressors that affect individuals made vulnerable by their early alcohol exposure. Clinical outcomes could be improved by prevention efforts directed at preventing prenatal alcohol use and reducing environmental stressors later in life, and by the early identification of PAE and its effects.

Current efforts to design research on developmental effects of prenatal opioid exposure can benefit from knowledge gained from 50 years of studies of fetal alcohol and prenatal drug exposures such as cocaine. Scientific advances in neurobiology, developmental psychopathology, infant assessments, genetics, and imaging support the principles of developmental neurotoxicology that guide research in prenatal exposures. Important to research design is accurate assessment of amount, frequency, and timing of exposure which benefits from accurate self-report and biomarkers of exposure. Identifying and control of pre- and postnatal factors that impact development are difficult and dependent on appropriate research design and selection of comparison groups and measurement of confounding, mediating, and moderating variables. Polysubstance exposure has increased due to the number of prescribed and nonprescribed substances used by pregnant women and varying combinations of drugs may have differential effects on the outcome. Multiple experimental and clinical assessments of infant behavior have been developed but predicting outcome before 18-24 months of age remains difficult. With some exceptions, prenatal substance exposure effect sizes have been small, and cognitive and behavioral effects tend to be specific rather than global. Studies require large sample sizes, adequate retention, and support for social services in at-risk samples. The ethical and legal contexts and stigma associated with drug/alcohol use disorder should be considered in order to prevent harm to families in research programs. Recognition of the pervasive use of addictive substances in this nation should lead to broad scientific efforts to understand how substances affect child outcomes and to initiate prevention and intervention where needed.

Background: In children with prenatal alcohol exposure, spatial working memory is affected and brain regions important for spatial working memory performance exhibit atypical neurodevelopment. We therefore hypothesized that children with prenatal alcohol exposure may also have atypical development of spatial working memory ability. Methods: We examined the relation between spatial working memory and age using a cross-sectional developmental trajectory approach in youth with and without histories of heavy prenatal alcohol exposure. The Cambridge Neuropsychological Test Automated Battery Spatial Working Memory subtest was administered to children 5.0 to 16.9 years old. Results: While the controls and children with prenatal alcohol exposure showed similar performance at younger ages, larger group differences were observed in older children. This effect was replicated in a separate sample. Conclusions: The atypical brain development that has previously been reported in children with heavy prenatal alcohol exposure may have clinically relevant implications for cognitive development; however, longitudinal cognitive analyses are needed.

Effects of prenatal alcohol exposure (PAE) are rarely measured in preschool children due to relative insensitivity of assessment methods at this age. To examine the potential of a nonverbal battery in early identification of cognitive problems in alcohol-exposed children, 291 prospectively identified Ukrainian children were evaluated using a test battery focusing on early executive functioning (EF) and visuospatial skills, areas of cognitive development particularly sensitive to PAE in older children. Tests included the Differential Ability Scales, 2nd Edition (DAS-2) and several NEPSY/NEPSY-II subtests, standardized in the United States. Others were adapted from commonly used non-standardized neuropsychological measures of EF (Preschool Spatial Span, Imitation Hand Game, A not B, Delayed Attention, Subject Ordered Pointing). Children in two sites in Ukraine, Rivne and Khmelnitsky, were tested at 3 ½-4 ½ years to identify effects of PAE. Although most children performed within the average range, Alcohol-Exposed preschoolers had lower scores on DAS-II Summary Scores as well as on specific subtests. To evaluate the effects of alcohol dose during the pre-pregnancy recognition period and during mid-gestation of pregnancy, generalized linear regression models were used controlling for demographic and individual variables. In addition to DAS-II variables, measures reflecting sustained attention, working memory and ability to shift cognitive set were impacted by alcohol dose. Early executive function appears to subsume these performance differences. In conclusion, findings indicate that the effects of PAE can be identified in the preschool period and reliably measured using tests assessing nonverbal and spatial skills supported by executive functioning.