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Fetal Alcohol Spectrum Disorders affect up to 5% of the population, with additional children affected by prenatal drug exposures. The majority of these children display symptoms of ADHD and poor emotional dysregulation, a common reason for seeking psychiatric care. However, high prevalence of comorbid look-alike symptoms and limited availability of evidence-based treatments complicates psychiatric decision making in this population. The goal of the current study is to report on the effectiveness of psychotropic medications in a case series of 16 individuals with prenatal alcohol/drug exposure and propose a model for psychiatric care for this population. In addition to traditional subjective reports, an objective continuous performance test (T.O.V.A.®) was used to aid with guiding treatment. We found that T.O.V.A.®-scores improved on average from - 6.5 to - 2.9 with our psychiatric approach (p = 0.03). T.O.V.A.®-measurements were helpful in differentiating ADHD symptoms from comorbid symptoms and to guide decision-making on starting and changing medications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The proposed symptoms for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE) were evaluated in children who participated in the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence study. Children "at-risk" for ND-PAE (n = 204) were contrasted to children with no prenatal alcohol exposure, alcohol-related dysmorphia or growth deficits (n = 908). Symptoms were defined based on neuropsychological testing using two diagnostic threshold levels (1.0 and 1.5 STD). Individuals at risk for ND-PAE had higher endorsement rates of the self-regulation and adaptive impairments at the 1.0 threshold and of the neurocognitive and self-regulation impairments at the 1.5 threshold. Endorsement of the disorder significantly differed at the 1.0 threshold. Receiver operating characteristic curve analysis indicated that having an IQ below 70 was not predictive of the diagnosis but modifications of the IQ criterion improved predictive validity. Discrimination validity was poor without documentation of PAE which continues to be a necessity for a diagnosis of ND-PAE., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical features and neurobehavioral impairments. Although 3 key facial features (short palpebral fissures, a smooth philtrum and a thin vermilion of the upper lip) are the only dysmorphic features taken into account for the diagnosis of Fetal Alcohol Syndrome (FAS) or partial FAS (pFAS), several other features are commonly seen in individuals with these diagnoses. The goals of our study were to determine if some of these secondary physical features also occur more frequently in children with alcohol-related neurodevelopmental disorder (ARND) relative to controls, and if a cluster of these features combined in a dysmorphology score could be used to identify those negatively impacted by PAE but who do not have the cardinal physical features that led to a diagnosis of FAS or pFAS., Methods: Among 2681 children recruited for the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP) study, 1726 had an FASD or sufficient evidence of PAE having occurred or not in their pregnancy. Children were then categorized into groups using the modified Hoyme diagnostic criteria (FAS (n = 24), pFAS (n = 99) and ARND (n = 87), and No FASD (n = 1516), including those with No FASD and a history of PAE (No FASD/PAE, n = 498) and those with No FASD and no history of PAE (No FASD/No PAE, n = 1018). The frequencies of 26 secondary dysmorphic features were compared among these groups, both individually and combined in non-weighted and weighted dysmorphic scores. Correlations of the total dysmorphic scores with an index of overall cognitive ability were also compared by group status., Results: Several of these features were significantly more frequent in children with FAS than in those with No FASD diagnosis with or without PAE but not in comparison to those with ARND. The number of features was also significantly higher in the FAS group as compared to all other groups for both weighted and unweighted dysmorphology scores but were not higher in the group with ARND when compared to the groups with No FASD either in the presence or absence of PAE. Although not diagnostic, higher total dysmorphology scores were predictive of lower general cognitive abilities in the group with ARND, suggesting severity of alcohol-related dysmorphology is predictive of severity of alcohol-related neurobehavioral impairment., Conclusion: Secondary physical features were not more frequent in children with ARND compared to children without an FASD diagnosis but were a marker for lower cognitive function. The use of secondary physical features to support a diagnosis of ARND was not supported in this sample., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Choline is essential for healthy cognitive development. Single nucleotide polymorphisms (SNPs; rs3199966(G), rs2771040(G)) within the choline transporter SLC44A1 increase risk for choline deficiency. In a choline intervention trial of children who experienced prenatal alcohol exposure (PAE), these alleles are associated with improved cognition., Objective: This study aimed to determine if SNPs within SLC44A1 are differentially associated with cognition in children with PAE compared with normotypic controls (genotype × exposure). A secondary objective tested for an association of these SNPs and cognition in controls (genotype-only)., Design: This is a secondary analysis of data from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Participants (163 normotypic controls, 162 PAE) underwent psychological assessments and were genotyped within SLC44A1. Choline status was not assessed. Association analysis between genotype × exposure was performed using an additive genetic model and linear regression to identify the allelic effect. The primary outcome was the interaction between SLC44A1 genotype × exposure status with respect to cognition. The secondary outcome was the cognitive-genotype association in normotypic controls., Results: Genotype × exposure analysis identified 7 SNPs in SLC44A1, including rs3199966(G) and rs2771040(G), and in strong linkage (D' ≥ 0.87), that were associated (adjusted P ≤ 0.05) with reduced performance in measures of general cognition, nonverbal and quantitative reasoning, memory, and executive function (β, 1.92-3.91). In controls, carriers of rs3199966(GT or GG) had worsened cognitive performance than rs3199966(TT) carriers (β, 0.46-0.83; P < 0.0001), whereas cognitive performance did not differ by rs3199966 genotype in those with PAE., Conclusions: Two functional alleles that increase vulnerability to choline deficiency, rs3199966(G) (Ser644Ala) and rs2771040(G) (3' untranslated region), are associated with worsened cognition in otherwise normotypic children. These alleles were previously associated with greater cognitive improvement in children with PAE who received supplemental choline. The findings endorse that choline benefits cognitive development in normotypic children and those with PAE., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: It is estimated that 1%-5% of children in the United States are affected by prenatal alcohol exposure while only a small percentage are so identified in clinical practice. One explanation for this discrepancy may be the way in which diagnostic criteria are operationalized., Methods: To evaluate the extent to which three commonly used systems for the diagnosis of Fetal Alcohol Spectrum Disorder (FASD) consistently identified children in a community sample, data from the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (COFASP) study were re-analyzed. In the data set, there were 2325 children with variables necessary to allow diagnosis by three systems commonly used in North America. These systems were (1) that used by COFASP, which is a revised modification of the Institute of Medicine's recommendations, (2) the 4-Digit Code, and (3) the most recent Canadian Guidelines. To determine the degree of association among these classifications, the Fleiss Multirater Kappa measure of agreement was applied., Results: Among these three systems, 408 children were classified as FASD, 208 by the CoFASP system, 319 by the 4-Digit Code, and 28 by the Canadian Guidelines. Agreement among the findings from the three systems varied from slight to fair., Conclusions: These results indicate a lack of consistency in these approaches to FASD diagnosis. Discrepancies result from differences in specifying the criteria used to define the diagnosis, including growth, physical features, neurobehavior, and alcohol-use thresholds. The question of their relative accuracy cannot be resolved without reference to a measure of validity that does not currently exist, and this suggests the need for a more empirically based diagnostic schema., (© 2022 Research Society on Alcohol.)

Background: The vascular system may be particularly vulnerable to prenatal alcohol exposure (PAE). Alterations in angiogenesis and epigenetic changes to vascular development have been implicated as a probable mechanism for this vulnerability., Methods: We assessed the long-term impact of prenatal alcohol exposure (PAE) on adult vascular health using a prospective cohort first identified while in utero. Participants with no PAE (n = 37, mean age = 36.7 [SD = 1.6] years) were compared to participants with PAE (n = 51, mean age = 36.3 [SD = 1.7] years). Their vascular health was assessed by arterial blood pressure (BP) and peripheral arterial tonometry, which yields an index of endothelial function (reactive hyperemia index) and a measure of arterial stiffness (augmentation index). Blood samples were collected to assess cholesterol levels and insulin resistance (glucose, hemoglobin A1C, and insulin). Path analysis was used to examine the direct and indirect effects of PAE on vascular health after adjusting for other known physical outcomes., Results: Participants with a history of PAE weighed less, trended towards being shorter, had smaller body mass, and had more alcohol-related dysmorphic features than those without PAE. Path analysis suggested that the impact of PAE on BP was through its indirect relationships with height, body mass index, and dysmorphic features and resulted in protective effects relative to the Contrast group who were disproportionately overweight. PAE was also found to have a direct negative effect on endothelial function. An index of total alcohol-related dysmorphic features was negatively had both a direct effect on arterial stiffness and an indirect effect on endothelial function., Conclusions: Prenatal alcohol exposures' impact on vascular function is not independent of other common physical and environmental factors but endothelial function and arterial stiffness seemed most compromised after controlling for these other factors. Level of alcohol-related dysmorphic features seems to be predictive of more adverse effects than endothelial function and vascular stiffness., (© 2022 Research Society on Alcohol.)

Psychiatric symptoms in children with Fetal Alcohol Spectrum Disorders (FASD) present with high prevalence and morbidity, often across symptom domains, e.g. ADHD-like symptoms, emotional dysregulation and sleep problems. Polypharmacy is often used, but no empirically-based guidelines exist regarding optimal treatment for these children. Moreover, stimulant use in these children is controversial as their responsiveness may be different due to altered neural circuitry associated with prenatal alcohol exposure. The objective of this review is to give an overview of existing data on pharmacological treatments of neurobehavioral symptoms in FASD. Our literature review yielded limited and conflicting clinical data on the effectiveness of pharmacological treatments for psychiatric symptoms in children with FASD, with some symptom domains lacking data altogether. We emphasize the need for clinical trials to guide pharmacological treatments in this complex population., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

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 (χ 2 ) 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 (χ 2  = 78.61, p < 0.001) and CC (χ 2  = 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., (© 2021 by the Research Society on Alcoholism.)

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, 2 nd 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.

Background: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples., Methods: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores., Results: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting., Conclusions: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared., (© 2021 by the Research Society on Alcoholism.)

Objective: Evidence suggests that prenatal alcohol exposure (PAE) may adversely impact insulin production and signaling but there is limited information on the range of these effects and their future health consequences., Method: A prospective cohort of predominantly African-American individuals identified while in utero and followed into adulthood were used to evaluate differences in various indicators of diabetes, including fasting plasma glucose, hemoglobin A1c (HbA1c), and insulin levels. The homeostatic model assessment of insulin resistance (HOMA-IR) was also computed. Body mass index (BMI) was calculated and normal defined as < 25 kg/m 2 . Participants were categorized as having PAE (n = 39) if their mothers drank at least 1 ounce of absolute alcohol per week or more during the 1 st trimester of pregnancy and as Controls (n = 22) if their mothers reported abstaining from alcohol consumption during pregnancy., Results: Mean age of the sample was 36.0 ± 1.5 years. Indices of glucose metabolism, including fasting plasma glucose and hemoglobin A1c levels, did not vary by group status but insulin levels and HOMA-IR values varied by group status and BMI level. PAE individuals with a normal BMI had lower insulin levels than Controls. However, in PAE subjects, there was a steeper increase in insulin levels relative to their BMI than in Control subjects. A cluster of 5 PAE cases had low levels of insulin and 4 of the 5 had severe cognitive impairment., Conclusions: The bidirectional effects on insulin level and insulin resistance associated with PAE may indicate differential rates of diabetes disease impact or differential PAE impact in the brain and peripheral areas involved in insulin production and signaling. These alterations may contribute to the metabolic disease risk associated with PAE., (© 2021 by the Research Society on Alcoholism.)

Background: The effects of prenatal alcohol exposure (PAE) are conceptualized as fetal alcohol spectrum disorder, with fetal alcohol syndrome (FAS) as the most severe. Many find it more difficult to characterize behavioral and cognitive effects of exposure on the central nervous system when physical signs are not present. In the current study, an operational definition of alcohol-related neurodevelopmental disorder (ARND) was examined to determine its usefulness in discrimination of children classified as ARND based on behavior (ARND/B) and cognition (ARND/C) from children in 4 contrast groups: (i) children exposed to study-defined "risky drinking"; (ii) children with any reported PAE; (iii) children classified as "Higher Risk" for developmental problems; and (iv) children classified as "Lower Risk.", Methods: A total of 1,842 children seen as part of a surveillance study (J Am Med Assoc, 319, 2018, 474) were evaluated for alcohol exposure and physical characteristics of FAS, and completed neurodevelopmental testing. Ninety-one were identified as either ARND/B or ARND/C and contrasted with other groups to further identify distinguishing patterns. Multinomial logistic regression (MLR) was used to examine the accuracy of classification and to identify factors contributing to such classification., Results: Children described as ARND/C were distinct from other groups based on cognition and behavior as well as demographic factors (e.g., age, race, SES), child characteristics (e.g., gestational age; sex), and other drug exposures, while those described as ARND/B differed only on behavior and other drug exposures. MLR models successfully discriminated ARND groups from children in other groups with accuracy ranging from 79% (Higher Risk) to 86.7% (Low Risk)., Conclusions: ARND has been a subject of debate. This analysis suggests the effects of alcohol on behavior and cognition even in the absence of the characteristic facial features and growth deficiency that can be identified. The results also indicate that it may be possible to distinguish such children from those in other high-risk groups., (© 2020 by the Research Society on Alcoholism.)

Background: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status., Methods: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis., Results: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1β, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-β, IL-10, and IL-15 was associated with neurodevelopmental delay., Conclusions: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

Relationships between neurodevelopmental functioning and hemodynamic changes in the prefrontal cortex (PFC) were contrasted between children with prenatal alcohol exposure (PAE) and children who differed relative to their history of PAE and the presence of other neurodevelopmental impairment. For all groups, deoxygenated hemoglobin (HBR) levels in the medial PFC area were negatively related to externalizing problems and levels in the medial and right lateral PFC were positively related to errors on a cognitive inhibition task. Hemodynamic changes in the medial and right lateral PFC of children with PAE demonstrated stronger relationships to aspects of executive functioning relative to contrast groups.

Background: Adaptive function and general intellectual function are two important and often correlated domains. While youth with prenatal alcohol exposure frequently demonstrate impairments in both domains, it is not clear whether the relation between these domains is consistent across levels of ability or whether, for example, adaptive function is less affected by intellectual function at higher ability levels. The aim of the current study was to test this relation in youth with and without prenatal alcohol exposure., Methods: As part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, Phase II, subjects with heavy prenatal alcohol exposure (AE) and nonexposed subjects with and without other clinical conditions or concerns (CON) completed a comprehensive neurobehavioral battery. Multiple regression analyses tested the relation between full scale IQ (FSIQ) and overall adaptive function. Interaction terms between Group and each variable were created to formally test for group differences. Three subsequent regression analyses tested which adaptive function domains (Communication, Daily Living Skills, Socialization) significantly contributed to results. Follow-up analyses examined correlations based on IQ range (low IQ <85; high IQ ≥85)., Results: The interaction between FSIQ and Group on overall adaptive function was significant; the relationship between FSIQ and adaptive function was weaker in the AE group than in the CON group. Regarding specific adaptive function domains, the interaction between FSIQ and Group was significant only in the Communication domain. Follow-up analyses showed, within the low IQ range, the correlation between FSIQ and Communication was stronger in the CON group than the AE group. Within the high IQ range, the correlation between FSIQ and Communication was significant only in the CON group., Conclusions: Although higher intellectual functioning was associated with better adaptive function ability among controls, this was not found among the alcohol-exposed youth where a general dampening of adaptive ability was noted. Further, the differential relationship between IQ and adaptive function between groups appears to be driven by communication abilities. These findings suggest that level of intellectual functioning of children with prenatal alcohol exposure does not fully account for caregiver-reported communication and overall adaptive function deficits particularly at higher levels of functioning., (© 2019 Wiley Periodicals, Inc.)

Background: Of the many negative outcomes associated with gestational alcohol use, one that has received relatively little attention is preterm birth and its possible contribution to effects of prenatal alcohol exposure (PAE) on development. To examine the increased risk for premature delivery associated with PAE and the joint influence of preterm birth and alcohol on child outcomes, analysis was carried out in a longitudinal cohort recruited in Western Ukraine., Methods: Alcohol-using women and low or nondrinking controls were identified prenatally for a clinical trial of multivitamins and minerals (MVM) in ameliorating effects of PAE. Women were interviewed to provide information about medical and social status and other drug use. At delivery, information was collected about infant (N = 686) status including gestational age (GA) in weeks. Finally, 441 infants were followed to 6 months of age and cognitive (Mental Developmental Index [MDI]) and motor development (Psychomotor Developmental Index [PDI]) (measured using the Bayley Scales of Infant Development, second Ed (BSID-II)., Results: Seven percent infants were born at <37 weeks GA. The odds ratio for preterm delivery for Alcohol Exposed versus Low/No Alcohol was 2.6 (95% Confidence Interval 1.37, 4.94) (p < .003); MVM supplements were associated with a lower rate of preterm delivery overall, but the relative proportion of preterm births did not vary by MVM supplement status between alcohol exposure groups. In mediation models of 6 month cognitive and motor development with reference to Barron and Kenney in 1986, GA significantly mediated alcohol effects (MDI: Z = -2.64, p < .008; PDI: Z = -2.35, p < .02) although PAE independently affected both outcomes (MDI: t = -5.6, p < .000; PDI: t = -3.19, p < .002)., Conclusion: Results suggest that PAE is associated with higher rates of preterm birth and that alcohol's effect on development in infancy may be both direct and mediated by shortened length of gestation., (© 2018 Wiley Periodicals, Inc.)

Background: Prenatal cocaine exposure (PCE) is associated with arousal dysregulation, but interactions between exposure and age are rarely investigated directly with longitudinal study designs. Our previous study had examined task-elicited emotional arousal and noted persistently high amygdala activations in the development of adolescents with PCE. However, while externally imposed emotional arousal could be considered a "state" effect depending on specific task stimuli, it is still unclear whether similar developmental alterations extend to intrinsic functional connectivity (FC), reflecting more of a "trait" effect., Methods: We used a longitudinal design and analyzed resting-state functional magnetic resonance imaging data acquired twice from 25 adolescents with PCE and 16 non-exposed controls. Both groups were each scanned first at the mean age of 14.3 and then again at 16.6 years. Seeding in bilateral amygdalae and comparing the 2 nd scan with the 1 st , we examined the interaction effect between PCE and age on FCs in the emotional network., Results: Compared with the younger age, we observed a generally decreased FC in the emotional network of the control group at the older age, but these FCs were generally increased at the older age in this same network of the PCE group. Additionally, this interaction effect of exposure by age in the right fusiform was positively correlated with the emotional interference imposed by external task stimuli., Conclusions: These results provided additional data directly characterizing developmental changes in the emotional network of adolescents with PCE, complementing and extending the notion of a PCE-associated long-term teratogenic effect on arousal regulation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Youth with heavy prenatal alcohol exposure have high rates of behavioral concerns and psychopathology, including increased oppositional and conduct behaviors. The relation between those concerns and executive function (EF) deficits is unknown. We investigated the association of oppositional and conduct behavior and EF in adolescents to inform targeted intervention., Methods: Subjects (N = 267) ages 10 to 17 years comprised 3 groups: alcohol-exposed with oppositional/conduct behaviors (AE+), alcohol-exposed without oppositional/conduct behaviors (AE-), and controls (CON). Group differences on direct neuropsychological (Delis-Kaplan Executive Function System [D-KEFS]) and indirect parent-report (Behavior Rating Inventory of Executive Function [BRIEF]) EF measures were tested with multivariate analysis of covariances, followed by univariate analysis of variances and pairwise comparisons. The contribution of attention-deficit/hyperactivity disorder (ADHD) within the AE groups was assessed in secondary analyses., Results: On the D-KEFS, there was an omnibus main effect of group, with significant main effects on 3 of 6 variables (CON>AE+, AE-). Within the AE groups, ADHD did not alter the results. On the BRIEF, there was an omnibus significant main effect of group, with significant main effects on all scales (CON

Background: Previous studies have had inconsistent findings regarding the quantity and frequency of prenatal alcohol exposure (PAE) that lead to deficits in growth and neurodevelopment. This may be due to imprecise methods of exposure classification. Our objective in this study was to employ longitudinal trajectory modeling of maternal drinking patterns associated with infant growth or neurodevelopmental deficits to a homogenous sample of mothers and infants., Methods: From a sample of 471 pregnant women prospectively enrolled in a longitudinal study in the Ukraine, we performed a longitudinal cluster analysis of drinking patterns across gestation. We employed multivariable regression analyses to determine if each trajectory group was associated with infant weight, length, or head circumference at birth or psychomotor or mental deficits in infancy., Results: We identified 5 distinct PAE trajectory groups: minimal or no PAE throughout gestation, low-to-moderate PAE with discontinuation early in gestation, low-to-moderate PAE sustained across gestation, moderate-to-high PAE with reduction early in gestation, and high PAE sustained across gestation. The highest-trajectory group was associated with deficits in infant weight and length at birth and deficits in psychomotor and mental performance at 6 to 12 months of age. Although confidence intervals overlapped, low-to-moderate sustained use was more strongly associated with most negative infant outcomes than moderate-to-high PAE with early reduction., Conclusions: With these findings, we confirm that high, sustained PAE confers the highest risk for adverse infant outcomes but demonstrate that even low-to-moderate PAE continued across gestation is associated with certain deficits. This approach may be used to help clinicians identify high-risk infants for targeted early intervention., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objectives: Caregivers of youth with heavy prenatal alcohol exposure report impaired communication, which can significantly impact quality of life. Using data collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we examined whether cognitive variables predict communication ability of youth with histories of heavy prenatal alcohol exposure., Methods: Subjects (ages 10-16 years) comprised two groups: adolescents with heavy prenatal alcohol exposure (AE) and non-exposed controls (CON). Selected measures of executive function (NEPSY, Delis-Kaplan Executive Function System), working memory (CANTAB), and language were tested in the child, while parents completed communication ratings (Vineland Adaptive Behavior Scales - Second Edition). Separate multiple regression analyses determined which cognitive domains predicted communication ability. A final, global model of communication comprised the three cognitive models., Results: Spatial Working Memory and Inhibition significantly contributed to communication ability across groups. Twenty Questions performance related to communication ability in the CON group only while Word Generation performance related to communication ability in the AE group only. Effects remained significant in the global model, with the exception of Spatial Working Memory., Conclusions: Both groups displayed a relation between communication and Spatial Working Memory and Inhibition. Stronger communication ability related to stronger verbal fluency in the AE group and Twenty Questions performance in the CON group. These findings suggest that alcohol-exposed adolescents may rely more heavily on learned verbal storage or fluency for daily communication while non-exposed adolescents may rely more heavily on abstract thinking and verbal efficiency. Interventions aimed at aspects of executive function may be most effective at improving communication ability of these individuals. (JINS, 2018, 24, 1026-1037).

Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-ɣ, IL-10, TNF-β, TNF-α, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Cortical abnormalities in prenatal alcohol exposure (PAE) are known, including in gyrification (LGI), thickness (CT), volume (CV), and surface area (CS). This study provides longitudinal and developmental context to the PAE cortical development literature., Experimental Design: Included: 58 children with PAE and 52 controls, ages 6-17 at enrollment, from four Collaborative Initiative on FASD (CIFASD) sites. Participants underwent a formal evaluation of physical anomalies and dysmorphic facial features associated with PAE. MRI data were collected on three platforms (Siemens, GE, and Philips) at four sites. Scans were spaced two years apart. Change in LGI, CT, CS, and CV were examined., Principal Observations: Several significant regional age-by-diagnosis linear and quadratic interaction effects in LGI, CT, and CV were found, indicating atypical developmental trajectories in PAE. No significant correlations were observed between cortical measures and IQ., Conclusions: Regional differences were seen longitudinally in CT, CV, and LGI in those with PAE. The findings represent important insights into developmental trajectories and may have implications for the timing of assessments and interventions in this population. It is noteworthy that cortical metrics did not correlate with IQ, suggesting that more specific aspects of cognitive development may need to be explored to provide further context., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Few studies have focused on the transition to adulthood in adults with prenatal alcohol exposure (PAE). In this study, we examine the occurrence of problem behavior at this transition, including mental health problems, substance use, and difficulties with the legal system. The sample is prospective and provides an opportunity to examine effects of a wide range of prenatal exposure. Adults with PAE were expected to show more problem behavior; the impact of level of exposure was examined as well., Method: The sample was drawn from a predominantly low-income, African-American population. Mothers of the alcohol-exposed participants (n=123) and those in the non-exposed SES-Control group (CONT) (n=59) were recruited at a prenatal visit when information on alcohol and drug use during pregnancy was collected. A disability contrast group (n=54) was recruited at adolescence. The adults with PAE were assigned to three groups varying in physical and cognitive effects of exposure. This report is based on the adults' responses to interviews or questionnaires on problem behavior and laboratory tests related to substance use., Results: Adults with PAE showed more problem behavior in all three areas than adults from the CONT group. For mental health problems, the exposed group showing cognitive, but not physical effects, had the highest scores; their scores were similar, however, to those of the disability contrast group on several scales. Results for outcomes on substance use and legal difficulties were less consistent, but, when significant effects occurred, the group that was exposed, but neither physically nor cognitively affected, was more likely to show negative outcomes. Males in this group were most involved in these behaviors., Conclusion: Effects of PAE continue into early adulthood and affect mental health problems, substance use, and interactions with the legal system. Adults who are exposed, but less physically affected, seem to be the most involved in problem behavior. More research is necessary to examine environmental effects in conjunction with PAE on these outcomes and to provide a basis for developing potential interventions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Disruption in the neural activation of the prefrontal cortex (PFC) in modulating arousal was explored in children with heavy prenatal alcohol exposure (PAE), who have known neurobehavioral impairment., Methods: During a task that elicits frustration, functional near-infrared spectroscopy (fNIRS) was used to measure PFC activation, specifically levels of oxygenated (HBO) and deoxygenated (HBR) hemoglobin, in children with PAE (n=18) relative to typically developing Controls (n=12) and a Clinical Contrast group with other neurodevelopmental or behavioral problems (n=14)., Results: Children with PAE had less activation during conditions with positive emotional arousal, as indicated by lower levels of HBO in the medial areas of the PFC and higher levels of HBR in all areas of the PFC sampled relative to both other groups. Children in the Control group demonstrated greater differentiation of PFC activity than did children with PAE. Children in the Clinical Contrast group demonstrated the greatest differences in PFC activity between valences of task conditions., Conclusions: Specific patterns of PFC activation differentiated children with PAE from typically developing children and children with other clinical problems., Significance: FNIRS assessments of PFC activity provide new insights regarding the mechanisms of commonly seen neurobehavioral dysfunction in children with PAE., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Considered the leading cause of developmental disabilities worldwide, fetal alcohol spectrum disorders (FASD) are a global health problem. To take advantage of neural plasticity, early identification of affected infants is critical. The cardiac orienting response (COR) has been shown to be sensitive to the effects of prenatal alcohol exposure and is an inexpensive, easy to administer assessment tool. The purpose of this study was to evaluate the COR effectiveness in assessing individual risk of developmental delay., Methods: As part of an ongoing longitudinal cohort study in Ukraine, live-born infants of women with some to heavy amounts of alcohol consumption in pregnancy were recruited and compared to infants of women who consumed low or no alcohol. At 6 and 12 months, infants were evaluated with the Bayley Scales of Infant Development-II. CORs were also collected during a habituation/dishabituation learning paradigm. Using a supervised logistic regression classifier, we compared the predictive utility of the COR indices to that of the 6-month Bayley scores for identification of developmental delay based on 12-month Bayley scores. Heart rate collected at each second (Standard COR) was compared to key features (Key COR) extracted from the response., Results: Negative predictive values (NPV) were 85% for Standard COR, 82% for Key COR, and 77% for the Bayley, and positive predictive values (PPV) were 66% for Standard COR, 62% for Key COR, and 43% for the Bayley., Conclusions: Predictive analysis based on the COR resulted in better NPV and PPV than the 6-month Bayley score. As the resources required to obtain a Bayley score are substantially more than in a COR-based paradigm, the findings are suggestive of its utility as an early scalable screening tool based on the COR. Further work is needed to test its long-term predictive accuracy., (Copyright © 2016 by the Research Society on Alcoholism.)

This study examined the association between fetal tobacco exposure (FTE) and focused attention at 9 months of child age, and the role of child sex and infant behavioral reactivity as potential moderators of this association. Data were obtained from 203 mothers and their infants (105 fetally exposed and 98 non-exposed) on infant focused attention and behavioral reactivity to a frustration task. FTE was ascertained via nicotine metabolites in infant meconium, reflecting primarily third trimester fetal exposure. Results demonstrated a main effect of FTE on focused attention, such that exposed infants exhibited lower levels of focused attention than non-exposed infants. Behavioral reactivity, but not infant sex, moderated the relationship between FTE and focused attention, such that exposed infants who were highly reactive to frustration had the lowest levels of focused attention. Results suggest that smoking interventions, even in the third trimester, may have a positive impact on attentional outcomes for infants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To develop and validate a hierarchical decision tree model that combines neurobehavioral and physical measures to identify children affected by prenatal alcohol exposure even when facial dysmorphology is not present., Study Design: Data were collected as part of a multisite study across the US. The model was developed after we evaluated more than 1000 neurobehavioral and dysmorphology variables collected from 434 children (8-16 years of age) with prenatal alcohol exposure, with and without fetal alcohol syndrome, and nonexposed control subjects, with and without other clinically-relevant behavioral or cognitive concerns. The model subsequently was validated in an independent sample of 454 children in 2 age ranges (5-7 years or 10-16 years). In all analyses, the discriminatory ability of each model step was tested with logistic regression. Classification accuracies and positive and negative predictive values were calculated., Results: The model consisted of variables from 4 measures (2 parent questionnaires, an IQ score, and a physical examination). Overall accuracy rates for both the development and validation samples met or exceeded our goal of 80% overall accuracy., Conclusions: The decision tree model distinguished children affected by prenatal alcohol exposure from nonexposed control subjects, including those with other behavioral concerns or conditions. Improving identification of this population will streamline access to clinical services, including multidisciplinary evaluation and treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children., Methods: Subjects were 407 youth with prenatal alcohol exposure (n = 192) and controls (n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses., Results: No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females., Conclusions: Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Prenatal alcohol exposure (PAE) is an established risk factor for neurodevelopmental deficits in the offspring. Prenatal depression has been associated with neurodevelopmental deficits in the offspring, although investigations into unmedicated prenatal depression have been inconsistent. We hypothesized that unmedicated prenatal depressive symptoms would independently and jointly with PAE predict neurodevelopmental outcomes in infant offspring., Methods: We studied 344 participants from a randomized clinical trial of multivitamin supplements in pregnant women in Ukraine. Women were recruited based upon periconceptional alcohol use and followed up to 12 months postpartum. Prenatal depressive symptoms were assessed at approximately 32 weeks of gestation using the Beck Depression Inventory score. Neurodevelopment was assessed with the Bayley Scales of Infant Development II Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 6 and 12 months postpartum. Generalized linear regression models were constructed to assess the independent and joint effects of prenatal depressive symptoms and PAE in models adjusted for sociodemographic and pregnancy characteristics., Results: PAE was independently associated with deficits in neurodevelopmental outcomes at 6 and 12 months, however, level of prenatal depressive symptoms was not. We found marginal evidence of synergism of depressive symptoms and PAE, with larger deficits in those with both exposures observed for the PDI-6 months (p = 0.05) and MDI-12 months (p = 0.09). Additionally, there was a suggestion of sexual dimorphism; females had stronger deficits from joint exposures than males (depressive symptom [MDI-6 months] female: -8.28, 95% CI -13.06, -3.49; male: 0.68, 95% CI -4.58, 5.94; p for interaction 0.04). While not statistically significant for the MDI or PDI at 12 months, the trend persisted., Conclusions: Infants exposed to PAE and prenatal depression may be at an increased risk of neurodevelopmental deficits. Healthcare providers should be aware of this possible synergism in their efforts to mitigate the neurodevelopmental effects of these co-occurring exposures., (Copyright © 2016 by the Research Society on Alcoholism.)

Prenatal cocaine exposure (PCE) is associated with long-term and negative effect on arousal regulation. Recent neuroimaging studies have examined brain mechanisms related to arousal dysregulation with cross-sectional experimental designs; but longitudinal changes in the brain, reflecting group differences in neurodevelopment, have never been directly examined. To directly assess the interaction of PCE and neurodevelopment, the present study used a longitudinal design to analyze functional magnetic resonance imaging (fMRI) data collected from 33 adolescents (21 with PCE and 12 non-exposed controls) while they performed the same working memory task with emotional distracters at two points in time. The mean age of participants was 14.3 years at time&#95;1 and 16.7 years at time&#95;2. With confounding factors statistically controlled, the fMRI data revealed significant exposure-by-time interaction in the activations of the amygdala and default mode network (DMN). For the control adolescents, brain activations associated with emotional arousal (amygdala) and cognitive effort (DMN) were both reduced at time&#95;2 as compared to that at time&#95;1. However, these activation reductions were not observed in the PCE group, indicating persistently high levels of emotional arousal and cognitive effort. In addition, correlations between longitudinal changes in the brain and in behavior have shown that adolescents with persistently high emotional arousal were more likely in need of high cognitive effort; and their cognitive performance was more likely to be affected by distractive challenges. The present results complement and extend previous findings from cross-sectional studies with further evidence supporting the view of PCE associated long-term teratogenic effects on arousal regulation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Although many studies have demonstrated effects of prenatal alcohol exposure (PAE) on physical, cognitive, and behavioral development in children, few have focused on the long term effects on adults. In this study, data are presented on adaptive function and entry into adult roles in a community sample of young adults with PAE. The expectation was that prenatally exposed adults would show lower adaptive functioning and more difficulty with entry into adult roles than the non-exposed control group and that these effects would be related to the severity of PAE effects., Method: The predominantly African-American, low income sample included adults with a wide range of prenatal exposure (n = 123) as well as control groups for socioeconomic (SES) (n =5 9) and disability (n = 54) status. The mothers of the alcohol-exposed and SES-control group participants were recruited before birth and offspring have been followed up periodically. The disability control group was recruited in adolescence. The adults were interviewed about adaptive function in day-to-day life and adult role entry. Collateral adults who were well-acquainted with each participant were interviewed concerning adaptive function., Results: Results showed that adults who were dysmorphic and/or cognitively affected by PAE had difficulty with adaptive function and entry into adult roles. Males showing cognitive effects with no physical effects were the most severely affected. Results for exposed adults not showing physical or cognitive effects were similar to or more positive than those of the control group for most outcomes., Conclusion: PAE has long-term effects on adaptive outcomes in early adulthood. Additional research should focus on possible interventions at this transition and on factors contributing to the adjustment of the exposed, but unaffected participants., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) result in behavioral issues related to poor executive function (EF). This overlap may hinder clinical identification of alcohol-exposed children. This study examined the relation between parent and neuropsychological measures of EF and whether parent ratings aid in differential diagnosis. Neuropsychological measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), were administered to four groups of children (8-16 years): alcohol-exposed with ADHD (AE+, n=80), alcohol-exposed without ADHD (AE-, n=36), non-exposed with ADHD (ADHD, n=93), and controls (CON, n=167). Primary caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF). For parent ratings, multivariate analyses of variance revealed main effects of Exposure and ADHD and an interaction between these factors, with significant differences between all groups on nearly all BRIEF scales. For neuropsychological measures, results indicated main effects of Exposure and ADHD, but no interaction. Discriminant function analysis indicated the BRIEF accurately classifies groups. These findings confirm compounded behavioral, but not neuropsychological, effects in the AE+ group over the other clinical groups. Parent-report was not correlated with neuropsychological performance in the clinical groups and may provide unique information about neurobehavior. Parent-report measures are clinically useful in predicting alcohol exposure regardless of ADHD. Results contribute to a neurobehavioral profile of prenatal alcohol exposure.

Background: Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) are associated with adaptive behavior deficits. This study examined the interaction between these 2 factors on parent ratings of adaptive behavior., Methods: As part of a multisite study, primary caregivers of 317 children (8 to 16 years, M = 12.38) completed the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Four groups of subjects were included: children with prenatal alcohol exposure with ADHD (AE+, n = 82), children with prenatal alcohol exposure without ADHD (AE-, n = 34), children with ADHD (ADHD, n = 71), and control children (CON, n = 130). VABS-II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [AE]) × 2 (ADHD diagnosis) between-subjects analyses of covariance., Results: There were significant main effects of AE (p < 0.001) and ADHD (p < 0.001) on all VABS-II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication, F(1, 308) = 7.49, p = 0.007, partial η(2) = 0.024, but not Daily Living Skills or Socialization domains (ps > 0.27). Follow-up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects (ADHD vs. CON) than exposed subjects (AE+ vs. AE-), and the effects of alcohol exposure were stronger in subjects without ADHD (AE- vs. CON) than in subjects with ADHD (AE+ vs., Adhd) Conclusion: As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these 2 factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broaden our understanding of how ADHD exacerbates behavioral outcomes in this population., (Copyright © 2014 by the Research Society on Alcoholism.)

This study examined direct and indirect associations between prenatal cocaine exposure (CE) and children's externalizing problems in kindergarten via higher maternal harshness and lower self-regulation in early childhood. Other environmental risk variables, such as child exposure to community violence and experience of hunger, were used as additional predictors. The sample consisted of 216 mother-infant dyads recruited at delivery from local area hospitals (116 cocaine-exposed, 100 nonexposed). Maternal harshness was coded from observations of mother-toddler interactions at 2 years of age, and children's self-regulation was measured at 3 years of age using several laboratory paradigms. Maternal reports of externalizing behavior problems were obtained at both time points and at kindergarten. Teacher reports were obtained and classroom observations of externalizing behaviors were conducted in the kindergarten classroom. Results indicated significant indirect associations between CE and maternal reports of externalizing problems via higher maternal harshness at 2 years and higher externalizing problems at 3 years of child age. A second indirect path from CE to externalizing problems in the school setting via higher maternal harshness at 2 years and lower self-regulation at 3 years was also significant. There were significant associations between community violence exposure and maternal reports of externalizing problems, and between hunger and externalizing problems in the school setting. Results highlight the role of parenting and self-regulation in early childhood as critical process variables in the indirect association between CE and externalizing behavior problems in kindergarten.

Objective: Neuropsychological functioning of individuals with attention-deficit/hyperactivity disorder (ADHD) or heavy prenatal alcohol exposure has been well documented independently. This study examined the interaction between both factors on cognitive performance in children., Method: As part of a multisite study, 344 children (8-16 y, M = 12.28, SD = 2.52) completed a comprehensive neuropsychological battery. Four subject groups were tested: children with histories of heavy prenatal alcohol exposure (AE) and ADHD (AE+, n = 90), alcohol-exposed without ADHD, (AE-, n = 38), nonexposed with ADHD (ADHD, n = 80), and nonexposed without ADHD (CON, n = 136)., Results: Separate 2(AE) × 2(ADHD) MANCOVAs revealed significant main and interactive effects of ADHD and AE on overall WISC-IV, D-KEFS, and CANTAB performance. Individual ANOVAs revealed significant interactions on 2 WISC-IV indices [Verbal Comprehension (VCI), Perceptual Reasoning (PRI)], and four D-KEFS and CANTAB subtests [Design Fluency, Verbal Fluency, Trail Making, Spatial Working Memory]. Follow-up analyses demonstrated no difference between AE+ and AE- groups on these measures. The combined AE+/- group demonstrated more severe impairment than the ADHD group on VCI and PRI, but there were no other differences between clinical groups., Conclusions: These results support a combined AE+/- group for neuropsychological research and indicate that, in some cases, the neuropsychological effects seen in ADHD are altered by prenatal alcohol exposure. The effects of alcohol exposure on verbal comprehension and perceptual reasoning were greater than those related to having ADHD without alcohol exposure, although both conditions independently resulted in cognitive impairment compared to controls. Clinically, these findings demonstrate task-dependent patterns of impairment across clinical disorders., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Prenatal cocaine exposure (PCE) is associated with arousal dysregulation, and alterations of amygdala activity in response to emotional arousal have previously been reported. However, voluntary regulation of emotional affect, enabling appropriate neural response to different streams of stimuli, must also engage prefrontal regions, yet the impact of PCE on these prefrontal mechanisms has not been investigated. Recent neuroimaging studies have shown the involvement of ventral prefrontal cortex (vPFC) in the modulation of amygdala reactivity and the mediation of effective emotional regulation. Based on these findings, using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study compared functional activations of the vPFC as well as its structural connectivity with the amygdala between groups of PCE and control adolescents. In a working memory task with emotional distracters, the PCE adolescents exhibited less capability of increasing their vPFC activation in response to increased memory load, which corresponded with their less suppressed amygdala activation. Reduced structural connectivity between the vPFC and the amygdala was also observed from DTI measurement in the PCE group. In addition, correlations between amygdala activation and (i) vPFC activation, as well as (ii) amygdala-vPFC structural connectivity, were observed in the control but not in the PCE group. These data complement previous findings of the impact of PCE on the activity of the amygdala and extend our understanding of the neurobiological mechanisms underlying the effect of PCE on arousal dysregulation reported in human and animal studies., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Heavy prenatal alcohol exposure (AE) results in a broad array of neurobehavioral deficits. Recent research has focused on identification of a neurobehavioral profile or profiles that will improve the identification of children affected by AE. This study aimed to build on our preliminary neurobehavioral profile to improve classification accuracy and test the specificity of the resulting profile in an alternate clinical group., Methods: A standardized neuropsychological test battery was administered to 3 groups of children: subjects with AE (n = 209), typically developing controls (CON, n = 185), and subjects with attention-deficit/hyperactivity disorder (ADHD, n = 74). We assessed a large sample from 6 sites in the United States and South Africa, using standardized methodology. Data were analyzed using 3 latent profile analyses including (i) subjects with fetal alcohol syndrome (FAS) and controls, (ii) subjects with AE without FAS and controls, and (iii) subjects with AE (with or without FAS) and subjects with ADHD., Results: Classification accuracy was moderate but significant across the 3 analyses. In analysis 1, overall classification accuracy was 76.1% (77.2% FAS, 75.7% CON). In the second analysis, overall classification accuracy was 71.5% (70.1% AE/non-FAS, 72.4% CON). In the third analysis, overall classification accuracy was 73.9% (59.8% AE, 75.7% ADHD). Subjects that were misclassified were examined for systematic differences from those that were correctly classified., Conclusions: The results of this study indicate that the neuropsychological effects of AE are clinically meaningful and can be used to accurately distinguish alcohol-affected children from both typically developing children and children with ADHD. Further, in combination with other recent studies, these data suggest that approximately 70% of children with heavy prenatal alcohol exposure are neurobehaviorally affected, while the remaining 30% are spared these often-devastating consequences, at least those in the domains under study. Refining the neurobehavioral profile will allow improved identification and treatment development for children affected by prenatal alcohol exposure., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: This study examined prevalence of psychiatric disorders and behavioral problems in children with and without prenatal alcohol exposure (AE) and attention-deficit/hyperactivity disorder (ADHD)., Methods: Primary caregivers of 344 children (8 to 16 years, M = 12.28) completed the Computerized Diagnostic Interview Schedule for Children-IV (C-DISC-4.0) and the Child Behavior Checklist (CBCL). Subjects comprised 4 groups: AE with ADHD (AE+, n = 85) and without ADHD (AE-, n = 52), and nonexposed with ADHD (ADHD, n = 74) and without ADHD (CON, n = 133). The frequency of specific psychiatric disorders, number of psychiatric disorders (comorbidity), and CBCL behavioral scores were examined using chi-square and analysis of covariance techniques., Results: Clinical groups had greater frequency of all psychiatric disorders, except for anxiety, where the AE- and CON groups did not differ. There was a combined effect of AE and ADHD on conduct disorder. For comorbidity, children with ADHD had increased psychiatric disorders regardless of AE, which did not have an independent effect on comorbidity. For CBCL scores, there were significant main effects of AE and ADHD on all scores and significant AE × ADHD interactions for Withdrawn/Depressed, Somatic Complaints, Attention, and all Summary scores. There was a combined effect of AE and ADHD on Externalizing, Total Problems, and Attention Problems., Conclusions: Findings indicate that ADHD diagnosis elevates children's risk of psychiatric diagnoses, regardless of AE, but suggest an exacerbated relation between AE and ADHD on conduct disorder and externalizing behavioral problems in children. Findings affirm a poorer behavioral prognosis for alcohol-exposed children with ADHD and suggest that more than 1 neurobehavioral profile may exist for individuals with AE., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Children with heavy prenatal alcohol exposure often meet criteria for attention-deficit/hyperactivity disorder (ADHD). ADHD research has examined subtype differences in symptomatology, including sluggish cognitive tempo (SCT). This construct is defined by behavioral symptoms including hypoactivity and daydreaming and has been linked to increased internalizing behaviors. The current study examined whether similar findings are displayed in children with prenatal alcohol exposure., Methods: As part of a multisite study, caregivers of 272 children (8 to 16 years) completed the SCT Scale and Child Behavior Checklist (CBCL). Four groups were included: alcohol-exposed children with ADHD (ALC+; n = 75), alcohol-exposed children without ADHD (ALC-; n = 35), nonexposed children with ADHD (ADHD; n = 60), and nonexposed children without ADHD (CON; n = 102). SCT and CBCL scores were analyzed using 2 (exposure) × 2 (ADHD) analyses of variance. Pearson's correlations measured the relationships between SCT, CBCL, and Full Scale IQ (FSIQ). Discriminant function analysis examined whether SCT items could accurately classify groups., Results: Analyses revealed significant main effects of exposure and ADHD on SCT and internalizing and externalizing scores and significant interaction effects on SCT and internalizing scores. SCT significantly correlated with internalizing, externalizing, and attention ratings in all groups and with FSIQ in ALC+. Discriminant function analysis indicated that specific SCT items could distinguish ALC- from CON., Conclusions: Alcohol-exposed children exhibited elevated SCT scores. Elevations were related to increased parent ratings of internalizing and externalizing behaviors and attention. These findings are observed in alcohol-exposed children regardless of ADHD symptoms and specific SCT items proved useful in distinguishing exposed children, suggesting clinical utility for this measure in further defining the neurobehavioral profile related to prenatal alcohol exposure., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains, including executive function (EF) and adaptive functioning. In the current study, the relation between these 2 domains was examined in children with histories of heavy prenatal alcohol exposure, nonexposed children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and typically developing controls., Methods: As part of a multisite study, 3 groups of children (8 to 18 years, M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure (ALC, n = 142), nonexposed children with ADHD (ADHD, n = 82), and typically developing controls (CON, n = 133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis-Kaplan Executive Function System (D-KEFS), and their primary caregivers completed the Vineland Adaptive Behavior Scales-II. Data were analyzed using regression analyses., Results: Analyses showed that EF measures were predictive of adaptive abilities, and significant interactions between D-KEFS measures and group were present. For the ADHD group, the relation between adaptive abilities and EF was more general, with 3 of the 4 EF measures showing a significant relation with adaptive score. In contrast, for the ALC group, this relation was specific to the nonverbal EF measures. In the CON group, performance on EF tasks did not predict adaptive scores over the influence of age., Conclusions: These results support prior research in ADHD, suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However, the relation between EF and adaptive ability differed by group, suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations, as well as demonstrate the ecological validity of laboratory measures of EF., (Copyright © 2012 by the Research Society on Alcoholism.)

Prenatal alcohol exposure (PAE) is associated with various adverse effects on human brain and behavior. Recently, neuroimaging studies have begun to identify PAE effects on specific brain structures. Investigation of such specific PAE effects is important for understanding the teratogenic mechanism of PAE on human brain, which is critical for differentiating PAE from other disorders. In this structural MRI study with young adults, PAE effects on the volumes of automatically segmented cortical and subcortical regions of interest (ROIs) were evaluated both through a group difference approach and a parametric approach. In the group difference approach (comparing among two PAE and a control groups), a disproportionate PAE effect was found in several occipital and temporal regions. This result is inconsistent with previous studies with child samples. Moreover, a gender difference in PAE effect was shown in some cortical ROIs. These findings suggest that sampling and gender may be important factors for interpreting specific PAE effects on human brain. With the parametric approach, it was demonstrated that the higher the PAE level, the smaller the entire brain, the lower the IQ. Several cortical and subcortical ROIs also exhibited a negative correlation between the PAE level and ROI volume. Furthermore, our data showed that the PAE effect on the brain could not be interpreted by the PAE effect on general physical growth until the young adult age. This study provides valuable insight into specific effects of PAE on human brain and suggests important implications for future studies in this field., (Copyright © 2011 Wiley-Liss, Inc.)

Prenatal alcohol exposure (PAE) is known to cause significant cognitive and attentional dysfunction. Given the relationship between default mode network (DMN) activity and task-related attentional modulation, it is possible that PAE affects activity of this network. In the present study, task-related deactivation as well as structural and resting state functional connectivity of the DMN were examined using diffusional tensor imaging and functional magnetic resonance imaging in non-dysmorphic and dysmorphic PAE populations and compared to healthy controls. The dysmorphic PAE group was found to have reduced DMN deactivation as compared to controls, indicating poorer attentional modulation during the cognitive task. Additionally, structural connectivity and baseline functional connectivity were lower in both PAE groups as compared to controls. Primarily the findings suggest that learning problems seen with PAE may be a combination of general attentional and specific cognitive deficits. A secondary implication is that DMN activity is affected to varying extents depending on the degree of PAE., (2011 Elsevier Ireland Ltd. All rights reserved.)

Functional neuroimaging offers the opportunity to understand the effect of prenatal alcohol exposure on the activities of the brain as well as providing a window into the relationship between neural activation and the behavioral outcomes that have been described in affected individuals. Several different methodologies have been used to examine the neurophysiological signal changes associated with different brain functions in prenatally exposed individuals and those diagnosed with fetal alcohol syndrome (FAS) or other fetal alcohol spectrum disorders (FASD). These include electroencephalography (EEG), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). These studies demonstrate that it is feasible to use these technologies with this clinical population and that the damage to the central nervous system associated with prenatal alcohol exposure has widespread functional implications; however, currently, the literature in these areas is limited and unsystematic. Functional MRI with this clinical population has just begun to explore the implications of prenatal alcohol exposure with the first paper published in 2005. Other methodologies are similarly limited in scope. Nonetheless, these functional neuroimaging studies suggest that prenatal alcohol exposure, or a diagnosis of FAS, may lead to restrictions in neural efficiency or a global decrement in processing resources.

Prenatal cocaine exposure (PCE) is associated with attention/arousal dysregulation and possible inefficiencies in some cognitive functions. However, the neurobiological bases of these teratogenic effects have not been well characterized. Because activities in the default mode network (DMN) reflect intrinsic brain functions that are closely associated with arousal regulation and cognition, alterations in the DMN could underlie cognitive effects related to PCE. With resting-state and task activation functional magnetic resonance imaging (fMRI), this study investigated the possible PCE related changes in functional brain connectivity and brain activation in the DMN. In the resting state, the PCE group was found to have stronger functional connectivity in the DMN, as compared to the nonexposed controls. During a working memory task with emotional distracters, the PCE group exhibited less deactivation in the DMN and their fMRI signal was more increased by emotional arousal. These data revealed additional neural effects related to PCE, and consistent with previous findings, indicate that PCE may affect behavior and functioning by increasing baseline arousal and altering the excitatory/inhibitory balancing mechanisms involved in cognitive resource allocation., (Copyright © 2010 Wiley-Liss, Inc.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fetal alcohol syndrome and fetal alcohol spectrum disorders are underdiagnosed in general treatment settings. Among the factors involved in identifying the effects of prenatal alcohol exposure are (1) the evidence for prenatal alcohol exposure; (2) the effects of the postnatal, caregiving environment; (3) comorbidities; and (4) differential diagnosis, which includes identifying the neurodevelopmental effects of alcohol and discriminating these effects from those characterizing other conditions. This article reviews findings on the neurodevelopmental effects of prenatal alcohol exposure, including learning and memory, motor and sensory/motor effects, visual/spatial skills, and executive functioning and effortful control. Encouraging clinicians to discriminate the effects of prenatal alcohol exposure from other conditions may require more education and training but ultimately will improve outcomes for affected children.

This study examined the associations between prenatal cocaine exposure and quality of mother-infant play interactions at 13 months of infant ages. We investigated whether maternal psychological distress and infant reactivity mediated or moderated this association. Participants consisted of 220 (119 cocaine exposed and 101 non-cocaine exposed) mother-infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher negative affect and lower sensitivity toward their infant during play interactions at 13 months, and that their infants were less responsive toward them. Contrary to hypothesis, this association was not mediated by maternal psychological distress or by infant reactivity. However, results for both the cocaine and non-cocaine exposed infants were supportive of a transactional model where lower maternal sensitivity at 1 month was predictive of higher infant reactivity at 7 months, which in turn was predictive of lower maternal warmth/sensitivity at 13 months, controlling for potential stability in maternal behavior. Results also indicated that as hypothesized, infant reactivity moderated the association between maternal cocaine use during pregnancy and maternal warmth/sensitivity at 13 months of age. Cocaine-using mothers who experienced their infants as being more reactive in early infancy were less warm/sensitive toward them in later infancy. Results have implications for parenting interventions that may be targeted toward improving maternal sensitivity among cocaine-using mothers with more reactive infants., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

While prenatal cocaine exposure (PCE) has been associated with arousal dysregulation and attentional impairments in both human and animal studies, the neurobiological bases of these teratogenic effects have not been well characterized. In the current study, we report functional neuroimaging observations of these effects in exposed youth. Using functional magnetic resonance imaging (fMRI), we embedded task-irrelevant emotional distracters in a working memory task to examine the interaction of emotional arousal and memory in 33 PCE and 23 non-exposed adolescents. Though with similar behavioral performance, the two groups exhibited different activation patterns associated with emotion-memory interactions. On the one hand, higher memory load attenuated emotion-related amygdala activation in controls but not in the exposed adolescents; on the other hand, prefrontal activation associated with memory load decreased in the presence of emotional distraction in the controls but increased in the exposed group. These group interaction differences suggest neurobiological substrates for arousal-associated neuronal alterations related to prenatal cocaine exposure. Consistent with previous findings in behavioral and physiological studies, the present neuroimaging data provided more in-depth evidence supporting the view that PCE has significant long-term teratogenic effect on arousal regulation system.

Deficits in auditory processing have been posited as one of the underlying neurodevelopmental consequences of maternal smoking during pregnancy that leads to later language and reading deficits. Fast auditory brainstem responses were used to assess differences in the sensory processing of auditory stimuli among infants with varying degrees of prenatal cigarette exposure. Maternal report of consumption of cigarettes and blood samples were collected in the hospital to assess exposure levels and participants were then seen at 6-months. To participate in the study, all infants had to pass the newborn hearing exam or a clinically administered ABR and have no known health problems. After controlling for participant age, maternal smoking during pregnancy was negatively related to latency of auditory brainstem responses. Of several potential covariates, only perinatal complications and maternal alcohol use were also related to latency of the ABR responses and maternal smoking level accounted for significant unique variance after controlling for these factors. These results suggest that the relationship between maternal smoking may lead to disruption in the sensory encoding of auditory stimuli.