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This study aimed to assess associations between prenatal and postnatal exposure to lead (Pb), mercury (Hg) and polychlorinated biphenyls (PCBs) and gray matter volume of key regions of the brain reward circuit, namely the caudate nucleus, putamen, nucleus accumbens (nAcc), the amygdala, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC). Structural magnetic resonance imaging (MRI) was conducted in 77 Inuit adolescents (mean age = 18.39) from Nunavik, Canada, who also completed the Brief Sensation Seeking Scale (BSSS-4) and Sensation Seeking – 2 (SS-2), two self-report questionnaires evaluating the tendency toward sensation seeking, which is a proxy of reward-related behaviors. Exposures to Pb, Hg and PCBs were measured in cord blood at birth, in blood samples at 11 years old and at time of testing (18 years old). Multivariate linear regressions were corrected for multiple comparisons and adjusted for potential confounders, such as participants’ sociodemographic characteristics and nutrient fish intake. Results showed that higher cord blood Pb levels predicted smaller gray matter volume in the bilateral nAcc, caudate nucleus, amygdala and OFC as well as in left ACC. A moderating effect of sex was identified, indicating that the Pb-related reduction in volume in the nAcc and caudate nucleus was more pronounced in female. Higher blood Hg levels at age 11 predicted smaller right amygdala independently of sex. No significant associations were found between blood PCBs levels at all three times of exposure. This study provides scientific support for the detrimental effects of prenatal Pb and childhood Hg blood concentrations on gray matter volume in key reward-related brain structures.

Exposure to environmental contaminants is an important public health concern for the Inuit population of northern Québec, who have been exposed to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb). During the last 25 years, the Nunavik Child Development Study (NCDS) birth cohort has reported adverse associations between these exposures and brain function outcomes. In the current study, we aimed to determine whether contaminant exposure is associated with alterations of the corpus callosum (CC), which plays an important role in various cognitive, motor and sensory function processes. Magnetic resonance imaging (MRI) was administered to 89 NCDS participants (mean age ± SD = 18.4 ± 1.2). Diffusion-weighted imaging was assessed to characterize the microstructure of the CC white matter in 7 structurally and functionally distinct regions of interest (ROIs) using a tractography-based segmentation approach. The following metrics were computed: fiber tract density, fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Multiple linear regression models adjusted for sex, age, current alcohol/drug use and fish nutrients (omega-3 fatty acids and selenium) were conducted to assess the association between diffusion-weighted imaging metrics and Hg, PCB 153 and Pb concentrations obtained at birth in the cord blood and postnatally (mean values from blood samples at 11 and 18 years of age). Exposures were not associated with fiber tract density. Nor were significant associations found with cord and postnatal blood Pb concentrations for FA. However, pre- and postnatal Hg and PCB concentrations were significantly associated with higher FA of several regions of the CC, namely anterior midbody, posterior midbody, isthmus, and splenium, with the most pronounced effects observed in the splenium. FA results were mainly associated with lower RD. This study shows that exposure to Hg and PCB 153 alters the posterior microstructure of the CC, providing neuroimaging evidence of how developmental exposure to environmental chemicals can impair brain function and behavior in late adolescence.

The ability to identify and interpret facial emotions plays a critical role in effective social functioning, which may be impaired in individuals with fetal alcohol spectrum disorders (FASD). We previously reported deficits in children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) on the “Reading the Mind in the Eyes” (RME) test, which assesses the interpretation of facial emotion. This follow‐up study in adolescents was designed to determine whether this impairment persists or represents a developmental delay; to classify the RME stimuli by valence (positive, negative, or neutral) and determine whether RME deficits differ by affective valence; and to explore how components of executive function mediate these associations. The RME stimuli were rated and grouped according to valence. Sixty‐two participants who had been administered the RME in late childhood (mean ± SD = 11.0 ± 0.4 years) were re‐administered this test during adolescence (17.2 ± 0.6 years). Overall and valence‐specific RME accuracy was examined in relation to prenatal alcohol exposure (PAE) and FASD diagnosis. Children with FAS (n= 8) and PFAS (n= 15) performed more poorly on the RME than non‐syndromal heavily exposed (HE; n= 19) and control individuals (n= 20). By adolescence, the PFAS group performed similarly to HE and controls, whereas the FAS group continued to perform more poorly. No deficits were seen for positively valenced items in any of the groups. For negative and neutral items, in late childhood individuals with FAS and PFAS performed more poorly than HE and controls, but by adolescence only the FAS group continued to perform more poorly. Test–retest reliability was moderate across the two ages. At both timepoints, the effects in the FAS group were partially mediated by Verbal Fluency but not by other aspects of executive function. Individuals with full FAS have greater difficulty interpreting facial emotions than those with non‐syndromal HE and healthy controls in both childhood and adolescence. By contrast, RME deficits in individuals with PFAS in childhood represent developmental delay. We previously reported poorer performance in children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) on the “Reading the Mind in the Eyes” assessment of the ability to interpret facial emotion. In this follow‐up of 62 adolescents, those with PFAS performed similarly to controls, but those with FAS continued to perform more poorly. The groups also differed depending on affective valence of the facial expressions. Performance by the FAS group was partially mediated by verbal fluency but not by other aspects of executive function.

Individuals with fetal alcohol spectrum disorders may exhibit a distinct pattern of dysmorphic facial features, growth restriction, and cognitive deficits, particularly in arithmetic. Magnitude comparison, a fundamental element of numerical cognition, is modulated by the numerical distance effect, with numbers closer in value more difficult to compare than those further apart, and by the automaticity of the association of numerical values with their symbolic representations (Arabic numerals). We examined event‐related potentials acquired during the Numerical Stroop numerical and physical tasks administered to 24 alcohol‐exposed adolescents (eight fetal alcohol syndrome (FAS), eight partial FAS (PFAS), eight heavily exposed (HE) nonsyndromal) and 23 typically developing (TD), same‐ age controls. The distance effect was assessed on the numerical task to examine differences in reaction time (RT) and accuracy when two numbers are close in value (e.g., 1 vs. 2) compared to when the numbers are less close (e.g., 1 vs. 6). Automaticity was assessed in the physical task by examining the degree to which RT and accuracy are reduced when the relative physical size of two numerals is incongruent with their numerical values (e.g., 1 vs. 6). Adolescents in all four groups performed behaviorally as expected on these relatively simple magnitude comparison tasks, but accuracy was poorer and RT was slower on both tasks in the FAS and PFAS than the HE and TD groups. At the neurophysiological level, in the numerical task, a higher level of prenatal alcohol exposure was associated with smaller P2p amplitude. In the physical task, only the TD and nonsyndromal HE groups exhibited the expected smaller P300 amplitude in the incongruent than the congruent condition. These findings suggest that magnitude comparison in alcohol‐exposed individuals may be mediated by recruitment of alternative neural pathways that are likely to be inefficient when number processing becomes more challenging. Magnitude comparison and automaticity were examined on the Numerical Stroop using event‐related potentials (ERP). Performance was poorer in adolescents with fetal alcohol syndrome (FAS) and partial FAS than nonsyndromal heavily exposed (HE) and controls. In the numerical task, prenatal alcohol was associated with smaller P2p amplitude; in the physical, only the HE and control groups exhibited the expected smaller P300 amplitude in the incongruent vs. congruent conditions. These findings identify aspects of number processing that are particularly affected in FAS.

Prenatal alcohol exposure (PAE) has been associated with compromised interhemispheric transfer of tactile stimuli in childhood and structural changes to the corpus callosum (CC). In this study, we used a finger localization task (FLT) to investigate whether interhemispheric transfer deficits persist in adolescence; whether effects of PAE on perceptual reasoning, working memory, and executive function are mediated by deficits in interhemispheric transfer of information; and whether CC size in childhood predicts FLT performance in adolescence. Participants, aged 16 to 17 years, were from the Cape Town Longitudinal Cohort, whose mothers were recruited during pregnancy and interviewed regarding their alcohol use using the timeline follow‐back method. Diagnoses of fetal alcohol syndrome (FAS) and partial FAS (PFAS) were determined by two expert dysmorphologists; nonsyndromal exposed children were designated as heavily exposed (HE); those born to abstainers or light drinkers, as controls. The FLT was administered to 74 participants (12 FAS, 16 PFAS, 14 HE and 32 controls). CC size at age 9 to 12 years was available for 35 participants (7 FAS, 13 PFAS, 5 HE and 10 control). Although the degree of PAE was similar in the FAS, PFAS, and HE groups, only the adolescents with FAS showed more transfer‐related errors than controls in conditions in which one finger was stimulated. FLT performance mediated the effects of FAS on perceptual reasoning and executive function. In the subsample for which neuroimaging data from childhood were available, there was an association among adolescents with PAE of smaller CC volumes with more transfer‐related errors on the one‐finger/hand hidden condition, suggesting that CC damage previously seen in childhood continues to impact function through adolescence. This study provides evidence of compromised interhemispheric transfer of information in adolescents with FAS, while those with PFAS or heavy exposed nonsyndromal individuals are apparently spared. It is the first to show that PAE effects on important aspects of cognitive function are partially mediated by deficits in the interhemispheric transfer of information. Prenatal alcohol exposure (PAE) is associated with corpus callosum (CC) changes and compromised inter‐hemispheric transfer of tactile information in childhood. Using finger localization, we found that adolescents with fetal alcohol syndrome (FAS) continued to demonstrate more transfer‐related errors, whereas those with partial FAS caught up. Among alcohol‐exposed children, transfer‐related errors increased with decreasing CC volume. PAE effects on perceptual reasoning, working memory, and executive function were mediated by inter‐hemispheric transfer deficits, indicating that childhood CC damage continues to impact function through adolescence.

Polychlorinated biphenyls are a family of synthetic hydrocarbon compounds that were used historically for a broad range of industrial purposes. Although banned in the 1970s, they continue to be ubiquitous in landfills, sediments, and wildlife. Prenatal polychlorinated biphenyl exposure was evaluated in a sample of children born to women who had eaten relatively large quantities of polychlorinated biphenyl-contaminated Lake Michigan fish. This exposure was found to be associated with poorer intellectual function after controlling statistically for a broad range of potential confounding variables. Deficits included poorer recognition memory in infancy, lower scores on a preschool IQ test, and poorer verbal IQ and reading comprehension at 11 years of age. Although breast-fed children were exposed postnatally to elevated levels of polychlorinated biphenyls from maternal milk, the adverse effects associated with prenatal exposure were markedly stronger in the children who were not breast-fed. It is not clear whether the adverse effects were attenuated in the breast-fed children due to certain nutrients in the breast milk or due to better quality of intellectual stimulation provided by the breast-feeding mothers. Virtually no adverse effects were found in relation to postnatal exposure to polychlorinated biphenyls from breast-feeding, indicating that the fetus is particularly vulnerable to this exposure. Key Words: Polychlorinated biphenyls; Prenatal exposure to toxic agents; Neurotoxicants and development; IQ; Breast-feeding, INTRODUCTION In recent years, longitudinal studies on exposure to relatively low levels of environmental contaminants have demonstrated statistically significant, albeit subtle, adverse effects on intellectual function in childhood. We summarize [...]

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. 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. 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. 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. 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. Prenatal alcohol exposure (PAE) effects on cognitive function were stronger than for behaviour problems or sustained attention. This analysis identified two domains of cognition—learning/memory and set‐shifting—that are particularly affected by PAE, and one domain, sustained attention, which is spared.

Prenatal alcohol exposure (PAE) is associated with smaller regional and global brain volumes. In rats, gestational choline supplementation mitigates adverse developmental effects of ethanol exposure. Our recent randomized, double‐blind, placebo‐controlled maternal choline supplementation trial showed improved somatic and functional outcomes in infants at 6.5 and 12 months postpartum. Here, we examined whether maternal choline supplementation protected the newborn brain from PAE‐related volume reductions and, if so, whether these volume changes were associated with improved infant recognition memory. Fifty‐two infants born to heavy‐drinking women who had participated in a choline supplementation trial during pregnancy underwent structural magnetic resonance imaging with a multi‐echo FLASH protocol on a 3T Siemens Allegra MRI (median age = 2.8 weeks postpartum). Subcortical regions were manually segmented. Recognition memory was assessed at 12 months on the Fagan Test of Infant Intelligence (FTII). We examined the effects of choline on regional brain volumes, whether choline‐related volume increases were associated with higher FTII scores, and the degree to which the regional volume increases mediated the effects of choline on the FTII. Usable MRI data were acquired in 50 infants (choline: n = 27; placebo: n = 23). Normalized volumes were larger in six of 12 regions in the choline than placebo arm (t≥ 2.05, p≤ 0.05) and were correlated with the degree of maternal choline adherence (β ≥ 0.28, p≤ 0.04). Larger right putamen and corpus callosum were related to higher FTII scores (r= 0.36, p= 0.02) with a trend toward partial mediation of the choline effect on recognition memory. High‐dose choline supplementation during pregnancy mitigated PAE‐related regional volume reductions, with larger volumes associated with improved 12‐month recognition memory. These results provide the first evidence that choline may be neuroprotective against PAE‐related brain structural deficits in humans.

Blood samples were collected from 28 mothers and from 38 school-aged children from Michigan farms on which there were polychlorinated biphenyl (PCB)-contaminated silos. The samples were analyzed for PCBs and other contaminants, including polybrominated biphenyis (PBBS) and dichlorodiphenyl trichloroethane (p,p'-DDT + p,p'-DDE) via packed column gas chromatography. The PCBs were quantified, using the Webb-McCall method, with Aroclors 1016 and 1260 used as reference standards. Approximately 42% of the children had serum PCB levels above the detection limit of 3.0 ng/ml. The values ranged from 3.1 to 23.3 ng/ml, with a mean of 6.8 ng/ml. In contrast, PCBs were detected in 86% of the mothers. The mean serum concentration was somewhat higher for the mothers (9.6 ng/ml), but the range was similar to that found for the children. PBBs were not detected in any of the children, but were present in trace amounts in 25% of the mothers. Conversely, DDT was present in 66% of the children and 93% of the mothers. As with PCBs, DDT concentrations were somewhat higher in the mothers. DDE accounted for 89% of the total DDT in serum. Various potential sources of exposure were evaluated as possible determinants of serum PCB levels, using hierarchical multiple regression. Years of residence on a silo farm and consumption of PCB-contaminated Great Lakes fish both accounted for significant portions of the variance in maternal serum PCB levels. Exposure via breast-feeding explained a large and highly significant proportion of the variance in the children's serum PCB concentrations, suggesting that breast milk was the primary source of PCB exposure for these children. Years of residence on a silo farm also explained a significant proportion of the variance in children's serum PCBs. The pattern of Webb-McCall elution peaks was similar in the children and mothers and closely resembled patterns observed in other Michigan cohorts exposed to PCBs through consumption of PCB-contaminated Great Lakes fish.

Infants may be exposed to polychlorinated biphenyls (PCBs) and related contaminants both in utero through the placenta, and after birth from breast milk. Fetal exposure to PCBs, by virtue of maternal consumption of fish from Lake Michigan, was studied in 236 children. The in utero exposure was measured on the basis of umbilical cord serum PCB concentration. The children who had been exposed in utero were assessed at four years of age to determine the effects of early PCB exposure on cognitive function. The study indicated that the PCB exposure was associated with poorer short-term memory in early childhood, both in terms of verbal and numerical memory. Short-term memory function is important in the development of reading and arithmetic skills. However, the exposed children showed no indication of mental retardation, gross impairment, or perceptual-motor impairment. The study suggested that long-term memory, a critical component of vocabulary recognition, was not affected. The vulnerability of the fetus to these toxins is most likely due to the fact that cells undergoing mitosis, or division, are particularly sensitive to toxins; the fetus lacks certain drug-metabolizing-detoxification capacities that are possessed by newborns; and incomplete development of the blood-brain barrier increases the vulnerability of the central nervous system. Although the impairment of short-term memory was subtle, it could affect future school performance. Further investigation of the effects of these toxins is desirable. (Consumer Summary produced by Reliance Medical Information, Inc.)

This paper reports findings from the first longitudinal study on the evolution of the physical phenotypes of fetal alcohol syndrome (FAS) and partial FAS (PFAS) from early childhood through adolescence. The sample consisted of 155 children (78 males and 77 females) born to women recruited at an antenatal clinic serving a Cape Coloured (mixed ancestry) population in Cape Town, South Africa. Two expert FASD dysmorphologists, blind regarding prenatal alcohol exposure, independently evaluated each child’s growth and dysmorphology at 4 clinics conducted over an 11‐year period. Case conferences were held to reach consensus regarding which children had FAS or PFAS growth and physical features using the Revised Institute of Medicine (2005) guidelines. The prevalence of the physical phenotype was stable across the 4 ages for about half of the children with FAS and about one‐third of those with PFAS but more variable for the others. Test–retest reliability was substantial for the FAS phenotype, but poorer for PFAS. Two distinct patterns were seen: a “strong phenotype” that was consistently identified and a less consistent one in which dysmorphic features and/or anthropometric deficits fluctuated or diminished with age. The physical phenotype was most apparent during early childhood and least apparent during puberty, due to differences in timing of the growth spurt and the evolving adult face. Short palpebral features and small head circumference diminished with age, flat philtrum fluctuated, while thin vermilion and weight and height restriction were stable. Key facial features that characterize FASD in early childhood diminish or evolve in some individuals, making diagnostic examinations that rely on these characteristics most sensitive during early childhood and school age. Moreover, puberty poses classification problems due to variability in timing of the growth spurt. Given that several features and small head circumference diminished with age, many individuals would be misdiagnosed if only examined at a later age. Expert FASD dysmorphologists examined 155 children born to heavy drinking and control women at four clinics conducted over an 11‐year period. The FAS physical phenotype was most apparent during childhood and least during puberty. Short palpebral features and small head circumference diminished with age, flat philtrum fluctuated, while thin vermilion and weight and height restriction were stable. Given that several features and small head circumference diminished, many individuals would be misdiagnosed if only examined at a later age.

Although deficits in the interpretation of affective facial expressions have been described clinically and in behavioral studies of fetal alcohol spectrum disorders (FASD), effects of prenatal alcohol exposure on the neural networks that mediate affective appraisal have not previously been examined. We administered a nonverbal event‐related fMRI affective appraisal paradigm to 64 children (mean age = 12.5 years; 18 with fetal alcohol syndrome (FAS) or partial FAS (PFAS), 18 nonsyndromal heavily exposed (HE), and 28 controls). Happy, sad, angry, fearful, and neutral faces and pixelated control images were presented sequentially in a randomized order. The child indicated whether the currently displayed face showed the same or different affect as the previous one. Data from whole‐brain analyses showed that all groups activated the appropriate face processing neural networks. Region of interest analyses indicated that, compared to HE and control children, the FAS/PFAS group exhibited greater blood oxygenation level–dependent (BOLD) signal changes when processing neutral faces than pixelated images in 2 regions that form part of the visual sensory social brain network, which plays an important role in the initial processing of facial affect. By contrast, BOLD signal when processing angry faces was weaker for the FAS/PFAS group in a region involved in the processing of facial identity and facial expressions and in a region involved in the recognition and selection of behavioral responses to aggressive behavior. These findings of greater BOLD signal in the FAS/PFAS group in response to neutral faces suggest less efficient neural processing of more difficult to interpret emotions, and the weaker BOLD response to angry faces suggests altered processing of angry stimuli. Although behavioral performance did not differ in this relatively simple affective appraisal task, these data suggest that in children with FAS and PFAS, the appraisal of neutral affect and anger is likely to be more effortful in more challenging and dynamic social contexts.

Prenatal alcohol exposure (PAE) has been linked to poorer performance on the Morris water maze (MWM), a test of spatial navigation in rodents that is dependent on hippocampal functioning. We recently confirmed these findings in children with PAE on a human analog of the MWM, the virtual water maze (VWM). Previous studies have shown that the hippocampus is particularly sensitive to PAE. Our aim was to determine whether hippocampal volume mediates the relation between PAE and virtual navigation. VWM and MRI hippocampal data were collected from 50 right‐handed 10‐year‐old children in a heavily exposed Cape Town, South African sample. PAE data had been collected from their mothers during pregnancy, and the children were examined by expert fetal alcohol spectrum disorder (FASD) dysmorphologists. In the VWM, the participant attempts to learn the location of a hidden platform in a virtual pool of water across a series of learning trials using only distal room cues. Hippocampal volumes were derived using FreeSurfer from MRI scans administered within 1 week of completing the VWM task. Both the fetal alcohol syndrome (FAS)/partial FAS and nonsyndromal heavy‐exposed (HE) groups had smaller hippocampal volumes than controls. PAE was associated with reduced right hippocampal volumes even after control for total intracranial volume (ICV). Hippocampal volume was also positively associated with VWM performance. The relation between PAE and VWM performance was partially mediated by right hippocampal volume but not by total ICV. These data confirm previous reports linking PAE to poorer spatial navigation on the VWM and are the first to provide direct evidence that volume reductions in this region partially mediate the relation of FASD diagnosis to place learning, suggesting that PAE specifically impairs the ability to encode the spatial information necessary for successful location of the hidden platform on a navigation task. Fetal alcohol spectrum disorders (FASD) are associated with impairments in spatial navigation and damage to the hippocampus. Individuals with lesions to the hippocampus exhibit impairments in spatial navigation. In a previous study, we showed that FASD was related poorer spatial navigation on the virtual water maze (VWM). This study found that FASD associated with reduced hippocampal volume even after controlling for reduced head size. Hippocampal volume partially mediated the effects of FASD on the virtual water maze.

Arithmetic is the domain of academic achievement most consistently related to prenatal alcohol exposure (PAE). Error detection, an important aspect of arithmetic processing, can be examined in a mathematical verification task. Electroencephalographic (EEG) studies using such tasks have shown bursts of synchronized theta‐band activity in response to errors. We assessed this activity for error detection in adolescents with PAE and typically developing (TD) matched controls. We predicted that the PAE group would show smaller theta bursts during error detection and weaker responses depending on the size of the error discrepancy. Participants’ mothers were recruited during pregnancy and interviewed about their alcohol consumption using a timeline follow‐back interview. Participants were followed from infancy and diagnosed for fetal alcohol syndrome (FAS) or partial FAS (PFAS) by expert dysmorphologists. EEGs were recorded for 48 adolescents during a verification task, which required differentiation between correct/incorrect solutions to simple equations; incorrect solutions had small or large deviations from correct solutions. Performance was good–excellent. The PAE group showed lower accuracy than the TD group: Accuracy was inversely related to diagnosis severity. The TD and heavily exposed (HE) nonsyndromal groups showed the expected differentiation in theta‐burst activity between correct/incorrect equations, but the FAS/PFAS groups did not. Degree of impairment in brain response to errors reflected severity of diagnosis: The HE group showed the same differentiation between correct/incorrect solutions as TD but failed to differentiate between levels of discrepancy; PFAS showed theta reactions only in response to large error discrepancies; and FAS did not respond to small or large discrepancies. Arithmetical error–related theta activity is altered by PAE and can be used to distinguish between exposed and nonexposed individuals and within diagnostic groups, supporting the use of numerical and quantitative processing patterns to derive a neurocognitive profile that could facilitate diagnosis and treatment of fetal alcohol spectrum disorders. Using a mathematical equations error detection task, adolescents prenatally exposed to alcohol demonstrated poorer accuracy and impaired brain responses. In the figure: topographic head maps of low theta (4 to 5 Hz) activity show greater differentiation between correct (Crr; e.g., 1 + 1 = 2) compared with incorrect solutions (L1, e.g., 1 + 1 = 3; L5, e.g., 1 + 1 = 7) for typically developing (TD) control adolescents, intermediate levels for the nonsyndromal heavily exposed (HE) group, and no differentiation in the fetal alcohol syndromal (FAS) and partial FASgroups.

Prenatal exposure to alcohol and drugs is associated with physical, cognitive, and behavioral problems across the offspring’s lifespan and an increased risk of alcohol and drug use in adolescent and young adult offspring. These prenatal effects continue to be evident after control for demographic background and parental alcohol and drug use. Behavior problems in childhood and adolescence associated with prenatal exposures may serve as a mediator of the prenatal exposure effects on offspring substance use.

Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris water maze (MWM), a test of spatial navigation. A previous study comparing boys with fetal alcohol syndrome (FAS) to controls found poorer performance on the virtual water maze (VWM), a human analogue of the MWM. We examined PAE effects on virtual navigation in both sexes using the VWM in a moderately exposed Detroit cohort (N = 104; mean = 19.4 year) and a heavily exposed Cape Town, South African cohort (N = 62; mean = 10.4 year). The task requires the participant to learn the location of a hidden platform in a virtual pool of water. The set of acquisition trials requires the participant to learn the location of the hidden platform and to return to that location repeatedly. The single‐probe trial requires the participant to return to that location without knowing that the platform has been removed. No effects of FASD diagnostic group or PAE were detected on virtual navigation in the Detroit moderately exposed cohort. By contrast, in the more heavily exposed Cape Town cohort, the FAS/partial FAS (PFAS) group took longer to locate the hidden platform during acquisition than nonsyndromal heavily exposed (HE) and control groups, an effect that persisted even after controlling for IQ. Among boys, both the FAS/PFAS and HE groups performed more poorly than controls during acquisition, and both boys and girls born to women who binge drank performed more poorly than those born to abstainers/light drinkers. Both amount and frequency of PAE were related to poorer performance during the probe trial at 10 years of age. These data demonstrate deficits in spatial navigation among heavily exposed syndromal boys and girls and in nonsyndromal exposed boys. Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris Water Maze (MWM), a test of spatial navigation. Using a human analogue of the MWM, we found that children with heavy prenatal alcohol exposure exhibit deficits in spatial navigation.

A growing body of evidence in animal models has implicated alcohol‐induced alterations in epigenetic programming as an important mechanism in fetal alcohol spectrum disorders (FASD). Imprinted genes, a subset of epigenetically regulated genes that are sensitive to the prenatal environment, are chiefly involved in growth and neurobehavior. We tested the hypothesis that alterations in placental imprinted gene expression mediate fetal alcohol growth restriction. Placental expression of 109 genes previously shown to be imprinted and expressed in the placenta was assessed using the NanoString™ nCounter Analysis System in flash‐frozen samples from 34 heavy drinkers and 31 control women in Cape Town, South Africa, from whom prospective pregnancy alcohol consumption data had been obtained. Length/height, weight, and head circumference were measured at 6.5 and 12 months and at an FASDdiagnostic clinic (at ages 1.1 to 4.6 years) that we organized. Imprinted gene expression between exposed and control placentas was compared using the limma R package. The relation of alcohol exposure to World Health Organization length‐for‐age z‐scores was examined before and after inclusion of expression for each alcohol‐related imprinted gene, using hierarchical mixed regression models with repeated measures. Heavy drinkers averaged 8 standard drinks on 2 to 3 days/wk (vs. 0 for controls). Prenatal alcohol exposure was associated with smaller length/height and weight during the postnatal period. Heavy exposure was related to alterations in expression of 11 of 93 expressed imprinted genes, including increased expression of 5 genes found to be negatively associated with growth and decreased expression of 3 genes positively associated with growth. Alcohol‐related alterations in expression of 5 genes statistically mediated the effect of prenatal alcohol exposure on length. These findings identify alcohol‐related alterations in placental imprinted gene expression as potential biomarkers of adverse effect in FASDand suggest that these alterations may play a mechanistic role in fetal alcohol growth restriction. Future studies are needed to determine whether alterations in imprinted gene expression also mediate FASDneurobehavioral deficits and whether such alterations are amenable to intervention. In this prospective longitudinal cohort of 34 heavy drinking mothers and 31 controls, prenatal alcohol exposure (PAE) was related to alterations in placental gene expression of 11 of 93 imprinted genes previously shown to be expressed in the placenta. For 8 of these genes, these alterations statistically mediated the relation of PAEto postnatal growth. These findings suggest that PAE‐related alterations in placental imprinted gene expression may play a mechanistic role in FASDand may serve as biomarkers of effect.

We recently demonstrated the acceptability and feasibility of a randomized, double‐blind choline supplementation intervention for heavy drinking women during pregnancy. In this study, we report our results relating to the efficacy of this intervention in mitigating adverse effects of prenatal alcohol exposure (PAE) on infant growth and cognitive function. Sixty‐nine Cape Coloured (mixed ancestry) heavy drinkers in Cape Town, South Africa, recruited in mid‐pregnancy, were randomly assigned to receive a daily oral dose of either 2 g of choline or placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape‐flavored drink. The primary outcome, eyeblink conditioning (EBC), was assessed at 6.5 months. Somatic growth was measured at birth, 6.5, and 12 months, recognition memory and processing speed on the Fagan Test of Infant Intelligence, at 6.5 and 12 months. Infants born to choline‐treated mothers were more likely to meet criterion for conditioning on EBC than the placebo group. Moreover, within the choline arm, degree of maternal adherence to the supplementation protocol strongly predicted EBC performance. Both groups were small at birth, but choline‐treated infants showed considerable catch‐up growth in weight and head circumference at 6.5 and 12 months. At 12 months, the infants in the choline treatment arm had higher novelty preference scores, indicating better visual recognition memory. This exploratory study is the first to provide evidence that a high dose of choline administered early in pregnancy can mitigate adverse effects of heavy PAE on EBC, postnatal growth, and cognition in human infants. These findings are consistent with studies of alcohol‐exposed animals that have demonstrated beneficial effects of choline supplementation on classical conditioning, learning, and memory. Choline supplementation has been shown to mitigate adverse effects of prenatal alcohol exposure on neurobehavior in animals, including eyeblink conditioning (EBC). In a randomized, double‐blind trial, human infants born to choline‐supplemented mothers showed greater increases in conditioned responses, compared with those whose mothers received placebo. Within the choline arm, degree of maternal adherence strongly predicted EBC performance. Choline‐treated infants also showed considerable catch‐up growth in weight and head circumference and better visual recognition memory compared to the placebo group.

Choline, an essential nutrient, serves as a methyl‐group donor for DNAmethylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double‐blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. Seventy heavy drinkers, recruited in mid‐pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape‐flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. Adherence was good‐to‐excellent (median doses taken = 74.0%; interquartile range = 53.9 to 88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow‐back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use. Choline supplementation has been shown to mitigate adverse effects of prenatal alcohol exposure on neurobehavior in animals, including eyeblink conditioning (EBC). In a randomized, double‐blind trial, human infants born to choline‐supplemented mothers showed greater increases in conditioned responses, compared with those whose mothers received placebo. Within the choline arm, degree of maternal adherence strongly predicted EBC performance. Choline‐treated infants also showed considerable catch‐up growth in weight and head circumference and better visual recognition memory compared to the placebo group.

Despite known risks of prenatal nutritional deficiencies and studies documenting increased prevalence of poor dietary intake among nonpregnant alcohol abusers, the nutritional status of heavy drinking pregnant women remains largely unstudied. Animal models have found interactions between prenatal ethanol exposure and micronutrients, such as choline, folate, B12, and iron, and human studies have reported that lower maternal weight and body mass confer increased fetal alcohol‐related risk. One hundred and twenty‐three heavy drinking Cape Coloured pregnant women and 83 abstaining controls were recruited at their first antenatal clinic visit. At 3 prenatal study visits, each gravida was interviewed about alcohol, smoking, and drug use and weight, height, and arm skinfolds were measured. Dietary intakes of energy, protein, fat, and major micronutrients were assessed from three 24‐hour recall interviews. The majority of women gained less than the recommended 0.42 kg/wk during pregnancy. Whereas methamphetamine use was associated with smaller biceps skinfolds, an indicator of body fat, alcohol consumption was not related to any anthropometric indicator. Alcohol was related to higher intake of phosphorus, choline, and vitamins B12 and D. Alcohol, cigarette, and methamphetamine use were related to lower vitamin C intake. Insufficient intake was reported by >85% of women for 10 of 22 key nutrients, and >50% for an additional 3 nutrients. Alcohol consumption during pregnancy was not associated with meaningful changes in diet or anthropometric measures in this population, suggesting that poor nutrition among drinkers does not confound the extensively reported effects of prenatal alcohol exposure on growth and neurobehavior. The poor gestational weight gain and high rates of insufficient intake for several nutrients in both the alcohol‐exposed and control groups are also of public health importance. Despite studies documenting increased prevalence of poor dietary intake among non‐pregnant alcohol abusers, the nutritional status of heavy drinking pregnant women remains largely unstudied. In this prospective study of heavy drinking pregnant women and abstainers/light‐drinkers in Cape Town, South Africa, poor gestational weight gain and insufficient nutrient intake were common. However, alcohol consumption during pregnancy was not associated with meaningful changes in diet or anthropometric measures, suggesting that poor nutrition among drinkers does not confound FASD outcomes reported in this community.

Our objective is to help clinicians detect the facial effects of prenatal alcohol exposure by developing computer‐based tools for screening facial form. All 415 individuals considered were evaluated by expert dysmorphologists and categorized as (i) healthy control (HC), (ii) fetal alcohol syndrome (FAS), or (iii) heavily prenatally alcohol exposed (HE) but not clinically diagnosable as FAS; 3D facial photographs were used to build models of facial form to support discrimination studies. Surface curvature‐based delineations of facial form were introduced. (i) Facial growth in FAS, HE, and control subgroups is similar in both cohorts. (ii) Cohort consistency of agreement between clinical diagnosis and HC‐FAS facial form classification is lower for midline facial regions and higher for nonmidline regions. (iii) Specific HC‐FAS differences within and between the cohorts include: for HC, a smoother philtrum in Cape Coloured individuals; for FAS, a smoother philtrum in Caucasians; for control‐FAS philtrum difference, greater homogeneity in Caucasians; for control‐FAS face difference, greater homogeneity in Cape Coloured individuals. (iv) Curvature changes in facial profile induced by prenatal alcohol exposure are more homogeneous and greater in Cape Coloureds than in Caucasians. (v) The Caucasian HE subset divides into clusters with control‐like and FAS‐like facial dysmorphism. The Cape Coloured HE subset is similarly divided for nonmidline facial regions but not clearly for midline structures. (vi) The Cape Coloured HE subset with control‐like facial dysmorphism shows orbital hypertelorism. Facial curvature assists the recognition of the effects of prenatal alcohol exposure and helps explain why different facial regions result in inconsistent control‐FAS discrimination rates in disparate ethnic groups. Heavy prenatal alcohol exposure can give rise to orbital hypertelorism, supporting a long‐standing suggestion that prenatal alcohol exposure at a particular time causes increased separation of the brain hemispheres with a concomitant increase in orbital separation. Heat‐mapped philtra are shown for Caucasian/Cape‐Coloured individuals with FAS: green resp. blue reflects similar curvature resp. greater convexity compared to controls. Caucasian philtra are flatter, more fully along length than Cape‐Coloured individuals. Red/black circles depict philtra clusters of similar heat maps. Caucasian philtra form fewer clusters reflecting homogeneity compared to Cape‐Coloured heterogeneity, quantified 0–1 reflecting complete homogeneity‐heterogeneity. Thus, facial curvature detects differences in location and degree of effect of prenatal alcohol exposure in Caucasian and Cape‐Coloured individuals that need consideration when diagnosing FAS.

Magnetic resonance imaging (MRI) studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure (PAE) but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latter's incomplete myelination. This study is the first to use volumetric structural MRIto investigate PAE effects in newborns using manual tracing and to examine the cross‐sectional area of the corpus callosum (CC). Forty‐three nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom‐designed birdcage coil for infants, which increases signal‐to‐noise ratio almost 2‐fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and fetal alcohol spectrum disorders diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi‐echo FLASHprotocol adapted for newborns, and a knowledge‐based procedure was used to hand‐segment the neonatal brains. CCwas disproportionately smaller in alcohol‐exposed neonates than controls after controlling for intracranial volume. By contrast, CCarea was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. Given that midline craniofacial anomalies have been recognized as a hallmark of fetal alcohol syndrome in humans and animal models since this syndrome was first identified, the CCdeficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CCduring the newborn period may provide an early indicator of fetal alcohol‐related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence. We used manually traced MRI images to investigate prenatal alcohol exposure effects on corpus callosum (CC) size in 43 nonsedated newborns. CC was disproportionately smaller in alcohol‐exposed neonates than controls after adjustment for intracranial volume. By contrast, CC area was unrelated to sex, gestational age, age at scan, smoking, marijuana, or methamphetamine exposure. Given that midline craniofacial anomalies are hallmarks of FAS, smaller CC may provide an early indicator of alcohol‐related cognitive deficits linked to this brain structure in childhood.

Response inhibition is a distinct aspect of executive function that is frequently impaired in children with fetal alcohol spectrum disorders (FASD). We used a Go/NoGo (GNG) task in a functional MRIprotocol to investigate differential activation of brain regions in the response inhibition network in children diagnosed with full or partial fetal alcohol syndrome (FAS/PFAS), compared with healthy controls. A rapid, event‐related task with 120 Go and 60 NoGo trials was used to study children aged 8 to 12 years—8 with FAS/PFAS, 17 controls. Letters were projected sequentially, with Go and NoGo trials randomly interspersed across the task. BOLDsignal in the whole brain was contrasted for the correct NoGo minus correct Go trials between the FAS/PFASand control groups. Compared to the FAS/PFASgroup, controls showed greater activation of the inferior frontal and anterior cingulate network linked to response inhibition in typically developing children. By contrast, the FAS/PFASgroup showed greater BOLDresponse in dorsolateral prefrontal cortex and other middle prefrontal regions, suggesting compensation for inefficient function of pathways that normally mediate inhibitory processing. All group differences were significant after control for potential confounding variables. None of the effects of prenatal alcohol exposure on activation of the regions associated with response inhibition were attributable to the effects of this exposure on IQ. This is the first FASD GNGstudy in which all participants in the exposed group met criteria for a diagnosis of full FASor PFAS. Although FASDis frequently comorbid with attention deficit hyperactivity disorder, the pattern of brain activation seen in these disorders differs, suggesting that different neural pathways mediate response inhibition in FASDand that different interventions for FASDare, therefore, warranted.

Previous event‐related potential (ERP) studies of response inhibition in children with fetal alcohol spectrum disorder (FASD) have used a visual Go/NoGo task to study the impact of prenatal alcohol exposure on response inhibition. No studies exist using auditory versions of the task; thus, it is unclear how the deficits observed in visual tasks translate into the auditory domain. This study examined ERPs using an auditory Go/NoGo paradigm in a sample of 35 school‐age children—18 with heavy prenatal alcohol exposure and 17 normally developing controls. Alcohol‐exposed children performed as well as controls in terms of inhibiting their responses; however, their reaction times were significantly slower under the Go condition. As in the ERPvisual Go/NoGo task previously administered to these children, group differences were seen in early perceptual processing, specifically related to stimulus discrimination, with a decrease in P2 amplitude in the alcohol‐exposed group. The control group exhibited greater N2 amplitude in the NoGo compared to the Go condition while the alcohol‐exposed group did not, suggesting a group difference in the neural substrates underlying conflict monitoring. The alcohol‐exposed group demonstrated longer latency P3 with reduced amplitude, suggesting poorer allocation of attention. The alcohol‐exposed group also exhibited a late positive component (LPC) similar to the one observed in the previous visual ERPstudy. This LPCmay indicate compensatory neurophysiological function related to resetting of attentional control networks in preparation for the next trial. None of the ERPoutcomes in this study were related to potential confounders which included cognitive and socioeconomic measures as well as ADHDdiagnosis. The observed ERPgroup differences point to elements of perceptual and attentional processing likely to be involved in the performance deficits often observed in children with FASD. We also observed changes in ERPs related to conflict monitoring/response inhibition, highlighting fetal alcohol‐related effects on how the brain responds when there is need to identify and respond to environmental cues by switching away from a prepotent motor response to an inhibited state. Our ERP study demonstrated prenatal alcohol effects on an auditory Go/NoGo task requiring switching away from a prepotent motor response. Although alcohol‐exposed children performed behaviorally as well as controls, their decreased P2 amplitude suggested poorer stimulus discrimination; greater N2 amplitude in the NoGo compared to the Go condition suggested an effect on the neural substrates mediating conflict monitoring; and longer latency P3 with reduced amplitude suggested poorer allocation of attention. These effects were not attributable to lower IQ or comorbid ADHD.

Prenatal alcohol exposure (PAE) is linked to impaired performance on tests of retrospective memory, but prospective memory (PM; the ability to remember and act on delayed intentions) has not been examined in alcohol‐exposed children. We investigated event‐based PMin children with heavy PAEand the degree to which associations between PAEand PMare influenced by IQ, executive functioning (EF), retrospective memory, and attention deficit/hyperactivity disorder (ADHD). We administered a computerized PMtask to 89 children (Mage = 11.1 years) whose mothers were recruited prenatally: 29 with fetal alcohol syndrome (FAS) or partial FAS(PFAS), 32 nonsyndromal heavily exposed (HE), and 28 Controls. We examined effects of diagnostic group, cue focality, and task difficulty on PMperformance. The association between a continuous measure of alcohol exposure and PMperformance was also examined after controlling for sociodemographic confounders. Mediation of alcohol effects on PMby IQ,EF, and retrospective memory scores was assessed as was the effect of ADHDon PMperformance. Children with FAS/PFASmade more PMerrors than either HEor Control children. PAEwas negatively related to PMperformance even after adjusting for sociodemographic confounders, EF, and retrospective memory. This relation was only partially mediated by IQ. PAEwas related to ADHD, but ADHDwas not related to PMperformance. Fetal alcohol‐related impairment in event‐based PMwas seen in children with FAS/PFAS. The effect of PAEon PMwas not attributable to impaired EFand retrospective memory and was not solely attributable to lower IQ. Consistent with previous studies, we found no effect of ADHDon event‐based PMperformance at this age. This is the first study documenting PMimpairment in children with heavy PAEand identifies a new domain of impairment warranting attention in diagnosis and management of fetal alcohol spectrum disorders. This is the first study to document prospective memory (PM) impairment in children with prenatal alcohol exposure. PMis the ability to remember and act on delayed intentions. Children with fetal and partial fetal alcohol syndrome exhibited poorer PMthan exposed nonsyndromal or control children. This deficit was partially mediated by IQbut not attributable to sociodemographic influences, executive function, retrospective memory, or ADHD. This study identifies a new domain of impairment warranting attention in diagnosis and management of FASD.

Animal studies have demonstrated adverse effects of prenatal alcohol exposure on placental development, but few studies have examined these effects in humans. Little is known about effects of prenatal exposure to methamphetamine, marijuana, and cigarette smoking on placental development. Placentas were collected from 103 Cape Coloured (mixed ancestry) pregnant women recruited at their first antenatal clinic visit in Cape Town, South Africa. Sixty‐six heavy drinkers and 37 nondrinkers were interviewed about their alcohol, cigarette smoking, and drug use at 3 antenatal visits. A senior pathologist, blinded to exposure status, performed comprehensive pathology examinations on each placenta using a standardized protocol. In multivariable regression models, effects of prenatal exposure were examined on placental size, structure, and presence of infections and meconium. Drinkers reported a binge pattern of heavy drinking, averaging 8.0 drinks/occasion across pregnancy on 1.4 d/wk. 79.6% smoked cigarettes; 22.3% used marijuana; and 17.5% used methamphetamine. Alcohol exposure was related to decreased placental weight and a smaller placenta‐to‐birthweight ratio. By contrast, methamphetamine was associated with larger placental weight and a larger placenta‐to‐birthweight ratio. Marijuana was also associated with larger placental weight. Alcohol exposure was associated with increased risk of placental hemorrhage. Prenatal alcohol, drug, and cigarette use were not associated with chorioamnionitis, villitis, deciduitis, or maternal vascular underperfusion. Alcohol and cigarette smoking were associated with a decreased risk of intrauterine passing of meconium, a sign of acute fetal stress and/or hypoxia; methamphetamine, with an increased risk. This is the first human study to show that alcohol, methamphetamine, and marijuana were associated with distinct patterns of pathology, suggesting different mechanisms mediating their effects on placental development. Given the growing body of evidence linking placental abnormalities to neurodevelopmental deficits, these findings may be important in the long‐term teratogenic effects of prenatal alcohol and drug exposure. In a prenatally recruited, prospective longitudinal cohort, alcohol exposure was related to decreased placental weight and a smaller placenta‐to‐birthweight ratio. By contrast, methamphetamine was associated with larger placental weight and a larger placenta‐to‐birthweight ratio; marijuana with larger placental weight. This is the first study to demonstrate distinct alcohol‐, methamphetamine‐, and marijuana‐related patterns of placental pathology. Given evidence linking placental abnormalities to neurodevelopmental deficits, these findings may be important in the teratogenic effects of prenatal alcohol and drug exposure.

Theory of mind (ToM) refers to the ability to understand and make inferences about other people's intentions, feelings, and beliefs. Although children with fetal alcohol spectrum disorders (FASD) are known to have deficits in social‐cognitive function, little is known about ToM in FASD. ToM ability was assessed using a developmentally sensitive ToM battery, including the reading the mind in the eyes (RME) test, a measure of mental inferential ability that has been found to be impaired in other clinical populations. IQand executive function (EF) were assessed as potential mediating variables. The battery was administered to 63 children (aged 9 to 11 years) from Cape Town, South Africa, whose mothers had been prospectively recruited during pregnancy. Children with fetal alcohol syndrome (FAS;n =8) and partial FAS(PFAS;n =19), as well as nonsyndromal heavily exposed children (n =17), were compared to children born to abstaining or light drinkers (n =19)from the same community. No FASDgroup differences were found on the less challenging ToM tasks. By contrast, children with FASand PFASperformed more poorly than controls on a more challenging ToM task, the RMEtest. A continuous measure of prenatal alcohol exposure (PAE) was more sensitive than FASDdiagnosis in that it was related to 4 higher‐order ToM measures, particularly the ability to attribute mental states assessed on RME. IQonly partially mediated the effect of exposure on RMEperformance, and these effects were not mediated by EF. Hence, the data suggest that these ToM measures tap into a specific alcohol‐related social‐cognitive deficit that does not merely reflect poorer EF. FASDdiagnosis and PAE were each also related to RMEafter control for attention deficit/hyperactivity disorder. These findings suggest that deficits in higher‐order ToM function may play a significant role in the social‐cognitive behavioral impairment in FASD. Fetal alcohol spectrum disorders (FASD) diagnosis and prenatal alcohol exposure were each related to deficits on the Reading the Mind in the Eyes task, indicating a deficit in affective information processing, even after control for the child IQ, executive function, and Attention Deficit/Hyperactivity Disorder. These findings suggest that deficits in higher‐order theory of mind function, specifically mentalizing through eye expression, may play a significant role in the behavioral impairment often described clinically in children with FASD.

Day and colleagues have presented the first data showing that the behavioral effects of low to moderate prenatal alcohol exposure seen in childhood and adolescence persist into adulthood. Using the Achenbach Adult Self‐Report, they found dose‐dependent effects of prenatal exposure on internalizing, externalizing, and attention problems that persist in young adults and, thus, appear to be permanent. To date, few studies have attempted to identify thresholds at which prenatal alcohol exposure is harmful, although the animal literature suggests that even 1 to 2 binge episodes can result in adverse effects in the offspring. Four prospective longitudinal studies have reported adverse effects at what can be characterized as moderate exposure levels based on NIAAAcriteria, but moderate drinking women often concentrate their alcohol use on 1 to 2 days per week, thereby engaging in binge drinking. In this study, binge drinking was not a strong predictor of adverse outcome when average daily dose was held constant, a conclusion that the authors note runs “counter to studies that have reported that binge drinking has a greater effect.” This inconsistency may be due to the difficulty of allocating variance that is shared (overlapping) between average daily dose and binge drinking (i.e., dose/occasion). Data from laboratory animal studies, in which dosage can be manipulated experimentally, demonstrate that a higher dose per occasion, the key feature of binge drinking, leads to more severe adverse effects. Day and colleagues' findings of adverse effects at low levels of exposure provides clear evidence that there is no safe level of drinking during pregnancy and that, even at low levels, drinking results in irreversible behavioral impairment. On the other hand, given the evidence from the animal and most human studies, it is important for all women who drink during pregnancy, even at light to moderate levels, to recognize that minimizing their intake per occasion and refraining from binge drinking can reduce risk to the fetus.

Background: Prenatal alcohol exposure is related to a wide range of neurocognitive effects. Eyeblink conditioning (EBC), which involves temporal pairing of a conditioned with an unconditioned stimulus, has been shown to be a potential biomarker of fetal alcohol exposure. A growing body of evidence suggests that white matter may be a specific target of alcohol teratogenesis, and the neural circuitry underlying EBC is known to involve the cerebellar peduncles. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that has proven useful for assessing central nervous system white matter integrity. This study used DTI to examine the degree to which the fetal alcohol‐related deficit in EBC may be mediated by structural impairment in the cerebellar peduncles.

Background: Alcohol consumption during pregnancy, a known teratogen often associated with drug use and smoking is a well‐known public health concern.

Background: Poor arithmetic performance is among the most sensitive outcomes associated with prenatal alcohol exposure and is also common in individuals with attention‐deficit hyperactivity disorder (ADHD). We hypothesized that prenatal alcohol exposure would be associated with deficits in the most fundamental aspects of number processing, representation of quantity and distance, whereas ADHD would be associated with deficits in calculation, the form of number processing most dependent on attention and memory.

Background: Classical eyeblink conditioning (EBC) involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Impairment of EBC has been demonstrated in studies of alcohol‐exposed animals and in children exposed prenatally at heavy levels.

Background: Although an extensive literature has documented a broad range of cognitive performance deficits in children with prenatal alcohol exposure, little is known about how the neurophysiological processes underlying these deficits may be affected. Event‐related potentials (ERPs), which reflect task‐specific changes in brain electrical activity, provide a method for examining multiple constituents of cognitive processing at the neural level.

INTRODUCTION:The objective of this report is to estimate the benefits of universal meconium screening for maternal drinking during pregnancy. Fetal alcohol spectrum disorder (FASD), including its most severe manifestation fetal alcohol syndrome (FAS), is preventable and remains a public health tragedy. The incidences of FAS and FASD have been conservatively estimated to be 0.97 and 10 per 1000 births, respectively. Meconium testing has been demonstrated to be a promising at‐birth method for detection of drinking during pregnancy. METHODS:The current costs of FAS and FASD, alcohol treatment programs, and meconium screening were estimated by literature review. Monetary values were converted roughly to equal dollars in 2006. RESULTS:Costs of adding meconium analysis to the current newborn screening program and of treatment for the identified mothers were estimated and compared to potential averted costs that may result from identification and intervention for mothers and affected infants. Three potential maternal treatment strategies are analyzed. Depending on the treatment type, the savings may range from $6 to $97 for every $1 spent on screening and treatment. DISCUSSION:It needs to be emphasized, however, that such screening is premature and that to be effective this screening can be implemented only if there is a societal willingness to institute prevention and intervention programs to improve both women's and children's health. Future research should be directed at improving detection and developing in‐depth prevention and remedial intervention programs. A thorough consideration of the ethical issues involved in such a screening program is also needed. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.

Background: Number processing deficits are frequently seen in children exposed to alcohol in utero.

Objectives: To examine biobehavioral responses to an acute pain event in a Cape Town, South Africa, cohort consisting of 28 Cape Colored (mixed ancestry) newborns (n= 14) heavily exposed to alcohol during pregnancy (exposed), and born to abstainers (n= 14) or light (≤0.5 oz absolute alcohol/d) drinkers (controls).

Background: The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes.

Background: Both executive function deficits and slower processing speed are characteristic of children with fetal alcohol exposure, but the temporal dynamics of neural activity underlying cognitive processing deficits in fetal alcohol spectrum disorder have rarely been studied. To this end, event‐related potentials (ERPs) were used to examine the nature of alcohol‐related effects on response inhibition by identifying differences in neural activation during task performance.

Background: Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults.

Background: Eyeblink conditioning (EBC) is a Pavlovian paradigm that involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Animal studies have shown that binge consumption of alcohol during pregnancy impairs EBC and that this impairment is likely mediated by a loss of neurons in the inferior olive and the cerebellar cortex and deep nuclei, as well as by a reduction in neural plasticity in the cerebellar deep nuclei.

Background: Rates of preterm delivery, a major proximate cause of perinatal morbidity and mortality, have been increasing. Prenatal alcohol exposure has been implicated in preterm delivery, although results have been inconsistent due to inadequate control for confounding factors, insufficient power, unreliable and inaccurate assessment of both exposure and gestational age, and lack of stratification of prematurity into severity levels. The purpose of this study was to examine the relation between maternal alcohol, cocaine and cigarette use during pregnancy, and extreme and mild preterm birth.