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Background: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. Methods: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. Results: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. Conclusions: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: The degree to which prenatal alcohol exposure (PAE) may influence alcohol and drug use in adulthood is difficult to determine. That is because PAE is highly correlated with environmental factors, including low socioeconomic status and exposure to parental drinking, and with behavioral problems, such as, attention‐deficit/hyperactivity disorder (ADHD), which are correlated with alcohol use and abuse. Methods: Participants were 121 young adults from our Detroit Longitudinal Cohort study. Mothers were recruited during pregnancy and interviewed about their alcohol consumption using a timeline follow‐back procedure. At 19 years, their offspring were interviewed regarding current and past use of alcohol, cigarettes, and other illicit drugs. Results: PAE was associated with greater alcohol, cannabis, and cigarette use. PAE, assessed using overall alcohol intake during pregnancy and alcohol dose per occasion, was associated with larger quantities of alcohol per occasion and greater alcohol tolerance in early adulthood. These effects persisted after control for demographic background, sex, age and education of participant, home environment, other prenatal drug exposure, and postnatal alcohol and drug use by the primary caregiver. Whereas ADHD predicted average alcohol consumed/month during young adulthood, PAE predicted alcohol dose/drinking occasion, and the effect on dose/occasion was not mediated by ADHD. Conclusions: The effects of PAE on alcohol and cannabis use in young adulthood are not attributable to being reared in an environment that is socioeconomically disadvantaged or in one in which there is extensive maternal drinking. Furthermore, PAE was related to enhanced alcohol tolerance in young adults, a risk factor for alcohol use disorder later in life. Although ADHD was associated with greater alcohol consumption in early adulthood, it did not mediate the effect of PAE on offspring's alcohol use. [ABSTRACT FROM AUTHOR]

Background 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 MRI protocol 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. Methods 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. BOLD signal in the whole brain was contrasted for the correct NoGo minus correct Go trials between the FAS/ PFAS and control groups. Results Compared to the FAS/ PFAS group, controls showed greater activation of the inferior frontal and anterior cingulate network linked to response inhibition in typically developing children. By contrast, the FAS/ PFAS group showed greater BOLD response 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. Conclusions This is the first FASD GNG study in which all participants in the exposed group met criteria for a diagnosis of full FAS or PFAS. Although FASD is 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 FASD and that different interventions for FASD are, therefore, warranted. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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. Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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. IQ and 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. Results No FASD group differences were found on the less challenging ToM tasks. By contrast, children with FAS and PFAS performed more poorly than controls on a more challenging ToM task, the RME test. A continuous measure of prenatal alcohol exposure (PAE) was more sensitive than FASD diagnosis in that it was related to 4 higher-order ToM measures, particularly the ability to attribute mental states assessed on RME. IQ only partially mediated the effect of exposure on RME performance, 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. FASD diagnosis and PAE were each also related to RME after control for attention deficit/hyperactivity disorder. Conclusions These findings suggest that deficits in higher-order ToM function may play a significant role in the social-cognitive behavioral impairment in FASD. [ABSTRACT FROM AUTHOR]

Background Previous studies using the California Verbal Learning Test-Children's Version ( CVLT-C) to examine effects of heavy prenatal alcohol exposure on verbal learning and memory have reported impaired information acquisition (i.e., encoding), rather than retrieval, as the primary mechanism underlying learning and memory impairment. We administered the CVLT-C to 2 independent cohorts to determine whether (i) effects on encoding are also seen at moderate exposure levels, using both categorical (diagnostic/exposure group) and continuous exposure measures; (ii) these deficits are specific or secondary to alcohol-related impairment in IQ; (iii) effects on retrieval can be detected over and above effects on initial encoding; and (iv) effects on learning are attributable to less efficient learning strategy use. Methods We administered the CVLT-C and Wechsler Intelligence Scale for Children to 151 Cape Town heavy and nonexposed children ( M = 10.3 years), and 291 Detroit adolescents recruited to over-represent moderate-to-heavy prenatal alcohol exposure ( M = 14.4 years). Results Effects on encoding in the heavily exposed Cape Town cohort and on retrieval in both cohorts were significant after adjustment for IQ. Although effects on retrieval were no longer significant in Cape Town after control for initial encoding, effects on recognition memory continued to be evident in Detroit. Children with full or partial fetal alcohol syndrome were less able to use the semantic cluster encoding strategy implicit in the CVLT-C. Conclusions Effects on verbal learning were seen primarily in the more heavily exposed Cape Town cohort; effects on recall and recognition memory were also seen at moderate exposure levels in Detroit. These effects were not attributable to alcohol-related impairment in overall intellectual competence. The finding that effects on retention continued to be evident after statistical adjustment for initial encoding in Detroit suggests that a fetal alcohol-related deficit in retrieval is not secondary to a failure to encode the initial information. These data confirm that this impairment in initial learning is mediated, in part, by failure to use the semantic cluster learning strategy. [ABSTRACT FROM AUTHOR]

Background Animal models have demonstrated fetal alcohol-related disruptions in neuroendocrine function in the hypothalamic-pituitary-gonadal axis and downstream effects on pubertal development and sexual behavior in males and females, but little is known about these effects in humans. This study examined whether prenatal alcohol exposure is associated with alterations in testosterone during adolescence and whether it affects timing of pubertal development. Methods The sample consisted of 265 African American adolescents from the Detroit Longitudinal Cohort Study for whom testosterone and/or pubertal development data were available. Subjects were offspring of women recruited at their first prenatal clinic visit to over represent moderate-to-heavy alcohol use, including a 5% random sample of low-level drinkers/abstainers. Mothers were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach and about their smoking and drug use and sociodemographic factors. At age 14 years, adolescents provided salivary samples, which were analyzed for testosterone (pg/ml), self-reported Tanner stages for pubertal development, and age at menarche (females). Results Prenatal alcohol exposure was related to elevated testosterone concentrations for males and females but not to changes in Tanner stages or age at menarche, after controlling for confounders. In regression models stratified by alcohol exposure, the expected relation between testosterone and pubic hair development was seen among males with light-to-no prenatal alcohol exposure, but not among those with moderate-to-heavy prenatal alcohol exposure. This interaction between testosterone and prenatal alcohol exposure was confirmed in multivariable models including an alcohol exposure group × testosterone interaction term and potential confounders. Conclusions This study is the first to show a relation between prenatal alcohol exposure and increased testosterone during adolescence and evidence of decreased testosterone responsiveness in tissues related to pubertal development in humans. Further studies examining androgen receptor expression and other hormonal and cellular factors affecting pubertal development may reveal important mechanisms underlying these teratogenic effects of alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Our aim was to test the hypothesis that emotional withdrawal is an early indicator of affective disorder in infants heavily exposed prenatally to alcohol, which is independent of alcohol-related effects on mother-infant interaction and temperament and discriminated between children later diagnosed with fetal alcohol syndrome ( FAS) and partial FAS ( PFAS) and predicted cognitive and affective outcomes at 5 and 9 years. Methods The sample consisted of Cape Coloured (mixed ancestry) infants, whose mothers were interviewed during pregnancy regarding their alcohol consumption using a timeline follow-back approach. Infant emotional withdrawal ( n = 85) was assessed on the Alarm Distress Baby Scale at 6.5 months. Mother-infant interaction was evaluated from video recordings during free play and infant feeding at 6.5 months ( n = 127). Infant temperament was assessed by maternal report on the EAS Temperament Survey at 13 months ( n = 119). Sociodemographic and psychological correlates of maternal alcohol use and infant iron deficiency were examined as potential confounders. The children were diagnosed for FAS/ PFAS by expert dysmorphologists at 5 years, cognitive and affective function at 5 and 9 years. Results Prenatal alcohol exposure was associated with increased infant emotional withdrawal and decreased activity, but unrelated to mother-infant interaction or any other temperament measures. Children later diagnosed with FAS and PFAS at 5 years exhibited more emotional withdrawal and less responsivity and activity as infants. Infant withdrawal, responsivity, quality of interaction, and maternal sensitivity also predicted poorer IQ and affective response at 5 and 9 years. When all 4 infant affective measures were examined simultaneously in a regression analysis, only infant emotional withdrawal persisted as a significant predictor of 9-year IQ. Conclusions This study is the first to document a direct effect of fetal alcohol exposure on emotional withdrawal in infancy. These data link prenatal alcohol to a specific aspect of infant affective function not attributable to mother-infant interaction, infant temperament, or other socioemotional aspects of the infant's environment and identify infant emotional withdrawal as an early indicator of affective disturbance, particularly in children later diagnosed with FAS and PFAS. [ABSTRACT FROM AUTHOR]

Background Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Methods Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed ( n = 11, age 19.5 ± 0.3 years) and control ( n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. Results There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. Conclusions These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood. [ABSTRACT FROM AUTHOR]

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. Methods: Thirteen children with fetal alcohol spectrum disorder (FASD) and 12 matched controls were scanned using DTI and structural MRI sequences. The DTI data were processed using a voxelwise technique, and the structural data were used for volumetric analyses. Prenatal alcohol exposure group and EBC performance were examined in relation to brain volumes and outputs from the DTI analysis. Results: Fractional anisotropy (FA) and perpendicular diffusivity group differences between alcohol-exposed and nonexposed children were identified in the left middle cerebellar peduncle. Alcohol exposure correlated with lower FA and greater perpendicular diffusivity in this region, and these correlations remained significant even after controlling for total brain and cerebellar volumes. Conversely, trace conditioning performance was related to higher FA and lower perpendicular diffusivity in the left middle peduncle. The effect of prenatal alcohol exposure on trace conditioning was partially mediated by lower FA in this region. Conclusions: This study extends recent findings that have used DTI to reveal microstructural deficits in white matter in children with FASD. This is the first DTI study to demonstrate mediation of a fetal alcohol-related effect on neuropsychological function by deficits in white matter integrity. [ABSTRACT FROM AUTHOR]

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. Two hundred and sixty-two inner-city, African American adolescents, who had been evaluated prospectively for prenatal alcohol exposure and ADHD, were assessed on a number-processing test comprised of 7 subtests. More heavily alcohol-exposed adolescents were 4 times more likely to meet diagnostic criteria for ADHD than those whose mothers abstained from alcohol use during pregnancy. Two dimensions of number processing were identified in a factor analysis-magnitude comparison and calculation. As hypothesized, prenatal alcohol exposure was more strongly related to the former and ADHD to the latter. Moreover, the relation of prenatal alcohol to calculation was fully mediated by magnitude comparison, whereas the relation of ADHD to calculation was mediated by IQ but not by magnitude comparison. These data confirm findings from previous studies identifying arithmetic as a particularly sensitive developmental endpoint for prenatal alcohol exposure. Whereas difficulties with arithmetic in ADHD are mediated by domain-general deficits in overall cognitive ability, fetal alcohol-related arithmetic difficulties are mediated primarily by a specific deficit in the core quantity system involving the ability to mentally represent and manipulate number. These data suggest that different interventions are likely to be effective for remediating arithmetic problems in children with prenatal alcohol exposure than in non-exposed children with ADHD. [ABSTRACT FROM AUTHOR]

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. Fetal alcohol syndrome (FAS) was diagnosed by expert dysmorphologists in a large sample of Cape Coloured, South African children. Delay EBC was examined in a new sample of 63 children at 11.3 years, and trace conditioning in 32 of the same children at 12.8 years. At each age, 2 sessions of 50 trials each were administered on the same day; 2 more sessions the next day, for children not meeting criterion for conditioning. Six of 34 (17.6%) children born to heavy drinkers were diagnosed with FAS, 28 were heavily exposed nonsyndromal (HE), and 29 were nonexposed controls. Only 33.3% with FAS and 42.9% of HE met criterion for delay conditioning, compared with 79.3% of controls. The more difficult trace conditioning task was also highly sensitive to fetal alcohol exposure. Only 16.7% of the FAS and 21.4% of HE met criterion for trace conditioning, compared with 66.7% of controls. The magnitude of the effect of diagnostic group on trace conditioning was not greater than the effect on short delay conditioning, findings consistent with recent rat studies. Longer latency to onset and peak eyeblink CR in exposed children indicated poor timing and failure to blink in anticipation of the puff. Extended training resulted in some but not all of the children reaching criterion. These data showing alcohol-related delay and trace conditioning deficits extend our earlier findings of impaired EBC in 5-year-olds to school-age. Alcohol-related impairment in the cerebellar circuitry required for both forms of conditioning may be sufficient to account for the deficit in both tasks. Extended training was beneficial for some exposed children. EBC provides a well-characterized model system for assessment of degree of cerebellar-related learning and memory dysfunction in fetal alcohol exposed children. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although both fetal and long-term growth restriction are well documented in fetal alcohol spectrum disorders, effects on pattern of growth trajectory have not been characterized. Furthermore, the degree to which growth trajectories are related to fetal alcohol-related neurocognitive deficits is unknown. METHODS: Ninety-three heavy drinking pregnant women and 64 controls were recruited at initiation of prenatal care in Cape Town, South Africa. Small for gestational age (SGA) was defined as birth weight <10th percentile. Length/height, weight, and head circumference were measured at 6.5 and 12 months and 5, 9, and 13 years. Four growth trajectories were identified: SGA with long-term postnatal growth restriction (length/height-for-age <10th percentile through 13 years); SGA with catch-up growth; no SGA or postnatal growth restriction; and late-onset postnatal stunting. IQ was assessed at 5 and 10 years, and learning, memory, and executive function at 10 years. RESULTS: Children born SGA with postnatal growth restriction were most heavily exposed. Exposure was intermediate for those born SGA with catch-up growth and lowest for those without prenatal or postnatal growth restriction. Effects on neurocognition were strongest in children with both prenatal and long-term growth restriction, more moderate in those with fetal growth restriction and postnatal catch-up, and weakest in those without growth restriction. CONCLUSIONS: These findings validate the use of growth restriction in the diagnosis of fetal alcohol spectrum disorders and identify growth trajectory as a biomarker of which heavily exposed children are at greatest risk for cognitive developmental deficits. [ABSTRACT FROM AUTHOR]