Prenatal alcohol exposure and cognition at midlife: Evidence of fluid cognition deficits in two cohorts.

BACKGROUND: Prenatal alcohol exposure (PAE) impacts cognition in childhood and early adulthood. Here we evaluate the cognitive abilities of middle-aged adults with and without a history of PAE. METHODS: Participants (N = 200) were recruited from longitudinal cohorts in the Atlanta and Seattle metropolitan areas and completed measures comprising the National Institutes of Health Toolbox's Fluid Cognition Composite. RESULTS: We found that individuals with PAE had lower Fluid Cognition Summary scores and lower Dimensional Change Card Sort and Flanker task subtest scores than non-PAE controls, after accounting for both potentially confounding demographic variables using propensity scores and the effects of study site. When we evaluated the effects of PAE with and without dysmorphic physical features, we found that middle-aged adults in both groups had lower fluid cognition scores than non-PAE controls. However, only the presence of PAE with dysmorphic features was associated with lower performance on the Dimensional Change Card Sort Test and Flanker tasks. CONCLUSION: While all participants with PAE had lower fluid cognition, those with PAE and dysmorphic features also exhibited specific deficits in their performance on measures of inhibition, attention, and cognitive flexibility. Thus, PAE is associated with ongoing cognitive deficits in middle adulthood, which can be observed most clearly among individuals with dysmorphic features.

Trajectories of prenatal alcohol exposure and behavioral outcomes: Findings from a community-based sample.

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

The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine.

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

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1ß, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1ß and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on information processing skills in Ukrainian infants.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) was explored in a clinical trial conducted in Ukraine. Cardiac orienting responses (ORs) during a habituation/dishabituation learning paradigm were obtained from 6 to 12 month-olds to assess neurophysiological encoding and memory. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to a group (No study-provided supplements, multivitamin/mineral supplement, or multivitamin/mineral supplement plus choline supplement). Heart rate was collected for 30 s prior to stimulus onset and 12 s post-stimulus onset. Difference values (∆HR) for the first 3 trials of each condition were aggregated for analysis. Gestational blood samples were collected to assess maternal nutritional status and changes as a function of the intervention. Choline supplementation resulted in a greater ∆HR on the visual habituation trials for all infants and for the infants with no PAE on the dishabituation trials. The latency of the response was reduced in both conditions for all infants whose mothers received choline supplementation. Change in gestational choline level was positively related to ∆HR during habituation trials and levels of one choline metabolite, dimethylglycine (DMG), predicted ∆HR during habituation trials and latency of responses. A trend was found between DMG and ∆HR on the dishabituation trials and latency of the response. Supplementation did not affect ORs to auditory stimuli. Choline supplementation when administered together with routinely recommended multivitamin/mineral prenatal supplements during pregnancy may provide a beneficial impact to basic learning mechanisms involved in encoding and memory of environmental events in alcohol-exposed pregnancies as well as non- or low alcohol-exposed pregnancies. Changes in maternal nutrient status suggested that one mechanism by which choline supplementation may positively impact brain development is through prevention of fetal alcohol-related depletion of DMG, a metabolic nutrient that can protect against overproduction of glycine, during critical periods of neurogenesis.

A randomized, placebo-controlled, double-blind trial of supplemental docosahexaenoic acid on cognitive processing speed and executive function in females of reproductive age with phenylketonuria: A pilot study.

Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12-47 years. Participants were randomly assigned to receive DHA (10mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).

Early identification of risk for effects of prenatal alcohol exposure.

OBJECTIVE: Fetal alcohol syndrome (FAS) and less severe outcomes are typically diagnosed later in childhood, although earlier diagnosis of the effects of exposure would allow intervention in infancy and prevention of associated secondary disabilities. Identification is particularly difficult in such high-risk groups as low-birthweight infants. The goal of this study was to develop methods for early identification of at-risk infants. METHOD: Three methods (microcephaly, heavy episodic drinking [> 5 drinks/occasion] in pregnancy and a cumulative risk index) identified neonates at risk for those developmental consequences of prenatal exposure that can be measured at 6 and 12 months (i.e., standard scores on Bayley Scales of Infant Development and growth measures). The usefulness of these methods was assessed by comparing those infants selected to an unexposed contrast group, while controlling for potentially confounding factors (e.g., race, socioeconomic status and birthweight). RESULTS: At 6 months, when 70 infants were tested, trends were found for lower language facet scores and lower scores on the Behavioral Regulation Scale; at 12 months, when 134 were tested, alcohol-exposed infants had significantly lower cognitive facet scores (p < .02) and were more likely to be classified as either mildly or significantly developmentally delayed (p < .02). CONCLUSIONS: It is possible to identify infants at risk for alcohol-related developmental delays using information available in the neonatal period, although it is not usually done. Of the three methods tested, a cumulative risk index based on maternal characteristics was found to be most predictive.

Impact of a camp experience on phenylalanine levels, knowledge, attitudes, and health beliefs relevant to nutrition management of phenylketonuria in adolescent girls.

OBJECTIVE: To evaluate the effectiveness of an education intervention in a summer camp setting on knowledge, attitudes, and health beliefs regarding metabolic control of phenylketonuria and dietary compliance. DESIGN: An observational study of a weeklong metabolic camp for adolescent girls with phenylketonuria (PKU) who were followed up over the course of 1 year. Observations also were made in 3 subsequent years of camp. INTERVENTION: The camp experience consisted of diet and disease education, sessions on reproductive development, and recreation. Group discussions on attitudes and perceptions about PKU related to dietary compliance were held with nutritionists and a pediatric psychologist. OUTCOME MEASURES: Biochemical and psychological data were collected on the first and last days of the camp to assess short-term effects of the intervention, then at quarterly intervals during the year to determine the long-term impact of the camp. Precamp and Postcamp plasma amino acid data for the subsequent 3 years were also collected. SUBJECTS/SETTING: Analyses were based on 13 adolescent girls with PKU in the first year of a camp at Emory University in Atlanta, Ga, and compared with data from 11 additional campers enrolled the second year, 8 in the third year, and 7 in the fourth year. Mean age +/- standard deviation of first-year campers was 13 +/- 2 years, mean IQ +/- standard deviation was 98 +/- 16, and 9 of 13 girls had menstruated. STATISTICAL ANALYSES PERFORMED: Short-term effects of the intervention were computed by comparing mean levels of response from the baseline period to those from the last day of camp using t tests for dependent samples. Repeated-measures analysis of variance was used to assess the long-term effects of the camp experience over the course of a year at regular quarterly intervals. RESULTS: Short-term effects of the education intervention were significant reductions in dietary phenylalanine intake, plasma phenylalanine levels, and perceived isolation. However, these effects progressively returned to baseline levels over the course of a year. The significant short- and long-term effects of increased knowledge of diet and disease persisted throughout the study period. APPLICATIONS/CONCLUSIONS: Short-term effects of the education intervention resulted in improved metabolic control associated with improved attitudes, increased knowledge of diet and disease, increased perceived support, and decreased barriers to dietary compliance in a camp setting.