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.

Prevalence of prenatal drinking assessed at an urban public hospital and a suburban private hospital.

BACKGROUND: Although the prevalence of fetal alcohol syndrome (FAS) varies within the population, few data are available concerning variation in the prevalence of prenatal drinking. METHODS: Postpartum women delivering singleton infants at two Atlanta hospitals in 1993 or 1994 were interviewed. Those delivering infants who were small for gestational age (SGA) (n = 638) were over-sampled relative to those delivering infants with birth weights that were appropriate for gestational age (AGA) (n = 247). The prevalence of prenatal drinking was estimated as a weighted average of reports from mothers of SGA and AGA infants. Estimates of the prevalence of FAS come from the Metropolitan Atlanta Congenital Defects Program (MACDP) of the Centers for Disease Control and Prevention. RESULTS: The prevalence of first-trimester drinking was half that reported for the three previous months (private hospital: 72% vs. 35%; public hospital: 52% vs. 28%). Most women (85%) reported abstaining throughout the second trimester. Fewer than 10% of women delivering at the public hospital (7.5%), but one-quarter of those delivering at the private hospital, reported third-trimester drinking. Binge, moderate and heavy drinking in pregnancy were more common among women delivering at the public hospital. Eight infants born at the public hospital during this period, but none of those born at the private hospital, were identified as possibly having FAS; four of the eight were identified as probably having FAS. CONCLUSIONS: These results have implications for health education programs. For example, obstetricians in private practice may wish to reaffirm their advice to abstain from drinking in the third trimester. They also suggest that prenatal abstinence programs be targeted at populations identified as most likely to engage in risky drinking.

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease).

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurological deterioration, even when carried out in minimally symptomatic patients.

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.

The effects of prenatal drug exposure, term status, and caregiving on arousal and arousal modulation in 8-week-old infants.

Prenatal exposure to cocaine, as well as other drugs, has been linked with "dysregulation," usually defined as problems in arousal and/or behavioral regulation. This study was designed to describe the physiological basis of dysregulation as a function of prenatal cocaine/polydrug exposure and term status. Eight-week-old infants were selected because they are just developing the ability to modulate arousal. One hundred-eighteen infants (23 preterm control, 27 preterm drug-exposed, 29 full-term control, and 39 full-term drug-exposed) completed a protocol during which heart rate (HR) and respiratory rate (RR) were measured. Drug group differences were found in baseline, arousal (response to stress), and arousal modulation (recovery from stress). A hierarchical multiple regression analysis was conducted to determine the portion of variance attributable to postnatal caregiving environment, term status, and specific drug exposure. Term status accounted for significant variance in arousal (both RR and HR), and in arousal modulation (only RR). Prenatal exposure to cocaine contributed a significant amount of unique variance in HR arousal whereas tobacco contributed significantly to HR arousal modulation. Prenatal drug exposure and preterm status contributed differently to dysregulation as measured by physiological responses.

Attentional response at eight weeks in prenatally drug-exposed and preterm infants.

To evaluate the effect of prenatal polydrug exposure on infant attention, 105 8-week-old African-American infants were presented a series of stimuli and their heart rates (HRs) were recorded. Infants were identified postnatally based on mothers' substance use. Four groups were tested: 1) preterm drug-exposed infants (n = 25); 2) full-term, drug-exposed (n = 32); 3) preterm nonexposed (n = 22); and 4) full-term, nonexposed (n = 26). Preterm infants' ages were corrected. Infant's baseline HRs were recorded and then stimuli presented in the following order: auditory (rattle), visual (red ring), and social (examiner's face and voice). There were no HR differences at baseline or in auditory or visual conditions. However, significant differences (F(2, 103) = 6.54, p < 0.01) were seen in response to social stimuli. Drug-exposed infants showed an acceleratory HR indicating distress or arousal and control infants showed a deceleratory response indicating focused attention and there was an interaction due to greater HR response in preterms. Hierarchical regression indicated cocaine (R2 = 0.034, p < 0.05) but not other drug use and instability in parenting (R2 = 0.137, p < 0.001) accounted for the observed differences.

Maternal drug use during pregnancy: are preterm and full-term infants affected differently?

This study examined whether preterm infants are more vulnerable to the effects of prenatal drug exposure than are full-term infants. The sample of 235 low-income African American mothers and their infants included 119 cocaine-polydrug users, 19 alcohol-only users, and 97 nonusers; 148 infants were full term and 87 were preterm. Direct effects of exposure on birth weight, birth length, ponderal index, and irritability were moderated by length of gestation: Fetal growth deficits were more extreme in later-born infants, whereas increases in irritability were more extreme in earlier born infants. Effects of exposure on cardiorespiratory reactivity to a neonatal exam were not moderated by length of gestation. In general, effects of exposure occurred for both cocaine-polydrug and alcohol only users and so could not be unambiguously attributed to either of these drugs alone.

A comparison of children affected by prenatal alcohol exposure and attention deficit, hyperactivity disorder.

Behavioral deficits are often noted in children with fetal alcohol syndrome (FAS) and other individuals with prenatal alcohol exposure, including mental retardation, learning problems, social problems, and deficits in attention. Because attention deficit, hyperactivity disorder (ADHD) has been diagnosed so frequently in children with FAS and other alcohol related birth defects, there has been speculation that alcohol is an etiological factor in ADHD. To examine the relationship between behavior characteristics of children with fetal alcohol exposure and those seen in children with a diagnosis of ADHD, 149 low socioeconomic status (SES), African-American children (mean age = 7.63 years) were given a battery of neuropsychological and behavioral tests. One hundred and twenty-two were a sub-sample from a longitudinal study of prenatal alcohol exposure, whereas twenty-seven were identified in an ADHD Clinic. Children were given two sets of tests: (1) "traditional model" of conventional behavioral and psychiatric measures of ADHD and externalizing behavior; and (2) measures of neurocognitive functioning reflecting a four-factor model of the neurological basis of the components of attention (Mirsky AF, in Integrated Theory and Practice in Clinical Neuropsychology, Hillsdale, NJ, Lawrence Erlbaum Associates, 1989). Results indicated that children with the physical characteristics associated with prenatal alcohol exposure and those with a diagnosis of ADHD had equivalent intellectual abilities with both clinical groups performing more poorly than contrast children from the same SES and ethnic groups. However, there were clear distinctions on behavioral and neurocognitive measures between the two clinical groups with those with ADHD performing more poorly on conventional tests sensitive to attentional problems and conduct disorder. When these two groups were compared on measures designed to measure the model of the four factors of attention by Mirsky, they were noted to have distinct patterns of deficits. These results suggested that the alcohol-affected children did not have the same neurocognitive and behavioral characteristics as children with a primary diagnosis of ADHD.

Maternal substance use: epidemiology, treatment outcome, and developmental effects: an annotated bibliography, 1995.

Understanding the effects of substance misuse by pregnant women and mothers of young children requires a knowledge of the epidemiology of women's drug and alcohol use and misuse, the treatment of pregnant and postpartum chemically dependent women, the impact of prenatal exposure on the offspring outcome and later development, and, finally, methodological issues related to these fields. This bibliography provides a list of recent and classic articles in these areas as well as information about the research in these areas.

Two-dimensional protein electrophoresis and multiple hypothesis testing to detect potential serum protein biomarkers in children with fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) surveillance and intervention efforts are hampered by the lack of a specific biochemical test for diagnosis of the syndrome. Based on the hypothesis that abnormalities in growth and development (key features of FAS) involve altered protein metabolism, we analyzed serum proteins by two-dimensional gel electrophoresis and image analysis to search for potential protein biomarkers of FAS. Serum samples from 12 participants in whom FAS had been diagnosed and 8 sex- and age-matched participants whose mothers did not consume alcohol were analyzed in duplicate to determine whether the integrated intensities of matched proteins are significantly altered in children with FAS. Multiple hypothesis testing on 34 of the gels consisting of more than 1700 spots per gel revealed 21 proteins that we classified as potential protein biomarkers of FAS on the basis of significant t-test differences at p < 0.02. We classified 8 of the proteins as candidate biomarkers on the basis of significant concentration differences between case and control subjects at p < 0.01. One of the proteins is clearly an isoform of retinol binding protein; two appear in the area of the gel where alcohol dehydrogenase is expected to appear; one appears to be an isoform of alpha-1-antitrypsin; three appear to be isoforms of the beta-chain of haptoglobin; three may be forms of immunoglobulin light chains; and several others have not been associated with known proteins. No single protein differentiated all case subjects from control subjects, but stepwise canonical discriminant analyses revealed four groups of spots that distinguished between FAS case and control subjects with no misclassifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral development in children prenatally exposed to drugs and alcohol.

Empirical research on the behavioral consequences to the offspring of use of recreational and addictive drugs and alcohol by pregnant women is reviewed. The current epidemic of cocaine use has raised the specter of a host of "cocaine babies" whose prenatally induced impairments will interfere with social and academic functioning and constitute an immense social burden. In fact, examination of effects of drug exposure on infant behavior and subsequent development suggests a much more subtle and complicated process which must take into account not only the child's prenatal exposure but the various other environmental factors which contribute to eventual outcome. These other factors include caregiving competence and social environment.

Impact of prenatal alcohol exposure on the newborn and the child.

Maternal use of alcohol during gestation is associated with FAS and less severe problems in exposed children, such as FAE and ARBD. This article reviewed the literature concerning the status of affected and exposed neonates and the available information on the developmental course of infants and children. Physical and behavioral characteristics of gestational alcohol exposure were described, and outcomes of retrospective and prospective research were reviewed. Currently, it is evident that heavy use and bingeing are associated with an increased risk to the offspring across a range of outcomes. Although the last 20 years of research in this area have provided a great deal of information, there remain unanswered questions regarding the course of the affected individual over the lifespan, the neuropsychologic status of children, and the relationship of prenatal exposure and the caregiving environment to the observed outcomes.