Identifying maternal self-reported alcohol use associated with fetal alcohol spectrum disorders.

BACKGROUND: The incidence of Fetal Alcohol Syndrome (FAS) has been estimated at 1 to 3 per 1,000 live births. Fetal Alcohol Spectrum Disorders (FASD) (which include FAS) are estimated to occur in about 1 in 100 births. Cessation of drinking during pregnancy can improve the outcome even if the unborn child is already affected. For individuals born with FASD, an early diagnosis appears to be a protective factor against secondary disabilities. A quick screening tool to identify newborn children at risk has been elusive. METHODS: A simple descriptive presentation is offered that shows where 36 individuals with FASD were found from among the many patterns and amounts of prenatal alcohol use that were reported by a sample of 1,439 pregnant women whose offspring were later examined within the first 7 years of life. RESULTS: Individuals with FASD (i.e., those with FAS, fetal alcohol effects, alcohol-related neurodevelopmental disorder ) were found within two aggregates of alcohol scores that together recommend a set of three to four alcohol questions. Within this derivation sample, one scoring of the questions yields almost 78% sensitivity and 97% specificity for FASD. Another scoring of the same instrument yields 100% sensitivity with 90% specificity. CONCLUSIONS: These new data may facilitate early identification of offspring who may be most in need of early intervention, namely those born with FASD.

On categorizations in analyses of alcohol teratogenesis.

In biomedical scientific investigations, expositions of findings are conceptually simplest when they comprise comparisons of discrete groups of individuals or involve discrete features or characteristics of individuals. But the descriptive benefits of categorization become outweighed by their limitations in studies involving dose-response relationships, as in many teratogenic and environmental exposure studies. This article addresses a pair of categorization issues concerning the effects of prenatal alcohol exposure that have important public health consequences: the labeling of individuals as fetal alcohol syndrome (FAS) versus fetal alcohol effects (FAE) or alcohol-related neurodevelopmental disorder (ARND), and the categorization of prenatal exposure dose by thresholds. We present data showing that patients with FAS and others with FAE do not have meaningfully different behavioral performance, standardized scores of IQ, arithmetic and adaptive behavior, or secondary disabilities. Similarly overlapping distributions on measures of executive functioning offer a basis for identifying alcohol-affected individuals in a manner that does not simply reflect IQ deficits. At the other end of the teratological continuum, we turn to the reporting of threshold effects in dose-response relationships. Here we illustrate the importance of multivariate analyses using data from the Seattle, Washington, longitudinal prospective study on alcohol and pregnancy. Relationships between many neurobehavioral outcomes and measures of prenatal alcohol exposure are monotone without threshold down to the lowest nonzero levels of exposure, a finding consistent with reports from animal studies. In sum, alcohol effects on the developing human brain appear to be a continuum without threshold when dose and behavioral effects are quantified appropriately.

Direct and indirect effects of prenatal alcohol damage on executive function.

Patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) often have difficulty functioning appropriately in everyday life and seem to employ poor problem-solving strategies. Tests of executive function are relevant for quantifying the functional deficits and underlying real-life problems associated with prenatal alcohol exposure. This study considers two pathways for the effects of prenatal alcohol on executive function: a direct effect and an indirect effect through prenatal alcohol's effect on IQ. We compared 30 men who had been diagnosed with FAS or FAE with young adults participating in a longitudinal prospective study (n = 419) and 15 control participants that comprised a comparison group. This study is unique in its analysis of the same battery of assessments of executive function in both a large low dose longitudinal study sample and a clinically diagnosed group. Participants were evaluated on 9 tests (including 58 scores) of executive function. For some but not all of the tests in this executive function battery, the decrement in the alcohol exposure group is greater than would be predicted from their IQ scores. We found that 3 of 6 Stroop scores, 2 of 4 Trails scores, 9 of 16 Wisconsin Card Sorting scores, 1 of 2 Ruff's Figural Fluency scores, and 2 of 4 Consonant Trigrams scores appear to be particularly sensitive to the direct effects of prenatal alcohol damage for patients with FAS and FAE. The findings suggest that these executive function tests would be particularly useful in clinical evaluations of persons suspected of fetal alcohol damage because they would not simply reflect deficits in IQ or facial stigmata.

Individual differences in auditory and visual attention among fetal alcohol-affected adults.

BACKGROUND: Deficits in attention are commonly identified among patients who have been prenatally exposed to alcohol, and they often affect the ability of the patients to function appropriately in society. METHODS: Eleven adult patients with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) were compared with nine adult subjects with no history of prenatal alcohol exposure, using four tests of visually and auditorially mediated attention. RESULTS: In relation to the comparison group, patients with FAS/FAE exhibited substantial deficits in both auditory and visual attention; the auditory deficits were greater. We observed two predominant patterns of deficits among patients with FAS/FAE, one involving both auditory and visual attention problems and the other involving less severe auditory problems and even fewer visual problems. Most subjects with FAS or FAE had some manifestations of attention problems in at least one of the tests of attention used in this study. We present a new graphical representation of individual auditory Continuous Performance Test data across a 6-min period, which, compared with conventional scores, more clearly reveals the markedly disrupted and variable attention patterns displayed by some individuals with FAS or FAE. CONCLUSIONS: These findings suggest that detailed analysis of the pattern of individual performance for each subject is an important aspect of Continuous Performance Test assessment. Our findings further suggest that intellectual performance (intelligence quotient score) alone is not sufficient to account for the patterns of disrupted attention for individuals with FAS/FAE. Assessment of individuals with FAS or FAE should include measurement of attentional functioning in both the visual and auditory modalities.

Prenatal alcohol exposure and family history of alcoholism in the etiology of adolescent alcohol problems.

OBJECTIVE: To examine the relative importance of prenatal alcohol exposure and family history of alcoholism for the prediction of adolescent alcohol problems. METHOD: In 1974-75, a population-based, longitudinal prospective study of alcohol and pregnancy began with self-report of alcohol use by pregnant women. In a 14-year follow-up, 439 parents provided information on the family history of alcohol problems for these adolescent offspring. The 14-year-old adolescents provided information on the frequency and quantity of their own alcohol consumption within the past month, on the consequences of their drinking over the past 3 years, and on their age at first intoxication. Additional covariates were assessed prenatally and at follow-up. RESULTS: Prenatal alcohol exposure was more predictive of adolescent alcohol use and its negative consequences than was family history of alcohol problems. Prenatal exposure retained a significant predictive effect even after adjustment for family history and other prenatal and environmental covariates. By contrast, the nominally significant correlation of family history with adolescent drinking is weaker after adjustment for prenatal alcohol exposure and disappears entirely after adjustment for other relevant covariates. We observed no evidence for an interactive effect of fetal exposure and family history in predicting adolescent alcohol use. CONCLUSIONS: Fetal alcohol exposure is a risk factor for adolescent alcohol involvement and alcohol-related problems and may account for variance in prediction of problems otherwise attributed to family history of alcoholism. Studies of alcoholism etiology and family history need to include consideration of even modest levels of fetal alcohol exposure.

A fetal alcohol behavior scale.

This research aimed to develop a Fetal Alcohol Behavior Scale (FABS) that describes the behavioral essence of fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE), regardless of age, race, sex, and IQ. Using a reference sample of 472 diagnosed patients with FAS or FAE, ages 2 to 51, five studies are described. The FABS demonstrates high item-to-scale reliability (Cronbach's alpha = 0.91) and good test-retest reliability (r = 0.69) over an average interval of 5 years. It identifies many of the subjects with known or presumed prenatal alcohol exposure in detection studies using both prison and general samples. FABS scores also predict dependent living among adult patients with FAS/FAE. The FABS is uncorrelated with IQ, sex, age, race, and diagnosis (FAS versus FAE). We outline areas of further work to define the specificity and utility of this FABS.

Association of prenatal alcohol exposure with behavioral and learning problems in early adolescence.

OBJECTIVE: To examine the association of moderate levels of prenatal alcohol exposure with learning and behavior in early adolescence. METHOD: A population-based cohort of 464 children were followed longitudinally from birth to age 14 years. Alcohol exposure was assessed via in-depth maternal self-report in the fifth month of pregnancy. At age 14, learning and behavior were assessed with multiple measures, tapping parent, teenager, and psychologist viewpoints, drawn from adolescent laboratory examination and parent phone interview. The underlying pattern of association between prenatal alcohol and adolescent outcome was detected using partial least-squares statistical techniques; confounding factors were dealt with by regression methods. RESULTS: Analyses revealed a statistically significant, subtle relationship between greater prenatal alcohol use and increased behavior/learning difficulties during adolescence, even after accounting for other developmental influences. "Binge" maternal drinking and exposure early in pregnancy were associated with a profile of adolescent antisocial behavior, school problems, and self-perceived learning difficulties. CONCLUSIONS: Fetal alcohol exposure (even at "social drinking" levels) is associated with developmental difficulties in adolescence that are consistent with problems seen earlier in life. Clinicians should understand the potential role prenatal alcohol exposure plays in behavioral and cognitive problems.

Neonatal neurobehavioral outcome following prenatal exposure to cocaine.

This substudy of a longitudinal prospective study was designed to assess neurodevelopmental and neurobehavioral performance in newborn infants who were maternally exposed to cocaine and other drugs of abuse or the other drugs without cocaine. Sample selection procedures were designed to permit statistical control for marijuana, alcohol, and tobacco. Cocaine was assessed with both self-report and radioimmunoassay of hair. One hundred ninety-one newborns with a mean age of 43 h were assessed for 35 to 40 min on tests of reflexes, activity level, head-turning preference, tremors, nonnutritive sucking, habituation, and state. The testers were blinded to the baby's drug exposure. Cocaine-exposed newborns were developmentally at risk on the tests administered compared to infants exposed to the other three drugs alone or in some combination. A dose-response effect was found: higher amounts of cocaine were associated with higher neurobehavioral risk scores.

Radioactivity in two tide-washed marsh areas in the eastern Irish Sea: a radiological assessment.

The doses received by man from exposure to artificial radionuclides deposited onto marsh land during tidal inundation on the English side of the Solway Firth and the Dee Estuary have been assessed. The range of total doses received by the different marsh user groups was similar in both study areas, varying from < 1 microSv year-1 to approximately 55 microSv year-1, with total dose dominated by the contribution from external exposure (generally 80% of the total). The maximum doses in both study areas were received by people working on the marshes and are well below the annual dose limit recommended by ICRP for members of the public (1 mSv year-1). The largest dose estimated (56 microSv year-1) is only 6% of the recommended dose limit.

Alteration of mitochondrial gene expression and disruption of respiratory function by the lipophilic antifolate pyrimethamine in mammalian cells.

To clone the mammalian gene(s) associated with a novel lipophilic antifolate resistance provoked by the antiparasitic drug pyrimethamine (Assaraf, Y. G., and Slotky, J. I. (1993) J. Biol. Chem. 268, 4556-4566), differential screening of a cDNA library from pyrimethamine-resistant (PyrR100) cells was used. This library was screened with total cDNA from wild-type and PyrR100 cells. Surprisingly, several differentially overexpressed cDNA clones were isolated from PyrR100 cells, many of which mapped to the mitochondrial genome. Several lines of evidence establish mitochondria as a new target for the cytotoxic activity of pyrimethamine. (a) At > or = 10 microM, pyrimethamine inhibited mitochondrial respiration in viable wild-type cells. (b) Electron microscopy revealed degenerated mitochondrial membrane cristae in PyrR100 cells. (c) Some mitochondrially encoded transcripts were prominently elevated, whereas the normally stable 12 S/16 S rRNA was decreased in PyrR100 cells. (d) Metabolic pulse-chase labeling suggested an increased turnover rate of mitochondrially synthesized proteins in PyrR100 cells. (e) The specific activity of the key respiratory enzymatic complex cytochrome c oxidase was reduced by 6-fold in PyrR100 cells. (f) Consequently, the rate of respiration in intact PyrR100 cells was reduced by 3-fold. We conclude that pyrimethamine and possibly lipophilic analogues of methotrexate possess a folinic acid nonrescuable toxicity involving disruption of mitochondrial inner membrane structure and respiratory function, thereby establishing a new organellar target for the cytotoxic effect elicited by lipid-soluble antifolates.

Prenatal alcohol and offspring development: the first fourteen years.

This report summarizes findings from a prospective longitudinal study of the effects of prenatal alcohol exposure on a birth cohort of 500 offspring selected from 1,529 consecutive pregnant women in prenatal care by mid-pregnancy at two representative community hospitals. Effects of prenatal alcohol observable on size measures at birth were insignificant after 8 months. Morphometric analysis of facial features identified effects only at the very highest alcohol exposure levels. By contrast, dose-dependent effects on neurobehavioral function from birth to 14 years have been established using partial least squares (PLS) methods jointly analysing multiple measures of both alcohol dose and outcome. Particularly salient effects included problems with attention, speed of information processing, and learning problems, especially arithmetic.

Prenatal alcohol exposure, birthweight, and measures of child size from birth to age 14 years.

OBJECTIVES: The purpose of the study was to examine the effect of prenatal alcohol exposure on offspring's weight, height, and head circumference from birth through 14 years of age. METHODS: This longitudinal prospective study examined a cohort of approximately 500 offspring (oversampled for heavier drinkers and stratified for smoking from a population of 1529 women in prenatal care at the 5th gestational month) at birth; 8 and 18 months; and 4, 7, and 14 years of age. Covariates were examined by means of multiple regression. Birth size measures were also examined as predictors of 7-year neurodevelopmental outcomes. RESULTS: Effects of alcohol were observed on weight, length, and head circumference at birth; these effects were not altered by adjustment for covariates including smoking. However, the birthweight effect is clearly transient: although alcohol effects remained observable at 8 months, they were not measurable thereafter through age 14 years. CONCLUSIONS: In this population-based sample, neither birthweight nor any later size measure was as useful an indicator of the enduring effects of prenatal alcohol exposure as were certain neurodevelopmental outcomes.

Drinking during pregnancy decreases word attack and arithmetic scores on standardized tests: adolescent data from a population-based prospective study.

Women (1529) were interviewed in midpregnancy, and a cohort of their children has been examined at various ages. The two standardized tests presented herein are part of a large battery of tests administered when the children were 14 years old. "Word Attack" (n = 462) measures phonological processing on a task involving the reading of pseudowords in nontimed performance. "Arithmetic" (n = 191) measures auditorily processed mental computations in timed performance. Scores on both tests were associated with prenatal alcohol exposure in a dose-dependent fashion. These effects were robust when considered in relation to a wide variety of potentially confounding variables, such as prenatal exposure to tobacco and other drugs, sociodemographic characteristics, and traumatic postnatal events. A variety of alcohol scores were related to these two performance measures, but those involving a massing of drinks on a given occasion had the strongest association. The higher the average number of drinks/occasion, the poorer the offspring performance on tasks thought to underlie numerical problem solving and reading proficiency. Earlier reports of prenatal, alcohol-related neurobehavioral deficits in childhood have now been extended into adolescence.

Maternal drinking during pregnancy: attention and short-term memory in 14-year-old offspring--a longitudinal prospective study.

A large and compelling experimental literature has documented the adverse impact of prenatal alcohol exposure on the developing brain of the offspring. This is the first report of adolescent attention/memory performance and its relationship with prenatal alcohol exposure in a population-based, longitudinal, prospective study (n = 462) involving substantial covariate control and "blind" examiners. Prenatal alcohol exposure was significantly related to attention/memory deficits in a dose-dependent fashion. A latent variable reflecting 13 measures of maternal drinking was correlated 0.26 with a latent variable representing 52 scores from 6 tests measuring various components of attention and short-term memory performance. The number of drinks/occasion was the strongest alcohol predictor. Fluctuating attentional states, problems with response inhibition, and spatial learning showed the strongest association with prenatal alcohol exposure. A latent variable reflecting the pattern of attention/memory deficits observed at 14 years correlated 0.67 with a composite pattern of deficits previously detected on neurobehavioral tests administered during the first 7 years of life. The 14-year attention/memory deficits observed in the present study appear to be the adolescent sequelae of deficits observed earlier in development. As is usual in such studies, not all exposed offspring showed deficits.

Caffeine use during pregnancy and child outcome: a 7-year prospective study.

Caffeine (from coffee, tea, cola, and/or chocolate) was the most frequently ingested drug among 1529 pregnant women interviewed in 1974-75. Linear and threshold effects of prenatal caffeine on pregnancy outcome and offspring development were examined in a cohort of approximately 500 offspring. After appropriate statistical adjustment for relevant covariates (cigarette smoking, alcohol, maternal size, demographics, etc.) prenatal caffeine exposure was not related to most newborn and infant outcome measures, including height, weight or head circumference, or to individually administered IQ and attention tests at 7 years of age. Only one isolated dependent variable of the many was significantly associated with prenatal caffeine exposure: namely breech presentation. However, since this report involved a secondary analysis of data gathered for other purposes, specifically designed studies would be required to determine the validity of the observed association for any particular variable. The general conclusion is that the long-term consequences of prenatal caffeine in this cohort are null.

Radiologic recommendation for breast biopsy on screening mammography reports.

Radiologic reports on screening mammography findings often obligate breast biopsy. Ready recommendation for biopsy of nonpalpable lesions imaged by x ray is a conservative radiologic policy but is unsettling for patients and creates an imperative bind for surgeons. Like the decision to send the patient with right lower quadrant abdominal pain home rather than to the operating room, the diagnosis that requires clinical confidence and precision is nonappendicitis. Noncancer of the breast is a similar diagnosis that can usually be made on clinical and mammographic findings rather than passing such patients through to invasive diagnosis. A series of 84 patients was referred for needle localization of nonpalpable mammographically detected lesions called suspicious on screening examination. Of these 84 patients, new radiographic reports reinterpreting the findings without biopsy were written on the original mammogram in 15 patients. This is a cancellation rate of 21 per cent. In 69 patients needle localization was carried out with the finding of cancer in 28 per cent, compared with the national average of 15 per cent. This higher than average yield caused concern whether any unbiopsied cancers had been followed, and a review of these patients was undertaken. In the log of patients referred for needle localization, the prereading by the mammographer performing the needle localization was recorded in advance of biopsy confirmation, and specificity proved to be 94 per cent and sensitivity 96 per cent. Of the cancers that were detected, 39 per cent were proven in patients older than 50 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine and the use of alcohol and other drugs during pregnancy.

Recent reports of adverse pregnancy outcomes associated with prenatal cocaine exposure have raised questions about the actual numbers of infants who are exposed to cocaine in utero. Whereas toxicologic urine screens obtained at delivery can detect cocaine use in the preceding few days, they fail to yield a comprehensive picture of use during and immediately before pregnancy. According to postpartum self-report, 15% of a teaching hospital sample and 3% of a private hospital sample of mothers had used cocaine during pregnancy or in the previous month (total = 876). Rates at the teaching hospital reflect a fifteenfold increase over the past 12-year period, when compared with previously obtained data. Cocaine users were significantly more likely to report that they drank alcohol, smoked cigarettes, and took other illicit drugs during pregnancy than women who denied using cocaine. Mothers at highest risk for cocaine use were those who were black (20%), were single-separated-divorced (24% to 33%), and had less than a high school education (21%).

Moderate prenatal alcohol exposure: effects on child IQ and learning problems at age 7 1/2 years.

This longitudinal, prospective, population-based study examined the long-term effects of moderate prenatal alcohol exposure on 482 school aged children. Maternal reports of alcohol use obtained during pregnancy were significantly related to child IQ, achievement test scores, and classroom behaviors in second grade children, even after statistical adjustment for appropriate covariates. Consumption of two drinks per day or more on the average was related to a 7-point decrement in IQ in 7-year-old children even after statistically adjusting for appropriate covariates. Low paternal education and more children in the household were identified as environmental factors exacerbating the effect of prenatal alcohol exposure on child IQ. Learning problems were associated with the alcohol "BINGE" pattern of five or more drinks on at least one occasion. This study shows that alcohol use patterns within the social drinking range can have long lasting effects on IQ and learning problems in young school aged children. These patterns should not be interpreted as biologic thresholds. It should also be noted that these are group effects of prenatal alcohol exposure, not necessarily predictable in the individual child, and that for the most part these children were functioning within the normal range of intelligence.

Neurobehavioral effects of prenatal alcohol: Part I. Research strategy.

This paper, Part I of a three-part series, reviews the literature on the neurobehavioral effects of prenatal alcohol exposure and describes a large group of tests assembled to assess neurobehavioral outcomes of alcohol teratogenesis in 7-year-old children. This paper presents the distribution of these test scores for our sample and discusses their relationships with an alcohol binge score and with full-scale IQ. This group of tests is suitable for children with a wide range of abilities and provides a broad assessment of neurobehavioral deficits. Part II of this series describes a new method of statistical analysis, Partial Least Squares (PLS), which is particularly well suited to complex multivariate data sets such as these, and with its aid, examines the effects of prenatal alcohol exposure on IQ, achievement, vigilance and classroom behavior, a total of 43 outcome scores. Part III examines prenatal alcohol effects on outcomes from the broad group of 164 scores deriving from 17 neuropsychologic tests, using the Partial Least Squares methodology, and summarizes the implications of our findings for the behavioral teratology of alcohol.

Neurobehavioral effects of prenatal alcohol: Part III. PLS analyses of neuropsychologic tests.

This paper is the third in a three-part series describing an investigation of the effects of prenatal alcohol exposure on the neurobehavioral functioning of 384 children about 7 1/2 years old. Here we describe the use of Partial Least Squares for data reduction and analysis of 158 neurobehavioral measures as they relate to 13 aspects of prenatal alcohol exposure. A general alcohol latent variable, emphasizing both binge and regular drinking patterns in the period prior to pregnancy recognition as well as during pregnancy, predicts a pattern of neurobehavioral deficit that includes attentional and memory deficits across both verbal and visual modalities; a variety of "process" variables reflecting poor integration and quality of responses; behavior patterns involving distractibility and poor organization; and an inflexible approach to problem-solving. The prominence of poorer spatial organization and arithmetic as primary outcomes of alcohol teratogenesis suggests a possible "nonverbal learning disability" pattern of deficit associated with prenatal alcohol exposure at the level of social drinking.