Teratogenic effects of alcohol in humans and laboratory animals.

The teratogenicity of alcohol has been demonstrated in humans through clinical studies, behavioral studies, and epidemiologic studies, and in animals through controlled laboratory experiments. In humans exposed to alcohol during gestation the effects can range from fetal alcohol syndrome in some offspring of chronic alcoholic women to reduced average birth weight in offspring of women reporting an average consumption of two to three drinks or more per day. The behavioral effects of such exposure may range from mental retardation in children with fetal alcohol syndrome to milder developmental and behavioral effects in infants born to social drinkers. In animals, exposure to alcohol in utero may result in death, malformation, and growth deficiency as well as behavioral and developmental abnormalities. The mechanisms of impairment and related risk factors are yet to be elucidated.

Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects.

OBJECTIVE: The authors' goal was to use structured clinical interviews to characterize the type and frequency of mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. METHOD: Twenty-five subjects who met criteria for fetal alcohol syndrome or fetal alcohol effects, who were older than 18 years old, and who had an IQ of greater than 70 were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders and the Structured Clinical Interview for DSM-III-R Personality Disorders. RESULTS: Eighteen of the 25 subjects had received psychiatric treatment. The most common axis I disorders were alcohol or drug dependence (15 subjects), depression (11 subjects), and psychotic disorders (10 subjects). The most common axis II disorders were avoidant (six subjects), antisocial (four subjects), and dependent (three subjects) personality disorders. CONCLUSIONS: This study suggests that adults with fetal alcohol syndrome or fetal alcohol effects suffer from substantial mental illness.

Impairments of number processing induced by prenatal alcohol exposure.

Prenatal alcohol exposure causes a variety of cognitive deficits, notably in mathematics and higher order processes such as abstraction. An exploratory battery was developed to examine specific types of number processing impairments in 29 adolescent and adult patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) relative to controls matched for age, gender, and educational level. The battery included 11 tests: number reading and writing, exact calculation (addition, multiplication, subtraction), approximate calculation (selecting a plausible result for an operation), number comparison, proximity judgment, and cognitive estimation. The results indicated particular difficulties in calculation and estimation tests, with intact number reading and writing ability. The greatest impairment was found in the cognitive estimation test, which is sensitive to frontal lobe lesions. The patterns of deficit described may reflect either the diffuseness of brain damage incurred from prenatal alcohol exposure, or a cumulative deficit in comprehension which may be important for the acquisition of higher-order mathematical abilities.

Independent dysmorphology evaluations at birth and 4 years of age for children exposed to varying amounts of alcohol in utero.

Two groups of 4-year-old children were examined by a dysmorphologist without knowledge of previous examination results or prenatal exposure and categorized as to whether or not they showed fetal alcohol effects. A priori classification of children into the two groups was on the basis of their mothers' self-report of drinking when interviewed during pregnancy. Children born to 108 mothers in a "heavier" drinking group (absolute alcohol concentration greater than or equal to 30 mL/d [1.0 oz/d]) were compared with a matched group of children born to 97 mothers whose average absolute alcohol concentration was less than 0.3 mL/d (0.01 oz/d). The percentage of children with fetal alcohol effects in the heavier drinking v the comparison group was 20.4% v 9.3%. When fetal alcohol effects were studied in relation to only the absolute alcohol concentration scores, there was a significantly greater chance of a child being classified as having fetal alcohol effects with increasing levels of alcohol exposure prior to recognition of pregnancy (P = .013). A logistic regression, run on the absolute alcohol concentration scores and other primary exposures, indicated that fetal alcohol effects classification was not significantly related to nicotine, caffeine, or marijuana but was significantly related to absolute alcohol concentration scores even after statistically adjusting for these other exposures (P = .002). Classification of fetal alcohol effects at 4 years of age was compared to a fetal alcohol effects classification obtained at birth by an independent dysmorphologist in a sample of 75 subjects examined at both ages, and 80% of the infants classified as having fetal alcohol effects at birth were classified as having fetal alcohol effects at 4 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Infant size at 8 months of age: relationship to maternal use of alcohol, nicotine, and caffeine during pregnancy.

To examine the relationship of maternal alcohol consumption, caffeine use, and smoking to infant size at 8 months of age, a follow-up cohort of 453 infants was examined at birth and again at their 8-month birthday. Even after adjustment for other relevant variables, maternal alcohol use during early pregnancy (average ounces of absolute alcohol by self-report) was significantly related to infant weight and length at 8 months of age but not as strongly related to head circumference. Maternal smoking and caffeine use during pregnancy were not significantly related to infant size at 8 months, although nicotine use had been highly related to the birth size in this sample. Maternal use of marijuana was significantly and negatively related to infant length at 8 months of age, but not to weight or head circumference. The magnitude of the growth retardation is smaller at 8 months than at birth in this sample of infants whose mothers are primarily white, married, and well-educated, and who report a variety of alcohol use patterns. Significance was tested using multiple regression analyses that adjusted for the effects of nicotine use, caffeine use, birth order, maternal height, and gestational age as well as sex and age of infant at examination.

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.

Fetal alcohol syndrome in twins of alcoholic mothers: concordance of diagnosis and IQ.

The effects of teratogens can be modified by genetic differences in fetal susceptibility and resistance. Twins of alcoholic mothers provide a unique opportunity to study this phenomenon with respect to alcohol teratogenesis. Sixteen pairs of twins, 5 MZ and 11 DZ, all heavily exposed to alcohol prenatally, were evaluated. They represented all available twins of alcohol-abusing mothers who were on the patient rolls of the authors. The rate of concordance for diagnosis was 5/5 for MZ and 7/11 for DZ twins. In two DZ pairs, one twin had fetal alcohol syndrome (FAS), while the other had fetal alcohol effects (FAE). In 2 other DZ pairs, one twin had no diagnosis while one had FAE. IQ scores were most similar within pairs of MZ twins and least similar within pairs of DZ twins discordant for diagnosis. Despite equivalent alcohol exposure within twin pairs, alcohol teratogenesis appears to be more uniformly expressed in MZ than in DZ twins. These data are interpreted as reflecting the modulating influence of genes in the expression of the teratogenic effects of alcohol.

Facial effects of fetal alcohol exposure: assessment by photographs and morphometric analysis.

This study was designed to assess the limits of alcohol-related facial dysmorphogenesis. Standard full face and lateral facial photographs were obtained on 21 7-year-old children who had been exposed gestationally to known, heavy quantities of ethanol. Only two of these children had been previously considered to have definite fetal alcohol syndrome (FAS). Similar photographs of 21 other 7-year-old children with negligible gestational ethanol exposure were obtained for control purposes. Copies of the 42 photographs were given to each of seven expert clinicians who were asked to select any child with an FAS-related facial appearance. Six of seven judges were accurate in identifying children with high levels of alcohol exposure as having a fetal alcohol-affected face. A set of homologous points on the photographs were then digitized and analyzed by newly developed morphometric methods to determine the facial shape characteristics that distinguish the selected photographs of highly exposed children. The analysis confirmed that the judges specifically identified children with facial changes consistent with those previously published as defining the face of the FAS: short palpebral fissures, a relatively long and flat midface, and a retrusive mandible. This methodology may be useful in more accurately delineating the facial phenotype in other conditions diagnosed primarily on the basis of subjective clinical criteria.

Studying alcohol teratogenesis from the perspective of the fetal alcohol syndrome: methodological and statistical issues.

Alcohol is a teratogenic drug and the effects appear to be grossly dose related. The severest effects are observable clinically as the fetal alcohol syndrome and are associated with heavy prenatal alcohol exposure and a history of chronic maternal abuse of alcohol. Hypotheses for subtler behavioral effects associated with lower levels of exposure can be generated from observation of the behavioral effects in FAS. Behavioral effects associated with various levels of prenatal alcohol exposure in humans include poor sucking and poor habituation in the newborn, poorer mental and motor development in infancy, and attentional and reaction time effects at four and seven years of age. Human behavioral teratology studies are necessarily complex due to the large number of covariates that affect behavior, modify the effects of teratogens, and influence interpretation. Challenging problems exist in assessing exposure, outcomes, and covariates. Common to assessment of all these classes of variables are the multiplicity of measurement and the indirect nature of the measurement. Answering specific questions about timing and dose effects demands careful statistical modeling procedures and large, complex data bases. Large data bases and indirect measurement problems suggest factor analytic extensions of current regression methodology, which we have proposed in this paper.

Cocaine exposure during pregnancy: improving assessment with radioimmunoassay of maternal hair.

OBJECTIVE: To compare radioimmunoassay of postpartum maternal hair samples with a structured maternal interview for the detection of cocaine use during pregnancy. METHODS: Radioimmunoassay of hair samples obtained postpartum was compared with self-report of cocaine use obtained by confidential, structured interviews of 405 postpartum women. RESULTS: Cocaine or benzoylecgonine was detected in the hair samples of 129 of the 148 women (87%) who reported using cocaine at least once during pregnancy. Thirty-six of 257 women (14%) who reported that they had used no cocaine during pregnancy had positive hair tests. Positive hair assay with negative self-report was significantly more common among women who were unmarried (P = .001), African-American (P < .001), and multiparous (P = .035). CONCLUSIONS: Hair analysis is a valuable complement to maternal self-report by interview. The methods used together provide a useful clinical and research technique yielding a comprehensive estimate of gestational cocaine exposure. Either method alone may result in misclassification of gestational cocaine exposure.

A test-retest study of intelligence in patients with fetal alcohol syndrome: implications for care.

Successive IQ scores of 40 patients with fetal alcohol syndrome or possible fetal alcohol effects were compared to examine stability of IQ into mid-adolescence. There were no significant differences in IQ scores across time for patients with fetal alcohol syndrome and fetal alcohol effects. Group means and individual IQ scores remained stable over the average test-retest interval of 8 years. These data demonstrate the long-term enduring consequences of prenatal brain damage in the fetal alcohol syndrome, an entirely preventable developmental disability.

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.

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.

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.

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.

Effects of prenatal alcohol exposure on social behavior in humans and other species.

Alcohol exposure during development causes central nervous system alterations in both humans and animals. Although the most common behavioral manifestation of these alterations is a reduction in cognitive abilities, it is becoming increasingly apparent that deficits in social behavior may be very prevalent sequelae of developmental alcohol exposure. In infancy and early childhood, deficits in attachment behavior and state regulation are seen in both alcohol-exposed people and animals, suggesting that these changes are largely the result of the alcohol exposure rather than maternal behavior. In the periadolescent period, people exposed to alcohol during development show a variety of difficulties in the social domain as measured by checklists filled out by either a parent or teacher. Rats exposed to alcohol during development show changes in play and parenting behaviors. In adulthood, prenatal alcohol exposure is related to high rates of trouble with the law, inappropriate sexual behavior, depression, suicide, and failure to care for children. These high rates all suggest that there may be fundamental problems in the social domain. In other animals, perinatal alcohol exposure alters aggression, active social interactions, social communication and recognition, maternal behavior, and sexual behavior in adults. In conclusion, research suggests that people exposed to alcohol during development may exhibit striking changes in social behavior; the animal research suggests that these changes may be largely the result of the alcohol insult and not the environment.

Prenatal alcohol exposure: comparability of effects in humans and animal models.

Much is known about the potential consequences of prenatal alcohol exposure through data developed in animals and man. However, little attempt has been made to compare the human and animal literature with respect to qualitative and quantitative similarities and differences. To this end, a comparison was made between the effects reported in humans following moderate levels of alcohol exposure and the neurobehavioral effects detected using animal models. A good deal of congruence was found with respect to qualitative endpoints. General functional categories, such as deficits in learning, inhibition, attention, regulatory behaviors, and motor performance were reported to be affected in both animals and children. Quantitatively, although the dose required to produce an effect differs across species, the resultant circulating blood alcohol levels are quite similar. In addition, while compelling data are limited, the magnitude of the observed effects are generally dose-related for both humans and animals.

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.

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.