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NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM Report of a Subcommittee of the National Advisory Council
on Alcohol Abuse May 12-13, 1997 U.S. Department of Health and Human Services TABLE OF CONTENTS Diagnosis Risk and Protective Factors Description of Epidemiology Portfolio Behavioral and Nonbehavioral Phenotypes Neurobehavioral Human Phenotype Mechanisms Lactational Alcohol Exposure Description of Basic Research Portfolio Public Health and Behavioral Intervention Biomarkers of Fetal Exposure to Alcohol Intervention for Individuals with FAS Description of Prevention/Intervention Portfolio RESEARCH OPPORTUNITIES IN SOUTH AFRICA A: Subcommittee for Review of FAS Portfolio B: Experts in FAS C: NIAAA Program Staff D: NIAAA Staff, Representatives from CDC, NICHD, NIDR, and Guests
FETAL ALCOHOL SYNDROME REPORT OF A SUBCOMMITTEE OF THE NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM Since the first alcohol and pregnancy award in FY72, NIAAA=s investment has grown steadily. A summary of FY96 FAS awards is detailed below.
The National Institute on Alcohol Abuse and Alcoholism=s (NIAAA) Subcommittee for the Review of the Extramural Research Portfolio for Fetal Alcohol Syndrome (FAS) met on 12-13 May 1997. The charge to the Subcommittee was to examine the appropriateness of the breadth, coverage, and balance of the FAS research portfolio, identifying research areas that are well covered and others which are either under-investigated or which otherwise warrant significantly increased attention. The Subcommittee was asked also to provide specific external advice and guidance on the scope and direction of the Institute=s extramural research activities in the FAS area. The Subcommittee for the Review of the Extramural Research Portfolio for FAS consisted of two NIAAA Advisory Council co-chairs and an advisory group of eight individuals. Six of these individuals have demonstrated expertise in alcohol-related areas and two individuals have demonstrated expertise in non-alcohol-related areas (see Appendix A). The review process was initiated by having experts (see Appendix B) in FAS prepare written assessments of the state of knowledge, gaps in knowledge, and research opportunities. NIAAA program staff (see Appendix C) presented the current extramural portfolio, categorized into the areas of basic research, epidemiology, and prevention/intervention. All information was shared with experts, selected NIAAA staff, and the co-chairs and advisory group 30 days before the meeting. On 12 and 13 May, experts and NIAAA program staff made abbreviated presentations of their material followed by discussion among all of the participants, including representatives from CDC, NICHD, NIDR, and guests (see Appendix D). After completing this process, the co-chairs and advisory group, with input from the experts, delineated the following gaps in knowledge and research opportunities. Epidemiology Diagnosis
Risk and Protective Factors
Basic Research Behavioral and Nonbehavioral Animal Phenotypes
Neurobehavioral Human Phenotype
Mechanisms
Lactational Alcohol Exposure
Prevention/Intervention Public Health and Behavioral Intervention
Biomarkers of Fetal Exposure to Alcohol
Intervention for Individuals with FAS
Research Opportunity in South Africa
State of Knowledge (Susan J. Astley, Ph.D.) Fetal Alcohol Syndrome (FAS) is a permanent birth-defect syndrome caused by maternal consumption of alcohol during pregnancy. The definition of FAS has changed little since the 1970s (Jones and Smith, 1973; Lemoine et al., 1968) when the condition was first described. The condition has been broadly characterized by prenatal and/or postnatal growth deficiency, a characteristic set of minor facial anomalies, and evidence of prenatal alteration in brain function. In the absence of specific case definitions with objective scales of measurement, diagnoses vary from clinic to clinic. Growth. One of the characteristics of FAS is prenatal and/or postnatal growth deficiency. Prenatal growth deficiency is defined at birth as reduced height and/or weight for gestational age. Postnatal growth deficiency is defined as reduced height and/or weight after control for parental height and postnatal influences. Established norms are used to help define growth retardation. Facial and Other Physical Anomalies. The cluster of minor facial anomalies most specific and sensitive to FAS include small palpebral fissures, a smooth philtrum, and a thin upper lip. Individuals with prenatal alcohol exposure are also at increased risk for other minor and major physical anomalies, including limb anomalies, congenital heart defects, cleft lip and palate, urinary tract defects, and other facial anomalies such as short, upturned nose, epicanthal folds, ptosis and clown eyebrows. These anomalies, individually or collectively, are not specific enough to prenatal alcohol exposure to serve as diagnostic criteria for FAS. Central Nervous System (CNS) Dysfunction. CNS dysfunction is the most disabling and permanent characteristic of FAS. Evidence of organic brain damage of prenatal origin may be detected structurally (e.g., abnormal CT/MRI images, microcephaly), neurologically (e.g., seizure disorders, neurologic disorders, abnormal EEG or PET), and/or functionally (e.g., cognitive/behavioral dysfunction on standardized neuropsychological tests). Maternal Alcohol Consumption. FAS is caused by maternal consumption of alcohol during pregnancy. Many factors influence the teratogenic impact on the fetus, including timing, frequency, and quantity of maternal consumption, maternal alcohol metabolism, and fetal susceptibility. Reliable information on maternal consumption of alcohol throughout pregnancy is rarely available. All prenatal, alcohol-related diagnoses should be accompanied by descriptors of alcohol exposure. Fetal outcome should be judged independent of alcohol exposure to minimize diagnostic bias. Partial Presentations of FAS. Most trained clinicians are able to make the diagnosis of FAS when the deficiencies in growth, facial characteristics, and brain functioning are severe and the alcohol exposure during pregnancy is verifiable and substantial. Most clinical presentations, however, have significant variability, with most characteristics being observed along a continuum. There have been attempts to describe these partial presentations as possible fetal alcohol effects (FAE; Clarren and Smith, 1978), alcohol-related birth defects (ARBD; Sokol and Clarren, 1989), and alcohol-related neurodevelopmental disorders (ARND; IOM, 1996); a history of documented maternal alcohol exposure is necessary. The issue of partial presentation is important and complex because afflicted individuals may be more difficult to classify in an objective and quantifiable manner and be perceived as less impaired. Consequently, such individuals may be at increased risk for inadequate care and at an increased likelihood for developing secondary disabilities. Distinctiveness of Presentation. Although isolated features in many birth-defect syndromes overlap with FAS, the unique combination of growth deficiency, specific facial anomalies, CNS dysfunction, and alcohol exposure differentiates FAS from all other syndromes. Although surveillance efforts to date have failed to provide sufficiently accurate estimates of the incidence/prevalence of FAS, this failure is due largely to variable diagnostic and reporting practices resulting from the absence of specific diagnostic case definitions. Accurate estimates of FAS can be achieved by focusing active surveillance efforts on the feature that is most sensitive and specific to FAS (facial phenotype) and using a specific and objective case definition to measure and reports its presence. Gaps in Knowledge and Research Opportunities There is a need to develop a quantitative, objective method of classifying the entire spectrum of possible consequences of alcohol consumption during pregnancy. The ADiagnostic Guide for FAS and Related Conditions@ by Astley and Clarren (1997) is an example of such an approach. This and other approaches need to be evaluated rigorously and a taxonomy developed that insures accurate comparisons across studies. There is a need to develop classification scales, with consensus criteria, for prenatal alcohol effects on CNS structure and function that are appropriate for different developmental stages. Accurate estimates of the prevalence of FAS and of partial presentations of FAS are needed. These estimates should include older children as well as adults, especially in populations where increased representation might be expected, e.g., learning disabled and attention deficit hyperactivity disorders. Ability to accomplish this goal will depend on the accuracy of diagnosis at various ages. Utilization of consensus criteria are necessary, including separate characterization of growth characteristics, facial anomalies, brain functioning, and extent of alcohol exposure Without the ability to determine prevalence and incidence rates, it will be difficult to determine the magnitude of the problem and the success of prevention efforts. Racial and gender-specific norms at birth for height, weight, and head circumference and how they change with age need to be developed. In lieu of such data, locally determined norms need to be used and stated. Many of the facial anomalies change with age. Racial and gender-specific norms need to be developed. Emphasis should be placed on characteristics that are measurable prenatally or at birth in order to increase the likelihood of early diagnosis and thereby enhance the possibility of early intervention. It is acknowledged that the ability to achieve this goal depends on the accuracy with which one can define/describe characteristics that are specific enough to be useful for diagnosis at these stages. Up to Table of Contents
State of Knowledge (Nancy L. Day, Ph.D.) Outcome is a function of prenatal dose. Reviews of the animal (Schenker et al., 1990) and human (Sampson et al., 1989) literature document that once a detectable level of consequences has been reached, the pattern of alcohol consumption during pregnancy can relate to outcome. In some instances, a dose-response relationship has been observed (Smith et al., 1986), whereas a threshold effect is reported in others (Goldschmidt et al., 1996). Similarly, episodic drinking predicts some relationships and not others (Day et al., 1991). Outcome is a function of developmental stage during prenatal exposure. Alcohol exposure can result in trimester-specific effects as well as duration of exposure effects. For example, maximal rate of growth for height is in the first trimester, for weight it is near the end of the second trimester, and in the third trimester for head circumference (Kliegman and Hulman, 1987). Hence, growth deficits can be related to alcohol exposure at specific times during development. Adverse outcomes in other systems also have been demonstrated to be associated with alcohol exposure at specific times (Day et al., 1994). Duration of exposure also has a decided effect. In general, exposure throughout pregnancy results in a more severe outcome than exposure during only a specific, limited time in pregnancy. In some instances, e.g. growth, alcohol exposure early in pregnancy can be compensated for by subsequent abstinence. Morphological abnormalities that are likely to accompany significant alcohol exposure during the first trimester, however, cannot be compensated for with subsequent abstinence. Outcome is a function of prenatal alcohol exposure and environmental background. Race and age have been shown to predict drinking patterns in women, with Caucasian women drinking more than African-American or Hispanic, and younger women drinking larger amounts. Although these relationships have been observed in drinking behavior during the first trimester, other factors appear to be predictive of subsequent consumption. Women who are still drinking in the third trimester are more likely to be African-American, have more life events, and be using tobacco and illicit drugs (Peindl, 1993). Also, such women are more likely to have poor nutrition, less stable social interactions, and more medical problems during pregnancy. Women who satisfy the criteria of alcohol abuse/dependence are even at greater risk because of the associated medical and social sequelae. Using a diagnosis of FAS rather than extent of drinking during pregnancy results in consistent findings, with the incidence of FAS being higher among African-Americans (Sokol et al., 1986) and in lower socioeconomic classes (Bingol et al., 1987). A particular striking finding is that the incidence of FAS after having a child with FAS is very high (70%; Abel and Sokol, 1987). After birth, the environment can be important in the development of a child. Women who drink heavily and/or are alcoholic are less likely to provide an optimal environment. Moreover, alcohol-exposed, low-income samples are more likely to exhibit significant growth deficits throughout the school years (Coles et al., 1991; Day et al., 1994) than middle-class samples (Streissguth et al., 1981). Gaps in Knowledge and Research Opportunities It is important develop screening instruments, with high sensitivity and specificity, to aid in identification of women who consume alcohol at risk levels during pregnancy. Research should be encouraged to identify similarities and differences between pregnant and nonpregnant women in (1) correlates and predictors of alcohol use and abuse, and (2) responses to treatment and prevention interventions. Such research can help determine to what extent existing and future research on women in general can be applied specifically to the design of prevention and intervention programs for pregnant women drinkers. Emphasis should be placed on identification of sociodemographic variables that are highly correlated with either risky drinking behavior during pregnancy or adverse birth outcomes. It is important to determine protective factors as well as post-birth environmental factors that maximize developmental recovery. It would be useful to determine if a relationship exists between genetic susceptibility to alcoholism and FAS. DESCRIPTION OF EPIDEMIOLOGY PORTFOLIO (Vivian Faden, Ph.D., DBE) There are longitudinal epidemiologic studies of drinking during pregnancy and subsequent outcome that have been ongoing for many years (2 grants for $911,125 in FY96). There are a number of other studies that are relevant to women drinking while pregnant. Studies of women=s drinking in general are important because the populations under study include women of childbearing age (1 grant for $887,180 in FY96). Drinking by adolescent girls is related to later drinking, engaging in risky sexual behavior, and teenage pregnancy (4 grants for $1,238,390 in FY96). In addition, studies of the etiology of drinking and the role that family history plays in the development of alcohol problems are also relevant to drinking, especially heavy drinking, by women during pregnancy (4 grants for $1,971,260 in FY96). Up to Table of Contents
BEHAVIORAL AND NONBEHAVIORAL ANIMAL PHENOTYPES State of Knowledge (Edward P. Riley, Ph.D.) Animal models have played a major role in determining the consequences of prenatal alcohol exposure. The phenotypic similarities between animals and humans have been extraordinary (Driscoll et al., 1990) and enabled critical periods of development and critical doses and patterns of alcohol consumption to be defined. Behavior. Animal models of fetal alcohol exposure have helped to identify alcohol as a prototypical behavioral teratogen. Motor Behavior, Activity, and Exploration - Alcohol exposure results in developmental delays or alterations in activity, exploration, and motor behavior. Although reports of overactivity are common, recent studies indicate that test conditions may influence expression (Mattson et al., 1993). Maternal age has been shown to interact with alcohol exposure and influence pregnancy outcome, and genetic variables can interact with alcohol exposure in determining behavioral outcomes (Melcer et al., 1995). Exposure to alcohol during the early brain growth spurt causes more severe motor deficits than later exposure (Thomas et al., 1996). Spatial Learning, Cognition, and Memory - Effects of prenatal alcohol exposure on measures of attention are not clear. In contrast, alcohol-related deficits in spatial learning have been demonstrated clearly (Blanchard et al., 1987) and can be influenced by age, gender, and developmental timing of alcohol exposure. Perseverative behaviors are more likely if exposure occurs during the latter phase of the third-trimester equivalent (Thomas et al., 1996). Sexual Behavior - Prenatal alcohol exposure appears to interfere with normal sexual differentiation in the male (Hard et al., 1984). Female animals can be partially masculinized or defeminized after prenatal alcohol exposure (McGivern et al., 1995). Pharmacological Challenge and Behavioral Dysfunction - Pharmacologic challenges have demonstrated an altered dopaminergic system following prenatal alcohol exposure, suggestive of an aberrant reward system (Gentry et al., 1995). Central Nervous System (CNS) Structure. Gross reduction in brain weight is the most consistent finding associated with prenatal alcohol exposure (West and Goodlett, 1990). Numerous changes have been described and include changes in generation, migration, and cell death; changes in axons and dendrites; changes in glial cells; and changes in biochemical and electrophysiological properties of neurons (Miller, 1992). Prenatal alcohol exposure results in damage to a number of specific brain regions, with the most thoroughly studied being the cerebellum and hippocampus. Exposure during the brain growth spurt may have greater effects than exposure at other developmental periods. Cerebellum - Animal studies have indicated that the developing cerebellum is particularly sensitive to damage after exposure to alcohol during the third-trimester equivalent. Output neurons of the cerebellum (Purkinje cells) are especially vulnerable, with variable sensitivity across lobules (Goodlett et al., 1990). Reductions in cerebellar granule cells have been reported also following alcohol exposure (Bonthius and West, 1991). Microscopic changes have been reported for orientation of dendritic spines and for altered glial sheaths of Purkinje cells (Smith and Davis, 1990). Hippocampus - The most consistent finding after alcohol exposure is the loss of pyramidal cells in the CA1 field (Bonthius and West, 1990). Changes in neuronal connectivity have been reported also. Sensory Alterations. Visual - A variety of ocular malformations and changes in retinal structure and function have been observed (Sulik et al., 1983). Optic nerve hypoplasia, altered myelin thickness, increased retinal vessel tortuosity, and decreased optic axons have been reported (Stromland and Pinazo-Duran, 1994). Auditory - Prenatal alcohol exposure can damage auditory sensory receptor cells and impair transmission in brainstem auditory pathways (Church et al., 1996). Olfactory - Agenesis, hypoplasia, and morphological defects have been observed in the olfactory bulbs of animals exposed to alcohol (Bonthius and West, 1991; Sulik et al., 1983). Birth Weight and Growth Pattern. Reduced body weight and length and microcephaly are dose related, with the equivalent of second and third trimesters being the most critical periods (Becker et al., 1994). Craniofacial Defects. Animals exposed to alcohol during early organogenesis demonstrate a pattern of craniofacial defects that are similar to those observed in children diagnosed as FAS (Sulik et al., 1981). Skeletal Anomalies. Alcohol exposure during organogenesis can result in skeletal anomalies, especially defects in limbs and digits (Becker et al., 1994). Urogenital Anomalies. Developing kidney and ureter are sensitive to alcohol exposure. Abnormal sexual development has also been reported (Becker et al., 1994). Cardiovascular Anomalies. Malformation of the heart and major vessels can result from alcohol exposure equivalent to weeks 3-4 in humans (Webster, 1989). Neuroendocrine. Prenatal alcohol exposure has been associated with altered neuroendocrine functioning, including hormones involved in sexual differentiation and behavior and stress-related responses (Becker et al., 1994). The effects of alcohol on reproduction, in general, are poorly understood and in need of research. Gaps in Knowledge and Research Opportunities Investigations of brain regions other than the cerebellum and hippocampus would be useful. Defining interrelationships among structure, physiology, and function would be of great value. Additional mechanistic studies of organ systems other than the CNS should be conducted. General descriptive studies in animals will probably have little utility. Studies designed to determine the influence of sensory deficits on functional and behavioral problems would be useful. Up to Table of Contents
NEUROBEHAVIORAL HUMAN PHENOTYPE State of Knowledge (Joseph L. Jacobson, Ph.D. and Edward P. Riley, Ph.D.) Neurobehavioral dysfunction is a cardinal feature of FAS and the most significant aspect of this developmental disability in terms of its impact on the individual and society. CNS Structure. Since few cases of alcohol-induced CNS damage have been studied at autopsy and imaging techniques have only recently been conducted, much of what is known of alcohol=s effects on the developing brain has come from animal studies. However, autopsies of children with FAS show similar findings to those observed in animal models with a wide range of neuropathological changes that are severe and diffuse, including microcephaly, holoprosencephaly, anencephaly, cerebral dysgenesis, hydrocephaly, ventricular abnormalities, agenesis of the corpus callosum and/or anterior commissure, and abnormalities of the basal ganglia, diencephalon, cerebellum, brainstem, optic nerve, and olfactory bulbs (Mattson and Riley, 1996). Quantitative MRI has confirmed alcohol=s neuropathological effects and also demonstrated size reductions in specific brain regions. Cerebellar damage has been among the most frequently reported brain abnormalities in children with FAS and has been documented with MRI (Sowell et al., 1996). The developing corpus callosum also appears to be sensitive to the effects of prenatal alcohol exposure (Riley et al., 1995). Autopsy studies of children with FAS have reported several cases with evidence of damage to the basal ganglia, and MRI studies confirm a reduction in size (Mattson et al., 1996). Current data suggest that the microcephaly typically seen in FAS is not related to a reduction in cortex nor to a reduction in cortical enfolding (Mattson et al., 1992). Sensory. Visual - About 90% of children diagnosed as FAS have ocular abnormalities that may contribute to described visual defects (Stromland, 1987). Anomalies involving the eye or associated structures include, ptosis, epicanthus, and short palpebral fissures. Strabismus and nystagmus have been reported also. Children with FAS suffer from a variety of internal eye alterations, including anterior segment anomalies, such as steep corneal curvature, hyperplastic primary vitreous, and glaucoma. Anomalies in the retina and optic nerve are among the most frequent anomalies observed in FAS children (Stromland, 1990). Auditory - Auditory dysfunction is highly correlated with eye anomalies and is often described in children with FAS (Church and Gerkin, 1988). It has been suggested that auditory event-related potentials (P300) may be useful for identifying FAS children (Kaneko et al., 1996). Olfactory - Prenatal alcohol exposure has been shown to affect the olfactory system as demonstrated by agenesis, hypoplasia, and morphological defects in the olfactory bulbs (Peiffer et al., 1979). Brain Metabolism. Three studies have been conducted, and there does not appear to be consistent findings. Some individuals have decreased cerebral glucose utilization, some have increased utilization, while others have reduced utilization in basal ganglia, cerebellum (Hannigan et al., 1995), and thalamic nuclei (Cambell et al., 1996). Electrophysiology. Nine of 18 FAS children were judged to have borderline or abnormal EEG that was distinctly different from Down syndrome and control children (Kaneko et al., 1996). In a P300 event-related potential study, FAS children also differed from Down syndrome and control children (Kaneko et al., 1996). Neurobehavior. Although the neurobehavioral deficits associated with FAS are devastating, subtler difficulties associated with intermittent heavy drinking during pregnancy among nonalcoholic women are far more prevalent. Attention - Attentional deficits have been reported consistently in studies of FAS children and have been reported also in children with prenatal alcohol exposure who do not satisfy criteria for FAS (Streissguth et al., 1995). Deficits in sustained attention have been reported (Brown et al., 1991) especially when tasks also require the active processing of information (Carmichael Olson et al., 1992). Although deficits have been observed in focussed attention in FAS children, performance was somewhat better than for children with attention-deficit/hyperactivity disorder and the groups had different profiles of deficits (Coles et al., 1997). Intellectual Functioning- Although FAS is often associated with significantly decreased IQ, many perform in the low-average to average range. Moreover, individuals whose mothers drank heavily during pregnancy but only manifest some of the alcohol-related dysmorphic features, also display lower IQ scores than expected (Streissguth et al., 1991). FAS children often exhibit considerable verbal facility (Kodituwakku et al., 1995), with consistent deficits in arithmetic. Deficits in arithmetic have also been found consistently in studies of non-FAS, alcohol-exposed children (Goldschmidt et al., 1996). Learning and Memory - Prenatal alcohol exposure is associated with reduced learning (Martin et al., 1977) and memory capabilities (Streissugth et al., 1989). Memory processes are affected adversely for verbal (Mattson et al., 1996) as well as nonverbal (Uecker and Nadel, 1996) material. Language - FAS case reports suggest the presence of speech and language disturbances (Abel, 1990). Deficits have been documented in word comprehension, naming ability, articulation, and expressive and receptive language skills. Motor and Activity- Most studies suggest an effect of prenatal alcohol exposure on motor development and motor skills. Persistent hyperactivity is commonly observed in FAS children (Steinhausen et al., 1993), even in the absence of intellectual impairment. Some investigators, however, find no evidence of hyperactivity or impulsivity in FAS children and suggest that social and environmental factors may contribute to the presence of hyperactivity (Coles et al., 1997). Executive Functioning - Children with FAS have difficulty with problem solving, cognitive flexibility, planning, and tend to perseverate on incorrect strategies (Kodituwakku et al, 1995; Mattson et al., 1996). Adaptive Behavior - There are few studies on the ability of children prenatally exposed to alcohol to develop adaptive daily living skills. Except in cases of severe mental retardation, ability to deal with structured daily living tasks is generally adequate, but most individuals with FAS exhibit poor judgment and considerable difficulty in organizing their lives (Streissguth et al., 1991). Gaps in Knowledge and Research Opportunities MRI assessment of more brain regions needs to be undertaken, particularly in those regions found to be altered in animal models of FAS. It should be determined whether deficits in specific sensory systems contribute to the functional deficits observed in FAS. Future neuropsychological research should be hypothesis driven, focusing on specific cognitive domains. Brain structure/function studies need to be conducted, utilizing new imaging techniques. The functional significance of alcohol-related neurodevelopmental deficits in FAS and in non-FAS children needs to be determined. It would be useful to determine if physiological alterations due to prenatal alcohol exposure contribute to the functional deficits observed in FAS. Research on adaptive behavior is preliminary and should be developed further and extended to studies of non-FAS, alcohol-exposed children Studies should be conducted to determine relationships between drinking patterns of pregnant women and resulting CNS structure and functional outcome. Up to Table of Contents
MECHANISMS OF DYSFUNCTION RESULTING FROM PRENATAL ALCOHOL EXPOSURE State of Knowledge (Kathleen K. Sulik, Ph.D. and Michael E. Charness, M.D.) It is unlikely that a single mechanism can explain all of the deleterious effects that result from alcohol exposure during pregnancy. Adverse outcomes include embryo lethality, congenital malformations, growth retardation, cognitive deficits, and behavioral abnormalities and are dependent upon species, strain, developmental stage, and dose (Rogers and Daston, 1997). Although alcohol exposure during pre-implantation can have adverse effects (Armant and Saunders, 1996), most research has been focused on post-implantation. Exposure to high peak blood alcohol concentrations (> 200 mg%) during the embryonic period can result in major malformations involving a number of organ systems, including cardiac, urogenital, musculo-skeletal, and CNS (Sulik et al., 1981). Exposure limited to the fetal period results primarily in functional deficits. Because the CNS effects appear to be especially long lasting and debilitating, a significant portion of research has been concentrated on brain malformations as well as cognitive and behavioral abnormalities. For example, alcohol exposure during the equivalent of the first trimester can result in major CNS malformations (Webster et al., 1980) and altered proliferation of neuronal precursor cells (Miller, 1992). Exposure during the equivalent of the second trimester can alter astroglial development (Guerri et al., 1993) and neuronal generation and migration, especially in the cerebral cortex and hippocampus (Miller, 1992). Exposure during the third trimester can alter the structure and function of the cerebellum and overall brain synaptogenesis and dendritic arborization. Pathogenesis includes excessive cell death, reduced cell proliferation, altered cell migration, loss of cell contacts/adhesion, altered cellular differentiation and function, and alterations in neuronal-glial interactions, with variability of outcome depending upon dose, timing, ability to recover, and cellular differences. The mechanistic basis for selective variability in responses of different cell types to alcohol-induced developmental toxicity is of critical significance. Proposed cellular mechanisms include altered membrane fluidity, free radical damage, effects on signaling mediators and other membrane constituents, L1 Cell Adhesion Molecules (L1 CAM), neurotrophic factors, and alcohol-mediated regulation of gene expression. Membrane Fluidity. The potential of alcohol-induced alterations in membrane fluidity should not be dismissed. This possibility is highlighted by the deficiency in cholesterol biosynthesis that can result in the Smith-Lemli-Opitz syndrome, which can be phenotypically similar to FAS. Both diminished cholesterol and high alcohol concentrations can increase membrane fluidity. Free Radical Damage. An excess of free radicals can damage cells because of their ability to initiate chain reactions of peroxidative damage to lipids, proteins, and DNA. Potential sources of increased free radical concentrations include generation during alcohol and acetaldehyde metabolism, mitochondrial damage following increased concentrations of intracellular calcium, and uteroplacental ischemia/reperfusion. Administration of GM1 ganglioside reduces oxygen free radical-induced damage (Mahadik et al., 1993) and diminishes alcohol=s teratogenicity (Hungund et al., 1994). Administration of free radical scavengers also reduces alcohol-induced cell death (Kotch et al., 1995). Signaling Mediators and Other Membrane Constituents. Altered NMDA receptor expression in various brain regions has been observed after alcohol exposure (Pantazis et al., 1993; Valles et al., 1995). Changes in NMDA receptor function may result in altered neuronal migration and in changes in intracellular calcium with concomitant pathophysiology (Hu and Ticku, 1995). Administration of GM1 ganglioside has been shown to protect cells against excessive increases in intracellular free calcium (Manev et al., 1993). Alcohol exposure can inhibit the adhesion/clustering of neuronal cells, consequently interfering with migratory movements as well as cellular interactions required for cell differentiation and viability (Charness et al., 1994). A spectrum of clinical mutations in L1 CAM (Fransen et al., 1996) is similar to those observed in FAS. Moreover, the differential alcohol sensitivity of L1-expressing cell lines may provide insight into why FAS occurs in only a small percentage of women who drink heavily during pregnancy. Neurotrophic Factors. Neurotrophins and other trophic factors have been demonstrated to be important in neural survival and synaptic plasticity (Henderson, 1996). Alcohol may deplete neurotrophic support by decreasing neurotrophic factors or by altering neurotrophic receptors (Valles et al., 1994). Alcohol has been shown to have variable effects on neurite outgrowth and may perturb brain development by enhancing neurite outgrowth in selected brain regions (Messing et al., 1991). Regulation of Gene Expression. Alcohol exposure has been suggested to result in a retinoic acid deficiency and subsequent gene expression abnormality (Deuster, 1991). Alcohol has been shown also to regulate certain genes that may be involved in cellular signal transduction (Miles et al., 1993) which is of importance in neurogenesis, neuronal differentiation, neuronal migration, axon targeting, and synapse formation. Gaps in Knowledge and Research Opportunities Research must keep pace with advances in molecular, cellular, and developmental biology as well as with clinical genetics, especially as the complexities of the human genome are unraveled and alterations linked to dysmorphogenesis. Emphasize new molecular genetics techniques to answer hypothesis-driven questions, including transgenic and gene knockout animals, and in vitro antisense techniques. Viral vectors for gene insertions is also a useful approach. In vitro, molecular characterization of alcohol sensitive versus insensitive cells could provide useful mechanistic information. Determine the mechanisms responsible for the initiation and sequential changes associated with alcohol-induced apoptotic and necrotic cell death. Investigations of the role of alcohol on the complex interactions associated with maternal/fetal biology are important. Up to Table of Contents
State of Knowledge (Julie A. Mennella, Ph.D.) Recent estimates indicate that 60% of infants in the U.S. are breast fed, with approximately 20% continuing for at least 6 months (Ryan, in press). These observations have prompted concern about safety and potential exposure to alcohol excreted into milk (Reider, 1990), especially since one study has indicated that alcohol consumption was not altered by lactational status (Little et al., 1990). However, lactating women who are advised not to drink consume less alcohol than those who receive no advice (Mennella, in press). The amount of alcohol in human milk is less than 2% of the maternal dose, but can alter infant sleeping patterns (Mennella and Beauchamp, 1991). Human infants consume less milk after maternal alcohol consumption, and the mothers are unaware of this (Mennella and Beauchamp, 1993). Although the data are somewhat limited, there is some suggestion that the depression in milk intake by breast-fed infants following maternal alcohol consumption may be due to pharmacological effects on the mother. Information on the effects of alcohol consumption on the composition of milk is limited to animals and suggests alterations in fatty acid profiles (Hungund et al., 1996) and immunological protection (Gottesfeld and LeGrue, 1990). Infants exposed daily to alcohol (at least 1 drink) in their mother=s milk have altered gross motor development (Little et al., 1989). Gaps in Knowledge and Research Opportunities Effects of short-term and long-term exposure to small amounts of alcohol on the infants= behavioral state, ontogeny of biological rhythms, development, and mother-infant interactions need to be studied. Little is known about the effects of alcohol consumption on the endocrine system in lactating women and their offspring. Effects of alcohol consumption on milk yield and composition (e.g., nutrients, metabolites, and immune factors) need to be delineated. Relationship between exposure to alcohol in breast-feeding infants and subsequent alcohol drinking behavior is largely unknown. Little is known on information medical professionals give to lactating women and parents= about lactation and alcohol use. Up to Table of Contents
DESCRIPTION OF BASIC RESEARCH PORTFOLIO (Laurie Foudin, Ph.D., DBR) Approximately 88% of the fetal alcohol grant portfolio is administered by the Division of Basic Research, reflecting that most of the portfolio is comprised of animal and in vitro studies addressing primarily mechanisms of teratogenesis and structural/temporal vulnerability of brain and associated behaviors. FAS Phenotype. Animal Behavior Studies - The field has moved away from descriptive studies that merely catalogue FAS deficits. Two largely descriptive behavioral grants are designed to examine altered offspring behavior resulting from combined exposure to alcohol and cocaine or prenatal stress. The study on prenatal stress is particularly significant because it is the only one in the portfolio using primates, and low-level alcohol exposure will be assessed. Another behavioral grant is following up on the observation that paternal alcohol consumption results in behavioral and endocrinological abnormalities, as well as altered drug sensitivity, in male offspring; this is the only funded research on paternal alcohol effects. Eight of the 11 animal behavioral studies attempt to elucidate the underlying neurobiological pathology that leads to altered behavior. These behaviors include aspects of learning and memory, stress responsiveness, motor function, sexually dimorphic behaviors, and circadian rhythms. Several studies correlate neuroanatomical and/or neurochemical changes in prefrontal cortex, hippocampus, and cerebellum with altered behaviors mediated by these brain regions. Human Studies - Two human longitudinal prospective studies are designed to characterize prenatal effects of alcohol on growth and neurobehavioral and cognitive functioning at different developmental stages and over a wide range of doses. One goal of these studies is to assess the contribution of alcohol exposure to the phenotype relative to other environmental variables. Another goal is to determine which deficits are developmental delays and which are permanent and what is the impact of the observed deficits on long-term psychopathology, neurocognitive functioning, social functioning, and academic achievement. Two clinical studies of FAS use MRI and electrophysiological techniques to evaluate structural and functional alterations that may relate to altered performance on specific neuropsychological tests. Treatment Research - The fetal alcohol research center has been exploring the possibility of manipulating the postnatal environment to ameliorate alcohol-related neurobehavioral deficits. Another study is examining whether specific motor-skill training will have therapeutic effects on altered cerebellar motor performance. Mechanisms of Teratogenesis. Pharmacology - Four grants are investigating dose threshold and specific periods of vulnerability; there appears to be relatively narrow time periods during gestation when alcohol exposure results in specific effects. Types of Mechanisms - The FY96 portfolio contains approximately 45 grants that focus on cellular and molecular mechanisms of teratogenesis. This shift to more mechanistic studies is due, in part, to increased understanding of biochemical events that mediate normal embryogenesis and fetal development. As a result, several potential molecular targets for alcohol-induced teratogenesis have been identified: global mechanisms, craniofacial dysmorphology, growth retardation, neuroteratogenesis, and other organ system teratogenesis. Studies on global mechanisms, defined as those that can explain effects on multiple organ systems, include the induction of hypoxia and oxidative stress, placental dysfunction, impaired fuel utilization, and altered retinoic acid homeostasis. Altered cellular signal transduction can be considered another global mechanism; however, for the most part, these projects focus on signaling pathways involved in the regulation of discrete cellular processes such as craniofacial tissue differentiation, cellular proliferation (growth retardation), neurogenesis, and development of the immune system. Nearly half of the mechanistic grants are devoted to some aspect of neuroteratogenesis. Hypotheses to explain perturbations of neuronal proliferation, cell survival and programmed cell death, cellular migration, and neurite outgrowth are being investigated; many of these projects are examining signal transduction pathways. In some studies, the results of manipulation with agonists and/or antagonists have suggested possible pharmacological interventions. Evidence from clinical case reports and from basic research on adult animals has stimulated several grants on development of the immune system. Some of these studies also serve as models for alcohol=s effects on cellular processes such as apoptosis. Other developmental systems being studied are the heart and reproductive systems. Lactational Alcohol Exposure - Alcohol exposure via breast milk has been associated with mild motor deficits. Two studies are examining alcohol-induced alterations in behavioral and physiological parameters, and the other is examining transfer of immunity to neonates via the mother=s milk. Summary of FY96 FAS Grants on Phenotype and mechanisms of Teratogenesis
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PUBLIC HEALTH AND BEHAVIORAL INTERVENTIONS State of Knowledge (Philip A. May, Ph.D.) Relatively little has been published on the social and psychological influences on heavy drinking during pregnancy. FAS prevention efforts have not been based on existing knowledge about health promotion and education, and little attention has been focused on characteristics of the group targeted for intervention (Waterson and Murray-Lyon, 1990). Finkelstein (1993) reviewed the literature on FAS prevention in treatment programs for alcohol and drug-dependent women and concluded that case management within a program that provided comprehensive, coordinated, and holistic treatment provided the best results. A comprehensive public health approach to prevention of FAS has been described (May, 1995). This approach based primary prevention efforts on the epidemiology of FAS and adult drinking patterns in a specified population. Secondary prevention related to early detection of drinking mothers and other women of child-bearing age and prompt and effective intervention to prevent FAS. Early detection was based, in part, on the presence of maternal risk factors: age > 25 years of age, parity, high quantity and frequency of drinking, a heavy drinking (male) partner, a family of origin with a substantial drinking history, low socioeconomic status, social/cultural patterns of heavy alcohol consumption within the woman=s reference group, length of drinking history, social mobility, sexual dysfunction, having never married or separated or divorced status, and a pattern of polysubstance abuse and cigarette use (May, 1995). Tertiary prevention was directed at women who had already produced a child with FAS characteristics. The Institute of Medicine (IOM; 1996) also recommended a comprehensive approach similar to that proposed by May (1995) and stressed research that included an evaluation of efforts. A rigorous review of the literature on techniques to reduce alcohol consumption during pregnancy (Schorling, 1993) revealed few studies with minimal scientific acumen and none that used a randomized design. Only two studies used a control group, and no between-group differences were observed. The area of FAS prevention and intervention is one in which basic methodological research designs have not been used. Current primary or universal prevention efforts, including the labeling of alcoholic beverages (Hankin et al., 1996), have been shown to be ineffective in changing the drinking behavior of pregnant women who have been heavy drinkers for long periods of time (Pascoe et al., 1995). Relatively few late-stage interventions have been described and evaluated. Gaps in Knowledge and Research Opportunities Active case ascertainment and surveillance should be emphasized, especially in contained and targeted small communities, because these procedures provide the most accurate information. Randomized clinical trials, including control conditions, should be conducted to test the efficacy of alcohol and family planning interventions for women at high risk for producing children with prenatal alcohol damage. Effective prevention initiatives for women who are moderate to heavy drinkers and have already given birth to an alcohol-damaged child need to be designed and evaluated according to acceptable scientific standards. Such studies should also identify barriers to access of care/intervention services. A cost/benefit analysis for prevention of prenatal alcohol damage, including the reduced costs to social/health care systems by early and accurate identification, would be useful. Control studies of the treatment of heavy-drinking women that randomize the use of techniques to influence both the targeted women and the male partners should be undertaken. A comprehensive, community-based study of FAS prevention should be undertaken, utilizing a pretest/posttest evaluation design with appropriate controls. Up to Table of Contents
BIOMARKERS OF FETAL EXPOSURE TO ALCOHOL State of Knowledge (Cynthia F. Bearer, M.D., Ph.D.) A biological marker for alcohol exposure during pregnancy could lead to earlier identification and intervention for affected infants, identification of women who consume excessive amounts of alcohol, identification of maternal under reporting of alcohol use, and improved understanding of dose-response relationships between alcohol exposure and alcohol-related birth defects (IOM, 1996). Although the relative number of women who drink heavily during pregnancy is small, the absolute number is large. The CDC (1994) reported that 0.3% of pregnant women consume > 60 drinks and 1.3% consume > 5 drinks on one occasion during the preceding month. Determination of alcohol use during pregnancy is one way to identify infants at risk for alcohol-related problems. Unfortunately, under reporting of alcohol consumption by pregnant women is known to occur (Ernhart et al., 1988) and responses on self-report questionnaires (Russell et al., 1994) can be inaccurate. Consequently, sensitive and specific biomarkers for alcohol consumption at the levels of > 2 drinks per day by pregnant women would be of great value. Possible sources of biomarkers include blood, saliva, hair, breath, and urine. Pregnant Women. Alcohol and Related Metabolites - Measurement of acute alcohol and its metabolite acetaldehyde are of limited use because of short half life. Ethyl glucuronide, cocaethylene, and fatty acid ethyl esters (FAEE) have been detected in the serum of women who consume alcohol but are yet to be demonstrated to be useful in pregnant women who consume alcohol. Induction of Enzymes which Metabolize Alcohol - Cytochrome P450 2E1, catalase, and fatty acid ethyl ester synthase may be useful, but insufficient research has been conducted in pregnant women who consume alcohol. Product of Interaction of Alcohol Metabolites and Cellular Components - Acetaldehyde-protein adducts and oxidation products have been detected in chronic alcoholics, but there has been insufficient research to determine their levels in pregnant women who consume alcohol. Alteration of Target Proteins - Although carbohydrate deficient transferrin (CDT) can be used to detect recent excessive alcohol consumption (Allen et al., 1994), there is concern whether female alcohol abuse can be detected (Lof et al., 1994). Moreover, CDT levels may vary according to the week of pregnancy (Stauber et al., 1996). Gamma glutamyltransferase, urinary dolichols, and other proteins appear to be unlikely markers of maternal alcohol exposure. Alcohol-Exposed Infants. FAEE have been detected in cord blood (Bearer et al., 1992) and meconium (Mac et al., 1994) from newborns delivered to alcoholics. FAEE is present also in meconium of infants born to nonalcoholics (Bearer et al., 1996) and is associated with maternal reports of alcohol consumption (Bearer et al., 1997). Meconium is metabolically inert and accumulates over the last 20-27 weeks of gestation. CDT has been detected in cord blood but has not been studied as a biomarker of fetal exposure to alcohol. Evaluation of serum proteins revealed 8 proteins with significant concentration differences between FAS children and controls (Robinson et al., 1995). A panel of 4 proteins was required to differentiate all those diagnosed as FAS from controls. It is unclear whether alcohol-exposed newborns without growth deficiencies will have alterations in serum proteins. Elevations in urinary dolichols have been reported in infants with FAS or characteristics of alcohol-related birth defects (Wisniewski et al., 1983).
Gaps in Knowledge and Research Opportunities Currently, there are no valid biomarkers for detection of maternal alcohol use at levels > 2 drinks per day or of fetal alcohol exposure that are useful for diagnostic purposes. Consequently, there needs to be more biomarker studies conducted in alcohol-exposed pregnant women and newborns. Studies of biomarkers should initially focus on samples that can be obtained noninvasively and are acceptable to the general public, such as maternal blood, urine, breath, saliva, and hair, and newborn umbilical cord blood, placenta, meconium, hair, breath, saliva, and urine. Biomarkers of low exposure to alcohol are of particular importance. Biomarkers that can document timing of exposure are desirable. Animal models should be used to develop dose-response relationships between biomarker and consequences. Up to Table of Contents
INTERVENTIONS FOR INDIVIDUALS WITH FAS State of Knowledge (Ken C. Winters, Ph.D.) Intervention efforts for newborns and infants who are diagnosed with FAS is defined as Atertiary@ or Aindicated@ (IOM, 1996) prevention. Intervention is directed primarily at preventing or minimizing CNS impairment and is possible because the CNS effects of prenatal alcohol exposure appear to be more significant later in the child=s development because of (1) time course of cognitive and motor development; (2) cumulative effects of the interaction of alcohol=s teratogenic effects and disruptive and impoverished environments; and/or (3) type of neurological damage associated with prenatal alcohol exposure (Coles and Platzman, 1992; Streissguth et al., 1993). Unfortunately, there are few, well-designed developmental studies of FAS with respect to intervention. Even though animal and human studies suggest that prenatal alcohol exposure can alter the structure and function of specific areas of the brain (Mattson et al., 1992), widespread observations indicate that the psychosocial environments of many individuals with FAS are inadequate, impoverished, and perhaps dysfunctional and consequently, may adversely affect cognitive processes independently or interactively (Nadel, 1985). These complexities contribute to the question of specificity of FAS symptoms and problems. While many individuals with FAS share similar behavior problems that are attributable to alcohol-related brain dysfunction, many of these behaviors are not easily distinguishable from impairments shown by individuals who are either mentally retarded, have specific learning disabilities, meet diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), or have been reared in dysfunctional families (Smith and Eckardt, 1991). In a noteworthy exception, Coles and colleagues (1994) observed differences in certain measures of attention between FAS and ADHD children of the same age and social status. Individual or environmental characteristics that protect or mitigate undesirable cognitive and behavioral outcomes in FAS have not been studied. The disruptive behavioral problems associated with FAS may be related, in part, to cognitive and neurobehavioral deficits. There is a range of potentially effective interventions for the FAS child that can be cataloged along a developmental continuum (IOM, 1996). For example, infants with FAS would likely benefit from developmental screening and early interventions; education interventions are appropriate for preschool and school-age children with FAS, and social-skills training and symptom-specific treatment are relevant for adolescents afflicted with FAS. Although the literature indicates that these interventions have been applied with varying degrees of intensity, little outcome data have been published to determine their effectiveness, and controlled studies with rigorous study designs are not existent. Animal models of FAS have proven useful in demonstrating that complex motor training im- proves alcohol-related deficits in fine motor and muscular coordination (Klinstova et al., 1997). Animal models of FAS are being used also to investigate pharmacological intervention, with mixed results (Hannigan et al., 1993). Gaps in Knowledge and Research Opportunities Developmental characteristics of FAS, through adulthood, need to be described, including variability in course and outcome; relationships with environmental factors such as social class and family functioning should be delineated. Similarities and differences in neurodevelopmental/behavioral characteristics among FAS, ADHD, and offspring of alcoholics should be determined. Beneficial effects of protective and intervention factors, especially education, forced enrichment, and others demonstrated to be of importance from studies of ADHD and in youth drug-use field, need to be determined, using random assignment and appropriate controls. Animal models of FAS offer the ability to identify potential behavioral and pharmacological interventions for children with FAS. Such models have a unique ability to clarify the underlying neurobiological mechanisms of various interventions. Behavioral management strategies for parents and teachers have been systematically applied to hundreds of developmentally disabled children, such as youth with autism, ADHD, and other mental disabilities. A scientific literature for children with FAS needs to be developed taking into consideration strategies already proven useful in related conditions. Psychopharmacological interventions have not received sufficient attention and should be studied, as well as in combination with behavioral, educational, and other interventions. These studies should use random assignment and appropriate controls. Up to Table of Contents
DESCRIPTION OF PREVENTION/INTERVENTION PORTFOLIO (Jan Howard, Ph.D., DCPR) There are three grants that relate to prevention of FAS for a total of $626,381 in FY96. One of these projects is investigating the utility of questionnaires in identifying alcohol-abusing pregnant women, and the others are designed to determine the population-based prevalence of FAS and characteristics of adult alcohol consumption in four American Indian communities. There are also components of two center grants that have been investigating the effects of warning labels and other health messages on the risks of consuming alcoholic beverages during pregnancy.
RESEARCH OPPORTUNITIES IN SOUTH AFRICA In September, 1996, an exploratory site visit was conducted in order to determine the feasibility of establishing collaborations with South African researchers to study a reported high incidence of FAS. An exceptionally high incidence of FAS (15% in some areas) was observed in relatively homogeneous populations wherein alcohol consumption has become such an integral part of the culture that there appears to be little stigma attached to drinking during pregnancy. Consequently, research with these populations provides a potentially unique opportunity to study FAS, including ethnographic studies of prevention and intervention. Up to Table of Contents
Abel EI: Fetal Alcohol Syndrome, Medical Economics, Oradell, NJ, 1990. Abel E, Sokol R: Incidence of fetal alcohol syndrome and economic impact of FAS-related anomalies. Drug Alcohol Depend 19: 51-70, 1987. Allen JP, et.al.: Carbohydrate-deficient transferrin as a measure of immoderate drinking: Remaining issues. Alcohol: Clin Exp Res 18: 799-812, 1994. Armant DR, Saunders DE: Exposure of embryonic cells to alcohol: Contrasting effects during preimplantation and postimplantation development. Sem Perinatology 20: 127-139, 1996. Astley SJ, Clarren SK: Diagnostic Guide for Fetal Alcohol Syndrome and Related Conditions. University of Washington, Seattle, 1997. Bearer CF, et.al.: Fatty acid ethyl esters in peripheral blood. Pediatr Res 31: 68A, 1992. Bearer CF, et.al.: FAEE: Biomarker for prenatal alcohol use. Alcohol: Clin Exp Res 20: 139A, 1996. Bearer CF, et.al.: Meconium FAEE and maternal ethanol use. Alcohol: Clin Exp Res 21: 119A, 1997. Becker HC, et.al.: Animal research: Charting the course for FAS. Alcohol Health Res World 18: 10-16, 1994. Bingol N, et.al.: The influence of socioeconomic factors on the occurrence of fetal alcohol syndrome. Adv J Alcohol Subst Abuse 6: 105-118, 1987. Blanchard BA, et.al.: Deficits on a spatial navigation task following prenatal exposure to ethanol. Neurotoxicol Teratology 9: 253-258, 1987. Bonthius DJ, West JR: Alcohol-induced neuronal loss in developing rats: Increased brain damage with binge exposure: Alcohol: Clin Exp Res 14: 107-118, 1990. Bonthius DJ, West JR: Permanent neuronal deficits in rats exposed to alcohol during the brain growth spurt. Teratology 44: 147-163, 1991. Brown RT, et.al.: Effects of prenatal alcohol exposure at school age. II. Attention and behavior. Neurotoxicol Teratology 13: 369-376, 1991. Cambell C, et.al.: Functional metabolic integrity of the brain in FAS. Alcohol: Clin Exp Res 20 (Suppl.): 32A, 1996. Carmichael Olson H: Neuropsychological deficits and life adjustment in adolescents and young adults with fetal alcohol syndrome. Alcohol: Clin Exp Res 16: 380, 1992. Charness M, et.al.: Ethanol inhibits neural cell-cell adhesion. J Biol Chem 269: 9304-9309, 1994. Church MW, et. al.: Effects of prenatal alcohol exposure and aging on auditory function in the rat: Preliminary results. Alcohol: Clin Exp Res 20: 172-179, 1996. Church MW, Gerkin KP: Hearing disorders in children with fetal alcohol syndrome: Findings from case reports. Pediatrics 82: 147-154, 1988. Clarren SK, Smith DW: The fetal alcohol syndrome. New Eng J Med 298: 1063-1067, 1978. Coles CD, et.al.: Effects of prenatal alcohol exposure at school age: I. Physical and cognitive development. Neurotoxicol Teratology 13: 1-11, 1991. Coles CD, et.al.: A comparison of information processing in children with fetal alcohol effects and attention deficit disorder. 18: 503, 1994. Coles CD, Platzman KA: Fetal alcohol effects in preschool children: Research, prevention, and intervention. OSAP Technical Manual, Drug Exposed Children, Ages 2-5:Identifying their Needs and Planning for Early Intervention. Office of Substance Abuse Prevention, Rockville, MD, 1992. Coles CD, et.al.: A comparison of children affected by prenatal alcohol exposure and attention deficit, hyperactivity disorder. Alcohol: Clin Exp Res 20: 150-161, 1997. Day N, et.al.: The effects of prenatal alcohol use on the growth of children at three years of age. Alcohol: Clin Exp Res 15: 67-71, 1991. Day N, et.al.: Alcohol, marijuana and tobacco: The effects of prenatal exposure on offspring growth and morphology at age six. Alcohol: Clin Exp Res 18: 786-794, 1994. Deuster G: A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol: Clin Exp Res 15: 568-572, 1991. Driscoll CD, et.al.: Prenatal alcohol exposure: Comparability of effects in humans and animal models. Neurotoxicol Teratology 12: 231-237, 1990. Ernhart CB, et.al.: Under reporting of alcohol use in pregnancy. Alcohol: Clin Exp Res 12: 506-511, 1988. Finkelstein W: Treatment programming for alcohol and drug dependent pregnant women. Int J Addict 28: 1275-1309, 1993. Fransen E, et.al.: The clinical spectrum of mutations in L1, a neural cell adhesion molecule. Am J Med Genetics 64: 73-77, 1996. Gentry G, et.al.: Effects of prenatal maternal ethanol on male offspring progressive-ratio performance and response to amphetamine. Neurotoxicol Teratology 17: 673-677, 1995. Goldschmidt L, et.al.: Prenatal alcohol exposure and academic achievement at age six: A nonlinear fit. Alcohol: Clin Exp Res 20: 763-770, 1996. Goodlett CR, et.al.: A single day of alcohol exposure during the brain growth spurt induces brain weight restriction and Purkinje cell loss. Alcohol 7: 107-114, 1990. Gottsfeld A, LeGrue SJ: Lactational alcohol exposure elicits long-term immune deficits and increased noradrenergic synaptic transmission in lymphoid organs. Life Sci 47: 457-465, 1990. Guerri C, et.al.: Derangement of astrogliogenesis as a possible mechanism involved in alcohol-induced alterations of central nervous system development. Alcohol Alcoholism Supp 12: 203-208, 1993. Hankin JR, et.al.: Heeding the alcoholic beverage warning label during pregnancy: Multiparae versus nulliparae. J Stud Alcohol 57: 171-177, 1996. Hannigan JH, et.al.: Environmental enrichment and the behavioral effects of prenatal exposure to alcohol in rats. Neurotoxicol Teratology 15: 261-266, 1993. Hannigan JH, et.al.: Brain metabolism in children with fetal alcohol syndrome (FAS): A positron emission tomography study. Alcohol: Clin Exp Res 19 (Suppl): 53A, 1995. Hard E, et.al.: Development of sexual behavior in prenatally ethanol-exposed rats. Drug Alcohol Dep 14: 51-61, 1984. Henderson CE: Role of neurotrophic factors in neuronal development. Curr Opin Neurobiol 6: 64-70, 1996. Hu XJ, Ticku MJ: Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons. Mol Brain Res 30: 347-356, 1995. Hungund BL, et.al.: Ganglioside GM1 reduces fetal alcohol effects in rat pups exposed to ethanol in utero. Alcohol: Clin Exp Res 18: 1248-1251, 1994. Hungund BL, et.al.: Maternal alcohol abuse and milk lipid composition. Alcohol: Clin Exp Res 20: 120A, 1996. Institute of Medicine (IOM): Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment, Stratton K, Howe C, Battaglia F (Eds.), National Academy Press, Washington DC, 1996. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 2: 999-1001, 1973. Kaneko WM, et.al.: Auditory event-related potentials in fetal alcohol syndrome and Down=s syndrome children. Alcohol: Clin Exp Res 20: 35-42, 1996. Kliegman R, Hulman S; Intrauterine growth retardation: Determinants of aberrant fetal growth, in Neonatal-Perinatal Medicine. Diseases of the Fetus and Infant (Fourth Ed.), Fanaroff A, Martin R (Eds.), CV Mosby Co., St. Louis MO, 1987. Klintsova AY, et.al.: Therapeutic motor training increases parallel fiber synapse number per Purkinje neuron in cerebellar cortex of rats given postnatal binge alcohol exposure: Preliminary report. Alcohol: Clin Exp Res 21:1257-1263, 1997. Kodituwakku PW, et.al.: Specific impairments in self-regulation in children exposed to alcohol prenatally. Alcohol: Clin Exp Res 19:1558-1564, 1995. Kotch LE, et.al.: Ethanol-induced teratogenesis: Free radical damage as a possible mechanism. Teratology 52: 128-136, 1995. Lemoine P, et.al.: Les enfants des parents alcooliques: Anomalies observees apropos de 127 cas. Ouest Med 21 476-482, 1968. Little RE: Maternal use of alcohol and breast-fed infants - Reply. New Eng J Med 322: 339, 1990. Little RE, et.al.: Maternal alcohol use during breast feeding and infant mental and motor development at one year. New Eng J Med 321: 425-430, 1989. Lof K, et.al.: Carbohydrate deficient transferrin as an alcohol marker among female heavy drinkers: A population-based study. Alcohol: Clin Exp Res 18: 889-894, 1994. Mac E, et.al.: A marker of fetal exposure to alcohol by meconium analysis. Pediatr Res 35: 238A, 1994. McGivern R, et.al.: Loss of reproductive competence at an earlier age in female rats exposed prenatally to ethanol. Alcohol: Clin Exp Res 19: 427-433, 1995. Mahadik SP, et.al.: Monosialoganglioside (GM1) restores membrane fatty acid levels in ischemic tissue after cortical focal ischemia in rat. Neurochem Int 23: 163-172, 1993. Manev H, et.al.: Protection by gangliosides against glutamate excitotoxicity. Adv Lipid Res 25: 269-288, 1993. Martin J, et.al.: Maternal alcohol ingestion and cigarette smoking and their effects on newborn conditioning. Alcohol: Clin Exp Res 1: 243-247, 1977. Mattson SN, Riley EP: Brain anomalies in fetal alcohol syndrome, in Fetal Alcohol Syndrome: From Mechanisms to Prevention, Abel EI (Ed.), CRC Press, Boca Raton, FL, 1996. Mattson SN, et.al.: Fetal alcohol syndrome: A case report of neuropsychological, MRI, and EEG assessment of two children. Alcohol: Clin Exp Res 16: 1001-1003, 1992. Mattson SN, et.al.: The behavioral teratogenicity of alcohol is not affected by pretreatment with aspirin. Alcohol 10: 51-57, 1993. Mattson SN, et.al.: Verbal learning and memory in children with fetal alcohol syndrome. Alcohol: Clin Exp Res 20: 810-816, 1996. Mattson SN, et.al.: A decrease in the size of the basal ganglia in children with fetal alcohol syndrome. Alcohol: Clin Exp Res 20: 1088-1093, 1996. May PA: A multi-level comprehensive approach to the prevention of Fetal Alcohol Syndrome (FAS) and other alcohol-related birth defects (ARBD). Int J Addict 30: 1549-1602, 1995. Melcer T, et.al.: Neonatal alcohol exposure and early development of motor skills in alcohol preferring and nonpreferring rats. Neurotoxicol Teratology 17: 103-110, 1995. Mennella JA, Beauchamp GK: The transfer of alcohol to human milk: Effects on flavor and the infant=s behavior. New Eng J Med 325: 8-13, 1991. Mennella JA, Beauchamp GK: Beer, breast feeding and folklore. Develop Psychobiol 26: 459-466, 1993. Messing RO, et.al.: Ethanol enhances growth factor-induced neurite formation in PC12 cells. Brain Res 565: 301-311, 1991. Miles MF, et.al.: Phosducin-like protein - an ethanol-responsive potential modulator of guanine nucleotide-binding protein function. Proc Nat Acad Sci USA 90: 10831-10835, 1993. Miller MW: Effects of prenatal exposure to ethanol on cell proliferation and neuronal migration, in Development of the Central Nervous System: Effects of Alcohol and Opiates, Miller MW (Ed.), Wiley-Liss, New York, 1992. Nadel M: Offspring with fetal alcohol effects: Identification and intervention. Alcohol Treat Quart 2: 105-116, 1985. Pantazis NJ, et.al.: NMDA prevents alcohol-induced neuronal cell death of cerebellar granule cells in culture. Alcohol: Clin Exp Res 19: 846-853, 1995. Pascoe JM, et.al.: Correlates of multigravida women=s binge drinking during pregnancy. Arch Pediatric Adolesc Med 149: 1325-1329, 1995. Peiffer JF, et.al.: Alcohol embryo- and fetopathy: Neuropathology of 3 children and 3 fetuses. J Neurol Sci 41: 125-137, 1979. Peindl K: Correlates and Predictors of Drinking Patterns. Dissertation. Submitted to the Department of Epidemiology, University of Pittsburgh, 1993. Reider MJ: Drugs and breast-feeding, in Maternal-Fetal Toxicology: A Clinician=s Guide, Koren G (Ed.), Marcel Dekker, Inc., New York, 1990. Riley EP, et.al.: Abnormalities of the corpus callosum in children exposed to alcohol prenatally. Alcohol: Clin Exp Res 19: 1198-1202, 1995. Robinson MK, et.al.: Two-dimensional protein electrophoresis and multiple hypothesis testing to detect potential serum protein biomarkers in children with fetal alcohol syndrome. Electrophoresis 16: 1176-1183, 1995. Rogers JM, Daston GP: Alcohols: ethanol and methanol, in Drug Toxicity in Embryonic Development, Kavlock RJ, Daston GP (Eds.), Springer, New York, 1997. Russell M, et.al.: Screening for pregnancy risk-drinking. Alcohol: Clin Exp Res 18:1156-1161, 1994. Ryan, AS: The resurgence of breast-feeding in the United States. Pediatrics, in press. Sampson P, et.al.: Neurobehavioral effects of prenatal alcohol: Part II. Partial least squares analysis. Neurotoxicol Teratology 11: 477-501, 1989. Schenker S, et.al.: Fetal alcohol syndrome: Current status of pathogenesis. Alcohol: Clin Exp Res 14: 635-647, 1990. Schorling JB: The prevention of prenatal alcohol use: A critical analysis of intervention studies. J Stud Alcohol 54: 261-267, 1993. Smith DE, Davies DL: Effect of perinatal administration of ethanol on the CA1 pyramidal cell of the hippocampus and Purkinje cell of the cerebellum: An ultrastructural survey. J Neurocytol 19: 708-717, 1990. Smith I, et.al.: The effect of volume and duration of exposure on neonatal physical and behavioral development. Neurobehav Toxicol Teratology 8: 375-381, 1986. Smith KJ, Eckardt MJ: The effects of prenatal alcohol on the central nervous system, in Recent Developments in Alcoholism. Volume Nine: Children of Alcoholics, Galanter M (Ed.), Plenum Press, New York, 1991. Sokol R, et.al.: Significant determinants of susceptibility to alcohol teratogenicity. Ann NY Acad Sci 477: 87-102, 1986. Sokol RJ, Clarren SK: Guidelines for use of terminology describing the impact of prenatal alcohol on the offspring. Alcohol: Clin Exp Res 13: 597-598, 1989. Sowell ER, et.al.: Abnormal development of the cerebellar vermis in children prenatally exposed to alcohol. Size reduction in lobules I-V. Alcohol: Clin Exp Res 20: 31-34, 1996. Stauber RE, et.al.: Increased carbohydrate-deficient transferrin during pregnancy: Relation to sex hormones. Alcohol Alcoholism 31: 389-392, 1996. Steinhausen H-C, et.al.: Long-term psychopathological and cognitive outcome of children with fetal alcohol syndrome. J Amer Acad Child Adol Psychiatry 32: 990-994, 1993. Streissguth AP, et.al.: The Seattle Longitudinal Prospective Study on alcohol and pregnancy. Neurobehav Toxicol Teratology 3: 223-233, 1981. Streissguth AP, et.al.: Neurobehavioral effects of prenatal alcohol. Part III. PLS analyses of neuropsychologic tests. Neurotoxicol Teratology 11: 493-507, 1989. Streissguth A, et.al.: Fetal Alcohol Syndrome in adolescents and adults. JAMA 265: 1961-1967, 1991. Streissguth AP, et.al.: The Enduring Effects of Prenatal Alcohol Exposure on Child Development: Birth Through Seven Years, a Partial Least Squares Solution. University of Michigan Press, Ann Arbor, MI, 1993. Streissguth AP, et.al.: Attention: Prenatal alcohol and continuities of vigilance and attentional problems from 4 through 14 years. Develop Psychopath 7: 419-446, 1995. Stromland K: Ocular involvement in the fetal alcohol syndrome. Survey Ophthal 31: 277-284, 1987. Stromland K: Contribution of ocular examination to the diagnosis of foetal alcohol syndrome in mentally retarded children. J Ment Deficiency Res 34: 429-435, 1990. Stromland K, Pinazo-Duran MD: Optic nerve hypoplasia: Comparative effects in children and rats exposed to alcohol during pregnancy. Teratology 50: 110-111, 1994. Sulik KK, et.al.: Fetal alcohol syndrome: Embryogenesis in a mouse model. Science 214: 936-938, 1981. Sulik KK, et.al.: Eye malformations following acute maternal ethanol exposure in an animal model for the fetal alcohol syndrome. Invest Ophthal Vis Sci 24: 283, 1983. Thomas JD, et.al.: Behavioral deficits induced by bingelike exposure to alcohol in neonatal rats: Importance of developmental timing and number of episodes. Dev Psychobiol 29: 433-452, 1996. Uecker A, Nadel L: Spatial locations gone awry: Object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychol 34: 209-233, 1996. Valles S, et.al.: Prenatal exposure to ethanol induces changes in the nerve growth factor and its receptor in proliferating astrocytes in primary culture. Brain Res 656: 281-286, 1994. Valles S, et.al.: Alcohol exposure during brain development reduces 3H-MK-801 binding and enhances metabotropic-glutamate receptor-stimulated phosphoinositide hydrolysis in rat hippocampus. Life Sci 56: 1373-1383, 1995. Watterson EJ, Murray-Lyon IM: Preventing alcohol-related birth damage: A review. Soc Sci Med 30: 349-364, 1990. Webster WS: Alcohol as a teratogen: A teratological perspective of the fetal alcohol syndrome, in Human Metabolism of Alcohol. Volume I: Pharmacokinetics, Medicolegal Aspects, and General Interests, Crow KE, Batt RD (Eds.), CRC Press, Boca Raton, FL, 1989. Webster WS, et.al.: Teratogenesis after acute alcohol exposure in inbred and outbred mice. Neurobehav Toxicol 2: 227-234, 1980. West JR, Goodlett CR: Teratogenic effects of alcohol on brain development. Ann Med 22: 319-325, 1990. Wisniewski KE, et.al.: Increased urinary dolichol in newborns whose mothers were heavy alcohol users. Ann Neurol 14: 382, 1983. Up to Table of Contents
Subcommittee for Review of FAS Portfolio Co-Chairs M. W. Perrine, Ph.D. Carrie L. Randall, Ph.D. Experts in Alcohol-Related Areas Frederick Beauvais, Ph.D. Charles R. Goodlett, Ph.D. Joan Hamilton Joanne Weinberg, Ph.D. Sharon C. Wilsnack, Ph.D. Migs Woodside Experts in Non-Alcohol-Related Areas Brigid L.M. Hogan, Ph.D. William E. Pelham, Jr., Ph.D.
Experts in FAS Susan J. Astley, Ph.D. Cynthia F. Bearer, M.D., Ph.D. Michael E. Charness, M.D. Nancy L. Day, Ph.D. Joseph L. Jacobson, Ph.D. Philip A. May, Ph.D. Julie A. Mennella, Ph.D. Edward P. Riley, Ph.D. Ann P. Streissguth, Ph.D. Kathleen K. Sulik, Ph.D. Ken C. Winters, Ph.D.
NIAAA Program Staff Vivian Faden, Ph.D. Laurie Foudin, Ph.D. Jan Howard, Ph.D.
NIAAA Staff, Representatives from CDC, NICHD, NIDR, and Guests Megan Adamson, M.D. Daryl Bertolucci Faye Calhoun, D.P.A. Felix de la Cruz, M.D., M.P.H. Mary Dufour, M.D., M.P.H. Michael J. Eckardt, Ph.D. R. Louise Floyd, R.N., D.S.N. Thomas Gentry, Ph.D. Enoch Gordis, M.D. Walter Hunt, Ph.D. Steve Long James Mills, M.D. Antonio Noronha, Ph.D. Norman Salem, Jr., Ph.D. Linda A. Thomas, Ph.D. Ernestine Vanderveen, Ph.D. Kenneth Warren, Ph.D. Sam Zakhari, Ph.D.
RECOMMENDATIONS SUBCOMMITTEE RECOMMENDATIONS ON AREAS OF ADDITIONAL FAS RESEARCH Although the incidence of FAS has been difficult to determine with precision, reasonable estimates range from 0.97 to 1.9/1000 live births (Alcohol and Health 9, 1997). Moreover, most experts agree that the incidence of partial presentations of FAS, including neurobehavioral anomalies, is much higher. Given the impact that FAS and partial presentations of FAS have on the individual and society, it is imperative to maintain a strong research program in these areas. Based upon the report of the Extramural Science Advisory Subcommittee on FAS, there are two major conceptual areas of research that warrant increased emphasis. Both of these areas require continued development of quantitative, objective methods of classifying the entire spectrum of possible consequences of alcohol consumption during pregnancy. I. Research on the prevention or reduction of alcohol consumption in
pregnant women, II. Research directed at improving the identification and treatment of
children with FAS Prevention of Alcohol Consumption during Pregnancy The causal agent of FAS and partial presentations of FAS is alcohol consumption during pregnancy. Even though FAS is a theoretically preventable condition, diagnosis at the above rates indicates that a significant number of women who are pregnant continue to consume alcoholic beverages in amounts that adversely affect their child. Universal or primary prevention approaches, including the labeling of alcoholic beverages (Hankin et al., 1996), have not been successful in those pregnant women most likely to give birth to an affected child, i.e., those who are heavy drinkers with long drinking careers (Serdula et al., 1992; Smith et al., 1987). There is an existing literature on intervention and prevention of excessive consumption of alcoholic beverages in women that could be utilized in developing effective prevention initiatives for identified high-risk populations for FAS and related partial presentations. FAS has been reported to be more prevalent in Native Americans, African Americans, lower socioeconomic classes, and women who have already given birth to a child diagnosed with FAS. Consequently, within these and other high-risk populations, successful prevention or reduction of alcohol consumption would be expected to significantly decrease the incidence of FAS. The development of valid markers and biomarkers for identifying women at high risk for having a child with alcohol-related effects is important. In particular, the determination of biomarkers for alcohol consumption during pregnancy would facilitate identification of high-risk pregnancies. Active surveillance, case-ascertainment techniques in well-defined small communities would enable accurate estimates of FAS in those communities. Moreover, these approaches could also provide an opportunity to test the utility of employing such proxy measures as intelligence, growth parameters, and facial anomalies to estimate FAS prevalence. Thus, small selected communities could be optimum settings for prevention/intervention studies. Specific areas of emphasis are:
Identification and Treatment of Affected Children Given the devastating impact of CNS dysfunction following prenatal alcohol exposure, intervention efforts for newborns and infants who are diagnosed with FAS or partial presentations of FAS should be directly primarily at the resulting neurocognitive and behavioral impairments. Intervention may be possible because the CNS effects of prenatal alcohol exposure appear to be more significant later in development, reflecting the (1) time course of cognitive and motor development; (2) cumulative effects of the interaction of alcohol=s teratogenic effects and disruptive and impoverished environments; and/or (3) varying types of neurological damage associated with prenatal alcohol exposure (Coles and Platzman, 1992; Streissguth et al., 1993). Unfortunately, there have been few well-designed developmental studies of FAS with respect to intervention. Animal and human studies suggest that prenatal alcohol exposure can alter the structure and function of specific areas of the brain (Mattson et al., 1992). Furthermore, widespread observations indicate that the psychosocial environments of many individuals with FAS are inadequate, impoverished, and perhaps dysfunctional, with consequent adverse effects on cognitive processes independently or interactively with changes in brain (Nadel, 1985). Individual or environmental characteristics that protect the individual or mitigate undesirable cognitive and behavioral outcomes in FAS-related presentations have not been well studied. Beneficial effects of protective and intervention factors, especially education, physical and occupational therapy, behavioral/environmental interventions, and others demonstrated to be of importance from studies of other developmental disabilities, need to be determined using random assignment and appropriate controls. Research with animal models of FAS offers the ability to identify potential behavioral, environmental, and pharmacological interventions for children with FAS. For example, animal models could be useful in determining the effects of pharmacological interventions and in demonstrating that complex motor training helps negate alcohol-related deficits in fine motor and muscular coordination (Klistova et al., 1997). Pharmacological interventions in children have not received sufficient attention and should be studied in and of themselves, as well as in combination with behavioral, educational, and other interventions. These studies should use random assignment and appropriate controls. Specific areas of emphasis are:
Other Considerations and Priorities Based upon the reports submitted to the Extramural Science Advisory Subcommittee on FAS, the following other areas of research also warrant special emphasis.
References Alcohol and Health 9, 1997. Coles CD, Platzman KA: Fetal alcohol effects in preschool children: Research prevention, and intervention. OSAP Technical Manual, Drug Exposed Children, Ages 2-5: Identifying Their Needs and Planning for Early Intervention. Office of Substance Abuse Prevention, Rockville, MD, 1992. Hankin JR, et al: Heeding the alcoholic beverage warning label during pregnancy: Multiparae versus nulliparae. J Stud Alcohol 57:171-177, 1996. Klinstova AY, et al: Therapeutic motor training increases parallel fiber synapse number per Purkinje neuron in cerebellar cortex of rats given postnatal binge alcohol exposure: Preliminary report. Alcohol:Clin Exp Res 21:1257-1263, 1997. Mattson SN, et al: Fetal alcohol syndrome: A case report of neuropsychological, MRI, and EEG assessment of two children. Alcohol:Clin Exp Res 16:1001-1003, 1992. Nadel M: Offspring with fetal alcohol effects: Identification and intervention. Alcohol Treat Quart 2:105-116, 1985. Serdula M, et al: Trends in alcohol consumption by pregnant women: 1985-1988. JAMA 265:876-879, 1991. Smith IF, et al: Identifying high-risk pregnant drinkers: Biological and behavioral correlates of continuous heavy drinking during pregnancy. J Stud Alcohol 48:304-309, 1987. Streissguth AP, et al: The Enduring Effects of Prenatal Alcohol Exposure on Child Development: Birth Through Seven Years, a Partial Least Squares Solution. University of Michigan Press Ann Arbor, MI, 1993.
Posted: June 1998 |
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Updated: October 2000
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