Prenatal exposure to alcohol.

Maternal alcohol consumption during pregnancy can cause serious birth defects, of which fetal alcohol syndrome (FAS) is the most devastating. Recognizable by characteristic craniofacial abnormalities and growth deficiency, this condition includes severe alcohol-induced damage to the developing brain. FAS children experience deficits in intellectual functioning; difficulties in learning, memory, problem-solving, and attention; and difficulties with mental health and social interactions. An FAS diagnosis, however, fails to identify prenatal-alcohol-exposed children who lack the characteristic facial defects and growth deficiency of FAS. Nonetheless, these often undiagnosed children may still experience serious fetal alcohol effects (FAE), including alcohol-induced mental impairments (i.e., alcohol-related neurodevelopment disorder) or alcohol-related abnormalities of the skeleton and certain organ systems (i.e., alcohol-related birth defects). Neuroimaging techniques can assist researchers in identifying FAE through precise pictures of brain abnormalities in persons prenatally exposed to alcohol. By understanding the mechanisms underlying FAE and the behavioral manifestations of the resulting structural brain damage, researchers can ultimately develop effective FAS prevention strategies that identify and assist high-risk women at varying levels of pregnancy.

F etal Alcohol Sy n d rome (FAS) is a set of specific birth defects caused by maternal alcohol consumption during pre g n a n c y. Scientists first identified the syndrome in France in 1968(Lemoine et al. 1968) and in the Un i t e d States in 1973(Jones et al. 1973. To d a y, FAS is considered the most common n o n h e re d i t a ry cause of mental re t a rd ation. Estimates of FAS pre valence va ry f rom 0.5 to 3.0 per 1,000 live births in most populations, with much higher rates occurring in some communities ( Stratton et al. 1996).
At birth, children with FAS are re cognizable by their apparent growth defic i e n c y and characteristic minor facial anomalies (i.e., craniofacial abnormalities) that tend to become less noticeable and adopt a more normal appearance as the child matures. Less evident at birt hbut far more devastating to FAS childre n and their families-are the lifelong effects of alcohol-induced damage to the developing brain. In addition to deficits in general intellectual functioning, persons with FAS often demonstrate difficulties with learning, memo ry, problem-solving, and attention as well as difficulties with mental health and social interactions.
Howe ve r, the diagnosis of FAS identifies only a re l a t i vely small pro p o rt i o n of children affected by alcohol exposure b e f o re birth. Many children with significant prenatal alcohol exposure lack the characteristic facial defects and g rowth deficiency of FAS but still have serious alcohol-induced mental impairments. This condition is re f e r red to as "a l c o h o l -related neuro d e ve l o p m e n t a l d i s o rd e r" (ARND). In addition, some p renatally exposed children without FAS facial features exhibit other alcoh o l -related physical abnormalities of the skeleton and certain organ systems; these anomalies are re f e r red to as alcoholrelated birth defects (ARBD).

Diagnosing the Effects of Prenatal Alcohol Exposure
Re s e a rchers first outlined the diagnostic criteria for FAS in 1973(Jones et al. 1973. Although the terms used to describe the condition have changed over the years, the diagnostic criteriag rowth deficiency, dysfunction of the central nervous system, and characteristic facial defects-have remained essentially the same. Perhaps the most immediately obvious effects of alcohol on the fetus is a pattern of abnormal facial features-small head circ u m f e rence, skin folds at the corner of the e yes, small eye openings, low nasal bridge, short nose, small midface, thin upper lip, and flat philtru m 1 (see figure , p. 33).
These facial abnormalities, howe ve r, are not present in all children who have been exposed to alcohol before birth. Mo re subtle neuroanatomical and neuro b e h a v i o r a l p roblems often occur in alcohol-exposed c h i l d ren without facial abnormalities. Re s e a rchers and clinicians have used the term "fetal alcohol effects" (FAE) for many years to describe children exposed to alcohol before birth who do not have the FA S facial features but who exhibit other critical hallmarks of FAS. Mo re re c e n t l y, the Institute of Medicine (IOM) of the National Academy of Sciences has classified the effects of prenatal alcohol exposure into five categories (see table 1, p. 34) ( Stratton et al. 1996)-three categories for children with all or some of the FA S facial features and two categories for child ren without any FAS facial features (i.e., ARBD and ARND). The diagnoses of both disorders re q u i re confirmation of the m o t h e r's alcohol use during pre g n a n c y in addition to a psychological or neuro l o gical assessment of the child. Without the identifiable FAS facial features, howe ve r, the categories ARBD and ARND are difficult to characterize .

Effects of Prenata l Alcohol Exposure on Brain Structure and Function
Although not as obvious at birth as the characteristic facial features associated with FAS, the effects of alcohol-induced damage to the developing brain and spinal cord, or central nervous system (CNS), are just as deleterious. The p roblems that result from this damage become apparent during childhood and adolescence. They include re d u c t i o n s in general intellectual functioning and academic skills as well as deficits in ve r b a l learning, spatial memory and re a s o n i n g , reaction time, balance, and other cognit i ve and motor skills. These deficits are p a rticularly serious, because they are perva s i ve and persist throughout the pers o n's life. In fact, some deficits, such as p roblems with social functioning, appear to worsen as the sufferer reaches adolescence and adulthood, possibly leading to an increased rate of mental health disorders. A greater understanding of both the structural damage to the CNS fro m alcohol exposure (i.e., the "n e u ro a n a t o mi c a l" effects) and the resulting behavioral manifestations (i.e., the "n e u ro b e h a v i o r a l" effects) is critical to future re s e a rch on e f f e c t i ve therapies for FAS.

Neuroimaging: Precise Pictures of Structural Damage to the Brain
Autopsies of the brains of children with FAS have demonstrated widespread and s e ve re damage, including the follow i n g : • Malformations of the brain tissue, both in the "gray matter" and "white matter" re g i o n s • Fa i l u re of certain brain regions (e.g., the corpus callosum) to deve l o p • Fa i l u re of certain cells to migrate to their appropriate locations during e m b ryonic brain deve l o p m e n t • A tendency for the tissue to die in some brain regions (e.g., the cere b e l l u m ) .
The extent of these abnormalities initially led re s e a rchers to conclude that neither a specific pattern of brain changes nor a consistent behavioral profile existed among children prenatally exposed to alcohol. Howe ve r, the use of neuro i m a gi n g techniques, such as magnetic re s onance imaging (MRI) and computed t o m o g r a p h y, to visualize the living brain has provided a more precise picture of the brain stru c t u re of children with FA S , including reduced overall brain size . Se veral brain stru c t u res, such as the c e rebellum and basal ganglia, appear to be especially sensitive to prenatal alcohol e x p o s u re. These findings suggest that alcohol exposure may cause specific, rather than global, deve l o p m e n t a l a b n o r m a l i t i e s .

Cerebellum
The cerebellum appears to be especially affected by prenatal alcohol exposure . This stru c t u re is located at the back of the brain and is thought to be invo l ve d primarily in movement but also in cogn i t i ve processes, such as attention. Case studies and autopsy re p o rts have show n that alcohol-exposed children with and without FAS exhibit smaller size and other abnormalities of the cere b e l l u m . The death of certain cells in the cere b e llum may be responsible for its re d u c e d s i ze. These specialized cells, called Pu rkinje cells, send out nerve signals in response to sensory and motor impulses f rom the rest of the nervous system.

Basal Ganglia
The basal ganglia are paired masses of gray matter located deep within the white matter of the cere b rum. They include a stru c t u re called the caudate nucleus, which governs vo l u n t a ry movem e n t as well as some cognitive functions related to perception, thinking, and m e m o ry. The volume of the basal ganglia is significantly reduced in children with FAS compared with other children.

Physical Measures of Altered Brain Function
In addition to pinpointing the stru c t u r a l changes in the brain, quantification of the resulting changes in brain function is of equal importance. If alcohol-induced changes in brain function could be identified early in a child's life, scientists may possibly mitigate some of the a d verse consequences as the child grow s . Re s e a rchers have used two toolsacoustic analyses of babies' cry patterns and electroencephalography (EEG)to physically measure changes in brain function that may help diagnose and determine the prognosis even for alcoholexposed children without full-blown FA S .

Acoustic Cry Analyses
The characteristics of an infant's cry, which are at least partly determined by the CNS, can be affected by pre n a t a l e x p o s u re to alcohol and other drugs. In one study of 3-day-old infants, re s e a rc h e r s examined three characteristics of cry i n g of babies both with and without pre n atal alcohol exposure: (1) the intensity at which a stimulus provokes crying (i.e., t h reshold); (2) the time between the stimulus and the infant's cry (i.e., latency); and (3) the highness or lowness of the c ry (i.e., pitch) (Zeskind et al. 1996). All three of these characteristics differe d significantly between the two groups of infants. Mo re ove r, the differences we re related to the amount of alcohol consumed by the mother during her pre gn a n c y. Although these findings indicate that prenatal alcohol exposure interf e re s with subtle aspects of neuro b e h a v i o r, re s e a rchers have yet to determine how d i f f e rences in cry characteristics may relate to later neurobehavioral outcomes, such as learning or attention.

EEGs
EEG analyses and neurological testing also may help to identify less seve re effects of alcohol exposure, such as ARND.
Re s e a rchers have used EEG measurements to compare children with FA S , c h i l d ren with Dow n's syndrome, and normally developing control subjects (Kaneko et al. 1996a , b). In those studies, c h i l d ren with prenatal alcohol exposure and children with Dow n's syndro m e had distinct profiles of brain electrical and neurological activity. The re s u l t s suggested that the effects of pre n a t a l alcohol exposure may specifically target the brain's left hemisphere as well as differ from the effects of other congenital disorders, such as Dow n's syndro m e .

Effects on Cognitive and Motor Functions
In recent years, re s e a rchers have inve s t igated more specific aspects of brain functioning and behavior, rather than overall intellectual functioning, in exploring the effects of prenatal alcohol e  Any of a number of anomalies (e.g., heart or kidney defects) present at birth that are associated with maternal alcohol consumption during pregnancy Alcohol-related neurodevelopmental disorder (ARND) No Yes Evidence of CNS abnormality (e.g., abnorm a l l y small head, abnormal brain structures, and specific neurological signs); evidence of a behavioral or cognitive disorder inconsistent with the expected developmental level, with hereditary factors, or with the environment; or evidence of both ( Mattson et al. 1998) children found that children with FAS, as well as alcoholexposed children who did not meet all the FAS criteria, experienced deficits i n n u m e rous areas. The most prominent o f these deficits we re in integrating visual information with coordinated movem e n t s , c o n t rolling precise move m e n t s (e.g., speed and coordination of finger m ovements), language, and general intellectual functioning.
Although re s e a rch has well established that heavy prenatal alcohol exposure leads to neurobehavioral impairment, the effects of lower levels of alcohol exposure a re not as clear. Many of the pro b l e m s linked to FAS also seem to exist in child ren whose mothers drank moderate amounts of alcohol when pregnant. These p roblems include deficits in general intellectual functioning, visual-spatial reasoning, attention, and academic a c h i e vement.

Learning and Memory
To assess learning and memory in child ren with and without FAS, re s e a rc h e r s g a ve the children a standard i zed test that showed differences in immediate recall, delayed recall, and recognition of w o rds that had been read aloud (Ma t t s o n et al. 1996). The study found that the FAS children did not learn as many w o rds as did the control group childre n , but the rate at which words we re forgott e n was the same in both groups. This finding suggests that children with FA S h a ve profound deficits in learning when material is presented verbally but are capable of retaining the information they learn. Re s e a rchers have obtained similar results among prenatal alcohol-exposed c h i l d ren without a diagnosis of FA S .
Another study of implicit memory (i.e., the unconscious recall of a pre v i o u s l y p e rformed task) compared children with heavy prenatal alcohol exposure (including FAS), children with Dow n's synd rome, and normally developing childre n ( Mattson and Riley 1999). The study results suggested that the alcoholexposed and the normally deve l o p i n g c h i l d ren we re equally able to use pre v iously learned information without being told to do so. In contrast, the childre n with Dow n's syndrome we re i m p a i re d on all memory tasks evaluated. Ove r a l l , these findings suggest that pre n a t a l alcohol exposure does not impair some types of memory and that despite some learning deficits, children with FAS are able to retain learned information.

Visual-Spatial Functioning
Only a few studies have assessed the visual-spatial functioning of persons with FAS-that is, the ability to see objects and understand their spatial re l a t i o nships. Alcohol-exposed children appear to have deficits in specific aspects of visual-spatial processing, including perceiving and remembering spatial re l ationships and recalling visual details.

Executive Functioning
Higher order cognitive processes called e xe c u t i ve functions are activities that re q u i re complex thought processes and behaviors, such as planning, organizing, sequencing, and other forms of abstract thinking. Persons with deficits in these a reas may have difficulty with self-care and independence. For example, ro utine activities that re q u i re a sequence of steps, such as getting dressed or writing a check, may be pro b l e m a t i c .
Two studies evaluated the abilities of alcohol-exposed children in planning, verbal fluency, using information held in short-term memory, using feedback to modify behavior, and set shifting (e.g., switching from naming animals to naming furniture and back to animals) ( Goodman et al. 1998;Kodituwakku et al. 1995). The alcohol-exposed childre n experienced more difficulties perf o r m i n g these tasks than did control childre n In one of the studies, the alcoholexposed children had difficulty only with c e rtain tasks involving memory skills; in other areas, they tested similarly to the control group children (Ko d i t u w a k k u et al. 1995). These findings support the conclusion that prenatal alcohol expos u re targets specific areas of the brain.
In another study, teenagers and adults with FAS or FAE had more difficulty in calculating and estimating magnitude compared with control subjects (Ko p e r a - Frye et al. 1996). Although the extent of these difficulties is unclear, they are related to lower overall intellectual ability. The study results support findings that persons with prenatal alcohol e x p o s u re experience specific pro b l e m s in mathematics and pro b l e m -s o l v i n g .

Attention
Problems in maintaining attention h a ve long been associated with FAS and a re quite common, affecting 60 perc e n t of children and adolescents with the s y n d rome. Deficits in attention also have been re p o rted for children exposed to re l a t i vely low levels of alcohol before b i rth. Various studies indicate, howe ve r, that the attention disruption associated with prenatal alcohol exposure differs from that arising from other diso rders, such as attention deficit hyperactivity disord e r. Such differences could h a ve important implications for diagnosing and treating attention disord e r s that are specifically attributable to prenatal alcohol exposure .

Motor Control
Motor control is a complex function influenced by the CNS; by the peripheral nervous system, which prov i d e s feedback to the CNS from the body's s e n s o ry organs (e.g., the eyes, ears, and skin); and by the vestibular system, which is located in the inner ear and is i n vo l ved in a person's sense of balance and the motor reactions used to maintain it. Defects in any of these systems can affect motor contro l .
Studies of humans and animals p renatally exposed to alcohol have consistently found impairments in the d e velopment of motor control. Fu rt h e r studies have suggested that balance deficits in alcohol-exposed persons may be attributable to problems of the CNS rather than the peripheral nervous system.

Effects on Mental Health and Psychosocial Behavior
Both the psychosocial and psyc h i a t r i c effects of prenatal alcohol exposure also p rofoundly influence the lives of alcoholexposed children and their families. Im p a i red social functioning, disturbed behaviors, and psychiatric disorders are common in people with FAS. These p roblems, which can occur with or without mental re t a rdation and persist into adulthood, often disrupt daily life and magnify other FA S -related pro b l e m s .

Mental Health
In a large study of secondary disabilities in persons of various ages with FAS or FAE, 94 percent of the participants had a history of mental health pro b l e m s ( St reissguth et al. 1996). At t e n t i o n deficits we re the most frequent pro b l e m s in children and adolescents and occurre d in 61 percent of the subjects. Among adults, depression was the most f requently re p o rted problem (52 perc e n t ) .
Other studies found that preschool and school-aged children prenatally exposed to alcohol showed behaviors characteristic of people with autism, such as impairments in social interaction and c o m m u n i c a t i o n .

Psychosocial Behavior
Other studies have indicated additional impairments in social abilities and psychological functioning in alcohol-exposed c h i l d ren. For example, compared with c o n t rol children, children pre n a t a l l y exposed to alcohol had greater pro b l e m s with respect to anxiety, social skills, and academic achievement; significantly higher scores on scales measuring behavioral problems, such as anxiety, depre ssion, and attention problems; and more deficits in social skills, such as manners and interactions with others. The differences in social skills we re greater at older ages, indicating that social skills deve loped more slowly in the FAS children.

Underlying Mechanisms of Alcohol-Induced Damage to the Fetus
Cu r rent re s e a rch on FAS seeks to delineate the specific mechanisms of damage to the fetus as well as the conditions that influence the extent of this damage. Nu m e rous factors complicate this re s e a rch. First, the process of deve l o pment itself is enormously complex and not yet fully understood. Second, multiple distinct mechanisms work simultaneously along different biochemical pathways and at different physical sites in the developing embryo. And third , the ways in which these alcohol-induced mechanisms produce damage to the fetus depend on several va r i a b l e s , including the timing, fre q u e n c y, and amount of maternal drinking during p regnancy; the mother's health status and habits; and the genetic makeup of the mother and fetus.
Alcohol exe rts its effects on the deve lo p i n g fetus through multiple actions at d i f f e rent sites. In the developing brain, for example, alcohol interf e res with n e rve cell (i.e., neuron) deve l o p m e n t and function in a variety of ways. Thus, in persons with FAS, certain brain re g i o n s h a ve not developed normally, cert a i n cells are not in their proper locations, and tissue has died off in some re g i o n s . At a different site in the deve l o p i n g e m b ryo-the cell layer that develops into the bones and cartilage of the head and face-alcohol exposure at critical stages of development induces the pre m a t u re cell death. This cell death is thought to be linked to the facial abnormalities found in FA S .
A developing embryo's susceptibility to specific FAS defects appears to be d i rectly related to the timing of maternal drinking, that is, whether drinking occurs during critical periods of vulnerability for different organ systems, regions, or cell types. Animal studies have also s h own that the type and extent of fetal damage are related to the pattern of maternal drinking, with binge drinking being particularly damaging. Other f a ctors modulating the effects of pre n a t a l alcohol exposure include the part i c u l a r p rofiles of blood alcohol concentrations p roduced, and the duration of exposure d u ri n g d e ve l o p m e n t. Mo re ove r, the effects of alcohol may be enhanced by other conditions that adversely affect the fetus, such as the use of tobacco and other drugs by the mother.

Candidate Mechanisms for Central Nervous System Damage
Re s e a rchers have identified numero u s mechanisms through which pre n a t a l alcohol exposure may adversely affect brain development. These mechanisms act on a variety of brain cells and brain molecules. Although some of these mechanisms are specific to nervous system tissue, others also affect deve l o pment of the craniofacial region or other body areas. Fi n a l l y, re g a rdless of the site of action, the timing, amount, and duration of alcohol exposure play a cru c i a l role in determining the type and extent of damage.

Timing of Exposure
In the developing brain, alcohol expos u re during various stages of deve l o pment can harm different populations of neurons through different pro c e s s e s . Some types of neurons are extremely vulnerable during the early stages of diff e rentiation and when synapses are being formed. In other instances, neurons die when alcohol exposure either prevents them from migrating properly or induces a delayed cell death that occurs after migration, even though exposure o c c u r red before migration start e d . Mo re ove r, multiple mechanisms may operate simultaneously to pro d u c e abnormal cell development or cell death.

Cell Death Modes
Cell death is the endpoint of many of the FAS mechanisms. It occurs by one of two re c o g n i zed pathways: (1) necrosis, a reaction to injury or disrupted cell metabolism, or (2) apoptosis, a "p rog r a m m e d" self-destruction that is nece s s a ry for normal development but can be triggered to an exc e s s i ve degree by

C h i l d ren pre n a t a l l y e x p o s e d to alcohol s h owed behaviors c h a racteristic of people with autism.
t oxins such as alcohol. While cell death by apoptosis is critical to healthy CNS d e velopment, this type of cell death also is invo l ved in a broad range of human CNS disorders, including amyo t rophic lateral sclerosis (ALS, or Lou Ge h r i g's disease) and Alzheimer's disease. Recent advances in know l e d g e about cell death modes provide the basis for FAS studies on the role of alcohol in inducing cell death in deve loping tissues.

Free-Radical Damage
Free radicals are highly re a c t i ve molecular fragments that may be formed as a by -p roduct of alcohol metabolism. Formation of these fragments likely plays an important role in pro d u c i n g cell damage in FAS, both in the CNS and in the craniofacial region. Nu m e ro u s studies have indicated that alcohol may damage or kill fetal cells by causing the b re a k d own of mitochondria, a pro c e s s that can be initiated by exc e s s i ve amounts of free radicals. Antioxidants (e.g., vitamin C, vitamin E, and glutathione) are molecules that neutralize free radicals. The addition of antioxidants to cell c u l t u res can pre vent cell death, suggesting the potential for therapies with a n t i oxidant tre a t m e n t .

Interference With Growth Factor Functions
Se veral chemicals, called growth factors, c o n t rol cell proliferation and pro m o t e cell surv i val in the developing fetus. Cu r rent re s e a rch indicates that alcohol e x p o s u re may disrupt the deve l o p i n g CNS by interfering with the pro d u c t i o n or function of some of these growth factors. These include molecules c a l l e d insulin-like growth factors, nerve grow t h f a c t o r, basic fibroblast growth factor, and a neuro t rophic growth factor.

Ad verse Effects on As t rocyte Fo rm a t i o n
A s t rocytes are star-shaped cells of the n e rvous system that, unlike neuro n s , do not actively transmit information to other cells. Ne ve rtheless, astro c y t e s interact intimately with neurons and other astrocytes and play critical ro l e s in the developing CNS. For example, cells that are precursors to astro c y t e s guide migrating neurons to their a p p ropriate destinations in the brain. One possible mechanism for alcoholinduced abnormalities in the fetus i n vo l ves errors in the process of astrocyte formation. Such alcohol-induced defects in astrocyte formation could explain why certain neurons are not found in the appropriate places in the brain after the normal migration period. Re c e n t l y, re s e a rchers also found that alcohol interf e res with the normal g rowth and function of astrocytes.

Abnormal Development of Neurotransmitter Systems
Ne u rotransmitters are chemicals that a l l ow communication among nerve cells. The neurotransmitters are re l e a s e d f rom an extension (i.e., the axon terminal) of the signal-emitting neuron, trave l a c ross a narrow gap between neuro n s , and bind to specific docking m o l e c u l e s (i.e., receptors) on the target neuro n . Alcohol significantly interf e res with two n e u rotransmitter systems that p l a y i m p o rtant roles in fetal brain deve l o pment, the serotonin system and the glutamate system. In rats, early pre n a t a l alcohol exposure significantly delays the development of sero t o n i n -u s i n g n e u rons, reducing serotonin levels and altering the binding of serotonin to receptors in many target sites during periods that are likely to be critical for normal brain development. Si m i l a r l y, p renatal alcohol exposure, even in moderate concentrations, results in a d e c rease in the number and function of c e rtain glutamate receptors-called Nm e t h y l -D-a s p a rtate (NMDA) re c e pt o r s -t h roughout deve l o p m e n t . A l c o h o l's effects on NMDA re c e p t o r s during critical periods of brain deve lopment may play a major role in the mental and behavioral deficiencies found in FAS.

Altered Glucose Transport and Uptake
All cells need the sugar glucose in ord e r to generate energy, metabolize free radicals, and synthesize vital chemicals, including neurotransmitters and nucleic acids. Se veral studies have demonstrated that alcohol can impair glucose transport and uptake during d e velopment. For example, cell culture studies show that alcohol exposure can reduce glucose uptake by certain brain n e u rons from fetal rats and by astrocytes from newborn rats. Fu rt h e r re s e a rch on the mechanisms of glucose t r a n s p o rt and uptake could contribute significantly to knowledge about alcoh o l's effects on developing cells.

Abnormal Cell Adhesion Molecules
Cell adhesion molecules influence the ability of CNS cells to migrate pro perly; to develop branching extensions, such as axons and dendrites; and to s u rv i ve. Defects in one particular cell adhesion molecule, called L1, can lead to abnormalities in brain deve l o p m e n t and mental deficiencies that are similar to those seen in children with FA S . Some cell culture studies have show n that low levels of alcohol interf e re with the ability of L1 to regulate the clustering or clumping together of cells that is needed for brain stru c t u res to deve l o p.

Altered Regulation of Gene Expression
The process of conve rting a gene's encoded information into a gene pro duct (e.g., a protein) is called gene expre ssion. In alcohol re s e a rch, scientists are p a rticularly interested in the expre s s i o n of certain genes (i.e., homeobox genes) that regulate the activation and timing of steps in the formation of specialize d tissues and organs in the body. Although re s e a rchers know that alcohol can affect the expression of some genes, it is uncertain whether these include homeobox genes. The lack of information on how alcohol affects the regulation of genes that control the formation of the CNS and other body parts creates a major gap in the current understanding of the mechanisms underlying FA S . C o n s e q u e n t l y, studies on alcoholinduced changes in gene expression during critical periods of deve l o p m e n t constitute one of the most pro m i s i n g a reas for new FAS re s e a rc h .

Candidate Mechanisms for Craniofacial Defects
In mouse and chicken embryos, as in humans, heavy exposure to alcohol duri n g c e rtain periods of development can g i ve rise to the craniofacial abnormalities associated with FAS. Animal studies h a ve linked these abnormalities to cell death by apoptosis of certain embryo n i c cells, called neural crest cells, during a ve ry defined and narrow period of vulnera b i l i t y in early embryonic deve l o p m e n t . One mechanism by which this occurs is thought to be the formation of f ree radicals. Two other possible mechanisms a re a deficiency in retinoic acid and a l t e red expression of homeobox genes.
Retinoic acid is a deriva t i ve of vitamin A (retinol), which is essential for c o n t rolling the normal pattern of deve lopment of tissues and organs in ve rt ebrate animals, including the deve l o pment of neural crest cells into craniofacial features. Retinoic acid likely acts in this capacity by binding to re c e p t o r s that regulate the expression of homeo b ox genes. Thus, certain retinoic acid receptors control the specific homeobox genes that regulate the timing and coordination of craniofacial deve l o p m e n t . Alcohol exposure at specific periods of e m b ryonic development can reduce the p roduction of retinoic acid. De f i c i e n c i e s or abnormalities in retinoic acid or its receptors, in turn, cause neural crest cells to die by apoptosis, leading to craniofacial defects.
• Pr i m a ry pre vention approaches that attempt to stop maternal drinking b e f o re it start s • Se c o n d a ry approaches that facilitate early detection and treatment of maternal drinking problems before they lead to FAS • Te rt i a ry approaches that attempt to change the behaviors of women who are at ve ry high risk because they have already delive red a child with diagnosable FAS or other alcoh o l -related disorders, such as ARBD and ARND.
Mo re re c e n t l y, the IOM's Committee to Study Fetal Alcohol Sy n d ro m e re v i ewed a vast body of FAS literature and proposed its own compre h e n s i ve recommendations that include a va r i e t y of pre vention measures (Stratton et al. 1996). These measures fall into thre e categories as follow s : • Un i versal approaches attempt to p romote the health and we l l -b e i n g of all people in society or in a particular community, without re g a rd to individual risk, through use of the media to educate the public and t h rough policy and enviro n m e n t a l c h a n g e .
• Se l e c t i ve pre ve n t i ve interve n t i o n s target persons and subgroups that a re at excess risk of developing the p roblem, such as women of childbearing age who drink alcohol. These interventions should be give n by health care providers who are trained to question women about their drinking and contraceptive histories and to deliver interve n t i o n s that are pro p o rtional to the woman's l e vel of risk.
• Indicated interventions are targeted to women who are at high risk of giving birth to an alcohol-impaire d child, because, for instance, they are drinking at a level that is likely to p roduce FAS-affected offspring or they have already delive red one child with FAS. These interventions should be offered in the form of brief interventions or more formal appro a c h e s as needed.

Universal Prevention Approaches
Most women reduce or cease their drinki n g during pre g n a n c y. This reduction may be linked, among others, to u n i ve r s a l p re vention messages in re a d i n g m a t e r i a l and in radio and television adve rt i s e m e n t s . One universal pre ve n t i o n strategy is the use of alcoholic beverage labels that warn about the risks of birth defects if women drink alcohol during pre g n a n c y. Howe ve r, warning labels appear to have a pre ve nt i ve effect on lighter drinkers but not on women who are the heaviest drinkers and who are t h e re by at greatest risk of bearing a child with FAS. Women who a re the heaviest and most long-term drinkers also tend to show the least amount of change in their drinking behavior once they become pre g n a n t .

Selective Prevention Approaches
Much information re g a rding risk factors for FAS (e.g., age, socioeconomic status, and spousal characteristics) is a vailable and can help provide appropriate population targets for selective and indicated pre vention strategies. The first challenge in implementing such pre vention strategies is to identify accurately and efficiently women at i n c reased risk of having FAS childre n t h rough screening in settings such as clinics that provide primary and pre n a t a l c a re to low-income women. Some guidel i n e s a re available for detecting higher risk drinkers in primary care settings. The identification of pro b l e m drinkers primarily relies on the use of s h o rt screening questionnaires. Ma n y of the most commonly used questionn a i res, howe ve r, are less accurate for women than for men. Reasons for this d i f f e rence probably include the incre a s e d stigma experienced by women who drink, which may lead them to underre p o rt alcohol problems. Women are also less likely to experience some of the more adverse consequences of drink-i n g , such as employment, economic, or social problems; thus, standard scre e ning instruments may fail to identify women whose drinking problems are e x p ressed in other ways.
Attempts to improve identification of women who drink during pre g n a n c y h a ve focused on comparing the accuracy of various screening instru m e n t s with each other and with informal questioning by health care workers. In one study (Chang et al. 1998), the T-ACE questionnaire (see table 2) was m o re effective than assessments by health care staff in identifying pre g n a n t women at risk for problem drinking. Mo re work is needed to develop instruments for use among general populations of women of childbearing age.
Once women at risk for having child ren with FAS are identified, seve r a l other questions become paramount, such as the women's readiness for change, the factors that affect readiness, and actual turning points tow a rd abstinence. Each item receives a score of 1 for a positive response (Ewing 1984).

T-ACE
• Tolerance-How many drinks can you hold? • Have people Annoyed you by complaining about your drinking? • Have you ever felt you ought to Cut down on your drinking? • Eye opener-Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover?
A score of 2 is given for a positive response to the tolerance question; 1 point each is scored for the other three questions (Sokol 1989).

TWEAK
• How many drinks can you hold? (Tolerance) • Does your spouse [or do your parents] ever Worry or complain about your drinking? • Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover? (Eye opener) • Have you ever awakened in the morning after drinking the night before and found that you could not remember a part of the evening before? (Amnesia) • Have you ever felt you ought to cut [Kut] down on your drinking?
Positive answers to the tolerance and worry questions score 2 points each; the other three questions score 1 point each (Chan et al. 1993).
These issues must be addressed and eva l ua t e d as they are in other alcohol re s e a rc h that does not invo l ve pregnant women.

Indicated Prevention Approaches
Ef f e c t i ve approaches to FAS pre ve n t i o n among the highest risk women, part i c ularly mothers who have previously give n b i rth to an alcohol-impaired child, would eliminate most of the existing FAS pro blem, because these women account for the majority of FAS cases. Reaching these high-risk women is problematic, howe ve r. For example, many heavily drinking p regnant women never present thems e l ves to prenatal clinics and are otherw i s e e l u s i ve. If they re c e i ve therapy for t h e i r alcohol dependence, such tre a t m e n t r a re l y includes an emphasis on FAS pre ve n t i o n . Fu rt h e r m o re, barriers to treatment clearly exist for these highest risk women.
For those women identified as having the greatest risk of an FAS birth, a wide range of indicated pre vention strategies exists, and re s e a rchers must determine which types of therapy are most effect i ve for which subtypes of women. Sp e c i f i c a l l y, investigators should comp a re the effectiveness of brief ve r s u s extended interventions; coerc i ve ve r s u s vo l u n t a ry therapies, such as motivational enhancement; and group ve r s u s individual approaches. Fu rt h e r m o re , studies should evaluate various pro t otypes of case management, social netw o rk therapy, support groups for FA S mothers, environmental change, and "social model" approaches to re c ove ry, such as the community re i n f o rc e m e n t a p p roach. Cu r rently used indicated prevention strategies include the follow i n g : • In t e n s i ve case management for alcohol-abusing women who have had FAS children • Programs that combine alcohol i n t e rventions with the promotion of c o n t r a c e p t i ve use • "A f t e rc a re" programs for women who h a ve given birth to children with FAS.
Howe ve r, re s e a rchers have not ye t determined the effectiveness of some of these appro a c h e s .
The IOM re p o rt (Stratton et al. 1996) recommends that any health c a re provider who encounters a woman who is abusing alcohol should consider brief intervention therapy, counseling re g a rding the risks of prenatal alcohol e x p o s u re, and (if appropriate) re f e r r a l to more formal alcohol abuse tre a t m e n t . For women who continue to abuse alcohol during pre g n a n c y, compre h e ns i ve clinical treatment programs may be n e c e s s a ry. These programs generally include medical and obstetric care in addition to alcohol and other dru g abuse services, which in turn invo l ve individual or group counseling, family t h e r a p y, referral to self-help gro u p s , p a renting skills training, and case management, as well as information on the effects and risks of alcohol consumption.
Some communities have mandated c o u rt -o rd e red or invo l u n t a ry part i c i p ation in alcohol abuse treatment for heavily drinking pregnant women as a means of pre venting FAS. These types of coerc i ve programs have stimulated legal and ethical debates in the literat u re concerning the comparative rights of the pregnant woman, the fetus, and society at large. Fu rt h e r m o re, the effect i veness of this approach has not been determined, although some encouraging findings exist. Consequently, eva l u ations comparing treatment completion rates and changes in actual drinking behavior of women for whom tre a t m e n t had been mandated and heavily drinking p regnant women without mandated t reatment are needed.

Summary
Imaging studies have demonstrated abnormalities of certain brain re g i o n s in persons exposed to alcohol pre n a t a l l y, w h e reas other regions seem to be spare d s t ructural damage. Si m i l a r l y, re s e a rc h s h ows that many neurobehavioral deficits a re notably linked to prenatal alcohol e x p o s u re, whereas other functions appear to remain intact. These studies s t rongly support the notion that alcohol has specific, rather than global, effects on the developing brain.
Ad vancements in our understanding of mechanisms of FAS damage will guide the development of new ways to p rotect against or limit alcohol-induced damage to the fetus. For example, the identification of specific mechanisms and biochemical markers of damage should accelerate early detection or a l l ow better prediction of specific types of damage in at-risk pregnancies. Su c h a d vances could help identify cases at g reatest risk for developmental disord e r s and improve outcomes through targeted i n t e rventions. From a public health pers p e c t i ve, knowledge of specific mechanisms of damage should be a powe rf u l tool for effective public education and counseling of alcohol-dependent women in their childbearing years and could help guide clinical decisions about the most effective allocation of medical and psychological support serv i c e s .
Pro g ress in the pre vention of FA S must begin with re s e a rch that establishes baseline information about the pre valence of FAS and identifies more pre c i s e l y those women who are at highest risk of bearing an alcohol-affected child. Eq u a l l y i m p o rtant, the effectiveness of differe n t FAS pre vention approaches must be determined through carefully contro l l e d e valuation studies. Each of the levels of p re vention (i.e., universal, selected, and indicated pre vention), as well as the specific modalities used within each, must be examined both in isolation and as part of c o m p re h e n s i ve programs. Because FA S and other adverse effects of drinking during pregnancy theoretically are 100-percent pre ventable, it is vital to make eve ry e f f o rt to achieve this goal. s