Upon completion of this course, the learner will be able to:
The term alcohol technically refers to a diverse class of organic chemicals. In the context of fetal alcohol syndrome (FAS), alcohol refers to a specific chemical, ethyl alcohol, which is found in alcoholic beverages. The general term alcohol is used here and elsewhere, and it is understood from the context that it refers to ethyl alcohol. Fetal Alcohol Syndrome (FAS) was first described by French scientists in 1968, and is a condition that is specific to prenatal maternal alcohol consumption. Alcohol-Related Birth Defects (ARBD) and Alcohol-Related Neurodevelopmental Disorders (ARND) are “catch-all” categories for outcomes associated with prenatal alcohol consumption, but may also result from other exposures. Major Points to Remember:
In 1968, French scientists were the first to describe FAS (1). Publication of its existence in the U.S. occurred in 1973 (2). Since these early reports considerable research has been performed that documents the characteristics of the FAS child as well as maternal characteristics associated with risk, the extent of the problem, and many issues related to treatment and prevention. In simplest terms, FAS is caused by prenatal exposure to “high” amounts of alcohol. The determination of “how much is too much” turns out to be a sticky problem. Diagnostic criteria refer to “maladaptive patterns of drinking associated with moderate to heavy alcohol consumption,” and in the extreme this is not particularly difficult to identify with reasonable certainty. However, defining limits for moderate amounts of alcohol is difficult, and the resulting potentially adverse effects cannot be excluded nor definitively demonstrated. In 1996, the Institute of Medicine (IOM) of the National Academy of Sciences published the findings of a committee that was formed to conduct a literature study of fetal alcohol syndrome and related birth defects, and to provide guidance for future research and prevention efforts (3). According to the IOM committee, “The lack of diagnostic criteria for or more definitive statements regarding possible effects of low to moderate exposure to alcohol should not be interpreted as contradictory to the Surgeon General’s warning against drinking alcohol during pregnancy.” Previous to the IOM report, the term Fetal Alcohol Effects (FAE) was used to describe children who have all of the diagnostic features of FAS, but at mild or less severe levels. In the IOM report the terms ARND and ARBD were recommended, and are currently preferred. The IOM report notes that ARBD and ARND are “catch-all” categories, and the outcomes are not specific to prenatal alcohol consumption. Thus, the causal link between maternal alcohol consumption and ARBD or ARND generally is not certain, and the role of other factors may need to be excluded. Both ARBD and ARND also require documented maternal alcohol exposure, and include outcomes linked to maternal alcohol consumption through human or animal research. Alcohol-Related Birth Defects (ARBD) includes a diverse array of physical birth defects: skeletal abnormalities, heart defects, cleft palate and other craniofacial abnormalities, kidney and other internal organ problems, vision and hearing problem. Alcohol-Related Neurodevelopmental Disorders (ARND) includes outcomes such as decreased cranial size at birth, structural brain abnormalities (e.g., microcephaly), abnormal neurological conditions (e.g., impaired fine motor skills, neurosensory hearing loss, poor tandem gait, and poor eye-hand coordination). The IOM report also includes a diagnosis of ARND as a result of behavior or cognitive abnormalities that cannot be explained by other familial or environmental factors, and of course there is a history of maternal alcohol consumption. Examples of behavior and cognitive abnormalities include:
1. Lemoine et al., Ouest Medecine 21, 476-482, 1968. 2. Jones, et al. Lancet 1, 1267-1271, 1973. 3. Institute of Medicine, Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment, Stratton, K., Howe, C., and Battaglia, F, Editors. National Academy Press, 1996. Defining Excessive Alcohol Consumption Major Points to Remember: Alcohol Consumption and FAS Alcohol consumption is often categorized in a general fashion as none, light, moderate, or heavy. The term alcohol abuse is often used in a general sense to indicate any heavy consumption that could prove hazardous to an individual’s health (including a fetus). There currently is no exact correspondence between the generally-stated categories of alcohol consumption and the assignment of actual levels of alcohol intake, either in terms of drinks per day or amount of ethanol per day. In fact, there is a great deal of variability in the published literature in the assignment of a measured amount of alcohol consumption (e.g., drinks per day) to a given general category of alcohol consumption. This variability exists not only between individual studies, but also between specific populations; for example, men versus women in general versus pregnant women. The IOM committee, in their review of FAS, decided to categorize exposure to alcohol in terms of a pattern of excessive intake, closely linked to the DSM-IV (Diagnostic and Statistical Manual) definitions of alcohol dependence and abuse. Alcohol consumption that results in dependence is considered a diagnosable disease. Clearly, alcoholic individuals who become pregnant are in a high risk category for delivery of an infant with FAS, ARBD, or ARND. However, not every mother with a history of heavy drinking will give birth to an FAS child. As will be described later, there are host factors and circumstances relative to fetal development that influence the outcome of alcohol consumption during pregnancy. Diagnostic and Statistical Manual (DSM-IV) Definitions(4) Alcohol use disorders – alcohol dependence and alcohol abuse characterized by maladaptive patterns of drinking associated with moderate to heavy alcohol consumption and moderate to severe alcohol-related problems. Alcohol abuse is considered less severe than alcohol dependence. Diagnosis of alcohol dependence—individual meets at least three of the following criteria over a 12 month period:
The term “alcoholism” is defined by the National Council on Alcoholism and Drug Dependence as “a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by continuous or periodically impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial.” Of course, an alcoholic is an individual with the disease alcoholism. The categorization of alcoholism as a disease implies that an etiology can be defined. In other words, we should be able to define both risk and preventive factors that potentially can be manipulated in preventive efforts to influence the outcome. For further information on
the diagnosis
of alcoholism read the following article: Read online at http://www.aafp.org/afp/20020201/441.html. References
Neonatal Abstinence Syndrome (NAS) Major Points to Remember:
Fetal Alcohol Exposure Major Points to Remember: Importance of Timing of Alcohol Exposure While it can be generally stated without ambiguity that maternal alcohol consumption during pregnancy causes FAS, it is much less clear exactly when and how this disastrous outcome takes place. Furthermore, as previously stated, not every mother with a history of heavy drinking during pregnancy will give birth to an FAS child. In addition to the maternal drinking habits, there may be differences in maternal metabolism, fetal susceptibility, and timing of the alcohol consumption in relation to fetal development that influence the toxic response to alcohol consumption. Principles of teratology proposed by Wilson (5) hold that the effects of an agent depend on the amount of exposure as well as the developmental stage at the time of exposure, the genotype of the host and interactions with environmental factors. It is upon this stage that alcohol acts out its role in the pathogenesis of FAS. Of course, human development starts with a single cell, the fertilized egg, and progresses through genetically-directed cell division and differentiation. Considerable research, mostly in laboratory animals and tissue culture, has been directed towards elucidating the critical stage of development in which alcohol acts, as well as the mechanism of action leading to cellular/organ dysfunction. While recognizing that development is continuous, it is convenient to define distinct stages of development for the sake of efficient presentation. The IOM report defines the following three prenatal developmental periods (post-fertilization): 1. Predifferentiation. Also referred to as the preimplantation period, this period involves an increase in cell number through rapid cell division. 2. Embryonic Period. This period includes the processes of gastrulation (formation of the three primary germ layers—ectoderm, mesoderm, and endoderm) and organogenesis (formation of organs). This period covers the time from implantation through about the eighth week of gestation in humans (organogenesis starts around the third week of gestation). 3. Fetal Period. This period is characterized by growth, tissue differentiation, and physiological maturation, and occurs from week nine to birth in humans. Most information on the effects of alcohol on specific prenatal periods of development comes from teratology studies in laboratory animals. Effects in the predifferentiation period generally result in prenatal mortality, and there are a few laboratory studies that have demonstrated an adverse effect of alcohol exposure other than mortality during this period (6). By comparison, effects of alcohol in the embryonic period have been extensively studied. Selective exposure of laboratory animals to alcohol on days that correspond to the third and fourth week of gestation in humans resulted in craniofacial defects similar to those seen in FAS, as well as a variety of brain defects (6). In contrast, these gross structural malformations generally are not observed when laboratory animals are exposed to alcohol during the fetal period. Exposure to alcohol during the fetal period appears to be associated with neurobehavioral effects, as well as highly selective histological abnormalities (e.g., ventricular septal hypertrophy). Importance of Amount and Frequency of Alcohol Exposure Obviously, the amount of alcohol consumed can impact the likelihood of an adverse birth outcome such as FAS. In fact, FAS is mostly associated with “high” amounts of alcohol consumption during pregnancy. However, “moderate” amounts of alcohol consumption may also result in adverse birth outcome such as ARBD and ARND. As previously stated, defining a threshold of alcohol consumption, below which adverse effects do not occur, is not possible. According to the CDC, there is no safe level of alcohol use during pregnancy (7). Perhaps equally important as the amount of alcohol, is the frequency of alcohol consumption. The technical term for this is a dose-rate effect. We want to know if the effect of a given dose of alcohol, say ten 12 ounce servings of beer, is the same whether the beer is consumed over 4 hours or 40 hours (note: A standard 12-ounce can of beer has the same amount of alcohol as a 4 ounce glass of wine or a 1-ounce shot of straight liquor). The answer may seem to be intuitively obvious to some readers, that consumption over 4 hours (binge-drinking) may cause a greater effect than that over 40 hours. However, whether this is true depends on the toxic effect, the metabolism and the mechanism of action of the toxicant. Studies in laboratory animals have indicated that consumption of high doses over short periods of time leads to greater risk (8). There are also some human studies that support a dose-rate effect, but these are more difficult conduct (more discussion on this is in the epidemiology section). Binge-drinking results in higher maternal blood alcohol concentrations which translate into exposure of the fetus to higher concentrations of alcohol and its metabolites. Higher concentrations over shorter periods of time can overwhelm metabolic defense mechanisms and lead to greater levels of cell death. When this occurs at a critical time during fetal development, the ultimate outcome may be FAS. Importance of Interacting Factors Contemporary models of disease recognize that the etiological basis of disease is multifactor in nature. The origin of FAS is no exception. Although excessive alcohol consumption is at the heart of the causal chain for FAS, there are many factors that potentially contribute to the sad ending. There are psychosocial and biological factors that lead to alcohol abuse in the first place. Factors such as poor nutrition, socioeconomic status, lack of medical care, level of social support, and pre-existing disease may play a role. Again, not every mother with a history of heavy drinking during pregnancy will give birth to an FAS child. For some cases of FAS, there may be more subtle influences such as co-exposure with other teratogens. Fitting these multiple factors into a coherent model that provides knowledge leading to effective prevention is a great challenge. Alcohol Can Kill Cells Mechanisms of action for toxicants can be described at several levels, from pathophysiological and organ dysfunction to cellular toxicity and dysfunction, and finally at the subcellular-molecular level. A consensus of many studies is that alcohol causes cell death. Studies may differ on the exact mechanism of cell death (e.g., necrosis versus apoptosis), but the result is the same: abnormal development. For example, neural crest cells form in conjunction with the neural tube (precursor to the central nervous system) during the embryonic period, and are important to the development of vital body structures. An example relevant to the features of FAS is the role of cranial nerve crest cells in the development of facial cartilage and bone. Laboratory research studies indicate that neural crest cells are sensitive to alcohol-induced injury and cell death, and the occurrence of this effect on cranial nerve crest cells has been purported to be the cause of characteristic FAS facial features (9). References
Alcohol Impact on the Brain Regions of the brain most affected by prenatal alcohol exposure
 Alcohol
Effects
on Executive Brain Functions (prefrontal cortex)
Fact: IQ Fetal alcohol syndrome is
the leading
known cause of mental retardation in western civilization, but most
have
normal range IQs despite alterations in executive functioning processes.
Fact: Possible Effects of Paternal Drinking While only the mother's
drinking can
cause FAS or ARND, the father's drinking can lower testosterone levels,
decrease healthy sperm, and increase the risk of disorders in the
offspring.
Preliminary animal studies indicate that alcohol can damage the DNA in
male sperm. Epidemiology of FAS, ARBD, and ARND
Major Points to Remember:
To fully understand the public health impact of FAS, ARBD, and ARND, and develop approaches to prevention, it is important to have knowledge on the occurrence of both exposure to the causative factors and the outcomes in a population. At the highest level, alcohol consumption during pregnancy is clearly a causative factor. However, there are many questions related to timing of exposure, amount and frequency of exposure, and a host of cofactors that may potentially modify the potency of exposure. On the outcome end of the equation, we wish to have knowledge on the magnitude of the problem related to specified populations. This knowledge aids in identifying susceptible populations, and provides guidance for health resource management. The frequency of occurrence of FAS and related disorders has been expressed as both incidence and prevalence for the same event: a developmental defect presumably initiated in the unborn developing fetus. This use of both incidence and prevalence to describe the same event is inconsistent, and the main problem arises from the frequent occurrence of spontaneous abortion among pregnant women exposed to alcohol. For a true measure of incidence of alcohol-related birth defects, a portion of these aborted fetuses would need to be included. May and Gossage (10) note that the term “birth prevalence” is more appropriate. It is convenient in this presentation to simply use the term prevalence and to express the prevalence as the number of cases per 1000 live births, unless otherwise indicated. General Population Estimates of FAS Prevalence It is commonly stated that alcohol is the leading known cause of mental and physical birth defects, surpassing both spina bifida and Down syndrome. While this statement is surely true, its simplicity hides some difficult issues surrounding efforts to understand for whom, where, and when the risk of FAS is greatest. The CDC, through their Birth Defects Monitoring Program (BDMP), has estimated the prevalence of FAS for the years 1979 to 1993 (11). A steady increase in FAS cases, from 0.1 per 1000 in 1979 to 0.67 per 1000 in 1993, was reported. The BDMP is an example of a passive surveillance system, and although this method is a relatively efficient and inexpensive method of data collection, this data are susceptible to certain types of bias (bias refers to an effect of data collection or analysis that leads to incorrect conclusions). For example, the BDMP data are based on a hospital discharge diagnosis using the ICD-9-CM code, 760.71, which implies alcohol exposure during pregnancy, but is not specific for FAS. Furthermore, there was a significant change in the proportion of U.S. births monitored from 30% in 1979 to 5% in 1993. There is a question whether the increase was actually due to better reporting among a smaller number of hospitals. Nonetheless, approaches considered to be more effective have yielded similar prevalence estimates. For example, CDC has carried out a multiple source method for FAS surveillance that utilizes data linkage from the Metropolitan Atlanta Developmental Disabilities Surveillance Program to the Metropolitan Atlanta Congenital Defects Program for the years 1981-1989 (11). This enables more accurate and complete case identification. In addition, cases were categorized as full FAS and partial FAS. The prevalence was reported for full FAS (0.1 per 1000) and both full and partial FAS (.25 per 1000). References
11.
Centers
for Disease Control and Prevention, Fetal Alcohol Website: Available
online
at: http://www.cdc.gov/ncbddd/fas/default.htm
State-based
Surveillance Program
Notice that the prevalence estimate for Alaska is 4 to 5 times that for the other states. This was due to due to a disproportionately high representation by a high risk population: Alaskan Natives (24% of all births and 89% of all cases). The prevalence among the Alaskan Natives was 5.6 per 1000, and this higher prevalence is representative for measurements of FAS prevalence among Native American populations. Prevalence for blacks in New York was also significantly higher than average at 1.6 per 1000. Prospective epidemiological studies generally can provide higher quality data than surveillance, but are conducted using more specific populations, and thus, the results may be less representative. However, estimates of FAS prevalence based on prospective epidemiological studies are in the range from 0.5 to 3 cases per 1000 live births, which is similar to levels based on surveillance. References
Major Points to Remember:
Major Points to Remember:
As noted earlier, some human studies indicate that binge-drinking may result in greater risk of FAS. However, it generally is difficult to study the influence of dose-rate on FAS occurrence in human populations. The main reason for this is that alcohol consumption information is collected after the fact, and as a result, the accuracy and completeness of exposure information are often compromised. Accurate exposure data is of great importance in epidemiological studies. Thus, despite the fact that a dose-rate effect (binge-drinking) is well-documented in laboratory animal studies, there are only a few studies in humans that support this important consideration. Accurate assessment of past exposure may be compromised by recall bias. This bias may not significantly impact validity if the objective of the study is just to compare risks at the extremes of alcohol consumption (e.g., abstainers versus alcoholics). However, if the objective is to evaluate a dose-response—the change in risk associated at lower, but still significant levels of alcohol consumption—then accurate assessment of exposure at all levels is important. Maier and West (14) reviewed epidemiological studies on the effects of maternal drinking patterns, and noted that several epidemiological studies have failed to find a relationship between binge-drinking and adverse birth outcomes; however, there are also studies that did find significant positive relationships. It appears that the devil is in the methodological details, and that a definitive answer on dose-rate effects for humans awaits more carefully controlled and conducted studies. A parallel issue that is extremely important to the prevention of FAS is the epidemiology and surveillance alcohol consumption during pregnancy. National health surveys, such as the Behavioral Risk Factor Surveillance System (BRFSS), and epidemiological studies of specific populations provide information on this concern. Drinking Patterns among Pregnant and Non-Pregnant Women in the U.S. One of the Healthy People
2010 objectives
is to decrease alcohol use among pregnant women to 94%
(15).
In a recent MMWR publication
(16),
CDC reported on trends in alcohol use among women of childbearing age,
based on data from the Behavioral Risk Factor Surveillance System
(BRFSS)
during 1991--1999. The report indicates that although the rate of
any alcohol use (i.e., at least one drink) during pregnancy had
increased
from 1991-1995, the rate has declined since 1995. However, rates
of binge drinking (i.e., >5 drinks on any one occasion) and frequent
drinking
(i.e., >7 drinks per week or >5 drinks on any one occasion)
during pregnancy
have not declined among pregnant women, and have substantially
increased
from 1991 to 1999. For example, the frequency of binge-drinking
was
less than 1% 1991 compared to 2.7% in 1999. CDC estimates that
this
translates into approximately 1 in 30 women who know they are pregnant
reporting “risk drinking” (7 or more drinks per week or 5 or more
drinks
on any one occasion). The report also compared drinking patterns among women with different characteristics. Pregnant women who reported any alcohol use, binge drinking, and frequent drinking were more likely to be greater than 30 years of age, employed, and unmarried. Non-pregnant women reporting any alcohol use were more likely to be white and to have higher education levels than their counterparts without these characteristics. Finally, non-pregnant women who reported binge drinking or frequent drinking tended to be aged <30 years. References
PowerPoint Presentations The remainder of the content will be presented utilizing PowerPoint Presentations. The PowerPoint Presentations will cover common developmental findings, assessment findings, diagnosis, interventions, and outcomes and measures. There will be post-test questions related to the written content and the PowerPoint Presentations.
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Conclusion •Most
research has been focused on prevention of alcohol use during
pregnancy,
mechanisms of alcohol damage in pregnancy, and proving that alcohol
causes
damage in pregnancy. More research is needed
and should focus on affected children of all ages. Studies are needed
to
find ways to distinguish FAS from other drug induced effects. Studies
need
to be conducted that do not focus on the mental retardation model,
because
of its lack of representation of some FAS children.
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