Fetal Alcohol Syndrome (FAS) is a pattern of mental, physical, and behavioral defects that may develop in the unborn child when its mother drinks during pregnancy. These defects occur primarily during the first trimester when the teratogenic effects of the alcohol have the greatest effect on the developing organs. The symptoms associated with FAS have been observed for many centuries, but it was not until 1968 that Lemoine and his associates formally described these symptoms in the scientific literature, and again in 1973 when Jones and associates designated a specific pattern of altered growth and dysmorphogenesis as the Fetal Alcohol Syndrome (Rostand, p. 302). The set of abnormalities characterized by Jones included; "intrauterine growth retardation, an unusual facies, psychomotor retardation, and a 25% incidence of congenital anomalies (especially cleft palate and cardiac malformations)" (Luke, p. 3330. The incidence of FAS world-wide, can be illustrated on the basis of the extreme to which the characteristics of mental, physical, and behavioral defects are exhibited in the newborn. Full characteristics are estimated to be present in 1.9 per 1,000 live births, and partial characteristics are evident in approximately 3-5 per 1,000 live births. The incidence of FAS increases dramatically when only alcoholic women are considered to 25 per 1,000 for full characteristics and as high as 90 per 1,000 for partial characteristics (Luke, p. 333).

Currently, FAS is the most common cause of birth defects leading to mental retardation. Down’s Syndrome and spina bifida, the other two most common causes, can be identified and managed during pregnancy. Yet, FAS remains the only cause of retardation that is completely preventable with maternal cooperation (Feld, p. 15). The annual cost associated with caring for children afflicted with FAS has been "conservatively estimated at about $321 million", an extremely high price for such a preventable disease (Luke, p. 333). Clearly the incidence of this syndrome could be greatly reduced, and possibly prevented, through education on the topic. This paper will present the metabolic basis of Fetal Alcohol Syndrome, the pathogenic basis for brain and facial anomalies associated with FAS, and the effects of maternal alcohol consumption on the immune system. Characteristics of diagnosing FAS will follow the discussion of those factors causing the symptoms of this disease.

As stated earlier, alcohol has its greatest effect on the developing embryo during the first trimester of pregnancy with its teratogenic effect causing mental retardation as well as characteristic craniofacial abnormalities that are characteristic of the disease. It has also been demonstrated with experimental animal models that there is a clear "dose-response" effect between the amount of alcohol consumed by the mother and the risk that is associated with developing FAS symptoms (Walpole, p. 875). It has been proposed by Walpole and associates that there are various degrees to which the fetus An be effected. Walpole uses the term "fetal alcohol syndrome" to refer to serious effects due to heavy maternal drinking and "fetal alcohol effect" to refer to those effects thought to occur with lower maternal alcohol intake (Walpole, p. 875). Regardless of the degree to which the developing fetus is affected, there is an underlying effect that is common to all fetuses born to alcohol consuming mothers. This effect is directly associated with the "direct or indirect consequences of alcohol metabolism" (Luke. p. 333).

Very few things are allowed to cross the maternal-fetus blood barrier, but alcohol and its metabolic product acetaldehyde can both do so readily. The ease at which alcohol passes through the barrier is due to its solubility characteristics. Alcohol is water and lipid-soluble, and thus it passes readily through all biological membranes, "equilibrating rapidly throughout the entire water volume of the maternal-placental-fetal unit" (Luke, p. 334). The amniotic fluid thus is a reservoir for the alcohol and acetaldehyde. Unlike adults, fetuses lack the necessary enzymes required to break down the substances once they have entered the blood supply. Therefore, the fetus is exposed to the effects of the alcohol for a much longer period of time. The effects of the alcohol on the placenta are also important to consider when describing of FAS. Alcohol and acetaldehyde may be directly toxic to the placenta as well as to the fetus. The result is "ethanol-associated placentotoxicity" which can undermine the primary function of the placenta; to provide nutrition to the developing fetus. As a result growth deficiency occurs which is a common characteristic of FAS(Luke, p.330).

The effect on the placenta can also be extended to include impairment of transport of various essential substances as well. Most notable of these deprived substances is the essential amino acids. This deficiency can also result in growth retardation due to the inability of the fetus to synthesize required proteins for development. This is the reason that alcohol has its greatest effect within the first 10 weeks of gestation when the organ systems are developing (Feld, p. 151). According to some researchers, this hypothesis of protein synthesis and affiliated effects on organ development can be demonstrated by ‘three basic observations:

1. In both human And non-human mammals, alcohol-related developmental abnormalities include a cluster of physical malformations involving many organ systems which are highly variable in their frequency and severity of expression. This suggests that alcohol is a non-specific teratogen that affects some developmental process common to all or most cell types. 2. The most common consistent manifestation of gestational alcohol abuse is intrauterine growth impairment, apparent clinically as reductions in head circumference, body length, body weight, and (at autopsy) individual organ weights. 3. Normal growth and development are dependent upon the accumulation and organization of protein. Alcohol directly and indirectly impairs protein synthesis in fetal and adult tissues. Through reductions in RNA and DNA, as well as total and subcellular protein contents, alcohol impairs cellular processes that are fundamental to growth (Luke, p. 335).

Zinc and folic acid have also been noted to be deficient in fetuses due to insufficient placental transfer (Luke, p. 334).

The effect of undernourishment caused by alcohol’s effect on the placenta and liver (by impairing the absorption, utilization, and metabolism of nutrients) were once thought to be the leading cause of symptoms associated with FAS. A comparative study of malnourished newborns of the "post-World War II famine in Holland" helped dispel this fact, however, and it is now accepted that other factors, as well, lead to the diagnostic characteristics associated with FAS (Luke, p. 335). The study involved comparing the effects of malnourished individuals with long-term impaired intellectual development, a common symptom of FAS. Those children who were malnourished having microcephaly at birth did not show signs of mental retardation in later development. In contrast, those children born to alcohol consuming mothers showed symptoms of FAS, the severity of which were highly predictive of the degree of impaired intellectual development later in life (Luke, p. 335). The dose-response relationship described above thus becomes relevant with other symptoms associated with FAS. Other metabolic effects of alcohol include "alcohol-related hypothermia, dehydration, fetal hypoxia and acidosis, and endocrine disturbances" all of which are shown to occur with increasing maternal alcohol intake (Luke, p. 335).

In addition to the metabolic effects listed above, ethyl alcohol also has a direct cytotoxic effect. The pharmacological effects of the ethanol are the result of cell membrane necrosis, leading to a general depression of cell function. All cells are affected, but these effects are most pronounced in cells with excitable membranes" (Luke, p. 333). Among the mechanisms that have been proposed for these cytotoxic abnormalities are "interference with cell proliferation, alterations in cytoskeletal elements, or extracellular matrix components’’ (Kotch, p. 169).

The pathogenic basis of the brain and facial abnormalities associated with this disease can be explained on the basis of the above mentioned cell death and the location at which this cell death occurs. According to Loire E. Kotch and associates, "acute teratogenic exposure of mouse embryos to ethanol in vivo results, within 12 hours of initial insult, in excessive cell death in selected cell populations. The patterns of excessive cell death observed following exposure of gestational, day 8 embryos vary somewhat temporospatially, but primarily involve the cell populations at the rim of the anterior neural plate" (Kotch, p. 168). The patterns of cell death observed by Kotch were correlated with subsequently observed malformations including "anencephaly, arhinencephaly, pituitary dysplasia, bilateral or unilateral cleft lip, maxillary hypoplasia, and median facial deficiencies and clefts" (Kotch, p. 168). Kotch states in her article that it is "well established that the cells at the junction of the neural and surface ectoderm. i.e. the neural crest cells, form the ectomesenchymal populations that are very significant contributors to the development of the face". She stated also that it is "generally accepted that the most rostral part of the prosencephalic neural folds do not produce neural crest cells; that those from the caudal rim of the prosencephalon and rostral mesencephalon contribute the cells that will populate the medial and lateral nasal prominence’s, and that the mesencephalic neural folds also contribute the neural crest cells that populate the maxillary prominence’s" (p. 173). With this information of normal development based on cell location, it is evident that cell death in specific locations will result in specific facial and cranial anomalies. Following are a few examples given by Kotch of specific anomalies based on cell death: 1) "isolated’ loss of cells in the rostral midline might yield pituitary hypoplasia and frontonasal dysplasia-like midline clefting; 2) effects along the rim of the prosencephalon that include the "territory of the medial nasal prominence’s, olfactory placodes, and lateral nasal prominence’s would be expected to result in arhinencephaly or small olfactory bulbs, and a small nose"; and 3) effects along the rim of the mesencephalon would be expected to yield a small maxillary region’’ (Kotch, p. 173). "In some circumstances, all of the facial prominence’s may be deficient enough so that what appears to be a rather typical cleft lip occurs. It would be expected that the individuals with cleft lip would have brains consistent with the holoprosencephaly/arhinencephaly spectrum" (Kotch, p. 173). However, as dramatic as these results are, Kotch is careful to distinguish that not all of these symptoms are typical of the human alcohol-related birth defects, although many of them have been reported in fetuses born to alcohol consuming mothers. As indicated by a high resorbtion rate in her study, however, many of these anomalies may actually be associated with a "high prenatal mortality rate" and thus may not be phenotypically expressed as less debilitating malformations (Kotch, p.175). As noted by E. L Abel, the spontaneous abortion rate in alcoholic women (indicated comparatively in the Kotch study by the resorption rate) is reported to be twice that of non-alcoholic women (Abel, p. 64).

Along with the noted metabolic effects and pathogenic effects causing brain and facial anomalies, recent evidence is suggesting that alcohol-related symptoms may also appear in the immune response of FAS children. The effect that this could have on these children is quite dramatic due to the vital role that the immune system has in maintaining the host’s homeostasis. The immune system is traditionally viewed as an intrinsically regulated system. New evidence now indicates however, that the immune responsiveness is also modulated by feedback mechanisms from the central nervous system. "According to these observations, activated immunocytes release lymphokines (‘immunotransmitters") which act as intrinsic regulators as well as signal-mediators to the brain. The latter, in turn, modulates responses of the challenged lymphocytes by sending signals via the autonomic...neuronal efferents, as well as the neuroendocrine humoral axis" (Gottesfeld, p.5). The effect of altering these communications can be the causal agent for decreasing immune responses in children afflicted with FAS.

Hormonal influence is also a mechanism of immune regulation that, according to Gottesfeld and associates, demands further attention in the research area. "Hormones released from the hypothalamo/pituitary-gonadal, adrenal and thyroid axes are thought to function as immunomodulators" as well (Gottesfeld, p. 6). Gottesfeld is thus making the hypothesis that the effect of hormones in utero can "in some way mediate the effects of alcohol exposure in utero or early postnatal development" (p. 6). Gottesfeld cites as an example that corticosteroid’s have potent "suppressive" effects on lymphocyte number and function and on neutrophil activity, and acknowledges the association that this may have with increased serum glucocorticoid levels be associated with prenatal alcohol exposure (p. 6).

With the severity and permanence of the symptoms associated with FAS, it is evident that education aimed at prevention of the syndrome is in desperate need. Unfortunately, not all educational factors are taken into consideration by expecting mothers and thus it becomes necessary for the practicing physician to understand and recognize the symptoms associated with Fetal Alcohol Syndrome. Diagnosing this syndrome can be based on three basic factors that must be present according to Steven M. Feld, MD. The first factor to look for is altered development, "including a specific pattern of facial malformations" including "small, widely spaced eyes (short palpebral fissures with epicanthal folds);" a short, upturned nose; flat (in appearance) midface (maxillary hypoplasia); and a flattened and elongated groove between the nose and upper lip. In addition. "the upper lip may be abnormally thin, and the circumference of the child’s head may be small (microcephaly) (Feld, p. 15).

The second factor associated with diagnosing the syndrome includes growth deficiency. The growth impairment begins prepartum and continues postpartum. The impairment in growth is usually manifested "in birth weight, length, and head circumference, and falls in the lowest tenth percentile; in fact, babies with FAS usually fall within the lowest three percentile of all children assessed" (Feld, p. 15).

The third factor is involvement of the central nervous system. This is usually manifested by mental retardation that persists throughout life. H "The average child’s IQ in the united States is 100, with 95 percent of children scoring between 70 and 130". The average FAS child "will score around 65--among the lowest five percent of all American children tested (Feld, p. 10). In addition to these common factors, other FAS children may exhibit other physical symptoms such as "cardiac defects, pectus excavatum, labial hypoplasia, aberrant palmar creases, hemangiomas, posteriorly rotated ears, ptosis and strabismus of the eyes, and prominent lateral palatine ridges" (Feld, p. 16).

It is evident that the degree to which symptoms may appear in Fetal Alcohol Syndrome is quite variable. In 1978, Clarren and Smith summarized the risk associated with maternal alcohol consumption on the developing fetus: "The variability of the phenotype probably results from variable dose exposure at variable gestational timings offset by the genetic background of the individual fetus. Nearly all patients recognized as having the full fetal-alcohol-syndrome phenotype are born to daily heavy alcohol users or relatively frequent heavy intermittent users. Chronic consumption of 89 ml of absolute alcohol or more per day—the equivalent of about six hard drinks--constitutes a major risk to the fetus. Lower levels of consumption or less frequent use of alcohol carries an unknown risk, and may be shown to be associated with less seriously affected children. No absolutely safe level of ethanol consumption has yet been established" (Luke, p. 335).

In the research obtained for this paper, there still seems to be "no absolutely safe level" of alcohol consumed by the mother. There is great agreement, however, that the dose-response relationship is very effective In estimating long-term effects based on the amount of alcohol consumed during the gestation period

REFERENCES:

Abel, E. L. "Fetal Alcohol Syndrome and Fetal Alcohol Effects". New York: Plenum Press (1984). p. 64.

Feld, S. M. "Fetal Alcohol Syndrome: Prevention Through Education". Medical Student, 19(2), pp. 15-17.

Gottesfeld, Z. and E. L. Abel "Maternal and Paternal Alcohol Use: Effects On The Immune System of the Offspring". Life Sciences, 48,1991, pp. 1-8.

Kotch, L. E. and K. K. Sulik "Experimental Fetal Alcohol Syndrome: Proposed pathogenic Basis for a Variety of Associated Facial and Brain Anomalies". American Journal of Medical Genetics, 44, 1992, pp. 168-176.

Luke, B. "The Metabolic Basis of the Fetal Alcohol Syndrome". International Journal of Fertility, 35(6), 1990, pp. 333-337.

Walpole, I. et.al. "Low to Moderate Maternal Alcohol Use Before and During Pregnancy, and Neurobehavioural Outcome in the Newborn Infant". Developmental Medicine and Child Neurology. 33, 1991, pp. 875-883.