Pathogenesis of fetal alcohol syndrome; overview with emphasis on the possible role of nutrition
Deborah K. Phillips
Pathogenesis of Fetal Alcohol Syndrome
Overview with Emphasis on the Possible Role of Nutrition
This brief review of the fetal alcohol syndrome (FAS) will synthesize current views of the pathogenesis of the syndrome, especially regarding the possible role of abnormal nutrient delivery to the fetus.
Since the time of antiquity, the potentially harmful effects of alcohol on unborn children have been speculated on. These concerns are evident in Judges 13:3-4, in the story of Samson. In this passage, Samson’s mother is cautioned, “Behold, thou shalt conceive and bear a son; and now drink no wine or strong drink. . . .” The Greeks also were concerned about the use of alcohol in pregnancy, as illustrated in Aristotle’s observation: “. . . foolish, drunken, or hare-brained women [for the] most part bring forth children like unto themselves, morose and languid. . .,” according to Warner and Rosett’s historical survey. Later, during England’s “gin epidemic” from 1720 to 1750, concerns over the effects of alcohol on developing fetuses surfaced again (Warner and Rosett 1975). Meanwhile, Benjamin Rush, the American statesman and physician, was busy on the other side of the Atlantic rallying public interest for the problems of alcohol abuse. The nineteenth century also was noted for the work of Samuel HOWE (Warner and Rosett 1975), who is credited with what is probably the first recorded epidemiological study on the effects of parental drinking.
Yet the issue of alcoholism in pregnancy was largely ignored during much of the twentieth century. Even the work of Lemoine et al. (1968) in France documenting congenital malformations, cranial-facial anomalies, and mental deficiencies in 127 children of families with serious drinking problems, sparked little interest. It was not until 1973, with the reports of Jones et al. and Jones and Smith that describe a distinct group of abnormalities in 11 children born to alcoholic women, that the potential harm to the fetus that has been exposed to alcohol was recognized by the scientific community. What followed were recognition and legitimization of FAS and a cascade of clinical and experimental studies confirming both the syndrome and a wide range of potential fetal alcohol effects.
The constellation of alcohol-related defects, known as Fetal Alcohol Sydrome, currently is thought to represent the most dramatic and specific patterns of malformations in a wide spectrum of adverse fetal outcomes that are related to maternal alcohol abuse. The minimal criteria for diagnosing FAS were established by the Fetal Alcohol Study Group (Rosett 1980) of the Research Society of Alcoholism in 1980. Their recommendations, based substantially on a review by Clarren and Smith (1978) include: * central nervous system involvement,
such as neurologic abnormalities,
developmental delays, or intellectual
deficits; and * characteristic cranial-facial
abnormalities with at least two out of the
three following signs:
1) microcephaly defined as head
circumference below the third percentile,
2) microophthalmia or short
palpebral fissures or both, and
3) poorly developed philtrum,
hypoplastic upper lip, and/or
flattening of the maxillary area. * prenatal and/or postnatal growth
retardation for weight, length, and/or
head circumference below the tenth
percentile when corrected for
gestational age; The FAS also may involve other, less-specific malformations, including cardiovascular anomalies, genitourinary defects, and musculoskeletal and cutaneous abnormalities.
A wide range of effects may fall short of the criteria for FAS. Rosett et al. (1981) advocates the term “fetal alcohol effects” (FAE) for those children who show partial expression of the syndrome. Clarren and Smith (1978) prefer a diagnosis of “suspected fetal alcohol effects” when the three main features of FAS cannot be identified, as many of the apparent, nonspecific effects of alcohol have been associated with other risk factors. For instance, differentiating between the effects of alcohol and the effects of anticonvulsant therapy may pose a problem in diagnosis (Hill 1976). Thus, the importance of accurate and detailed patient histories cannot be over-emphasized.
The estimated incidence of FAS varies between 1.7 and 5.9 per 1,000 live births (Abel 1982), depending on the population. The incidence of FAE is more difficult to estimate, because uniform diagnostic criteria have not yet been established. Most studies, however, report much higher rates for FAE than for the full syndrome (Abel 1982). Abel (1985) estimates the incidence of FAE at 3.1 per 100 live births, while other estimates approach 6 per 1,000 (Hanson et al. 1978).
EVIDENCE OF SYNDROME
One line of evidence for the existence of FAS is epidemiological. Based on collaborative Perinatal Project data, the risk for FAS in pregnancies complicated by chronic alcoholism was initially estimated, albeit in a retrospective review of a small number of women, at an astounding rate of 32 percent (Jones et al. 1974). Later studies cited a lower incidence. For Sokol and associates’ (1980) population in Cleveland, there was a 2.5 percent risk of FAS and a 50 percent risk of FAE in pregnancies associated with heavy alcohol abuse.
Further collateral epidemiological evidence for FAS derives from studies demonstrating the benefits of reduced alcohol consumption in pregnancy. Quellette et al. (1977) and Rosett et al. (1980) noted fewer abnormalities in children born to heavy drinkers who were able to reduce significantly their intake of alcohol during pregnancy, than in those continuing ethanol abuse. These improvements, associated with reductions in third-trimester alcohol consumption, also were independent of smoking, age, or parity. More recently, Halmesmaki (1988) found less growth retardation and fewer cases of FAE in children of women who were able to reduce their consumption of alcohol by at least 50 percent than in children of women who continued to drink. Similar observations have been reported by Seidenberg and Majewski (1978) in Germany, and by Wright and Toplis (1986) in England. These reports have obvious educational and therapeutic implications, and indirectly support the premise that ethanol consumption results in fetal abnormalities.
The experimental evidence for FAS is equally convincing. In a variety of animal models, including mice, rats, chickens, guinea pigs, beagles, rabbits, and monkeys, growth retardation or congenital malformations or both–often paralleling the features of human FAS–have been produced with the administration of ethanol (Henderson et al. 1981). These animal studies, while varying as to species sensitivity, have consistently demonstrated a relationship between alcohol ingestion and a wide range of detrimental effects. The ability to control experimentally the quantity, duration, and timing of alcohol exposure, which is not feasible in human subjects, has contributed significantly to our understanding of this problem. However, the precise mechanism of FAS remains unknown.
Recent investigations have focused on assessing the direct effect of alcohol vs. acetaldehyde toxicity, the roles of nutrition (perhaps via impaired placental function), synergistic effects of nicotine and caffeine, and any possible contribution to the development of the syndrome by the father. More specifically, mechanisms for FAS involving altered protein synthesis (Henderson et al. 1981), prostaglandin inhibition (Randall and Anton 1984), and hypoxia (Abel 1985) have been considered.
Alcohol vs. Acetaldehyde
Several studies have focused on the role of ethanol versus that of its primary metabolite, acetaldehyde, in the pathogenesis of FAS. The work of Brown et al. (1979) suggests that ethanol alone may cause FAS. In this study, rat embryos lacking the capacity to metabolize alcohol effectively were exposed to ethanol in tissue culture. Although no structural abnormalities were observed, significant reductions in a variety of growth parameters were noted. Acetaldehyde levels, however, were not monitored.
Blakley and Scott (1984) utilized 4-methylpyrazole (4-MP), an inhibitor of alcohol conversion to acetaldehyde, to distinguish between the effects of alcohol and acetaldehyde. The teratogenicity of ethanol per se was established, while the administration of acetaldehyde alone failed to induce significant increases in malformations or resorptions.
Daniels and Evans (1980) also sought to differentiate the effects of ethanol from acetaldehyde, but with a different approach. They used t-butanol, an alcohol not metabolized to acetaldehyde. Their results suggest that alcohols, independent of acetaldehyde, may be toxic to the developing embryo, barring any unique toxicity of t-botanol.
Other studies have focused on embryotoxicity of acetaldehyde alone. Using high doses of acetaldehyde on days 7-9 of gestation, O’Shea and Kaufman (1979) reported significant increases in resorption rates, central nervous system abnormalities, and growth retardation in mouse embryos. At term, the surviving mice remained growth retarded, but no malformations were observed.
Dreosti et al. (1981) and Streenathan et al. (1982) reported similar acetaldehyde-induced embryotoxicity, even at low acetaldehyde blood levels. More recently, Fisher (1988) explored ethanol metabolism by the placenta and demonstrated low levels of acetaldehyde production, resulting in 2 micromolar ([Mu]M) levels in the fetus. It was shown also that acetaldehyde may cross the human placenta from the maternal to the fetal compartments.
Whether these low levels of acetaldehyde contribute to placental or fetal injury in humans is not known. The concentration of acetaldehyde necessary to cause damage is a key issue, because levels in maternal blood usually do not exceed 50-100 [Mu], transfer of acetaldehyde across the placenta apparently is restricted, and the fetal liver is not thought to be able to metabolize ethanol to acetaldehyde efficiently. Thus, in our view, the available evidence suggests an inherent toxicity of ethanol on the developing fetus, but a deleterious effect of acetaldehyde may occur, as well.
The role of malnutrition in the pathogenesis of FAS also has been the subject of considerable investigation. Maternal alcoholism may be accompanied by poor nutrition. Because growth retardation is such a prominent feature in FAS, and the fetus critically depends on maternal nutrients for growth, it was postulated that malnutrition might be responsible for these adverse fetal effects.
Decreased availability of nutrients to the fetus could be due to poor maternal intake, decreased intestinal absorption of selected nutrients (i.e., thiamin or folate), impaired placental transfer, and/or deranged fetal utilization of selected foods (Fisher 1988). The evidence bearing on this is as follows: Animal studies using pair-feeding methods generally have demonstrated toxic effects of alcohol that are independent of malnutrition (Henderson et al. 1981). Some of these studies, to be sure, have been confounded by lower weight gain in animals given alcohol (Abel and Dintcheff 1978; Van Thiel et al. 1978), suggesting decreased nutrient absorption, but in others this appears to have been properly controlled (Randall and Taylor 1979; Henderson et al. 1979).
In any event, alcohol is toxic to the fetus acutely, when feeding would not seem to be a relevant variable (Henderson and Schenker 1977). Also, the pattern of malformation associated with FAS has not been recognized in children born to undernourished women (Smith 1947), in whom the off-spring typically show catch-up growth not seen with FAS. Finally, while more subtle nutritional deficits are difficult to detect with current methods, overt maternal malnutrition (assessed by history) often is absent with FAS or FAE (Henderson et al. 1981). Future prospective assessments of such patients as to nutritional impact (if any) are needed.
It would appear, therefore, on balance, that malnutrition is not essential to the development of ethanol-induced fetal injury, at least in the experimental setting. However, such a compounding effect of malnutrition, in addition to ethanol, in clinical circumstances cannot presently be ruled out. To assess this, extensive studies focusing on the effects of ethanol on placental transport of nutrients have been carried out.
Numerous rodent animal studies have shown impaired placental transport of amino acids in response to acute and, especially, chronic alcohol consumption in both in vitro and in vivo systems (Lin 1981; Fisher et al. 1982; Henderson et al. 1982; and Patwardhan et al. 1981). Likewise, Fisher et al. (1983) have observed impaired amino acid transport in nonhuman primates chronically exposed to ethanol, with blood levels not exceeding 60 milligrams per deciliter (mg/dl).
With humans, however, the available evidence suggests that this placenta is more resistant to the inhibitory effects of alcohol. The studies of Fisher et al. (1981) and Schenker et al. (1989) have examined the inhibitory effects of ethanol on amino acid transport by human placenta using placental slices, vesicles, and the perfused organ, and have observed this relative resistance. However, these studies were necessarily performed with short-term ethanol exposure; susceptibility of human placenta to chronic ethanol consumption has not been assessed.
Given the observations of Fisher et al. (1983) in nonhuman primates, more research with chronic alcohol administration in primates is needed. In conclusion, acutely, alcohol does not seem to impair amino acid transport by the human placenta. Definitive chronic ethanol studies in humans are not available.
The effects of ethanol on vitamin transport also have been investigated in this and in other laboratories. Recent studies have focused on the transport mechanisms of folate and thiamin; both vitamins are often found to be decreased in alcoholics. Folate is essential to DNA synthesis, and thiamin is required for myelination of the nervous system and for orderly carbohydrate metabolism.
Folate receptor activity recently has been shown to be reduced in rat placenta exposed to high-dose ethanol (Fisher et al. 1985). Yet, studies by Lin (1981) and Jones et al. (1981) have failed to reveal impaired folate transport in rats. Furthermore, folate deficits generally are not observed in rats with FAS after chronic ethanol exposure (Henderson et al. 1981). Folate supplements also have failed to prevent FAS in experimental animals (Lin 1981). Thus, the relevance of folate binding deficits is not known. No data on ethanol/folate interactions in human pregnancy are available. Thiamin appears to be transported to the fetus by the human placenta by active or facilitated transfer. Preliminary work in our unit using a human placental perfusion model has shown that moderate levels of ethanol do not significantly reduce the transport of thiamin in the acute setting. Baron (1982), on the other hand, has noted decreased fetal accumulation of 25-[[sup.3.H]] hydroxyvitamin D in rats exposed to ethanol on days 6-19 of pregnancy at maternal ethanol blood level approaching 100 mg/dl.
Zinc, another nutrient critical for normal growth, may be affected by alcohol ingestion in pregnancy. Flynn et al. (1981) noted that zinc levels in alcoholic women were significantly lower than in nonalcoholics. Moreover, the teratogenic effects of maternal zinc deficiency are similar to malformations associated with FAS (Hurley et al. 1971). One animal study has suggested that a maternal zinc deficiency may act as a coteratogen with ethanol in FAS (Keppen et al. 1985). However, Henderson and his associates (1979) have found normal zinc levels in rat fetuses chronically exposed to ethanol, and similar data were reported recently from studies involving pregnant monkeys that were given ethanol chronically (Fisher et al. 1988).
Other groups have reported decreases in zinc transport (Ghishan et al. 1982; Assadi and Ziai 1986) in rodents after chronic alcohol exposure. Ghishan et al. (1982) reported a 40 percent decrease in placental zinc transport and a 30 percent decrease in fetal zinc uptake in pregnant rats given chronic alcohol. Zinc supplementation failed to overcome this defect (Ghishan and Green 1983). More recently, Assadi and Ziai (1986) reported lower zinc levels in infants with FAS. Urinary excretion of zinc was noted to be increased in these infants, suggesting a causal relationship between urinary losses and lower plasma zinc. Because zinc plays an important role in DNA and protein synthesis, and current data are inconclusive, the possibility that an ethanol-induced zinc deficiency could contribute to FAS or FAE or both remains a reasonable one and requires further study (Assadi and Ziai 1986).
A few studies have focused on other minerals and trace elements. Suh and Firek (1982) reported diminished total fetal magnesium levels in rats exposed to ethanol. Microcirculatory changes have been reported with magnesium deficiency (Altura et al. 1989). Likewise, elevated maternal selenium levels have been reported in heavy drinkers, with concomitant reductions in umbilical levels, when compared to abstinent controls (Halmesmaki et al. 1986). However, selenium levels in infants with obvious FAE were no different from levels in normal infants born to problem drinkers. Given the role of selenium in the elimination of toxic peroxides (Halmesmaki et al. 1986), the possible implications of decreased selenium cannot be completely dismissed.
The effect of alcohol on glucose homeostasis in pregnancy has been the subject of several recent studies. Singh et al. (1984, 1986) showed that maternal alcohol consumption is accompanied by fetal growth retardation and reduced hepatic glycogen stores in rats. Consequently, glucose homeostasis may be impaired in the neonatal period as evidenced by lowered blood glucose and insulin levels in the ethanol-fed group. Hepatic glycogen synthase and phosphorylase also were lowered in the ethanol-fed group, and glucagon levels were not affected. Similar results were obtained by Witek-Janusek (1986).
Other studies have shown a distinct relationship between intrauterine growth retardation and hypoglycemia (Gruppuso et al. 1981; and Nitzan 1981). Regarding the mechanisms of ethanol-induced hypoglycemia, several possibilities exist. First, placental glucose transport may be impaired by ethanol. In perfused human placenta, ethanol administered acutely does not interfere with glucose transport (Schenker et al. 1989). Snyder et al. (1985), however, have demonstrated a small impairment in glucose transport in rats given ethanol chronically.
Other possibilities include reduced maternal nutrient intake and delayed maturation of fetal hepatic enzyme systems involved with glucose homeostasis. Studies using pair-feeding techniques have shown that reduced maternal nutritional intake does not solely account for glycogen depletion in ethanol-fed rats (Singh et al. 1984, 1986). Reductions in levels of hepatic enzymes responsible for regulating glycogen production and degradation may at least partially account for the observed hypoglycemia (Singh et al. 1986).
Whatever the mechanism(s), glucose remains the primary fuel for the developing fetus. Limits on the availability of glucose may, therefore, play an important role in the pathogenesis of FAS, particularly in terms of growth and development. The concept of fuel-mediated teratogenesis has been explored by Freinkel (1980) and Freinkel et al. (1984). They hypothesize that disturbances in fetal growth and development may be a direct result of fetal fuel deficits. Conclusive evidence for this is lacking, but one study has observed lowered glucose levels in growth-retarded rats resulting from hepatic artery ligation (Nitzan 1981).
Other studies also have concentrated on the effects of ethanol on fetal fuels and brain growth. Tanaka et al. (1982) have been able to offset such reductions in fetal brain weight by administering glucose to pregnant rats late in gestation. Singh et al. (1988) recently have noted a positive correlation between fetal brain wight and blood glucose concentrations. These findings suggest that ethanol-induced disturbances in glucose homeostasis may impair brain growth. Thus, fuel-mediated teratogenesis may play a role in the pathogenesis of FAS or FAE.
Nicotine and Caffeine
Other factors that may be involved in FAS include maternal smoking, caffeine intake, and the use of additional drugs. Because maternal alcoholism often is accompanied by smoking and high caffeine consumption, several studies have been devoted to these confounding variables. An approximate twofold increase of intrauterine growth retardation (IUGR) has been associated with heavy drinking when controlled for smoking (Kaminski et al. 1978). However, cigarette smoking contributes independently to IUGR, and the effects appear to be addictive when combined with heavy drinking (Little 1977; Soko et al. 1980). These additive effects amounted to a nearly fourfold increased risk of IUGR.
Mechanistically, little is known about the impact of smoking in FAS (Fisher et al. 1984). Smoking alone has been implicated in perinatal mortality associated with abruptio placenta, placenta previa, prolonged rupture of membranes, and maternal hemorrhage (Meyer and Tonascia 1977). This had led to suggestions that nicotine may impair placental blood flow (Lindblad et al. 1988). Others have suggested that nicotine may impair placental nutrient transport, especially at high concentrations, and when combined with ethanol intake. Recent data in our unit, however, indicate that the human-term placenta, exposed acutely to nicotine at 100-fold the concentration seen in smokers, does not show altered amino acid transport. Addition of ethanol, 400 mg/100 ml, also did not influence placental amino acid transport acutely (Schenker et al. in preparation). Chronic, mechanistic studies remain to be done.
Henderson and Schenker (1984) studied the effects of ethanol, with and without caffeine, on rat fetal growth and placental transport. Reductions in fetal survival, as well as in body and visceral weights, were observed in ethanol-fed rats when compared with controls. These effects appeared to be potentiated by the concomitant administration of caffeine, whereas caffeine intake alone did not significantly affect fetal growth or survival. Furthermore, placental uptake of AIB was reduced in ethanol-treated rats, but caffeine by itself did not alter its uptake.
If, however, ethanol-treated rats were given caffeine at the same time, placental AIB uptake was increased when compared to ethanol alone, but still was significantly lower than in pair-fed controls. Thus, ethanol-induced fetal injury may be exacerbated by the concomitant use of caffeine, but amino acid transport does not appear to be involved.
Ethanol might impair caffeine metabolism, resulting in increased caffeine levels. Indeed, ethanol does reduce the elimination of caffeine, if given acutely (Mitchell et al. 1983), but exerts only a modest effect with chronic administration (Mitchell et al. 1982). Conversely, it is doubtful that caffeine would interfere with ethanol metabolism, because caffeine undergoes microsomal metabolism and alcohol is metabolized primarily by cytosolic enzymes (Henderson and Schenker 1984).
Another explanation for the apparent potentiating property of caffeine to FAS is that caffeine and ethanol might together act in an additive, or synergistic, fashion on some system involved in fetal growth, such as protein synthesis (Henderson and Schenker 1984). Caffeine by itself probably does not adversely affect the fetus. However, because caffeine metabolism is impaired in pregnancy (Kling and Christensen 1979), the potential contribution of caffeine consumption to FAS cannot be dismissed, especially because caffeine is known to be transported rapidly across the placenta (Weathersbee and Lodge 1979) and because the metabolic systems for caffeine are immature in the fetus (Kling and Christensen 1979).
Relatively little is known about the effects of drugs such as marijuana or cocaine on the fetus, but recent reports suggest that these agents may per se lower fetal birth weight (Zuckerman et al. 1989).
Because growth retardation is such a prominent feature of FAS and FAE, it has been hypothesized that ethanol in some way retards protein synthesis. Much of the work in the area relating to the brain has been put forth by Tewari and Noble (1971). Several potential sites for ethanol to exert this effect on protein synthesis have been proposed (Henderson et al. 1981). As to the precise manner by which this occurs, available evidence suggests that RNA transport and aminoacyl-transfer RNA synthetases are primarily inhibited (Henderson et al. 1981). To be sure, the data have been somewhat discordant, depending on whether acute or chronic ethanol administration was employed; which species, organ, or organelle was studied; and the methodology employed (Henderson et al. 1981). For instance, hypothermia, which may accompany alcohol administration, per se, may depress protein synthesis, and the developing brain and kidney appear to be more susceptible to the effects of alcohol than do other tissues (Henderson et al. 1980). Moreover, in most reports, net protein synthesis was measured.
Little is known about the effects of ethanol on synthesis versus protein degradation, and oftentimes precursor pool sizes are not taken into account. Another difficulty relates to the use of the whole brain rather than of its components. Given the brain’s structural, functional, and developmental heterogenicity, measurements of overall protein synthesis may conceal important regional and subcellular differences (Henderson et al. 1981). Altered protein synthesis as a mechanism for FAS is attractive, but requires more documentation.
Ethanol-induced changes in prostaglandin (PG) production also have been linked with FAS. Pennington et al. (1983), in ethanol-exposed chick embryo, hypothesized that ethanol-induced growth retardation may result from elevations in cyclic-AMP, brought on by higher prostaglandin levels resulting from inhibition of prostaglandin dehydrogenase. Support for this hypothesis was provided by Randall and Anton (1984). Using aspirin to inhibit PG synthesis, they were able to reduce the rates of congenital malformations and prenatal mortality in ethanol-treated mice. Pennington et al. (1985) also observed that PG inhibitors, such as aspirin and indomethacin, may prevent alcohol-induced growth deficits. A more recent study (Ylikorkala et al. 1988) measured urinary PG and thromboxane levels in nondrinking pregnant women, those classified as heavy drinkers, and in their infants. Prostacyclin metabolites were elevated only in infants born to drinking mothers, but the increased output of prostenoid metabolites did not correlate with the occurrence of FAE. More studies are needed to determine if the use of PG inhibitors may prove useful in preventing or ameliorating the effects of maternal alcoholism on the fetus.
Compromised blood flow to the placenta and fetus is another possible explanation for the pathogenesis of FAS of FAE or both. In this scenario, ethanol could restrict the flow of oxygen or valuable nutrients or both to the fetus. Most of the evidence for a flow-related mechanism in human FAS is indirect, deriving from studies involving experimental animals. For example, Horiguchi et al. (1971) investigated the effects of ethanol infusions on maternal and fetal blood flow in third-trimester monkeys. With infusion of ethanol at 2 to 4 grams per kilogram (kg) into the maternal vein, they observed significant reductions in fetal blood pressure, an increase in fetal heart rate, and fetal acidosis, while only minimal changes were noted in the mothers. Later, Jones et al. (1981) measured cardiac output and blood flow to the placenta and kidneys in rats chronically exposed to ethanol. Only placental blood flow was altered. From this, they postulated that limitations of placental blood flow with chronic alcohol consumption may impair the transport capabilities of the placenta, and, in turn, may result in hypoxia and growth retardation.
Indirect evidence for a flow-related mechanism is suggested by Mukherjee and Hodgen’s (1982) observations in pregnant rhesus monkeys. A dramatic (albeit transient) collapse of umbilical vasculature was seen within minutes of infusing a 3 grams-per-decigram dose of ethanol. Fetal hypoxia and acidosis coincided with collapse of the umbilical vessels, while blood gas parameters remained unchanged in mothers. They postulated that repetitive alcohol–induced hypoxic insults might contribute to the central nervous system (CNS) derangements seen in FAS and in FAE.
Studies perfomed on isolated human umbilical cords and smooth muscle of other blood vessels also have shown contraction of the vessels in response to ethanol infusions (Altura et al. 1983). This effect could not be inhibited by pharmacologic antagonists or a PG inhibitor, suggesting a direct constrictive effect of alcohol on umbilical vessels.
The relationship between paternal alcoholism and FAS is even less well understood. Yet, prospective epidemiological evidence (Rosett et al. 1976) and isolated case reports (Bartoshesky et al. 1979) suggest an association between maternal and paternal alcoholism. Little and Singh (1987) employed regression analysis to demonstrate a relationship, independent of maternal drinking, between paternal alcohol consumption at the time of conception and a decrease in infant birth weight.
Animal studies have focused on the effects of ethanol on male reproduction function, as well as on the possible relationship between paternal alcoholism and FAS from either a mutagenic (Badr and Badr 1975) or teratogenic (Anderson et al. 1981) point of view. Ethanol clearly has been shown to impair male fertility in mice (Anderson et al. 1987; Anderson et al. 1983).
The possibility of a sperm-mediated mutagenic effect of ethanol has been controversial, with most results negative (Henderson et al. 1981). Evidence of chromosomal damage in humans also is lacking (Henderson et al. 1981). Thus, it appears that, although ethanol may impair male reproductive function, there is little firm evidence that paternal alcoholism accounts for the specific congenital defects seen in FAS.
While the existence of FAS now is beyond dispute, the mechanism(s) of this deleterious effect on alcohol still are uncertain. For instance, it appears that ethanol, per se, in an experimental setting, can damage the fetus. However, in a clinical setting, the roles of acetaldehyde, nicotine, and malnutrition are still debated. Of these, the adverse effects of smoking are perhaps best documented.
Malnutrition might have various mechanisms affecting FAS, including poor intake, poor maternal absorption, and impaired delivery via the placenta to the fetus. The latter has been most studied. Indeed, there is evidence that transfer of various amino acids, glucose, and zinc by the placenta may be impaired by ethanol intake, especially when ingested chronically. Whereas such an effect might interfere with orderly fetal growth, which is a key feature of FAS, the data for this still are not firm and are especially scant for humans.
As to specific mechanisms by which ethanol may impair fetal growth and development, impaired protein synthesis (perhaps, in part, due to lack of key substrates), abnormal delivery or regulation of glucose in the fetus, altered prostaglandin homeostasis, and hypoxia due to intermittent ischemia, are key considerations under investigation. Better understanding of the mechanism(s) involved may permit more meaningful therapeutic interventions.
PHOTO : A healthy child within the uterus. Maternal alcohol consumption during pregnancy can
PHOTO : adversely affect the proper growth and development of a fetus. Currently, fetal alcohol
PHOTO : syndrome is thought to represent the most dramatic specific malformations in a wide
PHOTO : spectrum of fetal defects associated with maternal alcohol abuse.
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